Loutfy, Samah AElberry, Mostafa HFarroh, Khaled YehiaMohamed, Hossam TahaMohamed, Aya AMohamed, ElChaimaa BFaraag, Ahmed Hassan IbrahimMousa, Shaker A2020-05-082020-05-0805/09/20202019) Hepatitis C. Cited 2 times. Accessed July 22 http://www.who.int/news-room/fact-sheets/detail/hepatitis-c 2 Elgharably, A., Gomaa, A.I., Crossey, M.M.E., Norsworthy, P.J., Waked, I., Taylor-Robinson, S.D. Hepatitis C in Egypt - past, present, and future (Open Access) (2017) International Journal of General Medicine, 10, pp. 1-6. Cited 53 times. https://www.dovepress.com/getfile.php?fileID=34163 doi: 10.2147/IJGM.S119301 View at Publisher 3 Tremblay, N., Park, A.Y., Lamarre, D. HCV NS3/4A protease inhibitors and the road to effective direct-acting antiviral therapies (2016) Hepatitis C Virus II: Infection and Disease, pp. 257-285. http://dx.doi.org/10.1007/978-4-431-56101-9 ISBN: 978-443156101-9; 978-443156099-9 doi: 10.1007/978-4-431-56101-9_10 View at Publisher 4 Boyd, S.D., Harrington, P., Komatsu, T.E., Naeger, L.K., Chan-Tack, K., Murray, J., Birnkrant, D., (...), Struble, K. HCV genotype 4, 5 and 6: Distribution of viral subtypes and sustained virologic response rates in clinical trials of approved direct-acting antiviral regimens (2018) Journal of Viral Hepatitis, 25 (8), pp. 969-975. Cited 6 times. http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1365-2893 doi: 10.1111/jvh.12896 View at Publisher 5 Nafisi, S., Roy, S., Gish, R., Manch, R., Kohli, A. Defining the possibilities: Is short duration treatment of chronic hepatitis C genotype 1 with sofosbuvir-containing regimens likely to be as effective as current regimens? (2016) Expert Review of Anti-Infective Therapy, 14 (1), pp. 41-56. Cited 3 times. doi: 10.1586/14787210.2016.1114883 View at Publisher 6 Jardim, A.C.G., Shimizu, J.F., Rahal, P., Harris, M. Plant-derived antivirals against hepatitis c virus infection (Open Access) (2018) Virology Journal, 15 (1), art. no. 34. Cited 9 times. http://www.virologyj.com/home/ doi: 10.1186/s12985-018-0945-3 View at Publisher 7 Calland, N., Dubuisson, J., Rouillé, Y., Séron, K. Hepatitis C virus and natural compounds: A new antiviral approach? (Open Access) (2012) Viruses, 4 (10), pp. 2197-2217. Cited 70 times. http://www.mdpi.com/1999-4915/4/10/2197/pdf doi: 10.3390/v4102197 View at Publisher 8 Assini, J.M., Mulvihill, E.E., Burke, A.C., Sutherland, B.G., Telford, D.E., Chhoker, S.S., Sawyez, C.G., (...), Huff, M.W. Naringenin prevents obesity, hepatic steatosis, and glucose intolerance in male mice independent of fibroblast growth factor 21 (Open Access) (2015) Endocrinology, 156 (6), pp. 2087-2102. Cited 39 times. http://press.endocrine.org/doi/pdf/10.1210/en.2014-2003 doi: 10.1210/en.2014-2003 View at Publisher 9 Khalaf, N., White, D., Kanwal, F., Ramsey, D., Mittal, S., Tavakoli-Tabasi, S., Kuzniarek, J., (...), El-Serag, H.B. Coffee and Caffeine Are Associated With Decreased Risk of Advanced Hepatic Fibrosis Among Patients With Hepatitis C (2015) Clinical Gastroenterology and Hepatology, 13 (8), pp. 1521-1531.e3. Cited 25 times. http://www.elsevier.com/inca/publications/store/6/7/2/7/4/3/index.htt doi: 10.1016/j.cgh.2015.01.030 View at Publisher 10 Anggakusuma, Colpitts, C.C., Schang, L.M., Rachmawati, H., Frentzen, A., Pfaender, S., Behrendt, P., (...), Steinmann, E. Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells (2014) Gut, 63 (7), pp. 1137-1149. Cited 70 times. http://gut.bmj.com/content/63/7/1137.full.pdf doi: 10.1136/gutjnl-2012-304299 View at Publisher 11 Wei, Z.