{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T18:56:28Z","timestamp":1792695388983,"version":"4.5.0"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81703921 81973800"],"award-info":[{"award-number":["81703921 81973800"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Liver fibrosis is a progressive liver damage condition caused by various factors and may progress toward liver cirrhosis, and even hepatocellular carcinoma. Many studies have found that the disfunction in metabolism could contribute to the development of liver fibrosis. Geniposide, derived from <jats:italic>Gardenia jasminoides<\/jats:italic> J. Ellis, has been demonstrated with therapeutic effects on liver fibrosis. However, the exact molecular mechanisms of such liver-protection remain largely unknown. The aim of this study was to explored the effect of geniposide on metabolic regulations in liver fibrosis. We used carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) to construct a mouse model of liver fibrosis and subsequently administered geniposide treatment. Therapeutic effects of geniposide on liver fibrosis were accessed through measuring the levels of hepatic enzymes in serum and the pathological changes in liver. We also investigated the effects of geniposide on inflammatory response, oxidative stress and apoptosis in liver. Furthermore, serum untargeted metabolomics were used to explore the metabolic regulatory mechanisms behind geniposide on liver fibrosis. Our results demonstrated that geniposide could reduce the levels of hepatic enzymes in serum and ameliorate the pathological changes in liver fibrosis mice. Geniposide enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased methane dicarboxylic aldehyde (MDA) levels in liver. Geniposide treatment also decreased the levels of interleukin (IL)-6, IL-1\u03b2, and tumor necrosis factor-alpha (TNF-a) in liver tissue homogenate. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining demonstrated that geniposide could reduce the apoptosis of hepatocytes. Geniposide increased the protein expression of B-cell lymphoma-2 (Bcl-2) and downregulated the protein expression of Bcl-2 Associated X (Bax), cleaved-Caspase 3, and cleaved-Caspase 9. Serum untargeted metabolomics analysis demonstrated that geniposide treatment improved the metabolic disorders including glycerophospholipid metabolism, arginine and proline metabolism, and arachidonic acid (AA) metabolism. In conclusion, our study demonstrated the protective effects of geniposide on liver fibrosis. We found that geniposide could treat liver fibrosis by inhibiting oxidative stress, reducing inflammatory response and apoptosis in the liver, and modulating glycerophospholipid, and arginine, proline, and AA metabolism processes.<\/jats:p>","DOI":"10.3389\/fphar.2021.772635","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T16:38:29Z","timestamp":1638290309000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":52,"title":["Geniposide Ameliorates Liver Fibrosis Through Reducing Oxidative Stress and Inflammatory Respose, Inhibiting Apoptosis and Modulating Overall Metabolism"],"prefix":"10.3389","volume":"12","author":[{"given":"Lu","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenju","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huantian","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19779","DOI":"10.1038\/s41598-019-56320-2","article-title":"Assessment of the Hepatoprotective Effect of Developed Lipid-Polymer Hybrid Nanoparticles (LPHNPs) Encapsulating Naturally Extracted \u03b2-Sitosterol against CCl4 Induced Hepatotoxicity in Rats","volume":"9","author":"Abdou","year":"2019","journal-title":"Sci. Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/j.sjbs.2016.05.005","article-title":"Antioxidant Effects of Captopril against lead Acetate-Induced Hepatic and Splenic Tissue Toxicity in Swiss Albino Mice","volume":"23","author":"Aldahmash","year":"2016","journal-title":"Saudi J. Biol. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"41","DOI":"10.3390\/nu13010041","article-title":"Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence","volume":"13","author":"Aljobaily","year":"2020","journal-title":"Nutrients"},{"key":"B5","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1128\/CVI.00420-09","article-title":"Single Lysophosphatidylcholine Components Exhibit Adjuvant Activities In Vitro and In Vivo","volume":"17","author":"Bach","year":"2010","journal-title":"Clin. Vaccin. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"12","DOI":"10.2174\/1389557515666150722102613","article-title":"Creatine and the Liver: Metabolism and Possible Interactions","volume":"16","author":"Barcelos","year":"2016","journal-title":"Mini Rev. Med. Chem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1023\/a:1027356412399","article-title":"Effect of Pentoxifylline on Arachidonic Acid Metabolism, Neutral Lipid Synthesis and Accumulation during Induction of the Lipocyte Phenotype by Retinol in Murine Hepatic Stellate Cell","volume":"254","author":"Cardoso","year":"2003","journal-title":"Mol. Cel Biochem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e76233","DOI":"10.1371\/journal.pone.0076233","article-title":"Lysophosphatidylcholine Triggers TLR2- and TLR4-Mediated Signaling Pathways but Counteracts LPS-Induced NO Synthesis in Peritoneal Macrophages by Inhibiting NF-\u03baB Translocation and MAPK\/ERK Phosphorylation","volume":"8","author":"Carneiro","year":"2013","journal-title":"PLoS One"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1182\/blood-2008-04-149831","article-title":"Inflammation-associated Lysophospholipids as Ligands for CD1d-Restricted T Cells in Human Cancer","volume":"112","author":"Chang","year":"2008","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","first-page":"156","DOI":"10.4062\/biomolther.2015.094","article-title":"Comparative Evaluation of Hepatoprotective Activities of Geniposide, Crocins and Crocetin by CCl4-Induced Liver Injury in Mice","volume":"24","author":"Chen","year":"2016","journal-title":"Biomol. Ther. (Seoul)"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2","DOI":"10.12032\/TMRPR20210217002","article-title":"Liver Fibrosis in Mice Treated with Yue-Ju-Bao-He Pills","volume":"1","author":"Chen","year":"2021","journal-title":"TMR Pharmacol. Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1016\/j.cgh.2020.05.008","article-title":"Effects of Tenofovir vs Entecavir on Risk of Hepatocellular Carcinoma in Patients with Chronic HBV Infection: A Systematic Review and Meta-Analysis","volume":"19","author":"Choi","year":"2021","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"858","DOI":"10.3389\/fphar.2020.00858","article-title":"Untargeted Metabolomic Analysis of the Effects and Mechanism of Nuciferine Treatment on Rats with Nonalcoholic Fatty Liver Disease","volume":"11","author":"Cui","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2","DOI":"10.53388\/tmr20200920199","article-title":"Omics Technology: an Important Tool in Mechanism Studies of Chinese Herbal Formulas","volume":"6","author":"Cui","year":"2021","journal-title":"Tradit. Med. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1007\/s00726-016-2172-9","article-title":"Creatine Supplementation Prevents Hyperhomocysteinemia, Oxidative Stress and Cancer-Induced Cachexia Progression in Walker-256 Tumor-Bearing Rats","volume":"48","author":"Deminice","year":"2016","journal-title":"Amino Acids"},{"key":"B16","doi-asserted-by":"publisher","first-page":"295","DOI":"10.12816\/0006468","article-title":"Pharmacological and Antioxidant Actions of Garlic and.or Onion in Non-alcoholic Fatty Liver Disease (NAFLD) in Rats","volume":"44","author":"El-Din","year":"2014","journal-title":"J. Egypt. Soc. Parasitol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1007\/s11684-019-0709-5","article-title":"High-throughput Metabolomics Reveals the Perturbed Metabolic Pathways and Biomarkers of Yang Huang Syndrome as Potential Targets for Evaluating the Therapeutic Effects and Mechanism of Geniposide","volume":"14","author":"Fang","year":"2020","journal-title":"Front. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.3390\/ijms18061149","article-title":"Strawberry (Cv. Romina) Methanolic Extract and Anthocyanin-Enriched Fraction Improve Lipid Profile and Antioxidant Status in HepG2 Cells","volume":"18","author":"Forbes-Hern\u00e1ndez","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1007\/s00535-012-0527-x","article-title":"Inflammation and Fibrogenesis in Steatohepatitis","volume":"47","author":"Fujii","year":"2012","journal-title":"J. Gastroenterol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1124\/mol.117.111047","article-title":"Effects of Farnesoid X Receptor Activation on Arachidonic Acid Metabolism, NF-kB Signaling, and Hepatic