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Live 2:30-4:30 PM  Mediterranean Diet and Lifestyle: A Symposium on Diet and Human Health:  October 19, 2018

Reporter: Stephen J. Williams, Ph.D.

 

2:30 Mediterranean Diet, Intangible Heritage and Sustainable Tourism?

Prof. Fabio Parasecoli, PhD.

 

 

Nutrition and Food Department, New York University

We focus on more of the cultural aspects and the relevance of this diet to tourism in Italy where there is a high rate of unemployment.  The diet is interesting from a touristic standpoint as the diet have the perspective of the different ingredients inherent in Italy.  The mediterranean diet food pyramid totally different than US.  How do we explain to consumers these medical concepts; for example in China, Germany they are using different ways to explain the benefits of this diet.

A Cultural Formation

  • a way of life, for tourism there is the way of life people want to adopt (easiest way to do this is go to the Mediterranean and learn the lifestyle)
  • so for example Olive Garden for marketing purposes sent a few chefs for half a day training so the image of learning to cook in the mediterranean diet style can be very powerful communicative tool
  • 2003 UNESCO Convention for Safeguarding the Culturing Heritage: protecting landscapes but then decided to protect other intangible heritage like oral, language, oral traditions like transmitting recipes, social and festive events (how do we cook how do we grow tomatoes, wheat etc)
  • UNESCO: promoted France Gastronomic, Mediterranean Diet, and traditional Mexican Cuisine (Mayan)
  • defined Greece, Italy, Morroco then included Cyprus Crotia and Portugal in the Mediterranean diet
  • has it been used for promotion: no UNESCO did not use this since does not safeguard the culture
  • (gastrodiplomacy); like Korea and kimchie; included in the list of cultural cuisine but can create tourist bubbles as you tourism places like hotels don’t always use; for reasons of economy or safety or accessibility , local food
  • Centrality of Territorio:  food consumed from tourist should come from the area

Sustainable Tourism: a form of tourism where have the intention to get to know the place;

have to think in three ways

  1. environmental
  2. social
  3. cultural

how do we make a circular economy so no waste; for example certain companies using food waste to make other products

Tourism clusters made of many groups; he is working on a way to jump start these networks in Nigeria;

Sustainable Food Supply Chain Tourism can be used as way to engage people and promote the diet

Question: are there regions where people are not adopting the diet because of taste, preferences

Yes there is always a problem with accessibility, affordability, trade issues and regional acceptance. For instance in Australia a big push back against the Mediterranean diet.  Medical professionals need to work with communication experts and media experts in developing ways to communicate the benefits since “no one wants to be preached at” and “as economies get richer people want to be more modern and try new things”

In Nigeria we are working with many different industries like transportation, engineers, the IT industry and chefs to build a scalable model

 

3.00 Italy as a Case Study: Increasing Students’ Level of Awareness of the Historical, Cultural, Political and Culinary Significance of Food

Prof. Lisa Sasson

Nutrition and Food Department, New York University

Started a program at NYU to understand food  from a nutritionist and historical point of view as a cultural heritage in Italy, but when students came back students mentioned it changed their food shopping habits

they described diet as wine, pasta, and olive oil

Artisional Production:  understanding the taste and flavor; she wanted them to learn about the food culture and educate their tastes

Food Memories: how we pass on recipes and food aromas, food tastes.  The students were experienced food in a unique way for the first time, experiencing what cheese, quality oil other foods when fresh tastes like.  Artisional foods may be expensive but need only a little of it because the tastes and flavors are so potent due to the phytochemicals

Within six months students:

  1. increased consumption of weekly wine consumption with meals
  2. increased consuming satisfying meals
  3. increased time consuming meals

In the womb the fetus is actually acquiring sense of taste (amniotic fluid changes with mother diet; can detect flavor chemicals)

Student Perceptions after a study Abroad Program

  • eating foods local and seasonal
  • replacing butter with quality olive oil
  • using herbs
  • very little sugar
  • unsweetened beverages
  • limiting red meats
  • fish a couple of times a week
  • dairy in moderation
  • no processed foods

Eating and Dining for Americans is a Challenge:  The students ate well and satisfying meals but ate alot but did not gain weight

3:30 Italian Migration and Global Diaspora

Dr. Vincenzo Milione, PhD

Director of Demographics Studies, Calandra Institute, City University of New York

for a PDF of this presentation please click heresbarro handout.

Dr. Millione used the U.S. Census Bureau Data to estimate the growth of the Italian diaspora descendants in host countries in the Americas and to determine the mixed global ancestry of Italian descendants.

  • Italian emigration to the US happened in two waves
  1.            Wave 1: early 1900 peaking between 1901 and 1911 (turn of century)
  2.            Wave 2: 1951-1971 (post WWII)

This pattern was similar between North and South America although South American had first Italian immigration; in 1860 we got rid of slavery so many jobs not filled new orleans

Developing a mathematical model of Italian diaspora: the model is centered on the host country population dynamics but descendants are separated into first generation and multi generation

Model dependent on:

  • birth and death rates
  • first generation population growth
  • multi generational population growth
  • emigration from host country over time

He was able to calculate an indices he termed Year of Italianization Change (YIC): the year the growth of the multi generation supercedes the first generation immigrant population 

Country Year of Italianlization Change (YIC)
Brazil 1911
Uruguay 1915
Argentina 1918
USA 1936
Venezuela 1963
Canada 1968
Australia 1988

 

note: as a result there is an increasing loss of language and traditional customs with host country cultural adaptation among the native born descendants

In addition, over the last 20 years Italian-American population growth demonstrates that Italian-American self-identity in the United States has increased.  The census data identified two ancestries of the respondent.  In mixed ancestry Italian-American respondents to the extent they identify Italian first demonstrating the strong Italian-American identity.

The foreign born Italian Americans mirror the immigration pattern of Italian immigration from Italy until 1980 where more Italian Americans self identify as foreign born in other countries and not in Italy

Summary

  • over 5 million Italians have emigrated from Italy from 1980 to present
  • most went to North and South America but many went to other global countries
  • the Italian immigration to the different countries in the Americas varies over the period of mass emigration when the growth of multi generational Italian descendants is greater then first generation Italians (Year of Italianization Change) goes from 1911 in Brazil to 1988 in Australia
  • Immigrants to the USA was not just from Italy but from almost all nations globally over all geographical continents
  • Italina immigrants descendants greatly grew after 1930 with appreciable increase with other ethnicities such that 61% of Italian Americans are mixed ancestry in 2014: to date mixed ancestry represents 98% of Italian Americans
  • younger italian americans more likely to have mixed ancestry with Central and South America, Asian and African ethnicities

over time during immigration eating habits has changed but more research is needed if and how the italian recipes and diet has changed as well

 

4:15 Conclusions

Prof. Antonio Giordano, MD, PhD.

To follow or Tweet on Twitter please use the following handles (@) and hashtags (#):

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#healthydiet

#MediterraneanDiet

#health

#nutrition

Please see related articles on Live Coverage of Previous Meetings on this Open Access Journal

Real Time Conference Coverage for Scientific and Business Media: Unique Twitter Hashtags and Handles per Conference Presentation/Session

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Live 12:00 – 1:00 P.M  Mediterranean Diet and Lifestyle: A Symposium on Diet and Human Health : October 19, 2018

Reporter: Stephen J. Williams, Ph.D.

12.00 The Italian Mediterranean Diet as a Model of Identity of a People with a Universal Good to Safeguard Health?

Prof. Antonino De Lorenzo, MD, PhD.

Director of the School of Specialization in Clinical Nutrition, University of Rome “Tor Vergata”

It is important to determine how our bodies interacts with the environment, such as absorption of nutrients.

Studies shown here show decrease in life expectancy of a high sugar diet, but the quality of the diet, not just the type of diet is important, especially the role of natural probiotics and phenolic compounds found in the Mediterranean diet.

The WHO report in 2005 discusses the unsustainability of nutrition deficiencies and suggest a proactive personalized and preventative/predictive approach of diet and health.

Most of the noncommunicable diseases like CV (46%) cancer 21% and 11% respiratory and 4% diabetes could be prevented and or cured with proper dietary approaches

Italy vs. the US diseases: in Italy most disease due to environmental contamination while US diet plays a major role

The issue we are facing in less than 10% of the Italian population (fruit, fibers, oils) are not getting the proper foods, diet and contributing to as we suggest 46% of the disease

The Food Paradox: 1.5 billion are obese; we notice we are eating less products of quality and most quality produce is going to waste;

  •  growing BMI and junk food: our studies are correlating the junk food (pre-prepared) and global BMI
  • modern diet and impact of human health (junk food high in additives, salt) has impact on microflora
  • Western Diet and Addiction: We show a link (using brain scans) showing correlation of junk food, sugar cravings, and other addictive behaviors by affecting the dopamine signaling in the substantia nigra
  • developed a junk food calculator and a Mediterranean diet calculator
  • the intersection of culture, food is embedded in the Mediterranean diet; this is supported by dietary studies of two distinct rural Italian populations (one of these in the US) show decrease in diet
  • Impact of diet: have model in Germany how this diet can increase health and life expectancy
  • from 1950 to present day 2.7 unit increase in the diet index can increase life expectancy by 26%
  • so there is an inverse relationship with our index and breast cancer

Environment and metal contamination and glyphosate: contribution to disease and impact of maintaining the healthy diet

  • huge problem with use of pesticides and increase in celiac disease

12:30 Environment and Health

Dr. Iris Maria Forte, PhD.

National Cancer Institute “Pascale” Foundation | IRCCS · Department of Research, Naples, Italy

Cancer as a disease of the environment.  Weinberg’s hallmarks of Cancer reveal how environment and epigenetics can impact any of these hallmarks.

Epigenetic effects

  • gene gatekeepers (Rb and P53)
  • DNA repair and damage stabilization

Heavy Metals and Dioxins:( alterations of the immune system as well as epigenetic regulations)

Asbestos and Mesothelioma:  they have demonstrated that p53 can be involved in development of mesothelioma as reactivating p53 may be a suitable strategy for therapy

Diet, Tomato and Cancer

  • looked at tomato extract on p53 function in gastric cancer: tomato extract had a growth reduction effect and altered cell cycle regulation and results in apoptosis
  • RBL2 levels are increased in extract amount dependent manner so data shows effect of certain tomato extracts of the southern italian tomato (     )

Antonio Giordano: we tested whole extracts of almost 30 different varieties of tomato.  The tomato variety  with highest activity was near Ravela however black tomatoes have shown high antitumor activity.  We have done a followup studies showing that these varieties, if grow elsewhere lose their antitumor activity after two or three generations of breeding, even though there genetics are similar.  We are also studying the effects of different styles of cooking of these tomatoes and if it reduces antitumor effect

please see post https://news.temple.edu/news/2017-08-28/muse-cancer-fighting-tomatoes-study-italian-food

 

To follow or Tweet on Twitter please use the following handles (@) and hashtags (#):

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@SbarroHealth

@Pharma_BI 

@ItalyinPhilly

@WHO_Europe

@nutritionorg

# hashtags


#healthydiet

#MediterraneanDiet

#health

#nutrition

Please see related articles on Live Coverage of Previous Meetings on this Open Access Journal

Real Time Conference Coverage for Scientific and Business Media: Unique Twitter Hashtags and Handles per Conference Presentation/Session

LIVE – Real Time – 16th Annual Cancer Research Symposium, Koch Institute, Friday, June 16, 9AM – 5PM, Kresge Auditorium, MIT

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HUBweek 2018, October 8-14, 2018, Greater Boston – “We The Future” – coming together, of breaking down barriers, of convening across disciplinary lines to shape our future

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Announcement 11AM- 5PM: Live Conference Coverage  from Mediterranean Diet and Lifestyle: A Symposium on Diet and Human Health @S.H.R.O. and Temple University October 19, 2018

Reporter: Stephen J. Williams, Ph.D.

 

 The Sbarro Health Research Organization, in collaboration with the Consulate General of Italy in Philadelphia will sponsor a symposium on the Mediterranean Diet and Human Health on October 19, 2018 at Temple University in Philadelphia, PA.  This symposium will discuss recent finding concerning the health benefits derived from a Mediterranean-style diet discussed by the leaders in this field of research.

Mediterranean Diet

The description of the Mediterranean Diet stems from the nutritionist Ancel Keys, who in 1945, in the wake of the US Fifth Army, landed in Southern Italy, where he observed one of the highest concentrations of centenarians in the world. He also noticed that cardiovascular diseases, widespread in the USA, were less frequent there. In particular, among the Southern Italians, the prevalence of “wellness” diseases such as hypertension and diabetes mellitus, was particularly associated with fat consumption, suggesting that the main factor responsible for the observations was the type of diet traditionally consumed among people facing the Mediterranean Sea, which is low in animal fat, as opposed to the Anglo-Saxon diet. The link between serum cholesterol and coronary heart disease mortality was subsequently demonstrated by the Seven Countries Study. Later, the concept of Mediterranean Diet was extended to a diet rich in fruits, vegetables, legumes, whole grains, fish and olive oil as the main source of lipid, shared among people living in Spain, Greece, Southern Italy and other countries facing the Mediterranean basin …

Prof. Antonino De Lorenzo, MD, PhD.

   

 

The Symposium will be held at:

Biolife Science Building, Room 234

Temple University, 1900 North 12th street

Philadelphia, PA 19122

 

For further information, please contact:

Ms. Marinela Dedaj – Sbarro Institute,  Office #: 215-204-9521

 

11:00 Welcome

Prof. Antonio Giordano, MD, PhD.

Director and President of the Sbarro Health Research Organization, College of Science and Technology, Temple University

 

Greetings

Fucsia Nissoli Fitzgerald

Deputy elected in the Foreign Circumscription – North and Central America Division

 

Consul General, Honorable Pier Attinio Forlano

General Consul of Italy in Philadelphia

 

11:30 The Impact of Environment and Life Style in Human Disease

Prof. Antonio Giordano MD, PhD.

 

12.00 The Italian Mediterranean Diet as a Model of Identity of a People with a Universal Good to Safeguard Health?

Prof. Antonino De Lorenzo, MD, PhD.

Director of the School of Specialization in Clinical Nutrition, University of Rome “Tor Vergata”

 

12:30 Environment and Health

Dr. Iris Maria Forte, PhD.

National Cancer Institute “Pascale” Foundation | IRCCS · Department of Research, Naples, Italy

 

13:00 Lunch

 

2:30 Mediterranean Diet, Intangible Heritage and Sustainable Tourism?

Prof. Fabio Parasecoli, PhD.

Nutrition and Food Department, New York University

 

3.00 Italy as a Case Study: Increasing Students’ Level of Awareness of the Historical, Cultural, Political and Culinary Significance of Food

Prof. Lisa Sasson

Nutrition and Food Department, New York University

 

3:30 Italian Migration and Global Diaspora

Dr. Vincenzo Milione, PhD

Director of Demographics Studies, Calandra Institute, City University of New York

 

4:00 Pasta Arte: New Model of Circular Agricultural Economy: When an Innovated Tradition Takes Care of You and of the Environment

Dr. Massimo Borrelli

CEO and Founder of Arte

 

4:15 Conclusions

Prof. Antonio Giordano, MD, PhD.

 

Coordinator of the Symposium, Dr. Alessandra Moia, PhD.

 

Prof. Antonio Giordano, MD, PhD.

Professor of Molecular Biology at Temple University in Philadelphia, PA where he is also Director of the Sbarro Institute for Cancer Research and Molecular Medicine. He is also Professor of Pathology at the University of Siena, Italy. He has published over 500 articles, received over 40 awards for his contributions to cancer research and is the holder of 17 patents.

 

Prof. Antonino De Lorenzo, MD, PhD.

Full Professor of Human Nutrition and Director of the Specialization School in Food Science at the University of Rome “Tor Vergata”. He is the Coordinator of the Specialization Schools in Food Science at the National University Council and Coordinator of the PhD. School of “Applied Medical-Surgical Sciences” Director of UOSD “Service of Clinical Nutrition, Parenteral Therapy and Anorexia”. He also serves as President of “Istituto Nazionale per la Dieta Mediterranea e la Nutrigenomica”.

 

Dr. Iris Maria Forte, PhD.

Iris Maria Forte is an oncology researcher of INT G. Pascale Foundation of Naples, Italy. She majored in Medical Biotechnology at the “Federico II” University of Naples, earned a PhD. in “Oncology and Genetics” at the University of Siena in 2012 and a Master of II level in “Environment and Cancer” in 2014. Iris Maria Forte has worked with Antonio Giordano’s group since 2008 and her research interests include both molecular and translational cancer research. She published 21 articles mostly focused in understanding the molecular basis of human cancer. She worked on different kinds of human solid tumors but her research principally focused on pleural mesothelioma and on cell cycle deregulation in cancer.

 

Prof. Fabio Parasecoli, PhD.

Professor in the Department of Nutrition and Food Studies. He has a Doctorate in Agricultural Sciences (Dr.sc.agr.) from Hohenheim University, Stuttgart (Germany), MA in Political Sciences from the Istituto Universitario Orientale, Naples (Italy), BA/MA in Modern Foreign Languages and Literature from the Università La Sapienza, Rome (Italy). His research explores the intersections among food, media, and politics. His most recent projects focus on Food Design and the synergies between Food Studies and design.

 

Prof. Lisa Sasson, MS

Dietetic Internship Director and a Clinical Associate Professor in the department. She has interests in dietetic education, weight and behavior management, and problem-based learning. She also is a private practice nutritionist with a focus on weight management. She serves as co-director of the Food, Nutrition and Culture program in Florence Italy, the New York State Dietetic Association and the Greater New York Dietetic Association (past president and treasurer).

 

Dr. Vincenzo Milione, PhD.

Director of Demographic Studies for The John D. Calandra Italian American Institute, Queens College, City University of New York. He has conducted social science research on Italian Americans. His research has included the educational and occupational achievements; Italian language studies at the elementary and secondary levels, high school non-completion rates; negative media portrayals of ethnic populations including migration studies and global diaspora.

 

Dr. Massimo Borrelli

Agricultural entrepreneur, Manager of the Italian Consortium for Biogas (CIB) and delegate for the Bioeconomy National Department of Confagricoltura. He developed A.R.T.E based on a model of agricultural circular economy, beginning and ending in the ground. He constructed the first biogas plant in the territory creating a new way to make agriculture, investing in research and development, experimentation and most of all, in people. In a few short years, he succeeded to close the production chain producing goods characterized by their high quality and usage of renewable energy.

 

Dr. Alessandra Moia, PhD.

Vice-President for Institutional and International Relations of the Istituto Nazionale per la Dieta Mediterranea e la Nutrigenomica (I.N.D.I.M.). Has managed relations with the academic institutions to increase awareness and develops projects for the diffusion of the Mediterranean Diet. She served as Director of Finance for the National Institute of Nutrition, for the Ministry of Agriculture and Forestry.

 

About the Sbarro Health Research Organization

The Sbarro Health Research Organization (SHRO) is non-profit charity committed to funding excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes and other chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism. To learn more about the SHRO please visit www.shro.org

To follow or Tweet on Twitter please use the following handles (@) and hashtags (#):

@ handles


@S_H_R_O 

@SbarroHealth

@Pharma_BI 

@ItalyinPhilly

@WHO_Europe

@nutritionorg

# hashtags


#healthydiet

#MediterraneanDiet

#health

#nutrition

Please see related articles on Live Coverage of Previous Meetings on this Open Access Journal

Real Time Conference Coverage for Scientific and Business Media: Unique Twitter Hashtags and Handles per Conference Presentation/Session

LIVE – Real Time – 16th Annual Cancer Research Symposium, Koch Institute, Friday, June 16, 9AM – 5PM, Kresge Auditorium, MIT

Real Time Coverage and eProceedings of Presentations on 11/16 – 11/17, 2016, The 12th Annual Personalized Medicine Conference, HARVARD MEDICAL SCHOOL, Joseph B. Martin Conference Center, 77 Avenue Louis Pasteur, Boston

Tweets Impression Analytics, Re-Tweets, Tweets and Likes by @AVIVA1950 and @pharma_BI for 2018 BioIT, Boston, 5/15 – 5/17, 2018

BIO 2018! June 4-7, 2018 at Boston Convention & Exhibition Center

LIVE 2018 The 21st Gabay Award to LORENZ STUDER, Memorial Sloan Kettering Cancer Center, contributions in stem cell biology and patient-specific, cell-based therapy

HUBweek 2018, October 8-14, 2018, Greater Boston – “We The Future” – coming together, of breaking down barriers, of convening across disciplinary lines to shape our future

 

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Curator: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, Hospital CEOs, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

  •  In a national survey, the Fiber Choice® line of chewable prebiotic fiber tablets and gummies, achieved the #1 share of gastroenterologist (GE) recommendations, more than four times greater than that for the nearest branded competitor
  • Fiber Choice contains a well-studied prebiotic fiber that promotes regularity and supports the growth of beneficial microorganisms for general digestive health
  • The convenience, taste and efficacy of Fiber Choice, makes it a GE-endorsed choice toward helping address the “fiber gap” in American diets

 Boca Raton, Fla. – (June 3, 2018) – IM HealthScience® (IMH), innovators of medical foods and dietary supplements, today announced a high-quality and replicated nationwide survey conducted among a representative and projectible sample of U.S. gastroenterologists, which revealed Fiber Choice® as the #1-recommended chewable prebiotic fiber brand.

The results of a ProVoice survey, fielded in May 2018 by IQVIA, showed Fiber Choice as the leader by far. Its share of gastroenterologist endorsements was more than four times greater than that of its nearest branded competitor.

Less than 3 percent of Americans get the recommended minimum amount of fiber, and 97 percent need to increase their fiber intake[1]. Although the recommended daily fiber intake is 25 to 38 grams[2], most Americans only get about half that amount. This “fiber gap” reflects a diet with relatively few high-fiber foods, such as fruits, vegetables, nuts, legumes and whole-grains, and is large enough for the U.S. government to deem it a public health concern for most of the U.S. population.

To help bridge this gap, gastroenterologists recommend fibers including Fiber Choice chewable tablets and gummies. For doctors, it’s a simple, convenient and tasty way to help their patients get the fiber needed for overall good digestive health.

“Dietary fiber is known for keeping our bodies regular,” said Michael Epstein, M.D., FACG, AGAF, a leading gastroenterologist and Chief Medical Advisor of IM HealthScience. “Most importantly, it’s essential that you get enough fiber in your diet. One way to do that is to supplement your daily intake of dietary fiber with natural, prebiotic fiber supplements.”

Inulin, the 100 percent natural prebiotic soluble fiber in Fiber Choice, has been studied extensively and has been shown to support laxation and overall digestive health as well as glycemic control, lowered cholesterol, improved cardiovascular health, weight control and better calcium absorption.

Fiber Choice can be found in the digestive aisle at Walmart, CVS, Target, Rite Aid and many other drug and food retailers.

About ProVoice Survey
ProVoice has the largest sample size of any professional healthcare survey in the U.S., with nearly 60,000 respondents across physicians, nurse practitioners, physician assistants, optometrists, dentists, and hygienists, measuring recommendations across more than 120 over-the-counter categories. Manufacturers use ProVoice for claim substantiation, promotion measurement, and HCP targeting.

IQVIA fielded replicated surveys in April 2018 and May 2018 respectively among U.S. gastroenterologists for IM HealthScience. The ProVoice survey methodology validated the claim at a 95 percent confidence level that “Fiber Choice® is the #1 gastroenterologist-recommended chewable prebiotic fiber supplement.”

About Fiber Choice®

The Fiber Choice® brand of chewables and gummies is made of inulin [pronounced: in-yoo-lin], a natural fiber found in many fruits and vegetables. Inulin works by helping to build healthy, good bacteria in the colon, while keeping food moving through the digestive system. This action has a beneficial and favorable effect in softening stools and improving bowel function.

Research shows that the digestive system does more than digest food; it plays a central role in the immune system. The healthy bacteria that live in the digestive tract promote immune system function, so prebiotic fiber helps nourish the body. Inulin also has secondary benefits, too, of possibly lowering cholesterol, balancing blood chemistry and regulating appetite, which can help reduce calorie intake and play a supporting role in weight management.

The usual adult dosage with Fiber Choice Chewable tablets is two tablets up to three times a day and for Fiber Choice Fiber Gummies is two gummies up to six per day.

About IM HealthScience®

IM HealthScience® (IMH) is the innovator of IBgard and FDgard for the dietary management of Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD), respectively. In 2017, IMH added Fiber Choice®, a line of prebiotic fibers, to its product line via an acquisition. The sister subsidiary of IMH, Physician’s Seal®, also provides REMfresh®, a well-known continuous release and absorption melatonin (CRA-melatonin™) supplement for sleep. IMH is a privately held company based in Boca Raton, Florida. It was founded in 2010 by a team of highly experienced pharmaceutical research and development and management executives. The company is dedicated to developing products to address overall health and wellness, including conditions with a high unmet medical need, such as digestive health. The IM HealthScience advantage comes from developing products based on its patented, targeted-delivery technologies called Site Specific Targeting (SST). For more information, visit www.imhealthscience.com to learn about the company, or www.IBgard.com,  www.FDgard.comwww.FiberChoice.com, and www.Remfresh.com.

This information is for educational purposes only and is not meant to be a substitute for the advice of a physician or other health care professional. You should not use this information for diagnosing a health problem or disease. The company will strive to keep information current and consistent but may not be able to do so at any specific time. Generally, the most current information can be found on www.fiberchoice.com. Individual results may vary.

SOURCE/REFERENCES

[1] Greger, Michael, M.D., FACLM. (2015, September 29). Where Do You Get Your Fiber? [Blog post]. Retrieved from https://nutritionfacts.org/2015/09/29/where-do-you-get-your-fiber/

[2] Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC: The National Academies Press. https://doi.org/10.17226/10490.

Other related articles published in this Open Access Online Scientific Journal include the following:

2018

Benefits of fiber in diet

https://pharmaceuticalintelligence.com/2018/03/14/benefits-of-fiber-in-diet/

2016

Nutrition & Aging: Dr. Simin Meydani appointed Vice Provost for Research @Tufts University

https://pharmaceuticalintelligence.com/2016/08/01/nutrition-aging-dr-simin-meydani-appointed-vice-provost-for-research-tufts-university/

2015

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

A heart-healthy diet has been the basis of atherosclerotic cardiovascular disease (ASCVD) prevention and treatment for decades. The potential cardiovascular (CV) benefits of specific individual components of the “food-ome” (defined as the vast array of foods and their constituents) are still incompletely understood, and nutritional science continues to evolve.

 

The scientific evidence base in nutrition is still to be established properly. It is because of the complex interplay between nutrients and other healthy lifestyle behaviours associated with changes in dietary habits. However, several controversial dietary patterns, foods, and nutrients have received significant media exposure and are stuck by hype.

 

Decades of research have significantly advanced our understanding of the role of diet in the prevention and treatment of ASCVD. The totality of evidence includes randomized controlled trials (RCTs), cohort studies, case-control studies, and case series / reports as well as systematic reviews and meta-analyses. Although a robust body of evidence from RCTs testing nutritional hypotheses is available, it is not feasible to obtain meaningful RCT data for all diet and health relationships.

 

Studying preventive diet effects on ASCVD outcomes requires many years because atherosclerosis develops over decades and may be cost-prohibitive for RCTs. Most RCTs are of relatively short duration and have limited sample sizes. Dietary RCTs are also limited by frequent lack of blinding to the intervention and confounding resulting from imperfect diet control (replacing 1 nutrient or food with another affects other aspects of the diet).

 

In addition, some diet and health relationships cannot be ethically evaluated. For example, it would be unethical to study the effects of certain nutrients (e.g., sodium, trans fat) on cardiovascular disease (CVD) morbidity and mortality because they increase major risk factors for CVD. Epidemiological studies have suggested associations among diet, ASCVD risk factors, and ASCVD events. Prospective cohort studies yield the strongest observational evidence because the measurement of dietary exposure precedes the development of the disease.

 

However, limitations of prospective observational studies include: imprecise exposure quantification; co-linearity among dietary exposures (e.g., dietary fiber tracks with magnesium and B vitamins); consumer bias, whereby consumption of a food or food category may be associated with non-dietary practices that are difficult to control (e.g., stress, sleep quality); residual confounding (some non-dietary risk factors are not measured); and effect modification (the dietary exposure varies according to individual/genetic characteristics).

 

It is important to highlight that many healthy nutrition behaviours occur with other healthy lifestyle behaviours (regular physical activity, adequate sleep, no smoking, among others), which may further confound results. Case-control studies are inexpensive, relatively easy to do, and can provide important insight about an association between an exposure and an outcome. However, the major limitation is how the study population is selected or how retrospective data are collected.

 

In nutrition studies that involve keeping a food diary or collecting food frequency information (i.e., recall or record), accurate memory and recording of food and nutrient intake over prolonged periods can be problematic and subject to error, especially before the diagnosis of disease.

 

The advent of mobile technology and food diaries may provide opportunities to improve accuracy of recording dietary intake and may lead to more robust evidence. Finally, nutrition science has been further complicated by the influences of funding from the private sector, which may have an influence on nutrition policies and practices.

 

So, the future health of the global population largely depends on a shift to healthier dietary patterns. Green leafy vegetables and antioxidant suppliments have significant cardio-protective properties when consumed daily. Plant-based proteins are significantly more heart-healthy compared to animal proteins.

 

However, in the search for the perfect dietary pattern and foods that provide miraculous benefits, consumers are vulnerable to unsubstantiated health benefit claims. As clinicians, it is important to stay abreast of the current scientific evidence to provide meaningful and effective nutrition guidance to patients for ASCVD risk reduction.

 

Available evidence supports CV benefits of nuts, olive oil and other liquid vegetable oils, plant-based diets and plant-based proteins, green leafy vegetables, and antioxidant-rich foods. Although juicing may be of benefit for individuals who would otherwise not consume adequate amounts of fresh fruits and vegetables, caution must be exercised to avoid excessive calorie intake. Juicing of fruits / vegetables with pulp removal increases calorie intake. Portion control is necessary to avoid weight gain and thus cardiovascular health.

 

There is currently no evidence to supplement regular intake of antioxidant dietary supplements. Gluten is an issue for those with gluten-related disorders, and it is important to be mindful of this in routine clinical practice; however, there is no evidence for CV or weight loss benefits, apart from the potential caloric restriction associated with a gluten free diet.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/28254181

 

https://www.sciencedirect.com/science/article/pii/S0735109713060294?via%3Dihub

 

http://circ.ahajournals.org/content/119/8/1161

 

http://refhub.elsevier.com/S0735-1097(17)30036-0/sref6

 

https://www.scopus.com/record/display.uri?eid=2-s2.0-0031709841&origin=inward&txGid=af40773f7926694c7f319d91efdcd40c

 

https://www.magonlinelibrary.com/doi/10.12968/hosp.2000.61.4.1875

 

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2548255

 

https://pharmaceuticalintelligence.com/2018/05/31/supplements-offer-little-cv-benefit-and-some-are-linked-to-harm-in-j-am-coll-cardiol/

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Consuming Risk Free Food & Beverages

Author: Debashree Chakrabarti, MSc., Biological Sciences, UMass Lowell (Expected May 2016)

Leading researchers and medical health professionals have raised their concern about the over all declining status of health and well being world wide. A rising trend in childhood obesity, cardiovascular diseases, clinical depression syndrome in young adults is reason enough to try and broaden the scope of plausible agents which result in people making bad health decisions.  As a witness to the emerging dietary trends adopted by children and young adults, it is natural to question the ethics of processed food and beverages industry. Does it seem reasonable the 2L bottles of soda cost $2 USD? There are more people claiming to not like water since it is flavorless. 100% fresh juices are subject to scrutiny for their lack of adequate fiber content and excess presence of sugars. Products with high fructose corn syrups, added preservatives in processed meat, ‘read to eat’ meals are agreeably cost effective and saves a lot of time, however the over riding damage is in the long run with deficient immune system and gain of unnatural toxins which the body finds hard to eliminate. Another marketing frenzy is visible in the neutraceuticals range of instant energy drinks, protein shakes and over the counter pills. The focus is towards having the visibly attractive, muscular body regardless of the compromised health. The companies do their bit of limiting the usage by adding a precaution statement and dosage remarks on the product labels. This is however not translated as useful information to the young consumers who do not foresee the detrimental outcomes in advance.

As the prices of insurance packages and medical aid is negotiated, the same effort needs invested in the regulation of consumer dietary products. We do not want a ban on Colas however, we do not also need them to be sold at prices cheaper than water. Fresh fruits and vegetables need not be price tagged astronomically driving population to adopt a risk driven lifestyle. Taking initiatives to promote urban farming and local gardens, reaching out to the people about their choices and how it impacts the global financial predicament is a need of the hour. We are ok with the attitude of “Don’t tell me how to live my life” in a world relying heavily on subsidized medicines. This has to change. Subsidized medicine is a privilege and should be benefited to those responsible. Researchers and big pharma companies are not the only stake holders in this fight against an exponentially growing illness of misinformed decisions. People need to be brought in and educated. This includes strong arming anyone who feels they have a right to abuse their health or the health of the world.

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Another paradigm to this discussion is the need for more extensive research hubs world wide and making the accessibility of advanced medicines available to the dense population regions in Asia, Africa and Middle East Arab countries which host the majority of the population and have the least of the resources. We need 100 Massachusetts world wide with cutting edge researchers deep diving and venture capitalists backing them up. A vision for 2050 must encompass every individual being aware of what it takes to damage a human body which is a very robust machine. Eating right and being able to afford health must not be difficult. Choices available in the stores must be rational to the level where the most ignorant of the lot is still consuming risk free substances. Given the fantastic evolutionary armaments we have, it takes a lot to be unwell and yet we seem to making it fairly easy to catch cold. Healthy people translate to healthy economy.

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The History and Creators of Total Parenteral Nutrition

Curator: Larry H. Bernstein, MD, FCAP

 

The History and Creators of Total Parenteral Nutrition

I am a pathologist who became involved in the measurement of acute and chronic malnutrition in hospitalized patients through my working with a burn surgeon, Walter Pleban, in the mid-1980s.  I had already been interested in this as a clinical pathology issue because the most abundant plasma protein, albumin, is markedly decreased, but that protein has a half-life of disappearance on 21 days.  This was problematic because it was inadequate for early recognition, or for response to feeding.  It became of considerable interest that two rapid turnover proteinhttp://www.ncbi.nlm.nih.gov/pubmed/20150597s – transthyretin (TTR)(then referred to as prealbumin) and retinol binding protein (RBP) that are synthesized by the liver have short half-lifes.  The measurement of TTR was then possible by an immunodiffusion assay on agarose overnight, but was not automated.  This changed with the introduction of an immunoassay for research use, and that offered by Beckman was ideal for the automated clinical laboratory.  One could then follow the level of TTR in the recovery phase.  There was some discussion for years about the fact that TTR might be considered an inverted acute phase protein because of a recognition that the liver decreases synthesis of TTR and produces acute phase proteins in the adaptive inflammatory response.  This is not insignificant, but it is also not quite relevant for reasons that have been addressed by Yves Ingenbleek and collaborators.  TTR is a key determinant of protein sufficiency and of sulfur homeostasis in health and disease.  I shall not say more, as the development of total parenteral (TPN), and also enteral (TEN) nutrition are of specific interest here.  However, the evaluation of patients’ nutritional status has widely been carried out by subjective global assessment, which is insufficient in a large population at risk.

 

History of parenteral nutrition.

