Mechanistic insights into the antiviral effects of curcumin and piperine against Hepatitis C virus: a study of their bioactive properties in hepatocarcinoma cells

Rute Lopes
OrcID
Dr.ª Lorrane Davi brito de Toledo
OrcID
Elisandra Márcia Rodrigues
OrcID
Drª. Ana Maria Minarelli Gaspar
OrcID
Dr. Paulo Inácio da Costa
OrcID

    Rute Lopes

    Universidade Estadual Paulista

    OrcID https://orcid.org/0000-0002-7634-741X

    Concluiu doutorado no programa de pós-graduação em Biotecnologia, no Instituto de Química e Faculdade de Ciências Farmacêuticas da UNESP de Araraquara. Mestre em Biotecnologia pela Universidade Estadual Paulista (UNESP), no Instituto de Química, em Araraquara (2015). Graduada em Biomedicina pela Universidade de Araraquara (UNIARA) em 2012. Possui especialização em Acupuntura Sistêmica pelo Centro Regional de Estudos e Terapias Avançadas (CREAT, 2015) e graduação em Imagem e Som pela Universidade Federal de São Carlos (UFSCar, 2004).

    Dr.ª Lorrane Davi brito de Toledo

    Universidade Estadual Paulista

    OrcID https://orcid.org/0000-0003-3736-4871

    Possui graduação em Ciências Biológicas pela Universidade do Oeste Paulista (2017) e mestrado em Biotecnologia pela Universidade Estadual Paulista Júlio de Mesquita Filho (2020). Atualmente é bolsista mestrado da Universidade Estadual Paulista Júlio de Mesquita Filho. Tem experiência na área de Genética, com ênfase em Mutagenese, atuando principalmente nos seguintes temas: spondias dulcis, micronucleus test, mutagenicity, cytotoxicity e comet assay.

    Elisandra Márcia Rodrigues

    Universidade Estadual Paulista

    OrcID https://orcid.org/0000-0002-1609-2507

    Possui graduação em Biomedicina pelo Centro Universitário Herminio Ometto de Araras (1999). Mestrado e Doutorado em Ciências Físicas e Biomoleculares pela Universidade de São Paulo - USP (2004 e 2008), respectivamente. Doutorado - sanduíche realizado na Universidade da Califórnia em Los Angeles (UCLA) com ênfase em aprendizado de técnicas de Biologia Molecular e Celular em cultura de Trypanosoma brucei. Pós-doutoramentos, sendo o primeiro na Universidade da Califórnia em Riverside (UCR), com aprendizado em técnicas moleculares para manutenção de cultura celular de Plasmodium falciparum (2009) e Expressão de Proteínas Heterólogas. Em seguida pós-doutoramento foi realizado no Instituto Nacional de Luz Sincrotron no Laboratório de Pesquisa em Biologia (CnPEM), na procura de alvos de inibidores para as doenças de Chagas e malária (2010-2011). Na sequência, as pesquisas de pós-doutorado foram realizadas na Universidade Paulista Júlio de Mesquita na Faculdade de Odontologia, com ênfase em melhoramento de materiais endodônticos avaliados em cultura celular de osteoblastos (SAOS-2) e células da polpa dental humana (hDPCs). No período de 2020 a 2023 trabalhou durante a pandemia na identificação do vírus Sars-Cov2 em células do epitélio naso-faríngeo para rastreamento da Covid-19. Tem experiência na área de Biologia, com ênfase em Biologia Molecular, Celular, Bioquímica, Microbiologia e Parasitologia. Desde 2022, realiza curso de graduação em Engenharia de Computação da Universidade Virtual do Estado de São Paulo (Univesp)

