Hepatitis C core protein inhibits induction of heme oxygenase-1 and sensitizes hepatocytes to cytotoxicity

Wen, Feng; Brown, Kyle E.; Britigan, Bradley E.; Schmidt, Warren N.

doi:10.1007/s10565-007-9027-9

Cited by 28 publications

(26 citation statements)

References 52 publications

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“…The expression of HO-1 was also reduced in cell lines that stably express HCV core protein, which suggests that core gene products are capable of regulating the expression of HO-1. These results are confirmed by Wen et al [77] have who shown that HCV core protein attenuates the induction of HO-1 by heme, heavy metals, and peroxides and contributes to hepatocellular damage by increasing both steady-state levels of prooxidants and the susceptibility of hepatocytes to damage by impairing their response to other sources of oxidative stress. Concerning the effects of HO-1 induction on hepatitis C, Shan et al [78] have shown a decrease in HCV replication, an effect similar to that described by Protzer et al [74] in HBV hepatitis.…”

Section: Hepatitis Csupporting

confidence: 79%

Natural heme oxygenase-1 inducers in hepatobiliary function

Volti¹,

Sacerdoti²,

Giacomo³

et al. 2008

WJG

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Section: Hepatitis Csupporting

confidence: 79%

Natural heme oxygenase-1 inducers in hepatobiliary function

Volti¹,

Sacerdoti²,

Giacomo³

et al. 2008

WJG

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“…An antiviral effect of HO-1 induction has been observed in infection studies of hepatitis C virus (HCV) (36), hepatitis B virus (HBV) (37), Ebola virus (38), enterovirus 71 (EV71) (39), vaccinia virus (40), and porcine reproductive and respiratory syndrome virus (41). Interestingly, HCV has been reported to downregulate HO-1 protein expression (42,43), although contrasting studies report HO-1 induction by HCV (44,45).…”

Section: Discussionmentioning

confidence: 99%

Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy

Gill

Kovacsics

Vance

et al. 2015

J Virol

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Expression of the cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly reduced in the brain prefrontal cortex of HIVpositive individuals with HIV-associated neurocognitive disorders (HAND). Furthermore, this HO-1 deficiency correlates with brain viral load, markers of macrophage activation, and type I interferon responses. In vitro, HIV replication in monocyte-derived macrophages (MDM) selectively reduces HO-1 protein and RNA expression and induces production of neurotoxic levels of glutamate; correction of this HO-1 deficiency reduces neurotoxic glutamate production without an effect on HIV replication. We now demonstrate that macrophage HO-1 deficiency, and the associated neurotoxin production, is a conserved feature of infection with macrophage-tropic HIV-1 strains that correlates closely with the extent of replication, and this feature extends to HIV-2 infection. We further demonstrate that this HO-1 deficiency does not depend specifically upon the HIV-1 accessory genes nef, vpr, or vpu but rather on HIV replication, even when markedly limited. Finally, antiretroviral therapy (ART) applied to MDM after HIV infection is established does not prevent HO-1 loss or the associated neurotoxin production. This work defines a predictable relationship between HIV replication, HO-1 loss, and neurotoxin production in MDM that likely reflects processes in place in the HIV-infected brains of individuals receiving ART. It further suggests that correcting this HO-1 deficiency in HIVinfected MDM could provide neuroprotection above that provided by current ART or proposed antiviral therapies directed at limiting Nef, Vpr, or Vpu functions. The ability of HIV-2 to reduce HO-1 expression suggests that this is a conserved phenotype among macrophage-tropic human immunodeficiency viruses that could contribute to neuropathogenesis. IMPORTANCEThe continued prevalence of HIV-associated neurocognitive disorders (HAND) underscores the need for adjunctive therapy that targets the neuropathological processes that persist in antiretroviral therapy (ART)-treated HIV-infected individuals. To this end, we previously identified one such possible process, a deficiency of the antioxidative and anti-inflammatory enzyme heme oxygenase-1 (HO-1) in the brains of individuals with HAND. In the present study, our findings suggest that the HO-1 deficiency associated with excess glutamate production and neurotoxicity in HIV-infected macrophages is a highly conserved phenotype of macrophage-tropic HIV strains and that this phenotype can persist in the macrophage compartment in the presence of ART. This suggests a plausible mechanism by which HIV infection of brain macrophages in ART-treated individuals could exacerbate oxidative stress and glutamate-induced neuronal injury, each of which is associated with neurocognitive dysfunction in infected individuals. Thus, therapies that rescue the HO-1 deficiency in HIV-infected individuals could provide additional neuroprotection to ART. H eme oxygenase-1 (HO-1) is a highly inducible phase II d...

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“…With high degree of differentiation, HepG2 cells retain many biological characteristics of hepatocytes and could synthesize nearly all human plasma proteins. It has been widely used as a cellular model to investigate the oxidative injury of hepatocytes elicited by H 2 O 2 [36–40], arachidonic acid and iron [41], hepatocytes toxicity induced by alcohol [42] or CYP2E1 [43], and hepatocellular injury by Hepatitis C virus [44]. HepG2 cells were cultured in a humidified atmosphere of 95% air plus 5% CO 2 in a 37°C incubator in Dulbecco's modified Eagle's medium supplemented with 10% heat-inactivated fetal bovine serum, 100 μ M streptomycin, and 100 U/mL penicillin.…”

Section: Methodsmentioning

confidence: 99%

N-Acetyl-Serotonin Protects HepG2 Cells from Oxidative Stress Injury Induced by Hydrogen Peroxide

Jiang

et al. 2014

Oxidative Medicine and Cellular Longevity

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Oxidative stress plays an important role in the pathogenesis of liver diseases. N-Acetyl-serotonin (NAS) has been reported to protect against oxidative damage, though the mechanisms by which NAS protects hepatocytes from oxidative stress remain unknown. To determine whether pretreatment with NAS could reduce hydrogen peroxide- (H2O2-) induced oxidative stress in HepG2 cells by inhibiting the mitochondrial apoptosis pathway, we investigated the H2O2-induced oxidative damage to HepG2 cells with or without NAS using MTT, Hoechst 33342, rhodamine 123, Terminal dUTP Nick End Labeling Assay (TUNEL), dihydrodichlorofluorescein (H2DCF), Annexin V and propidium iodide (PI) double staining, immunocytochemistry, and western blot. H2O2 produced dramatic injuries in HepG2 cells, represented by classical morphological changes of apoptosis, increased levels of malondialdehyde (MDA) and intracellular reactive oxygen species (ROS), decreased activity of superoxide dismutase (SOD), and increased activities of caspase-9 and caspase-3, release of cytochrome c (Cyt-C) and apoptosis-inducing factor (AIF) from mitochondria, and loss of membrane potential (ΔΨm). NAS significantly inhibited H2O2-induced changes, indicating that it protected against H2O2-induced oxidative damage by reducing MDA levels and increasing SOD activity and that it protected the HepG2 cells from apoptosis through regulating the mitochondrial apoptosis pathway, involving inhibition of mitochondrial hyperpolarization, release of mitochondrial apoptogenic factors, and caspase activity.

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Hepatitis C core protein inhibits induction of heme oxygenase-1 and sensitizes hepatocytes to cytotoxicity

Cited by 28 publications

References 52 publications

Natural heme oxygenase-1 inducers in hepatobiliary function

Natural heme oxygenase-1 inducers in hepatobiliary function

Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy

N-Acetyl-Serotonin Protects HepG2 Cells from Oxidative Stress Injury Induced by Hydrogen Peroxide

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