• ERK5 activation
• HMG‐CoA reductase inhibition
• hepatitis C virus
• statin
• virion release

• Humans
• Hepacivirus/drug effects
• Hepacivirus/physiology
• Lovastatin/pharmacology
• Virus Replication/drug effects
• Virion/drug effects
• Virion/metabolism
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
• Mitogen-Activated Protein Kinase 7/metabolism
• Phosphorylation
• Virus Release/drug effects
• RNA, Small Interfering/genetics
• RNA, Small Interfering/metabolism
• Cell Line
• Hepatitis C/virology
• Hepatitis C/metabolism
• Hepatitis C/drug therapy
• Antiviral Agents/pharmacology

• Japan Science and Technology Agency (JST)
• Japan International Cooperation Agency (JICA)
• 17fk0310103h1801 Japan Agency for Medical Research Development
• 18fk0310103h2102 Japan Agency for Medical Research Development
• 19fk0310103h2103 Japan Agency for Medical Research Development
• 20fk0310103h2104 Japan Agency for Medical Research Development
• 21fk0310103h2105 Japan Agency for Medical Research Development
• JSJSBP120188201 Japan Society for the Promotion of Science
• 18K08004 Japan Society for the Promotion of Science
• 22K08579 Japan Society for the Promotion of Science
• Research Center for Chemistry, National Research and Innovation Agency (BRIN)

• AlphaFold2
• COVID-19
• Monkeypox
• PLD
• molecular dynamics simulation
• network analysis

• Humans
• Monkeypox virus/genetics
• Monkeypox
• Molecular Docking Simulation
• COVID-19

Vitamin C is a well-known antioxidant and essential cofactor for numerous biological reactions. Several studies reported that vitamin C can improve the symptoms and prognosis of patients with sepsis and respiratory infection. We aimed to examine the effect of vitamin C when used in viral pneumonia patients with severe respiratory failure.

Total 201 patients with viral pneumonia were included, of them 35 patients used vitamin C. We performed a statistical analysis through a propensity score matching of the age and baseline characteristics of these patients.

There were differences between the vitamin C group and non-vitamin C group in terms of age (60±15 vs. 66±14, P=0.03), extracorporeal membrane oxygenation (28.6% vs. 5.4%, P<0.001), and procalcitonin (3±8 vs. 9±23, P=0.02). The 28-day mortality was not different between the two groups (20.0% vs. 24.7%, P=0.33). In the propensity-matched group, the 28-day mortality was not significantly different between the two groups (20.0% vs. 37.1%, P=0.07). Moreover, no difference was observed in shock reversal within 14 days (45.7% vs. 25.7%, P=0.08) and recovery after acute kidney injury (52.9% vs. 66.7%, P=0.41) between the two groups. Vitamin C was not a prognostic factor for 28-day mortality (P=0.33).

In this study adjunctive intravenous vitamin C therapy alone was not associated with improvement of the 28-day mortality and prognosis in patients with severe viral pneumonia with respiratory failure.

• Acute respiratory distress syndrome (ARDS)
• ascorbic acid
• critical care
• viral pneumonia

The current study aimed to encapsulate fluvastatin sodium (FVS), a member of the statins family possessing pleiotropic effects in rheumatoid arthritis (RA), into spanlastic nanovesicles (SNVs) for transdermal delivery. This novel delivery could surmount FVS associated oral encumbrances such as apparent first-pass effect, poor bioavailability and short elimination half-life, hence, accomplishing platform for management of RA. To consummate this objective, FVS-loaded SNVs were elaborated by thin film hydration method, utilizing either Span 60 or Span 80, together with Tween 80 or Brij 35 as an edge activator according to full factorial design (2⁴). Applying Design-Expert^® software, the influence of formulation variables on SNVs physicochemical properties and the optimized formulation selection were explored. Additionally, the pharmacokinetic studies were scrutinized in rats. Furthermore, in Freund's adjuvant-induced arthritis, rheumatoid markers, TNF-α, IL-10, p38 MAPK, and antioxidant parameters were measured. The optimum SNVs were nano-scaled spherical vesicles (201.54 ± 9.16 nm), having reasonable entrapment efficiency (71.28 ± 2.05%), appropriate release over 8 h (89.45 ± 3.64%) and adequate permeation characteristics across the skin (402.55 ± 27.48 µg/cm²). The pharmacokinetic study disclosed ameliorated bioavailability of the optimum SNVs gel by 2.79- and 4.59-fold as compared to the oral solution as well as the traditional gel, respectively. Moreover, it elicited a significant suppression of p38 MAPK expression and also significant improvement of all other measured biomarkers. Concisely, the foregoing findings proposed that SNVs can be auspicious for augmenting FVS transdermal delivery for management of RA.

