title: 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.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Weng
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Wan-Ling
authors.initials: WL
authors.lastname: Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Te-Hsien
authors.initials: TH
authors.lastname: Lin
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Chih-Ying
authors.initials: CY
authors.lastname: Chao
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: I-Cheng
authors.initials: IC
authors.lastname: Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Lee
authors.affiliation: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 11051, Taiwan.
authors.forename: Hsuan-Yuan
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Yih-Ru
authors.initials: YR
authors.lastname: Wu
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Kuo-Hsuan
authors.initials: KH
authors.lastname: Chang
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan.
authors.forename: Hsiang-Yu
authors.initials: HY
authors.lastname: Tang
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Cheng
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan. Electronic address: t43019@ntnu.edu.tw.
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan; Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 11051, Taiwan. Electronic address: jylin@ntnu.edu.tw.
authors.forename: Jung-Yaw
authors.initials: JY
authors.lastname: Lin
mesh_terms: D061745:Antioxidant Response Elements; D045744:Cell Line, Tumor; D047188:Chalcones / Q000494:pharmacology; D005786:Gene Expression Regulation; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D006035:Glycyrrhiza / Q000737:chemistry*; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D009474:Neurons; D018384:Oxidative Stress; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D066329:Protein Aggregates; D015398:Signal Transduction; D013482:Superoxide Dismutase; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014867:Water; D000099156:Superoxide Dismutase 2
chemical_list: D047188:Chalcones; D051549:Glutathione S-Transferase pi; D019695:Glycyrrhizic Acid; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); D051267:NF-E2-Related Factor 2; D010455:Peptides; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010936:Plant Extracts; D066329:Protein Aggregates; D013482:Superoxide Dismutase; D014157:Transcription Factors; D014867:Water; D000099156:Superoxide Dismutase 2; C495635:NFE2L2 protein, human; C486497:PPARGC1A protein, human; C097188:polyglutamine; C496541:HMOX1 protein, human; C447479:NQO1 protein, human; C496556:GSTP1 protein, human; C070840:licochalcone A
keywords: ATXN3; Ammonium glycyrrhizinate; Free radicals; Glycyrrhiza inflata; Licochalcone A; Mitochondrial biogenesis; NFE2L2; Oxidative stress; PPARGC1A; Spinocerebellar ataxia