Generic placeholder image

Current Molecular Pharmacology


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

Research Article

Daclatasvir and Sofosbuvir Mitigate Hepatic Fibrosis Through Downregulation of TNF-α / NF-κB Signaling Pathway

Author(s): Sherin Zakaria * and Alaa E. El-Sisi

Volume 13 , Issue 4 , 2020

Page: [318 - 327] Pages: 10

DOI: 10.2174/1874467213666200116114919

Price: $65


Background: Hepatic fibrosis is the major issue in chronic liver diseases such as chronic hepatitis C virus (HCV). The newly approved direct acting antiviral (DAA) agents such as Sofosbuvir (SOF) and daclatasvir (DAC) have been found to be associated with decreased fibrotic markers in HCV patients.

Aim: This study tried to explore whether the reported antifibrotic effect of these drugs is antiviral dependent or drug induced.

Method: Hepatic fibrosis was induced by (0.5ml/kg) CCl4 IP twice a week for six weeks. SOF (20 mg/kg/d) and DAC (30 mg/kg/d) were added in the last four weeks of treatments. Liver functions, fibrotic markers such as Hyaluronic acid and metalloproteinase-9 were detected using immunoassay. The expression of TNF-α/NF-κB signaling pathway as well as Bcl-2 were done using immunoassay.

Results: SOF and DAC exerted a potent antifibrotic effect evidenced by their activity against hyaluronic acid HA and metalloproteinase MMP-9 significantly (P≤0.001). This effect was further proved histopathologically where liver tissues from rats treated by drugs showed marked inhibition of collagen precipitation as well as inhibition of HSCs activation. This antifibrotic action was associated with decreased expression of TNF-α /NF-κB signaling pathway and induction of Bcl-2.

Conclusion: SOF/ DAC antifibrotic effect is independent of its antiviral activity. The molecular events associated with this effect were the downregulation of TNF-α / NF-κB signaling pathway and induction of Bcl-2.

Keywords: Sofosbuvir, daclatasvir, TNF-α, NF-κB, hepatic fibrosis, Bcl-2.

