Search Results (25)

Background: Transarterial chemoembolization (TACE) is the standard treatment for patients with intermediate-stage hepatocellular carcinoma (HCC); however, its survival benefits remain unsatisfactory. In this systematic review, we aimed to compare the clinical outcomes of tyrosine kinase inhibitors (TKIs) combined with TACE and TACE alone in patients with intermediate-stage HCC. Methods: A systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Randomized controlled trials (RCTs) comparing TACE plus TKIs with TACE alone in patients with HCC were retrieved from PubMed, Embase, and the Cochrane Library. The primary outcomes included overall survival (OS) and progression-free survival (PFS), reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Secondary outcomes included the overall response rate (ORR) and disease control rate (DCR), which were analyzed using risk ratios (RRs). Heterogeneity was assessed using the I² statistic. Results: Fourteen RCTs were included in this meta-analysis. Compared to TACE alone, TACE plus TKIs significantly improved PFS (HR = 0.74, 95% CI: 0.59–0.93, p = 0.01, I² = 87%) and the ORR (RR = 1.29, 95% CI: 1.11–1.51, p = 0.001), but not OS (HR = 0.84, 95% CI: 0.69–1.03, p = 0.10, I² = 65%) and the DCR (RR = 1.05, 95% CI: 0.99–1.11, p = 0.08). Subgroup analysis showed that TACE plus TKIs significantly increased OS in patients with hepatitis B virus (HBV) infection (HR = 0.67, 95% CI: 0.51–0.88), but not in those with hepatitis C virus (HCV) infection or those without HBV and HCV infection. Moreover, patients with HBV infection, male patients, and those with a good functional status (ECOG performance status of 0) had better PFS than others. Conclusions: Compared with TACE alone, TACE combined with TKIs can significantly improve PFS and the ORR in patients with intermediate-stage HCC. Furthermore, combination treatment can significantly improve OS in patients with HBV infection, but not in patients with HCV infection. Further research is required to optimize patient selection and treatment strategies. Full article

Background: Direct oral anticoagulants (DOACs) are recommended for the management of thrombosis prophylaxis, especially in patients with atrial fibrillation. As substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, they are implicated in potential drug–drug interactions. NS5A/NS5B inhibitors are direct-acting agents (DAAs) against the Hepatitis C Virus (HCV) infection that exert a mild inhibition of P-glycoprotein without effects on CYP3A4. A DOAC and NS5A/NS5B inhibitor co-administration may lead to an increased risk of bleeding. Real-world data on the concomitant use of DOACs and DAAs are scarce. On this purpose, we perform a retrospective analysis on the risk of vascular adverse events (bleeding and thrombosis) among HCV patients under DOAC/DAA therapy, even in advanced liver disease. Methods: Between May 2015 and April 2023, patients treated with sofosbuvir-based DAA regimens and DOACs were consecutively included in this study from 12 Italian medical centers. Baseline characteristics, especially concerning bleeding risk and liver function, were collected. The occurrence of bleeding events, classified as major and minor, was the primary endpoint. Secondary endpoints were the rate of any thrombotic events and/or the need for discontinuation of one or both treatments. Moreover, a cohort of patients, matched by demographic characteristics (age and sex), that switched to vitamin K antagonists (VKAs) during the antiviral treatment was compared with the DOAC/DAA group. Results: A total of 104 patients were included. Thirty-eight of them (36.5%) were cirrhotic. Atrial fibrillation was an indication for anticoagulation in almost all cases (76%). Rivaroxaban (35.6%) was the most used DOAC, followed by apixaban (26.9%), dabigatran (19.2%) and edoxaban (18.3%). Sofosbuvir/velpatasvir (78.8%) was the most prescribed DAA, and all patients were already on anticoagulant therapy before the start of DAAs. During concomitant DOAC/DAA treatment, no major bleeding events were recorded, while four minor bleeding events occurred, but none resulted in DAA or DOAC discontinuation. At univariate analysis, the only additional risk factor statistically related to bleeding events was the anticoagulant therapy (hazard ratio [HR]: 13.2, 95% confidence interval 1,6-109). Performing an evaluation by a LOGIT binomial analysis with demographic characteristics, the antiplatelet therapy remained statistically associated to bleeding events. No significant differences were found in the rate of clinically relevant bleeding when the main population was compared with the VKA-switched cohort. A single major bleeding event leading to anticoagulation and DAA discontinuation was reported in VKA-switched matched cohort. Conclusions: In our study, the concomitant use of NS5A/NS5B inhibitors with DOAC showed good safety, and the only risk factor associated with bleeding events was the concomitant antiplatelet therapy. These findings support the use of DOACs during sofosbuvir-based HCV treatment, even in advanced liver disease. Replacing DOACs with VKAs does not appear to be of clinical benefit. Full article