The concept of feeding patients entirely parenterally by injecting nutrient substances or fluids intravenously was advocated and attempted long before the successful practical development of total parenteral nutrition (TPN) four decades ago. Realization of this 400 year old seemingly fanciful dream initially required centuries of fundamental investigation coupled with basic technological advances and judicious clinical applications. Most clinicians in the 1950’s were aware of the negative impact of starvation on morbidity, mortality, and outcomes, but only few understood the necessity for providing adequate nutritional support to malnourished patients if optimal clinical results were to be achieved. The prevailing dogma in the 1960’s was that, “Feeding entirely by vein is impossible; even if it were possible, it would be impractical; and even if it were practical, it would be unaffordable.” Major challenges to the development of TPN included: (1) formulate complete parenteral nutrient solutions (did not exist), (2) concentrate substrate components to 5-6 times isotonicity without precipitation (not easily done), (3) demonstrate utility and safety of long-term central venous catheterization (not looked upon with favor by the medical hierarchy), (4) demonstrate efficacy and safety of long-term infusion of hypertonic nutrient solutions (contrary to clinical practices at the time), (5) maintain asepsis and antisepsis throughout solution preparation and delivery (required a major culture change), and (6) anticipate, avoid, and correct metabolic imbalances or derangements (a monumental challenge and undertaking). This presentation recounts approaches to, and solution of, some of the daunting problems as really occurred in a comprehensive, concise and candid history of parenteral nutrition.

 

Historical highlights of the development of total parenteral nutrition.
The events and discoveries thought to be the most significant prerequisites to the development of total parenteral nutrition (TPN) dating back to the early 17th century are chronicled. A more detailed description and discussion of the subsequent early modern highlights of the basic and clinical research beginning in the mid-20th century and the advances culminating in the first demonstration of the feasibility and practicality of TPN, and its successful, safe and efficacious applications clinically, are presented. Some of the reasoning, insights, and philosophy of a pioneer clinician-scientist in the field are shared with readers.

 

The History, Principles, and Practice of Parenteral Nutrition in Preterm Neonates

Stanley J. Dudrick , Alpin D. Malkan
Chapter in:  
Nutrition for the Preterm Neonate    27 June 2013   pp 193-213

The history of the successful development of Total Parenteral Nutrition (TPN), first in beagle puppies in the basic science laboratories, and its subsequent clinical translations initially to adults, and shortly thereafter, to a newborn infant, is recounted by the original developer of the techniques, data, and results that have led to its widespread application and acceptance throughout the world. The principles, practices, standards, techniques, observations, technology, and several of the countless details which were so essential in guiding this dream to reality, are woven throughout the narrative. The advances and milestones are traced along this passionate, relentless journey to the present day, when preterm infants are actually expected to live and thrive. The precision and conscientious attention which are essential to the judicious, safe, efficacious use of TPN in preterm neonates throughout all aspects of solution formulation and delivery, together with appropriate monitoring and assessment of outcomes, are described and discussed briefly. The multiple risks and complications associated with this complex life-saving technique are extensively tabulated, with the intention to teach, in order to avoid, prevent, or overcome them. Moreover, attention has been directed toward pointing out many of the persisting shortcomings of the technique which remain to be prevented, overcome, or corrected by future research efforts and experiences. Finally, the costs, philosophy, humanity, and future advancements necessary to apply TPN to the care of preterm infants in developing countries are stated with optimism and hope.

 

Brief History of Parenteral and Enteral Nutrition in the Hospital in the USA
Bruce R. Bistrian
Clinical Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Elia M, Bistrian B (eds): The Economic, Medical/Scientifi c and Regulatory Aspects of Clinical Nutrition Practice: What Impacts What?
Nestlé Nutr Inst Workshop Ser Clin Perform Program, vol. 12, pp 127–136, Nestec Ltd., Vevey/S. Karger AG, Basel, © 2009.

The meteoric rise in parenteral and enteral nutrition was largely a consequence of the development of total parenteral nutrition and chemically defined diets in the late 1960s and early 1970s and the recognition of the extensive prevalence of protein calorie malnutrition associated with disease in this same period. The establishment of Nutrition Support Services (NSS) using the novel, multidisciplinary model of physician, clinical nurse specialist, pharmacist, and dietitian, which, at its peak in the 1990s, approached 550 well-established services in about 10% of the US acute care hospitals, also fostered growth. The American Society of Parenteral and Enteral Nutrition, a multidisciplinary society reflecting the interaction of these specialties, was established in 1976 and grew from less than 1,000 members to nearly 8,000 by 1990. Several developments in the 1990s initially slowed and then stopped this growth. A system of payments, called diagnosis-related groups, put extreme cost constraints on hospital finances which often limited financial support for NSS teams, particularly the physician and nurse specialist members. Furthermore, as the concern for the nutritional status of patients spread to other specialties, critical care physicians, trauma surgeons, gastroenterologists, endocrinologists, and nephrologists often took responsibility for nutrition support in their area of expertise with a dwindling of the model of an internist or general surgeon with special skills in nutrition support playing the key MD role across the specialties. Nutrition support of the hospitalized patient has dramatically improved in the US over the past 35 years, but the loss of major benefits possible and unacceptable risks of invasive nutritional support if not delivered when appropriate, delivered without monitoring by nutrition experts, or employed where inappropriate or ineffective will require continued attention by medical authorities, hospitals, funding agencies, and industry in the future.

The rapid ascension of parenteral and enteral nutrition into an important component of clinical care in the hospital setting can be traced to three developments that occurred over an about 5-year period in the late 1960s and early 1970s. First and foremost was the first successful use of total parenteral nutrition (TPN), initially in beagle dogs to show the feasibility, and then its successful extension to 30 patients with chronic, complicated gastrointestinal disease by Dudrick et al. [1] at the University of Pennsylvania. At about the same time chemically defined or elemental diets were developed in normal volunteers to be employed in the US Mercury Space Program [2] where storage space and a low residue made these diets very desirable. These novel formulas were subsequently used in clinical conditions in which digestion and/or absorption was impaired and were provided usually through nasoenteric feeding tubes [3]. Both parenteral and enteral nutrition were initially studied in surgical patients in whom protein calorie malnutrition through gut malfunction had long been an often insurmountable problem. The third and final development was the identification of the extraordinary prevalence of malnutrition in hospitalized patients occurring in up to half of those on both surgical [4] and medical [5] services described in 1974 and 1976 respectively, when defined by simple anthropometric tools of weight, height, and upper arm anthropometry and serum albumin levels.

At this point one can view the glass as half full or half empty. From the optimistic or glass half full standpoint the period from 1975 to 1985 after the above advances could be described as a logarithmic phase of growth in clinical nutrition. Nutrition Support Services (NSS) using the novel, multidisciplinary model of physician, nurse specialist, pharmacist, and dietitian initially began in the early 1970s [6, 7] and at their high point probably approached 550 well-established services [8] in about 10% of America’s acute care hospitals by 1990. A number of studies during this early period demonstrated the ability of such groups to dramatically reduce the risk of catheter-related sepsis and to limit the development of electrolyte and metabolic abnormalities with TPN and to reduce complications and increase the adequacy of enteral nutrition [9]. Financial benefits were less certain in part due to difficulties to fully estimate costs and benefits [9], but at the very least were cost neutral in most circumstances [10].

The American Society of Parenteral and Enteral Nutrition which reflected this unique multidisciplinary membership of the NSS was established and had its first meeting in Chicago in 1976. Membership, initially less than 1,000 grew to nearly 8,000 by 1990 and was composed of approximately 20% physicians, 15% nurses, 15% pharmacists, and 50% dietitians in 1990. The annual ASPEN Clinical Congress, which continues to date, became an important venue to educate and train and provide a forum for the presentation of new research findings.

Finally from a personal perspective when I first became involved with nutrition support during my PhD training in Nutritional Biochemistry and Metabolism at MIT from 1972 to 1975, a period in which we were conducting the early surveys of nutritional status [4, 5], there was a general lack of appreciation for the nutritional status of patients. Protein calorie malnutrition was so widespread and undertreated that we developed a system of measurement of delayed cutaneous hypersensitivity to document cutaneous anergy [11] in order to convince clinicians that their patients required invasive nutritional support to reverse anergy. By 1990 there was a general appreciation that hospital protein calorie malnutrition was common, that invasive feeding could improve outcome, and that lack of feeding for periods of longer than 7–10 days in critically ill patients was an unacceptable practice. During this period from 1975 to 1990 there was a steady increase in the number of converts to better nutritional practices, particularly in surgical patients and in the critically ill in intensive care units, both medical and surgical. Testing for cutaneous anergy was abandoned at our medical center in the mid 1980s [12], principally because prolonged inadequate feeding became so uncommon, and there was little difficulty in convincing the primary physician of the need for invasive feeding when appropriate.

What happened subsequent to 1990? Now we can discuss the glass that is half empty, and this largely relates to medical funding. In the early 1980s the Medicare system in the US began a system of hospital payments based on diagnosis-related groups, where a fixed amount of money was paid according to diagnosis rather than actual costs. Medicare is the government system of reimbursement for patients 65 years or older, the disabled, or those receiving dialysis therapy. But the other source of hospital payments from medical care for the indigent through the government program Medicaid is the joint responsibility of the individual state and the federal government, and private insurance links their payments to government policy. The severe cost-containment pressures brought on by these changes in medical insurance have adversely affected nutrition support team staffing which began to have its greatest impact in the 1990s and was particularly harsh on hyperalimentation nurses and physicians involved in nutrition support. Although there are medical and financial costs associated with the termination of a nutrition support nurse [13], this cost must often be forcefully documented with hospital authorities, and generally can be in terms of unacceptable rates of catheter infection without their presence. With physicians there is no acknowledged medical specialty for clinical nutrition, although there was a split vote of 2–1 against by the American Board of Medical Specialties in the 1990s which would have accomplished this had it passed. Therefore, if the local hospital administrator or chairmen of medicine or surgery cannot be convinced of the value of providing partial financial support to nutrition support physicians for their clinical participation, then either it is done as a free service as an avocation by these individuals or done as a component of their underlying specialty. Thus most intensivists will provide parenteral and enteral nutrition as part of their care, as will many surgical specialists, particularly trauma surgeons, burn surgeons, and general surgeons. Oversight for home parenteral and enteral nutrition is often provided by gastroenterologists. However it is likely in many instances that nutritional care by these specialists is at an acceptable if perhaps not ideal level. For medical patients parenteral and enteral nutritional support is now often delivered under the care of dietitians which is reasonably good vis-à-vis enteral nutrition, but with parenteral nutrition may sometimes be outside their level of clinical competence, particularly for the management of fluid and electrolyte disorders and insulin management in diabetic patients. Dietitians have been less severely impacted by cost considerations, because there is a Joint Commission on Accreditation of Hospital Organizations (JCAHO) requirement that hospitals nutritionally monitor their patients. Pharmacists are also very important in the provision of parenteral nutrition, particularly by determining compatibilities of parenteral nutrition admixtures, checking the stability of orders from day-to-day, and by making certain of the completeness of parenteral regimens. Their continued availability to provide this level of expertise is also mandated by JCAHO as well as by their own professional standards.

There has also been a change in the membership of ASPEN that reflects this trend. After an initial fall of total members through the 1990s, the number has more recently stabilized, but there has been a dramatic decrease in nurses from nearly 1,000 to about 300 in 1999 and less than 200 at present (2006) with a concomitant increase in dietitians to about 60% of a total of 5,000 members, which has been relatively stable for the past 7 years, and a slowly diminishing number of physicians from 1,000 (20%) in 1999 to 735 (15%) in 2006. However both physician and pharmacist numbers have stabilized from 2001 to 2006, at approximately 750 and 620 members. Fellowship opportunities for physicians have also diminished, and there is some concern about what the future holds for physicians principally interested in parenteral and enteral nutrition. The second major American society for clinical nutrition after ASPEN was an independent group of academic physicians and PhD nutritionists interested in this field, the American Society for Clinical Nutrition. Last year by vote of its members it chose to disband and become a component of the American Society of Nutrition. Hopefully this group of individuals will maintain their interest in this field and continue to promote the improvement of parenteral and enteral nutrition for the hospitalized patient. However the likelihood of getting specialty recognition from the American Board of Medical Specialties is dim under the present conditions.

How does this bode for the future? Presumably there will always be some physicians trained in clinical nutrition, but some programs, like the exemplary program at MIT which trained many of the academic clinical nutritionists, have been discontinued and not been replaced. Certainly there is ample evidence for the need for such individuals. For instance one of the most important recent developments in clinical medicine has been the demonstration that tight blood glucose control in the critically ill can dramatically improve the morbidity and mortality of patients [18]. However this was primarily a study in cardiac surgical patients, and a similar study in medical patients by the same group demonstrated that tight blood glucose control improved morbidity but did not affect mortality [19]. In fact in those medical patients who received therapy for less than 3 days, mortality was actually increased. These superb innovative studies were primarily conducted by an endocrinologist who is a specialist in critical care. However an important variable in these two landmark studies, not previously commented on, is that in the surgical study the patients also received hypertonic dextrose initially for the first 24 h and TPN subsequently [18]. The medical patients in the second study received the initial hypertonic dextrose followed by inadequate nasogastric tube feeding for the first 3 days providing substantially less calories and grossly inadequate protein [19]. It may well be that it is the combination with tight glucose control in the setting of adequate feeding that is essential to achieve all the benefits rather than the control of hyperglycemia alone. Similarly a recent study in cardiac surgical patients receiving tight glucose control during their surgery and tight regulation of both treatment and control postoperatively showed no benefit and, in fact, a suggestion of harm in the treatment group [20]. Perhaps lowering blood glucose in cardiac patients not receiving hypertonic dextrose before revascularization may deprive the heart of an essential fuel. Having some physicians thoroughly trained in clinical nutrition to discern these possibilities may be important in the future to design and interpret the results of clinical trials.

 

For Patients Who Can’t Eat, Dr. Stanley Dudrick’s Intravenous Feeding System Is a Lifeline

Nearly 100 patients at the University of Texas Medical Center are undergoing similar nutritional therapy. Each owes his survival to Dr. Dudrick, who in 1972, at the precocious age of 37, became head of the center’s department of surgery.

Dudrick was turned from a fledgling cardiac surgeon into a pioneer nutritionist one day when he was an intern in Philadelphia. “We had three patients who had gone through successful surgery—but they all died,” he recalls. “I was terribly discouraged. Then the chairman of the surgery department said that, if I analyzed it, I’d see they really died of starvation. They couldn’t eat, and they didn’t have enough reserve tissues to draw on. I was too dumb to make that observation myself.”

Dudrick immersed himself in the study of how to provide food for those who can’t eat. From 10 to 40 percent of hospital deaths are still caused, he believes, by malnutrition. Patients with gastrointestinal cancer are especially vulnerable, as well as those with kidney or liver failure or burn trauma.

Sir Christopher Wren experimented with intravenous feeding of dogs as early as the 17th century. In its modern traditional form (most familiar in the glucose drip bottle), it cannot support life for long, however. Dudrick solved the problem by developing a complete nutritive compound. But he faced another obstacle: “We couldn’t put it in through the arm because the mixture was too thick and produced problems in the small veins. We couldn’t thin it down with water either, because that produced edema, or excess fluid in the connective tissue.

“Then,” Dudrick says, “we hit on the idea of putting it into larger veins, where the blood flow is so great that the nutritional substances would be diluted and rushed throughout the body.” Often the compound is pumped into the superior vena cava, through a catheter threaded through a smaller vein near the collarbone.

Dudrick’s nutrient, specially mixed for each patient, is composed of some 40 substances, including amino acids, glucose, vitamins and minerals. In some cases druggists or patients themselves can prepare the mixture.

Total Parenteral Nutrition (TPN) is Dudrick’s term for his technique. (Parenteral refers to bypassing the intestines.) In 1964 he astounded a medical convention in Germany with the news that he had raised six beagle puppies entirely on TPN for 287 days. In 1966 he first tried it on six humans with apparently terminal illness; all recovered and four are still alive. Since then Dudrick has used TPN on about 6,000 patients and has received two American Medical Association awards.

Eldest of four children of a Nanticoke, Pa. coal miner turned insurance agent, Dudrick decided on a medical career after watching the family doctor pull his mother through a near-fatal illness. Both his sisters are nurses. Still a crusader, he worries that, while half the nation’s doctors are aware of TPN, only five percent are using it. “It takes time,” he says, “for doctors to accept so much responsibility for dealing with such complex advances in human chemistry, metabolism and nutrition.”

Success will depend on campaigning for the technique, while simplifying it. “Someday we’ll have TPN down so that it will commonly be done in a general practitioner’s office,” Dudrick predicts. “That’s what I’m hoping for. I want to leave something better behind when I go, rather than just practice medicine the way it has always been done.”

Born in Rangoon, Burma on August 26, 1935, Khursheed N. Jeejeebhoy fled seven years later with his family to India to escape the Japanese invaders. He attended medical school in Vellore, India; trained in London, England; married and had three children; and in 1967, accepted a position at the Toronto General Hospital and the University of Toronto.From the beginning of his career, he was always on the forefront of research: he was one of the first to discover lactose intolerance. In 1970, with a surgical colleague, he was experimenting with TPN on post-surgical patients when Judy Ellis Taylor came into his care.

 

Dr. Khursheed Jeejeebhoy received his medical degree from the Christian Medical College Hospital in Vellore, India in 1959 and completed residency in India and the UK. He obtained his PhD from London University in 1963. He became division director of gastroenterology at the University of Toronto and the Toronto General Hospital. Currently, he is directs nutrition support and is a staff physician at St. Michael’s Hospital. He is also a professor of medicine, professor in the department of nutritional sciences and professor in the department of physiology, all at the University of Toronto. He has published over 500 peer-reviewed articles, abstracts and book chapters. He has a CIHR funded research program. He is on the editorial boards of nutritional journals and contributes to the Medical Post. He has received numerous awards throughout his career from Canada, USA and UK. He has been elected senior member of the Canadian Medical Association.

 

This determined young woman intended to live and expected him to save her. He took her up on her challenge and developed first a viable, long-term form of TPN, then a version Judy could use at home.With Judy such a success, Dr. Jeejeebhoy (Jeej to his patients and colleagues) bent his efforts to saving other lives with TPN and to learning more about the nutrients that the human body needs and in what dosages, both orally and intravenously, so that he could better nourish his patients and reduce their suffering. He has written over 350 papers and 100 books and chapters; was made professor of medicine, physiology, and nutrition at the University of Toronto; has lectured in virtually every country; and has taught many graduate students from Europe, North America, Asia, and Australia, as well as the first doctor allowed to leave China to study temporarily after China started opening up to the west.

His patients are intensely loyal to him, for his understanding, listening skills, expertise. In 1990, he moved to St. Michael’s Hospital and built up a TPN program there. He entered the commercial arena when he conducted research in and developed a radical new, nutritional way to improve the function of patients with congestive heart failure. MyLife Requirements “contains a patented combination of three nutrients, which interact synergistically and are needed by the heart to maintain optimal health and to function efficiently.  These nutrients are Coenzyme Q10, and the amino acids Taurine and Carnitine.” Due to the interesting regulation of L-carnitine by Health Canada, this supplement is available only in the US, not here in Canada.

At the end of 2007, he retired, sort of, a few years after becoming Professor Emeritus at the University of Toronto due to mandatory retirement at age 65. He closed his university lab at the end of 2007 when his last grant ran out. That ended a 40-year run of successful research grant applications and groundbreaking research. He embarked on a new role at St. Mike’s at the beginning of 2008, teaching at a Home TPN clinic; he continues to see patients part-time at a private clinic; and he conducts hospital rounds every week. His patients and colleagues would not allow complete retirement! Besides, Jeej is far too curious and interested in exploring new ideas to completely retire either!

 

 

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The Significant Burden of Childhood Malnutrition and Stunting

Curator: Larry H. Bernstein, MD, FCAP

Micronutrients

Quite a few  trace elements or micronutrients—vitamins and minerals—are important for health. Three very important micronutrient deficiencies in terms of health consequences for poor people in developing countries are:

Iron

  • In developing countries every second pregnant woman and about 40% of preschool children are estimated to be anemic.
  • In many developing countries, iron deficiency anemia is aggravated by worm infections, malaria and other infectious diseases such as HIV and tuberculosis.
  • The major health consequences include poor pregnancy outcome, impaired physical and cognitive development, increased risk of morbidity in children and reduced work productivity in adults. Anemia contributes to 20% of all maternal deaths. (WHO Iron Deficiency Anemia)

Vitamin A

  • Vitamin A deficiency  can cause night blindness and reduces the body’s resistance to disease. In children Vitamin A deficiency can also cause growth retardation.
  • An estimated 250 million preschool children are vitamin A deficient. An estimated 250,000 to 500 000 vitamin A-deficient children become blind every year, half of them dying within 12 months of losing their sight. (WHO Vitamin A Deficiencies)

Iodine

  • Iodine deficiency is one of the main cause of impaired cognitive development in children.
  • Serious iodine deficiency during pregnancy can result in stillbirth, spontaneous abortion, and congenital abnormalities such as cretinism, a grave, irreversible form of mental retardation that affects people living in iodine-deficient areas of Africa and Asia.
  • Iodine deficiency has a simple solution: iodized salt. Thanks to this intervention, the number of countries where iodine deficiency is a public health problem has halved over the past decade.  However 54 countries still have a serious iodine deficiency problem. (WHO Iodine Deficiencies)

Children and hunger

Children are the most visible victims of undernutrition.  Black et al (2013) estimate that undernutrition in the aggregate—including fetal growth restriction, stunting, wasting, and deficiencies of vitamin A and zinc along with suboptimum breastfeeding—is a cause of 3·1 million child deaths annually or 45% of all child deaths in 2011 (Black et al. 2013).  Undernutrition magnifies the effect of every disease, including measles and malaria. The estimated proportions of deaths in which undernutrition is an underlying cause are roughly similar for diarrhea (61%), malaria (57%), pneumonia (52%), and measles (45%) (Black 2003, Bryce 2005). Malnutrition can also be caused by diseases, such as the diseases that cause diarrhea, by reducing the body’s ability to convert food into usable nutrients.

Stunting

  • Globally 161 million under-five year olds were estimated to be stunted in 2013.
  • The global trend in stunting prevalence and numbers affected is decreasing. Between 2000 and 2013 stunting prevalence declined from 33% to 25% and numbers declined from 199 million to 161 million.
  • In 2013, about half of all stunted children lived in Asia and over one third in Africa. (UNICEF et al. 2014b)

Wasting and severe wasting ·

  • Globally, 51 million under-five year olds were wasted and 17 million were severely wasted in 2013.
  • Globally, wasting prevalence in 2013 was estimated at almost 8% and nearly a third of that was for severe wasting, totaling 3%. In 2013, approximately two thirds of all wasted children lived in Asia and almost one third in Africa, with similar proportions for severely wasted children. (UNICEF et al. 2014b)
  •  In 2013, approximately two thirds of all wasted children lived in Asia and almost one third in Africa, with similar proportions for severely wasted children. (UNICEF et al. 2014b)

Under-five Protein Energy Malnutrition Admitted at the University of In Nigeria Teaching Hospital, Enugu: a 10 year retrospective review

Agozie C Ubesie12*, Ngozi S Ibeziako12, Chika I Ndiokwelu3, Chinyeaka M Uzoka3 andChinelo A Nwafor3

Nutrition Journal 2012, 11:43  doi:10.1186/1475-2891-11-43

http://www.nutritionj.com/content/11/1/43

To determine the prevalence, risk factors, co-morbidities and case fatality rates of Protein Energy Malnutrition (PEM) admissions at the paediatric ward of the University of Nigeria Teaching Hospital Enugu, South-east Nigeria over a 10 year period.

Design

A retrospective study using case Notes, admission and mortality registers retrieved from the Hospital’s Medical Records Department.

Subjects

All children aged 0 to 59 months admitted into the hospital on account of PEM between 1996 and 2005.

Results

A total of 212 children with PEM were admitted during the period under review comprising of 127 (59.9%) males and 85(40.1%) females. The most common age groups with PEM were 6 to 12 months (55.7%) and 13 to 24 months (36.8%). Marasmus (34.9%) was the most common form of PEM noted in this review. Diarrhea and malaria were the most common associated co-morbidities. Majority (64.9%) of the patients were from the lower socio-economic class. The overall case fatality rate was 40.1% which was slightly higher among males (50.9%). Mortality in those with marasmic-kwashiokor and in the unclassified group was 53.3% and 54.5% respectively.

Conclusion

Most of the admissions and case fatality were noted in those aged 6 to 24 months which coincides with the weaning period. Marasmic-kwashiokor is associated with higher case fatality rate than other forms of PEM. We suggest strengthening of the infant feeding practices by promoting exclusive breastfeeding for the first six months of life, followed by appropriate weaning with continued breast feeding. Under-five children should be screened for PEM at the community level for early diagnosis and prompt management as a way of reducing the high mortality associated with admitted severe cases.

Globally, PEM continues to be a major health burden in developing countries and the most important risk factor for illnesses and death especially among young children [1]. The World Health Organization estimates that about 60% of all deaths, occurring among children aged less than five years in developing countries, could be attributed to malnutrition [2]. The improvement of nutrition therefore, is the main prerequisite for the reduction of high infant and under five mortality rates, the assurance of physical growth, social and mental development of children as well as academic achievement [3]. Sub-saharan Africa bears the brunt of PEM in the world. On the average, the PEM associated mortality in sub-Saharan Africa is between 25 and 35% [4,5]. In Nigeria, 22 to 40% of under-five mortality has been attributed to PEM [6]. PEM is also associated with a number of co-morbidities such as lower respiratory tract infections including tuberculosis, diarrhea diseases, malaria and anaemia [7,8]. These co-morbidities may prolong the duration of hospital stay and death among affected children.

There is a knowledge gap on the incidence and outcome of PEM seen in the Nigerian tertiary health facilities. In this study, the type of PEM among admitted under-five children, the associated morbidities, and duration of hospitalization and outcome at the University of Nigeria Teaching Hospital Enugu over a 10 year period is reviewed.

Relevant information was extracted from each retrieved case file and/or hospital registers and transferred into the proforma. Diagnosis of PEM was based on the Modified Wellcome Classification because it was the method used for clinical diagnosis by the clinicians. This classified PEM into kwashiorkor, underweight kwashiorkor, underweight, marasmus, marasmic kwashiorkor and there was also provision for unclassified PEM. Marasmus and the various forms of kwashiorkor are part of the recently defined Severe Acute Malnutrition (SAM) by the World Health Organization (WHO). The WHO defined SAM by a very low weight for height (below -3z scores of the median WHO growth standards), visible severe wasting or the presence of nutritional oedema [11,12]. Modified Wellcome classification uses weight for age and the presence or absence of oedema to classify PEM. The weights were measured using infant weighing scales (Waymaster) and stadiometers (Health Scale) depending on the age of the child. A total of 212 proforma were completed covering the entire period of the study.

Diagnosis of HIV was made using Enzyme Linked Immunosorbent Assay [ELISA] and Westerblot. In children aged less than 18 months, positive antibody test was combined with clinical features to make presumptive diagnosis of HIV infection. Diagnosis of malaria was confirmed using blood film and bronchopneumonia using chest X-ray. Diarrhea was defined as passage of watery or loose stools or an increase in frequency above normal for a child. Severe anaemia was defined using a packed cell volume of less than 15%. Sepsis was defined as clinical features of systemic inflammatory response (fever, tachycardia, tachypnea, leukocytosis or leukopenia) associated with infection. Diagnosis of tuberculosis was made in the presence of chronic cough that have lasted for more three weeks supported by varied combination of the following: positive family history of tuberculosis, positive mantoux, suggestive chest X-ray and elevated erythrocyte sedimentation rate. Diagnosis of scabies was clinical based on the typical itching papular rash located at the intertrigous areas. Chronic suppurative otitis media and rickets were suspected clinically and confirmed by culture of ear swab and X-ray of the limbs respectively.

Subjects

A total of 7703 children were admitted into the paediatric wards and 212 of them were cases of PEM during the period under review. This represented about 2.8% of the total paediatric admissions. One hundred and twenty seven (59.9%) were males while 85 (40.1) were females giving a male: female ratio of 1: 0.7. The age group studied was 6 to 59 months (under-5). The mean age of the participants was 15.4 ± 9.3 months.

PEM and demography

PEM was most common among the age groups 6 to 12 and 13 to 24 months, and these accounted for 55.7% and 36.8% of the study population respectively. There was however, no statistically significant difference between the age groups and various forms of PEM as shown in Table 1(χ² = 19.38, df =16, p = 0. 249). The most common form of PEM noted in this review was marasmus (34.9%). Except for marasmic-kwashiokor, more males than females had more of all the various types although this was not statistically significant (χ² = 8.382, df =4, p = 0. 079) as shown in Table2. Admissions for PEM were recorded more in 1996, 1999 and 2004 (15.1, 13.7 and 12.3% respectively), but there were no consistent pattern in the yearly admissions of children with PEM during the period under review (Figure 1).

PEM admissions according to the age groups (months)
PEM type 0-12 m (%) 13-24 m (%) 25-36 m (%) 37-60 m (%) 49-60 m (%)
Kwashiokor 16 (13.6) 19 (24.4) 3 (33.3) 1 (33.3) 1 (25)
Underweight 11 (9.3) 6 (7.7) 0 (0) 0 (0) 0 (0)
Marasmic-kwash 6 (5.1) 8 (10.3) 0 (0) 1 (33.3) 0 (0)
Marasmus 48 (40.7) 24 (30.8) 2 (22.2) 0 (0) 0 (0)
Unclassified 37 (31.4) 21 (26.9) 4 (44.4) 1 (33.3) 3 (75)
Total 118 (100) 78 (100) 9 (100) 3(100) 4 (100)

χ² = 19.38, df =16, P = 0. 249.

Table 3
The associated co-morbidities seen among patients
Co-morbidity Frequency
(%)
Diarrhea 48 (72.2)
Malaria 29 (43.9)
Sepsis 25 (37.9)
Severe anaemia 16 (24.2)
Bronchopneumonia. 11 (16.7)
HIV 9 (13.6)
Tuberculosis 8 (12.1)
other 5 (7.5)

The table shows the associated co-morbidities noted in the patients.

Table 4
Prevalence of PEM by breastfeeding pattern
Breastfeeding pattern Prevalence 95% Confidence Intervals
(%)
Exclusive breast feeding for 0–3 months 18.9 11.2 – 26.6
Predominant breastfeeding 0–3 months 48.6 38.8 – 58.4
Predominant breastfeeding 4–6 months 24.3 15.9 – 32.7
Breast milk substitutes 8.1 2.7 – 13.5

The table shows the prevalence of the various pattern of feeding for the children during their early infancy. The 95% confidence interval is also reported.

Ubesie et al.

Ubesie et al. Nutrition Journal 2012 11:43   doi:10.1186/1475-2891-11-43

Prognostic indicators

The duration of hospitalization was available in only 84 subjects and ranged from 0 to 62 days. The mean duration of hospitalization was 16 ± 15 days. Kwashiokor patients had the highest mean hospitalization days of 19.15 days while marasmic and underweight patients had the least days of 14.52 and 14.55 days respectively. There was no statistically significant difference in the mean hospitalization days for the various types of PEM (F = 0.317, df =4, P = 0. 866). A total of 85 (40.1%) children died while on admission, 124 (58.5%) recovered and were discharged home while 3 (1.4%) were discharged against medical advice. Mortality was higher among the males (50.9%) than females (34.1%) although this was not statistically significant (χ² = 0.723, df =2, P = 0. 697). Most of the deaths were recorded in the age groups 0–12 (55.3%) and 13–24 (36.5%) months although this difference was not statistically significant (χ² = 10.98, df =8, p = 0. 203). The marasmic-kwashiokor and unclassified groups had higher mortality rates (53.3% and 54.5% respectively) than the marasmus (37.8%) or kwashiorkor groups (30%). There was a statistically significant difference in the mortality rates of the various types of PEM as shown in Table 5 (χ² = 17.26, df =4, p = 0. 002) The number of complications ranged from none to four. Kwashiokor has the highest mean number of complications (2.06) while unclassified had the least number of 1.26. There was a statistically significant difference in the number of complications and the various PEM (F = 8.92, df =4, P <0.05)

High PEM associated mortality

The overall mortality in our study was 40.1% which although lower than the WHO estimated 60%[2] is still very high. Studies conducted in various parts of Africa have documented unacceptable high mortality rates among children admitted for PEM. In Oshogbo, South West Nigeria, Ibekwe and Ashworth [6] documented an average mortality rate of 22% over a five year period among 803 children admitted for PEM in a Nutritional Rehabilitation Center. Similarly, in a hospital based study in north-eastern Zambia, involving children below the age of five years, Gernaat et al.[4] documented an overall mortality rate of 25.8% among 288 children admitted for various types of severe/complicated malnutrition . Higher mortality rate for marasmic kwashiorkor than marasmus or kwashiorkor was noted in this review. Gernaat et al.[4] noted similar finding in their review among Zambian children admitted and managed for PEM. This reason for this is unclear. However, Ibekwe and Ashworth [6] did note that PEM associated mortality among oedematous patients was significantly higher compared to those with marasmus. It can be argued therefore, that presence of oedema in a malnourished child connotes poor prognosis. The mean duration of hospitalization was 16 days which is similar to 13.1 and 14.3 days reported by Cartmell et al. [13] but differs from the 35 days reported by Ibekwe and Ashworth [6]. Both this review and the study by Cartmell et al. were hospital based while that of Ibekwe and Ashworth was conducted in a Nutrition Rehabilitation Center. The pressure on bed spaces in a hospital setting could have contributed to earlier discharges in hospital settings.

Associated risk factors for PEM

Our review noted that PEM was more common among children from the lower social class (69.4%) and those predominantly breast fed for three months or less (48.6%) compared to exclusively breast fed children (18.9%). The reason for this may not be unconnected to the fact that poor families have low purchasing power for adequate nutritious foods for their families. Illiteracy on the other hand, may influence feeding practices. The low rate of exclusive breast feeding noted in this review despite the Baby Friendly Initiatives is also very worrisome. Poverty and illiteracy as risk factors for PEM have been documented in the literature. . In a case control study conducted in Dhaka, Bangladesh which involved children aged six to 24 months, Nahar et al.[15] compared 507 children with weight-for-age z-score (WAZ) < −3 matched for age, sex and place of residence with 500 children whose weight-for-age z-score (WAZ) were > −2.5 . They documented that severely-underweight children were more likely to have: undernourished poorly educated teenage mothers, history of shorter duration of predominant breastfeeding, and fathers who were poorly educated and unskilled day-labourers [15].

Diarrhea, malaria, sepsis and severe anaemia were the most prevalent associated co-morbidities from our review in that order. In Maputo, the most prevalent co-morbidities associated with PEM by Cartmell et al. were anaemia, bronchopneumonia, malaria and diarrhea. The prevalence of human immune deficiency virus (HIV) from our review was 13.6% and this compares to a prevalence of 12% in the Maputo study. This finding underscored the high rate of HIV infection among children with severe forms of PEM and the need to routinely screen such children for HIV when they present at a health facility.

Conclusions

Younger children aged less than two years accounted for most of the admissions in this review. Marasmic-kwashiokor was associated with higher case fatality rate than other types of PEM. There is need therefore to strengthen the infant feeding practices by promoting exclusive breastfeeding for the first 6 months of life, followed by appropriate weaning with continued breast feeding till second year of life. PEM was associated with high rate of mortality in this hospital setting and preventive strategies need to be emphasized instead.

Below are 10 interesting facts about poverty and malnutrition.