-Q., Zhang, Y.-H., Ke, C.-Z., Chen, H.-X., Ren, P., He, Y.-L., Hu, P., (...), Meng, Z.-J. Curcumin inhibits hepatitis B virus infection by down-regulating cccDNA-bound histone acetylation (Open Access) (2017) World Journal of Gastroenterology, 23 (34), pp. 6252-6260. Cited 10 times. https://www.wjgnet.com/1007-9327/journal/v23/i34/index.htm06 doi: 10.3748/wjg.v23.i34.6252 View at Publisher 12 Zorofchian Moghadamtousi, S., Abdul Kadir, H., Hassandarvish, P., Tajik, H., Abubakar, S., Zandi, K. A review on antibacterial, antiviral, and antifungal activity of curcumin (Open Access) (2014) BioMed Research International, 2014, art. no. 186864. Cited 292 times. http://www.hindawi.com/journals/biomed/ doi: 10.1155/2014/186864 View at Publisher 13 Pécheur, E.-I. Curcumin against hepatitis C virus infection: Spicing up antiviral therapies with 'nutraceuticals'? (2014) Gut, 63 (7), pp. 1035-1037. Cited 7 times. http://gut.bmj.com/content/63/7/1035.full.pdf doi: 10.1136/gutjnl-2013-305646 View at Publisher 14 Deljoo, S., Rabiee, N., Rabiee, M. Curcumin-hybrid nanoparticles in drug delivery system (Review) (2019) Asian J Nanosci Mat, 2 (1), pp. 66-91. Cited 3 times. 15 Farjadian, F., Moghoofei, M., Mirkiani, S., Ghasemi, A., Rabiee, N., Hadifar, S., Beyzavi, A., (...), Hamblin, M.R. Bacterial components as naturally inspired nano-carriers for drug/gene delivery and immunization: Set the bugs to work? (2018) Biotechnology Advances, 36 (4), pp. 968-985. Cited 23 times. www.elsevier.com/inca/publications/store/5/2/5/4/5/5/index.htt doi: 10.1016/j.biotechadv.2018.02.016 View at Publisher 16 Jayakumar, R., Selvamurugan, N., Nair, S.V., Tokura, S., Tamura, H. Preparative methods of phosphorylated chitin and chitosan-An overview (2008) International Journal of Biological Macromolecules, 43 (3), pp. 221-225. Cited 106 times. doi: 10.1016/j.ijbiomac.2008.07.004 View at Publisher 17 Akhtar, F., Rizvi, M.M.A., Kar, S.K. Oral delivery of curcumin bound to chitosan nanoparticles cured Plasmodium yoelii infected mice (2012) Biotechnology Advances, 30 (1), pp. 310-320. Cited 127 times. doi: 10.1016/j.biotechadv.2011.05.009 View at Publisher 18 Sun, L., Chen, Y., Zhou, Y., Guo, D., Fan, Y., Guo, F., Zheng, Y., (...), Chen, W. Preparation of 5-fluorouracil-loaded chitosan nanoparticles and study of the sustained release in vitro and in vivo (Open Access) (2017) Asian Journal of Pharmaceutical Sciences, 12 (5), pp. 418-423. Cited 34 times. http://www.journals.elsevier.com/asian-journal-of-pharmaceutical-sciences/recent-articles/ doi: 10.1016/j.ajps.2017.04.002 View at Publisher 19 Loutfy, S.A., El-Din, H.M.A., Elberry, M.H., Allam, N.G., Hasanin, M.T.M., Abdellah, A.M. Synthesis, characterization and cytotoxic evaluation of chitosan nanoparticles: In vitro liver cancer model (Open Access) (2016) Advances in Natural Sciences: Nanoscience and Nanotechnology, 7 (3), art. no. 035008. Cited 18 times. http://iopscience.iop.org/article/10.1088/2043-6262/7/3/035008/pdf doi: 10.1088/2043-6262/7/3/035008 View at Publisher 20 Ramana, L.N., Sharma, S., Sethuraman, S., Ranga, U., Krishnan, U.M. Evaluation of chitosan nanoformulations as potent anti-HIV therapeutic systems (2014) Biochimica et Biophysica Acta - General Subjects, 1840 (1), pp. 476-484. Cited 26 times. doi: 10.1016/j.bbagen.2013.10.002 View at Publisher 21 Thomsen, R., Christensen, M.H. MolDock: A new technique for high-accuracy molecular docking (2006) Journal of Medicinal Chemistry, 49 (11), pp. 3315-3321. Cited 1201 times. doi: 10.1021/jm051197e View at Publisher 22 (2013) Schrödinger LNY. Prime, Version 3. New York: Schrödinger, LLC., [computer program] 23 Tsutsumi, Y. L2-solutions for nonlinear schrödinger equations and nonlinear groups (1987) Funkcialaj Ekvacioj., 31, pp. 115-125. Cited 255 times. 