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Nitric Oxide. 2014 Aug 31;40:75-86. doi: 10.1016/j.niox.2014.05.007. Epub 2014 May 27.

Adenosine, a hepato-protective component in active hexose correlated compound: its identification and iNOS suppression mechanism.

Author information

1
Department of Surgery, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.
2
Applied Life Sciences, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Kyoto 606-8522, Japan.
3
Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan.
4
Department of Surgery, Kansai Medical University, Hirakata, Osaka 573-1010, Japan; Research Organization of Science and Technology, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan. Electronic address: okumura@hirakata.kmu.ac.jp.

Abstract

Supplementation of active hexose correlated compound (AHCC) improved the prognosis of postoperative hepatocellular carcinoma patients. Excess production of nitric oxide (NO) by inducible NO synthase (iNOS) is an inflammatory biomarker in liver injury. AHCC suppressed iNOS induction in hepatocytes, suggesting that AHCC has a potential liver-protective effect. However, the active component in AHCC responsible for NO suppressive activities has not been identified. The objective of this study was to identify this NO suppressive component and to investigate its mechanisms of action. AHCC was subjected to fractionation by cation exchanger, size exclusion chromatography, and normal- and reversed-phase HPLC. Aliquots of the fractions were added to primary cultured rat hepatocytes stimulated with interleukin (IL)-1β, and NO production was assayed. By activity-guided fractionation and electron spray ionization mass spectrometry analysis, adenosine was identified as one of the NO suppressive components in AHCC. Adenosine inhibited NO production, and reduced the expression of iNOS protein and mRNA. It had no effects on IκB degradation, but it inhibited NF-κB activation. Adenosine also inhibited the upregulation of type I IL-1 receptor (IL-1RI). Experiments with iNOS promoter-luciferase constructs revealed that adenosine decreased the levels of iNOS mRNA at the promoter transactivation and mRNA stabilization steps. Adenosine decreased the expression of the iNOS gene antisense transcript, which is involved in iNOS mRNA stability. Adenosine in AHCC suppressed iNOS induction by blocking NF-κB activation and the upregulation of the IL-1RI pathways, resulting in the inhibition of NO production.

KEYWORDS:

Active hexose correlated compound; Adenosine; Antisense transcript; Inducible nitric oxide synthase; Purification of nitric oxide suppressive component

PMID:
24878381
DOI:
10.1016/j.niox.2014.05.007
[Indexed for MEDLINE]

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