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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

Gentiopicroside Ameliorated Ductular Reaction and Inflammatory Response in DDC-induced Murine Cholangiopathies Model

Author(s): Juan Hao, Yi Xu, Kan Lu, Yiyue Chen, Jibo Liu, Xiaohong Shao, Chunling Zhu, Yaqin Ding, Xin Xie, Jian Wu* and Quanjun Yang*

Volume 17, 2024

Published on: 19 October, 2023

Article ID: e18761429251911 Pages: 14

DOI: 10.2174/0118761429251911231011092145

Price: $65

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Abstract

Background: Cholangiopathies comprise a spectrum of diseases without curative treatments. Pharmacological treatments based on bile acid (BA) metabolism regulation represent promising therapeutic strategies for the treatment of cholangiopathies. Gentiopicroside (GPS), derived from the Chinese medicinal herb Gentianae Radix, exerts pharmacological effects on bile acid metabolism regulation and oxidative stress.

Objective: The present study aims to investigate the effect of GPS on 3,5-diethoxycarbonyl-1,4dihydrocollidine (DDC)-induced cholangiopathy.

Methods: Two independent animal experiments were designed to evaluate the comprehensive effect of GPS on chronic DDC diet-induced cholangiopathy, including bile duct obliteration, ductular reaction, BA metabolism reprogramming, liver fibrosis, oxidative stress and inflammatory responses.

Results: In the first pharmacological experiment, three doses of GPS (5, 25 and 125 mg/kg) were injected intraperitoneally into mice fed a DDC diet for 14 days. DDC induced a typical ductular reaction, increased periductal fibrosis and mixed inflammatory cell infiltration in the portal areas. GPS treatment showed dose-dependent improvements in the ductular reaction, BA metabolism, fibrosis, oxidative stress and inflammatory response. In the second experiment, a high dose of GPS was injected intraperitoneally into control mice for 28 days, resulting in no obvious histologic changes and significant serologic abnormalities in liver function. However, GPS inhibited DDC-induced oxidative stress, serum and hepatic BA accumulation, proinflammatory cytokine production, and immunocyte infiltration. Specifically, the GPS-treated groups showed decreased infiltration of monocyte-derived macrophages and CD4+ and CD8+ T lymphocytes, as well as preserved Kupffer cells.

Conclusion: GPS alleviated chronic DDC diet-induced cholangiopathy disorder by improving the ductular reaction, periductal fibrosis, oxidative stress and inflammatory response. Its dosage-dependent pharmacological effects indicated that GPS warrants its further evaluation in clinical trials for cholangiopathy.