  1. Malnutrition takes two general forms. Protein-energy malnutrition, which is basically a lack of calories and protein. This form of malnutrition is the most lethal and is the type of malnutrition that is referred to when world hunger is discussed. The second type of malnutrition is micronutrient or vitamin and mineral deficiency.
  2. According to The United Nations Food and Agriculture Organization, it is estimated that nearly 870 million people of the 7.1 billion people in the world – or one in eight – were suffering from chronic undernourishment in 2010-2012.
  3. Poverty and malnutrition have a direct link – poverty is the main and principal cause of malnutrition. The World Bank estimated that in 2008 that there were about 1.35 million poor people in developing countries who live on $1.25 a day or less.
  4. In addition to poverty, the other main causes of malnutrition are harmful economic systems, war and conflict and climate change.
  5. The countries with the highest rates of malnutrition also have the lowest economic indicators.
  6. Children are the most vulnerable victims of malnutrition.  Poor nutrition plays a role in at least half of the 10.9 million child deaths each year.
  7. Mothers who lack access to proper nutrients bear malnourished children. These children face greater challenges in their ability to learn and thrive. They are more susceptible to illness and disease. Their compromised opportunities for healthy development and mental and physical agility usually means the cycle of poverty continues.
  8. In another link between poverty and malnutrition, the WHO reports that one out of three people in developing countries are affected by vitamin and mineral deficiencies.
  9. The world produces enough food to feed everyone. The real problem is that many people in the world do not have sufficient land to grow or income to purchase enough food. Poverty and malnutrition can create a self-sustaining cycle where there is never enough security or stability for recovery of health or economic development.
  10. Some countries address the problem of poverty and malnutrition by administering programs that provide assistance to those who suffer from a lack of nutrients in their diet by offering dietary supplements and fortified foods. This is seen as a cost-effective strategy in combating poverty and malnutrition.

– Nina Verfaillie

http://borgenproject.org/10-facts-poverty-malnutrition/

Chapter 12. Protein-energy malnutrition

http://www.fao.org/docrep/w0073e/w0073e05.htm

Protein-energy malnutrition (PEM) in young children is currently the most important nutritional problem in most countries in Asia, Latin America, the Near East and Africa. Energy deficiency is the major cause. No accurate figures exist on the world prevalence of PEM, but World Health Organization (WHO) estimates suggest that the prevalence of PEM in children under five years of age in developing countries has fallen progressively, from 42.6 percent in 1975 to 34.6 percent in 1995. However, in some regions this fall in percentage has not been as rapid as the rise in population; thus in some regions, such as Africa and South Asia, the number of malnourished children has in fact risen. In fact the number of underweight children worldwide has risen from 195 million in 1975 to an estimated 200 million at the end of 1994, which means that more than one-third of the world’s under-five population is still malnourished.

Failure to grow adequately is the first and most important manifestation of PEM. It often results from consuming too little food, especially energy, and is frequently aggravated by infections. A child who manifests growth failure may be shorter in length or height or lighter in weight than expected for a child of his or her age, or may be thinner than expected for height.

The conceptual framework described in Chapter 1 suggests that there are three necessary conditions to prevent malnutrition or growth failure:

  • adequate food availability and consumption;
  • good health and access to medical care; and
  • adequate care and feeding practices.

If any one of these is absent, PEM is a likely outcome.

The term protein-energy malnutrition entered the medical literature fairly recently, but the condition has been known for many years. In earlier literature it was called by other names, including protein-calorie malnutrition (PCM) and protein-energy deficiency.

The term PEM is used to describe a broad array of clinical conditions ranging from the mild to the serious. At one end of the spectrum, mild PEM manifests itself mainly as poor physical growth in children; at the other end of the spectrum, kwashiorkor (characterized by the presence of oedema) and nutritional marasmus (characterized by severe wasting) have high case fatality rates.

It has been known for centuries that grossly inadequate food intake during famine and food shortages leads to weight loss and wasting and eventually to death from starvation. However, it was not until the 1930s that Cicely Williams, working in Ghana, described in detail the condition she termed “kwashiorkor” (using the local Ga word meaning “the disease of the displaced child”). In the 1950s kwashiorkor began to get a great deal of attention. It was often described as the most important form of malnutrition, and it was believed to be caused mainly by protein deficiency. The solution seemed to be to make more protein-rich foods available to children at risk. This stress on kwashiorkor and on protein led to a relative neglect of nutritional marasmus and adequate food and energy intakes for children.

The current view is that most PEM is the result of inadequate intake or poor utilization of food and energy, not a deficiency of one nutrient and not usually simply a lack of dietary protein. It has also been increasingly realized that infections contribute importantly to PEM. Nutritional marasmus is now recognized to be often more prevalent than kwashiorkor. It is unknown why a given child may develop one syndrome as opposed to the other, and it is now seen that these two serious clinical forms of PEM constitute only the small tip of the iceberg. In most populations studied in poor countries, the point prevalence rate for kwashiorkor and nutritional marasmus combined is 1 to 5 percent, whereas 30 to 70 percent of children up to five years of age manifest what is now termed mild or moderate PEM, diagnosed mainly on the basis of anthropometric measurements.

Causes and epidemiology

PEM, unlike the other important nutritional deficiency diseases, is a macronutrient deficiency, not a micronutrient deficiency. Although termed PEM, it is now generally accepted to stem in most cases from energy deficiency, often caused by insufficient food intake. Energy deficiency is more important and more common than protein deficiency. It is very often associated with infections and with micronutrient deficiencies. Inadequate care, for example infrequent feeding, may play a part.

The cause of PEM (and of some other deficiency diseases prevalent in developing countries) should not, however, be viewed simply in terms of inadequate intake of nutrients. For satisfactory nutrition, foods and the nutrients they contain must be available to the family in adequate quantity; the correct balance of foods and nutrients must be fed at the right intervals; the individual must have an appetite to consume the food; there must be proper digestion and absorption of the nutrients in the food; the metabolism of the person must be reasonably normal; and there should be no conditions that prevent body cells from utilizing the nutrients or that result in abnormal losses of nutrients. Factors that adversely influence any of these requisites can be causes of malnutrition, particularly PEM. The aetiology, therefore, can be complex. Certain factors that contribute to PEM, particularly in the young child, are related to the host, the agent (the diet) and the environment. The underlying causes could also be categorized as those related to the child’s food security, health (including protection from infections and appropriate treatment of illness) and care, including maternal and family practices such as those related to frequency of feeding, breastfeeding and weaning.
Protein-Energy Malnutrition

  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Romesh Khardori, MD, PhD, FACP

http://emedicine.medscape.com/article/1104623-overview

The World Health Organization (WHO)[1] defines malnutrition as “the cellular imbalance between the supply of nutrients and energy and the body’s demand for them to ensure growth, maintenance, and specific functions.” The term protein-energy malnutrition (PEM) applies to a group of related disorders that include marasmus, kwashiorkor (see the images below), and intermediate states of marasmus-kwashiorkor. The term marasmus is derived from the Greek word marasmos, which means withering or wasting. Marasmus involves inadequate intake of protein and calories and is characterized by emaciation. The term kwashiorkor is taken from the Ga language of Ghana and means “the sickness of the weaning.” Williams first used the term in 1933, and it refers to an inadequate protein intake with reasonable caloric (energy) intake. Edema is characteristic of kwashiorkor but is absent in marasmus.

This photograph shows children and a nurse attendant at a Nigerian orphanage in the late 1960s. Notice four of the children with gray-blond hair, a symptom of the protein-deficiency disease kwashiorkor. Image courtesy of Dr. Lyle Conrad and the CDC Public Health Image Library.

This late 1960s photograph shows a seated, listless child who was among many kwashiorkor cases found in Nigerian relief camps during the Nigerian-Biafran war. Kwashiorkor is a disease brought on due to a severe dietary protein deficiency, and this child, whose diet fit such a deficiency profile, presented with symptoms including edema of legs and feet, light-colored, thinning hair, anemia, a pot-belly, and shiny skin. Image courtesy of Dr. Lyle Conrad and the CDC Public Health Image Library.

Studies suggest that marasmus represents an adaptive response to starvation, whereas kwashiorkor represents a maladaptive response to starvation. Children may present with a mixed picture of marasmus and kwashiorkor, and children may present with milder forms of malnutrition. For this reason, Jelliffe suggested the term protein-calorie (energy) malnutrition to include both entities.

Although protein-energy malnutrition affects virtually every organ system, this article primarily focuses on its cutaneous manifestations. Patients with protein-energy malnutrition may also have deficiencies of vitamins, essential fatty acids, and trace elements, all of which may contribute to their dermatosis.

In general, marasmus is an insufficient energy intake to match the body’s requirements. As a result, the body draws on its own stores, resulting in emaciation. In kwashiorkor, adequate carbohydrate consumption and decreased protein intake lead to decreased synthesis of visceral proteins. The resulting hypoalbuminemia contributes to extravascular fluid accumulation. Impaired synthesis of B-lipoprotein produces a fatty liver.

Protein-energy malnutrition also involves an inadequate intake of many essential nutrients. Low serum levels of zinc have been implicated as the cause of skin ulceration in many patients. In a 1979 study of 42 children with marasmus, investigators found that only those children with low serum levels of zinc developed skin ulceration. Serum levels of zinc correlated closely with the presence of edema, stunting of growth, and severe wasting. The classic “mosaic skin” and “flaky paint” dermatosis of kwashiorkor bears considerable resemblance to the skin changes of acrodermatitis enteropathica, the dermatosis of zinc deficiency.

In 2007, Lin et al[2] stated that “a prospective assessment of food and nutrient intake in a population of Malawian children at risk for kwashiorkor” found “no association between the development of kwashiorkor and the consumption of any food or nutrient.”

Marasmus and kwashiorkor can both be associated with impaired glucose clearance that relates to dysfunction of pancreatic beta-cells.[3] In utero, plastic mechanisms appear to operate, adjusting metabolic physiology and adapting postnatal undernutrition and malnutrition to define whether marasmus and kwashiorkor will develop.[4]

United States

Protein-energy malnutrition is the most common form of nutritional deficiency among patients who are hospitalized in the United States. As many as half of all patients admitted to the hospital have malnutrition to some degree. In a recent survey in a large children’s hospital, the prevalence of acute and chronic protein-energy malnutrition was more than one half. This is very much a disease that occurs in 21st century America, and a case in an 8-month-old child in suburban Detroit, Mich, was reported in 2010.[9] Additional cases of kwashiorkor have been noted to occur in the United States. An interesting report of a baby with a clinical picture imitating Stevens-Johnson syndrome but who in fact had kwashiorkor has been noted.[10] Babies solely fed on rice milk can develop kwashiorkor even in the United States.

In a survey focusing on low-income areas of the United States, 22-35% of children aged 2-6 years were below the 15th percentile for weight. Another survey showed that 11% of children in low-income areas had height-for-age measurements below the 5th percentile. Poor growth is seen in 10% of children in rural populations.

In hospitalized elderly persons, up to 55% are undernourished. Up to 85% of institutionalized elderly persons are undernourished. Studies have shown that up to 50% have vitamin and mineral intake that is less than the recommended dietary allowance and up to 30% of elderly persons have below-normal levels of vitamins and minerals.

International

In 2000, the WHO[11] estimated that malnourished children numbered 181.9 million (32%) in developing countries. In addition, an estimated 149.6 million children younger than 5 years are malnourished when measured in terms of weight for age. In south central Asia and eastern Africa, about half the children have growth retardation due to protein-energy malnutrition. This figure is 5 times the prevalence in the western world.

A cross-sectional study of Palestinian adolescents found that 55.66% of boys and 64.81% of girls had inadequate energy intake, with inadequate protein intake in 15.07% of boys and 43.08% of girls. The recommended daily allowance for micronutrients was met by less than 80% of the study subjects.[12]

Mortality/Morbidity

Approximately 50% of the 10 million deaths each year in developing countries occur because of malnutrition in children younger than 5 years. In kwashiorkor, mortality tends to decrease as the age of onset increases.

Race

Dermatologic findings appear more significant and occur more frequently among darker-skinned peoples. This finding is likely explained by the greater prevalence and the increased severity of protein-energy malnutrition in developing countries and not to a difference in racial susceptibility.

The hungry and forgotten

Reprints

chinese child

chinese child

Pilot projects in cooperation with the Ministry of Health have demonstrated the effectiveness of Ying Yang Bao, a simple easy-to-use complementary food supplement, in preventing and controlling childhood malnutrition.UNICEF has been supporting intensive efforts on finding solutions.

Even where children get the calories they need—as most do in rural China—they are not being fed the right things. In one study of 1,800 infants in rural Shaanxi province in China’s north-west, 49% were anaemic and 40% were significantly hampered in developing either cognitive or motor skills. Fewer than one in ten were stunted or wasting, meaning that in most cases the problem was not lack of calories, but lack of nutrients.

China shares this affliction with much of the developing world. But it has the resources to respond. Parents have the means to feed their babies properly. And with a relatively modest investment, the government could do a better job of improving childhood nutrition. The difficulties lie in educating parents—and officials.

“Babies are probably 50% malnourished” in poor rural areas, says Scott Rozelle, co-director of the Rural Education Action Programme (REAP), a research outfit at Stanford University which has done extensive tests on anaemia in rural China. “But almost no mums are malnourished.” Mr Rozelle says that in one of his surveys rural mothers showed a better understanding of how to feed pigs than babies: 71% said pigs need micronutrients, whereas only 20% said babies need them.

Mr Lu’s charity and REAP argue that a nutritional supplement called ying yang bao should be available to rural mothers. A powdery concoction of soyabeans, iron, zinc, calcium and vitamins, it is supposed to be sprinkled on food once a day. Each packet costs less than one yuan (16 cents) to produce and one yuan to distribute, paid by the government.

Trials conducted since 2006 have consistently shown that ying yang bao reduces anaemia and improves growth and development in infants and toddlers. But persuading parents of this (or grandparents, if the parents are off working in cities) has not been easy. About half give up feeding it to their children. “Poor people feel very suspicious”, Mr Lu says. They wonder if free supplements are unsafe, or fake. “Then they worry will we charge later?”

This may be the legacy in rural China of years of seeing government invest little—and often charge a lot—for basic services. Moreover, at the local level the workers who are meant to help mothers may well be family-planning officials responsible for controlling population, a role that hardly inspires trust.

At higher levels of government, too, officials need a lot of persuading that nutrition programmes are not a waste of public money. In 2011 China began instituting a programme similar to America’s federal school-lunch programme for the poor, at a cost of 16 billion yuan ($2.6 billion) a year. But one assessment suggests that perhaps half the schools are providing substandard, uncooked meals, partly because some local governments refuse to foot the bill for kitchens and cooks.

In 2012 the health ministry made a modest investment of 100m yuan to provide supplements to 270,000 babies in 100 counties. This year 400,000 babies in 300 counties are meant to get them. Later this year Mr Lu’s charity will begin a tiny pilot of an early-parenting programme, akin to America’s Head Start, in 50 villages, with 50 more villages being used for controlled comparison. James Heckman, an economist and Nobel laureate who has researched early-childhood development, is helping design the study. Such programmes look promising. But they are tiny.

Part of the problem in getting local or provincial governments to spend money on childhood nutrition is that the payoffs are years in the making. And the returns might not go to the village or province, but to cities miles away, in the form of more skilled workers who move there. Central ministries are keen to invest, Mr Lu says, but they want to spend their cash on things that officials crave more than children do—like buildings in villages for each ministry.

For Mr Lu one kind of building does promise a big payoff—village early-education centres, or preschools. His charity has set them up in 677 villages, often using redundant elementary schools. In Songjia village Tian Lin, 22, and her older sister, Tian Hongjiao, teach 26 children aged three to six, including the younger sister’s own three-year-old son. They cook lunch with whatever the children bring from home. Those with migrant-worker parents, who are a bit better off, may have a chunk of pork; others bring a meagre potato or vegetable. Either way all the children get a ying yang bao with their lunch.

In 2012 a study found the anaemia rate among the three- to five-year-olds in this county was close to 18%, more than twice the average for poor rural areas nationwide, according to Mr Lu’s CDRF. He reckons that, on coming to the centres, the children show only 20% of the memory retention of their urban counterparts and 40-60% of their language abilities and cognition. But nutritional supplements help. A study of nine- and ten-year olds, co-written by Mr Rozelle, found that taking a daily chewable vitamin with iron for six months not only cut anaemia levels. It also improved their maths.

pre-school centre in Songjia

pre-school centre in Songjia

Malnutrition Plagues Children of Rural China
China became an economic superpower in only a matter of decades. Forbes Magazine’s annual rich list reported that China has had 152 billionaires this past year. The once struggling nation has shown promising improvement. According to the World Bank, the number of impoverished people living in China dropped from 683 million in 1990 to 157 million in 2009. This improvement is a result of the rapid urbanization in China in recent years. Greater economic opportunity and government assistance is now available in cities. However, children in rural villages are stuck in a seemingly unbreakable cycle of poverty.

The children of rural China face a variety of challenges that are virtually nonexistent in the cities. Among one of the most glaring is the struggle against malnutrition. UNICEF estimates that there are 12.7 million stunted children in China; this life-long condition that results from severe malnutrition plagues children most during early childhood.

stunted due to malnutrition during his first two years of life.

Lttle Han’s elder brother (right) is 9-years-old and stands barely 1.2 meter tall. It is likely that he is stunted due to malnutrition during his first two years of life.

Back home, noodles without beef and porridge are the staple foods. For an average rural family in Hualong, potato is almost their sole source of vegetable.  Beef and mutton are only consumed during rare festive occasions.

Many families cannot afford to keep any sheep or cattle, therefore both milk and meat can be rarely found on the dining table.

“Babies eat the same food as their mothers after breastfeeding stops – we all know there is not enough nutrition for them, but we didn’t know what to do,” said Dr. Wang Chunhua, from the  township hospital,. She has delivered over 500 babies during her 10 years’ service in Hualong.

In addition to malnutrition, anemia takes a tremendous toll on rural Chinese children. Stanford University conducted a test on 1824 babies in China’s Shaanxi Province. Forty nine percent of the babies tested were anemic and 28 percent were near anemic. Furthermore, of all the babies tested, 40 percent displayed cognitive or motor problems.

Why are rates of anemia so high? Stanford reports that while the parents were generally willing to spend additional money on food for their children, they were uninformed on what type of nutritional value the food should have. Many micronutrients, such as iron, were missing, indicating that fresh fruits and vegetables were consumed infrequently. Additionally, further investigation revealed that mothers stopped breastfeeding after six months. From that point on, the child would typically eat rice porridge or soups.

Misinformed parents are often responsible for their children’s poor health. Parents often do not introduce solid food into children’s diets until they are 12 to 18 months old, though it is recommended that solid food make up half of a one-year-old’s diet. Many parents believe myths that babies cannot digest hard foods or that particular foods, like rice, are better for cognitive development.

Treating anemia and replenishing nutrients is actually quite easy. Stanford researchers state that simply taking iron supplements can counter anemia. To address the rampant malnutrition in China’s poor, rural provinces, UNICEF has begun to distribute a nutrition supplement called Ying Yang Bao. Ying Yang Bao is a small packet of powdered vitamins, minerals and proteins that can be mixed into solid foods like porridge.

Many rural Chinese families cannot afford to buy fresh fruits, vegetables and proteins like beef. Dairy products are also expensive and difficult to access. Often, noodles, porridge, rice and starches like potatoes constitute meals. Fortunately, the micronutrients in Ying Yang Bao are easily dissolved in porridges and soups.

UNICEF reports that, between 2008 and 2011, more than 30,000 rural children received Ying Yang Bao. After consumption, anemia levels were cut in half. A long-term solution to malnutrition is still in the works. While aid from UNICEF and other organizations is improving the health of rural children, education is a key issue to be addressed. Parents are misguided by myths and superstitions, which has led to the silent suffering on many children. A public education program has not been officially instituted, but would be another component of China’s long-term solution for malnutrition.

– Bridget Tobin

Child: Care, Health and Development

Volume 31Issue 4pages 417–423July 2005

  • feeding practices;
  • nutrition;
  • rural China

Abstract

Background  China has the largest population in the world with more than 70% of the people living in rural areas. Over 34% of children under the age of 5 years are responded to show moderate or severe growth stunting, so United Nations International Children’s Emergency Fund and Chinese Ministry of Health conducted this large-scale survey in China. This study aimed to learn the feeding practice, to find the problems in child-feeding practice and to provide evidence for the government to develop an approach to child malnutrition in rural China.

Methods  A structured  questionnaire  was  used  to  survey  21 036  mothers  of  children  with  age  of 0–24 months.

Results  Of the 20 915 children, 98.22% were breastfeeding and 24.36% were exclusively breastfeeding. The proportion of children with weekly protein intake was 78.47%. Among the infants under 4 months, the risk of pneumonia in the group of exclusive breastfeeding was 1.69%, while in the group of non-exclusive breastfeeding was 3.63%, showing a statistically significant difference between the two groups. The risk of diarrhoea in the group of exclusive breastfeeding and in the group of non-exclusive breastfeeding among the infants under 4 months was 24.37% and 40.86%, respectively, also showing a statistically significant difference between the two groups. For children with age 4–6 months, the complementary feeding contributed to a higher prevalence of diarrhoea, but not pneumonia.

Conclusions  The breastfeeding was very common, but the exclusive breastfeeding was quite low and the exclusive breastfeeding for children under the age of 4 months decreased the risks of pneumonia and diarrhoea. For children with age 4–6 months, the exclusive breastfeeding could decrease the risk of diarrhoea, too. Protein intake was insufficient for children in rural China. The rural people lacked health knowledge and were greatly influenced by traditional feeding practices.

Physical growth of children and adolescents in China over the past 35 years

Xin-Nan Zong a & Hui Li a

  1. Department of Growth and Development, Capital Institute of Pediatrics, No. 2 Yabao Road, Chaoyang District, Beijing 100020, China.

Correspondence to Hui Li (email: huiligrowth@163.com).

(Submitted: 18 June 2013 – Revised version received: 10 December 2013 – Accepted: 14 January 2014 – Published online: 05 June 2014.)

Bulletin of the World Health Organization 2014; 92:555-564. doi: http://dx.doi.org/10.2471/BLT.13.126243

Introduction

In 1978, the Government of China introduced economic reforms to convert the country’s planned economy into a free-market system. Since then, sustained economic productivity has greatly increased the food supply, average household income and personal expenditure on food.1,2 With increasing urbanization, the average Chinese diet has become higher in fat and calories, and lower in dietary fibre.3 Also, the level of physical activity during work and leisure time has declined.4In short, dietary changes after these economic reforms have been accompanied by a rise in diseases related to affluence.5,6

Child-growth assessments are useful not only for monitoring a population’s nutritional status, but also for gauging inequalities in human development among different populations.7 Although many growth and nutrition surveys among children and adolescents have been carried out in China,8,9 few have tried to link trends in child growth and nutrition to changes in economic development. One study that evaluated the effects of China’s economic reforms on the growth of children showed an increase in the average height of children in both rural and urban areas. However, the increase in urban areas was five times that of rural areas.10

Since the economic reforms, income inequalities have increased between western rural areas and coastal areas, as well as between and within rural and urban areas.11These inequalities have probably influenced the regional distribution of malnutrition and how this distribution has changed over time.12

The objective of this paper is to give an overall picture of long-term trends in the growth and nutritional status of Chinese children and adolescents by examining the results of seven large surveys conducted over the past 35 years. We focused on regional disparities in child and adolescent growth and nutritional status, as well as on changes in the pattern and rates of malnutrition after the transition to a more high-fat, high-energy-density and low-fibre diet in an attempt to determine if these changes were associated with the country’s economic development.

Methods

Data procurement

Growth and nutrition data

Data on the growth and nutritional status of children and adolescents between 0 and 18 years of age were extracted from published data and raw datasets of seven large surveys undertaken in one or more areas with different economic characteristics in China between 1975 and 2010. The following surveys were included: National Growth Survey of Children under 7 years in the Nine Cities of China; National Growth Survey for Rural Children under 7 years in the Ten Provinces of China; National Epidemiological Survey on Simple Obesity in Childhood; Chinese National Survey on Students’ Constitution and Health; China National Nutrition Survey; Chinese Food and Nutrition Surveillance system and China Health and Nutrition Survey. A summary of these surveys can be found in Table 1.

Classification of economic areas was based on five indices: regional gross domestic product (GDP), total yearly income per capita, average food consumption per capita, natural growth rate of population, and the regional social welfare index.8 The areas were categorized from highest to lowest economic status as large coastal cities, high, medium or low cities, high, medium or low rural areas and poor western rural areas.

Economic data

Development indicators for China were obtained from the World Bank;29 GDP per capita, the Gini index and the percentage of the population living in urban areas between 1970 and 2012.

Mortality data

Mortality rates for infants and for children less than 5 years of age between 1990 and 2013 were obtained from the Global Burden of Disease study.30

Dietary data

Dietary data for children and adolescents – daily intake of calories, fats, and protein – were obtained from the China Health and Nutrition Survey24 and the China National Nutrition Survey.20

Sedentary behaviour and physical activity

To describe trends in the level of physical activity, data on sedentary behaviour (hours per day watching television or videos or using the computer) and on passive commuting to and from school were obtained from replies to the China Health and Nutrition Survey questionnaire.25,26

Data analysis

Since the study designs, location and demographic characteristics of the population vary among the surveys, data from subsequent rounds of the same survey were used to assess trends. We assessed undernutrition using data for underweight and stunting. Underweight was defined as less than minus two standard deviations from the median weight-for-age of the reference population. Stunting was defined as less than minus two standard deviations from median height-for-age of the reference population. We assessed obesity using data for both overweight and obesity as defined by the Working Group on Obesity in China, adjusted for each year of age.31

We examined the statistical associations between physical growth and economic development using ecological comparisons and trends. To explore the relationship between height and GDP and urbanization and infant and child mortality rates, we calculated Pearson’s correlation coefficients (r), adjusting for sex. Trends in the prevalence of underweight, stunting, overweight and obesity were assessed using the χ2 test. SPSS version 13.0 (SPSS Inc., Chicago, United States of America) was used for the statistical analyses.

Results

Secular trends in growth

Between 1975 and 2010, the average height of children and adolescents increased steadily, without any tendency to plateau. The largest increment was noted around puberty, particularly among males, e.g. an increase of 11.9 cm in 13-year-old urban boys. The difference in height between the sexes at 18 years of age increased from 10.3 cm to 12.3 cm during this same period.

Body weight increased in both sexes and all age groups from 1985–2010. After 2005, in all age categories boys were heavier than girls (Fig. 1). To assess whether the increase in adolescents’ average height was associated with economic development – as captured by urbanization, GDP per capita and the Gini index – (Fig. 2), we looked for correlations between two of these indicators and the average height of adolescents 17–18 years of age.

Fig. 1. Changes in physical height and body weight of children and adolescents living in Chinese urban areas, 1975–2010

Fig. 1. Changes in physical height and body weight of children and adolescents living in Chinese urban areas, 1975–2010

Fig. 1. Changes in physical height and body weight of children and adolescents living in Chinese urban areas, 1975–2010

Sample size: n = 140 229 aged 0–18 years in 1975; n = 79 194 for children less than 7 years of age in 1985; n = 79 154 for children less than 7 years of age in 1995; n = 69 760 for children less than 7 years of age in 2005; n = 204 973 aged 7–18 years in 1985; n = 105 409 aged 7–18 years in 1995; n = 117 997 aged 7–18 years in 2005 and n = 107 574 aged 7–18 years in 2010.
Data sources: National Growth Survey of Children under 7 years in the Nine Cities of China13 and Chinese National Survey on Students Constitution and Health.32

Fig. 2. Trends in gross domestic product (GDP) per capita, Gini index, urban population and child mortality rate in China, 1975–2010

Height showed a close correlation with GDP

Height showed a close correlation with GDP

US$, United States dollars.
Data sources: GDP, Gini index and urban population from the World Bank;29 infant mortality and under-5 years mortality rates from the World population prospects: the 2010 revision.30

Height showed a close correlation with GDP per capita (r = 0.90, P < 0.0001) and with urbanization (r = 0.92, P < 0.0001). We also looked for a correlation between the decline in infant and under-5 mortality rates (Fig. 2) and average height and observed that they were both negatively correlated (r = −0.95; P < 0.0001), even after sex adjustment (r = −0.94; P < 0.0001).

Geographical disparities

Differences in height were observed in areas having different economic characteristics. Data from the National Growth Survey of Children under 7 years in Nine Cities of China and the National Growth Survey for Rural Children under 7 years in Ten Provinces of China showed that, on average, children of both sexes in rural areas were 2.1 cm (standard deviation, SD: 1.2) shorter than those in suburban areas and 3.6 cm (SD: 2.0) shorter than those in urban areas.

According to the Chinese National Survey on Students’ Constitution and Health, children and adolescents between 7 and 18 years of age who lived in a coastal city were taller, on average, than those living in other provincial capitals. They were also markedly taller, on average, than those living in medium-sized or small cities. Similar differences were observed among rural areas showing high, moderate and poor economic development (Fig. 3).

Fig. 3. Physical heighta in children and adolescents of different economic status groups, China, 2005

National Growth Survey of Children under 7 years in the Nine Cities of China

National Growth Survey of Children under 7 years in the Nine Cities of China

a Height was measured as length for children less than 3 years of age.
Sample size: n = 69 760 urban children less than 7 years of age; n = 69 015 suburban children less than 7 years of age; n = 95 925 rural children less than 7 years of age;n = 81 438 urban children and adolescents aged 7–18 years; n = 111 584 rural children and adolescents aged 7–18 years.
Data sources: National Growth Survey of Children under 7 years in the Nine Cities of China,13 National Growth Survey for Rural Children under 7 years in the Ten Provinces of China9 and Chinese National Survey on Students Constitution and Health.17,18

Trends in malnutrition

The prevalence of undernutrition in children less than 5 years of age was highest in poor rural areas. Compared with the 1990s, the overall prevalence of undernutrition has declined sharply – by 74% for underweight and 70% for stunting. Significant downward trends in the prevalence of both underweight and stunting were observed for all areas (P < 0.001). However, in poor rural areas in 2010, the prevalence of underweight and stunting was still high, at 8.0% and 20.3%, respectively (Fig. 4).

Fig. 4. Trends in underweighta and stuntingb in children less than 5 years of age, China, 1990–2010

below minus two standard deviations from median weight-for-age of the reference population

below minus two standard deviations from median weight-for-age of the reference population

a Underweight was defined as below minus two standard deviations from median weight-for-age of the reference population.
b Stunting was defined as below minus two standard deviations from median height-for-age of the reference population.
Sample size: n = 3200 rural children and n = 1130 urban children in 1990; n = 2139 rural children and n = 765 urban children in 1995; n = 10 729 rural children and n = 5770 urban children in 2000; n = 10 501 rural children and n = 5535 urban children in 2005; n = 10 596 rural children and n = 4803 urban children in 2010.
Data source: Chinese Food and Nutrition Surveillance System.21–23

In 2010, the combined prevalence of overweight and obesity was found to be highest among urban boys (23.2%), followed by rural boys (13.8%), urban girls (12.7%) and rural girls (8.6%). Significant increases were noted in the combined prevalence of overweight and obesity in all groups (P < 0.001) (Fig. 5). Between 1985 and 2010, the proportion of obese males increased faster than that of obese females. In urban areas, male obesity increased 0.34 percentage points per year, compared with 0.15 for female obesity. In rural areas, the increase was 0.18 percentage points per year for male obesity, compared with 0.10 for female obesity. The increase in obesity in urban areas between 1985 and 2000 was twice that of the increase in rural areas during the same time period. However, between 2005 and 2010, the annual increase in obesity in rural areas has outpaced that of urban areas (0.34 versus 0.30 percentage points in males and 0.17 versus 0.10 percentage points in females).

Fig. 6 (not shown) illustrates the burden of obesity in areas with different economic characteristics. Large coastal cities were the first to exhibit a rise in overweight and obesity and had the largest increase in prevalence – 32.6% (males) and 19.1% (females) in 2010. Similar increases followed in other areas: first in large, prosperous cities, followed by medium-sized cities with a large middle class and, finally, by the more affluent rural areas. Although an increase in obesity was noted between 1985 and 2010 in western rural areas with low economic development, these areas still had the lowest prevalence of obesity in 2010.

Trends in nutrition and physical activity

To assess whether factors associated with increased body weight in children and adolescents were affected by China’s economic reforms, we obtained data on fat and protein intake and level of physical activity. Between 1991 and 2009, people’s diets in China changed considerably. For children and adolescents between 7 and 17 years of age, the average daily fat intake increased from 55 to 66 g and the average daily protein intake decreased from 66 to 58 g. There was also an increase in fats as a proportion of total caloric intake and an increase in the proportion of children and adolescents obtaining more than 30% of their energy from fat. In addition, during this period time spent in front of a television, video or computer also increased, as did the proportion of children and adolescents who commuted to school in a motorized vehicle (Fig. 7)(not shown).

The economic transition

In the wake of the 1978 reforms, China underwent many changes in its social structures, living conditions and diet. This has been accompanied by a positive trend in the physical growth of children.33 An empirical division of China’s economic development into stages based on the time cycle of China growth surveys facilitates the analysis of its association with trends in children’s growth. In Stage I (before 1975) – out of scope of this analysis – a previous subtle upward trend in growth ceased and even reversed owing to the detrimental effects of famine. In Stage II (1975–1985), children’s growth began to improve again with the recovery of the national economy, and positive trends emerged in older age groups of children in the major cities. In Stage III (1985–1995), physical growth continued to improve in parallel with sustained economic growth. The increment in height among children in rural areas exceeded that seen in children living in urban areas because of improved living standards, health care and increased food supply in the rural areas in the mid-1980s.9 In Stage IV (1995–2005), even higher growth increments were documented among both urban and rural residents. According to data from 2005 to 2010 (Stage V), the increment has continued and does not seem to be levelling off.34

The growth of children in China has improved in recent decades and this improvement is more pronounced at puberty than at earlier or later ages, consistent with other population-based studies.35 The increase in height at the age of 18 years is already present in younger ages and the eventual increase in adult height is established during the first 2 years of life.

In the Netherlands, the secular increase in growth has come to a halt after 150 years, with males now 13.1 cm taller on average than females.36 Since sex difference in adult height widens gradually as secular increases in growth continue, the difference of 12.3 cm between the sexes in 2010 suggests that the positive trend in Chinese children may continue.

Before the economic reforms, food had been in short supply,3 but after 1978, when a policy of liberal food production was introduced and annual economic growth improved, people began to eat more meat and grains and less vegetables. Child growth and nutrition improved and overweight and obesity were still rare. In 1985 and 1986, the prevalence of obesity in children and adolescents was below 1% in large cities.15,19

In 1986, China started its first specific survey on obesity and found that the Chinese diet had become richer in fats and calories and lower in fibre, a change that was introducing an increased risk of chronic diseases.37,38 Obesity among infants and preschool children increased by a factor of 2.8 between 1986 and 2006.15 And between 1985 and 2010, overweight among school-aged children and adolescents increased from 1.11% to 9.62% and obesity from 0.13% to 4.95%.16 Additionally, between 1993 and 2009 the prevalence of obesity rose from 6.1% to 13.1% among children between the ages of 6 and 17 years.39 The higher prevalence of overweight males contrasts with the situation in some non-Asian countries.40

In 2012, for the first time in history, China’s urban population outnumbered its rural population.41 This urbanization can be seen as a double-edged sword. Although it has brought increased access to health care and improvements in basic health infrastructure for many, it has also brought about changes in diet and lifestyle, such as an increase in the availability of sweets and fast-food restaurants and in the use of television, personal computers and cars, all of which can pose substantial health risks.42,43

We have shown that in recent decades fat intake and physical inactivity have risen among Chinese children, with a resulting increase in childhood obesity and a documented decline in physical fitness. For instance, the capacity for endurance running among Chinese students declined significantly between 1985 and 2010.32,44

Dual burden of malnutrition

Large discrepancies still exist between rural and urban areas both in health conditions and in health care.45 Decades of observation suggest that despite improved growth in children belonging to all economic groups, a large growth disparity persists between the rural and suburban areas and the urban areas,9 and among different economic subgroups within these areas.17,18

Compared with the late 1980s and early 1990s,46 in 2010, malnutrition in childhood declined dramatically, owing to sustained economic development, sound nutrition policies, improved health services for women and children and broad implementation of child nutritional interventions.23 However, in the same year, nutrition in rural areas was still poor, with a high prevalence of underweight and stunting among children less than5 years of age. Another survey in 2009 reported 15.9% prevalence for stunting, 7.8% for underweight and 3.7% for wasting in poor rural ares.47

We have also observed a paradoxical situation: in 2006, prevalence of overweight children was as high as 16.8%, while that of stunting was 57.6% among the children in the same poor areas of China’s midwestern provinces.48 The coexistence of stunting and overweight in the same child is a result of protein and energy malnutrition, which retards height despite increased body weight,49 and Chinese rural children have a lower daily protein intake than urban children.24

Childhood obesity has become a serious public health problem in China.19,50 The current strategies for preventing and controlling malnutrition need to be re-examined. Research on obesity prevention and control needs to be improved and nutrition policies need to be aligned with appropriate obesity prevention strategies. Cross-sectoral collaboration such as between health and agriculture, needs to be promoted.

