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The Rutgers Global Health Institute, part of Rutgers Biomedical and Health Sciences, Rutgers University, New Brunswick, New Jersey – A New Venture Designed to Improve Health and Wellness Globally  

Author: 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

 

The newly formed Rutgers Global Health Institute, part of Rutgers Biomedical and Health Sciences (RBHS) of Rutgers University, New Brunswick, New Jersey (http://rbhs.rutgers.edu/), represents a new way of thinking by providing positive health outcomes to potential patients around the world affected by disease and/or by a negative environmental impact. The goal of the Institute is three-fold:

  • to improve the health and wellness of individuals and populations around the world,
  • to create a healthier world through innovation, engineering, and technology, and
  • to educate involved citizens and effective leaders in global health.

Richard G. Marlink, M.D., a former Harvard University professor recognized internationally for research and leadership in the fight against AIDS, was recently appointed as the inaugural Henry Rutgers Professor of Global Health and Director of the Rutgers Global Health Institute.

The Rutgers Global Health Institute was formed last year after research by the University into the most significant health issues affecting under-served and under-developed populations. While conducting research for its five-year strategic plan, the RBHS looked for bold and ambitious ways that they could take advantage of the changing health care environment and band together to tackle the world’s leading health and environmental causes, contributing to the betterment of society. One of the results was the formation of the Rutgers Global Health Institute, supporting cross-functionally Rutgers faculty, scientists, and clinicians who represent the best in their respective fields of health innovation, research and patient care related to global health.

More broadly, the RBHS, created in 2013, is one of the nation’s leading – and largest — academic health centers that provides health care education, research and clinical service and care. It is an umbrella organization that encompasses eight schools – Ernest Mario School of Pharmacy, Graduate School of Biomedical Sciences, New Jersey Medical School, Robert Wood Johnson Medical School, Rutgers School of Dental Medicine, School of Health Professions, School of Nursing and School of Public Health.

In addition, the RBHS encompasses six centers and institutes that provide cancer treatment and research, neuroscience, advanced biotechnology and medicine, environmental and occupational health and health care policy and aging research. Those centers and institutes are the Brain Health Institute, Center for Advanced Biotechnology and Medicine, Environmental and Occupational Health Sciences Institute, Institute for Health, Health Care Policy and Aging Research, Rutgers Cancer Institute of New Jersey, and Rutgers Institute for Translational Medicine and Research. And lastly, the RBHS includes the University Behavioral Health Care.

 

Rutgers Institute For Health Building

Image SOURCE: Photograph courtesy of the Rutgers Global Health Institute, Rutgers Biomedical and Health Sciences, Rutgers University, New Brunswick, New Jersey.   

 

Below is my interview with the Inaugural Henry Rutgers Professor of Global Health and Director of the Rutgers Global Health Institute Richard G. Marlink, M.D., which occurred in April, 2017.

You were recently appointed as the inaugural Henry Rutgers Professor of Global Health and Director of the new Rutgers Global Health Institute at Rutgers Biomedical and Health Sciences (RBHS). What are the goals of the new Institute?

Dr. Marlink: The overarching goal of the Rutgers Global Health Institute is to improve the health and wellness of individuals and populations in need both here and around the world, to create a healthier world through innovation, engineering, and technology, and to educate involved citizens and effective leaders in global health. We will do that by building on the aspiration of our originating organization — RBHS, which is to be recognized as one of the best academic health centers in the U.S., known for its education, research, clinical care, and commitment to improving access to health care and reducing health care disparities.

As the newly formed Rutgers Global Health Institute, we are embarking on an ambitious agenda to take advantage of the changing health care environment. Working across schools and disciplines at Rutgers University, we plan to have a significant impact within at least four signature programs identified by RBHS, which are cancer, environmental and occupational health, infection and inflammation, and public health. We also will include all other parts of Rutgers, as desired, beyond RBHS.

My background as a global health researcher, physician, and leader of grassroots health care delivery will help develop programs to undertake global health initiatives that assist populations locally and around the world. I believe that involved citizens, including students, can greatly impact major societal issues.

A key role in the strategic growth of Rutgers Biomedical and Health Sciences – an umbrella organization for eight schools, four centers and institutes and a behavioral health network — is to broaden the Rutgers University’s presence in the public health community globally to improve health and wellness. How will the new Rutgers Global Health Institute be part of this growth?

Dr. Marlink: Our RBHS Chancellor Brian Strom [M.D., M.P.H.] believes that we are positioned to become one of the finest research universities in the country, working cross-functionally with our three campuses in Newark, Camden and New Brunswick. In developing the strategic plan, Dr. Strom notes that we become much stronger and more capable and productive by leveraging our strengths to collaborate and working together across disciplines to best serve the needs of our community locally and globally.

Specifically, we are formulating plans to focus on these areas: old and new infectious disease epidemics; the expanding burden of noncommunicable diseases in poor populations; the social and environmental threats to health, poverty and humanitarian crises; and inadequate local and developing country health systems. We will support the development of global health research programs university-wide, the recruitment of faculty with interests in global health, and the creation of a web-based global health resource center for faculty and students with interests in these areas.

We are still a very young part of RBHS, and of Rutgers overall, so our plans are a work in progress. As tangible examples of our commitment to improving health and wellness globally, we plan to enhance global public health by establishing links between global public health and environmental and occupational health faculty in studies related to air pollution, climate change, and pesticide health.

Another example the Institute has in the works is expanding links with the School of Engineering. In fact, we are creating a senior-level joint faculty position with the School of Engineering and Rutgers-New Brunswick. Still other plans involve forging collaborative relationships between the Rutgers Cancer Program, under the auspices of Rutgers Cancer Institute of New Jersey, which is New Jersey’s only National Cancer Institute (NCI)-designated comprehensive cancer center, and other organizations and partners around the world, especially in poor and less-developed countries.

How is the Rutgers Global Health Institute strategically prepared for changing the health care paradigm?

Dr. Marlink: We intend to be an international global health leader in the health sciences, in public health, and in other related, but non-biomedical professions. This means that we will incorporate our learnings from laboratory sciences and the clinical, behavioral, and public health sciences, as well as from engineering, business, economics, law, and social sciences. This broad approach is critical in this health care environment as accountability for patient care is shifting to large groups of providers. Health care will be more value-driven and our health care teams must work collaboratively to be innovative. Our focus on health care is now also population-based, rather than only individual-based, and we are moving from large regional centers toward community centers, even in small and remote areas of the world. We are encouraged by rapid changes in technology that will provide new opportunities for shared knowledge, patient care and research.

Additionally, we are exploring ways to identify and recruit key faculty who will increase our breadth and depth of key disease areas as well as provide guidance on how to pursue science grants from the National Institute of Health (NIH)-funded program project grants and specialized research programs.

Currently, Rutgers University receives NIH funding for research in public health, population health, health promotion, wellness, health behavior, preventive medicine, and global health.

As a researcher, scholar and leader of grassroots health care delivery, how have your past positions prepared you for this new challenge? Your last position was the Bruce A. Beal, Robert L. Beal, and Alexander S. Beal Professor of the Practice of Public Health at Harvard University’s T.H. Chan School of Public Health and Executive Director of the Harvard AIDS Initiative.

Dr. Marlink: I have been a global health practitioner, researcher, and executive leader for almost three decades. I am trained in medical oncology and HIV medicine and have conducted clinical, epidemiological and implementation research in Africa since 1985. I was first introduced to global health when finishing my Hematology/Oncology fellowship at what is now the Beth Israel Deaconess Medical Center in the mid-1980’s in Boston.

During my Hematology/Oncology fellowship and after the co-organizing the first, hospital-based AIDS care clinic in the New England region, I was trying to learn the ropes in virology and molecular biology in the laboratory group of Max Essex at Harvard University. During that time in the mid-1980s, our laboratory group along with Senegalese and French collaborators discovered the first evidence for the existence of a new human retrovirus, HIV-2, a distinct second type of human AIDS virus, with its apparent origins in West Africa.

As a clinician, I was able to assist in Senegal, helping set up clinical care and create a research cohort in Dakar for hundreds of women sex workers infected with this new human retrovirus and care for them and their families. I discovered that a little can go a long way in poor settings, such as in Senegal. I became hooked on helping create solutions to help people in poor settings in Africa and elsewhere. Long-term partnerships and friendships have subsequently been made in many developing countries. Throughout my career, I have built successful partnerships with many governments, companies, and non-profit organizations, and those relationships have been the foundation to build successful public health partnerships in poor regions of the world.

