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Tang MB, Liu YX, Hu ZW, Luo HY, Zhang S, Shi CH, Xu YM. Study insights in the role of PGC-1α in neurological diseases: mechanisms and therapeutic potential. Front Aging Neurosci 2025; 16:1454735. [PMID: 40012862 PMCID: PMC11861300 DOI: 10.3389/fnagi.2024.1454735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 12/30/2024] [Indexed: 02/28/2025] Open
Abstract
Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which is highly expressed in the central nervous system, is known to be involved in the regulation of mitochondrial biosynthesis, metabolic regulation, neuroinflammation, autophagy, and oxidative stress. This knowledge indicates a potential role of PGC-1α in a wide range of functions associated with neurological diseases. There is emerging evidence indicating a protective role of PGC-1α in the pathogenesis of several neurological diseases. As such, a deeper and broader understanding of PGC-1α and its role in neurological diseases is urgently needed. The present review provides a relatively complete overview of the current knowledge on PGC-1α, including its functions in different types of neurons, basic structural characteristics, and its interacting transcription factors. Furthermore, we present the role of PGC-1α in the pathogenesis of various neurological diseases, such as intracerebral hemorrhage, ischemic stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and other PolyQ diseases. Importantly, we discuss some compounds or drug-targeting strategies that have been studied to ameliorate the pathology of these neurological diseases and introduce the possible mechanistic pathways. Based on the available studies, we propose that targeting PGC-1α could serve as a promising novel therapeutic strategy for one or more neurological diseases.
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Affiliation(s)
- Mi-bo Tang
- Department of Geriatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yi-xuan Liu
- Department of Geriatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Zheng-wei Hu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Hai-yang Luo
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shuo Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Chang-he Shi
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yu-ming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Diseases, Zhengzhou, Henan, China
- Henan Key Laboratory of Cerebrovascular Diseases, Zhengzhou University, Zhengzhou, Henan, China
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Lin TK, Huang CR, Lin KJ, Hsieh YH, Chen SD, Lin YC, Chao AC, Yang DI. Potential Roles of Hypoxia-Inducible Factor-1 in Alzheimer's Disease: Beneficial or Detrimental? Antioxidants (Basel) 2024; 13:1378. [PMID: 39594520 PMCID: PMC11591038 DOI: 10.3390/antiox13111378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
The major pathological characteristics of Alzheimer's disease (AD) include senile plaques and neurofibrillary tangles (NFTs), which are mainly composed of aggregated amyloid-beta (Aβ) peptide and hyperphosphorylated tau protein, respectively. The excessive production of reactive oxygen species (ROS) and neuroinflammation are crucial contributing factors to the pathological mechanisms of AD. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor critical for tissue adaption to low-oxygen tension. Growing evidence has suggested HIF-1 as a potential therapeutic target for AD; conversely, other experimental findings indicate that HIF-1 induction contributes to AD pathogenesis. These previous findings thus point to the complex, even contradictory, roles of HIF-1 in AD. In this review, we first introduce the general pathogenic mechanisms of AD as well as the potential pathophysiological roles of HIF-1 in cancer, immunity, and oxidative stress. Based on current experimental evidence in the literature, we then discuss the possible beneficial as well as detrimental mechanisms of HIF-1 in AD; these sections also include the summaries of multiple chemical reagents and proteins that have been shown to exert beneficial effects in AD via either the induction or inhibition of HIF-1.
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Affiliation(s)
- Tsu-Kung Lin
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833401, Taiwan; (T.-K.L.); (C.-R.H.); (S.-D.C.)
- College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
| | - Chi-Ren Huang
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833401, Taiwan; (T.-K.L.); (C.-R.H.); (S.-D.C.)
- College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
| | - Kai-Jung Lin
- Department of Family Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan;
| | - Yi-Heng Hsieh
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
| | - Shang-Der Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833401, Taiwan; (T.-K.L.); (C.-R.H.); (S.-D.C.)
| | - Yi-Chun Lin
- Department of Neurology, Taipei City Hospital Renai Branch, Taipei 106243, Taiwan;
| | - A-Ching Chao
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan
- Department of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Department of Sports Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Ding-I Yang
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
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Zeng Y, Guo M, Wu Q, Tan X, Jiang C, Teng F, Chen J, Zhang F, Ma X, Li X, Gu J, Huang W, Zhang C, Yuen-Kwan Law B, Long Y, Xu Y. Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1. J Adv Res 2024:S2090-1232(24)00361-8. [PMID: 39147198 DOI: 10.1016/j.jare.2024.08.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 07/15/2024] [Accepted: 08/12/2024] [Indexed: 08/17/2024] Open
Abstract
INTRODUCTION Gut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one and how specific gut-derived metabolites affect the progression of DKD remain largely unknown. OBJECTIVES This study aimed to investigate the potential roles of indole-3-propionic acid (IPA), a microbial metabolite of tryptophan, in DKD. METHODS Metagenomic sequencing was performed to analyze the microbiome structure in DKD. Metabolomics screening and validation were conducted to identify characteristic metabolites associated with DKD. The protective effect of IPA on DKD glomerular endothelial cells (GECs) was assessed through in vivo and in vitro experiments. Further validation via western blot, immunoprecipitation, gene knockout, and site-directed mutation elucidated the mechanism of IPA on mitochondrial injury. RESULTS Alterations in gut microbial community structure and dysregulated tryptophan metabolism were evident in DKD mice. Serum IPA levels were significantly reduced in DKD patients and correlated with fasting blood glucose, HbA1c, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). IPA supplementation ameliorated albuminuria, bolstered the integrity of the glomerular filtration barrier, and mitigated mitochondrial impairments in GECs. Mechanistically, IPA hindered SIRT1 phosphorylation-mediated ubiquitin-proteasome degradation, restoring SIRT1's role in promoting PGC-1α deacetylation and nuclear translocation, thereby upregulating genes associated with mitochondrial biosynthesis and antioxidant defense. CONCLUSION Our findings underscore the potential of the microbial metabolite IPA to attenuate DKD progression, offering novel insights and potential therapeutic strategies for its management.
