{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T13:06:57Z","timestamp":1779368817590,"version":"3.53.0"},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"vor","delay-in-days":49,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100019791","name":"\u0130stanbul Medipol \u00dcniversitesi","doi-asserted-by":"publisher","award":["Project No: 2020\/18"],"award-info":[{"award-number":["Project No: 2020\/18"]}],"id":[{"id":"10.13039\/100019791","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["iubmb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["BioFactors"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Ovarian response extremes are associated with distinct alterations in the follicular microenvironment, yet the underlying molecular mechanisms remain incompletely understood. This study investigated oxidative stress, antioxidant responses, apoptosis, and PI3K\/AKT\/mTOR signaling in granulosa cells from women undergoing intracytoplasmic sperm injection, stratified into poor (POR), normal (NOR), and high ovarian response (HOR) groups (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200930). Follicular fluid oxidative stress markers, antioxidant systems, and regulatory factors were analyzed, while intracellular reactive oxygen species, DNA fragmentation, and chromatin integrity were evaluated in granulosa cells. In addition, PI3K\/AKT\/mTOR pathway activity was assessed using immunohistochemistry and immunofluorescence. Compared with NOR, both POR and HOR groups exhibited increased oxidative stress, reflected by elevated MDA levels (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05), accompanied by divergent antioxidant responses, including reduced GSH levels in POR and a progressive increase in SOD activity from NOR to HOR (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05). Although melatonin and TGF\u2010\u03b2 levels did not differ significantly, melatonin showed a trend toward lower levels in POR and higher levels in HOR. Granulosa cell ROS production and apoptosis\u2010related markers were significantly increased in both response extremes, particularly in POR (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05). Consistently, PI3K\/AKT\/mTOR signaling displayed differential regulation, with reduced activation in POR and enhanced activation in HOR compared to NOR (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05). Overall, NOR appears to reflect a balanced redox and molecular state, whereas both poor and high responses are characterized by oxidative stress, cellular damage, and dysregulated PI3K\/AKT\/mTOR signaling. These findings suggest that deviation from physiological equilibrium, rather than response magnitude alone, is a key determinant of granulosa cell dysfunction and impaired follicular competence.\n                  <\/jats:p>","DOI":"10.1002\/biof.70102","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T03:50:36Z","timestamp":1776657036000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Extremes of Ovarian Response: Divergent\n                    <scp>PI3K<\/scp>\n                    \/\n                    <scp>AKT<\/scp>\n                    \/\n                    <scp>mTOR<\/scp>\n                    Signaling and Oxidative Stress Patterns in Low and High Responders Undergoing In\u00a0Vitro Fertilization"],"prefix":"10.1002","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2923-5869","authenticated-orcid":false,"given":"Oya","family":"Korkmaz","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medicine Malatya Turgut \u00d6zal University  Malatya T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seda","family":"Karabulut","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, International Faculty of Medicine Istanbul Medipol University  Istanbul T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pelin","family":"Macit","sequence":"additional","affiliation":[{"name":"In Vitro Fertilization Center Istanbul Okan University Hospital  Istanbul T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0130lknur","family":"Keskin","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medicine Istanbul Medipol University  Istanbul T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,19]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.12968\/hmed.2018.79.4.194"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s43043-023-00128-8"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13048-024-01551-9"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12905-022-01964-y"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2020.10.008"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10815-021-02323-w"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-018-1350-z"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2022-064711"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells12141830"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.730196"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22189838"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26136377"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11030477"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP-22-0126"},{"key":"e_1_2_14_16_1","first-page":"115","article-title":"Association of Follicular Fluid Antioxidant Activity With Aging and in Vitro Fertilization Outcome: A Cross\u2010Sectional Study","volume":"18","author":"Afrough M.","year":"2024","journal-title":"International Journal of Fertility and Sterility"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24119205"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-019-00036-1"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.5114\/pm.2022.124019"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2020.06.021"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0967199420000520"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0009-8981(86)90247-0"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3835(88)90084-5"},{"key":"e_1_2_14_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(86)90026-6"},{"key":"e_1_2_14_25_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0147075","article-title":"Chronic Exposure to Diquat Causes Reproductive Toxicity in Female Mice","volume":"11","author":"Zhang J. 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