{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T18:23:00Z","timestamp":1789064580046,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T00:00:00Z","timestamp":1652832000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019018","name":"CAMS Initiative for Innovative Medicine","doi-asserted-by":"publisher","award":["2021-1-I2M-030"],"award-info":[{"award-number":["2021-1-I2M-030"]}],"id":[{"id":"10.13039\/501100019018","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019018","name":"CAMS Initiative for Innovative Medicine","doi-asserted-by":"publisher","award":["81803592"],"award-info":[{"award-number":["81803592"]}],"id":[{"id":"10.13039\/501100019018","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019018","name":"CAMS Initiative for Innovative Medicine","doi-asserted-by":"publisher","award":["81630089"],"award-info":[{"award-number":["81630089"]}],"id":[{"id":"10.13039\/501100019018","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019018","name":"CAMS Initiative for Innovative Medicine","doi-asserted-by":"publisher","award":["2019-1007-10"],"award-info":[{"award-number":["2019-1007-10"]}],"id":[{"id":"10.13039\/501100019018","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2021-1-I2M-030"],"award-info":[{"award-number":["2021-1-I2M-030"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81803592"],"award-info":[{"award-number":["81803592"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81630089"],"award-info":[{"award-number":["81630089"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2019-1007-10"],"award-info":[{"award-number":["2019-1007-10"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2021-1-I2M-030"],"award-info":[{"award-number":["2021-1-I2M-030"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81803592"],"award-info":[{"award-number":["81803592"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81630089"],"award-info":[{"award-number":["81630089"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2019-1007-10"],"award-info":[{"award-number":["2019-1007-10"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Graduate Innovation Fund of Peking Union Medical College","award":["2021-1-I2M-030"],"award-info":[{"award-number":["2021-1-I2M-030"]}]},{"name":"Graduate Innovation Fund of Peking Union Medical College","award":["81803592"],"award-info":[{"award-number":["81803592"]}]},{"name":"Graduate Innovation Fund of Peking Union Medical College","award":["81630089"],"award-info":[{"award-number":["81630089"]}]},{"name":"Graduate Innovation Fund of Peking Union Medical College","award":["2019-1007-10"],"award-info":[{"award-number":["2019-1007-10"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Chronic hepatitis induced by hepatitis B virus (HBV) infection is a serious public health problem, leading to hepatic cirrhosis and liver cancer. Although the currently approved medications can reliably decrease the virus load and prevent the development of hepatic diseases, they fail to induce durable off-drug control of HBV replication in the majority of patients. The roots of Isatis indigotica Fortune ex Lindl., a traditional Chinese medicine, were frequently used for the prevention of viral disease in China. In the present study, (\u2212)-lariciresinol ((\u2212)-LRSL), isolated from the roots of Isatis indigotica Fortune ex Lindl., was found to inhibit HBV DNA replication of both wild-type and nucleos(t)ide analogues (NUCs)-resistant strains in vitro. Mechanism studies revealed that (\u2212)-LRSL could block RNA production after treatment, followed by viral proteins, and then viral particles and DNA. Promoter reporter assays and RNA decaying dynamic experiments indicated that (\u2212)-LRSL mediated HBV RNA reduction was mainly due to transcriptional inhibition rather than degradation. Moreover, (\u2212)-LRSL in a dose-dependent manner also inhibited other animal hepadnaviruses, including woodchuck hepatitis virus (WHV) and duck hepatitis B virus (DHBV). Combining the analysis of RNA-seq, we further found that the decrease in HBV transcriptional activity by (\u2212)-LRSL may be related to hepatocyte nuclear factor 1\u03b1 (HNF1\u03b1). Taken together, (\u2212)-LRSL represents a novel chemical entity that inhibits HBV replication by regulating HNF1\u03b1 mediated HBV transcription, which may provide a new perspective for HBV therapeutics.