{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T22:20:59Z","timestamp":1792448459190,"version":"4.5.0"},"reference-count":74,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T00:00:00Z","timestamp":1713830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Saud University, Riyadh","award":["RSPD2024R740"],"award-info":[{"award-number":["RSPD2024R740"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cisplatin is a potent compound in anti-tumor chemotherapy; however, its clinical utility is hampered by dose-limiting nephrotoxicity. This study investigated whether papaverine could mitigate cisplatin-induced kidney damage while preserving its chemotherapeutic efficacy. Integrative bioinformatics analysis predicted papaverine modulation of the mechanistic pathways related to cisplatin renal toxicity; notably, mitogen-activated protein kinase 1 (MAPK1) signaling. We validated protective effects in normal kidney cells without interfering with cisplatin cytotoxicity on a cancer cell line. Concurrent in vivo administration of papaverine alongside cisplatin in rats prevented elevations in nephrotoxicity markers, including serum creatinine, blood urea nitrogen, and renal oxidative stress markers (malondialdehyde, inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines), as tumor necrosis factor alpha (TNF-\u03b1), monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6). Papaverine also reduced apoptosis markers such as Bcl2 and Bcl-2\u2013associated X protein (Bax) and kidney injury molecule-1 (KIM-1), and histological damage. In addition, it upregulates antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) while boosting anti-inflammatory signaling interleukin-10 (IL-10). These effects were underlined by the ability of Papaverine to downregulate MAPK-1 expression. Overall, these findings show papaverine could protect against cisplatin kidney damage without reducing its cytotoxic activity. Further research would allow the transition of these results to clinical practice.<\/jats:p>","DOI":"10.3390\/molecules29091927","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T10:34:05Z","timestamp":1713868445000},"page":"1927","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Unraveling the Nephroprotective Potential of Papaverine against Cisplatin Toxicity through Mitigating Oxidative Stress and Inflammation: Insights from In Silico, In Vitro, and In Vivo Investigations"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0695-2251","authenticated-orcid":false,"given":"Shimaa A.","family":"Abass","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5851-3306","authenticated-orcid":false,"given":"Abdullah A.","family":"Elgazar","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanad S.","family":"El-kholy","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5074-7730","authenticated-orcid":false,"given":"Amal I.","family":"El-Refaiy","sequence":"additional","affiliation":[{"name":"Department of Agricultural Zoology and Nematology, Faculty of Agriculture (Girls), Al-Azhar University, Cairo 11884, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem A.","family":"Nawaya","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8426-4692","authenticated-orcid":false,"given":"Mashooq Ahmad","family":"Bhat","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4048-6717","authenticated-orcid":false,"given":"Foad A.","family":"Farrag","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0196-1976","authenticated-orcid":false,"given":"Abdelrahman","family":"Hamdi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8042-6009","authenticated-orcid":false,"given":"Marwa","family":"Balaha","sequence":"additional","affiliation":[{"name":"Department of Medical, Oral and Biotechnological Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, Via dei vestini, 31-66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3314-9202","authenticated-orcid":false,"given":"Mohammed A.","family":"El-Magd","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Klumpers, M.J., Witte, W.D., Gattuso, G., Schiavello, E., Terenziani, M., Massimino, M., Gidding, C.E., Vermeulen, S.H., Driessen, C.M., and Van Herpen, C.M. 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