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Archive for the ‘Nutrigenomics’ Category


The Journey of Antibiotic Discovery

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

 

The term ‘antibiotic’ was introduced by Selman Waksman as any small molecule, produced by a microbe, with antagonistic properties on the growth of other microbes. An antibiotic interferes with bacterial survival via a specific mode of action but more importantly, at therapeutic concentrations, it is sufficiently potent to be effective against infection and simultaneously presents minimal toxicity. Infectious diseases have been a challenge throughout the ages. From 1347 to 1350, approximately one-third of Europe’s population perished to Bubonic plague. Advances in sanitary and hygienic conditions sufficed to control further plague outbreaks. However, these persisted as a recurrent public health issue. Likewise, infectious diseases in general remained the leading cause of death up to the early 1900s. The mortality rate shrunk after the commercialization of antibiotics, which given their impact on the fate of mankind, were regarded as a ‘medical miracle’. Moreover, the non-therapeutic application of antibiotics has also greatly affected humanity, for instance those used as livestock growth promoters to increase food production after World War II.

 

Currently, more than 2 million North Americans acquire infections associated with antibiotic resistance every year, resulting in 23,000 deaths. In Europe, nearly 700 thousand cases of antibiotic-resistant infections directly develop into over 33,000 deaths yearly, with an estimated cost over €1.5 billion. Despite a 36% increase in human use of antibiotics from 2000 to 2010, approximately 20% of deaths worldwide are related to infectious diseases today. Future perspectives are no brighter, for instance, a government commissioned study in the United Kingdom estimated 10 million deaths per year from antibiotic resistant infections by 2050.

 

The increase in antibiotic-resistant bacteria, alongside the alarmingly low rate of newly approved antibiotics for clinical usage, we are on the verge of not having effective treatments for many common infectious diseases. Historically, antibiotic discovery has been crucial in outpacing resistance and success is closely related to systematic procedures – platforms – that have catalyzed the antibiotic golden age, namely the Waksman platform, followed by the platforms of semi-synthesis and fully synthetic antibiotics. Said platforms resulted in the major antibiotic classes: aminoglycosides, amphenicols, ansamycins, beta-lactams, lipopeptides, diaminopyrimidines, fosfomycins, imidazoles, macrolides, oxazolidinones, streptogramins, polymyxins, sulphonamides, glycopeptides, quinolones and tetracyclines.

 

The increase in drug-resistant pathogens is a consequence of multiple factors, including but not limited to high rates of antimicrobial prescriptions, antibiotic mismanagement in the form of self-medication or interruption of therapy, and large-scale antibiotic use as growth promotors in livestock farming. For example, 60% of the antibiotics sold to the USA food industry are also used as therapeutics in humans. To further complicate matters, it is estimated that $200 million is required for a molecule to reach commercialization, with the risk of antimicrobial resistance rapidly developing, crippling its clinical application, or on the opposing end, a new antibiotic might be so effective it is only used as a last resort therapeutic, thus not widely commercialized.

 

Besides a more efficient management of antibiotic use, there is a pressing need for new platforms capable of consistently and efficiently delivering new lead substances, which should attend their precursors impressively low rates of success, in today’s increasing drug resistance scenario. Antibiotic Discovery Platforms are aiming to screen large libraries, for instance the reservoir of untapped natural products, which is likely the next antibiotic ‘gold mine’. There is a void between phenotanypic screening (high-throughput) and omics-centered assays (high-information), where some mechanistic and molecular information complements antimicrobial activity, without the laborious and extensive application of various omics assays. The increasing need for antibiotics drives the relentless and continuous research on the foreground of antibiotic discovery. This is likely to expand our knowledge on the biological events underlying infectious diseases and, hopefully, result in better therapeutics that can swing the war on infectious diseases back in our favor.

 

During the genomics era came the target-based platform, mostly considered a failure due to limitations in translating drugs to the clinic. Therefore, cell-based platforms were re-instituted, and are still of the utmost importance in the fight against infectious diseases. Although the antibiotic pipeline is still lackluster, especially of new classes and novel mechanisms of action, in the post-genomic era, there is an increasingly large set of information available on microbial metabolism. The translation of such knowledge into novel platforms will hopefully result in the discovery of new and better therapeutics, which can sway the war on infectious diseases back in our favor.

