To investigate effects of iron on oxidative stress, heme oxygenase-1 (HMOX1) and hepatitis C viral (HCV) expression in human hepatoma cells stably expressing HCV proteins.
Effects of iron on oxidative stress, HMOX1, and HCV expression were assessed in CON1 cells. Measurements included mRNA by quantitative reverse transcription-polymerase chain reaction, and protein levels by Western blots.
Iron, in the form of ferric nitrilotriacetate, increased oxidative stress and up-regulated HMOX1 gene expression. Iron did not affect mRNA or protein levels of Bach1, a repressor of HMOX1. Silencing the up-regulation of HMOX1 nuclear factor-erythroid 2-related factor 2 (Nrf2) by Nrf2-siRNA decreased FeNTA-mediated up-regulation of HMOX1 mRNA levels. These iron effects were completely blocked by deferoxamine (DFO). Iron also significantly decreased levels of HCV core mRNA and protein by 80%-90%, nonstructural 5A mRNA by 90% and protein by about 50% in the Con1 full length HCV replicon cells, whereas DFO increased them.
Excess iron up-regulates HMOX1 and down-regulates HCV gene expression in hepatoma cells. This probably mitigates liver injury caused by combined iron overload and HCV infection.
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"We have previously shown that heme oxygenase-1 (HO-1), a pivotal cytoprotective gene, can be induced to inhibit HIV-1, West Nile virus, dengue, and Leishmania donovani infection of human monocyte-derived macrophages (MDM)12345. HO-1 induction has also been reported to suppress hepatitis B virus, hepatitis C virus, and malaria infections678910, Recently, Hill-Batorski et al. reported HO-1-dependent suppression of Ebola virus replication  , further establishing a key role for this endogenous enzyme in host defense. "
[Show abstract][Hide abstract]ABSTRACT: Small nuclear RNAs (snRNAs) are <200 nucleotide non-coding uridylate-rich RNAs. Although the functions of many snRNAs remain undetermined, a population of snRNAs is produced during the early phase of infection of cells by vaccinia virus. In the present study, we demonstrate a direct correlation between expression of the cytoprotective enzyme heme oxygenase-1 (HO-1), suppression of selective snRNA expression, and inhibition of vaccinia virus infection of macrophages. Hemin induced HO-1 expression, completely reversed virus-induced host snRNA expression, and suppressed vaccinia virus infection. This involvement of specific virus-induced snRNAs and associated gene clusters suggests a novel HO-1-dependent host-defense pathway in poxvirus infection.
Full-text · Article · Oct 2014 · Biochemical and Biophysical Research Communications
"Several studies indicate that HO-1 induction or overexpression in replicons inhibit HCV replication [14,15], while others have specified that it might be the products of the reaction catalyzed by HO-1 that are responsible for this process. It has been demonstrated that both iron and biliverdin display antiviral activity24252627. However, on the contrary, Kakizaki et al  note that iron enhances hepatitis C virus replication in cultured human hepatocytes. "
[Show abstract][Hide abstract]ABSTRACT: 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.
"BV Type I interferon induction Lehmann et al. (2010) Heme Anti-NS3/4A protease Zhu et al. (2010a) Heme HO-1 induction Shan et al. (2007), Zhu et al. (2008) ZnMP HO-1 induction and Bach 1 inhibition Hou et al. (2008) ZnMP Ubiquitination of NS5A Hou et al. (2010) Fe Antipolymerase Fillebeen et al. (2005) Fe Decreased HCV replication Yuasa et al. (2006), Zhu et al. (2010a) Fe HO-1 induction Hou et al. (2009) Zn Decreased viral replication Yuasa et al. (2006) HO-1 enzyme Enzyme overexpression Zhu et al. (2008) HBV Heme Anti-reverse transcriptase Lin and Hu (2008) HO-1 induction Protzer et al. (2007) HIV BV/BR Anti-HIV protease McPhee et al. (1996) Synthetic porphyrins Anti-HIV protease Decamp et al. (1992) Heme/MPs Anti-reverse transcriptase Levere et al. (1991), Staudinger et al. (1996), Argyris et al. (1999) HO-1 induction HO-1 induction Devadas and Dhawan (2006) MPs Gp120 inhibition Song et al. (1997) multiple viral target sites on different viruses indicates that these compounds would be also useful for patients with dual or even triple infections. Co-infected patients are a serious problem worldwide and invariably present with more severe medical disease, aggressive hepatitis, and a number of treatment dilemmas (den Brinker et al., 2000; Koziel and Peters, 2007; Zhou et al., 2011). "
[Show abstract][Hide abstract]ABSTRACT: 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.
Full-text · Article · Oct 2012 · Frontiers in Pharmacology