• Fluvastatin sodium
• p38 MAPK
• rheumatoid arthritis
• spanlastic nanovesicles
• transdermal delivery

• 25-hydroxyvitamin D
• antioxidant properties
• immunity
• performance
• piglets

• HP-β-CD
• bioavailability
• fluvastatin
• irritation test
• nanosuspensions

• Animals
• Biological Availability
• Cyclodextrins/administration & dosage
• Cyclodextrins/chemistry
• Cyclodextrins/pharmacokinetics
• Drug Stability
• Drug Tolerance
• Fluvastatin/administration & dosage
• Fluvastatin/chemistry
• Fluvastatin/pharmacokinetics
• Hydrogen-Ion Concentration
• Nanoparticles/administration & dosage
• Nanoparticles/chemistry
• Rats
• Rats, Wistar
• Suspensions/administration & dosage
• Suspensions/chemistry
• Suspensions/pharmacokinetics

Celastrol, a quinone methide triterpene isolated from the root extracts of Tripterygium wilfordii, can greatly induce the gene expression activity of heme oxygenase-1 (HO-1) to achieve disease prevention and control. HO-1 induction was recently shown to result in anti-HCV activity by inducing type I interferon and inhibiting hepatitis C virus (HCV) NS3/4A protease activity. The aim of the present study is to evaluate the anti-HCV activity of celastrol and characterize its mechanism of inhibition.

The anti-HCV activity of celastrol was evaluated using the HCV subgenomic replicon and HCVcc infection systems. The anti-HCV mechanism of celastrol targeting HO-1 expression was clarified using specific inhibitors against several signaling pathways. The transcriptional regulation of celastrol on target gene expression was determined using promoter-based reporter activity assay. The synergistic effect of celastrol and a numbers of clinically used anti-HCV drugs was determined via a drug combination assay.

Celastrol inhibited HCV replication in both the HCV subgenomic and HCVcc infection systems with EC50 values of 0.37 ± 0.022 and 0.43 ± 0.019 μM, respectively. Celastrol-induced heme oxygenase 1 (HO-1) expression promoted antiviral interferon responses and inhibition of NS3/4A protease activity, thereby blocking HCV replication. These antiviral effects were abrogated by treatment with the HO-1-specific inhibitor SnMP or silencing of HO-1 expression by transfection of shRNA, which indicates that HO-1 induction contributes to the anti-HCV activity of celastrol. JNK mitogen-activated protein kinase and nuclear factor erythroid 2-related factor 2 (Nrf2) were confirmed to be involved in the inductive effect of celastrol on HO-1 expression. Celastrol exhibited synergistic effects in combination with interferon-alpha, the NS5A inhibitor daclatasvir, and the NS5B inhibitor sofosbuvir.

Celastrol can serve as a potential supplement for blocking HCV replication. Targeting the JNK/Nrf2/HO-1 axis presents a promising strategy against HCV infection.

•

Celastrol inhibits HCV replication.

• Celastrol
• HCV
• Heme oxygenase 1
• JNK mitogen-activated protein kinase

• Drug resistance
• hepatitis C virus
• inhibitors

The aim of this study is to prepare fluvastatin nanostructured lipid carriers (FLV-NLCs) in order to find an innovative way to alleviate FLV-associated disadvantages. The limitations include poor solubility and extensive first-pass metabolism, resulting in low (30%) bioavailability and short elimination half-life (1–3 hours). FLV-NLCs were prepared by hot emulsification–ultrasonication method. Ten runs were created by three-level factorial design (32) to optimize FLV-NLCs formulation process. In this study, two factors, four responses, and three-level factorial design were endorsed. The studied variables were lipid:oil ratio (X₁) and sonication time (X₂). However, the responses parameter determined the particle size (Y₁, nm), entrapment efficiency percent (EE%, Y₂), particles zeta potential (Y₃), and 80% of the drug release after 24 hours (X₄). Furthermore, stability and in vivo pharmacokinetics were studied in rats. The optimized consisted formula had an average particle size of 165 nm with 75.32% entrapment efficiency and 85.32% of drug released after 24 hours, demonstrating a sustaining drug release over 24 hours. An in vivo pharmacokinetic study revealed enhanced bioavailability by >2.64-fold, and the mean residence time was longer than that of FLV. We concluded that NLCs could be promising carriers for sustained/prolonged FLV release with enhanced oral bioavailability.

