{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T05:32:30Z","timestamp":1777267950327,"version":"3.51.4"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T00:00:00Z","timestamp":1628121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Liver injury is a clinical disorder caused by toxins, drugs, and alcohol stimulation without effective therapeutic approaches thus far. Scutellarin (SCU), isolated from the edible herb <jats:italic>Erigeron breviscapus<\/jats:italic> (Vant.) Hand. -Mazz. showed potential hepatoprotective effects, but the mechanisms remain unknown. In this study, transcriptomics combined with nontargeted metabolomics and 16S rRNA amplicon sequencing were performed to elucidate the functional mechanisms of SCU in carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)\u2013induced liver injury in mice. The results showed that SCU exerted potential hepatoprotective effects against CCl<jats:sub>4<\/jats:sub>-induced liver injury by repressing CYP2E1 and I\u03baB\u03b1\/NF-\u03baB signaling pathways, modulating the gut microbiota (especially enriching <jats:italic>Lactobacillus<\/jats:italic>), and regulating the endogenous metabolites involved in lipid metabolism and bile acid homeostasis. SCU originates from a functional food that appears to be a promising agent to guard against liver injury.<\/jats:p>","DOI":"10.3389\/fphar.2021.710692","type":"journal-article","created":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T06:53:39Z","timestamp":1628146419000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":28,"title":["Protective Property of Scutellarin Against Liver Injury Induced by Carbon Tetrachloride in Mice"],"prefix":"10.3389","volume":"12","author":[{"given":"Zhimin","family":"Miao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Lai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingying","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingmin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianeng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1615\/JEnvironPatholToxicolOncol.2017019824","article-title":"The Hepatoprotective Effect of Clidemia Hirta against Carbon Tetrachloride (CCl4)-Induced Oxidative Stress and Hepatic Damage in Mice","volume":"36","author":"Amzar","year":"2017","journal-title":"J. Environ. Pathol. Toxicol. Oncol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"7489","DOI":"10.1038\/ncomms8489","article-title":"Ganoderma Lucidum Reduces Obesity in Mice by Modulating the Composition of the Gut Microbiota","volume":"6","author":"Chang","year":"2015","journal-title":"Nat. Commun."},{"key":"B3","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1002\/hep.29849","article-title":"DEP Domain-Containing mTOR-Interacting Protein Suppresses Lipogenesis and Ameliorates Hepatic Steatosis and Acute-On-Chronic Liver Injury in Alcoholic Liver Disease","volume":"68","author":"Chen","year":"2018","journal-title":"Hepatology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1016\/s0168-8278(02)00142-3","article-title":"Effect of Lactobacillus Johnsonii La1 and Antioxidants on Intestinal flora and Bacterial Translocation in Rats with Experimental Cirrhosis","volume":"37","author":"Chiva","year":"2002","journal-title":"J. Hepatol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.jhep.2018.02.005","article-title":"Apoptosis of Enterocytes and Nitration of Junctional Complex Proteins Promote Alcohol-Induced Gut Leakiness and Liver Injury","volume":"69","author":"Cho","year":"2018","journal-title":"J. Hepatol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"4194","DOI":"10.4049\/jimmunol.175.7.4194","article-title":"Cutting Edge: Bacterial Modulation of Epithelial Signaling via Changes in Neddylation of Cullin-1","volume":"175","author":"Collier-Hyams","year":"2005","journal-title":"J. Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"104353","DOI":"10.1016\/j.micpath.2020.104353","article-title":"Diverse Effects of Different Akkermansia Muciniphila Genotypes on Brown Adipose Tissue Inflammation and Whitening in a High-Fat-Diet Murine Model","volume":"147","author":"Deng","year":"2020","journal-title":"Microb. Pathogenesis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"104367","DOI":"10.1016\/j.phrs.2019.104367","article-title":"Gut Microbiota in Phytopharmacology: A Comprehensive Overview of Concepts, Reciprocal Interactions, Biotransformations and Mode of Actions","volume":"147","author":"Dey","year":"2019","journal-title":"Pharmacol. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/s41586-019-1742-x","article-title":"Bacteriophage Targeting of Gut Bacterium Attenuates Alcoholic Liver Disease","volume":"575","author":"Duan","year":"2019","journal-title":"Nature"},{"key":"B10","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1021\/jf8020199","article-title":"Effects of Elevated CO2 on grapevine (Vitis vinifera L.): Volatile Composition, Phenolic Content, and In Vitro Antioxidant Activity of Red Wine","volume":"57","author":"Gon\u00e7alves","year":"2009","journal-title":"J. Agric. Food Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1089\/jmf.2018.4357","article-title":"Lactobacillus Rhamnosus Granules Dose-Dependently Balance Intestinal Microbiome Disorders and Ameliorate Chronic Alcohol-Induced Liver Injury","volume":"23","author":"Gu","year":"2020","journal-title":"J. Med. Food"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e2000619","DOI":"10.1002\/cbdv.202000619","article-title":"Functional Food XingJiuTang Attenuates Alcohol\u2010Induced Liver Injury by Regulating SIRT1\/Nrf\u20102 Signaling Pathway","volume":"17","author":"Hao","year":"2020","journal-title":"Chem. Biodiversity"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1039\/c8fo01624k","article-title":"Characterization of Natural Melanin fromAuricularia Auriculaand its Hepatoprotective Effect on Acute Alcohol Liver Injury in Mice","volume":"10","author":"Hou","year":"2019","journal-title":"Food Funct."},{"key":"B14","doi-asserted-by":"publisher","first-page":"108612","DOI":"10.1016\/j.biopha.2019.108612","article-title":"Luteolin, a Flavonoid, as an Anticancer Agent: A Review","volume":"112","author":"Imran","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"B15","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1007\/s12602-020-09663-6","article-title":"Hepatoprotective Effect of Probiotic Lactic Acid Bacteria on Thioacetamide-Induced Liver Fibrosis in Rats","volume":"13","author":"Jantararussamee","year":"2021","journal-title":"Probiotics Antimicro. Prot."},{"key":"B16","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.molimm.2020.01.010","article-title":"Anti-inflammatory Effect of Acalypha Australis L. Via Suppression of NF-\u039ab Signaling in LPS-Stimulated RAW 264.7 Macrophages and LPS-Induced Septic Mice","volume":"119","author":"Kim","year":"2020","journal-title":"Mol. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1002\/hep.21221","article-title":"Favored T Helper 1 Response in a Mouse Model of Hepatosteatosis Is Associated with Enhanced T Cell-Mediated Hepatitis","volume":"44","author":"Kremer","year":"2006","journal-title":"Hepatology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1002\/hep.28289","article-title":"Inhibition of Hedgehog Signaling Ameliorates Hepatic Inflammation in Mice with Nonalcoholic Fatty Liver Disease","volume":"63","author":"Kwon","year":"2016","journal-title":"Hepatology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/s00299-007-0466-9","article-title":"Plant Regeneration of Erigeron Breviscapus (vant.) Hand. Mazz. And its Chromatographic Fingerprint Analysis for Quality Control","volume":"27","author":"Liu","year":"2007","journal-title":"Plant Cel Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"975","DOI":"10.3389\/fphar.2017.00975","article-title":"Scutellarin Suppresses NLRP3 Inflammasome Activation in Macrophages and Protects Mice against Bacterial Sepsis","volume":"8","author":"Liu","year":"2017","journal-title":"Front. Pharmacol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.mam.2017.06.002","article-title":"Interactions between Gut Bacteria and Bile in Health and Disease","volume":"56","author":"Long","year":"2017","journal-title":"Mol. Aspects Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/j.intimp.2015.06.036","article-title":"Quercetin Protects Mouse Liver against CCl4-Induced Inflammation by the TLR2\/4 and MAPK\/NF-\u03baB Pathway","volume":"28","author":"Ma","year":"2015","journal-title":"Int. Immunopharmacology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1096\/fj.14-259515","article-title":"Commensal Microbiota Is Hepatoprotective and Prevents Liver Fibrosis in Mice","volume":"29","author":"Mazagova","year":"2015","journal-title":"FASEB j."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2020\/8811021","article-title":"Scutellarein Aggravated Carbon Tetrachloride-Induced Chronic Liver Injury in Gut Microbiota-Dysbiosis Mice","volume":"2020","author":"Miao","year":"2020","journal-title":"Evidence-Based Complement. Altern. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1126\/science.1223813","article-title":"Host-gut Microbiota Metabolic Interactions","volume":"336","author":"Nicholson","year":"2012","journal-title":"Science"},{"key":"B26","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1042\/bst0140923","article-title":"Metabolism of Retinol in the Intestine and Liver","volume":"14","author":"Norum","year":"1986","journal-title":"Biochem. Soc. Trans."},{"key":"B27","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1124\/pr.111.005439","article-title":"Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy","volume":"65","author":"Obach","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.tox.2007.11.021","article-title":"The Current State of Serum Biomarkers of Hepatotoxicity","volume":"245","author":"Ozer","year":"2008","journal-title":"Toxicology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"111490","DOI":"10.1016\/j.fct.2020.111490","article-title":"Hepatoprotection of pine Nut Polysaccharide via NRF2\/ARE\/MKP1\/JNK Signaling Pathways against Carbon Tetrachloride-Induced Liver Injury in Mice","volume":"142","author":"Qu","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"111530","DOI":"10.1016\/j.biopha.2021.111530","article-title":"Polyphenol-rich Leaf of Aphanamixis Polystachya Averts Liver Inflammation, Fibrogenesis and Oxidative Stress in Ovariectomized Long-Evans Rats","volume":"138","author":"Rahman","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"B31","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1016\/j.cmet.2020.03.006","article-title":"Gut-Resident Lactobacilli Activate Hepatic Nrf2 and Protect against Oxidative Liver Injury","volume":"31","author":"Saeedi","year":"2020","journal-title":"Cel Metab."},{"key":"B32","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1007\/s10753-018-0898-0","article-title":"Saikosaponin B2 Suppresses Inflammatory Responses through IKK\/I\u03baB\u03b1\/NF-\u03baB Signaling Inactivation in LPS-Induced RAW 264.7 Macrophages","volume":"42","author":"Shin","year":"2019","journal-title":"Inflammation"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1002\/ptr.6641","article-title":"Protective Effects of Naringin against Drugs and Chemical Toxins Induced Hepatotoxicity: A Review","volume":"34","author":"Shirani","year":"2020","journal-title":"Phytotherapy Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.3390\/nu11061252","article-title":"Analysis of Health Benefits Conferred by Lactobacillus Species from Kefir","volume":"11","author":"Slattery","year":"2019","journal-title":"Nutrients"},{"key":"B35","doi-asserted-by":"publisher","first-page":"84","DOI":"10.3390\/ph13050084","article-title":"A Polyphenol-Rich Fraction from Eugenia Uniflora Exhibits Antioxidant and Hepatoprotective Activities In Vivo","volume":"13","author":"Sobeh","year":"2020","journal-title":"Pharmaceuticals"},{"key":"B36","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1053\/j.gastro.2019.04.023","article-title":"Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure","volume":"157","author":"Torres","year":"2019","journal-title":"Gastroenterology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/j.jhep.2018.03.011","article-title":"A Simple Diet- and Chemical-Induced Murine NASH Model with Rapid Progression of Steatohepatitis, Fibrosis and Liver Cancer","volume":"69","author":"Tsuchida","year":"2018","journal-title":"J. Hepatol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.cmet.2016.05.005","article-title":"Intestinal Crosstalk between Bile Acids and Microbiota and its Impact on Host Metabolism","volume":"24","author":"Wahlstr\u00f6m","year":"2016","journal-title":"Cel Metab."},{"key":"B39","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.chom.2016.01.003","article-title":"Intestinal REG3 Lectins Protect against Alcoholic Steatohepatitis by Reducing Mucosa-Associated Microbiota and Preventing Bacterial Translocation","volume":"19","author":"Wang","year":"2016","journal-title":"Cell Host & Microbe"},{"key":"B40","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.pharmthera.2018.05.006","article-title":"Clinical Benefits and Pharmacology of Scutellarin: A Comprehensive Review","volume":"190","author":"Wang","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e0138746","DOI":"10.1371\/journal.pone.0138746","article-title":"Amelioration of Chemotherapy-Induced Intestinal