Protein homeostatic regulators have been shown toameliorate single, loss-of-function protein diseases but not totreat broader animal disease models that may involve celldeath. Diseases often trigger protein homeostatic instabilitythat 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 cel-lular homeostasis in three different disease models of apopto-sis and inflammation involving hepatocytes andcardiomyocytes. We show that celastrol significantly recoversthe left ventricular function and myocardial remodeling fol-lowing models of acute myocardial infarction anddoxorubicin-induced cardiomyopathy by diminishing infarctsize, apoptosis, and inflammation. Celastrol prevents acuteliver dysfunction and promotes hepatocyte survival after toxicdoses of thioacetamide. Finally, we show that heat shockresponse (HSR) is necessary and sufficient for the recoveryabilities of celastrol. Our observations may have dramaticclinical implications to ameliorate entire disease processeseven after cellular injury initiation by using an orally deliveredHSR activator.

Sudhish Sharma&Rachana Mishra&Brandon L. Walker&Savitha Deshmukh&Manuela Zampino&Jay Patel&Mani Anamalai&David Simpson&Ishwar S. Singh&Shalesh Kaushal&Sunjay Kaushal

Received: 5 June 2014 /Revised: 5 August 2014 /Accepted: 8 August 2014 /Published online: 11 October 2014#Cell Stress Society International 2014