 

References:

 

https://www.mdpi.com/2079-6382/8/2/45/htm

 

https://www.ncbi.nlm.nih.gov/pubmed/19515346

 

https://www.ajicjournal.org/article/S0196-6553(11)00184-2/fulltext

 

https://www.ncbi.nlm.nih.gov/pubmed/21700626

 

http://www.med.or.jp/english/journal/pdf/2009_02/103_108.pdf

 

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

 

The bacterial makeup of human milk is influenced by the mode of breastfeeding, according to a new study. Although previously considered sterile, breast milk is now known to contain a low abundance of bacteria. While the complexities of how maternal microbiota influence the infant microbiota are still unknown, this complex community of bacteria in breast milk may help to establish the infant gut microbiota. Disruptions in this process could alter the infant microbiota, causing predisposition to chronic diseases such as allergies, asthma, and obesity. While it’s unclear how the breast milk microbiome develops, there are two theories describing its origins. One theory speculates that it originates in the maternal mammary gland, while the other theory suggests that it is due to retrograde inoculation by the infant’s oral microbiome.

 

To address this gap in knowledge scientists carried out bacterial gene sequencing on milk samples from 393 healthy mothers three to four months after giving birth. They used this information to examine how the milk microbiota composition is affected by maternal factors, early life events, breastfeeding practices, and other milk components. Among the many factors analyzed, the mode of breastfeeding (with or without a pump) was the only consistent factor directly associated with the milk microbiota composition. Specifically, indirect breastfeeding was associated with a higher abundance of potential opportunistic pathogens, such as Stenotrophomonas and Pseudomonadaceae. By contrast, direct breastfeeding without a pump was associated with microbes typically found in the mouth, as well as higher overall bacterial richness and diversity. Taken together, the findings suggest that direct breastfeeding facilitates the acquisition of oral microbiota from infants, whereas indirect breastfeeding leads to enrichment with environmental (pump-associated) bacteria.

 

The researchers argued that this study supports the theory that the breast milk microbiome is due to retrograde inoculation. Their findings indicate that the act of pumping and contact with the infant oral microbiome influences the milk microbiome, though they noted more research is needed. In future studies, the researchers will further explore the composition and function of the milk microbiota. In addition to bacteria, they will profile fungi in the milk samples. They also plan to investigate how the milk microbiota influences both the gut microbiota of infants and infant development and health. Specifically, their projects will examine the association of milk microbiota with infant growth, asthma, and allergies. This work could have important implications for microbiota-based strategies for early-life prevention of chronic conditions.

 

References:

 

https://www.genomeweb.com/sequencing/human-breast-milk-microbiome-affected-mode-feeding#.XIOH0igzZPY

 

http://childstudy.ca/2019/02/13/breastmilk-microbiome-linked-to-method-of-feeding/

 

https://gizmodo.com/pumping-breast-milk-changes-its-microbiome-1832568169

 

https://www.sciencedaily.com/releases/2019/02/190213124445.htm

 

https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(19)30049-6

 

https://www.unicef.org.uk/babyfriendly/news-and-research/baby-friendly-research/infant-health-research/epigenetics-microbiome-research/

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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

 

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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

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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

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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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“Minerals in Medicine” –  40 Minerals that are crucial to Human Health and Biomedicine: Exhibit by NIH Clinical Center and The Smithsonian Institution National Museum of Natural History

Reporter: Aviva Lev-Ari, PhD, RN

 

Friday, September 9, 2016

NIH Clinical Center and The Smithsonian Institution partner to launch Minerals in Medicine Exhibition

What

The National Institutes of Health Clinical Center, in partnership with The Smithsonian Institution National Museum of Natural History, will open a special exhibition of more than 40 minerals that are crucial to human health and biomedicine. “Minerals in Medicine” is designed to enthrall and enlighten NIH Clinical Center’s patients, their loved ones, and the NIH community. Media are invited into America’s Research Hospital, the NIH Clinical Center, to experience this unique exhibition during a ribbon cutting ceremony on Monday September 12 at 4pm.