Our study has shown that regional inequalities in child growth and nutrition in China accompany regional economic disparities. Therefore, to promote equitable growth for all children in China, strategies for optimal nutrition need to focus more closely on disadvantaged groups in the poor and underdeveloped areas.

References

  1. Chow G. China’s economic transformation. New York (NY): Blackwell Publishing; 2002.
  2. Hu ZL, Khan MS. Economic issues 8: why is China’s growth so fast? Washington (DC): International Monetary Fund; 1997.
  3. Du S, Lu B, Zhai F, Popkin BM. A new stage of the nutrition transition in China. Public Health Nutr. 2002;5(1A) 1a:169–74.http://dx.doi.org/10.1079/PHN2001290 pmid: 12027281
  4. Qin L, Stolk RP, Corpeleijn E. Motorized transportation, social status, and adiposity: the China Health and Nutrition Survey. Am J Prev Med. 2012;43(1):1–10. http://dx.doi.org/10.1016/j.amepre.2012.03.022 pmid: 22704739
  5. Campbell TC, Junshi C, Brun T, Parpia B, Yinsheng Q, Chumming C, et al. China: From diseases of poverty to diseases of affluence: Policy implications of the epidemiological transition. Ecol Food Nutr. 1992;27(2):133–44.http://dx.doi.org/10.1080/03670244.1992.9991235
  6. Van de Poel E, O’Donnell O, Van Doorslaer E. Urbanization and the spread of diseases of affluence in China. Econ Hum Biol. 2009;7(2):200–16.http://dx.doi.org/10.1016/j.ehb.2009.05.004 pmid: 19560989
  7. de Onis M, Frongillo EA, Blössner M. Is malnutrition declining? An analysis of changes in levels of child malnutrition since 1980. Bull World Health Organ. 2000;78(10):1222–33. pmid: 11100617
  8. Ji CY, Chen TJ. Secular changes in stature and body mass index for Chinese youth in sixteen major cities, 1950s-2005. Am J Hum Biol. 2008;20(5):530–7.http://dx.doi.org/10.1002/ajhb.20770 pmid: 18478539
  9. Li H, Zong X, Zhang J, Zhu Z. Physical growth of children in urban, suburban and rural mainland China: a study of 20 years change. Biomed Environ Sci. 2011;24(1):1–11. pmid: 21440834
  10. Shen T, Habicht JP, Chang Y. Effect of economic reforms on child growth in urban and rural areas of China. N Engl J Med. 1996;335(6):400–6.http://dx.doi.org/10.1056/NEJM199608083350606 pmid: 8663882
  11. Cook IG. Pressures of development on China’s cities and regions. In: Cannon T, editor. China’s economic growth: the impact on regions, migration and the environment. London: Macmillan; 2000.
  12. Jones-Smith JC, Gordon-Larsen P, Siddiqi A, Popkin BM. Cross-national comparisons of time trends in overweight inequality by socioeconomic status among women using repeated cross-sectional surveys from 37 developing countries, 1989–2007. Am J Epidemiol. 2011;173(6):667–75.http://dx.doi.org/10.1093/aje/kwq428 pmid: 21300855
listless child who was among many kwashiorkor cases

listless child who was among many kwashiorkor cases

This late 1960s photograph shows a seated, listless child who was among many kwashiorkor cases found in Nigerian relief camps during the Nigerian-Biafran war. Kwashiorkor is a disease brought on due to a severe dietary protein deficiency, and this child, whose diet fit such a deficiency profile, presented with symptoms including edema of legs and feet, light-colored, thinning hair, anemia, a pot-belly, and shiny skin. Image courtesy of Dr. Lyle Conrad and the CDC Public Health Image Library.

anemia

anemia

Even where children get the calories they need—as most do in rural China—they are not being fed the right things. In one study of 1,800 infants in rural Shaanxi province in China’s north-west, 49% were anemic and 40% were significantly hampered in developing either cognitive or motor skills. Fewer than one in ten were stunted or wasting, meaning that in most cases the problem was not lack of calories, but lack of micronutrients.

Part of the problem in getting local or provincial governments to spend money on childhood nutrition is that the payoffs are years in the making. And the returns might not go to the village or province, but to cities miles away, in the form of more skilled workers who move there. Central ministries are keen to invest, Mr Lu says, but they want to spend their cash on things that officials crave more than children do—like buildings in villages for each ministry.

For Mr Lu one kind of building does promise a big payoff—village early-education centres, or preschools. His charity has set them up in 677 villages, often using redundant elementary schools. In Songjia village Tian Lin, 22, and her older sister, Tian Hongjiao, teach 26 children aged three to six, including the younger sister’s own three-year-old son. They cook lunch with whatever the children bring from home. Those with migrant-worker parents, who are a bit better off, may have a chunk of pork; others bring a meagre potato or vegetable. Either way all the children get a ying yang bao with their lunch.

In 2012 a study found the anemia rate among the three- to five-year-olds in this county was close to 18%, more than twice the average for poor rural areas nationwide, according to Mr Lu’s CDRF. He reckons that, on coming to the centres, the children show only 20% of the memory retention of their urban counterparts and 40-60% of their language abilities and cognition. But nutritional supplements help. A study of nine- and ten-year olds, co-written by Mr Rozelle, found that taking a daily chewable vitamin with iron for six months not only cut anaemia levels. It also improved their maths.

children under the age of five, wasting and stunting

children under the age of five, wasting and stunting

Despite progress, malnutrition remains a challenge

http://www.irinnews.org/photo/Download.aspx?Source=Details&Year=2011&ImageID=201108100909210715

AKARTA, 30 August 2012 (IRIN) – While Indonesia in relative terms is cutting the number of malnourished children under the age of five, wasting and stunting – especially in certain pockets of the country – remain a major concern, say health experts.

Children_under_height_for_age_UN_HDR_2007-2008

Children_under_height_for_age_UN_HDR_2007-2008

Vitamin A deficiency

A few salient facts

  • An estimated 250 million preschool children are vitamin A deficient and it is likely that in vitamin A deficient areas a substantial proportion of pregnant women is vitamin A deficient.
  • An estimated 250 000 to 500 000 vitamin A-deficient children become blind every year, half of them dying within 12 months of losing their sight.

A collateral challenge

Vitamin A deficiency (VAD) is the leading cause of preventable blindness in children and increases the risk of disease and death from severe infections. In pregnant women VAD causes night blindness and may increase the risk of maternal mortality.

Vitamin A deficiency is a public health problem in more than half of all countries, especially in Africa and South-East Asia, hitting hardest young children and pregnant women in low-income countries.

Crucial for maternal and child survival, supplying adequate vitamin A in high-risk areas can significantly reduce mortality. Conversely, its absence causes a needlessly high risk of disease and death.

  • For children, lack of vitamin A causes severe visual impairment and blindness, and significantly increases the risk of severe illness, and even death, from such common childhood infections as diarrhoeal disease and measles.
  • For pregnant women in high-risk areas, vitamin A deficiency occurs especially during the last trimester when demand by both the unborn child and the mother is highest. The mother’s deficiency is demonstrated by the high prevalence of night blindness during this period. The impact of VAD on mother-to-child HIV transmission needs further investigation.

http://www.goldenrice.org/Content3-Why/why1_vad.php

The most damaging micronutrient deficiencies in the world are the consequence of low dietary intake of iron, vitamin A, iodine and zinc. Vitamin A deficiency (VAD) is prevalent among the poor whose diets are based mainly on rice or other carbohydrate-rich, micronutrient-poor calory sources. Rice does not contain any β-carotene (provitamin A), which their body could then convert into vitamin A. Dependence on rice as the predominant food source, therefore, necessarily leads to VAD, most severely affecting small children and pregnant women. In 2012 the World Health Organization reported that about 250 million preschool children are affected by VAD, and that providing those children with vitamin A could prevent about a third of all under-five deaths, which amounts to up to 2.7 million children that could be saved from dying unnecessarily.

VAD compromises the immune systems of approximately 40 percent of children under five in the developing world, greatly increasing the severeness of common childhood infections, often leading to deadly outcomes. VAD is most severe in Southeast Asia and Africa. For the 400 million rice-consuming poor, the medical consequences are fatal: impaired vision—, in extreme cases irreversible blindness; impaired epithelial integrity, exposing the affected individuals to infections; reduced immune response; impaired haemopoiesis (and hence reduced capacity to transport oxygen in the blood) and skeletal growth; among other debilitating afflictions.

Rice containing provitamin A could substantially reduce the problems described above. This can only be achieved using genetic engineering because there is no provitamin A in the rice seeds, even though it is present in the leaves. Thousands of rice varieties have been screened for this trait without success. Existing coloured rice varieties contain pigments that belong to a different chemical class.

Small children are most susceptible to micronutrient deficiencies. Initially a VAD affects their eyesight, but at the same time it impairs their immune system, and children fall prey to common infectious diseases. Vitamin A and zinc alone could save more thn a third of the 12 million children who die annually because of malnutrition worldwide.

Golden Rice has the potential to complement existing efforts that seek to reduce blindness and other VAD induced diseases. Those efforts include industrial fortification of basic foodstuffs with vitamin A, distribution of vitamin supplements, and increasing consumption of other foods rich in vitamin A.

Distribution of Vitamin A Deficiency (WHO, 2009)

Distribution of Vitamin A Deficiency (WHO, 2009)

Bibliography

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Cancer and Nutrition

Writer and Curator: Larry H. Bernstein, MD, FCAP

The following discussions have been a topic of great interest and much controversy. In this discussion I shall not cover the topics related to Alternative and Complementary Medicine that is discussed elsewhere.  However, there is significant reason to explore the relationships of vitamin and micronutrient insufficiencies to cancer. The following nutritional subjects will be the focus of these discussions.

  1. Transthyretin (TTR)
  2. Vitamin A (retinoids and retinol) and retinol-binding protein (RBP)
  3. Vitamin C
  4. Vitamin D
  5. Magnesium (Mg++)

Cancer, homocysteine, Alzheimer’s Disease, and cardiovascular disease

1 Transthyretin

1.1 Plasma Transthyretin Indicates the Direction of both Nitrogen Balance and Retinoid Status in Health and Disease

Ingenbleek Yves1 and Bienvenu Jacques2,3,*

1Laboratory of Nutrition, Faculty of Pharmacy, University Louis Pasteur Strasbourg 1, France; 2Laboratory of Immunology, Hospices Civils de Lyon and 3INSERM U 851, University Claude Bernard Lyon 1, France

The Open Clinical Chemistry Journal, 2008;  1:1-12
Abstract: Whatever the nutritional status and the disease condition, the actual transthyretin (TTR) plasma level is determined by opposing influences between anabolic and catabolic alterations. Rising TTR values indicate that synthetic processes prevail over tissue breakdown with a nitrogen balance (NB) turning positive as a result of efficient nutritional support and / or anti-inflammatory therapy. Declining TTR values point to the failure of sustaining NB as an effect of maladjusted dietetic management and / or further worsening of the morbid condition. Serial measurement of TTR thus appears as a dynamic index defining the direction of NB in acute and chronic disorders, serving as a guide to alert the physician on the validity of his therapeutic strategy. The level of TTR production by the liver also works as a limiting factor for the cellular bioavailability of retinol and retinoid derivatives which play major roles in the brain ageing process. Optimal protein nutritional status, as assessed by TTR values within the normal range, prevents the occurrence of vascular and cerebral damages while maintaining the retinoid-mediated memory, cognitive and behavioral activities of elderly persons.

INTRODUCTION  Measurement of transthyretin (TTR, formerly called prealbumin) was proposed as nutritional marker in The Lancet in 1972 [1]. This proposal was largely disregarded by the scientific community during the decade following its publication. TTR testing is now the most utilized nutritional marker worldwide, having received the strong support of the Prealbumin Consensus Group [2].  A minority of workers, however, remain doubtful [3] or even reluctant [4] to adopt TTR as nutritional index, stressing the point that its synthesis is also influenced by inflammatory conditions [3,4] and by other extra-nutritional factors such as natural or synthetic corticosteroids [5] and androgens [6]. The aim of the present review paper is to clarify the complex relationships linking malnutrition and inflammation, throwing further insight into a nutrition domain of increasing public health.

EVOLUTION, STRUCTURE AND FUNCTIONS  TTR is a highly conserved protein in vertebrate species already secreted by the choroid plexus of reptiles 300 millions years ago and remaining confined within the cerebrospinal fluid (CSF) [10]. Synthesis and secretion of TTR by the liver evolved much later, about 100 millions years ago, in birds and eutherian mammals [11]. Production of TTR by the liver and by the choroid plexus is regulated separately [12]. The human TTR gene has been localized on the long arm of the chromosome 18q23 [13]. The nucleotide sequences of the entire TTR gene, including the 5′ (transcription initiating site) and the 3′ (untranslated site) flanking regions have been described [14,15]. The gene spans 6.9 kilobases (kb) and consists of 4 exons and 3 introns [14,15]. The hepatic TTR mRNA measures 0.7 kb encoding a pro-TTR-monomer undergoing a cleaving process to release the native TTR monomer [16]. Four identical subunits each 127 amino acids (AAs) length coalesce noncovalently to generate the fully mature nonglycosylated molecule whose molecular mass (MM) reaches 55 kDa [17]. Two binding sites for thyroid hormones are buried inside the central channel of the TTR heterodimer [18]. The secondary, tertiary and quarternary conformation structures of the TTR protein have been reported using 1.8 Å Fourier analysis [18]. One TTR  monomer binds to a small companion protein (21 kDa MM) to which a single retinol is bound (all-trans-retinol), hence its RBP denomination [19]. X-ray crystallographic studies have shown that RBP possesses an eight-stranded -barrel core that completely encapsulates the retinol molecule [20]. Under usual circumstances, RBP is almost entirely saturated with retinol, explaining that the 3 components of the retinol circulating complex (RCC) of 76 kDa MM has a close 1:1:1 stoichiometry [21]. Aggregation of TTR to holo-RBP occurs within the endoplasmic reticulum prior to extracellular RCC secretion [22].  The TTR protein was first discovered in human CSF in 1942 [23] and soon after in human serum. Human TTR transports about 20% of the intravascular pool of both thyroid hormones (Thyroxine [T4], triiodothyronine [T3]) and at least 90-95% of the retinol circulating pool. The term transthyretin was recommended by the International Nomenclature Committee [26] stressing the dual conveying role played by TTR in all eutherians.

The biological half-life of TTR is approximately 2 days [27] whereas that of holo-RBP (RBP + bound retinol) is half a day [28]. By contrast, apo-RBP devoid of its retinol ligand displays a significantly reduced half-life of 3.5 hr [28] and undergoes rapid glomerular leakage with subsequent tubular disintegration and recycling of its AA residues. It is therefore assumed that TTR plays an important role in the safeguard of the retinol pool. The catabolic site of TTR is mainly the liver, followed by muscle mass, skin and kidneys [29].  The TTR molecule displays microheterogeneity [30] and tissue deposits occur throughout the normal ageing processes [31]. In contrast, TTR is characterized by a very large genetic polymorphism affecting about 100 different point mutations [32], leading to misfolded forms of the protein and occurrence of amyloid disorders in several organs. The tetrameric TTR protein is recognized as a component of the normal pancreatic cell structure, preserving its integrity against the risk of apoptosis [40]. Finally, normal TTR production is required for the maturation of brain neural stem cells [41] and for the control of spatial reference memory performances [42].

SIGNIFICANCE OF TTR THROUGHOUT THE HUMAN LIFESPAN  Significant alterations in the levels of protein intakes by humans affect protein synthesis, turnover and breakdown and determine the outcome of total body N (TBN).  Anabolism occurs when the rate of AA incorporation into protein exceeds that of oxidative losses, yielding a positive NB. Catabolism is the result of protein breakdown prevailing over protein synthesis [43]. Increasing gestational age is accompanied by a slow and predictable rise in TTR values correlated with birth weight and proved useful in distinguishing between small, appropriate and large for gestational age infants [47,48]. Starting from birth until 100 years of age, our reference TTR values [54] are those collected in the monograph ” Serum Proteins in Clinical Medicine ” edited by the Foundation for Blood Research. The plasma TTR concentrations in healthy neonates are approximately two thirds those measured in healthy mothers and thereafter increase slowly until the onset of puberty without displaying sexual differences. The rate of protein synthesis similarly increases linearly during the prepubertal period [55], consistent with superimposable N accretion rates [56]. Human puberty is characterized by major hormonal and metabolic alterations leading to increased height velocity and weight gain [60]. The onset of puberty requires close interrelationships between the effects triggered by growth hormone and  insulin-like growth factors, by thyroid and steroid hormones, by insulin and sex hormones [60]. Whereas androgens strongly promote the development of muscle mass in males and lipolytic effects on visceral and subcutaneous fat, estrogens have minimal effect on the female musculature while stimulating the accrual of subcutaneous fat depots [60]. Body composition studies indicate prepubertal redistribution of FM and FFM with a significantly higher S-shaped elevation of FFM in male adolescents compared with the blunted curve recorded in teenaged girls [61,62]. TTR values manifest closely paralleled sex- and age-peculiarities in process of time that are best explained by the deeper androgenic impregnation of male subjects [6,43]. The musculature is by weight the main component of FFM, representing 37% of body mass [61].  In healthy adults, the sex-related difference in plasma TTR-RBP concentrations is maintained at plateau levels after sexual maturity [54,63]. Normal TTR plasma values are stabilized around 290-320 mg/L in males and around 250-280 mg/L in females [54,63]. Starting from the sixties, TTR concentrations progressively decline over time, disclosing a steeper slope in elderly men that reflects a relatively more rapid deterioration of their muscle mass [43]. As a result, the earlier TTR sexual difference disappears by about the age of 70 years [43]. This correlates with the age-dependent curvilinear drop of TBN, characterized by an accelerated decrease after 65 years [64]. Taken together, the plasma TTR evolutionary patterns reveal a parallelism with FFM so that TTR serves as an indicator of muscle mass. The data show that age and gender are significant co-variates of TTR which require separate blood reference values [54].

TTR AS INDEX OF PROTEIN DEPLETION / REPLETION STATES  There exists a long-lasting debate aimed at identifying the most effective protein sources, level of energy-yielding substrates and the proportion among these for the support of protein metabolism. Under usual conditions, glucose functions as the major energy substrate for protein synthesis. If the carbohydrate energy is lacking, glucose must be synthesized by gluconeogenesis, mainly from the conversion of endogenous or dietary protein [65]. This corresponds to a form of nutritional wastage which augments the cost of protein synthesis, as documented by an increased urinary excretion of urea. The above metabolic pattern stands in broad conformity with the concept that ” protein synthesis occurs in the flame of sugars ” [66].

FAO/WHO/UNU recommends for healthy adults the safe level of 0.75 g k-1 day-1 protein intake [67]. Although this amount of protein sustains normal growth and keeps unmodified the concentration of most biological parameters, such intake appears to be marginally inadequate to maintain the metabolic reserve capacities that are required to mount optimal responses to stress [68]. Studies have disclosed that TTR plasma level and pool size remain unaltered because its synthetic and catabolic rates are both downregulated concomitantly [69]. Changes occurring during prolonged starvation causes the N balance to turn negative despite efforts to minimize protein catabolism [70]. There is a direct correlation between the rate of liver protein synthesis and intrahepatic concentrations of individual free AAs [71]. It is likely that the dietary limitation of some AAs such as tryptophan [72] or leucine [73] could specifically exert inhibitory effects on the transcriptional [74] or translational [75] regulation of protein synthesis. Consequently, protein depletion causes a decrease in TTR mRNA [72,74,76].

Transcription of the TTR gene in the liver is directed by CCAAT/enhancer binding protein (C/EBP) bound to nuclear factor 1 (NF1) [74]. Multiple hepatocyte nuclear factors (HNFs) function in the regulation of TTR gene expression [77]. It has been recently shown that one of them (HNF-4) plays prominent roles before and after injury [78]. The drop of liver TTR mRNA levels to about half as an effect of protein deprivation [74] is accompanied by a corresponding diminished secretion of mature TTR molecules in the bloodstream.

The rapidly turning over TTR protein is exquisitely sensitive to any change in protein and/or energy supply, being clearly situated on the cutting edge of the equipoise. This is documented in preterm infants in whom AA supply is responsible for maintaining normal protein synthesis which may be somewhat modulated by fluctuations in energy intake [79]. In the declared stage of protein malnutrition, the serial measurement of TTR may serve to grade the severity of the disease spectrum, from mild [90] to severe [1] forms. Both metabolic and structural N compartments undergo exhausting processes as documented by the fall of nitrogenous compounds in the urine of protein-depleted subjects [91]. The relative dominance of urea over ammonia catabolites [92] reflects the more intense turnover rate of tissues belonging to the readily mobilizable N pool. Decreased TTR plasma values are indeed correlated with the involution of the gut mucosa [93] and with the extent of liver dysfunction, more pronounced in the kwashiorkor disease with massive hepatic steatosis than in marasmus with limited fatty liver infiltration [1]. The structural N compartment nevertheless participates in the loss of body protein reserves, consistent with the reduced urinary output of creatinine [91], 3-methylhistidine [94] and soluble hydroxyproline [95]. The resulting sarcopenia [96,97] and the concomitant depression of immune mechanisms [98,99] render an account of the higher morbidity / mortality rates affecting TBN-depleted patients identified by the lowest TTR and RBP plasma concentrations [100]. The mortality risk of malnourished children in Central Africa becomes likely when SA and TTR reach the threshold of 16 g /L and 65 mg /L, respectively [101].

During nutritional rehabilitation from protein malnutrition, the restoration of visceral proteins occurs at different rates depending on the type of protein and the size of its plasma pool. TTR and RBP recovery appears as the main result of increased production rates by the liver [102]. Most studies contend the view that the trajectory outlined for TTR correlates with the fluctuations of body N mass, especially during the anabolic phase of growth and clinical recovery from protein malnutrition. Using impedance parameters for assessing the N compartment still remaining in place in the stressed body of adults undergoing renal dialysis, nephrologists were able to demonstrate close relationships between TTR and phase angle, reactance and resistance values [105]. In elderly noninfected persons, FFM index measured by dual X-ray absorptiometry exhibits the highest correlation with TTR (r = 0.64) compared to RBP (r = 0.52) [106]

TTR AS NITROGEN INDEX IN INFLAMMATORY DISORDERS  Inflammatory disorders of any cause are initiated by activated leukocytes releasing a shower of cytokines working as autocrine, paracrine and endocrine molecules [107]. Cytokines regulate the overproduction of acute-phase proteins (APPs), notably that of CRP, 1-acid glycoprotein (AGP), fibrinogen, haptoglobin, 1-antitrypsin and antichymotrypsin [107]. APPs contribute in several ways to defense and repair mechanisms, being characterized by proper kinetic and functional properties [107]. Interleukin-6 (IL-6) is regarded as a key mediator governing both the acute and chronic inflammatory processes, as documented by data recorded on burn [108], sepsis [109] and AIDS [110] patients. IL-6-NF possesses a high degree of homology with C/EBP-NF1 and competes for the same DNA response element of the IL-6 gene [111]. IL-6-NF is not expressed under normal circumstances, explaining why APP concentrations are kept at baseline levels. In stressful conditions, IL-6-NF causes a dramatic surge in APP values [107,112] with a concomitant suppressed synthesis of TTR as demonstrated in animal [113] and clinical [114] experiments.  Under acute stressful conditions, protein turnover is strongly stimulated by augmented tissue breakdown (mainly in the muscle mass) and enhanced specific tissues synthesis (mainly in the liver and at the site of injury). Proteolysis releases AA residues which are preferentially incorporated into the hepatic precursor pool involved in the production of APPs [115,116]. The rate at which proteins are degraded generally exceeds the rate of AA mobilization for protein synthesis [117,118] yielding a net negative NB associated with an increased urinary output of urea and ammonia [119]. Creatininuria and 3-methylhistidinuria are significantly elevated and remain highly correlated (r = 0.97) attesting to the substantial participation of the skeletal musculature to the stress responses [117]. The gap between degradative and synthetic processes widens in proportion to the severity of injury, resulting in correspondingly increased urinary N catabolites [43]. Serious injury affecting otherwise healthy adults may trigger urinary N losses reaching 40 g/day or 250 g/week, which corresponds to about 15% of TBN [43]. In long-lasting debilitating disorders, the persisting negative NB may deplete the baseline body cell mass by about 45%, carrying ominous prognostic significance [120].

Inadequate nutritional management [122], multiple injuries, occurrence of severe sepsis and metabolic complications result in persistent proteolysis [124] and subnormal TTR concentrations [66]. The evolutionary patterns of urinary N output and of TTR thus appear as mirror images of each other, which supports the view that TTR might well reflect the depletion of TBN in both acute and chronic disease processes. Even in the most complex stressful conditions, the synthesis of visceral proteins is submitted to opposing anabolic or catabolic influences yielding ultimately TTR as an end-product reflecting the prevailing tendency. Whatever the nutritional and/or inflammatory causal factors, the actual TTR plasma level and its course in process of time indicates the exhaustion or restoration of the body N resources, hence its likely (in)ability to assume defense and repair mechanisms. The serial measurement of TTR appears as a dynamic tool pointing to the direction and magnitude of NB, predicting therefore the disease outcome. Hundreds of studies are reporting the clinical usefulness of TTR measurement.  TTR is recommended for the assessment and nutritional follow-up of a large panel of hospitalized patients in internal medicine settings [130,131], in general surgery [132,133] and intensive care units [134,135]. Low TTR values thus appear to nonspecifically reflect the extent of liver damage rather than its etiology. Liver N tissue only represents by weight a minor proportion of TBN but its intense turnover rate (10 to 20-fold more rapid than that of muscle tissue) [43] and its critical involvement in the orchestration of most major metabolic and immune pathways [145] explains why liver failure of any cause is usually associated with varying degrees of clinical malnutrition [142].

The nutritional management of kidney patients has met noticeable improvement along the past decades. Until the mid 1980s TTR was regarded as unreliable and discarded, leaving the way for the general use of SA in kidney studies. The turning point came in 1987 when a careful statistical analysis stated that TTR was the most representative marker within a large battery of currently measured parameters [149]. The most recent studies clearly incline towards the common use of TTR superseding that of SA [8, 151-155]. It has been confirmed, mainly in intensive care renal units, that the serial measurement of TTR works as a strong independent predictor of long-term survival, allowing identification of the patients in need of nutritional intervention [151,155] or at risk of reduced life expectancy [154, 155]. Using proportional hazards regression models, the relative risk of death was inversely related to TTR concentrations in 8,157 hemodialyzed patients [155]. TTR is currently measured as nutritional marker in tropical areas where bacterial, viral and parasitic diseases are still highly prevalent, usually in connection with defective immune and vitamin A status, including malaria[156], trypanosomiasis [157], schistosomiasis [158], measles[159], shigellosis [160], and AIDS patients exhibit declining TTR values as the morbid condition worsens [161].

In westernized societies, elderly persons constitute a growing population group. A substantial proportion of them may develop a syndrome of frailty characterized by weight loss, clumsy gait, impaired memory and sensorial aptitudes, poor physical, mental and social activities, depressive trends. Hallmarks of frailty combine progressive depletion of both structural and metabolic N compartments [162]. Sarcopenia and limitation of muscle strength are naturally involutive events of normal ageing which may nevertheless be accelerated by cytokine-induced underlying inflammatory disorders [163,164]. Depletion of visceral resources is substantiated by the shrinking of FFM and its partial replacement by FM, mainly in abdominal organs, and by the down-regulation of indices of growth and protein status [162]. Due to reduced tissue reserves and diminished efficiency of immune and repair mechanisms, any stressful condition affecting old age may trigger more severe clinical impact whereas healing processes require longer duration with erratical setbacks. As a result, protein malnutrition is a common finding in most elderly patients [165] with significantly increased morbidity and mortality rates [166,167].

Measurement of visceral protein status is proved useful throughout the entire ageing lifespan. A wide range of co-morbidities associated with defective protein nutritional status is described in aging persons who become more prone to develop pressure sores [163], osteoporosis [170], oral candidiasis [171] and nuclear cataract [172].  The isolation and purification of rat TTR [173] has allowed to set up animal models. In normal rats, TTR manifests highly significant correlations with nutrient intakes and with visceral and carcass N stores [174]. In tumor-bearing rats, the progressive exhaustion of body protein mass towards cachexia states is correlated with declining TTR values [175]. TTR is currently utilized as indicator of protein nutritional status in cancer patients [176,177]. TTR is held as the most powerful test overall for evaluating visceral protein status of children with solid tumors [178] and leukemias [179] both at the time of diagnosis and throughout chemotherapy. In bone marrow transplantation for malignancies, TTR accurately reflects at any point changes in the patient’s clinical status [180]. TTR has proved to be a useful marker of nutritional alterations with prognostic implications in large bowel cancer [181], bronchopulmonary carcinoid tumor [182], ovarian carcinoma [183] and bladder epithelioma [184]. Many oncologists have observed a rapid TTR fall 2 or 3 months prior to the patient’s death [181]. In cancer patients submitted to surgical intervention, most postoperative complications occurred in subjects with preoperative TTR  180 mg/L [185]. Two independent studies came to the same conclusion that a TTR threshold of 100 mg/L is indicative of extremely weak survival likelihood and that these terminally ill patients better deserve palliative care rather than aggressive therapeutic strategies [185,186].

The AGP/TTR couple is recommended in chronic inflammatory disorders, notably in several cancer types [192,193]. Working along the same lines is the prognostic inflammatory and nutritional index (PINI) [194] which is successfully applied on large cohorts of patients. TTR also participates in the development of screening formulas recently generated by innovative analytical tools such as surface-enhanced laser desorption/ionization (SELDI) or matrix-assisted laser desorption/ionization (MALDI) coupled with time of flight mass spectrometry (TOF-MS). The advent of these sophisticated and costly proteomic fingerprinting studies of serum or other biological fluids are nevertheless promising in that they tentatively strive to identify the early stages of several disease conditions such as hepatitis B [195], tuberculosis [196], Alzheimer’s disease [197] or neoplastic disorders [198]. These proteomic detecting systems usually combine classical APP reactants with some minor biological compounds scarcely measured in routine laboratory practice such as cathepsin D, hemopexin, neopterin or vitronectin. The fact that most, if not all, of these fingerprinting formulas embody TTR measurement indicates that there exists among workers a large consensus considering this carrier-protein as the most reliable indicator of protein depletion in morbid circumstances.

PROGRESS IN TTR RESEARCH : THE BRAIN AGEING PROCESS  Dementia, defined as significant memory impairment and loss of intellectual functions, is a common and devastating public health problem, affecting an estimated 2-4% individuals over the age of 65 years. Two distinct clinicopathological conditions are usually taken into consideration as causative factors: Alzheimer’s disease (AD), a chronic and continuously progressing illness for which the only widely accepted risk conditions are age and family history of the disease; and cerebral infarction, a brain deteriorating process evolving along episodic and repetitive bouts so as to generate a syndrome of multi-infarct dementia (MID) [199]. The rates of both AD and MID increase dramatically with age, leading to coexisting pathologies with intermingled symptomatology [200]. In support to this mixed cases concept are the report of equally increased blood-brain barrier permeability in both AD and MID patients [201] and the accumulation of amyloid -protein in the brain of MID subjects mimicking AD pathology [202]. There exists considerable overlap between AD and MID clinical symptoms, giving rise to a continuum of patients in whom pure AD and pure MID represent the two extreme poles [200].  The elevated homocysteine (Hcy) values found in AD patients [208,209] are reportedly associated with dementia [208,210].

The choroid plexus is the sole site of mammalian brain involved in TTR production [214]. Its synthesis rate by the choroid epithelium is estimated 25 to 100 times higher than that of the liver on a weight basis [215]. As a result, TTR is a major component of CSF, constituting 10 to 25 % of total ventricular proteins [216] conveying up to 80% of intrathecal thyroxine [217]. TTR thus constitutes an hormonal carrierprotein fulfilling important ontogenic and functional properties in mammalian nervous structures, a concept further corroborated by the observation of its increased CSF concentration during the neonatal period [218]. The data imply that choroidal TTR facilitates the uptake of thyroxine from the bloodstream, governing its transport and delivery to brain tissues following a kinetic model developed by Australian workers [219]. In comparison, CSF contains 10 to 100 times lower RBP and retinol concentrations than plasma whilst retinyl esters from dietary origin are virtually absent [220]. Although it has been reported that minute amounts of RBP could be produced within the neuraxis [221], the sizeable proportion of retinol molecules required for brain maturation utilizes the RCC transport system to reach the choroid plexus. The very high receptor binding affinity expressed by neural tissues for RBP molecules [222] is confined within the endothelial cells of the brain microvasculature and within the choroidal epithelial cells, the two primary sites of the mammalian blood-brain barrier [223]. The contrast between high RBP binding affinities and low intrathecal concentrations makes it likely that holo-RBP does not experience significant transchoroidal diffusion, strongly suggesting that its retinol ligand is released in free form and readily taken up by membrane or intracellular receptors of neural cells. The dual TTR production, plasma-derived and choroid-secreted, allows complementary stimulation of brain activities. Thyroid hormones and retinoids indeed function in concert through the mediation of common heterodimeric motifs bound to DNA response elements [224,225]. The data also imply that the provision of thyroid molecules within the CSF works as a relatively stable secretory process, poorly sensitive to extracerebral influences [12] as opposed to the delivery of retinoid molecules whose plasma concentrations are highly dependent on nutritional and/or inflammatory alterations [66]. This last statement is documented by mice experiments [226] and clinical investigations [227] showing that the level of TTR production by the liver operates as a limiting factor for retinol transport. Defective TTR synthesis determines the occurrence of secondary hyporetinolemia which nevertheless results from entirely different kinetic mechanisms in the two quoted studies [226,227].

In the TTR knock-out mice model, holo-RBP molecules are normally synthetized and secreted by the liver but undergo rapid kidney leakage in the absence of stabilizing TTR molecules [228]. Despite very low levels of plasma retinol (about 5 % of wild type), these targeted mutated animals remain healthy and fertile, implying that efficient compensatory mechanisms take place. No such increased urinary output of RBP molecules occurs in malnourished patients who develop in proportion to their declining protein status electroretinographic abnormalities and ocular lesions which are pathognomonic symptoms of vitamin A deficiency [229]. During nutritional rehabilitation of malnourished subjects, the 3 RCC components gradually return to normal ranges even without retinol or carotene supplementation, indicating that the retinyl esters normally sequestered in liver stellate cells mandatorily need diet-induced synthesis of new TTR molecules before undergoing retinol conversion and binding as holo-RBP ligand [227]. The prominent place occupied by TTR in defining distal retinoid bioavailability has been too long unrecognized despite the warning expressing that ” overlooking the crucial role of TTR in vitamin A-metabolism results in unachieved or even misleading conclusions ” [66].