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Affiliation(s)
- Yan Zeng
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China
| | - Man Guo
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China
| | - Qi Wu
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China; Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Xiaozhen Tan
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China; Experimental Medicine Center, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Chunxia Jiang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China
| | - Fangyuan Teng
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China; Experimental Medicine Center, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Jiao Chen
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China
| | - Fanjie Zhang
- Department of Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Xiumei Ma
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610000, Sichuan, China
| | - Xinyue Li
- Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu 610000, Sichuan, China
| | - Junling Gu
- Department of Endocrinology, Yibin Second People's Hospital-West China Yibin Hospital, Sichuan University, Yibin 644000, Sichuan, China
| | - Wei Huang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China
| | - Chunxiang Zhang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Betty Yuen-Kwan Law
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China.
| | - Yang Long
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China; Experimental Medicine Center, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
| | - Yong Xu
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou 646000, Sichuan, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, Sichuan, China.
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Feng X, Zheng Y, Mao N, Shen M, Chu L, Fang Y, Pang M, Wang Z, Lin Z. Menaquinone-4 alleviates hypoxic-ischemic brain damage in neonatal rats by reducing mitochondrial dysfunction via Sirt1-PGC-1α-TFAM signaling pathway. Int Immunopharmacol 2024; 134:112257. [PMID: 38759366 DOI: 10.1016/j.intimp.2024.112257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/01/2024] [Accepted: 05/10/2024] [Indexed: 05/19/2024]
Abstract
BACKGROUND Hypoxic-ischemic encephalopathy (HIE) is a major contributor to neonatal mortality and neurodevelopmental disorders, but currently there is no effective therapy drug for HIE. Mitochondrial dysfunction plays a pivotal role in hypoxic-ischemic brain damage(HIBD). Menaquinone-4 (MK-4), a subtype of vitamin K2 prevalent in the brain, has been shown to enhance mitochondrial function and exhibit protective effects against ischemia-reperfusion injury. However, the impact and underlying molecular mechanism of MK-4 in HIE have not been fully elucidated. METHODS In this study, we established the neonatal rats HIBD model in vivo and oxygen-glucose deprivation and reperfusion (OGD/R) of primary neurons in vitro to explore the neuroprotective effects of MK-4 on HI damage, and illuminate the potential mechanism. RESULTS Our findings revealed that MK-4 ameliorated mitochondrial dysfunction, reduced oxidative stress, and prevented HI-induced neuronal apoptosis by activating the Sirt1-PGC-1α-TFAM signaling pathway through Sirt1 mediation. Importantly, these protective effects were partially reversed by EX-527, a Sirt1 inhibitor. CONCLUSION Our study elucidated the potential therapeutic mechanism of MK-4 in neonatal HIE, suggesting its viability as an agent for enhancing recovery from HI-induced cerebral damage in newborns. Further exploration into MK-4 could lead to novel interventions for HIE therapy.
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Affiliation(s)
- Xiaoli Feng
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China
| | - Yihui Zheng
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China
| | - Niping Mao
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China
| | - Ming Shen
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China
| | - Liuxi Chu
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Affiliated Cixi Hospital, Wenzhou Medical University, Cixi, Zhejiang 315300, China
| | - Yu Fang
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China
| | - Mengdan Pang
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China
| | - Zhouguang Wang
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Zhenlang Lin
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang 325027, China.
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Guo K, Lu Y. Acupuncture modulates the AMPK/PGC-1 signaling pathway to facilitate mitochondrial biogenesis and neural recovery in ischemic stroke rats. Front Mol Neurosci 2024; 17:1388759. [PMID: 38813438 PMCID: PMC11133568 DOI: 10.3389/fnmol.2024.1388759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 04/30/2024] [Indexed: 05/31/2024] Open
Abstract
Aims The main objective of this study was to investigate the role and mechanism of acupuncture on anti-nerve injury in the acute phase by regulating mitochondrial energy metabolism via monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) axis in rat ischemic stroke. Main methods Middle cerebral artery occlusion (MCAO) was established by middle cerebral artery occlusion/reperfusion. One-week of acupuncture was performed during the acute phase of ischemic stroke. The neurological function and brain tissue integrity were evaluated. Mitochondrial function (intracellular ATP level and the activity of mitochondrial respiratory chain complex I) and the level of NADH oxidase (NOX) were detected by enzymatic chemistry. Next, the potential molecular mechanisms were explored by western blotting, fluorescence quantitative PCR and immunohistochemistry method. Key findings (1) Acupuncture treatment for MCAO/R rats showed a significant improvement in the infarcted tissue accompanied by functional recovery in Zea-Longa score and balance beam score outcomes, motor function performances. (2) Acupuncture increased the levels of ATP and mitochondrial respiratory chain complex I, decreased the NOX levels in cerebral ischemia established by suture-occluded method. (3) Acupuncture reduced the necrosis dissolution of neuronal cells and meningeal edema, while promoting angiogenesis. (4) Quantitative immunohistochemical staining results showed acupuncture can increase the expression of AMPK, p-AMPK and the mitochondrial transcription factor PGC-1α, NRF2, TFAM and uncoupling protein 2 (UCP2). Meanwhile, acupuncture treatment up-regulated the expression of the corresponding protein. (5) Subsequently, acupuncture enhanced AMPK phosphorylation as well as the expression of PGC-1α, NRF2, TFAM and UCP2, implicated in mitochondrial synthesis and cellular apoptosis. (6) Finally, injections of AMPK antagonists and activators confirmed AMPK as a therapeutic target for the anti-nerve damage effects of acupuncture. Significance Acupuncture intervention relieved ischemic stroke progression in MCAO rats by promoting energy metabolism and mitochondrial biogenesis in the brain and alleviating neuronal apoptosis, which was mediated by eliciting AMPK/PGC-1α axis, among them AMPK is a therapeutic target.
