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Japanese Herbal Medicine Hochuekkito Inhibits the Expression of Proinflammatory Biomarker, Inducible Nitric Oxide Synthase, in Hepatocytes

Abstract

Miho Matsumiya, Masaki Kaibori, Yoshiro Araki, Takashi Matsuura, Masaharu Oishi, Yoshito Tanaka, Mikio Nishizawa, Tadayoshi Okumura and A-Hon Kwon

Hochuekkito (TJ-41) is used for the treatment of complaints in patients with general fatigue. However, there is little scientific evidence to demonstrate the liver-protective effects of TJ-41. In the inflamed liver, proinflammatory cytokines stimulate the induction of inducible nitric oxide synthase (iNOS). Over-production of NO by iNOS has been implicated as a factor in liver injury. We examined proinflammatory cytokine-stimulated hepatocytes as a simple in vitro injury model to determine liver-protective effects of TJ-41. The objective was to investigate whether TJ-41 influences iNOS induction and to determine its mechanism. Primary cultured rat hepatocytes were treated with interleukin (IL)-1β in the presence or absence of TJ-41. The induction of iNOS and its signaling pathway were analyzed. IL-1β produced increased levels of NO. This effect was inhibited by TJ-41, which exerted its maximal effects at 6 mg/ml. TJ-41 decreased the levels of iNOS protein and its mRNA expression. Experiments with nuclear extracts revealed that TJ- 41 inhibited the translocation of NF-κB to the nucleus and its DNA binding. TJ-41 also inhibited the activation of Akt, resulting in the reduction of type I IL-1 receptor mRNA and protein expression. Transfection experiments demonstrated that TJ-41 suppressed iNOS induction by the inhibition of promoter transactivation and mRNA stabilization. TJ-41 reduced the expression of an iNOS gene antisense-transcript, which is involved in iNOS mRNA stability. Results indicate that TJ-41 inhibits the induction of iNOS at both transcriptional and post-transcriptional steps, leading to the prevention of NO production. TJ-41 may have therapeutic potential for various liver injuries through the suppression of iNOS induction.

Avertissement: Ce résumé a été traduit à l'aide d'outils d'intelligence artificielle et n'a pas encore été examiné ni vérifié

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