{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:06:04Z","timestamp":1792623964487,"version":"4.5.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000},"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","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>Cholestasis is caused by intrahepatic retention of excessive toxic bile acids and ultimately results in hepatic failure. Da-Chai-Hu-Tang (DCHT) has been used in China to treat liver and gallbladder diseases for over 1800 years. Here, we demonstrated that DCHT treatment prevented acute intrahepatic cholestasis with liver injury in response to \u03b1-naphthylisothiocyanate (ANIT) not to bile duct ligation (BDL) induced-extrahepatic cholestasis. ANIT (80\u00a0mg\/kg) increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBiL), total bilirubin (TBiL), and total bile acids (TBA) which was attenuated by DCHT treatment in a dose-dependent manner. DCHT treatment at high dose of 1.875\u00a0g\/kg restored bile acid homeostasis, as evidenced by the recovery of the transcription of genes implicated in bile acid biosynthesis, uptake and efflux. DCHT treatment (1.875\u00a0g\/kg) reversed ANIT-evoked disordered glutathione homeostasis (as determined by GSH\/GSSG ratio) and increased in the mRNA levels for <jats:italic>Il6<\/jats:italic>, <jats:italic>Il1b<\/jats:italic> and <jats:italic>Tnfa<\/jats:italic> associated with liver inflammation. Using network pharmacology-based approaches, we identified 22 putative targets involved in DCHT treatment for intrahepatic cholestasis not extrahepatic cholestasis. In addition, as evidenced by dual-luciferase reporter assays, compounds from DCHT with high affinity of PPAR\u03b1 increased luciferase levels from a PPAR\u03b1-driven reporter. PPAR\u03b1 agonist fenofibrate was able to mimic the cytoprotective effect of DCHT on intrahepatic cholestasis, which was abolished by the PPAR\u03b1 antagonist GW6471. KEGG enrichment and western blot analyses showed that signaling axes of JNK\/IL-6\/NF-\u03baB\/STAT3 related to PPAR\u03b1 might be the principal pathway DCHT affects intrahepatic cholestasis. Taken together, the present study provides compelling evidence that DCHT is a promising formula against acute intrahepatic cholestasis with hepatotoxicity which works <jats:italic>via<\/jats:italic> PPAR\u03b1 activation.<\/jats:p>","DOI":"10.3389\/fphar.2022.847483","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T09:12:12Z","timestamp":1647335532000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPAR\u03b1"],"prefix":"10.3389","volume":"13","author":[{"given":"Shihao","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peike","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoting","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyuan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinwei","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher G.","family":"Proud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianling","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaikai","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/j.freeradbiomed.2009.06.017","article-title":"Role of Peroxisome Proliferator-Activated Receptor-Alpha in Fasting-Mediated Oxidative Stress","volume":"47","author":"Abdelmegeed","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.smim.2013.12.004","article-title":"Inhibition of IL-6 Family Cytokines by SOCS3","volume":"26","author":"Babon","year":"2014","journal-title":"Semin. Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.ejcb.2011.09.008","article-title":"Hepatic Acute Phase Proteins-Rregulation by IL-6- and IL-1-type Cytokines Involving STAT3 and its Crosstalk with NF-\u03bab-dependent Signaling","volume":"91","author":"Bode","year":"2012","journal-title":"Eur. J. Cel Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"25900","DOI":"10.1074\/jbc.M707692200","article-title":"Interleukin (IL) 1beta Induction of IL-6 Is Mediated by a Novel Phosphatidylinositol 3-kinase-dependent AKT\/IkappaB Kinase Alpha Pathway Targeting Activator Protein-1","volume":"283","author":"Cahill","year":"2008","journal-title":"J. Biol. Chem."},{"key":"B5","doi-asserted-by":"publisher","first-page":"12530","DOI":"10.1074\/jbc.275.17.12530","article-title":"The Murine and Human Cholesterol 7alpha-Hydroxylase Gene Promoters Are Differentially Responsive to Regulation by Fatty Acids Mediated via Peroxisome Proliferator-Activated Receptor Alpha","volume":"275","author":"Cheema","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1955","DOI":"10.1194\/jlr.R900010-JLR200","article-title":"Bile Acids: Regulation of Synthesis","volume":"50","author":"Chiang","year":"2009","journal-title":"J. Lipid Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"154338","DOI":"10.1016\/j.metabol.2020.154338","article-title":"The Role of Peroxisome Proliferator-Activated Receptors (PPAR) in Immune