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Archive for the ‘Myocardial metabolism, Myocardial ischemia, Myocardial adenine nucleotide metabolism’ Category


Regulatory MicroRNAs in Aberrant Cholesterol Transport and Metabolism

Curator: Marzan Khan, B.Sc

Aberrant levels of lipids and cholesterol accumulation in the body lead to cardiometabolic disorders such as atherosclerosis, one of the leading causes of death in the Western World(1). The physical manifestation of this condition is the build-up of plaque along the arterial endothelium causing the arteries to constrict and resist a smooth blood flow(2). This obstructive deposition of plaque is merely the initiation of atherosclerosis and is enriched in LDL cholesterol (LDL-C) as well foam cells which are macrophages carrying an overload of toxic, oxidized LDL(2). As the condition progresses, the plaque further obstructs blood flow and creates blood clots, ultimately leading to myocardial infarction, stroke and other cardiovascular diseases(2). Therefore, LDL is referred to as “the bad cholesterol”(2).

Until now, statins are most widely prescribed as lipid-lowering drugs that inhibit the enzyme 3-hydroxy-3methylgutaryl-CoA reductase (HMGCR), the rate-limiting step in de-novo cholesterol biogenesis (1). But some people cannot continue with the medication due to it’s harmful side-effects(1). With the need to develop newer therapeutics to combat cardiovascular diseases, Harvard University researchers at Massachusetts General Hospital discovered 4 microRNAs that control cholesterol, triglyceride, and glucose homeostasis(3)

MicroRNAs are non-coding, regulatory elements approximately 22 nucleotides long, with the ability to control post-transcriptional expression of genes(3). The liver is the center for carbohydrate and lipid metabolism. Stringent regulation of endogenous LDL-receptor (LDL-R) pathway in the liver is crucial to maintain a minimal concentration of LDL particles in blood(3). A mechanism whereby peripheral tissues and macrophages can get rid of their excess LDL is mediated by ATP-binding cassette, subfamily A, member 1 (ABCA1)(3). ABCA1 consumes nascent HDL particles- dubbed as the “good cholesterol” which travel back to the liver for its contents of triglycerides and cholesterol to be excreted(3).

Genome-wide association studies (GWASs) meta-analysis carried out by the researchers disclosed 4 microRNAs –(miR-128-1, miR-148a, miR-130b, and miR-301b) to lie close to single-nucleotide polymorphisms (SNPs) associated with abnormal metabolism and transport of lipids and cholesterol(3) Experimental analyses carried out on relevant cell types such as the liver and macrophages have proven that these microRNAs bind to the 3’ UTRs of both LDL-R and ABCA1 transporters, and silence their activity. Overexpression of miR-128-1 and miR148a in mice models caused circulating HDL-C to drop. Corroborating the theory under investigation further, their inhibition led to an increased clearance of LDL from the blood and a greater accumulation in the liver(3).

That the antisense inhibition of miRNA-128-1 increased insulin signaling in mice, propels us to hypothesize that abnormal expression of miR-128-1 might cause insulin resistance in metabolic syndrome, and defective insulin signaling in hepatic steatosis and dyslipidemia(3)

Further examination of miR-148 established that Liver-X-Receptor (LXR) activation of the Sterol regulatory element-binding protein 1c (SREBP1c), the transcription factor responsible for controlling  fatty acid production and glucose metabolism, also mediates the expression of miR-148a(4,5) That the promoter region of miR-148 contained binding sites for SREBP1c was shown by chromatin immunoprecipitation combined with massively parallel sequencing (ChIP-seq)(4). More specifically, SREBP1c attaches to the E-box2, E-box3 and E-box4 elements on miR-148-1a promoter sites to control its expression(4).

Earlier, the same researchers- Andres Naars and his team had found another microRNA called miR-33 to block HDL generation, and this blockage to reverse upon antisense targeting of miR-33(6).

These experimental data substantiate the theory of miRNAs being important regulators of lipoprotein receptors and transporter proteins as well as underscore the importance of employing antisense technologies to reverse their gene-silencing effects on LDL-R and ABCA1(4). Such a therapeutic approach, that will consequently lower LDL-C and promote HDL-C seems to be a promising strategy to treat atherosclerosis and other cardiovascular diseases(4).

References:

1.Goedeke L1,Wagschal A2,Fernández-Hernando C3, Näär AM4. miRNA regulation of LDL-cholesterol metabolism. Biochim Biophys Acta. 2016 Dec;1861(12 Pt B):. Biochim Biophys Acta. 2016 Dec;1861(12 Pt B):2047-2052

https://www.ncbi.nlm.nih.gov/pubmed/26968099

2.MedicalNewsToday. Joseph Nordgvist. Atherosclerosis:Causes, Symptoms and Treatments. 13.08.2015

http://www.medicalnewstoday.com/articles/247837.php

3.Wagschal A1,2, Najafi-Shoushtari SH1,2, Wang L1,2, Goedeke L3, Sinha S4, deLemos AS5, Black JC1,6, Ramírez CM3, Li Y7, Tewhey R8,9, Hatoum I10, Shah N11, Lu Y11, Kristo F1, Psychogios N4, Vrbanac V12, Lu YC13, Hla T13, de Cabo R14, Tsang JS11, Schadt E15, Sabeti PC8,9, Kathiresan S4,6,8,16, Cohen DE7, Whetstine J1,6, Chung RT5,6, Fernández-Hernando C3, Kaplan LM6,10, Bernards A1,6,16, Gerszten RE4,6, Näär AM1,2. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. . Nat Med.2015 Nov;21(11):1290

https://www.ncbi.nlm.nih.gov/pubmed/26501192

4.Goedeke L1,2,3,4, Rotllan N1,2, Canfrán-Duque A1,2, Aranda JF1,2,3, Ramírez CM1,2, Araldi E1,2,3,4, Lin CS3,4, Anderson NN5,6, Wagschal A7,8, de Cabo R9, Horton JD5,6, Lasunción MA10,11, Näär AM7,8, Suárez Y1,2,3,4, Fernández-Hernando C1,2,3,4. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med. 2015 Nov;21(11):1280-9.

https://www.ncbi.nlm.nih.gov/pubmed/26437365

5.Eberlé D1, Hegarty B, Bossard P, Ferré P, Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie. 2004 Nov;86(11):839-48.

https://www.ncbi.nlm.nih.gov/pubmed/15589694

6.Harvard Medical School. News. MicoRNAs and Metabolism.

https://hms.harvard.edu/news/micrornas-and-metabolism

7. MGH – Four microRNAs identified as playing key roles in cholesterol, lipid metabolism

http://www.massgeneral.org/about/pressrelease.aspx?id=1862

 

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

 

  • Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics,

on Amazon since 11/29/2015

http://www.amazon.com/dp/B018PNHJ84

 

HDL oxidation in type 2 diabetic patients

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2015/11/27/hdl-oxidation-in-type-2-diabetic-patients/

 

HDL-C: Target of Therapy – Steven E. Nissen, MD, MACC, Cleveland Clinic vs Peter Libby, MD, BWH

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/11/07/hdl-c-target-of-therapy-steven-e-nissen-md-macc-cleveland-clinic-vs-peter-libby-md-bwh/

 

High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/03/31/high-density-lipoprotein-hdl-an-independent-predictor-of-endothelial-function-artherosclerosis-a-modulator-an-agonist-a-biomarker-for-cardiovascular-risk/

 

Risk of Major Cardiovascular Events by LDL-Cholesterol Level (mg/dL): Among those treated with high-dose statin therapy, more than 40% of patients failed to achieve an LDL-cholesterol target of less than 70 mg/dL.

Reporter: Aviva Lev-Ari, PhD., RN

https://pharmaceuticalintelligence.com/2014/07/29/risk-of-major-cardiovascular-events-by-ldl-cholesterol-level-mgdl-among-those-treated-with-high-dose-statin-therapy-more-than-40-of-patients-failed-to-achieve-an-ldl-cholesterol-target-of-less-th/

 

LDL, HDL, TG, ApoA1 and ApoB: Genetic Loci Associated With Plasma Concentration of these Biomarkers – A Genome-Wide Analysis With Replication

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/18/ldl-hdl-tg-apoa1-and-apob-genetic-loci-associated-with-plasma-concentration-of-these-biomarkers-a-genome-wide-analysis-with-replication/

 

Two Mutations, in the PCSK9 Gene: Eliminates a Protein involved in Controlling LDL Cholesterol

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/15/two-mutations-in-a-pcsk9-gene-eliminates-a-protein-involve-in-controlling-ldl-cholesterol/

Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/15/artherogenesis-predictor-of-cvd-the-smaller-and-denser-ldl-particles/

 

A Concise Review of Cardiovascular Biomarkers of Hypertension

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/04/25/a-concise-review-of-cardiovascular-biomarkers-of-hypertension/

 

Triglycerides: Is it a Risk Factor or a Risk Marker for Atherosclerosis and Cardiovascular Disease ? The Impact of Genetic Mutations on (ANGPTL4) Gene, encoder of (angiopoietin-like 4) Protein, inhibitor of Lipoprotein Lipase

Reporters, Curators and Authors: Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/03/13/triglycerides-is-it-a-risk-factor-or-a-risk-marker-for-atherosclerosis-and-cardiovascular-disease-the-impact-of-genetic-mutations-on-angptl4-gene-encoder-of-angiopoietin-like-4-protein-that-in/

 

Excess Eating, Overweight, and Diabetic

Larry H Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2015/11/15/excess-eating-overweight-and-diabetic/

 

Obesity Issues

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2015/11/12/obesity-issues/

 

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Entire Family of Impella Abiomed Impella® Therapy Left Side Heart Pumps: FDA Approved To Enable Heart Recovery

Reporter: Aviva Lev-Ari, PhD, RN

 

Abiomed Impella® Therapy Receives FDA Approval for Cardiogenic Shock After Heart Attack or Heart Surgery

Entire Family of Impella Left Side Heart Pumps FDA Approved To Enable Heart Recovery

DANVERS, Mass., April 07, 2016 (GLOBE NEWSWIRE) — Abiomed, Inc. (NASDAQ:ABMD), a leading provider of breakthrough heart support technologies, today announced that it has received U.S. Food and Drug Administration (FDA) Pre-Market Approval (PMA) for its Impella 2.5™, Impella CP®, Impella 5.0™ and Impella LD™ heart pumps to provide treatment of ongoing cardiogenic shock. In this setting, the Impella heart pumps stabilize the patient’s hemodynamics, unload the left ventricle, perfuse the end organs and allow for recovery of the native heart.  This latest approval adds to the prior FDA indication of Impella 2.5 for high risk percutaneous coronary intervention (PCI), or Protected PCI™, received in March 2015.

With this approval, these are the first and only percutaneous temporary ventricular support devices that are FDA-approved as safe and effective for the cardiogenic shock indication, as stated below:

The Impella 2.5, Impella CP, Impella 5.0 and Impella LD catheters, in conjunction with the Automated Impella Controller console, are intended for short-term use (<4 days for the Impella 2.5 and Impella CP and <6 days for the Impella 5.0 and Impella LD) and indicated for the treatment of ongoing cardiogenic shock that occurs immediately (<48 hours) following acute myocardial infarction (AMI) or open heart surgery as a result of isolated left ventricular failure that is not responsive to optimal medical management and conventional treatment measures with or without an intra-aortic balloon pump.  The intent of the Impella system therapy is to reduce ventricular work and to provide the circulatory support necessary to allow heart recovery and early assessment of residual myocardial function.

The product labeling also allows for the clinical decision to leave Impella 2.5, Impella CP, Impella 5.0 and Impella LD in place beyond the intended duration of four to six days due to unforeseen circumstances.

The Impella products offer the unique ability to both stabilize the patient’s hemodynamics before or during a PCI procedure and unload the heart, which allows the muscle to rest and potentially recover its native function. Heart recovery is the ideal option for a patient’s quality of life and as documented in several clinical papers, has the ability to save costs for the healthcare system1,2,3.

Cardiogenic shock is a life-threatening condition in which the heart is suddenly unable to pump enough blood and oxygen to support the body’s vital organs. For this approval, it typically occurs during or after a heart attack or acute myocardial infarction (AMI) or cardiopulmonary bypass surgery as a result of a weakened or damaged heart muscle. Despite advancements in medical technology, critical care guidelines and interventional techniques, AMI cardiogenic shock and post-cardiotomy cardiogenic shock (PCCS) carry a high mortality risk and has shown an incremental but consistent increase in occurrence in recent years in the United States.

“This approval sets a new standard for the entire cardiovascular community as clinicians continue to seek education and new approaches to effectively treat severely ill cardiac patients with limited options and high mortality risk,” said William O’Neill, M.D., medical director of the Center for Structural Heart Disease at Henry Ford Hospital. “The Impella heart pumps offer the ability to provide percutaneous hemodynamic stability to high-risk patients in need of rapid and effective treatment by unloading the heart, perfusing the end organs and ultimately, allowing for the opportunity to recover native heart function.”

“Abiomed would like to recognize our customers, physicians, nurses, scientists, regulators and employees for their last fifteen years of circulatory support research and clinical applications. This FDA approval marks a significant milestone in the treatment of heart disease. The new medical field of heart muscle recovery has begun,” said Michael R. Minogue, President, Chairman and Chief Executive Officer of Abiomed. “Today, Abiomed only treats around 5% of this AMI cardiogenic shock patient population, which suffers one of the highest mortality risks of any patient in the heart hospital. Tomorrow, Abiomed will be able to educate and directly partner with our customers and establish appropriate protocols to improve the patient outcomes focused on native heart recovery.”

Abiomed Data Supporting FDA Approval

The data submitted to the FDA in support of the PMA included an analysis of 415 patients from the RECOVER 1 study and the U.S. Impella registry (cVAD Registry™), as well as an Impella literature review including 692 patients treated with Impella from 17 clinical studies. A safety analysis reviewed over 24,000 Impella treated patients using the FDA medical device reporting (“MDR”) database, which draws from seven years of U.S. experience with Impella.

