{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:49:56Z","timestamp":1791398996234,"version":"4.3.3"},"reference-count":91,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005851","name":"Shahid Beheshti University of Medical Sciences","doi-asserted-by":"publisher","award":["7654"],"award-info":[{"award-number":["7654"]}],"id":[{"id":"10.13039\/501100005851","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Early life stress (ELS) significantly contributes to metabolic and psychological disorders by triggering oxidative stress and disrupting the hypothalamic\u2013pituitary\u2013adrenal (HPA) axis. This research examined ELS effects on redox status, along with anxiety-like behavior, in adolescent male Wistar rats, also assessing saffron (Crocus sativus L.) extract\u2019s potential benefits. Rats were exposed to foot shock stress from postnatal days 15\u201319, with treatment groups receiving saline or saffron extract (10 mg\/kg) via intraperitoneal injection. Control groups were maintained without stress exposure. Elevated Plus Maze (EPM) and Open Field Test (OFT) were used to evaluate anxiety-like behaviors. Corticosterone, glucose, and insulin levels, oxidative stress markers [malondialdehyde (MDA), glutathione (GSH), and catalase activity] in the plasma, pancreas, and amygdala were determined, and the HOMA-\u03b2 index was estimated. Saffron extract markedly restored ELS effects by reducing fasting plasma glucose and corticosterone levels, while increasing insulin levels and the HOMA-\u03b2 index in adolescent offspring. Additionally, saffron extract inhibited oxidative stress, evidenced by reduced MDA, normalized catalase activity, and augmented GSH levels in the plasma, pancreas, and amygdala. Behaviorally, saffron extract-treated rats exhibited diminished anxiety-like behaviors, characterized by increased time spent in the open arms of the EPM and the center zone in the OFT. This study suggests that ELS induces disturbances in glucose metabolism and anxiety-like behavior, accompanied by oxidative stress and increased HPA axis activity. The protective role of saffron extract underscores its capability to serve as a medicinal compound for preventing and treating stress-induced metabolic and anxiety disorders.<\/jats:p>","DOI":"10.1371\/journal.pone.0359395","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:53:56Z","timestamp":1791395636000},"page":"e0359395","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early life stress caused glucose homeostasis impairment and anxiety-like behavior along with oxidative stress in adolescent male rat offspring: Protective effect of saffron extract"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3903-8343","authenticated-orcid":true,"given":"Siavash","family":"Shirzadeh Barough","sequence":"first","affiliation":[{"name":"Shahid Beheshti University of Medical Sciences","place":["Tehran, Iran"],"department":["Neurophysiology 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Wang","year":"2007","journal-title":"Diabetologia"},{"issue":"12","key":"pone.0359395.ref063","doi-asserted-by":"crossref","first-page":"3328","DOI":"10.3390\/cells10123328","article-title":"Lipotoxicity and \u03b2-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress","volume":"10","author":"EA Vilas-Boas","year":"2021","journal-title":"Cells"},{"key":"pone.0359395.ref064","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.mce.2015.06.025","article-title":"The balance between adaptive and apoptotic unfolded protein responses regulates \u03b2-cell death under ER stress conditions through XBP1, CHOP and JNK","volume":"413","author":"JY Chan","year":"2015","journal-title":"Mol Cell Endocrinol"},{"issue":"4","key":"pone.0359395.ref065","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1037\/abn0000094","article-title":"Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation","volume":"124","author":"D Pagliaccio","year":"2015","journal-title":"J Abnorm Psychol"},{"key":"pone.0359395.ref066","doi-asserted-by":"crossref","first-page":"107300","DOI":"10.1016\/j.phrs.2024.107300","article-title":"PI3K\/AKT signaling pathway: Molecular mechanisms and therapeutic potential in depression","volume":"206","author":"N Guo","year":"2024","journal-title":"Pharmacol Res"},{"issue":"13","key":"pone.0359395.ref067","doi-asserted-by":"crossref","first-page":"6379","DOI":"10.1073\/pnas.1817391116","article-title":"Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior","volume":"116","author":"M Soto","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pone.0359395.ref068","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.biochi.2004.10.019","article-title":"Positive and negative regulation of insulin signaling through IRS-1 phosphorylation","volume":"87","author":"P Gual","year":"2005","journal-title":"Biochimie"},{"issue":"2","key":"pone.0359395.ref069","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1074\/jbc.M101521200","article-title":"Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action","volume":"277","author":"V Aguirre","year":"2002","journal-title":"J Biol Chem"},{"issue":"2","key":"pone.0359395.ref070","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.tem.2005.01.008","article-title":"The role of insulin receptor signaling in the brain","volume":"16","author":"L Plum","year":"2005","journal-title":"Trends Endocrinol Metab"},{"key":"pone.0359395.ref071","doi-asserted-by":"crossref","first-page":"1716291","DOI":"10.3389\/fnagi.2026.1716291","article-title":"Brain insulin resistance: A key pathological hub linking metabolic and neuropsychiatric comorbidities","volume":"18","author":"S Tang","year":"2026","journal-title":"Front Aging 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McCormick","year":"2010","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"issue":"4","key":"pone.0359395.ref075","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S0149-7634(00)00014-2","article-title":"The