Retinol is a precursor substrate that must undergo a two step oxidation procedure to release firstly retinal and thereafter the two active all-trans- and 13-cis-retinoic acids (RAs) [225,230]. The latter converting steps are regulated by retinaldehyde dehydrogenase (RALDH) enzymes whose major sites of expression are the olfactory bulb, the striatum and the hippocampus [231,232]. The intracellular activities exerted by retinoid compounds are mediated by a large variety of specific receptors among which are cellular-RBP (CRBP), cellular-RA-BP (CRABP), RA-nuclear receptors (RARs) and retinoid X receptors (RXRs), each composed of 3 subtypes [225,232]. Retinol is the rate-limiting determinant of the concentration of both RA derivatives [233], implying that any fluctuation in protein status might entail corresponding alterations in the cellular bioavailability of retinoid compounds, with all the more rapid effects as all-trans-RA has a short biological half-life of less than 1 hr [234]. Because protein malnutrition is a common finding in as much as 50 % of elderly AD and MID patients [235], many of them could well suffer permanent hyporetinolemia still accelerating the declining concentration of retinoid molecules observed over the course of normal ageing [231].  Dietary vitamin A is required to modulate early development of brain structure and differentiation [236] together with neuronal plasticity, memory functioning and neurotransmitter signaling during adulthood [237].

The normal decrease of brain retinoid molecules throughout the ageing process principally affects the above-described major sites of RA synthesis [238], a regressive alteration even more pronounced in AD patients [231]. In murine models, early depletion of retinoids causes deposition of amyloid -peptides [239], initiating the formation of Alzheimer plaques. In aged animals, cognitive and memory deficits are associated with down-regulation of the expression of retinoid receptors which may recover their full activities under RA supplementation [240]. Administration of RA similarly restores expression of proteins involved in the control of amyloidogenic pathways [241]. Along the same preventive line is the demonstration that retinol disaggregates preformed amyloid fibrils, more effectively than does RA [242].  Alternatively, TTR participates in the maintenance of memory and normal cognitive processes during ageing by acting on the retinoid signalling pathway as recently reported on TTR-null knock-out mice model [42,243]. Moreover, TTR may bind amyloid -peptide in vitro, preventing its transformation into amyloid neurofibrils [244].

Protein malnutrition, as assessed by diminished TTR plasma values, causes the elevation of Hcy concentrations [245]. There exists an inverse correlation between both TTR and Hcy parameters, explaining why malnourished elderly persons incur increasing risk of Hcy-depended thrombovascular complications [213]. The defective mechanism is situated at the level of cystathionine–synthase (CS), an enzyme governing the crossroad of remethylation and transsulfuration pathways [246]. Japanese workers have recently provided experimental validation of the metabolic anomaly, showing that rats given methionine (Met)-deprived nutriture manifest depressed CS activity with subsequent elevation of Hcy plasma levels [247]. Among all essential AAs consumed in human nutrition, Met is regarded as the most critically available because its withdrawal from the customary diet causes the deepest negative NB, being almost as great as when a protein-free regimen is ingested [248]. Met is implicated in a large spectrum of metabolic and enzyme activities and participates in the conformation of a large number of molecules of survival importance [213]. Due to the fact that plant products are relatively Met-deficient, vegan subjects are more exposed than omnivorous to develop hyperhomocysteinemia – related disorders [249]. Dietary protein restriction may promote supranormal Hcy concentrations which appears as the dark side of adaptive attempts developed by the malnourished and/or stressed body to preserve Met homeostasis.  Summing up, we assume that the low TTR concentrations reported in the blood [235] and CSF [250] of AD or MID patients result in impairment of their normal scavenging capacity [244] and in the excessive accumulation of Hcy in body fluids [245], hence causing direct harmful damage to the brain and cardiac vasculature. In addition, depressed TTR concentrations indirectly inhibit the multitude of retinoid-dependent cerebral functioning pathways [231,243] allowing the development of amyloidogenic processes [239]. The practical consequences of these findings imply that the correct assessment of nutritional status is recommended in all elderly patients. The mental and cognitive dysfunctions of old age that are not genetically programmed but result from varying energy, protein and vitamin-deficiencies may be substantially prevented and sometimes improved provided that appropriate nutritional measures are undertaken.

CONCLUDING REMARKS  In spite of classical criticisms [3,4], TTR is regarded as a robust and reliable indicator of protein nutritional. Taking into account the gender- and age-specificities, TTR appears as the sole plasma protein reflecting the fluctuations of TBN pools. The relationship linking alterations of TTR plasma levels with body N reserves are documented both in animal models [175] and in human subjects [105,106].  Uncomplicated malnutrition primarily affects the metabolic N pool, reducing protein syntheses and NB to levels compatible with survival, an adaptive response well identified by declining TTR values. In inflammatory disorders, both metabolic and structural N pools participate in varying proportions in the cytokine-induced responses of the stressed body, resulting in TBN shrinking and concomitant depression of TTR concentrations. Abatement of the stressful condition and/or efficient nutritional rehabilitation allows restoration to normal levels of both TBN pools and TTR values following parallel slopes. TTR thus appears as a dynamic index predicting the outcome of the disease. We attached more importance to the trend outlined by its serial appraisal than to any single measurement.  Whatever the causal factor, depletion of TBN reserves attenuates the body’s capacity to mount appropriate immune and repair mechanisms. A number of clinical investigations have advocated the level of plasma TTR as predictor of the length of hospital stay (LOS) and of mortality rate [252, 255]. Not surprisingly, unrecognized malnutrition entails longer LOS, increased number of complications and higher care costs whereas early detection and treatment of high risk patients significantly alleviate the financial burden of hospitalization while improving the prognostic outcome of the patients [252-256]. The last statement is documented by the first prospective and randomized survey showing that reduced morbidity and mortality rates are depending on protein N intake and correlated with rising TTR concentrations [257]. Providing elderly persons with optimal protein nutritional status in order to insure their protection against the risk of neurodeterioration is the last message released by the fascinating TTR plasma protein.

Points to consider:

  1. Protein energy malnutrition has an unlikely causal relationship to carcinogenesis. Perhaps the opposite is true. However, cancer has a relationship to protein energy malnutrition without any doubt.  PEM is the consequence of cachexia, whether caused by dietary insufficiency, inflammatory or cancer.
  2. Protein energy malnutrition leads to hyperhomocysteinemia, and by that means, the relationship of dietary insufficiency of methionine has a relationship to heart disease. This is the significant link between veganism and cardiovascular disease, whether voluntary or by unavailability of adequate source.

1.2 Downsizing of Lean Body Mass is a Key Determinant of Alzheimer’s Disease

Yves Ingenbleek, and Larry H. Bernstein
Journal of Alzheimer’s Disease 44 (2015) 745–754
http://dx.doi.org:/10.3233/JAD-141950

Lean body mass (LBM) encompasses all metabolically active organs distributed into visceral and structural tissue compartments and collecting the bulk of N and K stores of the human body. Transthyretin (TTR) is a plasma protein mainly secreted by the liver within a trimolecular TTR-RBP-retinol complex revealing from birth to old age strikingly similar evolutionary patterns with LBM in health and disease. TTR is also synthesized by the choroid plexus along distinct regulatory pathways. Chronic dietary methionine (Met) deprivation or cytokine-induced inflammatory disorders generates LBM downsizing following differentiated physiopathological processes. Met-restricted regimens downregulate the transsulfuration cascade causing upstream elevation of homocysteine (Hcy) safeguarding Met homeostasis and downstream drop of hydrogen sulfide (H2S) impairing anti-oxidative capacities. Elderly persons constitute a vulnerable population group exposed to increasing Hcy burden and declining H2S protection, notably in plant-eating communities or in the course of inflammatory illnesses. Appropriate correction of defective protein status and eradication of inflammatory processes may restore an appropriate LBM size allowing the hepatic production of the retinol circulating complex to resume, in contrast with the refractory choroidal TTR secretory process. As a result of improved health status, augmented concentrations of plasma-derived TTR and retinol may reach the cerebrospinal fluid and dismantle senile amyloid plaques, contributing to the prevention or the delay of the onset of neurodegenerative events in elderly subjects at risk of Alzheimer’s disease.

Transthyretin and Lean Body Mass in Stable and Stressed State

https://pharmaceuticalintelligence.com/2013/12/01/transthyretin-and-lean-body-mass-in-stable-and-stressed-state/

A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

https://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-conundrum/

Stabilizers that prevent transthyretin-mediated cardiomyocyte amyloidotic toxicity

https://pharmaceuticalintelligence.com/2013/12/02/stabilizers-that-prevent-transthyretin-mediated-cardiomyocyte-amyloidotic-toxicity/

Thyroid Function and Disorders

https://pharmaceuticalintelligence.com/2015/02/05/thyroid-function-and-disorders/

Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation: a Compilation of Articles in the Journal http://pharmaceuticalintelligence.com

https://pharmaceuticalintelligence.com/2014/09/01/compilation-of-references-in-leaders-in-pharmaceutical-intelligence-about-proteomics-metabolomics-signaling-pathways-and-cell-regulation-2/

Malnutrition in India, high newborn death rate and stunting of children age under five years

https://pharmaceuticalintelligence.com/2014/07/15/malnutrition-in-india-high-newborn-death-rate-and-stunting-of-children-age-under-five-years/

Vegan Diet is Sulfur Deficient and Heart Unhealthy

https://pharmaceuticalintelligence.com/2013/11/17/vegan-diet-is-sulfur-deficient-and-heart-unhealthy/

How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

https://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-leads_to_hyperhomocysteinemia/

Amyloidosis with Cardiomyopathy

https://pharmaceuticalintelligence.com/2013/03/31/amyloidosis-with-cardiomyopathy/

Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets

https://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-of-therapeutic-targets/

Sepsis, Multi-organ Dysfunction Syndrome, and Septic Shock: A Conundrum of Signaling Pathways Cascading Out of Control

https://pharmaceuticalintelligence.com/2012/10/13/sepsis-multi-organ-dysfunction-syndrome-and-septic-shock-a-conundrum-of-signaling-pathways-cascading-out-of-control/

Automated Inferential Diagnosis of SIRS, sepsis, septic shock

https://pharmaceuticalintelligence.com/2012/08/01/automated-inferential-diagnosis-of-sirs-sepsis-septic-shock/

 

 

1.3 Transthyretin Blocks Retinol Uptake and Cell Signaling by the Holo-Retinol-Binding Protein Receptor STRA6

Daniel C. Berry, Colleen M. Croniger, Norbert B. Ghyselinck, Noa Noya
Vitamin A is secreted from cellular stores and circulates in blood bound to retinol-binding protein (RBP). In turn, holo-RBP associates in plasma with transthyretin (TTR) to form a ternary RBP-retinol-TTR complex. It is believed that binding to TTR prevents the loss of RBP by filtration in the kidney. At target cells, holo-RBP is recognized by STRA6, a plasma membrane protein that serves a dual role: it mediates uptake of retinol from extracellular RBP into cells, and it functions as a cytokine receptor that, upon binding holo-RBP, triggers a JAK/STAT signaling cascade. We previously showed that STRA6-mediated signaling underlies the ability of RBP to induce insulin resistance. TTR blocks the ability of holo-RBP to associate with STRA6 and thereby effectively suppresses both STRA6-mediated retinol uptake and STRA6-initiated cell signaling. Consequently, TTR protects mice from RBP-induced insulin resistance, reflected by reduced phosphorylation of insulin receptor and glucose tolerance tests. The data indicate that STRA6 functions only under circumstances where the plasma RBP level exceeds that of TTR and demonstrate that, in addition to preventing the loss of RBP, TTR plays a central role in regulating holo-RBP/STRA6 signaling.

1.4 Transthyretin Amyloidosis

1.4.1 (Adapted from a Review in Amyloid: Int J Exp Clin Invest 3:44-56, 1996)

While it was expected that variations in clinical presentation (FAP-I, II, III, IV) were the result of heterogeneity in etiology or pathogenesis of the hereditary amyloidosis, it was not until the discovery by Costa, et al., in 1978 showing transthyretin as a constituent of the fibril deposits, that the biochemical basis of these syndromes could be pursued (Costa, et al., 1978).  This resulted in the discovery of the first variant form of transthyretin mutation reported in 1983.  In 1989 there were approximately 12 known mutations and in 2002 there are at least 90.  Over 80 of these mutations are associated with amyloidosis.  In addition, there is evidence that normal transthyretin may for amyloid especially in the heart and be the basis for senile cardiac amyloidosis (Westermark, 1990).

The transthyretin amyloidoses by definition are all associated with tissue deposits of fibrils having transthyretin as a major protein constituent.  While there are a number of other constituents of the amyloid deposits, including proteoglycan, amyloid P component, and various lipoproteins, it is transthyretin that is the essential ingredient in this type of amyloid.

It would appear that the signals for down regulating production of transthyretin (cytokines such as IL1 and IL6) are the same as those which cause the positive acute phase response of serum amyloid A and C reactive protein (Costa, et al., 1986).  The negative acute phase phenomenon of transthyretin is used by clinicians to monitor nutritional status of their patients.

Transthyretin is firmly entrenched in the phylogenetic evolution of vertebrate species being present in both birds and reptiles and its primary structure has been stable throughout evolution (Richardson, 1994).

While plasma transthyretin is predominantly synthesized by the adult liver, it is also synthesized by the choroids plexus of the brain and mRNA is also present in the retinal pigment epithelium, pituitary and pancreas19, 20 .  Choroid plexus synthesis would appear to be necessary for the thyroid hormone across the basement membrane into the cerebral spinal space.

The binding of RBP to transthyretin saves this small protein (21,000 daltons) from plasma clearance via filtration in the kidney.  However, when the complex gives up retinal, RBP dissociates from transthyretin and goes to meet its fate.  Transthyretin evidently can recirculate to bind more RBP-vitamin A.  Plasma residence time of transthyretin is approximately 20-24 hours, representing a plasma half-life of no more than 15 hours  (Benson, et al., 1996).  This is really very rapid turnover for a plasma protein, compared to plasma residence time of apolipoprotein AI which is 5 days, and that of albumin which is approximately 27 days (t ½ =19 days).

Most variants of transthyretin are not associated with amyloidosis.  Most variants of transthyretin are not associated with any postulated “hot spots” in the coding region.  The Ser6 variant is the only known polymorphism, prevalence of approximately 12% in the Caucasian population.  All the other mutations are present in less than 2% of the population, except in the restricted areas of Northern Sweden where greater than 2% of inhabitants have the Met30 gene and in African Americans, when considered as a group, where approximately 3% have a Val122Ile mutation.  One possible explanation of the large number of pathogenic mutations in transthyretin is that the amyloidosis is a delayed onset disease and, therefore, there is a lessened degree of selection against perpetuation of a pathogenic mutation.

Variations on the theme include the involvement of the vitreous of the eye in a number of the kindreds.  Approximately a third of transthyretin mutations are associated with vitreous deposits of amyloid; however, this finding is not uniform within families.  In different kindreds, a single mutation may have different presentations.  Most notably, Swedish patients with Met30 transthyretin have a high incidence of vitreous opacities with presentation at a fairly advanced age (58 years); whereas Portuguese patients have a lower incidence of vitreous opacities, but have presentation of neuropathy at an early age (mean 32 or 33 years).  Some transthyretin variants present as pure cardiomyopathy (e.g. Met111) (Frederikson, et al., 1962).   The Indiana/Swiss kindred (Ser84) has 100% incidence of cardiomyopathy (Benson and Dwulet, 1983) and this also appears to be true for the Appalachian kindred (Ala60) (Benson, et al., 1987).

Significant renal amyloidosis is less common than cardiac amyloidosis in most of the kindreds.  Recently attention has been directed toward kindreds having transthyretin amyloidosis with extensive leptomeningeal amyloid.  This is the hallmark of the Ohio kindred with oculoleptomeningeal amyloidosis (Gly30) (Goren, et al., 1980; Peterson, et al., 1997) and a recently reported kindred from Hungary (Gly18) in which the first clinical manifestation is dementia (Vidal, et al.,1996).  The His69 mutation has been associated with vitreous opacities alone (Zeldenrust, et al., 1994), but in another family causes oculoleptomeningeal amyloidosis.   Features of the disease in particular kindreds make familiarity with the different clinical expressions of the various transthyretin variants essential.

1.4.2 An insight to the conserved water mediated dynamics of catalytic His88 and its recognition to thyroxin and RBP binding residues in human transthyretin

Avik Banerjeea & Bishnu P. Mukhopadhyaya
http://dx.doi.org:/10.1080/07391102.2014.984632

Human transthyretin (hTTR) is a multifunctional protein involved in several amyloidogenic diseases. Besides transportation of thyroxin and vitamin-A, its role towards the catalysis of apolipoprotein-A1 and Aβ-peptide are also drawing interest. The role of water molecules in the catalytic mechanism is still unknown. Extensive analyses of 14 high-resolution X-ray structures of human transthyretin and MD simulation studies have revealed the presence of eight conserved hydrophilic centres near its catalytic zone which may be indispensable for the function, dynamics and stability of the protein. Three water molecules (W1, W2 and W3) form a cluster and play an important role in the recognition of the catalytic and RBP-binding residues. They also induce the reorganisation of the His88 for coupling with other catalytic residues (His90, Glu92). Another water molecule (W5) participate in inter-monomer recognition between the catalytic and thyroxin binding sites. The rest four water molecules (W6, W*, W# and W†) form a distorted tetrahedral cluster and impart stability to the catalytic core of hTTR. The conserved water mediated recognition dynamics of the different functional sites may provide some rational clues towards the understanding of the activity and mechanism of hTTR.

1.4.3 Amyloid Formation by Human Carboxypeptidase D Transthyretin-like Domain under Physiological Conditions*

Javier Garcia-Pardo, Ricardo Graña-Montes, Marc Fernandez-Mendez, et al.

Proteins can form amyloid aggregates from initially folded states. The transthyretin-like domain of human carboxypeptidase D forms amyloid aggregates without extensive unfolding. The monomeric transthyretin fold has an inherent propensity to aggregate due to the presence of preformed amyloidogenic structural elements. Generic aggregation from initially folded states would have a huge impact on cell proteostasis.

1.5 Evolutionary changes to transthyretin: evolution of transthyretin biosynthesis Samantha J. Richardson
FEBS Journal 276 (2009) 5342–53
http://dx.doi.org:/10.1111/j.1742-4658.2009.07244.x

Thyroid hormones are involved in growth and development, particularly of the brain. Thus, it is imperative that these hormones get from their site of synthesis to their sites of action throughout the body and the brain. This role is fulfilled by thyroid hormone distributor proteins. Of particular interest is transthyretin, which in mammals is synthesized in the liver, choroid plexus, meninges, retinal and ciliary pigment epithelia, visceral yolk sac, placenta, pancreas and intestines, whereas the other thyroid hormone distributor proteins are synthesized only in the liver. Transthyretin is synthesized by all classes of vertebrates; however, the tissue specificity of transthyretin gene expression varies widely between classes. This review summarizes what is currently known about the evolution of transthyretin synthesis in vertebrates and presents hypotheses regarding tissue-specific synthesis of transthyretin in each vertebrate class.

1.6  Distinctive binding and structural properties of piscine transthyretin

C Folli, N Pasquato, I Ramazzina, R Battistutta, G Zanotti, R Berni
FEBS Letters 555 (2003) 279-284
http://dx.doi.org:/10.1016/S0014-5793(03)01248-1

The thyroid hormone binding protein transthyretin (TTR) forms a macromolecular complex with the retinol-specific carrier retinol binding protein (RBP) in the blood of higher vertebrates. Piscine TTR is shown here to exhibit high binding affinity for L-thyroxine and negligible affinity for RBP. The 1.56 Ang resolution X-ray structure of sea bream TTR, compared with that of human TTR, reveals a high degree of conservation of the thyroid hormone binding sites. In contrast, some amino acid di¡erences in discrete regions of sea bream TTR appear to be responsible for the lack of protein-protein recognition, providing evidence for the crucial role played by a limited number of residues in the interaction between RBP and TTR. Overall, this study makes it possible to draw conclusions on evolutionary relationships for RBPs and TTRs of phylogenetically distant vertebrates.

1.7 Protein  Synthesis  at the Blood-Brain Barrier: The Major Proteins  Ecreted By Amphibian Choroid Plexus Is A Lipocalin

  1. Achen, PJ. Harms, T Thomas, SJ. Richardson, REH. Wettenhall, G Schreiber J Biol Chemistry Nov 1992; 267(32): 23167-70Among the proteins secreted by choroid plexus of vertebrates, one protein is much more  abundant than all others. In  mammals, birds, and reptiles  this protein is transthyretin, a tetramer of identical 15-kDa sub- units. In this study choroid plexus from frogs, tadpoles, and toads incubated in  vitro were found to synthesize and secrete one predominant protein. However, this consisted of one single 20-kDa polypeptide chain. It was expressed throughout  amphibian metamorphosis. Part of its amino acid sequence was determined and used for construction of oligonucleotides for polymerase chain reaction. The amplified DNA was used to screen a toad choroid plexus cDNA library. Full-length cDNA clones were isolated and sequenced. The derived amino acid sequence for the encoded protein was 183 amino acids long, including a 20-amino acid preseg- ment. The calculated molecular weight of the mature protein was 18,500. Sequence comparison with other proteins showed that the protein belonged to the lipocalin superfamily. Its expression was highest in choroid plexus, much lower in other brain areas, and absent from liver.  Since no transthyretin was detected in proteins secreted from amphibian choroid plexus, abundant synthesis and secretion of transthyretin in choroid plexus must have  evolved only after the stage of the amphibians.

2 Vitamin A

2.1 Retinoic acid pathways and cancer

2.1.1 Vitamin A, Cancer Treatment and Prevention: The New Role of Cellular Retinol Binding Proteins

Elena Doldo,Gaetana Costanza,Sara Agostinelli,Chiara Tarquini, et al.
BioMed Research International 2015; Article ID 624627, 14 pages
http://dx.doi.org/10.1155/2015/624627

Retinol and vitamin A derivatives influence cell differentiation, proliferation, and apoptosis and play an important physiologic role in a wide range of biological processes. Retinol is obtained from foods of animal origin. Retinol derivatives are fundamental for vision, while retinoic acid is essential for skin and bone growth. Intracellular retinoid bioavailability is regulated by the presence of specific cytoplasmic retinol and retinoic acid binding proteins (CRBPs and CRABPs). CRBP-1, the most diffuse CRBP isoform, is a small 15KD acytosolic protein widely expressed and evolutionarily conserved in many tissues. CRBP-1 acts as chaperone and regulates the uptake, subsequent esterification, and bioavailability of retinol. CRBP-1 plays a major role in wound healing and arterial tissue remodeling processes. In the last years, the role of CRBP-1-related retinoid signaling during cancer progression became object of several studies. CRBP-1 downregulation associates with a more malignant phenotype in breast, ovarian, and nasopharyngeal cancers.Reexpression of CRBP-1 increased retinol sensitivity and reduced viability of ovarian cancer cells in vitro. Further studies are needed to explore new therapeutic strategies aimed at restoring CRBP-1-mediated intracellular retinol trafficking and the meaning of CRBP-1 expression in cancer patients’ screening for a more personalized and efficacy retinoid therapy.

Metabolism of Retinol and Its Derivatives. Vitamin A can be acquired from the diet either as preformed vitamin A (primarily as retinyl ester, retinol, and in much smaller amount as retinoic acid) or provitamin A carotenoids (Figure1). Dietary retinyl esters are converted to retinol within the lumen of the small intestine or the intestinal mucosa and then reesterified to form retinyl ester (RE) within the enterocyte [1]. Provitamin A carotenoids, absorbed by the mucosal cells, are converted first to retinaldehyde and then to retinol [1]. After secretion of the nascent chylomicrons into the lymphatic system, the bulk of dietary vitamin A is taken up by hepatocytes and hydrolyzed again.The free retinol binds the epididymal retinoic acid binding protein (ERABP) and the retinol binding protein (RBP) [2] and into plasma transthyretin. Free retinol can be transferred to hepatic stellate cells for storage. Hepatocytes and hepatic stellate cells are very rich in retinyl ester hydrolases and in cellular retinol binding protein type 1 (CRBP-1). CRBP-1 is necessary to solubilize retinol in the aqueous environment of the cell [1].

Intracellular Trafficking of Retinoids. A cell-surface receptor named stimulated by retinoic acid 6 (STRA6) mediates vitamin A uptake from RBP [3]. Intracellular retinoid bioavailability is regulated by the presence of specific cytoplasmic retinol and retinoic acid binding proteins, CRBPs and CRABPs (Figure2). In the cytoplasm vitamin A and derivatives are bound to cytoplasmic proteins: cellular retinol binding proteins (CRBPs) which comprised four isoforms, CRBP-1 and CRBP-2 and CRBP-3 and CRBP-4. CRBP-1, are the most represented isoform in many tissues. Cellular retinoic acid binding proteins (CRABPs) comprised two isoforms, CRABP-1 and CRABP-2. CRBPs specifically bind retinol, while CRABPs and well-characterized members of the fatty acid binding proteins (FABPs) bind retinoic acid (RA). These proteins control the availability of ligands and determine the physiological response of cells and tissues to vitamin A [4]. Cellular retinoic acid binding proteins may regulate the interactions between retinoic acids and their nuclear receptors by regulating the concentrationof present retinoic acids [5]. Retinoids can activate gene expression by specific nuclear retinoid acid receptors. Two distinct classes of nuclear proteins, the retinoic acid receptors (RARs), and the retinoid X receptors (RXRs) have been identified. Each class consists of 𝛼, 𝛽,and 𝛾 subtypes. RARs and RXRs form either homodimers or heterodimers and function as transacting nuclear transcriptional factors [6]. RAR can be activated by both all-trans and 9-cis RA, whereas RXR is only activated by 9-cis-RA.

2.1.2 Retinoids, retinoic acid receptors, and cancer.

Tang XH1, Gudas LJ.
Annu Rev Pathol. 2011; 6:345-64
http://dx.doi.org:/10.1146/annurev-pathol-011110-130303

Retinoids (i.e., vitamin A, all-trans retinoic acid, and related signaling molecules) induce the differentiation of various types of stem cells. Nuclear retinoic acid receptors mediate most but not all of the effects of retinoids. Retinoid signaling is often compromised early in carcinogenesis, which suggests that a reduction in retinoid signaling may be required for tumor development. Retinoids interact with other signaling pathways, including estrogen signaling in breast cancer. Retinoids are used to treat cancer, in part because of their ability to induce differentiation and arrest proliferation. Delivery of retinoids to patients is challenging because of the rapid metabolism of some retinoids and because epigenetic changes can render cells retinoid resistant. Successful cancer therapy with retinoids is likely to require combination therapy with drugs that regulate the epigenome, such as DNA methyltransferase and histone deacetylase inhibitors, as well as classical chemotherapeutic agents. Thus, retinoid research benefits both cancer prevention and cancer treatment.
2.1.3 Molecular pathways: current role and future directions of the retinoic acid pathway in cancer prevention and treatment.

Connolly RM1Nguyen NKSukumar S.
Clin Cancer Res. 2013 Apr 1; 19(7):1651-9
http://dx.doi.org:/10.1158/1078-0432.CCR-12-3175

Retinoids and their naturally metabolized and synthetic products (e.g., all-trans retinoic acid, 13-cis retinoic acid, bexarotene) induce differentiation in various cell types. Retinoids exert their actions mainly through binding to the nuclear retinoic acid receptors (α, β, γ), which are transcriptional and homeostatic regulators with functions that are often compromised early in neoplastic transformation. The retinoids have been investigated extensively for their use in cancer prevention and treatment. Success has been achieved with their use in the treatment of subtypes of leukemia harboring chromosomal translocations. Promising results have been observed in the breast cancer prevention setting, where fenretinide prevention trials have provided a strong rationale for further investigation in young women at high risk for breast cancer. Ongoing phase III randomized trials investigating retinoids in combination with chemotherapy in non-small cell lung cancer aim to definitively characterize the role of retinoids in this tumor type. The limited treatment success observed to date in the prevention and treatment of solid tumors may relate to the frequent epigenetic silencing of RARβ. Robust evaluation of RARβ and downstream genes may permit optimized use of retinoids in the solid tumor arena.

Vitamin A is derived from animal and plant food sources and has critical functions in many aspects of human biology. Its natural derivatives and metabolized products (retinoids) such as β-carotene, retinol, retinal, isotetrinoin, all-trans retinoic acid (ATRA), 9-cis retinoic acid, and 13-cis retinoic acid have important roles in cell differentiation, growth, and apoptosis (1). Synthetic retinoids are also available and include bexarotene and fenretinide. In clinical practice, retinoids have a wide range of dermatologic indications including for psoriasis, acneiform, and keratinization disorders (2). Systemic retinoids are approved by the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (3) and acute promyelocytic leukemia (APL; refs. 4, 5). However, the chemopreventive and therapeutic effects of retinoids in solid tumors remain controversial. Therefore, an overview of the research to date and future directions in this area is the focus of this review.

Retinoic acid and the retinoic acid receptor pathway

Retinoic acids (RA) exert their functions through their specific receptors. The 2 distinct classes of receptors are retinoic acid receptors (RAR) and retinoic X receptors (RXR). Each class contains 3 different subtypes—α, β, and γ (6). ATRA and fenretinide can bind specifically to RARS, 13-cis RA and bexarotene only to RXRS, and 9-cis RA to RARS or RXRS (refs. 1, 5; Table 1). The expression of these receptors is regulated by the receptors themselves, other nuclear receptors such as ERα, or by other subtypes in the same family (5, 7). Upon the binding of ligands, RARs and RXRs form heterodimers and function as ligand-dependent transcription factors to activate their downstream effectors by binding to the retinoic acid response elements (RARE) located in the 5′-region of RA downstream genes (5). The above model of RAR or RXR function via binding to RARE is considered the RA classical or genomic pathway. Activation of the classical pathway will trigger cell differentiation, cell arrest, and eventual apoptosis (8).

Table 1. Select clinical trials evaluating retinoids in solid tumors

Retinoid Other names Target Clinical trial setting
ATRA Tretinoin RAR Advanced NSCLC Phase II randomized (n = 107)
13-cis RA Isotretinoin Roaccutane Accutane RXR Primary prevention: H+N cancer
Advanced solid tumorsPhase I (n = 13)
Metastatic breast cancer Phase II randomized (n = 99)
9-cis RA Alitretinoin RAR RXR Metastatic breast cancerPhase I (n = 12)
Fenretinide 4-OH Phenylretinamide RAR Primary prevention: women at high risk of breast cancer Randomized double-blind 2 × 2 design (n = 235)
Secondary prevention: early breast cancerPhase III randomized (n = 2,867)
Bexarotene RXR Chemotherapy-naïve advanced NSCLC Phase III randomized (n = 623)
Metastatic  breast cancer Phase II single arm (n = 148)

The function of RA and its receptors involves not only the classical pathway but also multiple other important pathways. RAs have been shown to regulate NF-κB (9), IFN-γ (10), TGF-β (11), VEGF (12), mitogen-activated protein kinase (MAPK; ref. 13), and chromatin remodeling (14). Furthermore, RARs and RXRs can form heterodimers with other types of receptors, including the estrogen receptor-α (ERα; refs. 7, 15), AP-1 receptor (16), peroxisome proliferator-activated receptor (PPAR; ref. 17), liver X receptors (LXR; refs. 18, 19), and vitamin D receptor (VDR; ref. 20; Fig. 1). When RARs/RXRs heterodimerize with these receptors, they are involved in regulating their partner receptor’s pathways, referred to as nonclassical or nongenomic pathways (5). Interestingly, these pathways often regulate processes that have functions opposite to the classical pathway. For example, a study has shown that RA activation of the PPARβ/δ pathway resulted in upregulation of prosurvival genes (17), contrary to the known differentiation function of RARs and RXRs in response to RA. The function of RAs, which involves nongenomic pathways, may provide opportunities for cancer cells to develop resistance to RA treatment, discussed later in this review. Another important function of RARA is the regulation of stem cell differentiation (11). RAs target stem cells via both genomic and nongenomic pathways such as the Notch pathway and inflammation (10, 11). In summary, RAs and their receptors play important roles as regulators of critical processes in cells.

RARs and their action

RARs and their action

The RARs and their action. In a series of enzymatic steps, vitamin A (retinol) is metabolized through the oxidizing action of retinaldehyde (RDH) to retinal, and by retinaldehyde dehydrogenase (RALDH), to RA. RA has 3 different isomers: all-trans, 9-cis, and 13-cis RA. RA is transported to the nucleus by the protein cellular RA–binding protein (CRABP) and delivered to the RARα. RARα heterodimerizes with and binds to RARE present most often in gene promoters. In the classical pathway of RA action, RA binds to dimers of RARα and RXRs (α, β, or γ) to induce expression of its downstream target genes, including RARβ. Upon activation, RARβ can regulate its own expression and that of its downstream genes, the function of which is mainly to inhibit cell growth. Alternatively, RA can be bound and transported to the nucleus by other factors such as FABP5. This delivers RA to other nonclassical receptors such as PPARβ/δ and ERα which activate nongenomic pathways such as PDK-1/Akt or the ERα pathway. Contrary to the differentiation functions attributed to the classical pathway, the nongenomic pathways exert strong antiapoptotic and proliferative effects on cancer cells. It is believed that the classical and nongenomic pathways are controlled by the relative abundance of their own ligands. RA has a stronger affinity for RARs than for the other receptors, and the classical pathway plays a dominant role over the nongenomic pathways. Thus, if RA is present with other ligands such as estrogen, signaling through the classical pathway is preferred to result in cell differentiation and growth inhibition.

http://clincancerres.aacrjournals.org/content/19/7/1651/F1.small.gif

Retinoids and cancer

The retinoids have been investigated extensively for the prevention and treatment of cancer, predominantly because of their ability to induce cellular differentiation and arrest proliferation. RA-regulated tumor suppressor genes, when expressed, can inhibit tumor growth (21). Among the 3 RARs, RARβ has been well known for its tumor-suppressive effects in epithelial cells (5822). Exogenous expression of the RARβ gene can cause RA-dependent and -independent apoptosis and growth arrest (23). RARβ-induced growth arrest and apoptosis is mediated through RARα (24). As RA ligand-bound RARα binds to the RARE on the RARβ promoter, multiple activator proteins assemble at the site and result in the upregulation of the RARβ gene (5). The expression of RARβ results in the transactivation and expression of a number of its target genes that mediate cell differentiation and death (5, 68). The ability of ATRA to initiate differentiation of promyelocytic leukemic cells to granulocytes is the basis of the dramatic success of retinoic acid therapy for acute promyelocytic leukemia harboring the RAR/PML translocation (4) and confirms the important role of RARβ in tumor growth inhibition. It is also becoming increasingly clear that RARβ expression is lost early in carcinogenesis or is epigenetically silenced (25) in many solid tumors, providing an opportunity for novel treatment strategies to be investigated using retinoids together with epigenetic modifiers that promote reexpression of silenced genes, described further below.

The retinoids have an established role in the treatment of certain hematologic malignancies, with FDA approval for use in cutaneous T-cell lymphoma and APL. Bexarotene (an RXR-selective retinoid or rexinoid) is associated with an overall response rate of approximately 50% in patients with refractory advanced-stage mycosis fungoides, a cutaneous T-cell lymphoma (3). ATRA, a synthetic retinoid, exhibited improvements in disease-free and overall survival when compared with chemotherapy alone in APL, with long-term remissions occurring in almost 70% of cases (4). The success of retinoids in treating this disease relates to the underlying chromosomal translocation and production of the PML/RARα fusion protein and the ability of retinoids to induce differentiation and inhibition of cell growth in this setting (26, 27). Clinical trials investigating the role of retinoids in the prevention and treatment of solid tumors will now be outlined with a focus on cancers of the upper aerodigestive tract (oropharyngeal and lung) and breast (Table 1).