In addition, the Company also provided a benchmark analysis of Impella patients in the real-world Impella cVAD registry vs. these same patient groups in the Abiomed AB5000/BVS 5000 Registry. The Abiomed BVS 5000 product was the first ventricular assist device (VAD) ever approved by the FDA in 1991 based on 83 patient PMA study. In 2003, the AB5000 Ventricle received FDA approval and this also included a PMA study with 60 patients.

For this approval, the data source for this benchmark analysis was a registry (“AB/BVS Registry”) that contained 2,152 patients that received the AB5000 and BVS 5000 devices, which were originally approved for heart recovery. The analysis examined by the FDA used 204 patients that received the AB5000 device for the same indications. This analysis demonstrated significantly better outcomes with Impella in these patients.

The Company believes this is the most comprehensive review ever submitted to the FDA for circulatory support in the cardiogenic shock population.

  1. Maini B, Gregory D, Scotti DJ, Buyantseva L. Percutaneous cardiac assist devices compared with surgical hemodynamic support alternatives: Cost-Effectiveness in the Emergent Setting.Catheter Cardiovasc Interv. 2014 May 1;83(6):E183-92.
  2. Cheung A, Danter M, Gregory D. TCT-385 Comparative Economic Outcomes in Cardiogenic Shock Patients Managed with the Minimally Invasive Impella or Extracorporeal Life Support. J Am Coll Cardiol. 2012;60(17_S):. doi:10.1016/j.jacc.2012.08.413.
  3. Gregory D, Scotti DJ, de Lissovoy G, Palacios I, Dixon, Maini B, O’Neill W. A value-based analysis of hemodynamic support strategies for high-risk heart failure patients undergoing a percutaneous coronary intervention. Am Health Drug Benefits. 2013 Mar;6(2):88-99


ABOUT IMPELLA

Impella 2.5 received FDA PMA approval for high risk PCI in March 2015, is supported by clinical guidelines, and is reimbursed by the Centers for Medicare & Medicaid Services (CMS) under ICD-9-CM code 37.68 for multiple indications. The Impella RP® device received Humanitarian Device Exemption (HDE) approval in January 2015. The Impella product portfolio, which is comprised of Impella 2.5, Impella CP, Impella 5.0, Impella LD, and Impella RP, has supported over 35,000 patients in the United States.

The ABIOMED logo, ABIOMED, Impella, Impella CP, and Impella RP are registered trademarks of Abiomed, Inc. in the U.S.A. and certain foreign countries.  Impella 2.5, Impella 5.0, Impella LD, and Protected PCI are trademarks of Abiomed, Inc.

ABOUT ABIOMED
Based in Danvers, Massachusetts, Abiomed, Inc. is a leading provider of medical devices that provide circulatory support.  Our products are designed to enable the heart to rest by improving blood flow and/or performing the pumping of the heart.  For additional information, please visit: www.abiomed.com

FORWARD-LOOKING STATEMENTS
This release includes forward-looking statements.  These forward-looking statements generally can be identified by the use of words such as “anticipate,” “expect,” “plan,” “could,” “may,” “will,” “believe,” “estimate,” “forecast,” “goal,” “project,” and other words of similar meaning.  These forward-looking statements address various matters including, the Company’s guidance for fiscal 2016 revenue. Each forward-looking statement contained in this press release is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statement.  Applicable risks and uncertainties include, among others, uncertainties associated with development, testing and related regulatory approvals, including the potential for future losses, complex manufacturing, high quality requirements, dependence on limited sources of supply, competition, technological change, government regulation, litigation matters, future capital needs and uncertainty of additional financing, and the risks identified under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended March 31, 2015 and the Company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015, each filed with the Securities and Exchange Commission, as well as other information the Company files with the SEC.  We caution investors not to place considerable reliance on the forward-looking statements contained in this press release.  You are encouraged to read our filings with the SEC, available at www.sec.gov, for a discussion of these and other risks and uncertainties.  The forward-looking statements in this press release speak only as of the date of this release and the Company undertakes no obligation to update or revise any of these statements.  Our business is subject to substantial risks and uncertainties, including those referenced above.  Investors, potential investors, and others should give careful consideration to these risks and uncertainties.

For more information, please contact: Aimee Genzler Director, Corporate Communications 978-646-1553 agenzler@abiomed.com Ingrid Goldberg Director, Investor Relations igoldberg@abiomed.com

SOURCE
http://investors.abiomed.com/releasedetail.cfm?ReleaseID=964113

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Christopher J. Lynch, MD, PhD, the New Office of Nutrition Research, Director

Curator: Larry H. Bernstein, MD, FCAP

 

Christopher J. Lynch to direct Office of Nutrition Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

http://www.nih.gov/news-events/news-releases/christopher-j-lynch-direct-office-nutrition-research

 

Christopher J. Lynch, Ph.D., has been named the new director of the Office of Nutrition Research (ONR) and chief of the Nutrition Research Branch within the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Lynch officially assumed his new roles on Feb. 21, 2016. NIDDK is part of the National Institutes of Health.

Lynch will facilitate nutrition research within NIDDK and — through ONR — across NIH, in part by forming and leading a trans-NIH strategic working group. He will also continue and extend ongoing efforts at NIDDK to collaborate widely to advance nutrition research.

“Dr. Lynch is a leader in the nutrition community and his expertise will be vital to guiding the NIH strategic plan for nutrition research,” said NIH Director Francis S. Collins, M.D., Ph.D.  “As NIH works to expand nutrition knowledge, Dr. Lynch’s understanding of the field will help identify information gaps and create a framework to support future discoveries to ultimately improve human health.”

NIH supports a broad range of nutrition research, including studies on the effects of nutrient and dietary intake on human growth and disease, genetic influences on human nutrition and metabolism and other scientific areas. ONR was established in August 2015 to help NIH develop a strategic plan to expand mission-specific nutrition research.

NARRATIVE:
Our laboratory is dedicated to developing cures for metabolic diseases like Obesity, Diabetes and MSUD. We have several projects:
Project 1: How Antipsychotic Drugs Exert Obesity and Metabolic Disease Side effects
Project 2: Impact of Branched Chain Amino Acid (BCAA) signaling and metabolism in obesity and diabetes.
Project 3: Adipose tissue transplant as a treatment for Maple Syrup Urine Disease.
Project 4: How Gastric Bypass Surgery Provides A Rapid Cure For Diabetes And Other Obesity Co-Morbidities Like Hypertension
Project 5: Novel Mechanism Of Action Of Cannabinoid Receptor 1 Blockers For Improvement Of Diabetes

Timeline

  1. Klingerman CM, Stipanovic ME, Hajnal A, Lynch CJ. Acute Metabolic Effects of Olanzapine Depend on Dose and Injection Site. Dose Response. 2015 Oct-Dec; 13(4):1559325815618915.

View in: PubMed

  1. Lynch CJ, Kimball SR, Xu Y, Salzberg AC, Kawasawa YI. Global deletion of BCATm increases expression of skeletal muscle genes associated with protein turnover. Physiol Genomics. 2015 Nov; 47(11):569-80.

View in: PubMed

  1. Lynch CJ, Xu Y, Hajnal A, Salzberg AC, Kawasawa YI. RNA sequencing reveals a slow to fast muscle fiber type transition after olanzapine infusion in rats. PLoS One. 2015; 10(4):e0123966.

View in: PubMed

  1. Shin AC, Fasshauer M, Filatova N, Grundell LA, Zielinski E, Zhou JY, Scherer T, Lindtner C, White PJ, Lapworth AL, Ilkayeva O, Knippschild U, Wolf AM, Scheja L, Grove KL, Smith RD, Qian WJ, Lynch CJ, Newgard CB, Buettner C. Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism. Cell Metab. 2014 Nov 4; 20(5):898-909.

View in: PubMed

  1. Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. 2014 Dec; 10(12):723-36.

View in: PubMed

  1. Olson KC, Chen G, Xu Y, Hajnal A, Lynch CJ. Alloisoleucine differentiates the branched-chain aminoacidemia of Zucker and dietary obese rats. Obesity (Silver Spring). 2014 May; 22(5):1212-5.

View in: PubMed

  1. Zimmerman HA, Olson KC, Chen G, Lynch CJ. Adipose transplant for inborn errors of branched chain amino acid metabolism in mice. Mol Genet Metab. 2013 Aug; 109(4):345-53.

View in: PubMed

  1. Olson KC, Chen G, Lynch CJ. Quantification of branched-chain keto acids in tissue by ultra fast liquid chromatography-mass spectrometry. Anal Biochem. 2013 Aug 15; 439(2):116-22.

View in: PubMed

  1. She P, Olson KC, Kadota Y, Inukai A, Shimomura Y, Hoppel CL, Adams SH, Kawamata Y, Matsumoto H, Sakai R, Lang CH, Lynch CJ. Leucine and protein metabolism in obese Zucker rats. PLoS One. 2013; 8(3):e59443.

View in: PubMed

  1. Lackey DE, Lynch CJ, Olson KC, Mostaedi R, Ali M, Smith WH, Karpe F, Humphreys S, Bedinger DH, Dunn TN, Thomas AP, Oort PJ, Kieffer DA, Amin R, Bettaieb A, Haj FG, Permana P, Anthony TG, Adams SH. Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. Am J Physiol Endocrinol Metab. 2013 Jun 1; 304(11):E1175-87.

View in: PubMed

  1. Klingerman CM, Stipanovic ME, Bader M, Lynch CJ. Second-generation antipsychotics cause a rapid switch to fat oxidation that is required for survival in C57BL/6J mice. Schizophr Bull. 2014 Mar; 40(2):327-40.

View in: PubMed

  1. Carr TD, DiGiovanni J, Lynch CJ, Shantz LM. Inhibition of mTOR suppresses UVB-induced keratinocyte proliferation and survival. Cancer Prev Res (Phila). 2012 Dec; 5(12):1394-404.

View in: PubMed

  1. Lynch CJ, Zhou Q, Shyng SL, Heal DJ, Cheetham SC, Dickinson K, Gregory P, Firnges M, Nordheim U, Goshorn S, Reiche D, Turski L, Antel J. Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K(ATP) channels. Am J Physiol Endocrinol Metab. 2012 Mar 1; 302(5):E540-51.

View in: PubMed

  1. Albaugh VL, Singareddy R, Mauger D, Lynch CJ. A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers. PLoS One. 2011; 6(8):e22662.

View in: PubMed

  1. She P, Zhang Z, Marchionini D, Diaz WC, Jetton TJ, Kimball SR, Vary TC, Lang CH, Lynch CJ. Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington’s disease. Am J Physiol Endocrinol Metab. 2011 Jul; 301(1):E49-61.

View in: PubMed

  1. Fogle RL, Hollenbeak CS, Stanley BA, Vary TC, Kimball SR, Lynch CJ. Functional proteomic analysis reveals sex-dependent differences in structural and energy-producing myocardial proteins in rat model of alcoholic cardiomyopathy. Physiol Genomics. 2011 Apr 12; 43(7):346-56.

View in: PubMed

  1. Zhou Y, Jetton TL, Goshorn S, Lynch CJ, She P. Transamination is required for {alpha}-ketoisocaproate but not leucine to stimulate insulin secretion. J Biol Chem. 2010 Oct 29; 285(44):33718-26.

View in: PubMed

  1. Agostino NM, Chinchilli VM, Lynch CJ, Koszyk-Szewczyk A, Gingrich R, Sivik J, Drabick JJ. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice. J Oncol Pharm Pract. 2011 Sep; 17(3):197-202.

View in: PubMed

  1. Li J, Romestaing C, Han X, Li Y, Hao X, Wu Y, Sun C, Liu X, Jefferson LS, Xiong J, Lanoue KF, Chang Z, Lynch CJ, Wang H, Shi Y. Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity. Cell Metab. 2010 Aug 4; 12(2):154-65.

View in: PubMed

  1. Culnan DM, Albaugh V, Sun M, Lynch CJ, Lang CH, Cooney RN. Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat. Am J Physiol Gastrointest Liver Physiol. 2010 Sep; 299(3):G751-60.

View in: PubMed

  1. Hajnal A, Kovacs P, Ahmed T, Meirelles K, Lynch CJ, Cooney RN. Gastric bypass surgery alters behavioral and neural taste functions for sweet taste in obese rats. Am J Physiol Gastrointest Liver Physiol. 2010 Oct; 299(4):G967-79.

View in: PubMed

  1. Lang CH, Lynch CJ, Vary TC. BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice. Am J Physiol Regul Integr Comp Physiol. 2010 Sep; 299(3):R935-44.

View in: PubMed

  1. Albaugh VL, Vary TC, Ilkayeva O, Wenner BR, Maresca KP, Joyal JL, Breazeale S, Elich TD, Lang CH, Lynch CJ. Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents. Schizophr Bull. 2012 Jan; 38(1):153-66.

View in: PubMed

  1. Fogle RL, Lynch CJ, Palopoli M, Deiter G, Stanley BA, Vary TC. Impact of chronic alcohol ingestion on cardiac muscle protein expression. Alcohol Clin Exp Res. 2010 Jul; 34(7):1226-34.

View in: PubMed

  1. Lang CH, Frost RA, Bronson SK, Lynch CJ, Vary TC. Skeletal muscle protein balance in mTOR heterozygous mice in response to inflammation and leucine. Am J Physiol Endocrinol Metab. 2010 Jun; 298(6):E1283-94.

View in: PubMed

  1. Albaugh VL, Judson JG, She P, Lang CH, Maresca KP, Joyal JL, Lynch CJ. Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis. Mol Psychiatry. 2011 May; 16(5):569-81.

View in: PubMed

  1. Lang CH, Lynch CJ, Vary TC. Alcohol-induced IGF-I resistance is ameliorated in mice deficient for mitochondrial branched-chain aminotransferase. J Nutr. 2010 May; 140(5):932-8.

View in: PubMed

  1. She P, Zhou Y, Zhang Z, Griffin K, Gowda K, Lynch CJ. Disruption of BCAA metabolism in mice impairs exercise metabolism and endurance. J Appl Physiol (1985). 2010 Apr; 108(4):941-9.

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  1. Herman MA, She P, Peroni OD, Lynch CJ, Kahn BB. Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J Biol Chem. 2010 Apr 9; 285(15):11348-56.

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  1. Li P, Knabe DA, Kim SW, Lynch CJ, Hutson SM, Wu G. Lactating porcine mammary tissue catabolizes branched-chain amino acids for glutamine and aspartate synthesis. J Nutr. 2009 Aug; 139(8):1502-9.

