{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:59:09Z","timestamp":1785560349876,"version":"3.56.0"},"reference-count":21,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006109","name":"VEGA","doi-asserted-by":"publisher","award":["1\/0620\/24"],"award-info":[{"award-number":["1\/0620\/24"]}],"id":[{"id":"10.13039\/501100006109","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1\/0620\/24"],"award-info":[{"award-number":["1\/0620\/24"]}],"id":[{"id":"https:\/\/ror.org\/02z80ct15","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006108","name":"KEGA","doi-asserted-by":"crossref","award":["049SPU-4\/2025"],"award-info":[{"award-number":["049SPU-4\/2025"]}],"id":[{"id":"10.13039\/501100006108","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005357","name":"Slovak Research and Development Agency","doi-asserted-by":"crossref","award":["APVV-18-03122"],"award-info":[{"award-number":["APVV-18-03122"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"crossref"}]},{"award":["APVV-18-03122"],"award-info":[{"award-number":["APVV-18-03122"]}],"id":[{"id":"https:\/\/ror.org\/037nx0e70","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Isorhamnetin is a naturally occurring flavonoid with reported antioxidant, anti-inflammatory, and anticancer properties. Although its biological activities have been extensively investigated, its effects on ovarian cell physiology remain insufficiently characterized. This study aimed to evaluate the influence of isorhamnetin on the viability, steroid hormone secretion, apoptosis, and growth factor signalling in human ovarian cell lines representing both non-tumour and tumour phenotypes. Methods: Human granulosa (HGL5), granulosa tumour (COV434), and epithelial ovarian carcinoma (OVCAR-3) cell lines were treated with isorhamnetin at concentrations of 5\u201380 \u03bcg\/mL for 24 h. Cell viability was determined using the AlamarBlueTM assay. The secretion of progesterone, 17\u03b2-estradiol, and the presence of transforming growth factor \u03b22 (TGF-\u03b22), transforming growth factor \u03b2 receptor 2 (TGFBR2), and apoptosis-inducing factor (AIF) was quantified by enzyme-linked immunosorbent assay (ELISA). Results: Isorhamnetin significantly reduced cell viability in a dose-dependent manner, with tumour cell lines exhibiting greater sensitivity than non-tumour granulosa cells. A significant decrease in viability was observed in OVCAR-3 cells from 10 \u03bcg\/mL onward, whereas COV434 cells showed significant reductions at concentrations of 20 \u03bcg\/mL and higher. In contrast, HGL5 cell viability was significantly affected only at the highest concentration (80 \u03bcg\/mL). No significant changes were detected in the secretion of progesterone, 17\u03b2-estradiol, TGF-\u03b22, or TGFBR2 in any of the examined cell lines. A significant reduction in AIF production was observed only in HGL5 cells treated with 80 \u03bcg\/mL isorhamnetin. Conclusions: Isorhamnetin preferentially decreased the viability of ovarian tumour cells while exerting only limited effects on non-tumour granulosa cells, indicating preferential cytotoxic activity toward malignant ovarian cells. The absence of significant changes in steroid hormone production and TGF-\u03b2 suggests that its antiproliferative effects involve molecular pathways that were not investigated in the present study. These findings support further investigation of isorhamnetin as a potential natural compound for ovarian cancer prevention or adjunctive therapy.<\/jats:p>","DOI":"10.3390\/ph19081196","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:38:54Z","timestamp":1785411534000},"page":"1196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Isorhamnetin and Female Reproduction: Effects on Viability, Hormone Secretion, and Growth Factors"],"prefix":"10.3390","volume":"19","author":[{"given":"Michal","family":"Mihal","sequence":"first","affiliation":[{"name":"AgroBioTech Research Centre, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3072-2171","authenticated-orcid":false,"given":"Denis","family":"Bazany","sequence":"additional","affiliation":[{"name":"AgroBioTech Research Centre, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0570-259X","authenticated-orcid":false,"given":"Petr","family":"Slama","sequence":"additional","affiliation":[{"name":"Department of Animal Morphology, Physiology and Genetics, Faculty of AgriSciences, Mendel University in Brno, Zem\u011bd\u011blsk\u00e1 1\/1665, 613 00 Brno, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Kolesarova","sequence":"additional","affiliation":[{"name":"AgroBioTech Research Centre, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia"},{"name":"Institute of Applied Biology, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, 949 76 Nitra, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/10715762.2019.1702656","article-title":"Hormones and Oxidative Stress: An Overview","volume":"54","author":"Chainy","year":"2020","journal-title":"Free Radic. Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sirotkin, A.V., and Kolesarova, A. (2022). Chapter 1\u2014Female Reproductive System and Its Regulation. Environmental Contaminants and Medicinal Plants Action on Female Reproduction, Academic Press.","DOI":"10.1016\/B978-0-12-824292-6.00024-6"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"269","DOI":"10.33549\/physiolres.935060","article-title":"Rooibos (Aspalathus linearis) and Its Constituent Quercetin Can Suppress Ovarian Cell Functions and Their Response to FSH","volume":"72","author":"Sirotkin","year":"2023","journal-title":"Physiol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"113434","DOI":"10.1016\/j.jep.2020.113434","article-title":"Ethnomedicinal Uses, Phytochemistry and Dermatological Effects of Hippophae rhamnoides L.: A Review","volume":"266","author":"Pundir","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3443","DOI":"10.1016\/j.fct.2010.09.019","article-title":"Antioxidant, Cytoprotective and Antibacterial Effects of Sea Buckthorn (Hippophae rhamnoides L.) Leaves","volume":"48","author":"Upadhyay","year":"2010","journal-title":"Food Chem. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Qin, Y., Jiang, W., Li, A., Gao, M., Liu, H., Gao, Y., Tian, X., and Gong, G. (2021). The Combination of Paraformaldehyde and Glutaraldehyde Is a Potential Fixative for Mitochondria. Biomolecules, 11.","DOI":"10.3390\/biom11050711"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9261","DOI":"10.1039\/D0FO03165H","article-title":"Isorhamnetin Attenuates High-Fat and High-Fructose Diet Induced Cognitive Impairments and Neuroinflammation by Mediating MAPK and NF\u03baB Signaling Pathways","volume":"12","author":"Mulati","year":"2021","journal-title":"Food Funct."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Li, Y., Fan, B., Pu, N., Ran, X., Lian, T., Cai, Y., Xing, W., and Sun, K. (2022). Isorhamnetin Suppresses Human Gastric Cancer Cell Proliferation through Mitochondria-Dependent Apoptosis. Molecules, 27.","DOI":"10.3390\/molecules27165191"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Han, Y., Yuan, C., Zhou, X., Han, Y., He, Y., Ouyang, J., Zhou, W., Wang, Z., Wang, H., and Li, G. (2021). Anti-Inflammatory Activity of Three Triterpene from Hippophae rhamnoides L. in Lipopolysaccharide-Stimulated RAW264.7 Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222112009"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"935","DOI":"10.3892\/mmr.2014.1886","article-title":"Isorhamnetin Suppresses Colon Cancer Cell Growth through the PI3K-Akt-mTOR Pathway","volume":"9","author":"Li","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chauhan, A.K., Kim, J., Lee, Y., Balasubramanian, P.K., and Kim, Y. (2019). Isorhamnetin Has Potential for the Treatment of Escherichia Coli-Induced Sepsis. Molecules, 24.","DOI":"10.3390\/molecules24213984"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Mihal, M., Roychoudhury, S., Sirotkin, A.V., and Kolesarova, A. (2023). Sea Buckthorn, Its Bioactive Constituents, and Mechanism of Action: Potential Application in Female Reproduction. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1244300"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.rvsc.2018.07.010","article-title":"Can Xylene and Quercetin Directly Affect Basic Ovarian Cell Functions?","volume":"119","author":"Tarko","year":"2018","journal-title":"Res. Vet. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"755","DOI":"10.33549\/physiolres.934680","article-title":"Ovarian Steroid Hormone Secretion by Human Granulosa Cells After Supplementation of Sambucus nigra L. Extract","volume":"70","author":"Baldovska","year":"2021","journal-title":"Physiol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kolesarova, A., Baldovska, S., Kohut, L., Vasicek, J., Ivanisova, E., Arvay, J., Duracka, M., and Roychoudhury, S. (2023). Modulatory Effect of Pomegranate Peel Extract on Key Regulators of Ovarian Cellular Processes in Vitro. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1277155"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ye, L., Ma, R.-H., Zhang, X.-X., Thakur, K., Zhang, J.-G., Khan, M.R., Busquets, R., and Wei, Z.-J. (2022). Isorhamnetin Induces Apoptosis and Suppresses Metastasis of Human Endometrial Carcinoma Ishikawa Cells via Endoplasmic Reticulum Stress Promotion and Matrix Metalloproteinase-2\/9 Inhibition In Vitro and In Vivo. Foods, 11.","DOI":"10.3390\/foods11213415"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.phymed.2017.11.007","article-title":"Seabuckthorn Berry Polysaccharide Extracts Protect against Acetaminophen Induced Hepatotoxicity in Mice via Activating the Nrf-2\/HO-1-SOD-2 Signaling Pathway","volume":"38","author":"Wang","year":"2018","journal-title":"Phytomedicine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6535","DOI":"10.1021\/acs.jafc.1c01543","article-title":"Isorhamnetin Promotes Estrogen Biosynthesis and Proliferation in Porcine Granulosa Cells via the PI3K\/Akt Signaling Pathway","volume":"69","author":"Li","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"205","DOI":"10.4103\/1673-5374.290875","article-title":"Role of Apoptosis-Inducing Factor in Perinatal Hypoxic-Ischemic Brain Injury","volume":"16","author":"Rodriguez","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"110939","DOI":"10.1016\/j.cbi.2024.110939","article-title":"Quercetin Attenuates Cisplatin-Induced Mitochondrial Apoptosis via PI3K\/Akt Mediated Inhibition of Oxidative Stress in Pericytes and Improves the Blood Labyrinth Barrier Permeability","volume":"393","author":"Huang","year":"2024","journal-title":"Chem.-Biol. Interact."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1302\/2046-3758.108.BJR-2021-0086","article-title":"The Role of TGF-\u03922 in Cartilage Development and Diseases","volume":"10","author":"Duan","year":"2021","journal-title":"Bone Jt. 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