2.1.4 Retinoid Pathway and Cancer Therapeutics

Nathan Bushue and Yu-Jui Yvonne Wan
Adv Drug Deliv Rev. 2010 Oct 30;  62(13): 1285–1298.
http://dx.doi.org/10.1016%2Fj.addr.2010.07.003

The retinoids are a class of compounds that are structurally related to vitamin A. Retinoic acid, which is the active metabolite of retinol, regulates a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids exert their effects through a variety of binding proteins including cellular retinol binding protein (CRBP), retinol-binding proteins (RBP), cellular retinoic acid-binding protein (CRABP), and nuclear receptors i.e. retinoic acid receptor (RAR) and retinoid × receptor (RXR). Because of the pleiotropic effects of retinoids, understanding the function of these binding proteins and nuclear receptors assists us in developing compounds that have specific effects. This review summarizes our current understanding of how retinoids are processed and act with the emphasis on the application of retinoids in cancer treatment and prevention.

Vitamin A and its derivatives (retinoids) exert a wide range of effects on embryonic development, cell growth, differentiation, and apoptosis. Vitamin A has been used as a treatment for thousands of years. The Egyptian papyruses Kahun 1 (ca. 1825 B.C.) and Ebers (ca. 1500 B.C.) described how the liver was used to cure eye diseases such as night blindness. Greek scholar Hippocrates (460-327 B.C.) described in the second book of “Prognostics” a method for curing night blindness: “raw beef liver, as large as possible, soaked in honey, to be taken once or twice by mouth.” Chinese medicine used pigs’ liver as a remedy for night blindness, as described by Sun-szu-mo (7th century A.D.) in his “1000 Golden Remedies”. Given that the liver is where the body stores excess vitamin A, the liver represents the best source of vitamin A available for treatment in the pre-pharmaceutical world.

The effect of vitamin A on growth was first described in a mouse experiment done by G. Lunin (1881) [2], in which one group of mice was fed pure casein, fat, sucrose, minerals, and water, and another group was fed whole dried milk. The milk-fed group was healthy and grew normally, while the other group was sick and ultimately died. Thus, something in milk was essential for survival. Elmer McCollum at University of Wisconsin-Madison as well as Lafayette Mendel and Thomas Burr Osborne at Yale University independently discovered vitamin A. McCollum began his study in 1907 by feeding cows hay with wheat, oats, or yellow maize.

Wheat-fed cows did not thrive, became blind and gave birth to dead calves prematurely. Oat-fed cows fared somewhat better, but the yellow maize-fed cows were in excellent condition, produced vigorous calves, and had no miscarriages. McCollum postulated that performing the same nutritional study using small animals, such as rodents, which require less food, provide faster reproduction and experimental outcome. Using rats, he found a diet of pure protein, pure milk sugar, minerals, and lard (or olive oil) inhibited growth, while addition of butterfat or an ether extract of egg yolk to the diet restored health. Thinking that he had found a fat-soluble factor that promoted growth in rats, he saponified butterfat, extracted the unsaponifiable mixture into ether, and added the extract to oliveoil and that extract could support growth. This essential component to support growth and development was named “fat-soluble factor A,” and later renamed vitamin A [1].

There are over 4,000 natural and synthetic molecules structurally and/or functionally related to vitamin A. Vitamin A cannot be synthesized by any animal species and is only obtained through diet in the form of retinol, retinyl ester, or β-carotene (Figure 1). Ingested vitamin A is stored as retinyl esters in hepatic stellate cells. Retinol is reversibly oxidized by retinol dehydrogenases to yield retinal. Subsequently, retinal may be irreversibly oxidized to all-trans retinoic acid (all-trans RA) by retinal dehydrogenases and further oxidized by cytochrome P450 enzymes (mainly CYP26) in hepatic tissue. Retinol has six biologically active isoforms that include all-trans, 11-cis, 13-cis, 9, 13-di-cis, 9-cis, and 11, 13-di-cis, with all-trans being the predominant physiological form. Endogenous retinoids with biological activity include all-trans RA, 9-cis RA, 11-cis retinaldehyde, 3,4-didehydro RA, and perhaps 14-hydroxy-4, 14-retro retinol, 4-oxo RA, and 4-oxo retinol [35]. All-trans RA isomerizes under experimental and physiological conditions. Different isomers activate different receptors and thus lead to different biological effects. RAs designed to be receptor specific can improve efficacy and avoid unwanted side effects. Retinoids that specifically bind to RXR are called rexinoids and have been effective in cancer treatment. Retinoids are comprised of three units: a bulky hydrophobic region, a linker unit, and a polar terminus, which is usually a carboxylic acid. Modification of each unit has generated many more compounds. Please refer to recent reviews [68].

2.1.4.1 Retinoid Pathway 

Retinoid Pathway  nihms229611f1

Retinoid Pathway nihms229611f1

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991380/bin/nihms229611f1.jpg

Retinoids absorbed from food are converted to retinol and bound to CRBP in the intestine. Then, retinol is converted to retinyl esters and enters into blood circulation. The liver up takes retinyl esters, which are converted to retinol-RBP complex in the hepatocyte. In the serum, the retinol-RBP complex is bound to transthyretin (TTR) in a 1:1 ratio to prevent elimination by the kidney and to ensure retinol is delivered to the target cell. The uptake of retinol by the target cell is mediated by a trans-membrane protein named “stimulated by retinoic acid 6” (STRA6), which is a RBP receptor. In the target cell, retinol either binds to CRBP or is oxidized to retinaldehyde by retinol dehydrogenase (RDH) in a reversible reaction. Then, retinaldehyde can be oxidized by retinaldehyde dehydrogenase (RALDH) to RA. In the target cell, RA either binds to CRABP or enters the nucleus and binds to nuclear receptors to regulate gene transcription. Alternatively, RA can mediate via nongenomic mechanism and regulate cellular function. Hepatocytes not only process retinoids, but also are the target cells. In addition, hepatocytes located next to the storage site (stellate cell). Thus, retinoid-mediated signaling must have a profound effect in regulating hepatocyte function and phenotype [36190191].

2.1.4.2 Retinoid Binding Proteins

There are various types of retinoid-binding proteins, which locate in intracellular and extracellular compartments and associate with isomeric forms of retinoids. Hence, retinoids are either associated with cellular membranes or bound to a specific retinoid binding protein. These binding proteins along with nuclear receptors mediate the action of retinoids. Their interactions are summarized in figure 1. Retinoid-binding proteins solubilize and stabilize retinoids in aqueous spaces. In addition to this general role, specific retinoid-binding proteins have distinct functions in regulating transport and metabolism of specific retinoids. For example, the parent vitamin A molecule, all-trans retinol, circulates in blood bound to serum retinol binding protein (RBP). Inside the cells, all-trans retinol and its oxidation product, all-trans retinal, are associated with different isoforms of cellular retinol-binding proteins (CRBP), while all-trans RA intracellularly binds to cellular retinoic acid-binding protein isoforms (CRABP).

2.1.4.3 RBP

Retinol is secreted from its storage pools and circulates in blood by binding to RBP. The main storage site for vitamin A and the main site of synthesis of RBP is the liver, although other tissues (including adipose tissue, kidney, lung, heart, skeletal muscle, spleen, eye and testis) also express this protein. Secretion of RBP from the liver is regulated by the availability of retinol [9]. Vitamin A deficiency inhibits RBP secretion, leading to protein accumulation in the endoplasmic reticulum of hepatic parenchymal cells. In the presence of retinol, RBP associates with retinol, moves to the Golgi apparatus and is secreted into blood. The mechanism by which retinol initiates RBP secretion from cells is not known. In blood, RBP is bound to the small protein transthyretin, which in addition to associating with RBP functions as a carrier protein for thyroid hormones. Binding of RBP to transthyretin prevents the loss of this smaller protein by filtration in the renal glomeruli. The transthyretin-RBP-retinol complex transports retinol in the circulation and delivers it to target tissues [10].

Important insights into the biological role of RBP have been obtained by studies of mice and humans in which the RBP gene is disrupted. RBP-deficient mice display both reduced blood retinol levels and impaired visual function during the first months of life. When maintained on a vitamin A-sufficient diet, they acquire normal vision by 5 months of age, even though their blood retinol level remains low. A striking phenotype of the RBP-null mice is that they possess larger than normal hepatic vitamin A storage, but are dependent on a continuous dietary intake of vitamin A [11], further proving the importance of RBP as a transporting protein. A study of two human siblings that harbored point mutations in their RBP gene and exhibited undetectable plasma RBP levels revealed that these sisters suffered from night blindness and mild retinal dystrophy but did not exhibit other clinical symptoms of vitamin A deficiency [12]. Taken together, RBP is critical for the mobilization of retinol from hepatic storage pools; however, RBP is not essential for the delivery of retinol to target tissues. Supply of vitamin A to target tissues in the absence of RBP is likely to be accomplished via newly absorbed retinyl esters or β-carotene present in circulating chylomicrons. Increased RBP has been shown to contribute to insulin resistance and type 2 diabetes [11]. All-trans RA has recently been shown to increase insulin sensitivity in diabetic mice while lowering RBP [13]. The effect on binding proteins must be considered when retinoids are used for disease treatment.

2.1.4.4 SRA6

The stimulated by retinoic acid gene 6 (STRA6) encodes the cell surface RBP receptor, which binds specifically to RBP and mediates retinol uptake from holo-RBP [14]. STRA6 is a widely expressed transmembrane protein. In mouse mammary epithelial cells, STRA6 expression can be up regulated by Wnt1 and retinoids. In addition, STRA6 mRNA levels are up regulated in mouse mammary gland tumors and human colorectal tumors [15]. Importantly, while the RBP-null mice and humans give rise to relative mild phenotypes, STRA6-null mice develop anophthalmia, congenital heart defects, diaphragmatic hernias, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. These findings suggest that STRA6 may have additional functions that are not related to RBP transport [16].

2.1.4.5 CRBP

CRBPs belong to the family of fatty acid binding proteins in which expression of CRBP family members are tissue specific. For example, CRBP-II is expressed only in the enterocytes of the intestine, while CRBP-I and -III are expressed throughout embryonic and adult tissues [17]. Knockout studies for CRBP isoforms have identified differences in function due to altered tissue localization. CRBP-I knockout mice are healthy. However, they have low levels of hepatic retinyl esters [18], and their hepatic lipid droplets appear to be smaller and less abundant than in wild type littermates. CRBP-II-null mice have impaired retinol uptake, but they develop and reproduce normally under vitamin A-enriched diet, albeit with reduced retinol storage [19]. Reduction of vitamin A in the maternal diet of CRBP-II-null mice during gestation results in neonatal mortality immediately following birth [19]. CRBP-III null mice have impaired vitamin A incorporation into milk, but they are otherwise healthy [20]. CRBP-I and CRBP-III compensate for each other to maintain normal retinoid homeostasis, but the compensation is incomplete during lactation [20]. The binding affinity of CRBP-I towards retinol is about 100-fold higher than that of CRBP-II. They display a similar binding affinity towards retinal and CRBP-II associates with retinol and retinal with similar affinities. CRBPs, and especially CRBP-I with its high affinity for retinol, may sequester retinol from its ability to disrupt cell membranes. Epigenetic silencing of CRBP is a common event in human cancers [21]. Silencing CRBP reduces the availability of retinyl esters in the bloodstream and decreases the body’s ability to metabolize retinol [22].

2.1.4.6 CRABP

CRABP-I and -II have been identified with a high affinity for all-trans RA. In humans, these isoforms display 74 percent sequence identity and are highly conserved among species; however, these CRABP isoforms display different patterns of expression across cells and developmental stages. In adults, CRABP-I is expressed ubiquitously, while CRABP-II is only expressed in the skin, uterus, ovary, and the choroid plexus. Both CRABPs are widely expressed in the embryo, although they do not usually co-exist in the same cells. The biological functions of CRABPs are not completely understood. In mouse knockout stu dies, disruption of either CRABP-I or -II only display mild defects in limb development [23], which suggests CRABPs may be involved in generation of appropriate RA concentration gradients in the developing limb bud. Both CRABP isoforms are present in cytosol and nucleus and thus may deliver the ligand directly to the nuclear receptor. The differential role of these two binding proteins remains to be studied (reviewed in [24] and [25]). Increased CRABP-I expression may also contribute to RA resistance of cancer cells [26]. The effect of CRABP on cancer therapy deserves more attention.

2.1.4.7 Retinoic Acid Receptors

The major breakthrough in understanding RA’s function occurred upon identifying and cloning the receptors for RA [2728]. RA regulates gene expression by binding to its nuclear receptors, which in turn activates transcription of their downstream target genes. Thus, retinoids exert their biological functions primarily by regulating gene expression. This was predicted by Sporn and Roberts in 1983, when they wrote: “Ultimately, it would appear that the problem of the molecular mechanism of action of retinoids in control of differentiation and carcinogenesis is converging on one of the central problems of all biology, the control of gene expression.” [29]

2.1.4.8 RAR and RXR

Two distinct classes of receptors for retinoids have been identified: retinoic acid receptors (RAR) and retinoid × receptors (RXR). Each class of receptor contains three subtypes – α, β, and γ. RARs can be activated by both all-trans and 9-cis-RA, while, RXRs are exclusively activated by 9-cis RA. However, due to the conversion of all-trans to 9-cis RA, high concentrations (10−5 M) of all-trans RA can also activate gene transcription in cells transfected with RXRs [30].

RXRs can form homo- and heterodimers with other receptors. In fact, RXRs are promiscuous receptors forming heterodimers with many different kinds of receptors, which include receptors for fatty acids [peroxisomal proliferator activated receptors (PPAR)], bile acids [farnesoid × receptor (FXR)], oxysterols [liver × receptor (LXR)], xenobiotics [pregnane × receptor (PXR) and constitutive androstane receptor (CAR)], vitamin D [vitamin D receptor (VDR)], and RA (RAR). RXRs can also form homodimers. Hypervitaminosis A leads to bone fracture suggesting that vitamin A and D compete for the same receptor [31]. Within these heterodimers, RXRs can exist as both active and silent partners. When it serves as an active partner, 9-cis RA and the ligand for the heterodimeric partner can activate the heterodimer, and addition both ligands give synergistic induction in gene transcription. For example, RXR is an active partner for PPAR. Similarly, heterodimeric complexes of RXR with LXR or FXR also retain 9-cis RA responsiveness. Thus, RAs can regulate PPAR- and FXR-mediated pathways [32]. Recently, we demonstrated that RAs could also activate PXR-, VDR, and CAR-mediated signaling and thus regulated xenobiotic metabolism and potentially its own oxidation [3335]. When RXR serves as a silent partner, the heterodimer of RXR and its partner does not respond to RA. Regardless of their active or silent role, RXRs must be present in order to exert biological actions of various nuclear receptors. Using hepatocyte RXRα-deficient mice [3637], we have demonstrated that RXRα does play vital roles in xenobiotic (alcohol, acetaminophen) and endobiotic (fatty acid, cholesterol, amino acid, and carbohydrate) metabolism [3340]. Thus, RXR functions as an auxiliary factor and determines the effects of other hormones, making RXR a master regulator. The structure of nuclear receptors is summarized in recent review articles [738].

Existing data suggest that the binding protein and receptor work together to exert the specific effect of RAs. For example, RAs can bind to both PPARβ, the receptor for fatty acids, and RAR. Fatty acid-binding protein 5 (FABP5) and CRABP-II are specific binding proteins that channel RAs from the cytosol into the nucleus for binding to either PPARβ or RAR, respectively [39]. The ratio of FABP5/CRABP-II concentrations determines which receptor is activated. By activating PPARβ, RAs induce expression of genes affecting lipid and glucose homeostasis, such as the insulin-signaling gene pyruvate dehydrogenase kinase 1 (PDK1), which enhances insulin action. Hence, RAs stimulate lipolysis and reduce triglyceride content. RA implantation into obese mice causes up regulation of PPARβ as well as an increased expression of PPARβ target genes, including PDK1, which led to weight loss [40].

2.1.4.9 Retinoids and Cancer

Retinoids are widely used to treat visual and dermatological diseases. Their effect on cancer prevention and treatment has received a lot of attention. This review focuses on the action of retinoids on cancer. Retinoids have been used as potential chemotherapeutic or chemopreventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. Epidemiological studies show that lower vitamin A intake results in a higher risk of developing cancer, which aligns with observations of vitamin A-deficient animals [61]. Altered expression of RA receptors is also associated with malignant transformation of animal tissues or cultured cells. Furthermore, retinoids suppress carcinogenesis in tumorigenic animal models for skin, oral, lung, breast, bladder, ovarian, and prostate [6268]. In humans, retinoids reverse premalignant human epithelial lesions, induce the differentiation of myeloid cells, and prevent lung, liver, and breast cancer [6973].

The following is a summary of how major retinoids may work in cancer treatment or prevention.

2.1.4.9.1 All-trans RA (tretinoin)

All-trans RA is the most abundant natural retinoid and has been widely studied for many years. It is currently in clinical trials for the treatment of lymphoma, leukemia, melanoma, lung cancer, cervical cancer, kidney cancer, neuroblastoma, and glioblastoma. The most effective clinical usage of all-trans RA in human disease was demonstrated in treatment of a rare leukemia, acute promyelocytic leukemia (APL). APL is characterized by selected expansion of immature myeloid precursors or malignant myeloid cells blocked at the promyelocytic stage of hemopoietic development. APL cells invariably express aberrant fusion proteins involving the DNA and ligand binding domain of RARα [7475]. Other fusion partners include the promyelocytic leukemia zinc finger gene, the nucleophosmin gene, the nuclear mitotic apparatus gene, and the Stat5b gene, while the most common fusion partner is promyelocytic leukemia protein (PML). The PML-RARα chimeric receptor is created by a balanced reciprocal chromosomal translocation, t(15;17)(q22:q11). The expressed PML-RARα chimeric receptor alters normal function of RARs. PML-RARα can form a homodimer through the coiled-coil motif of PML, inhibiting RARα’s ability to bind to RA responsive elements, thereby preventing activation of downstream target genes [7677]. In addition, RXR is an essential component of the oncogenic PML/RARα complex suggesting RXR can be a drug target for APL [7879]. In 1995, the FDA approved all-trans RA for treating APL. The all-trans RA-induced differentiation of APL cells is due to both its ability to promote the degradation of the mutant PML-RARα and the dissociation of its co-repressors [80]. All-trans RA also causes cell cycle arrest at G1 phase and inhibits cell proliferation [81]. In addition, high concentration of all-trans RA induces post-maturation apoptosis of APL-blasts through the induction of the tumor-selective death ligand tumor necrosis factor-related apoptosis-inducing ligand TRAIL [82].

RA syndrome is a life-threatening complication seen in APL patients treated with all-trans RA. This syndrome is characterized by dyspnea, fever, weight gain, hypotension, and pulmonary infiltrates. It can be effectively treated by giving dexamethasone and holding off all-trans RA treatment in severe cases. An elevated white count is sometimes associated with this syndrome, but is not a prerequisite. The etiology of RA syndrome is not clear; several causes have been speculated including a capillary leak syndrome from cytokine release from the differentiating myeloid cells. Alternatively, all-trans RA may cause the maturing myeloid cells to acquire the ability to infiltrate organs such as the lung [83].

2.1.4.9.2. 9-cis RA (alitretinoin)

9-cis RA differentiates itself from all-trans RA in its ability to activate both RAR and RXR. In addition, 9-cis RA activates PPAR, FXR, PXR, VDR, and CAR via RXR. In preclinical studies, 9-cis RA is effective in the prevention of mammary and prostate cancer [8485] and it has also been FDA-approved for the topical treatment of cutaneous lesions of Kaposi’s sarcoma [86]. In addition, 9-cis RA and all-trans RA can individually induce apoptosis of human liver cancer cells [87]. 9-cis RA not only regulates nuclear genes, but also mitochondria gene transcription [88].

2.1.4.9.3. 13-cis RA (isotretinoin)

13-cis RA is unique that it exhibits immunomodulatory and anti-inflammatory responses. It inhibits ornithine decarboxylase, thereby decreasing polyamine synthesis and keratinization [89]. 13-cis RA noticeably reduces the production of sebum and shrinks the sebaceous glands [90]. It stabilizes keratinization and prevents comedones formation [9192]. The exact mechanism of action is unknown. This combination of regulating proliferation, differentiation, and inflammation could make 13-cis RA a more effective drug in comparison to other retinoids, which may cause inflammation and irritation [93].

13-cis RA is in clinical trial for different types of cancers, and thyroid cancer received a lot of attention. In follicular thyroid cancer cells, 13-cis RA induces radioiodine avidity of cells formerly unable to accumulate radioiodine [94]. In human thyroid carcinoma cell lines, retinoids induce the expression of type I iodothyronine-5′-deiodinase and sodium/iodide-symporter, which are the thyroid differentiation markers [95]. However, approximately 30% of thyroid tumors dedifferentiate after treatment and thus develop into highly malignant anaplastic thyroid carcinomas [96]. 13-cis RA is also used to treat non-operable thyroid follicular tumors, which fail to uptake radioiodine. 13-cis RA increases the radioiodide uptake in some patients. The beneficial outcome of this treatment was interpreted as partial re-differentiation of thyroid cancer cells. This effect of 13-cis RA requires the existence of functional RXR [96]. The effect of 13-cis RA on thyroid cancer has been reviewed extensively [97]. Besides thyroid cancer, utilizing 13-cis RA for maintenance therapy has significantly improved the outcome of patients with a high-risk form of neuroblastoma [98]. Along the same line of work, Krüppel zinc-finger protein ZNF423 is critical for RA signaling and is likely a prognostic marker for neuroblastoma [99]. 13-cis RA is also effective in preventing head and neck cancer, which is discussed below.

2.1.4.9.4. Synthetic Retinoids

N-(4-hydroxyphenyl) retinamide (Fenretinide or 4HPR) was first synthesized in the late 1960s by R. W. Pharmaceuticals. Since then, the biological properties of fenretinide have been of great interest. Currently, fenretinide is one of the most promising clinically tested retinoids. The modification of the carboxyl end of all-trans RA with an N-4-hydroxyphenyl group resulted in increased efficacy as a chemoprevention agent as well as reduced toxicity when compared with other retinoids [100]. Animal models have demonstrated that treatment with fenretinide prevents chemically induced cancers of the breast, prostate, bladder, and skin [101104]. Furthermore, the combination of tamoxifen with fenretinide produces efficacy greater than either chemical alone [105].

Natural retinoids like all-trans RA induce differentiation and/or cytostasis in target cells [106108], while fenretinide has distinct biologic effects including the induction of apoptosis by generating reactive oxygen species (ROS) and lipid second messengers [104]. The apoptotic effect of fenretinide has been documented in a variety of cancer cells including transformed T cells, B cells and breast epithelial cells, as well as bladder, breast, cervical, colon, embryonal, esophageal, head and neck, lung, ovarian, pancreatic, prostate, and skin carcinomas [100]. Furthermore, fenretinide does not induce point mutations or chromosomal aberrations, and is therefore not genotoxic [109]. These qualities suggest that fenretinide could be used for a long-term chemopreventive modality. In animal models, fenretinide has demonstrated chemopreventive efficacy against carcinogenesis of the breast [110], prostate, pancreas, and skin [104111112]. Moreover, in a clinical setting, fenretinide slowed the progression of prostate cancer in men diagnosed with an early stage of the disease [113]. Fenretinide protected against the development of ovarian cancer and a second breast malignancy in premenopausal women who had been treated to prevent the progression of early-stage breast cancer [114]. It also prevented relapse and the formation of secondary primary lesions in patients following the surgical removal of oral leukoplakia [115]. Recent studies also illustrated the anti-angiogenic [116] and anti-fibrotic [117] effect of fenretinide. Furthermore, long-term fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis [118].

The mechanisms associated with fenretinide-induced apoptosis have been explored, but are not well-understood [100]. The components that lead to ROS generation and cause cell death are largely unknown. Depending on cell types and models used, the effect of fenretinide has been shown to be RARβ-dependent or -independent [119]. Our data showed that fenretinide-induced apoptosis of human liver cancer cells was RARβ-dependent [120]. Furthermore, induction and cytoplasmic localization of Nur77 dictates the sensitivity of liver cancer cell to fenretinide-induced apoptosis [121]. It seems that fenretinide enriches the cytoplasmic Nur77 to target mitochondria and induce cell death. The relationship between RARβ and Nur77 in mediating fenretinide-induced apoptosis remains to be determined.

A retinoid-related molecule 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecar-boxylic acid (AHPN) (also called CD437) and it’s analog (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) also have Nur77-dependent apoptotic effects [122124]. AHPN is structurally distinct from fenretinide. AHPN-induced apoptosis activates JNK [125127], which is required for maximal apoptosis induction and precedes mitochondrial depolarization. Induction of apoptosis of breast and prostate cancer cells by AHPN is also associated with its inhibition of Akt activity [128]. Thus, induction of JNK and inhibition of Akt phosphorylation of Nur77 contribute to Nur77 nuclear export mediated by AHPN [129].

While many synthesized RAs are promising for cancer treatment, only a few are FDA-approved or currently undergoing clinical trials for cancer therapy. A number of retinoids, which have been FDA-approved for dermatological purposes, have potential for cancer treatment. Bexarotene (Targretin) is a synthetic retinoid approved by the FDA to treat skin problems caused by cutaneous T-cell lymphoma that are unresponsive to other treatments [130]. Other synthetic retinoids, such as TAC-101 (Taiho Pharmaceutical, Tokyo, Japan) has shown efficacy in inhibiting tumor growth in the liver and markedly increases survival in both the primary HCC and metastatic colon cancer models [131]. TAC-101 is currently in phase II trial for hepatocellular carcinoma and has shown good preliminary success [132]. Another, Tazarotene (AVAGE) (Allergan, Irvine, CA) is in phase I trials for the treatment of lymphoma [133]. Please see table 1 for a brief characterization of some of retinoids that are in use or in clinical trials.

3  Vitamin C

3.1 American Cancer Society

http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/herbsvitaminsandminerals/vitamin-c

Vitamin C is an essential vitamin the human body needs to function well. It is a water-soluble vitamin that cannot be made by the body, and must be obtained from foods or other sources. Vitamin C is found in abundance in citrus fruits such as oranges, grapefruit, and lemons, and in green leafy vegetables, tomatoes, potatoes, strawberries, red or green peppers, and cantaloupe.

Vitamin C is found in many vegetables and fruits, especially oranges, grapefruits, and peppers. Many studies have shown a link between eating foods rich in vitamin C, such as fruits and vegetables, and a reduced risk of cancer. On the other hand, the few studies in which vitamin C has been given as a supplement have not shown a reduced cancer risk.

This suggests that the activity of fruits and vegetables in preventing cancer is due to a combination of many things such as vitamins, fiber, and other phytochemicals and not to vitamin C alone (see Phytochemicals). Clinical trials of high doses vitamin C as a treatment for cancer have not shown any benefit. High doses of vitamin C can cause side effects in some people.

3.2 Intravenous vitamin C for cancer

Oct 4, 2013 | By Dr. Ronald Hoffman

For more than 20 years, the Hoffman Center has been using high-dose vitamin C drips in its cancer support protocols. The initial impetus was from Linus Pauling who, together with Ewan Cameron, pioneered the use of high-dose C in cancer in the 1960s.

Now, there’s new interest in this modality for fighting cancer based on new, exciting research under way at the National Institutes of Health.

Cameron and Pauling found that vitamin C helped cancer patients live about four times longer than cancer patients not given vitamin C. They administered high-dose vitamin C in the form of sodium ascorbate given orally and intravenously to treat more than 1,000 cancer patients.

Nonetheless, vitamin C for cancer suffered a setback when Dr. Charles Moertel of the Mayo Clinic, an arch foe of nutritional therapies for cancer, sought to disprove Pauling’s thesis. But he did not follow the Pauling/Cameron instructions or regimen.

Moertel selected a cohort of terminal colon cancer patients who had not responded to all forms of conventional treatment, including surgery, chemo and radiation, and administered 10 grams of vitamin C to them orally. When the patients failed to demonstrate improved survival over patients not receiving vitamin C in the study, Moertel pronounced the vitamin C/cancer hypothesis defunct.

Moertel failed to note that the benefits achieved by Pauling and Cameron’s patients were obtained via both IV and oral C. He ultimately succumbed to cancer himself years later.

Alternative practitioners, meanwhile, sought to resurrect IV vitamin C as a tool in the treatment of cancer, but not until recently has serious academic research resumed.

Dr. Hugh Riordan of Kansas treated hundreds of cancer patients with doses of vitamin C up to 200,000 mg (200 grams) per day in infusions lasting 4-12 hours several times a week. He compiled a series of case histories documenting impressive responses but passed recently, before his work was generally acknowledged.

His protegee, Dr. Jeanne Drisko, Director, KU Integrative Medicine, has undertaken a series of clinical trials to validate the benefits of IV vitamin C in cancer. An FDA approved trial is now underway.

Research at the National Institutes of Health is beginning to suggest that vitamin C deserves another chance to find its niche in the arsenal of anti-cancer therapies. Studies now suggest that even high dose vitamin C given by mouth is poorly absorbed. Blood levels “max out” at doses of 500 mg given several times during the day.

But vitamin C given intravenously is another story. When delivered in a “drip,” much higher concentrations of C can be attained. At these higher concentrations, vitamin C has different characteristics than if given orally. While oral vitamin C boosts immunity and assists tissue repair, it is too weak to do much to kill or inhibit cancer cells. But at high doses delivered directly into the bloodstream, it may act to increase levels of hydrogen peroxide deep in the tissues where cancer cells lurk. Peroxide-mediated killing is one of the white blood cells’ key mechanisms for fighting infection and cancer.

Research currently under way has shown that high concentrations of vitamin C can stop the growth or even kill a wide range of cancer cells. Only intravenous administration of vitamin C can deliver the high doses found to be effective against cancer.

IV vitamin C, when administered by a trained, experienced physician, is safe and well-tolerated, even at doses as high as 100,000 mg (100 grams) per day. Proper blood tests must be done to ensure that it is well-tolerated, and the patient must be monitored. Doses must be gradually adjusted upward. Not all patients are candidates for IV vitamin C. Vitamin C can be safely administered even while patients are undergoing chemo and radiation; in fact, the FDA-approved trial at the University of Kansas Medical Center explicitly permits the co-administration of vitamin C with conventional treatments.

3.3 IV Vitamin C Kills Cancer Cells

by Dr. Julian Whitaker

By now, most people know that vitamin C is a potent antioxidant that has the power to boost immune function, increase resistance to infection, and protect against a wide range of diseases.

But there’s an entirely different and largely unknown role of vitamin C, and that is its ability—when administered in very high doses by intravenous (IV) infusions—to kill cancer cells.

Vitamin C interacts with iron and other metals to create hydrogen peroxide. In high concentrations, hydrogen peroxide damages the DNA and mitochondria of cancer cells, shuts down their energy supply, and kills them outright. Best of all—and unlike virtually all conventional chemotherapy drugs that destroy cancer cells—it is selectively toxic. No matter how high the concentration, vitamin C does not harm healthy cells.

Lab studies reveal that this therapy is effective against many types of cancer, including lung, brain, colon, breast, pancreatic, and ovarian. Animal studies show that when human cancers are grafted into animals, high-dose IV vitamin C decreases tumor size by 41 to 53 percent “in diverse cancer types known for both their aggressive growth and limited treatment options.” Additionally, numerous patient case reports have been written up in medical journals.

Why IV Administration Is Essential

The only way to get blood levels of vitamin C to the concentrations required to kill cancer cells is to administer it intravenously. The body tightly controls levels of this vitamin by limiting intestinal absorption. If you took 10 g (10,000 mg) of vitamin C by mouth at one time, you would only absorb around 500 mg—and you’d get a serious case of diarrhea!

Intravenous administration, however, bypasses this control mechanism, and blood levels rise in a dose-dependent manner. For example, 10 g of IV vitamin C raises blood levels 25 times higher than the same dose taken orally, and this increases up to 70-fold as doses get larger.

4 Expert Q&A: Vitamin D and Cancer Risk

http://www.cancer.net/navigating-cancer-care/prevention-and-healthy-living/diet-and-nutrition/expert-qa-vitamin-d-and-cancer-risk

Vitamin D is one of several nutrients that the body needs to stay healthy. It may also play a role in reducing the risk of cancer, and several research studies are exploring this link. Cancer.Net talked with Richard Goldberg, MD, to learn more about current research on vitamin D and what people should know.

Q: What is the role of vitamin D in the body, and what are some sources of this vitamin?

A: One role of vitamin D is to regulate the absorption of calcium by the body. Calcium is the main component of bones and is important in the function of all cells in the body, particularly the heart. People who are vitamin D deficient (don’t get enough) can have weakened bones (a condition called osteoporosis in adults and rickets or osteomalacia in children). Too little calcium (called hypocalcemia) in the body can lead to irregular heartbeat and muscle spasms.

Milk, fish, eggs, and fortified cereals and orange juice are good sources of vitamin D. Milk manufactured in the United States is generally fortified with vitamin D as a way to prevent deficiencies from occurring. Supplemental vitamins are also a source.

Unlike other vitamins that the body cannot produce by itself, vitamin D can either be absorbed directly from the intestine or made from compounds in foods. The body can make vitamin D from nutrients related to cholesterol. These nutrients are then converted to vitamin D as they circulate in the blood when a person’s skin is exposed to sunlight.

Too much vitamin D can also be bad for a person, leading to drowsiness, kidney stones, bone or muscle weakness, and elevated blood calcium, a condition called hypercalcemia that can cause confusion and, in extreme cases, death.

Q: When getting vitamin D from sunlight, how long should a person be exposed to the sun? What are the risks of too much sun exposure?

A: While 90% of the body’s vitamin D comes from exposure to sun (in the absence of vitamin D supplements), the amount of sun exposure needed to produce adequate vitamin D levels is actually quite limited. Sun exposure at the equator is far more intense than in such northern cities as Boston or London, for instance, and is more intense anywhere in summer than in winter. However, it takes only five to ten minutes of exposing the hands and face three times a week to receive adequate sun exposure in the summer in Boston. Exposure of more skin, such as when wearing a bathing suit, requires only a very short time in the sun. Use of sunblock is very important when sun exposure is longer than that to prevent skin cancer, including melanoma, and other sun-induced damage such as wrinkling and pigmentation changes (sunspots). Learn more about protecting your skin from the sun.

Q: How might vitamin D work to help lower the risk of cancer?

A: Laboratory studies have shown that vitamin D deficiency can lead to decreased communication between cells and leads them to stop sticking to one another, a condition that could cause cancer cells to spread. Compared with normal cells, cancer cells remain in an immature state, and vitamin D appears to have a role in making cells mature. Vitamin D also appears to play a role in regulating cellular reproduction, which malfunctions (doesn’t work properly) in cancer. Higher levels of vitamin D lead to cellular adherence, maturation, and communication between cells, all of which may lower cancer risk.

Q: What does research show about vitamin D levels and cancer?

A: Studies in populations have shown that low vitamin D levels are a risk factor for cancer in general, and particularly for prostatecolorectal, and breast cancers.

There are also data that correlate high blood levels of vitamin D with a reduced risk of breast and colorectal cancers. These levels can best be achieved by taking supplemental vitamin D. In colorectal cancer, calcium supplementation may also reduce the risk of polyps (noncancerous growths that may develop on the inner wall of the colon and rectum) and cancer. Numerous studies have tested cancer risk by giving patients supplemental vitamin D, with or without calcium supplementation. While the results are somewhat variable, substantial reduction (on the order of 50%) in the odds of breast and colon cancers with supplementation, have been noted in some studies. People with a personal history of these types of cancer and their relatives may wish to discuss supplementation with their doctors.