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  1. Lu G, Sun H, She P, Youn JY, Warburton S, Ping P, Vondriska TM, Cai H, Lynch CJ, Wang Y. Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. J Clin Invest. 2009 Jun; 119(6):1678-87.

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  1. Nairizi A, She P, Vary TC, Lynch CJ. Leucine supplementation of drinking water does not alter susceptibility to diet-induced obesity in mice. J Nutr. 2009 Apr; 139(4):715-9.

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  1. Meirelles K, Ahmed T, Culnan DM, Lynch CJ, Lang CH, Cooney RN. Mechanisms of glucose homeostasis after Roux-en-Y gastric bypass surgery in the obese, insulin-resistant Zucker rat. Ann Surg. 2009 Feb; 249(2):277-85.

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  1. Culnan DM, Cooney RN, Stanley B, Lynch CJ. Apolipoprotein A-IV, a putative satiety/antiatherogenic factor, rises after gastric bypass. Obesity (Silver Spring). 2009 Jan; 17(1):46-52.

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  1. She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab. 2007 Dec; 293(6):E1552-63.

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  1. She P, Reid TM, Bronson SK, Vary TC, Hajnal A, Lynch CJ, Hutson SM. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle. Cell Metab. 2007 Sep; 6(3):181-94.

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  1. Vary TC, Lynch CJ. Nutrient signaling components controlling protein synthesis in striated muscle. J Nutr. 2007 Aug; 137(8):1835-43.

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  1. Vary TC, Deiter G, Lynch CJ. Rapamycin limits formation of active eukaryotic initiation factor 4F complex following meal feeding in rat hearts. J Nutr. 2007 Aug; 137(8):1857-62.

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  1. Vary TC, Anthony JC, Jefferson LS, Kimball SR, Lynch CJ. Rapamycin blunts nutrient stimulation of eIF4G, but not PKCepsilon phosphorylation, in skeletal muscle. Am J Physiol Endocrinol Metab. 2007 Jul; 293(1):E188-96.

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  1. Vary TC, Lynch CJ. Meal feeding stimulates phosphorylation of multiple effector proteins regulating protein synthetic processes in rat hearts. J Nutr. 2006 Sep; 136(9):2284-90.

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  1. Lynch CJ, Gern B, Lloyd C, Hutson SM, Eicher R, Vary TC. Leucine in food mediates some of the postprandial rise in plasma leptin concentrations. Am J Physiol Endocrinol Metab. 2006 Sep; 291(3):E621-30.

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  1. Albaugh VL, Henry CR, Bello NT, Hajnal A, Lynch SL, Halle B, Lynch CJ. Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity (Silver Spring). 2006 Jan; 14(1):36-51.

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  1. Vary TC, Lynch CJ. Meal feeding enhances formation of eIF4F in skeletal muscle: role of increased eIF4E availability and eIF4G phosphorylation. Am J Physiol Endocrinol Metab. 2006 Apr; 290(4):E631-42.

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  1. Vary TC, Goodman S, Kilpatrick LE, Lynch CJ. Nutrient regulation of PKCepsilon is mediated by leucine, not insulin, in skeletal muscle. Am J Physiol Endocrinol Metab. 2005 Oct; 289(4):E684-94.

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  1. Vary TC, Lynch CJ. Biochemical approaches for nutritional support of skeletal muscle protein metabolism during sepsis. Nutr Res Rev. 2004 Jun; 17(1):77-88.

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  1. Lynch CJ, Halle B, Fujii H, Vary TC, Wallin R, Damuni Z, Hutson SM. Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR. Am J Physiol Endocrinol Metab. 2003 Oct; 285(4):E854-63.

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  1. Lynch CJ, Hutson SM, Patson BJ, Vaval A, Vary TC. Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats. Am J Physiol Endocrinol Metab. 2002 Oct; 283(4):E824-35.

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  1. Lynch CJ, Patson BJ, Anthony J, Vaval A, Jefferson LS, Vary TC. Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. Am J Physiol Endocrinol Metab. 2002 Sep; 283(3):E503-13.

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  1. Vary TC, Lynch CJ, Lang CH. Effects of chronic alcohol consumption on regulation of myocardial protein synthesis. Am J Physiol Heart Circ Physiol. 2001 Sep; 281(3):H1242-51.

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  1. Lynch CJ, Patson BJ, Goodman SA, Trapolsi D, Kimball SR. Zinc stimulates the activity of the insulin- and nutrient-regulated protein kinase mTOR. Am J Physiol Endocrinol Metab. 2001 Jul; 281(1):E25-34.

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Global deletion of BCATm increases expression of skeletal muscle genes associated with protein turnover.

Lynch CJ1Kimball SR2Xu Y2Salzberg AC3Kawasawa YI4.   Author information
Physiol Genomics. 2015 Nov;47(11):569-80.  http://dx.doi.org:/10.1152/physiolgenomics.00055.2015

Consumption of a protein-containing meal by a fasted animal promotes protein accretion in skeletal muscle, in part through leucine stimulation of protein synthesis and indirectly through repression of protein degradation mediated by its metabolite, α-ketoisocaproate. Mice lacking the mitochondrial branched-chain aminotransferase (BCATm/Bcat2), which interconverts leucine and α-ketoisocaproate, exhibit elevated protein turnover. Here, the transcriptomes of gastrocnemius muscle from BCATm knockout (KO) and wild-type mice were compared by next-generation RNA sequencing (RNA-Seq) to identify potential adaptations associated with their persistently altered nutrient signaling. Statistically significant changes in the abundance of 1,486/∼39,010 genes were identified. Bioinformatics analysis of the RNA-Seq data indicated that pathways involved in protein synthesis [eukaryotic initiation factor (eIF)-2, mammalian target of rapamycin, eIF4, and p70S6K pathways including 40S and 60S ribosomal proteins], protein breakdown (e.g., ubiquitin mediated), and muscle degeneration (apoptosis, atrophy, myopathy, and cell death) were upregulated. Also in agreement with our previous observations, the abundance of mRNAs associated with reduced body size, glycemia, plasma insulin, and lipid signaling pathways was altered in BCATm KO mice. Consistently, genes encoding anaerobic and/or oxidative metabolism of carbohydrate, fatty acids, and branched chain amino acids were modestly but systematically reduced. Although there was no indication that muscle fiber type was different between KO and wild-type mice, a difference in the abundance of mRNAs associated with a muscular dystrophy phenotype was observed, consistent with the published exercise intolerance of these mice. The results suggest transcriptional adaptations occur in BCATm KO mice that along with altered nutrient signaling may contribute to their previously reported protein turnover, metabolic and exercise phenotypes.

 

RNA sequencing reveals a slow to fast muscle fiber type transition after olanzapine infusion in rats.

Lynch CJ1Xu Y1Hajnal A2Salzberg AC3Kawasawa YI4. Author information
PLoS One. 2015 Apr 20;10(4):e0123966. http://dx.doi.org:/10.1371/journal.pone.0123966. eCollection 2015.

Second generation antipsychotics (SGAs), like olanzapine, exhibit acute metabolic side effects leading to metabolic inflexibility, hyperglycemia, adiposity and diabetes. Understanding how SGAs affect the skeletal muscle transcriptome could elucidate approaches for mitigating these side effects. Male Sprague-Dawley rats were infused intravenously with vehicle or olanzapine for 24h using a dose leading to a mild hyperglycemia. RNA-Seq was performed on gastrocnemius muscle, followed by alignment of the data with the Rat Genome Assembly 5.0. Olanzapine altered expression of 1347 out of 26407 genes. Genes encoding skeletal muscle fiber-type specific sarcomeric, ion channel, glycolytic, O2- and Ca2+-handling, TCA cycle, vascularization and lipid oxidation proteins and pathways, along with NADH shuttles and LDH isoforms were affected. Bioinformatics analyses indicate that olanzapine decreased the expression of slower and more oxidative fiber type genes (e.g., type 1), while up regulating those for the most glycolytic and least metabolically flexible, fast twitch fiber type, IIb. Protein turnover genes, necessary to bring about transition, were also up regulated. Potential upstream regulators were also identified. Olanzapine appears to be rapidly affecting the muscle transcriptome to bring about a change to a fast-glycolytic fiber type. Such fiber types are more susceptible than slow muscle to atrophy, and such transitions are observed in chronic metabolic diseases. Thus these effects could contribute to the altered body composition and metabolic disease olanzapine causes. A potential interventional strategy is implicated because aerobic exercise, in contrast to resistance exercise, can oppose such slow to fast fiber transitions.

 

Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.

Shin AC1Fasshauer M1Filatova N1Grundell LA1Zielinski E1Zhou JY2Scherer T1Lindtner C1White PJ3Lapworth AL3,Ilkayeva O3Knippschild U4Wolf AM4Scheja L5Grove KL6Smith RD2Qian WJ2Lynch CJ7Newgard CB3Buettner C8. Author information
Cell Metab. 2014 Nov 4;20(5):898-909. http://dx.doi.org:/10.1016/j.cmet.2014.09.003   Epub 2014 Oct 9

Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes.

 

Branched-chain amino acids in metabolic signalling and insulin resistance.

Lynch CJ1Adams SH2Author information
Nat Rev Endocrinol. 2014 Dec; 10(12):723-36. http://dx.doi.org:/10.1038/nrendo.2014.171

Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM.

 

Leucine and protein metabolism in obese Zucker rats.

She P1Olson KCKadota YInukai AShimomura YHoppel CLAdams SHKawamata YMatsumoto HSakai RLang CHLynch CJAuthor information
PLoS One. 2013;8(3):e59443. http://dx.doi.org:/10.1371/journal.pone.0059443   Epub 2013 Mar 20.

Branched-chain amino acids (BCAAs) are circulating nutrient signals for protein accretion, however, they increase in obesity and elevations appear to be prognostic of diabetes. To understand the mechanisms whereby obesity affects BCAAs and protein metabolism, we employed metabolomics and measured rates of [1-(14)C]-leucine metabolism, tissue-specific protein synthesis and branched-chain keto-acid (BCKA) dehydrogenase complex (BCKDC) activities. Male obese Zucker rats (11-weeks old) had increased body weight (BW, 53%), liver (107%) and fat (∼300%), but lower plantaris and gastrocnemius masses (-21-24%). Plasma BCAAs and BCKAs were elevated 45-69% and ∼100%, respectively, in obese rats. Processes facilitating these rises appeared to include increased dietary intake (23%), leucine (Leu) turnover and proteolysis [35% per g fat free mass (FFM), urinary markers of proteolysis: 3-methylhistidine (183%) and 4-hydroxyproline (766%)] and decreased BCKDC per g kidney, heart, gastrocnemius and liver (-47-66%). A process disposing of circulating BCAAs, protein synthesis, was increased 23-29% by obesity in whole-body (FFM corrected), gastrocnemius and liver. Despite the observed decreases in BCKDC activities per gm tissue, rates of whole-body Leu oxidation in obese rats were 22% and 59% higher normalized to BW and FFM, respectively. Consistently, urinary concentrations of eight BCAA catabolism-derived acylcarnitines were also elevated. The unexpected increase in BCAA oxidation may be due to a substrate effect in liver. Supporting this idea, BCKAs were elevated more in liver (193-418%) than plasma or muscle, and per g losses of hepatic BCKDC activities were completely offset by increased liver mass, in contrast to other tissues. In summary, our results indicate that plasma BCKAs may represent a more sensitive metabolic signature for obesity than BCAAs. Processes supporting elevated BCAA]BCKAs in the obese Zucker rat include increased dietary intake, Leu and protein turnover along with impaired BCKDC activity. Elevated BCAAs/BCKAs may contribute to observed elevations in protein synthesis and BCAA oxidation.

 

Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity.

Lackey DE1Lynch CJOlson KCMostaedi RAli MSmith WHKarpe FHumphreys SBedinger DHDunn TNThomas APOort PJKieffer DAAmin RBettaieb AHaj FGPermana PAnthony TGAdams SH.
Am J Physiol Endocrinol Metab. 2013 Jun 1; 304(11):E1175-87. http://dx.doi.org:/10.1152/ajpendo.00630.2012

Elevated blood branched-chain amino acids (BCAA) are often associated with insulin resistance and type 2 diabetes, which might result from a reduced cellular utilization and/or incomplete BCAA oxidation. White adipose tissue (WAT) has become appreciated as a potential player in whole body BCAA metabolism. We tested if expression of the mitochondrial BCAA oxidation checkpoint, branched-chain α-ketoacid dehydrogenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WAT BCKD protein (E1α subunit) was significantly reduced by 35-50% in various obesity models (fa/fa rats, db/db mice, diet-induced obese mice), and BCKD component transcripts significantly lower in subcutaneous (SC) adipocytes from obese vs. lean Pima Indians. Treatment of 3T3-L1 adipocytes or mice with peroxisome proliferator-activated receptor-γ agonists increased WAT BCAA catabolism enzyme mRNAs, whereas the nonmetabolizable glucose analog 2-deoxy-d-glucose had the opposite effect. The results support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2 diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studies comparing lean vs. insulin-sensitive or insulin-resistant obese subjects revealed an unexpected negligible uptake of BCAA from human abdominal SC WAT. This suggests that SC WAT may not be an important contributor to blood BCAA phenotypes associated with insulin resistance in the overnight-fasted state. mRNA abundances for BCAA catabolic enzymes were markedly reduced in omental (but not SC) WAT of obese persons with metabolic syndrome compared with weight-matched healthy obese subjects, raising the possibility that visceral WAT contributes to the BCAA metabolic phenotype of metabolically compromised individuals.

 

Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K(ATP) channels.

