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Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes
Peroxisome proliferator-activated receptor γ (PPARγ) is recognized as a key regulator of insulin resistance. In this study, we searched for novel PPARγ agonists in a library of structurally diverse organic compounds and determined that podophyllotoxin exhibits partial agonist activity toward PPARγ....
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112511/ https://www.ncbi.nlm.nih.gov/pubmed/27853282 http://dx.doi.org/10.1038/srep37323 |
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author | Zhang, Xiangming Liu, Huijuan Sun, Bo Sun, Yan Zhong, Weilong Liu, Yanrong Chen, Shuang Ling, Honglei Zhou, Lei Jing, Xiangyan Qin, Yuan Xiao, Ting Sun, Tao Zhou, Honggang Yang, Cheng |
author_facet | Zhang, Xiangming Liu, Huijuan Sun, Bo Sun, Yan Zhong, Weilong Liu, Yanrong Chen, Shuang Ling, Honglei Zhou, Lei Jing, Xiangyan Qin, Yuan Xiao, Ting Sun, Tao Zhou, Honggang Yang, Cheng |
author_sort | Zhang, Xiangming |
collection | PubMed |
description | Peroxisome proliferator-activated receptor γ (PPARγ) is recognized as a key regulator of insulin resistance. In this study, we searched for novel PPARγ agonists in a library of structurally diverse organic compounds and determined that podophyllotoxin exhibits partial agonist activity toward PPARγ. Eight novel podophyllotoxin-like derivatives were synthesized and assayed for toxicity and functional activity toward PPARγ to reduce the possible systemic toxic effects of podophyllotoxin and to maintain partial agonist activity toward PPARγ. Cell-based transactivation assays showed that compounds (E)-3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-4-(4(trifluoromethyl)styryl)dihydrofuran-2(3H)-one (3a) and (E)-4-(3-acetylstyryl)-3-(hydroxyl (3,4,5-trimethoxyphenyl)methyl)dihydrofuran-2(3H)-one (3f) exhibited partial agonist activity. An experiment using human hepatocarcinoma cells (HepG2) that were induced to become an insulin-resistant model showed that compounds 3a and 3f improved insulin sensitivity and glucose consumption. In addition, compounds 3a and 3f significantly improved hyperglycemia and insulin resistance in high-fat diet-fed streptozotocin (HFD-STZ)-induced type 2 diabetic rats at a dose of 15 mg/kg/day administered orally for 45 days, without significant weight gain. Cell toxicity testing also showed that compounds 3a and 3f exhibited weaker toxicity than pioglitazone. These findings suggested that compounds 3a and 3f improved insulin resistance in vivo and in vitro and that the compounds exhibited potential for the treatment of type 2 diabetes mellitus. |
format | Online Article Text |
id | pubmed-5112511 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-51125112016-11-23 Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes Zhang, Xiangming Liu, Huijuan Sun, Bo Sun, Yan Zhong, Weilong Liu, Yanrong Chen, Shuang Ling, Honglei Zhou, Lei Jing, Xiangyan Qin, Yuan Xiao, Ting Sun, Tao Zhou, Honggang Yang, Cheng Sci Rep Article Peroxisome proliferator-activated receptor γ (PPARγ) is recognized as a key regulator of insulin resistance. In this study, we searched for novel PPARγ agonists in a library of structurally diverse organic compounds and determined that podophyllotoxin exhibits partial agonist activity toward PPARγ. Eight novel podophyllotoxin-like derivatives were synthesized and assayed for toxicity and functional activity toward PPARγ to reduce the possible systemic toxic effects of podophyllotoxin and to maintain partial agonist activity toward PPARγ. Cell-based transactivation assays showed that compounds (E)-3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-4-(4(trifluoromethyl)styryl)dihydrofuran-2(3H)-one (3a) and (E)-4-(3-acetylstyryl)-3-(hydroxyl (3,4,5-trimethoxyphenyl)methyl)dihydrofuran-2(3H)-one (3f) exhibited partial agonist activity. An experiment using human hepatocarcinoma cells (HepG2) that were induced to become an insulin-resistant model showed that compounds 3a and 3f improved insulin sensitivity and glucose consumption. In addition, compounds 3a and 3f significantly improved hyperglycemia and insulin resistance in high-fat diet-fed streptozotocin (HFD-STZ)-induced type 2 diabetic rats at a dose of 15 mg/kg/day administered orally for 45 days, without significant weight gain. Cell toxicity testing also showed that compounds 3a and 3f exhibited weaker toxicity than pioglitazone. These findings suggested that compounds 3a and 3f improved insulin resistance in vivo and in vitro and that the compounds exhibited potential for the treatment of type 2 diabetes mellitus. Nature Publishing Group 2016-11-17 /pmc/articles/PMC5112511/ /pubmed/27853282 http://dx.doi.org/10.1038/srep37323 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Zhang, Xiangming Liu, Huijuan Sun, Bo Sun, Yan Zhong, Weilong Liu, Yanrong Chen, Shuang Ling, Honglei Zhou, Lei Jing, Xiangyan Qin, Yuan Xiao, Ting Sun, Tao Zhou, Honggang Yang, Cheng Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes |
title | Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes |
title_full | Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes |
title_fullStr | Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes |
title_full_unstemmed | Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes |
title_short | Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes |
title_sort | novel podophyllotoxin derivatives as partial pparγ agonists and their effects on insulin resistance and type 2 diabetes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112511/ https://www.ncbi.nlm.nih.gov/pubmed/27853282 http://dx.doi.org/10.1038/srep37323 |
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