{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:57:38Z","timestamp":1790812658766,"version":"4.1.0"},"reference-count":66,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Aim: The aim of the present study is to investigate the effect of long-term zinc supplementation, which is important for the activation of various enzymes that contribute to antioxidant and antifibrotic activities, on the improvement of serum fibrotic markers in patients with autoimmune hepatitis (AIH). Methods: A total of 38 patients with AIH under regular treatment at our hospital who provided their consent for being treated with polaprezinc (75 mg twice daily) were included and classified into 2 groups: the patients with zinc elevation (n = 27) and the patients without zinc elevation (n = 11). Serum biomarker of fibrosis, protein expression levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were evaluated. Results: A significant difference was found between the variability of serum procollagen type \u2162 and collagen type \u2163-7S between the 2 groups before and after zinc administration for more than 24 months (p = 0.043 and p = 0.049). In the patients with zinc elevation, no significant changes were found in collagenase (MMP-1 and MMP-13) before and after zinc administration, whereas a significant increase in the expression of gelatinase (MMP-2 and MMP-9) was found after administration (p = 0.021 and p = 0.005). As for the relative ratio of MMPs to TIMPs, only MMP-9 to TIMP-1 showed a significant increase (p = 0.004). Conclusions: Long-term treatment with polaprezinc has been demonstrated to safely improve serum fibrosis indices through increases in MMP-2\/-9 and MMP-9\/TIMP-1 and is expected to be well combined with direct antifibrotic therapies such as molecularly targeted agents.<\/jats:p>","DOI":"10.3390\/jcm10112465","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T10:38:39Z","timestamp":1622630319000},"page":"2465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Zinc Administration and Improved Serum Markers of Hepatic Fibrosis in Patients with Autoimmune Hepatitis"],"prefix":"10.3390","volume":"10","author":[{"given":"Kei","family":"Moriya","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6295-3283","authenticated-orcid":false,"given":"Norihisa","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3158-5318","authenticated-orcid":false,"given":"Tadashi","family":"Namisaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Takaya","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiko","family":"Sawada","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4361-0592","authenticated-orcid":false,"given":"Hideto","family":"Kawaratani","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Kaji","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, 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Kashihara, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6675-0475","authenticated-orcid":false,"given":"Takemi","family":"Akahane","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Mitoro","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Yamao","sequence":"additional","affiliation":[{"name":"Department of Endoscopy, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, 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Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1111\/hepr.13347","article-title":"Emerging Novel Treatments for Autoimmune Liver Diseases","volume":"49","author":"Tanaka","year":"2019","journal-title":"Hepatol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2015). EASL Clinical Practice Guidelines: Autoimmune hepatitis. J. Hepatol., 63, 971\u20131004.","DOI":"10.1016\/j.jhep.2015.06.030"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1002\/hep.23584","article-title":"Diagnosis and management of autoimmune hepatitis","volume":"51","author":"Manns","year":"2010","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1002\/hep.25658","article-title":"Long-term outcome of Japanese patients with type 1 Autoimmune hepatitis","volume":"56","author":"Yoshizawa","year":"2012","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1097\/RHU.0000000000000215","article-title":"Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Disease on High-Dose Glucocorticoid","volume":"21","author":"Chew","year":"2015","journal-title":"J. Clin. Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1053\/j.gastro.2020.05.032","article-title":"Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: Results from an international registry","volume":"159","author":"Brenner","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Consani Fern\u00e1ndez, S.A., D\u00edaz Cu\u00f1a, C.L., Fern\u00e1ndez Rey, L., Rost\u00e1n Sellanes, S., Maciel Oleggini, G., and Facal Castro, J.A. (2020). Infections in systemic autoimmune diseases. Reumatol. Clin., in press.","DOI":"10.1016\/j.reumae.2020.06.011"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/ajg.2015.139","article-title":"Long-Term Prognostic Significance of Persisting Histological Activity Despite Biochemical Remission in Autoimmune Hepatitis","volume":"110","author":"Dhaliwal","year":"2015","journal-title":"Am. J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1053\/j.gastro.2015.04.043","article-title":"Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients With nonalcoholic fatty liver disease","volume":"149","author":"Angulo","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1002\/hep.510280632","article-title":"Prognosis of chronic hepatitis C: Results of a large, prospective cohort study","volume":"28","author":"Niederau","year":"1998","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"457","DOI":"10.3109\/00365520903555861","article-title":"Characteristics and long-term outcome of patients with autoimmune hepatitis related to the initial treatment response","volume":"45","author":"Werner","year":"2010","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1053\/j.gastro.2011.02.065","article-title":"Long-term outcomes of patients with autoimmune hepatitis managed at a nontransplant center","volume":"140","author":"Hoeroldt","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_14","first-page":"1022","article-title":"Epidemiology and causes of death in a Swedish cohort of patients with autoimmune hepatitis","volume":"52","author":"Marschall","year":"2017","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1447S","DOI":"10.1093\/jn\/130.5.1447S","article-title":"The antioxidant properties of zinc","volume":"130","author":"Powell","year":"2000","journal-title":"J. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1007\/s10620-006-9462-0","article-title":"Zinc and the liver: An active interaction","volume":"52","author":"Stamoulis","year":"2007","journal-title":"Dig. Dis. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/S0016-5085(79)80170-5","article-title":"Collagen Types in Normal and Cirrhotic Liver","volume":"76","author":"Rojkind","year":"1979","journal-title":"Gastroenterology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/S0016-5085(84)80024-4","article-title":"Decrease in Liver Collagen Accumulation in Carbon Tetrachloride-Injured and Normal Growing Rats Upon Administration of Zinc","volume":"86","author":"Anttinen","year":"1984","journal-title":"Gastroenterology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/0005-2744(77)90205-4","article-title":"Evidence for Mammalian Collagenases As Zinc Ion Metalloenzymes","volume":"485","author":"Seltzer","year":"1977","journal-title":"Biochim. Biophys. Acta Enzym."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5807","DOI":"10.1039\/c1cc11485a","article-title":"Emission from a tetrazine derivative complexed with zinc ion in aqueous solution: A unique water-soluble fluorophore","volume":"47","author":"Yuasa","year":"2011","journal-title":"Chem. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0009-2797(03)00087-5","article-title":"Involvement of Intracellular Glutathione in Zinc Deficiency-Induced Activation of Hepatic Stellate Cells","volume":"146","author":"Ohkita","year":"2003","journal-title":"Chem. Interactions"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.jhep.2005.10.013","article-title":"Natural History and Prognostic Indicators of Survival in Cirrhosis: A Systematic Review of 118 Studies","volume":"44","author":"Pagliaro","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.jhep.2006.04.014","article-title":"Bone Marrow-Derived Fibrocytes Participate in Pathogenesis of Liver Fibrosis","volume":"45","author":"Kisseleva","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1053\/j.gastro.2009.07.006","article-title":"Negligible Contribution of Bone Marrow-Derived Cells to Collagen Production During Hepatic Fibrogenesis in Mice","volume":"137","author":"Higashiyama","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1038\/ncomms3823","article-title":"Fate Tracing Reveals Hepatic Stellate Cells As Dominant Contributors to Liver Fibrosis Independent of Its Aetiology","volume":"4","author":"Mederacke","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7473","DOI":"10.1038\/srep07473","article-title":"Eggshell Membrane Ameliorates Hepatic Fibrogenesis in Human C3A Cells and Rats through Changes in PPAR\u03b3-Endothelin 1 Signaling","volume":"4","author":"Jia","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1074\/jbc.M109.076216","article-title":"CD38-mediated Ca2+ signaling contributes to angiotensin II-induced activation of hepatic stellate cells: Attenuation of hepatic fibrosis by CD38 ablation","volume":"285","author":"Kim","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.3748\/wjg.v21.i5.1531","article-title":"Interleukin-22 Ameliorates Liver Fibrogenesis by Attenuating Hepatic Stellate Cell Activation and Downregulating the Levels of Inflammatory Cytokines","volume":"21","author":"Lu","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"14778","DOI":"10.3748\/wjg.v20.i40.14778","article-title":"Halofuginone