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Affiliation(s)
| | - Yan Lu
- Department of Acupuncture, Shandong University of Traditional Chinese Medicine, Jinan, China
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Narne P, Phanithi PB. Role of NAD + and FAD in Ischemic Stroke Pathophysiology: An Epigenetic Nexus and Expanding Therapeutic Repertoire. Cell Mol Neurobiol 2023; 43:1719-1768. [PMID: 36180651 PMCID: PMC11412205 DOI: 10.1007/s10571-022-01287-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 09/15/2022] [Indexed: 11/03/2022]
Abstract
The redox coenzymes viz., oxidized β-nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD) by way of generation of optimal reducing power and cellular energy currency (ATP), control a staggering array of metabolic reactions. The prominent cellular contenders for NAD+ utilization, inter alia, are sirtuins (SIRTs) and poly(ADP-ribose) polymerase (PARP-1), which have been significantly implicated in ischemic stroke (IS) pathogenesis. NAD+ and FAD are also two crucial epigenetic enzyme-required metabolites mediating histone deacetylation and poly(ADP-ribosyl)ation through SIRTs and PARP-1 respectively, and demethylation through FAD-mediated lysine specific demethylase activity. These enzymes and post-translational modifications impinge on the components of neurovascular unit, primarily neurons, and elicit diverse functional upshots in an ischemic brain. These could be circumstantially linked with attendant cognitive deficits and behavioral outcomes in post-stroke epoch. Parsing out the contribution of NAD+/FAD-synthesizing and utilizing enzymes towards epigenetic remodeling in IS setting, together with their cognitive and behavioral associations, combined with possible therapeutic implications will form the crux of this review.
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Affiliation(s)
- Parimala Narne
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana State, 500046, India.
| | - Prakash Babu Phanithi
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana State, 500046, India.
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Ryan F, Khoshnam SE, Khodagholi F, Ashabi G, Ahmadiani A. How cytosolic compartments play safeguard functions against neuroinflammation and cell death in cerebral ischemia. Metab Brain Dis 2021; 36:1445-1467. [PMID: 34173922 DOI: 10.1007/s11011-021-00770-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 06/06/2021] [Indexed: 11/26/2022]
Abstract
Ischemic stroke is the second leading cause of mortality and disability globally. Neuronal damage following ischemic stroke is rapid and irreversible, and eventually results in neuronal death. In addition to activation of cell death signaling, neuroinflammation is also considered as another pathogenesis that can occur within hours after cerebral ischemia. Under physiological conditions, subcellular organelles play a substantial role in neuronal functionality and viability. However, their functions can be remarkably perturbed under neurological disorders, particularly cerebral ischemia. Therefore, their biochemical and structural response has a determining role in the sequel of neuronal cells and the progression of disease. However, their effects on cell death and neuroinflammation, as major underlying mechanisms of ischemic stroke, are still not understood. This review aims to provide a comprehensive overview of the contribution of each organelle on these pathological processes after ischemic stroke.
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Affiliation(s)
- Fari Ryan
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Centre, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghorbangol Ashabi
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, PO Box: 1417613151, Tehran, Iran.
| | - Abolhassan Ahmadiani
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Huang JB, Hsu SP, Pan HY, Chen SD, Chen SF, Lin TK, Liu XP, Li JH, Chen NC, Liou CW, Hsu CY, Chuang HY, Chuang YC. Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activates Vascular Endothelial Growth Factor That Protects Against Neuronal Cell Death Following Status Epilepticus through PI3K/AKT and MEK/ERK Signaling. Int J Mol Sci 2020; 21:ijms21197247. [PMID: 33008083 PMCID: PMC7583914 DOI: 10.3390/ijms21197247] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 09/25/2020] [Accepted: 09/28/2020] [Indexed: 12/13/2022] Open
Abstract
Status epilepticus may cause molecular and cellular events, leading to hippocampal neuronal cell death. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) is an important regulator of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2), also known as fetal liver kinase receptor 1 (Flk-1). Resveratrol is an activator of PGC-1α. It has been suggested to provide neuroprotective effects in epilepsy, stroke, and neurodegenerative diseases. In the present study, we used microinjection of kainic acid into the left hippocampal CA3 region in Sprague Dawley rats to induce bilateral prolonged seizure activity. Upregulating the PGC-1α pathway will increase VEGF/VEGFR2 (Flk-1) signaling and further activate some survival signaling that includes the mitogen activated protein kinase kinase (MEK)/mitogen activated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways and offer neuroprotection as a consequence of apoptosis in the hippocampal neurons following status epilepticus. Otherwise, downregulation of PGC-1α by siRNA against pgc-1α will inhibit VEGF/VEGFR2 (Flk-1) signaling and suppress pro-survival PI3K/AKT and MEK/ERK pathways that are also accompanied by hippocampal CA3 neuronal cell apoptosis. These results may indicate that the PGC-1α induced VEGF/VEGFR2 pathway may trigger the neuronal survival signaling, and the PI3K/AKT and MEK/ERK signaling pathways. Thus, the axis of PGC-1α/VEGF/VEGFR2 (Flk-1) and the triggering of downstream PI3K/AKT and MEK/ERK signaling could be considered an endogenous neuroprotective effect against apoptosis in the hippocampus following status epilepticus.
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Affiliation(s)
- Jyun-Bin Huang
- Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (J.-B.H.); (H.-Y.P.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-D.C.); (S.-F.C.); (T.-K.L.); (N.-C.C.); (C.-W.L.)
| | - Shih-Pin Hsu
- Department of Neurology, E-Da Hospital/School of Medicine, I-Shou University, Kaohsiung 824, Taiwan;
| | - Hsiu-Yung Pan
- Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (J.-B.H.); (H.-Y.P.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-D.C.); (S.-F.C.); (T.-K.L.); (N.-C.C.); (C.-W.L.)
| | - Shang-Der Chen
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-D.C.); (S.-F.C.); (T.-K.L.); (N.-C.C.); (C.-W.L.)
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.)
| | - Shu-Fang Chen
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-D.C.); (S.-F.C.); (T.-K.L.); (N.-C.C.); (C.-W.L.)
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Tsu-Kung Lin
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-D.C.); (S.-F.C.); (T.-K.L.); (N.-C.C.); (C.-W.L.)
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Xuan-Ping Liu
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.)
| | - Jie-Hau Li
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.)
| | - Nai-Ching Chen
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-D.C.); (S.-F.C.); (T.-K.L.); (N.-C.C.); (C.-W.L.)
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Chia-Wei Liou
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-D.C.); (S.-F.C.); (T.-K.L.); (N.-C.C.); (C.-W.L.)