[1]
Tam, P.K.H.; Yiu, R.S.; Lendahl, U.; Andersson, E.R. Cholangiopathies - Towards a molecular understanding. EBioMedicine, 2018, 35, 381-393.
[http://dx.doi.org/10.1016/j.ebiom.2018.08.024] [PMID: 30236451]
[2]
Lazaridis, K.N.; Strazzabosco, M.; LaRusso, N.F. The cholangiopathies: Disorders of biliary epithelia. Gastroenterology, 2004, 127(5), 1565-1577.
[http://dx.doi.org/10.1053/j.gastro.2004.08.006] [PMID: 15521023]
[3]
Banales, J.M.; Huebert, R.C.; Karlsen, T.; Strazzabosco, M.; LaRusso, N.F.; Gores, G.J. Cholangiocyte pathobiology. Nat. Rev. Gastroenterol. Hepatol., 2019, 16(5), 269-281.
[http://dx.doi.org/10.1038/s41575-019-0125-y] [PMID: 30850822]
[4]
Durchschein, F; Krones, E; Pollheimer, MJ Genetic loss of the muscarinic M3 receptor markedly alters bile formation and cholestatic liver injury in mice. Hepatol Res, 2018, 48, E68-E77.
[5]
Ohira, H; Takahashi, A; Zeniya, M Clinical practice guidelines for autoimmune hepatitis. Hepatol Res, 2022, 2022, 13776.
[http://dx.doi.org/10.1111/hepr.13776]
[6]
Salas-Silva, S.; Simoni-Nieves, A.; Lopez-Ramirez, J.; Bucio, L.; Gómez-Quiroz, L.E.; Gutiérrez-Ruiz, M.C.; Roma, M.G. Cholangiocyte death in ductopenic cholestatic cholangiopathies: Mechanistic basis and emerging therapeutic strategies. Life Sci., 2019, 218, 324-339.
[http://dx.doi.org/10.1016/j.lfs.2018.12.044] [PMID: 30610870]
[7]
Trussoni, C.E.; O’Hara, S.P.; LaRusso, N.F. Cellular senescence in the cholangiopathies: A driver of immunopathology and a novel therapeutic target. Semin. Immunopathol., 2022, 44(4), 527-544.
[8]
Menon, S.; Holt, A. Large-duct cholangiopathies: Aetiology, diagnosis and treatment. Frontline Gastroenterol., 2019, 10(3), 284-291.
[http://dx.doi.org/10.1136/flgastro-2018-101098] [PMID: 31288256]
[9]
Dumortier, J.; Conti, F.; Scoazec, J.Y. Posttransplant immune-mediated cholangiopathies. Curr. Opin. Gastroenterol., 2022, 38(2), 98-103.
[http://dx.doi.org/10.1097/MOG.0000000000000815] [PMID: 35098931]
[10]
Cariello, M.; Gadaleta, R.M.; Moschetta, A. The gut-liver axis in cholangiopathies: Focus on bile acid based pharmacological treatment. Curr. Opin. Gastroenterol., 2022, 38(2), 136-143.
[http://dx.doi.org/10.1097/MOG.0000000000000807] [PMID: 35034082]
[11]
Zhang, X.; Zhan, G.; Jin, M.; Zhang, H.; Dang, J.; Zhang, Y.; Guo, Z.; Ito, Y. Botany, traditional use, phytochemistry, pharmacology, quality control, and authentication of Radix Gentianae Macrophyllae -A traditional medicine: A review. Phytomedicine, 2018, 46, 142-163.
[http://dx.doi.org/10.1016/j.phymed.2018.04.020] [PMID: 30097114]
[12]
Xu, S.; Kong, F.; Sun, Z.; Xi, Y.; Qi, F.; Sun, J. Hepatoprotective effect and metabonomics studies of radix gentianae in rats with acute liver injury. Pharm. Biol., 2021, 59(1), 1170-1178.
[http://dx.doi.org/10.1080/13880209.2021.1969414] [PMID: 34465274]
[13]
Ren, L.; Sun, D.; Zhou, X.; Yang, Y.; Huang, X.; Li, Y.; Wang, C.; Li, Y. Chronic treatment with the modified Longdan Xiegan Tang attenuates olanzapine-induced fatty liver in rats by regulating hepatic de novo lipogenesis and fatty acid beta-oxidation-associated gene expression mediated by SREBP-1c, PPAR-alpha and AMPK-alpha. J. Ethnopharmacol., 2019, 232, 176-187.
[http://dx.doi.org/10.1016/j.jep.2018.12.034] [PMID: 30590197]
[14]
