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This study aimed to investigate whether alamandine modulates chronic stress\u2013induced alterations in the intestine and liver by assessing histopathological changes, inflammatory responses, and oxidative stress parameters in a chronic unpredictable mild stress (CUMS) model. Male rats were exposed to CUMS for 35\u00a0days, and the effects of Alamandine and the Mas receptor antagonist A779 were evaluated. Serum inflammatory cytokines (TNF-\u03b1, IL-6), liver cytokines (IL-6, IL-1\u03b2), oxidative stress markers including superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA), as well as biochemical parameters (AST, ALT, total protein) were analyzed. Histopathological examination of intestinal and colonic tissues was also performed. CUMS significantly increased serum cortisol and pro-inflammatory cytokines, indicating systemic inflammation, while elevated IL-6 and IL-1\u03b2 levels in liver tissue suggested a localized inflammatory response. Oxidative stress findings showed impaired antioxidant defense and increased lipid peroxidation. Despite these changes, AST, ALT, and total protein levels remained unchanged, indicating no overt hepatic injury. Histologically, CUMS caused intestinal villus degeneration, inflammatory infiltration, and reduced goblet cell numbers, whereas the colon exhibited milder epithelial alterations. Alamandine treatment attenuated inflammatory and oxidative responses and improved intestinal mucosal integrity, with partial restoration of goblet cells. These findings suggest that alamandine attenuates chronic stress\u2013induced inflammatory, oxidative, and histopathological alterations in intestinal and hepatic tissues. The results further support a potential protective role of the RAS pathway in peripheral tissue injury associated with chronic stress.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>Chronic stress induces inflammation, oxidative stress, and intestinal mucosal damage. Alamandine attenuates these alterations and improves intestinal histopathological changes through modulation of the protective RAS pathway.<\/jats:p>","DOI":"10.1007\/s00210-026-05612-2","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T01:22:58Z","timestamp":1783041778000},"page":"20403-20415","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Alamandine attenuates stress-induced inflammation, oxidative stress, and intestinal histopathological alterations in a chronic unpredictable mild stress model of depression"],"prefix":"10.1007","volume":"399","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8593-1415","authenticated-orcid":false,"given":"Aysu","family":"Kilic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6946-217X","authenticated-orcid":false,"given":"Betul Esra","family":"Ipek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8787-3108","authenticated-orcid":false,"given":"Yasin Ali","family":"Cimen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0239-7403","authenticated-orcid":false,"given":"Mert","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6054-0752","authenticated-orcid":false,"given":"Fatma Bedia Karakaya","family":"Cimen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4300-7213","authenticated-orcid":false,"given":"Emine Rumeysa","family":"Hekimoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2706-9625","authenticated-orcid":false,"given":"Huri","family":"Demirci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1870-229X","authenticated-orcid":false,"given":"Savas","family":"Ustunova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"5612_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yhbeh.2020.104880","volume":"127","author":"AF Almeida-Santos","year":"2021","unstructured":"Almeida-Santos AF, de Melo LA, Gon\u00e7alves SCA, Oliveira Amaral LB, Santos RAS, Campagnole-Santos MJ, Kangussu LM (2021) Alamandine through MrgD receptor induces antidepressant-like effect in transgenic rats with low brain angiotensinogen. 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