• factorial design
• hyperlipidemia
• nano-vesicles
• statins

• HCV
• andrographolide
• heme oxygenase-1
• nuclear factor erythroid 2-related factor 2
• p38 MAPK

• Core protein
• De novo initiated RNA synthesis
• Genotype-specific interaction
• Hepatitis C virus
• RNA-dependent RNA polymerase

Hepatitis C virus (HCV) causes a clinically important disease affecting 3% of the world population. HCV is a single-stranded, positive-sense RNA virus belonging to the genus Hepacivirus within the Flaviviridae family. The virus establishes a chronic infection in the face of an active host oxidative defence, thus adaptation to oxidative stress is key to virus survival. Being a small RNA virus with a limited genomic capacity, we speculate that HCV deploys a different strategy to evade host oxidative defence. Instead of counteracting oxidative stress, it utilizes oxidative stress to facilitate its own survival. Translation is the first step in the replication of a plus strand RNA virus so it would make sense if the virus can exploit the host oxidative defence in facilitating this very first step. This is particularly true when HCV utilizes an internal ribosome entry site element in translation, which is distinctive from that of cap-dependent translation of the vast majority of cellular genes, thus allowing selective translation of genes under conditions when global protein synthesis is compromised. Indeed, we were the first to show that HCV translation was stimulated by an important pro-oxidant-hydrogen peroxide in hepatocytes, suggesting that HCV is able to adapt to and utilize the host anti-viral response to facilitate its own translation thus allowing the virus to thrive under oxidative stress condition to establish chronicity. Understanding how HCV translation is regulated under oxidative stress condition will advance our knowledge on how HCV establishes chronicity. As chronicity is the initiator step in disease progression this will eventually lead to a better understanding of pathogenicity, which is particularly relevant to the development of anti-virals and improved treatments of HCV patients using anti-oxidants.

• Hepatitis C virus
• Oxidative stress
• Hydrogen peroxide
• Translation
• Internal ribosome entry site
• Chronicity
• Persistence

• Adaptation, Biological
• Hepacivirus/physiology
• Hepatitis C, Chronic/etiology
• Humans
• Oxidative Stress
• Protein Biosynthesis
• Viral Proteins/biosynthesis

• Hepatitis C Virus
• Interferon
• Ribavirin therapy

• HBV X protein
• IFN-β
• PKCα
• hepatocarcinogenesis
• p21 (Cip1/WAF1)

• Active Transport, Cell Nucleus
• Animals
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Cell Proliferation
• Cell Transformation, Viral
• Cyclin D1/genetics
• Cyclin D1/metabolism
• Cyclin-Dependent Kinase Inhibitor p21/genetics
• Cyclin-Dependent Kinase Inhibitor p21/metabolism
• Cytoplasm/metabolism
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Humans
• Interferon-beta/metabolism
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Mice
• Mice, Transgenic
• Phosphorylation
• Protein Kinase C-alpha/metabolism
• RNA Interference
• Retinoblastoma Protein/metabolism
• Signal Transduction
• Trans-Activators/genetics
• Trans-Activators/metabolism
• Transfection
• Up-Regulation
• Viral Regulatory and Accessory Proteins

• Antimalarials/analysis
• Antimalarials/pharmacology
• Cell Line, Tumor
• Drug Evaluation, Preclinical
• Drug Synergism
• Genome, Viral/genetics
• Genotype
• Hepacivirus/drug effects
• Hepacivirus/genetics
• Hepacivirus/physiology
• Humans
• Interferon-alpha/pharmacology
• RNA, Viral/metabolism
• Ribavirin/pharmacology
• Time Factors
• Virus Replication/drug effects
• Vitamin E/pharmacology

