{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:20:13Z","timestamp":1790803213395,"version":"4.1.0"},"reference-count":55,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,5,27]],"date-time":"2019-05-27T00:00:00Z","timestamp":1558915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology Taiwan","award":["MOST107-2320-B-010-040-MY3"],"award-info":[{"award-number":["MOST107-2320-B-010-040-MY3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background and Aims: Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, which occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension. Activated hepatic perivascular stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines, such as TGF-\u03b21. The inhibition of TGF-\u03b21 function or synthesis is a major target for the development of antifibrotic therapies. Our previous study showed that the water and ethanol extracts of Graptopetalum paraguayense (GP), a Chinese herbal medicine, can prevent dimethylnitrosamine (DMN)-induced hepatic inflammation and fibrosis in rats. Methods: We used rat hepatic stellate HSC-T6 cells and a diethylnitrosamine (DEN)-induced rat liver injury model to test the potential mechanism of GP extracts and its fraction, HH-F3. Results: We demonstrated that GP extracts and HH-F3 downregulated the expression levels of extracellular matrix (ECM) proteins and inhibited the proliferation and migration via suppression of the TGF-\u03b21 pathway in rat hepatic stellate HSC-T6 cells. Moreover, the HH-F3 fraction decreased hepatic collagen content and reduced plasma AST, ALT, and \u03b3-GT activities in a DEN-induced rat liver injury model, suggesting that GP\/HH-F3 has hepatoprotective effects against DEN-induced liver fibrosis. Conclusion: These findings indicate that GP\/HH-F3 may be a potential therapeutic agent for the treatment of liver fibrosis. The inhibition of TGF-\u03b2-mediated fibrogenesis may be a central mechanism by which GP\/HH-F3 protects the liver from injury.<\/jats:p>","DOI":"10.3390\/ijms20102592","type":"journal-article","created":{"date-parts":[[2019,5,27]],"date-time":"2019-05-27T11:19:27Z","timestamp":1558955967000},"page":"2592","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Graptopetalum paraguayense Inhibits Liver Fibrosis by Blocking TGF-\u03b2 Signaling In Vivo and In Vitro"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5468-5859","authenticated-orcid":false,"given":"Wei-Hsiang","family":"Hsu","sequence":"first","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se-Chun","family":"Liao","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yau-Jan","family":"Chyan","sequence":"additional","affiliation":[{"name":"Development of Natural Resource, Institute of Pharmaceutics, Development Center for Biotechnology (DCB), Taipei 11571, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Wen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Surgery &amp; Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Lan","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Education and Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma-Li","family":"Siu","sequence":"additional","affiliation":[{"name":"Development of Natural Resource, Institute of Pharmaceutics, Development Center for Biotechnology (DCB), Taipei 11571, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Chuan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Pharmacy, National Taiwan University, Taipei 10050, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuh-Shan","family":"Chung","sequence":"additional","affiliation":[{"name":"Development of Natural Resource, Institute of Pharmaceutics, Development Center for Biotechnology (DCB), Taipei 11571, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Ying F.","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan"},{"name":"Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis","volume":"115","author":"Bataller","year":"2005","journal-title":"J. Clin. Invest."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1055\/s-2008-1040452","article-title":"Structure of the extracellular matrix in normal and fibrotic liver: Collagens and glycoproteins","volume":"10","author":"Schuppan","year":"1990","journal-title":"Semin. Liver Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S369","DOI":"10.1111\/j.1440-1746.2004.03705.x","article-title":"Pathogenesis of cirrhosis","volume":"19","author":"Wanless","year":"2004","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1172\/JCI114886","article-title":"Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo","volume":"86","author":"Maher","year":"1990","journal-title":"J. Clin. Invest."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/0016-5085(90)91307-R","article-title":"Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis","volume":"98","author":"Milani","year":"1990","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.5858\/2007-131-1728-HSCALF","article-title":"Hepatic stellate cells and liver fibrosis","volume":"131","author":"Moreira","year":"2007","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1097\/00042737-200402000-00001","article-title":"How can transforming growth factor beta be targeted usefully to combat liver fibrosis?","volume":"16","author":"Shek","year":"2004","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1002\/hep.21135","article-title":"Id1 is a critical mediator in TGF-beta-induced transdifferentiation of rat hepatic stellate cells","volume":"43","author":"Wiercinska","year":"2006","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1053\/jhep.2001.25349","article-title":"The role of Smad3 in mediating mouse hepatic stellate cell activation","volume":"34","author":"Schnabl","year":"2001","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/S0016-5085(03)00666-8","article-title":"Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats","volume":"125","author":"Dooley","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.foodchem.2004.03.022","article-title":"Studies