Inflammation","volume":"94","author":"Gai","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.cca.2020.07.039","article-title":"Cell Metabolic Profiling of Colorectal Cancer via 1H NMR","volume":"510","author":"Ge","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.3390\/ijerph16081440","article-title":"Protective Effects of Ammannia Baccifera against CCl4-Induced Oxidative Stress in Rats","volume":"16","author":"Goodla","year":"2019","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B23","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1517\/14728222.11.4.515","article-title":"Therapeutic Targets in the Mitochondrial Apoptotic Pathway","volume":"11","author":"H\u00e4cker","year":"2007","journal-title":"Expert Opin. Ther. Targets"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1080\/15548627.2016.1235124","article-title":"Autophagy Induced by AXL Receptor Tyrosine Kinase Alleviates Acute Liver Injury via Inhibition of NLRP3 Inflammasome Activation in Mice","volume":"12","author":"Han","year":"2016","journal-title":"Autophagy"},{"key":"B25","doi-asserted-by":"publisher","first-page":"9014","DOI":"10.3390\/ijms13079014","article-title":"Hepatoprotective Effects of Berberis Vulgaris L. Extract\/\u03b2 Cyclodextrin on Carbon Tetrachloride-Induced Acute Toxicity in Mice","volume":"13","author":"Hermenean","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"9636897211002762","DOI":"10.1177\/09636897211002762","article-title":"Telocytes Enhances M1 Differentiation and Phagocytosis while Inhibits Mitochondria-Mediated Apoptosis via Activation of NF-\u03baB in Macrophages","volume":"30","author":"Huang","year":"2021","journal-title":"Cel Transpl."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1002\/ptr.6329","article-title":"Morin Enhances Auranofin Anticancer Activity by Up-Regulation of DR4 and DR5 and Modulation of Bcl-2 through Reactive Oxygen Species Generation in Hep3B Human Hepatocellular Carcinoma Cells","volume":"33","author":"Hwang-Bo","year":"2019","journal-title":"Phytother. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"G1083","DOI":"10.1152\/ajpgi.00568.2005","article-title":"Mechanisms of Liver Injury. II. Mechanisms of Neutrophil-Induced Liver Cell Injury during Hepatic Ischemia-Reperfusion and Other Acute Inflammatory Conditions","volume":"290","author":"Jaeschke","year":"2006","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1126\/science.1061781","article-title":"Lysophosphatidylcholine as a Ligand for the Immunoregulatory Receptor G2A","volume":"293","author":"Kabarowski","year":"2001","journal-title":"Science"},{"key":"B30","doi-asserted-by":"publisher","first-page":"45","DOI":"10.5142\/jgr.2013.37.45","article-title":"Red Ginseng Extract Protects against Carbon Tetrachloride-Induced Liver Fibrosis","volume":"37","author":"Ki","year":"2013","journal-title":"J. Ginseng Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1080\/14767050802556075","article-title":"Lysophosphatidylcholine Induces Endothelial Cell Injury by Nitric Oxide Production through Oxidative Stress","volume":"22","author":"Kim","year":"2009","journal-title":"J. Matern. Fetal. Neonatal. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/1746-6148-9-123","article-title":"Multiparametric and Semiquantitative Scoring Systems for the Evaluation of Mouse Model Histopathology-Aa Systematic Review","volume":"9","author":"Klopfleisch","year":"2013","journal-title":"BMC Vet. Res."},{"key":"B78","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1016\/j.cca.2011.04.013","article-title":"The Role of Oxidative Stress in Non-Alcoholic Steatohepatitis","volume":"412","author":"Koek","year":"2011","journal-title":"Clin Chim Acta."},{"key":"B33","doi-asserted-by":"publisher","first-page":"8189","DOI":"10.3390\/molecules19068189","article-title":"Standardized Salvia Miltiorrhiza Extract Suppresses Hepatic Stellate Cell Activation and Attenuates Steatohepatitis Induced by a Methionine-Choline Deficient Diet in Mice","volume":"19","author":"Lee","year":"2014","journal-title":"Molecules"},{"key":"B34","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.cmet.2006.03.007","article-title":"The Ratio of Phosphatidylcholine to Phosphatidylethanolamine Influences Membrane Integrity and Steatohepatitis","volume":"3","author":"Li","year":"2006","journal-title":"Cell Metab."