The role of cytokine cascade in impaired liver regeneration and development of candidate pharmaceutical(s) to regulate this mechanism

细胞因子级联在肝脏再生受损中的作用以及调节该机制的候选药物的开发

• 批准号: 16590585
• 负责人: MORIWAKI Hisataka
• 金额: $ 2.18万
• 依托单位: Gifu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590585/
• 关键词: TGF-β; impaired liver regeneration; cytokine; kallikrein; protease inhibitor; TNF-α; IFN-γ; IFN-γ

We conducted a study to investigate the mechanism of impaired liver regeneration induced by lipopolysaccharide (LPS) in mouse and obtained the following results.1. LPS induces tumor necrosis factor-α(TNF-α), thereby activating plasma kallikrein. Plasma kallikrein cleaves latent transforming growth factor-β, that is produced hepatic stellate cells. Cleaved (or activated) TGF-β strongly inhibits liver regeneration.2. The receptor responsible to this process is TNFR-1 but not TNFR-2 or Fas.3. TNF-α also recruits heat shock protein (HSP) to stimulate liver fibrosis, while the mode of action by HSP is dual.4. NIK-333, a candidate pharmaceutical under clinical development, reduces the emergence of TNF-α-positive oval cells and inhibits stellate cell activation. Thus, NIK-333 seems to be a promising compound to regulate the process as described above.The role of cytokine cascade in impaired liver regeneration was elucidated in a series of experiments, and a candidate compound to regulate this mechanism was also identified.

本实验研究了脂多糖（lipopolysaccharide，LPS）诱导小鼠肝再生障碍的机制，取得了以下结果. LPS诱导肿瘤坏死因子-α（TNF-α），从而激活血浆激肽释放酶。血浆激肽释放酶裂解肝星状细胞产生的潜在转化生长因子-β。切割（或活化）的TGF-β强烈抑制肝脏再生。负责这一过程的受体是TNFR-1，而不是TNFR-2或Fas。TNF-α还可募集热休克蛋白（HSP）刺激肝纤维化，而HSP的作用方式是双重的. NIK-333是一种正在临床开发的候选药物，可减少TNF-α阳性卵圆细胞的出现并抑制星状细胞活化。因此，NIK-333似乎是一个有前途的化合物来调节上述过程。在一系列实验中阐明了细胞因子级联在受损的肝再生中的作用，并且还鉴定了调节该机制的候选化合物。

项目成果

Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid

• DOI: 10.1093/carcin/bgg090
• 发表时间: 2003-08-01
• 期刊: CARCINOGENESIS
• 影响因子: 4.7
• 作者: Matsushima-Nishiwaki, R;Okuno, M;Moriwaki, H
• 通讯作者: Moriwaki, H

Prevention of rat hepatocarcinogenesis by acyclic retinoid is accompanied by reduction in emergence of both TNF-a- expressing oval-like cells and activated hepatic stellate cells.

无环类维生素A预防大鼠肝癌的发生伴随着表达TNF-α的卵圆样细胞和活化的肝星状细胞的出现的减少。

• 发表时间: 2005
• 期刊: Nutr Cancer 51
• 作者: Sano T;Kojima S;Moriwaki H;Tanaka T;(他11名)
• 通讯作者: (他11名)

Acyclic retinoid in the chemoprevention of hepatocellular carcinoma

无环维A酸在肝细胞癌化学预防中的应用

• 发表时间: 2004
• 期刊: Int J Oncol 24
• 作者: Kojima S et al.

The ring finger protein, RNF8, interacts with retinoid X receptoraand entances its transcription- stimulating activity.

无名指蛋白 RNF8 与类视黄醇 X 受体相互作用并发挥其转录刺激活性。

• 发表时间: 2004
• 期刊: J Biol Chem 279
• 作者: Suzuki K;Fukui H;Chiba T;et al.;Takano Y
• 通讯作者: Takano Y

Acyclic retinoid, NIK-333, inhibits N-diethylnitrosamine-induced rat hepatocarcinogenesis through suppression of TGF-α

无环维甲酸 NIK-333 通过抑制 TGF-α 抑制 N-二乙基亚硝胺诱导的大鼠肝癌发生

• 发表时间: 2004
• 期刊: Carcinogenesis 25
• 作者: Kagawa M;Sano T;Ishibashi N;Okuno M;et al.
• 通讯作者: et al.