• biliverdin
• carbon monoxide
• heme oxygenase-1
• porcine circovirus type 3
• viral replication

• Swine
• Animals
• Heme Oxygenase-1/genetics
• Heme Oxygenase-1/metabolism
• Biliverdine/pharmacology
• Carbon Monoxide/metabolism
• Circovirus/genetics
• Circovirus/metabolism
• Reactive Oxygen Species
• Antiviral Agents/pharmacology

• National Key Research and Development Program of China
• Introduction Program of High-Level Innovation and Entrepreneurship Talents in Jiangsu Province
• The 111 Project D18007
• Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)

Heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme degradation, is involved in the maintenance of cellular homeostasis, exerting a cytoprotective role by its antioxidative and anti-inflammatory functions. HO-1 and its end products, biliverdin, carbon monoxide and free iron (Fe²⁺), confer cytoprotection against inflammatory and oxidative injury. Additionally, HO-1 exerts antiviral properties against a diverse range of viral infections by interfering with replication or activating the interferon (IFN) pathway. Severe cases of coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are characterized by systemic hyperinflammation, which, in some cases, leads to severe or fatal symptoms as a consequence of respiratory failure, lung and heart damage, kidney failure, and nervous system complications. This review summarizes the current research on the protective role of HO-1 in inflammatory diseases and against a wide range of viral infections, positioning HO-1 as an attractive target to ameliorate clinical manifestations during COVID-19.

• hydrogen
• inflammation
• maternal-fetal infection
• miscarriage
• nanoagents
• oxidative stress
• placenta
• silicon

• acidic pH
• chemoresistance
• desmoplasia
• extracellular matrix
• hypoxia
• metabolism
• pancreatic ductal adenocarcinoma
• treatment
• tumor microenvironment

• 813834; H2020-MSCA-ITN-2018 European Marie Skłodowska-Curie Innovative Training Network

• cancer chemotherapy
• telomerase enzymatic activity
• telomerase reverse transcriptase
• telomere
• zinc protoporphyrin

• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Enzyme Inhibitors/administration & dosage
• Enzyme Inhibitors/pharmacology
• HEK293 Cells
• Humans
• Inhibitory Concentration 50
• Microscopy, Confocal
• Protoporphyrins/administration & dosage
• Protoporphyrins/pharmacology
• Telomerase/antagonists & inhibitors
• Telomerase/metabolism
• Telomere/metabolism

• I01 BX000159 BLRD VA
• I01 BX004434 BLRD VA

• antiviral therapy
• oxidative stress
• reactive oxygen species
• viral infections

• antiviral effect
• biliverdin
• carbon monoxide
• heme oxygenase-1
• pseudorabies virus

• antiviral agents
• hepatitis C genotype
• hepatitis C virus
• porphyrins

With respect to their genome and their structure, the human hepatitis B virus (HBV) and hepatitis C virus (HCV) are complete different viruses. However, both viruses can cause an acute and chronic infection of the liver that is associated with liver inflammation (hepatitis). For both viruses chronic infection can lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) play a central role in a variety of chronic inflammatory diseases. In light of this, this review summarizes the impact of both viruses on ROS-generating and ROS-inactivating mechanisms. The focus is on the effect of both viruses on the transcription factor Nrf2 (nuclear factor erythroid 2 (NF-E2)-related factor 2). By binding to its target sequence, the antioxidant response element (ARE), Nrf2 triggers the expression of a variety of cytoprotective genes including ROS-detoxifying enzymes. The review summarizes the literature about the pathways for the modulation of Nrf2 that are deregulated by HBV and HCV and describes the impact of Nrf2 deregulation on the viral life cycle of the respective viruses and the virus-associated pathogenesis.