<\/jats:p>","DOI":"10.3390\/molecules27103223","type":"journal-article","created":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T23:14:26Z","timestamp":1652915666000},"page":"3223","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["(\u2212)-Lariciresinol Isolated from the Roots of Isatis indigotica Fortune ex Lindl. Inhibits Hepatitis B Virus by Regulating Viral Transcription"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4847-4868","authenticated-orcid":false,"given":"Lu","family":"Yang","sequence":"first","affiliation":[{"name":"CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Yan","sequence":"additional","affiliation":[{"name":"CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Wang","sequence":"additional","affiliation":[{"name":"CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Wu","sequence":"additional","affiliation":[{"name":"CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhuan","family":"Li","sequence":"additional","affiliation":[{"name":"CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1016\/j.jhep.2011.02.015","article-title":"Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection","volume":"55","author":"Lucifora","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1007\/s12072-017-9829-7","article-title":"Hepatitis B virus: Virology, molecular biology, life cycle and intrahepatic spread","volume":"11","author":"Karayiannis","year":"2017","journal-title":"Hepatol. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104925","DOI":"10.1016\/j.antiviral.2020.104925","article-title":"Hepatitis B virus biology and life cycle","volume":"182","author":"Tsukuda","year":"2020","journal-title":"Antiviral. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.1002\/med.21707","article-title":"Development of anti-influenza agents from natural products","volume":"40","author":"Zhang","year":"2020","journal-title":"Med. Res. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"112442","DOI":"10.1016\/j.jep.2019.112442","article-title":"Advances in anti hepatic fibrotic therapy with Traditional Chinese Medicine herbal formula","volume":"251","author":"Li","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e15297","DOI":"10.1097\/MD.0000000000015297","article-title":"Effect of Fufang Biejia Ruangan Tablet on lowering biochemical and virological parameters of hepatic fibrosis in patients with chronic hepatitis B: Protocol for a systematic review and meta-analysis of randomized controlled trials and cohort studies","volume":"98","author":"Huang","year":"2019","journal-title":"Medicine"},{"key":"ref_7","first-page":"775","article-title":"Entecavir combined with Fufang Biejia Ruangan tablet in treatment of chronic hepatitis B patients with liver fibrosis: 96-week efficacy analyses","volume":"36","author":"Yang","year":"2016","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao J. South. Med. Univ."},{"key":"ref_8","first-page":"1337","article-title":"Clinical effects of qianggan capsule on the liver tissue pathology and PDGF-BB, TGF-beta1, TIMP-1, and MMP-1 factors in patients with chronic hepatitis B","volume":"31","author":"Wang","year":"2011","journal-title":"Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi Chin. J. Integr. Tradit. West. Med."},{"key":"ref_9","first-page":"978","article-title":"Clinical and pathological study on effects of Qianggan Capsule combined lamivudine on hepatic fibrosis in patients with chronic hepatitis B","volume":"26","author":"Wang","year":"2006","journal-title":"Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi Chin. J. Integr. Tradit. West. Med"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"112782","DOI":"10.1016\/j.jep.2020.112782","article-title":"Antiviral activity of a polysaccharide from Radix Isatidis (Isatis indigotica Fortune) against hepatitis B virus (HBV) in vitro via activation of JAK\/STAT signal pathway","volume":"257","author":"Wang","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.jff.2015.08.026","article-title":"An arabinogalactan from Isatis indigotica and its adjuvant effects on H1N1 influenza and hepatitis B antigens","volume":"18","author":"Shan","year":"2015","journal-title":"J. Funct. Foods"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1093\/jpp\/rgab014","article-title":"Isatis indigotica: A review of phytochemistry, pharmacological activities and clinical applications","volume":"73","author":"Chen","year":"2021","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"188","DOI":"10.3748\/wjg.v22.i1.188","article-title":"Naturally derived anti-hepatitis B virus agents and their mechanism of action","volume":"22","author":"Wu","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s11101-021-09758-0","article-title":"Plant-derived lignans as potential antiviral agents: A systematic review","volume":"21","author":"Xu","year":"2021","journal-title":"Phytochem. Rev. Proc. Phytochem. Soc. Eur."