Effect of Active Hexose Correlated Compound on the Production of Nitric Oxide in Hepatocytes

Abstract

Background: Active hexose correlated compound (AHCC) is a“ complex compound” containing polysaccharides. AHCC has been reported to improve the prognosis of postoperative hepatocellular carcinoma patients. However, the molecular mechanism of this improvement is not fully understood. In the diseased liver, nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) is considered to be a causal factor for various hepatopathies. In this study, the possibility of AHCC regulation of NO production by iNOS was pursued as a potential liver-protecting mechanism. Methods: Primary cultured rat hepatocytes were treated with interleukin-1β (IL-1β) in the presence or absence of AHCC. NO production, iNOS induction, and iNOS signal were analyzed. Results: IL-1β stimulated iNOS induction through the activation of nuclear factorκ B (NFκB), leading to NO production. The addition of AHCC inhibited NO production, showing >80% inhibition at 8 mg/mL. AHCC also decreased the levels of iNOS protein and mRNA. However, AHCC influenced neither the degradation of inhibitory protein κB (IκB) nor the activation of NFκB stimulated by IL-1β. Transfection experiments with an iNOS promoter-luciferase construct (iNOS-Luc) revealed that AHCC had no effect on the transactivation activity of the iNOS promoter. By contrast, AHCC inhibited the activity of iNOS-Luc containing a 3′untranslated region (UTR) with adenosine and uridine (AU)–rich elements, which shows the stabilizing activity of iNOS mRNA. Conclusions: Results indicated that AHCC inhibits the induction of iNOS at the level of transcription, causing a decrease in NO production in hepatocytes. AHCC seems to decrease the levels of iNOS mRNA by reducing mRNA stabilization rather than inhibiting its synthesis.

It is possible that the inhibitory effect of active hexose correlated compound (AHCC) on the production of nitric oxide through the inhibition of inducible nitric oxide synthase induction is associated with AHCC-induced protection against liver failure.

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