Beyond taking in the minerals’ arresting beauty, spectators can learn about their important role in keeping the human body healthy, and in enabling the creation of life-saving medicines and cutting edge medical equipment that is used in the NIH Clinical Center and healthcare facilities worldwide. The exhibition, which is on an eighteen-month loan from the National Museum of Natural History, includes specimens that were handpicked from the museum’s vast collection by NIH physicians in partnership with Smithsonian Institution geologists. Some of the minerals on display were obtained regionally as they are part of the Maryland and Virginia landscape.

Who

  • John I. Gallin, M.D., Director of the NIH Clinical Center
  • Jeffrey E. Post, Ph.D., Smithsonian Institution National Museum of Natural History, Chair of the Department of Mineral Sciences and Curator of the National Gem and Mineral Collection

When

Monday, September 12, 2016, 4:00 – 5:00 p.m.

Where

NIH Clinical Center (Building 10), 10 Center Drive, Bethesda, MD, 20892; 1st Floor near Admissions

How

RSVP encouraged, but not required, to attend in person. NIH Visitors Map: http://www.ors.od.nih.gov/maps/Pages/NIH-Visitor-Map.aspx

About the NIH Clinical Center: The NIH Clinical Center is the clinical research hospital for the National Institutes of Health. Through clinical research, clinician-investigators translate laboratory discoveries into better treatments, therapies and interventions to improve the nation’s health. More information: http://clinicalcenter.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

SOURCE

https://www.nih.gov/news-events/news-releases/nih-clinical-center-smithsonian-institution-partner-launch-minerals-medicine-exhibition

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Adenosine Receptor Agonist Increases Plasma Homocysteine

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

The Adenosine Receptor Agonist 5’-N-Ethylcarboxamide-Adenosine Increases Mouse Serum Total Homocysteine Levels, Which Is a Risk Factor for Cardiovascular Diseases

Spring Zhou Editor at Scientific Research Publishing

I would like to share this paper with you. Any comments on this article are welcome.

 

An increase in total homocysteine (Hcy) levels (protein-bound and free Hcy in the serum) has been identified as a risk factor for vascular diseases. Hcy is a product of the methionine cycle and is a precursor of glutathione in the transsulfuration pathway. The methionine cycle mainly occurs in the liver, with Hcy being exported out of the liver and subsequently bound to serum proteins. When the non-specific adenosine receptor agonist 5’-N-ethylcarboxamide-adenosine (NECA; 0.1 or 0.3 mg/kg body weight) was intraperitoneally administered to mice that had been fasted for 16 h, total Hcy levels in the serum significantly increased 1 h after its administration. The NECA treatment may have inhibited transsulfuration because glutathione levels were significantly decreased in the liver. After the intraperitoneal administration of a high dose of NECA (0.3 mg/kg body weight), elevations in total Hcy levels in the serum continued for up to 10 h. The mRNA expression of methionine metabolic enzymes in the liver was significantly reduced 6 h after the administration of NECA. NECA-induced elevations in total serum Hcy levels may be maintained in the long term through the attenuated expression of methionine metabolic enzymes.

 

Comments:

  1.  Is level of protein consumption a factor?
  2. Is reliance on plant food products a factor?
  3. What are the levels of transthyretin?
  4. Is there a concomitant decrease in vitamin A or vitamin D?

 

 

The Adenosine Receptor Agonist 5’-N-Ethylcarboxamide-Adenosine Increases Mouse Serum Total Homocysteine Levels, Which Is a Risk Factor for Cardiovascular Diseases

Shigeko Fujimoto Sakata*, Koichi Matsuda, Yoko Horikawa, Yasuto Sasaki     Faculty of Nutrition, Kobe Gakuin University, Kobe, Japan.

http://www.scirp.org/journal/PaperInformation.aspx    DOI: 10.4236/pp.2015.610048

