Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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The sirtuin family consists of seven NAD+-dependent enzymes affecting a broad array of regulatory protein networks by primarily catalyzing the deacetylation of key lysine residues in regulatory proteins. The enzymatic activity of SIRT1 can be enhanced by small molecule activators known as SIRT1 activator compounds (STACs). We tested the therapeutic potential of the STAC SRT3025 in two preclinical models of severe infection, the murine cecal ligation and puncture (CLP) model to induce peritonitis and intratracheal installation of Streptococcus pneumoniae to induce severe bacterial pneumonia. ⋯ SRT3025 treatment was also accompanied by striking changes in the transcription profiles in multiple inflammatory and metabolic pathways in liver, spleen, small bowel, and lung tissue. Remarkably, these organ-specific changes in the transcriptome analyses were similar following CLP or pneumococcal challenge despite different sets of pathogens at disparate sites of infection. Pharmacologic activation of SIRT1 modulates the innate host response and could represent a novel treatment strategy for severe infection.
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Visfatin is produced in and secreted from adipocytes. Increased circulating visfatin level is observed in obese subjects. Previous studies demonstrated that visfatin was involved in obesity-related cardiovascular diseases. ⋯ Visfatin upregulated CD36 and SRA expression and downregulated ABCA1 and ABCG1 expression, subsequently increased ox-LDL uptake and decreased cholesterol efflux, and finally promoted foam cell formation via the PI3K- and ERK-dependent pathways.
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Intestinal ischemia-reperfusion (I/R) occurs in various clinical situations and causes local and remote organ injury, especially in the lungs, leading to significant morbidity and mortality. The maintenance of mitochondrial biogenesis is essential for cell survival and is regulated in part by sirtuin 1 (SIRT1), an energy-sensing enzyme. We hypothesized that SIRT1 activation with SRT1720 would reduce local and remote organ injury after intestinal I/R. ⋯ Lung injury, as measured by histological architecture and myeloperoxidase activity, and lung apoptosis were also improved after the SRT1720 treatment. SRT1720 preserved mitochondrial biogenesis and mass, leading to inhibition of inflammation and oxidative stress, thereby protecting against intestinal I/R-induced injury. Thus, the SIRT1-mediated pathway is a promising target for the treatment of intestinal I/R injury.
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Ischemic conditioning induces a series of cellular modifications that may prevent injury from further hypoxic episodes, but there are few data in sepsis. In this randomized controlled study, we evaluated the effects of ischemic conditioning on the microcirculation, organ function, and survival time in an ovine model of septic shock. Sepsis was induced in 14 anesthetized, mechanically ventilated adult sheep by injecting autologous feces into the abdominal cavity. ⋯ Microcirculatory variables were better preserved in the conditioned than in the control group from 6 h after randomization: the median proportion of perfused vessels was 91 (89-93)% versus 89 (86-90)% (P = 0.024) and there was less heterogeneity. Oliguria, hypotension, and death occurred later in the conditioned than in the control group. In this sepsis model, remote ischemic pre- and post-conditioning therefore decreased organ dysfunction, preserved the microcirculation, and prolonged survival.
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Systemic hypertension and left ventricular hypertrophy (LVH) are major risk factors of cardiac arrest. However, the impacts of hypertension and LVH on the outcome of cardiopulmonary resuscitation (CPR) and post-resuscitation hypothermia are still undetermined. ⋯ In this rat model, systemic hypertension and LVH did not affect ROSC. However, survival was dismal due to elevated severity of cardiac and cerebral injury in hypertensive animals regardless of short-duration hypothermia.