Responses","volume":"114","author":"Christofides","year":"2021","journal-title":"Metabolism"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1500","DOI":"10.1021\/acs.jproteome.7b00838","article-title":"Targeted Metabolomics Reveals a Protective Role for Basal PPAR\u03b1 in Cholestasis Induced by \u03b1-Naphthylisothiocyanate","volume":"17","author":"Dai","year":"2018","journal-title":"J. Proteome Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"3000","DOI":"10.1111\/bph.13928","article-title":"Inhibition of JNK Signalling Mediates PPAR\u03b1-dependent protection against Intrahepatic Cholestasis by Fenofibrate","volume":"174","author":"Dai","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2340","DOI":"10.1194\/jlr.R900012-JLR200","article-title":"Bile Acid Transporters","volume":"50","author":"Dawson","year":"2009","journal-title":"J. Lipid Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"32048","DOI":"10.1074\/jbc.274.45.32048","article-title":"Peroxisome Proliferator-Activated Receptor Alpha Negatively Regulates the Vascular Inflammatory Gene Response by Negative Cross-Talk with Transcription Factors NF-kappaB and AP-1","volume":"274","author":"Delerive","year":"1999","journal-title":"J. Biol. Chem."},{"key":"B12","doi-asserted-by":"publisher","first-page":"36703","DOI":"10.1074\/jbc.M004045200","article-title":"Induction of IkappaBalpha Expression as a Mechanism Contributing to the Anti-inflammatory Activities of Peroxisome Proliferator-Activated Receptor-Alpha Activators","volume":"275","author":"Delerive","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B13","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/s0300-483x(01)00459-0","article-title":"Role of MRP2 and GSH in Intrahepatic Cycling of Toxins","volume":"167","author":"Dietrich","year":"2001","journal-title":"Toxicology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.3892\/mmr.2017.8051","article-title":"Beneficial Effect of Resveratrol on \u03b1-naphthyl I-sothiocyanate-induced C-holestasis via R-egulation of the FXR P-athway","volume":"17","author":"Ding","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"B15","doi-asserted-by":"publisher","first-page":"7242","DOI":"10.3748\/wjg.v23.i40.7242","article-title":"Dachaihu Decoction Ameliorates Pancreatic Fibrosis by Inhibiting Macrophage Infiltration in Chronic Pancreatitis","volume":"23","author":"Duan","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.jhep.2009.04.009","article-title":"EASL Clinical Practice Guidelines: Management of Cholestatic Liver Diseases","volume":"51","year":"2009","journal-title":"J. Hepatol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2431","DOI":"10.1016\/0006-2952(74)90234-2","article-title":"Influence of Alpha-Naphthylisothiocyanate (ANIT) on Microsomal Cytochrome P-450, Protein and Phospholipid Content in Rat Liver","volume":"23","author":"Gallenkamp","year":"1974","journal-title":"Biochem. Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.bbamcr.2006.04.014","article-title":"Principles of Hepatic Organic Anion Transporter Regulation during Cholestasis, Inflammation and Liver Regeneration","volume":"1773","author":"Geier","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"B19","doi-asserted-by":"publisher","first-page":"W32","DOI":"10.1093\/nar\/gku293","article-title":"SwissTargetPrediction: a Web Server for Target Prediction of Bioactive Small Molecules","volume":"42","author":"Gfeller","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1002\/hep.27744","article-title":"Fibrates and Cholestasis","volume":"62","author":"Ghonem","year":"2015","journal-title":"Hepatology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1002\/hep.26155","article-title":"Fibrates as Adjuvant Therapy for Chronic Cholestatic Liver Disease: its Time Has Come","volume":"57","author":"Ghonem","year":"2013","journal-title":"Hepatology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.cytogfr.2009.11.005","article-title":"Dangerous Liaisons: STAT3 and NF-kappaB Collaboration and Crosstalk in Cancer","volume":"21","author":"Grivennikov","year":"2010","journal-title":"Cytokine Growth Factor. Rev."},{"key":"B23","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/j.biochi.2011.02.009","article-title":"Hypoxia-induced SOCS3 Is Limiting STAT3 Phosphorylation and NF-\u039ab Activation in Congenital Heart Disease","volume":"93","author":"Gu","year":"2011","journal-title":"Biochimie"},{"key":"B24","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/s13063-020-4068-y","article-title":"Effect of Daesiho-Tang on Obesity with Non-alcoholic Fatty Liver Disease: a Study Protocol for a Randomised, Double-Blind, Placebo-Controlled Pilot Trial","volume":"21","author":"Han","year":"2020","journal-title":"Trials"},{"key":"B25","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1002\/ddr.21214","article-title":"Network Pharmacology: a Rosetta Stone for Traditional Chinese Medicine","volume":"75","author":"Hao","year":"2014","journal-title":"Drug Dev. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1111\/jphp.12285","article-title":"Da-Chaihu-Tang Alters the Pharmacokinetics of Nifedipine in Rats and a Treatment Regimen to Avoid This","volume":"66","author":"He","year":"2014","journal-title":"J. Pharm. Pharmacol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/toxsci\/kfz146","article-title":"The Protective Roles of PPAR\u03b1 Activation in Triptolide-Induced Liver Injury","volume":"171","author":"Hu","year":"2019","journal-title":"Toxicol. Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1016\/j.bbrc.2006.07.095","article-title":"Berberine Inhibits 3T3-L1 Adipocyte Differentiation through the PPARgamma Pathway","volume":"348","author":"Huang","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B29","doi-asserted-by":"publisher","first-page":"28947","DOI":"10.1074\/jbc.M002782200","article-title":"The Peroxisome Proliferator-Activated Receptor Alpha (PPARalpha) Regulates Bile Acid Biosynthesis","volume":"275","author":"Hunt","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1038\/nature04870","article-title":"Nuclear Factor-kappaB in Cancer Development and Progression","volume":"441","author":"Karin","year":"2006","journal-title":"Nature"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1515\/CCLM.2006.261","article-title":"Stone or Stricture as a Cause of Extrahepatic Cholestasis--Do Liver Function Tests Predict the Diagnosis?","volume":"44","author":"Karvonen","year":"2006","journal-title":"Clin. Chem. Lab. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/S1875-5364(13)60037-0","article-title":"Traditional Chinese Medicine Network Pharmacology: Theory, Methodology and Application","volume":"11","author":"Li","year":"2013","journal-title":"Chin. J. Nat. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/bs.apha.2015.04.003","article-title":"Bile Acid Metabolism and Signaling in Cholestasis, Inflammation, and Cancer","volume":"74","author":"Li","year":"2015","journal-title":"Adv. Pharmacol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"2237","DOI":"10.21037\/apm-19-271","article-title":"International Traditional Chinese Medicine Guideline for Diagnostic and Treatment Principles of Diabetes","volume":"9","author":"Lian","year":"2020","journal-title":"Ann. Palliat. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1053\/j.gastro.2018.04.032","article-title":"Mechanisms of MAFG Dysregulation in Cholestatic Liver Injury and Development of Liver Cancer","volume":"155","author":"Liu","year":"2018","journal-title":"Gastroenterology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3143","DOI":"10.1016\/j.bbagen.2012.09.008","article-title":"Glutathione Synthesis","volume":"1830","author":"Lu","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"B37","doi-asserted-by":"publisher","first-page":"736837","DOI":"10.1155\/2012\/736837","article-title":"Glutathione Homeostasis and Functions: Potential Targets for Medical Interventions","volume":"2012","author":"Lushchak","year":"2012","journal-title":"J. Amino Acids"},{"key":"B38","doi-asserted-by":"publisher","first-page":"16492","DOI":"10.1073\/pnas.2002672117","article-title":"JNK-mediated Disruption of Bile Acid Homeostasis Promotes Intrahepatic Cholangiocarcinoma","volume":"117","author":"Manieri","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B39","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1016\/s0022-2275(20)32398-1","article-title":"Peroxisome Proliferator-Activated Receptor Alpha (PPARalpha) and Agonist Inhibit Cholesterol 7alpha-Hydroxylase Gene (CYP7A1) Transcription","volume":"41","author":"Marrapodi","year":"2000","journal-title":"J. Lipid Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1002\/hep.1840140324","article-title":"Mechanisms and Regulation of Bile Secretion","volume":"14","author":"Nathanson","year":"1991","journal-title":"Hepatology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"4847941","DOI":"10.1155\/2021\/4847941","article-title":"Redox-Dependent Effects in the Physiopathological Role of Bile Acids","volume":"2021","author":"Orozco-Aguilar","year":"2021","journal-title":"Oxid Med. Cel Longev."},{"key":"B42","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/j.jhep.2014.10.039","article-title":"Molecular Mechanism of PPAR\u03b1 Action and its Impact on Lipid Metabolism, Inflammation and Fibrosis in Non-alcoholic Fatty Liver Disease","volume":"62","author":"Pawlak","year":"2015","journal-title":"J. Hepatol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"D833","DOI":"10.1093\/nar\/gkw943","article-title":"DisGeNET: a Comprehensive Platform Integrating Information on Human Disease-Associated Genes and Variants","volume":"45","author":"Pi\u00f1ero","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/s1665-2681(19)32126-x","article-title":"Cholestasis: Human Disease and Experimental Animal Models","volume":"2","author":"Rodr\u00edguez-Garay","year":"2003","journal-title":"Ann. Hepatol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/1758-2946-6-13","article-title":"TCMSP: a Database of Systems Pharmacology for Drug Discovery from Herbal Medicines","volume":"6","author":"Ru","year":"2014","journal-title":"J. Cheminform."