• Hepatitis C virus
• Hepatits B virus
• Nrf2
• liver regeneration
• reactive oxygen species

• Animals
• Hepacivirus/pathogenicity
• Hepacivirus/physiology
• Hepatitis B/metabolism
• Hepatitis B/pathology
• Hepatitis B virus/pathogenicity
• Hepatitis B virus/physiology
• Hepatitis C/metabolism
• Hepatitis C/pathology
• Humans
• Kelch-Like ECH-Associated Protein 1/metabolism
• NF-E2-Related Factor 2/metabolism
• Signal Transduction
• Virus Replication/physiology

• Gemcitabine
• Heme oxygenase-1 (HO-1)
• Pancreatic ductal adenocarcinoma (PDAC)
• SnPP
• ZnPP

Heme oxygenase-1 (HO-1), a rate-limiting enzyme involved in the degradation of heme, is induced in response to a wide range of stress conditions. HO-1 exerts antiviral activity against a broad range of viruses, including the Hepatitis C virus, the human immunodeficiency virus, and the dengue virus by inhibiting viral growth. It has been reported that HO-1 displays antiviral activity against the Zika virus (ZIKV) but the mechanisms of viral inhibition remain largely unknown. Using a ZIKV RNA replicon with the Green Fluorescent Protein (GFP) as a reporter protein, we were able to show that HO-1 expression resulted in the inhibition of viral RNA replication. Conversely, we observed a decrease in HO-1 expression in cells replicating the ZIKV RNA replicon. The study of human cells infected with ZIKV showed that the HO-1 expression level was significantly lower once viral replication was established, thereby limiting the antiviral effect of HO-1. Our work highlights the capacity of ZIKV to thwart the anti-replicative activity of HO-1 in human cells. Therefore, the modulation of HO-1 as a novel therapeutic strategy against ZIKV infection may display limited effect.

• Zika virus
• antiviral
• heme-oxygenase 1
• viral replication

• DNA Replication
• Down-Regulation
• Green Fluorescent Proteins
• HEK293 Cells
• Heme/metabolism
• Heme Oxygenase-1/genetics
• Heme Oxygenase-1/metabolism
• Hemin/pharmacology
• Humans
• RNA, Viral
• Replicon
• Virus Replication
• Zika Virus/genetics
• Zika Virus/physiology
• Zika Virus Infection/drug therapy

• Candida
• HIV
• Leishmania
• Mycobacterium
• Plasmodium
• Salmonella
• carbon monoxide
• dengue
• heme oxygenase 1
• hepatitis
• influenza and microbial infections
• malaria
• sepsis
• tuberculosis

Pristimerin (Pris) is bioactive natural quinonoid triterpene that has anti-inflammatory and anti-cancer activities. Meanwhile, its effect against hepatitis needs to be elucidated. This investigation aimed to evaluate the ability of Pris to protect against autoimmune hepatitis (AIH). A mouse model of AIH was established using single concanavalin A (Con A) intravenous injection. Mice were treated with Pris at two different doses (0.4 and 0.8 mg/kg) for 5 days prior to Con A challenge. Markers of hepatic injury, oxidative, inflammatory, and apoptotic damage were estimated. Results have revealed that Pris pretreatment ameliorated Con A-induced hepatic damage. There was decrease in the elevated serum indices of hepatic damage (ALT, AST, ALP, and LDH) and improvement of the histopathological picture of the liver. Pris effectively decreased Con A-induced neutrophil infiltration into the hepatic tissue as presented by amelioration of the level and immuno-expression of myeloperoxidase (MPO). Additionally, Pris attenuated Con A-induced increase in CD4+ T-cells in hepatic tissue. Lipid peroxidation was significantly depressed simultaneously with enhancement of the antioxidant capacity in Pris pretreated animals. Pris also enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression and its binding capacity. In addition, Pris increased mRNA expression of heme-oxygenase-1 (HO-1) and restored its normal level. Furthermore, Pris decreased the level and immuno-expression of nuclear factor kappa-B (NF-κB) as well as the downstream inflammatory cascade (TNF-α, IL-6, and IL-1β). Finally, Pris showed inhibitory effect on Con A-induced apoptotic alteration in liver as it decreased the mRNA expression and levels the apoptotic markers (Bax and caspase-3) and increased mRNA expression and level of the anti-apoptotic protein (Bcl2). In conclusion, this study demonstrates the potent hepatoprotective efficacy of Pris against Con A-induced hepatitis which may be related to anti-oxidative, anti-inflammatory, and anti-apoptotic pathways. Pris could serve as a new candidate for the management of hepatitis.

