Hepatitis C: From inflammatory pathogenesis to antiinflammatory/hepatoprotective therapy
|
摘要
Hepatitis C virus(HCV) infection commonly causes progressive liver diseases that deteriorate from chronic inflammation to fibrosis, cirrhosis and even to hepatocellular carcinoma. A long-term, persistent and uncontrolled inflammatory response is a hallmark of these diseases and further leads to hepatic injury and more severe disease progression. The levels of inflammatory cytokines and chemokines change with the states of infection and treatment, and therefore, they may serve as candidate biomarkers for disease progression and therapeutic effects. The mechanisms of HCV-induced inflammation involve classic pathogen pattern recognition, inflammasome activation, intrahepatic inflammatory cascade response, and oxidative and endoplasmic reticulum stress. Direct-acting antivirals(DAAs) are the first-choice therapy for effectively eliminating HCV, but DAAs alone are not sufficient to block the uncontrolled inflammation and severe liver injury in HCV-infected individuals. Some patients who achieve a sustained virologic response after DAA therapy are still at a long-term risk for progression to liver cirrhosis and hepatocellular carcinoma. Therefore, coupling with antiinflammatory/hepatoprotective agents with anti-HCV effects is a promising therapeutic regimen for these patients during or after treatment with DAAs. In this review, we discuss the relationship between inflammatory mediators and HCV infection, summarize the mechanismsof HCV-induced inflammation, and describe the potential roles of anti-inflammatory/hepatoprotective drugs with anti-HCV activity in the treatment of advanced HCV infection.
Hepatitis C virus(HCV) infection commonly causes progressive liver diseases that deteriorate from chronic inflammation to fibrosis, cirrhosis and even to hepatocellular carcinoma. A long-term, persistent and uncontrolled inflammatory response is a hallmark of these diseases and further leads to hepatic injury and more severe disease progression. The levels of inflammatory cytokines and chemokines change with the states of infection and treatment, and therefore, they may serve as candidate biomarkers for disease progression and therapeutic effects. The mechanisms of HCV-induced inflammation involve classic pathogen pattern recognition, inflammasome activation, intrahepatic inflammatory cascade response, and oxidative and endoplasmic reticulum stress. Direct-acting antivirals(DAAs) are the first-choice therapy for effectively eliminating HCV, but DAAs alone are not sufficient to block the uncontrolled inflammation and severe liver injury in HCV-infected individuals. Some patients who achieve a sustained virologic response after DAA therapy are still at a long-term risk for progression to liver cirrhosis and hepatocellular carcinoma. Therefore, coupling with antiinflammatory/hepatoprotective agents with anti-HCV effects is a promising therapeutic regimen for these patients during or after treatment with DAAs. In this review, we discuss the relationship between inflammatory mediators and HCV infection, summarize the mechanismsof HCV-induced inflammation, and describe the potential roles of anti-inflammatory/hepatoprotective drugs with anti-HCV activity in the treatment of advanced HCV infection.
Hepatitis C virus(HCV) infection commonly causes progressive liver diseases that deteriorate from chronic inflammation to fibrosis, cirrhosis and even to hepatocellular carcinoma. A long-term, persistent and uncontrolled inflammatory response is a hallmark of these diseases and further leads to hepatic injury and more severe disease progression. The levels of inflammatory cytokines and chemokines change with the states of infection and treatment, and therefore, they may serve as candidate biomarkers for disease progression and therapeutic effects. The mechanisms of HCV-induced inflammation involve classic pathogen pattern recognition, inflammasome activation, intrahepatic inflammatory cascade response, and oxidative and endoplasmic reticulum stress. Direct-acting antivirals(DAAs) are the first-choice therapy for effectively eliminating HCV, but DAAs alone are not sufficient to block the uncontrolled inflammation and severe liver injury in HCV-infected individuals. Some patients who achieve a sustained virologic response after DAA therapy are still at a long-term risk for progression to liver cirrhosis and hepatocellular carcinoma. Therefore, coupling with antiinflammatory/hepatoprotective agents with anti-HCV effects is a promising therapeutic regimen for these patients during or after treatment with DAAs. In this review, we discuss the relationship between inflammatory mediators and HCV infection, summarize the mechanismsof HCV-induced inflammation, and describe the potential roles of anti-inflammatory/hepatoprotective drugs with anti-HCV activity in the treatment of advanced HCV infection.
引文
1 Rebbani K,Tsukiyama-Kohara K.HCV-Induced Oxidative Stress:Battlefield-Winning Strategy.Oxid Med Cell Longev 2016;2016:7425628[PMID:27293514 DOI:10.1155/2016/7425628]
2 Perlin CM,Ferreira VL,Borba HHL,Wiens A,Ivantes CAP,Lenzi L,Pontarolo R.Quality of life in Brazilian patients with treated or untreated chronic hepatitis C.Rev Inst Med Trop Sao Paulo 2017;59:e81[PMID:29267589 DOI:10.1590/S1678-9946201759081]
3 Wong RJ,Gish RG.Metabolic Manifestations and Complications Associated With Chronic Hepatitis C Virus Infection.Gastroenterol Hepatol(NY)2016;12:293-299[PMID:27499712]
4 Heim MH,Thimme R.Innate and adaptive immune responses in HCV infections.J Hepatol 2014;61:S14-S25[PMID:25443342DOI:10.1016/j.jhep.2014.06.035]
5 Zeremski M,Petrovic LM,Talal AH.The role of chemokines as inflammatory mediators in chronic hepatitis C virus infection.JViral Hepat 2007;14:675-687[PMID:17875002 DOI:10.1111/j.1365-2893.2006.00838.x]
6 Geddawy A,Ibrahim YF,Elbahie NM,Ibrahim MA.Direct Acting Anti-hepatitis C Virus Drugs:Clinical Pharmacology and Future Direction.J Transl Int Med 2017;5:8-17[PMID:28680834 DOI:10.1515/jtim-2017-0007]
7 Conti F,Buonfiglioli F,Scuteri A,Crespi C,Bolondi L,Caraceni P,Foschi FG,Lenzi M,Mazzella G,Verucchi G,Andreone P,Brillanti S.Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals.J Hepatol 2016;65:727-733[PMID:27349488 DOI:10.1016/j.jhep.2016.06.015]
8 Huang JF,Yu ML,Dai CY,Chuang WL.Glucose abnormalities in hepatitis C virus infection.Kaohsiung J Med Sci 2013;29:61-68[PMID:23347806 DOI:10.1016/j.kjms.2012.11.001]
9 D’Elia RV,Harrison K,Oyston PC,Lukaszewski RA,Clark GC.Targeting the“cytokine storm”for therapeutic benefit.Clin Vaccine Immunol 2013;20:319-327[PMID:23283640 DOI:10.1128/CVI.00636-12]
10 Huang CF,Hsieh MY,Yang JF,Chen WC,Yeh ML,Huang CI,Dai CY,Yu ML,Lin ZY,Chen SC,Chuang WL,Huang JF.Serum hs-CRP was correlated with treatment response to pegylated interferon and ribavirin combination therapy in chronic hepatitis C patients.Hepatol Int 2010;4:621-627[PMID:21063486 DOI:10.1007/s12072-010-9200-8]
11 Morgan TR,Ghany MG,Kim HY,Snow KK,Shiffman ML,De Santo JL,Lee WM,Di Bisceglie AM,Bonkovsky HL,Dienstag JL,Morishima C,Lindsay KL,Lok AS;HALT-C Trial Group.Outcome of sustained virological responders with histologically advanced chronic hepatitis C.Hepatology 2010;52:833-844[PMID:20564351 DOI:10.1002/hep.23744]
12 Hsu CC,Lien JC,Chang CW,Chang CH,Kuo SC,Huang TF.Yuwen02f1 suppresses LPS-induced endotoxemia and adjuvantinduced arthritis primarily through blockade of ROS formation,NFkB and MAPK activation.Biochem Pharmacol 2013;85:385-395[PMID:23142712 DOI:10.1016/j.bcp.2012.11.002]
13 Costantini S,Capone F,Guerriero E,Maio P,Colonna G,Castello G.Serum cytokine levels as putative prognostic markers in the progression of chronic HCV hepatitis to cirrhosis.Eur Cytokine Netw 2010;21:251-256[PMID:21081303 DOI:10.1684/ecn.2010.0214]
14 Zeremski M,Dimova R,Brown Q,Jacobson IM,Markatou M,Talal AH.Peripheral CXCR3-associated chemokines as biomarkers of fibrosis in chronic hepatitis C virus infection.J Infect Dis 2009;200:1774-1780[PMID:19848607 DOI:10.1086/646614]
15 Zampino R,Marrone A,Restivo L,Guerrera B,Sellitto A,Rinaldi L,Romano C,Adinolfi LE.Chronic HCV infection and inflammation:Clinical impact on hepatic and extra-hepatic manifestations.World J Hepatol 2013;5:528-540[PMID:24179612 DOI:10.4254/wjh.v5.i10.528]
16 Neuman MG,Schmilovitz-Weiss H,Hilzenrat N,Bourliere M,Marcellin P,Trepo C,Mazulli T,Moussa G,Patel A,Baig AA,Cohen L.Markers of inflammation and fibrosis in alcoholic hepatitis and viral hepatitis C.Int J Hepatol 2012;2012:231210[PMID:22530132 DOI:10.1155/2012/231210]
17 Jonsson JR,Barrie HD,O’Rourke P,Clouston AD,Powell EE.Obesity and steatosis influence serum and hepatic inflammatory markers in chronic hepatitis C.Hepatology 2008;48:80-87[PMID:18571785 DOI:10.1002/hep.22311]
18 Aroucha DC,do Carmo RF,Moura P,Silva JL,Vasconcelos LR,Cavalcanti MS,Muniz MT,Aroucha ML,Siqueira ER,CahúGG,Pereira LM,Coêlho MR.High tumor necrosis factor-α/interleukin-10 ratio is associated with hepatocellular carcinoma in patients with chronic hepatitis C.Cytokine 2013;62:421-425[PMID:23602201 DOI:10.1016/j.cyto.2013.03.024]
19 Knobler H,Schattner A.TNF-{alpha},chronic hepatitis C and diabetes:a novel triad.QJM 2005;98:1-6[PMID:15625348 DOI:10.1093/qjmed/hci001]
20 Falasca K,Ucciferri C,Dalessandro M,Zingariello P,Mancino P,Petrarca C,Pizzigallo E,Conti P,Vecchiet J.Cytokine patterns correlate with liver damage in patients with chronic hepatitis B and C.Ann Clin Lab Sci 2006;36:144-150[PMID:16682509]
21 Jia H,Du J,Zhu S,Ma Y,Cai H.Clinical observation of serum IL-18,IL-10 and sIL-2R levels in patients with chronic hepatitis C pre-and post antiviral treatment.Chin Med J(Engl)2003;116:605-608[PMID:12875732]
22 Fallahi P,Ferrari SM,Giuggioli D,Sebastiani M,Colaci M,Ferri C,Antonelli A.Chemokines in the Pathogenesis and as Therapeutical Markers and Targets of HCV Chronic Infection and HCVExtrahepatic Manifestations.Curr Drug Targets 2017;18:786-793[PMID:26240054 DOI:10.2174/1389450116666150804105937]
23 Larrubia JR,Benito-Martínez S,Calvino M,Sanz-de-Villalobos E,Parra-Cid T.Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection.World J Gastroenterol 2008;14:7149-7159[PMID:19084927 DOI:10.3748/wjg.14.7149]
24 You CR,Park SH,Jeong SW,Woo HY,Bae SH,Choi JY,Sung YC,Yoon SK.Serum IP-10 Levels Correlate with the Severity of Liver Histopathology in Patients Infected with Genotype-1 HCV.Gut Liver 2011;5:506-512[PMID:22195251 DOI:10.5009/gnl.2011.5.4.506]
25 Harvey CE,Post JJ,Palladinetti P,Freeman AJ,Ffrench RA,Kumar RK,Marinos G,Lloyd AR.Expression of the chemokine IP-10(CXCL10)by hepatocytes in chronic hepatitis C virus infection correlates with histological severity and lobular inflammation.J Leukoc Biol 2003;74:360-369[PMID:12949239DOI:10.1189/jlb.0303093]
26 Larrubia JR,Calvino M,Benito S,Sanz-de-Villalobos E,Perna C,Pérez-Hornedo J,González-Mateos F,García-Garzón S,Bienvenido A,Parra T.The role of CCR5/CXCR3 expressing CD8+cells in liver damage and viral control during persistent hepatitis C virus infection.J Hepatol 2007;47:632-641[PMID:17560677 DOI:10.1016/j.jhep.2007.04.009]
27 Butera D,Marukian S,Iwamaye AE,Hembrador E,Chambers TJ,Di Bisceglie AM,Charles ED,Talal AH,Jacobson IM,Rice CM,Dustin LB.Plasma chemokine levels correlate with the outcome of antiviral therapy in patients with hepatitis C.Blood 2005;106:1175-1182[PMID:15860662 DOI:10.1182/blood-2005-01-0126]
28 Yamauchi K,Akbar SM,Horiike N,Michitaka K,Onji M.Increased serum levels of macrophage inflammatory protein-3alpha in chronic viral hepatitis:prognostic importance of macrophage inflammatory protein-3alpha during interferon therapy in chronic hepatitis C.J Viral Hepat 2002;9:213-220[PMID:12010510DOI:10.1046/j.1365-2893.2002.00354.x]
29 Kaplanski G,Farnarier C,Payan MJ,Bongrand P,Durand JM.Increased levels of soluble adhesion molecules in the serum of patients with hepatitis C.Correlation with cytokine concentrations and liver inflammation and fibrosis.Dig Dis Sci 1997;42:2277-2284[PMID:9398806 DOI:10.1023/A:1018818801824]
30 Fukuda R,Ishimura N,Ishihara S,Chowdhury A,Morlyama N,Nogami C,Miyake T,Niigaki M,Tokuda A,Satoh S,Sakai S,Akagi S,Watanabe M,Fukumoto S.Intrahepatic expression of proinflammatory cytokine mRNAs and interferon efficacy in chronic hepatitis C.Liver 1996;16:390-399[PMID:9021719 DOI:10.1111/j.1600-0676.1996.tb00768.x]
31 Nishitsuji H,Funami K,Shimizu Y,Ujino S,Sugiyama K,Seya T,Takaku H,Shimotohno K.Hepatitis C virus infection induces inflammatory cytokines and chemokines mediated by the cross talk between hepatocytes and stellate cells.J Virol 2013;87:8169-8178[PMID:23678168 DOI:10.1128/JVI.00974-13]
32 Li K,Li NL,Wei D,Pfeffer SR,Fan M,Pfeffer LM.Activation of chemokine and inflammatory cytokine response in hepatitis C virusinfected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates.Hepatology2012;55:666-675[PMID:22030901 DOI:10.1002/hep.24763]
33 Wagoner J,Austin M,Green J,Imaizumi T,Casola A,Brasier A,Khabar KS,Wakita T,Gale M Jr,Polyak SJ.Regulation of CXCL-8(interleukin-8)induction by double-stranded RNAsignaling pathways during hepatitis C virus infection.J Virol 2007;81:309-318[PMID:17035306 DOI:10.1128/JVI.01411-06]
34 Chattergoon MA,Latanich R,Quinn J,Winter ME,Buckheit RW3rd,Blankson JN,Pardoll D,Cox AL.HIV and HCV activate the inflammasome in monocytes and macrophages via endosomal Tolllike receptors without induction of type 1 interferon.PLo S Pathog2014;10:e1004082[PMID:24788318 DOI:10.1371/journal.ppat.1004082]
35 Negash AA,Ramos HJ,Crochet N,Lau DT,Doehle B,Papic N,Delker DA,Jo J,Bertoletti A,Hagedorn CH,Gale M Jr.IL-1βproduction through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease.PLo S Pathog 2013;9:e1003330[PMID:23633957 DOI:10.1371/journal.ppat.1003330]
36 Dolganiuc A,Oak S,Kodys K,Golenbock DT,Finberg RW,KurtJones E,Szabo G.Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation.Gastroenterology 2004;127:1513-1524[PMID:15521019 DOI:10.1053/j.gastro.2004.08.067]
37 Machida K,Cheng KT,Sung VM,Levine AM,Foung S,Lai MM.Hepatitis C virus induces toll-like receptor 4 expression,leading to enhanced production of beta interferon and interleukin-6.J Virol 2006;80:866-874[PMID:16378988 DOI:10.1128/JVI.80.2.866-874.2006]
38 Nattermann J,Nischalke HD,Feldmann G,Ahlenstiel G,Sauerbruch T,Spengler U.Binding of HCV E2 to CD81 induces RANTES secretion and internalization of CC chemokine receptor 5.J Viral Hepat 2004;11:519-526[PMID:15500552 DOI:10.1111/j.1365-2893.2004.00545.x]
39 Yu GY,He G,Li CY,Tang M,Grivennikov S,Tsai WT,Wu MS,Hsu CW,Tsai Y,Wang LH,Karin M.Hepatic expression of HCV RNA-dependent RNA polymerase triggers innate immune signaling and cytokine production.Mol Cell 2012;48:313-321[PMID:22959272 DOI:10.1016/j.molcel.2012.07.032]
40 Basu A,Meyer K,Lai KK,Saito K,Di Bisceglie AM,Grosso LE,Ray RB,Ray R.Microarray analyses and molecular profiling of Stat3 signaling pathway induced by hepatitis C virus core protein in human hepatocytes.Virology 2006;349:347-358[PMID:16545852 DOI:10.1016/j.virol.2006.02.023]
41 Davis BK,Wen H,Ting JP.The inflammasome NLRs in immunity,inflammation,and associated diseases.Annu Rev Immunol2011;29:707-735[PMID:21219188 DOI:10.1146/annurevimmunol-031210-101405]
42 Martinon F,Burns K,Tschopp J.The inflammasome:a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.Mol Cell 2002;10:417-426[PMID:12191486 DOI:10.1016/S1097-2765(02)00599-3]
43 Capone F,Guerriero E,Colonna G,Maio P,Mangia A,Castello G,Costantini S.Cytokinome profile evaluation in patients with hepatitis C virus infection.World J Gastroenterol 2014;20:9261-9269[PMID:25071319 DOI:10.3748/wjg.v20.i28.9261]
44 Chen W,Xu Y,Li H,Tao W,Xiang Y,Huang B,Niu J,Zhong J,Meng G.HCV genomic RNA activates the NLRP3 inflammasome in human myeloid cells.PLoS One 2014;9:e84953[PMID:24400125 DOI:10.1371/journal.pone.0084953]
45 Shrivastava S,Mukherjee A,Ray R,Ray RB.Hepatitis C virus induces interleukin-1β(IL-1β)/IL-18 in circulatory and resident liver macrophages.J Virol 2013;87:12284-12290[PMID:24006444 DOI:10.1128/JVI.01962-13]
46 Burdette D,Haskett A,Presser L,McRae S,Iqbal J,Waris G.Hepatitis C virus activates interleukin-1βvia caspase-1-inflammasome complex.J Gen Virol 2012;93:235-246[PMID:21994322 DOI:10.1099/vir.0.034033-0]
47 Farag NS,Breitinger U,El-Azizi M,Breitinger HG.The p7viroporin of the hepatitis C virus contributes to liver inflammation by stimulating production of Interleukin-1β.Biochim Biophys Acta Mol Basis Dis 2017;1863:712-720[PMID:27979709 DOI:10.1016/j.bbadis.2016.12.006]
48 Vollmar B,Menger MD.The hepatic microcirculation:mechanistic contributions and therapeutic targets in liver injury and repair.Physiol Rev 2009;89:1269-1339[PMID:19789382 DOI:10.1152/physrev.00027.2008]
49 Atzori L,Poli G,Perra A.Hepatic stellate cell:a star cell in the liver.Int J Biochem Cell Biol 2009;41:1639-1642[PMID:19433304 DOI:10.1016/j.biocel.2009.03.001]
50 Sidiropoulos K,Viteri G,Sevilla C,Jupe S,Webber M,OrlicMilacic M,Jassal B,May B,Shamovsky V,Duenas C,Rothfels K,Matthews L,Song H,Stein L,Haw R,D’Eustachio P,Ping P,Hermjakob H,Fabregat A.Reactome enhanced pathway visualization.Bioinformatics 2017;33:3461-3467[PMID:29077811 DOI:10.1093/bioinformatics/btx441]
51 Schulze-Krebs A,Preimel D,Popov Y,Bartenschlager R,Lohmann V,Pinzani M,Schuppan D.Hepatitis C virus-replicating hepatocytes induce fibrogenic activation of hepatic stellate cells.Gastroenterology 2005;129:246-258[PMID:16012951 DOI:10.1053/j.gastro.2005.03.089]
52 Devhare PB,Sasaki R,Shrivastava S,Di Bisceglie AM,Ray R,Ray RB.Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells.J Virol 2017;91[PMID:28077652 DOI:10.1128/JVI.02225-16]
53 Florimond A,Chouteau P,Bruscella P,Le Seyec J,Mérour E,Ahnou N,Mallat A,Lotersztajn S,Pawlotsky JM.Human hepatic stellate cells are not permissive for hepatitis C virus entry and replication.Gut 2015;64:957-965[PMID:25063678 DOI:10.1136/gutjnl-2013-305634]
54 Sasaki R,Devhare PB,Steele R,Ray R,Ray RB.Hepatitis Cvirus-induced CCL5 secretion from macrophages activates hepatic stellate cells.Hepatology 2017;66:746-757[PMID:28318046DOI:10.1002/hep.29170]
55 Takahashi K,Asabe S,Wieland S,Garaigorta U,Gastaminza P,Isogawa M,Chisari FV.Plasmacytoid dendritic cells sense hepatitis C virus-infected cells,produce interferon,and inhibit infection.Proc Natl Acad Sci USA 2010;107:7431-7436[PMID:20231459DOI:10.1073/pnas.1002301107]
56 Brault C,Levy PL,Bartosch B.Hepatitis C virus-induced mitochondrial dysfunctions.Viruses 2013;5:954-980[PMID:23518579 DOI:10.3390/v5030954]
57 Fujita N,Sugimoto R,Ma N,Tanaka H,Iwasa M,Kobayashi Y,Kawanishi S,Watanabe S,Kaito M,Takei Y.Comparison of hepatic oxidative DNA damage in patients with chronic hepatitis B and C.J Viral Hepat 2008;15:498-507[PMID:18331251 DOI:10.1111/j.1365-2893.2008.00972.x]
58 Ivanov AV,Bartosch B,Smirnova OA,Isaguliants MG,Kochetkov SN.HCV and oxidative stress in the liver.Viruses 2013;5:439-469[PMID:23358390 DOI:10.3390/v5020439]
59 Tsutsumi T,Matsuda M,Aizaki H,Moriya K,Miyoshi H,Fujie H,Shintani Y,Yotsuyanagi H,Miyamura T,Suzuki T,Koike K.Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon,prohibitin,in cells expressing hepatitis C virus core protein.Hepatology 2009;50:378-386[PMID:19591124 DOI:10.1002/hep.22998]
60 de Mochel NS,Seronello S,Wang SH,Ito C,Zheng JX,Liang TJ,Lambeth JD,Choi J.Hepatocyte NAD(P)H oxidases as an endogenous source of reactive oxygen species during hepatitis Cvirus infection.Hepatology 2010;52:47-59[PMID:20578128DOI:10.1002/hep.23671]
61 Boudreau HE,Emerson SU,Korzeniowska A,Jendrysik MA,Leto TL.Hepatitis C virus(HCV)proteins induce NADPH oxidase4 expression in a transforming growth factor beta-dependent manner:a new contributor to HCV-induced oxidative stress.JVirol 2009;83:12934-12946[PMID:19812163 DOI:10.1128/JVI.01059-09]
62 Reuter S,Gupta SC,Chaturvedi MM,Aggarwal BB.Oxidative stress,inflammation,and cancer:how are they linked?Free Radic Biol Med 2010;49:1603-1616[PMID:20840865 DOI:10.1016/j.freeradbiomed.2010.09.006]
63 Kuroki M,Ariumi Y,Ikeda M,Dansako H,Wakita T,Kato N.Arsenic trioxide inhibits hepatitis C virus RNA replication through modulation of the glutathione redox system and oxidative stress.J Virol 2009;83:2338-2348[PMID:19109388 DOI:10.1128/JVI.01840-08]
64 Presser LD,McRae S,Waris G.Activation of TGF-β1 promoter by hepatitis C virus-induced AP-1 and Sp1:role of TGF-β1 in hepatic stellate cell activation and invasion.PLoS One 2013;8:e56367[PMID:23437118 DOI:10.1371/journal.pone.0056367]
65 Machida K,Cheng KT,Lai CK,Jeng KS,Sung VM,Lai MM.Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species,leading to DNAdamage and STAT3 activation.J Virol 2006;80:7199-7207[PMID:16809325 DOI:10.1128/JVI.00321-06]
66 Tardif KD,Waris G,Siddiqui A.Hepatitis C virus,ER stress,and oxidative stress.Trends Microbiol 2005;13:159-163[PMID:15817385 DOI:10.1016/j.tim.2005.02.004]
67 von dem Bussche A,Machida R,Li K,Loevinsohn G,Khander A,Wang J,Wakita T,Wands JR,Li J.Hepatitis C virus NS2 protein triggers endoplasmic reticulum stress and suppresses its own viral replication.J Hepatol 2010;53:797-804[PMID:20801537 DOI:10.1016/j.jhep.2010.05.022]
68 Liberman E,Fong YL,Selby MJ,Choo QL,Cousens L,Houghton M,Yen TS.Activation of the grp78 and grp94 promoters by hepatitis C virus E2 envelope protein.J Virol 1999;73:3718-3722[PMID:10196264]
69 Merquiol E,Uzi D,Mueller T,Goldenberg D,Nahmias Y,Xavier RJ,Tirosh B,Shibolet O.HCV causes chronic endoplasmic reticulum stress leading to adaptation and interference with the unfolded protein response.PLoS One 2011;6:e24660[PMID:21949742 DOI:10.1371/journal.pone.0024660]
70 Hasnain SZ,Lourie R,Das I,Chen AC,McGuckin MA.The interplay between endoplasmic reticulum stress and inflammation.Immunol Cell Biol 2012;90:260-270[PMID:22249202 DOI:10.1038/icb.2011.112]
71 Waris G,Tardif KD,Siddiqui A.Endoplasmic reticulum(ER)stress:hepatitis C virus induces an ER-nucleus signal transduction pathway and activates NF-kappaB and STAT-3.Biochem Pharmacol 2002;64:1425-1430[PMID:12417255 DOI:10.1016/S0006-2952(02)01300-X]
72 Kacheva S,Lenzen S,Gurgul-Convey E.Differential effects of proinflammatory cytokines on cell death and ER stress in insulin-secreting INS1E cells and the involvement of nitric oxide.Cytokine 2011;55:195-201[PMID:21531147 DOI:10.1016/j.cyto.2011.04.002]
73 Xue X,Piao JH,Nakajima A,Sakon-Komazawa S,Kojima Y,Mori K,Yagita H,Okumura K,Harding H,Nakano H.Tumor necrosis factor alpha(TNFalpha)induces the unfolded protein response(UPR)in a reactive oxygen species(ROS)-dependent fashion,and the UPR counteracts ROS accumulation by TNFalpha.J Biol Chem2005;280:33917-33925[PMID:16107336 DOI:10.1074/jbc.M505818200]
74 Federico A,Aitella E,Sgambato D,Savoia A,De Bartolomeis F,Dallio M,Ruocco E,Pezone L,Abbondanza C,Loguercio C,Astarita C.Telaprevir may induce adverse cutaneous reactions by a T cell immune-mediated mechanism.Ann Hepatol 2015;14:420-424[PMID:25864225]
75 Kim S,Han KH,Ahn SH.Hepatitis C Virus and Antiviral Drug Resistance.Gut Liver 2016;10:890-895[PMID:27784846 DOI:10.5009/gnl15573]
76 Dyson JK,Hutchinson J,Harrison L,Rotimi O,Tiniakos D,Foster GR,Aldersley MA,McPherson S.Liver toxicity associated with sofosbuvir,an NS5A inhibitor and ribavirin use.J Hepatol 2016;64:234-238[PMID:26325535 DOI:10.1016/j.jhep.2015.07.041]
77 Wang C,Ji D,Chen J,Shao Q,Li B,Liu J,Wu V,Wong A,Wang Y,Zhang X,Lu L,Wong C,Tsang S,Zhang Z,Sun J,Hou J,Chen G,Lau G.Hepatitis due to Reactivation of Hepatitis B Virus in Endemic Areas Among Patients With Hepatitis C Treated With Direct-acting Antiviral Agents.Clin Gastroenterol Hepatol 2017;15:132-136[PMID:27392759 DOI:10.1016/j.cgh.2016.06.023]
78 Lam P,Cheung F,Tan HY,Wang N,Yuen MF,Feng Y.Hepatoprotective Effects of Chinese Medicinal Herbs:A Focus on Anti-Inflammatory and Anti-Oxidative Activities.Int J Mol Sci2016;17:465[PMID:27043533 DOI:10.3390/ijms17040465]
79 Chua LS.Review on liver inflammation and antiinflammatory activity of Andrographis paniculata for hepatoprotection.Phytother Res 2014;28:1589-1598[PMID:25043965 DOI:10.1002/ptr.5193]
80 Domitrovi?R,Poto?njak I.A comprehensive overview of hepatoprotective natural compounds:mechanism of action and clinical perspectives.Arch Toxicol 2016;90:39-79[PMID:26377694 DOI:10.1007/s00204-015-1580-z]
81 Kriss M,Burchill M.HCV and nonhepatic malignancy:Is preemptive direct-acting antiviral therapy indicated prior to treatment?Hepatology 2018;67:4-6[PMID:28768054 DOI:10.1002/hep.29414]
82 Federico A,Dallio M,Loguercio C.Silymarin/Silybin and Chronic Liver Disease:A Marriage of Many Years.Molecules 2017;22[PMID:28125040 DOI:10.3390/molecules22020191]
83 Neha,Jaggi AS,Singh N.Silymarin and Its Role in Chronic Diseases.Adv Exp Med Biol 2016;929:25-44[PMID:27771919DOI:10.1007/978-3-319-41342-6_2]
84 Polyak SJ,Ferenci P,Pawlotsky JM.Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection.Hepatology 2013;57:1262-1271[PMID:23213025DOI:10.1002/hep.26179]
85 Stanca E,Serviddio G,Bellanti F,Vendemiale G,Siculella L,Giudetti AM.Down-regulation of LPCAT expression increases platelet-activating factor level in cirrhotic rat liver:potential antiinflammatory effect of silybin.Biochim Biophys Acta 2013;1832:2019-2026[PMID:23851051 DOI:10.1016/j.bbadis.2013.07.005]
86 Gordon A,Hobbs DA,Bowden DS,Bailey MJ,Mitchell J,Francis AJ,Roberts SK.Effects of Silybum marianum on serum hepatitis Cvirus RNA,alanine aminotransferase levels and well-being in patients with chronic hepatitis C.J Gastroenterol Hepatol 2006;21:275-280[PMID:16460486 DOI:10.1111/j.1440-1746.2006.04138.x]
87 Hawke RL,Schrieber SJ,Soule TA,Wen Z,Smith PC,Reddy KR,Wahed AS,Belle SH,Afdhal NH,Navarro VJ,Berman J,Liu QY,Doo E,Fried MW;SyNCH Trial Group.Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C.J Clin Pharmacol 2010;50:434-449[PMID:19841158 DOI:10.1177/0091270009347475]
88 Wen Z,Dumas TE,Schrieber SJ,Hawke RL,Fried MW,Smith PC.Pharmacokinetics and metabolic profile of free,conjugated,and total silymarin flavonolignans in human plasma after oral administration of milk thistle extract.Drug Metab Dispos 2008;36:65-72[PMID:17913795 DOI:10.1124/dmd.107.017566]
89 Ferenci P,Scherzer TM,Kerschner H,Rutter K,Beinhardt S,Hofer H,Sch?niger-Hekele M,Holzmann H,Steindl-Munda P.Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy.Gastroenterology 2008;135:1561-1567[PMID:18771667 DOI:10.1053/j.gastro.2008.07.072]
90 Rutter K,Scherzer TM,Beinhardt S,Kerschner H,St?ttermayer AF,Hofer H,Popow-Kraupp T,Steindl-Munda P,Ferenci P.Intravenous silibinin as‘rescue treatment’for on-treatment nonresponders to pegylated interferon/ribavirin combination therapy.Antivir Ther 2011;16:1327-1333[PMID:22155914 DOI:10.3851/IMP1942]
91 Tipoe GL,Leung TM,Liong EC,Lau TY,Fung ML,Nanji AA.Epigallocatechin-3-gallate(EGCG)reduces liver inflammation,oxidative stress and fibrosis in carbon tetrachloride(CCl4)-induced liver injury in mice.Toxicology 2010;273:45-52[PMID:20438794 DOI:10.1016/j.tox.2010.04.014]
92 Lee MH,Yoon S,Moon JO.The flavonoid naringenin inhibits dimethylnitrosamine-induced liver damage in rats.Biol Pharm Bull2004;27:72-76[PMID:14709902 DOI:10.1248/bpb.27.72]
93 Chao WW,Lin BF.Isolation and identification of bioactive compounds in Andrographis paniculata(Chuanxinlian).Chin Med2010;5:17[PMID:20465823 DOI:10.1186/1749-8546-5-17]
94 Tsai HR,Yang LM,Tsai WJ,Chiou WF.Andrographolide acts through inhibition of ERK1/2 and Akt phosphorylation to suppress chemotactic migration.Eur J Pharmacol 2004;498:45-52[PMID:15363974 DOI:10.1016/j.ejphar.2004.07.077]
95 Lim JC,Chan TK,Ng DS,Sagineedu SR,Stanslas J,Wong WS.Andrographolide and its analogues:versatile bioactive molecules for combating inflammation and cancer.Clin Exp Pharmacol Physiol 2012;39:300-310[PMID:22017767 DOI:10.1111/j.1440-1681.2011.05633.x]
96 Chatuphonprasert W,Jarukamjorn K,Kondo S,Nemoto N.Synergistic increases of metabolism and oxidation-reduction genes on their expression after combined treatment with a CYP1Ainducer and andrographolide.Chem Biol Interact 2009;182:233-238[PMID:19737545 DOI:10.1016/j.cbi.2009.09.001]
97 Jaruchotikamol A,Jarukamjorn K,Sirisangtrakul W,Sakuma T,Kawasaki Y,Nemoto N.Strong synergistic induction of CYP1A1expression by andrographolide plus typical CYP1A inducers in mouse hepatocytes.Toxicol Appl Pharmacol 2007;224:156-162[PMID:17825862 DOI:10.1016/j.taap.2007.07.008]
98 Kapil A,Koul IB,Banerjee SK,Gupta BD.Antihepatotoxic effects of major diterpenoid constituents of Andrographis paniculata.Biochem Pharmacol 1993;46:182-185[PMID:8347130 DOI:10.1016/0006-2952(93)90364-3]
99 Suebsasana S,Pongnaratorn P,Sattayasai J,Arkaravichien T,Tiamkao S,Aromdee C.Analgesic,antipyretic,anti-inflammatory and toxic effects of andrographolide derivatives in experimental animals.Arch Pharm Res 2009;32:1191-1200[PMID:19784573DOI:10.1007/s12272-009-1902-x]
100 Li J,Huang W,Zhang H,Wang X,Zhou H.Synthesis of andrographolide derivatives and their TNF-alpha and IL-6expression inhibitory activities.Bioorg Med Chem Lett 2007;17:6891-6894[PMID:17962017 DOI:10.1016/j.bmcl.2007.10.009]
101 Lee JC,Tseng CK,Young KC,Sun HY,Wang SW,Chen WC,Lin CK,Wu YH.Andrographolide exerts anti-hepatitis C virus activity by up-regulating haeme oxygenase-1 via the p38 MAPK/Nrf2pathway in human hepatoma cells.Br J Pharmacol 2014;171:237-252[PMID:24117426 DOI:10.1111/bph.12440]
102 Chandramohan V,Kaphle A,Chekuri M,Gangarudraiah S,Bychapur Siddaiah G.Evaluating Andrographolide as a Potent Inhibitor of NS3-4A Protease and Its Drug-Resistant Mutants Using In Silico Approaches.Adv Virol 2015;2015:972067[PMID:26587022 DOI:10.1155/2015/972067]
103 Esatbeyoglu T,Huebbe P,Ernst IM,Chin D,Wagner AE,Rimbach G.Curcumin--from molecule to biological function.Angew Chem Int Ed Engl 2012;51:5308-5332[PMID:22566109DOI:10.1002/anie.201107724]
104 Mantzorou M,Pavlidou E,Vasios G,Tsagalioti E,Giaginis C.Effects of curcumin consumption on human chronic diseases:Anarrative review of the most recent clinical data.Phytother Res2018;32:957-975[PMID:29468820 DOI:10.1002/ptr.6037]
105 Shehzad A,Rehman G,Lee YS.Curcumin in inflammatory diseases.Biofactors 2013;39:69-77[PMID:23281076 DOI:10.1002/biof.1066]
106 Sordillo PP,Helson L.Curcumin suppression of cytokine release and cytokine storm.A potential therapy for patients with Ebola and other severe viral infections.In Vivo 2015;29:1-4[PMID:25600522]
107 Tang Y,Zheng S,Chen A.Curcumin eliminates leptin’s effects on hepatic stellate cell activation via interrupting leptin signaling.Endocrinology 2009;150:3011-3020[PMID:19299451 DOI:10.1210/en.2008-1601]
108 Samuhasaneeto S,Thong-Ngam D,Kulaputana O,Suyasunanont D,Klaikeaw N.Curcumin decreased oxidative stress,inhibited NF-kappaB activation,and improved liver pathology in ethanolinduced liver injury in rats.J Biomed Biotechnol 2009;2009:981963[PMID:19606259 DOI:10.1155/2009/981963]
109 Fu Y,Zheng S,Lin J,Ryerse J,Chen A.Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation.Mol Pharmacol 2008;73:399-409[PMID:18006644 DOI:10.1124/mol.107.039818]
110 Chen MH,Lee MY,Chuang JJ,Li YZ,Ning ST,Chen JC,Liu YW.Curcumin inhibits HCV replication by induction of heme oxygenase-1 and suppression of AKT.Int J Mol Med 2012;30:1021-1028[PMID:22922731 DOI:10.3892/ijmm.2012.1096]
111 Kim K,Kim KH,Kim HY,Cho HK,Sakamoto N,Cheong J.Curcumin inhibits hepatitis C virus replication via suppressing the Akt-SREBP-1 pathway.FEBS Lett 2010;584:707-712[PMID:20026048 DOI:10.1016/j.febslet.2009.12.019]
112 Anggakusuma,Colpitts CC,Schang LM,Rachmawati H,Frentzen A,Pfaender S,Behrendt P,Brown RJ,Bankwitz D,Steinmann J,Ott M,Meuleman P,Rice CM,Ploss A,Pietschmann T,Steinmann E.Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells.Gut 2014;63:1137-1149[PMID:23903236 DOI:10.1136/gutjnl-2012-304299]
113 Azzam HS,Goertz C,Fritts M,Jonas WB.Natural products and chronic hepatitis C virus.Liver Int 2007;27:17-25[PMID:17241377 DOI:10.1111/j.1478-3231.2006.01408.x]
114 Yu YY,Wang QH,Zhu LM,Zhang QB,Xu DZ,Guo YB,Wang CQ,Guo SH,Zhou XQ,Zhang LX.A clinical research on oxymatrine for the treatment of chronic hepatitis B.Zhonghua Gan Zang Bing Za Zhi 2002;10:280-281[PMID:12223140]
115 Chen N,Liu YH,Liu XJ,Chen YR,Guo YH,Liu M.[Oxymatrine inhibits target cell infection in the HCVcc system].Zhonghua Gan Zang Bing Za Zhi 2016;24:40-45[PMID:26983388 DOI:10.3760/cma.j.issn.1007-3418.2016.01.008]
116 Chen Y,Li J,Zeng M,Lu L,Qu D,Mao Y,Fan Z,Hua J.[The inhibitory effect of oxymatrine on hepatitis C virus in vitro].Zhonghua Gan Zang Bing Za Zhi 2001;9 Suppl:12-14[PMID:11509127]
117 Li J,Li C,Zeng M.[Preliminary study on therapeutic effect of oxymatrine in treating patients with chronic hepatitis C].Zhongguo Zhong Xi Yi Jie He Za Zhi 1998;18:227-229[PMID:11475748]
118 Li YH,Wu ZY,Tang S,Zhang X,Wang YX,Jiang JD,Peng ZG,Song DQ.Evolution of matrinic ethanol derivatives as anti-HCVagents from matrine skeleton.Bioorg Med Chem Lett 2017;27:1962-1966[PMID:28320615 DOI:10.1016/j.bmcl.2017.03.025]
119 Basile A,Pascale M,Franceschelli S,Nieddu E,Mazzei MT,Fossa P,Turco MC,Mazzei M.Matrine modulates HSC70 levels and rescuesΔF508-CFTR.J Cell Physiol 2012;227:3317-3323[PMID:22170045 DOI:10.1002/jcp.24028]
120 Du NN,Li X,Wang YP,Liu F,Liu YX,Li CX,Peng ZG,Gao LM,Jiang JD,Song DQ.Synthesis,structure-activity relationship and biological evaluation of novel N-substituted matrinic acid derivatives as host heat-stress cognate 70(Hsc70)down-regulators.Bioorg Med Chem Lett 2011;21:4732-4735[PMID:21757347DOI:10.1016/j.bmcl.2011.06.071]
121 Peng ZG,Fan B,Du NN,Wang YP,Gao LM,Li YH,Li YH,Liu F,You XF,Han YX,Zhao ZY,Cen S,Li JR,Song DQ,Jiang JD.Small molecular compounds that inhibit hepatitis C virus replication through destabilizing heat shock cognate 70 messenger RNA.Hepatology 2010;52:845-853[PMID:20593456 DOI:10.1002/hep.23766]
122 Zhao HW,Zhang ZF,Chai X,Li GQ,Cui HR,Wang HB,Meng YK,Liu HM,Wang JB,Li RS,Bai ZF,Xiao XH.Oxymatrine attenuates CCl4-induced hepatic fibrosis via modulation of TLR4-dependent inflammatory and TGF-β1 signaling pathways.Int Immunopharmacol 2016;36:249-255[PMID:27179304 DOI:10.1016/j.intimp.2016.04.040]
123 Chai NL,Fu Q,Shi H,Cai CH,Wan J,Xu SP,Wu BY.Oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells.World J Gastroenterol 2012;18:4199-4206[PMID:22919254 DOI:10.3748/wjg.v18.i31.4199]
124 Wu XL,Zeng WZ,Jiang MD,Qin JP,Xu H.Effect of Oxymatrine on the TGFbeta-Smad signaling pathway in rats with CCl4-induced hepatic fibrosis.World J Gastroenterol 2008;14:2100-2105[PMID:18395914 DOI:10.3748/wjg.14.2100]
125 Shi GF,Li Q.Effects of oxymatrine on experimental hepatic fibrosis and its mechanism in vivo.World J Gastroenterol 2005;11:268-271[PMID:15633229 DOI:10.3748/wjg.v11.i2.268]
126 Yang W,Zeng M,Fan Z,Mao Y,Song Y,Jia Y,Lu L,Chen CW,Peng YS,Zhu HY.[Prophylactic and therapeutic effect of oxymatrine on D-galactosamine-induced rat liver fibrosis].Zhonghua Gan Zang Bing Za Zhi 2002;10:193-196[PMID:12113677]
127 Liu Y,Xu Y,Ji W,Li X,Sun B,Gao Q,Su C.Anti-tumor activities of matrine and oxymatrine:literature review.Tumour Biol 2014;35:5111-5119[PMID:24526416 DOI:10.1007/s13277-014-1680-z]
128 Lao Y.Clinical study on effect of matrine injection to protect the liver function for patients with primary hepatic carcinoma after trans-artery chemo-embolization(TAE).Zhong Yao Cai 2005;28:637-638[PMID:16252735]
129 Weiskirchen R.Hepatoprotective and Anti-fibrotic Agents:It’s Time to Take the Next Step.Front Pharmacol 2016;6:303[PMID:26779021 DOI:10.3389/fphar.2015.00303]
130 Huang H,Chen Y,Ye J.Inhibition of hepatitis C virus replication by peroxidation of arachidonate and restoration by vitamin E.Proc Natl Acad Sci USA 2007;104:18666-18670[PMID:18003907DOI:10.1073/pnas.0708423104]
131 Melhem A,Stern M,Shibolet O,Israeli E,Ackerman Z,Pappo O,Hemed N,Rowe M,Ohana H,Zabrecky G,Cohen R,Ilan Y.Treatment of chronic hepatitis C virus infection via antioxidants:results of a phase I clinical trial.J Clin Gastroenterol 2005;39:737-742[PMID:16082287]
132 Tee HP,Kaffes AJ.Non-small-bowel lesions encountered during double-balloon enteroscopy performed for obscure gastrointestinal bleeding.World J Gastroenterol 2010;16:1885-1889[PMID:20397267 DOI:10.3748/wjg.v16.i15.1885]
133 Beloqui O,Prieto J,Suárez M,Gil B,Qian CH,García N,Civeira MP.N-acetyl cysteine enhances the response to interferon-alpha in chronic hepatitis C:a pilot study.J Interferon Res 1993;13:279-282[PMID:8228388]
134 Yang XY,Zhuo Q,Wu TX,Liu GJ.Bicyclol for chronic hepatitis C.Cochrane Database Syst Rev 2007;:CD004994[PMID:17253534DOI:10.1002/14651858.CD004994.pub2]
135 Liu GT.Bicyclol:a novel drug for treating chronic viral hepatitis B and C.Med Chem 2009;5:29-43[PMID:19149648 DOI:10.2174/157340609787049316]
136 Zhen YZ,Li NR,He HW,Zhao SS,Zhang GL,Hao XF,Shao RG.Protective effect of bicyclol against bile duct ligation-induced hepatic fibrosis in rats.World J Gastroenterol 2015;21:7155-7164[PMID:26109801 DOI:10.3748/wjg.v21.i23.7155]
137 Gu Y,Zhao J,Yao XM,Li Y.Effects of bicyclol on immunological liver fibrosis in rats.J Asian Nat Prod Res 2010;12:388-398[PMID:20496196 DOI:10.1080/10286021003789047]
138 Hu QW,Liu GT.Effects of bicyclol on dimethylnitrosamineinduced liver fibrosis in mice and its mechanism of action.Life Sci 2006;79:606-612[PMID:16603200 DOI:10.1016/j.lfs.2006.02.025]
139 Li Y,Li Y,Liu GT.[Protective effects of bicyclol on liver fibrosis induced by carbon tetrachloride].Zhonghua Yi Xue Za Zhi 2004;84:2096-2101[PMID:15730626 DOI:10.3760/j:issn:0376-2491.2004.24.012]
140 Lou XE,Xu N,Yao HP,Chen Z.Bicyclol attenuates proinflammatory cytokine and chemokine productions in CpG-DNA-stimulated L02 hepatocytes by inhibiting p65-NF-kappaB and p38-MAPK activation.Pharmazie 2010;65:206-212[PMID:20383942 DOI:10.1691/ph.2010.9679]
141 Paracha UZ,Fatima K,Alqahtani M,Chaudhary A,Abuzenadah A,Damanhouri G,Qadri I.Oxidative stress and hepatitis C virus.Virol J 2013;10:251[PMID:23923986 DOI:10.1186/1743-422X-10-251]
2 Perlin CM,Ferreira VL,Borba HHL,Wiens A,Ivantes CAP,Lenzi L,Pontarolo R.Quality of life in Brazilian patients with treated or untreated chronic hepatitis C.Rev Inst Med Trop Sao Paulo 2017;59:e81[PMID:29267589 DOI:10.1590/S1678-9946201759081]
3 Wong RJ,Gish RG.Metabolic Manifestations and Complications Associated With Chronic Hepatitis C Virus Infection.Gastroenterol Hepatol(NY)2016;12:293-299[PMID:27499712]
4 Heim MH,Thimme R.Innate and adaptive immune responses in HCV infections.J Hepatol 2014;61:S14-S25[PMID:25443342DOI:10.1016/j.jhep.2014.06.035]
5 Zeremski M,Petrovic LM,Talal AH.The role of chemokines as inflammatory mediators in chronic hepatitis C virus infection.JViral Hepat 2007;14:675-687[PMID:17875002 DOI:10.1111/j.1365-2893.2006.00838.x]
6 Geddawy A,Ibrahim YF,Elbahie NM,Ibrahim MA.Direct Acting Anti-hepatitis C Virus Drugs:Clinical Pharmacology and Future Direction.J Transl Int Med 2017;5:8-17[PMID:28680834 DOI:10.1515/jtim-2017-0007]
7 Conti F,Buonfiglioli F,Scuteri A,Crespi C,Bolondi L,Caraceni P,Foschi FG,Lenzi M,Mazzella G,Verucchi G,Andreone P,Brillanti S.Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals.J Hepatol 2016;65:727-733[PMID:27349488 DOI:10.1016/j.jhep.2016.06.015]
8 Huang JF,Yu ML,Dai CY,Chuang WL.Glucose abnormalities in hepatitis C virus infection.Kaohsiung J Med Sci 2013;29:61-68[PMID:23347806 DOI:10.1016/j.kjms.2012.11.001]
9 D’Elia RV,Harrison K,Oyston PC,Lukaszewski RA,Clark GC.Targeting the“cytokine storm”for therapeutic benefit.Clin Vaccine Immunol 2013;20:319-327[PMID:23283640 DOI:10.1128/CVI.00636-12]
10 Huang CF,Hsieh MY,Yang JF,Chen WC,Yeh ML,Huang CI,Dai CY,Yu ML,Lin ZY,Chen SC,Chuang WL,Huang JF.Serum hs-CRP was correlated with treatment response to pegylated interferon and ribavirin combination therapy in chronic hepatitis C patients.Hepatol Int 2010;4:621-627[PMID:21063486 DOI:10.1007/s12072-010-9200-8]
11 Morgan TR,Ghany MG,Kim HY,Snow KK,Shiffman ML,De Santo JL,Lee WM,Di Bisceglie AM,Bonkovsky HL,Dienstag JL,Morishima C,Lindsay KL,Lok AS;HALT-C Trial Group.Outcome of sustained virological responders with histologically advanced chronic hepatitis C.Hepatology 2010;52:833-844[PMID:20564351 DOI:10.1002/hep.23744]
12 Hsu CC,Lien JC,Chang CW,Chang CH,Kuo SC,Huang TF.Yuwen02f1 suppresses LPS-induced endotoxemia and adjuvantinduced arthritis primarily through blockade of ROS formation,NFkB and MAPK activation.Biochem Pharmacol 2013;85:385-395[PMID:23142712 DOI:10.1016/j.bcp.2012.11.002]
13 Costantini S,Capone F,Guerriero E,Maio P,Colonna G,Castello G.Serum cytokine levels as putative prognostic markers in the progression of chronic HCV hepatitis to cirrhosis.Eur Cytokine Netw 2010;21:251-256[PMID:21081303 DOI:10.1684/ecn.2010.0214]
14 Zeremski M,Dimova R,Brown Q,Jacobson IM,Markatou M,Talal AH.Peripheral CXCR3-associated chemokines as biomarkers of fibrosis in chronic hepatitis C virus infection.J Infect Dis 2009;200:1774-1780[PMID:19848607 DOI:10.1086/646614]
15 Zampino R,Marrone A,Restivo L,Guerrera B,Sellitto A,Rinaldi L,Romano C,Adinolfi LE.Chronic HCV infection and inflammation:Clinical impact on hepatic and extra-hepatic manifestations.World J Hepatol 2013;5:528-540[PMID:24179612 DOI:10.4254/wjh.v5.i10.528]
16 Neuman MG,Schmilovitz-Weiss H,Hilzenrat N,Bourliere M,Marcellin P,Trepo C,Mazulli T,Moussa G,Patel A,Baig AA,Cohen L.Markers of inflammation and fibrosis in alcoholic hepatitis and viral hepatitis C.Int J Hepatol 2012;2012:231210[PMID:22530132 DOI:10.1155/2012/231210]
17 Jonsson JR,Barrie HD,O’Rourke P,Clouston AD,Powell EE.Obesity and steatosis influence serum and hepatic inflammatory markers in chronic hepatitis C.Hepatology 2008;48:80-87[PMID:18571785 DOI:10.1002/hep.22311]
18 Aroucha DC,do Carmo RF,Moura P,Silva JL,Vasconcelos LR,Cavalcanti MS,Muniz MT,Aroucha ML,Siqueira ER,CahúGG,Pereira LM,Coêlho MR.High tumor necrosis factor-α/interleukin-10 ratio is associated with hepatocellular carcinoma in patients with chronic hepatitis C.Cytokine 2013;62:421-425[PMID:23602201 DOI:10.1016/j.cyto.2013.03.024]
19 Knobler H,Schattner A.TNF-{alpha},chronic hepatitis C and diabetes:a novel triad.QJM 2005;98:1-6[PMID:15625348 DOI:10.1093/qjmed/hci001]
20 Falasca K,Ucciferri C,Dalessandro M,Zingariello P,Mancino P,Petrarca C,Pizzigallo E,Conti P,Vecchiet J.Cytokine patterns correlate with liver damage in patients with chronic hepatitis B and C.Ann Clin Lab Sci 2006;36:144-150[PMID:16682509]
21 Jia H,Du J,Zhu S,Ma Y,Cai H.Clinical observation of serum IL-18,IL-10 and sIL-2R levels in patients with chronic hepatitis C pre-and post antiviral treatment.Chin Med J(Engl)2003;116:605-608[PMID:12875732]
22 Fallahi P,Ferrari SM,Giuggioli D,Sebastiani M,Colaci M,Ferri C,Antonelli A.Chemokines in the Pathogenesis and as Therapeutical Markers and Targets of HCV Chronic Infection and HCVExtrahepatic Manifestations.Curr Drug Targets 2017;18:786-793[PMID:26240054 DOI:10.2174/1389450116666150804105937]
23 Larrubia JR,Benito-Martínez S,Calvino M,Sanz-de-Villalobos E,Parra-Cid T.Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection.World J Gastroenterol 2008;14:7149-7159[PMID:19084927 DOI:10.3748/wjg.14.7149]
24 You CR,Park SH,Jeong SW,Woo HY,Bae SH,Choi JY,Sung YC,Yoon SK.Serum IP-10 Levels Correlate with the Severity of Liver Histopathology in Patients Infected with Genotype-1 HCV.Gut Liver 2011;5:506-512[PMID:22195251 DOI:10.5009/gnl.2011.5.4.506]
25 Harvey CE,Post JJ,Palladinetti P,Freeman AJ,Ffrench RA,Kumar RK,Marinos G,Lloyd AR.Expression of the chemokine IP-10(CXCL10)by hepatocytes in chronic hepatitis C virus infection correlates with histological severity and lobular inflammation.J Leukoc Biol 2003;74:360-369[PMID:12949239DOI:10.1189/jlb.0303093]
26 Larrubia JR,Calvino M,Benito S,Sanz-de-Villalobos E,Perna C,Pérez-Hornedo J,González-Mateos F,García-Garzón S,Bienvenido A,Parra T.The role of CCR5/CXCR3 expressing CD8+cells in liver damage and viral control during persistent hepatitis C virus infection.J Hepatol 2007;47:632-641[PMID:17560677 DOI:10.1016/j.jhep.2007.04.009]
27 Butera D,Marukian S,Iwamaye AE,Hembrador E,Chambers TJ,Di Bisceglie AM,Charles ED,Talal AH,Jacobson IM,Rice CM,Dustin LB.Plasma chemokine levels correlate with the outcome of antiviral therapy in patients with hepatitis C.Blood 2005;106:1175-1182[PMID:15860662 DOI:10.1182/blood-2005-01-0126]
28 Yamauchi K,Akbar SM,Horiike N,Michitaka K,Onji M.Increased serum levels of macrophage inflammatory protein-3alpha in chronic viral hepatitis:prognostic importance of macrophage inflammatory protein-3alpha during interferon therapy in chronic hepatitis C.J Viral Hepat 2002;9:213-220[PMID:12010510DOI:10.1046/j.1365-2893.2002.00354.x]
29 Kaplanski G,Farnarier C,Payan MJ,Bongrand P,Durand JM.Increased levels of soluble adhesion molecules in the serum of patients with hepatitis C.Correlation with cytokine concentrations and liver inflammation and fibrosis.Dig Dis Sci 1997;42:2277-2284[PMID:9398806 DOI:10.1023/A:1018818801824]
30 Fukuda R,Ishimura N,Ishihara S,Chowdhury A,Morlyama N,Nogami C,Miyake T,Niigaki M,Tokuda A,Satoh S,Sakai S,Akagi S,Watanabe M,Fukumoto S.Intrahepatic expression of proinflammatory cytokine mRNAs and interferon efficacy in chronic hepatitis C.Liver 1996;16:390-399[PMID:9021719 DOI:10.1111/j.1600-0676.1996.tb00768.x]
31 Nishitsuji H,Funami K,Shimizu Y,Ujino S,Sugiyama K,Seya T,Takaku H,Shimotohno K.Hepatitis C virus infection induces inflammatory cytokines and chemokines mediated by the cross talk between hepatocytes and stellate cells.J Virol 2013;87:8169-8178[PMID:23678168 DOI:10.1128/JVI.00974-13]
32 Li K,Li NL,Wei D,Pfeffer SR,Fan M,Pfeffer LM.Activation of chemokine and inflammatory cytokine response in hepatitis C virusinfected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates.Hepatology2012;55:666-675[PMID:22030901 DOI:10.1002/hep.24763]
33 Wagoner J,Austin M,Green J,Imaizumi T,Casola A,Brasier A,Khabar KS,Wakita T,Gale M Jr,Polyak SJ.Regulation of CXCL-8(interleukin-8)induction by double-stranded RNAsignaling pathways during hepatitis C virus infection.J Virol 2007;81:309-318[PMID:17035306 DOI:10.1128/JVI.01411-06]
34 Chattergoon MA,Latanich R,Quinn J,Winter ME,Buckheit RW3rd,Blankson JN,Pardoll D,Cox AL.HIV and HCV activate the inflammasome in monocytes and macrophages via endosomal Tolllike receptors without induction of type 1 interferon.PLo S Pathog2014;10:e1004082[PMID:24788318 DOI:10.1371/journal.ppat.1004082]
35 Negash AA,Ramos HJ,Crochet N,Lau DT,Doehle B,Papic N,Delker DA,Jo J,Bertoletti A,Hagedorn CH,Gale M Jr.IL-1βproduction through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease.PLo S Pathog 2013;9:e1003330[PMID:23633957 DOI:10.1371/journal.ppat.1003330]
36 Dolganiuc A,Oak S,Kodys K,Golenbock DT,Finberg RW,KurtJones E,Szabo G.Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation.Gastroenterology 2004;127:1513-1524[PMID:15521019 DOI:10.1053/j.gastro.2004.08.067]
37 Machida K,Cheng KT,Sung VM,Levine AM,Foung S,Lai MM.Hepatitis C virus induces toll-like receptor 4 expression,leading to enhanced production of beta interferon and interleukin-6.J Virol 2006;80:866-874[PMID:16378988 DOI:10.1128/JVI.80.2.866-874.2006]
38 Nattermann J,Nischalke HD,Feldmann G,Ahlenstiel G,Sauerbruch T,Spengler U.Binding of HCV E2 to CD81 induces RANTES secretion and internalization of CC chemokine receptor 5.J Viral Hepat 2004;11:519-526[PMID:15500552 DOI:10.1111/j.1365-2893.2004.00545.x]
39 Yu GY,He G,Li CY,Tang M,Grivennikov S,Tsai WT,Wu MS,Hsu CW,Tsai Y,Wang LH,Karin M.Hepatic expression of HCV RNA-dependent RNA polymerase triggers innate immune signaling and cytokine production.Mol Cell 2012;48:313-321[PMID:22959272 DOI:10.1016/j.molcel.2012.07.032]
40 Basu A,Meyer K,Lai KK,Saito K,Di Bisceglie AM,Grosso LE,Ray RB,Ray R.Microarray analyses and molecular profiling of Stat3 signaling pathway induced by hepatitis C virus core protein in human hepatocytes.Virology 2006;349:347-358[PMID:16545852 DOI:10.1016/j.virol.2006.02.023]
41 Davis BK,Wen H,Ting JP.The inflammasome NLRs in immunity,inflammation,and associated diseases.Annu Rev Immunol2011;29:707-735[PMID:21219188 DOI:10.1146/annurevimmunol-031210-101405]
42 Martinon F,Burns K,Tschopp J.The inflammasome:a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.Mol Cell 2002;10:417-426[PMID:12191486 DOI:10.1016/S1097-2765(02)00599-3]
43 Capone F,Guerriero E,Colonna G,Maio P,Mangia A,Castello G,Costantini S.Cytokinome profile evaluation in patients with hepatitis C virus infection.World J Gastroenterol 2014;20:9261-9269[PMID:25071319 DOI:10.3748/wjg.v20.i28.9261]
44 Chen W,Xu Y,Li H,Tao W,Xiang Y,Huang B,Niu J,Zhong J,Meng G.HCV genomic RNA activates the NLRP3 inflammasome in human myeloid cells.PLoS One 2014;9:e84953[PMID:24400125 DOI:10.1371/journal.pone.0084953]
45 Shrivastava S,Mukherjee A,Ray R,Ray RB.Hepatitis C virus induces interleukin-1β(IL-1β)/IL-18 in circulatory and resident liver macrophages.J Virol 2013;87:12284-12290[PMID:24006444 DOI:10.1128/JVI.01962-13]
46 Burdette D,Haskett A,Presser L,McRae S,Iqbal J,Waris G.Hepatitis C virus activates interleukin-1βvia caspase-1-inflammasome complex.J Gen Virol 2012;93:235-246[PMID:21994322 DOI:10.1099/vir.0.034033-0]
47 Farag NS,Breitinger U,El-Azizi M,Breitinger HG.The p7viroporin of the hepatitis C virus contributes to liver inflammation by stimulating production of Interleukin-1β.Biochim Biophys Acta Mol Basis Dis 2017;1863:712-720[PMID:27979709 DOI:10.1016/j.bbadis.2016.12.006]
48 Vollmar B,Menger MD.The hepatic microcirculation:mechanistic contributions and therapeutic targets in liver injury and repair.Physiol Rev 2009;89:1269-1339[PMID:19789382 DOI:10.1152/physrev.00027.2008]
49 Atzori L,Poli G,Perra A.Hepatic stellate cell:a star cell in the liver.Int J Biochem Cell Biol 2009;41:1639-1642[PMID:19433304 DOI:10.1016/j.biocel.2009.03.001]
50 Sidiropoulos K,Viteri G,Sevilla C,Jupe S,Webber M,OrlicMilacic M,Jassal B,May B,Shamovsky V,Duenas C,Rothfels K,Matthews L,Song H,Stein L,Haw R,D’Eustachio P,Ping P,Hermjakob H,Fabregat A.Reactome enhanced pathway visualization.Bioinformatics 2017;33:3461-3467[PMID:29077811 DOI:10.1093/bioinformatics/btx441]
51 Schulze-Krebs A,Preimel D,Popov Y,Bartenschlager R,Lohmann V,Pinzani M,Schuppan D.Hepatitis C virus-replicating hepatocytes induce fibrogenic activation of hepatic stellate cells.Gastroenterology 2005;129:246-258[PMID:16012951 DOI:10.1053/j.gastro.2005.03.089]
52 Devhare PB,Sasaki R,Shrivastava S,Di Bisceglie AM,Ray R,Ray RB.Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells.J Virol 2017;91[PMID:28077652 DOI:10.1128/JVI.02225-16]
53 Florimond A,Chouteau P,Bruscella P,Le Seyec J,Mérour E,Ahnou N,Mallat A,Lotersztajn S,Pawlotsky JM.Human hepatic stellate cells are not permissive for hepatitis C virus entry and replication.Gut 2015;64:957-965[PMID:25063678 DOI:10.1136/gutjnl-2013-305634]
54 Sasaki R,Devhare PB,Steele R,Ray R,Ray RB.Hepatitis Cvirus-induced CCL5 secretion from macrophages activates hepatic stellate cells.Hepatology 2017;66:746-757[PMID:28318046DOI:10.1002/hep.29170]
55 Takahashi K,Asabe S,Wieland S,Garaigorta U,Gastaminza P,Isogawa M,Chisari FV.Plasmacytoid dendritic cells sense hepatitis C virus-infected cells,produce interferon,and inhibit infection.Proc Natl Acad Sci USA 2010;107:7431-7436[PMID:20231459DOI:10.1073/pnas.1002301107]
56 Brault C,Levy PL,Bartosch B.Hepatitis C virus-induced mitochondrial dysfunctions.Viruses 2013;5:954-980[PMID:23518579 DOI:10.3390/v5030954]
57 Fujita N,Sugimoto R,Ma N,Tanaka H,Iwasa M,Kobayashi Y,Kawanishi S,Watanabe S,Kaito M,Takei Y.Comparison of hepatic oxidative DNA damage in patients with chronic hepatitis B and C.J Viral Hepat 2008;15:498-507[PMID:18331251 DOI:10.1111/j.1365-2893.2008.00972.x]
58 Ivanov AV,Bartosch B,Smirnova OA,Isaguliants MG,Kochetkov SN.HCV and oxidative stress in the liver.Viruses 2013;5:439-469[PMID:23358390 DOI:10.3390/v5020439]
59 Tsutsumi T,Matsuda M,Aizaki H,Moriya K,Miyoshi H,Fujie H,Shintani Y,Yotsuyanagi H,Miyamura T,Suzuki T,Koike K.Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon,prohibitin,in cells expressing hepatitis C virus core protein.Hepatology 2009;50:378-386[PMID:19591124 DOI:10.1002/hep.22998]
60 de Mochel NS,Seronello S,Wang SH,Ito C,Zheng JX,Liang TJ,Lambeth JD,Choi J.Hepatocyte NAD(P)H oxidases as an endogenous source of reactive oxygen species during hepatitis Cvirus infection.Hepatology 2010;52:47-59[PMID:20578128DOI:10.1002/hep.23671]
61 Boudreau HE,Emerson SU,Korzeniowska A,Jendrysik MA,Leto TL.Hepatitis C virus(HCV)proteins induce NADPH oxidase4 expression in a transforming growth factor beta-dependent manner:a new contributor to HCV-induced oxidative stress.JVirol 2009;83:12934-12946[PMID:19812163 DOI:10.1128/JVI.01059-09]
62 Reuter S,Gupta SC,Chaturvedi MM,Aggarwal BB.Oxidative stress,inflammation,and cancer:how are they linked?Free Radic Biol Med 2010;49:1603-1616[PMID:20840865 DOI:10.1016/j.freeradbiomed.2010.09.006]
63 Kuroki M,Ariumi Y,Ikeda M,Dansako H,Wakita T,Kato N.Arsenic trioxide inhibits hepatitis C virus RNA replication through modulation of the glutathione redox system and oxidative stress.J Virol 2009;83:2338-2348[PMID:19109388 DOI:10.1128/JVI.01840-08]
64 Presser LD,McRae S,Waris G.Activation of TGF-β1 promoter by hepatitis C virus-induced AP-1 and Sp1:role of TGF-β1 in hepatic stellate cell activation and invasion.PLoS One 2013;8:e56367[PMID:23437118 DOI:10.1371/journal.pone.0056367]
65 Machida K,Cheng KT,Lai CK,Jeng KS,Sung VM,Lai MM.Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species,leading to DNAdamage and STAT3 activation.J Virol 2006;80:7199-7207[PMID:16809325 DOI:10.1128/JVI.00321-06]
66 Tardif KD,Waris G,Siddiqui A.Hepatitis C virus,ER stress,and oxidative stress.Trends Microbiol 2005;13:159-163[PMID:15817385 DOI:10.1016/j.tim.2005.02.004]
67 von dem Bussche A,Machida R,Li K,Loevinsohn G,Khander A,Wang J,Wakita T,Wands JR,Li J.Hepatitis C virus NS2 protein triggers endoplasmic reticulum stress and suppresses its own viral replication.J Hepatol 2010;53:797-804[PMID:20801537 DOI:10.1016/j.jhep.2010.05.022]
68 Liberman E,Fong YL,Selby MJ,Choo QL,Cousens L,Houghton M,Yen TS.Activation of the grp78 and grp94 promoters by hepatitis C virus E2 envelope protein.J Virol 1999;73:3718-3722[PMID:10196264]
69 Merquiol E,Uzi D,Mueller T,Goldenberg D,Nahmias Y,Xavier RJ,Tirosh B,Shibolet O.HCV causes chronic endoplasmic reticulum stress leading to adaptation and interference with the unfolded protein response.PLoS One 2011;6:e24660[PMID:21949742 DOI:10.1371/journal.pone.0024660]
70 Hasnain SZ,Lourie R,Das I,Chen AC,McGuckin MA.The interplay between endoplasmic reticulum stress and inflammation.Immunol Cell Biol 2012;90:260-270[PMID:22249202 DOI:10.1038/icb.2011.112]
71 Waris G,Tardif KD,Siddiqui A.Endoplasmic reticulum(ER)stress:hepatitis C virus induces an ER-nucleus signal transduction pathway and activates NF-kappaB and STAT-3.Biochem Pharmacol 2002;64:1425-1430[PMID:12417255 DOI:10.1016/S0006-2952(02)01300-X]
72 Kacheva S,Lenzen S,Gurgul-Convey E.Differential effects of proinflammatory cytokines on cell death and ER stress in insulin-secreting INS1E cells and the involvement of nitric oxide.Cytokine 2011;55:195-201[PMID:21531147 DOI:10.1016/j.cyto.2011.04.002]
73 Xue X,Piao JH,Nakajima A,Sakon-Komazawa S,Kojima Y,Mori K,Yagita H,Okumura K,Harding H,Nakano H.Tumor necrosis factor alpha(TNFalpha)induces the unfolded protein response(UPR)in a reactive oxygen species(ROS)-dependent fashion,and the UPR counteracts ROS accumulation by TNFalpha.J Biol Chem2005;280:33917-33925[PMID:16107336 DOI:10.1074/jbc.M505818200]
74 Federico A,Aitella E,Sgambato D,Savoia A,De Bartolomeis F,Dallio M,Ruocco E,Pezone L,Abbondanza C,Loguercio C,Astarita C.Telaprevir may induce adverse cutaneous reactions by a T cell immune-mediated mechanism.Ann Hepatol 2015;14:420-424[PMID:25864225]
75 Kim S,Han KH,Ahn SH.Hepatitis C Virus and Antiviral Drug Resistance.Gut Liver 2016;10:890-895[PMID:27784846 DOI:10.5009/gnl15573]
76 Dyson JK,Hutchinson J,Harrison L,Rotimi O,Tiniakos D,Foster GR,Aldersley MA,McPherson S.Liver toxicity associated with sofosbuvir,an NS5A inhibitor and ribavirin use.J Hepatol 2016;64:234-238[PMID:26325535 DOI:10.1016/j.jhep.2015.07.041]
77 Wang C,Ji D,Chen J,Shao Q,Li B,Liu J,Wu V,Wong A,Wang Y,Zhang X,Lu L,Wong C,Tsang S,Zhang Z,Sun J,Hou J,Chen G,Lau G.Hepatitis due to Reactivation of Hepatitis B Virus in Endemic Areas Among Patients With Hepatitis C Treated With Direct-acting Antiviral Agents.Clin Gastroenterol Hepatol 2017;15:132-136[PMID:27392759 DOI:10.1016/j.cgh.2016.06.023]
78 Lam P,Cheung F,Tan HY,Wang N,Yuen MF,Feng Y.Hepatoprotective Effects of Chinese Medicinal Herbs:A Focus on Anti-Inflammatory and Anti-Oxidative Activities.Int J Mol Sci2016;17:465[PMID:27043533 DOI:10.3390/ijms17040465]
79 Chua LS.Review on liver inflammation and antiinflammatory activity of Andrographis paniculata for hepatoprotection.Phytother Res 2014;28:1589-1598[PMID:25043965 DOI:10.1002/ptr.5193]
80 Domitrovi?R,Poto?njak I.A comprehensive overview of hepatoprotective natural compounds:mechanism of action and clinical perspectives.Arch Toxicol 2016;90:39-79[PMID:26377694 DOI:10.1007/s00204-015-1580-z]
81 Kriss M,Burchill M.HCV and nonhepatic malignancy:Is preemptive direct-acting antiviral therapy indicated prior to treatment?Hepatology 2018;67:4-6[PMID:28768054 DOI:10.1002/hep.29414]
82 Federico A,Dallio M,Loguercio C.Silymarin/Silybin and Chronic Liver Disease:A Marriage of Many Years.Molecules 2017;22[PMID:28125040 DOI:10.3390/molecules22020191]
83 Neha,Jaggi AS,Singh N.Silymarin and Its Role in Chronic Diseases.Adv Exp Med Biol 2016;929:25-44[PMID:27771919DOI:10.1007/978-3-319-41342-6_2]
84 Polyak SJ,Ferenci P,Pawlotsky JM.Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection.Hepatology 2013;57:1262-1271[PMID:23213025DOI:10.1002/hep.26179]
85 Stanca E,Serviddio G,Bellanti F,Vendemiale G,Siculella L,Giudetti AM.Down-regulation of LPCAT expression increases platelet-activating factor level in cirrhotic rat liver:potential antiinflammatory effect of silybin.Biochim Biophys Acta 2013;1832:2019-2026[PMID:23851051 DOI:10.1016/j.bbadis.2013.07.005]
86 Gordon A,Hobbs DA,Bowden DS,Bailey MJ,Mitchell J,Francis AJ,Roberts SK.Effects of Silybum marianum on serum hepatitis Cvirus RNA,alanine aminotransferase levels and well-being in patients with chronic hepatitis C.J Gastroenterol Hepatol 2006;21:275-280[PMID:16460486 DOI:10.1111/j.1440-1746.2006.04138.x]
87 Hawke RL,Schrieber SJ,Soule TA,Wen Z,Smith PC,Reddy KR,Wahed AS,Belle SH,Afdhal NH,Navarro VJ,Berman J,Liu QY,Doo E,Fried MW;SyNCH Trial Group.Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C.J Clin Pharmacol 2010;50:434-449[PMID:19841158 DOI:10.1177/0091270009347475]
88 Wen Z,Dumas TE,Schrieber SJ,Hawke RL,Fried MW,Smith PC.Pharmacokinetics and metabolic profile of free,conjugated,and total silymarin flavonolignans in human plasma after oral administration of milk thistle extract.Drug Metab Dispos 2008;36:65-72[PMID:17913795 DOI:10.1124/dmd.107.017566]
89 Ferenci P,Scherzer TM,Kerschner H,Rutter K,Beinhardt S,Hofer H,Sch?niger-Hekele M,Holzmann H,Steindl-Munda P.Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy.Gastroenterology 2008;135:1561-1567[PMID:18771667 DOI:10.1053/j.gastro.2008.07.072]
90 Rutter K,Scherzer TM,Beinhardt S,Kerschner H,St?ttermayer AF,Hofer H,Popow-Kraupp T,Steindl-Munda P,Ferenci P.Intravenous silibinin as‘rescue treatment’for on-treatment nonresponders to pegylated interferon/ribavirin combination therapy.Antivir Ther 2011;16:1327-1333[PMID:22155914 DOI:10.3851/IMP1942]
91 Tipoe GL,Leung TM,Liong EC,Lau TY,Fung ML,Nanji AA.Epigallocatechin-3-gallate(EGCG)reduces liver inflammation,oxidative stress and fibrosis in carbon tetrachloride(CCl4)-induced liver injury in mice.Toxicology 2010;273:45-52[PMID:20438794 DOI:10.1016/j.tox.2010.04.014]
92 Lee MH,Yoon S,Moon JO.The flavonoid naringenin inhibits dimethylnitrosamine-induced liver damage in rats.Biol Pharm Bull2004;27:72-76[PMID:14709902 DOI:10.1248/bpb.27.72]
93 Chao WW,Lin BF.Isolation and identification of bioactive compounds in Andrographis paniculata(Chuanxinlian).Chin Med2010;5:17[PMID:20465823 DOI:10.1186/1749-8546-5-17]
94 Tsai HR,Yang LM,Tsai WJ,Chiou WF.Andrographolide acts through inhibition of ERK1/2 and Akt phosphorylation to suppress chemotactic migration.Eur J Pharmacol 2004;498:45-52[PMID:15363974 DOI:10.1016/j.ejphar.2004.07.077]
95 Lim JC,Chan TK,Ng DS,Sagineedu SR,Stanslas J,Wong WS.Andrographolide and its analogues:versatile bioactive molecules for combating inflammation and cancer.Clin Exp Pharmacol Physiol 2012;39:300-310[PMID:22017767 DOI:10.1111/j.1440-1681.2011.05633.x]
96 Chatuphonprasert W,Jarukamjorn K,Kondo S,Nemoto N.Synergistic increases of metabolism and oxidation-reduction genes on their expression after combined treatment with a CYP1Ainducer and andrographolide.Chem Biol Interact 2009;182:233-238[PMID:19737545 DOI:10.1016/j.cbi.2009.09.001]
97 Jaruchotikamol A,Jarukamjorn K,Sirisangtrakul W,Sakuma T,Kawasaki Y,Nemoto N.Strong synergistic induction of CYP1A1expression by andrographolide plus typical CYP1A inducers in mouse hepatocytes.Toxicol Appl Pharmacol 2007;224:156-162[PMID:17825862 DOI:10.1016/j.taap.2007.07.008]
98 Kapil A,Koul IB,Banerjee SK,Gupta BD.Antihepatotoxic effects of major diterpenoid constituents of Andrographis paniculata.Biochem Pharmacol 1993;46:182-185[PMID:8347130 DOI:10.1016/0006-2952(93)90364-3]
99 Suebsasana S,Pongnaratorn P,Sattayasai J,Arkaravichien T,Tiamkao S,Aromdee C.Analgesic,antipyretic,anti-inflammatory and toxic effects of andrographolide derivatives in experimental animals.Arch Pharm Res 2009;32:1191-1200[PMID:19784573DOI:10.1007/s12272-009-1902-x]
100 Li J,Huang W,Zhang H,Wang X,Zhou H.Synthesis of andrographolide derivatives and their TNF-alpha and IL-6expression inhibitory activities.Bioorg Med Chem Lett 2007;17:6891-6894[PMID:17962017 DOI:10.1016/j.bmcl.2007.10.009]
101 Lee JC,Tseng CK,Young KC,Sun HY,Wang SW,Chen WC,Lin CK,Wu YH.Andrographolide exerts anti-hepatitis C virus activity by up-regulating haeme oxygenase-1 via the p38 MAPK/Nrf2pathway in human hepatoma cells.Br J Pharmacol 2014;171:237-252[PMID:24117426 DOI:10.1111/bph.12440]
102 Chandramohan V,Kaphle A,Chekuri M,Gangarudraiah S,Bychapur Siddaiah G.Evaluating Andrographolide as a Potent Inhibitor of NS3-4A Protease and Its Drug-Resistant Mutants Using In Silico Approaches.Adv Virol 2015;2015:972067[PMID:26587022 DOI:10.1155/2015/972067]
103 Esatbeyoglu T,Huebbe P,Ernst IM,Chin D,Wagner AE,Rimbach G.Curcumin--from molecule to biological function.Angew Chem Int Ed Engl 2012;51:5308-5332[PMID:22566109DOI:10.1002/anie.201107724]
104 Mantzorou M,Pavlidou E,Vasios G,Tsagalioti E,Giaginis C.Effects of curcumin consumption on human chronic diseases:Anarrative review of the most recent clinical data.Phytother Res2018;32:957-975[PMID:29468820 DOI:10.1002/ptr.6037]
105 Shehzad A,Rehman G,Lee YS.Curcumin in inflammatory diseases.Biofactors 2013;39:69-77[PMID:23281076 DOI:10.1002/biof.1066]
106 Sordillo PP,Helson L.Curcumin suppression of cytokine release and cytokine storm.A potential therapy for patients with Ebola and other severe viral infections.In Vivo 2015;29:1-4[PMID:25600522]
107 Tang Y,Zheng S,Chen A.Curcumin eliminates leptin’s effects on hepatic stellate cell activation via interrupting leptin signaling.Endocrinology 2009;150:3011-3020[PMID:19299451 DOI:10.1210/en.2008-1601]
108 Samuhasaneeto S,Thong-Ngam D,Kulaputana O,Suyasunanont D,Klaikeaw N.Curcumin decreased oxidative stress,inhibited NF-kappaB activation,and improved liver pathology in ethanolinduced liver injury in rats.J Biomed Biotechnol 2009;2009:981963[PMID:19606259 DOI:10.1155/2009/981963]
109 Fu Y,Zheng S,Lin J,Ryerse J,Chen A.Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation.Mol Pharmacol 2008;73:399-409[PMID:18006644 DOI:10.1124/mol.107.039818]
110 Chen MH,Lee MY,Chuang JJ,Li YZ,Ning ST,Chen JC,Liu YW.Curcumin inhibits HCV replication by induction of heme oxygenase-1 and suppression of AKT.Int J Mol Med 2012;30:1021-1028[PMID:22922731 DOI:10.3892/ijmm.2012.1096]
111 Kim K,Kim KH,Kim HY,Cho HK,Sakamoto N,Cheong J.Curcumin inhibits hepatitis C virus replication via suppressing the Akt-SREBP-1 pathway.FEBS Lett 2010;584:707-712[PMID:20026048 DOI:10.1016/j.febslet.2009.12.019]
112 Anggakusuma,Colpitts CC,Schang LM,Rachmawati H,Frentzen A,Pfaender S,Behrendt P,Brown RJ,Bankwitz D,Steinmann J,Ott M,Meuleman P,Rice CM,Ploss A,Pietschmann T,Steinmann E.Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells.Gut 2014;63:1137-1149[PMID:23903236 DOI:10.1136/gutjnl-2012-304299]
113 Azzam HS,Goertz C,Fritts M,Jonas WB.Natural products and chronic hepatitis C virus.Liver Int 2007;27:17-25[PMID:17241377 DOI:10.1111/j.1478-3231.2006.01408.x]
114 Yu YY,Wang QH,Zhu LM,Zhang QB,Xu DZ,Guo YB,Wang CQ,Guo SH,Zhou XQ,Zhang LX.A clinical research on oxymatrine for the treatment of chronic hepatitis B.Zhonghua Gan Zang Bing Za Zhi 2002;10:280-281[PMID:12223140]
115 Chen N,Liu YH,Liu XJ,Chen YR,Guo YH,Liu M.[Oxymatrine inhibits target cell infection in the HCVcc system].Zhonghua Gan Zang Bing Za Zhi 2016;24:40-45[PMID:26983388 DOI:10.3760/cma.j.issn.1007-3418.2016.01.008]
116 Chen Y,Li J,Zeng M,Lu L,Qu D,Mao Y,Fan Z,Hua J.[The inhibitory effect of oxymatrine on hepatitis C virus in vitro].Zhonghua Gan Zang Bing Za Zhi 2001;9 Suppl:12-14[PMID:11509127]
117 Li J,Li C,Zeng M.[Preliminary study on therapeutic effect of oxymatrine in treating patients with chronic hepatitis C].Zhongguo Zhong Xi Yi Jie He Za Zhi 1998;18:227-229[PMID:11475748]
118 Li YH,Wu ZY,Tang S,Zhang X,Wang YX,Jiang JD,Peng ZG,Song DQ.Evolution of matrinic ethanol derivatives as anti-HCVagents from matrine skeleton.Bioorg Med Chem Lett 2017;27:1962-1966[PMID:28320615 DOI:10.1016/j.bmcl.2017.03.025]
119 Basile A,Pascale M,Franceschelli S,Nieddu E,Mazzei MT,Fossa P,Turco MC,Mazzei M.Matrine modulates HSC70 levels and rescuesΔF508-CFTR.J Cell Physiol 2012;227:3317-3323[PMID:22170045 DOI:10.1002/jcp.24028]
120 Du NN,Li X,Wang YP,Liu F,Liu YX,Li CX,Peng ZG,Gao LM,Jiang JD,Song DQ.Synthesis,structure-activity relationship and biological evaluation of novel N-substituted matrinic acid derivatives as host heat-stress cognate 70(Hsc70)down-regulators.Bioorg Med Chem Lett 2011;21:4732-4735[PMID:21757347DOI:10.1016/j.bmcl.2011.06.071]
121 Peng ZG,Fan B,Du NN,Wang YP,Gao LM,Li YH,Li YH,Liu F,You XF,Han YX,Zhao ZY,Cen S,Li JR,Song DQ,Jiang JD.Small molecular compounds that inhibit hepatitis C virus replication through destabilizing heat shock cognate 70 messenger RNA.Hepatology 2010;52:845-853[PMID:20593456 DOI:10.1002/hep.23766]
122 Zhao HW,Zhang ZF,Chai X,Li GQ,Cui HR,Wang HB,Meng YK,Liu HM,Wang JB,Li RS,Bai ZF,Xiao XH.Oxymatrine attenuates CCl4-induced hepatic fibrosis via modulation of TLR4-dependent inflammatory and TGF-β1 signaling pathways.Int Immunopharmacol 2016;36:249-255[PMID:27179304 DOI:10.1016/j.intimp.2016.04.040]
123 Chai NL,Fu Q,Shi H,Cai CH,Wan J,Xu SP,Wu BY.Oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells.World J Gastroenterol 2012;18:4199-4206[PMID:22919254 DOI:10.3748/wjg.v18.i31.4199]
124 Wu XL,Zeng WZ,Jiang MD,Qin JP,Xu H.Effect of Oxymatrine on the TGFbeta-Smad signaling pathway in rats with CCl4-induced hepatic fibrosis.World J Gastroenterol 2008;14:2100-2105[PMID:18395914 DOI:10.3748/wjg.14.2100]
125 Shi GF,Li Q.Effects of oxymatrine on experimental hepatic fibrosis and its mechanism in vivo.World J Gastroenterol 2005;11:268-271[PMID:15633229 DOI:10.3748/wjg.v11.i2.268]
126 Yang W,Zeng M,Fan Z,Mao Y,Song Y,Jia Y,Lu L,Chen CW,Peng YS,Zhu HY.[Prophylactic and therapeutic effect of oxymatrine on D-galactosamine-induced rat liver fibrosis].Zhonghua Gan Zang Bing Za Zhi 2002;10:193-196[PMID:12113677]
127 Liu Y,Xu Y,Ji W,Li X,Sun B,Gao Q,Su C.Anti-tumor activities of matrine and oxymatrine:literature review.Tumour Biol 2014;35:5111-5119[PMID:24526416 DOI:10.1007/s13277-014-1680-z]
128 Lao Y.Clinical study on effect of matrine injection to protect the liver function for patients with primary hepatic carcinoma after trans-artery chemo-embolization(TAE).Zhong Yao Cai 2005;28:637-638[PMID:16252735]
129 Weiskirchen R.Hepatoprotective and Anti-fibrotic Agents:It’s Time to Take the Next Step.Front Pharmacol 2016;6:303[PMID:26779021 DOI:10.3389/fphar.2015.00303]
130 Huang H,Chen Y,Ye J.Inhibition of hepatitis C virus replication by peroxidation of arachidonate and restoration by vitamin E.Proc Natl Acad Sci USA 2007;104:18666-18670[PMID:18003907DOI:10.1073/pnas.0708423104]
131 Melhem A,Stern M,Shibolet O,Israeli E,Ackerman Z,Pappo O,Hemed N,Rowe M,Ohana H,Zabrecky G,Cohen R,Ilan Y.Treatment of chronic hepatitis C virus infection via antioxidants:results of a phase I clinical trial.J Clin Gastroenterol 2005;39:737-742[PMID:16082287]
132 Tee HP,Kaffes AJ.Non-small-bowel lesions encountered during double-balloon enteroscopy performed for obscure gastrointestinal bleeding.World J Gastroenterol 2010;16:1885-1889[PMID:20397267 DOI:10.3748/wjg.v16.i15.1885]
133 Beloqui O,Prieto J,Suárez M,Gil B,Qian CH,García N,Civeira MP.N-acetyl cysteine enhances the response to interferon-alpha in chronic hepatitis C:a pilot study.J Interferon Res 1993;13:279-282[PMID:8228388]
134 Yang XY,Zhuo Q,Wu TX,Liu GJ.Bicyclol for chronic hepatitis C.Cochrane Database Syst Rev 2007;:CD004994[PMID:17253534DOI:10.1002/14651858.CD004994.pub2]
135 Liu GT.Bicyclol:a novel drug for treating chronic viral hepatitis B and C.Med Chem 2009;5:29-43[PMID:19149648 DOI:10.2174/157340609787049316]
136 Zhen YZ,Li NR,He HW,Zhao SS,Zhang GL,Hao XF,Shao RG.Protective effect of bicyclol against bile duct ligation-induced hepatic fibrosis in rats.World J Gastroenterol 2015;21:7155-7164[PMID:26109801 DOI:10.3748/wjg.v21.i23.7155]
137 Gu Y,Zhao J,Yao XM,Li Y.Effects of bicyclol on immunological liver fibrosis in rats.J Asian Nat Prod Res 2010;12:388-398[PMID:20496196 DOI:10.1080/10286021003789047]
138 Hu QW,Liu GT.Effects of bicyclol on dimethylnitrosamineinduced liver fibrosis in mice and its mechanism of action.Life Sci 2006;79:606-612[PMID:16603200 DOI:10.1016/j.lfs.2006.02.025]
139 Li Y,Li Y,Liu GT.[Protective effects of bicyclol on liver fibrosis induced by carbon tetrachloride].Zhonghua Yi Xue Za Zhi 2004;84:2096-2101[PMID:15730626 DOI:10.3760/j:issn:0376-2491.2004.24.012]
140 Lou XE,Xu N,Yao HP,Chen Z.Bicyclol attenuates proinflammatory cytokine and chemokine productions in CpG-DNA-stimulated L02 hepatocytes by inhibiting p65-NF-kappaB and p38-MAPK activation.Pharmazie 2010;65:206-212[PMID:20383942 DOI:10.1691/ph.2010.9679]
141 Paracha UZ,Fatima K,Alqahtani M,Chaudhary A,Abuzenadah A,Damanhouri G,Qadri I.Oxidative stress and hepatitis C virus.Virol J 2013;10:251[PMID:23923986 DOI:10.1186/1743-422X-10-251]