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.antiviral.2007.12.011","article-title":"The role of helioxanthin in inhibiting human hepatitis B viral replication and gene expression by interfering with the host transcriptional machinery of viral promoters","volume":"77","author":"Tseng","year":"2008","journal-title":"Antiviral. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.fitote.2012.01.009","article-title":"Anti-HBV activities of Streblus asper and constituents of its roots","volume":"83","author":"Chen","year":"2012","journal-title":"Fitoterapia"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Turton, K.L., Meier-Stephenson, V., Badmalia, M.D., Coffin, C.S., and Patel, T.R. (2020). Host Transcription Factors in Hepatitis B Virus RNA Synthesis. Viruses, 12.","DOI":"10.3390\/v12020160"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8937","DOI":"10.1128\/JVI.75.19.8937-8948.2001","article-title":"Replication of the wild type and a natural hepatitis B virus nucleocapsid promoter variant is differentially regulated by nuclear hormone receptors in cell culture","volume":"75","author":"Tang","year":"2001","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1006\/viro.1999.0148","article-title":"Activation of promoters for cellular lipogenic genes by hepatitis B virus large surface protein","volume":"269","author":"Foo","year":"2000","journal-title":"Virology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1111\/jcmm.16137","article-title":"Neddylation inhibitor MLN4924 has anti-HBV activity via modulating the ERK-HNF1\u03b1-C\/EBP\u03b1-HNF4\u03b1 axis","volume":"25","author":"Xie","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"115131","DOI":"10.1016\/j.taap.2020.115131","article-title":"Baicalin down-regulating hepatitis B virus transcription depends on the liver-specific HNF4alpha-HNF1alpha axis","volume":"403","author":"Xia","year":"2020","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.lfs.2017.05.015","article-title":"Protocatechuic acid inhibits hepatitis B virus replication by activating ERK1\/2 pathway and down-regulating HNF4alpha and HNF1alpha in vitro","volume":"180","author":"Dai","year":"2017","journal-title":"Life Sci."},{"key":"ref_23","first-page":"1025","article-title":"Saikosaponin C exerts anti-HBV effects by attenuating HNF1\u03b1 and HNF4\u03b1 expression to suppress HBV pgRNA synthesis","volume":"68","author":"Pan","year":"2019","journal-title":"Inflamm. Res. Off. J. Eur. Histamine Res. Soc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.antiviral.2011.08.012","article-title":"The main hepatitis B virus (HBV) mutants resistant to nucleoside analogs are susceptible in vitro to non-nucleoside inhibitors of HBV replication","volume":"92","author":"Billioud","year":"2011","journal-title":"Antiviral. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1002\/jmr.801","article-title":"BAY 41-4109 has multiple effects on Hepatitis B virus capsid assembly","volume":"19","author":"Stray","year":"2006","journal-title":"J. Mol. Recognit."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6931","DOI":"10.1128\/JVI.00582-13","article-title":"Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids","volume":"87","author":"Campagna","year":"2013","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.antiviral.2017.11.009","article-title":"HBsAg mRNA degradation induced by a dihydroquinolizinone compound depends on the HBV posttranscriptional regulatory element","volume":"149","author":"Zhou","year":"2018","journal-title":"Antiviral. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Mao, R., Nie, H., Cai, D., Zhang, J., Liu, H., Yan, R., Cuconati, A., Block, T.M., Guo, J.T., and Guo, H. (2013). Inhibition of hepatitis B virus replication by the host zinc finger antiviral protein. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003494"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.jep.2015.08.037","article-title":"Lariciresinol-4-O-beta-D-glucopyranoside from the root of Isatis indigotica inhibits influenza A virus-induced pro-inflammatory response","volume":"174","author":"Li","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"867","DOI":"10.3892\/ijmm.2013.1274","article-title":"Antiviral activity of Isatis indigotica root-derived clemastanin B against human and avian influenza A and B viruses in vitro","volume":"31","author":"Yang","year":"2013","journal-title":"Int. J. Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1186\/s13287-019-1438-z","article-title":"The impact of hepatocyte nuclear factor-1alpha on liver malignancies and cell stemness with metabolic consequences","volume":"10","author":"Wang","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.jhep.2017.11.026","article-title":"The molecular functions of hepatocyte nuclear factors\u2014In and beyond the liver","volume":"68","author":"Lau","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7017","DOI":"10.3748\/wjg.v22.i31.7017","article-title":"Roles of hepatocyte nuclear factors in hepatitis B virus infection","volume":"22","author":"Kim","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1210\/jc.2003-031308","article-title":"Promoter-specific repression of hepatocyte nuclear factor (HNF)-1 beta and HNF-1 alpha transcriptional activity by an HNF-1 beta missense mutant associated with Type 5 maturity-onset diabetes of the young with hepatic and biliary manifestations","volume":"89","author":"Kitanaka","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5875","DOI":"10.1128\/JVI.76.12.5875-5881.2002","article-title":"Regulation of hepatocyte nuclear factor 1 activity by wild-type and mutant hepatitis B virus X proteins","volume":"76","author":"Li","year":"2002","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6908","DOI":"10.1128\/JVI.78.13.6908-6914.2004","article-title":"Regulation of hepatitis B virus core promoter by transcription factors HNF1 and HNF4 and the viral X protein","volume":"78","author":"Zheng","year":"2004","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1111\/j.1478-3231.2010.02423.x","article-title":"Hepatocyte metabolic signalling pathways and regulation of hepatitis B virus expression","volume":"31","author":"Shaul","year":"2011","journal-title":"Liv. Int."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Lin, J., Gu, C., Shen, Z., Liu, Y., Wang, W., Tao, S., Cui, X., Liu, J., and Xie, Y. (2017). Hepatocyte nuclear factor 1alpha downregulates HBV gene expression and replication by activating the NF-kappaB signaling pathway. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174017"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12297","DOI":"10.1021\/jf404292w","article-title":"Structure-plant growth inhibitory activity relationship of lariciresinol","volume":"61","author":"Yamauchi","year":"2013","journal-title":"J. Agric. Food Chem."},{"key":"ref_40","first-page":"688","article-title":"Studies on chemical constituents in root of Isatis indigotica","volume":"32","author":"Zuo","year":"2007","journal-title":"China J. Chin. Mater. Med."},{"key":"ref_41","first-page":"1193","article-title":"Chemical constituents from water extract of Radix isatidis","volume":"41","author":"He","year":"2006","journal-title":"Acta Pharm. Sin."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1002\/jmv.20453","article-title":"High replicative full-length lamivudine-resistant hepatitis B virus isolated during acute exacerbations","volume":"77","author":"Zhang","year":"2005","journal-title":"J. Med. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12472","DOI":"10.1128\/JVI.01123-07","article-title":"Characterization of the intracellular deproteinized relaxed circular DNA of hepatitis B virus: An intermediate of covalently closed circular DNA formation","volume":"81","author":"Guo","year":"2007","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1128\/JVI.77.3.1885-1893.2003","article-title":"Conditional replication of duck hepatitis B virus in hepatoma cells","volume":"77","author":"Guo","year":"2003","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Wang, Y.X., Yang, L., Wang, H.Q., Zhao, X.Q., Liu, T., Li, Y.H., Zeng, Q.X., Li, Y.H., and Song, D.Q. (2018). Synthesis and Evolution of Berberine Derivatives as a New Class of Antiviral Agents against Enterovirus 71 through the MEK\/ERK Pathway and Autophagy. Molecules, 23.","DOI":"10.3390\/molecules23082084"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/10\/3223\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:14:06Z","timestamp":1760138046000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/10\/3223"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,18]]},"references-count":45,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["molecules27103223"],"URL":"https:\/\/doi.org\/10.3390\/molecules27103223","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,18]]}}}