• apoptosis
• hemeoxygenase-1
• hepatitis
• nuclear factor erythroid-related factor 2 (Nrf2)
• nuclear factor kappa-B
• pristimerin

Heme oxygenase-1 (HO-1) is a protein secreted by immune cells as a part of immune response mechanism.HO-1 can be induced by variety agents that causingoxidative stress, such as exposure to 100% oxygenat2,4 ATA pressure.It plays a vital role in maintaining cellular homeostasis.This study was conducted to identify the effect of hyperbaric oxygen exposure in cultured ofPBMCthat infected by HIV-1.

Primary culture of PBMCs were isolated from 16 healthy volunteers and HIV-1 infected MT4 cell line by co-culture. The PBMCs were aliquoted into two wells as control group and treatment group. The 16 samples of HIV-1 infected PBMCwere exposed to oxygen at 2,4 ATA in animal hyperbaric chamber forthree times in 30 minutes periods with 5 minutes spacing period, that called 1 session.

The Treatment done on 5 sessions within 5 days. 16 samples of HIV-1 infected PMBCs that have no hyperbaric treatment became control group.The supernatant were measured the HO-1 production by ELISA andmRNA expression of HO-1 by real time PCR and the number ofantigen p24 HIV-1by ELISA.

The result showed that there was no increasing of HO-1 at both mRNA level and protein level, there was a decreasing number of antigen p24 HIV-1 at the treatment group. In addition, hyperbaric exposure could not increase the expression of HO-1, more over the viral replication might be reduced by other mechanism.

Hyperbaric oxygen could increases cellular adaptive response of PBMCs infected HIV-1 through increased expression of proteins that can inhibit HIV viralreplication.

• HIV-1
• heme oxygenase-1 (HO-1)
• hyperbaric oxygen
• mRNA
• qPCR

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

• PQS
• Pseudomonas quinolone signal
• cystic fibrosis
• heme oxygenase-1
• oxidative stress

• carcinogenesis
• hepatitis B virus
• hepatitis C virus
• pathogenesis
• reactive oxygen species

• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Hepatitis B/metabolism
• Hepatitis C/metabolism
• Humans
• Liver Neoplasms/virology
• Oxidative Stress
• Signal Transduction

Telomerase repairs the telomeric ends of chromosomes and is active in nearly all malignant cells. Hepatitis C virus (HCV) is known to be oncogenic and potential interactions with the telomerase system require further study. We determined the effects of HCV infection on human telomerase reverse transcriptase (TERT) expression and enzyme activity in primary human hepatocytes and continuous cell lines.

Primary human hepatocytes and Huh-7.5 hepatoma cells showed early de novo TERT protein expression 2–4 days after infection and these events coincided with increased TERT promoter activation, TERT mRNA, and telomerase activity. Immunoprecipitation studies demonstrated that NS3-4A protease-helicase, in contrast to core or NS5A, specifically bound to the C-terminal region of TERT through interactions between helicase domain 2 and protease sequences. Increased telomerase activity was noted when NS3-4A was transfected into cells, when added to reconstituted mixtures of TERT and telomerase RNA, and when incubated with high molecular weight telomerase ‘holoenzyme’ complexes. The NS3-4A catalytic effect on telomerase was inhibited with primuline or danoprevir, agents that are known to inhibit NS3 helicase and protease activities respectively. In HCV infected cells, NS3-4A could be specifically recovered with telomerase holoenzyme complexes in contrast to NS5A or core protein. HCV infection also activated the effector caspase 7 which is known to target TERT. Activation coincided with the appearance of lower molecular weight carboxy-terminal fragment(s) of TERT, chiefly sized at 45 kD, which could be inhibited with pancaspase or caspase 7 inhibitors.

HCV infection induces TERT expression and stimulates telomerase activity in addition to triggering Caspase activity that leads to increased TERT degradation. These activities suggest multiple points whereby the virus can influence neoplasia. The NS3-4A protease-helicase can directly bind to TERT, increase telomerase activity, and thus potentially influence telomere repair and host cell neoplastic behavior.

