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Posts Tagged ‘Diabetes mellitus type 2’


Plant-based Nutrition, Neutraceuticals and Alternative Medicine: Article Compilation the Journal PharmaceuticalIntelligence.com

Curator: Larry H. Bernstein, MD, FCAP

 

  1. Green tea polyphenols alleviate early BBB damage
    https://pharmaceuticalintelligence.com/2013/07/31/green-tea-polyphenols-alleviate-early-bbb-damage-during/
  2. What do you know about Plants and Neutraceuticals?

Author and Curator, Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/30/what-do-you-know-about-plants-and-neutraceuticals/

  1. The Final Considerations of the Role of Platelets and Platelet Endothelial Reactions in Atherosclerosis and Novel Treatments

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/10/15/the-final-considerations-of-the-role-of-platelets-and-platelet-endothelial-reactions-in-atherosclerosis-and-novel-treatments/

  1. Endothelial Function and Cardiovascular Disease

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/10/25/endothelial-function-and-cardiovascular-disease/

  1. NO Nutritional remedies for hypertension and atherosclerosis. It’s 12 am: do you know where your electrons are?

Author and Reporter: Meg Baker, Ph.D., Registered Patent Agent

https://pharmaceuticalintelligence.com/2012/10/07/no-nutritional-remedies-for-hypertension-and-atherosclerosis-its-12-am-do-you-know-where-your-electrons-are/

  1. Cocoa and Heart Health

Reporter: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/11/17/cocoa-and-heart-health/

  1. Metabolomics: its applications in food and nutrition research

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

https://pharmaceuticalintelligence.com/2013/05/12/metabolomics-its-applications-in-food-and-nutrition-research/

  1. Japanese knotweed extract (Polygonum cuspidatum) Resveratrol 98%

Reporter: Larry H Bernstein, MD, FCAP   Stanford Lee, Shanghai Natural Bio-engineering Co., Ltd
Key products: resveratrol, curcumin,artemisinin,artemether,artesunate,dihydroartemisinin,Lumefantrine,etc
https://www.linkedin.com/today/post/article/20140805055958-283555965-japanese-knotweed-extract-polygonum-cuspidatum-resveratrol-98?/

https://pharmaceuticalintelligence.com/2014/08/20/japanese-knotweed-extract-polygonum-cuspidatum-resveratrol-98/

  1. Antimicrobial resistance
    Reporter: Larry H Bernstein, MD, FCAP   
    https://pharmaceuticalintelligence.com/2014/08/18/antimicrobial-resistance/
  2. Macrocycles in new drug discovery
    Reporter: Larry H Bernstein, MD, FCAP     Jamie MallinsonIan Collins
    Future Medicinal Chemistry, Jul 2012, Vol. 4, No. 11, Pages 1409-1438.

Natural product macrocycles and their synthetic derivatives

https://pharmaceuticalintelligence.com/2014/08/16/macrocycles-in-new-drug-discovery/

  1. Lipid Metabolism

ALA and LA, LCPUFAs (EPA, DHA, and AA), eicosanoids, delta-3-desaturase, prostaglandins, leukotrienes

Ginseng fights fatigue in cancer patients, Mayo Clinic-led study finds https://pharmaceuticalintelligence.com/2014/08/15/lipid-metabolism/

  1. Ginseng fights fatigue in cancer patients, Mayo Clinic-led study finds

Reporter: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/10/ginseng-fights-fatigue-in-cancer-patients-mayo-clinic-led-study-finds/

  1. Scientists develop new cancer-killing compound from salad plant / 1,200 times more specific in killing certain kinds of cancer cells than currently available drugs
    Reporter: Larry H Bernstein, MD, FCAP
    https://pharmaceuticalintelligence.com/2014/07/17/scientists-develop-new-cancer-killing-compound-from-salad-plant-1200-times-more-specific-in-killing-certain-kinds-of-cancer-cells-than-currently-available-drugs/
  2. Protein heals wounds, boosts immunity and protects from cancer – Lactoferrin
    Reporter: Larry H Bernstein, MD, FCAP
    https://pharmaceuticalintelligence.com/2014/07/17/protein-heals-wounds-boosts-immunity-and-protects-from-cancer-lactoferrin/
  3. Inula helenium ( elecampane ) 100% Effective against MRSA in vitro, 200 Strains
    Reporter: Larry H Bernstein, MD, FCAP
    https://pharmaceuticalintelligence.com/2014/07/15/inula-helenium-elecampane-100-effective-against-mrsa-in-vitro-200-strains/
  4. Thymoquinone, an extract of nigella sativa seed oil, blocked pancreatic cancer cell growth and killed the cells by enhancing the process of programmed cell death.
    Reporter: Larry H Bernstein, MD, FCAP
    https://pharmaceuticalintelligence.com/2014/07/15/thymoquinone-an-extract-of-nigella-sativa-seed-oil-blocked-pancreatic-cancer-cell-growth-and-killed-the-cells-by-enhancing-the-process-of-programmed-cell-death/
  5. Cinnamon is lethal weapon against E. coli O157:H7
    Reporter: Larry H Bernstein, MD, FCAP
    https://pharmaceuticalintelligence.com/2014/07/15/cinnamon-is-lethal-weapon-against-e-coli-o157h7/
  6. Garlic compound fights source of food-borne illness better than antibiotics (100 times more effective than two popular antibiotics )

Reporter: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/15/garlic-compound-fights-source-of-food-borne-illness-better-than-antibiotics-100-times-more-effective-than-two-popular-antibiotics/

  1. Reference Genes in the Human Gut Microbiome: The BGI Catalogue

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/07/14/reference-genes-in-the-human-gut-microbiome-the-bgi-catalogue/

  1. Study suggests consuming whey protein before meals could help improve blood glucose control in people with diabetes
    Reporter: Larry H Bernstein, MD, FCAP
    https://pharmaceuticalintelligence.com/2014/07/12/study-suggests-consuming-whey-protein-before-meals-could-help-improve-blood-glucose-control-in-people-with-diabetes/
  2. Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease
    Larry H. Bernstein, MD, FCAP, Curator
    https://pharmaceuticalintelligence.com/2014/07/06/omega-3-fatty-acids-depleting-the-source-and-protein-insufficiency-in-renal-disease/
  3. Health benefit of anthocyanins from apples and berries noted for men
    Larry H. Bernstein, MD, FCAP, Curator
    https://pharmaceuticalintelligence.com/2014/07/06/health-benefit-of-anthocyanins-from-apples-and-berries-noted-for-men/
  4. Carrots Cut Men’s Prostate Cancer Risk by 50%
    Larry H. Bernstein, MD, FCAP, Reporter
    https://pharmaceuticalintelligence.com/2014/07/03/carrots-cut-mens-prostate-cancer-risk-by-50/
  5. A Recipe To Make Cannabis Oil For A Chemotherapy Alternative
    Larry H. Bernstein, MD, FCAP, Reporter
    https://pharmaceuticalintelligence.com/2014/07/02/a-recipe-to-make-cannabis-oil-for-a-chemotherapy-alternative/
  6. Plant flavonoid found to reduce inflammatory response in the brain: luteolin
    Larry H. Bernstein, MD, FCAP, Reporter
    https://pharmaceuticalintelligence.com/2014/06/29/plant-flavonoid-found-to-reduce-inflammatory-response-in-the-brain-luteolin/
  7. Omega-3 fatty acids protect eyes against retinopathy, study finds
    Larry H. Bernstein, MD, FCAP, Reporter
    https://pharmaceuticalintelligence.com/2014/06/28/omega-3-fatty-acids-protect-eyes-against-retinopathy-study-finds/
  8. Scientists identify new pathogenic and protective microbes associated with severe diarrhea
    Larry H. Bernstein, MD, FCAP, Reporter
    https://pharmaceuticalintelligence.com/2014/06/28/scientists-identify-new-pathogenic-and-protective-microbes-associated-with-severe-diarrhea/
  9. 2,000-year-old herb regulates autoimmunity and inflammation / Chang Shan, from a type of hydrangea that grows in Tibet and Nepal
    Larry H. Bernstein, MD, FCAP, Reporter
    https://pharmaceuticalintelligence.com/2014/06/27/2000-year-old-herb-regulates-autoimmunity-and-inflammation-chang-shan-from-a-type-of-hydrangea-that-grows-in-tibet-and-nepal/
  10. Turmeric-based drug effective on Alzheimer flies
    Larry H. Bernstein, MD, FCAP, Reporter
    https://pharmaceuticalintelligence.com/2014/06/27/turmeric-based-drug-effective-on-alzheimer-flies/
  11. Plant flavonoid luteolin blocks cell signaling pathways in colon cancer cells
    Larry H. Bernstein, MD, FCAP, Reporter
    https://pharmaceuticalintelligence.com/2014/06/26/plant-flavonoid-luteolin-blocks-cell-signaling-pathways-in-colon-cancer-cells/
  12. Study Finds Shu Gan Liang Xue Herbal Formula Has Breast Cancer Anti Tumor Effect
    Larry H. Bernstein, MD, FCAP, Reporter
    https://pharmaceuticalintelligence.com/2014/06/25/study-finds-shu-gan-liang-xue-herbal-formula-has-breast-cancer-anti-tumor-effect/
  13. HMPC Q&A Documents on Herbal Medicinal Products published
    Larry H. Bernstein, MD, FCAP, Reporter
    https://pharmaceuticalintelligence.com/2014/06/25/hmpc-qa-documents-on-herbal-medicinal-products-published/
  14. Garden Cress Extract Kills 97% of Breast Cancer Cells in Vitro
    Larry H. Bernstein, MD, FCAP, Reporter
    https://pharmaceuticalintelligence.com/2014/06/21/garden-cress-extract-kills-97-of-breast-cancer-cells-in-vitro/
  15. Moringa Oleifera Kills 97% of Pancreatic Cancer Cells in Vitro
    Larry H. Bernstein, MD, FCAP, Reporter
    https://pharmaceuticalintelligence.com/2014/06/21/moringa-oleifera-kills-97-of-pancreatic-cancer-cells-in-vitro/

16. The Discovery and Properties of Avemar – Fermented Wheat Germ Extract: Carcinogenesis Suppressor
Larry H. Bernstein, MD, FCAP, Author and Curator
https://pharmaceuticalintelligence.com/2014/06/09/the-discovery-and-properties-of-avemar-fermented-wheat-germ-extract-carcinogenesis-suppressor-2/

 


 

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


Compilation of References by Leaders in Pharmaceutical Business Intelligence in the Journal http://pharmaceuticalintelligence.com about
Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation

Curator: Larry H Bernstein, MD, FCAP

Proteomics

  1. The Human Proteome Map Completed

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

https://pharmaceuticalintelligence.com/2014/08/28/the-human-proteome-map-completed/

  1. Proteomics – The Pathway to Understanding and Decision-making in Medicine

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/06/24/proteomics-the-pathway-to-
understanding-and-decision-making-in-medicine/

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

Author and Curator, Larry H Bernstein, MD, FCAP

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

  1. Expanding the Genetic Alphabet and Linking the Genome to the Metabolome

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-                metabolome/

5. Genomics, Proteomics and standards

Larry H Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/06/genomics-proteomics-and-standards/

6. Proteins and cellular adaptation to stress

Larry H Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/08/proteins-and-cellular-adaptation-to-stress/

 

Metabolomics

  1. Extracellular evaluation of intracellular flux in yeast cells

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2014/08/25/extracellular-evaluation-of-intracellular-flux-in-yeast-cells/

  1. Metabolomic analysis of two leukemia cell lines. I.

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2014/08/23/metabolomic-analysis-of-two-leukemia-cell-lines-_i/

  1. Metabolomic analysis of two leukemia cell lines. II.

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2014/08/24/metabolomic-analysis-of-two-leukemia-cell-lines-ii/

  1. Metabolomics, Metabonomics and Functional Nutrition: the next step in nutritional metabolism and biotherapeutics

Reviewer and Curator, Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/22/metabolomics-metabonomics-and-functional-nutrition-the-next-step-          in-nutritional-metabolism-and-biotherapeutics/

  1. Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation

Larry H. Bernstein, MD, FCAP, Reviewer and curator

https://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle-              metabolism-provides-homeomeostatic-regulation/

Metabolic Pathways

  1. Pentose Shunt, Electron Transfer, Galactose, more Lipids in brief

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

https://pharmaceuticalintelligence.com/2014/08/21/pentose-shunt-electron-transfer-galactose-more-lipids-in-brief/

  1. Mitochondria: More than just the “powerhouse of the cell”

Ritu Saxena, PhD

https://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

  1. Mitochondrial fission and fusion: potential therapeutic targets?

Ritu saxena

https://pharmaceuticalintelligence.com/2012/10/31/mitochondrial-fission-and-fusion-potential-therapeutic-target/

4.  Mitochondrial mutation analysis might be “1-step” away

Ritu Saxena

https://pharmaceuticalintelligence.com/2012/08/14/mitochondrial-mutation-analysis-might-be-1-step-away/

  1. Selected References to Signaling and Metabolic Pathways in PharmaceuticalIntelligence.com

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/14/selected-references-to-signaling-and-metabolic-pathways-in-                     leaders-in-pharmaceutical-intelligence/

  1. Metabolic drivers in aggressive brain tumors

Prabodh Kandal, PhD

https://pharmaceuticalintelligence.com/2012/11/11/metabolic-drivers-in-aggressive-brain-tumors/

