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Characterizing Withaferin A as a novel NRF2 inducer: implications for liver disease prevention

Palliyaguru, Dushani (2016) Characterizing Withaferin A as a novel NRF2 inducer: implications for liver disease prevention. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Intercepting the rising rates of non-communicable diseases is currently one of the most exigent public health challenges faced by all nations around the world. Prevention of these diseases using molecules that have dietary origin may be most attractive because of their safety, cost-effectiveness and feasibility of oral administration. However, the mechanism of action of such plant-based agents remains largely unknown. In recent years, the stress responsive transcription factor Nrf2, has been validated as a target for disease chemoprevention with several small molecules. Withania somnifera (WS) is a plant that has been used in Ayurveda (an ancient form of medicine in South Asia) for millennia. In the recent past, withanolides isolated from WS, such as Withaferin A (WA) have been demonstrated to be preventive and therapeutic against multiple diseases in experimental models. While scientific research performed on WS and WA has exploded in the past decade, much regarding the mode of action and molecular targets involved remain unknown. The goal of this dissertation was to determine if WA is an inducer of Nrf2 signaling and to explore whether the cytoprotective response elicited by WA resulted in prevention of liver toxicity. Here, WA has been characterized as a potent inducer of Nrf2 signaling that profoundly protects mice against acetaminophen hepatotoxicity but not against non-alcoholic fatty liver disease caused by methionine-choline deficient diet. Further, it was shown that WA pharmacologically induces Nrf2 signaling in a Keap1-independent, PI3K-dependent manner. Public health significance: the identification of an agent isolated from a medicinal plant abundantly used in traditional medicine, as a novel Nrf2 inducer provides an opportunity to expand the current repertoire of Nrf2 inducers so that culturally-appropriate chemoprevention programs can be designed to fight the global burden of non-communicable disease.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Palliyaguru, Dushanidlp46@pitt.eduDLP46
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBarchowsky, Aaronaab20@pitt.eduAAB20
Committee MemberSingh, Shivendra Vsinghs@upmc.eduSVS2
Committee MemberOpresko, Patricia Lplo4@pitt.eduPLO4
Thesis AdvisorKensler, Thomas W.tkensler@pitt.eduTKENSLER
Date: 29 June 2016
Date Type: Publication
Defense Date: 26 January 2016
Approval Date: 29 June 2016
Submission Date: 30 March 2016
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 164
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Withaferin A, Nrf2, liver toxicity, Disease prevention
Date Deposited: 29 Jun 2016 17:40
Last Modified: 01 May 2017 05:15


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