},{"key":"B35","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.jpba.2016.06.033","article-title":"Serum Metabonomics Study of the Hepatoprotective Effect of Corydalis Saxicola Bunting on Carbon Tetrachloride-Induced Acute Hepatotoxicity in Rats by (1)H NMR Analysis","volume":"129","author":"Liang","year":"2016","journal-title":"J. Pharm. Biomed. Anal."},{"key":"B36","doi-asserted-by":"publisher","first-page":"38","DOI":"10.12032\/TMR2021033122710.53388\/tmr20210331227","article-title":"Pharmacological Research Progress of Ursolic Acid for the Treatment of Liver Diseases","volume":"6","author":"Liang","year":"2021","journal-title":"Tradit. Med. Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1016\/j.jhep.2013.05.007","article-title":"Reversal of Cirrhosis: an Achievable Goal of Hepatitis B Antiviral Therapy","volume":"59","author":"Liaw","year":"2013","journal-title":"J. Hepatol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"675201","DOI":"10.1155\/2015\/675201","article-title":"Polysaccharides from Enteromorpha Prolifera Improve Glucose Metabolism in Diabetic Rats","volume":"2015","author":"Lin","year":"2015","journal-title":"J. Diabetes Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.intimp.2019.04.016","article-title":"Geniposide, a Sonic Hedgehog Signaling Inhibitor, Inhibits the Activation of Hepatic Stellate Cell","volume":"72","author":"Lin","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"B40","doi-asserted-by":"publisher","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 1H-NMR-Based Metabonomics and Network Pharmacology Approaches","volume":"159","author":"Liu","year":"2018","journal-title":"J. Pharm. Biomed. Anal."},{"key":"B41","doi-asserted-by":"publisher","first-page":"117443","DOI":"10.1016\/j.lfs.2020.117443","article-title":"The Mechanisms of Lysophosphatidylcholine in the Development of Diseases","volume":"247","author":"Liu","year":"2020","journal-title":"Life Sci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"6053727","DOI":"10.1155\/2018\/6053727","article-title":"Geniposide Protects against Obesity-Related Cardiac Injury through AMPK\u03b1- and Sirt1-dependent Mechanisms","volume":"2018","author":"Ma","year":"2018","journal-title":"Oxid. Med. Cel Longev."},{"key":"B43","doi-asserted-by":"publisher","first-page":"344","DOI":"10.3389\/fphar.2016.00344","article-title":"Hepatoprotective Effect and Chemical Assessment of a Selected Egyptian Chickpea Cultivar","volume":"7","author":"Mekky","year":"2016","journal-title":"Front. Pharmacol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.3390\/cells8111311","article-title":"Roles of the Hepatic Endocannabinoid and Apelin Systems in the Pathogenesis of Liver Fibrosis","volume":"8","author":"Melgar-Lesmes","year":"2019","journal-title":"Cells"},{"key":"B45","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.tibs.2013.12.006","article-title":"Many Players in BCL-2 Family Affairs","volume":"39","author":"Moldoveanu","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1016\/s0891-5849(03)00465-9","article-title":"Effect of Olive Oil Minor Components on Oxidative Stress and Arachidonic Acid Mobilization and Metabolism by Macrophages RAW 264.7","volume":"35","author":"Moreno","year":"2003","journal-title":"Free Radic. Biol. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2044","DOI":"10.1074\/jbc.M507867200","article-title":"Proline Oxidase, a Proapoptotic Gene, Is Induced by Troglitazone: Evidence for Both Peroxisome Proliferator-Activated Receptor Gamma-dependent and -independent Mechanisms","volume":"281","author":"Pandhare","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B49","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.biochi.2015.03.015","article-title":"Effects of Geniposide on Hepatocytes Undergoing Epithelial-Mesenchymal Transition in Hepatic Fibrosis by Targeting TGF\u03b2\/Smad and ERK-MAPK Signaling Pathways","volume":"113","author":"Park","year":"2015","journal-title":"Biochimie"},{"key":"B50","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s11010-018-3339-3","article-title":"Effect of Diosmin on Apoptotic Signaling Molecules in N-Nitrosodiethylamine-Induced Hepatocellular Carcinoma in Experimental Rats","volume":"449","author":"Perumal","year":"2018","journal-title":"Mol. Cel Biochem."