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1.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652639

RESUMO

Hepatitis C is affecting millions of people around the globe annually, which leads to death in very high numbers. After many years of research, hepatitis C virus (HCV) remains a serious threat to the human population and needs proper management. The in silico approach in the drug discovery process is an efficient method in identifying inhibitors for various diseases. In our study, the interaction between Epigallocatechin-3-gallate, a component of green tea, and envelope glycoprotein E2 of HCV is evaluated. Epigallocatechin-3-gallate is the most promising polyphenol approved through cell culture analysis that can inhibit the entry of HCV. Therefore, various in silico techniques have been employed to find out other potential inhibitors that can behave as EGCG. Thus, the homology modelling of E2 protein was performed. The potential lead molecules were predicted using ligand-based as well as structure-based virtual screening methods. The compounds obtained were then screened through PyRx. The drugs obtained were ranked based on their binding affinities. Furthermore, the docking of the topmost drugs was performed by AutoDock Vina, while its 2D interactions were plotted in LigPlot+. The lead compound mms02387687 (2-[[5-[(4-ethylphenoxy) methyl]-4-prop-2-enyl-1,2,4-triazol-3-yl] sulfanyl]-N-[3(trifluoromethyl) phenyl] acetamide) was ranked on top, and we believe it can serve as a drug against HCV in the future, owing to experimental validation.


Assuntos
Catequina/análogos & derivados , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas do Envelope Viral/genética , Antivirais/química , Antivirais/farmacologia , Catequina/química , Catequina/farmacologia , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/virologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Polifenóis/química , Polifenóis/farmacologia , Chá/química , Proteínas do Envelope Viral/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos
2.
Recent Results Cancer Res ; 217: 91-105, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33200363

RESUMO

Persistent infection with hepatitis C virus (HCV) is a major risk factor for hepatocellular carcinoma (HCC). Accumulating evidence suggests that not only inflammation and subsequent fibrosis but also HCV itself are associated with hepatocarcinogenesis. To date, studies using transgenic mouse and cell-culture models, in which HCV proteins are expressed, indicate the direct pathogenicity of HCV, including oncogenic activity. In particular, the core protein of HCV induces excessive oxidative stress by impairing the mitochondrial electron transfer system by disrupting the function of the molecular chaperone, prohibitin. HCV also modulates intracellular signaling pathways, including mitogen-activated protein kinase, promoting the proliferation of hepatocytes. In addition, HCV induces disorders in lipid and glucose metabolism, thereby accelerating the progression of liver fibrosis and the development of HCC. Due to the development of direct-acting antivirals, which was made possible by basic research, HCV can be eradicated from almost all infected patients. However, such patients can develop HCC long after eradication of HCV, suggesting the genetic and/or epigenetic changes induced by HCV may be persistent. These results enhance our understanding of the role of HCV in hepatocarcinogenesis and will facilitate the development of therapeutic and preventive strategies for HCV-induced HCC.


Assuntos
Carcinoma Hepatocelular , Hepacivirus , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Animais , Antivirais , Carcinoma Hepatocelular/etiologia , Hepacivirus/patogenicidade , Hepatite C Crônica/complicações , Humanos , Neoplasias Hepáticas/etiologia , Camundongos , Vírus Oncogênicos
3.
Channels (Austin) ; 14(1): 403-412, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33092458

RESUMO

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has prompted an urgent need to identify effective medicines for the prevention and treatment of the disease. A comparative analysis between SARS-CoV-2 and Hepatitis C Virus (HCV) can expand the available knowledge regarding the virology and potential drug targets against these viruses. Interestingly, comparing HCV with SARS-CoV-2 reveals major similarities between them, ranging from the ion channels that are utilized, to the symptoms that are exhibited by patients. Via this comparative analysis, and from what is known about HCV, the most promising treatments for COVID-19 can focus on the reduction of viral load, treatment of pulmonary system damages, and reduction of inflammation. In particular, the drugs that show most potential in this regard include ritonavir, a combination of peg-IFN, and lumacaftor-ivacaftor. This review anaylses SARS-CoV-2 from the perspective of the role of ion homeostasis and channels in viral pathomechanism. We also highlight other novel treatment approaches that can be used for both treatment and prevention of COVID-19. The relevance of this review is to offer high-quality evidence that can be used as the basis for the identification of potential solutions to the COVID-19 pandemic.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Hepacivirus/metabolismo , Canais Iônicos/metabolismo , Pneumonia Viral/metabolismo , Animais , Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Hepacivirus/patogenicidade , Hepatite C/metabolismo , Hepatite C/virologia , Humanos , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia
4.
Molecules ; 25(21)2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33105694