Mucositis by Orally Administered Probiotics in a Mouse Model","volume":"10","author":"Yeung","year":"2015","journal-title":"PLoS One"},{"key":"B42","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.intimp.2014.01.019","article-title":"Protective Effects of the Total Saponins from Dioscorea Nipponica Makino against Carbon Tetrachloride-Induced Liver Injury in Mice through Suppression of Apoptosis and Inflammation","volume":"19","author":"Yu","year":"2014","journal-title":"Int. Immunopharmacology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"eaax6208","DOI":"10.1126\/sciadv.aax6208","article-title":"Citrus Polymethoxyflavones Attenuate Metabolic Syndrome by Regulating Gut Microbiome and Amino Acid Metabolism","volume":"6","author":"Zeng","year":"2020","journal-title":"Sci. Adv."},{"key":"B44","doi-asserted-by":"publisher","first-page":"569104","DOI":"10.3389\/fimmu.2020.569104","article-title":"Bifidobacterium Animalis Ssp. Lactis 420 Mitigates Autoimmune Hepatitis through Regulating Intestinal Barrier and Liver Immune Cells","volume":"11","author":"Zhang","year":"2020","journal-title":"Front. Immunol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.3389\/fimmu.2018.01034","article-title":"Consumption of Goats' Milk Protects Mice from Carbon Tetrachloride-Induced Acute Hepatic Injury and Improves the Associated Gut Microbiota Imbalance","volume":"9","author":"Zhang","year":"2018","journal-title":"Front. Immunol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"112795","DOI":"10.1016\/j.jep.2020.112795","article-title":"Hepatoprotective Effects of Total Phenylethanoid Glycosides from Acanthus ilicifolius L. Against Carbon Tetrachloride-Induced Hepatotoxicity","volume":"256","author":"Zhang","year":"2020","journal-title":"J. Ethnopharmacology"},{"key":"B47","doi-asserted-by":"publisher","first-page":"112966","DOI":"10.1016\/j.jpba.2019.112966","article-title":"Xiaoyan Lidan Formula Ameliorates \u03b1-naphthylisothiocyanate-induced Intrahepatic Cholestatic Liver Injury in Rats as Revealed by Non-targeted and Targeted Metabolomics","volume":"179","author":"Zhang","year":"2020","journal-title":"J. Pharm. Biomed. Anal."},{"key":"B48","doi-asserted-by":"publisher","first-page":"106662","DOI":"10.1016\/j.intimp.2020.106662","article-title":"Salidroside Protects Mice against CCl4-Induced Acute Liver Injury via Down-Regulating CYP2E1 Expression and Inhibiting NLRP3 Inflammasome Activation","volume":"85","author":"Zhang","year":"2020","journal-title":"Int. Immunopharmacology"},{"key":"B49","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1016\/j.freeradbiomed.2020.10.320","article-title":"Hyperoside from Z. Bungeanum Leaves Restores Insulin Secretion and Mitochondrial Function by Regulating Pancreatic Cellular Redox Status in Diabetic Mice","volume":"162","author":"Zhang","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"B50","first-page":"315","article-title":"Protective Effects of Erigeron Breviscapus Hand.- Mazz. (EBHM) Extract in Retinal Neurodegeneration Models","volume":"24","author":"Zhu","year":"2018","journal-title":"Mol. Vis."},{"key":"B51","doi-asserted-by":"publisher","first-page":"152760","DOI":"10.1016\/j.phymed.2018.11.020","article-title":"Schisandra Fruits for the Management of Drug-Induced Liver Injury in China: A Review","volume":"59","author":"Zhu","year":"2019","journal-title":"Phytomedicine"},{"key":"B52","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.phrs.2015.09.013","article-title":"PAPep, a Small Peptide Derived from Human Pancreatitis-Associated Protein, Attenuates Corneal Inflammation In Vivo and In Vitro through the IKK\u03b1\/\u03b2\/I\u03baB\u03b1\/NF-\u039ab Signaling Pathway","volume":"102","author":"Zhu","year":"2015","journal-title":"Pharmacol. Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1038\/s41586-019-1291-3","article-title":"Mapping Human Microbiome Drug Metabolism by Gut Bacteria and Their Genes","volume":"570","author":"Zimmermann","year":"2019","journal-title":"Nature"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.710692\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T06:53:41Z","timestamp":1628146421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.710692\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,5]]},"references-count":53,"alternative-id":["10.3389\/fphar.2021.710692"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.710692","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,5]]},"article-number":"710692"}}