Estimating Platelet Mitochondrial Function in Patients with Sepsis - WB NMRs (part-II)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
TISSUE(S): Blood
DISEASE(S): Sepsis
PROVIDER: ST001295 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description: Not available
| ST001294 | MetabolomicsWorkbench
Project description:BackgroundThe diaphragm is the primary muscle of inspiration, and its dysfunction is frequent during sepsis. However, the mechanisms associated with sepsis and diaphragm dysfunction are not well understood. In this study, we evaluated the morphophysiological changes of the mitochondrial diaphragm 5 days after sepsis induction.MethodsMale C57Bl/6 mice were divided into two groups, namely, cecal ligation and puncture (CLP, n = 26) and sham-operated (n = 19). Mice received antibiotic treatment 8 h after surgery and then every 24 h until 5 days after surgery when mice were euthanized and the diaphragms were collected. Also, diaphragm function was evaluated in vivo by ultrasound 120 h after CLP. The tissue fiber profile was evaluated by the expression of myosin heavy chain and SERCA gene by qPCR and myosin protein by using Western blot. The Myod1 and Myog expressions were evaluated by using qPCR. Diaphragm ultrastructure was assessed by electron microscopy, and mitochondrial physiology was investigated by high-resolution respirometry, Western blot, and qPCR.ResultsCecal ligation and puncture mice developed moderated sepsis, with a 74% survivor rate at 120 h. The diaphragm mass did not change in CLP mice compared with control, but we observed sarcomeric disorganization and increased muscle thickness (38%) during inspiration and expiration (21%). Septic diaphragm showed a reduction in fiber myosin type I and IIb mRNA expression by 50% but an increase in MyHC I and IIb protein levels compared with the sham mice. Total and healthy mitochondria were reduced by 30% in septic mice, which may be associated with a 50% decrease in Ppargc1a (encoding PGC1a) and Opa1 (mitochondria fusion marker) expressions in the septic diaphragm. The small and non-functional OPA1 isoform also increased 70% in the septic diaphragm. These data suggest an imbalance in mitochondrial function. In fact, we observed downregulation of all respiratory chain complexes mRNA expression, decreased complex III and IV protein levels, and reduced oxygen consumption associated with ADP phosphorylation (36%) in CLP mice. Additionally, the septic diaphragm increased proton leak and downregulated Sod2 by 70%.ConclusionThe current model of sepsis induced diaphragm morphological changes, increased mitochondrial damage, and induced functional impairment. Thus, diaphragm damage during sepsis seems to be associated with mitochondrial dysfunction.
| S-EPMC8452856 | biostudies-literature
Project description:BackgroundTo describe the effect of mechanical ventilation on diaphragm mitochondrial oxygen consumption, ATP production, reactive oxygen species (ROS) generation, and cytochrome c oxidase activity and content, and their relationship to diaphragm strength in an experimental model of sepsis.MethodsA cecal ligation and puncture (CLP) protocol was performed in 12 rats while 12 controls underwent sham operation. Half of the rats in each group were paralyzed and mechanically ventilated. We performed blood gas analysis and lactic acid assays 6 h after surgery. Afterwards, we measured diaphragm strength and mitochondrial oxygen consumption, ATP and ROS generation, and cytochrome c oxidase activity. We also measured malondialdehyde (MDA) content as an index of lipid peroxidation, and mRNA expression of the proinflammatory interleukin-1β (IL-1β) in diaphragms.ResultsCLP rats showed severe hypotension, metabolic acidosis, and upregulation of diaphragm IL-1β mRNA expression. Compared to sham controls, spontaneously breathing CLP rats showed lower diaphragm force and increased susceptibility to fatigue, along with depressed mitochondrial oxygen consumption and ATP production and cytochrome c oxidase activity. These rats also showed increased mitochondrial ROS generation and MDA content. Mechanical ventilation markedly restored mitochondrial oxygen consumption and ATP production in CLP rats; lowered mitochondrial ROS production by the complex 3; and preserved cytochrome c oxidase activity.ConclusionIn an experimental model of sepsis, early initiation of mechanical ventilation restores diaphragm mitochondrial function.
