Browsing by Author "Suzuki, Chitose"

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    A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β1 pathways
    (SpringerNature, 2017-05-15) Shima, Hisato; Sasaki, Kensuke; Suzuki, Takehiro; Mukawa, Chikahisa; Obara, Ten; Oba, Yuki; Matsuo, Akihiro; Kobayashi, Takayasu; Mishima, Eikan; Watanabe, Shun; Akiyama, Yasutoshi; Kikuchi, Koichi; Matsuhashi, Tetsuro; Oikawa, Yoshitsugu; Nanto, Fumika; Akiyama, Yukako; Ho, Hsin-Jung; Suzuki, Chitose; Saigusa, Daisuke; Masamune, Atsushi; Tomioka, Yoshihisa; Masaki, Takao; Ito, Sadayoshi; Hayashi, Ken-ichiro; Abe, Takaaki; Department of Biology, School of Science
    Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-β1 and TNF-α is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-α activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-α effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-α activity was mediated by inhibiting IκB kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-β1 effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-β1-induced fibrotic gene expression. In unilateral ureter obstructed mouse kidney, which is a renal fibrosis model, MA-35 attenuated renal inflammation and fibrosis with the downregulation of inflammatory cytokines and fibrotic gene expressions. Furthermore, MA-35 inhibited TGF-β1-induced H3K4me1 histone modification of the fibrotic gene promoter, leading to a decrease in the fibrotic gene expression. MA-35 affects multiple signaling pathways involved in the fibrosis and may recover epigenetic modification; therefore, it could possibly be a novel therapeutic drug for fibrosis.