Withaferin A induces Nrf2-dependent protection against liver injury: Role of Keap1-independent mechanisms.

Details

Serval ID
serval:BIB_746390FB4DC0
Type
Article: article from journal or magazin.
Collection
Publications
Title
Withaferin A induces Nrf2-dependent protection against liver injury: Role of Keap1-independent mechanisms.
Journal
Free radical biology & medicine
Author(s)
Palliyaguru D.L., Chartoumpekis D.V., Wakabayashi N., Skoko J.J., Yagishita Y., Singh S.V., Kensler T.W.
ISSN
1873-4596 (Electronic)
ISSN-L
0891-5849
Publication state
Published
Issued date
12/2016
Peer-reviewed
Oui
Volume
101
Pages
116-128
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural
Publication Status: ppublish
Abstract
Small molecules of plant origin offer presumptively safe opportunities to prevent carcinogenesis, mutagenesis and other forms of toxicity in humans. However, the mechanisms of action of such plant-based agents remain largely unknown. In recent years the stress responsive transcription factor Nrf2 has been validated as a target for disease chemoprevention. Withania somnifera (WS) is a herb used in Ayurveda (an ancient form of medicine in South Asia). 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. The goals of this study are to evaluate withanolides such as WA as well as Withania somnifera root extract as inducers of Nrf2 signaling, to probe the underlying signaling mechanism of WA and to determine whether prevention of acetaminophen (APAP)-induced hepatic toxicity in mice by WA occurs in an Nrf2-dependent manner. We observed that WA profoundly protects wild-type mice but not Nrf2-disrupted mice against APAP hepatotoxicity. WA is a potent inducer of Nrf2-dependent cytoprotective enzyme expression both in vivo and in vitro. Unexpectedly, WA induces Nrf2 signaling at least in part, in a Keap1-independent, Pten/Pi3k/Akt-dependent manner in comparison to prototypical Nrf2 inducers, sulforaphane and CDDO-Im. The identification of WA as an Nrf2 inducer that can signal through a non-canonical, Keap1-independent pathway provides an opportunity to evaluate the role of other regulatory partners of Nrf2 in the dietary and pharmacological induction of Nrf2-mediated cytoprotection.
Keywords
Acetaminophen/antagonists & inhibitors, Acetaminophen/toxicity, Animals, Chemical and Drug Induced Liver Injury/genetics, Chemical and Drug Induced Liver Injury/metabolism, Chemical and Drug Induced Liver Injury/pathology, Chemical and Drug Induced Liver Injury/prevention & control, Cytotoxins/antagonists & inhibitors, Cytotoxins/toxicity, Fibroblasts/cytology, Fibroblasts/drug effects, Fibroblasts/metabolism, Gene Expression Regulation, Kelch-Like ECH-Associated Protein 1/genetics, Kelch-Like ECH-Associated Protein 1/metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 2/deficiency, NF-E2-Related Factor 2/genetics, PTEN Phosphohydrolase/genetics, PTEN Phosphohydrolase/metabolism, Phosphatidylinositol 3-Kinases/genetics, Phosphatidylinositol 3-Kinases/metabolism, Plant Roots/chemistry, Primary Cell Culture, Protective Agents/isolation & purification, Protective Agents/pharmacology, Proto-Oncogene Proteins c-akt/genetics, Proto-Oncogene Proteins c-akt/metabolism, Signal Transduction, Withania/chemistry, Withanolides/isolation & purification, Withanolides/pharmacology, Hepatotoxicity, Nrf2, Pten, Stress response, Withaferin A
Pubmed
Web of science
Create date
03/09/2023 20:25
Last modification date
23/09/2023 6:55
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