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32. alpha-lipoic acid prevents the induction of iNOS gene expression through destabilization of its mRNA in proinflammatory cytokine-stimulated hepatocytes.

Author

Yamada M, Kaibori M, Tanaka H, Habara K, Hijikawa T, Tanaka Y, Oishi M, Okumura T, Nishizawa M, Kwon AH, Yamada, Masanori, Kaibori, Masaki, Tanaka, Hironori, Habara, Kozo, Hijikawa, Takeshi, Tanaka, Yoshito, Oishi, Masaharu, Okumura, Tadayoshi, Nishizawa, Mikio, and Kwon, A-Hon

Abstract

Background/aims: α-Lipoic acid (α-LA) has been reported to reduce ischemia-reperfusion injury (IRI). Proinflammatory cytokines stimulate the induction of inducible nitric oxide synthase (iNOS) gene expression, leading to excess production of NO and resulting in liver injury including IRI. We hypothesized that inhibition of iNOS induction underlies the protective effects of α-LA on the liver. The objective was to investigate whether α-LA directly influences iNOS induction in cultured hepatocytes, which is used as a simple in vitro injury model, and the mechanism involved.Methods: Primary cultured rat hepatocytes were treated with interleukin (IL)-1β in the presence or absence of α-LA. The induction of iNOS and NO production and its signal were analyzed.Results: α-LA inhibited the expression of iNOS mRNA and protein dose- and time-dependently, resulting in decreases in NO production. α-LA had no effects on the degradation of IκB proteins and activation of NF-κB. In contrast, α-LA inhibited the upregulation of type I IL-1 receptor stimulated by IL-1β, although α-LA had no effect on Akt activation. Transfection experiments with iNOS promoter-luciferase constructs revealed that α-LA had no effect on the transactivation of the iNOS promoter, but decreased the stabilization of iNOS mRNA. Further, α-LA inhibited the expression of an iNOS gene antisense-transcript, which is involved in iNOS mRNA stability.Conclusions: Results indicate that α-LA inhibits the induction of iNOS gene expression at a posttranscriptional step via iNOS mRNA stabilization, rather than promoter activation. It may provide useful therapeutic effects through the suppression of iNOS induction involved in liver injury. [ABSTRACT FROM AUTHOR]

Published
2012
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38. SNP profile within the human major histocompatibility complex reveals an extreme and interrupted level of nucleotide diversity.

Author

Gaudieri, S, Dawkins, R L, Habara, K, Kulski, J K, and Gojobori, T

Abstract

The human major histocompatibility complex (MHC) is characterized by polymorphic multicopy gene families, such as HLA and MIC (PERB11); duplications; insertions and deletions (indels); and uneven rates of recombination. Polymorphisms at the antigen recognition sites of the HLA class I and II genes and at associated neutral sites have been attributed to balancing selection and a hitchhiking effect, respectively. We, and others, have previously shown that nucleotide diversity between MHC haplotypes at non-HLA sites is unusually high (>10%) and up to several times greater than elsewhere in the genome (0.08%-0.2%). We report here the most extensive analysis of nucleotide diversity within a continuous sequence in the genome. We constructed a single nucleotide polymorphism (SNP) profile that reveals a pattern of extreme but interrupted levels of nucleotide diversity by comparing a continuous sequence within haplotypes in three genomic subregions of the MHC. A comparison of several haplotypes within one of the genomic subregions containing the HLA-B and -C loci suggests that positive selection is operating over the whole subgenomic region, including HLA and non-HLA genes. [The sequence data for the multiple haplotype comparisons within the class I region have been submitted to DDBJ/EMBL/GenBank under accession nos. AF029061, AF029062, and AB031005-AB031010. Additional sequence data have been submitted to the DDBJ data library under accession nos. AB031005-AB03101 and AF029061-AF029062.]

Published
2000

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