    Drª. Ana Maria Minarelli Gaspar

    Universidade Estadual Paulista

    OrcID https://orcid.org/0000-0002-7168-9971

    Possui graduação em Odontologia pela Universidade Estadual de Campinas (1985), mestrado em Ciências Odontológicas pela Universidade Estadual Paulista Júlio de Mesquita Filho (1987); doutorado em Ciências Morfofuncionais pela Universidade de São Paulo (1994) e Livre Docente em Anatomia pela Universidade Estadual Paulista Júlio de Mesquita Filho (2012). Credenciada nos Programas de Pós-Graduação como orientadora, níveis Mestrado e Doutorado, Programa Interunidades em Bioengenharia, da Universidade de São Paulo (USP/SC) a partir de 05/2008, e no Programa de Biotecnologia/IQ-UNESP, a partir de 10/2012. Atuou como Professor Associado (MS5) na Universidade Estadual Paulista Júlio de Mesquita Filho; ocupou a Chefia do Departamento de Morfologia no período de 18/10/2004 a 17/10/2008; vice chefia no período de 17/10/2008 a 16/10/2010 e ocupou a Chefia do Departamento de Morfologia no período de 17/10/2010 a 02/05/2013. Tem vasta experiência na área de testes in vivo com Biomateriais. Aposentou-se no dia 22/02/2019.

    Dr. Paulo Inácio da Costa

    Universidade Estadual Paulista

    OrcID https://orcid.org/0000-0002-3350-8308

    Bacharel em Ciências Biológicas Modalidade Médica pela Faculdade de Ciências e Letras Barão de Mauá (1986) com mestrado na área de Ciências, sub área Bioquímica, Imunologia de Venenos Ofídicos, pela Faculdade de Medicina de Ribeirão Preto-Universidade de São Paulo (1991), doutorado em Ciências, sub área Bioquímica, Biologia Molecular de Parasitas, pela Faculdade de Medicina de Ribeirão Preto-Universidade de São Paulo (1997), Livre-Docência em Imunologia Clínica, Epidemiologia Molecular de Retrovírus, pela Faculdade de Ciências Farmacêuticas da Universidade Estadual Paulista "Júlio de Mesquita Filho" (2007). Atua como Professor Associado Voluntário da Faculdade de Ciências Farmacêuticas-UNESP/ Campus de Araraquara-SP, nas disciplinas de Imunologia Clínica, Imunologia Aplicada à Farmácia, Imunologia Aplicada à Biotecnologia, Biotecnologia Diagnóstica e Políticas Públicas de Saúde. Coordenador e Responsável Técnico pelo Laboratório de Imunologia Clínica e Biologia Molecular, referência regional em Imunofenotipagem linfocitária, Isolamento e Quantificação Viral-Rede Nacional de Laboratórios do Departamento de DST/Aids e Hepatites Virais/Ministério da Saúde, desde 1997. Atuou como membro do Comitê Assessor e Grupo Técnico para a área da qualidade e monitoramento da Rede Nacional de Laboratórios de CD4/CD8 e Carga Viral do HIV. Atua em parceria com outros pesquisadores da UNESP, USP, UFSCar e CTI/MCT, áreas Imunoquímica e Biologia Molecular, no desenvolvimento de testes diagnósticos com princípios imunocromatográficos, imunossensores e genossensores eletroquímicos para doenças virais (HIV, HCV e SARS-CoV-2), parasitárias (Chagas, leishmaniose canina) e tumorais; como também a pesquisa de novos biomarcadores para doenças crônico-degenerativas.

Keywords

Hepatitis C
Virus
Curcumin
Piperine

Abstract

Natural bioactive compounds (NBCs) has been reported to possess antiviral and hepatoprotective effects, like curcumin (CL) and piperine (PP). Herein, we report a study of hepatitis C virus biosynthesis and its molecular mechanisms in human hepatocarcinoma cells, expressing or not the HCV (SGR-JFH1) when exposed to CL, PP and its association (CL/PP). Inhibiting concentration (IC50) to CL were 30,95 ± 1,05 µM for Huh-7.5 and 41,96 ± 1,02 µM for SGR-JFH1 cells. For PP, the IC50 were 165,4 ± 1,15 and 200,3 ± 1,05 µM for Huh-7.5 and SGR-JFH1, respectively. An decrease in Cl/PP IC50 were observed with 26,02 ± 1,05 µM for Huh-7.5 and 19,74 ± 1,02 µM for SGR-JFH1. CL and PP induced inhibition of apoptosis. CL treatment at IC20 caused a slight increase of AMPK-α phosphorylation pathway in SGR-JFH1. Caspase-3 was expressed in IC10, and the other pathways were inhibited. HCV cells exposed to PP showed stimulated phosphorylation of FoxO-3a, as well as of the Bax/Bcl-2 in both NBC concentrations. In the CL/PP treatment, the phosphorylation of Akt1 and the Bax/Bcl-2 were shown to be intensified in SGR-JFH1. This work provides a new insight to the control of hepatitis C, when exposure to CL and PP.

