{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T05:22:31Z","timestamp":1782624151097,"version":"3.54.5"},"reference-count":25,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp; Molecular Tox"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Myocardial ischemia\u2010reperfusion injury (MI\/R) leads to the inevitable clinical consequences of myocardial infarction and subsequent heart failure. Trimetazidine (TMZ), an anti\u2010ischemic agent, exerts protective potential in MI\/R but had limited efficacy for some patients. Here we sought to investigate the single and combined application of gentiopicroside (GPS) and TMZ in MI\/R. Notably, GPS had little cytotoxicity to cardiomyocytes. GPS attenuated hypoxia\/reoxygenation (H\/R)\u2010induced cell death, reactive oxygen species production, lactate dehydrogenase and malondialdehyde releases, and antioxidant stress enzyme superoxide dismutase activity, indicating the protective efficacy of GPS against H\/R\u2010induced oxidative injury. Importantly, GPS enhanced the protective efficacy of TMZ against H\/R\u2010mediated cardiomyocyte injury. Additionally, GPS mitigated the transcription and releases of pro\u2010inflammatory cytokine interleukin\u20106 and tumor necrosis factor\u2010\u03b1 in H\/R\u2010treated cardiomyocytes, which were enhanced after co\u2010treatment with TMZ. Mechanistically, GPS activated the AMP\u2010activated protein kinase (AMPK) signaling to inhibit H\/R\u2010induced NOD\u2010like receptor pyrin domain\u2010containing protein 3 (NLRP3) inflammasome, which was further enhanced after costimulation with TMZ. Importantly, blocking the AMPK signaling reversed the protective roles of GPS and its combination with TMZ in H\/R\u2010induced oxidative insult and inflammation. In vivo, both GPS and TMZ alleviated the abnormal cardiac structure, cardiomyocyte apoptosis, and cardiac dysfunction in MI\/R rats, which were further enhanced after administration with GPS and TMZ together. Furthermore, GPS intensified TMZ\u2010mediated inhibition of oxidative injury, inflammation, and the AMPK\/NLRP3 signaling in MI\/R rats. Collectively, GPS enhances the protective efficacy of TMZ against MI\/R injury through AMPK activation\u2010mediated inhibition of NLRP3 inflammasome signaling, implying a promising therapeutic agent for the treatment of MI\/R.<\/jats:p>","DOI":"10.1002\/jbt.23366","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T07:04:10Z","timestamp":1681715050000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Gentiopicroside enhances the protective effect of trimetazidine against myocardial ischemia\u2010reperfusion injury via the AMPK\/NLRP3 inflammasome signaling"],"prefix":"10.1002","volume":"37","author":[{"given":"Yu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cardiology Yiwu Central Hospital Yiwu Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Cardiology Yiwu Central Hospital Yiwu Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningning","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Cardiology Yiwu Central Hospital Yiwu Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9309-1367","authenticated-orcid":false,"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Yiwu Central Hospital Yiwu Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000757"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.02.032"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ehf2.13144"},{"key":"e_1_2_11_5_1","first-page":"1","volume":"2021","author":"Xiang M.","year":"2021","journal-title":"Oxid. 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