Cite this paper

Sakata, S. , Matsuda, K. , Horikawa, Y. and Sasaki, Y. (2015) The Adenosine Receptor Agonist 5’-N-Ethylcarboxamide-Adenosine Increases Mouse Serum Total Homocysteine Levels, Which Is a Risk Factor for Cardiovascular Diseases. Pharmacology & Pharmacy, 6, 461-470. doi: 10.4236/pp.2015.610048.
An increase in total serum homocysteine levels (total Hcy: serum protein-bound and free Hcy) has been identified as a risk factor for cardiovascular disease [1] [2] and liver fibrosis [3]. The normal range of total Hcy in adults is typically 5 – 15 μM, with the mean level being approximately 10 μM [2]. Plasma Hcy concentrations were previously found to be strongly associated with the presence and number of small infarctions, or infarction of the putamen in elderly diabetic patients [4]. High levels of Hcy have been shown to induce endoplasmic reticulum (ER) stress and increase the production of reactive oxygen species (ROS) [5]. Hcy has strong reducibility and modifies disulfide bonds in proteins. Only 1% to 2% of Hcy occurs as thiol homocysteine in the serum; 75% of Hcy has been suggested to bind to proteins through disulfide bonds with protein cysteines [6]. Hcy is formed as an intermediary in methionine metabolism [7] [8]. Methionine metabolism mainly occurs in the livers of mammals. Methionine receives an adenosine group from ATP to become S-adenosylmethionine (AdoMet) in the methionine cycle. This reaction is catalyzed in the liver by liver-specific methionine adenosyltransferase I/III (MAT I/III), which is encoded by the methionine adenosyltransferase 1A (MAT1A) gene [9]. AdoMet then transfers its methyl group to a large number of compounds, a process that is catalyzed by various methyltransferases (e.g., glycine N-methyltransferase: GNMT; DNA methyltransferase; phosphatidylethanolamine N-methyl- transferase), to produce S-adenosylhomocysteine (AdoHcy). Hcy is formed from AdoHcy by AdoHcy hydrolase (SAHH). The reaction that generates Hcy from AdoHcy is reversible, and AdoHcy from Hcy is shown to be thermodynamically favored over the synthesis of Hcy [10]. A previous study reported that Hcy levels were very low in the liver [11]. This reaction then proceeds toward the synthesis of Hcy when the products (Hcy and adenosine) are removed by further metabolism [12]. Three enzymes metabolize Hcy, with the betaine-homocysteine S-methyltransferase (BHMT) and methionine synthase (MS) reactions both yielding methionine. A large proportion of Hcy in the liver is remethylated by BHMT [3]. The third enzyme, cystathionine β-synthase (CBS) catalyzes Hcy to cystathionine in the transsulfuration pathway. Previous studies of whole body methionine kinetics demonstrated that 62% of Hcy was converted to cystathionine during each cycle in males fed a basal diet, resulting in the production of glutathione (GSH), while 38% of Hcy was remethylated to methionine [13]. Hcy is located at an important regulatory branch point: remethylation to methionine; conversion to cystathionine; export from the cells.
A decrease in intracellular ATP levels, accompanied by the accumulation of 5’-AMP and subsequently adenosine, is known to follow ischemia. Adenosine levels in interstitial fluids were shown to increase 100 – 1000- fold from basal levels (10 – 300 nM) with ischemia [14]. Furthermore, adenosine levels in hepatocytes were increased by a hypoxic challenge, with excess amounts of adenosine being exported out of cells [14]. Adenosine levels were also found to increase 10-fold due to hypoxia, stress, and inflammation [15]. Adenosine has been shown to activate A1, A2a, and A3 receptors with EC50 values in the range of 0.2 – 0.7 μM, and also A2b receptors with an EC50 of 24 μM [16]. A1 and A3 receptors have been classified as adenylate cyclase inhibitory receptors, and A2a and A2b receptors as adenylate cyclase-activating receptors [17]. The activation of adenosine receptors accompanied by ischemia may increase total Hcy levels in the serum because hepatic ischemia is known to decrease the content of GSH and activity of MAT [18].
We previously reported that the non-specific adenosine receptor agonist 5’-N-ethylcarboxamide-adenosine (NECA) increased serum glucose levels and the expression of a glucogenic enzyme (glucose 6-phosphatase) in the liver [19] [20]. Based on the dose of NECA administered in these studies and plasma concentrations after the administration of other adenosine agonists [21], it was inferred that the serum NECA concentration was in the μM range and also that NECA activated adenosine A2b receptors. In the present study, we measured methionine metabolites, including Hcy, in NECA-treated mice in order to determine whether the activation of adenosine receptors increased total Hcy levels in the serum. The results obtained clearly demonstrated that NECA increased total Hcy levels in the serum.
Measurement of Methionine Metabolites AdoMet and AdoHcy levels in the liver were measured using an HPLC method [25] and total GSH in the liver was measured using a microtiter plate assay [26], as described previously [23]. Total Hcy and total cysteine levels (total Cys: free and protein-bound cysteine) in the serum were measured using an HPLC method [27]. Briefly, a mixture of 50 μL of serum, 25 μL of an internal standard, and 25 μL of phosphate-buffered saline (PBS, pH 7.4) was incubated with 10 μL of 100 mg/mL TCEP for 30 min at room temperature in order to reduce and release protein-bound thiols. After this incubation, 90 μL of 100 mg/mL trichloroacetic acid containing 1 mmol/L EDTA was added for deproteinization, centrifuged at 15,000 ×g for 10 min, and 50 μL of the supernatant was added to a tube containing 10 μL of 1.55 mol/L NaOH; 125 μL of 0.125 mol/L borate buffer containing 4 mmol/L EDTA, pH 9.5; and 50 μL of 1 mg/mL SBD-F in the borate buffer. The sample was then incubated for 60 min at 60˚C. HPLC was performed on a Waters M-600 pump equipped with a Waters 2475 Multi λ Fluorescence Detector (385 nm excitation, 515 nm emission). The separation of SBD-derivatized thiols was performed on a μ-BONDASPHERE C18 column (Waters, 5 μm, 100 A, 150 × 3.9 mm) with a 20-μL injection volume and 0.1 mol/L acetate buffer, pH 5.5, containing 30 ml/L methanol as the mobile phase at a flow rate of 1.0 mL/min and column temperature of 29˚C.
3.1. Effects of NECA on Total Hcy and Total Cys Levels in the Serum As shown in Table 1, serum total Hcy and total Cys levels significantly increased after 16 h of fasting. The administration of a low dose of NECA (NECA0.1 group) to mice fasted for 16 h resulted in higher serum total Hcy levels than those in the control group at 1 h (Experiment 1). Serum total Hcy levels were also significantly elevated at 3 h (Experiment 2), but were not significantly different from those in the control group at 6 h (Experiment 3). The administration of a high dose of NECA (NECA0.3 group) resulted in significantly higher serum total Hcy levels than those in the control group at 1 h, 3 h, 6 h, and 10 h (Experiments 4, 5, 6, and 7), gradually increasing Hcy levels to 19.7 μM. The effects of NECA on serum total Cys levels were the same as those on total Hcy levels.
Table 1. Effects of NECA on the content of total homocysteine and total cysteine in the serum.