Hepatitis C virus (HCV) infects approximately 3% of the world’s population. Currently licensed treatment of HCV chronic infection with pegylated-interferon-α and ribavirin, is not fully effective against all HCV genotypes and is associated to severe side effects. Thus, development of novel therapeutics and identification of new targets for treatment of HCV infection is necessary. Current opinion is orienting to target antiviral drug discovery to the host cell pathways on which the virus relies, instead of against viral structures. Many intracellular signaling pathways manipulated by HCV for its own replication are finely regulated by the oxido-reductive (redox) state of the host cell. At the same time, HCV induces oxidative stress that has been found to affect both virus replication as well as progression and severity of HCV infection. A dual role, positive or negative, for the host cell oxidized conditions on HCV replication has been reported so far. This review examines current information about the effect of oxidative stress on HCV life cycle and the main redox-regulated intracellular pathways activated during HCV infection and involved in its replication.

Although hepatitis C virus (HCV) affects approximately 130–170 million people worldwide, no vaccines are available. HCV is an important cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma, leading to the need for liver transplantation. In this study, curcumin, a constituent used in traditional Chinese medicine, has been evaluated for its anti-HCV activity and mechanism, using a human hepatoma cell line containing the HCV genotype 1b subgenomic replicon. Below the concentration of 20% cytotoxicity, curcumin dose-dependently inhibited HCV replication by luciferase reporter gene assay, HCV RNA detection and HCV protein analysis. Under the same conditions, curcumin also dose-dependently induced heme oxygenase-1 with the highest induction at 24 h. Hemin, a heme oxygenase-1 inducer, also inhibited HCV protein expression in a dose-dependent manner. The knockdown of heme oxygenase-1 partially reversed the curcumin-inhibited HCV protein expression. In addition to the heme oxygenase-1 induction, signaling molecule activities of AKT, extracellular signal-regulated kinases (ERK) and nuclear factor-κB (NF-κB) were inhibited by curcumin. Using specific inhibitors of PI3K-AKT, MEK-ERK and NF-κB, the results suggested that only PI3K-AKT inhibition is positively involved in curcumin-inhibited HCV replication. Inhibition of ERK and NF-κB was likely to promote HCV protein expression. In summary, curcumin inhibited HCV replication by heme oxygenase-1 induction and AKT pathway inhibition. Although curcumin also inhibits ERK and NF-κB activities, it slightly increased the HCV protein expression. This result may provide information when curcumin is used as an adjuvant in anti-HCV therapy.

Hepatitis C virus (HCV) is the leading cause of liver fibrosis, cirrhosis and hepatocellular carcinoma. It is believed that continuous liver cell apoptosis contributes to HCV pathogenesis. Recent studies have shown that HCV infection can sensitize host cells to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis, but the mechanism by which HCV regulates the TRAIL pathway remains unclear.

Using a sub-genomic replicon and full length virus, JFH-1, we demonstrate that HCV can sensitize host cells to TRAIL-induced apoptosis by up-regulating two TRAIL receptors, death receptor 4 (DR4) and death receptor 5 (DR5). Furthermore, the HCV replicon enhanced transcription of DR5 via Sp1, and the HCV-mediated up-regulation of DR4 and DR5 required MEK1 activity. HCV infection also stimulated the activity of MEK1, and the inhibition of MEK1 activity or the knockdown of MEK1 increased the replication of HCV.

Our studies demonstrate that HCV replication sensitizes host cells to TRAIL-induced apoptosis by up-regulating DR4 and DR5 via a MEK1 dependent pathway. These findings may help to further understand the pathogenesis of HCV infection and provide a therapeutic target.

• Alcohols/adverse effects
• Antioxidants
• Antiviral Agents/therapeutic use
• Hepacivirus/pathogenicity
• Hepatitis C/drug therapy
• Hepatitis C/pathology
• Hepatitis C/virology
• Humans
• Oxidative Stress

• Antiviral Agents
• Base Sequence
• Cell Line
• Drug Resistance, Viral/genetics
• Ethanol/pharmacology
• Genetic Variation/drug effects
• Hepacivirus/genetics
• Humans
• Oxidative Stress
• RNA, Viral/genetics
• Reactive Oxygen Species/pharmacology

• R56 AI083353 NIAID NIH HHS
• 1R56AI083353-01A1 NIAID NIH HHS

• hepatitis c virus
• vitamin d
• hepatocellular carcinoma
• bone mineral density
• fracture
• fibrosis
• sustained virological response
• interferon
• ribavirin

