Celastrol, an oral heat shock activator, ameliorates multiple animal disease models of cell death
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- 作者：Sudhish Sharma (1)
Rachana Mishra (1)
Brandon L. Walker (1)
Savitha Deshmukh (1)
Manuela Zampino (1)
Jay Patel (1)
Mani Anamalai (1)
David Simpson (1)
Ishwar S. Singh (1)
Shalesh Kaushal (2)
Sunjay Kaushal (1) - 关键词：Cardiomyopathy ; Myocardial infarct ; Heat shock response ; HSPs ; Celastrol
- 刊名：Cell Stress and Chaperones
- 出版年：2015
- 出版时间：January 2015
- 年：2015
- 卷：20
- 期：1
- 页码：185-201
- 全文大小：7,595 KB
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Rachana Mishra (1)
Brandon L. Walker (1)
Savitha Deshmukh (1)
Manuela Zampino (1)
Jay Patel (1)
Mani Anamalai (1)
David Simpson (1)
Ishwar S. Singh (1)
Shalesh Kaushal (2)
Sunjay Kaushal (1)
1. Division of Cardiac Surgery, University of Maryland Medical Center, 110 S. Paca Street, 7th Floor, Baltimore, MD, 21201, USA
2. Retina Specialty Institute, 6717 North 11th Place Suite C, Gainesville, FL, 32605, USA - ISSN：1466-1268
文摘
Protein homeostatic regulators have been shown to ameliorate single, loss-of-function protein diseases but not to treat broader animal disease models that may involve cell death. Diseases often trigger protein homeostatic instability that disrupts the delicate balance of normal cellular viability. Furthermore, protein homeostatic regulators have been delivered invasively and not with simple oral administration. Here, we report the potent homeostatic abilities of celastrol to promote cell survival, decrease inflammation, and maintain cellular homeostasis in three different disease models of apoptosis and inflammation involving hepatocytes and cardiomyocytes. We show that celastrol significantly recovers the left ventricular function and myocardial remodeling following models of acute myocardial infarction and doxorubicin-induced cardiomyopathy by diminishing infarct size, apoptosis, and inflammation. Celastrol prevents acute liver dysfunction and promotes hepatocyte survival after toxic doses of thioacetamide. Finally, we show that heat shock response (HSR) is necessary and sufficient for the recovery abilities of celastrol. Our observations may have dramatic clinical implications to ameliorate entire disease processes even after cellular injury initiation by using an orally delivered HSR activator.