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In this study, we report on reciprocal relationship between the expression of estrogen receptors (ERs) \u03b1 and \u03b2 (ER\u03b1 and ER\u03b2) and generation of ROS\/RNS in amylin\/A\u03b2<jats:sub>1\u201342<\/jats:sub>\u2010treated INS\u20101 cells. That is, pharmacological activation of ERs in INS\u20101 cells significantly decreases ROS\/RNS generation, but blockage of ERs increases ROS\/RNS generation. Silibinin is a natural polyphenolic flavonoid isolated from milk thistle with phytoestrogen activities, also known as silybin. Treatment with silibinin down\u2010regulated ROS\/RNS production induced by treatment with amylin\/A\u03b2<jats:sub>1\u201342<\/jats:sub> in the cells. Silencing ERs expression with siRNAs targeting ERs showed that the protective effect of silibinin was markedly weakened, indicating that silibinin protection is largely attributed to activation of ERs' signaling. The binding of silibinin to ERs implies that the protective effect of silibinin on amylin\/A\u03b2<jats:sub>1\u201342<\/jats:sub>\u2010treated INS\u20101 cells owes to down\u2010regulation of ROS\/RNS through the activation of ERs phosphorylation. Amylin and A\u03b2<jats:sub>1\u201342<\/jats:sub> cotreatment enhanced furthermore ROS\/RNS generation and cytotoxicity through further down\u2010regulation of ERs phosphorylation, and this was reversed by silibinin. Silibinin also protects INS\u20101 cells from amylin and A\u03b2<jats:sub>1\u201342<\/jats:sub> cotreatment. These results indicate that protective effect of silibinin is mediated by enhancement of ERs phosphorylation that depresses ROS\/RNS generation in amylin\/A\u03b2<jats:sub>1\u201342<\/jats:sub>\u2010treated INS\u20101 cells.<\/jats:p>","DOI":"10.1002\/ptr.6293","type":"journal-article","created":{"date-parts":[[2019,2,7]],"date-time":"2019-02-07T06:34:49Z","timestamp":1549521289000},"page":"998-1009","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Silibinin protects rat pancreatic \u03b2\u2010cell through up\u2010regulation of estrogen receptors' signaling against amylin\u2010 or A\u03b2<sub>1\u201342<\/sub>\u2010induced reactive oxygen species\/reactive nitrogen species generation"],"prefix":"10.1002","volume":"33","author":[{"given":"Jing","family":"Yang","sequence":"first","affiliation":[{"name":"Wuya College of Innovation Shenyang Pharmaceutical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Sun","sequence":"additional","affiliation":[{"name":"Wuya College of Innovation Shenyang Pharmaceutical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanxing","family":"Xu","sequence":"additional","affiliation":[{"name":"Wuya College of Innovation Shenyang Pharmaceutical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiwei","family":"Liu","sequence":"additional","affiliation":[{"name":"Wuya College of Innovation Shenyang Pharmaceutical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihiko","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Wuya College of Innovation Shenyang Pharmaceutical University  Shenyang China"},{"name":"Department of Chemistry and Life science, School of Advanced Engineering Kogakuin University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shunji","family":"Hattori","sequence":"additional","affiliation":[{"name":"Nippi Research Institute of Biomatrix Nippi, Incorporated  Toride Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuko","family":"Ushiki\u2010Kaku","sequence":"additional","affiliation":[{"name":"Nippi Research Institute of Biomatrix Nippi, Incorporated  Toride Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Onodera","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Sciences Showa Pharmaceutical University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin\u2010ichi","family":"Tashiro","sequence":"additional","affiliation":[{"name":"Department of Medical Education and Primary Care Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6416-8756","authenticated-orcid":false,"given":"Takashi","family":"Ikejima","sequence":"additional","affiliation":[{"name":"Wuya College of Innovation Shenyang Pharmaceutical University  Shenyang China"},{"name":"Key Laboratory of Computational Chemistry\u2010Based Natural Antitumor Drug Research &amp; 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