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• W4386467014 abstract "Septic myocardial injury is one of the most life-threatening organ dysfunction. The γ-secretase-based approaches have been developed as potential strategies for diverse diseases management. Unfortunately, the role of γ-secretase inhibitor in septic myocardial injury is unclarified. The present study aims to investigate the effect of γ-secretase inhibitor in septic myocardial injury and reveal its mechanism.The mouse model of septic myocardial injury was established by intraperitoneally injection of lipopolysaccharide (LPS), and γ-secretase inhibitor MW167 was applied in this model. RNA-sequencing analysis and further bioinformatics analyses were used to screen differential expressed genes (DEGs) and potentially enriched pathways between LPS and LPS + MW167 mice. Pathological examination was performed using haematoxylin and eosin (HE) staining. SD-1029 was used to block JAK2/STAT3 signaling in H9C2 cells and western blot analysis quantified JAK2/STAT3-related proteins.LPS induced myocardial injury accompanied with significant inflammatory infiltration and more apoptotic cells. Transcriptome sequencing screened 36 DEGs and bioinformatics identified JAK2/STAT3 signaling pathway was significantly enriched. Further in vitro experiments showed that γ-secretase inhibitor MW167 activated JAK2/STAT3 pathway. Additionally, MW167 restored cell viability, decreased myocardial injury markers including cardiac troponin I (cTnI) and brain natriuretic peptide (BNP), inhibited pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor-α (TNF-α) and reduced nitric oxide (NO), cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS) release. Application of SD-1029 reversely deteriorated LPS-induced myocardial injury and inflammatory response in γ-secretase inhibitor-treated myocardial cells.The results demonstrate that γ-secretase inhibitor alleviates septic myocardial injury via activating JAK2/STAT3 signaling, and provide novel therapeutic direction for septic myocardial injury." @default.
• W4386467014 created "2023-09-07" @default.
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• W4386467014 date "2023-09-06" @default.
• W4386467014 modified "2023-09-27" @default.
• W4386467014 title "γ‐Secretase inhibitor alleviates lipopolysaccharide‐induced myocardial injury through regulating <scp>JAK2</scp>/<scp>STAT3</scp> signaling" @default.
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• W4386467014 doi "https://doi.org/10.1002/tox.23962" @default.
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