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CDK2 phosphorylation associated with Werner proteins (WRN) contributes to WRN's Genetic double-strand split restoration walkway selection.
significantly increased occludin (51 ± 17%) and claudin-1 (77 ± 9%) expression. FMT exerted also a significant restoring effect in TJ by increasing occludin (56 ± 15%) and claudin-1 (84 ± 7%) expression. The beneficial effects of these treatments on gut barrier function led to significant reduction of systemic endotoxemia (EU/ml, mean ± SD Group I 0,93 ± 0,36, Group II 2,14 ± 1,74, Group III 1,48 ± 0,53, Group IV 1,61 ± 0,58,), while FMT additionally decreased IL-6 and IL-10 levels. Conclusion Fecal microbiota transplantation and stress dose hydrocortisone administration in septic rats induce a multifactorial improvement of the gut mechanical and immunological barriers, preventing endotoxemia and leading to improved survival.Results from preclinical sepsis studies using rodents are often criticized as not being reproducible in humans. Using a murine model, we previously reported that visceral adipose tissues (VAT) are highly active during the acute inflammatory response, serving as a major source of inflammatory and coagulant mediators. The purpose of this study was to determine whether these findings are recapitulated in patients with sepsis and to evaluate their clinical significance. VAT and plasma were obtained from patients undergoing intra-abdominal operations with non-inflammatory conditions (control), local inflammation, or sepsis. In mesenteric and epiploic VAT, gene expression of pro-inflammatory (TNFα, IL-6, IL-1α, IL-1β) and pro-coagulant (PAI-1, PAI-2, TSP-1, TF) mediators was increased in sepsis compared to control and local inflammation groups. In the omentum, increased expression was limited to IL-1β, PAI-1, and PAI-2, showing a depot-specific regulation. Histological analyses showed little correlation between cellular infiltration and gene expression, indicating a resident source of these mediators. Notably, a strong correlation between PAI-1 expression in VAT and circulating protein levels was observed, both being positively associated with markers of acute kidney injury (AKI). In another cohort of septic patients stratified by incidence of AKI, circulating PAI-1 levels were higher in those with versus without AKI, thus extending these findings beyond intra-abdominal cases. This study is the first to translate upregulation of VAT mediators in sepsis from mouse to human. Collectively, the data suggest that development of AKI in septic patients is associated with high plasma levels of PAI-1, likely derived from resident cells within VAT.Background Evidence implying that metabolism reprogramming plays an important role in the regulation of sepsis is increasing; however, whether it has a similar role in septic organ dysfunction remains unclear. find more Here we provide evidence to support a new role of uncoupling protein-2 (UCP2)-regulated Warburg effect, i.e., aerobic glycolysis, in promoting mitochondrial injury in the kidney. Methods To imitate sepsis condition, male C57BL/6 mice were operated by the cecal ligation puncture (CLP) in vivo, whereas a normal human kidney cell line (HK-2) was treated with lipopolysaccharide (LPS) in vitro. UCP2 siRNA pretreatment was performed to knock down UCP2 expression in vitro. The glycolysis metabolite was detected by liquid chromatography/tandem mass spectrometry (LC-MS) in vivo and detected by commercial kits in vitro. Oxidative phosphorylation (OXPHOS) level and glycolysis level were monitored by measuring the oxygen consumption rate (OCR, indicative of respiration) and extracellular acidification rate (ECAR, indicative of glycolysis) in vitro. Exogenous lactate was supplied to stimulate HK-2 cells and indicators of mitochondrial dysfunction were also assessed. Results Aerobic glycolysis is enhanced in septic tubular epithelial cells, and the glycolysis inhibitor 2-deoxyglucose (2-DG) can partially restore mitochondrial membrane potential (MMP or ΔΨm) and decrease the reactive oxygen species (ROS) production. With the knockdown of ucp2, the aerobic glycolysis level upregulates, and mitochondrial injury increases. Conclusions These results provide insights on a new mechanism of metabolic regulation of mitochondrial injury and the importance of targeting aerobic glycolysis for the treatment of septic acute kidney injury.Na/H exchanger 1 (NHE1) is a ubiquitously expressed protein on mammalian plasma membranes and involved in cell apoptosis and tissue injury. Our previous study found that NHE1 inhibition prevents burn-induced acute lung injury (ALI). However, the potential mechanism of NHE1 in burn-induced ALI is still unclear. This study investigated the role of NHE1 in burn-induced apoptosis of human pulmonary microvascular endothelial cells (HPMVECs). Based on the western blot analyses, real-time PCR, fluorescence spectroscopy, and apoptosis analysis, we found that burn serum significantly induced NHE1 activation, promoted intracellular Na accumulation and elevated apoptosis ratio. Inhibition of NHE1 with cariporide reversed burn-induced intracellular Na accumulation and cell apoptosis. Different doses of cariporide also significantly decreased Cai concentrations and calpain activity induced by burn serum. Furthermore, inhibition of PI3K contributed to the increase of NHE1 activation and cell apoptosis, whereas the inhibition of p38 MAPK led to inhibition of NHE1 activation and significant decreases of cell apoptosis. The data demonstrate that NHE1 activation facilitates burn-induced endothelial cell apoptosis, mediated by Ca-dependent pathway. PI3K-Akt and p38 MAPK were found to be upstream regulators of NHE1. This study provides new mechanisms underlying burn-induced ALI.A novel atmospheric plasma device that uses indirect, non-thermal plasma generated from room air is being studied for its effects on wound disinfection in animal wounds of monogenic and polygenic murine models of type 2 diabetes. As a proof-of-concept report, the goal of this study was to demonstrate the efficacy and safety of the indirect non-thermal plasma (INTP) device in disinfecting polycarbonate filters established with Pseudomonas aeruginosa (PAO1) biofilms as well as wound disinfection in diabetic murine wounds. Dorsal excisional wounds in BALB/c, polygenic TALLYHO, and monogenic db/db mice established with PAO1 infection all demonstrated a 3-log colony-forming unit (CFU) reduction when subjected to a course of 20-minute INTP treatments. Importantly, blood glucose and body weights in these animals were not significantly impacted by plasma treatment over the study period. Plasma safety was also analyzed via complete blood count and comprehensive metabolic panels, showing no deleterious systemic effects after three consecutive days of 20-minute plasma applications.
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