},{"key":"B51","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.jconrel.2020.02.049","article-title":"Hyperbranched Lipoid-Based Lipid Nanoparticles for Bidirectional Regulation of Collagen Accumulation in Liver Fibrosis","volume":"321","author":"Qiao","year":"2020","journal-title":"J. Control. Release"},{"key":"B52","doi-asserted-by":"publisher","first-page":"108760","DOI":"10.18632\/oncotarget.21897","article-title":"Dissect New Mechanistic Insights for Geniposide Efficacy on the Hepatoprotection Using Multiomics Approach","volume":"8","author":"Qiu","year":"2017","journal-title":"Oncotarget"},{"key":"B53","doi-asserted-by":"publisher","first-page":"17523","DOI":"10.1038\/s41598-020-73721-w","article-title":"Evaluation of the Antitumor Effects of PP242 in a colon Cancer Xenograft Mouse Model Using Comprehensive Metabolomics and Lipidomics","volume":"10","author":"Rashid","year":"2020","journal-title":"Sci. Rep."},{"key":"B54","doi-asserted-by":"publisher","first-page":"3284","DOI":"10.1021\/acs.jproteome.5b00307","article-title":"NMR Metabolomics Show Evidence for Mitochondrial Oxidative Stress in a Mouse Model of Polycystic Ovary Syndrome","volume":"14","author":"Selen","year":"2015","journal-title":"J. Proteome Res."},{"key":"B55","doi-asserted-by":"publisher","first-page":"483","DOI":"10.3389\/fphar.2020.00483","article-title":"Hepatoprotective and Anti-Oxidative Effects of Total Flavonoids from Qu Zhi Qiao (Fruit of Citrus Paradisi cv.Changshanhuyou) on Nonalcoholic Steatohepatitis In Vivo and In Vitro through Nrf2-ARE Signaling Pathway","volume":"11","author":"Shi","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.bbalip.2019.02.004","article-title":"Hepatic Stellate Cell Activation: A Source for Bioactive Lipids","volume":"1864","author":"Shmarakov","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Cel Biol. Lipids"},{"key":"B57","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1055\/s-0029-1186197","article-title":"Luteolin Inhibits Lysophosphatidylcholine-Induced Apoptosis in Endothelial Cells by a Calcium\/mitocondrion\/caspases-dependent Pathway","volume":"76","author":"Song","year":"2010","journal-title":"Planta Med."},{"key":"B58","doi-asserted-by":"publisher","first-page":"e0173598","DOI":"10.1371\/journal.pone.0173598","article-title":"Metabolomic Mechanisms of Gypenoside against Liver Fibrosis in Rats: An Integrative Analysis of Proteomics and Metabolomics Data","volume":"12","author":"Song","year":"2017","journal-title":"PLoS One"},{"key":"B59","doi-asserted-by":"publisher","first-page":"3285","DOI":"10.3390\/ijms19113285","article-title":"Arachidonic Acid Metabolites in Cardiovascular and Metabolic Diseases","volume":"19","author":"Sonnweber","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B60","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.fct.2018.07.048","article-title":"Anthocyanins Isolated from Blueberry Ameliorates CCl4 Induced Liver Fibrosis by Modulation of Oxidative Stress, Inflammation and Stellate Cell Activation in Mice","volume":"120","author":"Sun","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1038\/nrm2952","article-title":"Mitochondria and Cell Death: Outer Membrane Permeabilization and beyond","volume":"11","author":"Tait","year":"2010","journal-title":"Nat. Rev. Mol. Cel Biol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"3061","DOI":"10.3892\/or.2015.3942","article-title":"Cantharidin Inhibits Cell Proliferation and Promotes Apoptosis in Tongue Squamous Cell Carcinoma through Suppression of miR-214 and Regulation of P53 and Bcl-2\/Bax","volume":"33","author":"Tian","year":"2015","journal-title":"Oncol. Rep."},{"key":"B63","doi-asserted-by":"publisher","first-page":"1964","DOI":"10.3390\/molecules24101964","article-title":"Zerumbone Protects against Carbon Tetrachloride (CCl4)-Induced Acute Liver Injury in Mice via Inhibiting Oxidative Stress and the Inflammatory Response: Involving the TLR4\/NF-\u03baB\/COX-2 Pathway","volume":"24","author":"Wang","year":"2019","journal-title":"Molecules"},{"key":"B64","doi-asserted-by":"publisher","first-page":"8890182","DOI":"10.1155\/2020\/8890182","article-title":"Kang-Xian Pills Inhibit Inflammatory Response and Decrease Gut Permeability to Treat Carbon Tetrachloride-Induced Chronic Hepatic Injury through Modulating Gut Microbiota","volume":"2020","author":"Wang","year":"2020","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"B65","doi-asserted-by":"publisher","first-page":"3799","DOI":"10.1002\/ptr.7086","article-title":"Geniposide Suppresses Liver Injury in a Mouse Model of DDC-Induced Sclerosing Cholangitis","volume":"35","author":"Wen","year":"2021","journal-title":"Phytother. Res."