{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T18:59:31Z","timestamp":1780513171351,"version":"3.54.1"},"reference-count":36,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,11,27]],"date-time":"2022-11-27T00:00:00Z","timestamp":1669507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Regional Development Fund","award":["KK.01.1.1.01.0006"],"award-info":[{"award-number":["KK.01.1.1.01.0006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: The aim of this study was to analyze the expression of genes on transcriptomic levels involved in inflammatory immune responses and the development of fibrosis in patients with chronic hepatitis C. Materials and Methods: Expression patterns of 84 selected genes were analyzed with real-time quantitative RT PCR arrays in the peripheral blood of treatment-naive patients with chronic hepatitis C and healthy controls. The panel included pro- and anti-fibrotic genes, genes coding for extracellular matrix (EMC) structural constituents and remodeling enzymes, cell adhesion molecules, inflammatory cytokines, chemokines and growth factors, signal transduction members of the transforming growth factor- beta (TGF-\u00df) superfamily, transcription factors, and genes involved in epithelial to mesenchymal transition. Results: The expression of SMAD-6 coding for a signal transduction TGF-beta superfamily member as well as MMP-8 coding for an ECM protein were significantly increased in CHC patients compared with controls. Conclusions: Chronic hepatitis C was also characterized by a significant downregulation of a set of genes including CAV-1, CTGF, TIMP-3, MMP-1, ITGA-1, LOX, ITGA-2, PLG and CEBPB encoding various biological response modifiers and transcription factors. Our results suggest that chronic hepatitis C is associated with distinct patterns of gene expression modulation in pathways associated with the regulation of immune responses and development of fibrosis.<\/jats:p>","DOI":"10.3390\/medicina58121734","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T03:28:49Z","timestamp":1669606129000},"page":"1734","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Distinct Expression Patterns of Genes Coding for Biological Response Modifiers Involved in Inflammatory Responses and Development of Fibrosis in Chronic Hepatitis C: Upregulation of SMAD-6 and MMP-8 and Downregulation of CAV-1, CTGF, CEBPB, PLG, TIMP-3, MMP-1, ITGA-1, ITGA-2 and LOX"],"prefix":"10.3390","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9362-7213","authenticated-orcid":false,"given":"Leona","family":"Radmani\u0107","sequence":"first","affiliation":[{"name":"Department of Immunological and Molecular Diagnostics, University Hospital for Infectious Diseases, \u201cDr. Fran Mihaljevi\u0107\u201d, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4783-2114","authenticated-orcid":false,"given":"Petra","family":"Kora\u0107","sequence":"additional","affiliation":[{"name":"Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lana","family":"Gorenec","sequence":"additional","affiliation":[{"name":"Department of Immunological and Molecular Diagnostics, University Hospital for Infectious Diseases, \u201cDr. Fran Mihaljevi\u0107\u201d, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0776-3671","authenticated-orcid":false,"given":"Petra","family":"\u0160imi\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Immunological and Molecular Diagnostics, University Hospital for Infectious Diseases, \u201cDr. Fran Mihaljevi\u0107\u201d, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1212-3302","authenticated-orcid":false,"given":"Kristian","family":"Boduli\u0107","sequence":"additional","affiliation":[{"name":"Research Department, University Hospital for Infectious Diseases, \u201cDr. Fran Mihaljevi\u0107\u201d, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Vince","sequence":"additional","affiliation":[{"name":"Department of Viral Hepatitis, University Hospital for Infectious Diseases, \u201cDr. Fran Mihaljevi\u0107\u201d, HR-10000 Zagreb, Croatia"},{"name":"School of Medicine, University of Zagreb, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9852-5806","authenticated-orcid":false,"given":"Snje\u017eana \u017didovec","family":"Lepej","sequence":"additional","affiliation":[{"name":"Department of Immunological and Molecular Diagnostics, University Hospital for Infectious Diseases, \u201cDr. Fran Mihaljevi\u0107\u201d, HR-10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,27]]},"reference":[{"key":"ref_1","unstructured":"International Committee for Taxonomy of Viruses (2021, April 20). HCV Classification. Available online: https:\/\/talk.ictvonline.org\/ictv_wikis\/flaviviridae\/w\/sg_flavi\/56\/hcv-classification."