Aqueous extract of Glycyrrhiza inflata inhibits aggregation by upregulating PPARGC1A and NFE2L2-ARE pathways in cell models of spinocerebellar ataxia 3.

Abstract

Spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 and dentatorubropallidoluysian atrophy, as well as Huntington disease, are a group of neurodegenerative disorders caused by a CAG triplet-repeat expansion encoding a long polyglutamine (polyQ) tract in the respective mutant proteins. The cytoplasmic and nuclear aggregate formation, a pathological hallmark of polyQ diseases, is probably the initial process triggering the subsequent pathological events. Compromised oxidative stress defense capacity and mitochondrial dysfunction have emerged as contributing factors to the pathogenesis of polyQ diseases. The roots of licorice (Glycyrrhiza species) have long been used as an herbal medicine. In this study, we demonstrate the aggregate-inhibitory effect of Glycyrrhiza inflata herb extract and its constituents licochalcone A and ammonium glycyrrhizinate (AMGZ) in both 293 and SH-SY5Y ATXN3/Q75 cells, SCA3 cell models. The reporter assay showed that G. inflata herb extract, licochalcone A, and AMGZ could enhance the promoter activity of peroxisome proliferator-activated receptor γ, coactivator 1α (PPARGC1A), a known regulator of mitochondrial biogenesis and antioxidative response genes. G. inflata extract, licochalcone A, and AMGZ upregulated PPARGC1A expression and its downstream target genes, SOD2 and CYCS, in the 293 ATXN3/Q75 cell model. The expression of nuclear factor erythroid 2-related factor 2 (NFE2L2), the principal transcription factor that binds to antioxidant-responsive elements (AREs) to promote ARE-dependent gene expression when the cells respond to oxidative stress, and its downstream genes, HMOX1, NQO1, GCLC, and GSTP1, was also increased by G. inflata herb extract, licochalcone A, and AMGZ. Knockdown of PPARGC1A increased aggregates in ATXN3/Q75 cells and also attenuated the aggregate-inhibiting effect of the tested compounds. G. inflata extract and its constituents significantly elevated GSH/GSSG ratio and reduced reactive oxidative species in ATXN3/Q75 cells. The study results suggest that the tested agents activate PPARGC1A activity and NFE2L2-ARE signaling to increase mitochondrial biogenesis, decrease oxidative stress, and reduce aggregate formation in SCA3 cellular models.

• Authors: Chiung-Mei Chen, Yu-Ting Weng, Wan-Ling Chen, Te-Hsien Lin, Chih-Ying Chao, Chih-Hsin Lin, I-Cheng Chen, Li-Ching Lee, Hsuan-Yuan Lin, Yih-Ru Wu, Yi-Chun Chen, Kuo-Hsuan Chang, Hsiang-Yu Tang, Mei-Ling Cheng, Guey-Jen Lee-Chen, Jung-Yaw Lin
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 71 Pg. 339-350 (Jun 2014) ISSN: 1873-4596 [Electronic] United States
• PMID: 24675225 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Chalcones
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• PPARGC1A protein, human
• Peptides
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Plant Extracts
• Protein Aggregates
• Transcription Factors
• Water
• polyglutamine
• Glycyrrhizic Acid
• HMOX1 protein, human
• Heme Oxygenase-1
• Superoxide Dismutase
• superoxide dismutase 2
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human
• GSTP1 protein, human
• Glutathione S-Transferase pi
• licochalcone A

Topics

• Antioxidant Response Elements
• Cell Line, Tumor
• Chalcones (pharmacology)
• Gene Expression Regulation
• Glutathione S-Transferase pi (genetics, metabolism)
• Glycyrrhiza (chemistry)
• Glycyrrhizic Acid (pharmacology)
• HEK293 Cells
• Heme Oxygenase-1 (genetics, metabolism)
• Humans
• Machado-Joseph Disease (genetics, metabolism, pathology)
• Models, Biological
• NAD(P)H Dehydrogenase (Quinone) (genetics, metabolism)
• NF-E2-Related Factor 2 (agonists, genetics, metabolism)
• Neurons
• Oxidative Stress
• Peptides (antagonists & inhibitors, chemistry, metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Plant Extracts (chemistry, isolation & purification, pharmacology)
• Plant Roots (chemistry)
• Protein Aggregates
• Signal Transduction
• Superoxide Dismutase
• Transcription Factors (agonists, genetics, metabolism)
• Water