In the 1990s, I helped create the Botswana-Harvard Partnership for HIV Research and Education (BHP). Through this partnership, the Government of Botswana and BHP have worked together to combat the AIDS epidemic in Botswana. Under my direction, and in partnership with the Botswana Ministry of Health, BHP launched the KITSO AIDS Training Program in 1999. Kitso is the Setswana word for ‘knowledge.”

KITSO is the national training program for physicians, nurses, and pharmacists, which has trained more than 14,000 health professionals in HIV/AIDS care and antiretroviral treatment. KITSO training modules address issues, such as antiretroviral therapy, HIV/AIDS-related disease management, gender-specific HIV issues, task-sharing, supportive and palliative care, and various psychosocial and counseling themes.

In addition, I was the Botswana County Director for Harvard Chan School’s 3-country President’s Emergency Plan AIDS Relief (PEPFAR) grant, The Botswana PEPFAR effort includes a Clinical and Laboratory Master Training Program and the creation of the Botswana Ministry of Health’s Monitoring and Evaluation Unit. Concurrently, I was the Principal Investigator of Project HEART in five African countries with the Elizabeth Glaser Pediatric AIDS Foundation.

Also in Botswana, in 2000, I was a co-founder of a distinct partnership involving a large commitment to the Government of Botswana from the Bill and Melinda Gates and Merck Foundations.  This commitment continues as an independent non-governmental organization (NGO) to provide support for various AIDS prevention and care efforts in Botswana and the region.

All these global health experiences, it seems, have led me to my new role at the Rutgers Global Health Institute.

What is your advice for ways that the business community or university students can positively impact major societal issues?

Dr. Marlink: My advice is to be optimistic and follow that desire to want to make a difference. Margaret Mead, the American cultural anthropologist, said years ago, “Never doubt that a small group of thoughtful, committed citizens can change the world; indeed, it’s the only thing that ever has.” I believe that to be our guiding principle as we embark on this new initiative.

I also believe that students should become specialized in specific areas prior to going fully into “global health,” as they develop in their careers, since they will then add more value later. For example, students should be grounded in the theory of global health in their undergraduate studies and then develop a specialization, such as becoming a statistician, economist, or medical doctor, to make a longer and greater impact in improving global health. As for the business community, we are looking for committed individuals who are specialized in specific areas to bring their knowledge to our organization, as partners in the fight against disease, improving the environment, or helping with humanitarian issues. We are committed to improving health and wellness, increasing access to the best health care, and reducing health disparities.

What is it about your current role that you enjoy the most?

Dr. Marlink: I enjoy building research, learning, and clinical programs, as I have in the HIV arena since the early 1980s. At that time, there were limited resources and funding, but a willingness among universities, non-governmental organizations, hospitals and the pharmaceutical industry to make a difference. Today in my new role, I’d like all of us to have an impact on health and wellness for those in need – to build programs from the ground up while partnering with organizations with the same goal in mind. I know it can be done.

Over my career, when I have a patient here or in a developed country who has been diagnosed with cancer, but is cured or in remission, that puts a huge smile on my face and in my heart. It also impacts you for the rest of your life. Or when I see an infant born without HIV because of the local country programs that are put in place, that also makes me feel so fulfilled, so happy.

I have worked with many talented individuals who have become great friends and partners over my career who have helped create a positive life for under-served populations around the world. We need to remember that progress happens with one person at a time or one program at a time. That’s how you truly improve health around the world.

 

Headshot - 2016

Image SOURCE: Photograph of Inaugural Henry Rutgers Professor of Global Health and Director of the Rutgers Global Health Institute at Rutgers Biomedical and Health Sciences, courtesy of Rutgers University, New Brunswick, New Jersey.

Richard G. Marlink, M.D.
Inaugural Henry Rutgers Professor of Global Health

Director of the Rutgers Global Health Institute

Rutgers Biomedical and Health Sciences

Richard G. Marlink, M.D., a Harvard University professor recognized internationally for research and leadership in the fight against AIDS, was recently appointed as the inaugural Henry Rutgers Professor of Global Health and Director of a new Rutgers Global Health Institute at Rutgers Biomedical and Health Sciences (RBHS). His role is to develop the strategic growth of RBHS by broadening the Rutgers University’s presence in the public health community to improve health and wellness.

Previously, Dr. Marlink was the Bruce A. Beal, Robert L. Beal, and Alexander S. Beal Professor of the Practice of Public Health at Harvard’s T.H. Chan School of Public Health and Executive Director of the Harvard AIDS Initiative.

At the start of the AIDS epidemic, Dr. Marlink was instrumental in setting up the first, hospital-based HIV/AIDS clinic in Boston, Massachusetts, and studied the impact of the HIV virus in west and central Africa. After helping to start the Botswana-Harvard Partnership in 1996, he founded the Kitso AIDS Training Program, which would become Botswana’s national AIDS training program. Kitso means knowledge in the local Setswana language.

Dr. Marlink was the principal investigator for the Tshepo Study, the first large-scale antiretroviral treatment study in Botswana, in addition to conducting other clinical and epidemiological studies in the region. Also in Botswana, he was the country director for Harvard’s contribution to the joint Botswana and United States governments’ HIV/AIDS and TB training, monitoring and evaluation PEPFAR effort.

In the mid-1980s in Senegal, Dr. Marlink was part of the team of Senegalese, French and American researchers who discovered and then studied the second type of human AIDS virus, HIV-2. Since then, he has been involved in multiple HIV/AIDS care, treatment and prevention programs in many African countries, including in Botswana, Côte d’Ivoire (Ivory Coast), Democratic Republic of the Congo, Kenya, Lesotho, Malawi, Mozambique, Rwanda, Senegal, South Africa, Swaziland, Tanzania, Uganda, Zambia and Zimbabwe. He has also organized initiatives to enhance HIV/AIDS care in Brazil, Puerto Rico and Thailand.

Dr. Marlink has served as the scientific director, the vice president for implementation and the senior adviser for medical and scientific affairs at the Elizabeth Glaser Pediatric AIDS Foundation, where he was principal investigator of Project HEART, a five-country CDC/PEPFAR effort in Africa. That project began in 2004 and by 2011 had placed more than 1 million people living with HIV into care clinics. More than 565,000 of these people were placed on life-saving antiretroviral treatment.

Since 2000, Dr. Marlink has been the founding member of the board of directors of the African Comprehensive HIV/AIDS Partnerships, a public-partnership among the government of Botswana and the Bill and Melinda Gates and Merck Foundations to provide ongoing support for numerous HIV/AIDS prevention, care and treatment efforts in that country.

He has authored or co-authored more than 130 scientific articles; written a textbook, Global AIDS Crisis: A Reference Handbook; and co-edited the book, AIDS in Africa, 2nd Edition. Additionally, he served as chief editor for two special supplements to the journal AIDS and as executive editor of the seminal 320-author, three-volume textbook, From the Ground Up: A Guide to Building Comprehensive HIV/AIDS Care Programs in Resource Limited Settings.

A trained fellow in hematology/oncology at the Beth Israel Deaconess Medical Center at Harvard Medical School, Dr. Marlink received his medical degree from the University of New Mexico and his bachelor’s degree from Brown University.

 

Editor’s note:

We would like to thank Marilyn DiGiaccobe, head of Partnerships and Strategic Initiatives, at the Rutgers Global Health Institute, for the help and support she provided during this interview.