24 Nayeem, A., Sitkoff, D., Krystek Jr., S. A comparative study of available software for high-accuracy homology modeling: From sequence alignments to structural models (2006) Protein Science, 15 (4), pp. 808-824. Cited 107 times. http://www.proteinscience.org/cgi/reprint/15/4/808 doi: 10.1110/ps.051892906 View at Publisher 25 Adedeji, A.O., Singh, K., Sarafianos, S.G. Structural and biochemical basis for the difference in the helicase activity of two different constructs of sars-cov helicase (2012) Cellular and Molecular Biology, 58 (1), pp. 115-121. Cited 34 times. http://www.cellmolbiol.com/admin/articles_generaux/2012V58Th1P115-121.pdf doi: 10.1170/T929 View at Publisher 26 Ibrahim, S.A.L., Farroh, K.Y., Elberry, M.H., Mohamed, E.-C., Faraag, A.H.I. Inventors; Arab Republic of Egypt, Ministry of Scientific Research. A method for preparation of anti HCV compounds against genotype 4a. 1120–2018, STDF ID: 15108 27 Iraolagoitia, X.L.R., Martini, M.F. Ca2+ adsorption to lipid membranes and the effect of cholesterol in their composition (2010) Colloids and Surfaces B: Biointerfaces, 76 (1), pp. 215-220. Cited 31 times. doi: 10.1016/j.colsurfb.2009.10.037 View at Publisher 28 Emam, A.N., Loutfy, S.A., Mostafa, A.A., Awad, H., Mohamed, M.B. Cyto-toxicity, biocompatibility and cellular response of carbon dots-plasmonic based nano-hybrids for bioimaging (Open Access) (2017) RSC Advances, 7 (38), pp. 23502-23514. Cited 44 times. http://pubs.rsc.org/en/journals/journalissues doi: 10.1039/c7ra01423f View at Publisher 29 Zhu, Z.-J., Ghosh, P.S., Miranda, O.R., Vachet, R.W., Rotello, V.M. Multiplexed screening of cellular uptake of gold nanoparticles using laser desorption/ionization mass spectrometry (2008) Journal of the American Chemical Society, 130 (43), pp. 14139-14143. Cited 98 times. doi: 10.1021/ja805392f View at Publisher 30 Nunez, R. DNA measurement and cell cycle analysis by flow cytometry (2001) Current Issues in Molecular Biology, 3 (3), pp. 67-70. Cited 173 times. View at Publisher 31 Karaliotas, G.I., Mavridis, K., Scorilas, A., Babis, G.C. Quantitative analysis of the mRNA expression levels of BCL2 and BAX genes in human osteoarthritis and normal articular cartilage: An investigation into their differential expression (Open Access) (2015) Molecular Medicine Reports, 12 (3), pp. 4514-4521. Cited 19 times. http://www.spandidos-publications.com/mmr/12/3/4514/download doi: 10.3892/mmr.2015.3939 View at Publisher 32 Zekri, A.-R.N., Bahnassy, A.A., Hafez, M.M., Hassan, Z.K., Kamel, M., Loutfy, S.A., Sherif, G.M., (...), Daoud, S.S. Characterization of chronic HCV infection-induced apoptosis (Open Access) (2011) Comparative Hepatology, 10, art. no. 4. Cited 16 times. http://www.comparative-hepatology.com/content/10/1/4 doi: 10.1186/1476-5926-10-4 View at Publisher 33 Jiang, X.-H., Xie, Y.-T., Cai, Y.