  1. Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

Writer and Curator, Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/10/22/metabolite-identification-combining-genetic-and-metabolic-                        information-genetic-association-links-unknown-metabolites-to-functionally-related-genes/

  1. Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation

Larry H Bernstein, MD, FCAP, author and curator

https://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic-            glycolysis-metabolic-adaptation/

  1. Therapeutic Targets for Diabetes and Related Metabolic Disorders

Reporter, Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/08/20/therapeutic-targets-for-diabetes-and-related-metabolic-disorders/

10.  Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation

Larry H. Bernstein, MD, FCAP, Reviewer and curator

https://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle-              metabolism-provides-homeomeostatic-regulation/

11. The multi-step transfer of phosphate bond and hydrogen exchange energy

Larry H. Bernstein, MD, FCAP, Curator:

https://pharmaceuticalintelligence.com/2014/08/19/the-multi-step-transfer-of-phosphate-bond-and-hydrogen-                          exchange-energy/

12. Studies of Respiration Lead to Acetyl CoA

https://pharmaceuticalintelligence.com/2014/08/18/studies-of-respiration-lead-to-acetyl-coa/

13. Lipid Metabolism

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

https://pharmaceuticalintelligence.com/2014/08/15/lipid-metabolism/

14. Carbohydrate Metabolism

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

https://pharmaceuticalintelligence.com/2014/08/13/carbohydrate-metabolism/

15. Update on mitochondrial function, respiration, and associated disorders

Larry H. Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-                   disorders/

16. Prologue to Cancer – e-book Volume One – Where are we in this journey?

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

https://pharmaceuticalintelligence.com/2014/04/13/prologue-to-cancer-ebook-4-where-are-we-in-this-journey/

17. Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

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

https://pharmaceuticalintelligence.com/2014/04/04/introduction-the-evolution-of-cancer-therapy-and-cancer-research-          how-we-got-here/

18. Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K

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

https://pharmaceuticalintelligence.com/2013/11/01/inhibition-of-the-cardiomyocyte-specific-kinase-tnni3k/

19. The Binding of Oligonucleotides in DNA and 3-D Lattice Structures

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

https://pharmaceuticalintelligence.com/2013/05/15/the-binding-of-oligonucleotides-in-dna-and-3-d-lattice-structures/

20. Mitochondrial Metabolism and Cardiac Function

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

https://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

21. How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

Curator: Larry H. Bernstein, MD, FCAP

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

22. AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo

Author and Curator: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2013/03/12/ampk-is-a-negative-regulator-of-the-warburg-effect-and-suppresses-         tumor-growth-in-vivo/

23. A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

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

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

24. Mitochondrial Damage and Repair under Oxidative Stress

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

https://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

25. Nitric Oxide and Immune Responses: Part 2

Author and Curator: Aviral Vatsa, PhD, MBBS

https://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/

26. Overview of Posttranslational Modification (PTM)

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

https://pharmaceuticalintelligence.com/2014/07/29/overview-of-posttranslational-modification-ptm/

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

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

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

28. Update on mitochondrial function, respiration, and associated disorders

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

https://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-                  disorders/

29. Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2014/07/06/omega-3-fatty-acids-depleting-the-source-and-protein-insufficiency-         in-renal-disease/

30. Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Larry H. Bernstein, MD, FCAP, writer, and Aviva Lev- Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/27/larryhbernintroduction_to_cardiovascular_diseases-                                  translational_medicine-part_2/

31. Epilogue: Envisioning New Insights in Cancer Translational Biology
Series C: e-Books on Cancer & Oncology

Author & Curator: Larry H. Bernstein, MD, FCAP, Series C Content Consultant

https://pharmaceuticalintelligence.com/2014/03/29/epilogue-envisioning-new-insights/

32. Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone                         and Neurotransmitter

Writer and Curator: Larry H Bernstein, MD, FCAP and
Curator and Content Editor: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-                    hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocy

33. Cardiac Contractility & Myocardial Performance: Therapeutic Implications of Ryanopathy (Calcium Release-                           related Contractile Dysfunction) and Catecholamine Responses

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC
Author and Curator: Larry H Bernstein, MD, FCAP
and Article Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-      and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-                    contractile/

34. Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Author and Curator: Larry H Bernstein, MD, FCAP Author: Stephen Williams, PhD, and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

35. Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-                           cytoskeleton/

36. Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-Sepsis-and-the-Cardiovascular-System-at-its-              End-Stage/

37. The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

Demet Sag, PhD, Author and Curator

https://pharmaceuticalintelligence.com/2013/08/04/the-delicate-connection-ido-indolamine-2-3-dehydrogenase-and-               immunology/

38. IDO for Commitment of a Life Time: The Origins and Mechanisms of IDO, indolamine 2, 3-dioxygenase

Demet Sag, PhD, Author and Curator

https://pharmaceuticalintelligence.com/2013/08/04/ido-for-commitment-of-a-life-time-the-origins-and-mechanisms-of-             ido-indolamine-2-3-dioxygenase/

39. Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

Curator: Demet Sag, PhD, CRA, GCP

https://pharmaceuticalintelligence.com/2013/07/31/confined-indolamine-2-3-dehydrogenase-controls-the-hemostasis-           of-immune-responses-for-good-and-bad/

40. Signaling Pathway that Makes Young Neurons Connect was discovered @ Scripps Research Institute

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/26/signaling-pathway-that-makes-young-neurons-connect-was-                     discovered-scripps-research-institute/

41. Naked Mole Rats Cancer-Free

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

https://pharmaceuticalintelligence.com/2013/06/20/naked-mole-rats-cancer-free/

42. Late Onset of Alzheimer’s Disease and One-carbon Metabolism

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

https://pharmaceuticalintelligence.com/2013/05/06/alzheimers-disease-and-one-carbon-metabolism/

43. Problems of vegetarianism

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

https://pharmaceuticalintelligence.com/2013/04/22/problems-of-vegetarianism/

44.  Amyloidosis with Cardiomyopathy

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

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

45. Liver endoplasmic reticulum stress and hepatosteatosis

Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/03/10/liver-endoplasmic-reticulum-stress-and-hepatosteatosis/

46. The Molecular Biology of Renal Disorders: Nitric Oxide – Part III

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/the-molecular-biology-of-renal-disorders/

47. Nitric Oxide Function in Coagulation – Part II

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

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-function-in-coagulation/

48. Nitric Oxide, Platelets, Endothelium and Hemostasis

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/08/nitric-oxide-platelets-endothelium-and-hemostasis/

49. Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/09/14/interaction-of-nitric-oxide-and-prostacyclin-in-vascular-endothelium/

50. Nitric Oxide and Immune Responses: Part 1

Curator and Author:  Aviral Vatsa PhD, MBBS

https://pharmaceuticalintelligence.com/2012/10/18/nitric-oxide-and-immune-responses-part-1/

51. Nitric Oxide and Immune Responses: Part 2

Curator and Author:  Aviral Vatsa PhD, MBBS

https://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/

52. Mitochondrial Damage and Repair under Oxidative Stress

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

53. Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-                 century-view/

54. Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                  proteolysis-and-cell-apoptosis/

55. Ubiquitin-Proteosome pathway, Autophagy, the Mitochondrion, Proteolysis and Cell Apoptosis: Part III

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                   proteolysis-and-cell-apoptosis-reconsidered/

56. Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-and-inos-have-key-roles-in-kidney-diseases/

57. New Insights on Nitric Oxide donors – Part IV

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/new-insights-on-no-donors/

58. Crucial role of Nitric Oxide in Cancer

Curator and Author: Ritu Saxena, Ph.D.

https://pharmaceuticalintelligence.com/2012/10/16/crucial-role-of-nitric-oxide-in-cancer/

59. Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-         a-concomitant-influence-on-mitochondrial-function/

60. Targeting Mitochondrial-bound Hexokinase for Cancer Therapy

Curator and Author: Ziv Raviv, PhD, RN 04/06/2013

https://pharmaceuticalintelligence.com/2013/04/06/targeting-mitochondrial-bound-hexokinase-for-cancer-therapy/

61. Biochemistry of the Coagulation Cascade and Platelet Aggregation – Part I

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/biochemistry-of-the-coagulation-cascade-and-platelet-aggregation/

Genomics, Transcriptomics, and Epigenetics

  1. What is the meaning of so many RNAs?

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

https://pharmaceuticalintelligence.com/2014/08/06/what-is-the-meaning-of-so-many-rnas/

  1. RNA and the transcription the genetic code

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

https://pharmaceuticalintelligence.com/2014/08/02/rna-and-the-transcription-of-the-genetic-code/

  1. A Primer on DNA and DNA Replication

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

https://pharmaceuticalintelligence.com/2014/07/29/a_primer_on_dna_and_dna_replication/

4. Synthesizing Synthetic Biology: PLOS Collections

Reporter: Aviva Lev-Ari

https://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

5. Pathology Emergence in the 21st Century

Author and Curator: Larry Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/03/pathology-emergence-in-the-21st-century/

6. RNA and the transcription the genetic code

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

https://pharmaceuticalintelligence.com/2014/08/02/rna-and-the-transcription-of-the-genetic-code/

7. A Great University engaged in Drug Discovery: University of Pittsburgh

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2014/07/15/a-great-university-engaged-in-drug-discovery/

8. microRNA called miRNA-142 involved in the process by which the immature cells in the bone  marrow give                              rise to all the types of blood cells, including immune cells and the oxygen-bearing red blood cells

Aviva Lev-Ari, PhD, RN, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/24/microrna-called-mir-142-involved-in-the-process-by-which-the-                   immature-cells-in-the-bone-marrow-give-rise-to-all-the-types-of-blood-cells-including-immune-cells-and-the-oxygen-             bearing-red-blood-cells/

9. Genes, proteomes, and their interaction

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

https://pharmaceuticalintelligence.com/2014/07/28/genes-proteomes-and-their-interaction/

10. Regulation of somatic stem cell Function

Larry H. Bernstein, MD, FCAP, Writer and Curator    Aviva Lev-Ari, PhD, RN, Curator

https://pharmaceuticalintelligence.com/2014/07/29/regulation-of-somatic-stem-cell-function/

11. Scientists discover that pluripotency factor NANOG is also active in adult organisms

Larry H. Bernstein, MD, FCAP, Reporter

https://pharmaceuticalintelligence.com/2014/07/10/scientists-discover-that-pluripotency-factor-nanog-is-also-active-in-           adult-organisms/

12. Bzzz! Are fruitflies like us?

Larry H Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/07/bzzz-are-fruitflies-like-us/

13. Long Non-coding RNAs Can Encode Proteins After All

Larry H Bernstein, MD, FCAP, Reporter

https://pharmaceuticalintelligence.com/2014/06/29/long-non-coding-rnas-can-encode-proteins-after-all/

14. Michael Snyder @Stanford University sequenced the lymphoblastoid transcriptomes and developed an
allele-specific full-length transcriptome

Aviva Lev-Ari, PhD, RN, Author and Curator

https://pharmaceuticalintelligence.com/014/06/23/michael-snyder-stanford-university-sequenced-the-lymphoblastoid-            transcriptomes-and-developed-an-allele-specific-full-length-transcriptome/

15. Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease: Views by Larry H                                     Bernstein, MD, FCAP

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/16/commentary-on-biomarkers-for-genetics-and-genomics-of-                        cardiovascular-disease-views-by-larry-h-bernstein-md-fcap/

16. Observations on Finding the Genetic Links in Common Disease: Whole Genomic Sequencing Studies

Author an curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/05/18/observations-on-finding-the-genetic-links/

17. Silencing Cancers with Synthetic siRNAs

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/

18. Cardiometabolic Syndrome and the Genetics of Hypertension: The Neuroendocrine Transcriptome Control Points

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/12/cardiometabolic-syndrome-and-the-genetics-of-hypertension-the-neuroendocrine-transcriptome-control-points/

19. Developments in the Genomics and Proteomics of Type 2 Diabetes Mellitus and Treatment Targets

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2013/12/08/developments-in-the-genomics-and-proteomics-of-type-2-diabetes-           mellitus-and-treatment-targets/

20. Loss of normal growth regulation

Larry H Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2014/07/06/loss-of-normal-growth-regulation/

21. CT Angiography & TrueVision™ Metabolomics (Genomic Phenotyping) for new Therapeutic Targets to Atherosclerosis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/11/15/ct-angiography-truevision-metabolomics-genomic-phenotyping-for-           new-therapeutic-targets-to-atherosclerosis/

22.  CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

Genomics Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/30/cracking-the-code-of-human-life-the-birth-of-bioinformatics-                      computational-genomics/

23. Big Data in Genomic Medicine

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/12/17/big-data-in-genomic-medicine/

24. From Genomics of Microorganisms to Translational Medicine

Author and Curator: Demet Sag, PhD

https://pharmaceuticalintelligence.com/2014/03/20/without-the-past-no-future-but-learn-and-move-genomics-of-                      microorganisms-to-translational-medicine/

25. Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/01/06/summary-of-genomics-and-medicine-role-in-cardiovascular-diseases/

 26. Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious                      Depression

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/02/19/genomic-promise-for-neurodegenerative-diseases-dementias-autism-        spectrum-schizophrenia-and-serious-depression/

