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1.
RSC Adv ; 13(41): 29004-29022, 2023 Sep 26.
Article in English | MEDLINE | ID: mdl-37807973

ABSTRACT

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) are currently being evaluated in clinical trials as potential curative therapies for HBV. This study used in silico computational modeling to provide insights into the binding characteristics between the HBV core protein and two pyrrole-scaffold inhibitors, JNJ-6379 and GLP-26, both in the CAM-Normal (CAM-N) series. Molecular dynamics simulations showed that the pyrrole inhibitors displayed similar general binding-interaction patterns to NVR 3-778, another CAM-N, with hydrophobic interactions serving as the major driving force. However, consistent with their higher potency, the pyrrole inhibitors exhibited stronger nonpolar interactions with key residues in a solvent-accessible region as compared to NVR 3-778. This feature was facilitated by distinct hydrogen bond interactions of the pyrrole scaffold inhibitors with the residue 140 in chain B of the HBV core protein (L140B). Based on these findings, novel CAM-N compounds were designed to mimic the interaction with L140B residue while maximizing nonpolar interactions in the solvent-accessible region. Several 1H-pyrrole-2-carbonyl substituted pyrrolidine-based compounds with various hydrophobic side chains were synthesized and evaluated. Through analyses of the structure-activity and structure-druggability relations of a series of compounds, CU15 emerged as the most promising lead CAM-N compound, exhibiting sub-nanomolar potency and good pharmacokinetic profiles. Overall, the study demonstrated a practical approach to leverage computational methods for understanding key target binding features for rationale-based design, and for guiding the identification of novel compounds.

2.
Asian Pac J Cancer Prev ; 19(8): 2191-2197, 2018 Aug 24.
Article in English | MEDLINE | ID: mdl-30139224

ABSTRACT

There is increasing evidence that host genetic variations may influence the natural history of chronic hepatitis C virus (HCV) infection. The aim of this study was to determine the association between single nucleotide polymorphisms (SNPs) of PNPLA3 (rs738409), COX-2 (rs689465) and DHCR7 (rs12785878) and advanced liver fibrosis in Thai patients. A total of 220 patients with HCV mono-infection, 200 patients with HCV/HIV co-infection and 200 healthy controls were enrolled. The SNPs were detected by allelic discrimination using real-time PCR with TaqMan probes. Liver stiffness measurement (LSM) was assessed by transient elastography. Our results showed that the distribution of the studied SNPs were not significantly different between the HCV mono- and co-infected groups. The frequencies AG and GG genotypes of rs689465 and GG genotype of rs12785878 were less commonly found in the HCV mono- and co-infected groups compare with healthy controls (P<0.01). Among patients with HCV infection, older age, HIV co-infection, GG genotype of rs738409 and GG genotype of rs689465 were independently associated with advanced liver fibrosis (LSM≥9.5 kPa) in multivariate analysis. Moreover, the percentage of patients with advanced liver fibrosis increased significantly along with the accumulated numbers of these risk genotypes. In conclusion, PNPLA3 (rs738409) and COX-2 (rs689465) polymorphisms were associated with advanced liver fibrosis in patients with HCV mono- and co-infection, suggesting that these variants might play an important role in progressive liver fibrosis in these patients.


Subject(s)
Coinfection/complications , Cyclooxygenase 2/genetics , HIV Infections/complications , Hepatitis C/complications , Lipase/genetics , Liver Cirrhosis/etiology , Membrane Proteins/genetics , Oxidoreductases Acting on CH-CH Group Donors/genetics , Polymorphism, Single Nucleotide/genetics , Adult , Biomarkers/metabolism , Case-Control Studies , Coinfection/virology , Female , Follow-Up Studies , Genotype , HIV/isolation & purification , HIV Infections/virology , Hepacivirus/isolation & purification , Hepatitis C/virology , Humans , Liver Cirrhosis/diagnosis , Liver Cirrhosis/epidemiology , Male , Middle Aged , Prognosis , Thailand/epidemiology
3.
Sci Rep ; 6: 31855, 2016 08 22.
Article in English | MEDLINE | ID: mdl-27546060

ABSTRACT

Vascular leakage is a life-threatening complication of dengue virus (DENV) infection. Previously, association between "paracellular" endothelial hyperpermeability and plasma leakage had been extensively investigated. However, whether "transcellular" endothelial leakage is involved in dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) remained unknown. We thus investigated effects of DENV (serotype 2) infection on transcellular transport of albumin, the main oncotic plasma protein, through human endothelial cell monolayer by Western blotting, immunofluorescence staining, fluorescence imaging, and fluorometry. The data showed that Alexa488-conjugated bovine serum albumin (Alexa488-BSA) was detectable inside DENV2-infected cells and its level was progressively increased during 48-h post-infection. While paracellular transport could be excluded using FITC-conjugated dextran, Alexa488-BSA was progressively increased and decreased in lower and upper chambers of Transwell, respectively. Pretreatment with nystatin, an inhibitor of caveolae-dependent endocytic pathway, significantly decreased albumin internalization into the DENV2-infected cells, whereas inhibitors of other endocytic pathways showed no significant effects. Co-localization of the internalized Alexa488-BSA and caveolin-1 was also observed. Our findings indicate that DENV infection enhances caveolae-mediated albumin transcytosis through human endothelial cells that may ultimately induce plasma leakage from intravascular compartment. Further elucidation of this model in vivo may lead to effective prevention and better therapeutic outcome of DHF/DSS.


