{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T15:32:24Z","timestamp":1782747144693,"version":"3.54.5"},"reference-count":52,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T00:00:00Z","timestamp":1687564800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2020R1C1C1005500"],"award-info":[{"award-number":["2020R1C1C1005500"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Hepatic fibrosis is the first stage of liver disease, and can progress to a chronic status, such as cirrhosis or hepatocellular carcinoma. Excessive production of extracellular matrix (ECM) components plays an important role in the development of fibrosis. Mechanistically, transforming growth factor beta (TGF\u03b2)-induced phosphorylation of Smad is thought to be a key signaling pathway in the development of liver fibrosis. Although the natural isoquinoline alkaloid oxoglaucine (1,2,9,10-tetramethoxy-7H-dibenzo(de,g)quinolin-7-one) exerts numerous beneficial effects, including anti-cancer, anti-inflammatory, and anti-osteoarthritic effects in diverse cell types, the effects of oxoglaucine on liver fibrosis and fibrogenic gene expression have not been fully elucidated. The aim of this study is to evaluate the signaling pathway and antifibrotic activity of isoquinoline alkaloid oxoglaucine in TFG\u03b2-induced hepatic fibrosis in vitro. Using Hepa1c1c7 cells and primary hepatocytes, we demonstrated that oxoglaucine treatment resulted in inhibition of the expression of fibrosis markers such as collagen, fibronectin, and alpha-SMA. Subsequent experiments showed that oxoglaucine suppressed TGF\u03b2-induced phosphorylation of Smad2 and reactive oxygen species (ROS) generation, without altering cell proliferation. We further determined that the increase in Smad7 by oxoglaucine treatment is responsible for the inhibition of Smad2 phosphorylation and the anti-fibrogenic effects. These findings indicate that oxoglaucine plays a crucial role in suppression of fibrosis in hepatocytes, thereby making it a potential drug candidate for treatment of liver fibrosis.<\/jats:p>","DOI":"10.3390\/molecules28134971","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T05:11:54Z","timestamp":1687756314000},"page":"4971","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Oxoglaucine Suppresses Hepatic Fibrosis by Inhibiting TGF\u03b2-Induced Smad2 Phosphorylation and ROS Generation"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7664-593X","authenticated-orcid":false,"given":"Bakhovuddin","family":"Azamov","sequence":"first","affiliation":[{"name":"Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7691-5686","authenticated-orcid":false,"given":"Kwang-Min","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Life Science and Environmental Biochemistry, Life and Industry Convergence Research Institute, Pusan National University, Miryang 50463, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0692-0150","authenticated-orcid":false,"given":"Jin","family":"Hur","sequence":"additional","affiliation":[{"name":"Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4031-9088","authenticated-orcid":false,"given":"Shakhnoza","family":"Muradillaeva","sequence":"additional","affiliation":[{"name":"Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3881-9760","authenticated-orcid":false,"given":"Wan-Seog","family":"Shim","sequence":"additional","affiliation":[{"name":"Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0881-0609","authenticated-orcid":false,"given":"Chanhee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5004-3389","authenticated-orcid":false,"given":"Parkyong","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis","volume":"115","author":"Bataller","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12945","DOI":"10.3748\/wjg.v20.i36.12945","article-title":"Hepatocellular carcinoma in nonalcoholic fatty liver: Role of environmental and genetic factors","volume":"20","author":"Dongiovanni","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S38","DOI":"10.1016\/S0168-8278(02)00429-4","article-title":"Liver fibrosis\u2014From bench to bedside","volume":"38","author":"Friedman","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3181\/0707-MR-190","article-title":"Mechanisms of fibrogenesis","volume":"233","author":"Kisseleva","year":"2008","journal-title":"Exp. Biol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"671640","DOI":"10.3389\/fphar.2021.671640","article-title":"Cellular Mechanisms of Liver Fibrosis","volume":"12","author":"Acharya","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"C789","DOI":"10.1152\/ajpcell.00230.2013","article-title":"Cellular mechanisms of tissue fibrosis","volume":"305","author":"Mallat","year":"2013","journal-title":"5. Novel insights into liver fibrosis. Am. J. Physiol. Cell. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7879","DOI":"10.3892\/mmr.2017.7641","article-title":"PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics (Review)","volume":"16","author":"Ying","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2917","DOI":"10.1038\/s41401-022-00907-5","article-title":"Hepatocyte-derived VEGFA accelerates the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma via activating hepatic stellate cells","volume":"43","author":"Shen","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrneph.2016.48","article-title":"TGF-beta: The master regulator of fibrosis","volume":"12","author":"Meng","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1111\/resp.13415","article-title":"TGF-beta: Master regulator of inflammation and fibrosis","volume":"23","author":"Stewart","year":"2018","journal-title":"Respirology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"a022053","DOI":"10.1101\/cshperspect.a022053","article-title":"Signaling Receptors for TGF-beta Family Members","volume":"8","author":"Heldin","year":"2016","journal-title":"Cold Spring Harb. Perspect Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/S0002-9440(10)62324-3","article-title":"Transforming growth factor-beta and platelet-derived growth factor signal via c-Jun N-terminal kinase-dependent Smad2\/3 phosphorylation in rat hepatic stellate cells after acute liver injury","volume":"166","author":"Yoshida","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1101\/gad.1350705","article-title":"Smad transcription factors","volume":"19","author":"Massague","year":"2005","journal-title":"Genes Dev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10055","DOI":"10.1074\/jbc.M409381200","article-title":"SMAD and p38 MAPK signaling pathways independently regulate alpha1(I) collagen gene expression in unstimulated and transforming growth factor-beta-stimulated hepatic stellate cells","volume":"280","author":"Tsukada","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4850","DOI":"10.2174\/092986712803341520","article-title":"Role of oxidative stress and molecular changes in liver fibrosis: A review","volume":"19","author":"Uribe","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"12477","DOI":"10.1074\/jbc.C100008200","article-title":"Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation","volume":"276","author":"Ebisawa","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/39369","article-title":"Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling","volume":"389","author":"Heuchel","year":"1997","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4488","DOI":"10.1128\/MCB.01636-06","article-title":"Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formation","volume":"27","author":"Zhang","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1038\/sj.bjp.0702702","article-title":"Bronchodilator and anti-inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes","volume":"127","author":"Cortijo","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1021\/np9800046","article-title":"Antiplatelet aggregation constituents from Annona purpurea","volume":"61","author":"Chang","year":"1998","journal-title":"J. Nat. Prod."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1023\/A:1016479622383","article-title":"In vivo efficacy of antifungal oxoaporphine alkaloids in experimental disseminated candidiasis","volume":"4","author":"Clark","year":"1987","journal-title":"Pharm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11408","DOI":"10.1039\/C5DT00926J","article-title":"Water-soluble oxoglaucine-Y(III), Dy(III) complexes: In vitro and in vivo anticancer activities by triggering DNA damage, leading to S phase arrest and apoptosis","volume":"44","author":"Wei","year":"2015","journal-title":"Dalton. Trans."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1177\/1534734618819660","article-title":"The Effect of Parietin Isolated from Rheum ribes L on In Vitro Wound Model Using Human Dermal Fibroblast Cells","volume":"18","author":"Gundogdu","year":"2019","journal-title":"Int. J. Low Extrem. Wounds"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.ejphar.2007.02.033","article-title":"Emodin, an anthraquinone derivative from Rheum officinale Baill, enhances cutaneous wound healing in rats","volume":"567","author":"Tang","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.apsb.2019.04.003","article-title":"Emodin alleviates cardiac fibrosis by suppressing activation of cardiac fibroblasts via upregulating metastasis associated protein 3","volume":"9","author":"Xiao","year":"2019","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.fitote.2009.05.016","article-title":"Toll-like receptor-mediated anti-inflammatory action of glaucine and oxoglaucine","volume":"80","author":"Remichkova","year":"2009","journal-title":"Fitoterapia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2931","DOI":"10.1111\/bph.15466","article-title":"Oxoglaucine mediates Ca(2+) influx and activates autophagy to alleviate osteoarthritis through the TRPV5\/calmodulin\/CAMK-II pathway","volume":"178","author":"Zhong","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1006\/phrs.1996.9994","article-title":"Immunopharmacological activity of aporphinoid alkaloid oxoglaucine","volume":"35","author":"Ivanovska","year":"1997","journal-title":"Pharmacol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1172\/JCI88881","article-title":"Liver inflammation and fibrosis","volume":"127","author":"Koyama","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_30","first-page":"531","article-title":"Oxoglaucine-lanthanide complexes: Synthesis, crystal structure and cytotoxicity","volume":"34","author":"Liu","year":"2014","journal-title":"Anticancer. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"36803","DOI":"10.1074\/jbc.M005912200","article-title":"Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration","volume":"275","author":"Bakin","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_32","first-page":"628","article-title":"Involvement of extracellular signal-regulated kinase 2 and stress-activated protein kinase\/Jun N-terminal kinase activation by transforming growth factor beta in the negative growth control of breast cancer cells","volume":"57","author":"Frey","year":"1997","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17300","DOI":"10.1038\/s41598-020-74179-6","article-title":"Dermal fibroblasts have different extracellular matrix profiles induced by TGF-beta, PDGF and IL-6 in a model for skin fibrosis","volume":"10","author":"Juhl","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1002\/hep.27332","article-title":"Hepatic inflammation and fibrosis: Functional links and key pathways","volume":"61","author":"Seki","year":"2015","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.cell.2008.07.025","article-title":"TGF-beta: A master of all T cell trades","volume":"134","author":"Li","year":"2008","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.redox.2015.09.009","article-title":"Reciprocal regulation of TGF-beta and reactive oxygen species: A perverse cycle for fibrosis","volume":"6","author":"Liu","year":"2015","journal-title":"Redox. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1038\/ncb2329","article-title":"The AMPK signalling pathway coordinates cell growth, autophagy and metabolism","volume":"13","author":"Mihaylova","year":"2011","journal-title":"Nat. Cell. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1124\/mol.115.099549","article-title":"AMPK Inhibits the Stimulatory Effects of TGF-beta on Smad2\/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition","volume":"88","author":"Lin","year":"2015","journal-title":"Mol. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s00109-011-0748-0","article-title":"AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: Impact on healthspan and lifespan","volume":"89","author":"Salminen","year":"2011","journal-title":"J. Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"754976","DOI":"10.3389\/fphar.2021.754976","article-title":"Ferulic Acid Ameliorates Hepatic Inflammation and Fibrotic Liver Injury by Inhibiting PTP1B Activity and Subsequent Promoting AMPK Phosphorylation","volume":"12","author":"Wu","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s001090050374","article-title":"Differential regulation of transforming growth factor receptors by angiotensin II and transforming growth factor-beta1 in vascular smooth muscle","volume":"77","author":"Siegert","year":"1999","journal-title":"J. Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e410","DOI":"10.1002\/ctm2.410","article-title":"Rebalancing TGF-beta\/Smad7 signaling via Compound kushen injection in hepatic stellate cells protects against liver fibrosis and hepatocarcinogenesis","volume":"11","author":"Yang","year":"2021","journal-title":"Clin. Transl. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1074\/jbc.M115.694281","article-title":"Smad7 Protein Interacts with Receptor-regulated Smads (R-Smads) to Inhibit Transforming Growth Factor-beta (TGF-beta)\/Smad Signaling","volume":"291","author":"Yan","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"H2211-9","DOI":"10.1152\/ajpheart.00966.2011","article-title":"TGF-beta and Smad3 modulate PI3K\/Akt signaling pathway in vascular smooth muscle cells","volume":"302","author":"Suwanabol","year":"2012","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.tibs.2013.10.001","article-title":"Signaling interplay between transforming growth factor-beta receptor and PI3K\/AKT pathways in cancer","volume":"38","author":"Zhang","year":"2013","journal-title":"Trends Biochem. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.freeradbiomed.2019.01.026","article-title":"The influence of alkaloids on oxidative stress and related signaling pathways","volume":"134","author":"Afonso","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/s41418-019-0474-7","article-title":"Autophagy in cancer: Moving from understanding mechanism to improving therapy responses in patients","volume":"27","author":"Thorburn","year":"2020","journal-title":"Cell. Death Differ."},{"key":"ref_48","first-page":"5747","article-title":"The role of autophagy in hepatic fibrosis","volume":"13","author":"Sun","year":"2021","journal-title":"Am. J. Transl. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1080\/15548627.2015.1058473","article-title":"Macrophage autophagy protects against liver fibrosis in mice","volume":"11","author":"Lodder","year":"2015","journal-title":"Autophagy"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.jpba.2018.06.065","article-title":"Investigation of the hepatoprotective effect of Corydalis saxicola Bunting on carbon tetrachloride-induced liver fibrosis in rats by (1)H-NMR-based metabonomics and network pharmacology approaches","volume":"159","author":"Liu","year":"2018","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1111\/jcmm.16267","article-title":"PPARgamma\/NF-kappaB and TGF-beta1\/Smad pathway are involved in the anti-fibrotic effects of levo-tetrahydropalmatine on liver fibrosis","volume":"25","author":"Yu","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"100086","DOI":"10.1016\/j.xpro.2020.100086","article-title":"Protocol for Primary Mouse Hepatocyte Isolation","volume":"1","author":"Goldstein","year":"2020","journal-title":"STAR Protoc."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/13\/4971\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:59:55Z","timestamp":1760126395000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/13\/4971"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,24]]},"references-count":52,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["molecules28134971"],"URL":"https:\/\/doi.org\/10.3390\/molecules28134971","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,24]]}}}