5 Magnesium and Cancer Research

5.1  Dr Sircus on Mar 18, 2010
http://drsircus.com/medicine/magnesium/magnesium-and-cancer

Aleksandrowicz et al in Poland conclude that inadequacy of magnesium and antioxidants are important risk factors in predisposing to leukemias.[2] Other researchers found that 46% of the patients admitted to an ICU in a tertiary cancer center presented hypomagnesemia. They concluded that the incidence of hypomagnesemia in critically ill cancer patients is high.[3]In animal studies we find that magnesium deficiency has caused lymphopoietic neoplasms in young rats. A study of rats surviving magnesium deficiency sufficient to cause death in convulsions during early infancy in some, and cardiorenal lesions weeks later in others, disclosed that some of survivors had thymic nodules or lymphosarcoma.[4]

One would not normally think that Magnesium (Mg) deficiency can paradoxically increase the risk of, or protect against cancer yet we will find that just as severe dehydration or asphyxiation can cause death magnesium deficiency can directly lead to cancer. When you consider that over 300 enzymes and ion transport require magnesium and that its role in fatty acid and phospholipids acid metabolism affects permeability and stability of membranes, we can see that magnesium deficiency would lead to physiological decline in cells setting the stage for cancer. Anything that weakens cell physiology will lead to the infections that surround and penetrate tumor tissues. These infections are proving to be an integral part of cancer. Magnesium deficiency poses a direct threat to the health of our cells. Without sufficient amounts our cells calcify and rot. Breeding grounds for yeast and fungi colonies they become, invaders all too ready to strangle our life force and kill us.

Over 300 different enzymes systems rely upon magnesium to facilitate their catalytic action, including ATP metabolism, creatine-kinase activation, adenylate-cyclase, and sodium-potassium-ATPase.[5]

It is known that carcinogenesis induces magnesium distribution disturbances, which cause magnesium mobilization through blood cells and magnesium depletion in non-neoplastic tissues. Magnesium deficiency seems to be carcinogenic, and in case of solid tumors, a high level of supplemented magnesium inhibits carcinogenesis.[6] Both carcinogenesis and magnesium deficiency increase the plasma membrane permeability and fluidity. Scientists have in fact found out that there is much less Mg++ binding to membrane phospholipids of cancer cells, than to normal cell membranes.[7]

Magnesium protects cells from aluminum, mercury, lead, cadmium, beryllium and nickel.

Magnesium in general is essential for the survival of our cells but takes on further importance in the age of toxicity where our bodies are being bombarded on a daily basis with heavy metals.Glutathione requires magnesium for its synthesis.[8] Glutathione synthetase requires ?-glutamyl cysteine, glycine, ATP, and magnesium ions to form glutathione.[9] In magnesium deficiency, the enzyme y-glutamyl transpeptidase is lowered.[10] According to Dr. Russell Blaylock, low magnesium is associated with dramatic increases in free radical generation as well as glutathione depletion and this is vital since glutathione is one of the few antioxidant molecules known to neutralize mercury.[11]Without the cleaning and chelating work of glutathione (magnesium) cells begin to decay as cellular filth and heavy metals accumulates; excellent environments to attract deadly infection/cancer.

There is drastic change in ionic flux from the outer and inner cell membranes both in the impaired membranes of cancer, and in Mg deficiency.

Anghileri et al[12],[13] proposed that modifications of cell membranes are principal triggering factors in cell transformation leading to cancer. Using cells from induced cancers, they found that there is much less magnesium binding to membrane phospholipids of cancer cells, than to normal cell membranes.[14] It has been suggested that Mg deficiency may trigger carcinogenesis by increasing membrane permeability.[15] Magnesium deficient cells membranes seem to have a smoother surface than normal, and decreased membrane viscosity, analogous to changes in human leukemia cells.[16],[17] There is drastic change in ionic flux from the outer and inner cell membranes (higher Ca and Na; lower Mg and K levels), both in the impaired membranes of cancer, and of Mg deficiency. And we find that lead (Pb) salts, are more leukemogenic when given to Mg deficient rats, than when they are given to Mg-adequate rats, suggesting that Mg is protective.[18]

Magnesium has an effect on a variety of cell membranes through a process involving calcium channels and ion transport mechanisms. Magnesium is responsible for the maintenance of the trans-membrane gradients of sodium and potassium.

Long ago researchers postulated that magnesium supplementation of those who are Mg deficient, like chronic alcoholics, might decrease emergence of malignancies[19] and now modern researchers have found that all types of alcohol — wine, beer or liquor — add equally to the risk of developing breast cancer in women. The researchers, led by Dr. Arthur Klatsky of the Kaiser Permanente Medical Care Program in Oakland, Calif., revealed their findings at a meeting of the European Cancer Organization in Barcelona in late 2007. It was found that women who had one or two drinks a day increased their risk of developing breast cancer by 10 percent. Women who had more than three drinks a day raised their risk by 30 percent. The more one drinks the more one drives down magnesium levels.

Breast cancer is the second most common cancer killer of women, after lung cancer. It will be diagnosed in 1.2 million people globally this year and will kill 500,000.

According to data published in the British Journal of Cancer in 2002, 4 percent of all breast cancers — about 44,000 cases a year — in the United Kingdom are due to alcohol consumption. It’s an important question though, and one not asked by medical or health officials, is it the alcohol itself or the resultant drop in magnesium levels that is cancer provoking? Though some studies have shown that light- to moderate alcohol use can protect against heart attacks it does us no good to drink if it causes cancer. Perhaps if magnesium was supplemented in women drinkers who were studied there would have been no increase of cancer from drinking.

Alcohol has always been known to deplete magnesium, and is one of the first supplements given to alcoholics when they stop and attempt to detoxify and withdraw.

Researchers from the School of Public Health at the University of Minnesota have just concluded thatdiets rich in magnesium reduced the occurrence of colon cancer.[20] A previous study from Sweden[21] reported that women with the highest magnesium intake had a 40 per cent lower risk of developing the cancer than those with the lowest intake of the mineral.

Magnesium stabilizes ATP[22], allowing DNA and RNA transcriptions and repairs.[23]

The anti-colon cancer effects of calcium are linked to magnesium levels, says a new study. Researchers from Vanderbilt University found that low ratios of the minerals were associated with reduced risk of colorectal cancer, according to findings presented at the Seventh Annual American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research. Both high magnesium and calcium levels have been linked to reduced risks of colon cancer but studies have also shown that high calcium levels inhibit the absorption of magnesium. According to Qi Dai, MD, PhD, and co-workers, Americans have high calcium intake, but also a high incidence of colorectal cancer. “If calcium levels were involved alone, you’d expect the opposite direction. There may be something about these two factors combined – the ratio of one to the other – that might be at play,” said Dai. The risk of colorectal cancer adenoma recurrence was reduced by 32 per cent among those with baseline calcium to magnesium ratio below the median in comparison to no reduction for those above the median,” said Dai.[24]

Pre-treatment hypomagnesemia has been reported in young leukemic children, 78% of whom have histories of anorexia, and have excessive gut and urinary losses of Mg.[25]

Several studies have shown an increased cancer rate in regions with low magnesium levels in soil and drinking water, and the same for selenium. In Egypt the cancer rate was only about 10% of that in Europe and America. In the rural fellah it was practically non-existent. The main difference was an extremely high magnesium intake of 2.5 to 3g in these cancer-free populations, ten times more than in most western countries.[26]

5.2 Magnesium and cancer: a dangerous liason.

Castiglioni S, Maier JA.
Magnes Res. 2011 Sep; 24(3):S92-100
http://dx.doi.org:/10.1684/mrh.2011.0285

A complex relationship links magnesium and cancer. The aim of this review is to revisit current knowledge concerning the contribution of magnesium to tumorigenesis, from transformed cells to animal models, and ending with data from human studies. Cultured neoplastic cells tend to accumulate magnesium. High intracellular levels of the cation seem to confer a metabolic advantage to the cells, contribute to alterations of the genome, and promote the acquisition of an immortal phenotype. In magnesium-deficient mice, low magnesium both limits and fosters tumorigenesis, since inhibition of tumor growth at its primary site is observed in the face of increased metastatic colonization. Epidemiological studies identify magnesium deficiency as a risk factor for some types of human cancers. In addition, impaired magnesium homeostasis is reported in cancer patients, and frequently complicates therapy with some anti-cancer drugs. More studies should be undertaken in order to disclose whether a simple and inexpensive intervention to optimize magnesium intake might be helpful in the prevention and treatment of cancer.

Even though cancer-associated death rates are falling steadily, the global burden of cancer continues to increase primarily as a result of an aging population, but also because of the adoption of cancer-causing behaviors, including smoking and a western-type diet [1]. In particular, statistical and epidemiological data point to diet as responsible for about 35% of human cancer mortality [2]. There is general agreement about the inverse correlation between the risk of cancer and the regular consumption of fruit, cereals and vegetables, rich sources of many beneficial micronutrients, vitamins and minerals. Magnesium, which is predominantly obtained by eating unprocessed grains and green leafy vegetables, is an essential micronutrient implicated in a wide variety of regulatory, metabolic and structural activities [3]. The occidental diet is relatively deficient in magnesium Presented in part at the European Magnesium Meeting – EUROMAG Bologna 2011, San Giovanni in Monte, Bologna, Italy, June 8-10, 2011. because of the processing of many food items and the preference for calorie-rich, micronutrient-poor foods [4]. Magnesium deficiency complicates chronic gastrointestinal and renal diseases, diabetes mellitus, alcoholism, and therapies with some classes of diuretics and anticancer drugs [4]. A review of the literature reveals the relationship between magnesium and cancer, from the cellular level through to animal models and humans. Although controversy exists about the role of magnesium in tumors, most of the results available point to low magnesium as a factor contributing to tumorigenesis.

5.1.1 Magnesium acts as a secondary messenger, and activates a vast array of enzymes [3, 5]. Since magnesium participates in all major metabolic processes, as well as redox reactions, it is no surprise that it has a direct role in controlling cell survival and growth. In normal diploid cells, the total concentration of magnesium increases throughout the G1 and S phases of the cell cycle. Accordingly, low extracellular magnesium markedly inhibits their proliferation [3]. Conversely, neoplastic cells are refractory to the proliferative inhibition by low extracellular magnesium but, being extremely avid for the cation, it accumulates in these cells even when cultured in low magnesium levels [6]. This avidity is due, at least in part, to an impairment of Na-dependent magnesium extrusion [7], and to the overexpression of one of the magnesium transporters, namely transient receptor potential melastatin (TRPM)7 [8]. High intracellular magnesium seems to provide a selective advantage for the transformed cells since magnesium contributes to regulating enzymes of various metabolic pathways and of the systems involved in DNA repair. Indeed, magnesium forms complexes with ATP, ADP and GTP, necessary for the activity of enzymes implicated in the transfer of phosphate groups such as glucokinase, phosphofructokinase, phosphoglycerate kinase and pyruvate kinase [9], enzymes of glycolysis known to be the pathway used preferentially by neoplastic cells to produce energy [10]. Magnesium also forms complexes with DNA polymerase, ribonucleases, adenylcyclase, phosphodiesterases,guanylate-cyclase, ATPases and GTPases, being therefore implicated in the metabolism of nucleic acids and proteins, and in signal transduction [9]. Since mutation is a driving force in the development of cancer, it is worth noting that magnesium is involved in the inhibition of N-methylpurine DNA-glycosidase, which initiates base excision repair in DNA by removing a wide variety of alkylated, deaminated, and lipid peroxidation-induced purine adducts [11]. In addition, the nuclear Ser/Thr phosphatase PPM1D (also known as WIP1), which is overexpressed in various human primary tumors, requires magnesium for its activity. PPM1D is involved in the regulation of several essential signaling pathways implicated in tumorigenesis [12, 13]. In particular, PPM1D dephosphorylates and, therefore, inactivates the p53 tumor suppressor gene, a canonical suppressor of proliferation. It also complements several oncogenes, such as Ras, Myc, and HER-2/neu, for cellular transformation both in vitro and in vivo [12].

On these bases, it is possible to conclude that high intracellular magnesium has a role in promoting genetic instability. Another peculiarity of tumor cells is their limitless proliferative potential [14, 15]. It is therefore relevant to point out that magnesium is required to activate telomerase [16-18], a specialized DNA polymerase that extends telomeric DNA and counters the progressive telomere erosion associated with cell duplication. The presence of telomerase activity correlates with a resistance to induction of both senescence and apoptosis which are considered to be crucial anticancer defenses [14, 15]. These points are summarized in figure 1, which also underlines the contribution of high intracellular magnesium to some of the hallmarks of cancer, as highlighted by Hanahan and Weinberg [14, 15]. Mentioning only studies performed on neoplastic cells would be simplistic, since tumors are more than just masses of proliferating cancer cells. Rather, they are complex, heterotypic tissues where normal cells in the stroma, far from being passive bystanders, actively collaborate to cancer development and progression [14, 15]. Many of the growth signals driving the proliferation of and invasion by carcinoma cells originate from the stromal cell components of the tumor mass. It is therefore worth noting that low magnesium modulates the functions of a variety of normal cells present in the tumor microenvironment. In particular, endothelial cells cultured in low magnesium release higher amounts of metalloproteases and growth factors [19]. Similar results were obtained in cultured human fibroblasts (unpublished results). In addition, low magnesium promotes endothelial and fibroblast senescence [20], and senescent cells can modify the tissue environment in a way that synergizes with oncogenic mutations to promote the progression of cancers [21]. Only the behavior of microvascular endothelial cells cultured in low magnesium seems not to fit with the picture described above. It is well known that angiogenesis is crucial to nourish the tumor and facilitate its spreading, but low extracellular magnesium impairs acquisition of the angiogenic phenotype by microvascular endothelial cells. Exposure to low magnesium retards endothelial proliferation, migration and differentiation in vitro ([22] and manuscript submitted). Accordingly, magnesium-deficient mice develop tumors which are significantly less vascularized than the controls [23].

Figure 1. Neoplastic cells tend to have high intracellular concentrations of magnesium, which contribute to the regulation of various metabolic pathways and of systems involved in DNA repair, thus providing a selective advantage for the transformed cells. The figure also links the effects of high intracellular concentrations of magnesium on cell functions to some hallmarks of cancer as highlighted by Hanahan and Weinberg [14, 15].

5.1.2 Low magnesium and cancer: a focus on human studies

Several epidemiological studies have provided evidence that a correlation exists between dietary magnesium and various types of cancer. High levels of magnesium in drinking water protect against oesophageal and liver cancer [36, 37]. In addition, magnesium concentration in drinking water is inversely correlated with death from breast, prostate, and ovarian cancers, whereas no correlation existed for other tumors [36, 38, 39]. Epidemiological studies conducted in various countries demonstrate an association between low intake of magnesium and the risk of colon cancer [40-43]. In addition, a large population-based prospective study in Japan shows a significant inverse correlation between dietary intake of magnesium and colon cancer in men but not in women [44]. Intriguingly, the association between low intake of magnesium and colon cancer is linked to the increased formation of N-nitroso compounds, most of which are potent carcinogens [43]. A further link between magnesium and colon neoplasia is highlighted by the association of adenomatous and hyperplastic polyps, which might progress to carcinoma, with a genetic polymorphism of TRPM7 [45], an ubiquitous ion channel with a central role in magnesium uptake and homeostasis [46]. Results concerning the contribution of magnesium to lung cancer are controversial. A first case-control study correlates low dietary magnesium with increased lung cancer risk both in men and women [47]. This link is more evident in the elderly, current smokers, drinkers and in those with a late-stage disease. To explain the protective effect of magnesium against lung cancer, the authors recall that magnesium regulates cell multiplication, protects against the oxidative stress invariably associated with magnesium deficiency [48], and maintains genomic stability. A recent prospective analysis however, does not support the previous report [49]. These contrasting data could result from recall bias, the difficulty in evaluating diet composition and the fact that smoking is a very strong risk factor for lung cancer.

Conclusion Although the evidence is still fragmentary, most of the data available point to magnesium as a chemopreventive agent, so that optimizing magnesium intake might represent an effective and low-cost preventive measure to reduce cancer risk. Doubts remain about supplementing cancer patients with magnesium. The recently revived interest in the relationship between magnesium and tumors, both in experimental and clinical oncology, should encourage more studies that would advance our understanding of the role of magnesium in tumors, and could explore the possibility that optimizing magnesium homeostasis might prevent cancer or help in its treatment.

5.3 A Magnesium Deficiency Increases Cancer Risk Significantly

Wed, May 21, 2008 by: Mark Sircus

http://www.naturalnews.com/023279_magnesium_cancer_calcium.html#ixzz3ZCT65Fiv

Aleksandrowicz et al in Poland conclude that inadequacy of Mg (Magnesium) and antioxidants are important risk factors in predisposing to leukemias. Other researchers found that 46% of the patients admitted to an ICU (Intensive Care Unit) in a tertiary cancer center presented hypomagnesemia.

They concluded that the incidence of hypomagnesemia in critically ill cancer patients is high. In animal studies we find that Mg deficiency has caused lymphopoietic neoplasms in young rats. A study of rats surviving Mg deficiency sufficient to cause death in convulsions during early infancy in some, and cardiorenal lesions weeks later in others, disclosed that some of survivors had thymic nodules or lymphosarcoma.

One would not normally think that Magnesium (Mg) deficiency can paradoxically increase the risk of, or protect against cancer yet we will find that just as severe dehydration or asphyxiation can cause death, magnesium deficiency can directly lead to cancer. When you consider that over 300 enzymes and ion transport require magnesium and that its role in fatty acid and phospholipid acid metabolism affects permeability and stability of membranes, we can see that magnesiumdeficiency would lead to physiological decline in cells setting the stage for cancer. Anything that weakens cell physiology will lead to the infections that surround and penetrate tumor tissues. These infections are proving to be an integral part of cancer. Magnesium deficiency poses a direct threat to the health of our cells. Without sufficient amounts, our cells calcify and rot in. Breeding grounds for yeast and fungi colonies they become, invaders all too ready to strangle our life force and kill us.

Over 300 different enzymes systems rely upon magnesium to facilitate their catalytic action, including ATP metabolism, creatine-kinase activation, adenylate-cyclase, and sodium-potassium-ATPase.

It is known that carcinogenesis induces magnesium distribution disturbances, which cause magnesium mobilization through blood cells and magnesium depletion in non-neoplastic tissues. Magnesium deficiency seems to be carcinogenic, and in case of solid tumors, a high level of supplemented magnesium inhibits carcinogenesis. Both carcinogenesis and magnesium deficiency increase the plasma membrane permeability and fluidity. Scientists have in fact found out that there is much less Mg++ binding to membrane phospholipids of cancer cells, than to normal cell membranes.

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Diet and Diabetes

Writer and Curator: Larry H Bernstein, MD, FCAP 

 

Bile acid signaling in lipid metabolism: Metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice

Yunpeng Qi, Changtao Jiang, Jie Cheng, Kristopher W. Krausz, et al.

Biochimica et Biophysica Acta 1851 (2015) 19–29

http://dx.doi.org/10.1016/j.bbalip.2014.04.008

Bile acid synthesis is the major pathway for catabolism of cholesterol. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway in the liver and plays an important role in regulating lipid, glucose and energy metabolism. Transgenic mice overexpressing CYP7A1 (CYP7A1-tg mice) were resistant to high fat diet (HFD)-induced obesity, fatty liver, and diabetes. However the mechanism of resistance to HFD-induced obesity of CYP7A1-tg mice has not been determined. In this study, metabolomic and lipidomic profiles of CYP7A1-tg mice were analyzed to explore the metabolic alterations in CYP7A1-tg mice that govern the protection against obesity and insulin resistance by using ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry combined with multivariate analyses. Lipidomics analysis identified seven lipid markers including lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides that were significantly decreased in serum of HFD-fed CYP7A1-tgmice.Metabolomics analysis identified 13metabolites in bile acid synthesis including taurochenodeoxy-cholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, taurocholic acid, and tauro-β-muricholic acid (T-β-MCA) that differed between CYP7A1-tg and wild-type mice. Notably, T-β-MCA, an antagonist of the farnesoid X receptor (FXR) was significantly increased in intestine of CYP7A1-tg mice. This study suggests that reducing 12α-hydroxylated bile acids and increasing intestinal T-β-MCA may reduce high fat diet-induced increase of phospholipids, sphingomyelins and ceramides, and ameliorate diabetes and obesity. This article is part of a Special Issue entitled Linking transcription to physiology in lipidomics.

Bile acid synthesis is the major pathway for catabolism of cholesterol to bile acids. In the liver, cholesterol 7α-hydroxylase (CYP7A1) is the first and rate-limiting enzyme of the bile acid biosynthetic pathway producing two primary bile acids, cholic acid (CA, 3α, 7α, 12α-OH) and chenodeoxycholic acid (CDCA, 3α, 7α-OH) in humans. Sterol-12α hydroxylase (CYP8B1) catalyzes the synthesis of CA. In mice, CDCA is converted to α-muricholic acid (α-MCA: 3α, 6β, 7α-OH) and β-muricholic acid (β-MCA: 3α, 6β, 7β-OH). Bile acids are conjugated to taurine or glycine, secreted into the bile and stored in the gallbladder. After a meal, bile acids are released into the gastrointestinal tract. In the intestine, conjugated bile acids are first de-conjugated and then 7α-dehydroxylase activity in the gut flora converts CA to deoxycholic acid (DCA: 3α, 12α), and CDCA to lithocholic acid (LCA: 3α), two major secondary bile acids in humans.

In humans, most bile acids are glycine or taurine-conjugated and CA, CDCA and DCA are the most abundant bile acids. In mice, most bile acids are taurine-conjugated and CA and α- and β-MCAs are the most abundant bile acids. Bile acids facilitate absorption of dietary fats, steroids, and lipid soluble vitamins into enterocytes and are transported via portal circulation to the liver for metabolism and distribution to other tissues and organs. About 95% of bile acids are reabsorbed in the ileum and transported to the liver to inhibit CYP7A1 and bile acid synthesis. Enterohepatic circulation of bile acids provides a negative feedback mechanism to maintain bile acid homeostasis. Alteration of bile acid synthesis, secretion and transport causes cholestatic liver diseases, gallstone diseases, fatty liver disease, diabetes and obesity.

 Bile acid synthesis

 

Bile acid synthesis. In the classic bile acid synthesis pathway, cholesterol is converted to cholic acid (CA, 3α, 7α, 12α) and chenodeoxycholic acid (CDCA, 3α, 7α). CYP7A1 is the rate-limiting enzyme and CYP8B1 catalyzes the synthesis of CA. In mouse liver, CDCA is converted to α-muricholic acid (α-MCA, 3α, 6β, 7α) and β-MCA (3α, 6β, 7β). Most bile acids in mice are taurine (T)-conjugated and secreted into bile. In the intestine, gut bacteria de-conjugate bile acids and then remove the 7α-hydroxyl group from CA and CDCA to form secondary bile acids deoxycholic acid (DCA, 3α, 12α) and lithocholic acid (LCA, 3α), respectively. T-α-MCA and T-β-MCA are converted to T-hyodeoxycholic acid (THDCA, 3α, 6α), T-ursodeoxycholic acid (TUDCA, 3α, 7β), T-hyocholic acid (THCA, 3α, 6α, 7α) and T-murideoxycholic acid (TMDCA, 3α, 6β). These secondary bile acids are reabsorbed and circulated to liver to contribute to the bile acid pool. Secondary bile acids ω-MCA (3α, 6α, 7β) and LCA are excreted into feces.

Two FXR-dependent mechanisms are known to inhibit bile acid synthesis.  In the liver bile acid-activated FXR induces a negative receptor small heterodimer partner (SHP) to inhibit trans-activation activity of hepatic nuclear factor 4α(HNF4α) and liver receptor homologue-1 (LRH-1) that bind to the bile acid response element in the CYP7A1 and CYP8B1 gene promoters (Fig. 2, Pathway 1). In the intestine, bile acids activate FXR to induce fibroblast growth factor (mouse FGF15, or human FGF19), which activates hepatic FGF receptor 4 (FGFR4) and cJun N-terminal kinase 1/2 (JNK1/2) and extracellular-regulated kinase (ERK1/2) signaling of mitogen-activated protein kinase (MAPK) pathways to inhibit trans-activation of CYP7A1/CYP8B1 gene by HNF4α (Pathway 2). Several FXR-independent cell-signaling pathways have been reported and are shown as Pathway 3 (Fig. 2). Conjugated bile acids are known to activate several protein kinase Cs (PKC) and growth factor receptors, epidermal growth factor receptor (EGFR), and insulin receptor (IR) signaling to inhibit CYP7A1/CYP8B1 and bile acid synthesis via activating the ERK1/2, p38 and JNK1/2 pathways.

 

Bile acid signaling pathways. Bile acids activate FXR, TGR5 and cell signaling pathways to inhibit CYP7A1 and CYP8B1 gene transcription.

1) Hepatic FXR/SHP pathway: bile acid activated-FXR induces SHP, which inhibits HNF4α and LRH-1 trans-activation of CYP7A1 and CYP8B1 gene transcription in hepatocytes. Bile acid response element binds HNF4α and LRH-1.

2) Intestinal FXR/FGF19/FGFR4 pathway: in the intestine, FXR induces FGF15 (mouse)/FGF19 (human), which is secreted into portal circulation to activate FGF receptor 4 (FGFR4) in hepatocytes. FGFR4 signaling stimulates JNK1/2 and ERK1/2 pathways of MAPK signaling to inhibit CYP7A1 gene transcription by phosphorylation and inhibition of HNF4α binding activity.

3) FXR-independent signaling pathways: Conjugated bile acids activate PKCs,which activate the MAPK pathways to inhibit CYP7A1. Bile acids also activate insulin receptor (IR) signaling IRS/PI3K/PDK1/AKT, possibly via activation of epidermal growth factor receptor (EGFR) signaling, MAPKs (MEK, MEKK), to inhibit CYP7A1 gene transcription. The secondary bile acid TLCA activates TGR5 signaling in Kupffer cells. TGR5 signaling may regulate CYP7A1 by an unknown mechanism. TCA activates sphingosine-1-phosphate (S1P) receptor 2 (S1PR2), which may activate AKT and ERK1/2 to inhibit CYP7A1. S1P kinase 1 (Sphk1) phosphorylates sphingosine (Sph) to S-1-P, which activates S1PR2. On the other hand, nuclear SphK2 interacts with and inhibits histone deacetylase (HDAC1/2) and may induce CYP7A1. The role of S1P, SphK2, and S1PR2 signaling in regulation of bile acid synthesis is not known.

 

When challenged with an HFD, CYP7A1-tg mice had lower body fat mass and higher lean mass compared to wild-type mice. As a platform for comprehensive and quantitative description of the set of lipid species, lipidomics was used to investigate the mechanism of this phenotype. By use of an unsupervised PCA model with the cumulative R2X 0.677 for serum and 0.593 for liver, CYP7A1-tg and wild-type mice were clearly separated based on the scores plot (Supplementary Fig. S2), indicating that these two groups have distinct lipidomic profiles. Supervised PLS-DA models were then established to maximize the difference of metabolic profiles between CYP7A1-tg and wild-type groups as well as to facilitate the screening of lipid marker metabolites (Fig. 3).

PLS-DA analysis of CYP7A1-tg and wild-type (WT)mice challenged with HFD. Based on the score plots, distinct lipidomic profiles of male CYP7A1-tg and wild-type groups were shown for serum (A) and liver samples (B). Based on the loading plots (C for serum and D for liver) the most significant ions that led to the separation between CYP7A1-tg and wild-type groups were obtained and identified as follows: 1. LPC16:0; 2. LPC18:0; 3. LPC18:1; 4. LPC 18:2; 5. PC16:0-20:4; 6. PC16:0-22:6; 7. SM16:0. (not shown)

Fig. 5. OPLS-DA highlighted thirteen markers in bile acid pathway that contribute significantly to the clustering of CYP7A1-tg and wild-type (WT) mice. Ileum bile acids are shown. (not shown)

(A) In the score plot, female CYP7A1-tg andWTmicewere well separated;

(B) using a statistically significant thresholds of variable confidence approximately 0.75 in the S-plot, a number of ions were screened out as potential markers, which were later identified as 13 bile acid metabolites, including α-MCA, TCA, CDCA, and TCDCA etc.

Our recent study of CYP7A1-tg mice revealed that increased CYP7A1 expression and enlarged bile acid pool resulted in significant improvement of lipid homeostasis and resistance to high-fed diet-induced hepatic steatosis, insulin resistance, and obesity in CYP7A1-tg mice. In this study, metabolomics and lipidomics were employed to characterize the metabolic profiles of CYP7A1-tg mice and to provide new insights into the critical role of bile acids in regulation of lipid metabolism and metabolic diseases. Lipidomics analysis of serum lipid profiles of high fat diet-fed CYP7A1-tg identified 7 lipidomic markers that were reduced in CYP7A1-tg mice compared to wild type mice. Metabolomics analysis identified 13 bile acid metabolites that were altered in CYP7A1-tg mice. In CYP7A1-tg mice, TCA and TDCA were reduced, whereas T-β-MCA was increased in the intestine compared to that of wild type mice. The decrease of serum LPC, PC, SM and CER, and 12α-hydroxylated bile acids, and increase of T-β-MCA may contribute to the resistance to diet-induced obesity and diabetes in CYP7A1-tg mice (Fig. 8).

The present metabolomics and lipidomics analysis revealed that even upon challenging with HFD, CYP7A1-tg mice had reduced lipid levels including LPC, PC, SM and CER. Metabolomics studies of human steatotic liver tissues and HFD-fed mice showed that serum and liver LPC and PC and other lipids levels were increased compared with non-steatotic livers, suggesting altered lipid metabolism contributes to non-alcoholic fatty liver disease (NAFLD). In HFD-fed CYP7A1-tg mice, reduced serum PC, LPC, SM and CER levels suggest a role for bile acids in maintaining phospholipid homeostasis to prevent NAFLD. SMs are important membrane phospholipids that interact with cholesterol in membrane rafts and regulate cholesterol distribution and homeostasis. A role for SM and CER in the pathogenesis of insulin resistance, diabetes and obesity and development of atherosclerosis has been reported. CER has a wide range of biological functions in cellular signaling such as activating protein kinase C and c-Jun N-terminal kinase (JNK), induction of β-cell apoptosis and insulin resistance. CER increases reactive oxidizing species and activates the NF-κB pathway, which induces proinflammatory cytokines, diabetes and insulin resistance. CER is synthesized from serine and palmitoyl-CoA or hydrolysis of SM by acid sphingomyelinase (ASM). HFD is known to increase CER and SM in liver. The present observation of decreased SM and CER levels in HFD-fed CYP7A1-tg mice indicated that bile acids might reduce HFD-induced increase of SM and CER. DCA activates an ASM to convert SM to CER, and Asm−/− hepatocytes are resistant to DCA induction of CER and activation of the JNK pathway [65]. In CYP7A1-tg mice, enlarged bile acid pool inhibits CYP8B1 and reduces CA and DCA levels. Thus, decreasing DCA may reduce ASM activity and SM and CER levels, and contribute to reducing inflammation and improving insulin sensitivity in CYP7A1-tg mice. It has been reported recently that in diabetic patients, serum 12α-hydroxylated bile acids are increased and correlated to insulin resistance [66].

Fig. 8. Mechanisms of anti-diabetic and anti-obesity function of bile acids in CYP7A1-tg mice. In CYP7A1-tg mice, overexpressing CYP7A1 increases bile acid pool size and reduces cholic acid by inhibiting CYP8B1. Lipidomics analysis revealed decreased serum LPC, PC, SM and CER. These lipidomic markers are increased in hepatic steatosis and NAFLD. Bile acids may reduce LPC, PC, SM and CER levels and protect against high fat diet-induced insulin resistance and obesity in CYP7A1-tgmice. Metabolomics analysis showed decreased intestinal TCA and TDCA and increased intestinal T-β-MCA in CYP7A1-tgmice.High fat diets are known to increase CA synthesis and intestinal inflammation. It is proposed that decreasing CA and  DCA synthesis may increase intestinal T-β-MCA,which antagonizes FXR signaling to increase bile acid synthesis and prevent high fat diet-induced insulin resistance and obesity. (not shown)

In conclusion,metabolomics and lipidomicswere employed to characterize the metabolic profiles of CYP7A1-tg mice, aiming to provide new insights into the mechanism of bile acid signaling in regulation of lipid metabolism and maintain lipid homeostasis. A number of lipid and bile acid markers were unveiled in this study. Decreasing of lipid markers, especially SM and CER may explain the improved insulin sensitivity and obesity in CYP7A1-tg mice. Furthermore, this study uncovered that enlarged bile acid pool size and altered bile acid composition may reduce de-conjugation by gut microbiota and increase tauroconjugated muricholic acids, which partially inhibit intestinal FXR signaling without affecting hepatic FXR signaling. This study is significant in applying metabolomics for diagnosis of lipid biomarkers for fatty liver diseases, obesity and diabetes. Increasing CYP7A1 activity and bile acid synthesis coupled to decreasing CYP8B1 and 12α-hydroxylated bile acids may be a therapeutic strategy for treating diabetes and obesity.

 

Bile acids are nutrient signaling hormones

Huiping Zhou, Phillip B. Hylemon
Steroids 86 (2014) 62–68
http://dx.doi.org/10.1016/j.steroids.2014.04.016

Bile salts play crucial roles in allowing the gastrointestinal system to digest, transport and metabolize nutrients. They function as nutrient signaling hormones by activating specific nuclear receptors (FXR, PXR, Vitamin D) and G-protein coupled receptors [TGR5, sphingosine-1 phosphate receptor 2 (S1PR2), muscarinic receptors]. Bile acids and insulin appear to collaborate in regulating the metabolism of nutrients in the liver. They both activate the AKT and ERK1/2 signaling pathways. Bile acid induction of the FXR-a target gene, small heterodimer partner (SHP), is highly dependent on the activation PKCf, a branch of the insulin signaling pathway. SHP is an important regulator of glucose and lipid metabolism in the liver. One might hypothesize that chronic low grade inflammation which is associated with insulin resistance, may inhibit bile acid signaling and disrupt lipid metabolism. The disruption of these signaling pathways may increase the risk of fatty liver and non-alcoholic fatty liver disease (NAFLD). Finally, conjugated bile acids appear to promote cholangiocarcinoma growth via the activation of S1PR2.

 

In the past, bile salts were considered to be just detergent molecules that were required for the solubilization of cholesterol in the gall bladder, promoting the digestion of dietary lipids and stimulating the absorption of lipids, cholesterol and fat-soluble vitamins in the intestines. Bile salts were also known to stimulate bile flow, promote cholesterol secretion from the liver, and have antibacterial properties. However, in 1999, three independent laboratories reported that bile acids were natural ligands for the farnesoid X receptor (FXR-α) . The recognition that bile acids activated specific nuclear receptors started a renaissance in the field of bile acid research. Since 1999, bile acids have been reported to activate other nuclear receptors (pregnane X receptor, vitamin D receptor), G protein coupled receptors [TGR5, sphingosine-1-phosphate receptor 2 (S1PR2), muscarinic receptor 2 (M2)] and cell signaling pathways (JNK1/2, AKT, and ERK1/2). Deoxycholic acid (DCA), a secondary bile acid, has also been reported to activate the epidermal growth factor receptor (EGFR). It is now clear that bile acids function as hormones or nutrient signaling molecules that help to regulate glucose, lipid, lipoprotein, and energy metabolism as well as inflammatory responses.