Lynch CJ1Zhou QShyng SLHeal DJCheetham SCDickinson KGregory PFirnges MNordheim UGoshorn SReiche D,Turski LAntel J.   Author information
Am J Physiol Endocrinol Metab. 2012 Mar 1;302(5):E540-51.
http://dx.doi.org:/10.1152/ajpendo.00258.2011

Here, we examined the chronic effects of two cannabinoid receptor-1 (CB1) inverse agonists, rimonabant and ibipinabant, in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia. Rimonabant and ibipinabant (10 mg·kg⁻¹·day⁻¹) elicited body weight-independent improvements in insulinemia and glycemia during 10 wk of chronic treatment. To elucidate the mechanism of insulin lowering, acute in vivo and in vitro studies were then performed. Surprisingly, chronic treatment was not required for insulin lowering. In acute in vivo and in vitro studies, the CB1 inverse agonists exhibited acute K channel opener (KCO; e.g., diazoxide and NN414)-like effects on glucose tolerance and glucose-stimulated insulin secretion (GSIS) with approximately fivefold better potency than diazoxide. Followup studies implied that these effects were inconsistent with a CB1-mediated mechanism. Thus effects of several CB1 agonists, inverse agonists, and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known CB1 activities. In vivo rimonabant and ibipinabant caused glucose intolerance in CB1 but not SUR1-KO mice. Electrophysiological studies indicated that, compared with diazoxide, 3 μM rimonabant and ibipinabant are partial agonists for K channel opening. Partial agonism was consistent with data from radioligand binding assays designed to detect SUR1 K(ATP) KCOs where rimonabant and ibipinabant allosterically regulated ³H-glibenclamide-specific binding in the presence of MgATP, as did diazoxide and NN414. Our findings indicate that some CB1 ligands may directly bind and allosterically regulate Kir6.2/SUR1 K(ATP) channels like other KCOs. This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia.

 

Transamination is required for {alpha}-ketoisocaproate but not leucine to stimulate insulin secretion.

Zhou Y1Jetton TLGoshorn SLynch CJShe PAuthor information
J Biol Chem. 2010 Oct 29;285(44):33718-26. http://dx.doi.org:/10.1074/jbc.M110.136846

It remains unclear how α-ketoisocaproate (KIC) and leucine are metabolized to stimulate insulin secretion. Mitochondrial BCATm (branched-chain aminotransferase) catalyzes reversible transamination of leucine and α-ketoglutarate to KIC and glutamate, the first step of leucine catabolism. We investigated the biochemical mechanisms of KIC and leucine-stimulated insulin secretion (KICSIS and LSIS, respectively) using BCATm(-/-) mice. In static incubation, BCATm disruption abolished insulin secretion by KIC, D,L-α-keto-β-methylvalerate, and α-ketocaproate without altering stimulation by glucose, leucine, or α-ketoglutarate. Similarly, during pancreas perfusions in BCATm(-/-) mice, glucose and arginine stimulated insulin release, whereas KICSIS was largely abolished. During islet perifusions, KIC and 2 mM glutamine caused robust dose-dependent insulin secretion in BCATm(+/+) not BCATm(-/-) islets, whereas LSIS was unaffected. Consistently, in contrast to BCATm(+/+) islets, the increases of the ATP concentration and NADPH/NADP(+) ratio in response to KIC were largely blunted in BCATm(-/-) islets. Compared with nontreated islets, the combination of KIC/glutamine (10/2 mM) did not influence α-ketoglutarate concentrations but caused 120 and 33% increases in malate in BCATm(+/+) and BCATm(-/-) islets, respectively. Although leucine oxidation and KIC transamination were blocked in BCATm(-/-) islets, KIC oxidation was unaltered. These data indicate that KICSIS requires transamination of KIC and glutamate to leucine and α-ketoglutarate, respectively. LSIS does not require leucine catabolism and may be through leucine activation of glutamate dehydrogenase. Thus, KICSIS and LSIS occur by enhancing the metabolism of glutamine/glutamate to α-ketoglutarate, which, in turn, is metabolized to produce the intracellular signals such as ATP and NADPH for insulin secretion.

 

Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice.

Agostino NM1Chinchilli VMLynch CJKoszyk-Szewczyk AGingrich RSivik JDrabick JJ.
J Oncol Pharm Pract. 2011 Sep; 17(3):197-202. http://dx.doi.org:/10.1177/1078155210378913

Tyrosine kinase is a key enzyme activity utilized in many intracellular messaging pathways. Understanding the role of particular tyrosine kinases in malignancies has allowed for the design of tyrosine kinase inhibitors (TKIs), which can target these enzymes and interfere with downstream signaling. TKIs have proven to be successful in the treatment of chronic myeloid leukemia, renal cell carcinoma and gastrointestinal stromal tumor, and other malignancies. Scattered reports have suggested that these agents appear to affect blood glucose (BG). We retrospectively studied the BG concentrations in diabetic (17) and nondiabetic (61) patients treated with dasatinib (8), imatinib (39), sorafenib (23), and sunitinib (30) in our clinical practice. Mean declines of BG were dasatinib (53 mg/dL), imatinib (9 mg/dL), sorafenib (12 mg/dL), and sunitinib (14 mg/dL). All these declines in BG were statistically significant. Of note, 47% (8/17) of the patients with diabetes were able to discontinue their medications, including insulin in some patients. Only one diabetic patient developed symptomatic hypoglycemia while on sunitinib. The mechanism for the hypoglycemic effect of these drugs is unclear, but of the four agents tested, c-kit and PDGFRβ are the common target kinases. Clinicians should keep the potential hypoglycemic effects of these agents in mind; modification of hypoglycemic agents may be required in diabetic patients. These results also suggest that inhibition of a tyrosine kinase, be it c-kit, PDGFRβ or some other undefined target, may improve diabetes mellitus BG control and it deserves further study as a potential novel therapeutic option.

 

Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity.

Li J1Romestaing CHan XLi YHao XWu YSun CLiu XJefferson LSXiong JLanoue KFChang ZLynch CJWang HShi Y.    Author information
Cell Metab. 2010 Aug 4;12(2):154-65. http://dx.doi.org:/10.1016/j.cmet.2010.07.003

Oxidative stress causes mitochondrial dysfunction and metabolic complications through unknown mechanisms. Cardiolipin (CL) is a key mitochondrial phospholipid required for oxidative phosphorylation. Oxidative damage to CL from pathological remodeling is implicated in the etiology of mitochondrial dysfunction commonly associated with diabetes, obesity, and other metabolic diseases. Here, we show that ALCAT1, a lyso-CL acyltransferase upregulated by oxidative stress and diet-induced obesity (DIO), catalyzes the synthesis of CL species that are highly sensitive to oxidative damage, leading to mitochondrial dysfunction, ROS production, and insulin resistance. These metabolic disorders were reminiscent of those observed in type 2 diabetes and were reversed by rosiglitazone treatment. Consequently, ALCAT1 deficiency prevented the onset of DIO and significantly improved mitochondrial complex I activity, lipid oxidation, and insulin signaling in ALCAT1(-/-) mice. Collectively, these findings identify a key role of ALCAT1 in regulating CL remodeling, mitochondrial dysfunction, and susceptibility to DIO.

 

BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice.

Lang CH1Lynch CJVary TC.   Author information
Am J Physiol Regul Integr Comp Physiol. 2010 Sep; 299(3):R935-44.
http://dx.doi.org:/10.1152/ajpregu.00297.2010

Endotoxin (LPS) and sepsis decrease mammalian target of rapamycin (mTOR) activity in skeletal muscle, thereby reducing protein synthesis. Our study tests the hypothesis that inhibition of branched-chain amino acid (BCAA) catabolism, which elevates circulating BCAA and stimulates mTOR, will blunt the LPS-induced decrease in muscle protein synthesis. Wild-type (WT) and mitochondrial branched-chain aminotransferase (BCATm) knockout mice were studied 4 h after Escherichia coli LPS or saline. Basal skeletal muscle protein synthesis was increased in knockout mice compared with WT, and this change was associated with increased eukaryotic initiation factor (eIF)-4E binding protein-1 (4E-BP1) phosphorylation, eIF4E.eIF4G binding, 4E-BP1.raptor binding, and eIF3.raptor binding without a change in the mTOR.raptor complex in muscle. LPS decreased muscle protein synthesis in WT mice, a change associated with decreased 4E-BP1 phosphorylation as well as decreased formation of eIF4E.eIF4G, 4E-BP1.raptor, and eIF3.raptor complexes. In BCATm knockout mice given LPS, muscle protein synthesis only decreased to values found in vehicle-treated WT control mice, and this ameliorated LPS effect was associated with a coordinate increase in 4E-BP1.raptor, eIF3.raptor, and 4E-BP1 phosphorylation. Additionally, the LPS-induced increase in muscle cytokines was blunted in BCATm knockout mice, compared with WT animals. In a separate study, 7-day survival and muscle mass were increased in BCATm knockout vs. WT mice after polymicrobial peritonitis. These data suggest that elevating blood BCAA is sufficient to ameliorate the catabolic effect of LPS on skeletal muscle protein synthesis via alterations in protein-protein interactions within mTOR complex-1, and this may provide a survival advantage in response to bacterial infection.

 

Alcohol-induced IGF-I resistance is ameliorated in mice deficient for mitochondrial branched-chain aminotransferase.

Lang CH1Lynch CJVary TCAuthor information
J Nutr. 2010 May;140(5):932-8. http://dx.doi.org:/10.3945/jn.109.120501

Acute alcohol intoxication decreases skeletal muscle protein synthesis by impairing mammalian target of rapamycin (mTOR). In 2 studies, we determined whether inhibition of branched-chain amino acid (BCAA) catabolism ameliorates the inhibitory effect of alcohol on muscle protein synthesis by raising the plasma BCAA concentrations and/or by improving the anabolic response to insulin-like growth factor (IGF)-I. In the first study, 4 groups of mice were used: wild-type (WT) and mitochondrial branched-chain aminotransferase (BCATm) knockout (KO) mice orally administered saline or alcohol (5 g/kg, 1 h). Protein synthesis was greater in KO mice compared with WT controls and was associated with greater phosphorylation of eukaryotic initiation factor (eIF)-4E binding protein-1 (4EBP1), eIF4E-eIF4G binding, and 4EBP1-regulatory associated protein of mTOR (raptor) binding, but not mTOR-raptor binding. Alcohol decreased protein synthesis in WT mice, a change associated with less 4EBP1 phosphorylation, eIF4E-eIF4G binding, and raptor-4EBP1 binding, but greater mTOR-raptor complex formation. Comparable alcohol effects on protein synthesis and signal transduction were detected in BCATm KO mice. The second study used the same 4 groups, but all mice were injected with IGF-I (25 microg/mouse, 30 min). Alcohol impaired the ability of IGF-I to increase muscle protein synthesis, 4EBP1 and 70-kilodalton ribosomal protein S6 kinase-1 phosphorylation, eIF4E-eIF4G binding, and 4EBP1-raptor binding in WT mice. However, in alcohol-treated BCATm KO mice, this IGF-I resistance was not manifested. These data suggest that whereas the sustained elevation in plasma BCAA is not sufficient to ameliorate the catabolic effect of acute alcohol intoxication on muscle protein synthesis, it does improve the anabolic effect of IGF-I.

 

Impact of chronic alcohol ingestion on cardiac muscle protein expression.

Fogle RL1Lynch CJPalopoli MDeiter GStanley BAVary TCAuthor information
Alcohol Clin Exp Res. 2010 Jul;34(7):1226-34. http://dx.doi.org:/10.1111/j.1530-0277.2010.01200.x

BACKGROUND:

Chronic alcohol abuse contributes not only to an increased risk of health-related complications, but also to a premature mortality in adults. Myocardial dysfunction, including the development of a syndrome referred to as alcoholic cardiomyopathy, appears to be a major contributing factor. One mechanism to account for the pathogenesis of alcoholic cardiomyopathy involves alterations in protein expression secondary to an inhibition of protein synthesis. However, the full extent to which myocardial proteins are affected by chronic alcohol consumption remains unresolved.

METHODS:

The purpose of this study was to examine the effect of chronic alcohol consumption on the expression of cardiac proteins. Male rats were maintained for 16 weeks on a 40% ethanol-containing diet in which alcohol was provided both in drinking water and agar blocks. Control animals were pair-fed to consume the same caloric intake. Heart homogenates from control- and ethanol-fed rats were labeled with the cleavable isotope coded affinity tags (ICAT). Following the reaction with the ICAT reagent, we applied one-dimensional gel electrophoresis with in-gel trypsin digestion of proteins and subsequent MALDI-TOF-TOF mass spectrometric techniques for identification of peptides. Differences in the expression of cardiac proteins from control- and ethanol-fed rats were determined by mass spectrometry approaches.

RESULTS:

Initial proteomic analysis identified and quantified hundreds of cardiac proteins. Major decreases in the expression of specific myocardial proteins were observed. Proteins were grouped depending on their contribution to multiple activities of cardiac function and metabolism, including mitochondrial-, glycolytic-, myofibrillar-, membrane-associated, and plasma proteins. Another group contained identified proteins that could not be properly categorized under the aforementioned classification system.

CONCLUSIONS:

Based on the changes in proteins, we speculate modulation of cardiac muscle protein expression represents a fundamental alteration induced by chronic alcohol consumption, consistent with changes in myocardial wall thickness measured under the same conditions.

 

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Heart-Failure–Related Mortality Rate: CDC Reports comparison of 2000, 2012, 2014  – the decease is steadily reversed

Reporter: Aviva Lev-Ari, PhD, RN

 

The report, which examined heart-failure trends between 2000 and 2014, showed that the age-adjusted rate for HF-related mortality was 105.4 per 100,000 population in 2000 and only 81.4 per 100,000 in 2012 (P<0.05). However, the rate then started a slow but steady climb, reaching 84.0 per 100,000 in 2014.

Not so surprising: men of all ages still had a higher death rate vs women in 2014, and black individuals had a higher rate than whites (91.5 vs 87.3 deaths per 100,000) and Hispanics (53.3 per 100,000).

 

CDC: Heart-Failure–Related Mortality Rate Climbs After Decade-Long Decrease

Deborah Brauser

January 04, 2016

http://www.medscape.com/viewarticle/856704?nlid=95763_3866&src=wnl_edit_medp_card&uac=93761AJ&spon=2&impID=944924&faf=1

NCHS Data Brief

Number 231, December 2015

Recent Trends in Heart Failure-related Mortality: United States, 2000–2014

PDF Version Adobe PDF file (351 KB)

Hanyu Ni, Ph.D.; and Jiaquan Xu, M.D.