RESUMO

Viral infections and associated diseases are responsible for a substantial number of mortality and public health problems around the world. Each year, infectious diseases kill 3.5 million people worldwide. The current pandemic caused by COVID-19 has become the greatest health hazard to people in their lifetime. There are many antiviral drugs and vaccines available against viruses, but they have many disadvantages, too. There are numerous side effects for conventional drugs, and active mutation also creates drug resistance against various viruses. This has led scientists to search herbs as a source for the discovery of more efficient new antivirals. According to the World Health Organization (WHO), 65% of the world population is in the practice of using plants and herbs as part of treatment modality. Additionally, plants have an advantage in drug discovery based on their long-term use by humans, and a reduced toxicity and abundance of bioactive compounds can be expected as a result. In this review, we have highlighted the important viruses, their drug targets, and their replication cycle. We provide in-depth and insightful information about the most favorable plant extracts and their derived phytochemicals against viral targets. Our major conclusion is that plant extracts and their isolated pure compounds are essential sources for the current viral infections and useful for future challenges.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Herpes Simples/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Antivirais/química , Antivirais/classificação , Antivirais/isolamento & purificação , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Descoberta de Drogas , HIV/efeitos dos fármacos , HIV/patogenicidade , HIV/fisiologia , Infecções por HIV/patologia , Infecções por HIV/virologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/patogenicidade , Hepacivirus/fisiologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Herpes Simples/patologia , Herpes Simples/virologia , Humanos , Influenza Humana/patologia , Influenza Humana/virologia , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/patogenicidade , Orthomyxoviridae/fisiologia , Pandemias , Compostos Fitoquímicos/química , Compostos Fitoquímicos/classificação , Compostos Fitoquímicos/isolamento & purificação , Plantas Medicinais , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Simplexvirus/efeitos dos fármacos , Simplexvirus/patogenicidade , Simplexvirus/fisiologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
5.
APMIS ; 128(11): 593-602, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32870528

RESUMO

Induction of broad Th1 cellular immune responses and cytokines is crucial characteristics for vaccines against intracellular infections such as hepatitis C virus (HCV). Plants (especially oilseed tissues) and plant-immunomodulators (like oil bodies) offer cost-effective and scalable possibilities for the production of immunologically relevant and safe vaccine antigens and adjuvants, respectively. Herein, we provide data of the murine immunization by transgenic canola oilseed-derived HCV core protein (HCVcp) soluble extract (TSE) and Escherichia coli- derived rHCVcp in combination with Canola oil bodies (oil) compared to that of the Freund's (FA) adjuvant. Mice immunized by TSE+ oil developed both strong humeral (IgG) and Th1-biased cellular responses, manifested by high levels of IFN-γ and lower IgG1/IgG2a ratio and IL-4 secretion. Results of the intracellular cytokine staining indicated that TSE+ oil immunization in mice triggered both CD4+ and CD8+ T cells to release IFN-γ, while CD4+ cells were mostly triggered when FA was used. Analyses by qRT-PCR indicated that a combination of rHCVcp/TSE with oil body induced high levels of IL-10 cytokines compared to that of the FA adjuvant. These characteristics are important properties for the design of an HCV vaccine candidate and indicate the potential of Canola-derived antigen and oil bodies in addressing these concerns.


Assuntos
Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Células Th1/efeitos dos fármacos , Proteínas do Core Viral/administração & dosagem , Vacinas contra Hepatite Viral/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Hepacivirus/imunologia , Hepacivirus/patogenicidade , Hepatite C Crônica/imunologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Imunidade Celular/efeitos dos fármacos , Imunoglobulina G/biossíntese , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-10/biossíntese , Interleucina-10/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Óleo de Brassica napus/administração & dosagem , Óleo de Brassica napus/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Células Th1/imunologia , Células Th1/virologia , Proteínas do Core Viral/biossíntese , Proteínas do Core Viral/imunologia , Vacinas contra Hepatite Viral/biossíntese
6.
Nucleic Acids Res ; 48(16): 9235-9249, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32810257

RESUMO

Hepatitis C virus (HCV) replication requires annealing of a liver specific small-RNA, miR-122 to 2 sites on 5' untranslated region (UTR). Annealing has been reported to (a) stabilize the genome, (b) stimulate translation and (c) promote the formation of translationally active Internal Ribosome Entry Site (IRES) RNA structure. In this report, we map the RNA element to which small RNA annealing promotes HCV to nucleotides 1-44 and identify the relative impact of small RNA annealing on virus translation promotion and genome stabilization. We mapped the optimal region on the HCV genome to which small RNA annealing promotes virus replication to nucleotides 19-37 and found the efficiency of viral RNA accumulation decreased as annealing moved away from this region. Then, by using a panel of small RNAs that promote replication with varying efficiencies we link the efficiency of lifecycle promotion with translation stimulation. By contrast small RNA annealing stabilized the viral genome even if they did not promote virus replication. Thus, we propose that miR-122 annealing promotes HCV replication by annealing to an RNA element that activates the HCV IRES and stimulates translation, and that miR-122 induced HCV genome stabilization is insufficient alone but enhances virus replication.