• Antiviral Agents/adverse effects
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/metabolism
• Hepacivirus/immunology
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/immunology
• Hepatitis C, Chronic/metabolism
• Humans
• Interferons/adverse effects
• Liver Neoplasms/complications
• Liver Neoplasms/metabolism
• Osteoporosis/complications
• Osteoporosis/metabolism
• Ribavirin/adverse effects
• Vitamin D/pharmacology
• Vitamin D/therapeutic use
• Vitamin D Deficiency/complications
• Vitamin D Deficiency/immunology
• Vitamin D Deficiency/metabolism
• Vitamins/pharmacology
• Vitamins/therapeutic use

• R01 DA031095 NIDA NIH HHS
• DK090317 NIDDK NIH HHS
• R01 DK090317 NIDDK NIH HHS
• AI07655803 NIAID NIH HHS
• R01 DA016156 NIDA NIH HHS
• R21 CA152514 NCI NIH HHS
• DK00720236 NIDDK NIH HHS
• DA031095 NIDA NIH HHS
• CA152514 NCI NIH HHS

• antigen presenting cells
• cd4+ t cells
• cd8+ t cells
• cytotoxic t lymphocytes (ctl)
• cytokines
• cyp2e1
• dendritic cells (dcs)
• hcv
• hcv core protein
• ns5a protein
• hepatocytes
• hepatocellular carcinoma (hcc)
• innate and adaptive immunity
• lieber-decarli diet
• lipopolysaccharide (lps)
• mitochondrial ca²⁺
• mitochondrial dysfunction
• mn-superoxide dismutase (sod2)
• proteasome
• reactive oxygen species (ros)
• toll-like receptor 4 (tlr4)
• transgenic mice

• Animals
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/virology
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/immunology
• Chemical and Drug Induced Liver Injury/metabolism
• Chemical and Drug Induced Liver Injury/virology
• Ethanol/adverse effects
• Hepacivirus/immunology
• Hepatitis C/immunology
• Hepatitis C/pathology
• Hepatocytes/drug effects
• Hepatocytes/virology
• Humans
• Immune System/drug effects
• Immune System/virology
• Liver Neoplasms/etiology
• Liver Neoplasms/immunology
• Liver Neoplasms/virology

• AA017232 NIAAA NIH HHS
• AA-008169 NIAAA NIH HHS
• AA014372 NIAAA NIH HHS
• R37 AA014372-06A1 NIAAA NIH HHS
• R01 AA014372 NIAAA NIH HHS
• R01 AA008169 NIAAA NIH HHS
• R01 AA012863 NIAAA NIH HHS
• R01 AA002666 NIAAA NIH HHS
• R21 AA017232 NIAAA NIH HHS
• AA02666 NIAAA NIH HHS
• AA012863 NIAAA NIH HHS
• R37 AA014372 NIAAA NIH HHS
• R37 AA002666 NIAAA NIH HHS

• Biliverdine/metabolism
• Biliverdine/pharmacology
• Cells, Cultured
• Heme Oxygenase-1/metabolism
• Hepacivirus/drug effects
• Hepacivirus/physiology
• Interferons/drug effects
• Interferons/physiology
• Virus Replication/drug effects

AIM: To elucidate the effect of antioxidants, resveratrol (RVT) and astaxanthin (AXN), on hepatitis C virus (HCV) replication.

METHODS: We investigated the effect of recent popular antioxidant supplements on replication of the HCV replicon system OR6. RVT is a strong antioxidant and a kind of polyphenol that inhibits replication of various viruses. AXN is also a strong antioxidant. The replication of HCV RNA was assessed by the luciferase reporter assay. An additive effect of antioxidants on antiviral effects of interferon (IFN) and ribavirin (RBV) was investigated.

RESULTS: This is the first report to investigate the effect of RVT and AXN on HCV replication. In contrast to other reported viruses, RVT significantly enhanced HCV RNA replication. Vitamin E also enhanced HCV RNA replication as reported previously, although AXN didnot affect replication. IFN and RBV significantly reduced HCV RNA replication, but these effects were dose-dependently hampered and attenuated by the addition of RVT. AXN didnot affect antiviral effects of IFN or RBV.

CONCLUSION: These results suggested that RVT is not suitable as an antioxidant therapy for chronic hepatitis C.

• Replicon system
• Luciferase assay
• Ribavirin
• Interferon
• Polyphenol
• Astaxanthin