},{"key":"B46","doi-asserted-by":"publisher","first-page":"baq020","DOI":"10.1093\/database\/baq020","article-title":"GeneCards Version 3: the Human Gene Integrator","volume":"2010","author":"Safran","year":"2010","journal-title":"Database (Oxford)"},{"key":"B47","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1002\/biof.1476","article-title":"Glutathione Compartmentalization and its Role in Glutathionylation and Other Regulatory Processes of Cellular Pathways","volume":"45","author":"Scir\u00e8","year":"2019","journal-title":"BioFactors"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1748","DOI":"10.1096\/fj.02-1186fje","article-title":"Activation of PPAR-Alpha in Streptozotocin-Induced Diabetes Is Essential for Resistance against Acetaminophen Toxicity","volume":"17","author":"Shankar","year":"2003","journal-title":"FASEB J."},{"key":"B49","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.bbrc.2004.07.102","article-title":"Interleukin-6 Regulates Hepatic Transporters during Acute-phase Response","volume":"322","author":"Siewert","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1993","DOI":"10.1002\/hep.27171","article-title":"Transcriptional Dynamics of Bile Salt export Pump during Pregnancy: Mechanisms and Implications in Intrahepatic Cholestasis of Pregnancy","volume":"60","author":"Song","year":"2014","journal-title":"Hepatology"},{"key":"B51","doi-asserted-by":"publisher","first-page":"112","DOI":"10.19664\/j.cnki.1002-2392.190128","article-title":"Pharmacological Effect and Clinical Application of Dachaihu Decoction","volume":"2019","author":"Song","year":"2019","journal-title":"Acta Chin. Med. Pharmacol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"52438","DOI":"10.3791\/52438","article-title":"Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis","volume":"96","author":"Tag","year":"2015","journal-title":"J. Vis. Exp."},{"key":"B53","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1517\/14728222.2016.1102889","article-title":"Recent Advances in the Exploration of the Bile Salt export Pump (BSEP\/ABCB11) Function","volume":"20","author":"Telbisz","year":"2016","journal-title":"Expert Opin. Ther. Targets"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1056\/NEJM199810223391707","article-title":"Molecular Pathogenesis of Cholestasis","volume":"339","author":"Trauner","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"B55","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/0378-8741(89)90098-6","article-title":"Effect of Shosaikoto, Daisaikoto and Sannoshashinto (Traditional Japanese and Chinese Medicines) on Experimental Hyperlipidemia in Rats","volume":"26","author":"Umeda","year":"1989","journal-title":"J. Ethnopharmacol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1146\/annurev-pharmtox-010818-021059","article-title":"Drug Therapies for Chronic Cholestatic Liver Diseases","volume":"60","author":"Wagner","year":"2020","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1016\/j.bbalip.2019.05.014","article-title":"Hepatocyte Peroxisome Proliferator-Activated Receptor \u03b1 Regulates Bile Acid Synthesis and Transport","volume":"1864","author":"Xie","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Cel Biol Lipids"},{"key":"B58","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.3390\/ijms19041260","article-title":"The Role of PPAR and its Cross-Talk with CAR and LXR in Obesity and Atherosclerosis","volume":"19","author":"Xu","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B59","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.phrs.2004.02.003","article-title":"Effects of Dai-Saiko-To (Da-Chai-Hu-Tang) on Plasma Lipids and Atherosclerotic Lesions in Female Heterozygous Heritable Kurosawa and Kusanagi-Hypercholesterolemic (KHC) Rabbits","volume":"50","author":"Yoshie","year":"2004","journal-title":"Pharmacol. Res."},{"key":"B60","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1042\/BJ20020588","article-title":"Signal Transducers and Activators of Transcription 3 (STAT3) Inhibits Transcription of the Inducible Nitric Oxide Synthase Gene by Interacting with Nuclear Factor kappaB","volume":"367","author":"Yu","year":"2002","journal-title":"Biochem. J."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.847483\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T09:12:18Z","timestamp":1647335538000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.847483\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,15]]},"references-count":60,"alternative-id":["10.3389\/fphar.2022.847483"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.847483","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,15]]},"article-number":"847483"}}