3.2. Effects of NECA on Other Methionine Metabolite Levels in the Liver We previously reported that fasting for 16 h decreased AdoMet and GSH levels, and increased AdoHcy levels in the livers of mice [23]. In the present study, as shown in Table 2, the administration of a low dose of NECA (NECA0.1 group) to mice fasted for 16 h resulted in lower liver GSH levels than those in the control group at 1 h (Experiment 1). Liver GSH levels were also significantly lower at 3 h (Experiment 2), while GSH levels were not significantly different from those in the control group at 6 h (Experiment 3). The administration of a high dose of NECA (NECA0.3 group) resulted in liver GSH levels that were significantly lower than those in the control group at 1 h, 6 h, and 10 h (Experiments 4, 6, and 7). The effects of NECA on total Hcy levels in the serum and GSH levels in the liver were similar at each dose and time. Furthermore, the low and high doses of NECA both led to significantly higher AdoMet levels than those in the control group at 1 h (Experiments 1 and 4). AdoMet levels at 3 h, 6 h, and 10 h were not significantly different from those in the control group (Experiments 2, 3, 5, 6, and 7). AdoHcy levels were significantly lower in the NECA0.3 group than in the control group 6 h and 10 h after the administration of NECA (Experiments 6 and 7), while the administration of a low dose of NECA had less of an impact on AdoHcy levels.

Table 2. Effects of NECA on the content of methionine metabolites in the liver.

3.3. Effects of NECA on mRNA Expression of Methionine Cycle Enzymes in the Liver Figure 1 shows changes in the mRNA expression of methionine cycle enzymes in Experiments 4, 5, and 6. The expression of methionine cycle enzymes did not significantly change 1 h after the administration of NECA. The expression of MAT1A mRNA was significantly decreased in the liver 6 h after the NECA treatment, while that of MAT2A was increased. The changes observed in the expression of MAT in the present study were consistent with previous findings obtained in ischemic livers [18] or with liver regeneration [28]. The expression of GNMT, which eliminates excess AdoMet, was significantly decreased 6 h after the NECA treatment. The expression of CBS, which converts Hcy to cystathionine through the transsulfuration pathway, and BHMT, which converts Hcy to methionine, was also decreased at 6 h.

