{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T14:16:09Z","timestamp":1784297769572,"version":"3.55.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Oxidative stress contributes greatly to initiation and progression of liver injury. Activation of nuclear-factor erythroid 2-related factor 2 (Nrf2) has been considered as an attractive strategy for preventing and treating the oxidative damage related to liver injury. This study aimed to find an efficacious agent to activate Nrf2\/HO-1 signaling pathway from clinically used therapeutic agents and to characterize the usefulness for preventing and treating CCl<jats:sub>4<\/jats:sub>-induced acute liver injury. For this purpose, a series of clinically used therapeutic agents were collected and their activation potentials on Nrf2 were assayed by using 293T-Nrf2-luc cell line. Among all tested therapeutic agents, midazolam was found with good Nrf2 activation effect and this agent could significantly ameliorate CCl<jats:sub>4<\/jats:sub>-induced damage to HepG2 cells. <jats:italic>In vivo<\/jats:italic> animal tests showed that pretreatment with midazolam reduced the liver pathological tissue damage and the serum levels of ALT and AST in CCl<jats:sub>4<\/jats:sub>-induced liver injury mice. Further investigations showed that midazolam could strongly up-regulate the expression of both Nrf2 and HO-1 in the mice liver, accompanied by increasing of the levels of antioxidant enzyme SOD and reducing the production of MDA, as well as reducing the pro-inflammatory cytokines (IL-6, TNF-\u03b1) secretion. Collectively, our results clearly demonstrate that midazolam can ameliorate CCl<jats:sub>4<\/jats:sub>-induced acute liver injury and oxidative stress <jats:italic>via<\/jats:italic> activating the Nrf2 signaling pathway.<\/jats:p>","DOI":"10.3389\/fphar.2022.940137","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T05:40:29Z","timestamp":1657258829000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Midazolam Ameliorates Acute Liver Injury Induced by Carbon Tetrachloride via Enhancing Nrf2 Signaling Pathway"],"prefix":"10.3389","volume":"13","author":[{"given":"Yongyan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yadi","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangbo","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1111\/1755-5922.12207","article-title":"Impact of Antioxidant Supplementations on Cardio-Renal Protection in Cardiac Surgery: an Updated and Comprehensive Meta-Analysis and Systematic Review","volume":"34","author":"Ali- Hasan- Al- Saegh","year":"2016","journal-title":"Cardiovasc Ther."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e59","DOI":"10.1016\/j.jss.2011.01.038","article-title":"Oxidative Stress in Laparoscopic versus Open Abdominal Surgery: a Systematic Review","volume":"169","author":"Arsalani-Zadeh","year":"2011","journal-title":"J. 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