-P., Ren, J., Ma, T. Effects of hepatitis C virus core protein and nonstructural protein 4B on the Wnt/β-catenin pathway (Open Access) (2017) BMC Microbiology, 17 (1), art. no. 124. Cited 3 times. http://www.biomedcentral.com/bmcmicrobiol/ doi: 10.1186/s12866-017-1032-4 View at Publisher 34 Jahromi, M.A.M., Al-Musawi, S., Pirestani, M., Ramandi, M.F., Ahmadi, K., Rajayi, H., Hassan, Z.M., (...), Mirnejad, R. Curcumin-loaded chitosan tripolyphosphate nanoparticles as a safe, natural and effective antibiotic inhibits the infection of staphylococcus aureus and pseudomonas aeruginosa in vivo (Open Access) (2014) Iranian Journal of Biotechnology, 12 (3), art. no. e1012. Cited 24 times. http://ijbiotech.com/jufile?c2hvd1BERj02NDUyJl9hY3Rpb249c2hvd1BERiZhcnRpY2xlPTY0NTImX29iPTdiNzI2YzIzMWViZDc5OTdkZjA4NGJlNmJhODg2MmJl doi: 10.15171/ijb.1012 View at Publisher 35 Das, R.K., Kasoju, N., Bora, U. Encapsulation of curcumin in alginate-chitosan-pluronic composite nanoparticles for delivery to cancer cells (2010) Nanomedicine: Nanotechnology, Biology, and Medicine, 6 (1), pp. 153-160. Cited 387 times. doi: 10.1016/j.nano.2009.05.009 View at Publisher 36 Mandrol, P.S., Bhat, K., Prabhakar, A.R. An in vitro evaluation of cytotoxicity of curcumin against human dental pulp fibroblasts (Open Access) (2016) Journal of Indian Society of Pedodontics and Preventive Dentistry, 34 (3), pp. 269-272. Cited 6 times. http://www.jisppd.com/ doi: 10.4103/0970-4388.186757 View at Publisher 37 Samrot, A.V., Burman, U., Philip, S.A., Shobana, N., Chandrasekaran, K. Synthesis of curcumin loaded polymeric nanoparticles from crab shell derived chitosan for drug delivery (Open Access) (2018) Informatics in Medicine Unlocked, 10, pp. 159-182. Cited 20 times. http://www.journals.elsevier.com/informatics-in-medicine-unlocked doi: 10.1016/j.imu.2017.12.010 View at Publisher 38 Zhou, N., Zan, X., Wang, Z., Wu, H., Yin, D., Liao, C., Wan, Y. Galactosylated chitosan-polycaprolactone nanoparticles for hepatocyte-targeted delivery of curcumin (2013) Carbohydrate Polymers, 94 (1), pp. 420-429. Cited 54 times. doi: 10.1016/j.carbpol.2013.01.014 View at Publisher 39 Mirakabad, F.S.T., Akbarzadeh, A., Milani, M., Zarghami, N., Taheri-Anganeh, M., Zeighamian, V., Badrzadeh, F., (...), Rahmati-Yamchi, M. A Comparison between the cytotoxic effects of pure curcumin and curcumin-loaded PLGA-PEG nanoparticles on the MCF-7 human breast cancer cell line (2016) Artificial Cells, Nanomedicine and Biotechnology, 44 (1), pp. 423-430. Cited 52 times. http://www.tandfonline.com/loi/ianb20#.VmugQbfovcs doi: 10.3109/21691401.2014.955108 View at Publisher 40 Nair, R.S., Morris, A., Billa, N., Leong, C.-O. An Evaluation of Curcumin-Encapsulated Chitosan Nanoparticles for Transdermal Delivery (2019) AAPS PharmSciTech, 20 (2), art. no. 69. Cited 5 times. http://www.springerlink.com/content/1530-9932/ doi: 10.1208/s12249-018-1279-6 View at Publisher 41 CHOU, T.‐C., TALALAY, P. Generalized Equations for the Analysis of Inhibitions of Michaelis‐Menten and Higher‐Order Kinetic Systems with Two or More Mutually Exclusive and Nonexclusive Inhibitors (1981) European Journal of Biochemistry, 115 (1), pp. 207-216. Cited 327 times. doi: 10.1111/j.1432-1033.1981.tb06218.x View at Publisher 42 Kumar, N.P., Sharma, P., Kumari, S.S., Brahma, U., Nekkanti, S., Shankaraiah, N., Kamal, A. Synthesis of substituted phenanthrene-9-benzimidazole conjugates: Cytotoxicity evaluation and apoptosis inducing studies (2017) European Journal of Medicinal Chemistry, 140, pp. 128-140. Cited 10 