Assuntos
Instabilidade Genômica/genética , Hepatite C/genética , MicroRNAs/genética , Biossíntese de Proteínas , Regiões 5' não Traduzidas/genética , Proteínas Argonauta/genética , Genoma Viral/genética , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/virologia , Humanos , Sítios Internos de Entrada Ribossomal/genética , Estabilidade de RNA/genética , Sequências Reguladoras de Ácido Nucleico/genética , Replicação Viral/genética
7.
Orv Hetil ; 161(35): 1449-1455, 2020 08.
Artigo em Húngaro | MEDLINE | ID: mdl-32822323

RESUMO

Autophagy plays an important role in the homeostasis of the cells and it may be upregulated in response to several types of stresses. Deregulation of autophagy is a key mechanism in the pathogenesis and progression of several liver diseases. Deficient autophagy can contribute to liver steatosis, to endoplasmic reticulum stress and to the progression of non-alcoholic fatty liver disease. Chronic alcohol consumption inhibits autophagy. The accumulated mutant protein in the endoplasmic reticulum can be degraded by autophagy in alpha-1-antitrypsin deficiency. Hepatitis C and B viruses may exploit the autophagy pathway to promote the own replication. Hepatitis C virus non-structural protein 5A and 5B have roles in the induction of autophagosomes. MicroRNAs regulate multiple physiological, pathological functions and autophagy through the modulation of gene expression. MicroRNA-122 is involved in HCV replication. In HBV-infected livers, the microRNA pathways related to cell death, DNA damage, recombination and signal transduction were activated. MicroRNA-122 effects multiple important factors which regulate the lipid and carbohydrate metabolisms in human non-alcoholic fatty liver disease. Oxidative stress and free oxygen radicals generation involved in alcoholic liver diseases development are regulated by microRNAs through different pathways. MicroRNAs control autophagy process and autophagy regulates the expression of microRNA-s. The exploration of their interactions contributes to understanding the development of liver diseases. Orv Hetil. 2020; 161(35): 1499-1455.


Assuntos
Autofagia , Carcinoma Hepatocelular/patologia , Hepacivirus/patogenicidade , Hepatite C Crônica/patologia , Hepatite C , Fígado/virologia , MicroRNAs/genética , Carcinoma Hepatocelular/virologia , Estresse do Retículo Endoplasmático , Hepacivirus/fisiologia , Hepatite C Crônica/virologia , Hepatite Viral Humana/fisiopatologia , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Estresse Oxidativo
8.
PLoS One ; 15(7): e0236447, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697788

RESUMO

The hepatitis C virus (HCV) nonstructural protein 3-4A (NS3-4A) protease is a key component of the viral replication complex and the target of protease inhibitors used in current clinical practice. By cleaving and thereby inactivating selected host factors it also plays a role in the persistence and pathogenesis of hepatitis C. Here, we describe ovarian cancer immunoreactive antigen domain containing protein 1 (OCIAD1) as a novel cellular substrate of the HCV NS3-4A protease. OCIAD1 was identified by quantitative proteomics involving stable isotopic labeling using amino acids in cell culture coupled with mass spectrometry. It is a poorly characterized membrane protein believed to be involved in cancer development. OCIAD1 is cleaved by the NS3-4A protease at Cys 38, close to a predicted transmembrane segment. Cleavage was observed in heterologous expression systems, the replicon and cell culture-derived HCV systems, as well as in liver biopsies from patients with chronic hepatitis C. NS3-4A proteases from diverse hepacivirus species efficiently cleaved OCIAD1. The subcellular localization of OCIAD1 on mitochondria was not altered by NS3-4A-mediated cleavage. Interestingly, OCIAD2, a homolog of OCIAD1 with a cysteine residue in a similar position and identical subcellular localization, was not cleaved by NS3-4A. Domain swapping experiments revealed that the sequence surrounding the cleavage site as well as the predicted transmembrane segment contribute to substrate selectivity. Overexpression as well as knock down and rescue experiments did not affect the HCV life cycle in vitro, raising the possibility that OCIAD1 may be involved in the pathogenesis of hepatitis C in vivo.