The emergence of drug-resistance-inducing mutations in Hepatitis C virus (HCV) coupled with genotypic heterogeneity has made targeting NS3/4A serine protease difficult. In this work, we investigated the mutagenic variations in the binding pocket of Genotype 3 (G3) HCV NS3/4A and evaluated ligands for efficacious inhibition. We report mutations at 14 positions within the ligand-binding residues of HCV NS3/4A, including H57R and S139P within the catalytic triad. We then modelled each mutational variant for pharmacophore-based virtual screening (PBVS) followed by covalent docking towards identifying a potential covalent inhibitor, i.e., cpd-217. The binding stability of cpd-217 was then supported by molecular dynamic simulation followed by MM/GBSA binding free energy calculation. The free energy decomposition analysis indicated that the resistant mutants alter the HCV NS3/4A–ligand interaction, resulting in unbalanced energy distribution within the binding site, leading to drug resistance. Cpd-217 was identified as interacting with all NS3/4A G3 variants with significant covalent docking scores. In conclusion, cpd-217 emerges as a potential inhibitor of HCV NS3/4A G3 variants that warrants further in vitro and in vivo studies. This study provides a theoretical foundation for drug design and development targeting HCV G3 NS3/4A. Full article

Nature provides us with a rich source of compounds with a wide range of applications, including the creation of innovative drugs. Despite advancements in chemically synthesized therapeutics, natural compounds are increasingly significant, especially in cancer treatment, a leading cause of death globally. One promising approach involves the use of natural inhibitors of checkpoint kinase 2 (Chk2), a critical regulator of DNA repair, cell cycle arrest, and apoptosis. Chk2’s activation in response to DNA damage can lead to apoptosis or DNA repair, influencing glycolysis and mitochondrial function. In cancer therapy, inhibiting Chk2 can disrupt DNA repair and cell cycle progression, promoting cancer cell death and enhancing the efficacy of radiotherapy and chemotherapy. Additionally, Chk2 inhibitors can safeguard non-cancerous cells during these treatments by inhibiting p53-dependent apoptosis. Beyond oncology, Chk2 inhibition shows potential in treating hepatitis C virus (HCV) infections, as the virus relies on Chk2 for RNA replication in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), in which DNA damage plays a crucial role. Plant-derived Chk2 inhibitors, such as artemetin, rhamnetin, and curcumin, offer a promising future for treating various diseases with potentially milder side effects and broader metabolic impacts compared to conventional therapies. The review aims to underscore the immense potential of natural Chk2 inhibitors in various therapeutic contexts, particularly in oncology and the treatment of other diseases involving DNA damage and repair mechanisms. These natural Chk2 inhibitors hold significant promise for revolutionizing the landscape of cancer treatment and other diseases. Further research into these compounds could lead to the development of innovative therapies that offer hope for the future with fewer side effects and enhanced efficacy. Full article