 27.  BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Sudipta Saha, PhD

https://pharmaceuticalintelligence.com/2012/12/04/brca1-a-tumour-suppressor-in-breast-and-ovarian-cancer-functions-         in-transcription-ubiquitination-and-dna-repair/

28. Personalized medicine gearing up to tackle cancer

Ritu Saxena, PhD

https://pharmaceuticalintelligence.com/2013/01/07/personalized-medicine-gearing-up-to-tackle-cancer/

29. Differentiation Therapy – Epigenetics Tackles Solid Tumors

Stephen J Williams, PhD

      https://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

30. Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

     Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/17/mechanism-involved-in-breast-cancer-cell-growth-function-in-early-          detection-treatment/

31. The Molecular pathology of Breast Cancer Progression

Tilde Barliya, PhD

https://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression

32. Gastric Cancer: Whole-genome reconstruction and mutational signatures

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational-                   signatures-2/

33. Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine –                                                       Part 1 (pharmaceuticalintelligence.com)

Aviva  Lev-Ari, PhD, RN

http://pharmaceuticalntelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomarkers-and-personalized-medicine-part-1/

34. LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer                                         Personalized Treatment: Part 2

A Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic-       drug-selection-in-cancer-personalized-treatment-part-2/

35. Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-        research-part-3/

36. Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of                           Cancer Scientific Leaders @http://pharmaceuticalintelligence.com

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/13/7000/Harnessing_Personalized_Medicine_for_ Cancer_Management-      Prospects_of_Prevention_and_Cure/

37.  GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico
effect of the inhibitor in its “virtual clinical trial”

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/14/gsk-for-personalized-medicine-using-cancer-drugs-needs-alacris-             systems-biology-model-to-determine-the-in-silico-effect-of-the-inhibitor-in-its-virtual-clinical-trial/

38. Personalized medicine-based cure for cancer might not be far away

Ritu Saxena, PhD

  https://pharmaceuticalintelligence.com/2012/11/20/personalized-medicine-based-cure-for-cancer-might-not-be-far-away/

39. Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/24/human-variome-project-encyclopedic-catalog-of-sequence-variants-         indexed-to-the-human-genome-sequence/

40. Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/10/inspiration-from-dr-maureen-cronins-achievements-in-applying-                genomic-sequencing-to-cancer-diagnostics/

41. The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover-         of-dna-wcrick-41953/

42. What can we expect of tumor therapeutic response?

Author and curator: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/12/05/what-can-we-expect-of-tumor-therapeutic-response/

43. Directions for genomics in personalized medicine

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

https://pharmaceuticalintelligence.com/2013/01/27/directions-for-genomics-in-personalized-medicine/

44. How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Stephen J Williams, PhD

https://pharmaceuticalintelligence.com/2012/10/31/how-mobile-elements-in-junk-dna-prote-cancer-part1-transposon-            mediated-tumorigenesis/

45. mRNA interference with cancer expression

Author and Curator, Larry H. Bernstein, MD, FCAP

 https://pharmaceuticalintelligence.com/2012/10/26/mrna-interference-with-cancer-expression/

46. Expanding the Genetic Alphabet and linking the genome to the metabolome

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-               metabolome/

47. Breast Cancer, drug resistance, and biopharmaceutical targets

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/09/18/breast-cancer-drug-resistance-and-biopharmaceutical-targets/

48.  Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression                            Analysis

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/12/24/breast-cancer-genomic-profiling-to-predict-survival-combination-of-           histopathology-and-gene-expression-analysis

49. Gastric Cancer: Whole-genome reconstruction and mutational signatures

Aviva  Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational-                   signatures-2/

50. Genomic Analysis: FLUIDIGM Technology in the Life Science and Agricultural Biotechnology

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/08/22/genomic-analysis-fluidigm-technology-in-the-life-science-and-                   agricultural-biotechnology/

51. 2013 Genomics: The Era Beyond the Sequencing Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2013_Genomics

52. Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/Paradigm Shift in Human Genomics_/

Signaling Pathways

  1. Proteins and cellular adaptation to stress

Larry H Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2014/07/08/proteins-and-cellular-adaptation-to-stress/

  1. A Synthesis of the Beauty and Complexity of How We View Cancer:
    Cancer Volume One – Summary

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

https://pharmaceuticalintelligence.com/2014/03/26/a-synthesis-of-the-beauty-and-complexity-of-how-we-view-cancer/

  1. Recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes in
    serous endometrial tumors

Sudipta Saha, PhD

https://pharmaceuticalintelligence.com/2012/11/19/recurrent-somatic-mutations-in-chromatin-remodeling-ad-ubiquitin-           ligase-complex-genes-in-serous-endometrial-tumors/

4.  Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Stephen J Williams, PhD

https://pharmaceuticalintelligence.com/2012/11/30/histone-deacetylase-inhibitors-induce-epithelial-to-mesenchymal-              transition-in-prostate-cancer-cells/

5. Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                   proteolysis-and-cell-apoptosis/

6. Signaling and Signaling Pathways

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2014/08/12/signaling-and-signaling-pathways/

7.  Leptin signaling in mediating the cardiac hypertrophy associated with obesity

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2013/11/03/leptin-signaling-in-mediating-the-cardiac-hypertrophy-associated-            with-obesity/

  1. Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2013/11/01/sensors-and-signaling-in-oxidative-stress/

  1. The Final Considerations of the Role of Platelets and Platelet Endothelial Reactions in Atherosclerosis and Novel
    Treatments

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2013/10/15/the-final-considerations-of-the-role-of-platelets-and-platelet-                      endothelial-reactions-in-atherosclerosis-and-novel-treatments

10.   Platelets in Translational Research – Part 1

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2013/10/07/platelets-in-translational-research-1/

11.  Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and
Cardiovascular Calcium Signaling Mechanism

Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to e-SERIES A:
Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-             smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

12. The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and
Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia,
Similarities and Differences, and Pharmaceutical Targets

     Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to
e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and
Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-       kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-           differen/

13.  Nitric Oxide Signalling Pathways

Aviral Vatsa, PhD, MBBS

https://pharmaceuticalintelligence.com/2012/08/22/nitric-oxide-signalling-pathways/

14. Immune activation, immunity, antibacterial activity

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2014/07/06/immune-activation-immunity-antibacterial-activity/

15.  Regulation of somatic stem cell Function

Larry H. Bernstein, MD, FCAP, Writer and Curator    Aviva Lev-Ari, PhD, RN, Curator

https://pharmaceuticalintelligence.com/2014/07/29/regulation-of-somatic-stem-cell-function/

16. Scientists discover that pluripotency factor NANOG is also active in adult organisms

Larry H. Bernstein, MD, FCAP, Reporter

https://pharmaceuticalintelligence.com/2014/07/10/scientists-discover-that-pluripotency-factor-nanog-is-also-active-in-adult-organisms/

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Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD)


Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD)

Curator:  Larry H. Bernstein, MD, FCAP

This is a multipart article that develops the pathological effects of type-2 diabetes in the progression of a systemic inflammatory disease with a development of neuropathy, and fully developing into cardiovascular disease.  It also identifies a systemic relationship to the development of chronic obstructive pulmonary disease (COPD).

The more we learn about diabetes, we learn about its generalized systemic effects.

This article has the following SIX Parts:

Part 1. Role of Autonomic Cardiovascular Neuropathy in Pathogenesis of ischemic heart disease in patients with diabetes mellitus

Part 2. A Longitudinal Cohort Study of the Cardiovascular Experience of Individuals at High Risk for Diabetes

Part 3.  Clinical significance of cardiovascular dysmetabolic syndrome

Part 4.   Waist circumference a good indicator of future risk for type 2 diabetes and cardiovascular disease

Part 5.   How to use C-reactive protein in acute coronary care

Part 6.  Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony

INTRODUCTION

Type 2 diabetes mellitus is a common chronic disease which develops insidiously over time, and is associated with obesity, nutritional imbalance (high fructose beverages, high starch and processed foods, carbohydrate excess intake, and an imbalance of proinflammatory to anti-inflammatory polyunsaturated  fatty acids), which makes it an acquired and manageable disease.  The long term effects of T2DM is played out on cardiovascular disease and stroke-risk, obstructive sleep apnea, progressive renal insufficiency, development of neuropathy, congestive heart failure and chronic obstructive pulmonary disease, all of which are occuring related to an systemic inflammatory condition that proceeds for some time prior to the identification of overt diabetes.
A detailed story of a significant part of these associations continues in the SIX Part series.

Part 1. Role of Autonomic Cardiovascular Neuropathy in Pathogenesis of ischemic heart disease in patients with diabetes mellitus

This article is an abstract only of a related publication of the pathogenesis of autonomic neuropathy in diabetics leading to ischemic heart disease.

Subjects: Medicine (General), Medicine, Medicine (General),
Health Sciences Authors: Popović-Pejičić Snježana, Todorović-Đilas Ljiljana, Pantelinac Pavle
Publisher: Društvo lekara Vojvodine Srpskog lekarskog društva
Publication: Medicinski Pregled 2006; 59(3-4): Pp 118-123 (2006) ISSN(s): 0025-8105  Added to DOAJ: 2010-11-11
http://dx.doi.org/10.2298/MPNS0604118P  http://www.doiserbia.nb.rs/img/doi/0025-8105/2006/0025-81050604118P.pdf

Keywords: diabetes mellitus, autonomic nervous system diseases, heart diseases, myocardial ischemia, comorbidity

Introduction.

Diabetes is strongly associated with macrovascular complications, among which

  • ischemic heart disease is the major cause of mortality.

Autonomic neuropathy increases the risk of complications, which calls for an early diagnosis. The aim of this study was to determine

  • both presence and extent of cardiac autonomic neuropathy,

in regard to the type of diabetes mellitus, as well as

  • its correlation with coronary disease and
  • major cardiovascular risk factors.

Material and methods. We have examined 90 subjects, classified into three groups, with 30 patients each: those with type 1 diabetes, type 2 diabetes and control group of healthy subjects. All patients underwent

  • cardiovascular tests (Valsalva maneuver, deep breathing test, response to standing, blood pressure response to standing sustained, handgrip test),
  • electrocardiogram,
  • treadmill exercise test and
  • filled out a questionnaire referring to major cardiovascular risk factors: smoking, obesity, hypertension, and dyslipidemia.

Results. Our results showed that cardiovascular autonomic neuropathy was

  • more frequent in type 2 diabetes,
  • manifesting as autonomic neuropathy.

In patients with autonomic neuropathy, regardless of the type of diabetes,

  • the treadmill test was positive, i.e. strongly correlating with coronary disease.

In regard to coronary disease risk factors,

  • the most frequent correlation was found for obesity and hypertension.

Discussion

Cardiovascular autonomic neuropathy is considered to be the principal cause of arteriosclerosis and coronary disease. Our results showed that the occurrence of cardiovascular autonomic neuropathy increases the risk of coronary disease due to dysfunction of autonomic nervous system.

Conclusions

Cardiovascular autonomic neuropathy is a common complication of diabetes that significantly correlates with coronary disease. Early diagnosis of cardiovascular autonomic neuropathy points to increased cardiovascular risk, providing a basis for preventive and therapeutic measures.

Part 2. A Longitudinal Cohort Study of the Cardiovascular Experience of Individuals at High Risk for Diabetes

This second part is a description of a longitudinal cohort study of individuals at high-risk for diabetes.  Unlike the SSA study, the study is not focused on protein-energy malnutrition.

Protocol for ADDITION-PRO: a longitudinal cohort study of the cardiovascular experience of individuals at high risk for diabetes recruited from Danish primary care

Subjects: Public aspects of medicine, Medicine, Public Health, Health Sciences
Authors: Johansen NB, Hansen Anne-Louise S, Jensen TM, Philipsen A, Rasmussen SS, Jørgensen ME, Simmons RK, Lauritzen T, Sandbæk A, Witte DR
Publisher: BioMed Central    Date of publication: 2012 Dec Published in: BMC Public Health 2012; 12(1): 1078    ISSN(s): 1471-2458   Added to DOAJ: 2013-03-12 http://dx.doi.org/10.1186/1471-2458-12-1078       http://www.biomedcentral.com/1471-2458/12/1078

Keywords: Diabetes, Cardiovascular disease, Primary care, Complications, Microvascular, Impaired fasting glucose, Impaired glucose intolerance, Aortic stiffness, Physical activity, Body composition

Background

Screening programmes for type 2 diabetes inevitably find more individuals at high risk for diabetes than people with undiagnosed prevalent disease. While well established guidelines for the treatment of diabetes exist, less is known about treatment or prevention strategies for individuals found at high risk following screening. In order to make better use of the opportunities for primary prevention of diabetes and its complications among this high risk group, it is important to

  • quantify diabetes progression rates and to examine
  • the development of early markers of cardiovascular disease and
  • microvascular diabetic complications.

We also require a better understanding of the

  • mechanisms that underlie and drive early changes in cardiometabolic physiology.

The ADDITION-PRO study was designed to address these issues among individuals at different levels of diabetes risk recruited from Danish primary care.

Methods/Design

ADDITION-PRO is a population-based, longitudinal cohort study of individuals at high risk for diabetes. 16,136 eligible individuals were identified at high risk following participation in a stepwise screening programme in Danish general practice between 2001 and 2006.

