{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T23:40:17Z","timestamp":1792885217690,"version":"4.5.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T00:00:00Z","timestamp":1650412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002655","name":"Terry Fox Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002655","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Hydrogen sulfide (H<jats:sub>2<\/jats:sub>S) is an endogenously gas transmitter signaling molecule with known antioxidant, anti-inflammatory, and cytoprotective properties. Although accumulating evidence shows the therapeutic potential of H<jats:sub>2<\/jats:sub>S in various hepatic diseases, its role in cyclophosphamide (CP)-induced hepatotoxicity remains elusive. The present study was undertaken to investigate the impact of endogenous and exogenous H<jats:sub>2<\/jats:sub>S on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in CP-induced hepatotoxicity. Either an H<jats:sub>2<\/jats:sub>S donor (NaHS (100\u00a0\u03bcM\/kg) or an H2S blocker [<jats:sc>dl<\/jats:sc>-propargylglycine (PAG) (30\u00a0mg\/kg, i. p.)], was administered for 10\u00a0days before a single ip injection of CP (200\u00a0mg\/kg). NaHS attenuated conferred hepatoprotection against CP-induced toxicity, significantly decreasing serum hepatic function tests and improving hepatic histopathology. Additionally, NaHS-treated rats exhibited antioxidant activity in liver tissues compared with the CP group. The upregulated hepatic levels of TLR2\/4 and their downstream signaling molecules including c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-\u03baB) were also suppressed by NaHS protective treatment. NaHS showed anti-inflammatory and antiapoptotic effects; reducing hepatic level tumor necrosis factor-alpha (TNF-\u03b1) and caspase-3 expression. Interestingly, the cytotoxic events induced in CP-treated rats were not significantly altered upon the blocking of endogenous H<jats:sub>2<\/jats:sub>S. Taken together, the present study suggested that exogenously applied H<jats:sub>2<\/jats:sub>S rather than the endogenously generated H<jats:sub>2<\/jats:sub>S, displayed a hepatoprotective effect against CP-induced hepatotoxicity that might be mediated by TLRs-JNK\/NF-\u03baB pathways.<\/jats:p>","DOI":"10.3389\/fphar.2022.850066","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T17:42:05Z","timestamp":1655487725000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":73,"title":["TLRs-JNK\/ NF-\u03baB Pathway Underlies the Protective Effect of the Sulfide Salt Against Liver Toxicity"],"prefix":"10.3389","volume":"13","author":[{"given":"Rania","family":"Abdel-latif","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gehan Hussein","family":"Heeba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soha Osama","family":"Hassanin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaimaa","family":"Waz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr","family":"Amin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"346","DOI":"10.3390\/biom9080346","article-title":"Galangin Activates Nrf2 Signaling and Attenuates Oxidative Damage, Inflammation, and Apoptosis in a Rat Model of Cyclophosphamide-Induced Hepatotoxicity","volume":"9","author":"Aladaileh","year":"2019","journal-title":"Biomolecules"},{"key":"B2","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.biopha.2018.12.112","article-title":"Olea Europaea Leaf Extract Up-Regulates Nrf2\/ARE\/HO-1 Signaling and Attenuates Cyclophosphamide-Induced Oxidative Stress, Inflammation and Apoptosis in Rat Kidney","volume":"111","author":"ALHaithloul","year":"2019","journal-title":"Biomed. 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