Cutting cardiovascular risk in barbershops

http://dx.doi.org/10.1016/j.jomh.2009.07.00

Interferon gamma (IFN-γ) disrupts energy expenditure and metabolic homeostasis by suppressing SIRT1 transcription

Chronic inflammation impairs metabolic homeostasis and is intimately correlated with the pathogenesis of type 2 diabetes. The pro-inflammatory cytokine IFN-γ is an integral part of the metabolic inflammation circuit and contributes significantly to metabolic dysfunction. The underlying mechanism, however, remains largely unknown. In the present study, we report that IFN-γ disrupts the expression of genes key to cellular metabolism and energy expenditure by repressing the expression and activity of SIRT1 at the transcription level. Further analysis reveals that IFN-γ requires class II transactivator (CIITA) to repress SIRT1 transcription. CIITA, once induced by IFN-γ, is recruited to the SIRT1 promoter by hypermethylated in cancer 1 (HIC1) and promotes down-regulation of SIRT1 transcription via active deacetylation of core histones surrounding the SIRT1 proximal promoter. Silencing CIITA or HIC1 restores SIRT1 activity and expression of metabolic genes in skeletal muscle cells challenged with IFN-γ. Therefore, our data delineate an IFN-γ/HIC1/CIITA axis that contributes to metabolic dysfunction by suppressing SIRT1 transcription in skeletal muscle cells and as such shed new light on the development of novel therapeutic strategies against type 2 diabetes

Dissecting the physiology and pathophysiology of glucagon-like peptide-1

Copyright © 2018 Paternoster and Falasca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. An aging world population exposed to a sedentary life style is currently plagued by chronic metabolic diseases, such as type-2 diabetes, that are spreading worldwide at an unprecedented rate. One of the most promising pharmacological approaches for the management of type 2 diabetes takes advantage of the peptide hormone glucagon-like peptide-1 (GLP-1) under the form of protease resistant mimetics, and DPP-IV inhibitors. Despite the improved quality of life, long-term treatments with these new classes of drugs are riddled with serious and life-threatening side-effects, with no overall cure of the disease. New evidence is shedding more light over the complex physiology of GLP-1 in health and metabolic diseases. Herein, we discuss the most recent advancements in the biology of gut receptors known to induce the secretion of GLP-1, to bridge the multiple gaps into our understanding of its physiology and pathology

Rhesus Macaque Theta Defensins Suppress Inflammatory Cytokines and Enhance Survival in Mouse Models of Bacteremic Sepsis

Theta-defensins (θ-defensins) are macrocyclic antimicrobial peptides expressed in leukocytes of Old World monkeys. The peptides are broad spectrum microbicides in vitro and numerous θ-defensin isoforms have been identified in granulocytes of rhesus macaques and Olive baboons. Several mammalian α- and β-defensins, genetically related to θ-defensins, have proinflammatory and immune-activating properties that bridge innate and acquired immunity. In the current study we analyzed the immunoregulatory properties of rhesus θ-defensins 1–5 (RTDs 1–5). RTD-1, the most abundant θ-defensin in macaques, reduced the levels of TNF, IL-1α, IL-1β, IL-6, and IL-8 secreted by blood leukocytes stimulated by several TLR agonists. RTDs 1–5 suppressed levels of soluble TNF released by bacteria- or LPS-stimulated blood leukocytes and THP-1 monocytes. Despite their highly conserved conformation and amino acid sequences, the anti-TNF activities of RTDs 1–5 varied by as much as 10-fold. Systemically administered RTD-1 was non-toxic for BALB/c mice, and escalating intravenous doses were well tolerated and non-immunogenic in adult chimpanzees. The peptide was highly stable in serum and plasma. Single dose administration of RTD-1 at 5 mg/kg significantly improved survival of BALB/c mice with E. coli peritonitis and cecal ligation-and-puncture induced polymicrobial sepsis. Peptide treatment reduced serum levels of several inflammatory cytokines/chemokines in bacteremic animals. Collectively, these results indicate that the anti-inflammatory properties of θ-defensins in vitro and in vivo are mediated by the suppression of numerous proinflammatory cytokines and blockade of TNF release may be a primary effect