{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:11:51Z","timestamp":1788959511528,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Hypoxia triggers pulmonary inflammation and oxidative stress, leading to endothelial dysfunction, apoptosis and lung injury. Although the flavonoid orientin exhibits potent antioxidant and anti-inflammatory properties, its pharmacokinetic behavior remains incompletely characterized. Nanoparticle-based delivery systems may enhance efficacy. This study investigated whether Orientin delivered via chitosan nanoparticles (CNP\u2013orientin) protects against hypoxia-induced pulmonary inflammation, oxidative stress, and tissue injury in rats. Methods: A total of 48 female Sprague\u2013Dawley rats were randomized into four normoxic and four hypoxic groups (n = 6 per group). Rats in the hypoxic groups were exposed to intermittent hypoxia (7% O2, 8 h\/day for 7 days). Hypoxic rats were allocated to experimental groups, including an untreated hypoxia group and groups receiving orientin alone, chitosan nanoparticles alone or orientin-loaded chitosan nanoparticles (CNP\u2013orientin), while normoxic rats served as controls. Hypoxic exposure was conducted using a controlled glove box system. At the end of the protocol, blood samples were collected for serum inflammatory marker analysis, and lung tissues were harvested to assess oxidative stress parameters, hypoxia- and inflammation-related signaling pathways, apoptosis-related gene expression, and histopathological lung injury and fibrosis. Results: Intermittent hypoxia significantly increased pulmonary HIF-1\u03b1 and iNOS expression, oxidative stress markers (increased malondialdehyde and decreased superoxide dismutase and glutathione), pro-inflammatory cytokines (TNF-\u03b1, IL-1\u03b2), apoptotic signaling and histopathological lung injury compared with normoxic controls (p &lt; 0.05). Treatment with orientin or chitosan nanoparticles alone attenuated hypoxia-associated biochemical and molecular alterations compared to untreated hypoxic rats (p &lt; 0.05). Notably, CNP\u2013orientin treatment significantly attenuated multiple oxidative stress, inflammatory, and apoptosis-related alterations compared with untreated hypoxic rats (p &lt; 0.05). These protective effects were observed despite the substantially lower orientin-equivalent dose in the CNP\u2013orientin formulation compared with free orientin. NF-\u03baB and TNF-\u03b1 expression, caspase-3 levels, antioxidant markers, and Bcl-2 expression differed significantly among hypoxic groups (p &lt; 0.05). Histopathological lung injury and Modified Ashcroft fibrosis scores were significantly lower in the CNP\u2013orientin group than in the untreated hypoxic group (p &lt; 0.01 and p &lt; 0.001, respectively). Conclusions: Orientin-loaded chitosan nanoparticles effectively mitigate hypoxia-induced pulmonary inflammation, oxidative stress, apoptosis and fibrotic injury. These findings identify CNP\u2013orientin as a promising nanotherapeutic strategy for hypoxia-associated lung diseases and support further translational investigations.<\/jats:p>","DOI":"10.3390\/biom16091306","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T12:26:11Z","timestamp":1788956771000},"page":"1306","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chitosan\u2013Orientin Nanoparticles Attenuate Hypoxia-Induced Pulmonary Inflammation in Rats"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7490-3913","authenticated-orcid":false,"given":"G\u00fclfem","family":"\u00d6zduygu","sequence":"first","affiliation":[{"name":"Department of Pulmonology, Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0130hsan","family":"Topalo\u011flu","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Faculty of Medicine, Kafkas University, Kars 36000, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6662-9600","authenticated-orcid":false,"given":"\u00c7a\u011fr\u0131","family":"Atasoy","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Faculty of Medicine, Kafkas University, Kars 36000, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eren","family":"Erdo\u011fdu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5258-2856","authenticated-orcid":false,"given":"G\u00fcntu\u011f","family":"Bat\u0131han","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Faculty of Medicine, Canakkale Onsekiz Mart University, Canakkale 14020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Semih","family":"\u00c7ift\u00e7i","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Faculty of Medicine, Kafkas University, Kars 36000, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volkan","family":"Gelen","sequence":"additional","affiliation":[{"name":"Department of Physiology, Veterinary Faculty, Kafkas University, Kars 36000, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"K\u00fcbra","family":"Kaya","sequence":"additional","affiliation":[{"name":"Department of Physiology, Veterinary Faculty, Kafkas University, Kars 36000, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adem","family":"Kara","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Science, Erzurum Technical University, Erzurum 25000, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Ali","family":"Ye\u015filda\u011f","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Faculty of Engineering and Architecture, Kafkas University, Kars 36000, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif","family":"Erba\u015f","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Veterinary Faculty, Atat\u00fcrk University, Erzurum 25000, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7849-4117","authenticated-orcid":false,"given":"Deniz","family":"Ekinci","sequence":"additional","affiliation":[{"name":"Department of Agricultural Biotechnology, Faculty of Agriculture, Ondokuz May\u0131s University, Samsun 25000, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.chest.2016.09.001","article-title":"Hypoxic pulmonary vasoconstriction: From molecular mechanisms to medicine","volume":"151","author":"Wu","year":"2017","journal-title":"Chest"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1089\/ars.2021.0027","article-title":"Oxidative stress and endothelial dysfunction in sepsis and acute inflammation","volume":"35","author":"Joffre","year":"2021","journal-title":"Antioxid. 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