  • All individuals with impaired glucose regulation at screening,
  • those who developed diabetes following screening, and
  • a random sub-sample of those at lower levels of diabetes risk

were invited to attend a follow-up health assessment in 2009–2011 (n = 4,188), of whom 2,082 (50%) attended. The health assessment included

  • detailed measurement of anthropometry,
  • body composition,
  • biochemistry,
  • physical activity and
  • cardiovascular risk factors including aortic stiffness and central blood pressure.

All ADDITION-PRO participants are being followed for incident cardiovascular disease and death.

Discussion

The ADDITION-PRO study is designed to increase

  • understanding of cardiovascular risk and
  • its underlying mechanisms among individuals at high risk of diabetes.

Key features of this study include

  • (i) a carefully characterised cohort at different levels of diabetes risk;
  • (ii) detailed measurement of cardiovascular and metabolic risk factors;
  • (iii) objective measurement of physical activity behaviour; and
  • (iv) long-term follow-up of hard clinical outcomes including mortality and cardiovascular disease.

Results will inform policy recommendations concerning cardiovascular risk reduction and treatment among individuals at high risk for diabetes. The detailed phenotyping of this cohort will also allow a number of research questions concerning early changes in cardiometabolic physiology to be addressed.

Part 3.  Clinical significance of cardiovascular dysmetabolic syndrome

This study also addresses the issue of diabetes insulin resistance leading to cardiovascular dysmetabolic syndrome.

Subjects: Diseases of the circulatory (Cardiovascular) system,
Specialties of internal medicine, Internal medicine, Medicine, Cardiovascular, Medicine (General), Health Sciences
Authors: Deedwania Prakash C Publisher: BioMed Central            Date of publication: 2002 Jan
Published in: Trials 2002; 3: 1(2)   ISSN(s): 1468-6708  Added to DOAJ: 2004-06-03
http://dx.doi.org/10.1186/1468-6708-3-2   http://cvm.controlled-trials.com/content/3/1/2

Keywords: cardiovascular dysmetabolic syndrome, coronary heart disease, diabetes mellitus, hyperinsulinemia, insulin resistance

Although diabetes mellitus is predominantly a metabolic disorder,

  • recent data suggest that it is as much a vascular disorder.
  • Cardiovascular complications are the leading cause
    • of death and disability in patients with diabetes mellitus.

A number of recent reports have emphasized that

  • many patients already have atherosclerosis in progression
  • at the time they are diagnosed with clinical evidence of diabetes mellitus.

The increased risk of atherosclerosis and cardiovascular complications in diabetic patients is related to

  • the frequently associated dyslipidemia, hypertension, hyperglycemia, hyperinsulinemia, and endothelial dysfunction.

The evolving knowledge regarding the variety of

  • metabolic,
  • hormonal, and
  • hemodynamic abnormalities in patients with diabetes mellitus

has led to efforts designed for early identification of individuals at risk of subsequent disease. It has been suggested that

  • insulin resistance, the key abnormality in type II diabetes,
  • often precedes clinical features of diabetes by 5–6 years.

Careful attention to the criteria described for the cardiovascular dysmetabolic syndrome

  • should help identify those at risk at an early stage.

The application of nonpharmacologic as well as newer emerging pharmacologic therapies can have beneficial effects

  • in individuals with cardiovascular dysmetabolic syndrome and/or diabetes mellitus
  • by improving insulin sensitivity and related abnormalities.

Early identification and implementation of appropriate therapeutic strategies would be necessary

  • to contain the emerging new epidemic of cardiovascular disease related to diabetes.

Part 4.   Waist circumference a good indicator of future risk for type 2 diabetes and cardiovascular disease

Subjects: Public aspects of medicine, Medicine, Public Health, Health Sciences
Authors: Siren Reijo, Eriksson Johan G, Vanhanen Hannu
Publisher: BioMed Central      Date of publication: 2012 Aug
Published in: BMC Public Health 2012; 12: 1(631)    ISSN(s): 1471-2458   Added to DOAJ: 2013-03-12
http://dx.doi.org/10.1186/1471-2458-12-631    http://www.biomedcentral.com/1471-2458/12/631

Keywords: Waist circumference, Type 2 diabetes, Cardiovascular disease, Middle-aged men

Background

Abdominal obesity is a more important risk factor than overall obesity in

  • predicting the development of type 2 diabetes and cardiovascular disease.

From a preventive and public health point of view it is crucial that

  • risk factors are identified at an early stage,
  • in order to change and modify behaviour and lifestyle in high risk individuals.

Methods

Data from a community based study was used to assess

  • the risk for type 2 diabetes,
  • cardiovascular disease and
  • prevalence of metabolic syndrome in middle-aged men.

In order to identify those with increased risk for type 2 diabetes and/or cardiovascular disease

  • sensitivity and specificity analysis were performed, including
  • calculation of positive and negative predictive values, and
  • corresponding 95% CI for eleven different cut-off points,
    • with 1 cm intervals (92 to 102 cm), for waist circumference.

Results

A waist circumference ≥94 cm in middle-aged men,

  • identified those with increased risk for type 2 diabetes
  • and/or for cardiovascular disease

with a sensitivity of 84.4% (95% CI 76.4% to 90.0%), and a specificity of 78.2% (95% CI 68.4% to 85.5%). The positive predictive value was 82.9% (95% CI 74.8% to 88.8%), and negative predictive value 80.0% (95% CI 70.3% to 87.1%), respectively .

Conclusions

Measurement of waist circumference in middle-aged men

  • is a reliable test to identify individuals at increased risk for type 2 diabetes and cardiovascular disease.

This measurement should be used more frequently in daily practice in primary care

  • in order to identify individuals at risk and when planning health counselling and interventions.

Part 5.  How to use C-reactive protein in acute coronary care

Luigi M. Biasucci, Wolfgang Koenig, Johannes Mair, Christian Mueller, Mario Plebani, Bertil Lindahl, Nader Rifai,Per Venge,Christian Hamm, and the Study Group on Biomarkers in Cardiology of the Acute Cardiovascular Care Association of the European Society of Cardiology
Department of Cardiology B, Aarhus University Hospital, Tage Hansens Gade2, Aarhus DK-8000,Denmark; Germany, U.K., U.S., Italy
European Heart Journal Advance Access published Nov 7, 2013.  Current Opinion.  http://dx.doi.org/10.1093/eurheartj/eht435

Introduction

 C-reactive protein (CRP) is an acute phase protein and an established marker for detection, risk stratification, and monitoring of infections, and inflammatory and necrotic processes.. Because C-reactive protein is sensitive but not specific, its values must be nterpreted  in the clinical context. Inpatients with acute myocardial infarction (AMI), CRP increases within 4–6h of symptoms, peaks 2–4 days later,and returns to baseline after 7–10 days.

CRP has gained interest recently as a marker for risk stratification in acute coronary syndrome (ACS) when measured by high-sensitivity CRP assays. These assays have greater analytical sensitivity and reliably measure CRP concentrations within the reference range with low imprecision (5–10%). Because of evidence that atherosclerosis is an inflammatory disease, high-sensitivity CRP can be used as a biomarker of risk
in primary prevention and in patients with known cardiovascular disease. The aim of this review is to evaluate the use of CRP in patients with acute coronary disease.

The in-vitro stability of high-sensitivity C-reactive protein is excellent. Specific blood sampling conditions aren’t necessary.  However, retesting may be necessary with some assays if there is marked lipaemia.  Baseline and subsequent measures are in good for agreement for risk stratification despite biological variability of 30–60%.

The upper reference limit is method-dependent but usually 8mg/L for standard assays. The distribution of high-sensitivity CRP concentrations is skewed in both genders with a 50th percentile of_1.5mg/L (excluding women on hormone replacement therapy). Race differences have been reported. Most studies have reported no relationship with age,  but to circadian and seasonal variation. CRP concentrations are increased by smoking, obesity, and hormone replacement therapy and reduced by exercise, moderate alcohol drinking, and statin use. Correction for these factors is essential in reference range studies. CRP assays are not standardized. We recommend  the use of third-generation high-sensitivity CRP assays that combine features of standard and high-sensitivity CRP assays.  Required assay precision should be < 10% in the range of 3 and 10 mg/L.

Biochemical and analytical issues

Critical clinical concepts

(1) CRP concentrations are reported in mg/L
(2) CRP test results are method-dependent

  •  classification of patients into risk categories is usually comparable
(3) Third generation CRP assay are recommended
(4) No specific patient preparation before blood sampling is necessary
(5) The in-vitro stability of CRP is high

This is only a portion of the published concensus document. What is relevant to this discussion is that the hs-CRP is an extremely valuable marker for inflammatory disease.  It is not ordered often enough because of the broad range of values that we have become accustomed to for years, and it is elevated in rheumatologic conditions, but even then, it is widely used in pediatrics because children may present with rapidly emergent sepsis with very minimal sympoms.
The hs-CRP has opened a window to subliminal inflammatory disease that is diabetes, with accompanied arteriolar endothelial inflammation.

Part 6.  Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony

Subjects: Diseases of the circulatory (Cardiovascular) system,
Specialties of internal medicine, Internal medicine, Medicine, Cardiovascular, Medicine (General), Health Sciences
Authors: Mirrakhimov Aibek E
Publisher: BioMed Central      Date of publication: Oct 2012   ISSN(s): 1475-2840
Published in: Cardiovascular Diabetology 2012; 11(1):132   Added to DOAJ: 2013-03-12
http://dx.doi.org/10.1186/1475-2840-11-132      http://www.cardiab.com/content/11/1/132

Keywords: COPD, Dysglycemia, Insulin resistance, Obesity, Metabolic syndrome, Diabetes mellitus endothelial dysfunction, Vasculopathy

Chronic obstructive pulmonary disease, metabolic syndrome and diabetes mellitus

  • are common and underdiagnosed medical conditions.

It was predicted that chronic obstructive pulmonary disease

  • will be the third leading cause of death worldwide by 2020.

The healthcare burden of this disease is even greater

  • if we consider the significant impact of chronic obstructive pulmonary disease on
    • the cardiovascular morbidity and mortality.

Chronic obstructive pulmonary disease

  • may be considered as a novel risk factor for new onset type 2 diabetes mellitus via

multiple pathophysiological alterations such as:

  1. inflammation and oxidative stress,
  2. insulin resistance,
  3. weight gain and
  4. alterations in metabolism of adipokines.

On the other hand, diabetes may act as an independent factor,

  • negatively affecting pulmonary structure and function.

Diabetes is associated with an increased risk of

  1. pulmonary infections,
  2. disease exacerbations and
  3. worsened COPD outcomes.

On the top of that, coexistent OSA

  • may increase the risk for type 2 DM in some individuals.

The current scientific data necessitate a greater outlook on chronic obstructive pulmonary disease and

  • chronic obstructive pulmonary disease may be viewed as a risk factor for
  • the new onset type 2 diabetes mellitus.

Conversely, both types of diabetes mellitus should be viewed as

  • strong contributing factors for the development of obstructive lung disease.

Such approach can potentially improve the outcomes and medical control for both conditions,

  • and, thus, decrease the healthcare burden of these major medical problems.

CONCLUSIONS

This discussion  presents a spectrum of cardiovascular risk associated with type 2 diabetes mellitus, with high risk for CVD, stroke, endothelial dysfunction, and an association with obesity, measured by waist circumference, and an underlying proinflammatory state that can be measured by CRP.

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Larry H Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2013-12-08/larryhbern/Developments-in-the-Genomics-and-Proteomics-of-Type-2-Diabetes-Mellitus-and-Treatment-Targets

Researchers Solve a Mystery about Type 2 Diabetes Drug

AB SCIEX TripleTOF® and QTRAP® technologies support breakthrough medical study.
Published: Friday, November 22, 2013
Researchers from St. Vincent’s Institute of Medical Research in Melbourne, Australia, in collaboration with researchers at McMaster University in Canada, are reportedly the first to discover how the type 2 diabetes drug metformin actually works, providing a molecular understanding that could lead to the development of more effective therapies. Mass spectrometry technologies from AB SCIEX played a critical role in the analysis that led to this breakthrough finding.  The research is published in this month’s issue of the journal Nature Medicine.
Doctors have known for decades that metformin helps treat type 2 diabetes.  However, questions had lingered for more than 50 years whether this drug, which is available as a generic drug,
  • worked to lower blood glucose in patients by directly working on the glucose.
People with type 2 diabetes have high blood sugar levels and have trouble converting sugar in their blood into energy because of low levels of insulin. For treating this condition, metformin is considered the most widely prescribed anti-diabetic drug in the world.
Until now, no one had been able to explain adequately how this drug lowers blood sugar. According to this new study, the drug works by reducing harmful fat in the liver. People who take metformin reportedly often have a fatty liver, which is frequently caused by obesity.
“Fat is likely a key trigger for pre-diabetes in humans,” said Professor Bruce Kemp, PhD, the Head of Protein Chemistry and Metabolism at St. Vincent’s Institute of Medical Research.  “Our study indicates that
  • metformin doesn’t directly reduce sugar metabolism, as previously suspected, but instead
  •  reduces fat in the liver, which in turn allows insulin to work effectively.”
The breakthrough in pinning down how the drug functions began with the researchers making
  • genetic mutations to the genes of two enzymes, ACC1 and ACC2,
in mice, so they could no longer be controlled.  What happened next surprised the researchers:
  • the mice didn’t get fat as expected,
but Associate Professor Gregory Steinberg, PhD at McMaster University noticed that
  • the mice had fatty livers and a pre-diabetic condition.
Then the researchers put the mice on
  • a high fat diet and they became fat, while metformin
  • did not lower the blood sugar levels of the mutant mice.
The findings are expected to help researchers better directly target the condition, which affects over 100 million people around the world, according to published reports. It is also believed that with the mystery of metformin solved, the application of the drug could go beyond just diabetes and potentially be used to treat other medical conditions.
“AB SCIEX mass spectrometry solutions help researchers explore big questions and conduct breakthrough studies, such as this remarkable type 2 diabetes study,” said Rainer Blair, President of AB SCIEX.   “In order to understand disease at the molecular level, researchers need the sensitive detection and reproducible quantitation provided by AB SCIEX tools. We enable the research community to solve biological mysteries and rethink the possibilities to transform health.
For the research conducted by the Australian and Canadian researchers, the analysis at the molecular level was optimized on AB SCIEX instrumentation, including the AB SCIEX TripleTOF® 5600 and the AB SCIEX QTRAP® 5500 system.
The TripleTOF system, with its high-speed, high-quality MS/MS capabilities,
  • was used for the discovery of key proteins and phosphopeptides.
The QTRAP system, with its high sensitivity MRM (multiple reaction monitoring) capabilities,
  • was used for quantitation of metabolites, including nucleotides and malonyl-CoA. 

