{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T04:50:17Z","timestamp":1783486217482,"version":"3.55.0"},"reference-count":50,"publisher":"The Endocrine Society","issue":"8","license":[{"start":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T00:00:00Z","timestamp":1655078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"JSPS KAKENHI","award":["19K18006"],"award-info":[{"award-number":["19K18006"]}]},{"DOI":"10.13039\/100008695","name":"Japan Foundation for Applied Enzymology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008695","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Regulatory mechanisms of iodothyronine deiodinases (DIOs) require further elucidation, and conventional methods for evaluating DIOs are unsuitable for high-throughput screening (HTS). Here we explored factors of transcriptional regulation of 3 types of DIOs (DIO1, DIO2, and DIO3) from a chemical library using our designed HTS. We constructed HTS based on a promoter assay and performed a screen of 2480 bioactive compounds. For compounds that were clinically approved, we validated hit compounds through a retrospective cohort study in our department that evaluated changes in thyroid function in patients using the compounds as drug therapy. Furthermore, we verified the involvement of DIOs using mice treated with the compounds. Of the hit compounds, 6 and 7 compounds transcriptionally up- and downregulated DIO1, respectively; 34 transcriptionally upregulated DIO2; and 5 and 2 compounds transcriptionally up- and downregulated DIO3, respectively. The cohort study clarified the clinical effects of some hit compounds: ritodrine increased free triiodothyronine (fT3)\/free thyroxine (fT4) ratio and decreased serum thyroid-stimulating hormone (TSH) levels, tadalafil increased serum fT3 levels, and tyrosine kinase inhibitors (TKIs) decreased serum fT3 and fT4 levels and increased serum TSH levels. Following in vivo experiments using treated mice, consistent results were observed in ritodrine, which upregulated DIO2 in the thyroid gland. In conclusion, we completed HTS for DIOs and obtained attractive hit compounds. Our cohort study revealed the clinical significance of ritodrine, sildenafil, and TKIs. We hope our unique method will contribute to analyzing various targets and lists of hit compounds will promote understanding of DIOs.<\/jats:p>","DOI":"10.1210\/endocr\/bqac090","type":"journal-article","created":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T14:06:35Z","timestamp":1655129195000},"source":"Crossref","is-referenced-by-count":12,"title":["High-throughput Screening in Combination With a Cohort Study for Iodothyronine Deiodinases"],"prefix":"10.1210","volume":"163","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4236-502X","authenticated-orcid":false,"given":"Ichiro","family":"Yamauchi","sequence":"first","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoriko","family":"Sakane","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto , Japan"},{"name":"Sugawa Clinic , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Okuno","sequence":"additional","affiliation":[{"name":"Medical Research Support Center, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Sugawa","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuro","family":"Hakata","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Kyoto 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