{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:37:25Z","timestamp":1790620645603,"version":"4.1.0"},"reference-count":58,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Hepatocellular carcinoma (HCC) is an aggressive cancer with poor prognosis and high mortality rates. The increasing mortality associated with HCC highlights the urgent need for alternative therapeutic approaches. Natural products and their structural analogs have shown promise as novel treatment options. This study aimed to evaluate the potential therapeutic effects of the natural flavonoids apigenin and chrysin, administered individually and in combination, in an experimental HCC model.\n                    <jats:italic>Forty\u2010eight<\/jats:italic>\n                    rats were divided into five groups: Control, DEN, DEN\u2009+\u2009Apigenin, DEN\u2009+\u2009Chrysin, and DEN\u2009+\u2009Combination. HCC was induced by intraperitoneal administration of diethylnitrosamine (DEN, 150\u2009mg\/kg), followed by oral 2\u2010acetylaminofluorene (2\u2010AAF, 20\u2009mg\/kg) according to a standardized protocol. Subsequently, Apigenin and chrysin were administered orally at 50\u2009mg\/kg for 8 weeks following tumor induction. At the end of the treatment, biochemical and histopathological analyses were performed on blood and liver tissue samples. Compared to controls, DEN\u2010induced HCC was associated with activation of tumor\u2010promoting signaling pathways, as evidenced by increased levels of survivin, annexin\u2010V, smoothened, sonic hedgehog, jagged1, and notch1, alongside reduced caspase\u20103 expression. Histological examination revealed normal liver architecture in controls, while DEN\u2010treated rats showed varying degrees of fibrosis (62.5% moderate to severe), inflammatory lesions, regenerative nodules, and 87.5% moderate to severe inflammation. Treatment groups displayed marked reductions in fibrosis and inflammation, with the most pronounced effects observed in DEN\u2009+\u2009Apigenin and combination groups. These findings suggest that apigenin, chrysin, and their combination may exert antitumor effects in experimental HCC, with apigenin demonstrating comparatively more pronounced activity based on biochemical and histopathological findings.\n                  <\/jats:p>","DOI":"10.1002\/jbt.70998","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T13:26:34Z","timestamp":1782393994000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Potential Therapeutic Effects of Chrysin and Apigenin in a Diethylnitrosamine\u2010Induced Hepatocellular Carcinoma Rat Model"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3572-0270","authenticated-orcid":false,"given":"Fatma","family":"Tedik","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry Kahramanmara\u015f Necip Faz\u0131l City Hospital Kahramanmara\u015f Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0208-8929","authenticated-orcid":false,"given":"Nevin","family":"\u0130lhan","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Faculty of Medicine, Firat University Elazig Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7503-2416","authenticated-orcid":false,"given":"Solmaz","family":"Bodur","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Faculty of Medicine, Adiyaman University Adiyaman Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5507-7983","authenticated-orcid":false,"given":"Buket","family":"Berk","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Faculty of Medicine, Firat University Elazig Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8407-5792","authenticated-orcid":false,"given":"Hatice","family":"Er\u00f6ks\u00fcz","sequence":"additional","affiliation":[{"name":"Department of Pathology Faculty of Veterinary Medicine, Firat University Elazig Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21155461"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-021-08904-3"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12253-019-00585-5"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000484066"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/1934578X211067294"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-032-08530-6_8"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15164063"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-11641-7"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.4103\/0973-7847.134247"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2016.3282"},{"issue":"1","key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13046-017-0514-4","article-title":"Chrysin Inhibited Tumor Glycolysis and Induced Apoptosis in Hepatocellular Carcinoma by Targeting Hexokinase\u20102","volume":"36","author":"Xu D.","year":"2017","journal-title":"Journal of experimental & clinical cancer research: CR"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2011.11.013"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.2322"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.17827\/aktd.1267942"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.4014\/jmb.2201.01010"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14061160"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9404"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0217009"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2010.04.029"},{"issue":"5","key":"e_1_2_9_21_1","first-page":"113","article-title":"Ameliorative Effects of Quercetin and Naringenin on diethylnitrosamine\/2\u2010acetyl Aminoflourine\u2010Induced Nephrotoxicity in Male Wistar Rats","volume":"6","author":"Abdel\u2010Moneim A.","year":"2016","journal-title":"American Journal of Biochemistry"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1177\/1559325818789835"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.12275"},{"issue":"1","key":"e_1_2_9_24_1","first-page":"1","article-title":"Hedyotis Diffusa Willd. 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