Interleukin-10 (IL-10) is a pleiotropic cytokine with both immune enhancement and immunosuppression activities, but the main role is immunosuppression and anti-inflammatory ability. In order to use the immunosuppressive function of IL-10, many viruses, such as SARS-CoV-2, hepatitis B virus and EB virus, can evade the host’s immune surveillance and clearance by increasing the expression of host IL-10. However, it has not been reported whether the aquatic animal infection virus can upregulate the expression of host IL-10 and the mechanisms are still unknown. Spring viremia of carp (SVC) is a fatal viral disease for many fish species and is caused by spring viremia of carp virus (SVCV). This disease has caused significant economic losses in the aquaculture industry worldwide. In this study, the expression of carp IL-10 with or without infection of SVCV in epithelioma papulosum cyprinid (EPC) cells, carp head kidney (cHK) primary cells and common carp tissues were analyzed using RT-PCR and ELISA. The results show that SVCV infection induced carp IL-10 mRNA and protein expression, both in vitro and in vivo. However, the upregulation of carp IL-10 by SVCV was hindered by specific inhibitors of the JAK inhibitor (CP-690550), STAT3 inhibitor (STA-21), NF-κB inhibitor (BAY11-7082) and p38 MAPK (mitogen-activated protein kinase) inhibitor (SB202190), but not JNK inhibitor (SP600125). Furthermore, the results demonstrated that JAK1, JAK2, JAK3, TYK2 and STAT5 played important roles in carp IL-10 production induced by SVCV infection. Taken together, SVCV infection significantly induced carp IL-10 expression and the upregulation trigged in JAK-STAT, NF-κB and p38MAPK pathways. To our knowledge, this is the first time that a fish infection virus upregulated the host IL-10 expression through the JAK-STAT, NF-κB and p38MAPK pathways. Altogether, fish viruses may have a similar mechanism as human or other mammalian viruses to escape host immune surveillance and clearance. Full article

Hepatitis C virus (HCV) is a dangerous virus that is responsible for a large number of infections and deaths worldwide. In the treatment of HCV, it is important that the drugs are effective and do not have additional hepatotoxic effects. The aim of this study was to test the in silico activity of 1893 terpenes against the HCV NS5B polymerase (PDB-ID: 3FQK). Two drugs, sofosbuvir and dasabuvir, were used as controls. The GOLD software (CCDC) and InstaDock were used for docking. By using the results obtained from PLP.Fitness (GOLD), pKi, and binding free energy (InstaDock), nine terpenes were finally selected based on their scores. The drug-likeness properties were calculated using Lipinski’s rule of five. The ADMET values were studied using SwissADME and pkCSM servers. Ultimately, it was shown that nine terpenes have better docking results than sofosbuvir and dasabuvir. These were gniditrin, mulberrofuran G, cochlearine A, ingenol dibenzoate, mulberrofuran G, isogemichalcone C, pawhuskin B, 3-cinnamyl-4-oxoretinoic acid, DTXSID501019279, and mezerein. Each docked complex was submitted to 150 ns-long molecular dynamics simulations to ascertain the binding stability. The results show that mulberrofuran G, cochlearine A, and both stereoisomers of pawhuskin B form very stable interactions with the active site region where the reaction product should form and are, therefore, good candidates for use as effective competitive inhibitors. The other compounds identified in the docking screen either afford extremely weak (or even hardly any) binding (such as ingenol dibenzoate, gniditrin, and mezerein) or must first undergo preliminary movements in the active site before attaining their stable binding conformations, in a process which may take from 60 to 80 ns (for DTXSID501019279, 3-cinnamyl-4-oxoretinoic acid or isogemichalcone C). Full article