 

Key findings

Data from the National Vital Statistics System, Mortality

  • The age-adjusted rate for heart failure-related deaths decreased from 2000 through 2012 but increased from 2012 through 2014.
  • The death rate for heart failure was higher for the
    non-Hispanic black population than for the non-Hispanic white and Hispanic populations.
  • The death rate was higher for men than for women in all age groups. The gap in the death rate for adults aged 45–64 and 85 and over increased over time.
  • The percentage of heart failure-related deaths that occurred in a hospital decreased from 2000 through 2014.
  • The percentage of heart failure-related deaths for adults aged 45 and over with coronary heart disease as the underlying cause of death decreased 32%, from 34.9% in 2000 to 23.9% in 2014.

Heart failure is a major public health problem associated with significant hospital admission rates, mortality, and costly health care expenditures, despite advances in the treatment and management of heart failure and heart failure-related risk factors (1–4). Using data from the multiple cause of death files, this report describes the trends in heart failure-related mortality from 2000 through 2014 for the U.S. population, by age, sex, race and Hispanic origin, and place of death. Heart failure-related deaths were identified as those with heart failure reported anywhere on the death certificate, either as an underlying or contributing cause of death. Changes in the underlying causes of heart failure-related deaths are also described in this report.

Keywords: mortality, heart failure, trend, National Vital Statistics System

SOURCE

http://www.cdc.gov/nchs/data/databriefs/db231.htm

 

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Calcium Channel Blocker Potential for Angina

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Pranidipine    

ANTHONY MELVIN CRASTO, PhD

str1

https://newdrugapprovals.files.wordpress.com/2015/12/str116.jpg

 

File:Pranidipine structure.svg

Pranidipine , OPC-13340, FRC 8411

Acalas®

NDA Filing in Japan

A calcium channel blocker potentially for the treatment of angina pectoris and hypertension.

 

CAS No. 99522-79-9

  • Molecular FormulaC25H24N2O6
  • Average mass 448.468

 

see dipine series………..http://organicsynthesisinternational.blogspot.in/p/dipine-series.html

manidipine

 

PAPER

Der Pharmacia Sinica, 2014, 5(1):11-17

https://newdrugapprovals.files.wordpress.com/2015/12/str113.jpg

pelagiaresearchlibrary.com/der-pharmacia-sinica/vol5-iss1/DPS-2014-5-1-11-17.pdf

 

Names
IUPAC name

methyl (2E)-phenylprop-2-en-1-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Other names

2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-methyl O3-[(E)-3-phenylprop-2-enyl] ester
Identifiers
99522-79-9 Yes
ChEMBL ChEMBL1096842 
ChemSpider 4940726 
Jmol interactive 3D Image
MeSH C048161
PubChem 6436048
UNII 9DES9QVH58 Yes

 

 

 

PATENT SUBMITTED GRANTED
Process for the preparation of 1,4 – dihydropyridines and novel 1,4-dihydropyridines useful as therapeutic agents [US2003230478] 2003-12-18
Advanced Formulations and Therapies for Treating Hard-to-Heal Wounds [US2014357645] 2014-08-19 2014-12-04
METHODS OF TREATING CARDIOVASCULAR AND METABOLIC DISEASES [US2014322199] 2012-08-06 2014-10-30
Protein Carrier-Linked Prodrugs [US2014323402] 2012-08-10 2014-10-30
sGC STIMULATORS [US2014323448] 2014-04-29 2014-10-30
TREATMENT OF ARTERIAL WALL BY COMBINATION OF RAAS INHIBITOR AND HMG-CoA REDUCTASE INHIBITOR [US2014323536] 2012-12-07 2014-10-30
Agonists of Guanylate Cyclase Useful For the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders [US2014329738] 2014-03-28 2014-11-06
METHODS, COMPOSITIONS, AND KITS FOR THE TREATMENT OF CANCER [US2014335050] 2012-05-25 2014-11-13
ROR GAMMA MODULATORS [US2014343023] 2012-09-18 2014-11-20
High-Loading Water-Soluable Carrier-Linked Prodrugs [US2014296257] 2012-08-10 2014-10-02 

 

 

Synthesis, isolation and use of a common key intermediate for calcium antagonist inhibitors

Neelakandan K.a,b, Manikandan H.b , B. Prabhakarana*, Santosha N.a , Ashok Chaudharia *, Mukund Kulkarnic , Gopalakrishnan Mannathusamyb and Shyam Titirmarea
a API Research Centre, Emcure Pharmaceutical Limited, Hinjawadi, Pune, India bDepartment of Chemistry, Annamalai University, Chidhambaram, India cDepartment of Chemistry, Pune University, Pune, India _________________________________________________________________________________

Pelagia Research Library     www.pelagiaresearchlibrary.com      Der Pharmacia Sinica, 2014, 5(1):11-17

 

The compound (3) synthesized from Nitrobenzaldehyde, tertiary butyl acetoacetate and piperidine can be used as a common intermediate for the production of calcium channel blockers like Nicardipine hydrochloride (1) and Pranidipine hydrochloride (2) with high purity.

 

The last twenty years have witnessed discoveries of calcium antagonists associated with multicoated pharmacodynamics potential which include not only antihypertensive and antiarrhythmic effects of the drugs but also action against excessive calcium entry in the cell of cardiovascular system and subsequent cell damage. Among many classes of calcium channel blockers, 1,4-dihydropyrimidine based drug molecules represented by Felodipine, Clevidipine, Benidipine, Nicardipine and Pranidipine are by far the best to reduce systemic vascular resistance and arterial pressure.

The reported synthetic approaches however proceed with complicated work ups, laborious purification procedures, highly expensive chemicals and low overall yields. (Scheme-I).

Synthetic scheme of Nicardipine and Pranidipine In view of the draw backs associated with previous synthetic approaches there is a strong need for environmentfriendly high yielding process applicable to the multi-kilogram production of calcium antagonist inhibitors. Herein, we report a scalable synthesis for Nicardipine hydrochloride (1) and Pranidipine hydrochloride (2) in fairly high overall yield using key intermediate 3-nitro benzylidene acid (3).Compound (3) was synthesized in two steps using 3-nitrobenzaldehyde, tertiary butyl acetoacetate and piperidine as a base to furnish tertiary butyl ester derivative (10). This was followed by hydrolysis of (10) in TFA and DCM to furnish compound (3) which would serve as a precursor for synthesis of versatile calcium antagonist inhibitors (Scheme-II).

Reported routes for synthesis of Benidipine,1,2 Lercanadipine,3-6 Nimodipine,7-11 Barnidipine12-14 and Manidipine15-16 were explored in our laboratory which involve reaction of nitro benzaldehyde with tertiary butyl acetoacetate using piperidine as a base to get tertiary butyl ester derivative (10). This is further treated with respective reagents to get various calcium channel blockers as shown in scheme 4. Since reported procedures involve in-situ generation of intermediate (3) and its reaction with corresponding fragments, it results in the formation of by-products which ultimately decrease the yield and increase the cost of API.

A novel process of manufacturing benzylidine acid derivative (3) was developed. Use of this intermediate was demonstrated by synthesis of Nicardipine and Pranidipine. This protocol may be employed for synthesis of other calcium channel blockers. In conclusion, a highly efficient, reproducible and scalable process for the synthesis of calcium channel blockers has been developed using (3) as the key intermediate.

 

[1] US 63 365 (Kyowa Hakko; appl.15.4.1982; J-prior.17.4.1981). [2] US 4 448 964 (Kyowa Hakko;15.5.1984; J-prior.17.4.1981). [3] Leonardi, A. et al.: Eur. J. Med.Chem. (EJMCA5) 33,399 (1988). [4] EP 153 016 (Recordati Chem. and Pharm.; appl. 21.1.1985; GB-prior. 14.2.1984). [5] US 4 705 797 (Recordati;10.11.1987; GB-prior. 14.2.1984). [6] WO 9 635 668 (Recordati Chem. and Pharm.; appl. 9.5.1996; I-prior. 12.5.1995). [7] DOS 2 117 571 (Bayer; appl. 10.4.1971). [8] DE 2 117 573 (Bayer; prior.10.4.1971) [9] US 3 799 934 (Bayer;26.3.1974;D-prior.10.4.1971). [10] US 3 932 645 (Bayer;13.1.1976;D-prior.10.4.1971). [11] Meyer, H. et al.: Arzneim.-Forsch. (ARZNAD) 31, 407 (1981); 33, 106 (1983). [12] DE 2 904 552 (Yamanouchi Pharm.; appl. 7.2.1979; J-prior.14.2.1978). [13] US 4 220 649 (Yamanouchi;2.9.1980; J-prior.14.2.1978). [14] CN 85 107 590( Faming Zhuanli Sheqing Gonhali S.; appl. 11.10.1985; J-prior.24.1.1985). [15] EP 94 159 (Takeda; appl. 15.4.1983; J-prior. 10.5.1982). [16] US 4 892 875 (Takeda;9.1.1990; J-prior. 10.5.1982, 11.1.1983).

 

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Nuts and health in aging

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Nut consumption and age-related disease

Giuseppe GrossoRamon Estruch

MATURITAS · OCT 2015     http://dx.doi.org/10.1016/j.maturitas.2015.10.014

Current knowledge on the effects of nut consumption on human health has rapidly increased in recent years and it now appears that nuts may play a role in the prevention of chronic age-related diseases. Frequent nut consumption has been associated with better metabolic status, decreased body weight as well as lower body weight gain over time and thus reduce the risk of obesity. The effect of nuts on glucose metabolism, blood lipids, and blood pressure are still controversial. However, significant decreased cardiovascular risk has been reported in a number of observational and clinical intervention studies. Thus, findings from cohort studies show that increased nut consumption is associated with a reduced risk of cardiovascular disease and mortality (especially that due to cardiovascular-related causes). Similarly, nut consumption has been also associated with reduced risk of certain cancers, such as colorectal, endometrial, and pancreatic neoplasms. Evidence regarding nut consumption and neurological or psychiatric disorders is scarce, but a number of studies suggest significant protective effects against depression, mild cognitive disorders and Alzheimer’s disease. The underlying mechanisms appear to include antioxidant and anti-inflammatory actions, particularly related to their mono- and polyunsaturated fatty acids (MUFA and PUFA, as well as vitamin and polyphenol content. MUFA have been demonstrated to improve pancreatic beta-cell function and regulation of postprandial glycemia and insulin sensitivity. PUFA may act on the central nervous system protecting neuronal and cell-signaling function and maintenance. The fiber and mineral content of nuts may also confer health benefits. Nuts therefore show promise as useful adjuvants to prevent, delay or ameliorate a number of chronic conditions in older people. Their association with decreased mortality suggests a potential in reducing disease burden, including cardiovascular disease, cancer, and cognitive impairments.

 

Global life expectancy has increased from 65 years in 1990 to about 71 years in 2013 [1]. As life expectancy has increased, the number of healthy years lost due to disability has also risen in most countries, consistent with greater morbidity [2]. Reduction of mortality rates in developed countries has been associated with a shift towards more chronic non-communicable diseases [1]. Cardiovascular diseases (CVDs) and related risk factors, such as hypertension, diabetes mellitus, hypercholesterolemia, and obesity are the top causes of death globally, accounting for nearly one-third of all deaths worldwide [3]. Equally, the estimated incidence, mortality, and disability- adjusted life-years (DALYs) for cancer rose to 14.9 million incident cancer cases, 8.2 million deaths, and 196.3 million DALYs, with the highest impact of prostate and breast cancer in men and women, respectively [4]. Depression is a leading cause of disability worldwide (in terms of total years lost due to disability), especially in high-income countries, increasing from 15th to 11th rank (37% increase) and accounting for 18% of total DALYs (almost 100 million DALYs) [5]. Overall, the global rise in chronic non-communicable diseases is congruent with a similar rise in the elderly population. The proportion of people over the age of 60 is growing faster than any other age group and is estimated to double from about 11% to 22% within the next 50 years [6]. Public health efforts are needed to face this epidemiological and demographic transition, both improving the healthcare systems, as well as assuring a better health in older people. Accordingly, a preventive approach is crucial to dealing with an ageing population to reduce the burden of chronic disease.

In this context, lifestyle behaviors have demonstrated the highest impact for older adults in preventing and controlling the morbidity and mortality due to non- communicable diseases [7]. Unhealthy behaviors, such as unbalanced dietary patterns, lack of physical activity and smoking, play a central role in increasing both cardiovascular and cancer risk [7]. Equally, social isolation and depression in later life may boost health decline and significantly contribute to mortality risk [8]. The role of diet in prevention of disability and death is a well-established factor, which has an even more important role in geriatric populations. Research has focused on the effect of both single foods and whole dietary patterns on a number of health outcomes, including mortality, cardiovascular disease (CVD), cancer and mental health disorders (such as cognitive decline and depression) [9-13]. Plantbased dietary patterns demonstrate the most convincing evidence in preventing chronic non-communicable diseases [14-17]. Among the main components (including fruit and vegetables, legumes and cereals), only lately has attention focused on foods such as nuts. Knowledge on the effect of nut consumption on human health has increased rapidly in recent years. The aim of this narrative review is to examine recent evidence regarding the role of nut consumption in preventing chronic disease in older people.

Tree nuts are dry fruits with an edible seed and a hard shell. The most popular tree nuts are almonds (Prunus amigdalis), hazelnuts (Corylus avellana), walnuts (Juglans regia), pistachios (Pistachia vera), cashews (Anacardium occidentale), pecans (Carya illinoiensis), pine nuts (Pinus pinea), macadamias (Macadamia integrifolia), Brazil nuts (Bertholletia excelsa), and chestnuts (Castanea sativa). When considering the “nut” group, researchers also include peanuts (Arachis hypogea), which technically are groundnuts. Nuts are nutrient dense foods, rich in proteins, fats (mainly unsaturated fatty acids), fiber, vitamins, minerals, as well as a number of phytochemicals, such as phytosterols and polyphenols [18]. Proteins account for about 10-25% of energy, including individual aminoacids, such as L-arginine, which is involved in the production of nitric oxide (NO), an endogenous vasodilatator [19].