• Blotting, Western
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Cell Line, Tumor
• Cells, Cultured
• Fluorescent Antibody Technique
• Hepacivirus/pathogenicity
• Hepatocytes/metabolism
• Humans
• Immunoprecipitation
• Promoter Regions, Genetic/genetics
• RNA/metabolism
• Telomerase/metabolism
• Viral Nonstructural Proteins/genetics
• Viral Nonstructural Proteins/metabolism

• I01 BX000159 BLRD VA
• Veterans Affairs Merit Review

• Antiviral Agents/pharmacology
• Bilirubin/biosynthesis
• Biliverdine/biosynthesis
• Cell Line, Tumor
• Drug Synergism
• Heme Oxygenase-1/metabolism
• Hepacivirus/drug effects
• Hepacivirus/physiology
• Humans
• Interferons/pharmacology
• Isothiocyanates/pharmacology
• Models, Biological
• NF-E2-Related Factor 2/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• RNA, Viral/metabolism
• Replicon/drug effects
• Sulfoxides
• Transcriptional Activation/drug effects
• Up-Regulation/drug effects
• Viral Nonstructural Proteins/metabolism
• Virus Replication/drug effects

HCV (hepatitis C virus) is a member of the Flaviviridae family that contains a single-stranded positive-sense RNA genome of approximately 9600 bases. HCV is a major causative agent for chronic liver diseases such as steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma which are caused by multifactorial processes. Elevated levels of reactive oxygen species (ROS) are considered as a major factor contributing to HCV-associated pathogenesis. This review summarizes the mechanisms involved in formation of ROS in HCV replicating cells and describes the interference of HCV with ROS detoxifying systems. The relevance of ROS for HCV-associated pathogenesis is reviewed with a focus on the interference of elevated ROS levels with processes controlling liver regeneration. The overview about the impact of ROS for the viral life cycle is focused on the relevance of autophagy for the HCV life cycle and the crosstalk between HCV, elevated ROS levels, and the induction of autophagy.

• Antioxidants
• Glycyrrhizin
• Hepatitis C virus
• N-acetylcysteine
• Oxidative stress
• Reactive oxygen species
• S-adenosylmethionine
• Silymarin
• Vitamin E

Mycobacterium abscessus (M.abs) is a rapidly growing mycobacterial species that infects macrophages, and is an important pathogen in patients with cystic fibrosis. We studied the early stages of M.abs infection of macrophages, with emphasis on the role of heme-oxygenase-1 (HO-1) in this infection. THP-1 cells were activated using TPA into macrophage-like cells and infected with M.abs for different time points. M.abs infection robustly induced HO-1 expression in the THP-1 cells. Production of HO-1 was p38 MAPK-dependent, as p38 inhibitors suppressed HO-1 induction. Pretreatment with HO-1 inhibitors tin-protoporphyrin (SnPP) significantly inhibited M.abs growth inside macrophages. Furthermore, inhibiting HO-1 using HO-1 siRNA or the HO-1 upstream signaling molecule; Nrf2 using Nrf2 siRNA resulted in similar inhibition of M.abs. In contrast, inducing HO-1 did not increase M.abs intracellular growth above control. Products of HO-1 metabolism of heme are bilirubin, biliverdin, carbon monoxide (CO) and iron. The addition of either bilirubin or biliverdin, but not CO, completely restored the SnPP inhibitory effect and partially that with HO-1 siRNA. To understand the mechanisms, we used Syto-62 labeled M.abs to infect macrophages. Interestingly, HO-1 inhibition promoted M.abs-containing phagosome fusion with lysosomes, which should enhance M.abs killing. M.abs infection enhanced THP-1 ROS production as demonstrated by increased DHE, DCF fluorescence, and EPR signal. HO-1 inhibition further increased ROS production in infected macrophages. Our results indicate that HO-1 induction is important for M.abs growth during the early stages of infection, and that the HO-1 products bilirubin and biliverdin, perhaps through modulation of intracellular ROS levels, may be involved.

•

HO-1 induction is important for Mycobacterium abscessus growth inside infected macrophages during the early stages of infection.

