4β-Hydroxywithanolide E from Goldenberry (Whole Fruits of Physalis peruviana L.) as a Promising Agent against Chronic Obstructive Pulmonary Disease
- 11 March 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Natural Products
- Vol. 83 (4), 1217-1228
- https://doi.org/10.1021/acs.jnatprod.9b01265
Abstract
Environmental toxicant- and oxidant-induced [e.g., cigarette smoke (CS)] respiratory oxidative stress and inflammatory response play a vital role in the onset and progression of COPD. The nuclear factor erythroid 2-related factor 2 (Nrf2) represents an important mechanism for regulating intracellular oxidative stress and inflammatory response and is a promising target for developing agents against COPD. Herein, a bioactivity-guided purification of goldenberry (whole fruits of Physalis peruviana L.) led to the isolation of a novel and potent Nrf2 activator 4β-hydroxywithanolide E (4β-HWE). Our study indicated that (i) 4β-HWE activated the Nrf2-mediated defensive response through interrupting Nrf2-Keap1 protein–protein interaction (PPI) via modification of Cys151 and Cys288 cysteine residues in Keap1 and accordingly suppressing the ubiquitination of Nrf2. (ii) 4β-HWE enhanced intracellular antioxidant capacity and inhibited oxidative stress in normal human lung epithelial Beas-2B cells and wild-type AB zebrafish. (iii) 4β-HWE blocked LPS-stimulated inflammatory response and inhibited LPS-stimulated NF-κB activation in RAW 264.7 murine macrophages. (iv) 4β-HWE effectively suppressed oxidative stress and inflammatory response in a CS-induced mice model of pulmonary injury. Collectively, these results display the feasibility of using 4β-HWE to prevent or alleviate the pathological progression of COPD and suggest that 4β-HWE is a candidate or a leading molecule against COPD.Keywords
Funding Information
- National Natural Science Foundation of China (81673558, 81874341)
- Key Research and Development Program of Shandong Province (2018GSF118085)
- Multidisciplinary Research and Innovation Program of Shandong University (2020QNQT007)
- Qilu Young Scholars Program of Shandong University
This publication has 49 references indexed in Scilit:
- Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary DiseaseAmerican Journal of Respiratory and Critical Care Medicine, 2013
- Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary diseaseToxicology and Applied Pharmacology, 2011
- Crosstalk of reactive oxygen species and NF-κB signalingCell Research, 2010
- 4β-Hydroxywithanolide E from Physalis peruviana (golden berry) inhibits growth of human lung cancer cells through DNA damage, apoptosis and G2/M arrestBMC Cancer, 2010
- Targeting Nrf2 with the triterpenoid CDDO- imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in miceProceedings of the National Academy of Sciences of the United States of America, 2009
- The Antioxidant Defense System Keap1-Nrf2 Comprises a Multiple Sensing Mechanism for Responding to a Wide Range of Chemical CompoundsMolecular and Cellular Biology, 2009
- Dual roles of Nrf2 in cancerPharmacological Research, 2008
- Oridonin Confers Protection against Arsenic-Induced Toxicity through Activation of the Nrf2-Mediated Defensive ResponseEnvironmental Health Perspectives, 2008
- Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1–Cul3 interactionToxicology and Applied Pharmacology, 2008
- Inflammatory cells in the airways in COPDThorax, 2006