Hepatitis C virus (HCV) genotype 4 is highly prevalent in the Middle East and parts of Africa. Subtype 4d has recently spread among high-risk groups in Europe. However, 4d infectious culture systems are not available, hampering studies of drugs, as well as neutralizing antibodies relevant for HCV vaccine development. We determined the consensus 4d sequence from a chronic hepatitis C patient by next-generation sequencing, generated a full-length clone thereof (pDH13), and demonstrated that pDH13 RNA-transcripts were viable in the human-liver chimeric mouse model, but not in Huh7.5 cells. However, a JFH1-based DH13 Core-NS5A 4d clone encoding A1671S, T1785V, and D2411G was viable in Huh7.5 cells, with efficient growth after inclusion of 10 additional substitutions [4d(C5A)-13m]. The efficacies of NS3/4A protease- and NS5A- inhibitors against genotypes 4a and 4d were similar, except for ledipasvir, which is less potent against 4d. Compared to 4a, the 4d(C5A)-13m virus was more sensitive to neutralizing monoclonal antibodies AR3A and AR5A, as well as 4a and 4d patient plasma antibodies. In conclusion, we developed the first genotype 4d infectious culture system enabling DAA efficacy testing and antibody neutralization assessment critical to optimization of DAA treatments in the clinic and for vaccine design to combat the HCV epidemic. Full article

The main protease (M^pro) of the betacoronavirus SARS-CoV-2 is an attractive target for the development of treatments for COVID-19. Structure-based design is a successful approach to discovering new inhibitors of the M^pro. Starting from crystal structures of the M^pro in complexes with the Hepatitis C virus NS3/4A protease inhibitors boceprevir and telaprevir, we optimized the potency of the alpha-ketoamide boceprevir against the M^pro by replacing its P1 cyclobutyl moiety by a γ-lactam as a glutamine surrogate. The resulting compound, MG-78, exhibited an IC₅₀ of 13 nM versus the recombinant M^pro, and similar potency was observed for its P1′ N-methyl derivative MG-131. Crystal structures confirmed the validity of our design concept. In addition to SARS-CoV-2 M^pro inhibition, we also explored the activity of MG-78 against the M^pro of the alphacoronavirus HCoV NL63 and against enterovirus 3C proteases. The activities were good (0.33 µM, HCoV-NL63 M^pro), moderate (1.45 µM, Coxsackievirus 3C^pro), and relatively poor (6.7 µM, enterovirus A71 3C^pro), respectively. The structural basis for the differences in activities was revealed by X-ray crystallo-graphy. We conclude that the modified boceprevir scaffold is suitable for obtaining high-potency inhibitors of the coronavirus M^pros but further optimization would be needed to target enterovirus 3C^pros efficiently. Full article

Treatment with interferon-free direct-acting antivirals (DAA) has become the gold standard in chronic hepatitis C virus (HCV) infection. Nevertheless, little research about the metabolic impact of achieving sustained virological response (SVR) is available in HCV/HIV co-infected patients. This research aimed to evaluate early anthropometric, lipid and liver parameters changes after achieving SVR 12 weeks after treatment (SVR12). A real-life retrospective descriptive before-after study assessed 128 DAA treatment episodes from 2015 to 2019 in HCV/HIV co-infected patients. Anthropometric parameters (weight, body mass index), lipid profile, genotype (GT) and viral load, liver data (basics laboratory necroinflammatory parameters and transient elastography (TE)) were collected before treatment with DAA (baseline), and when SVR12 was achieved. Significant increases (p < 0.01) were found in the early lipid profile, measured by LDLc (84.6 ± 35.0 vs. 108.6 ± 35.1 mg/dL) and total cholesterol (161.3 ± 41.0 vs. 183.3 ± 41.6 mg/dL). Significant changes (p < 0.05) were found in liver parameters, measured by ALT (58.2 ± 34.0 vs. 22.0 ± 16.0 U/L), bilirubin (0.8 ± 0.6 vs. 0.6 ± 0.5 mg/dL), albumin (4.2 ± 0.4 vs. 4.3 ± 0.3 g/dL) and liver stiffness (LS) (13.7 ± 13.3 vs. 11.8 ± 12.1 kPa). The main conclusions were that the use of DAA has an early negative impact on lipid metabolism. Achieving SVR12 against HCV leads to an early improvement in liver function and LS in HCV/HIV co-infected patients without interference with antiretroviral treatment (ART) and DAA. Short-term close lipid monitoring may be necessary when combining protease inhibitors. HCV-GT-3/HIV co-infected patients might require further close monitoring for residual fibrosis. These findings can be relevant for actual clinical practice. Full article