adolescent brain and age-related behavioral manifestations","volume":"24","author":"LP Spear","year":"2000","journal-title":"Neurosci Biobehav Rev"},{"issue":"6","key":"pone.0359395.ref076","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/nrn2639","article-title":"Effects of stress throughout the lifespan on the brain, behaviour and cognition","volume":"10","author":"SJ Lupien","year":"2009","journal-title":"Nat Rev Neurosci"},{"key":"pone.0359395.ref077","doi-asserted-by":"crossref","first-page":"101620","DOI":"10.1016\/j.dcn.2025.101620","article-title":"Understanding adolescent anxiety through a neurodevelopmental lens: A comparative review of rodents and humans","volume":"76","author":"CR Cody","year":"2025","journal-title":"Dev Cogn Neurosci"},{"key":"pone.0359395.ref078","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0014-2999(03)01272-X","article-title":"The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review","volume":"463","author":"L Prut","year":"2003","journal-title":"Eur J Pharmacol"},{"issue":"2","key":"pone.0359395.ref079","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/nprot.2007.44","article-title":"The use of the elevated plus maze as an assay of anxiety-related behavior in rodents","volume":"2","author":"AA Walf","year":"2007","journal-title":"Nat Protoc"},{"key":"pone.0359395.ref080","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.neubiorev.2016.05.013","article-title":"Mechanisms contributing to prefrontal cortex maturation during adolescence","volume":"70","author":"A Caballero","year":"2016","journal-title":"Neurosci Biobehav Rev"},{"key":"pone.0359395.ref081","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.neuroscience.2012.10.048","article-title":"Stress and the developing adolescent brain","volume":"249","author":"L Eiland","year":"2013","journal-title":"Neuroscience"},{"issue":"4","key":"pone.0359395.ref082","doi-asserted-by":"crossref","first-page":"214","DOI":"10.34172\/jkmu.2024.34","article-title":"The Effect of Saffron and its Active Compounds on Oxidative Stress Markers in Diabetic Rats: A Systematic Review and Meta-analysis of Animal Studies","volume":"31","author":"Y Mohammadi","year":"2024","journal-title":"Journal of Kerman University of Medical Sciences"},{"key":"pone.0359395.ref083","first-page":"493","article-title":"Protective Effects of Crocus Sativus L. Extract and Crocin against Chronic-Stress Induced Oxidative Damage of Brain, Liver and Kidneys in Rats","volume":"4","author":"AR Bandegi","year":"2014","journal-title":"Adv Pharm Bull"},{"issue":"23","key":"pone.0359395.ref084","doi-asserted-by":"crossref","first-page":"4855","DOI":"10.3390\/nu15234855","article-title":"Effects of Saffron Extract (Affron\u00ae) with 100 mg\/kg and 200 mg\/kg on Hypothalamic-Pituitary-Adrenal Axis and Stress Resilience in Chronic Mild Stress-Induced Depression in Wistar Rats","volume":"15","author":"C-Y Kim","year":"2023","journal-title":"Nutrients"},{"issue":"3","key":"pone.0359395.ref085","doi-asserted-by":"crossref","first-page":"303","DOI":"10.3390\/molecules21030303","article-title":"Constituents of Saffron (Crocus sativus L.) as Potential Candidates for the Treatment of Anxiety Disorders and Schizophrenia","volume":"21","author":"N Pitsikas","year":"2016","journal-title":"Molecules"},{"issue":"6","key":"pone.0359395.ref086","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1002\/ptr.2597","article-title":"Anxiolytic and hypnotic effect of Crocus sativus aqueous extract and its constituents, crocin and safranal, in mice","volume":"23","author":"H Hosseinzadeh","year":"2009","journal-title":"Phytother Res"},{"issue":"6","key":"pone.0359395.ref087","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/hup.2434","article-title":"Saffron (Crocus sativus) for depression: A systematic review of clinical studies and examination of underlying antidepressant mechanisms of action","volume":"29","author":"AL Lopresti","year":"2014","journal-title":"Hum Psychopharmacol"},{"issue":"4","key":"pone.0359395.ref088","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.bjp.2019.01.011","article-title":"Saffron (Crocus sativus) aqueous extract reverses the hypothalamus-pituitary-adrenal axis activity in rat model of post-traumatic stress disorder","volume":"29","author":"S Asalgoo","year":"2019","journal-title":"Revista Brasileira de Farmacognosia"},{"issue":"2","key":"pone.0359395.ref089","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1080\/13543776.2017.1355909","article-title":"Saffron and its derivatives, crocin, crocetin and safranal: A patent review","volume":"28","author":"M Rameshrad","year":"2018","journal-title":"Expert Opin Ther Pat"},{"issue":"6","key":"pone.0359395.ref090","doi-asserted-by":"crossref","first-page":"8610","DOI":"10.1002\/jcp.27843","article-title":"Antidiabetic potential of saffron and its active constituents","volume":"234","author":"H Yaribeygi","year":"2019","journal-title":"J Cell Physiol"},{"issue":"10","key":"pone.0359395.ref091","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1111\/j.1460-9568.2007.05522.x","article-title":"Long-term behavioural and molecular alterations associated with maternal separation in rats","volume":"25","author":"M Lippmann","year":"2007","journal-title":"Eur J Neurosci"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0359395","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:54:10Z","timestamp":1791395650000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0359395"}},"subtitle":[],"editor":[{"given":"Habib","family":"Yaribeygi","sequence":"first","affiliation":[{"name":"Semnan University of Medical Sciences and Health Services","place":["IRAN, ISLAMIC REPUBLIC OF"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":91,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,10,7]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0359395","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]}}}