Translational research : the journal of laboratory and clinical medicine
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Sepsis-induced acute lung injury (ALI) is a serious complication of sepsis and the predominant cause of death. Exosomes released by lung tissue cells critically influence the progression of ALI during sepsis by modulating the inflammatory microenvironment. However, the molecular mechanisms by which exosome-mediated intercellular signaling exacerbates ALI in septic infection remain undefined. ⋯ These interconnected events culminate in macrophage pyroptosis, thereby amplifying the release of inflammatory cytokines. Our findings demonstrate that exosomal Tenascin-C, released from AECs under unresolved ER stress, exacerbates acute lung injury by intensifying sepsis-associated inflammatory responses. This research provides new insights into the complex cellular interactions underlying sepsis-induced ALI.
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Peripheral neuropathy (PN) is a severe and frequent complication of obesity, prediabetes, and type 2 diabetes characterized by progressive distal-to-proximal peripheral nerve degeneration. However, a comprehensive understanding of the mechanisms underlying PN, and whether these mechanisms change during PN progression, is currently lacking. Here, gene expression data were obtained from distal (sciatic nerve; SCN) and proximal (dorsal root ganglia; DRG) injury sites of a high-fat diet (HFD)-induced mouse model of obesity/prediabetes at early and late disease stages. ⋯ The role of the immune system and inflammation in disease progression was supported by an increase in the percentage of immune cells in the SCN with PN progression. Finally, when comparing these data to transcriptomic signatures from human patients with PN, we observed conserved pathways related to metabolic dysregulation across species, highlighting the translational relevance of our mouse data. Our findings demonstrate that PN is associated with distinct site-specific molecular re-programming in the peripheral nervous system, identifying novel, clinically relevant therapeutic targets.
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The prevalence of renal ischemia/reperfusion injury (IRI) in premenopausal women is considerably lower than that in age-matched men. This suggests that sex-related differences in mitochondrial function and homeostasis may contribute to sexual dimorphism in renal injury, though the mechanism remains unclear. Mouse model of unilateral left renal IRI with contralateral kidney enucleation, Ovariectomy in female mice, and a human embryonic kidney (HEK) cell model of hypoxia-reoxygenation were used to study how estrogen affects the sexual dimorphism of renal IRI through SIRT3 in vitro and in vivo, respectively. ⋯ Mechanistically, the SIRT3 level is E2-dependent and that E2 increases the SIRT3 protein level via estrogen receptor. SIRT3 targeted an i-AAA protease, yeast mitochondrial AAA metalloprotease (YME1L1), and hydrolyzed long optic atrophy 1 (L-OPA) to short-OPA1 (S-OPA1) by deacetylating YME1L1, regulating mitochondrial dynamics toward fusion to reduce oxidative stress and ERS. These findings explored the mechanism by how estrogen alleviates renal IRI and providing a basis for potential therapeutic interventions targeting SIRT3.
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Blood-brain-barrier (BBB) disruption is a pathological hallmark of ischemic stroke, and inflammation occurring at the BBB contributes to the pathogenesis of ischemic brain injury. Lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, is elevated in patients with acute stroke. The activity of LPS is controlled by acyloxyacyl hydrolase (AOAH), a host enzyme that deacylates LPS to inactivated forms. ⋯ Furthermore, virus-mediated overexpression of AOAH induced a substantial decrease in neutrophil recruitment that was accompanied by reducing BBB damage and stroke volumes. Our findings show the importance of AOAH in regulating neutrophil-dependent BBB breakdown and cerebral infarction. Consequently, strategies that modulate AOAH may be a new therapeutic approach for treatment of ischemic stroke.
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Post-ischemic angiogenesis is critical for perfusion recovery and tissue repair. ELABELA (ELA) plays an essential role in embryonic heart development and vasculogenesis. However, the mechanism of ELA on post-ischemic angiogenesis is poorly characterized. ⋯ Our results indicated that endothelial ELA is a positive regulator of post-ischemic angiogenesis via upregulating VEGFR2 expression. Targeting ELA may be a potential therapeutic option for peripheral arterial diseases.