for fibrosis, regeneration and cancer in the gastrointestinal tract","volume":"20","author":"Pines","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1016\/j.drudis.2012.05.012","article-title":"Farnesoid X Receptor Targeting to Treat Nonalcoholic Steatohepatitis","volume":"17","author":"Adorini","year":"2012","journal-title":"Drug Discov. Today"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1177\/0960327112438928","article-title":"Sulfasalazine prevents the increase in TGF-\u03b2, COX-2, nuclear NFkappaB translocation and fibrosis in CCl4-induced liver cirrhosis in the rat","volume":"31","author":"Shibayama","year":"2012","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.trsl.2014.10.003","article-title":"Melatonin Limits the Expression of Profibrogenic Genes and Ameliorates the Progression of Hepatic Fibrosis in Mice","volume":"165","author":"Crespo","year":"2015","journal-title":"Transl. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1177\/1535370213514922","article-title":"The Peripheral Cannabinoid Receptor 1 Antagonist VD60 Efficiently Inhibits Carbon Tetrachloride-Intoxicated Hepatic Fibrosis Progression","volume":"239","author":"Wei","year":"2014","journal-title":"Exp. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1136\/gut.2010.211136","article-title":"Amelioration of Hepatic Fibrosis by NK Cell Activation","volume":"60","author":"Muhanna","year":"2010","journal-title":"Gut"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.jhep.2013.04.029","article-title":"Impaired CD4+ T Cell Stimulation of NK Cell Anti-Fibrotic Activity May Contribute to Accelerated Liver Fibrosis Progression in HIV\/HCV Patients","volume":"59","author":"Eisenhardt","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/1479-5876-9-55","article-title":"Safety and Pharmacokinetics of Recombinant Human Hepatocyte Growth Factor (rh-HGF) in Patients With Fulminant Hepatitis: A Phase I\/II Clinical Trial, Following Preclinical Studies to Ensure Safety","volume":"9","author":"Ido","year":"2011","journal-title":"J. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.jss.2015.07.042","article-title":"Enhanced Effects of Novel Oridonin Analog CYD0682 for Hepatic Fibrosis","volume":"199","author":"Bohanon","year":"2015","journal-title":"J. Surg. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"15245","DOI":"10.1038\/ncomms15245","article-title":"Zinc Is a Potent and Specific Inhibitor of IFN-\u03bb3 Signalling","volume":"8","author":"Read","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s12576-017-0521-4","article-title":"Physiological Roles of Zinc Transporters: Molecular and Genetic Importance in Zinc Homeostasis","volume":"67","author":"Hara","year":"2017","journal-title":"J. Physiol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1021\/pr050361j","article-title":"Counting the zinc-proteins encoded in the human genome","volume":"5","author":"Andreini","year":"2006","journal-title":"J. Proteome Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1007\/s00775-011-0797-4","article-title":"Zinc homeostasis and signaling in health and diseases: Zinc signaling","volume":"16","author":"Fukada","year":"2011","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Hosui, A., Kimura, E., Abe, S., Tanimoto, T., Onishi, K., Kusumoto, Y., Sueyoshi, Y., Matsumoto, K., Hirao, M., and Yamada, T. (2018). Long-Term Zinc Supplementation Improves Liver Function and Decreases the Risk of Developing Hepatocellular Carcinoma. Nutrients, 10.","DOI":"10.20944\/preprints201810.0496.v1"},{"key":"ref_43","first-page":"178","article-title":"Zinc Supplementation Therapy Improves the Outcome of Patients With Chronic Hepatitis C","volume":"51","author":"Matsumura","year":"2012","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"292","DOI":"10.3164\/jcbn.jcbn08-246","article-title":"Zinc Supplementation Improves the Outcome of Chronic Hepatitis C and Liver Cirrhosis","volume":"45","author":"Matsuoka","year":"2009","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"213","DOI":"10.3177\/jnsv.53.213","article-title":"Zinc Supplementation Prevents the Increase of Transaminase in Chronic Hepatitis C Patients During Combination Therapy With Pegylated Interferon Alpha-2b and Ribavirin","volume":"53","author":"Murakami","year":"2007","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1080\/00365520701272409","article-title":"Efficacy of Zinc Administration in Patients With Hepatitis C Virus-Related Chronic Liver Disease","volume":"42","author":"Himoto","year":"2007","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1111\/hepr.13388","article-title":"Hypozincemia Is Associated With Human Hepatocarcinogenesis in Hepatitis C virus-related Liver Cirrhosis","volume":"49","author":"Shigefuku","year":"2019","journal-title":"Hepatol. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.bbadis.2012.11.002","article-title":"Extracellular Matrix Degradation in Liver Fibrosis: Biochemistry and Regulation","volume":"1832","author":"Iredale","year":"2013","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1161\/01.RES.0000070112.80711.3D","article-title":"Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry","volume":"92","author":"Visse","year":"2003","journal-title":"Circ. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.matbio.2015.01.004","article-title":"Matrix metalloproteinases in liver injury, repair and fibrosis","volume":"44\u201346","author":"Duarte","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"222","DOI":"10.3109\/10409238.2013.770819","article-title":"Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): The next decade","volume":"48","author":"Vandooren","year":"2013","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.matbio.2015.03.005","article-title":"The Role of TIMPs in Regulation of Extracellular Matrix Proteolysis","volume":"44\u201346","author":"Arpino","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5523","DOI":"10.3892\/mmr.2017.7262","article-title":"Polaprezinc Inhibits Liver Fibrosis and Proliferation in Hepatocellular Carcinoma","volume":"16","author":"Ye","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.lfs.2011.10.022","article-title":"Polaprezinc Prevents Ongoing Thioacetamide-Induced Liver Fibrosis in Rats","volume":"90","author":"Kono","year":"2012","journal-title":"Life Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1111\/j.1440-1746.2008.05393.x","article-title":"Polaprezinc Attenuates Liver Fibrosis in a Mouse Model of Non-Alcoholic Steatohepatitis","volume":"23","author":"Sugino","year":"2008","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1872-034X.2007.00065.x","article-title":"Possible Inhibitory Effect of Oral Zinc Supplementation on Hepatic Fibrosis through Downregulation of TIMP-1: A Pilot Study","volume":"37","author":"Takahashi","year":"2007","journal-title":"Hepatol. Res."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Latronico, T., Mascia, C., Pati, I., Zuccala, P., Mengoni, F., Marocco, R., Tieghi, T., Belvisi, V., Lichtner, M., and Vullo, V. (2016). Liver Fibrosis in HCV Monoinfected and HIV\/HCV Coinfected Patients: Dysregulation of Matrix Metalloproteinases (MMPs) and Their Tissue Inhibitors TIMPs and Effect of HCV Protease Inhibitors. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17040455"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/S0168-8278(97)80423-0","article-title":"Circulating Matrix Metalloproteinase-2 and Tissue Inhibitor of Metalloproteinase-1 As Serum Markers of Fibrosis in Patients With Chronic Hepatitis C: Relationship to Interferon Reponse","volume":"26","author":"Kasahara","year":"1997","journal-title":"J. Hepatol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/ijc.1635","article-title":"Clinical Role of MMP-2\/TIMP-2 Imbalance in Hepatocellular Carcinoma","volume":"97","author":"Giannelli","year":"2002","journal-title":"Int. J. Cancer"},{"key":"ref_60","first-page":"96","article-title":"Clinical Significance of Serum Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Chronic Liver Disease","volume":"31","author":"Watanabe","year":"2006","journal-title":"Tokai J. Exp. Clin. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1111\/1744-9987.12398","article-title":"A case of copper deficiency-induced pancytopenia with maintenance hemodialysis outpatient treated with polaprezinc","volume":"20","author":"Kadoya","year":"2016","journal-title":"Ther Apher. Dial."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1111\/hepr.13461","article-title":"Evaluation of Treatment With Zinc Acetate Hydrate in Patients With Liver Cirrhosis Complicated by Zinc Deficiency","volume":"50","author":"Ozeki","year":"2019","journal-title":"Hepatol. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12011-019-01851-y","article-title":"Effects of Zinc Acetate on Serum Zinc Concentrations in Chronic Liver Diseases: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial and a Dose Adjustment Trial","volume":"195","author":"Katayama","year":"2019","journal-title":"Biol. Trace Element Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1111\/1744-9987.13461","article-title":"Comparison of Zinc Acetate Hydrate and Polaprezinc for Zinc Deficiency in Patients on Maintenance Hemodialysis: A single-center, open-label, Prospective Randomized Study","volume":"24","author":"Okamoto","year":"2020","journal-title":"Ther. Apher. Dial."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Kodama, H., Tanaka, M., Naito, Y., Katayama, K., and Moriyama, M. (2020). Japan\u2019s Practical Guidelines for Zinc Deficiency With a Particular Focus on Taste Disorders, Inflammatory Bowel Disease, and Liver Cirrhosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082941"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1093\/ajcn\/50.1.141","article-title":"Inorganic Zinc and the Intestinal Absorption of Ferrous Iron","volume":"50","author":"Crofton","year":"1989","journal-title":"Am. J. Clin. 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