Mihailović, V.; Katanić, J.; Mišić, D.; Stanković, V.; Mihailović, M.; Uskoković, A.; Arambašić, J.; Solujić, S.; Mladenović, M.; Stanković, N. Hepatoprotective effects of secoiridoid-rich extracts from Gentiana cruciata L. against carbon tetrachloride induced liver damage in rats. Food Funct., 2014, 5(8), 1795-1803.
[http://dx.doi.org/10.1039/C4FO00088A] [PMID: 24912992]
[15]
Mihailovic, V; Mihailovic, M; Uskokovic, A Hepatoprotective effects of Gentiana asclepiadea L. extracts against carbon tetrachloride induced liver injury in rats. Food Chem. Toxicol., 2013, 52, 83-90.
[16]
Zhang, Y.; Yang, X.; Wang, S.; Song, S.; Yang, X. Gentiopicroside prevents alcoholic liver damage by improving mitochondrial dysfunction in the rat model. Phytother. Res., 2021, 35(4), 2230-2251.
[http://dx.doi.org/10.1002/ptr.6981] [PMID: 33300653]
[17]
Jin, M.; Feng, H.; Wang, Y.; Yan, S.; Shen, B.; Li, Z.; Qin, H.; Wang, Q.; Li, J.; Liu, G. Gentiopicroside ameliorates oxidative stress and lipid accumulation through nuclear factor erythroid 2-related factor 2 activation. Oxid. Med. Cell. Longev., 2020, 2020, 1-13.
[http://dx.doi.org/10.1155/2020/2940746] [PMID: 32655764]
[18]
He, K.; Ma, Y.B.; Cao, T.W.; Wang, H.L.; Jiang, F.Q.; Geng, C.A.; Zhang, X.M.; Chen, J.J. Seven new secoiridoids with anti-hepatitis B virus activity from Swertia angustifolia. Planta Med., 2012, 78(8), 814-820.
[http://dx.doi.org/10.1055/s-0031-1298381] [PMID: 22441835]
[19]
Tang, X.; Yang, Q.; Yang, F.; Gong, J.; Han, H.; Yang, L.; Wang, Z. Target profiling analyses of bile acids in the evaluation of hepatoprotective effect of gentiopicroside on ANIT-induced cholestatic liver injury in mice. J. Ethnopharmacol., 2016, 194, 63-71.
[http://dx.doi.org/10.1016/j.jep.2016.08.049] [PMID: 27582267]
[20]
Xu, L.; Sheng, T.; Liu, X.; Zhang, T.; Wang, Z.; Han, H. Analyzing the hepatoprotective effect of the Swertia cincta Burkill extract against ANIT-induced cholestasis in rats by modulating the expression of transporters and metabolic enzymes. J. Ethnopharmacol., 2017, 209, 91-99.
[http://dx.doi.org/10.1016/j.jep.2017.07.031] [PMID: 28734962]
[21]
Fuchs, C.D.; Trauner, M. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat. Rev. Gastroenterol. Hepatol., 2022, 19(7), 432-450.
[http://dx.doi.org/10.1038/s41575-021-00566-7] [PMID: 35165436]
[22]
Han, H; Xu, L; Xiong, K; Zhang, T; Wang, Z. Exploration of hepatoprotective effect of gentiopicroside on alpha-naphthylisothiocyanate-induced cholestatic liver injury in rats by comprehensive proteomic and metabolomic signatures. Cellular Physiol. Biochem., 2018, 49, 1304-19.
[http://dx.doi.org/10.1159/000493409]
[23]
Mariotti, V.; Cadamuro, M.; Spirli, C.; Fiorotto, R.; Strazzabosco, M.; Fabris, L. Animal models of cholestasis: An update on inflammatory cholangiopathies. Biochim. Biophys. Acta Mol. Basis Dis., 2019, 1865(5), 954-964.
[http://dx.doi.org/10.1016/j.bbadis.2018.07.025] [PMID: 30398152]
[24]
Gijbels, E; Pieters, A; De Muynck, K; Vinken, M; Devisscher, L Rodent models of cholestatic liver disease: A practical guide for translational research. Liver Int. : official J. Int. Assoc. Study Liver, 2021, 41, 6565-682.
[http://dx.doi.org/10.1111/liv.14800]
[25]
