Potential role of heme metabolism in the inducible expression of heme oxygenase-1.

BACKGROUND: The degradation of heme significantly contributes to cytoprotective effects against oxidative stress and inflammation. The enzyme heme oxygenase-1 (HO-1), involved in the degradation of heme, forms carbon monoxide (CO), ferrous iron, and bilirubin in conjunction with biliverdin reductase, and is induced by various stimuli including oxidative stress and heavy metals. We examined the involvement of heme metabolism in the induction of HO-1 by the inducers sulforaphane and sodium arsenite. METHODS: We examined the expression of HO-1 in sulforaphane-, sodium arsenite- and CORM3-treated HEK293T cells, by measuring the transcriptional activity and levels of mRNA and protein. RESULTS: The blockade of heme biosynthesis by succinylacetone and N-methyl protoporphyrin, which are inhibitors of heme biosynthesis, markedly decreased the induction of HO-1. The knockdown of the first enzyme in the biosynthesis of heme, 5-aminolevulinic acid synthase, also decreased the induction of HO-1. The cessation of HO-1 induction occurred at the transcriptional and translational levels, and was mediated by the activation of the heme-binding transcriptional repressor Bach1 and translational factor HRI. CO appeared to improve the expression of HO-1 at the transcriptional and translational levels. CONCLUSIONS: We demonstrated the importance of heme metabolism in the stress-inducible expression of HO-1, and also that heme and its degradation products are protective factors for self-defense responses. GENERAL SIGNIFICANCE: The key role of heme metabolism in the stress-inducible expression of HO-1 may promote further studies on heme and its degradation products as protective factors of cellular stresses and iron homeostasis in specialized cells, organs, and whole animal systems.

Bardoxolone methyl as a novel potent antiviral agent against hepatitis B and C viruses in human hepatocyte cell culture systems.

Antiviral drugs against hepatitis B virus (HBV) relieve symptoms experienced by patients with hepatitis; however, these drugs cannot eliminate HBV infection from all patients completely. On the other hand, direct antiviral agents (DAAs) against hepatitis C virus (HCV) can achieve near-complete elimination of HCV infection. However, recent reports have claimed that DAAs pose a risk for HBV reactivation among patients with HBV and HCV co-infection. This suggests that an effective anti-viral strategy for both HBV and HCV would be extremely useful. We hypothesized that an activator of nuclear factor-erythroid factor 2 (Nrf2) could be a candidate, because heme oxygenase-1 (HO-1), a product of the Nrf2-target gene, was shown to be related to suppression of genome replication in both HBV and HCV. In this study, the potential of bardoxolone methyl (BARD), an Nrf2 activator, was examined in cell culture systems against HBV and HCV. We investigated that BARD had a suppressive effect on the production of extracellular HBV DNA in several HBV culture systems. In addition, BARD treatment reduced the levels of intracellular HBV pregenome RNA (pgRNA), a transcript from the HBV genome and a template of HBV genome replication. HCV genome replication was also suppressed in HCV subgenomic replicon-bearing cells by BARD treatment. BARD might be a novel treatment for patients with HBV and HCV co-infection.