Bardoxolone Methyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease

D de Zeeuw, T Akizawa, P Audhya, GL Bakris, M Chin, ….,and GM Chertow, for the BEACON Trial Investigators
Type 2 diabetes mellitus is the most important cause of progressive chronic kidney disease in the developed and developing worlds. Various therapeutic approaches to slow progression, including
  • restriction of dietary protein,
  • glycemic control, and
  • control of hypertension,
have yielded mixed results.1-3 Several randomized clinical trials have shown that
  • inhibitors of the renin–angiotensin–aldosterone system significantly reduce the risk of progression,4-6 although
  • the residual risk remains high.7
None of the new agents tested during the past decade have proved effective in late-stage clinical trials.8-12
Oxidative stress and impaired antioxidant capacity intensify 
  • with the progression of chronic kidney disease.13
In animals with chronic kidney disease,
  • oxidative stress and inflammation
  • are associated with impaired activity of the nuclear 1 factor (erythroid-derived 2)–related factor 2 (Nrf2) transcription factor.
The synthetic triterpenoid bardoxolone methyl and its analogues are the most potent known activators of the Nrf2 pathway. Studies involving humans,14 including persons with type 2 diabetes mellitus and stage 3b or 4 chronic kidney disease, have shown that
  • bardoxolone methyl can reduce the serum creatinine concentration for up to 52 weeks.15
We designed the Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: the Occurrence of Renal Events (BEACON) trial to test the hypothesis that
  • treatment with bardoxolone methyl reduces the risk of end-stage renal disease (ESRD) or death from cardiovascular causes
among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease.

Methods

Study Design and Oversight

The BEACON trial was a phase 3, randomized, double-blind, parallel-group, international, multicenter trial of
  • once-daily administration of bardoxolone methyl (at a dose of 20 mg in an amorphous spray-dried dispersion formulation), as compared with placebo.
Participants were receiving background conventional therapy that included 
  • inhibitors of the renin–angiotensin–aldosterone system,
  • insulin or other hypoglycemic agents, and, when appropriate,
  • other cardiovascular medications.
The trial design and the characteristics of the trial participants at baseline have been described previously.16,17
Reata Pharmaceuticals sponsored the trial. The trial was jointly designed by employees of the sponsor and the academic investigators who were members of the steering committee. The steering committee, which was led by the academic investigators and included members who were employees of the sponsor, supervised the trial design and operation. An independent data and safety monitoring committee reviewed interim safety data every 90 days or on an ad hoc basis on request. The sponsor collected the trial data and transferred them to independent statisticians at Statistics Collaborative. The sponsor also contracted a second independent statistical group (Axio Research) to support the independent data and safety monitoring committee. The trial protocol was approved by the institutional review board at each participating study site. The protocol and amendments are available with the full text of this article at NEJM.org. The steering committee takes full responsibility for the integrity of the data and the interpretation of the trial results and for the fidelity of the study to the protocol. The first and last authors wrote the first draft of the manuscript. All the members of the steering committee made the decision to submit the manuscript for publication.

Study Population

Briefly, we included adults with 
  • type 2 diabetes mellitus and
  • an estimated glomerular filtration rate (GFR) of 15 to <30 ml per minute per 1.73 m2 BSA.
  1. Persons with poor glycemic control,
  2. uncontrolled hypertension, or
  3. a recent cardiovascular event (≤12 weeks before randomization) or
  4. New York Heart Association class III or IV heart failure were excluded.
Additional inclusion and exclusion criteria are listed in Table S1 in the Supplementary Appendix, available at NEJM.org. All the patients provided written informed consent.

Randomization and Intervention

 Randomization was stratified according to study site with the use of variable-sized blocks. The steering committee, sponsor, investigators, and trial participants were unaware of the group assignments. After randomization,
  • patients received either bardoxolone methyl or placebo.
The prescription of all other medications was at the discretion of treating physicians, who were encouraged to adhere to published clinical-practice guidelines. Patients underwent event ascertainment and laboratory testing according to the study schema shown in Figure S1 in the Supplementary Appendix. Ambulatory blood-pressure monitoring was performed in a substudy that included 174 patients (8%).
The statistical analysis plan defined the study period as the number of days from randomization to a common study-termination date. In the case of patients who were still receiving the study drug on the termination date, data on vital events were collected for an additional 30 days.
Outcomes
 The primary composite outcome was ESRD or death from cardiovascular causes. We defined ESRD as
  • the need for maintenance dialysis for 12 weeks or more or kidney transplantation.
If a patient died before undergoing dialysis for 12 weeks, the independent events-adjudication committee adjudicated whether the need for dialysis represented ESRD or acute renal failure. Patients who declined dialysis and who subsequently died were categorized as having had ESRD. All ESRD events were adjudicated. Death from cardiovascular causes was defined as death due to either cardiovascular or unknown causes.
The trial had three prespecified secondary outcomes —
  1. first, the change in estimated GFR as calculated with the use of the four-variable Modification of Diet in Renal Disease study equation, with serum creatinine levels calibrated to an isotope-dilution standard for mass spectrometry;
  2. second, hospitalization for heart failure or death due to heart failure; and
  3. third, a composite outcome of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death from cardiovascular causes.

The events-adjudication committee, whose members were unaware of the study assignments, evaluated whether

  • ESRD events,
  • cardiovascular events,
  • neurologic events, and
  • deaths
met the prespecified criteria for primary and secondary outcomes (described in detail in the Supplementary Appendix).
Statistical Analysis
We calculated that we needed to enroll 2000 patients on the basis of the following assumptions:

  • a two-sided type I error rate of 5%, an event rate of 24% for the primary composite outcome in the placebo group during the first 2 years of the study,
  • a hazard ratio of 0.68 (bardoxolone methyl vs. placebo) for the primary composite outcome,
  • discontinuation of the study drug by 13.5% of the patients in the bardoxolone methyl group each year, and
  • a 2.5% annual loss to follow-up in each group.

Under these assumptions, if 300 patients had a primary composite outcome, the statistical power would be 85%.

We collected and analyzed all outcome data in accordance with the intention-to-treat principle. We calculated Kaplan–Meier product-limit estimates of
  • the cumulative incidence of the primary composite outcome.
We computed hazard ratios and 95% confidence intervals with the use of Cox proportional-hazards regression models with adjustment for

  • the baseline estimated GFR and urinary albumin-to-creatinine ratio.

We performed analogous analyses for secondary time-to-event outcomes. Given the abundance of early adverse events, we also report discrete cumulative incidences at 4 weeks and 52 weeks.

For longitudinal analyses of estimated GFR, we performed mixed-effects regression analyses using

  1. study group,
  2. time,
  3. the interaction of study group with time,
  4. estimated GFR at baseline,
  5. the interaction of baseline estimated GFR with time, and
  6. urinary albumin-to-creatinine ratio as covariates, and
  7. we compared the means between the bardoxolone methyl group and the placebo group.
We adopted similar approaches when examining the effects of treatment on other continuous measures assessed at multiple visits. Since the between-group difference in the primary composite outcome was not significant,
secondary and other outcomes with P values of less than 0.05 were considered to be nominally significant.
Statistical analyses were performed with the use of SAS software, version 9.3 (SAS Institute). Additional details of the statistical analysis are provided in the Supplementary Appendix.

Results

Patients

From June 2011 through September 2012, a total of 2185 patients underwent randomization, including 1545 (71%) in the United States, 334 (15%) in the European Union, 133 (6%) in Australia, 87 (4%) in Canada, 46 (2%) in Israel, and 40 (2%) in Mexico. Figure S2 in the Supplementary Appendix shows the disposition of the study participants.
As shown in Table 1Table 1Baseline Characteristics of the Patients in the Intention-to-Treat Population., the patients were diverse with respect to age, sex, race or ethnic group, and region of origin;
  • diabetic retinopathy and neuropathy were common conditions among the patients,
  • as was overt cardiovascular disease.
See Table S2 in the Supplementary Appendix for a more detailed description of the characteristics of the patients at baseline; Figure S3 in the Supplementary Appendix shows the distribution of baseline estimated GFR and urinary albumin-to-creatinine ratio.
Drug Exposure
The median duration of exposure to the study drug was 7 months (interquartile range, 3 to 11) among patients randomly assigned to bardoxolone methyl and
  • 8 months (interquartile range, 5 to 11) among those randomly assigned to placebo.
Figure S4 in the Supplementary Appendix shows the time to discontinuation of the study drug. Table S3 in the Supplementary Appendix shows the reasons that patients discontinued the study drug and the reasons that patients discontinued the study.
  • The median duration of follow-up was 9 months in both groups.

Outcomes

Primary Composite Outcome
A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92) (Figure 1AFigure 1Kaplan–Meier Plots of the Time to the First Event of the Primary Outcome and Its Components.).
  • Death from cardiovascular causes occurred in 27 patients randomly assigned to bardoxolone methyl and in 19 randomly assigned to placebo (hazard ratio, 1.44; 95% CI, 0.80 to 2.59; P=0.23) (Figure 1B).
  • ESRD developed in 43 patients randomly assigned to bardoxolone methyl and in 51 randomly assigned to placebo (hazard ratio, 0.82; 95% CI, 0.55 to 1.24; P=0.35) (Figure 1C).

One patient in each group died from cardiovascular causes after the development of ESRD. The mean (±SD) estimated GFR

  • before the development of ESRD was 18.1±8.3 ml per minute per 1.73 m^2 in the bardoxolone methyl group and
  • 14.9±4.0 ml per minute per 1.73 m2 in the placebo group.
Secondary Outcomes
During the study period, 96 patients in the bardoxolone methyl group had heart-failure events (93 patients with at least one hospitalization due to heart failure and 3 patients who died from heart failure without hospitalization),
  • as compared with 55 in the placebo group (55 patients with at least one hospitalization due to heart failure and
  • no patients who died from heart failure without hospitalization) (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001) (Figure 2AFigure 2Kaplan–Meier Plots of the Time to the First Event of the Discrete Secondary Outcomes.).
A total of 139 patients in the bardoxolone methyl group, as compared with 86 in the placebo group, had
  • a composite outcome event of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death from cardiovascular causes (hazard ratio, 1.71; 95% CI, 1.31 to 2.24; P<0.001) (Figure 2B).
Incidences of Composite Outcomes and Rates of Death from Any Cause
The cumulative incidences of the primary composite outcome and of the two secondary composite outcomes at 4 weeks and at 52 weeks are shown in Table S4 in the Supplementary Appendix. The rates of death from any cause are shown in Figure S5 in the Supplementary Appendix. From the time of randomization to the end of follow-up, 75 patients died: 44 patients in the bardoxolone methyl group and 31 in the placebo group (hazard ratio, 1.47; 95% CI, 0.93 to 2.32; P=0.10). The causes of death are listed in Table S5 in the Supplementary Appendix.

Estimated GFR

Patients randomly assigned to placebo had a significant mean decline in the estimated GFR from the baseline value (−0.9 ml per minute per 1.73 m2; 95% CI, −1.2 to −0.5), whereas those randomly assigned to bardoxolone methyl had a significant mean increase from the baseline value (5.5 ml per minute per 1.73 m2; 95% CI, 5.2 to 5.9). The difference between the two groups was 6.4 ml per minute per 1.73 m2 (95% CI, 5.9 to 6.9; P<0.001) (Figure 3AFigure 3Estimated Glomerular Filtration Rate (GFR), Body Weight, and Urinary Albumin-to-Creatinine Ratio.).
Physiological Variables
Physiological variables are shown in Table S6 in the Supplementary Appendix. The mean body weight remained stable in the placebo group
  • but declined steadily and substantially in the bardoxolone methyl group (Figure 3B).
There was a significantly smaller decrease from baseline in mean systolic blood pressure in the bardoxolone methyl group than in the placebo group (between-group difference, 1.5 mm Hg [95% CI, 0.5 to 2.5]), and
  • the mean diastolic blood pressure increased from baseline in the bardoxolone methyl group whereas it decreased in the placebo group (between-group difference, 2.1 mm Hg [95% CI, 1.6 to 2.6]).
Blood-pressure results from the substudy in which ambulatory blood-pressure monitoring was performed were similar in direction but were more pronounced (between-group difference of 7.9 mm Hg [95% CI, 3.8 to 12.0] in systolic blood pressure and 3.2 mm Hg [95% CI, 1.3 to 5.2] in diastolic blood pressure).
  • Heart rate also increased significantly in the bardoxolone methyl group, as compared with the placebo group (between-group difference, 3.8 beats per minute; 95% CI, 3.2 to 4.4).
Other Laboratory Variables
Data on laboratory variables are shown in Table S7 in the Supplementary Appendix.
  • The urinary albumin-to-creatinine ratio increased significantly in the bardoxolone methyl group, as compared with the placebo group (Figure 3C).
  • Serum magnesium, albumin, hemoglobin, and glycated hemoglobin levels decreased significantly in the bardoxolone methyl group, as compared with the placebo group.
  • The level of B-type natriuretic peptide increased significantly by week 24 in the bardoxolone methyl group, as compared with the placebo group.
Adverse Events
The rates of serious adverse events are summarized in Table 2Table 2Most Commonly Reported Serious Adverse Events in the Intention-to-Treat Population. Serious adverse events occurred more frequently in the bardoxolone methyl group than in the placebo group (717 events in 363 patients vs. 557 events in 295 patients). There were 11 neoplastic events in the bardoxolone methyl group and 10 in placebo group. The most commonly reported adverse events are summarized in Table S8 in the Supplementary Appendix.

Discussion

The current trial was designed to determine whether bardoxolone methyl, an activator of the cytoprotective Nrf2 pathway, would reduce the risk of ESRD
  • among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease
  • who were receiving guideline-based conventional therapy.
The trial was terminated early because of safety concerns, driven primarily by an increase in cardiovascular events in the bardoxolone methyl group. Bardoxolone methyl did not lower the risk of ESRD or of death from cardiovascular causes, although too few events occurred during the trial to reliably determine the true effect of the drug on the primary composite outcome.
Given the truncated duration of the trial and the number of adjudicated events (46% of the events planned), and assuming no change in any of the original assumptions, we estimated the conditional power of the trial to be less than 40%. Although patients treated with bardoxolone methyl had a significant increase in the estimated GFR, as compared with those who received placebo,
  • there was a significantly higher incidence of heart failure and of the composite outcome of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death from cardiovascular causes in the bardoxolone methyl group.
  • There were numerically more deaths from any cause among patients treated with bardoxolone methyl than among those in the placebo group.
Bardoxolone methyl is among the first orally available antioxidant Nrf2 activators. A small previous study showed that bardoxolone methyl
  • reduced inflammation and oxidative stress13 and
  • induced a decline in the serum creatinine level.
In the 52-Week Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes (BEAM) trial,15 227 patients with type 2 diabetes mellitus and an estimated GFR of 20 to 45 ml per minute per 1.73 m2
  • had a significant increase in the estimated GFR (mean change, 8.2 to 11.4 ml per minute per 1.73 m2, depending on the dose group)
  • that was sustained over the entire trial period.
Muscle spasms and hypomagnesemia were the most common adverse events;
  • there was no increase in the rate of heart failure or other cardiovascular events.
The current trial was designed to determine whether the change in estimated GFR that we anticipated on the basis of the results of the BEAM trial would translate into a slower progression toward ESRD. Although in the current trial ESRD developed in fewer patients in the bardoxolone methyl group than in the placebo group, the early termination of the trial precludes conclusion of the effect on ESRD events.
The mechanism linking bardoxolone methyl to heart failure is unknown. Since an excess in heart-failure events was unanticipated, echocardiography was not performed routinely before randomization. Although weight declined significantly in the bardoxolone methyl group, we were unable to determine whether there was loss of body fat, intracellular (skeletal muscle) water, or extracellular (interstitial) water.
The fall in serum albumin and hemoglobin levels may reflect hemodilution caused by fluid retention.
Bardoxolone methyl also increased blood pressure.
An increase in preload due to volume expansion and an increase in afterload (as reflected by increased blood pressure),
  • coupled with an increase in heart rate,
  • constitute a potentially potent combination of factors that are likely to precipitate heart failure in an at-risk population.
The rise in the level of B-type natriuretic peptide with bardoxolone methyl
  • is consistent with an increase in left ventricular wall stress owing to one or more of these mediators or to unrecognized factors such as
  • impaired diastolic filling of the left ventricle.
After recognizing the initial increase in heart-failure events, the independent data and safety monitoring committee tried to identify
  • clinical characteristics that were associated with patients who were at elevated risk for heart failure
  • after the initiation of bardoxolone methyl therapy (with the possibility of modifying eligibility criteria or otherwise altering the trial),
but the committee was unable to do so. Other, noncardiovascular adverse events were also observed more frequently among patients exposed to bardoxolone methyl than among those who received placebo. Whether the effects of Nrf2 activation, or one or more counterregulatory responses, rendered this particular population vulnerable, is unknown. Zoja et al.18 found an increase in albuminuria and blood pressure along with weight loss in Zucker diabetic fatty rats treated with an analogue of bardoxolone methyl; these effects were not observed in other studies in Zucker diabetic fatty rats or other rodent models or in 1-year toxicologic studies in monkeys.19-21
Why were these adverse effects identified in the current trial and not in the BEAM trial?
  1. First, the number of patient-months of drug exposure in the current trial was roughly 10 times that in the BEAM trial.
  2. Second, the population in the present trial had more severe chronic kidney disease than did the population in the BEAM trial.
Observational studies have shown significantly higher rates of death and cardiovascular events, including heart failure,
  • among patients with stage 4 chronic kidney disease than among patients with stage 3 chronic kidney disease.22
Finally, our trial used an amorphous spray-dried dispersion formulation of bardoxolone methyl at a fixed dose rather than at an adjusted dose. We chose the 20-mg dose and the specific formulation used in the BEACON trial
  1. on the basis of four phase 2 studies of chronic kidney disease (three studies used the crystalline formulation, and one used the amorphous formulation),
  2. a crossover pharmacokinetics study involving humans that used both formulations, and
  3. several studies in animals that used both formulations (Meyer C: personal communication),
to provide an activity and safety profile that was similar to that observed with 75 mg of the crystalline formulation, which was one of the dose levels tested in the BEAM trial.
In conclusion, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of the primary composite outcome of ESRD or death from cardiovascular causes. Significantly increased risks of heart failure and of the composite cardiovascular outcome (nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death from cardiovascular causes) prompted termination of the trial.
Alto, CA 93034, or at gchertow@stanford.edu.
Investigators in the Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: the Occurrence of Renal Events (BEACON) trial are listed in the Supplementary Appendix, available at NEJM.org.
Table 1. Baseline Characteristics of the Patients in the Intention-to-Treat Population.

Fig 1. Kaplan–Meier Plots of the Time to the First Event of the Primary Outcome and Its Components.

nejmoa1303154_f1   Kaplan–Meier Plot of Cumulative Probabilities of the Primary and Secondary End Points and Death.

Fig 2. Kaplan–Meier Plots of the Time to the First Event of the Discrete Secondary Outcomes

nejmoa1303154_f2  Kaplan–Meier Plot of Cumulative Probabilities of Acute Kidney Injury and Hyperkalemia
Fig 3.  Estimated Glomerular Filtration Rate (GFR), Body Weight, and Urinary Albumin-to-Creatinine Ratio
Table 2  Most Commonly Reported Serious Adverse Events in the Intention-to-Treat Population

References

    1  Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med 1994;330:877-884
    2  The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-2572
    3  Parving HH, Andersen AR, Smidt UM, Svendsen PA. Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1983;1:1175-1179
    4  Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869
    5 Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-860
   6  Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-878
    7  Heerspink HJ, de Zeeuw D. The kidney in type 2 diabetes therapy. Rev Diabet Stud 2011;8:392-402
    8  Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019-2032
    9   Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204-2213
    10   Packham DK, Wolfe R, Reutens AT, et al. Sulodexide fails to demonstrate renoprotection in overt type 2 diabetic nephropathy. J Am Soc Nephrol 2012;23:123-130
Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy
Linda F. Fried, M.D., M.P.H., Nicholas Emanuele, M.D., Jane H. Zhang, Ph.D., Mary Brophy, M.D., Todd A. Conner, Pharm.D., William Duckworth, M.D., David J. Leehey, M.D., Peter A. McCullough, M.D., M.P.H., Theresa O’Connor, Ph.D., Paul M. Palevsky, M.D., Robert F. Reilly, M.D., Stephen L. Seliger, M.D., Stuart R. Warren, J.D., Pharm.D., Suzanne Watnick, M.D., Peter Peduzzi, Ph.D., and Peter Guarino, M.P.H., Ph.D. for the VA NEPHRON-D Investigators
N Engl J Med 2013; 369:1892-1903November 14, 2013DOI: 10.1056/NEJMoa1303154
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Background
Combination therapy with angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain.
Methods
We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m2 of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥30 ml per minute per 1.73 m2 if the initial estimated GFR was ≥60 ml per minute per 1.73 m2 or a decline of ≥50% if the initial estimated GFR was <60 ml per minute per 1.73 m2), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury.
Results
The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001).
Conclusions
Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.)
A complete list of investigators in the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study is provided in the Supplementary Appendix, available at NEJM.org.
Figure 1  Kaplan–Meier Plot of Cumulative Probabilities of the Primary and Secondary End Points and Death.
Figure 2 Kaplan–Meier Plot of Cumulative Probabilities of Acute Kidney Injury and Hyperkalemia

The End of Dual Therapy with Renin–Angiotensin–Aldosterone System Blockade?

Nov 14, 2013       de Zeeuw D.  (Editorial)
 N Engl J Med 2013; 369:1960-1962
Treatment aimed at multiple risk factors and specific markers such as glucose level, blood pressure, body weight, cholesterol levels, and albuminuria has been the main focus to slow cardiovascular and renal risk among patients with diabetes. Among the agents used, those that interrupt the renin–angiotensin–aldosterone system (RAAS) have shown protection that extends beyond decreasing blood pressure. In part, these additional effects may be explained by a decrease in albuminuria.1 Therefore, angiotensin-converting–enzyme (ACE) inhibitors and angiotensin II–receptor blockers (ARBs) have become first-choice drugs in patients with diabetes. Despite some success, the residual cardiovascular and renal risk among patients with diabetes remains

Diabetes: Mouse Studies Point to Kinase as Treatment Target

Published: Nov 24, 2013
By Kristina Fiore, Staff Writer, MedPage Today

Targeting a pathway that plays a major role in both hepatic glucose production and insulin sensitivity may eventually help treat type 2 diabetes, researchers reported.
In a series of experiments in mice, researchers found that inhibition of the kinase CaMKII — or even some of its downstream components — lowered blood glucose and insulin levels, Ira Tabas, MD, PhD, of Columbia University Medical Center in New York City, and colleagues reported online in Cell Metabolism.
The pathway is activated by glucagon signaling in the liver, and appears to have roles in both insulin resistance as well as hepatic glucose production in the liver.
In an earlier study, Tabas and colleagues showed that inhibiting the CaMKII pathway lowered hepatic glucose production by suppressing p38-mediated FoxO1 nuclear localization.
In the current study, they found CaMKII inhibition suppresses levels of the pseudo-kinase TRB3 to improve Akt-phosphorylation, thereby improving insulin sensitivity.
Thus this single pathway targets “two cardinal features of type 2 diabetes — hyperglycemia and defective insulin signaling,” the researchers wrote.
“When we realized we had one common pathway that was responsible for these two disparate processes that, in essence, comprises all of type 2 diabetes, we though it would be an ideal target for new drug therapy,” Tabas told MedPage Today.
Tabas and colleagues conducted several experiments to evaluate the CaMKII pathway.
In one experiment in obese mice, they found that

  • no matter how CaMKII was knocked out, it led to lower blood glucose levels and lower fasting plasma insulin levels in response to a glucose challenge.

The improvements also occurred

  • when they knocked out downstream processes, including p38 and MAPK-activating protein kinase 2 (MK2).

“Thus liver p38 and MK2, like CaMKII, play an important role in the development of hyperglycemia and hyperinsulinemia in obese mice,” they wrote.
In further analyses, the researchers discovered

  • deleting or inhibiting any of these three elements ultimately improved insulin-induced Akt-phosphorylation in obese mice —
  • an important part of improving insulin sensitivity.

And unlike the effects on hepatic glucose production, these changes didn’t occur through effects on FoxO1.
Instead, inhibiting the CaMKII pathway suppressed levels of the pseudo-kinase TRB3, which likely occurred because of suppression of ATF4

  • all of which led to an increase in Akt-phosphorylation and insulin sensitivity.

Indeed, when mice were made to overexpress TRB3, the improvement in phosphorylation disappeared, “indicating that

  • the suppression of TRB3 by CaMKII deficiency is causally important in the improvement in insulin signaling,” they wrote.

As a result, there “appear to be two separate CaMKII pathways,

  • one involved in CaMKII-p38-FoxO1 dependent hepatic glucose production, and
  • the other involved in defective insulin-induced p-Akt,” they wrote.

The findings suggest the possibility of a drug that can target both hyperglycemia and insulin resistance in type 2 diabetes, they said.

Association Between a Genetic Variant Related to Glutamic Acid Metabolism and Coronary Heart Disease in Individuals With Type 2 Diabetes

Lu Qi; Qibin Qi; S Prudente; C Mendonca; F Andreozzi; et al.
JAMA. 2013;310(8):821-828.     http://dx.doi.org/10.1001/jama.2013.276305.

Importance

Diabetes is associated with an elevated risk of coronary heart disease (CHD). Previous studies have suggested that the genetic factors predisposing to excess cardiovascular risk may be different in diabetic and nondiabetic individuals.

Objective

To identify genetic determinants of CHD that are specific to patients with diabetes.

Design, Setting, and Participants

We studied 5 independent sets of CHD cases and CHD-negative controls from the Nurses’ Health Study (enrolled in 1976 and followed up through 2008), Health Professionals Follow-up Study (enrolled in 1986 and followed up through 2008), Joslin Heart Study (enrolled in 2001-2008), Gargano Heart Study (enrolled in 2001-2008), and Catanzaro Study (enrolled in 2004-2010). Included were a total of 1517 CHD cases and 2671 CHD-negative controls, all with type 2 diabetes. Results in diabetic patients were compared with those in 737 nondiabetic CHD cases and 1637 nondiabetic CHD-negative controls from the Nurses’ Health Study and Health Professionals Follow-up Study cohorts. Exposures included 2 543 016 common genetic variants occurring throughout the genome.

Main Outcomes and Measures

Coronary heart disease—defined as fatal or nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or angiographic evidence of significant stenosis of the coronary arteries.

Results

A variant on chromosome 1q25 (rs10911021) was consistently associated with CHD risk among diabetic participants,

  • with risk allele frequencies of 0.733 in cases vs 0.679 in controls (odds ratio, 1.36 [95% CI, 1.22-1.51]; P = 2 × 10−8).

No association between this variant and CHD was detected among nondiabetic participants, with risk allele frequencies of 0.697 in cases vs 0.696 in controls (odds ratio, 0.99 [95% CI, 0.87-1.13]; P = .89),

  • consistent with a significant gene × diabetes interaction on CHD risk (P = 2 × 10−4).

Compared with protective allele homozygotes, rs10911021 risk allele

  • homozygotes were characterized by a 32% decrease in the expression of the neighboring glutamate-ammonia ligase (GLUL) gene in human endothelial cells (P = .0048).
  • A decreased ratio between plasma levels of γ-glutamyl cycle intermediates pyroglutamic and glutamic acid was also shown in risk allele homozygotes (P = .029).

Conclusion and Relevance

A single-nucleotide polymorphism (rs10911021) was identified that was significantly associated with CHD among persons with diabetes but not in those without diabetes and was functionally related to glutamic acid metabolism, suggesting a mechanistic link.

Adipocyte Heme Oxygenase-1 Induction Attenuates Metabolic Syndrome In Both Male And Female Obese Mice

Angela Burgess1,2, Ming Li2, Luca Vanella1, Dong Hyun Kim1, Rita Rezzani4, et al.

1Department of Physiology and Pharmacology, University of Toledo, Toledo, OH 43614
2Department of Pharmacology, New York Medical College, Valhalla, NY 10595
3Department of Medicine, New York Medical College, Valhalla, NY 10595
4Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy
5Department of Pediatrics and Center for Applied Genomics, Charles University, Prague, Czech Republic
6The Rockefeller University, New York, New York 10065

Hypertension. 2010 December ; 56(6): 1124–1130.    http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.151423

Abstract

Increases in visceral fat are associated with
  • increased inflammation,
  • dyslipidemia,
  • insulin resistance,
  • glucose intolerance and
  • vascular dysfunction.
We examined the effect of the potent heme oxygenase (HO)-1 inducer, cobalt protoporphyrin (CoPP), on regulation of adiposity and glucose levels in both female and male obese mice. Both lean and obese mice were administered CoPP intraperitoneally, (3mg/kg/once a week) for 6 weeks. Serum levels of
  1. adiponectin,
  2. TNFα,
  3. IL-1β and
  4. IL-6, and
  5. HO-1,
  6. PPARγ,
  7. pAKT, and
  8. pMPK protein expression
were measured in adipocytes and vascular tissue . While female obese mice continued to gain weight at a rate similar to controls, induction of HO-1 slowed the rate of weight gain in male obese mice. HO-1 induction led to lowered blood pressure
levels in obese males and females mice similar to that of lean male and female mice.
HO-1 induction also produced a significant decrease in the plasma levels of IL-6, TNF-α, IL-1β and fasting glucose of obese females compared to untreated female obese mice. HO-1 induction
  • increased the number and
  • decreased the size of adipocytes of obese animals.
HO-1 induction increased adiponectin, pAKT, pAMPK, and PPARγ levels in adipocyte of obese animals. Induction of HO-1, in adipocytes was associated with
  • an increase in adiponectin and
  • a reduction in inflammatory cytokines.
These findings offer the possibility of treating not only hypertension, but also other detrimental metabolic consequences of obesity
  • including insulin resistance and dyslipidemia in obese populations
  • by induction of HO-1 in adipocytes.
Introduction
Moderate to severe obesity is associated with increased risk for cardiovascular complications and insulin resistance in humans1, 2 and animals3, 4. Cardiovascular risk is specifically associated with increased intra-abdominal fat. Women in their reproductive years have a higher BMI than males, which largely reflects increased overall subcutaneous adipose tissue or “gynoid” obesity, this is not associated with increased cardiovascular risk5. However, due to increases in visceral fat with aging, after the age of 60 the fat distribution in females more closely resembles that in males6. Increased androgen levels also often occur after the menopausal transition. These changes in visceral fat content and androgen levels correlate with both central obesity and insulin resistance and are an important determinant of cardiovascular risk7.
Heme oxygenase (HO) catalyzes the breakdown of heme, a potentially harmful pro-oxidant, into its products biliverdin and carbon monoxide, with a concomitant release of iron (reviewed in8). While HO-2 is expressed constitutively, HO-1 is inducible in response to oxidative stress and its induction has been reported to normalize vascular and renal function9–11. Further, induction of HO-1 slows weight gain, decreases levels of TNF-α and IL-6 and increases serum levels of adiponectin in obese rats and obese diabetic mice4, 9, 12.
The association observed between HO-1 and adiponectin has led to the proposal of the existence of a cytoprotective HO-1/adiponectin axis4, 13. Previously, L’Abbate et al,14 have shown that induction of HO-1 is associated with a parallel increase in the serum levels of adiponectin, which has well-documented
  1. insulin-sensitizing,
  2. antiapoptotic,
  3. antioxidative and
  4. anti-inflammatory properties.
Adiponectin is an abundant protein secreted from adipocytes. Once secreted, it mediates its actions by binding to a set of receptors, such as
  • adipoR1 and adipoR2, and also
  • through induction of AMPK signaling pathways15, 16.
In addition, increases in adiponectin play a protective role against TNF mediated endothelial activation17.
In this study, we evaluated the effect of CoPP, a potent inducer of HO-1,
  • on visceral and subcutaneous fat distribution in both female and male obese mice.
We show for the first time a resistance to weight reduction upon administration of CoPP in female obese mice but
  • a significant decrease in inflammatory cytokines.
Despite continued obesity,
  1. CoPP normalized blood pressure levels,
  2. decreased circulating cytokines, and
  3. increased insulin sensitivity in obese females.
CoPP treatment of obese mice
  • increased the number and
  • reduced the size of adipocytes.
CoPP treatment of both male and female obese mice reversed the reduction in adiponectin levels seen in obesity. This study suggests that in spite of continued obesity,
  • HO-1 induction in female obese mice serves a protective role against obesity associated metabolic consequences via expansion of healthy smaller insulin-sensitive adipocytes.

Results

Effect of induction of HO-1 on body weight, appearance, and fat content of female and male obese mice. Previously, we have shown CoPP treatment results in the prevention of weight gain in several male models of obesity including obese and db/db mice and Zucker fat rats4, 12. We extended our studies to examine the effect of CoPP on weight gain in female obese mice. CoPP-treatment prevented weight gain in male obese mice when compared to age-matched male controls (Figure S1). The revention of body weight gain was accompanied by a
reduction in visceral fat in male obese mice. However, female obese mice administered CoPP did not lose weight but continued to gain weight at the same rate as untreated female obese mice (Figure S1). This was in spite of food intake being comparable between the two
groups. CoPP administration decreased subcutaneous fat content in both obese males and females (p<0.05; p<0.05, respectively). CoPP produced a decrease (p<0.05) in visceral fat in male but not in female obese mice when compared to untreated obese mice (Figure S1D).
We examined adipocyte size by haematoxilin-eosin staining in both lean, obese and CoPP treated obese female mice (Figure 1A, upper panel). CoPP treatment resulted in a decrease in adipocyte size (p<0.05) compared to untreated obese animals (Figure 1A, lower left panel). We then examined the number of adipocytes in lean, obese and CoPP-treated obese female mice. The number of adipocytes (mean±SE) in lean, obese and CoPP-treated obese animals was 40.83±3.50, 18.33±1.80 and 32.00±1.67 respectively indicating that CoPP treatment of obese mice increased the number of adipocytes to levels similar to those in lean animals (Figure 1A, lower right panel). Similar results were seen in male animals.
The induction of HO-1 was associated with a reduction in blood pressure (BP). Systolic blood pressure in obese female mice was 142 ± 6.5 mm Hg compared to obese-CoPP treated, 109 ± 8.1 mm Hg, p<0.05. The value in obese female mice treated with CoPP is similar to the blood pressure seen in lean female mice (110 ± 9.6 mm Hg). The systolic blood pressure in obese male mice was 144± 4.5 mm Hg compared to obese-CoPP treated, 104 ± 3.6 mm Hg, p<0.05.
We further examined whether CoPP affects HO-1 expression in adipocyte using immunohistochemistry and western blot analysis. Immunostaining showed increased levels of HO-1 (green staining), located on the surface of adipocytes, after CoPP treatment (p<0.05), compared with female obese mice, Figure 1B. As seen in Figure 1C, HO-1 and

HO-2 levels in adipocyte isolated from lean, untreated female obese mice or female obese mice treated with CoPP. Densitometry analysis showed that HO-1 was increased
significantly in female obese mice treated with CoPP, compared to non-treated female obese mice, p<0.05, which is in agreement with immunohistochemistry results. This pattern of HO expression in obesity occurs in other tissues, including aortas, kidneys and hearts of male obese mice4, 13.
Effect of CoPP on HO-1 expression and HO activity in female and male obese mice
HO-1 protein levels were increased by CoPP treatments in liver and renal tissues similar to that seen in adipocytes. Western blot analysis showed significant differences  (p<0.05) in the ratio of HO-1 to actin in renal of male and female obese and lean mice (Figure S 2A). Obesity decreasd HO-1 levels in both sexes when compared to age matched lean animals.
In addition, HO-1 levels were significantly (p<0.05) lower in obese females compared to obese males (Figure S 2A). This reflects a less active HO system in both male and female
obese animals compared to age matched lean controls. Next, we compared the effect of CoPP on male and female HO-1 gene expression in adipocytes. CoPP increased HO-1
expression in both male and female obese animals compared to untreated obese animals (Figure S 2B, p<0.001 and p<0.001, respectively). Similar results of HO-1 expression were seen in liver tissues (Result not shown).
Effect of CoPP on cytokine levels in female and male obese mice
CoPP administration resulted in a significnt increase in the levels of plasma adiponectin in both female (p<0.001) and male obese (p<0.001) mice (Figure 2A). Untreated female obese animals exhibited a significant (p<0.05) increase in plasma IL-6 levels when compared to age-matched male obese mice (Figure 2B). CoPP decreased plasma IL-6 levels in both female and male obese mice (p<0.05A )p<0.01, respectively) when compared to untreated obese miec. Similar results were observed with plasma TNF-α and IL-1β levels (Figure 2C and 2D). These results indicate that though female obese mice exhibited elevated serum levels of inflammatory cytokines compared to male obese mice, CoPP acts with equal efficacy in both female and male obese animals in reducing inflammation while simultaneously increasing serum adiponectin levels (Figure 2). 

Effect of CoPP on blood glucose and LDL levels in female and male obese mice 

Fasting glucose levels were determined after the development of insulin resistance. CoPP produced a decrease in glucose levels in both fasting female (p<0.05) and male (p<0.001) obese mice when compared to untreated obese control animals (Figure 3A). CoPP reduced LDL levels in both male (p<0.01) and female (p<0.05) obese mice when compared to untreated obese controls (Figure 3B). Treatment with SnMP, increased LDL levels. In separate experiments two weeks apart, glucose levels and insulin sensitivity were determined after development of insulin resistance (Fig. 4A and B). Blood glucose levels in female obese mice were elevated (p<0.01) 30 min after glucose administration and remained elevated. In CoPP-treated female obese mice produced a decrease in glucose but not in the vehicle-treated female obese mice (p<0.01).