 

REFERENCE/SOURCE

Rutgers Biomedical and Health Sciences (http://rbhs.rutgers.edu/)

Other related articles

Retrieved from https://aids.harvard.edu/ 

Retrieved from http://b.3cdn.net/glaser/515eaa8068b5e71d44_mlbrof7xw.pdf 

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

2016

CRISPR/Cas9 and HIV1 

https://pharmaceuticalintelligence.com/2016/04/16/crisprcas9-and-hiv1/

Concerns About Viruses

https://pharmaceuticalintelligence.com/2016/01/29/concerns-about-viruses/

CD-4 Therapy for Solid Tumors

https://pharmaceuticalintelligence.com/2016/05/02/cd-4-therapy-for-solid-tumors/

Novel Discoveries in Molecular Biology and Biomedical Science

https://pharmaceuticalintelligence.com/2016/05/30/novel-discoveries-in-molecular-biology-and-biomedical-science/

Scientists eliminate HIV1 DNA from the genome and prevent reinfection

https://pharmaceuticalintelligence.com/2016/03/23/scientists-eliminate-hiv1-dna-from-the-genome-and-prevent-reinfection/

Double Downside of HIV CRISPR therapy

https://pharmaceuticalintelligence.com/2016/04/09/double-downside-of-hiv-crispr-therapy/

2015

Where Infection meets with Cancer: Kaposi’s sarcoma (KS) is the most common cancer in HIV-1-infected persons and is caused by one of only 7 human cancer viruses, i.e., human herpesvirus 8 (HHV-8)

https://pharmaceuticalintelligence.com/2015/10/20/where-infection-meets-with-cancer-kaposis-sarcoma-ks-is-the-most-common-cancer-in-hiv-1-infected-persons-and-is-caused-by-one-of-only-7-human-cancer-viruses-i-e-human-herpesvirus-8-hhv/

Antibody shows promise as treatment for HIV

https://pharmaceuticalintelligence.com/2015/04/09/antibody-shows-promise-as-treatment-for-hiv/

2014

AIDS: Origin of HIV pandemic ‘was 1920s Kinshasa’

https://pharmaceuticalintelligence.com/2014/10/10/aids-origin-of-hiv-pandemic-was-1920s-kinshasa/

2013

Scientists discover how AIDS virus enters key immune cells

https://pharmaceuticalintelligence.com/2013/12/31/scientists-discover-how-aids-virus-enters-key-immune-cells/

Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

https://pharmaceuticalintelligence.com/2013/04/17/heroes-in-medical-research-dr-robert-ting-ph-d-and-retrovirus-in-aids-and-cancer/

2012

Nanotechnology and HIV/AIDS treatment

https://pharmaceuticalintelligence.com/2012/12/25/nanotechnology-and-hivaids-treatment/

HIV vaccine: Caltech puts us One step further

https://pharmaceuticalintelligence.com/2012/08/31/hiv-vaccine-caltech-puts-us-one-step-further/

Bone Marrow Transplant Eliminates Signs of HIV Infection

https://pharmaceuticalintelligence.com/2012/07/29/bone-marrow-transplant-eliminates-signs-of-hiv-infection/

Getting Better: Documentary Videos on Medical Progress — in Surgery, Leukemia, and HIV/AIDS

https://pharmaceuticalintelligence.com/2012/08/23/getting-better-documentary-videos-on-medical-progress-in-surgery-leukemia-and-hivaids/

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Vaccine for Heart Disease

Writer and Curator: Larry, MD, FCAP 

 

 

Introduction

Research investigators at Wayne State University in collaboration with La Jolla Institute for Allergy and Immunology (LJAI) are developing a T-cell peptide-based vaccine for cardiovascular disease, specifically, to reduce immune-based inflammatory plaques in arteries.  The scientists published their findings in the December 2013 issue of Frontiers in Immunology, titled “Atheroprotective vaccination with MCH-II restricted peptides from Apo B-100.”  These experiments show proof of concept for the development of an autoantigen-specific vaccine for reducing the amount of atherosclerotic plaques in mice.
The published work was done in the laboratory of Klaus Ley, M.D., a prominent vascular biolist of LIAI based on the discovery by Harley Tse, Ph.D., Professor of immunology and microbiology at Wayne Stae University School of Medicine, and Wayne State’s Cardiovascular Research Institute with Michael Shae, Ph.D., adjunct assistant professor of immunology and microbiology.Shaw and Tse are the first to demonstrate that two T-cell epitopes of the autoantigen apoB100 are deeply involved in the development of the disease. The discovery is reported in J Immunol Clin Res Apr-Jun, 2014; 2: “Identification of two immunogenic T cell epitopes of ApoB100 and their Autoimmune Implications.”

 

Atheroprotective Vaccination with MHC-II Restricted Peptides from ApoB-100.

Tse K, Gonen A, Sidney J, Ouyang H, Witztum JL, Sette A, Tse H, Ley K
Front Immunol. 2013 Dec 27; 4:493.
http://dx.doi.org:/10.3389/fimmu.2013.00493 eCollection 2013.

BACKGROUND:  Subsets of CD4(+) T-cells have been proposed to serve differential roles in the development of atherosclerosis. Some T-cell types are atherogenic (T-helper type 1), while others are thought to be protective (regulatory T-cells). Lineage commitment toward one type of helper T-cell versus another is strongly influenced by the inflammatory context in which antigens are recognized. Immunization of atherosclerosis-prone mice with low-density lipoprotein (LDL) or its oxidized derivative (ox-LDL) is known to be atheroprotective. However, the antigen specificity of the T-cells induced by vaccination and the mechanism of protection are not known.

METHODS: Identification of two peptide fragments (ApoB3501-3516 and ApoB978-993) from murine ApoB-100 was facilitated using I-Ab prediction models, and their binding to I-Ab determined. Utilizing a vaccination scheme based on complete and incomplete Freund’s adjuvant (CFA and IFA) [1 × CFA + 4 × IFA], we immunized Apoe(-/-)mice with ApoB3501-3516 or ApoB978-993 emulsified in CFA once and subsequently boosted in IFA four times over 15 weeks. Spleens, lymph nodes, and aortas were harvested and evaluated by flow cytometry and real time RT-PCR. Total atherosclerotic plaque burden was determined by aortic pinning and by aortic root histology.

RESULTS:  Mice immunized with ApoB3501-3516 or ApoB978-993 demonstrated 40% reduction in overall plaque burden when compared to adjuvant-only control mice. Aortic root frozen sections from ApoB3501-3516 immunized mice showed a >60% reduction in aortic sinus plaque development. Aortas from both ApoB3501-3516 and ApoB978-993 immunized mice contained significantly more mRNA for IL-10. Both antigen-specific IgG1 and IgG2c titers were elevated in ApoB3501-3516 or ApoB978-993 immunized mice, suggesting helper T-cell immune activity after immunization.

CONCLUSION: Our data show that MHC Class II restricted ApoB-100 peptides can be atheroprotective, potentially through a mechanism involving elevated IL-10.

Atherosclerosis is decreased in ApoB3501–3516 and ApoB978–993

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873602/bin/fimmu-04-00493-g001.jpg

Atherosclerosis is decreased in ApoB3501–3516 and ApoB978–993-treated mice compared to controls. (A) Vaccination schedule: 8-week-old female Apoe−/− mice were immunized once with either PBS or peptide in CFA, then boosted four more times with PBS or peptide in IFA. WD was maintained for 13 weeks. Mice were sacrificed and organs harvested at 23 weeks of age. (B,C) Results of aortic pinning analysis after Sudan IV staining are shown with representative photographs. N = 12–15 in each group, *p < 0.05 when compared to 1× CFA + 4× IFA group. (D) Representative aortic root staining sections after ORO staining, counter-stained with hematoxylin. (E) Plaque area from aortic roots stained from each group. Lesion sizes from 30 to 40 μm distal to start of the aortic valve were averaged per group. N = 5 in each group, *p < 0.05 when compared to 1× CFA + 1× IFA control group.

 

Inhibition of T cell response to native low density lipoprotein reduces atherosclerosis

Andreas Hermansson, DFJ Ketelhuth, D Strodthoff, M Wurm, E. Hansson, et al.
J. Exp. Med. Mar 2015; 207(5): 1081-1093
http://www.jem.org/cgi/doi/10.1084/jem.20092243

Atherosclerosis is a chronic inflammatory disease in which lipoproteins accumulate, eliciting an inflammatory response in the arterial wall. Adaptive immune responses that engage clonally expanded T cell populations contribute to this process, as do innate immune responses that are mounted by macrophages and other cells. Several studies have suggested that components of low-density lipoprotein (LDL) particles trigger vascular inflammation (Tabas et al., 2007; Hartvigsen et al., 2009).

As a consequence of oxidation, the double bonds of fatty acid residues in phospholipids, cholesteryl esters, and triglycerides are cleaved, thus generating reactive aldehydes and truncated lipids (Esterbauer et al., 1990). Among the latter, modified phospholipids, such as lysophosphatidylcholine and oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (ox-PAPC), induce endothelial cells, macrophages, and B1-type B cells to initiate innate immune responses, effecting adhesion molecule expression, chemokine production, and secretion of natural antibodies containing germline IgM sequences (Leitinger et al., 1997; Binder et al., 2004; Gharavi et al., 2007).