Assuntos
Hepacivirus/enzimologia , Hepatite C Crônica/patologia , Interações entre Hospedeiro e Microrganismos , Proteínas de Neoplasias/metabolismo , Proteínas não Estruturais Virais/metabolismo , Biópsia , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Células HEK293 , Hepacivirus/patogenicidade , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Fígado/patologia , Fígado/virologia , Mitocôndrias/metabolismo , Modelos Moleculares , Proteínas de Neoplasias/genética , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Domínios Proteicos/genética , Homologia de Sequência de Aminoácidos , Especificidade por Substrato/genética , Proteínas não Estruturais Virais/antagonistas & inibidores
9.
J Vasc Interv Radiol ; 31(6): 953-960, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32376182

RESUMO

PURPOSE: To investigate the impact of direct-acting antivirals (DAAs) and 12-week sustained virologic response (SVR12) in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) treated by interventional oncology (IO) therapies. MATERIALS AND METHODS: Retrospective analysis of patients diagnosed from 2005 to 2016 with HCC and receiving IO therapies. A total of 478 patients met inclusion criteria. Patients were age 29-90 years (mean 63.6 ± 9.4 years) and 78.9% (n =3 77) male. Two hundred and eighty-five (57%) patients had chronic HCV, 93 (33%) received DAAs, and 63 (68%) achieved SVR12. Liver function, tumor characteristics, and IO therapy including ablation, image-guided transcatheter tumor therapies (ITTT) (eg, chemoembolization and radioembolization), and combination locoregional therapy were assessed in analysis. RESULTS: Median overall survival (OS) of the cohort was 26.7 months (95% confidence interval [CI] 21.9-29.9). OS for ablation, combination locoregional therapy and ITTT, was 37.3 (CI 30.7-49.9), 29.3 (CI 24.2-38.0), and 19.7 months (CI 16.5-22.8), respectively (P < .0001). OS in patients with HCV was 30.7 months (CI 24.2-35.2) versus 22.2 months in non-HCV patients (CI 17.8-27.8, P = .03). Patients with HCV who received DAA had higher survival, 49.2 months (CI 36.5-not reached) versus those not receiving DAA, 18.5 months (CI 14.1-25.3, P < .0001). OS was 71.8 months (CI 42.3-not reached) for patients who achieved SVR12 after DAA versus 26.7 months in the non-SVR12 group (CI 15.9-31.1, P < .0001). Multivariable analysis revealed independent factors for OS including IO treatment type, DAA use and achieving SVR12 (P < .05). CONCLUSIONS: DAA use and SVR12 is associated with higher OS in patients with HCV-related HCC treated by IO therapies.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/terapia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Neoplasias Hepáticas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/virologia , Feminino , Hepacivirus/patogenicidade , Hepatite C/diagnóstico , Hepatite C/mortalidade , Hepatite C/virologia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resposta Viral Sustentada , Fatores de Tempo , Resultado do Tratamento
10.
Int J Nanomedicine ; 15: 2699-2715, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368050

RESUMO

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, respectively. 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.


Assuntos
Antivirais/farmacologia , Curcumina/farmacologia , Hepacivirus/efeitos dos fármacos , Nanopartículas/química , Antivirais/química , Linhagem Celular , Quitosana/química , Curcumina/administração & dosagem , Curcumina/química , Genótipo , Hepacivirus/genética , Hepacivirus/patogenicidade , Humanos , Neoplasias Hepáticas/virologia , Nanopartículas/uso terapêutico , Proteínas do Core Viral/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
11.
Sci Rep ; 10(1): 6736, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317646

RESUMO

Hepatic steatosis (HS) is frequently observed in HIV-infected patients. It is not known whether HIV infection is an independent risk factor for HS development. We aimed to analyze whether HIV coinfection was associated with a higher frequency of HS in patients with chronic hepatitis C. This was a retrospective cross-sectional study. 574 subjects with chronic hepatitis C virus (HCV) infection were included, 246 (43%) of them coinfected with HIV. All of them underwent transient elastography with controlled attenuation parameter (CAP) measurement. HS was defined as CAP ≥ 248 dB/m. 147 individuals (45%) showed HS in the HCV-monoinfected group and 100 (40.7%) in the HIV/HCV-coinfected group (p = 0.318). HS was associated with body mass index (BMI) [<25 Kg/m2 vs. ≥25 Kg/m2, 67 (23.5%) vs. 171 (62.9%); p = 0.001], with plasma HDL-cholesterol [<50 mg/dL vs. ≥50 mg/dL, 122 (48.6%) vs. 95 (37.5%), p = 0.012], with plasma triglycerides [<150 mg/dL vs. ≥150 mg/dL, 168 (40.2%) vs. 65 (52.4%); p = 0.016] and with plasma total cholesterol [<200 mg/dL vs. ≥200 mg/dL, 181 (41%) vs. 53 (52.5%); p = 0.035]. In the multivariate analysis, HS was associated with BMI [adjusted OR (AOR) = 1.264 (1.194-1.339); p = 0.001], age [AOR = 1.029 (1.001-1.058); p = 0.047] and HCV genotype 3 infection [AOR = 1.901 (1.081-2.594); p = 0.026]. HIV coinfection was not associated with HS [AOR = 1.166 (0.719-1.892); p = 0.534]. In conclusion, HIV coinfection is not related with an increased frequency of HS in HCV-infected patients.