on the inhibitory effect of Graptopetalum paraguayense E. Walther extracts on mushroom tyrosinase","volume":"89","author":"Huang","year":"2005","journal-title":"Food Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.foodchem.2004.06.022","article-title":"Studies on the antioxidative activity of Graptopetalum paraguayense E. Walther","volume":"91","author":"Chung","year":"2005","journal-title":"Food Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1016\/j.foodchem.2005.10.053","article-title":"Studies on the inhibitory effect of Graptopetalum paraguayense E. Walther extracts on the angiotensin converting enzyme","volume":"100","author":"Chen","year":"2007","journal-title":"Food Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1002\/jsfa.3774","article-title":"Antihypertensive and antioxidant effects of the Graptopetalum paraguayense E. Walther extract in spontaneously hypertensive rats","volume":"89","author":"Chung","year":"2009","journal-title":"J. Sci. Food Agric."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.jep.2010.12.029","article-title":"Hepatoprotection of Graptopetalum paraguayense E. Walther on CCl4-induced liver damage and inflammation","volume":"134","author":"Duh","year":"2011","journal-title":"J. Ethnopharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1142\/S0192415X08005837","article-title":"In vitro antioxidant and antiproliferative activity of the stem extracts from Graptopetalum paraguayense","volume":"36","author":"Chen","year":"2008","journal-title":"Am. J. Chin. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hsu, W.H., Chang, C.C., Huang, K.W., Chen, Y.C., Hsu, S.L., Wu, L.C., Tsou, A.P., Lai, J.M., and Huang, C.Y. (2015). Evaluation of the medicinal herb Graptopetalum paraguayense as a treatment for liver cancer. PloS ONE, 10.","DOI":"10.1371\/journal.pone.0121298"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7788","DOI":"10.18632\/oncotarget.3050","article-title":"Gluconeogenesis, lipogenesis, and HBV replication are commonly regulated by PGC-1alpha-dependent pathway","volume":"6","author":"Jhuang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Su, L.J., Chang, C.C., Yang, C.H., Hsieh, S.J., Wu, Y.C., Lai, J.M., Tseng, T.L., Huang, C.Y., and Hsu, S.L. (2013). Graptopetalum paraguayense ameliorates chemical-induced rat hepatic fibrosis in vivo and inactivates stellate cells and Kupffer cells in vitro. PloS ONE, 8.","DOI":"10.1371\/journal.pone.0053988"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"256561","DOI":"10.1155\/2012\/256561","article-title":"Evaluation of the Chinese Medicinal Herb, Graptopetalum paraguayense, as a Therapeutic Treatment for Liver Damage in Rat Models","volume":"2012","author":"Su","year":"2012","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_21","first-page":"S122","article-title":"Transforming growth factor-beta and hepatocyte transdifferentiation in liver fibrogenesis","volume":"23","author":"Dooley","year":"2008","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Tang, L.X., He, R.H., Yang, G., Tan, J.J., Zhou, L., Meng, X.M., Huang, X.R., and Lan, H.Y. (2012). Asiatic acid inhibits liver fibrosis by blocking TGF-beta\/Smad signaling in vivo and in vitro. PloS ONE, 7.","DOI":"10.1371\/journal.pone.0031350"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e714","DOI":"10.1038\/cddis.2013.244","article-title":"TGF-beta1 regulates cell fate during epithelial-mesenchymal transition by upregulating survivin","volume":"4","author":"Lee","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1111\/j.1478-3231.2009.02011.x","article-title":"Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in mice","volume":"29","author":"Latella","year":"2009","journal-title":"Liver Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1053\/j.gastro.2008.04.038","article-title":"Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage","volume":"135","author":"Dooley","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4619","DOI":"10.1242\/jcs.01481","article-title":"MAP kinases and cell migration","volume":"117","author":"Huang","year":"2004","journal-title":"J. Cell Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1167\/iovs.03-0700","article-title":"Role of p38 MAP kinase in regulation of cell migration and proliferation in healing corneal epithelium","volume":"45","author":"Saika","year":"2004","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1038\/mt.2008.160","article-title":"Dual Therapeutic Effects of Interferon-alpha Gene Therapy in a Rat Hepatocellular Carcinoma Model With Liver Cirrhosis","volume":"16","author":"Huang","year":"2008","journal-title":"Mol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.biopha.2017.01.107","article-title":"Sorafenib: A potential therapeutic drug for hepatic fibrosis and its outcomes","volume":"88","author":"Ma","year":"2017","journal-title":"Biomed. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1590\/1414-431x20143962","article-title":"Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model","volume":"48","author":"Stefano","year":"2015","journal-title":"Braz. J. Med. Biol Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"509","DOI":"10.3748\/wjg.v12.i4.509","article-title":"Molecular therapy for hepatic injury and fibrosis: Where are we?","volume":"12","author":"Prosser","year":"2006","journal-title":"World J. Gastroenterol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.cca.2007.02.038","article-title":"Biomarkers of liver fibrosis: Clinical translation of molecular pathogenesis or based on liver-dependent malfunction tests","volume":"381","author":"Gressner","year":"2007","journal-title":"Clin. Chim. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1440-1746.2011.07002.x","article-title":"What\u2019s new in liver fibrosis? The origin of myofibroblasts in liver fibrosis","volume":"27","author":"Iwaisako","year":"2012","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.phymed.2004.10.003","article-title":"The efficacy of Liv-52 on liver cirrhotic patients: A randomized, double-blind, placebo-controlled first approach","volume":"12","author":"Huseini","year":"2005","journal-title":"Phytomedicine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1111\/j.1365-2893.2008.00971.x","article-title":"Effects of silymarin on the resolution of liver fibrosis induced by carbon tetrachloride in rats","volume":"15","author":"Tsai","year":"2008","journal-title":"J. Viral. Hepat."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1111\/j.1872-034X.2011.00829.x","article-title":"Therapeutic effects of the oriental herbal medicine Sho-saiko-to on liver cirrhosis and carcinoma","volume":"41","author":"Lee","year":"2011","journal-title":"Hepatol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Takahashi, Y., Soejima, Y., Kumagai, A., Watanabe, M., Uozaki, H., and Fukusato, T. (2014). Inhibitory effects of Japanese herbal medicines sho-saiko-to and juzen-taiho-to on nonalcoholic steatohepatitis in mice. PloS ONE, 9.","DOI":"10.1371\/journal.pone.0087279"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.jep.2005.10.021","article-title":"In vitro protective effects of salvianolic acid B on primary hepatocytes and hepatic stellate cells","volume":"105","author":"Lin","year":"2006","journal-title":"J. Ethnopharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nature02006","article-title":"Smad-dependent and Smad-independent pathways in TGF-beta family signalling","volume":"425","author":"Derynck","year":"2003","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Vallee, A., Lecarpentier, Y., and Vallee, J.N. (2017). Thermodynamic Aspects and Reprogramming Cellular Energy Metabolism during the Fibrosis Process. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122537"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1096\/fj.03-1273rev","article-title":"TGF-beta signaling and the fibrotic response","volume":"18","author":"Leask","year":"2004","journal-title":"FASEB J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1136\/gut.2005.088690","article-title":"Emerging insights into Transforming growth factor beta Smad signal in hepatic fibrogenesis","volume":"56","author":"Inagaki","year":"2007","journal-title":"Gut"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1053\/j.gastro.2004.08.028","article-title":"From quiescence to activation: Gene regulation in hepatic stellate cells","volume":"127","author":"Rippe","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1053\/j.gastro.2008.03.003","article-title":"Mechanisms of hepatic fibrogenesis","volume":"134","author":"Friedman","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2009.09.026","article-title":"Oxidative stress and glutathione in TGF-beta-mediated fibrogenesis","volume":"48","author":"Liu","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.1478-3231.2005.01192.x","article-title":"Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis","volume":"26","author":"Liu","year":"2006","journal-title":"Liver Int."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.matbio.2005.03.003","article-title":"Transdifferentiation-dependent expression of alpha-SMA in hepatic stellate cells does not involve TGF-beta pathways leading to coinduction of collagen type I and thrombospondin-2","volume":"24","author":"Lindert","year":"2005","journal-title":"Matrix Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1053\/gast.2003.50012","article-title":"Liver fibrosis: Insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors","volume":"124","author":"Yang","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1177\/0023677215570086","article-title":"Diethylnitrosamine (DEN)-induced carcinogenic liver injury in mice","volume":"49","author":"Tolba","year":"2015","journal-title":"Lab. Anim."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.jhep.2008.07.024","article-title":"A rodent model of NASH with cirrhosis, oval cell proliferation and hepatocellular carcinoma","volume":"49","author":"Oliveira","year":"2008","journal-title":"J. Hepatol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/j.1478-3231.2006.01424.x","article-title":"New molecular targets for hepatocellular carcinoma: The ErbB1 signaling system","volume":"27","author":"Berasain","year":"2007","journal-title":"Liver Int."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.tibs.2014.04.004","article-title":"Emerging roles of the p38 MAPK and PI3K\/AKT\/mTOR pathways in oncogene-induced senescence","volume":"39","author":"Xu","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1111\/j.1440-1746.2008.05573.x","article-title":"Effects of rhubarb on migration of rat hepatic stellate cells","volume":"24","author":"Lin","year":"2009","journal-title":"J. Gastroenterol. Hepatol"},{"key":"ref_54","first-page":"23","article-title":"Wound-healing assay","volume":"294","author":"Rodriguez","year":"2005","journal-title":"Methods Mol. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.3892\/ol.2016.4155","article-title":"20(S)-Protopanaxadiol saponins inhibit SKOV3 cell migration","volume":"11","author":"Li","year":"2016","journal-title":"Oncol. Lett."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/10\/2592\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:55:17Z","timestamp":1760187317000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/10\/2592"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,27]]},"references-count":55,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["ijms20102592"],"URL":"https:\/\/doi.org\/10.3390\/ijms20102592","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,27]]}}}