• HO-1
• Mycobacterium abscessus
• Oxidative stress
• THP-1 cells

Hepatitis C virus (HCV) is not usually cleared by our immune system, leading to the development of chronic hepatitis C infection. Chronic HCV induces the production of various cytokines, predominantly by Kupffer cells (KCs), and creates a pro-inflammatory state in the liver. The chronic dysregulated production of interferon (IFN) and other cytokines by KCs also promotes innate immune tolerance. Ribavirin (RBV) monotherapy has been shown to decrease inflammation in liver of patients with chronic hepatitis C. Sustained virological response (SVR) is significantly higher when IFN is combined with RBV in chronic HCV (cHCV) infection. However, the mechanism of their synergy remains unclear. Previous theories have attempted to explain the anti-HCV effect based on direct action of RBV alone on the virus or on the immune system; however, these theories have serious shortcomings. We propose that hemolysis, which universally occurs with RBV therapy and which is considered a limiting side effect, is precisely the mechanism by which the anti-HCV effect is exerted. Passive hemolysis results in anti-inflammatory/antiviral actions within the liver that disrupt the innate immune tolerance, leading to the synergy of RBV with IFN-α. Ribavirin-induced hemolysis floods the hepatocytes and KCs with heme, which is metabolized and detoxified by heme oxygenase-1 (HMOX1) to carbon monoxide (CO), biliverdin and free iron (which induces ferritin). These metabolites of heme possess anti-inflammatory and antioxidant properties. Thus, HMOX1 plays an extremely important anti-oxidant, anti-inflammatory and cytoprotective role, particularly in KCs and hepatocytes. HMOX1 has been noted to have anti-viral effects in hepatitis C infected cell lines. Additionally, it has been shown to enhance the response to IFN-α by restoring interferon-stimulated genes (ISGs). This mechanism can be clinically corroborated by the following observations that have been found in patients undergoing RBV/IFN combination therapy for cHCV: (1) SVR rates are higher in patients who develop anemia; (2) once anemia (due to hemolysis) occurs, the SVR rate does not depend on the treatment utilized to manage anemia; and (3) ribavirin analogs, such as taribavirin and levovirin, which increase intrahepatic ribavirin levels and which produce lesser hemolysis, are inferior to ribavirin for treating cHCV. This mechanism can also explain the observed RBV synergy with direct antiviral agents. This hypothesis is testable and may lead to newer and safer medications for treating cHCV infection.

• Chronic hepatitis C
• Therapy
• Ribavirin
• Hemolysis
• Heme oxygenase-1

• Anemia, Hemolytic/blood
• Anemia, Hemolytic/chemically induced
• Anemia, Hemolytic/immunology
• Animals
• Antiviral Agents/adverse effects
• Antiviral Agents/therapeutic use
• Drug Synergism
• Drug Therapy, Combination
• Heme Oxygenase-1/metabolism
• Hemolysis/drug effects
• Hepacivirus/drug effects
• Hepacivirus/immunology
• Hepatitis C, Chronic/blood
• Hepatitis C, Chronic/diagnosis
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/immunology
• Hepatitis C, Chronic/physiopathology
• Hepatitis C, Chronic/virology
• Host-Pathogen Interactions
• Humans
• Inflammation Mediators/metabolism
• Ribavirin/adverse effects
• Ribavirin/therapeutic use
• Treatment Outcome

To analyze the expression of HMOX1 and miR-122 in liver biopsy samples obtained from HCV mono-and HIV/HCV co-infected patients in relation to selected clinical parameters, histological examination and IL-28B polymorphism as well as to determine whether HMOX1 expression is dependent on Bach-1.

The study group consisted of 90 patients with CHC: 69 with HCV mono and 21 with HIV/HCV co-infection. RT-PCR was used in the analysis of HMOX1, Bach-1 and miR-122 expression in liver biopsy samples and in the assessment of IL-28B single-nucleotide polymorphism C/T (rs12979860) in the blood. Moreover in liver biopsy samples an analysis of HO-1 and Bach-1 protein level by Western Blot was performed.

HCV mono-infected patients, with lower grading score (G<2) and higher HCV viral load (>600000 IU/mL) demonstrated higher expression of HMOX1. In patients with HIV/HCV co-infection, the expression of HMOX1 was lower in patients with lower lymphocyte CD4 count and higher HIV viral load. IL28B polymorphism did not affect the expression of either HMOX1 or miR-122. Higher HMOX1 expression correlated with higher expression of Bach-1 (Spearman’s ρ = 0.586, p = 0.000001) and miR-122 (Spearman’s ρ = 0.270, p = 0.014059).