Immune responses to oxidized low-density lipoprotein (oxLDL) are proposed to be important in atherosclerosis. To identify the mechanisms of recognition that govern T cell responses to LDL particles, we generated T cell hybridomas from human ApoB100 transgenic (huB100tg) mice that were immunized with human oxLDL. Surprisingly, none of the hybridomas responded to oxidized LDL, only to native LDL and the purified LDL apolipoprotein ApoB100.

However, sera from immunized mice contained IgG antibodies to oxLDL, suggesting that T cell responses to native ApoB100 help B cells making antibodies to oxLDL. ApoB100 responding CD4+ T cell hybridomas were MHC class II–restricted and expressed a single T cell receptor (TCR) variable (V)  chain, TRBV31, with different V chains. Immunization of huB100tgxLdlr/ mice with a TRBV31-derived peptide induced anti-TRBV31 antibodies that blocked T cell recognition of ApoB100. This treatment significantly reduced atherosclerosis by 65%, with a concomitant reduction of macrophage infiltration and MHC class II expression in lesions. In conclusion, CD4+ T cells recognize epitopes on native ApoB100 protein, this response is associated with a limited set of clonotypic TCRs, and blocking TCR-dependent antigen recognition by these T cells protects against atherosclerosis.

 

Impact of multiple antigenic epitopes from ApoB100, hHSP60 and Chlamydophila pneumoniae on atherosclerotic lesion development in Apobtm2SgyLdlrtm1HerJ mice

Xinjie Lu, Min Xia, V Endresz, I Faludi, A Szabo, et al.
Atherosclerosis Nov 2012; 225(1): 56–68
http://www.sciencedirect.com.scopeesprx.elsevier.com/science/article/pii/S0021915012004935
http://dx.doi.org:/10.1016/j.atherosclerosis.2012.07.021

Highlights

► We produced 5 constructs using dendroaspin as a scaffold for immunization study. ► All constructs have the effect on lesion reduction. ► Modulation in atherosclerosis-related autoimmunity appears by Tregs.

Atherosclerosis is increasingly recognized as a complex chronic inflammatory disease of the arterial walls [1], [2] and [3], as evidenced by the presence of inflammatory cells, activated immune cells and cytokines in lesions, all of which indicate involvement of the immune system. Atherosclerotic plaques are known to contain macrophage-derived foam cells in which macrophages interact with T-cells to produce a wide array of cytokines that can exert both pro- and anti-inflammatory effects.

 

Antibodies against aldehyde-modified ApoB100, a major constituent of low-density lipoprotein, reduce atherosclerosis in mice expressing human ApoB100, suggesting an immunogenic role of ApoB100. Antibodies against epitopes of the human heat shock protein 60 (hHSP60) molecule (hHSP60153–163: AELKKQSKPVT and hHSP60303-312: PGFGDNRKNQ) are present in atherosclerotic patients and share considerable homology with human cytomegalovirus (HCMV)-derived protein (immediate early protein UL122) and Porphyromonas gingivalis microbial HSP60. Sequence homology between microbial HSP60 and hHSP60 has been suggested to result in immunological cross-reactivity, which may play a role in atherogenesis. Titers of Cpn antibodies are not always positively associated with the Cpn organism in atheroma; however, these antibodies might exert cross-reactivity to non-Cpn antigens.

Immunization of mice with a single construct containing multiple epitopes derived from ApoB100, hHSP60 and Cpn was more effective in reducing early atherosclerotic lesions through the induction of a specific Treg-cell response than was the construct containing either mono- or bi-epitopes. This approach offers attractive opportunities for the design of protein-based, multivalent vaccines against atherosclerosis.

 

Immunization with a combination of ApoB and HSP60 epitopes significantly reduces early atherosclerotic lesion in Apobtm2SgyLdlrtm1Her/J mice

Xinjie Lu, Daxin Chen, Valeria Endreszb, Min Xia, Ildiko Faludi, et. al.
Atherosclerosis 212 (2010) 472–480
http://dx.doi.org:/10.1016/j.atherosclerosis.2010.06.007

Objective: HSP60 is emerging as an immune-dominant target of autoantibodies in atherosclerosis and recent studies have revealed oxLDL as a key antigen in the development of atherosclerosis. In this study, we assay whether immunizing Apobtm2SgyLdlrtm1Her/J mice with a combination of ApoB and human HSP60 peptides has an additive effect on athero-protection compared to ApoB or HSP60 peptides applied alone by following atherosclerotic lesion development. Methods and results: In this study, 2 weeks after the first immunization, Apobtm2SgyLdlrtm1Her/J mice were placed on a high-fat diet for 8 weeks followed by 2 weeks on a normal diet allowing the mice to adapt to the environment before sacrifice. High levels of ApoB and HSP60 antibodies were detectable in week 2 and week 12 following the first immunization with KLH-conjugated ApoB and HSP60 peptides either individually or in combination. Histological analyses demonstrated that mice immunized with both, ApoB and HSP60 peptides, showed the most significant reduction in atherosclerotic lesions (41.3%; p < 0.001) compared to a reduction of 14.7% (p < 0.05) and 21.1% (p < 0.01) in mice immunized with ApoB or HSP60 peptides, respectively; control mice were immunized with either PBS or adjuvant alone. These results

were further supported by significant differences in the cellular and humoral immune responses between test animals. Conclusions: Immunization with a combination of ApoB and HSP60 peptide antigens significantly reduced early atherosclerotic lesions in the Apobtm2SgyLdlrtm1Her/J mouse model of atherosclerosis. This approach offers promise as a novel strategy for developing anti-atherosclerotic agents.

 

Chlamydophila (Chlamydia) pneumoniae infection promotes vascular smooth muscle cell adhesion and migration through IQ domain GTPase-activating protein 1

Lijun Zhang, Xiankui Li, Lijun Zhang, Beibei Wang, Tengteng Zhang, Jing Ye
Microb Pathogen 2012; 53(5–6): 207–213
http://dx.doi.org:/10.1016/j.micpath.2012.07.005

Highlights

► C. pneumoniae infection increases the adhesion of vascular smooth muscle cells. ► C. pneumoniae infection promotes the migration of vascular smooth muscle cells. ► IQGAP1 expression was increased in the infected vascular smooth muscle cells. ► Depletion of IQGAP1 inhibits the infection-induced cell adhesion and migration.

The mechanisms for Chlamydophila (Chlamydia) pneumoniae (C. pneumoniae) infection-induced atherosclerosis are still unclear. Cell adhesion has important roles in vascular smooth muscle cell (VSMC) migration required in the development of atherosclerosis. However, it is still unknown whether IQ domain GTPase-activating protein 1 (IQGAP1) plays pivotal roles in C. pneumoniae infection-induced the adhesion and migration of rat primary VSMCs. Accordingly, in this study, we demonstrated that rat primary VSMC adhesion (P < 0.001) and migration (P < 0.01) measured by cell adhesion assay and Transwell assay, respectively, were significantly enhanced after C. pneumoniae infection. Reverse transcription-polymerase chain reaction analysis revealed that the mRNA expression levels of IQGAP1 in the infected rat primary VSMCs were found to increase gradually to reach a peak and then decrease gradually to a level similar to the control. We further showed that the increases in rat primary VSMC adhesion to Matrigel (P < 0.001) and migration (P < 0.01) caused by C. pneumoniae infection were markedly inhibited after IQGAP1 knockdown by a pool of four short hairpin RNAs. Taken together, our results suggest that C. pneumoniae infection may promote the adhesion and migration of VSMCs possibly by upregulating the IQGAP1 expression.

 

Rosiglitazone negatively regulates c-Jun N-terminal kinase and toll-like receptor 4 proinflammatory signalling during initiation of experimental aortic aneurysms

Grisha Pirianov, Evelyn Torsney, Franklyn Howe, Gillian W. Cockerill
Atherosclerosis 2012; 225(1): 69–75
http://dx.doi.org:/10.1016/j.atherosclerosis.2012.07.034

Highlights

► Rosiglitazone has a marked effect on both aneurysm rupture and development. ► Rosiglitazone modulates inflammation by blocking TLR4/JNK signalling. ► Specific antagonists of JNK and TLR4 may be therapeutic for aneurysms.