Graphical Abstract
Global Burden of Hepatitis C Working Group. Global burden of disease (GBD) for hepatitis C. J. Clin. Pharmacol., 2004, 44(1), 20-29.
[ ] [PMID: 14681338]
El-Zanaty, F.; Way, A. Egypt Demographic and Health Survey 2008.(Ministry of Health, El-Zanaty and Associates, and Macro International.): Cairo, Egypt , 2009.
Ministry of Health and Population [Egypt], El-Zanaty and Associates [Egypt] and ICF International. Egypt Health Issues Survey 2015. (Cairo, Egypt and Rockville, Maryland, USA: Ministry of Health and Population and ICF International, 2015)., , 2015.
WHO. Hepatitis C fact sheet no. 164 [updated July 2015], , 2016.
Lee, J.W.; Kim, Y.I.; Kim, Y.; Choi, M.; Min, S.; Joo, Y.H.; Yim, S.V.; Chung, N. Grape seed proanthocyanidin inhibits inflammatory responses in hepatic stellate cells by modulating the MAPK, Akt and NF-κB signaling pathways. Int. J. Mol. Med., 2017, 40(1), 226-234.
[ ] [PMID: 28534957]
Bataller, R.; Paik, Y.H.; Lindquist, J.N.; Lemasters, J.J.; Brenner, D.A. Hepatitis C virus core and nonstructural proteins induce fibrogenic effects in hepatic stellate cells. Gastroenterology, 2004, 126(2), 529-540.
[ ] [PMID: 14762790]
Gong, G.; Waris, G.; Tanveer, R.; Siddiqui, A. Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-kappa B. Proc. Natl. Acad. Sci. USA, 2001, 98(17), 9599-9604.
[ ] [PMID: 11481452]
Poli, G. Pathogenesis of liver fibrosis: role of oxidative stress. Mol. Aspects Med., 2000, 21(3), 49-98.
[ ] [PMID: 10978499]
Sebastiani, G.; Gkouvatsos, K.; Pantopoulos, K. Chronic hepatitis C and liver fibrosis. World J. Gastroenterol., 2014, 20(32), 11033-11053.
[ ] [PMID: 25170193]
Lawitz, E.; Poordad, F.F.; Pang, P.S.; Hyland, R.H.; Ding, X.; Mo, H.; Symonds, W.T.; McHutchison, J.G.; Membreno, F.E. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet, 2014, 383(9916), 515-523.
[ ] [PMID: 24209977]
Sulkowski, M.S.; Gardiner, D.F.; Rodriguez-Torres, M.; Reddy, K.R.; Hassanein, T.; Jacobson, I.; Lawitz, E.; Lok, A.S.; Hinestrosa, F.; Thuluvath, P.J.; Schwartz, H.; Nelson, D.R.; Everson, G.T.; Eley, T.; Wind-Rotolo, M.; Huang, S.P.; Gao, M.; Hernandez, D.; McPhee, F.; Sherman, D.; Hindes, R.; Symonds, W.; Pasquinelli, C.; Grasela, D.M. AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N. Engl. J. Med., 2014, 370(3), 211-221.
[ ] [PMID: 24428467]
Ahmed, OA; Elsebaey, MA; Fouad, MHA; Elashry, H Outcomes and predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection., 2018.
Kim, D.D.; Hutton, D.W.; Raouf, A.A.; Salama, M.; Hablas, A.; Seifeldin, I.A.; Soliman, A.S. Cost-effectiveness model for hepatitis C screening and treatment: Implications for Egypt and other countries with high prevalence. Glob. Public Health, 2015, 10(3), 296-317.
[ ] [PMID: 25469976]
Ayoub, H.H.; Abu-Raddad, L.J. Impact of treatment on hepatitis C virus transmission and incidence in Egypt: A case for treatment as prevention. J. Viral Hepat., 2016, 31, 12671.
[PMID: 28039923]
Salas-Villalobosa, T.B.; Lozano-Sepúlvedaa, S.A.; Rincón-Sánchezb, A.R.; Govea-Salasc, M.; Rivas-Estillaa, A.M. Mechanisms involved in liver damage resolution after hepatitis C virus clearance. Medicina Universitaria., 2017, 19(75), 100-107.