},{"key":"B66","doi-asserted-by":"publisher","first-page":"119","DOI":"10.3892\/ijmm.2014.1777","article-title":"PE-induced A-poptosis in SMMC-7721 C-ells: I-nvolvement of Erk and Stat S-ignalling P-athways","volume":"34","author":"Xue","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"B67","doi-asserted-by":"publisher","first-page":"7299","DOI":"10.3748\/wjg.v26.i46.7299","article-title":"Untargeted Metabolomics Characteristics of Nonobese Nonalcoholic Fatty Liver Disease Induced by High-Temperature-Processed Feed in Sprague-Dawley Rats","volume":"26","author":"Xue","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"963","DOI":"10.3389\/fmicb.2018.00963","article-title":"Splenectomy Leads to Amelioration of Altered Gut Microbiota and Metabolome in Liver Cirrhosis Patients","volume":"9","author":"Liu","year":"2018","journal-title":"Front. Microbiol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"30","DOI":"10.53388\/tmr20210316225","article-title":"Advances in Traditional Chinese Medicine for Liver Disease Therapy in 2020","volume":"6","author":"Yang","year":"2021","journal-title":"Tradit. Med. Res."},{"key":"B70","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.3389\/fphys.2019.01421","article-title":"Liver Cirrhosis Patients Who Had Normal Liver Function before Liver Cirrhosis Development Have the Altered Metabolic Profiles before the Disease Occurrence Compared to Healthy Controls","volume":"10","author":"Yoo","year":"2019","journal-title":"Front. Physiol."},{"key":"B71","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1007\/s10571-019-00749-6","article-title":"Geniposide Alleviates Traumatic Brain Injury in Rats via Anti-inflammatory Effect and MAPK\/NF-kB Inhibition","volume":"40","author":"Yuan","year":"2020","journal-title":"Cell Mol. Neurobiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"134749","DOI":"10.1016\/j.neulet.2020.134749","article-title":"Geniposide Effectively Reverses Cognitive Impairment and Inhibits Pathological Cerebral Damage by Regulating the mTOR Signal Pathway in APP\/PS1 Mice","volume":"720","author":"Zhang","year":"2020","journal-title":"Neurosci. Lett."},{"key":"B72","doi-asserted-by":"publisher","first-page":"33340","DOI":"10.1038\/srep33340","article-title":"Oncogenic Mutations Differentially Affect Bax Monomer, Dimer, and Oligomeric Pore Formation in the Membrane","volume":"6","author":"Zhang","year":"2016","journal-title":"Sci. Rep."},{"key":"B73","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.jpba.2017.10.029","article-title":"Serum Metabonomics Study of the Hepatoprotective Effect of Amarogentin on CCl4-Induced Liver Fibrosis in Mice by GC-TOF-MS Analysis","volume":"149","author":"Zhang","year":"2018","journal-title":"J. Pharm. Biomed. Anal."},{"key":"B74","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1002\/iub.1704","article-title":"Ligustrazine Suppresses Neuron Apoptosis via the Bax\/Bcl-2 and Caspase-3 Pathway in PC12 Cells and in Rats with Vascular Dementia","volume":"70","author":"Zhao","year":"2018","journal-title":"IUBMB Life"},{"key":"B75","doi-asserted-by":"publisher","first-page":"1814","DOI":"10.1002\/jcp.22906","article-title":"Zearalenone Induces Apoptosis and Necrosis in Porcine Granulosa Cells via a Caspase-3- and Caspase-9-dependent Mitochondrial Signaling Pathway","volume":"227","author":"Zhu","year":"2012","journal-title":"J. Cel Physiol."},{"key":"B76","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ijbiomac.2019.03.043","article-title":"The Hepatoprotective Effect of Polysaccharides from Pleurotus Ostreatus on Carbon Tetrachloride-Induced Acute Liver Injury Rats","volume":"131","author":"Zhu","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"B77","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1186\/s12906-020-02957-w","article-title":"Hepatoprotective Effects and Mechanisms of Ixeris Denticulate Water Extract on Liver Cirrhosis in Experimental Rat","volume":"20","author":"Zhu","year":"2020","journal-title":"BMC Complement. Med. Ther."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.772635\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T16:38:37Z","timestamp":1638290317000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.772635\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,24]]},"references-count":77,"alternative-id":["10.3389\/fphar.2021.772635"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.772635","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,24]]},"article-number":"772635"}}