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Chung-Yao Hsu
- Department of Neurology, School of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Hung-Yi Chuang
- Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital and School of Public Health, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Yao-Chung Chuang
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-D.C.); (S.-F.C.); (T.-K.L.); (N.-C.C.); (C.-W.L.)
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.)
- Department of Neurology, School of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Biological Science, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
- Correspondence:
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9
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Lu M, Guo J, Wu B, Zhou Y, Wu M, Farzaneh M, Khoshnam SE. Mesenchymal Stem Cell-Mediated Mitochondrial Transfer: a Therapeutic Approach for Ischemic Stroke. Transl Stroke Res 2020; 12:212-229. [PMID: 32975692 DOI: 10.1007/s12975-020-00853-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 09/14/2020] [Accepted: 09/16/2020] [Indexed: 12/17/2022]
Abstract
Stroke is the leading cause of death and adult disability worldwide. Mitochondrial dysfunction is one of the hallmarks of stroke-induced neuronal death, and maintaining mitochondrial function is essential in cell survival and neurological progress following ischemic stroke. Stem cell-mediated mitochondrial transfer represents an emerging therapeutic approach for ischemic stroke. Accumulating evidence suggests that mesenchymal stem cells (MSCs) can directly transfer healthy mitochondria to damaged cells, and rescue mitochondrial damage-provoked tissue degeneration. This review summarizes the research on MSCs-mediated mitochondrial transfer as a therapeutic strategy against ischemic stroke.
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Affiliation(s)
- Meng Lu
- Academy of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, China.,Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang, 050091, China.,Department of Formulaology, Basic Medicine College, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Jindong Guo
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang, 050091, China.,Department of Formulaology, Basic Medicine College, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Bowen Wu
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang, 050091, China.,Department of Biochemistry, Basic Medicine College, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Yuhui Zhou
- Academy of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, China.,Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang, 050091, China.,Department of Formulaology, Basic Medicine College, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Mishan Wu
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang, 050091, China. .,Department of Formulaology, Basic Medicine College, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
| | - Maryam Farzaneh
- Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Esmaeil Khoshnam
- Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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10
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PGC-1 α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1452696. [PMID: 32215168 PMCID: PMC7085407 DOI: 10.1155/2020/1452696] [Citation(s) in RCA: 385] [Impact Index Per Article: 77.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 02/20/2020] [Indexed: 02/07/2023]
Abstract
Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is a transcriptional coactivator described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species detoxification. PGC-1α is highly expressed in tissues with high energy demands, and it is clearly associated with the pathogenesis of metabolic syndrome and its principal complications including obesity, type 2 diabetes mellitus, cardiovascular disease, and hepatic steatosis. We herein review the molecular pathways regulated by PGC-1α, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome. PGC-1α regulates the expression of mitochondrial antioxidant genes, including manganese superoxide dismutase, catalase, peroxiredoxin 3 and 5, uncoupling protein 2, thioredoxin 2, and thioredoxin reductase and thus prevents oxidative injury and mitochondrial dysfunction. Dysregulation of PGC-1α alters redox homeostasis in cells and exacerbates inflammatory response, which is commonly accompanied by metabolic disturbances. During inflammation, low levels of PGC-1α downregulate mitochondrial antioxidant gene expression, induce oxidative stress, and promote nuclear factor kappa B activation. In metabolic syndrome, which is characterized by a chronic low grade of inflammation, PGC-1α dysregulation modifies the metabolic properties of tissues by altering mitochondrial function and promoting reactive oxygen species accumulation. In conclusion, PGC-1α acts as an essential node connecting metabolic regulation, redox control, and inflammatory pathways, and it is an interesting therapeutic target that may have significant benefits for a number of metabolic diseases.
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11
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Resveratrol Promotes Mitochondrial Biogenesis and Protects against Seizure-Induced Neuronal Cell Damage in the Hippocampus Following Status Epilepticus by Activation of the PGC-1α Signaling Pathway. Int J Mol Sci 2019; 20:ijms20040998. [PMID: 30823590 PMCID: PMC6412811 DOI: 10.3390/ijms20040998] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 02/13/2019] [Accepted: 02/21/2019] [Indexed: 12/27/2022] Open
Abstract
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is known to regulate mitochondrial biogenesis. Resveratrol is present in a variety of plants, including the skin of grapes, blueberries, raspberries, mulberries, and peanuts. It has been shown to offer protective effects against a number of cardiovascular and neurodegenerative diseases, stroke, and epilepsy. This study examined the neuroprotective effect of resveratrol on mitochondrial biogenesis in the hippocampus following experimental status epilepticus. Kainic acid was microinjected into left hippocampal CA3 in Sprague Dawley rats to induce bilateral prolonged seizure activity. PGC-1α expression and related mitochondrial biogenesis were investigated. Amounts of nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), cytochrome c oxidase 1 (COX1), and mitochondrial DNA (mtDNA) were measured to evaluate the extent of mitochondrial biogenesis. Increased PGC-1α and mitochondrial biogenesis machinery after prolonged seizure were found in CA3. Resveratrol increased expression of PGC-1α, NRF1, and Tfam, NRF1 binding activity, COX1 level, and mtDNA amount. In addition, resveratrol reduced activated caspase-3 activity and attenuated neuronal cell damage in the hippocampus following status epilepticus. These results suggest that resveratrol plays a pivotal role in the mitochondrial biogenesis machinery that may provide a protective mechanism counteracting seizure-induced neuronal damage by activation of the PGC-1α signaling pathway.
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12
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Chen SD, Yang JL, Hwang WC, Yang DI. Emerging Roles of Sonic Hedgehog in Adult Neurological Diseases: Neurogenesis and Beyond. Int J Mol Sci 2018; 19:ijms19082423. [PMID: 30115884 PMCID: PMC6121355 DOI: 10.3390/ijms19082423] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 08/10/2018] [Accepted: 08/13/2018] [Indexed: 12/14/2022] Open
Abstract
Sonic hedgehog (Shh), a member of the hedgehog (Hh) family, was originally recognized as a morphogen possessing critical characters for neural development during embryogenesis. Recently, however, Shh has emerged as an important modulator in adult neural tissues through different mechanisms such as neurogenesis, anti-oxidation, anti-inflammation, and autophagy. Therefore, Shh may potentially have clinical application in neurodegenerative diseases and brain injuries. In this article, we present some examples, including ours, to show different aspects of Shh signaling and how Shh agonists or mimetics are used to alter the neuronal fates in various disease models, both in vitro and in vivo. Other potential mechanisms that are discussed include alteration of mitochondrial function and anti-aging effect; both are critical for age-related neurodegenerative diseases. A thorough understanding of the protective mechanisms elicited by Shh may provide a rationale to design innovative therapeutic regimens for various neurodegenerative diseases.