References

  1. World Health Orgnization. Global hepatitis report, 2021. [http://www.who.who.int/news-room/hepatitits-c,July27,2021/publications/global-hepatitis/en/]. [Accessed: 14 oct 2021].
  2. World Health Orgnization. Hepatitis C (fact sheet). [https://www.who.int/news-room/fact-sheets/detail/hepatitis-c]. [Accessed: 09 Mar 2022].
  3. Centers for disease control and prevention. Hepatitis C FAQs for health professionals. [https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#section1]. [Accessed: 6 Jun 2021].
  4. Gonzalez FA, Van den Eynde E, Perez-Hoyos S, Navarro J, Curran A, Burgos J, et al. Liver stiffness and aspartate aminotransferase levels predict the risk for liver fibrosis progression in hepatitis C virus/HIV-coinfected patients. HIV Med. 2015; 16: 211-218. [http://dx.doi.org/10.1111/hiv.12197].
  5. Pokorska-Śpiewak M, Kowalik-Mikołajewska B, Aniszewska M, Walewska-Zielecka B, Marczyńska M. The influence of hepatitis B and C virus coinfection on liver histopathology in children. Eur J Pediatr. 2015; 174: 345-353. [http://dx.doi.org/10.1007/s00431-014-2402-7].
  6. Manns MP, Buti M, Gane E, Pawlotsky JM, Razavi H, Terrault N, et al. Hepatitis C virus infection. Nat Rev Dis Primers. 2017; 3: 17006. [http://dx.doi.org/10.1038/nrdp.2017.6].
  7. Biesalski HK, Gragsted LO, Elmadfa I, Grossklaus R, Müller M, Schrenk D, et al. Bioactive compounds: Definition and assessment of activity. Nutrition. 2009; 25: 1202-1205. [http://dx.doi.org/10.1016/j.nut.2009.04.023].
  8. Calland N, Dubuisson J, Rouillé Y, Séron K. Hepatitis C virus and natural compounds: a new antiviral approach? Viruses 2012; 4: 2197–2217. [http://dx.doi.org/10.3390/v4102197].
  9. Shishodia S, Sethi G, Aggarwal BB. Curcumin: getting back to the roots. Ann N Y Acad Sci. 2005; 1056: 206-217. [http://dx.doi.org/10.1196/annals.1352.010].
  10. Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009; 41: 40-59. [http://dx.doi.org/10.1016/j.biocel.2008.06.010].
  11. Rechtman MM, Har-Noy O, Bar-Yishay I, Fishman S, Adamovich Y, Shaul Y, et al. Curcumin inhibits hepatitis B virus via down-regulation of the metabolic coactivator PGC-1α. FEBS Lett. 2010; 584: 2485-2490. [http://dx.doi.org/10.1016/j.febslet.2010.04.067].
  12. Anggakusuma, Colpitts CC, Schang LM, Rachmawati H, Frentzen A, Pfaender S, et al. Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells. Gut. 2014; 63: 1137-1149. [http://dx.doi.org/10.1136/gutjnl-2012-304299] .
  13. Kumar D, Basu S, Parija L, Rout D, Manna S, Dandapat J, et al. Curcumin and ellagic acid synergistically induce ROS generation, DNA damage, p53 accumulation and apoptosis in HeLa cervical carcinoma cells. Biomed. Pharmacother. 2016; 81: 31-37. [http://dx.doi.org/10.1016/j.biopha.2016.03.037].
  14. Musso G, Cassader M, Gambino R. Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nat Rev Drug Discov. 2016; 15: 249-274. [http://dx.doi.org/10.1038/nrd.2015.3].
  15. Chen LC, Chen YC, Su CY, Wong WP, Sheu MT, Ho HO. Development and characterization of lecithin-based self-assembling mixed polymeric micellar (saMPMs) drug delivery systems for curcumin. Sci Rep. 2016; 6: 37122. [http://dx.doi.org/10.1038/srep37122].