Development and rupture of aortic aneurysms (AA) is a complex process involving inflammation, cell death, tissue and matrix remodelling. The thiazolidinediones (TZDs) including Rosiglitazone (RGZ) are a family of drugs which act as agonists of the nuclear peroxisome proliferator-activated receptors and have a broad spectrum of effects on a number of biological processes in the cardiovascular system. In our previous study we have demonstrated that RGZ has a marked effect on both aneurysm rupture and development, however, the precise mechanism of this is unknown.

Methods and results  In the present study, we examined possible targets of RGZ action in the early stages of Angiotensin II-induced AA in apolipoprotein E-deficient mice. For this purpose we employed immunoblotting, ELISA and antibody array approaches. We found that RGZ significantly inhibited c-Jun N-terminal kinase (JNK) phosphorylation and down-regulated toll-like receptor 4 (TLR4) expression at the site of lesion formation in response to Angiotensin II infusion in the initiation stage (6–72 h) of experimental AA development. Importantly, this effect was also associated with a decrease of CD4 antigen and reduction in production of TLR4/JNK-dependant proinflammatory chemokines MCP-1 and MIP-1α.  Conclusion These data suggest that RGZ can modulate inflammatory processes by blocking TLR4/JNK signalling in initiation stages of AA development.

 

Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine.

Gonen A, Hansen LF, Turner WW, Montano EN, Que X,…, Hartvigsen K.
J Lipid Res. 2014 Oct;55(10):2137-55.
http://dx.doi.org:/10.1194/jlr.M053256.  Epub 2014 Aug 20.

Immunization with homologous malondialdehyde (MDA)-modified LDL (MDA-LDL) leads to atheroprotection in experimental models supporting the concept that a vaccine to oxidation-specific epitopes (OSEs) of oxidized LDL could limit atherogenesis. However, modification of human LDL with OSE to use as an immunogen would be impractical for generalized use. Furthermore, when MDA is used to modify LDL, a wide variety of related MDA adducts are formed, both simple and more complex. To define the relevant epitopes that would reproduce the atheroprotective effects of immunization with MDA-LDL, we sought to determine the responsible immunodominant and atheroprotective adducts. We now demonstrate that fluorescent adducts of MDA involving the condensation of two or more MDA molecules with lysine to form malondialdehyde-acetaldehyde (MAA)-type adducts generate immunodominant epitopes that lead to atheroprotective responses. We further demonstrate that a T helper (Th) 2-biased hapten-specific humoral and cellular response is sufficient, and thus, MAA-modified homologous albumin is an equally effective immunogen. We further show that such Th2-biased humoral responses per se are not atheroprotective if they do not target relevant antigens. These data demonstrate the feasibility of development of a small-molecule immunogen that could stimulate MAA-specific immune responses, which could be used to develop a vaccine approach to retard or prevent atherogenesis.

 

Low density lipoprotein oxidation and atherogenesis: from experimental models to clinical studies.

Napoli C
G Ital Cardiol. 1997 Dec; 27(12):1302-14.

Oxidative modifications of low-density lipoproteins (LDL) (“oxidation hypothesis”) appears to be the pathophysiologic mechanism implicated in early atherogenesis. Oxidized LDL (ox-LDL) may also induce several pro-atherogenic mechanisms, such as the regulation of vascular tone, by interfering with nitric oxide, the stimulation of cytokines and chemotactic factors (MCP-1, M-CSF, VCAM-1, etc.) and transcription factors (AP1 and NFk beta). These phenomena complicate the spectrum of direct and indirect actions of ox-LDL. The immunogenicity of ox-LDL was used to generate monoclonal antibodies against many epitopes of ox-LDL, such as malondialdehyde-lysine (MDA-2) or 4-hydroxynonenal-lysine (NA59). These antibodies showed the occurrence of ox-LDL in vivo. Another issue is the role of the humoral and cellular immune system in atherogenesis, in particular whether the immune response to ox-LDL enhances or reduces early atherogenesis. Moreover, the induction of autoantibodies against ox-LDL and the recognition by “natural” antibodies, and the use of the antigens to screen human sera may serve as a marker of atherosclerosis. In this review, we have stressed the importance of methodologic approach in the assessment of LDL-oxidation and the fact that lipoprotein (a) may also undergo oxidative modifications. Several clinical conditions are associated with increased rate of LDL-oxidation. Recently, we have observed the presence of LDL oxidation-specific epitopes in human fetal aortas. Antioxidants studies in primary prevention of atherosclerosis have produced contradictory results. This may be explained in part by the selection of patients who had advanced lesions and were often smokers. New trails suggest that antioxidants be administered early in children. Lastly, antioxidant studies in the secondary prevention of coronary heart disease (CHAOS, WACS, and HOPE) show clear evidence of the benefits of antioxidants in reducing new cardiovascular events.

 

Summary:

Atheroprotective Vaccine

Tech ID: 19640 / UC Case 2006-250-0
http://www.ucop.edu//ncd/12343.html

Atherosclerosis is a chronic inflammatory disease and immunological mechanisms are of central importance. It is known that oxidized LDL and its oxidized moieties were a major class of immunodominant epitopes within the atherosclerotic plaque. Oxidation of LDL leads to the generation of a variety of oxidized lipids and oxidized lipid-apo-B adducts.

Technology Description

UC San Deigo researchers proposed that an immunization strategy could be used to inhibit the progression of atherosclerosis by showing that immunization of rabbits and/or mice (and ultimately humans) with MDA-LDL could inhibit atherosclerosis. To develop a safe vaccine for human use would require the identification of the specific immunogenic oxidation-specific epitope(s) that provides the atheroprotective immunity. Until now, the mechanism of the protection, that is, the immunodominant epitope(s) has not yet been determined.

UC San Diego researchers have been able to identify a small group of MDA-derived adducts which are immunodominant and atheroprotective in mice following immunization. The invention described here has the potential to provide an antigen to formulate a wholly synthetic vaccine to inhibit  the development of atherosclerosis in man. Furthermore, in vivo levels of the adducts, and the autoantibodies recognizing them, may be used as diagnostic tools in patients with cardiovascular and other inflammatory diseases.

State Of Development

Mice have been immunized with the adducts resulting in atheroprotection. Techniques are currently being developed for a totally synthetic immunogen suitable for human clinical studies. Assays are also being developed.

Intellectual Property Info

A patent application has been filed on this technology.

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Alteration in Reduced Glutathione level in Red Blood Cells: Role of Melatonin

Author: Shilpa Chakrabarti, PhD

List of abbreviation:
DTNB- 5,5- dithiobis,2-nitrobenzoic acid
t-BHP- Tertiary butyl hydroperoxide
GSH-Reduced glutathione
GSSG- Oxidised glutathione

Objective: The study was taken up to see the effect of melatonin on the alteration of reduced glutathione level in red blood cells.

Pineal melatonin is involved in many physiological functions, the most important among them being sleep promotion and circadian regulation. This pineal product exhibits characteristic diurnal rhythm of synthesis and secretion, which attains its peak at night followed by a gradual decrease during the daytime. Melatonin detoxifies highly toxic hydroxyl and peroxyl radicals in vitro, scavenges hydrochlorous acid, as well as peroxynitrite. It has also been reported to increase the synthesis of glutathione and of several antioxidant enzymes [1].

Method: The present study was undertaken to understand the modulation of intracellular reduced glutathione (GSH) by melatonin in human red blood cells according to the oscillatory circadian changes in levels of this hormone.We have also studied the dose-dependent effect of melatonin on GSH in erythrocytes obtained from blood at two different times, subjected to oxidative stress by incubating with tert-butyl hydroperoxide (t-BHP) [2]. We used t-BHP as pro-oxidant [3]. Erythrocyte GSH was measured following the method of Beutler [4]. The method was based on the ability of the –SH group to reduce 5,5- dithiobis,2-nitrobenzoic acid (DTNB) and form a yellow coloured anionic product whose OD is measured at 412 nm.