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Affiliation(s)
- Shang-Der Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City 83301, Taiwan.
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City 83301, Taiwan.
- College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan.
| | - Jenq-Lin Yang
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City 83301, Taiwan.
| | - Wei-Chao Hwang
- Department of Neurology, Taipei City Hospital, Taipei 11556, Taiwan.
| | - Ding-I Yang
- Institute of Brain Science, National Yang-Ming University, Taipei 11221, Taiwan.
- Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
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13
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Yang JL, Mukda S, Chen SD. Diverse roles of mitochondria in ischemic stroke. Redox Biol 2018; 16:263-275. [PMID: 29549824 PMCID: PMC5854930 DOI: 10.1016/j.redox.2018.03.002] [Citation(s) in RCA: 322] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 03/01/2018] [Accepted: 03/06/2018] [Indexed: 12/15/2022] Open
Abstract
Stroke is the leading cause of adult disability and mortality in most developing and developed countries. The current best practices for patients with acute ischemic stroke include intravenous tissue plasminogen activator and endovascular thrombectomy for large-vessel occlusion to improve clinical outcomes. However, only a limited portion of patients receive thrombolytic therapy or endovascular treatment because the therapeutic time window after ischemic stroke is narrow. To address the current shortage of stroke management approaches, it is critical to identify new potential therapeutic targets. The mitochondrion is an often overlooked target for the clinical treatment of stroke. Early studies of mitochondria focused on their bioenergetic role; however, these organelles are now known to be important in a wide range of cellular functions and signaling events. This review aims to summarize the current knowledge on the mitochondrial molecular mechanisms underlying cerebral ischemia and involved in reactive oxygen species generation and scavenging, electron transport chain dysfunction, apoptosis, mitochondrial dynamics and biogenesis, and inflammation. A better understanding of the roles of mitochondria in ischemia-related neuronal death and protection may provide a rationale for the development of innovative therapeutic regimens for ischemic stroke and other stroke syndromes.
Review of current treatment of ischemic stroke indicates deficiency in the contemporary methods. Discuss the mitochondrial ROS-related signaling that affect neuronal fate after ischemic stroke. Mechanisms of mitochondrial dynamics and mitophagy could be pivotal for ischemic stroke. Inhibiting mitochondrion-induced inflammatory response is a potential treatment for ischemic stroke.
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Affiliation(s)
- Jenq-Lin Yang
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Kaohsiung 83301, Taiwan, ROC
| | - Sujira Mukda
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Kaohsiung 83301, Taiwan, ROC; Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, 25/25 Phuttamonthon 4 Road, Salaya, Nakhon Pathom 73170, Thailand
| | - Shang-Der Chen
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Kaohsiung 83301, Taiwan, ROC; Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Kaohsiung 83301, Taiwan, ROC; College of Medicine, Chang Gung University, 259 Wenhua 1st Road, Taoyuan 33302, Taiwan, ROC.
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14
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The Effects of Resveratrol on Inflammation and Oxidative Stress in a Rat Model of Chronic Obstructive Pulmonary Disease. Molecules 2017; 22:molecules22091529. [PMID: 28895883 PMCID: PMC6151812 DOI: 10.3390/molecules22091529] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 09/06/2017] [Indexed: 11/20/2022] Open
Abstract
Oxidative stress and inflammation are hypothesized to contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Resveratrol (trans-3,5,4′-trihydroxystilbene) is known for its antioxidant and anti-inflammatory properties. The study aimed to investigate the effects of resveratrol in a rat model with COPD on the regulation of oxidative stress and inflammation via the activation of Sirtuin1 (SIRTl) and proliferator-activated receptor-γ coactivator-1α (PGC-1α). Thirty Wistar rats were randomly divided into three groups: control group, COPD group and resveratrol intervention group. The COPD model was established by instilling with lipopolysaccharide (LPS) and challenging with cigarette smoke (CS). The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) in serum were measured. The levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured. The expression levels of SIRT1 and PGC-1α in the lung tissues were examined by immunohistochemistry as well as real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and western blotting analysis. After the treatment with resveratrol (50 mg/kg), compared with the COPD group, alleviation of inflammation and reconstruction in the small airways of the lungs were seen. Resveratrol might be correlated not only with the lower level of MDA and the higher activity of SOD, but also with the upregulation of SIRT1 and PGC-1α expression. Resveratrol treatment decreased serum levels of IL-6 and IL-8. Our findings indicate that resveratrol had a therapeutic effect in our rat COPD model, which is related to the inhibition of oxidative stress and inflammatory response. The mechanism may be related to the activation and upgrading of the SIRT1/PGC-1α signaling pathways. Thus resveratrol might be a therapeutic modality in COPD.
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15
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Li L, Xiao L, Hou Y, He Q, Zhu J, Li Y, Wu J, Zhao J, Yu S, Zhao Y. Sestrin2 Silencing Exacerbates Cerebral Ischemia/Reperfusion Injury by Decreasing Mitochondrial Biogenesis through the AMPK/PGC-1α Pathway in Rats. Sci Rep 2016; 6:30272. [PMID: 27453548 PMCID: PMC4958997 DOI: 10.1038/srep30272] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 06/29/2016] [Indexed: 01/01/2023] Open
Abstract
Sestrin2 (Sesn2) exerts neuroprotective properties in some neurodegenerative diseases. However, the role of Sesn2 in stroke is unclear. The AMP-activated protein kinase/peroxisome proliferator-activated receptor γ coactivator-1α (AMPK/PGC-1α) pathway plays an important role in regulating mitochondrial biogenesis, which helps prevent cerebral ischemia/reperfusion (I/R) injury. Here, we aimed to determine whether Sesn2 alleviated I/R damage by regulating mitochondrial biogenesis through the AMPK/PGC-1α signaling pathway. To be able to test this, Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h with Sesn2 silencing. At 24 h after reperfusion, we found that neurological deficits were exacerbated, infarct volume was enlarged, and oxidative stress and neuronal damage were greater in the Sesn2 siRNA group than in the MCAO group. To explore protective mechanisms, an AMPK activator was used. Expression levels of Sesn2, p-AMPK, PGC-1α, NRF-1, TFAM, SOD2, and UCP2 were significantly increased following cerebral I/R. However, upregulation of these proteins was prevented by Sesn2 small interfering RNA (siRNA). In contrast, activation of AMPK with 5′-aminoimidazole-4-carboxamide riboside weakened the effects of Sesn2 siRNA. These results suggest that Sesn2 silencing may suppress mitochondrial biogenesis, reduce mitochondrial biological activity, and finally aggravate cerebral I/R injury through inhibiting the AMPK/PGC-1α pathway.
