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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Chronic kidney disease (CKD)-related vascular calcification (VC) is a common degenerative phenomenon of the vessel wall and its pathological basis is the phenotypic transformation of vascular smooth muscle cells (VSMCs). Zinc finger and BR-C (Broad-Complex), ttk (tramtrack), and bab (bric à brac) (BTB) domain containing 16 (ZBTB16) have been reported to be expressed in the aortic tissues in a rat model of VC. This work is conducted to reveal the functions of ZBTB16 on VC in CKD and to probe its involved reaction mechanisms. ⋯ Moreover, silencing with ZBTB16 inactivated Wingless-related integration site (Wnt)/β-catenin pathway. LiCl (Wnt/β-catenin agonist) reversed the protective effects of ZBTB16 knockdown on the calcification and osteoblastic transformation in vitro. Together, ZBTB16 silencing may downregulate Wnt/β-catenin pathway to protect against CKD-associated VC via repressing the osteoblastic transformation of VSMCs.
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Septic cardiomyopathy is linked to a dysregulation in mitochondrial integrity and elevated mortality rates, for which an efficacious treatment remains elusive. PDS is a panaxadiol saponin extracted from ginseng stem and leaf. ⋯ DEX and PDS enhance antioxidant defense by degrading Keap1 to activate Nrf2; activate mitochondrial occurrence protein PGC-1α and fusion protein OPA1, Mfn1, and Mfn2 expression; and inhibit phosphorylation of mitochondrial fission protein Drp1, aiming to maintain normal structure and function of mitochondrial, thereby preserving oxidative phosphorylation capacity. In summary, our findings highlighted the protective efficacy of PDS and DEX in maintaining mitochondrial in LPS-induced cardiomyopathy, and mechanism improving mitochondrial quality control at least in part by promoting Nrf2 activation.
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Background: Ubiquitination and deubiquitination are involved in the progression of human diseases, including acute pneumonia. In this study, we aimed to explore the functions of ubiquitin-specific peptidase 9X-linked (USP9X) in lipopolysaccharide (LPS)-treated WI-38 cells. Methods: WI-38 cells were treated with LPS to induce the cellular damage and inflammation. 3-(4, 5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and 5-ethynyl-2'-deoxyuridine (EdU) assay were performed to examine the proliferation of LPS-treated WI-38 cells. ⋯ USP9X knockdown restored the effects of LPS on WI-38 cell proliferation, apoptosis, inflammation, and oxidative stress, but these effects of USP9X knockdown were further abolished by TBL1XR1 overexpression. In addition, USP9X promoted the NF-κB signaling pathway by the deubiquitination of TBL1XR1. Conclusion: USP9X promoted the apoptosis, inflammation, and oxidative stress of LPS-stimulated WI-38 cells through the deubiquitination of TBL1XR1.
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Liver ischemia reperfusion (IR) injury significantly impacts clinical outcomes by increasing the risk of hepatic dysfunction after liver surgery. Fatty livers are more susceptible to IR stress. Recent studies have demonstrated that S100A9 plays a crucial role in both IR injury and the progression of liver steatosis. ⋯ Intriguingly, S100A9 facilitated ATF4 nuclear translocation and enhanced NEK7/NLRP3 inflammasome activation in macrophages. In conclusion, our study identified S100A9 as a key regulator responsible for macrophage NLRP3 inflammasome activation and subsequent inflammatory injury in fatty liver IR process. Targeting TLR2/ATF4 signaling may offer a novel therapeutic strategy for mitigating S100A9-mediated liver injury.
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Background: Mechanical ventilation (MV) is a clinically important measure for respiratory support in critically ill patients. Although moderate tidal volume MV does not cause lung injury, it can further exacerbate lung injury in a pathological state such as sepsis. This pathological process is known as the "two-hit" theory, whereby an initial lung injury (e.g., infection, trauma, or sepsis) triggers an inflammatory response that activates immune cells, presenting the lung tissue in a fragile state and rendering it more susceptible to subsequent injury. ⋯ Different species of HMGB1 knockout mice have different lung-protective mechanisms in the two-hit model, and location is the key to function. Specifically, LysM HMGB1 -/- mice due to the deletion of HMGB1 in myeloid cells resulted in a pulmonary-protective mechanism that was associated with a downregulation of the inflammatory response. EC-HMGB1 -/- mice are deficient in HMGB1 owing to endothelial cells, resulting in a distinct pulmonary-protective mechanism independent of the inflammatory response and more relevant to the improvement of alveolar-capillary permeability. iHMGB1 -/- mice, which are systemically HMGB1-deficient, share both of these lung-protective mechanisms.