Hepatis virus C (HCV) infection causes liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. The objective of our study was to examine the effects of the HCV nonstructural protein (NS) 3/4A inhibitor glecaprevir/NS5A inhibitor pibrentasvir on real-world HCV patients in the northern part of Tokyo, Japan. Although 106 patients were consecutively included, a total of 102 HCV-infected patients with chronic hepatitis or compensated cirrhosis, who received 8- or 12-week combination treatment with glecaprevir/pibrentasvir and were followed up to week 12 after the end of treatment were analyzed retrospectively. Only three patients discontinued treatment due to adverse events; however, they achieved a sustained virologic response at 12 weeks (SVR12). Finally, SVR rates were 99.0% (101/102). Only one patient without liver cirrhosis was a treatment relapser who received hepatic resection for HCC approximately two years after commencement of the 8-week combination treatment with glecaprevir/pibrentasvir. After the exclusion of patients with HCV genotype 1b and P32 deletion in the HCV NS5A region, a 12-week combination of glecaprevir/pibrentasvir led to SVR12 in all nine direct-acting antiviral-experienced patients. Glecaprevir/pibrentasvir had a high efficacy and an acceptable safety profile for real-world HCV patients in a single hospital in Japan. Full article

Background: Hepatitis C virus infection remains common in patients with chronic kidney disease, including those on maintenance dialysis. The relationship between hepatitis C virus infection and chronic kidney disease is bi-directional; in fact, HCV is both a cause and consequence of chronic kidney disease. According to a systematic review with meta-analysis of observational studies (n = 23 studies) (n = 574,081 patients on long-term dialysis), anti-HCV positive serologic status was an independent and significant risk factor for death in patients with advanced chronic kidney disease on long-term dialysis. The overall estimate for adjusted mortality (all-cause death risk) with HCV was 1.26 (95% CI, 1.18; 1.34) (p < 0.0001). Interferon-based therapies are biased by low efficacy/safety in chronic kidney disease, but the advent of direct-acting antiviral drugs has made a paradigm shift in the treatment of HCV-infection. These medications give interruption of viral replication because they target specific non-structural viral proteins; four classes of DAAs exist-NS3/4A protease inhibitors, NS5A inhibitors, NS5B nucleoside and non-nucleoside polymerase inhibitors. All-oral, interferon-free, ribavirin-free combinations of DAAs are now available. Aim: The goal of this narrative review is to report the available treatment options for HCV in advanced chronic kidney disease. Methods: We have made an extensive review of the medical literature and various research engines have been adopted. Results: Some combinations of DAAs are currently recommended for HCV in advanced CKD (including patients on maintenance dialysis): elbasvir/grazoprevir; glecaprevir/pibrentasvir; and sofosbuvir-based regimens. Solid evidence, based on registration and “real life” studies supports their efficacy (SVR rates > 90%) and safety even in patients with advanced CKD. No dosage adjustment is necessary and treatment duration is 8–12 weeks. However, recent data highlight that many patients with advanced CKD remain untreated, and numerous barriers to antiviral treatment of HCV still exist. Whether successful antiviral therapy with DAAs will translate into improved survival in the advanced CKD population is another point of future research. Full article

We report the in vitro efficacy of ion-channel inhibitors amantadine, memantine and rimantadine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In VeroE6 cells, rimantadine was most potent followed by memantine and amantadine (50% effective concentrations: 36, 80 and 116 µM, respectively). Rimantadine also showed the highest selectivity index, followed by amantadine and memantine (17.3, 12.2 and 7.6, respectively). Similar results were observed in human hepatoma Huh7.5 and lung carcinoma A549-hACE2 cells. Inhibitors interacted in a similar antagonistic manner with remdesivir and had a similar barrier to viral escape. Rimantadine acted mainly at the viral post-entry level and partially at the viral entry level. Based on these results, rimantadine showed the most promise for treatment of SARS-CoV-2. Full article

