Tarik Zahra,b,y , Vijay K. Bodac,d,y , Jian Gee,f,y , Lexiang Yua,g , Zhongzhi Wuc,d , Jianwen Quee,f,h, *, Wei Lic,d, *, Li Qianga,g, *
a Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA
b Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY 10032, USA
c Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
d Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
e Division of Digestive and Liver Diseases, Columbia University, New York, NY 10032, USA
f Center for Human Development, Columbia University, New York, NY 10027, USA
g Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
h Department of Medicine, Columbia University, New York, NY 10032, USA
*Corresponding authors.
E-mail addresses: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (Jianwen Que), 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (Wei Li), 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (Li Qiang).
These authors made equal contributions to this work.
Peer review under the responsibility of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Received 22 October 2023; received in revised form 13 December 2023; accepted 5 January 2024
KEY WORDS Estrogen receptor b; Aging; Metabolism; Skin injury; Muscle metabolism; Small molecule conjugates; Regeneration; Adiposity
Abstract
Estrogen is imperative to mammalian reproductivity, metabolism, and aging. However, the hormone activating estrogen receptor (ERs) a can cause major safety concerns due to the enrichment of ERa in female tissues and certain malignancies. In contrast, ERb is more broadly expressed in metabolic tissues and the skin. Thus, it is desirable to generate selective ERb agonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERa activation. Here, we report the design and of small molecule conjugates containing selective non-steroid ERb agonists Gtx878 or genistein. Treatment of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity, visceral adipose integrity, skeletal muscle function, and skin health, with validation in vitro. We further uncovered the benefits of ERb conjugates in the skin using two inducible skin injury mouse models, showing increased skin basal cell proliferation, epidermal thickness, and wound healing. Therefore, our ERb-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.
https://doi.org/10.1016/j.apsb.2024.01.014
2211-3835 ª 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese
Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