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Affiliation(s)
- Lingyu Li
- Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.,Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China
| | - Lina Xiao
- Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China
| | - Yanghao Hou
- Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China.,Department of Pathophysiology, Chongqing Medical University, Chongqing, People's Republic of China
| | - Qi He
- Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China.,Department of Pathophysiology, Chongqing Medical University, Chongqing, People's Republic of China
| | - Jin Zhu
- Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.,Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China
| | - Yixin Li
- Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.,Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China
| | - Jingxian Wu
- Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.,Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China
| | - Jing Zhao
- Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China.,Department of Pathophysiology, Chongqing Medical University, Chongqing, People's Republic of China
| | - Shanshan Yu
- Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.,Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China
| | - Yong Zhao
- Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.,Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China
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16
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Chuang YC, Lin TK, Yang DI, Yang JL, Liou CW, Chen SD. Peroxisome proliferator-activated receptor-gamma dependent pathway reduces the phosphorylation of dynamin-related protein 1 and ameliorates hippocampal injury induced by global ischemia in rats. J Biomed Sci 2016; 23:44. [PMID: 27175924 PMCID: PMC4865999 DOI: 10.1186/s12929-016-0262-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 05/06/2016] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Dynamin-related protein 1 (Drp1) is a mitochondrial fission protein that, upon phosphorylation at serine 616 (p-Drp1(Ser616)), plays a pivotal role in neuronal death after ischemia. In the present study, we hypothesized that peroxisome proliferator-activated receptor-gamma (PPARγ)-dependent pathway can reduce the expression of p-Drp1(Ser616) and ameliorate hippocampal injury induced by global ischemia in rats. RESULTS We found that pretreatment of the rats with Mdivi-1, a selective Drp1 inhibitor, decreased the level of transient global ischemia (TGI)-induced p-Drp1(Ser616) and reduced cellular contents of oxidized proteins, activated caspase-3 expression as well as the extent of DNA fragmentation. Delivery of siRNA against Drp1 attenuated the expression of p-Drp1(Ser616) that was accompanied by alleviation of the TGI-induced protein oxidation, activated caspase-3 expression and DNA fragmentation in hippocampal proteins. Exogenous application of pioglitazone, a PPARγ agonist, reduced the p-Drp1(Ser616) expression, decreased TGI-induced oxidative stress and activated caspase-3 expression, lessened the extents of DNA fragmentation, and diminished the numbers of TUNEL-positive neuronal cells; all of these effects were reversed by GW9662, a PPARγ antagonist. CONCLUSIONS Our findings thus indicated that inhibition of TGI-induced p-Drp1(Ser616) expression by Drp1 inhibitor and Drp1-siRNA can decrease protein oxidation, activated caspase-3 expression and neuronal damage in the hippocampal CA1 subfield. PPARγ agonist, through PPARγ-dependent mechanism and via decreasing p-Drp1(Ser616) expression, can exert anti-oxidative and anti-apoptotic effects against ischemic neuronal injury.
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Affiliation(s)
- Yao-Chung Chuang
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Department of Neurology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tsu-Kung Lin
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ding-I Yang
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
| | - Jenq-Lin Yang
- Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chia-Wei Liou
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Shang-Der Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan. .,Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
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17
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Jiang J, Zhang L, Xia XB. Small interfering RNA targeting PGC-1α inhibits VEGF expression and tube formation in human retinal vascular endothelial cells. Int J Ophthalmol 2015; 8:877-83. [PMID: 26558195 DOI: 10.3980/j.issn.2222-3959.2015.05.05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 05/27/2015] [Indexed: 11/02/2022] Open
Abstract
AIM To determine whether small interfering RNA (siRNA) of PGC-1α could inhibit vascular endothelial growth factor (VEGF) expression and tube formation in human retinal vascular endothelial cells (hRVECs). METHODS hRVECs transfected with peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) siRNA were incubated for 24h and then placed into a normoxic (20%, O2) or hypoxic (1%, O2) environment for another 16h. PGC-1α mRNA and protein levels were detected by real-time PCR and Western blot. VEGF mRNA and protein levels were detected by real-time PCR and ELISA. Cell proliferation was evaluated by BrdU incorporation assay. Forty-eight hours after siRNA transfection, hRVECs were planted into Matrigel-coated plates and cultured under normoxic (20%, O2) or hypoxic (1%, O2) conditions for another 48h. The tube formation of hRVECs was observed under an optical microscope and quantified by counting the number of branch points and calculating the total tube length. RESULTS PGC-1α mRNA and protein levels were significantly reduced by PGC-1α siRNA, and VEGF mRNA and protein levels also decreased significantly. The percentage of BrdU-labeled cells in siPGC-1α groups were significantly decreased compared with control siRNA groups under normoxia and hypoxia in cell proliferation assay. In the tube formation assay, PGC-1α siRNA treated cells formed significantly fewer tubes. CONCLUSION Blocking PGC-1α expression can inhibit VEGF expression in hRVECs and inhibit their ability to form tubes under both normoxic and hypoxic conditions.