Effect of Obesity on Protein Expression Levels of pAKT, pAMPK, and PPARγ levels in female and male obese mice

Western blot analysis of adipocytes harvested from fat tissues,showed significant  differences in basal protein expression levels of pAKT and pAMPK in untreated female obese mice compared to untreated obese male mice. pAMPK levels were higher in obese females compared to obese males (Figure 5A, p< 0.05). This was also the case for pAKT protein levels, where increased levels of pAKT were seen in obese females compared to obese males (Figure 5B, p<0.05). CoPP treatment increased pAMPK and pAKT levels in bothe obese females and obese males. In addition, CoPP administration increased PPARγ levels, in both male (p<0.001) and female (p<0.05) obese mice (Figures 5C).

Discussion

In the current study, we show for the first time that induction of HO-1 regulates adiposity in both male and female animals via an increase in adipocyte HO-1 protein levels. A second novel finding is that induction of HO-1 was associated not only with a decrease in adipocyte cell size but with an increase in adipocyte cell number. Further, induction of HO-1 affects visceral and subcutaneous fat distribution and metabolic function in male obese mice differently than in female obese mice. Despite continued obesity, upregulation of HO-1 induced major improvements in the metabolic profile of female obese mice exhibiting symptoms of Type 2 diabetes including: high plasma levels of proinflammatory cytokines, hyperglycemia, dyslipidemia, and low adiponectin levels. CoPP treatment resulted in increased serum adiponectin levels and decreased blood pressure. Adiponectin is exclusively secreted from adipose tissue, and its expression is higher in subcutaneous rather than invisceral adipose tissue. Increased adiponectin levels reduce adipocyte size and increase adipocyte number12, resulting in smaller, more insulin sensitive adipocytes. Adiponectin has recently attracted much attention because it has insulin-sensitizing properties that enhance fatty acid oxidation, liver insulin action, and glucose uptake and positively affect serum trglyceride levels18–21. Levels of circulating adiponectin are inversely correlated with plasma levels of oxidized LDL in patients with Type 2 diabetes and coronary artery disease, which suggests that low adiponectin levels are associated with an increased oxidative state in the arterial wall22. Thus, increases in adiponectin mediated by upregulation of HO-1 may account for improved insulin sensitivity and reduced levels of LDL and inflammatory cytokines (TNF-α, IL-1β, and IL-6 levels) in both male and female mice.

 Females continued to gain weight in spite of the metabolic improvements. One plausible explanation for this anomaly is the direct effects of HO-1 on adiponectin mediating clonal expansion of pre-adipocytes. This supports the concept that expansion of adipogenesis leads to an increased number of adipocytes of smaller cell size; smaller adipocytes are considered to be healthy, insulin sensitive adipocyte cells that are capable of producing adiponectin23. This hypothesis is supported by the increase in the number of smaller adipocytes seen in
CoPP-treated female obese animals without affecting weight gain when compared to female obese animals. Similar results for the presence were seen in males indicating that this effect is not sex specific.
Upregulation of HO-1 was also associated with increased levels of adipocyte pAKT, and pAMPK and PPARγ levels. Previous studies have indicated that insulin resistance and  impaired PI3K/pAKT signaling can lead to the of endothelial dysfunction24. In the current study, increased HO-1 expression was associated with increases in both AKT and AMPK phosphorylation; these actions may protect renal arterioles from insulin mediated endothelial damage. By this mechanism, increased levels of HO-1 limit oxidative stress and facilitate activation of an adiponectin-pAMPK-pAKT pathway and increased insulin sensitivity. Induction of adiponectin and activation of the pAMPK-AKT pathway has been shown to provide vascular protection25, 26. A reduction in AMPK and AKT levels may also explain why inhibition of HO activity in CoPP-treated obese mice  increased inflammatory cytokine levels while decreasing adiponectin. The action of CoPP in increasing pAKT, pAMPK and PPARγ is associated with improved glucose tolerance and decreased insulin resistant.

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Under Nutrition Early in Life may lead to Obesity

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

With the growing worldwide obesity epidemic, including huge populations in developing countries, such as China, India, Mexico and Brazil, the causes of this health and economic catastrophe have been increasingly studied. It is well known that metabolic syndrome and obesity exhibit a high correlation with low or absent physical exercise practices and the consumption of calorie-rich diets in developing countries; however, although the inhabitants may actually experience a nutrition transition, high levels of overweight and obese individuals could not be justified solely by diet and physical inactivity, other hallmarks, such as metabolic programming by the under nutrition early in life and epigenetic modification could also be underlining the obesity onset.

In addition to the pathophysiological aspects that have emerged from studies on metabolic programming caused by environmental insults during fetal life, another interesting point that is relevant to this issue is the role of epigenetic changes in the increased risk of developing metabolic diseases, such as type 2 diabetes and obesity, later in life. Epigenetic mechanisms, such as DNA methylation and/or nucleoprotein acetylation/methylation, are crucial to the normal/physiological development of several tissues in mammals, and they involve several mechanisms to guarantee fluctuations of enzymes and other proteins that regulate the metabolism. As previously reviewed, the intrauterine phase of development is particularly important for the genomic processes related to genes associated with metabolic pathways. Therefore, this phase of life may be particularly important for nutritional disturbance. In humans who experienced the Dutch famine Winter in 1944–1945 and in rats that were deprived of food in utero, epigenetic modifications were detected in the insulin-like growth factor 2 (IGF2) and pancreatic and duodenal home box 1 (Pdx1), which are the major factors involved in pancreas development and pancreatic β-cell maturation. Although it is known that the pancreas and the pancreatic β-cells develop/maturate during the embryonic phase, the postnatal life is also crucial for the maintenance processes that control the β-cell mass, such as proliferation, neogenesis and apoptosis. Nevertheless, no data on metabolic programming as the result of protein-restricted diet during lactation only have yet been reported, and no direct association with epigenetic modifications has been observed; on the other hand, because stressor insults during the milk suckling phase can lead to disturbances in glucose metabolism, hypothalamic neurons, ANS activity and β-cell mass/function of the pancreatic β-cells in rodents, further studies are needed on this topic.

Two decades ago, it was observed that low birth weight was related to adult chronic, non-transmissible diseases, such as type 2 diabetes, cardiovascular disease and obesity. It has been speculated that a nutritional injury during perinatal growth, including uterine and early postnatal life, may contribute to adapting the adult metabolism toward nutritional restriction. However, if an abundant diet is offered to people who have been undernourished during the perinatal life, this opportunity induces a metabolic shift toward the storage of energy and high fat tissue accumulation, thus leading to high risks of the onset of metabolic/coronary diseases onset. These observations led to the introduction of the term DOHaD (Developmental Origins of Health and Disease) previously known as the Barker thrifty phenotype hypothesis. Currently, the concept of DOHaD is extended to any other insults during perinatal life, pregnancy and/or lactation, such as underweight, overweight, diabetic or hyperplasic mothers. This concept also includes any type of stressful situations that may predispose babies or pups to develop metabolic disorders when they reach adulthood.

Source References:

 

http://www.nutritionandmetabolism.com/content/9/1/80

 

http://www.ncbi.nlm.nih.gov/pubmed/19955786?dopt=Abstract&holding=f1000,f1000m,isrctn

 

http://www.ncbi.nlm.nih.gov/pubmed/12886432?dopt=Abstract&holding=f1000,f1000m,isrctn

 

http://www.ncbi.nlm.nih.gov/pubmed/8733829?dopt=Abstract&holding=f1000,f1000m,isrctn

 

http://www.ncbi.nlm.nih.gov/pubmed/9478036?dopt=Abstract&holding=f1000,f1000m,isrctn

 

 

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Reporter: Aviva Lev-Ari, PhD, RN

 

A New Protein Target for Controlling Diabetes

Researchers at the University of California, San Diego School of Medicine have identified a previously unknown biological mechanism involved in the regulation of pancreatic islet beta cells, whose role is to produce and release insulin. The discovery suggests a new therapeutic target for treating dysfunctional beta cells and type 2 diabetes, a disease affecting more than 25 million Americans.

Writing in the April 11, 2013 issue of Cell, Jerrold M. Olefsky, MD, associate dean for scientific affairs and distinguished professor of medicine, and colleagues say a transmembrane binding protein called fractalkine, which typically mediates cell-to-cell adhesion though its receptor, CX3CR1, can also be released from cells to circulate in the blood and stimulate insulin secretion.

“Our discovery of fractalkine’s role in beta cells is novel and has never been talked about in prior literature,” said Olefsky. More importantly, the research highlights fractalkine’s apparently vital role in normal, healthy beta cell function. In mouse models and in cultured human islets, the researchers found administering the protein stimulated insulin secretion and improved glucose tolerance, both key factors in diabetes.  In contrast, fractalkine had no effect in mice or islets when the fractalkine receptor was deleted.

“Whether or not decreased fractalkine or impaired fractalkine signaling are causes of decreased beta cell function in diabetes is unknown,” said Olefsky. “What we do know, without doubt, is that administration of fractalkine improves or restores insulin secretion in all of the mouse models we have examined, as well as in human islet cells.”

Olefsky said fractalkine or a protein analog could prove “a potential treatment to improve insulin secretion in type 2 diabetic patients. It might also improve beta cell function or beta cell health, beyond simply increasing insulin secretion, since fractalkine prevents beta cell apoptosis (cell death) and promotes the beta cell differentiation program.

“If successfully developed, this could be an important new complement to the therapeutic arsenal we use in type 2 diabetes,” Olefsky continued. “It is not likely to ‘cure’ diabetes, but it would certainly do a good job at providing glycemic control.”

Co-authors of this study include Yun Sok Lee, Hidetaka Morinaga, and William Lagakos, UCSD Department of Medicine, Division of Endocrinology and Metabolism; Jane J. Kim and Ayse G. Kayali, UCSD Department of Pediatrics; Susan Taylor and Malik Keshwani, UCSD Department of Pharmacology; Guy Perkins, National Center for Microscopy and Imaging Research at UCSD; Hui Dong, UCSD Department of Medicine, Division of Gastroenterology; and Ian R. Sweet, Department of Medicine, University of Washington.

Funding came, in part, from the National Institutes of Health (grants DK-033651, DK-074868, T32-DK-007494 and DK-063491) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH (U54-HD-012303-25).

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Reporter: Aviva Lev-Ari, PhD, RN

 

The healing element is also the enemy – an enigma probed by Hebrew University Lautenberg Center researchers

April 3, 2013

Jerusalem – The same factor in our immune system that is instrumental in enabling us to fight off severe and dangerous inflammatory ailments is also a player in doing the opposite at a later stage, causing the suppression of our immune response.

Why and how this happens and what can be done to mediate this process for the benefit of mankind is the subject of an article published online in the journal Immunity by Ph.D. student Moshe Sade-Feldman and Professor Michal Baniyash of the Lautenberg Center for General and Tumor Immunology at The Hebrew University Faculty of Medicine.
Chronic inflammation poses a major global health problem and is common to different pathologies — such as autoimmune diseases (diabetes, rheumatoid arthritis, lupus and Crohn’s), chronic inflammatory disorders, chronic infections (HIV, leprosy, leishmaniasis) and cancer. Cumulative data indicate that at a certain stage of each of these diseases, the immune system becomes suppressed and results in disease progression.
In their previous work, The Hebrew University researchers had shown that in the course of chronic inflammation, unique immune system cells with suppressive features termed myeloid derived suppressor cells (MDSCs) are generated in the bone marrow and migrate into the body’s organs and blood, imposing a general immune suppression.
A complex network of inflammatory compounds persistently secreted by the body’s normal or cancerous cells support MDSC accumulation, activation and suppressive functions. One of these compounds is tumor necrosis factor-a (TNF-a), which under acute immune responses (short episodes), displays beneficial effects in the initiation of immune responses directed against invading pathogens and tumor cells.
However, TNF-a also displays harmful features under chronic responses, as described in pathologies such as rheumatoid arthritis, psoriasis, type II diabetes, Crohn’s disease and cancer, leading to complications and disease progression. Therefore, today several FDA- approved TNF-a blocking reagents are used in the clinic for the treatment of such pathologies.
What has remained unclear until now, however, is just how TNF-a plays its deleterious role in manipulating the host’s immune system towards the generation of a suppressive environment.
In their work, The Hebrew University researchers discovered the mechanisms underlying the TNF-a  function, a key to controlling this factor and manipulating it, perhaps, for the benefit of humans.  Using experimental mouse models, they showed unequivocally how TNF-a is critical in the induction of immune suppression generated during chronic inflammation. The TNF-a was seen to directly affect the accumulation and suppressive function of MDSCs, leading to an impaired host’s immune responses as reflected by the inability to respond against invading pathogens or against developing tumors.
Further, the direct role of how TNF-a works in humans was mimicked by injecting the FDA-approved anti-TNF-a drug, etanercept, into mice at the exacerbated stage of an inflammatory response, when MDSC accumulation was observed in the blood. The etanercept treatment changed the features of MDSCs and abolished their suppressive activity, leading to the restoration of the host’s immune function.
Taken together, the results show clearly how the TNF-a-mediated inflammatory response, whether acute or chronic, will dictate its beneficial or harmful consequence on the immune system. While during acute inflammation TNF-a is vital for immediate immune defense against pathogens and clearance of tumor cells, during chronic inflammation — under conditions where the host is unable to clear the pathogen or the tumor cells — TNF-a is harmful due to the induction of immune suppression.
These results, providing new insight into the relationship between TNF-a and the development of an immune suppression during chronic inflammation, may aid in the generation of better therapeutic strategies against various pathologies when elevated TNF-a and MDSC levels are detected, as seen, for example, in tumor growths.

 

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