Assuntos
Fígado Gorduroso/epidemiologia , Infecções por HIV/epidemiologia , HIV/patogenicidade , Hepacivirus/patogenicidade , Hepatite C Crônica/epidemiologia , Fígado/patologia , Índice de Massa Corporal , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Coinfecção , Estudos Transversais , Técnicas de Imagem por Elasticidade , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/patologia , Fígado Gorduroso/virologia , Feminino , HIV/crescimento & desenvolvimento , Infecções por HIV/diagnóstico por imagem , Infecções por HIV/patologia , Infecções por HIV/virologia , Hepacivirus/crescimento & desenvolvimento , Hepatite C Crônica/diagnóstico por imagem , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Fígado/diagnóstico por imagem , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Espanha/epidemiologia , Triglicerídeos/sangue
12.
PLoS One ; 15(4): e0230756, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32282805

RESUMO

BACKGROUND: In the foreseeable future, patients with hepatitis C virus (HCV) with good healthcare access will all have been cured and the lost to follow-up (LFU) HCV-population will increasingly exist of hard-to-reach patients. Efforts to retrieve these individuals with HCV have been moderately successful so far. A deeper understanding of the reasons for loss to follow-up and the underlying processes is lacking. AIMS: To explore reasons for previous loss to follow-up in patients with HCV who have been brought back into care. METHODS: In 2017, fifteen patients with HCV who were evaluated at the University Medical Center Utrecht (UMCU) Infectious diseases outpatient clinic as part of the "REtrieval And cure of Chronic Hepatitis C" (REACH)-project were included in this study through convenience sampling. Face-to-face semi-structured in-depth interviews were conducted and a qualitative analysis based on the grounded theory was applied. RESULTS: A basic socio- psychological process named "maintaining the achieved balance" was uncovered in patients with HCV who were LFU. This "achieved balance" is the result of a transformative process following the initial HCV diagnosis. It is a steadfast stance in which participants keep HCV out of sight and in the margin of their lives in order to reestablish an optimal state of well-being. The balancing perspective is subsequently defended by repeated evasive behavioral patterns to avoid confrontation with the disease. CONCLUSION: The balancing perspective gives insight into why individuals with HCV were not retained in care but also why they remained LFU thereafter. Physicians should realize that this mindset can be persistent and repeated efforts may be needed to finally trace and retrieve these patients.


Assuntos
Hepatite C Crônica/diagnóstico , Hepatite C Crônica/epidemiologia , Adulto , Estudos de Avaliação como Assunto , Feminino , Acesso aos Serviços de Saúde , Hepacivirus/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Biochim Biophys Acta Biomembr ; 1862(7): 183296, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32268133

RESUMO

The hepatitis C virus (HCV) is a major cause of liver diseases ranging from liver inflammation to advanced liver diseases like cirrhosis and hepatocellular carcinoma (HCC). HCV infection is restricted to the liver, and more specifically to hepatocytes, which represent around 80% of liver cells. The mechanism of HCV entry in human hepatocytes has been extensively investigated since the discovery of the virus 30 years ago. The entry mechanism is a multi-step process relying on several host factors including heparan sulfate proteoglycan (HSPG), low density lipoprotein receptor (LDLR), tetraspanin CD81, Scavenger Receptor class B type I (SR-BI), Epidermal Growth Factor Receptor (EGFR) and Niemann-Pick C1-like 1 (NPC1L1). Moreover, in order to establish a persistent infection, HCV entry is dependent on the presence of tight junction (TJ) proteins Claudin-1 (CLDN1) and Occludin (OCLN). In the liver, tight junction proteins play a role in architecture and homeostasis including sealing the apical pole of adjacent cells to form bile canaliculi and separating the basolateral domain drained by sinusoidal blood flow. In this review, we will highlight the role of liver tight junction proteins in HCV infection, and we will discuss the potential targeted therapeutic approaches to improve virus eradication.


Assuntos
Hepatite C/genética , Interações Hospedeiro-Patógeno/genética , Junções Íntimas/genética , Internalização do Vírus , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/virologia , Hepatócitos/virologia , Humanos , Fígado/patologia , Fígado/virologia , Proteínas de Membrana Transportadoras/genética , Ocludina/genética , Receptores de LDL/genética , Tetraspanina 28/genética , Junções Íntimas/virologia
14.
Diagn Microbiol Infect Dis ; 97(2): 115025, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32147132

RESUMO

Host single nucleotide polymorphisms (SNPs) in different genes can play a role in chronic hepatitis C virus (HCV) infection and influence the presence of hepatic fibrosis and comorbidities such as hepatic steatosis. We assessed the combined effect of SNPs in the PNPLA3, MTTP, TM6SF2, and IFNL3/IFNL4 genes in 288 Brazilian patients who were chronically infected with HCV. Hepatic fibrosis was observed in 246 (85.4%) patients and hepatic steatosis in 141 (49.0%) patients. PNPLA3 rs738409 (CG/GG) (P = 0.044) and TM6SF2 rs58542926 (CT) (P = 0.004) were alone associated with fibrosis, and PNPLA3 rs738409 (P < 0.05, in distinct genetic models) was associated with steatosis. Multiple logistic regression of each SNP combined with HCV genotype 3 infection showed that MTTP rs1800591 (GT/TT) combined with HCV genotype 3 was associated with a 6.72-fold increased chance of hepatic steatosis (P = 0.013). In the analysis of SNPs combined 2 by 2, no influence on hepatic fibrosis or steatosis was observed.


