Dataset Information

A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-? and TGF-?₁ pathways.

ABSTRACT: Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-?₁ (TGF-?₁) and tumor necrosis factor-? (TNF-?) play key roles in progression of renal fibrosis, dual blockade of TGF-?₁ and TNF-? is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-? activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-? effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-? activity was mediated by inhibiting I?B kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-?₁ effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-?₁-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-?₁-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.

SUBMITTER: Shima H

PROVIDER: S-EPMC5432497 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β1 pathways.

Shima Hisato H Sasaki Kensuke K Suzuki Takehiro T Mukawa Chikahisa C Obara Ten T Oba Yuki Y Matsuo Akihiro A Kobayashi Takayasu T Mishima Eikan E Watanabe Shun S Akiyama Yasutoshi Y Kikuchi Koichi K Matsuhashi Tetsuro T Oikawa Yoshitsugu Y Nanto Fumika F Akiyama Yukako Y Ho Hsin-Jung HJ Suzuki Chitose C Saigusa Daisuke D Masamune Atsushi A Tomioka Yoshihisa Y Masaki Takao T Ito Sadayoshi S Hayashi Ken-Ichiro KI Abe Takaaki T

Scientific reports 20170515 1

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 deriva ...[more]

PMID: 28507324

Similar Datasets

Project description:Ma Xing Shi Gan Decoction (MXD), a classical traditional Chinese medicine prescription, is widely used for the treatment of upper respiratory tract infection. However, the effect of MXD against particulate matters with diameter of less than 2.5 ?m (PM2.5) induced lung injury remains to be elucidated. In this study, rats were stimulated with PM2.5 to induce lung injury. MXD was given orally once daily for five days. Lung tissues were harvested to assess pathological changes and edema. Myeloperoxidase (MPO) activity and malonaldehyde (MDA) content in lung were determined to evaluate the degree of injury. To assess the barrier disruption, the bronchoalveolar lavage fluid (BALF) was collected to determine the total protein content and count the number of neutrophils and macrophages. For evaluating the activation of macrophage in lung tissue, CD68 was detected using immunohistochemistry (IHC). The levels of inflammatory factors including tumor necrosis factor-alpha (TNF-?), interleukin-1beta (IL-1?), and interleukin-6 (IL-6) in BALF and serum were measured. In vitro, a PM2.5-activated RAW 264.7 macrophages inflammatory model was introduced. To evaluate the protective effect of MXD-medicated serum, the cell viability and the release of inflammatory factors were measured. The effects of MXD on the High mobility group box-1/Toll-like receptor 4/Nuclear factor-kappa B (HMGB1/TLR4/NF?B) pathway in lung tissue and RAW 264.7 cells were assessed by Western blot. For further confirming the protective effect of MXD was mediated by inhibiting the HMGB1/TLR4/NF?B pathway, RAW 264.7 cells were incubated with MXD-medicated serum alone or MXD-medicated serum plus recombinant HMGB1 (rHMGB1). MXD significantly ameliorated the lung injury in rats, as evidenced by decreases in the pathological score, lung edema, MPO activity, MDA content, CD68 positive macrophages number, disruption of alveolar capillary barrier and the levels of inflammatory factors. In vitro, MXD-medicated serum increased cell viability and inhibited the release of inflammatory cytokines. Furthermore, MXD treatment was found to inhibit HMGB1/TLR4/NF?B signal pathway both in vivo and in vitro. Moreover, the protection of MXD could be reversed by rHMGB1 in RAW 264.7. Taken together, these results suggest MXD protects rats from PM2.5 induced acute lung injury, possibly through the modulation of HMGB1/TLR4/NF?B pathway and inflammatory responses.

Dataset Information

A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-? and TGF-?₁ pathways.

Publications

A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β<sub>1</sub> pathways.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-? and TGF-?1 pathways.

Publications

A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β<sub>1</sub> pathways.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-? and TGF-?₁ pathways.