A suspension of packed red blood cells in phosphate-buffered saline (PBS) containing glucose was treated with melatonin taken at different concentrations. A stock solution (10mM) of melatonin was prepared in absolute ethanol; further dilutions (100 uM–10 nM) were done with PBS. The concentration of ethanol was alwaysThe in vitro effect of melatonin was evaluated by incubating erythrocytes with melatonin at different doses (10 uM –1 nM final concentration) of melatonin for 30 minutes at 37°C. After washing the erythrocytes with the buffer, to remove any amount of the compound, and finally, packed erythrocytes were used for the assay of GSH. In parallel control experiments, blood was incubated with ethanol (final concentration not more than 0.01% (v/v)) but without melatonin.Oxidative stress was induced in vitro by using tert-butyl hydroperoxide both in presence and absence of melatonin. Use of TBHP is in accordance with the published reports [5].

Results and Discussion: The experiment demonstrated that erythrocyte GSH level increased in nocturnal samples which highlights the role of endogenous melatonin in the circadian changes in cellular glutathione level. Exogenous melatonin demonstrated a protective effect against t-BHP-induced peroxidative damage in both diurnal and nocturnal samples, the effect being more pronounced in aliquots containing very low concentration of melatonin (10 nM – 1 nM) [6]. Melatonin was found to inhibit GSH oxidation in a dose-dependent manner.

Melatonin has been found to upregulate cellular glutathione level to check lipid peroxidation in brain cells [7]. We may say that the incubation of the red cells with melatonin for an extended period (more than 30 minutes) may not have the same effects on the level of glutathione in these cells [12]. Melatonin may act as pro-oxidant in the cells exposed to the indoleamine for longer time. Also, the half-life period of pineal melatonin is for 30 to 60 minutes, as reviewed by Karasek and Winczyk [11].The recycling of glutathione in the cells depends on an NADPH-dependent glutathione enzyme system which includes glutathione peroxidise, glutathione reductase, and γ-glutamyl-cysteine synthase forming a meshwork of an antioxidative system. The stimulatory effect of melatonin on the regulation of the antioxidant enzymes has been reported [8].Since melatonin has an amphiphilic nature, its antioxidative efficiency crosses the cellular membrane barriers in a non-receptor-mediated mechanism. Another explanation of melatonin’s antioxidative activity may be based on its role in the upregulation of some antioxidant enzymes directly. Blanco et al had reported that glutathione reductase and glutathione peroxidase, the major constituents of the glutathione-redox system being stimulated by melatonin [9]. The plasma GSH/GSSG redox state is controlled by multiple processes, which includes synthesis of GSH from its constitutive amino acids, cyclic oxidation and reduction involving GSH peroxidase and GSSG reductase, transport of GSH into the plasma, and the degradation of GSH and GSSG by γ-glutamyltranspeptidase. The increase in erythrocyte GSH concentration after melatonin administration can be related Blanco et al’s report on the known stimulation of γ-glutamylcysteine synthase,a rate-limiting enzyme in reduced glutathione synthesis, by melatonin [10].

Conclusion: On the basis of our study, we may conclude that melatonin affects the glutathione level in red blood cells in a circadian manner. The rhythmic pattern of glutathione level confirms the relationship between physiological melatonin and erythrocyte GSH level and pharmacological dosage of the drug. The role of melatonin as an antioxidant and its activity in relation to these biomarkers has been studied in the above experiments.

Key words: Glutathione, circadian rhythm,, melatonin, biomarkers, oxidative stress

REFERENCES


1. D. Bonnefont-Rousselot and F. Collin, “Melatonin: action as antioxidant and potential applications in human disease and aging,” Toxicology, vol. 278, no. 1, pp. 55–67, 2010. http://www.drvitaminsolutions.com/images/products/Melatonin%20as%20antioxidant%20and%20potential%20applications%20in%20human%20disease%20and%20aging.pdf
2. A. V.Domanski, E. A. Lapshina, and I. B. Zavodnik, “Oxidative processes induced by tert-butyl hydroperoxide in human red blood cells: chemiluminescence studies,” Biochemistry (Moscow), vol. 70, no. 7, pp. 761–769, 2005. http://link.springer.com/article/10.1007%2Fs10541-005-0181-5
3. Z. Cˇervinkova´, P. Krˇiva´kova´, A. La´bajova´ et al., “Mechanisms participating in oxidative damage of isolated rat hepatocytes,” Archives of Toxicology, vol. 83, no. 4, pp. 363–372, 2009. http://www.ncbi.nlm.nih.gov/pubmed/16097939
4. E. Beutler, A Manual of Biochemical Methods, Grunne and Stratton, New York, NY, USA, 1984.
5. P. Di Simplicio, M. G. Cacace, L. Lusini, F. Giannerini, D. Giustarini, and R. Rossi, “Role of protein -SH groups in redox homeostasis—the erythrocyte as a model system,” Archives of Biochemistry and Biophysics, vol. 355, no. 2, pp. 145–152, 1998.
6. S. Chakravarty and S. I. Rizvi., “Day and Night GSH andMDA Levels in Healthy Adults and Effects of Different Doses ofMelatonin on These Parameters” International Journal of Cell Biology, vol. 2011, pp. Article ID 404591.http://www.hindawi.com/journals/ijcb/2011/404591/9CDay+and+Night+GSH+andMDA+Levels+in+Healthy+Adults+and+Effects+of+Different+Doses+ofMelatonin+on+These+Parameters”&gt;
7. S. R. Pandi-Perumal, V. Srinivasan, G. J. M. Maestroni, D. P. Cardinali, B. Poeggeler, and R. Hardeland, “Melatonin: nature’s most versatile biological signal?” FEBS Journal, vol. 273, no. 13, pp. 2813–2838, 2006.http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2006.05322.x/full
8. R. J. Reiter, R. C. Carneiro, and C. S. Oh, “Melatonin in relation to cellular antioxidative defense mechanisms,” Hormone and Metabolic Research, vol. 29, no. 8, pp. 363–372, 1997.http://www.ncbi.nlm.nih.gov/pubmed/9288572
9. Y.Urata, S.Honma, S. Goto et al., “Melatonin induces gammaglutamylcysteine synthetase mediated by activator protein-1in human vascular endothelial cells,” Free Radical Biology and Medicine, vol. 27, no. 1-2, pp. 838–847, 1997.http://www.ncbi.nlm.nih.gov/pubmed/10515588
10. R. A. Blanco, T. R. Ziegler, B. A. Carlson et al., “Diurnal variation in glutathione and cysteine redox states in human plasma,” American Journal of Clinical Nutrition, vol. 86, no. 4, pp. 1016–1023, 2007. http://www.ncbi.nlm.nih.gov/pubmed/17921379
11. M. Karasek, K. Winczyk, “Melatonin in humans,” Journal of Phsiology and Pharmacology, vol. 57, no. 5, pp. 19-39, 2006. http://www.jpp.krakow.pl/journal/archive/11_06_s5/articles/02_article.html
12. A. Krokosz ,J. Grebowski, Z. Szweda-Lewandowska et al., ” Can melatonin delay oxidative damage of human
erythrocytes during prolonged incubation?” Advances in Medical Sciences, vol. 58, no. 1, 2013.http://www.researchgate.net/publication/236614971_Can_melatonin_delay_oxidative_damage_of_human_erythrocytes_during_prolonged_incubation

 

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

Antioxidant micronutrients, such as vitamins and carotenoids, exist in abundance in fruit and vegetables and have been known to contribute to the body’s defence against reactive oxygen species. Numerous epidemiological studies have demonstrated that a high dietary consumption of fruit and vegetables rich in carotenoids or with high serum carotenoid concentrations results in lower risks of certain cancers, diabetes and cardiovascular disease. These epidemiological studies have suggested that antioxidant carotenoids may have a protective effect against diabetes or cardiovascular disease. However, the consumption of carotenoids in pharmaceutical forms for the treatment or prevention of these chronic diseases cannot be recommended, because some large randomized controlled trials did not reveal any reduction in cardiovascular events or type 2 diabetes with b-carotene. High doses of carotenoids used in the supplementation studies could have a pro-oxidant effect. Therefore, it is favourable to intake carotenoids from foods through the combination of other nutrients such as vitamins, minerals or phytochemicals, not by supplements.

