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Nuclear factor-erythroid 2-related factor 2 (Nrf2) is persistently activated in many human tumors including acute myeloid leukemia (AML). Therefore, inhibition of Nrf2 activity may be a promising target in leukemia therapy. Here, we used an antioxidant response element-luciferase reporter system to identify a novel pyrazolyl hydroxamic acid derivative, 1-(4-(tert-Butyl)benzyl)-3-(4-chlorophenyl)-N-hydroxy-1H pyrazole-5-carboxamide (4f), that inhibited Nrf2 activity. 4f had a profound growth-inhibitory effect on three AML cell lines, THP-1, HL-60 and U937, and a similar anti-growth effect in a chick embryo model. Moreover, flow cytometry of AML cells revealed increased apoptosis with 4f (10 μM) treatment for 48 h. The protein levels of cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase were enhanced in all three AML cell types. Furthermore, Nrf2 protein level was downregulated by 4f. Upregulation of Nrf2 by tert-butylhydroquinone (tBHQ) or Nrf2 overexpression could ameliorate 4f-induced growth inhibition and apoptosis. Treatment with 4f reduced both B-cell lymphoma-2 (Bcl-2) expression and Bcl-2/Bcl-2-associated X protein (Bax) ratio, which indicated that 4f induced apoptosis, at least in part, via mitochondrial-dependent signaling. Therefore, as an Nrf2 inhibitor, the pyrazolyl hydroxamic acid derivative 4f may be a promising agent in AML therapy.

Background: Because of the shared transmission routes, co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HIV) is very common. Accumulated clinical evidence showed that one could alter the infectious course of the other virus in HIV and HCV co-infected individuals. However, little is known on the molecular basis of HIV/HCV interactions and their modulations on hosts., Methods: In this study, treatment-naive HIV, HCV mono-/co-infected individuals with CD4⁺ T cell counts >300/μl were recruited and their gene expression profiles were investigated by microarray assays. The differentially expressed genes were identified and validated by quantitative real-time PCR (qRT-PCR). To further understand the biological meanings of the gene expression profiles in these three groups, GSEA analysis (version 2.0, Broad Institute http://www.broad.mit.edu/gsea) was performed., Results: By gene set enrichment analysis, we revealed that gene sets of cell cycle progression, innate immune response and some transcription factors in CD4⁺ T cells were mainly affected by HIV; while genes associated with GPCR signaling were the major targets of HCV. Metabolic pathways were modulated by both HCV and HIV viruses., Conclusions: This study for the first time offers gene profiling basis for HCV/HIV mono-/co- infections in human beings. HIV infection displayed the great impact on transcription profile of CD4⁺ T cells in HIV/HCV co-infected individuals. Genes related to cell cycle arrest were significantly mediated by HIV which may lead to dysfunction of CD4⁺ T cells and acceleration of HCV-related disease progression in the co-infections.

Heme oxygenase-1 (HO-1) system catalyzes heme to biologically active products: carbon monoxide, biliverdin/bilirubin and free iron. It is involved in maintaining cellular homeostasis and many physiological and pathophysiological processes. A growing body of evidence indicates that HO-1 activation may play an important protective role in acute and chronic inflammation of gastrointestinal tract. This review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal inflammation studied to date. The ability to upregulate HO-1 by pharmacological means or using gene therapy may offer therapeutic strategies for gastrointestinal inflammation in the future.

Background/aims: Glucose-regulated protein 78 (GRP78), being a major chaperone, is implicated in the progression of hepatocellular carcinoma (HCC), and elevated GRP78 levels in tissues had been known to be related with poor prognosis in patients with HCC. In the present study, we investigated the possible association between the polymorphisms of haplotypic block in the 3' untranslated region (UTR) of GRP78 and HCC risk in a Han Chinese population., Methodology: DNA from 576 unrelated patients with HCC and 539 sex- and age-matched healthy controls was typed for rs16927997, rs1140763 and rs12009 in the GRP78 gene by TaqMan assays. Polymorphism distributions were computed by logistic regression to test the association of certain alleles, genotypes, haplotypes and diplotypes with HCC risk., Results: Linkage disequilibrium (LD) analysis identified a total of 3 haplotypes and 6 diplotypes in this region. The distributions of allelotype, genotype, haplotype and diplotype in HCC patients were not significantly different from that in controls., Conclusion: The present study suggested that polymorphisms in the 3' UTR of GRP78 were not useful diagnostic markers to predict the HCC risk.

Heme oxygenase-1 (HO-1) system catabolizes heme into three products: carbon monoxide, biliverdin/bilirubin and free iron. It is involved in many physiological and pathophysiological processes. A great deal of data has demonstrated the roles of HO-1 in the formation, growth and metastasis of tumors. The interest in this system by investigators involved in gastrointestinal tumors is fairly recent, and few papers on HO-1 have touched upon this subject. This review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal tumors studied to date. The implications for possible therapeutic manipulation of HO-1 in gastrointestinal tumors are also discussed.