Hao, J.; Shen, X.; Lu, K.; Xu, Y.; Chen, Y.; Liu, J.; Shao, X.; Zhu, C.; Ding, Y.; Xie, X.; Wu, J.; Yang, Q. Costunolide alleviated DDC induced ductular reaction and inflammatory response in murine model of cholestatic liver disease. J. Tradit. Complement. Med., 2023, 13(4), 345-357.
[http://dx.doi.org/10.1016/j.jtcme.2023.02.008] [PMID: 37396159]
[26]
Pose, E.; Sancho-Bru, P.; Coll, M. 3,5-Diethoxycarbonyl-1,4-dihydrocollidine diet: a rodent model in cholestasis research. Methods Mol. Biol., 2019, 1981, 249-257.
[http://dx.doi.org/10.1007/978-1-4939-9420-5_16] [PMID: 31016659]
[27]
Miyao, M; Ozeki, M; Abiru, H Bile canalicular abnormalities in the early phase of a mouse model of sclerosing cholangitis. Digestive Liver Disease, 2013, 45, 216-225.
[http://dx.doi.org/10.1016/j.dld.2012.09.007]
[28]
Fickert, P.; Stöger, U.; Fuchsbichler, A.; Moustafa, T.; Marschall, H.U.; Weiglein, A.H.; Tsybrovskyy, O.; Jaeschke, H.; Zatloukal, K.; Denk, H.; Trauner, M. A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis. Am. J. Pathol., 2007, 171(2), 525-536.
[http://dx.doi.org/10.2353/ajpath.2007.061133] [PMID: 17600122]
[29]
Jemail, L.; Miyao, M.; Kotani, H.; Kawai, C.; Minami, H.; Abiru, H.; Tamaki, K. Pivotal roles of Kupffer cells in the progression and regression of DDC-induced chronic cholangiopathy. Sci. Rep., 2018, 8(1), 6415.
[http://dx.doi.org/10.1038/s41598-018-24825-x] [PMID: 29686325]
[30]
Xue, H.; Fang, S.; Zheng, M.; Wu, J.; Li, H.; Zhang, M.; Li, Y.; Wang, T.; Shi, R.; Ma, Y. Da-Huang-Xiao-Shi decoction protects against3, 5-diethoxycarbonyl-1,4-dihydroxychollidine-induced chronic cholestasis by upregulating bile acid metabolic enzymes and efflux transporters. J. Ethnopharmacol., 2021, 269, 113706.
[http://dx.doi.org/10.1016/j.jep.2020.113706] [PMID: 33346024]
[31]
Niu, Y.T.; Zhao, Y.P.; Jiao, Y.F.; Zheng, J.; Yang, W.L.; Zhou, R.; Niu, Y.; Sun, T.; Li, Y.X.; Yu, J.Q. Protective effect of gentiopicroside against dextran sodium sulfate induced colitis in mice. Int. Immunopharmacol., 2016, 39, 16-22.
[http://dx.doi.org/10.1016/j.intimp.2016.07.003] [PMID: 27394986]
[32]
Yang, S.Q.; Chen, Y.D.; Li, H.; Hui, X.; Gao, W.Y. Geniposide and gentiopicroside suppress hepatic gluconeogenesis via regulation of AKT-FOXO1 pathway. Arch. Med. Res., 2018, 49(5), 314-322.
[http://dx.doi.org/10.1016/j.arcmed.2018.10.005] [PMID: 30409503]
[33]
Liu, Z; Gu, Y; Shin, A; Zhang, S; Ginhoux, F. Analysis of myeloid cells in mouse tissues with flow cytometry. STAR protoc., 2020, 1(1), 100029.
[http://dx.doi.org/10.1016/j.xpro.2020.100029]
[34]
Cossarizza, A.; Chang, H.D.; Radbruch, A.; Abrignani, S.; Addo, R.; Akdis, M.; Andrä, I.; Andreata, F.; Annunziato, F.; Arranz, E.; Bacher, P.; Bari, S.; Barnaba, V.; Barros-Martins, J.; Baumjohann, D.; Beccaria, C.G.; Bernardo, D.; Boardman, D.A.; Borger, J.; Böttcher, C.; Brockmann, L.; Burns, M.; Busch, D.H.; Cameron, G.; Cammarata, I.; Cassotta, A.; Chang, Y.; Chirdo, F.G.; Christakou, E.; Čičin-Šain, L.; Cook, L.; Corbett, A.J.; Cornelis, R.; Cosmi, L.; Davey, M.S.; De Biasi, S.; De Simone, G.; del Zotto, G.; Delacher, M.; Di Rosa, F.; Di