  16. Tawani A, Amanullah A, Mishra A, Kumar A. Evidences for piperine inhibiting cancer by targeting human G-quadruplex DNA sequences. Sci Rep. 2016; 6: 39239. [http://dx.doi.org/10.1038/srep39239].
  17. Lai LH, Fu QH, Liu Y, Jiang K, Guo QM, Chen QY, et al. Piperine suppresses tumor growth and metastasis in vitro and in vivo in a 4T1 murine breast cancer model. Acta Pharmacol Sin. 2012; 33: 523–530. [http://dx.doi.org/10.1038/aps.2011.209].
  18. Randino R, Grimaldi M, Persico M, De Santis A, Cini E, Cabri W, et al. Investigating the neuroprotective effects of turmeric extract: structural interactions of β-amyloid peptide with single curcuminoids. Sci Rep. 2016; 6: 38846. [http://dx.doi.org/10.1038/srep38846].
  19. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Pl Med. 1998; 64: 353-356. [http://dx.doi.org/10.1055/s-2006-957450].
  20. Zhou J, Donatelli SS, Gilvary DL, Tejera MM, Eksioglu EA, Chen X, et al. Therapeutic targeting of myeloid-derived suppressor cells involves a novel mechanism mediated by clusterin. Sci Rep. 2016; 6: 29521. [http://dx.doi.org/10.1038/srep29521].
  21. Rieger AM, Nelson KL, Konowalchuk JD, Barreda DR. Modified annexin V/propidium iodide apoptosis assay for accurate assessment of cell death. J Vis Exp. 2011; 24(50): 2597. [https://doi.org/10.3791/2597].
  22. Xiang J, Wan C, Guo R, Guo D. Is hydrogen peroxide a suitable apoptosis inducer for all cell types? BioMed Res Int. 2016; 2016: 7343965. [http://dx.doi.org/10.1155/2016/7343965].
  23. ISO 10993-5 (2005) Biological Evaluation of Medical Devices – Part 5: Tests for in vitro cytotoxicity. Geneva, Switzerland: International Standards Organization, Geneva, Switzerland.
  24. Li M, Gao M, Fu Y, Chen C, Meng X, Fan A, Kong D, et al. Acetal-linked polymeric prodrug micelles for enhanced curcumin delivery. Colloids Surf B Biointerfaces. 2016; 140: 11-18. [http://dx.doi.org/10.1016/j.colsurfb.2015].
  25. Jiang J, Jin H, Liu L, Pi J, Yang F, Cai J. Curcumin disturbed cell-cycle distribution of HepG2 cells via cytoskeletal arrangement. Scanning. 2013; 35: 253-260. [http://dx.doi.org/10.1002/sca.21058].
  26. Prasad NS, Raghavendra R, Lokesh BR, Naidu KA. Spice phenolics inhibit human PMNL-5 lipoxygenase. Prostaglandins Leukot Essent Fatty Acids. 2004; 70: 521-528. [http://dx.doi.org/10.1016/j.plefa.2003.11.006].
  27. Raghavendra RH, Naidu KA. Spice active principles as the inhibitors of human platelet aggregation and thromboxane biosynthesis. Prostaglandins Leukot Essent Fatty Acids. 2009; 81: 73-78. [http://dx.doi.org/0.1016/j.plefa.2009.04.009].
  28. Derosa G, Maffioli P, Simental-Mendía LE, Bo S, Sahebkar A. Effect of curcumin on circulating interleukin-6 concentrations A systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. 2016; 111: 394-404. [http://dx.doi.org/10.1016/j.phrs.2016.07.004].
  29. Rinwa P, Kumar A. Piperine potentiates the protective effects of curcumin against chronic unpredictable stress-induced cognitive impairment and oxidative damage in mice. Brain Res. 2012; 1488: 38-50. [http://dx.doi.org/10.1016/j.brainres.2012.10.002].
  30. Singh S, Kumar P. Neuroprotective Activity of Curcumin in Combination with Piperine against Quinolinic Acid Induced Neurodegeneration in Rats. Pharmacology. 2016; 97: 151-160. [http://dx.doi.org/10.1159/000443896.0].
  31. Olmedo E, Costa J, López-Labrador FX, Forns X, Ampurdanés S, Maluenda MD, et al. Comparative study of a modified competitive RT-PCR and Amplicor HCV monitor assays for quantitation of hepatitis C virus RNA in serum. J Med Virol. 1999; 58: 35-43. [http://dx.doi.org/10.1002/(sici)1096-9071(199905)58:1<35::aid-jmv5>3.0.co;2-v].
  32. Elkady A, Tanaka Y, Kurbanov F, Sugauchi F, Sugiyama M, Khan A, et al. Performance of two Real-Time RT-PCR assays for quantitation of hepatitis C virus RNA: evaluation on HCV genotypes 1-4. J Med Virol. 2010; 82: 1878-888. [http://dx.doi.org/10.1002/jmv.21911].
  33. Vrtačnik P, Kos Š, Bustin SA, Marc J, Ostanek B. Influence of trypsinization and alternative procedures for cell preparation before RNA extraction on RNA integrity. Anal Biochem. 2014; 463: 38-44. [http://dx.doi.org/10.1016/j.ab.2014.06.017].
  34. Kim K, Kim KH, Kim HY, Cho HK, Sakamoto NJ. Cheong. Curcumin inhibits hepatitis C virus replication via suppressing the Akt-SREBP-1 pathway. FEBS Lett. 2010; 584: 707-712. [http://dx.doi.org/10.1016/j.febslet.2009.12.019].
  35. Chen MH, Lee MY, Chuang JJ, Li YZ, Ning ST, Chen JC, et al. Curcumin inhibits HCV replication by induction of heme oxygenase-1 and suppression of AKT. Int J Mol Med. 2012; 30: 1021-1028. [https://doi.org/10.3892/ijmm.2012.1096].
  36. Assis RP, Arcaro CA, Gutierres VO, Oliveira JO, Costa PI, Bavieira AM, et al. Combined effects of curcumin and lycopene or bixin in yoghurt on inhibition of LDL oxidation and increases in HDL and paraoxonase levels in streptozotocin-diabetic rats. Int J Mol Sci. 2017; 18: 332. [https://doi.org/10.3390/ijms18040332].
  37. Adinolfi LE, Rinaldi L, Guerrera B, Restivo L, Marrone A, Giordano M, et al. NAFLD and NASH in HCV infection: prevalence and significance in hepatic and extrahepatic manifestations. Int J Mol Sci. 2016; 17: 803. [https://doi.org/10.3390/ijms17060803].
  38. Prata TVG, Silva DSRD, Manchiero C, Dantas BP, Mazza CC, Nunes AKDS, et al. MTTP polymorphisms and hepatic steatosis in individuals chronically infected with hepatitis C virus. Arch Virol. 2019; 164: 2559–2563. [https://doi.org/10.1007/s00705- 019-04352-4].
  39. Magri MC, Manchiero C, Prata TVG, Nunes AKDS, Oliveira Junior JS, Dantas BP, et al. The influence of gene-chronic hepatitis C virus infection on hepatic fibrosis and steatosis. Diagn Microbiol Infect Dis. 2020; 97(2): 115025. [https://doi.org/10.1016/j.diagmicrobio. 2020.115025].
  40. Zampino R, Ingrosso D, Durante-Mangoni E, Capasso R, Tripodi MF, Restivo L, et al. Microsomal triglyceride transfer protein (MTP) -493G/T gene polymorphism contributes to fat liver accumulation in HCV genotype 3 infected patients. J Viral Hepat. 2008; 15: 740-746. [https://doi.org/10.1111/j.1365-2893.2008.00994.x] .
  41. Cai T, Dufour JF, Muellhaupt B, Gerlach T, Heim M, Moradpour D, et al. Viral genotype-specific role of PNPLA3, PPARG, MTTP, and IL28B in hepatitis C virus-associated steatosis. J Hepatol. 2011; 55: 529-535. [https://doi.org/10.1016/j.jhep.2010.12.020].
  42. Liu Y, Conlon DM, Bi X, Slovik KJ, Shi J, Edelstein HI, Millar JS, et al. Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress. Cell Rep. 2017; 19: 1456-1466. [https://doi.org/10.1016/j.celrep.2017.04.064].
  43. Winther M, Shpitzen S, Yaacov O, Landau J, Oren L, Foroozan-Rosenberg L, et al. In search of a genetic explanation for LDLc variability in an FH family: common SNPs and a rare mutation in MTTP explain only part of LDL variability in an FH family. J Lipid Res. 2019; 60: 1733-1740. [https://doi.org/10.1194/jlr.M092049].
  44. Ellis KL, Hooper AJ, Burnett JR, GF Watts. Progress in the care of common inherited atherogenic disorders of apolipoprotein B metabolism. Nat Rev Endocrinol. 2016; 12: 467-484. [https://doi.org/10.1038/nrendo.2016.69].
  45. Charlton-Menys V, Durrington PN. Human cholesterol metabolism and therapeutic molecules. Exp Physiol. 2008; 93: 27-42. [https://doi.org/10.1113/expphysiol.2007.035147].
  46. Parhofer KG. The treatment of disorders of lipid metabolism. Dtsch Arztebl Int. 2016; 113: 262-268. [https://doi.org/10.3238/arztebl.2016.0261].
  47. Crowley LC, Marfell BJ, Scott AP, Waterhouse NJ. Quantitation of apoptosis and necrosis by annexin V binding, propidium iodide uptake, and flow cytometry. Cold Spring Harb Protoc. 2016; 2016:. [https://doi.org/10.1101/pdb.prot087288].
  48. Aggarwal BB, Deb L, Prasad S. Curcumin differs from tetrahydrocurcumin for molecular targets, signaling pathways and cellular responses. Molecules 2015; 20: 185-205. [https://doi.org/10.3390/molecules20010185] .
  49. J Wang, Wang C, Bu G. Curcumin inhibits the growth of liver cancer stem cells through the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Exp Ther Med. 2018; 15: 3650-3658. [https://doi.org/10.3892/etm.2018.5805].
  50. Shiu TY, Huang SM, Shih YL, Chu HC, Chang WK, Hsieh TY. Hepatitis C virus core protein down-regulates p21Waf1/Cip1 and inhibits curcumin-induced apoptosis through microRNA-345 targeting in human hepatoma cells. PLoS One. 2017; 12: e0181299. [https://doi.org/10.1371/journal.pone.0181299].
  51. Wu LY, Chen CW, Chen LK, Chou HY, Chang CL, Juan CC. Curcumin Attenuates Adipogenesis by Inducing Preadipocyte Apoptosis and Inhibiting Adipocyte Differentia-tion. Nutrients. 2019; 11: 2307. [https://doi.org/10.3390/nu11102307].
  52. Han SZ, Liu HX, Yang LQ, Cui LD, Xu Y. Piperine (PP) enhanced mitomycin-C (MMC) therapy of human cervical cancer through suppressing bcl-2 signaling pathway via inactivating STAT3/NF-κB. Biomed Pharmacother. 2017; 96: 1403-1410. [https://doi.org/10.1016/j.biopha.2017.11.022].
  53. Lin Y, Xu J, Liao H, Li L, Pan L. Piperine induces apoptosis of lung cancer A549 cells via p53-dependent mitochondrial signaling pathway. Tumour Biol 35(2014) 3305-10. [https://doi.org/10.1007/s13277-013-1433-4].
  54. Gunasekaran V, Elangovan K, Niranjali Devaraj S. Targeting hepatocellular carcinoma with piperine by radical-mediated mitochondrial pathway of apoptosis: An in vitro and in vivo study. Food Chem Toxicol. 2017; 105: 106-118. [https://doi.org/10.1016/j.fct.2017.03.029].
  55. Tikhanovich I, Kuravi S, Campbell RV, Kharbanda KK, Artigues A, Villar MT, et al. Regulation of FOXO3 by phosphorylation and methylation in hepatitis C virus infection and alcohol exposure. Hepatology. 2014; 59(1): 58-70. [https://doi.org/10.1002/hep.26618].
  56. Tikhanovich I, Cox J, Weinman SA. Forkhead box class O transcription factors in liver function and disease. J Gastroenterol Hepatol. 2013; 28: 125-131. [https://doi.org/10.1111/jgh.12021].
  57. Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018; 19: 121-135. [https://doi.org/10.1038/nrm.2017.95].
  58. Mankouri J, Tedbury PR, Gretton S, Hughes ME, Griffin SD, Dallas ML, et al. Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase. Proc Natl Acad Sci U S A. 2010; 107(25): 11549–11554. [https://doi.org/10.1073/pnas.0912426107].
  59. Liu Z, Cui C, Xu P, Dang R, Cai H, Liao D, et al. Curcumin activates AMPK pathway and regulates lipid metabolism in rats following prolonged clozapine exposure. Front Neurosci. 2017; 11: 558. [https://doi.org/10.3389/fnins.2017.00558].
  60. Seren S, M Mutchnick, Hutchinson D, Harmanci O, Bayraktar Y, Mutchnick S, et al. Potential role of lycopene in the treatment of hepatitis C and prevention of hepatocellular carcinoma. Nutr Cancer. 2008; 60(6): 729-735. Disponível em: [https://doi.org/10.1080/01635580802419772] .
  61. Dolka I, Król M, Sapierzyński R. Evaluation of apoptosis-associated protein (Bcl-2, Bax, cleaved caspase-3 and p53) expression in canine mammary tumors: an immunohistochemical and prognostic study. Res Vet Sci. 2016; 105: 124-133. [http://dx.doi.org/10.1016/j.rvsc.2016.02.004].
  62. Salakou S, Kardamakis D, Tsamandas AC, Zolota V, Apostolakis E, V Tzelepi, et al. Increased bax/bcl-2 ratio up-regulates caspase-3 and increases apoptosis in the thymus of patients with Myasthenia gravis. In Vivo. 2007; 21(1): 123-132. [https://pubmed.ncbi.nlm.nih.gov/17354625/].
  63. Masalova OV, Lesnova EI, Solyev PN, Zakirova NF, Prassolov VS, Kochetkov SN, et al. Modulation of cell death pathways by hepatitis C virus proteins in Huh7.5 hepatoma cells. Int J Mol Sci. 2017; 18(11): 2346. [https://doi.org/10.3390/ijms18112346].
  64. Pal MK, Jaiswar SP, Srivastav AK, Goyal S, Dwivedi A, Verma A, et al. Synergistic effect of piperine and paclitaxel on cell fate via cyt-c, bax/bcl-2-caspase-3 pathway in ovarian adenocarcinomas SKOV-3 cells. Eur J Pharmacol. 2016; 791: 751–762. [http://dx.doi.org/10.1016/j.ejphar.2016.10.019].
  65. Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017; 169: 381-405. [https://doi.org/10.1016/j.cell.2017.04.001].
  66. Liu Z, Tian Y, Machida K, Lai MM, Luo G, Foung SK, Ou JH. Transient activation of the PI3K-AKT pathway by hepatitis C virus to enhance viral entry. J Biol Chem. 2012; 287: 41922-41930. [https://doi.org/10.1074/jbc.M112.414789].
  67. Shi Q, Hoffman B, Liu Q. PI3K-Akt signaling pathway upregulates hepatitis C virus RNA translation through the activation of SREBPs. Virology. 2016; 490: 99-108. [https://doi.org/10.1016/j.virol.2016.01.012] .
  68. Zhao Y, Hu X, Liu Y, Dong S, Wen Z, He W, et al. ROS signaling under metabolic stress: cross-talk between AMPK and AKT pathway. Mol Cancer. 2017; 16: 79. [https://doi.org/10.1186/s12943-017-0648-1].
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Mechanistic insights into the antiviral effects of curcumin and piperine against Hepatitis C virus: a study of their bioactive properties in hepatocarcinoma cells. Rev Fitos [Internet]. 2025 Apr. 22 [cited 2025 Dec. 25];19:e1813. Available from: https://revistafitos.far.fiocruz.br/index.php/revista-fitos/article/view/1813
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