Ishikawa, T.; Imai, M.; Owaki, T.; Sato, H. Serum Wisteria floribunda Agglutinin Positive Mac-2-Binding Protein and Fib-4 Index on the Clinical Course of Patients with Chronic Hepatitis C Receiving Daclatasvir/Asunaprevir Therapy. Ann Digest Liver Dis., 2017, 1, 1001.
Lee, H.W.; Oh, S.R.; Kim, D.Y.; Jeong, Y.; Kim, S.; Kim, B.K.; Kim, S.U.; Kim, D.Y.; Ahn, S.H.; Han, K.H.; Park, J.Y. Daclatasvir Plus Asunaprevir for the Treatment of Patients with Hepatitis C Virus Genotype 1b Infection: Real-World Efficacy, Changes in Liver Stiffness and Fibrosis Markers, and Safety. Gut Liver, 2018, 12(3), 324-330.
[ ] [PMID: 29409309]
Elsharkawy, A.; Alem, S.A.; Fouad, R.; El Raziky, M.; El Akel, W.; Abdo, M.; Tantawi, O. AbdAllah, M.; Bourliere, M.; Esmat, G. Changes in liver stiffness measurements and fibrosis scores following sofosbuvir based treatment regimens without interferon. J. Gastroenterol. Hepatol., 2017, 32(9), 1624-1630.
[ ] [PMID: 28177543]
Said, M.M.; Azab, S.S.; Saeed, N.M.; El-Demerdash, E. Antifibrotic Mechanism of Pinocembrin: Impact on Oxidative Stress, Inflammation and TGF-β/Smad Inhibition in Rats. Ann. Hepatol., 2018, 17(2), 307-317.
[ ] [PMID: 29469035]
Ferreira, A.C.; Zaverucha-do-Valle, C.; Reis, P.A.; Barbosa-Lima, G.; Vieira, Y.R.; Mattos, M.; Silva, P.P.; Sacramento, C.; de Castro Faria Neto, H.C.; Campanati, L.; Tanuri, A.; Brüning, K.; Bozza, F.A.; Bozza, P.T.; Souza, T.M.L. Sofosbuvir protects Zika virus-infected mice from mortality, preventing short- and long-term sequelae. Sci. Rep., 2017, 7(1), 9409.
[ ] [PMID: 28842610]
Kai, Y.; Hikita, H.; Tatsumi, T.; Nakabori, T.; Saito, Y.; Morishita, N.; Tanaka, S.; Nawa, T.; Oze, T.; Sakamori, R.; Yakushijin, T.; Hiramatsu, N.; Suemizu, H.; Takehara, T. Emergence of hepatitis C virus NS5A L31V plus Y93H variant upon treatment failure of daclatasvir and asunaprevir is relatively resistant to ledipasvir and NS5B polymerase nucleotide inhibitor GS-558093 in human hepatocyte chimeric mice. J. Gastroenterol., 2015, 50(11), 1145-1151.
[ ] [PMID: 26208695]
Reitman, S.; Frankel, S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am. J. Clin. Pathol., 1957, 28(1), 56-63.
[ ] [PMID: 13458125]
Banchroft, J.D.; Stevens, A.; Turner, D.R. Theory and practice of histological techniquesNew York; London, San Francisco, Tokyo: Churchil Livingstone, 1996.
Ishak, K.; Baptista, A.; Bianchi, L.; Callea, F.; De Groote, J.; Gudat, F.; Denk, H.; Desmet, V.; Korb, G.; MacSween, R.N. Histological grading and staging of chronic hepatitis. J. Hepatol., 1995, 22(6), 696-699.
[ ] [PMID: 7560864]
Friedman, S.L. Liver fibrosis - from bench to bedside. J. Hepatol., 2003, 38(Suppl. 1), S38-S53.
[ ] [PMID: 12591185]
Ibrahim, M.A.; Abdel-Aziz, A.; El-Sheikh, A.; Kamel, M.; Khalil, A.Z.; Abdelhaleem, H. Hepatic effect of sofosbuvir and daclatasvir in thioacetamide-induced liver injury in rats. Clin. Exp. Hepatol., 2018, 4(3), 175-181.
[ ] [PMID: 30324142]
Dyson, J.K.; Hutchinson, J.; Harrison, L.; Rotimi, O.; Tiniakos, D.; Foster, G.R.; Aldersley, M.A.; McPherson, S. Liver toxicity associated with sofosbuvir, an NS5A inhibitor and ribavirin use. J. Hepatol., 2016, 64(1), 234-238.
[ ] [PMID: 26325535]
Mazzarelli, C.; Bruce, M.; Imbert, S.; Cannon, M.D. FRI-093 - Direct fibrosis markers kinetic in patients undergoing antiviral treatment with DAA for chronic hepatitis C. J. Hepatol., 2018, 68(Suppl. 1), S403.