The fatty acids composition of nuts involves saturated fats for 415% and unsaturated fatty acids for 30-60% of the content. Unsaturated fatty acids are different depending on the nut type, including monounsaturated fatty acids (MUFA, such as oleic acid in most of nuts, whereas polyunsaturated fatty acids (PUFA, such as alpha-linolenic acid) in pine nuts and walnuts [20]. Also fiber content is similar among most nut types (about 10%), although pine nuts and cashews hold the least content. Vitamins contained in nuts are group B vitamins, such as B6 (involved in many aspects of macronutrient metabolism) and folate (necessary for normal cellular function, DNA synthesis and metabolism, and homocysteine detoxification), as well as tocopherols, involved in anti-oxidant mechanisms [21]. Among minerals contained in vegetables, nuts have an optimal content in calcium, magnesium, and potassium, with an extremely low amount of sodium, which is implicated on a number of pathological conditions, such as bone demineralization, hypertension and insulin resistance[22]. Nuts are also rich in phytosterols, non-nutritive components of certain plant-foods that exert both structural (at cellular membrane phospholipids level) and hormonal (estrogen-like) activities [23]. Finally, nuts have been demonstrated to be a rich source of polyphenols, which account for a key role in their antioxidant and anti-inflammatory effects.

 

Metabolic disorders are mainly characterized by obesity, hypertension, dyslipidemia, and hyperglycemia/ hyperinsulinemia/type-2 diabetes, all of which act synergistically to increase morbidity and mortality of aging population.

Obesity Increasing high carbohydrate and fat food intake in the last decades has contributed significantly to the rise in metabolic disorders. Nuts are energy-dense foods that have been thought to be positively associated with increased body mass index (BMI). As calorie-dense foods, nuts may contain 160–200 calories per ounce. The recommendation from the American Heart  Association to consume 5 servings per week (with an average recommended serving size of 28 g) corresponds to a net increase of 800–1000 calories per week, which may cause weight gain. However, an inverse relation between the frequency of nut consumption and BMI has been observed in large cohort studies [24]. Pooling the baseline observations of BMI by category of nut consumption in 5 cohort studies found a significant decreasing trend in BMI values with increasing nut intake [24]. While the evidence regarding nut consumption and obesity is limited, findings so far are encouraging [25, 26]. When the association between nut consumption and body weight has been evaluated longitudinally over time, nut intake was associated with a slightly lower risk of weight gain and obesity [25]. In the Nurses’ Health Study II (NHS II), women who eat nuts ≥2 times per week had slightly less weight gain (5.04 kg) than did women who rarely ate nuts (5.55 kg) and marginally significant 23% lower risk of obesity after 9-year follow-up [25]. Further evaluation of the NHS II data and the Physicians’ Health Study (PHS) comprising a total of 120,877 US women and men and followed up to 20 years revealed that 4-y weight change was inversely associated with a 1-serving increment in the intake of nuts (20.26 kg) [27]. In the “Seguimiento Universidad de Navarra” (SUN) cohort study, a significant decreased weight change has been observed over a period of 6 years [26]. After adjustment for potential confounding factors the analysis was no longer significant, but overall no weight gain associated with >2 servings per week of nuts has been observed. Finally, when considering the role of the whole diet on body weight, a meta-analysis of 31 clinical trials led to the conclusion of a null effect of nut intake on body weight, BMI, and waist circumference [28].

Glucose metabolism and type-2 diabetes The association between nut consumption and risk of type-2 diabetes in prospective cohort studies is controversial [29-32]. A pooled analysis relied on the examination of five large cohorts, including the NHS, the Shanghai Women’s Health Study, the Iowa Women’s Health Study, and the PHS, and two European studies conducted in Spain (the PREDIMED trial) and Finland including a total of more than 230,000 participants and 13,000 cases, respectively. Consumption of 4 servings per week was associated with 13% reduced risk of type-2 diabetes without effect modification by age [29]. In contrast, other pooled analyses showed non-significant reduction of risk for increased intakes of nuts, underlying that the inverse association between the consumption of nuts and diabetes was attenuated after adjustment for confounding factors, including BMI [30]. However, results from experimental studies showed promising results. Thus, nut consumption has been demonstrated to exert beneficial metabolic effects due to their action on post-prandial glycemia an insulin sensitivity. A number of RCTs have demonstrated positive effects of nut consumption on post-prandial glycemia in healthy individuals [33-38]. Moreover, a meta-analysis of RCTs on the effects of nut intake on glycemic control in diabetic individuals including 12 trials and a total of 450 participants showed that diets with an emphasis on nuts (median dose = 56 g/d) significantly lowered HbA1c (Mean Difference [MD] : -0.07%; 95% confidence interval [CI]: -0.10, -0.03%; P = 0.0003) and fasting glucose (MD : -0.15 mmol/L; 95% CI: -0.27, -0.02 mmol/L; P = 0.03) compared with control diets [39]. No significant treatment effects were observed for fasting insulin and homeostatic model assessment (HOMA-IR), despite the direction of effect favoring diet regimens including nuts.

Blood lipids and hypertension Hypertension and dyslipidemia are major risk factors for CVD. Diet alone has a predominant role in blood pressure and plasma lipid homeostasis. One systematic review [40] and 3 pooled quantitative analyses of RCTs [41-43] evaluated the effects of nut consumption on lipid profiles. A general agreement was relevant on certain markers, as daily consumption of nuts (mean = 67 g/d) induced a pooled reduction of total cholesterol concentration (10.9 mg/dL [5.1% change]), low-density lipoprotein cholesterol concentration (LDL-C) (10.2 mg/dL [7.4% change]), ratio of LDL-C to high-density lipoprotein cholesterol concentration (HDL-C) (0.22 [8.3% change]), and ratio of total cholesterol concentration to HDL-C (0.24 [5.6% change]) (P <0.001 for all) [42]. All meta-analyses showed no significant effects of nut (including walnut) consumption on HDL cholesterol or triglyceride concentrations in healthy individuals [41], although reduced plasma triglyceride levels were found in individuals with hypertriglyceridemia [42]. Interestingly, the effects of nut consumption were dose related, and different types of nuts had similar effects on blood lipid concentrations.

There is only limited evidence from observational studies to suggest that nuts have a protective role on blood pressure. A pooled analysis of prospective cohort studies on nut consumption and hypertension reported a decreased risk associated with increased intake of nuts [32]. Specifically, only a limited number of cohort studies have been conducted exploring the association between nut consumption and hypertension (n = 3), but overall reporting an 8% reduced risk of hypertension for individuals consuming >2 servings per week (Risk Ratio [RR] = 0.92, 95% CI: 0.87-0.97) compared with never/rare consumers, whereas consumption of nuts at one serving per week had similar risk estimates (RR = 0.97, 95% CI: 0.83, 1.13) [32]. These findings are consistent with results obtained in a pooled analysis of 21 experimental studies reporting the effect of consuming single or mixed nuts (in doses ranging from 30 to 100 g/d) on systolic (SBP) and diastolic blood pressure (DBP) [44]. A pooled analysis found a significant reduction in SBP in participants without type2 diabetes [MD: -1.29 mmHg; 95% CI: -2.35, -0.22; P = 0.02] and DBP (MD: -1.19; 95% CI: -2.35, -0.03; P = 0.04), whereas subgroup analyses of different nut types showed that pistachios, but not other nuts, significantly reduced SBP (MD: -1.82; 95% CI: -2.97, -0.67; P = 0.002) and SBP (MD: -0.80; 95% CI: -1.43, -0.17; P = 0.01) [44].

Nut consumption and CVD risk Clustering of metabolic risk factors occurs in most obese individuals, greatly increasing risk of CVD. The association between nut consumption and CVD incidence [29-31] and mortality [24] has been explored in several pooled analyses of prospective studies. The overall risk calculated for CVD on a total of 8,862 cases was reduced by 29% for individuals consuming 7 servings per week (RR = 0.71, 95% CI: 0.59, 0.85) [30]. A meta-analysis including 9 studies on coronary artery disease (CAD) including 179,885 individuals and 7,236 cases, reporting that 1-serving/day increment would reduce risk of CAD of about 20% (RR = 0.81, 95% CI: 0.72, 0.91) [31]. Similar risk estimates were calculated for ischemic heart disease (IHD), with a comprehensive reduced risk of about 25-30% associated with a daily intake of nuts [29, 30]. Findings from 4 prospective studies have been pooled to estimate the association between nut consumption and risk of stroke, and a non-significant/borderline reduced risk was found [29-31, 45]. CVD mortality was explored in a recent meta-analysis including a total of 354,933 participants, 44,636 cumulative incident deaths, and 3,746,534 cumulative person-years [24]. One serving of nuts per week and per day resulted in decreased risk of CVD mortality (RR = 0.93, 95% CI: 0.88, 0.99 and RR =0.61, 95% CI: 0.42, 0.91, respectively], primarily driven by decreased coronary artery disease (CAD) deaths rather than stroke deaths [24]. Overall, all pooled analyses demonstrated a significant association between nut consumption and cardiovascular health. However, it has been argued that nut consumption was consistently associated with healthier background characteristics reflecting overall healthier lifestyle choices that eventually lead to decreased CVD mortality risk.

Nut consumption and cancer risk Cancer is one of the leading causes of death in the elderly population. After the evaluation of the impact on cancer burden of food and nutrients, it has been concluded that up to one third of malignancies may be prevented by healthy lifestyle choices. Fruit and vegetable intake has been the focus of major attention, but studies on nut consumption and cancer are scarce. A recent metaanalysis pooled together findings of observational studies on cancer incidence, including a total of 16 cohort and 20 casecontrol studies comprising 30,708 cases, compared the highest category of nut consumption with the lowest category and found a lower risk of any cancer of 25% (RR = 0.85, 95% CI: 0.86, 0.95) [46]. When the analysis was conducted by cancer site, highest consumption of nuts was associated with decreased risk of colorectal (RR = 0.76, 95% CI: 0.61, 0.96), endometrial (RR = 0.58, 95% CI: 0.43, 0.79), and pancreatic cancer (RR = 0.71, 95% CI: 0.51, 0.99), with only one cohort study was conducted on the last [46]. The potential protective effects of nut consumption on cancer outcomes was supported also by pooled analysis of 3 cohort studies [comprising the PREDIMED, the NHS, the HPS, and the Health Professionals Follow-Up Study (HPFS) cohorts] showing a decreased risk of cancer death for individuals consuming 3-5 servings of nuts per week compared with never eaters (RR = 0.86, 95% CI: 0.75, 0.98) [24]. The analysis was recently updated by including results from the Netherlands Cohort Study reaching a total of 14,340 deaths out of 247,030 men and women observed, confirming previous results with no evidence of between-study heterogeneity (RR = 0.85, 95% CI: 0.77, 0.93) [47]. However, a dose- response relation showed the non-linearity of the association, suggesting that only moderate daily consumption up to 5 g reduced risk of cancer mortality, and extra increased intakes were associated with no further decreased risk.

Nut consumption and affective/cognitive disorders Age-related cognitive decline is one of the most detrimental health problems in older people. Cognitive decline is a paraphysiological process of aging, but timing and severity of onset has been demonstrated to be affected by modifiable lifestyle factors, including diet. In fact, the nature of the age- related conditions leading to a mild cognitive impairment (MCI) differs by inflammation-related chronic neurodegenerative diseases, such as dementia, Alzheimer’s disease, Parkinson’s disease and depression. Evidence restricted to nut consumption alone is scarce, but a number of studies have been conducted on dietary patterns including nuts as a major component. A pooled analysis synthesizing findings of studies examining the association between adherence to a traditional Mediterranean diet and risk of depression (n = 9), cognitive decline (n = 8), and Parkinson’s disease (n = 1) showed a reduction of risk of depression (RR = 0.68, 95% CI: 0.54, 0.86) and cognitive impairment (RR = 0.60, 95% CI: 0.43, 0.83) in individuals with increased dietary adherence [10].

The study that first found a decreased risk of Alzheimer’s disease in individuals highly adherent to the Mediterranean diet was conducted in over 2,000 individuals in the Washington/Hamilton Heights-Inwood Columbia Aging Project (WHICAP), a cohort of non-demented elders aged 65 and older living in a multi-ethnic community of Northern Manhattan in the US (Hazard Ratio [HR] = 0.91, 95% CI: 0.83, 0.98) [48]. These results have been replicated in further studies on the Mediterranean diet, however nut consumption was not documented [49, 50]. A number of observational studies also demonstrated a significant association between this dietary pattern and a range of other cognitive outcomes, including slower global cognitive decline [51]. However, evidence from experimental studies is limited to the PREDIMED trial, providing interesting insights on the association between the Mediterranean diet supplemented with mixed nuts and both depression and cognitive outcomes. Regarding depression, the nutritional intervention with a Mediterranean diet supplemented with nuts showed a lower risk of about 40% in participants with type-2 diabetes (RR = 0.59, 95% CI: 0.36, 0.98) compared with the control diet [52]. However the effect was not significant in the whole cohort overall [52]. Regarding cognitive outcomes after a mean follow-up of 4.1 years, findings from the same trial showed significant improvements in memory and global cognition tests for individuals allocated to the Mediterranean diet supplemented with nuts [adjusted differences: -0.09 (95% CI: -0.05, 0.23), P = 0.04 and -0.05 (95% CI: -0.27, 0.18), P = 0.04, respectively], compared to control group, showing that Mediterranean diet plus mixed nuts is associated with improved cognitive function [53].

 

Potential mechanisms of protection of nut consumption Despite the exact mechanisms by which nuts may ameliorate human health being largely unknown, new evidence has allowed us to start to better understand the protection of some high-fat, vegetable, energy-dense foods such as nuts. Non- communicable disease burden related with nutritional habits is mainly secondary to exaggerated intakes of refined sugars and saturated fats, such as processed and fast- foods. Nuts provide a number of nutrient and non-nutrient compounds and it is only recently that scientists have tried to examine their effects on metabolic pathways.

Metabolic and cardiovascular protection With special regard to body weight and their potential effects in decreasing the risk of obesity (or weight gain, in general), nuts may induce satiation (reduction in the total amount of food eaten in a single meal) and satiety (reduction in the frequency of meals) due to their content in fibers and proteins, which are associated with increased release of glucagon-like protein 1 (GLP-1) and cholecystokinin (CCK), gastrointestinal hormones with satiety effects [54, 55]. The content in fiber of nuts may also increase thermogenesis and resting energy expenditure, and reduce post- prandial changes of glucose, thus ameliorating inflammation and insulin resistance. Moreover, the specific content profile of MUFA and PUFA provides readily oxidized fats than saturated or trans fatty acids, leading to reduced fat accumulation [56, 57]. The beneficial effects of nuts toward glucose metabolism may be provided by their MUFA content that improves the efficiency of pancreatic beta-cell function by enhancing the secretion of GLP1, which in turn helps the regulation of postprandial glycemia and insulin sensitivity [58]. MUFA and PUFA are also able to reduce serum concentrations of the vasoconstrictor thromboxane 2, which might influence blood pressure regulation. Together with polyphenols and anti-oxidant vitamins, nuts may also ameliorate inflammatory status at the vascular level, reducing circulating levels of soluble cellular adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, which are released from the activated endothelium and circulating monocytes [59]. Moreover, nuts may improve vascular reactivity due to their content in L-arginine, which is a potent precursor of the endogenous vasodilator nitric oxide. Nuts content in microelements is characterized by a mixture that may exert a direct effect in modulating blood pressure, including low content of sodium and richness in magnesium, potassium and calcium, which may interact to beneficially influence blood pressure
Despite the exact mechanisms by which nuts may ameliorate human health being largely unknown, new evidence has allowed us to start to better understand the protection of some high-fat, vegetable, energy-dense foods such as nuts. Non- communicable disease burden related with nutritional habits is mainly secondary to exaggerated intakes of refined sugars and saturated fats, such as processed and fast- foods. Nuts provide a number of nutrient and non-nutrient compounds and it is only recently that scientists have tried to examine their effects on metabolic pathways.

Cancer protection The potential mechanisms of action of nuts that may intervene in the prevention of cancer have not been totally elucidated. Numerous hypotheses have been proposed on the basis of basic research exploring the antioxidant and anti-inflammatory compounds characterizing nuts [61]. Vitamin E can regulate cell differentiation and proliferation, whereas polyphenols (particularly flavonoids such as quercetin and stilbenes such as resveratrol) have been shown to inhibit chemically-induced carcinogenesis [62]. Polyphenols may regulate the inflammatory response and immunological activity by acting on the formation of the prostaglandins and pro-inflammatory cytokines, which may be an important mechanism involved in a number of cancers, including colorectal, gastric, cervical and pancreatic neoplasms [62]. Among other compounds contained in nuts, dietary fiber may exert protective effects toward certain cancers (including, but not limited to colorectal cancer) by the aforementioned metabolic effects as well as increasing the volume of feces and anaerobic fermentation, and reducing the length of intestinal transit. As a result, the intestinal mucosa is exposed to carcinogens for a reduced time and the carcinogens in the colon are diluted [62]. Finally, there is no specific pathway demonstrating the protective effect of PUFA intake against cancer, but their interference with cytokines and prostaglandin metabolism may inhibit a state of chronic inflammation that may increase cancer risk [63].

Cognitive aging and neuro-protection There is no universal mechanism of action for nuts with regard to age-related conditions. A number of systemic biological conditions, such as oxidative stress, inflammation, and reduced cerebral blood flow have been considered as key factors in the pathogenesis of both normal cognitive ageing and chronic neurodegenerative disease [64]. Nuts, alone or as part of healthy dietary patterns, may exert beneficial effects due to their richness in antioxidants, including vitamins, polyphenols and unsaturated fatty acids, that may be protective against the development of cognitive decline and depression [65, 66]. Both animal studies and experimental clinical trials demonstrated vascular benefits of nuts, including the aforementioned lowering of inflammatory markers and improved endothelial function, which all appear to contribute to improved cognitive function [67]. The antioxidant action may affect the physiology of the ageing brain directly, by protecting neuronal and cell-signaling function and maintenance. Moreover, certain compounds contained in nuts may directly interact with the physiology and functioning of the brain. For instance, walnuts are largely composed of PUFA, especially ALA, which have been suggested to induce structural change in brain areas associated with affective experience [66]. Moreover, PUFA have been associated with improved symptoms in depressed patients, suggesting an active role in the underlying pathophysiological mechanisms [68]. Thus, the mechanisms of action of nut consumption on age-related cognitive and depressive disorders are complex, involving direct effects on brain physiology at the neuronal and cellular level and indirect effects by influencing inflammation.

 

Summary From an epidemiological point of view, nut eaters have been associated with overall healthier lifestyle habits, such as increased physical activity, lower prevalence of smoking, and increased consumption of fruits and vegetables [24]. These variables represent strong confounding factors in determining the effects of nuts alone on human health and final conclusions cannot be drawn. Nevertheless, results from clinical trials are encouraging. Nuts show promise as useful adjuvants to prevent, delay or ameliorate a number of chronic conditions in older people.

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Role of Inflammation in Disease

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Inflamed  

The debate over the latest cure-all craze.

BY

Medical Dispatch NOVEMBER 30, 2015 ISSUE     http://www.newyorker.com/magazine/2015/11/30/inflamed

 

The National Institutes of Health recently designated inflammation a priority.

 

The National Institutes of Health recently designated inflammation a priority.
CREDIT ILLUSTRATION BY CHAD HAGEN

 

Several years ago, I fell at the gym and ripped two tendons in my wrist. The pain was excruciating, and within minutes my hand had swollen grotesquely and become hot to the touch. I was reminded of a patient I’d seen early in medical school, whose bacterial infection extended from his knee to his toes. Latin was long absent from the teaching curriculum, but, as my instructor examined the leg, he cited the four classic symptoms of inflammation articulated by the Roman medical writer Celsus in the first century: rubor, redness; tumor, swelling; calor, heat; and dolor, pain. In Latin, inflammatio means “setting on fire,” and as I considered the searing pain in my injured hand I understood how the condition earned its name.

Inflammation occurs when the body rallies to defend itself against invading microbes or to heal damaged tissue. The walls of the capillaries dilate and grow more porous, enabling white blood cells to flood the damaged site. As blood flows in and fluid leaks out, the region swells, which can put pressure on surrounding nerves, causing pain; inflammatory molecules may also activate pain fibres. The heat most likely results from the increase in blood flow.
The key white blood cell in inflammation is called a macrophage, and for decades it has been a subject of study in my hematology laboratory and in many others. Macrophages were once cast as humble handmaidens of the immune system, responsible for recognizing microbes or debris and gobbling them up. But in recent years researchers have come to understand that macrophages are able to assemble, within themselves, specialized platforms that pump out the dozens of molecules that promote inflammation. These platforms, called inflammasomes, are like pop-up factories—quickly assembled when needed and quickly dismantled when the crisis has passed.

For centuries, scientists have debated whether inflammation is good or bad for us. Now we believe that it’s both: too little, and microbes fester and spread in the body, or wounds fail to heal; too much, and nearby healthy tissue can be degraded or destroyed. The fire of inflammation must be tightly controlled—turned on at the right moment and, just as critically, turned off. Lately, however, several lines of research have revealed that low-level inflammation can simmer quietly in the body, in the absence of overt trauma or infection, with profound implications for our health. Using advanced technologies, scientists have discovered that heart attacks, diabetes, and Alzheimer’s disease may be linked to smoldering inflammation, and some researchers have even speculated about its role in psychiatric conditions.

As a result, understanding and controlling inflammation has become a central goal of modern medical investigation. The internal research arm of the National Institutes of Health recently designated inflammation a priority, mobilizing several hundred scientists and hundreds of millions of dollars to better define its role in health and disease; in 2013, the journal Science devoted an entire issue to the subject. This explosion in activity has captured the public imagination. In best-selling books and on television and radio talk shows, threads of research are woven into cure-all tales in which inflammation is responsible for nearly every malady, and its defeat is the secret to health and longevity. New diets will counter the inflammation simmering in your gut and restore your mental equilibrium. Anti-inflammatory supplements will lift your depression and ameliorate autism. Certain drugs will tamp down the silent inflammation that degrades your tissues, improving your health and extending your life. Everything, and everyone, is inflamed.

Such claims aside, there is genuine evidence that inflammation plays a role in certain health conditions. In atherosclerosis, blood flow to the heart or the brain is blocked, resulting in a heart attack or a stroke. For a long time, atherosclerosis was thought to result mainly from eating fatty foods, which clogged the arteries. “Atherosclerosis was all about fats and grease,” Peter Libby, a professor at Harvard Medical School and a cardiologist at Brigham and Women’s Hospital, in Boston, told me recently. “Most physicians saw atherosclerosis as a straight plumbing problem.”

During his cardiology training, Libby studied immunology, and he became fascinated with the work of Rudolf Virchow, a nineteenth-century German pathologist. Virchow speculated that atherosclerosis might be an active process, caused by inflamed blood vessels, not one caused simply by the accumulation of fat. In the mid-nineteen-nineties, in studies with mice, Libby, working in parallel with other groups of scientists, found that low-density lipoproteins—LDLs, those particles of “bad” cholesterol—can work their way into the lining of arteries. There, they sometimes trigger an inflammatory response, which can cause blood clots that block the artery. Libby and others began to understand that atherosclerosis wasn’t a mere plumbing problem but also an immune disease—“our body’s defenses turned against ourselves,” he told me.

Paul Ridker, a cardiovascular expert and a colleague of Libby’s at Harvard and Brigham and Women’s, moved the research beyond the laboratory. He found that many patients who’d had heart attacks, despite lacking factors such as high blood pressure, high cholesterol, and a history of smoking, had an elevated level of C-reactive protein, a molecule produced in response to inflammation, in their blood. After demonstrating, in a separate study, that cholesterol-reducing statins could also reduce C-reactive-protein levels, Ridker launched the Jupiter trial, in which people with elevated levels of C-reactive protein but normal cholesterol levels were given a placebo or a statin medication. In 2008, the published results showed that the subjects who received the statin saw their levels of C-reactive protein drop and were less likely three and a half years later to suffer a heart attack. This suggested that elevated cholesterol isn’t the only factor at work in cardiovascular disease, and that in some cases statins, acting as anti-inflammatory agents, could be used to treat the condition.
The benefit was modest: the statin treatment reduced the risk of heart attack in only about one per cent of the patients. Still, that figure is statistically significant, and for one in every hundred patients—a hundred in every ten thousand—it’s meaningful. An independent safety-monitoring board ended the study early, saying that it was unethical to continue once it was clear that statins provided a benefit not available to the subjects on the placebo. (Critics argue that shortening the trial, which was funded by a drug company, exaggerated the potential benefits and underestimated long-term harm, but the researchers strongly disagree.) The N.I.H. and other scientific groups are funding new studies to further explore whether anti-inflammatory drugs—for example, low doses of immunomodulatory agents that are used for treating severe arthritis—can help prevent cardiovascular disease.
Another chronic condition that has been linked to inflammation is Type II diabetes. People with this condition can’t adequately use insulin, a molecule that enables the body’s cells to take glucose out of the bloodstream and derive energy from it. Their organs fail and glucose builds to dangerous levels in the blood. Recently, researchers have found macrophages in the pancreases of people with Type II diabetes. The macrophages release inflammatory molecules that are thought to impair insulin activity. One of these inflammatory molecules is called interleukin-1, and in 2007 the New England Journal of Medicine reported on a clinical trial in which an interleukin-1 blocker proved to be modestly effective at lowering blood-sugar levels in Type II diabetics. This suggests that, by blocking inflammation, it might be possible to restore insulin activity and alleviate some of the symptoms of diabetes.

Alzheimer’s disease, too, seems to show a link to inflammation. Alzheimer’s results from the buildup of amyloid and tau proteins in the brain; specialized cells called glial cells, which are related to macrophages, recognize these proteins as debris and release inflammatory molecules to get rid of them. This inflammation is thought to further impair the working of neurons, worsening Alzheimer’s. The connection is tantalizing, but it’s important to note that it doesn’t mean that inflammation causes Alzheimer’s. Nor is there strong evidence that inflammation contributes to other forms of dementia where the brain isn’t filled with protein debris. And in clinical trials anti-inflammatory drugs like naproxen and ibuprofen have failed to ameliorate or prevent Alzheimer’s.

 

On September 18, 2015, scientists at the N.I.H. convened a meeting to publicly present their research priorities, one of which is to decipher the consequences of inflammation. It’s increasingly apparent that inflammation plays some role in many health conditions, but scientists are far from grasping the nature of that relationship, the mechanisms involved, or the extent to which treating inflammation is helpful.

“We really don’t know how much inflammation contributes to diabetes, Alzheimer’s, depression, and other disorders,” Michael Gottesman, a director of research at the N.I.H., told me. “We know a lot about the mouse and its immune response. Much, much less is understood in humans. As we learn more, we see how much more we need to learn.” Gottesman pointed out that, of the thousand or so proteins circulating in our bloodstream, about a third are involved in inflammation and in our immune response, so simply detecting their presence doesn’t reveal much about their potential involvement in any particular disease. “Correlation is not causation,” he emphasized. “Because you find an inflammatory protein in a certain disorder, it doesn’t mean that it is causing that disorder.”
This lack of certainty hasn’t dampened the enthusiasm of a growing number of doctors who believe that inflammation is the source of a wide range of conditions, including dementia, depression, autism, A.D.H.D., and even aging. One of the most prominent such voices is that of Mark Hyman, whose books—including “The Blood Sugar Solution 10-Day Detox Diet”—are best-sellers. Hyman serves as a personal health adviser to Bill and Hillary Clinton and to the King and Queen of Jordan. Recently, he was recruited by the Cleveland Clinic with millions of dollars in funding to establish a center based on his ideas. Trained in family medicine, Hyman told me that he considers himself a new type of doctor. “I am a doctor who treats root causes and addresses the body as a dynamic system,” he wrote in an e-mail. “Being an inflammalogist is part of that.”

Studies with human subjects clearly indicate that, in cases where inflammation underlies a chronic condition, the inflammation is local: in the arteries (heart disease); or in the brain (Alzheimer’s); or in the pancreas (diabetes). And though there are associations between various forms of inflammatory disease—for example, people with psoriasis or periodontal disease have a somewhat higher risk of heart disease—it has not been proved that there is a causal connection. Hyman and other doctors, such as the neurologist David Perlmutter, promote a more radical idea: that certain foods and environmental toxins cause smoldering inflammation, which somehow spreads to other areas of the body, including the brain, degrading one’s health, mental acuity, and life span.