Assuntos
Fígado Gorduroso/genética , Hepatite C Crônica/genética , Cirrose Hepática/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Brasil , Proteínas de Transporte/genética , Fígado Gorduroso/virologia , Feminino , Estudos de Associação Genética , Genótipo , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C Crônica/virologia , Humanos , Interferons/genética , Lipase/genética , Cirrose Hepática/virologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade
15.
PLoS One ; 15(1): e0224875, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31995556

RESUMO

INTRODUCTION: Guidelines advocate the treatment of HCV in all HIV/HCV co-infected individuals. The aim of this randomized, open-label study (ClinicalTrials.gov identifier: NCT02707601; https://clinicaltrials.gov/ct2/show/NCT02707601) was to evaluate the safety/efficacy of ledipasvir/sofosbuvir (LDV/SOF) co-administered with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or rilpivirine/F/TAF (R/F/TAF) in HIV-1/HCV co-infected participants. METHODS: Participants with HIV-1 RNA <50 copies/mL and chronic HCV-genotype (GT) 1 (HCV treatment-naïve ± compensated cirrhosis or HCV treatment-experienced non-cirrhotic) were randomized 1:1 to switch to E/C/F/TAF or R/F/TAF. If HIV suppression was maintained at Week 8, participants received 12 weeks of LDV/SOF. The primary endpoint was sustained HCV virologic response 12 weeks after LDV/SOF completion (SVR12). RESULTS: Of 150 participants, 148 received ≥1 dose of HIV study drug and 144 received LDV/SOF (72 in each F/TAF group; 83% GT1a, 94% HCV treatment-naïve, 12% cirrhotic). Overall, SVR12 was 97% (95% confidence interval: 93-99%). Black race did not affect SVR12. Of four participants not achieving SVR12, one had HCV relapse, one had HCV virologic non-response due to non-adherence, and two missed the post-HCV Week 12 visit. Of 148 participants, 96% receiving E/C/F/TAF and 95% receiving R/F/TAF maintained HIV suppression at Week 24; no HIV resistance was detected. No participant discontinued LDV/SOF or E/C/F/TAF due to adverse events; one participant discontinued R/F/TAF due to worsening of pre-existing hypercholesterolemia. Renal toxicity was not observed in either F/TAF regimen during LDV/SOF co-administration. In conclusion, high rates of HCV SVR12 and maintenance of HIV suppression were achieved with LDV/SOF and F/TAF-based regimens. CONCLUSION: This study supports LDV/SOF co-administered with an F/TAF-based regimen in HIV-1/HCV-GT1 co-infected patients.


Assuntos
Coinfecção/tratamento farmacológico , Combinação de Medicamentos , Infecções por HIV/tratamento farmacológico , Hepatite C/tratamento farmacológico , Adenina/administração & dosagem , Adenina/análogos & derivados , Adulto , Idoso , Benzimidazóis/administração & dosagem , Coinfecção/virologia , Farmacorresistência Viral/efeitos dos fármacos , Emtricitabina/administração & dosagem , Feminino , Fluorenos/administração & dosagem , Infecções por HIV/complicações , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Hepacivirus/patogenicidade , Hepatite C/complicações , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/isolamento & purificação , Sofosbuvir/administração & dosagem , Tenofovir/administração & dosagem
16.
Biomed Pharmacother ; 124: 109838, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31981943

RESUMO

Hepatocellular carcinoma (HCC) is a malignant primary liver cancer with poor prognosis. Most previous studies on anti-HCC effects of traditional Chinese medicines (TCM) have focused on the mechanism of direct action and few researchers considered that TCM can inhibit tumor progression and improve prognosis of HCC patients through regulating tumor microenvironment (TME). In this study, network pharmacology combined bioinformatics methods were employed to analysis mechanism of Bombyx batryticatus (B. batryticatus, one of the most frequently used traditional Chinese animal medicines, has been used in some Asian countries for centuries as an anticancer agent, anti-inflammatory agent, and antioxidant.) in regulating TME of HCC. The results showed that 24 core targets and 2 compounds were identified from overlapping between differential expression genes related to HCC in the cancer genome atlas (TCGA) database and targets of B. batryticatus in TCMSP database. For further analyzing the role of TME heterogeneity of HCC on anti-HCC mechanism of B. batryticatus, the correlation of core targets related with overall survival of HCC with TME cells in hepatitis C or hepatitis B virus-associated hepatocellular carcinoma (VIR) and non-hepatitis C or hepatitis B virus-associated hepatocellular carcinoma (NVIR) were calculated, respectively. The results showed that AKR1C3, SPP1 were significantly related with macrophages in VIR and other targets including NR1I2, CYP1A2 and CYP3A4 were significantly associated with macrophages in NVIR; the target protein AKR1C3 was significantly negative correlated with macrophages M1 in VIR (cor=-0.35, P-value<0.001) and the correlation between AKR1C3 and macrophages M1 was poor in NVIR group (cor = 0.064, P-value = 0.36). Additionally, survival curve of AKR1C3 showed that poor prognosis in VIR group can be related to high level of AKR1C3 (HR = 2.32, 95 % CI: 1.18-4.56, P-value = 0.012), and no signified gene can be found in NVIR group (P-value>0.05). In conclusion, the molecular mechanism of anti-HCC of B. batryticatus can be related to the tumor microenvironment to some extent. B. batryticatus may exert its anti-cancer effects and improve prognosis of patients by regulating macrophages M1 in VIR and NVIR through acting on different targets.


Assuntos
Antineoplásicos/farmacologia , Bombyx/química , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antineoplásicos/isolamento & purificação , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Cerâmica/metabolismo , Biologia Computacional , Feminino , Regulação Neoplásica da Expressão Gênica , Hepacivirus/patogenicidade , Vírus da Hepatite B/patogenicidade , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Medicina Tradicional Chinesa/métodos , Pessoa de Meia-Idade , Prognóstico , Microambiente Tumoral/imunologia
17.
PLoS One ; 15(1): e0224977, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31940353

RESUMO

BACKGROUND: An elevated gamma gap (>4 g/dL), the difference between serum total protein and albumin, can trigger testing for chronic infections or monoclonal gammopathy, despite a lack of evidence supporting this clinical threshold. METHODS: Using the National Health and Nutrition Examination Survey (NHANES) 1999-2014, gamma gap was derived in three subpopulations based on availability of testing for human immunodeficiency virus (HIV; N = 25,680), hepatitis C (HCV; N = 45,134), and monoclonal gammopathy of unknown significance (MGUS; N = 6,118). Disease status was confirmed by HIV antibody and Western blot, HCV RNA test, or electrophoresis with immunofixation. Sensitivity, specificity, and likelihood ratios were calculated for different gamma gap thresholds. Area under the curve (AUC) was used to assess performance and cubic splines were used to characterize the relationship between the gamma gap and each disease. RESULTS: Mean gamma gaps of participants with HIV, HCV, or MGUS ranged from 3.4-3.8 g/dL. The AUC was 0.80 (95%CI: 0.75,0.85) for HIV, 0.74 (0.72,0.76) for HCV, and 0.64 (0.60,0.69) for MGUS. An elevated gamma gap of over 4 g/dL corresponded to sensitivities of 39.3%, 19.0%, and 15.4% and specificities of 98.4%, 97.8%, and 95.4% for HIV, HCV, and MGUS, respectively. A higher prevalence of all three diseases was observed at both low and high gamma gaps. DISCUSSION: An elevated gamma gap of 4 g/dL is insensitive for HIV, HCV, or MGUS, but has a high specificity for HIV and HCV, suggesting that the absence of an elevated gamma gap does not rule out HIV, HCV, or MGUS. Conversely, an elevated gap may justify further testing for HIV and HCV, but does not justify electrophoresis in the absence of additional clinical information.


Assuntos
Proteínas Sanguíneas , Infecções por HIV/sangue , Hepatite C/sangue , Gamopatia Monoclonal de Significância Indeterminada/sangue , Albumina Sérica , Adulto , Idoso , Feminino , HIV/patogenicidade , Infecções por HIV/virologia , Hepacivirus/patogenicidade , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/epidemiologia , Gamopatia Monoclonal de Significância Indeterminada/patologia
18.
J Biol Chem ; 295(7): 1843-1856, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31929110

RESUMO

Viruses depend on the host cell translation machinery for their replication, and one common strategy is the presence of internal ribosome entry sites (IRESs) in the viral RNAs, using different sets of host translation initiation factors. The hepatitis C virus (HCV) IRES binds eukaryotic translation initiation factor 3 (eIF3), but the exact functional role of the eIF3 complex and of its subunits remains to be precisely defined. Toward this goal, here we focused on eIF3 subunit e. We used an in vitro assay combining a ribosome-depleted rabbit reticulocyte lysate and ribosomes prepared from HeLa or Huh-7.5 cells transfected with either control or eIF3e siRNAs. eIF3e silencing reduced translation mediated by the 5'UTR of various cellular genes and HCV-like IRESs. However, this effect was not observed with the bona fide HCV IRES. Silencing of eIF3e reduced the intracellular levels of the c, d, and l subunits of eIF3 and their association with the eIF3 core subunit a. A pulldown analysis of eIF3 subunits associated with the HCV IRES disclosed similar effects and that the a subunit is critical for binding to the HCV IRES. Carrying out HCV infections of control and eIF3e-silenced Huh-7.5 cells, we found that in agreement with the in vitro findings, eIF3e silencing does not reduce HCV replication and viral protein expression. We conclude that unlike for host cellular mRNAs, the entire eIF3 is not required for HCV RNA translation, favoring viral expression under conditions of low eIF3e levels.


Assuntos
Fator de Iniciação 3 em Eucariotos/genética , Hepacivirus/genética , Hepatite C/genética , Sítios Internos de Entrada Ribossomal/genética , Animais , Linhagem Celular , Hepacivirus/patogenicidade , Hepatite C/patologia , Hepatite C/virologia , Humanos , Ligação Proteica/genética , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , RNA Viral/química , RNA Viral/genética , Coelhos , Ribossomos/química , Ribossomos/genética , Proteínas Virais/química , Proteínas Virais/genética
19.
PLoS One ; 15(1): e0227114, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31899786

RESUMO

The discovery of hepaciviruses in non-human hosts has accelerated following the advancement of high-throughput sequencing technology. Hepaciviruses have now been described in reptiles, fish, birds, and an extensive array of mammals. Using metagenomic sequencing on pooled samples of field-collected Culex annulirostris mosquitoes, we discovered a divergent hepacivirus-like sequence, named Jogalong virus, from the Kimberley region in northern Western Australia. Using PCR, we screened the same 300 individual mosquitoes and found just a single positive sample (1/300, 0.33%). Phylogenetic analysis of the hepacivirus NS5B protein places Jogalong virus within the genus Hepacivirus but on a distinct and deeply rooted monophyletic branch shared with duck hepacivirus, suggesting a notably different evolutionary history. Vertebrate barcoding PCR targeting two mitochondrial genes, cytochrome c oxidase subunit I and cytochrome b, indicated that the Jogalong virus-positive mosquito had recently fed on the tawny frogmouth (Podargus strigoides), although it is currently unknown whether this bird species contributes to the natural ecology of this virus.


Assuntos
Culex/virologia , Genoma Viral , Hepacivirus/genética , Mosquitos Vetores/virologia , Filogenia , Animais , Hepacivirus/classificação , Hepacivirus/patogenicidade , Proteínas Virais/genética , Austrália Ocidental
20.
J Biol Chem ; 295(3): 800-807, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31836663

RESUMO

Sodium taurocholate cotransporting polypeptide (NTCP) is expressed at the surface of human hepatocytes and functions as an entry receptor of hepatitis B virus (HBV). Recently, we have reported that epidermal growth factor receptor (EGFR) is involved in NTCP-mediated viral internalization during the cell entry process. Here, we analyzed which function of EGFR is essential for mediating HBV internalization. In contrast to the reported crucial function of EGFR-downstream signaling for the entry of hepatitis C virus (HCV), blockade of EGFR-downstream signaling proteins, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and signal transducer and activator of transcription (STAT), had no or only minor effects on HBV infection. Instead, deficiency of EGFR endocytosis resulting from either a deleterious mutation in EGFR or genetic knockdown of endocytosis adaptor molecules abrogated internalization of HBV via NTCP and prevented viral infection. EGFR activation triggered a time-dependent relocalization of HBV preS1 to the early and late endosomes and to lysosomes in concert with EGFR transport. Suppression of EGFR ubiquitination by site-directed mutagenesis or by knocking down two EGFR-sorting molecules, signal-transducing adaptor molecule (STAM) and lysosomal protein transmembrane 4ß (LAPTM4B), suggested that EGFR transport to the late endosome is critical for efficient HBV infection. Cumulatively, these results support the idea that the EGFR endocytosis/sorting machinery drives the translocation of NTCP-bound HBV from the cell surface to the endosomal network, which eventually enables productive viral infection.


Assuntos
Endocitose/genética , Endossomos/genética , Receptores ErbB/genética , Hepatite B/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/química , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Endossomos/química , Receptores ErbB/química , Células Hep G2 , Hepacivirus/química , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite B/metabolismo , Hepatite B/virologia , Vírus da Hepatite B/química , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , MAP Quinase Quinase 1/genética , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas Oncogênicas/química , Proteínas Oncogênicas/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio , Fosfatidilinositol 3-Quinases/genética , Fosfoproteínas/química , Fosfoproteínas/genética , Fatores de Transcrição STAT/genética , Simportadores , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Internalização do Vírus
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