Hepatitis C virus (HCV) is an international challenge. Since the discovery of NS5A direct-acting antivirals, researchers turned their attention to pursue novel NS5A inhibitors with optimized design and structure. Herein we explore highly potent hepatitis C virus (HCV) NS5A inhibitors; the novel analogs share a common symmetrical prolinamide 2,7-diaminofluorene scaffold. Modification of the 2,7-diaminofluorene backbone included the use of (S)-prolinamide or its isostere (S,R)-piperidine-3-caboxamide, both bearing different amino acid residues with terminal carbamate groups. Compound 26 exhibited potent inhibitory activity against HCV genotype (GT) 1b (effective concentration (EC₅₀) = 36 pM and a selectivity index of >2.78 × 10⁶). Compound 26 showed high selectivity on GT 1b versus GT 4a. Interestingly, it showed a significant antiviral effect against GT 3a (EC₅₀ = 1.2 nM). The structure-activity relationship (SAR) analysis revealed that picomolar inhibitory activity was attained with the use of S-prolinamide capped with R- isoleucine or R-phenylglycine residues bearing a terminal alkyl carbamate group. Full article

Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protein from HCV, has been sought after as a potential anti-HCV drug target. Several classes of compounds, such as amantadine and rimantadine have been testified for p7 inhibition. However, the efficacies of these compounds are not high. Here, we screened some novel p7 inhibitors with amantadine scaffold for the inhibitor development. The dissociation constant (Kd) of 42 ARD-series compounds were determined by nuclear magnetic resonance (NMR) titrations. The efficacies of the two best inhibitors, ARD87 and ARD112, were further confirmed using viral production assay. The binding mode analysis and binding stability for the strongest inhibitor were deciphered by molecular dynamics (MD) simulation. These ARD-series compounds together with 49 previously published compounds were further analyzed by molecular docking. Key pharmacophores were identified among the structure-similar compounds. Our studies suggest that different functional groups are highly correlated with the efficacy for inhibiting p7 of HCV, in which hydrophobic interactions are the dominant forces for the inhibition potency. Our findings provide guiding principles for designing higher affinity inhibitors of p7 as potential anti-HCV drug candidates. Full article

Background: We recently identified 39 human microRNAs, which effectively suppress hepatitis B virus (HBV) replication in hepatocytes. Chronic HBV infection often results in active, hepatitis-related liver fibrosis; hence, we assessed whether any of these microRNAs have anti-fibrotic potential and predicted that miR-6133-5p may target several fibrosis-related genes. Methods: The hepatic stellate cell line LX-2 was transfected with an miR-6133-5p mimic and subsequently treated with Transforming growth factor (TGF)-β. The mRNA and protein products of the COL1A1 gene, encoding collagen, and the ACTA2 gene, an activation marker of hepatic stellate cells, were quantified. Results: The expression of COL1A1 and ACTA2 was markedly reduced in LX-2 cells treated with miR-6133-5p. Interestingly, phosphorylation of c-Jun N-terminal kinase (JNK) was also significantly decreased by miR-6133-5p treatment. The expression of several predicted target genes of miR-6133-5p, including TGFBR2 (which encodes Transforming Growth Factor Beta Receptor 2) and FGFR1 (which encodes Fibroblast Growth Factor Receptor 1), was also reduced in miR-6133-5p-treated cells. The knockdown of TGFBR2 by the corresponding small interfering RNA greatly suppressed the expression of COL1A1 and ACTA2. Treatment with the JNK inhibitor, SP600125, also suppressed COL1A1 and ACTA2 expression, indicating that TGFBR2 and JNK mediate the anti-fibrotic effect of miR-6133-5p. The downregulation of FGFR1 may result in a decrease of phosphorylated Akt, ERK (extracellular signal-regulated kinase), and JNK. Conclusion: miR-6133-5p has a strong anti-fibrotic effect, mediated by inactivation of TGFBR2, Akt, and JNK. Full article