The metabolic syndrome is a clustering of metabolic abnormalities that increase the risk for diabetes and cardiovascular disease. Typically, it includes excess weight, hyperglycaemia, evaluated blood pressure, low concentration of HDL-cholesterol, and hypertriacylglycerolaemia. This syndrome is emerging as one of the major medical and public health problems in Japan, and persons with this syndrome have an increased risk of morbidity and mortality due to cardiovascular disease and diabetes. Recently, many studies have examined the associations of dietary patterns with the metabolic syndrome and shown that diets rich in fruit and vegetables have been inversely associated with the metabolic syndrome. These previous reports suggest that a high intake of fruit and vegetables may reduce the risk of the metabolic syndrome through the beneficial combination of antioxidants, fibre, minerals, and other phytochemicals. Some recent cross-sectional and case–control studies have shown the associations of serum antioxidant status with the metabolic syndrome. Ford et al. reported that low intake and/or low serum concentrations of vitamins and carotenoids were associated with the risk of the metabolic syndrome. Although very few data are available about the associations of antioxidant carotenoids with the metabolic syndrome, people who have the metabolic syndrome are more likely to have increased oxidative stress than people who do not have this syndrome.

In some recent studies, it has been reported that oxidative stress, which is an imbalance between pro-oxidants and antioxidants, occurs more frequently in metabolic syndrome subjects than in non-metabolic syndrome subjects. Oxidative stress may play a key role in the pathophysiology of diabetes and cardiovascular disease. On the other hand, smoking is a potent oxidative stress in man. This increment of oxidative stress induced by smoking may develop insulin resistance, and increased insulin resistance may result in the clustering of the metabolic abnormality. Therefore, antioxidants could have a beneficial effect on reducing the risk of these conditions in smokers. However, there is limited information about the interaction of serum antioxidant carotenoids and the metabolic syndrome with smoking habit. This study was aimed to investigate the interaction of serum carotenoid concentrations and the metabolic syndrome with smoking. The association of the concentrations of six serum carotenoids, i.e. lutein, lycopene, a-carotene, b-carotene, b-cryptoxanthin and zeaxanthin, with metabolic syndrome status stratified by smoking status was evaluated crosssectionally.

In this study, the associations of the serum carotenoids with the metabolic syndrome stratified by smoking habit were evaluated cross-sectionally. A total of 1073 subjects (357 male and 716 female) who had received health examinations in the town of Mikkabi, Shizuoka Prefecture, Japan, participated in the study. Inverse associations of serum carotenoids with the metabolic syndrome were more evident among current smokers than non-smokers. These results support that antioxidant carotenoids may have a protective effect against development of the metabolic syndrome, especially in current smokers who are exposed to a potent oxidative stress.

Source References:

http://www.ncbi.nlm.nih.gov/pubmed/18445303

http://www.ncbi.nlm.nih.gov/pubmed/19450371

http://www.ncbi.nlm.nih.gov/pubmed/21216053

http://www.ncbi.nlm.nih.gov/pubmed/19631019

http://www.ncbi.nlm.nih.gov/pubmed/12324189

http://www.ncbi.nlm.nih.gov/pubmed/18689373

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Benefits of Functional Foods in Nutrient Imbalance of Vulnerable Populations

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

There are clear distinctions between a food and a drug. Nutraceuticals, however, occupy a place between the two. Nutraceuticals are naturally derived phytochemicals with potential health benefits and without the characteristics of being essential nutrients. Foods that contain these non-essential substances with potential health benefits may qualify as “functional foods.” As defined by the Food and Nutrition Board of the National Academy of Sciences, the term functional food refers to foods that provide health benefits beyond basic nutrition. Examples of these are

  • psyllium seeds (soluble fiber),
  • soy foods (isoflavones),
  • cranberry juice (proanthocyanidins),
  • purple grape juice (resveratrol),
  • tomatoes (lycopene), and
  • green tea (catechins).

The bioactive components of functional foods:

  • flavonols,
  • monomeric and polymeric flavan-3-ols,
  • highly coloured anthocyanins, and
  • phenolic acids

may be increased in or added to traditional foods. An example is a genetically modified tomato high in lycopene, which has potent antioxidant capabilities.

The risk of nutrient imbalance is highest in vulnerable populations unable to access essential or conditionally essential nutrients. To a large extent, the

  • very young and the
  • frail elderly

are the select groups who might benefit most from alleviating this risk. The lack of adequate nutrition may be due to seasonal and unexpected losses of agricultural produce; however, poverty is a factor on a global scale as a result of growing economic disparities. The question then becomes what role functional foods offer to improve recognized population nutritional deficiencies. The range of work being done on functional foods is impressive, from

  • modified oils that contain heart-healthy ω-3 fatty acids to
  • cassava plants developed with an increased protein content to help counter malnutrition in developing nations.

However, the nutraceutical industry has responded to and relies on the untested expectations of the healthiest members of the world’s population rather than its more vulnerable ones. Due largely to economic causes, those in need are less likely to receive the benefits of nutraceuticals from whole foods or from manufactured foods or supplements. This is particularly striking where the source is locally available and extracted for commerce but is unaffordable or unavailable to the native population.

The rapid advances in biotechnology and functional foods confront us with a need to address the benefits of these with regard to improving health and managing or decreasing disease risks. Conventional dietary recommendations have focused on the consumption of fruits, vegetables, legumes, and whole grains, a decreased sugar intake, and an emphasis on plant oils, recommendations that have unproved benefits for the prevention of chronic diseases and that have complexities involving individual, environmental, and genetic influences.

Although the potential benefits of phytochemicals could have an impact on health status for vulnerable populations, the recommendations focused on plant foods do not address the primary concerns of the undernutrition associated with a poor quality of protein intake. Taken individually, plant sources do not provide a balanced amino acid profile necessary for protein synthesis, being deficient in lysine and/or methionine. Animal sources of protein, specifically meat and fish, also provide essential fatty acids not found in plant sources of protein and that may be otherwise limited. In addition, plants may contain antinutritional factors (wheat, cassava roots, cabbages, soy beans), and plant-based diets may be deficient in important essential nutrients.

Programs must focus on the sustainable production and local processing of indigenous products that can be used by needy populations to improve their nutritional intake and enhance economic stability. In addition, dietary recommendations must not exclude important sources of nutrition for more vulnerable populations by focusing primarily on plant-based sources of food, decreasing saturated fat, and de-emphasizing the importance of high-value biologic protein. The global economic crisis has touched the lives of 80% of the population in most developing countries with a threat to the development of a generation of children (approximately 250 million) who are most vulnerable in the first 2 years of life. An investment in nutrition in this circumstance has a high value, and the use of complementary food supplements to increase a meal’s nutrient content is warranted.

A recent proposal has concluded there are health benefits for foods and food constituents put together in a synergic diet pattern, suggesting that the interrelation between constituents within whole foods is significant, and has recommended dietary variety and the selection of nutrient-rich foods. Providing vulnerable populations with an adequate supply of whole foods should take precedence over the recommendation of food products in supplying not only essential macro- and micronutrients and energy but also phytochemicals whose value to the human diet is still to be determined.

Source References:

http://www.sciencedirect.com/science/article/pii/S0899900711003133

 

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             Melatonin and its effect on acetylcholinesterase activity in erythrocytes

Author: S. Chakravarty, PhD

Objective: The study was conducted to see the effect of melatonin on the activity of acetylcholinesterase in red blood cells.

Mammalian red blood cells contain membrane-bound acetylcholinesterase which acts as biomarkers of oxidative imbalance. Melatonin is a powerful free radical scavenger and upregulates several antioxidant enzymes to reduce oxidative stress. Being an effective antioxidant, it may initiate variation in erythrocyte acetylcholinesterase activity.

The study was carried out on twenty-nine subjects of both sexes who gave their informed consent for the use of their blood samples for the study (Chakravarty and Rizvi, 2011a). The red cells isolated from blood collected at two different timings of the day, viz., 10:00 a.m. and 10:00 p.m.,were subjected to in vitro treatment with melatonin in a dose-dependant manner followed by the assay of enzyme activity (Ellman et al., 1961).

Acetylcholinesterase (AChE) is also found on the red blood cell membranes, where it constitutes the Yt blood group of antigen, which is a blood-group determining protein. AChE has the features of a secreted rather than a transmembrane protein because it lacks long hydrophobic stretches, other than that which forms the signal peptide (Li et al., 1991). Besides, acetylcholinesterase activity in erythrocytes may be considered as a marker of central cholinergic status (Kaizer et al., 2008). AChE shows highest activity in the immature rat brain is at 6.00 a.m. and lowest after midnight, which undergoes a reversal after attaining maturity (Moudgil and Kanungo, 1973). The enzyme also exhibits annual changes in its activity (Lewandowski, 2008). Acetylcholinesterase activity has been used to for studying the activity pattern of human erythrocytes (Prall et al., 1998). Free radicals and increased oxidative stress have been found to reduce AChE activity (Molochkina et al., 2005). This indicates that melatonin may have some relation with the circadian rhythmicity of acetylcholinesterase activity.

The concentration-dependant assay of AChE activity in red cells bear close relation with the circadian rhythm in humans thus sharing a similar conclusion with that mentioned by Moudgil and Kanungo (Moudgil and Kanungo, 1973). The effect of melatonin on enzyme functions in erythrocytes follows rhythmic modulation with day/night cycle. The samples obtained in the morning exhibit significantly higher activity of acetylcholinesterase than those obtained during the night-time. The samples collected at two different timings of the day show different response to in vitro melatonin treatment. The rise in AChE activity is more pronounced at low doses of melatonin. Our results indicate significant increase in acetylcholinesterase activity in diurnal as well as nocturnal blood samples at different concentrations of exogenous melatonin (Rizvi and Chakravarty, 2011). At supraphysiological doses, the enzyme activity exhibits no significant change, owing to the prooxidative influence exerted by melatonin (Marchiafava and Longoni, 1999).

Acetylcholinesterase activity is affected by the hydrophobic environment of the cell membrane and depends on the plasma membrane fluidity and surface charge of the cell (Klajnert et al., 2004).  The activity of AChE depends largely on the biophysical features of membrane. Oxidative stress decreases the fluidity of membrane lipid bilayer, thus affecting its normal functions (Goi et al., 2005).  Such are the ill-effects of oxidative radicals that tend to increase with aging. The decrease in AChE correlates significantly with age-induced oxidative stress (Jha and Rizvi, 2009).  On the basis of our study we conclude that melatonin modulates acetylcholinesterase activity in erythrocytes. The rhythmicity observed in the activity of acetylcholinesterase in response to the melatonin confirms our opinion on the relationship between the enzyme function, pineal secretion and pharmacological dosage of the indole antioxidant.

References:

  1. Chakravarty S, Rizvi SI, Circadian modulation of sodium-potassium ATPase and sodium-proton exchanger in human erythrocytes: in vitro effect of melatonin. <a href="80-6. "http://www.ncbi.nlm.nih.gov/pubmed/21366966
  2. Ellman GL, Courtney KD,      Andres Jr V, Featherstone RM, A new and rapid colorimeteric determination of acetylcholinesterase activity. Biochem Pharmacol 1961; 7(2): 88–95.
  3. Goi G, Cazzola R,      Tringali C, Massaccesi L, Volpe SR, Rondanelli M, Ferrari      E, Herrera      CJ, Cestaro      B, Lombardo      A, Venerando      B, Erythrocyte membrane alterations during      ageing affect beta-D-glucuronidase and neutral sialidase in elderly      healthy subjects. Exp Gerontol 2005; 40(3): 219-25.
  4. http://www.ncbi.nlm.nih.gov/pubmed/?term=alterations+during++++++ageing+affect+beta-D-glucuronidase+and+neutral+sialidase+in+elderly++++++healthy+subjects.

  5. Jha R, Rizvi SI, Age-dependant  decline in erythrocyte acetylcholinesterase activity: correlation with oxidative stress. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2009; 153(3):195–8.
  6. http://www.ncbi.nlm.nih.gov/pubmed/19851431

  7. Kaizer RR, Correa MC, Gris LR, Da Rosa CS, Bohrer D, Morsch VM, Schetinger MR, Effect of long-term exposure to aluminum on the acetylcholinesterase activity in the central nervous system and erythrocytes. Neurochem Res 2008; 33(11):2294-301.
  8. http://www.ncbi.nlm.nih.gov/pubmed/?term=Effect+of+long-term+exposure+to+aluminum+on+the+acetylcholinesterase+activity+in+the+central+nervous+system+and+erythrocytes.

  9. Klajnert B, Sadowska M,      Bryszewska M, The effect of polyamidoamine dendrimers on human erythrocyte membrane acetylcholinesterase activity. Bioelectrochem 2004; 65(1): 23-6.
  10. http://www.ncbi.nlm.nih.gov/pubmed/?term=The+effect+of+polyamidoamine+dendrimers+on+human+erythrocyte+membrane+acetylcholinesterase+activity.

  11. Lewandowski MH, Annual changes of circadian acetylcholinesterase activity in the brain stem compared to locomotor activity of the mouse under LD 12/12. J Interdisiplinary Cycle Res 1990; 21 (1): 25-32.
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Day and Night Variation in Melatonin Level affects Plasma Membrane Redox System in Red Blood Cells

Author: Shilpa Chakravarty, PhD

Melatonin is a well-established antioxidant and sleep-regulating hormone. Over the past fifty years, its efficiency as a regulator of circadian rhythm and several other physiological functions has been studied extensively in different species. As a free-radical scavenger, melatonin has shown its activity in coordination with its circadian nature. One of the most important biomarkers of oxidative stress studied in red blood cells is the plasma membrane redox system (PMRS).

As a part of the research activity, PMRS activity has been summarised in this article. The experiments with PMRS and ascorbate free-radical reductase (AFR reductase) have been conducted in vitro.

The study was carried out on 61 healthy individuals of both sexes (aged 20-30) having no acute or chronic diseases (such as diabetes mellitus, asthma, or tuberculosis) or any organ dysfunction and had not taken any medication. Blood samples were collected at two different timings at 10:00AM and 10:00PM.  Red blood cell-membrane, was in retrospect a good experimental system to try to extract and isolate membrane proteins for biochemical assays. Two factors that have favoured it for experimental use are availability and simplicity. Results from its study have been replicated in every other mammalian cell type, and in some crucial points, the patterns shown by RBC
proteins have led the way to such interpretations of extensive physiological studies.

PMRS transfers electrons from extracellular substates to intracellular electron acceptors incorporating AFR reductase. An increase in PMRS activity indicates the ability of the cell to combat oxidative damage.The aging of human red cells may well be attributed to free radical induced oxidative damage. Maintenance of redox state of sulphydryl residues and reduction of lipid hydroperoxides at the expense of electron donors, such as ascorbate and NADH, is essential for normal energy metabolism in the cell. The neutralisation of oxidants also involves some membrane proteins that comprise the PMRS. The rise in PMRS activity is required to maintain a balanced NAD+/NADH ratio that is essential for normal energy metabolism. It leads to cell survival and membrane homeostasis under stress conditions and during calorie restriction in eukaryotes. The day and night variation in PMRS activity shows that the antioxidative behaviour of melatonin is also influenced by its circadian mode of action. While melatonin is an effective antioxidant against cellular toxicity, it also increases the PMRS activity in red blood cells at night. During the day, when the pineal secretion is low, the PMRS activity is also suppressed.

However, if subjected to in vitro treatment with melatonin, at such a concentration that lies close to the maximal melatonin level in the plasma (maximal secretion of melatonin occurs during the scotopic phase of the day), PMRS increases in red blood cells. This shows that the circadian nature of the hormone not only pertains to its pineal production but also to exogenous administration of the drug.

REFERENCES

  1. Chakravarty S,  Rizvi SI (2012) Modulation of human erythrocyte redox status by melatonin: A protective mechanism against oxidative damage. Neurosci Lett. 518:32-35.
  2. Karasek M,  Winczyk K (2006) Melatonin in humans. Neurosci Lett518:32-35.
  3. Hardeland R, Pandi-Perumal SR (2005) Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutr Metab. (Lond) 2:22.
  4. Hardeland R,  Coto-Montes A, Poeggeler B (2003)  Circadian rhythms, oxidative stress and antioxidative defense mechanisms. Chronobiol Int. 20:921-962.
  5. Hyun D.H., Hernandez J.O., Mattson M.P., de Cabo R., (2006)  The plasma membrane redox system in aging, Ageing Res. Rev. 209–220.
  6. Hyun D.H., Emerson S.S., Jo D.G., Mattson M.P., de Cabo R., (2006) Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging, Proceedings of the National Academy of Sciences of the United States of  America 103: 19908–19912.
  7. Rizvi S.I., Jha R., Maurya P.K., (2006)  Erythrocyte plasma membrane redox system in human aging, Rejuvenation Research 9: 470–474.

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