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Affiliation(s)
- Jian Jiang
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Lu Zhang
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Xiao-Bo Xia
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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Chuang YC, Yang JL, Yang DI, Lin TK, Liou CW, Chen SD. Roles of Sestrin2 and Ribosomal Protein S6 in Transient Global Ischemia-Induced Hippocampal Neuronal Injury. Int J Mol Sci 2015; 16:26406-16. [PMID: 26556340 PMCID: PMC4661822 DOI: 10.3390/ijms161125963] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 10/23/2015] [Accepted: 10/23/2015] [Indexed: 12/25/2022] Open
Abstract
Recent studies suggested that sestrin2 is a crucial modulator for the production of reactive oxygen species (ROS). In addition, sestrin2 may also regulate ribosomal protein S6 (RpS6), a molecule important for protein synthesis, through the effect of mammalian target of rapamycin (mTOR) complex that is pivotal for longevity. However, the roles of sestrin2 in cerebral ischemia, in which oxidative stress is one of the major pathogenic mechanisms, are still less understood. In this study, we hypothesized that sestrin2 may protect hippocampal CA1 neurons against transient global ischemia (TGI)-induced apoptosis by regulating RpS6 phosphorylation in rats. We found that sestrin2 expression was progressively increased in the hippocampal CA1 subfield 1–48 h after TGI, reaching the maximal level at 24 h, and declined thereafter. Further, an increased extent of RpS6 phosphorylation, but not total RpS6 protein level, was observed in the hippocampal CA1 subfield after TGI. The sestrin2 siRNA, which substantially blocked the expression of TGI-induced sestrin2, also abolished RpS6 phosphorylation. TGI with reperfusion may induce oxidative stress with the resultant formation of 8-hydroxy-deoxyguanosine (8-OHdG). We found that sestrin2 siRNA further augmented the formation of 8-OHdG induced by TGI with reperfusion for 4 h. Consistently, sestrin2 siRNA also enhanced apoptosis induced by TGI with reperfusion for 48 h based on the analysis of DNA fragmentation by agarose gel electrophoresis, DNA fragmentation sandwich ELISA, and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Together these findings indicated that TGI-induced sestrin2 expression contributed to RpS6 phosphorylation and neuroprotection against ischemic injury in the hippocampal CA1 subfield.
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Affiliation(s)
- Yao-Chung Chuang
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan.
- Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
- Department of Neurology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 833, Taiwan.
| | - Jenq-Lin Yang
- Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
| | - Ding-I Yang
- Institute of Brain Science, National Yang-Ming University, Taipei 112, Taiwan.
| | - Tsu-Kung Lin
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan.
| | - Chia-Wei Liou
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan.
| | - Shang-Der Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan.
- Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
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Abstract
Cerebral ischemia is among the leading causes of death worldwide. It is characterized by a lack of blood flow to the brain that results in cell death and damage, ultimately causing motor, sensory, and cognitive impairments. Today, clinical treatment of cerebral ischemia, mostly stroke and cardiac arrest, is limited and new neuroprotective therapies are desperately needed. The Sirtuin family of oxidized nicotinamide adenine dinucleotide (NAD+)-dependent deacylases has been shown to govern several processes within the central nervous system as well as to possess neuroprotective properties in a variety of pathological conditions such as Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease, among others. Recently, Sirt1 in particular has been identified as a mediator of cerebral ischemia, with potential as a possible therapeutic target. To gather studies relevant to this topic, we used PubMed and previous reviews to locate, select, and resynthesize the lines of evidence presented here. In this review, we will first describe some functions of Sirt1 in the brain, mainly neurodevelopment, learning and memory, and metabolic regulation. Second, we will discuss the experimental evidence that has implicated Sirt1 as a key protein in the regulation of cerebral ischemia as well as a potential target for the induction of ischemic tolerance.
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Affiliation(s)
- Kevin B Koronowski
- Department of Neurology and Neuroscience Program, Cerebral Vascular Disease Research Laboratories, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Miguel A Perez-Pinzon
- Department of Neurology and Neuroscience Program, Cerebral Vascular Disease Research Laboratories, Miller School of Medicine, University of Miami, Miami, Florida, USA
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20
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Curcumin prevents cerebral ischemia reperfusion injury via increase of mitochondrial biogenesis. Neurochem Res 2014; 39:1322-31. [PMID: 24777807 DOI: 10.1007/s11064-014-1315-1] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 04/07/2014] [Accepted: 04/18/2014] [Indexed: 11/27/2022]
Abstract
Curcumin is known to have neuroprotective properties in cerebral ischemia reperfusion (I/R) injury. However, the underlying molecular mechanisms remain largely unknown. Recently, emerging evidences suggested that increased mitochondrial biogenesis enabled preventing I/R injury. Here, we sought to determinate whether curcumin alleviates I/R damage through regulation of mitochondrial biogenesis. Sprague-Dawley rats were subjected to a 2-h period of right middle cerebral artery occlusion followed by 24 h of reperfusion. Prior to onset of occlusion, rats had been pretreated with either low (50 mg/kg, intraperitoneal injection) or high (100 mg/kg, intraperitoneal injection) dose of curcumin for 5 days. Consequently, we found that curcumin pretreatment enabled improving neurological deficit, diminishing infarct volume and increasing the number of NeuN-labeled neurons in the I/R rats. Accordingly, the index of mitochondrial biogenesis including nuclear respiratory factor-1, mitochondrial transcription factor A and mitochondrial number significantly down-regulated in I/R rats were reversed by curcumin pretreatment in a dose-dependent manner, and the mitochondrial uncoupling protein 2 presented the similar change. Taken together, our findings provided novel evidence that curcumin may exert neuroprotective effects by increasing mitochondrial biogenesis.