Figure 1 shows changes in the mRNA expression of methionine cycle enzymes in Experiments 4, 5, and 6. The expression of methionine cycle enzymes did not significantly change 1 h after the administration of NECA. The expression of MAT1A mRNA was significantly decreased in the liver 6 h after the NECA treatment, while that of MAT2A was increased. The changes observed in the expression of MAT in the present study were consistent with previous findings obtained in ischemic livers [18] or with liver regeneration [28]. The expression of GNMT, which eliminates excess AdoMet, was significantly decreased 6 h after the NECA treatment. The expression of CBS, which converts Hcy to cystathionine through the transsulfuration pathway, and BHMT, which converts Hcy to methionine, was also decreased at 6 h.
Figure 1. Effects of NECA on the mRNA expression of methionine cycle enzymes in the mouse liver. Northern hybridization was performed on the liver RNA of mice in experiments 4, 5, and 6. The mean ± SEM of the ratio of each enzyme mRNA to the level of the 18S rRNA signal is shown as an arbitrary unit. Unpaired Student’s t-tests were used to compare NECA- treated groups with the control groups. *p < 0.05, **p < 0.01: significantly different from each control.
4. Discussion In the present study, an increase in total Hcy levels and AdoMet levels, and decrease in GSH levels occurred 1 h after the NECA treatment. These results were not due to changes in the expression of methionine metabolic enzymes, which remained unchanged 1 h after the NECA treatment (Figure 1). The effects of NECA on methionine metabolism are summarized in Figure 2. No previous study has demonstrated that adenosine has the ability to directly affect CBS; however, the overproduction of carbon monoxide (CO), which is generated by heme oxygenase (HO), is found to inhibit transsulfuration [11]. CO has been shown to inhibit CBS activity and increase AdoMet concentrations [11]. Adenosine and NECA were previously reported to markedly induce HO in macrophages [29]. Hcy, which is a substrate of CBS, may be increased by NECA via the CO-induced inhibition of CBS, and GSH may be decreased by the CO-induced inhibition of transsulfuration. However, the mechanism by which NECA affects transsulfuration in the short term has not yet been elucidated.
Figure 2. Effects of NECA on the methionine metabolic pathway. MAT: methionine adenosyltransferase, GNMT: glycine N-methyltransferase, CBS: cystathionine β-synthase, BHMT: betaine-homocysteine S-methyltransferase, MS: methionine synthase (Map is based on Sakata SF 2005).
GSH was maintained at a low level for up to 10 h by the NECA0.3 treatment and transsulfuration may have been continuously inhibited by the NECA0.3 treatment. Total Hcy levels were also continuously increased for up to 10 h by the NECA0.3 treatment, and decreased AdoHcy levels were observed 6 h and 10 h after the NECA0.3 treatment. Long-term elevations in serum total Hcy levels by NECA may be maintained by attenuating the expression of methionine metabolic enzymes via the following mechanisms: The expression of methionine metabolic enzymes in the liver was reduced 6 h after the NECA0.3 treatment (Figure 1); the flow of the methionine cycle may have been decreased by changes in the expression of MAT (decreased liver-specific MAT1A expression and increased non-liver type MAT2A expression) because MATIII (Km for methionine: 215 μM – 7 mM) is the true liver-specific isoform responsible for methionine metabolism [30] and the generation rate of AdoMet by MATII (non-liver type enzyme) was modest with a low Km (80 μM for methionine) [31]; inhibition of the methyltransferases, BHMT [32] and GNMT [33], induces hyperhomocysteinemia; decreases in AdoHcy levels may be caused by reductions in methyltransferase levels. However, the mechanisms by which NECA continuously increased total Hcy levels have not yet been elucidated in detail. 5. Conclusion The present study confirmed that the non-specific adenosine receptor agonist NECA continuously increased total Hcy levels in the serum. The inhibition of adenosine receptors may decrease the risk of cardiovascular diseases because an increase in serum total Hcy levels is a known risk factor.

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