Santo, J.; Diefenbach, A.; Dong, J.; Dörner, T.; Dress, R.J.; Dutertre, C.A.; Eckle, S.B.G.; Eede, P.; Evrard, M.; Falk, C.S.; Feuerer, M.; Fillatreau, S.; Fiz-Lopez, A.; Follo, M.; Foulds, G.A.; Fröbel, J.; Gagliani, N.; Galletti, G.; Gangaev, A.; Garbi, N.; Garrote, J.A.; Geginat, J.; Gherardin, N.A.; Gibellini, L.; Ginhoux, F.; Godfrey, D.I.; Gruarin, P.; Haftmann, C.; Hansmann, L.; Harpur, C.M.; Hayday, A.C.; Heine, G.; Hernández, D.C.; Herrmann, M.; Hoelsken, O.; Huang, Q.; Huber, S.; Huber, J.E.; Huehn, J.; Hundemer, M.; Hwang, W.Y.K.; Iannacone, M.; Ivison, S.M.; Jäck, H.M.; Jani, P.K.; Keller, B.; Kessler, N.; Ketelaars, S.; Knop, L.; Knopf, J.; Koay, H.F.; Kobow, K.; Kriegsmann, K.; Kristyanto, H.; Krueger, A.; Kuehne, J.F.; Kunze-Schumacher, H.; Kvistborg, P.; Kwok, I.; Latorre, D.; Lenz, D.; Levings, M.K.; Lino, A.C.; Liotta, F.; Long, H.M.; Lugli, E.; MacDonald, K.N.; Maggi, L.; Maini, M.K.; Mair, F.; Manta, C.; Manz, R.A.; Mashreghi, M.F.; Mazzoni, A.; McCluskey, J.; Mei, H.E.; Melchers, F.; Melzer, S.; Mielenz, D.; Monin, L.; Moretta, L.; Multhoff, G.; Muñoz, L.E.; Muñoz-Ruiz, M.; Muscate, F.; Natalini, A.; Neumann, K.; Ng, L.G.; Niedobitek, A.; Niemz, J.; Almeida, L.N.; Notarbartolo, S.; Ostendorf, L.; Pallett, L.J.; Patel, A.A.; Percin, G.I.; Peruzzi, G.; Pinti, M.; Pockley, A.G.; Pracht, K.; Prinz, I.; Pujol-Autonell, I.; Pulvirenti, N.; Quatrini, L.; Quinn, K.M.; Radbruch, H.; Rhys, H.; Rodrigo, M.B.; Romagnani, C.; Saggau, C.; Sakaguchi, S.; Sallusto, F.; Sanderink, L.; Sandrock, I.; Schauer, C.; Scheffold, A.; Scherer, H.U.; Schiemann, M.; Schildberg, F.A.; Schober, K.; Schoen, J.; Schuh, W.; Schüler, T.; Schulz, A.R.; Schulz, S.; Schulze, J.; Simonetti, S.; Singh, J.; Sitnik, K.M.; Stark, R.; Starossom, S.; Stehle, C.; Szelinski, F.; Tan, L.; Tarnok, A.; Tornack, J.; Tree, T.I.M.; van Beek, J.J.P.; van de Veen, W.; van Gisbergen, K.; Vasco, C.; Verheyden, N.A.; von Borstel, A.; Ward-Hartstonge, K.A.; Warnatz, K.; Waskow, C.; Wiedemann, A.; Wilharm, A.; Wing, J.; Wirz, O.; Wittner, J.; Yang, J.H.M.; Yang, J. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition). Eur. J. Immunol., 2021, 51(12), 2708-3145.
[http://dx.doi.org/10.1002/eji.202170126] [PMID: 34910301]
[35]
Chi, M.; Zhang, H.; Wang, Y.; Sun, X.; Yang, Q.; Guo, C. Silibinin alleviates muscle atrophy caused by oxidative stress induced by cisplatin through ERK/FoxO and JNK/FoxO pathways. Oxid. Med. Cell. Longev., 2022, 2022, 1-22.
[http://dx.doi.org/10.1155/2022/5694223] [PMID: 35096269]
[36]
Xie, X.; Li, H.; Wang, Y.; Wan, Z.; Luo, S.; Zhao, Z.; Liu, J.; Wu, X.; Li, X.; Li, X. Therapeutic effects of gentiopicroside on adjuvant-induced arthritis by inhibiting inflammation and oxidative stress in rats. Int. Immunopharmacol., 2019, 76, 105840.
[http://dx.doi.org/10.1016/j.intimp.2019.105840] [PMID: 31487614]
[37]
Fragoulis, A; Schenkel, J; Herzog, M Nrf2 ameliorates DDC-induced sclerosing cholangitis and biliary fibrosis and improves the regenerative capacity of the liver. Toxicol. Sci., 2019, 169, 485-498.
[38]
Jiang, A.; Okabe, H.; Popovic, B.; Preziosi, M.E.; Pradhan-Sundd, T.; Poddar, M.; Singh, S.; Bell, A.; England, S.G.; Nagarajan, S.; Monga, S.P. Loss of Wnt secretion by macrophages promotes hepatobiliary injury after administration of 3,5-diethoxycarbonyl-1, 4-dihydrocollidine diet. Am. J. Pathol., 2019, 189(3), 590-603.
[http://dx.doi.org/10.1016/j.ajpath.2018.11.010] [PMID: 30610845]
[39]