The notion of a gut-brain connection seems to derive from studies with mice, including one that showed that introducing a bacterium into a mouse’s gastrointestinal tract led to behavioral changes, such as a reluctance to navigate mazes. But there’s scant evidence that anything similar happens in people, or any rigorous study to show that “anti-inflammatory diets” reduce depression. Earlier this year, the journal Brain, Behavior, and Immunity published a meta-analysis of more than fifty clinical studies that found inflammatory molecules in patients with depression. The paper revealed that there was little consistency from study to study about which molecules correlated to the condition. Steven Hyman, a former director of the National Institute of Mental Health and now the head of the Stanley Center at the Broad Institute (and no relation to Mark Hyman), in Cambridge, Massachusetts, noted that depression is “one of those topics where exuberant theorization vastly outstrips the data.”

Nonetheless, Mark Hyman holds fast to his view. “Inflammation is the final common pathway for pretty much all chronic diseases,” he told me. His recommended solution is an “anti-inflammatory diet”—omitting sugar, caffeine, beans, dairy, gluten, and processed foods, as well as taking a variety of supplements, including probiotics, fish oil, Vitamins C and D, and curcumin, a key molecule in turmeric. Hyman introduced me to one of the patients he had treated with his anti-inflammatory diet and supplements, a forty-seven-year-old hedge-fund manager in Cambridge named Jim Silverman. Two decades ago, Silverman began noticing blood in his stool. A colonoscopy resulted in a diagnosis of ulcerative colitis. In the ensuing years, Silverman was treated by gastroenterologists with aspirin-based medication, anti-inflammatory suppositories, and even corticosteroids, but the problem persisted. Then, five years ago, on a flight home from a business conference, he happened to sit next to Hyman, who told him that he could cure colitis.
“I thought, What a bullshitter,” Silverman said. He travelled anyway to Hyman’s UltraWellness Center, in Lenox, Massachusetts, to consult with him. Hyman told him that dairy was inflaming his bowel. Silverman was skeptical, but he kept track of his diet and bleeding episodes, and ultimately concluded that restricting dairy products resulted in long periods without bleeding. He now thinks that he could be suffering from a dairy allergy. In addition to avoiding dairy products, he continues to follow the anti-inflammatory regimen of supplements prescribed by Hyman. “I’m just taking it because I’m doing well,” he said. “I have no idea if it’s doing anything, but I don’t want to rock the boat.”

I asked Gary Wu, a professor of gastroenterology at the Perelman School of Medicine, at the University of Pennsylvania, and one of the world’s experts on the gut microbiome, about the alleged value of treating inflammatory bowel disease by restricting specific foods. Recently, in the journal Gastroenterology, Wu and his colleagues published a comprehensive review of scientific studies on diet and inflammatory bowel disease. They found only two dietary interventions that had been proved to reduce inflammation: an “elemental diet,” which is a liquid mixture of amino acids, simple sugars, and triglycerides, and a slightly more complex liquid diet. The liquid mixtures are typically administered with a tube placed through the nose. “The diet is not palatable,” Wu said. “And you don’t eat during the day. There is no intake of whole foods at all.”

David Agus, a cancer specialist and a professor of medicine and engineering at the University of Southern California, is equally skeptical of Hyman’s claims for the anti-inflammation diet. Agus, who is perhaps best known for being the doctor on “CBS This Morning,” recently received a multimillion-dollar grant from the National Cancer Institute to study how inflammation may spur the growth of tumors. “This notion that foods cause inflammation and foods can block inflammation, there’s zero data that it changes clinical outcomes,” he told me. “If the idea gets people to eat fruits and vegetables, I love it, but it’s not real.” Agus noted that vitamins don’t counter inflammation, and that it’s been shown, in rigorous clinical trials, that they may increase one’s risk of developing cancer.
Still, Agus views inflammation as a component not only of cancer but also of chronic diseases like diabetes and dementia. Rather than special diets, he supports preventively taking approved anti-inflammatory medications, such as aspirin and statins, and scrupulously scheduling the standard vaccinations in order to prevent infections. In “The End of Illness,” Agus encourages the reader to “reduce your daily dose of inflammation” by, among other things, not wearing high heels, since these can inflame your feet and the inflammation could possibly affect your vital organs. When I pressed him on that suggestion, he told me, “What I meant is that if your feet hurt all day it’s probably not a good thing. The downside is you just wear a different pair of shoes. The upside is it gave you an understanding of inflammation and its role in disease.”

Mark Hyman, at times, acknowledges the possible limits of his paradigm. When I asked him about the alleged link among gut inflammation, diet, and psychological disorders, he conceded that some of his evidence was anecdotal, derived from his own clinical practice. He mentioned the case of a child with asthma, eczema, and A.D.H.D., whom he treated with “an elimination diet, taking him off processed foods, and giving him supplements.” The child’s allergic problems improved and his behavior was markedly better, Hyman said: “It was a light-bulb moment. I saw secondary effects on the brain that came out of treating physical problems.”

He also cited studies of patients with rheumatoid arthritis, a painful and debilitating auto-immune condition that inflames and erodes the joints, who became less depressed after being treated with inflammatory blockers. But had the anti-inflammatory treatment directly lifted their depression, or had their mood improved simply because they were more mobile and in less pain? I told Hyman that it was hard to connect the dots. “For sure,” he said.

 

Connecting the dots is a challenge even for scientists who are actively involved in inflammation research. One afternoon, I visited Ramnik Xavier, the chair of gastroenterology at Massachusetts General Hospital and an expert in Crohn’s disease and ulcerative colitis. The bowel is inflamed in both conditions: ulcerative colitis affects the colon, whereas Crohn’s disease can affect any part of the digestive system. But the nature of inflammation varies almost from person to person and involves interactions among DNA, many kinds of gastrointestinal cells, and the peculiarities of the gut microbiome. “Lots of cells, lots of genes, lots of bugs,” Xavier said.

Xavier, a compact man with a laconic manner and thick black hair marked by streaks of gray, initially studied the role of specialized white blood cells, known as T-cells and B-cells, in defending the body against the development of colitis. Eventually, with Mark Daly, a geneticist at the Broad Institute, Xavier began to search for genes that predispose people to inflammatory bowel disease and for genes that might protect them against it. The two scientists, as part of an international consortium, have identified at least a hundred and sixty areas of DNA that are associated with an increased risk of inflammatory bowel disease; Xavier’s lab has zeroed in on about two dozen genes within these regions of DNA.
One of the frustrations of treating inflammation is that our weapons against it are so imprecise. Drugs like naproxen and ibuprofen are the equivalent of peashooters. At the other extreme, cannon-like steroids shut down the immune system, raising the risk of infection, eroding the bones, predisposing the patient to diabetes, and causing mood swings. Even the peashooters can cause collateral damage: aspirin may help to protect against colon cancer, heart attack, and stroke, but it also raises the risk of gastrointestinal bleeding. Ibuprofen, naproxen, and similar drugs were labelled by the F.D.A. as increasing the risk of heart attack and stroke in people who’ve never suffered either condition, and clinical trials failed to show that they prevent or ameliorate dementia. (Although these drugs reduce inflammation, they may also alter the lining of blood vessels and increase the risk of clots.) Statins lower the chance of a heart attack, but there is growing concern not only about the side effect of muscle pain but also about increasing the likelihood of diabetes. And the absolute benefits of these preventive medications is slight, measured in single digits.

In the lab at the Broad Institute, Xavier and his team were trying to discover new treatments that can block inflammation in a targeted manner. The day I visited, they were assessing molecules associated with colitis, especially one called interleukin-10, or IL-10, which is known to decrease inflammation. In a cavernous room, I watched as a robotic arm moved among racks of plastic plates, each containing hundreds of small wells in which chemical compounds were being tested. Some people with Crohn’s disease have genetic mutations that disable the salubrious effects of IL-10. Xavier is trying to identify molecules that can compensate for this deficiency, in the hope that such molecules might eventually be turned into drugs to treat this subset of patients.

But other patients suffer from a different manifestation of Crohn’s—they can’t fully clear debris from cells in their gut, so it builds up, triggering inflammation. In a neighboring lab, members of Xavier’s research team were trying to develop drugs for that condition, too. A robotic arm was handling plates that contained genetically engineered cells and moving them under a fluorescent microscope. The images appeared on a computer screen—fields of cells studded with yellow and green dots, like the sky in van Gogh’s “Starry Night.”

On another visit, Xavier took me to his clinic at Mass General. Patients, ranging from the very young to the elderly, were reclining in Barcaloungers as nurses and physicians intravenously administered potent anti-inflammatory drugs. Later, I spoke by phone to one of Xavier’s patients, a forty-nine-year-old woman named Maria Ray, who received a diagnosis of colitis in 1998. She was treated with sulfa drugs and corticosteroids, which controlled the problem for several years, but in 2004, after a series of flare-ups, she underwent surgery to remove her colon. Soon after, she developed ulcers on her skin, arthritis of her knees and elbows, and inflammation in both eyes. Xavier prescribed other drugs, and for two years her condition improved, but lately her skin lesions and eye inflammation have returned. “We hoped surgery would cure her ulcerative colitis,” Xavier said. “But we don’t really understand why there is such an overactive immune system now inflaming these other parts of her body.”
At the very least, the fact that Ray has symptoms in many organs, despite the removal of her colon, complicates the simplistic view that treating the gut will suppress inflammation elsewhere. Moreover, there’s no evidence that patients with Crohn’s or colitis are more likely than average to develop dementia and other cognitive disorders. “What we see in mice is not always reproduced in people,” Xavier said.

 

Perhaps no aspect of inflammation is more compelling, or illusory, than the idea that it may be responsible for aging. An internist friend in Manhattan told me that healthy patients occasionally come in to her office carrying Mark Hyman’s books, eager to live longer by following his anti-inflammation life style. When I asked Hyman if he could introduce me to someone who follows his longevity regimen, he readily offered himself. “I’m aiming to live to a hundred and twenty,” he said.

The notion stems from grains of evidence, such as studies that have shown an increase in inflammation with age. The genesis of aging is still a mystery. It may occur for a host of reasons—a waning of the energy generated by the mitochondria within cells, the tendency of DNA to grow fragile and more mutation-prone over time—and it’s much too simplistic to attribute the process to inflammation alone. Luigi Ferrucci, the scientific director of the National Institute on Aging, conducted some of the early research on inflammation and aging, and for a while, he told me, he believed the avenue held promise. On the morning we spoke, he had just finished his daily six-mile run. Sixty-one years old, born in Livorno, on the coast of Tuscany, Ferrucci is an animated man with a stubbly beard who favors crew-neck sweaters. In the past four decades, he has studied thousands of people in order to identify the biological processes that result in aging. He measured scores of molecules in the blood, hoping to find clues that would lead him to the cause of aging’s hallmarks, particularly sarcopenia, or loss of muscle mass, and cognitive decline.

His most illuminating studies involved people in late middle age who showed no sign of heart disease, diabetes, dementia, or other conditions that might be associated with inflammation. He found that a single inflammatory molecule, called interleukin-6, was the most powerful predictor of who would eventually become disabled. Healthy patients with high levels of the IL-6 molecule aged more quickly and grew sicker than those without the inflammatory molecule. “I thought I had discovered the cause of aging and was going to win the Nobel Prize,” Ferrucci said, laughing.
But then he found other subjects with no evidence of inflammation, and without elevated levels of IL-6 or other inflammatory molecules, whose bodies nevertheless began to decline. “We are looking at the layer, not at the core of the problem,” he said. “Inflammation may accelerate aging in some people—but it is a manifestation of something that is occurring underneath.” He reiterated the point that correlation is not causation. “If you have the curiosity of the scientist, you can’t stop there, because you want to know why,” he said. “You want to break the toy so you can see how it’s working inside.”

Toward that end, Ferrucci recently organized a large team of collaborators and launched a new clinical study, GESTALT, which stands for Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing. Groups of healthy people will be studied intensively as they age, with detailed analyses of their DNA, RNA, proteins, metabolic capacity, and other sophisticated parameters, every two years for at least a decade. “Then we can say what mechanisms account for increased inflammation with aging, and the loss of muscle mass, or the loss of memory, or the loss of energy capacity or fitness,” Ferrucci said. “These have never really been addressed on a deep level in humans.”

In the meantime, he sticks to a Mediterranean diet, mainly out of fealty to his heritage. (Ferrucci is known among his N.I.H. colleagues as a gourmet Italian cook.) The media recently gave much attention to a study, published in 2013 in the New England Journal of Medicine, on the benefits of a Mediterranean diet in preventing heart attack or stroke. But, as Ferrucci noted, the benefits weren’t clearly related to inflammation and they accrued to a very small percentage of the subjects on the diet. “Believe me, if there were a diet that prevented aging, I would be on it,” he said.

We’d all like a simple solution for complex medical problems. We’re desperate to feel in command of our lives, particularly as we age and see friends and family afflicted by Alzheimer’s, stroke, and heart failure. “My patients, understandably, are very focussed on the foods they eat, wanting control, hoping they won’t have to take immune-suppressive treatments,” Gary Wu, the University of Pennsylvania gastroenterologist, told me.

Some years ago, I became obsessed with a restrictive diet—no bread, cheese, ice cream, cookies—in an attempt to lower my cholesterol levels. (My father died of a heart attack in his fifties, and I was haunted by his fate.) After nearly six months, I’d lost some fifteen pounds, but my cholesterol level had hardly budged, and I’d become so vigilant about everything I ate that I stopped enjoying meals. Gradually, I resumed a balanced and more reasonable diet and regained an appreciation for one of life’s fundamental pleasures.

Scientists may yet discover that inflammation contributes to disease in unexpected ways. But it’s important to remember, too, that inflammation serves a vital role in the body. “We are playing with one of the primary mechanisms selected by nature to maintain the integrity of our body against the thousand environmental attacks that we receive every day,” Ferrucci said. “Inflammation is part of our maintenance and repair system. Without it, we can’t heal.”

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