{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:09:59Z","timestamp":1792091399564,"version":"4.4.0"},"reference-count":74,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,2]],"date-time":"2022-10-02T00:00:00Z","timestamp":1664668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Cisplatin (CIS) is an effective chemotherapeutic agent against different cancers. The use of CIS is associated with acute lung injury (ALI) and other adverse effects, and oxidative stress and inflammation were implicated in its toxic effects. Candesartan (CAN), an angiotensin II (Ang II) receptor blocker, showed beneficial effects against oxidative stress and inflammation. Therefore, this study investigated the potential of CAN to prevent CIS-induced oxidative stress, inflammation, and lung injury in rats, pointing to the involvement of TLR4\/NF-\u03baB, JAK1\/STAT3, PPAR\u03b3, and Nrf2\/HO-1 signaling. The rats received CAN (5 mg\/kg) for 10 days and were challenged with a single dose of CIS (7 mg\/kg) on day 7. CIS caused injury to the alveoli and the bronchial tree, increased lipid peroxidation, nitric oxide, myeloperoxidase, TLR-4, NF-\u03baB p65, iNOS, TNF-\u03b1, IL-6, IL-1\u03b2, and caspase-3, and decreased cellular antioxidants and IL-6 in the lungs of rats. CAN effectively prevented tissue injury, suppressed TLR-4\/ NF-\u03baB signaling, and ameliorated oxidative stress, inflammatory markers, and caspase-3 in CIS-administered rats. CAN enhanced antioxidants and IL-10, decreased Ang II, increased Ang (1\u20137), suppressed the phosphorylation of JAK1 and STAT3, and upregulated SOCS3 in CIS-administered rats. These effects were associated with the downregulation of Keap1 and enhanced Nrf2, GCLC, HO-1, and PPAR\u03b3. In conclusion, CAN prevented CIS-induced lung injury by attenuating oxidative stress, suppressing TLR-4\/NF-\u03baB and JAK1\/STAT3 signaling, Ang II, and pro-inflammatory mediators, and upregulating PPAR\u03b3, and Nrf2\/HO-1 signaling.<\/jats:p>","DOI":"10.3390\/ph15101222","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T01:21:07Z","timestamp":1665364867000},"page":"1222","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Candesartan Attenuates Cisplatin-Induced Lung Injury by Modulating Oxidative Stress, Inflammation, and TLR-4\/NF-\u03baB, JAK1\/STAT3, and Nrf2\/HO-1 Signaling"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8580-4179","authenticated-orcid":false,"given":"Ahmed M.","family":"Atwa","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo 11829, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omnia A. M.","family":"Abd El-Ghafar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef 62521, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emad H. M.","family":"Hassanein","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somya E.","family":"Mahdi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghadir A.","family":"Sayed","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo 11829, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3746-8582","authenticated-orcid":false,"given":"Reem S.","family":"Alruhaimi","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifa A.","family":"Alqhtani","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7133-6121","authenticated-orcid":false,"given":"Mohammed F.","family":"Alotaibi","sequence":"additional","affiliation":[{"name":"Physiology Department, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0279-6500","authenticated-orcid":false,"given":"Ayman M.","family":"Mahmoud","sequence":"additional","affiliation":[{"name":"Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt"},{"name":"Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejphar.2014.07.025","article-title":"Cisplatin in cancer therapy: Molecular mechanisms of action","volume":"740","author":"Dasari","year":"2014","journal-title":"Eur. 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