Yang, R; Zhao, Q; Hu, DD; Xiao, XR; Huang, JF; Li, F Metabolomic analysis of cholestatic liver damage in mice. Food Chem. Toxicol., 2018, 120, 253-260.
[http://dx.doi.org/10.1016/j.fct.2018.07.022]
[40]
Li, W.K.; Wang, G.F.; Wang, T.M.; Li, Y.Y.; Li, Y.F.; Lu, X.Y.; Wang, Y.H.; Zhang, H.; Liu, P.; Wu, J.S.; Ma, Y.M. Protective effect of herbal medicine Huangqi decoction against chronic cholestatic liver injury by inhibiting bile acid-stimulated inflammation in DDC-induced mice. Phytomedicine, 2019, 62, 152948.
[http://dx.doi.org/10.1016/j.phymed.2019.152948] [PMID: 31129431]
[41]
Glaser, F.; John, C.; Engel, B.; Höh, B.; Weidemann, S.; Dieckhoff, J.; Stein, S.; Becker, N.; Casar, C.; Schuran, F.A.; Wieschendorf, B.; Preti, M.; Jessen, F.; Franke, A.; Carambia, A.; Lohse, A.W.; Ittrich, H.; Herkel, J.; Heeren, J.; Schramm, C.; Schwinge, D. Liver infiltrating T cells regulate bile acid metabolism in experimental cholangitis. J. Hepatol., 2019, 71(4), 783-792.
[http://dx.doi.org/10.1016/j.jhep.2019.05.030] [PMID: 31207266]
[42]
Camilleri, M. Bile acid detergency: Permeability, inflammation, and effects of sulfation. Am. J. Physiol. Gastrointest. Liver Physiol., 2022, 322(5), G480-G488.
[http://dx.doi.org/10.1152/ajpgi.00011.2022] [PMID: 35258349]
[43]
Zheng, S.; Cao, P.; Yin, Z.; Wang, X.; Chen, Y.; Yu, M.; Xu, B.; Liao, C.; Duan, Y.; Zhang, S.; Han, J.; Yang, X. Apigenin protects mice against 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholestasis. Food Funct., 2021, 12(5), 2323-2334.
[http://dx.doi.org/10.1039/D0FO02910F] [PMID: 33620063]
[44]
Woolbright, BL Inflammation: Cause or consequence of chronic cholestatic liver injury. Food Chem. Toxicol., 2020, 137, 111133.
[45]
Wu, R; Zhang, Y; Cheng, Q The effect of biliary obstruction, biliary drainage and bile reinfusion on bile acid metabolism and gut microbiota in mice. Liver Int., 2022, 42, 135-148.
[http://dx.doi.org/10.1111/liv.15047]
[46]
Terada, M.; Horisawa, K.; Miura, S.; Takashima, Y.; Ohkawa, Y.; Sekiya, S.; Matsuda-Ito, K.; Suzuki, A. Kupffer cells induce Notch-mediated hepatocyte conversion in a common mouse model of intrahepatic cholangiocarcinoma. Sci. Rep., 2016, 6(1), 34691.
[http://dx.doi.org/10.1038/srep34691] [PMID: 27698452]
[47]
Trauner, M.; Nevens, F.; Shiffman, M.; Drenth, J.P.H.; Bowlus, C.; Blasco, V.M.V.; Andreone, P.; Pencek, R.; Malecha, E.S.; Macconell, L.; Shapiro, D. Durable response in the markers of cholestasis through 36 months of open-label extension study of obeticholic acid in primary biliary cholangitis. J. Hepatol., 2018, 68, S224-S225.
[http://dx.doi.org/10.1016/S0168-8278(18)30665-2]
[48]
Liang, Z.; Chen, X.; Shi, J.; Hu, H.; Xue, Y.; Ung, C.O.L. Efficacy and safety of traditional Chinese medicines for non-alcoholic fatty liver disease: A systematic literature review of randomized controlled trials. Chin. Med., 2021, 16(1), 9.
[http://dx.doi.org/10.1186/s13020-020-00422-x] [PMID: 33430929]
[49]
Zhu, J.; Seo, J.E.; Wang, S.; Ashby, K.; Ballard, R.; Yu, D.; Ning, B.; Agarwal, R.; Borlak, J.; Tong, W.; Chen, M. The development of a database for herbal and dietary supplement induced liver toxicity. Int. J. Mol. Sci., 2018, 19(10), 2955.
[http://dx.doi.org/10.3390/ijms19102955] [PMID: 30274144]

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