HMOX1 and miR-122 play an important role in the pathogenesis of CHC in HCV mono-and HIV/HCV co-infected patients. Reduced expression of HMOX1 in patients with HIV/HCV co-infection may indicate a worse prognosis in this group. Our results do not support the importance of Bach-1 in repression of HMOX1 in patients with chronic hepatitis C.

Chronic hepatitis C is characterized by metabolic disorders and a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that lead in the long term to hepatocellular carcinoma. Many lines of evidence suggest that mitochondrial dysfunctions, including modification of metabolic fluxes, generation and elimination of oxidative stress, Ca²⁺ signaling and apoptosis, play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory, probably due to the use of artificial expression and replication systems. In vivo studies are hampered by the fact that innate and adaptive immune responses will overlay mitochondrial dysfunctions induced directly in the hepatocyte by HCV. Thus, the molecular aspects underlying HCV-induced mitochondrial dysfunctions and their roles in viral replication and the associated pathology need yet to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems.

• Adult
• Antiviral Agents/therapeutic use
• Female
• Gene Expression
• Heme/metabolism
• Heme Oxygenase (Decyclizing)/genetics
• Heme Oxygenase (Decyclizing)/metabolism
• Heme Oxygenase-1/genetics
• Heme Oxygenase-1/metabolism
• Hepacivirus
• Hepatitis C/drug therapy
• Hepatitis C/genetics
• Hepatitis C/virology
• Humans
• Leukocytes/metabolism
• Leukocytes/virology
• Liver/metabolism
• Liver/virology
• Male
• Metabolic Networks and Pathways/genetics
• Middle Aged
• Oxidoreductases Acting on CH-CH Group Donors/genetics
• ROC Curve
• Treatment Outcome

• hepatitis c
• oxidative stress
• nrf2/are pathway
• antioxidant defense
• iron homeostasis
• regulation.

• Animals
• Antioxidants/metabolism
• Hepacivirus/physiology
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/genetics
• Hepatitis C, Chronic/metabolism
• Hepatitis C, Chronic/virology
• Humans
• Iron Overload/metabolism
• Liver/metabolism
• Liver/virology
• NF-E2-Related Factor 2/metabolism
• Oxidative Stress
• Reactive Oxygen Species/metabolism
• Response Elements
• Signal Transduction

Hepatitis C virus, human immunodeficiency virus, and hepatitis B virus are chronic viral infections that cause considerable morbidity and mortality throughout the world. In the decades following the identification and sequencing of these viruses, in vitro experiments demonstrated that heme oxygenase-1, its oxidative products, and related compounds of the heme oxygenase system inhibit replication of all 3 viruses. The purpose of this review is to critically evaluate and summarize the seminal studies that described and characterized this remarkable behavior. It will also discuss more recent work that discovered the antiviral mechanisms and target sites of these unique antiviral agents. In spite of the fact that these viruses are diverse pathogens with quite profound differences in structure and life cycle, it is significant that heme and related compounds show striking similarity for viral target sites across all three species. Collectively, these findings strongly indicate that we should move forward and develop heme and related tetrapyrroles into versatile antiviral agents that could be used therapeutically in patients with single or multiple viral infections.

• HBV
• HCV
• HIV
• Heme
• biliverdin
• metalloporphyrins
• proteases
• viruses

• Antioxidants/metabolism
• Biopsy
• Fatty Liver/complications
• Fatty Liver/metabolism
• Fatty Liver/pathology
• Heme Oxygenase-1/metabolism
• Hepacivirus
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/metabolism
• Hepatitis C, Chronic/pathology
• Humans
• Immunohistochemistry
• Non-alcoholic Fatty Liver Disease
• Oxidative Stress/physiology
• RNA, Messenger/analysis
• Real-Time Polymerase Chain Reaction

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

• Gene Expression
• Heme Oxygenase-1
• Hepatitis C Virus
• Liver Cirrhosis
• Non-alcoholic Fatty Liver Disease
• Oxidative Stress

Dengue virus infection is a public health threat to hundreds of millions of individuals in the tropical regions of the globe. Although Dengue infection usually manifests itself in its mildest, though often debilitating clinical form, dengue fever, life-threatening complications commonly arise in the form of hemorrhagic shock and encephalitis. The etiological basis for the virus-induced pathology in general, and the different clinical manifestations in particular, are not well understood. We reasoned that a detailed knowledge of the global biological processes affected by virus entry into a cell might help shed new light on this long-standing problem.