Subject(s)
Caveolae/metabolism , Endothelial Cells/metabolism , Serum Albumin, Human/metabolism , Severe Dengue/metabolism , Capillary Permeability , Cell Line , Dengue Virus/physiology , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelial Cells/virology , Humans , Models, Biological , Nystatin/pharmacology , Transcytosis/drug effects
4.
Exp Biol Med (Maywood) ; 241(16): 1803-10, 2016 10.
Article in English | MEDLINE | ID: mdl-27190255

ABSTRACT

Interferons play important roles in defense mechanisms against viral infection, and thus interferon therapy has been a standard treatment in chronic hepatitis B patients. Interferons signaling pathways promote interferon-inducible genes including microRNAs. In this research, we aimed to determine microRNAs expression profiles in vitro and in vivo For in vitro model, Huh7 cells were transfected with or without hepatitis B virus plasmid for 6 h, and then treated with 100 ng of pegylated-interferon alpha-2a for 24 h. In vivo, we defined microRNAs expression profiles in pair-liver tissues of chronic hepatitis B patients in comparison between before and after treatment of pegylated-interferon alpha-2a for 48 weeks. Cellular small RNAs were extracted followed by library preparation. To determine microRNAs expression profiles, the next-generation sequencing was carried out on MiSeq platform (Illumina®). In vitro analysis demonstrated that microRNAs can be classified into up-regulated and down-regulated microRNAs in response to hepatitis B virus, interferon, and combination of hepatitis B virus and interferon. Moreover, in vivo analysis revealed microRNAs profiles in non-responders, responders without hepatitis B surface antigen clearance, and responders with hepatitis B surface antigen clearance. The target genes of the candidate microRNAs were determined in terms of roles in cellular pathways and immune response, which might be related to treatment in chronic hepatitis B patients. Results revealed that two down-regulated microRNAs including miR-185-5p and miR-186-5p were correlated in both in vitro and in vivo studies. These two microRNAs might be represented as specific hepatic microRNAs responding to hepatitis B virus and pegylated-interferon alpha-2a treatment, which may remarkable and attractive for further study involving in the association of their target genes and prediction of pegylated-interferon alpha-2a response. Interestingly, microRNAs expression patterns might be useful for understanding the response mechanism and serve as biomarkers for prediction of pegylated-interferon alpha-2a treatment response in patients with chronic hepatitis B.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis B, Chronic/metabolism , Interferon-alpha/therapeutic use , Liver/metabolism , MicroRNAs/metabolism , Polyethylene Glycols/therapeutic use , Adult , Female , Gene Expression Regulation/drug effects , Hepatitis B virus , Hepatitis B, Chronic/drug therapy , Humans , Liver/virology , Male , Recombinant Proteins/therapeutic use , Transcriptome/drug effects
5.
Asian Pac J Cancer Prev ; 16(18): 8377-82, 2015.
Article in English | MEDLINE | ID: mdl-26745088

ABSTRACT

BACKGROUND: The aim of this study was to evaluate any association between a single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409, C>G) and the development and prognosis in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Two hundred heathy controls and 388 HCC cases were included: 211 with HBV, 98 patients with HCV, 29 with alcoholic steatohepatitis (ASH) and 52 with non-alcoholic steatohepatitis (NASH). The SNP was determined by real-time PCR based on TaqMan assays. RESULTS: The prevalence of rs738409 genotypes CC, CG and GG in controls was 91 (45.5%), 88 (44.0%), and 21 (10.5%), respectively, while the corresponding genotypes in all patients with HCC was 158 (40.7%), 178 (45.9%), and 52 (13.4%). The GG genotype had significantly higher distribution in patients with ASH/NASH-related HCC compared with controls (OR=2.34, 95% CI=1.16-4.71, P=0.018), and viral-related HCC cases (OR=2.15, 95% CI=1.13-4.08, P=0.020). However, the frequency of the GG genotype was similar between controls and patients with viral-related HCC. At initial diagnosis, HBV-related HCC were larger and at more advanced BCLC stage than the other HCC groups. There were no significant differences between the GG and non-GG groups regarding clinical characteristics, tumor stage and overall survival. CONCLUSIONS: These data suggest an influence of the PNPLA3 polymorphism on the occurrence of HCC in patients with ASH/NASH but not among those with chronic viral hepatitis. However, the polymorphism was not associated with the prognosis of HCC.


Subject(s)
Carcinoma, Hepatocellular/genetics , Fatty Liver, Alcoholic/genetics , Hepatitis, Chronic/genetics , Lipase/genetics , Liver Neoplasms/genetics , Membrane Proteins/genetics , Non-alcoholic Fatty Liver Disease/genetics , Polymorphism, Single Nucleotide/genetics , Aged , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/virology , Case-Control Studies , Disease Progression , Fatty Liver, Alcoholic/pathology , Fatty Liver, Alcoholic/virology , Female , Follow-Up Studies , Genotype , Hepatitis, Chronic/pathology , Hepatitis, Chronic/virology , Humans , Liver Neoplasms/pathology , Liver Neoplasms/virology , Male , Middle Aged , Neoplasm Staging , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/virology , Prognosis , Real-Time Polymerase Chain Reaction , Retrospective Studies , Risk Factors
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