{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T04:52:19Z","timestamp":1767847939716,"version":"3.49.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,5,15]],"date-time":"2017-05-15T00:00:00Z","timestamp":1494806400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,15]],"date-time":"2017-05-15T00:00:00Z","timestamp":1494806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-\u03b2<jats:sub>1<\/jats:sub> (TGF-\u03b2<jats:sub>1<\/jats:sub>) and tumor necrosis factor-\u03b1 (TNF-\u03b1) play key roles in progression of renal fibrosis, dual blockade of TGF-\u03b2<jats:sub>1<\/jats:sub> and TNF-\u03b1 is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-\u03b1 activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-\u03b1 effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-\u03b1 activity was mediated by inhibiting I\u03baB kinase phosphorylation, which attenuated the LPS\/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-\u03b2<jats:sub>1<\/jats:sub> effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-\u03b2<jats:sub>1<\/jats:sub>-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-\u03b2<jats:sub>1<\/jats:sub>-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.<\/jats:p>","DOI":"10.1038\/s41598-017-01702-7","type":"journal-article","created":{"date-parts":[[2017,5,9]],"date-time":"2017-05-09T09:38:23Z","timestamp":1494322703000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-\u03b1 and TGF-\u03b21 pathways"],"prefix":"10.1038","volume":"7","author":[{"given":"Hisato","family":"Shima","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kensuke","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takehiro","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chikahisa","family":"Mukawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ten","family":"Obara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Oba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiro","family":"Matsuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayasu","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3706-2745","authenticated-orcid":false,"given":"Eikan","family":"Mishima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shun","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasutoshi","family":"Akiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Kikuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuro","family":"Matsuhashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshitsugu","family":"Oikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumika","family":"Nanto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukako","family":"Akiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsin-Jung","family":"Ho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chitose","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Saigusa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Masamune","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihisa","family":"Tomioka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takao","family":"Masaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sadayoshi","family":"Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken-ichiro","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaaki","family":"Abe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,5,15]]},"reference":[{"key":"1702_CR1","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1056\/NEJMra1300575","volume":"372","author":"DC Rockey","year":"2015","unstructured":"Rockey, D. C., Bell, P. D. & Hill, J. A. Fibrosis\u2013a common pathway to organ injury and failure. The New England journal of medicine \n                           372, 1138\u20131149, doi:10.1056\/NEJMra1300575 (2015).","journal-title":"The New England journal of medicine"},{"key":"1702_CR2","doi-asserted-by":"publisher","first-page":"R1456","DOI":"10.1152\/ajpregu.00620.2005","volume":"292","author":"KK Meldrum","year":"2007","unstructured":"Meldrum, K. K. et al. TNF-alpha neutralization ameliorates obstruction-induced renal fibrosis and dysfunction. American journal of physiology. Regulatory, integrative and comparative physiology \n                           292, R1456\u20131464, doi:10.1152\/ajpregu.00620.2005 (2007).","journal-title":"American journal of physiology. Regulatory, integrative and comparative physiology"},{"key":"1702_CR3","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/ki.2015.51","volume":"88","author":"S Neelisetty","year":"2015","unstructured":"Neelisetty, S. et al. Renal fibrosis is not reduced by blocking transforming growth factor-beta signaling in matrix-producing interstitial cells. Kidney international \n                           88, 503\u2013514, doi:10.1038\/ki.2015.51 (2015).","journal-title":"Kidney international"},{"key":"1702_CR4","doi-asserted-by":"publisher","first-page":"3686","DOI":"10.1093\/ndt\/gfs381","volume":"27","author":"M Yanagita","year":"2012","unstructured":"Yanagita, M. Inhibitors\/antagonists of TGF-beta system in kidney fibrosis. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association \n                           27, 3686\u20133691, doi:10.1093\/ndt\/gfs381 (2012).","journal-title":"Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association"},{"key":"1702_CR5","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/nrneph.2016.48","volume":"12","author":"XM Meng","year":"2016","unstructured":"Meng, X. M., Nikolic-Paterson, D. J. & Lan, H. Y. TGF-beta: the master regulator of fibrosis. Nature reviews. Nephrology \n                           12, 325\u2013338, doi:10.1038\/nrneph.2016.48 (2016).","journal-title":"Nature reviews. Nephrology"},{"key":"1702_CR6","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1124\/jpet.114.219816","volume":"352","author":"HW Yao","year":"2015","unstructured":"Yao, H. W. & Li, J. Epigenetic modifications in fibrotic diseases: implications for pathogenesis and pharmacological targets. The Journal of pharmacology and experimental therapeutics \n                           352, 2\u201313, doi:10.1124\/jpet.114.219816 (2015).","journal-title":"The Journal of pharmacology and experimental therapeutics"},{"key":"1702_CR7","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1096\/fj.02-1134fje","volume":"17","author":"S Imagawa","year":"2003","unstructured":"Imagawa, S. et al. A GATA-specific inhibitor (K-7174) rescues anemia induced by IL-1beta, TNF-alpha, or L-NMMA. FASEB journal: official publication of the Federation of American Societies for Experimental Biology \n                           17, 1742\u20131744, doi:10.1096\/fj.02-1134fje (2003).","journal-title":"FASEB journal: official publication of the Federation of American Societies for Experimental Biology"},{"key":"1702_CR8","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1620\/tjem.236.225","volume":"236","author":"T Suzuki","year":"2015","unstructured":"Suzuki, T. et al. Mitochonic Acid 5 (MA-5), a Derivative of the Plant Hormone Indole-3-Acetic Acid, Improves Survival of Fibroblasts from Patients with Mitochondrial Diseases. The Tohoku journal of experimental medicine \n                           236, 225\u2013232, doi:10.1620\/tjem.236.225 (2015).","journal-title":"The Tohoku journal of experimental medicine"},{"key":"1702_CR9","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1681\/ASN.2015060623","volume":"27","author":"T Suzuki","year":"2016","unstructured":"Suzuki, T. et al. Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage. Journal of the American Society of Nephrology: JASN \n                           27, 1925\u20131932, doi:10.1681\/asn.2015060623 (2016).","journal-title":"Journal of the American Society of Nephrology: JASN"},{"key":"1702_CR10","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/0022-1759(84)90147-9","volume":"68","author":"DA Flick","year":"1984","unstructured":"Flick, D. A. & Gifford, G. E. Comparison of in vitro cell cytotoxic assays for tumor necrosis factor. 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Inhibition of SET Domain-Containing Lysine Methyltransferase 7\/9 Ameliorates Renal Fibrosis. Journal of the American Society of Nephrology: JASN \n                           27, 203\u2013215, doi:10.1681\/asn.2014090850 (2016).","journal-title":"Journal of the American Society of Nephrology: JASN"},{"key":"1702_CR21","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1038\/ki.2015.121","volume":"88","author":"YB Sun","year":"2015","unstructured":"Sun, Y. B. et al. Smad3 deficiency protects mice from obesity-induced podocyte injury that precedes insulin resistance. Kidney international \n                           88, 286\u2013298, doi:10.1038\/ki.2015.121 (2015).","journal-title":"Kidney international"},{"key":"1702_CR22","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.1093\/rheumatology\/keq169","volume":"49","author":"S Lloyd","year":"2010","unstructured":"Lloyd, S., Bujkiewicz, S., Wailoo, A. J., Sutton, A. J. & Scott, D. 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Molecules \n                           18, 6620\u20136662, doi:10.3390\/molecules18066620 (2013).","journal-title":"Molecules"},{"key":"1702_CR27","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1038\/90976","volume":"7","author":"K Nakada","year":"2001","unstructured":"Nakada, K. et al. Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nature medicine \n                           7, 934\u2013940, doi:10.1038\/90976 (2001).","journal-title":"Nature medicine"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01702-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01702-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01702-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T04:17:32Z","timestamp":1671769052000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01702-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,15]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["1702"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-01702-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,15]]},"assertion":[{"value":"3 January 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 April 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 May 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"1884"}}