A bacterial two-hybrid screen using DENV2 structural proteins as bait was performed, and the results were used to feed a manually curated, global dengue-human protein interaction network. Gene ontology and pathway enrichment, along with network topology and microarray meta-analysis, were used to generate hypothesis regarding dengue disease biology.

Combining bioinformatic tools with two-hybrid technology, we screened human cDNA libraries to catalogue proteins physically interacting with the DENV2 virus structural proteins, Env, cap and PrM. We identified 31 interacting human proteins representing distinct biological processes that are closely related to the major clinical diagnostic feature of dengue infection: haemostatic imbalance. In addition, we found dengue-binding human proteins involved with additional key aspects, previously described as fundamental for virus entry into cells and the innate immune response to infection. Construction of a DENV2-human global protein interaction network revealed interesting biological properties suggested by simple network topology analysis.

Our experimental strategy revealed that dengue structural proteins interact with human protein targets involved in the maintenance of blood coagulation and innate anti-viral response processes, and predicts that the interaction of dengue proteins with a proposed human protein interaction network produces a modified biological outcome that may be behind the hallmark pathologies of dengue infection.

• hepatitis c virus
• biliverdin
• bilirubin
• ns3/4a protease

• Antiviral Agents/pharmacology
• Biliverdine/pharmacology
• Cell Line, Tumor
• Heme Oxygenase-1/pharmacology
• Hepacivirus/drug effects
• Humans
• Kinetics
• Peptide Hydrolases/metabolism
• Protease Inhibitors/pharmacology
• Serine Proteinase Inhibitors
• Viral Nonstructural Proteins/antagonists & inhibitors
• Virus Replication/drug effects

• I01 BX000159 BLRD VA
• R01 DK058597 NIDDK NIH HHS
• R21 DK068453 NIDDK NIH HHS
• R01 DK058597-4 NIDDK NIH HHS

Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. HO-1 not only protects against oxidative stress and apoptosis, but has received a great deal of attention in recent years because of its potent anti-inflammatory functions. Studies with HO-1 knockout animal models have led to major advances in the understanding of how HO-1 might regulate inflammatory immune responses, although little is known on the underlying mechanisms. Due to its beneficial effects the targeted induction of this enzyme is considered to have major therapeutic potential for the treatment of inflammatory disorders. This review discusses current knowledge on the mechanisms that mediate anti-inflammatory protection by HO-1. More specifically, the article deals with the role of HO-1 in the pathophysiology of viral hepatitis, inflammatory bowel disease, and pancreatitis. The effects of specific HO-1 modulation as a potential therapeutic strategy in experimental cell culture and animal models of these gastrointestinal disorders are summarized. In conclusion, targeted regulation of HO-1 holds major promise for future clinical interventions in inflammatory diseases of the gastrointestinal tract.

• Antioxidant
• Heme oxygenase
• Hepatitis
• Immunity
• Inflammation
• Inflammatory bowel disease
• Oxidative stress
• Pancreatitis

• Total hip arthroplasty
• antioxidant enzymes.
• metal ions
• oxidative stress

• Antiviral Agents/therapeutic use
• Gene Expression Regulation, Enzymologic
• Genetic Variation
• Heme Oxygenase-1/genetics
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/ethnology
• Hepatitis C, Chronic/genetics
• Humans
• Prognosis
• Promoter Regions, Genetic
• Racial Groups/genetics
• Treatment Outcome
• United States

• R01 DK038825 NIDDK NIH HHS

• microrna
• heme oxygenase-1
• hepatitis c virus
• 3′-utr
• reporter gene assay