times. http://www.journals.elsevier.com/european-journal-of-medicinal-chemistry/ doi: 10.1016/j.ejmech.2017.09.006 View at Publisher 43 Pistritto, G., Trisciuoglio, D., Ceci, C., Alessia Garufi, D'Orazi, G. Apoptosis as anticancer mechanism: Function and dysfunction of its modulators and targeted therapeutic strategies (2016) Aging, 8 (4), pp. 603-619. Cited 145 times. http://www.aging-us.com/http://www.impactaging.com/index.html doi: 10.18632/aging.100934 View at Publisher 44 Foucquier, J., Guedj, M. Analysis of drug combinations: current methodological landscape (Open Access) (2015) Pharmacology Research and Perspectives, 3 (3), art. no. e00149. Cited 310 times. http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2052-1707http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2052-1707 doi: 10.1002/prp2.149 View at Publisher 45 Gesing, A., Masternak, M.M., Wang, F., Lewinski, A., Karbownik-Lewinska, M., Bartke, A. Decreased expression level of apoptosis-related genes and/or proteins in skeletal muscles, but not in hearts, of growth hormone receptor knockout mice (2011) Experimental Biology and Medicine, 236 (2), pp. 156-168. Cited 16 times. http://ebm.rsmjournals.com/cgi/reprint/236/2/156 doi: 10.1258/ebm.2010.010202 View at Publisher 46 Kusuma, A., Colpitts, C.C., Schang, L.M. Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells (2013) J Hepatol, 58, pp. S473-S473. Cited 3 times.11769114https://doi.org/10.2147/IJN.S241702https://t.ly/oi6BScopusView references (46) Purpose: Current direct-acting antiviral agents for treatment of hepatitis C virus genotype 4a (HCV-4a) have been reported to cause adverse effects, and therefore less toxic antivirals are needed. This study investigated the role of curcumin chitosan (CuCs) nanocomposite as a potential anti-HCV-4a agent in human hepatoma cells Huh7. Methods: Docking of curcumin and CuCs nanocomposite and binding energy calculations were carried out. Chitosan nanoparticles (CsNPs) and CuCs nanocomposite were prepared with an ionic gelation method and characterized with TEM, zeta size and potential, and HPLC to calculate encapsulation efficiency. Cytotoxicity studies were performed on Huh7 cells using MTT assay and confirmed with cellular and molecular assays. Anti-HCV-4a activity was determined using real-time PCR and Western blot. Results: The strength of binding interactions between protein ligand complexes gave scores with NS3 protease, NS5A polymerase, and NS5B polymerase of-124.91,-159.02, and-129.16, for curcumin respectively, and-68.51,-54.52, and-157.63 for CuCs nanocomposite, respec-tively. CuCs nanocomposite was prepared at sizes 29–39.5 nm and charges of 33 mV. HPLC detected 4% of curcumin encapsulated into CsNPs. IC50 was 8 µg/mL for curcumin and 25 µg/ mL for the nanocomposite on Huh7 but was 25.8 µg/mL and 34 µg/mL on WISH cells. CsNPs had no cytotoxic effect on tested cell lines. Apoptotic genes’ expression revealed the caspase-dependent pathway mechanism. CsNPs and CuCs nanocomposite demonstrated 100% inhibition of viral entry and replication, which was confirmed with HCV core protein expression. Conclusion: CuCs nanocomposite inhibited HCV-4a entry and replication compared to curcumin alone, suggesting its potential role as an effective therapeutic agent. © 2020 Loutfy et alenCaspase-dependent pathwaychitosan curcumin nanocompositeDockingHepatitis C virus genotype 4aHuh7Articlehttps://doi.org/10.2147/IJN.S241702