Reif, S.; Somech, R.; Brazovski, E.; Reich, R.; Belson, A.; Konikoff, F.M.; Kessler, A. Matrix metalloproteinases 2 and 9 are markers of inflammation but not of the degree of fibrosis in chronic hepatitis C. Digestion, 2005, 71(2), 124-130.
[ ] [PMID: 15785038]
Han, Y.P.; Yan, C.; Zhou, L.; Qin, L.; Tsukamoto, H. A matrix metalloproteinase-9 activation cascade by hepatic stellate cells in trans differentiation in the three-dimensional extracellular matrix. J. Biol. Chem., 2007, 282(17), 12928-12939.
[ ] [PMID: 17322299]
Sudo, K.; Yamada, Y.; Moriwaki, H.; Saito, K.; Seishima, M. Lack of tumor necrosis factor receptor type 1 inhibits liver fibrosis induced by carbon tetrachloride in mice. Cytokine, 2005, 29(5), 236-244.
[ ] [PMID: 15760680]
Knittel, T.; Mehde, M.; Kobold, D.; Saile, B.; Dinter, C.; Ramadori, G. Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-alpha and TGF-beta1. J. Hepatol., 1999, 30(1), 48-60.
[ ] [PMID: 9927150]
Pradere, J.P.; Kluwe, J.; De Minicis, S.; Jiao, J.J.; Gwak, G.Y.; Dapito, D.H.; Jang, M.K.; Guenther, N.D.; Mederacke, I.; Friedman, R.; Dragomir, A.C.; Aloman, C.; Schwabe, R.F. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology, 2013, 58(4), 1461-1473.
[ ] [PMID: 23553591]
Karin, M. Nuclear factor-kappaB in cancer development and progression. Nature, 2006, 441(7092), 431-436.
[ ] [PMID: 16724054]
Cheung, M.C.M.; Walker, A.J.; Hudson, B.E.; Verma, S.; McLauchlan, J.; Mutimer, D.J.; Brown, A.; Gelson, W.T.H.; MacDonald, D.C.; Agarwal, K.; Foster, G.R.; Irving, W.L. HCV Research UK. Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. J. Hepatol., 2016, 65(4), 741-747.
[ ] [PMID: 27388925]
Nault, J.C.; Colombo, M. Hepatocellular carcinoma and direct acting antiviral treatments: Controversy after the revolution. J. Hepatol., 2016, 65(4), 663-665.
[ ] [PMID: 27417216]
Reig, M.; Mariño, Z.; Perelló, C.; Iñarrairaegui, M.; Ribeiro, A.; Lens, S.; Díaz, A.; Vilana, R.; Darnell, A.; Varela, M.; Sangro, B.; Calleja, J.L.; Forns, X.; Bruix, J. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon free therapy. J. Hepatol., 2016, 65(4), 719-726.
[ ] [PMID: 27084592]
Robert, S. B., Jr The possible association between DAA treatment for HCV infection and HCC recurrence. Gastroenterol. Hepatol. (N. Y.), 2016, 12(12), 776-779.
[PMID: 28035203]
Huang, A.C.; Mehta, N.; Dodge, J.L.; Yao, F.Y.; Terrault, N.A. Direct-acting antivirals do not increase the risk of hepatocellular carcinoma recurrence after local-regional therapy or liver transplant waitlist dropout. Hepatology, 2018, 68(2), 449-461.
[ ] [PMID: 29476694]
Singal, A.G.; Rich, N.E.; Mehta, N.; Branch, A.; Pillai, A.; Hoteit, M.; Volk, M.; Odewole, M.; Scaglione, S.; Guy, J.; Said, A.; Feld, J.J.; John, B.V.; Frenette, C.; Mantry, P.; Rangnekar, A.S.; Oloruntoba, O.; Leise, M.; Jou, J.H.; Bhamidimarri, K.R.; Kulik, L.; Tran, T.; Samant, H.; Dhanasekaran, R.; Duarte-Rojo, A.; Salgia, R.; Eswaran, S.; Jalal, P.; Flores, A.; Satapathy, S.K.; Wong, R.; Huang, A.; Misra, S.; Schwartz, M.; Mitrani, R.; Nakka, S.; Noureddine, W.; Ho, C.; Konjeti, V.R.; Dao, A.; Nelson, K.; Delarosa, K.; Rahim, U.; Mavuram, M.; Xie, J.J.; Murphy, C.C.; Parikh, N.D. Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study. Gastroenterology, 2019, 156(6), 1683-1692.
[ ] [PMID: 30660729]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy