The precise control of cardiomyocyte viability is imperative to combat myocardial ischemia-reperfusion injury (I/R), in which apoptosis and pyroptosis putatively contribute to the process. Recent researches indicated that GSDMD is involved in I/R as an executive protein of pyroptosis. However, its effect on other forms of cell death is unclear. We identified that GSDMD and GSDMD-N levels were significantly upregulated in the I/R myocardium of mice. Knockout of GSDMD conferred the resistance of the hearts to reperfusion injury in the acute phase of I/R but aggravated reperfusion injury in the chronic phase of I/R. Mechanistically, GSDMD deficiency induced the activation of PARylation and the consumption of NAD+ and ATP, leading to cardiomyocyte apoptosis. Moreover, PJ34, a putative PARP-1 inhibitor, reduced the myocardial injury caused by GSDMD deficiency. Our results reveal a novel action modality of GSDMD in the regulation of cardiomyocyte death; inhibition of GSDMD activates PARylation, suggesting the multidirectional role of GSDMD in I/R and providing a new theory for clinical treatment.
PURPOSE Bladder urothelial carcinoma (BLCA), the most common urinary tract malignancy, has a high recurrence rate and poor survival at late stages. Necroptosis, a form of programmed cell death, is involved in cancer development and progression, but its function in BLCA prognosis remains unclear. This study sought to investigate the role of necroptosis in the development and prognosis of BLCA. METHODS Clinical information and RNA expression matrix data were obtained from the databases. Survival analysis was performed to obtain survival- and necroptosis-related genes and identify any that overlapped. Consensus clustering analysis was used to create different subgroups by combining the overlapping gene expression matrix and clinical information. The tumor immune microenvironment and immune status of the different subgroups were determined using ESTIMATE, MCPcounter, and ssGSEA analysis. We performed differential analysis on the gene expression matrix of molecular subpopulations to find and screen out differentially expressed genes (DEGs). GO, KEGG, GSVA, and GSEA analyses were used to elucidate the underlying mechanisms of the DEGs. Lasso Cox regression analysis was used to build a prognostic risk model and perform a pan-cancer analysis of the screened genes. The results were used to define potential roles for these genes in other cancers and assess the efficacy of the risk model. RESULTS Cluster analysis identified two subgroups, C1 and C2, with significantly different survival rates. ESTIMATE, MCPcounter, and ssGSEA analyses showed that high immune scores, tumor purity, and immune status were associated with poorer prognoses. GO and KEGG functional enrichment analyses indicated that DEGs were mainly focused on tumor proliferation, invasion, and immunity and GSEA analysis suggested that necroptosis may affect Toll-like receptor signaling pathways, MAPK cascade regulation of leukocyte trafficking, and cytokine-cytokine receptor interaction pathways. Lasso Cox regression analysis was used to model the prognostic risk while screening for representative necroptosis-associated genes, ANXA1, ATAD3A, and TRPC6, with high potential for survival prediction in BLCA patients. The pan-cancer analysis indicated that the three representative genes were also differentially expressed in other cancer types. CONCLUSION Expression of necroptosis-related genes such as ANXA1, ATAD3A, and TRPC6 correlate with the immune microenvironment of BLCA patients and have the potential for use in disease prognostics.
Context: Muscone is a chemical monomer derived from musk. Although many studies have confirmed the cardioprotective effects of muscone, the effects of muscone on cardiac hypertrophy and its potential mechanisms are unclear. Objective: The aim of the present study was to investigate the effect of muscone on angiotensin (Ang) II-induced cardiachypertrophy. Materials and methods: The viability of H9C2 and AC16 cells was assessed by CCK8 assay. The expression of proteins was evaluated by RT-PCR and Western blot analysis. Echocardiographic paraments were obtained by a Visual sonics high resolution Vevo 2100 system. H&E staining was used to assess myocardial structural changes. Masson trichrome staining was used to assess degree of fibrosis. Serum Biochemical Indexes were detected by automatic chemistry analyzer. Results: In the present study, we found for the first time that muscone exerted inhibitory effects on Ang II-induced cardiac hypertrophy and cardiac injury in mice. Secondly, we showed that muscone attenuated cardiac injury by reducing the secretion of proinflammatory cytokines and promoting the secretion of anti-inflammatory cytokines. Moreover, we found that muscone exerted cardioprotective effects by inhibiting phosphorylation of key proteins in the STAT3, MAPK and TGF-β/SMAD pathways. In addition, the in vivo and in vitro validation found no significant toxicity or side effects of muscone on normal cells and organs. Discussion and conclusions: Muscone could attenuate Ang II-induced cardiac hypertrophy, in part, by inhibiting the STAT3, MAPK, and TGF-β/SMAD signaling pathways.
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