| S-EPMC8025065 | biostudies-literature
Project description: Not available
| ST001319 | MetabolomicsWorkbench
Project description:Melatonin (N-acetyl-5-methoxytryptamine) has been shown to have a cardioprotective effect against myocarditis. However, the mechanisms underlying the protective role of melatonin (MLT) in sepsis-induced myocarditis are yet to be revealed. In this study, MLT was administrated to mice, 14 days before cecal ligation puncture surgery. Echocardiography results showed that MLT alleviated cardiac dysfunction in sepsis-induced myocarditis. Furthermore, MLT reduced cardiac inflammation by inhibiting the expression of Il-1α, Il-1β, Il-6, and Mcp-1 messenger RNA (mRNA) levels. The RNA sequencing (RNA-seq) assays with heart tissues showed that MLT maintains the mitochondrial function in sepsis-caused myocarditis. Additionally, the production of reactive oxygen species (ROS) in heart tissues was suppressed by MLT. Taken together, in evaluating the therapeutic effect of MLT on sepsis-induced myocarditis, the results showed that MLT alleviated cardiac damage by regulating mitochondrial function and mitochondrial ROS.
| S-EPMC8542660 | biostudies-literature
Project description:OBJECTIVE:This study was aimed at investigating the regulation of mitochondrial function by histone deacetylase 6 (HDAC6) and the role of HDAC6 in the development and progression of sepsis. RESULTS:HDAC6 downregulated PHB1 and subsequently promoted the development of CLP-induced sepsis. Inhibition of HDAC6 significantly attenuated CLP-induced sepsis through inhibition of mitochondrial dysfunction and reduced oxidant production, thus protecting the rats from oxidative injury. CONCLUSIONS:In this sepsis model, HDAC6 inhibits the expression and function of PHB1 and alters the function of the mitochondrial respiratory chain mediated by PHB1, thus enhancing the production of oxidants and increasing oxidative stress and thereby leading to severe oxidative injury in multiple organs. METHODS:The expression of HDAC6 and prohibitin 1 (PHB1) in humans and in a rat model of sepsis was measured by quantitative reverse-transcription PCR and western blotting. Sepsis induction by cecal ligation and puncture (CLP) was confirmed by histological analysis. Concentrations of different sepsis markers were measured by an enzyme-linked immunosorbent assay, and mitochondrial function was assessed via the mitochondrial respiratory control rate.
| S-EPMC7138540 | biostudies-literature
Project description:Sepsis-associated organ dysfunction plays a critical role in its high mortality, mainly in connection with mitochondrial dysfunction. Whether the inhibition of mitochondrial fission is beneficial to sepsis-related organ dysfunction and underlying mechanisms are unknown. Cecal ligation and puncture induced sepsis in rats and dynamic related protein 1 knockout mice, lipopolysaccharide-treated vascular smooth muscle cells and cardiomyocytes, were used to explore the effects of inhibition of mitochondrial fission and specific mechanisms. Our study showed that mitochondrial fission inhibitor Mdivi-1 could antagonize sepsis-induced organ dysfunction including heart, vascular smooth muscle, liver, kidney, and intestinal functions, and prolonged animal survival. The further study showed that mitochondrial functions such as mitochondrial membrane potential, adenosine-triphosphate contents, reactive oxygen species, superoxide dismutase and malonaldehyde were recovered after Mdivi-1 administration via improving mitochondrial morphology. And sepsis-induced inflammation and apoptosis in heart and vascular smooth muscle were alleviated through inhibition of mitochondrial fission and mitochondrial function improvement. The parameter trends in lipopolysaccharide-stimulated cardiomyocytes and vascular smooth muscle cells were similar in vivo. Dynamic related protein 1 knockout preserved sepsis-induced organ dysfunction, and the animal survival was prolonged. Taken together, this finding provides a novel effective candidate therapy for severe sepsis/septic shock and other critical clinical diseases.
| S-EPMC8457550 | biostudies-literature
Project description:Sepsis is a life-threatening condition caused by a dysregulated host response to infection.Although our understanding in the pathophysiological features of sepsis has increased significantly during the past decades, there is still lack of mechanism of sepis.Neutrophils are important regulators against invading pathogens, and their role during sepsis has been studied extensively. However, whether neutrophils could inhibit the immune response of CD8+T cells and the mechanism is unkown in sepsis.
2022-07-06 | GSE186054 | GEO
Project description: Not available
| ST001354 | MetabolomicsWorkbench
Project description:The mechanism(s) for septic cardiomyopathy in humans is not known. To address this, we performed transcriptional profiling of hearts from patients who died from sepsis, in comparison to non-failing human donor hearts that could not be transplanted for technical reasons.
2016-09-22 | GSE79962 | GEO