Bile acids are synthesized from cholesterol in liver hepatocytes, conjugated to either glycine or taurine and actively secreted via ABC transporters on the canalicular membrane into biliary bile. Conjugated bile acids are often referred to as bile salts. Bile acid synthesis represents a major output pathway of cholesterol from the body. Bile acids are actively secreted from hepatocytes via the bile salt export protein (BSEP, ABCB11) along with phospholipids by ABCB4 and cholesterol by ABCG5/ABCG8 in a fairly constant ratio under normal conditions. Bile acids are detergent molecules and form mixed micelles with cholesterol and phospholipids, which help to keep cholesterol in solution in the gall bladder. Eating stimulates the gall bladder to contract, emptying its contents into the small intestines. Bile salts are crucial for the solubilization and absorption of cholesterol and lipids as well as lipid soluble vitamins (A, D, E, and K). They activate pancreatic enzymes and form mixed micelles with lipids in the small intestines, promoting their absorption. Bile acids are efficiently recovered from the intestines, primarily the ileum, by the apical sodium dependent transporter (ASBT). Bile acids are secreted from ileocytes, on the basolateral side, by the organic solute OSTα/OSTβ transporter. Secondary bile acids, formed by 7α-dehydroxylation of primary bile acids by anaerobic gut bacteria, can be passively absorbed from the large bowel or secreted in the feces. Absorbed bile acids return to the liver via the portal blood where they are actively transported into hepatocytes primarily via the sodium taurocholate cotransporting polypeptide (NTCP, SLC10A1). Bile acids are again actively secreted from the hepatocytes into the bile, stimulating bile flow and the secretion of cholesterol and phospholipids. Bile acids undergo enterohepatic circulation several times each day (Fig. 1). During their enterohepatic circulation approximately 500–600 mg/day are lost via fecal excretion and must be replaced by new bile acid synthesis in the liver. The bile acid pool size is tightly regulated as excess bile acids can be highly toxic to mammalian cells.

Enterohepatic circulation of bile acids

 

Enterohepatic circulation of bile acids. Bile acids are synthesized and conjugated mainly to glycine or taurine in hepatocytes. Bile acids travel to the gall bladder for storage during the fasting state. During digestion, bile acids travel to the duodenum via the common bile duct. 95% of the bile acids delivered to the duodenum are absorbed back into blood within the ileum and circulate back to the liver through the portal vein. 5% of bile acids are lost in feces.

There are two pathways of bile acid synthesis in the liver, the neutral pathway and the acidic pathway (Fig. 2). The neutral pathway is believed to be the major pathway of bile acid synthesis in humans under normal physiological conditions. The neutral pathway is initiated by cholesterol 7α-hydroxylase (CYP7A1), which is the rate-limiting step in this biochemical pathway. CYP7A1 is a cytochrome P450 monooxygenase, and the gene encoding this enzyme is highly regulated by a feed-back repressive mechanism involving the FXR-dependent induction of fibroblast growth factor 15/19 (FGF15/19) by bile acids in the intestines. FGF15/19 binds to the fibroblast growth factor receptor 4 (FGFR4)/β-Klotho complex in hepatocytes activating both the JNK1/2 and ERK1/2 signaling cascades. Activation of the JNK1/2 pathway has been reported to down-regulate CYP7A1 mRNA in hepatocytes. FGFR4 and β-Klotho mice have increased levels of CYP7A1 and upregulated bile acid synthesis. Moreover, treatment of FXR mice with a specific FXR agonist failed to repress CYP7A1 in the liver. These results support an important role of FGF15, synthesized in the intestines by activation of FXR, in the regulation of CYP7A1 and bile acid synthesis in the liver. CYP7A1 has also been reported to be down-regulated by glucagon and pro-inflammatory cytokines and up-regulated by glucose and insulin during the postprandial period.

Fig. 2. (not shown) Biosynthetic pathways of bile acids. Two major pathways are involved in bile acid synthesis. The neutral (or classic) pathway is controlled by cholesterol 7α-hydroxylase (CYP7A1) in the endoplasmic reticulum. The acidic (or alternative) pathway is controlled by sterol 27-hydroxylase (CYP27A1) in mitochondria. The sterol 12α-hydroxylase (CYP8B1) is required to synthesis of cholic acid (CA). The oxysterol 7α-hydroxylase (CYP7B1) is involved in the formation of chenodeoxycholic acid (CDCA) in acidic pathway. The neutral pathway is also able to form CDCA by CYP27A1.

The neutral pathway of bile acid synthesis produces both cholic acid (CA) and chenodeoxycholic acid (CDCA) (Fig. 2). The ratio of CA and CDCA is primarily determined by the activity of sterol 12α-hydroxylase (CYP8B1). The gene encoding CYP8B1 is also highly regulated by bile acids. Bile acids induce the gene encoding small heterodimer partner (SHP) in the liver via activation of the farnesoid X receptor (FXR-α). SHP is an orphan nuclear receptor without a DNA binding domain. It interacts with several transcription factors, including hepatocyte nuclear factor 4 (HNF4α) and liver-related homolog-1 (LRH-1), and acts as a dominant negative protein to inhibit transcription. In this regard, a liver specific knockout of LRH-1 completely abolished the expression of CYP8B1, but had little effect on CYP7A1. These results suggest that the interaction of SHP with LRH-1, caused by bile acids, may be the key regulator of hepatic CYP8B1 and the ratio of CA/CDCA. The acidic or alternative pathway of bile acid synthesis is initiated in the inner membrane of mitochondria by sterol 27-hydroxylase (CYP27A1). This enzyme also has low sterol 25-hydroxylase activity. CYP27A1 is capable of further oxidizing the 27-hydroxy group to a carboxylic acid. Unlike, CYP7A1, CYP27A1 is widely expressed in various tissues in the body where it may produce regulatory oxysterols. Even though CYP27A1 is the initial enzyme in the acidic pathway of bile acid synthesis, it may not be the rate limiting step. The inner mitochondrial membrane is very low in cholesterol content. Hence, cholesterol transport into the mitochondria appears to be the rate limiting step.

The acidic pathway of bile acid synthesis is now being viewed as an important pathway for generating regulatory oxysterols. For example, 25-hydroxy-cholesterol and 27-hydroxycholesterol are natural ligands for the liver X receptor (LXR), which is involved in regulating cholesterol and lipid metabolism. Moreover, recent studies report that 25-hydroxycholesterol, formed by CYP27A1, can be converted into 5-cholesten-3β-25-diol-3-sulfate in the liver. The sulfated 25-hydroxycholesterol is a regulator of inflammatory responses, lipid metabolism and cell proliferation, and is located in the liver. Recent evidence suggests that sulfated 25-hydroxycholesterol is a ligand for peroxisome proliferator-activated receptor gamma (PPARc), which is a major regulator of inflammation and lipid metabolism. The 7α-hydroxylation of oxysterols is catalyzed by oxysterol 7α-hydroxylase (CYP7B1). This biotransformation allows some of these oxysterols to be converted to bile acids. Finally, oxysterols generated in extrahepatic tissues can be transported to the liver and metabolized into bile acids.

Bile acids can activate several different nuclear receptors (FXR, PXR and Vitamin D) and GPCRs (TGR5, S1PR2, and [M2] Muscarinic receptor). The ability of different bile acids to activate FXR-α occurs in the following order CDCA > LCA = DCA > CA; for the pregnane X receptor (PXR) LCA > DCA > CA and the vitamin D receptor, 3-oxo-LCA > LCA > DCA > CA. LCA is the best activator of PXR and the vitamin D receptor which correlates with the hydrophobicity and toxicity of this bile acid toward mammalian cells. Activation of PXR and the vitamin D receptor induces genes encoding enzymes which metabolize LCA into a more hydrophilic and less toxic metabolite. These nuclear receptors appear to function in the protection of cells from hydrophobic bile acids. In contrast, FXR-α appears to play a much more extensive role in the body by regulating bile acid synthesis, transport, and enterohepatic circulation. Moreover, FXR-α also participates in the regulation of glucose, lipoprotein and lipid metabolism in the liver as well as a suppressor of inflammation in the liver and intestines.

TGR5, also referred to as membrane-type bile acid receptor (MBAR), was the first GPCR to be reported to be activated by bile acids in the order LCA > DCA > CDCA > CA. TGR5 is a Gas type receptor which activates adenyl cyclase activity increasing the rate of the synthesis of c-AMP. TGR5 is widely expressed in human tissues, including: intestinal neuroendocrine cells, gall bladder, spleen, brown adipose tissue, macrophages and cholangiocytes, but not hepatocytes. TGR5 may play a role in various physiological processes in the body. TGR5 appears to be important in regulating energy metabolism. It has been postulated that bile acids may activate TGR5 in brown adipose tissue, activating type 2-iodothyroxine deiodinase and leading to increased levels of thyroid hormone and stimulation of energy metabolism. Moreover, TGR5 has been reported to promote the release of glucagon-like peptide-1 release from neuroendocrine cells, which increases insulin release in the pancreas. These results suggest that TGR5 may play a role in glucose homeostasis in the body. TGR5 is a potential target for drug development for treating type 2 diabetes and other metabolic disorders.

Interrelationship between sphingosine 1-phosphate receptor 2 and the insulin signaling pathway

 

Interrelationship between sphingosine 1-phosphate receptor 2 and the insulin signaling pathway in regulating hepatic nutrient metabolism. S1PR2, sphingosine 1-phosphate receptor 2; Src, Src Kinase; EGFR, epidermal growth factor receptor; PPARa, peroxisome proliferator-activated receptor alpha; NTCP, Na+/taurocholate cotransporting polypeptide; BSEP, bile salt export pump; PC, phosphotidylcholine; PECK, phosphoenolpyruvate carboxykinase; G6Pase, glucose-6-phosphatase; PDK1, phosphoinositide-dependent protein kinase 1; AKT, protein kinase B; SREBP, sterol regulatory element-binding protein; PKCf, protein kinase C zeta; FXR, farnesoid X receptor; SHP, small heterodimeric partner; MDR3, phospholipid transporter (ABCB4); GSK3b, glycogen synthase kinase 3 beta.

 

Both unconjugated and conjugated bile acids activate the insulin signaling (AKT) and ERK1/2 pathways in hepatocytes. Interesting, insulin and bile acids both activated glycogen synthase activity to a similar extent in primary rat hepatocytes. Moreover, the addition of both insulin and bile acids to the culture medium resulted in an additive effect on activation of glycogen synthase activity in primary hepatocytes. Infusion of taurocholate (TCA) into the chronic bile fistula rat rapidly activated the AKT and ERK1/2 signaling pathway and glycogen synthase activity. In addition, there was a rapid down-regulation of the gluconeogenic genes, PEP carboxykinase (PEPCK) and glucose-6-phophatase (G-6-Pase) and a marked up-regulation of SHP mRNA in these sample livers. These results suggest that TCA functions much like insulin to regulate hepatic glucose metabolism both in vitro and in vivo.

It has been reported that PKCζ phosphorylates FXR-α and may allow for its activation of target gene expression. In contrast, phosphorylation of FXR-α by AMPK inhibits the ability of FXR to induce target genes. PKCζ has been reported to be important for the translocation of the bile acid transporters NTCP (SLC10A1) and BSEP (ABC B11) to the basolateral and canalicular membranes, respectively. Finally, it has been recently reported that PKCζ phosphorylates SHP allowing both to translocate to the nucleus and down-regulate genes via epigenetic mechanisms. In total, these results all suggest that the insulin signaling pathway is an important regulator of FXR-α activation and bile acid signaling in the liver.

The activation of the insulin signaling pathway and FXR-α appear to collaborate in the coordinate regulation of glucose, bile acid and lipid metabolism in the liver. SHP, an FXR target gene, is an important pleotropic regulator of multiple metabolic pathways in the liver (Fig. 3). The S1PR2 appears to be an important regulator of hepatic lipid metabolism as S1PR2 mice rapidly (2 weeks) develop overt fatty livers on a high fat diet as compared to wild type mice (unpublished data). It is well established that inflammation and the synthesis of inflammatory cytokines i.e. TNFα inhibit insulin signaling by activation of the JNK1/2 signaling pathway, which phosphorylates insulin receptor substrate 1. Inflammation is believed to be an important factor in the development of type 2 diabetes and fatty liver disease. A Western diet is correlated with low grade chronic inflammation and insulin resistance. Inhibition of the insulin signaling pathway may decrease the ability of bile acids to activate FXR-α, induce SHP and other FXR target genes, leading to an increased risk of fatty liver and non-alcoholic fatty liver disease (NAFLD).

There appears to be extensive interplay between bile salts and insulin signaling in the regulation of nutrient metabolism in both the intestines and liver. Bile salts play a key role in the solubilization and absorption of nutrients from the intestines. The absorption of nutrients stimulates the secretion of insulin from the pancreas. Moreover, bile acids may also stimulate the secretion of insulin by activating TGR5 in intestinal neuroendocrine cells resulting in the secretion of glucagon-like peptide-1. In the liver, bile salts and insulin both activate the AKT and ERK1/2 signaling pathways which yields a stronger signal than either alone. The activation of PKCζ, a branch of the insulin signaling pathway, is required for the optimal induction of FXR target genes and the regulation of the cellular location of bile acid transporters

 

Fruit and vegetable consumption and risk of type 2 diabetes mellitus: A dose-response meta-analysis of prospective cohort studies

  1. Wu, D. Zhang, X. Jiang, W. Jiang
    Nutrition, Metabolism & Cardiovascular Diseases (2015) 25, 140-147
    http://dx.doi.org/10.1016/j.numecd.2014.10.004

Background and aims: We conducted a dose-response meta-analysis to summarize the evidence from prospective cohort studies regarding the association of fruit and vegetable consumption with risk of type 2 diabetes mellitus (T2DM). Methods and results: Pertinent studies were identified by searching Embase and PubMed through June 2014. Study-specific results were pooled using a random-effect model. The dose-response relationship was assessed by the restricted cubic spline model and the multivariate random-effect meta-regression. We standardized all data using a standard portion size of 106 g. The Relative Risk (95% confidence interval) [RR (95% CI)] of T2DM was 0.99 (0.98-1.00) for every 1 serving/day increment in fruit and vegetable (FV) (P < 0.18), 0.98 (0.95-1.01) for vegetable (P < 0.12), and 0.99 (0.97-1.00) for fruit (P < 0.05). The RR (95%CI) of T2DM was 0.99 (0.97-1.01), 0.98 (0.96-1.01), 0.97 (0.93-1.01), 0.96 (0.92-1.01), 0.96 (0.91-1.01) and 0.96 (0.91-1.01) for 1, 2, 3, 4, 5 and 6 servings/day of FV (P for non-linearity < 0.44). The T2DM risk was 0.96 (0.95-0.99), 0.94 (0.90-0.98), 0.94 (0.89-0.98), 0.96 (0.91-1.01), 0.98 (0.92-1.05) and 1.00 (0.93-1.08) for 1, 2, 3, 4, 5 and 6 servings/day of vegetable (P for non-linearity < 0.01). The T2DM risk was 0.95 (0.93-0.97), 0.91 (0.89-0.94), 0.88 (0.85-0.92), 0.92 (0.88-0.96) and 0.96 (0.92-1.01) for 0.5, 1, 2, 3 and 4 servings/day of fruit (P for non-linearity < 0.01). Conclusions: Two-three servings/day of vegetable and 2 servings/day of fruit conferred a lower risk of T2DM than other levels of vegetable and fruit consumption, respectively.

dose-response analysis between total fruit and vegetable consumption and risk of type 2 diabetes mellitus

 

The dose-response analysis between total fruit and vegetable consumption and risk of type 2 diabetes mellitus. The solid line and the long dash line represent the estimated relative risk and its 95% confidence interval.

 

Healthy behaviours and 10-year incidence of diabetes: A population cohort study

G.H. Long , I. Johansson , O. Rolandsson , …, E. Fhärm, L.Weinehall, et al.
Preventive Medicine 71 (2015) 121–127
http://dx.doi.org/10.1016/j.ypmed.2014.12.013

Objective. To examine the association between meeting behavioral goals and diabetes incidence over 10 years in a large, representative Swedish population. Methods. Population-based prospective cohort study of 32,120 individuals aged 35 to 55 years participating in a health promotion intervention in Västerbotten County, Sweden (1990 to 2013). Participants underwent an oral glucose tolerance test, clinical measures, and completed diet and activity questionnaires. Poisson regression quantified the association between achieving six behavioral goals at baseline – body mass index (BMI) < 25 kg/m2, moderate physical activity, non-smoker, fat intake  < 30% of energy, fibre intake ≥15 g/4184 kJ and alcohol intake ≤ 20 g/day – and diabetes incidence over 10 years. Results. Median interquartile range (IQR) follow-up time was 9.9 (0.3) years; 2211 individuals (7%) developed diabetes. Only 4.4% of participants met all 6 goals (n = 1245) and compared to these individuals, participants meeting 0/1 goals had a 3.74 times higher diabetes incidence (95% confidence interval (CI) = 2.50 to 5.59), adjusting for sex, age, calendar period, education, family history of diabetes, history of myocardial infarction and long-term illness. If everyone achieved at least four behavioral goals, 14.1% (95% CI: 11.7 to 16.5%) of incident diabetes cases might be avoided. Conclusion. Interventions promoting the achievement of behavioral goals in the general population could significantly reduce diabetes incidence.

 

Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): A population based study

Shira Zelber-Sagi, Dorit Nitzan-Kaluski, Rebecca Goldsmith, et al.
Journal of Hepatology 47 (2007) 711–717
http://dx.doi.org:/10.1016/j.jhep.2007.06.020

Background/Aims: Weight loss is considered therapeutic for patients with NAFLD. However, there is no epidemiological evidence that dietary habits are associated with NAFLD. Dietary patterns associated with primary NAFLD were investigated. Methods: A cross-sectional study of a sub-sample (n = 375) of the Israeli National Health and Nutrition Survey. Exclusion criteria were any known etiology for secondary NAFLD. Participants underwent an abdominal ultrasound, biochemical tests, dietary and anthropometric evaluations. A semi-quantitative food-frequency questionnaire was administered. Results: After exclusion, 349 volunteers (52.7% male, mean age 50.7 ± 10.4, 30.9% primary NAFLD) were included. The NAFLD group consumed almost twice the amount of soft drinks (P = 0.03) and 27% more meat (P < 0.001). In contrast, the NAFLD group consumed somewhat less fish rich in omega-3 (P = 0.056). Adjusting for age, gender, BMI and total calories, intake of soft drinks and meat was significantly associated with an increased risk for NAFLD (OR = 1.45, 1.13–1.85 95% CI and OR = 1.37, 1.04–1.83 95% CI, respectively). Conclusions: NAFLD patients have a higher intake of soft drinks and meat and a tendency towards a lower intake of fish rich in omega-3. Moreover, a higher intake of soft drinks and meat is associated with an increased risk of NAFLD, independently of age, gender, BMI and total calories.

 

The association between types of eating behavior and dispositional mindfulness in adults with diabetes. Results from Diabetes MILES. The Netherlands

Sanne R. Tak, Christel Hendrieckx, Giesje Nefs, Ivan Nyklícek, et al.
Appetite 87 (2015) 288–295
http://dx.doi.org/10.1016/j.appet.2015.01.006

Although healthy food choices are important in the management of diabetes, making dietary adaptations is often challenging. Previous research has shown that people with type 2 diabetes are less likely to benefit from dietary advice if they tend to eat in response to emotions or external cues. Since high levels of dispositional mindfulness have been associated with greater awareness of healthy dietary practices in students and in the general population, it is relevant to study the association between dispositional mindfulness and eating behavior in people with type 1 or 2 diabetes. We analyzed data from Diabetes MILES – The Netherlands, a national observational survey in which 634 adults with type 1 or 2 diabetes completed the Dutch Eating Behavior Questionnaire (to assess restrained, external and emotional eating behavior) and the Five Facet Mindfulness Questionnaire-Short Form (to assess dispositional mindfulness), in addition to other psychosocial measures. After controlling for potential confounders, including  demographics, clinical variables and emotional distress, hierarchical linear regression analyses showed that higher levels of dispositional mindfulness were associated with eating behaviors that were more restrained (β = 0.10) and less external (β = −0.11) and emotional (β = −0.20). The mindfulness subscale ‘acting with awareness’ was the strongest predictor of both external and emotional eating behavior, whereas for emotional eating, ‘describing’ and ‘being non-judgmental’ were also predictive. These findings suggest that there is an association between dispositional mindfulness and eating behavior in adults with type 1 or 2 diabetes. Since mindfulness interventions increase levels of dispositional mindfulness, future studies could examine if these interventions are also effective in helping people with diabetes to reduce emotional or external eating behavior, and to improve the quality of their diet.

 

Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome

Ali Abid, Ola Taha, William Nseir, Raymond Farah, Maria Grosovski, Nimer Assy
Journal of Hepatology 51 (2009) 918–924
http://dx.doi.org:/10.1016/j.jhep.2009.05.033

Background/Aims: The independent role of soft drink consumption in non-alcoholic fatty liver disease (NAFLD) patients remains unclear. We aimed to assess the association between consumption of soft drinks and fatty liver in patients with or without metabolic syndrome. Methods: We recruited 31 patients (age: 43 ± 12 years) with NAFLD and risk factors for metabolic syndrome, 29 patients with NAFLD and without risk factors for metabolic syndrome, and 30 gender- and age-matched individuals without NAFLD. The degree of fatty infiltration was measured by ultrasound. Data on physical activity and intake of food and soft drinks were collected during two 7-day periods over 6 months using a food questionnaire. Insulin resistance, inflammation, and oxidant–antioxidant markers were measured.
Results: We found that 80% of patients with NAFLD had excessive intake of  soft drink beverages (>500 cm3/day) compared to 17% of healthy controls (p < 0.001). The NAFLD group consumed five times more carbohydrates from soft drinks compared to healthy controls (40% vs. 8%, p < 0.001). Seven percent of patients consumed one soft drink per day, 55% consumed two or three soft drinks per day, and 38% consumed more than four soft drinks per day for most days and for the 6-month period. The most common soft drinks were Coca-Cola (regular: 32%; diet: 21%) followed by fruit juices (47%). Patients with NAFLD with metabolic syndrome had similar malonyldialdehyde, paraoxonase, and C-reactive protein (CRP) levels but higher homeostasis model assessment (HOMA) and higher ferritin than NAFLD patients without metabolic syndrome (HOMA: 8.3 ± 8 vs. 3.7 ± 3.7 mg/dL, p < 0.001; ferritin: 186 ± 192 vs. 87 ± 84 mg/dL, p < 0.01). Logistic regression analysis showed that soft drink consumption is a strong predictor of fatty liver (odds ratio: 2.0; p < 0.04) independent of metabolic syndrome and CRP level. Conclusions: NAFLD patients display higher soft drink consumption independent of metabolic syndrome diagnosis. These findings might optimize NAFLD risk stratification.

 

Dietary predictors of arterial stiffness in a cohort with type 1 and type 2 diabetes

K.S. Petersen, J.B. Keogh, P.J. Meikle, M.L. Garg, P.M. Clifton
Atherosclerosis 238 (2015) 175-181
http://dx.doi.org/10.1016/j.atherosclerosis.2014.12.012

Objective: To determine the dietary predictors of central blood pressure, augmentation index and pulse wave velocity (PWV) in subjects with type 1 and type 2 diabetes. Methods: Participants were diagnosed with type 1 or type 2 diabetes and had PWV and/or pulse wave analysis performed. Dietary intake was measured using the Dietary Questionnaire for Epidemiological Studies Version 2 Food Frequency Questionnaire. Serum lipid species and carotenoids were measured, using liquid chromatography electrospray ionization- tandem mass spectrometry and high performance liquid chromatography, as biomarkers  of dairy and vegetable intake, respectively. Associations were determined using linear regression adjusted for potential confounders. Results: PWV (n = 95) was inversely associated with reduced fat dairy intake (β = -0.01; 95% CI -0.02, -0.01; p = 0 < 0.05) in particular yoghurt consumption (β = 0.04; 95% CI -0.09, -0.01; p = 0 < 0.05) after multivariate adjustment. Total vegetable consumption was negatively associated with PWV in the whole cohort after full adjustment (β =0.04; 95% CI -0.07, -0.01; p < 0.05). Individual lipid species, particularly those containing 14:0, 15:0, 16:0, 17:0 and 17:1 fatty acids, known to be of ruminant origin, in lysophosphatidylcholine, cholesterol ester, diacylglycerol, phosphatidylcholine, sphingomyelin and triacylglycerol classes were positively associated with intake of full fat dairy, after adjustment for multiple comparisons. However, there was no association between serum lipid species and PWV. There were no dietary predictors of central blood pressure or augmentation index after multivariate adjustment. Conclusion: In this cohort of subjects with diabetes reduced fat dairy intake and vegetable consumption were inversely associated with PWV. The lack of a relationship between serum lipid species and PWV suggests that the fatty acid composition of dairy may not explain the beneficial effect.

In this cohort with type 1 and type 2 diabetes there was an inverse association between reduced fat dairy intake, in particular yoghurt consumption, and PWV, which persisted after multivariate adjustment. Serum lipid species, known to be of ruminant origin, were positively associated with full fat dairy consumption; however there was no association between these lipid species and PWV. In addition, higher vegetable intake was also associated with lower PWV. There were no dietary predictors of central blood pressure or augmentation index identified in this cohort.

In this study there was no relationship between augmentation index and PWV, which has been previously reported. Augmentation index is not a direct measure of arterial stiffness and is influenced by the timing and magnitude of the wave reflection. In contrast, PWV is a robust measure of arterial stiffness as it is determined by measuring the velocity of the waveform between the carotid and femoral arteries. Previously, it has been shown that in a population with diabetes PWV was elevated compared with healthy controls, however augmentation index was not different. Lacy et al.  concluded that augmentation index is not a reliable measure of arterial stiffness in people with diabetes. This may explain why we did not see an association between augmentation index and dietary intake, despite seeing correlations with PWV.

 

Curcumin ameliorates diabetic nephropathy by inhibiting the activation of the SphK1-S1P signaling pathway

Juan Huang, Kaipeng Huang, Tian Lan, Xi Xie, .., Peiqing Liu, Heqing Huang
Molecular and Cellular Endocrinology 365 (2013) 231–240
http://dx.doi.org/10.1016/j.mce.2012.10.024

Curcumin, a major polyphenol from the golden spice Curcuma longa commonly known as turmeric, has been recently discovered to have renoprotective effects on diabetic nephropathy (DN). However, the mechanisms underlying these effects remain unclear. We previously demonstrated that the sphingosine kinase 1-sphingosine 1-phosphate (SphK1-S1P) signaling pathway plays a pivotal role in the pathogenesis of DN. This study aims to investigate whether the renoprotective effects of curcumin on DN are associated with its inhibitory effects on the SphK1-S1P signaling pathway. Our results demonstrated that the expression and activity of SphK1 and the production of S1P were significantly down-regulated by curcumin in diabetic rat kidneys and glomerular mesangial cells (GMCs) exposed to high glucose (HG). Simultaneously, SphK1-S1P-mediated fibronectin (FN) and transforming growth factor-beta 1 (TGF-b1) overproduction were inhibited. In addition, curcumin dose dependently reduced SphK1 expression and activity in GMCs transfected with SphKWT and significantly suppressed the increase in SphK1-mediated FN levels. Furthermore, curcumin inhibited the DNA-binding activity of activator protein 1 (AP-1), and c-Jun small interference RNA (c-Jun-siRNA) reversed the HG-induced up-regulation of SphK1. These findings suggested that down-regulation of the SphK1-S1P pathway is probably a novel mechanism by which curcumin improves the progression of DN. Inhibiting AP-1 activation is one of the therapeutic targets of curcumin to modulate the SphK1-S1P signaling pathway, thereby preventing diabetic renal fibrosis.

The creation of the STZ-induced DN model relies on the level and continuous cycle of high blood glucose in vivo. Long-term hyperglycemia induces significant structural changes in the kidney, including glomerular hypertrophy, GBM thickening, and later glomerulosclerosis and tubulointerstitial fibrosis, leading to microalbuminuria and elevated Cr levels. These effects usually occur at around 8–12 weeks after diabetes formation. In the current study, the experimental diabetic model was induced by a single intraperitoneal injection of STZ (60 mg/kg). When the experiment was terminated at 12 weeks, FBG, KW/BW, BUN, Cr, and UP 24 h were significantly increased and body weight was remarkably decreased in the STZ-induced diabetic rats compared with those in the normal control group. Furthermore, PAS staining of the kidneys revealed the induction of glomerular hypertrophy, mesangial matrix expansion, and increased regional adhesion of the glomerular tuft to the Bowman’s capsule in the diabetic rats. This finding indicated the emergence of the diabetic renal injury model characterized by renal hypertrophy, glomerulus damage, and renal dysfunction. As the limited water solubility of curcumin, various methods such as heat treatment, mild alkali and sodium carboxymethyl cellulose are used to increase the solubility of curcumin before administration. Based on our previous study, we employed 1% sodium carboxymethyl cellulose as the vehicle to solubilize curcumin. Compared with the diabetic group, curcumin treatment slightly reduced FBG level and significantly decreased KW/BW, BUN, Cr, and UP 24 h. Moreover, curcumin remarkably improved glomerular pathological changes in the diabetic kidneys. Consistent with previous studies, the current results demonstrated that curcumin prominently ameliorated renal function and renal parenchymal alterations in the diabetic renal injury model. Previous studies revealed that the amelioration of renal dysfunction in diabetes by curcumin was partly related to its function in inhibiting inflammatory injury. Based on these findings, the current experiment further explored whether the renoprotective effects of curcumin are associated with the regulation of the SphK1-S1P signaling pathway.

S1P is a polar sphingolipid metabolite acting as an extracellular mediator and an intracellular second messenger. Ample evidence proves that S1P participates in cell growth, proliferation, migration, adhesion, molecule expression, and angiogenesis. The formation of S1P is catalyzed by SphK1. Recently, the SphK1-S1P signaling pathway has gained considerable attention because of its potential involvement in the progression of DN. Hyperglycemia, AGE, and oxidative stress can activate SphK1 and can increase the intracellular level of S1P. Geoffroy et al. (2004) reported that the treatment of cells with low AGE concentration increases SphK activity and S1P production, thereby and S1P content were significantly increased simultaneously with the up-regulated expression of FN and TGF-β1 (mRNA and protein) in the diabetic rat kidneys. These findings indicated the activation of the SphK1-S1P signaling pathway and the appearance of pathological alterations, including ECM accumulation. After curcumin treatment for 12 weeks, elevations of the said indexes were significantly inhibited. HG remarkably activated the SphK1-S1P signaling pathway and increased FN and TGF-β1 expressions in GMCs. Curcumin dramatically suppressed the SphK1-S1P pathway as well as FN and TGF-β1 levels in a dose-dependent manner. Overall, these results indicated that curcumin ameliorated the pathogenic progression of DN by inhibiting the activation of the SphK1-S1P signaling pathway, resulting in the down-regulation of TGF-β1 and the subsequent reduction of ECM accumulation.

SphK1 expression is mediated by a novel AP-1 element located within the first intron of the human SphK1 gene. AP-1 sites are also found in rat SphK1 promoter from NCBI. Numerous studies indicated that curcumin can inhibit the activity of AP-1 and is widely used as an AP-1 inhibitor. Therefore, further elucidating the link between the inhibition of the SphK1-S1P signaling pathway by curcumin and the suppression of AP-1 activity is important. The data showed that treatment with c-Jun-siRNA significantly down-regulated the basal levels of SphK1 expression. Thus, inhibiting AP-1 activity is one of the therapeutic targets of curcumin in modulating the SphK1-S1P signaling pathway, thereby inhibiting diabetic renal fibrosis.

In summary, curcumin inhibited SphK1 expression and activity, reduced S1P content, and effectively inhibited increased FN and TGF-β1 expressions mediated by the SphK1-S1P signaling pathway. Moreover, the inhibitory effect of curcumin on SphK1-S1P was independent of its hypoglycemic and anti-oxidant roles and might be closely related to the inhibition of AP-1 activity. Our findings suggested that the SphK1-S1P pathway might be a novel mechanism by which curcumin attenuates renal fibrosis and ameliorates DN. In addition, the present study provides further experimental evidence for the clinical application and new drug exploration of curcumin.

 

Antidiabetic Activity of Hydroalcoholic Extracts of Nardostachys jatamansi in Alloxan-induced Diabetic Rats

  1. A. Aleem, B. Syed Asad, Tasneem Mohammed, et al.
    British Journal of Medicine & Medical Research 4(28): 4665-4673, 2014

A review of literature indicates that diabetes mellitus was fairly well known and well conceived as an entity in India with complications like angiopathy, retinopathy, nephropathy, and causing neurological disorders. The antidiabetic study was carried out to estimate the anti-hyperglycemic potential of Nardostachys Jatamansi rhizome’s hydroalcoholic extracts in alloxan induced diabetic rats over a period of two weeks. The hydroalcoholic extract HAE1 at a dose (500mg/kg) exhibited significant antihyperglycemic activity than extract HAE2 at a dose (500mg/kg) in diabetic rats. The hydroalcoholic extracts showed improvement in different parameters associated with diabetes, like body weight, lipid profile and biochemical parameters. Extracts also showed improvement in regeneration of β-cells of pancreas in diabetic rats. Histopath-ological studies strengthen the healing of pancreas by hydroalcoholic extracts (HAE1& HAE2) of Nardostachys Jatamansi, as a probable mechanism of their antidiabetic activity.
Metabolic syndrome and serum carotenoids : findings of a cross-sectional study in Queensland, Australia

Coyne, T, Ibiebele, T,… McClintock, C and Shaw, J
Brit J Nutrition: Int J Nutr Sci 2009; 102(11). pp. 1668-1677
Several components of the metabolic syndrome, particularly diabetes and cardiovascular disease, are known to be oxidative stress-related conditions and there is research to suggest that antioxidant nutrients may play a protective role in these conditions. Carotenoids are compounds derived primarily from plants and several have been shown to be potent antioxidant nutrients. The aim of this study was to examine the associations between metabolic syndrome status and major serum carotenoids in adult Australians. Data on the presence of the metabolic syndrome, based on International Diabetes Federation criteria, were collected from 1523 adults aged 25 years and over in six randomly selected urban centers in Queensland, Australia, using a cross sectional study design. Weight, height, BMI, waist circumference, blood  pressure, fasting and 2-hour blood glucose and  lipids were determined, as well as five serum carotenoids. Mean serum alpha-carotene, beta-carotene and the sum of the five carotenoid concentrations were significantly lower (p<0.05) in persons with the metabolic syndrome (after adjusting for age, sex, education, BMI status, alcohol intake, smoking, physical activity status and vitamin/mineral use) than persons without the syndrome. Alpha, beta and total carotenoids also decreased significantly (p<0.05) with increased number of components of the metabolic syndrome, after adjusting for these confounders. These differences were significant among former smokers and non-smokers, but not in current smokers. Low concentrations of serum alpha-carotene, beta carotene and the sum of five carotenoids appear to be associated with metabolic syndrome status. Additional research, particularly longitudinal studies, may help to determine if these associations are causally related to the metabolic syndrome, or are a result of the pathologies of the syndrome.

Although there is no universal definition of the metabolic syndrome, it is generally described as a constellation of pathologies or anthropometric conditions, which include central obesity, glucose intolerance, lipid abnormalities, and hypertension. It is, however, universally accepted that the presence of the metabolic syndrome is associated with increased risk of type 2 diabetes and cardiovascular disease. The prevalence of the metabolic syndrome in developed countries varies widely depending upon definitions used and age ranges included, but is estimated to be 24% among adults 20 years and over in the US. Given the impending worldwide epidemic of obesity, diabetes and cardiovascular disease, strategies aimed at greater understanding of the pathology of the syndrome, as well as strategies aimed at preventing or treating persons with the syndrome are urgently required.

Few studies have investigated associations of antioxidant nutrients and the metabolic syndrome. Ford and colleagues reported lower levels of several carotenoids and vitamins C and E among those with metabolic syndrome present compared with those without the syndrome in the Third National Health and Nutrition Examination Survey. Sugiura et al.  suggested that several carotenoids may exert a protective effect against the development of the metabolic syndrome, especially among current smokers. Confirming these findings in another population may add strength to these associations.

Our study showed significantly lower concentrations of β-carotene, α-carotene and the sum of the five carotenoids among those with the metabolic syndrome present compared to those without. We also found decreasing concentrations of all the carotenoids tested as the number of the metabolic syndrome components increased. These findings are consistent with data reported by Ford et al. from the third 262 National Health and Nutrition Examination Survey (NHANES III). In the NHANES III study, significantly lower concentrations of all the carotenoids, except lycopene, were found among persons with the metabolic syndrome compared with those without, after adjusting for  confounding factors similar to those in our study.

 

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