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1016\/S0140-6736(19)32320-7","article-title":"Hepatitis C","volume":"394","author":"Spearman","year":"2019","journal-title":"Lancet"},{"key":"ref_3","unstructured":"WHO (2021, April 20). Global Hepatitis Report 2017. Available online: http:\/\/www.who.int\/hepatitis\/publications\/global-hepatitis-report2017\/en\/."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"604894","DOI":"10.3389\/fmed.2021.604894","article-title":"Novel immune subsets and related cytokines: Emerging players in the progression of liver fibrosis","volume":"8","author":"Wan","year":"2021","journal-title":"Front. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Roehlen, N., Crouchet, E., and Baumert, T.F. (2020). Liver fibrosis: Mechanistic concepts and therapeutic perspectives. Cells, 9.","DOI":"10.3390\/cells9040875"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1002\/cbin.10790","article-title":"Molecular interplays in hepatic stellate cells: Apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis","volume":"41","author":"Ramos","year":"2017","journal-title":"Cell Biol. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1053\/j.gastro.2020.09.065","article-title":"Fibrosis regression after eradication of hepatitis C virus: From bench to bedside","volume":"160","author":"Rockey","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.hbpd.2018.04.003","article-title":"Hepatic fibrosis: It is time to go with hepatic stellate cell-specific therapeutic targets","volume":"17","author":"Ezhilarasan","year":"2018","journal-title":"Hepatobiliary Pancreat. Dis Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3748\/wjg.v19.i1.49","article-title":"Performance of liver stiffness measurements by transient elastography in chronic hepatitis","volume":"19","author":"Ferraioli","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0065-2776(00)75003-6","article-title":"TGF-beta signaling by Smad proteins","volume":"75","author":"Miyazono","year":"2000","journal-title":"Adv. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1053\/j.gastro.2016.09.033","article-title":"Infection of hepatocytes with HCV increases cell surface levels of heparan sulfate proteoglycans, uptake of cholesterol and lipoprotein, and virus entry by up-regulating SMAD6 and SMAD7","volume":"152","author":"Zhang","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1053\/j.gastro.2016.11.029","article-title":"SMAD about hepatitis C virus cell entry and liver disease","volume":"152","author":"Colpitts","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1053\/j.gastro.2021.04.064","article-title":"TGF-\u03b2 signaling in liver, pancreas, and gastrointestinal diseases and cancer","volume":"161","author":"Gough","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/dvdy.338","article-title":"TGF-\u03b2 superfamily co-receptors in cancer","volume":"251","author":"Pawlak","year":"2021","journal-title":"Dev. Dyn."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"614472","DOI":"10.3389\/fcell.2020.614472","article-title":"Energy and dynamics of caveolae trafficking","volume":"8","author":"Matthaeus","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"606122","DOI":"10.3389\/fonc.2021.606122","article-title":"The biomarker potential of caveolin-1 in penile cancer","volume":"11","author":"Panic","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1369\/0022155412468590","article-title":"Relation between ultrastructural localization, changes in caveolin-1, and capillarization of liver sinusoidal endothelial cells in human hepatitis C-related cirrhotic liver","volume":"61","author":"Yamazaki","year":"2013","journal-title":"J. Histochem. Cytochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1007\/s00535-003-1161-4","article-title":"Elevated expression of caveolin-1 at protein and mRNA level in human cirrhotic liver: Relation with nitric oxide","volume":"38","author":"Yokomori","year":"2003","journal-title":"J. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cokakli, M., Erdal, E., Nart, D., Yilmaz, F., Sagol, O., Kilic, M., Karademir, S., and Atabey, N. (2009). Differential expression of Caveolin-1 in hepatocellular carcinoma: Correlation with differentiation state, motility and invasion. BMC Cancer, 9.","DOI":"10.1186\/1471-2407-9-65"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8760","DOI":"10.1038\/s41598-019-45114-1","article-title":"Liver sinusoidal endothelial cells (LSECs) modifications in patients with chronic hepatitis C","volume":"9","author":"Baiocchini","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e10474","DOI":"10.1590\/1414-431x202010474","article-title":"MicroRNA-629-5p promotes osteosarcoma proliferation and migration by targeting caveolin 1","volume":"54","author":"Gao","year":"2021","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_22","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_23","doi-asserted-by":"crossref","unstructured":"Cabral-Pacheco, G.A., Garza-Veloz, I., Castruita-De la Rosa, C., Ramirez-Acu\u00f1a, J.M., Perez-Romero, B.A., Guerrero-Rodriguez, J.F., Martinez-Avila, N., and Martinez-Fierro, M.L. (2020). The roles of matrix metalloproteinases and their inhibitors in human diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249739"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.clinbiochem.2012.02.004","article-title":"Characterization of metalloproteinases, oxidative status and inflammation levels in the different stages of fibrosis in HCV patients","volume":"45","author":"Capone","year":"2012","journal-title":"Clin. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1080\/09674845.2017.1278888","article-title":"Circulating levels of collagen III and MMP-1 in patients with chronic hepatitis C co-infected with hepatitis B virus","volume":"74","author":"Attallah","year":"2017","journal-title":"Br. J. Biomed. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.jconrel.2021.03.016","article-title":"Matrix metalloproteinase-1 decorated polymersomes, a surface-active extracellular matrix therapeutic, potentiates collagen degradation and attenuates early liver fibrosis","volume":"332","author":"Geervliet","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.2741\/4067","article-title":"Regulation of hepatic stellate cells by connective tissue growth factor","volume":"17","author":"Huang","year":"2012","journal-title":"Front. Biosci. Landmark Ed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"105961","DOI":"10.1016\/j.biocel.2021.105961","article-title":"Selective deletion of connective tissue growth factor attenuates experimentally-induced pulmonary fibrosis and pulmonary arterial hypertension","volume":"134","author":"Tam","year":"2021","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"588","DOI":"10.18821\/0869-2084-2019-64-10-588-593","article-title":"Biomarkers of angiogenesis and endothelial dysfunction in children and adolescents with chronic viral hepatitis","volume":"64","author":"Batyrova","year":"2019","journal-title":"Klin. Lab. Diagn."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.virol.2004.11.009","article-title":"Molecular profiling of early stage liver fibrosis in patients with chronic hepatitis C virus infection","volume":"332","author":"Asselah","year":"2005","journal-title":"Virol. J."},{"key":"ref_31","first-page":"23","article-title":"Lysyl oxidase inhibition in primary myelofibrosis: A renewed strategy","volume":"1","author":"Piasecki","year":"2020","journal-title":"Arch. Stem. Cell Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"535673","DOI":"10.3389\/fmicb.2020.535673","article-title":"Transcriptome and miRNome analysis provide new insight into host lipid accumulation, innate immunity, and viral persistence in hepatitis C virus infection in vitro","volume":"11","author":"Li","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Radmani\u0107, L., Boduli\u0107, K., \u0160imi\u010di\u0107, P., Vince, A., and \u017didovec-Lepej, S. (2022). The effect of treatment-induced viral eradication on cytokine and growth factor expression in chronic hepatitis C. Viruses, 14.","DOI":"10.3390\/v14081613"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Baskic, D., Vukovic, V., Popovic, S., Jovanovic, D., Mitrovic, S., Djurdjevic, P., Avramovic, D., Arsovic, A., Bankovic, D., and Cukic, J. (2019). Chronic Hepatitis C: Conspectus of immunological events in the course of fibrosis evolution. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0221142"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13639","DOI":"10.1038\/s41598-022-17954-x","article-title":"Comprehensive bioinformatic analysis of MMP1 in hepatocellular carcinoma and establishment of relevant prognostic model","volume":"12","author":"Dai","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s40265-020-01458-x","article-title":"Strategies targeting the innate immune response for the treatment of hepatitis C virus-associated liver fibrosis","volume":"81","author":"Resino","year":"2021","journal-title":"Drugs"}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/12\/1734\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:27:50Z","timestamp":1760146070000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/12\/1734"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,27]]},"references-count":36,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["medicina58121734"],"URL":"https:\/\/doi.org\/10.3390\/medicina58121734","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,27]]}}}