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Guo F, Jin WL, Li LY, Song WY, Wang HW, Gou XC, Mi YJ, Wang Q, Xiong L. M9, a novel region of amino-Nogo-A, attenuates cerebral ischemic injury by inhibiting NADPH oxidase-derived superoxide production in mice. CNS Neurosci Ther 2013; 19:319-28. [PMID: 23490284 DOI: 10.1111/cns.12083] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Revised: 01/27/2013] [Accepted: 02/02/2013] [Indexed: 01/09/2023] Open
Abstract
AIMS In acute stroke, neurological damage is due to oxidative stress and neuronal apoptotic death. This study investigated whether Nogo-A 290-562 residues region (M9), fused to the transduction domain of the HIV trans-activator (TAT) protein, is neuroprotective against cerebral ischemia and the mechanisms. METHODS Transient focal cerebral ischemia was induced by middle cerebral artery occlusion in male C57BL/6J mice. TAT-M9, its mutation or vehicle was applied via intraperitoneal injection at the onset of reperfusion. The neurobehavioral scores, infarction volumes, neuronal apoptosis, and the ratio of Bax/Bcl-2 were evaluated. Malondialdehyde (MDA), reactive oxygen species (ROS) levels, and NADPH oxidase activation were measured in the presence or absence of the NADPH oxidase inhibitor apocynin or activator tetrabromocinnamic acid (TBCA). RESULTS Immunofluorescence results confirmed that TAT-M9 was transduced into brain parenchyma, and it significantly improved neurological behavior, reduced infarct volumes, protected neuronal cells from apoptosis, inhibited activation of NADPH oxidase, and decreased MDA and ROS contents. Furthermore, apocynin imitated the beneficial effects of TAT-M9, while TBCA abolished them. CONCLUSIONS Our results demonstrate that TAT-M9 administration attenuates cerebral ischemia by inhibiting NADPH oxidase-mediated oxidative damage and neuronal apoptosis in mice. TAT-M9 may be a potential treatment for cerebrovascular disease.
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Affiliation(s)
- Fan Guo
- Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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Pantazi E, Zaouali MA, Bejaoui M, Folch-Puy E, Abdennebi HB, Roselló-Catafau J. Role of sirtuins in ischemia-reperfusion injury. World J Gastroenterol 2013; 19:7594-7602. [PMID: 24616566 PMCID: PMC3837258 DOI: 10.3748/wjg.v19.i43.7594] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 09/16/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) remains an unresolved and complicated situation in clinical practice, especially in the case of organ transplantation. Several factors contribute to its complexity; the depletion of energy during ischemia and the induction of oxidative stress during reperfusion initiate a cascade of pathways that lead to cell death and finally to severe organ injury. Recently, the sirtuin family of nicotinamide adenine dinucleotide-dependent deacetylases has gained increasing attention from researchers, due to their involvement in the modulation of a wide variety of cellular functions. There are seven mammalian sirtuins and, among them, the nuclear/cytoplasmic sirtuin 1 (SIRT1) and the mitochondrial sirtuin 3 (SIRT3) are ubiquitously expressed in many tissue types. Sirtuins are known to play major roles in protecting against cellular stress and in controlling metabolic pathways, which are key processes during IRI. In this review, we mainly focus on SIRT1 and SIRT3 and examine their role in modulating pathways against energy depletion during ischemia and their involvement in oxidative stress, apoptosis, microcirculatory stress and inflammation during reperfusion. We present evidence of the beneficial effects of sirtuins against IRI and emphasize the importance of developing new strategies by enhancing their action.
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Expression Pattern of Peroxisome Proliferator-Activated Receptors in Rat Hippocampus following Cerebral Ischemia and Reperfusion Injury. PPAR Res 2012; 2012:596394. [PMID: 23304113 PMCID: PMC3523613 DOI: 10.1155/2012/596394] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2012] [Revised: 10/30/2012] [Accepted: 11/14/2012] [Indexed: 02/01/2023] Open
Abstract
The present study was designed to investigate the pattern of time-dependent expression of peroxisome proliferator-activated receptors (PPARα, β, and γ) after global cerebral ischemia and reperfusion (I/R) damage in the rat hippocampus. Male Sprague Dawley (SD) rats were subjected to global cerebral I/R. The rat hippocampi were isolated to detect the expression of PPARs mRNA and protein levels at 30 min–30 d after I/R by RT-PCR and Western blot analysis, respectively. The expression levels of PPARs mRNA and protein in the rat hippocampus significantly increased and peaked at 24 h for PPARα and γ (at 48 h for PPARβ) after I/R, then gradually decreased, and finally approached control levels on d 30. The present results suggest that global cerebral I/R can cause obvious increases of hippocampal PPARs mRNA and protein expression within 15 d after I/R. These findings may help to guide the experimental and clinical therapeutic use of PPARs agonists against brain injury.
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Acute resveratrol treatment modulates multiple signaling pathways in the ischemic brain. Neurochem Res 2012; 37:2686-96. [PMID: 22878646 DOI: 10.1007/s11064-012-0858-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 07/15/2012] [Accepted: 07/28/2012] [Indexed: 12/19/2022]
Abstract
Resveratrol has several beneficial effects, including reductions of oxidative stress, inflammatory responses and apoptosis. It has been known that resveratrol is a sirtuin 1 (SIRT1) activator and protective effects of resveratrol are mediated by Akt and mitogen-activated protein kinases. However, it is not examined whether these pathways are regulated by resveratrol in the ischemic brain. Previously, we found that acute resveratrol treatment reduces brain injury induced by transient focal ischemic stroke. In the present study, we defined the signaling pathways modulated by resveratrol in ischemia by examining SIRT1 expression and phosphorylation of Akt, ERK1/2 and p38 in the ischemic cortex. Resveratrol increased expression of SIRT1 and phosphorylation of Akt and p38 but inhibited the increase in phosphorylation of ERK1/2. Gene and protein levels of peroxisome proliferator-activated receptor γ coactivator 1α, a downstream molecule of SIRT1, and mRNA levels of its target genes antioxidative superoxide dismutase 2 and uncoupling protein 2 were elevated. Resveratrol also increased phosphorylation of cyclic AMP-response-element-binding protein and transcription of the anti-apoptotic gene Bcl-2. These results suggest that various neuroprotective actions of resveratrol, including anti-oxidative, anti-apoptotic and inflammatory effects, are mediated via modulation of multiple signaling pathways in the ischemic brain.
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25
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Chuang YC, Lin TK, Huang HY, Chang WN, Liou CW, Chen SD, Chang AYW, Chan SHH. Peroxisome proliferator-activated receptors γ/mitochondrial uncoupling protein 2 signaling protects against seizure-induced neuronal cell death in the hippocampus following experimental status epilepticus. J Neuroinflammation 2012; 9:184. [PMID: 22849356 PMCID: PMC3444895 DOI: 10.1186/1742-2094-9-184] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 07/20/2012] [Indexed: 11/23/2022] Open
Abstract
Background Status epilepticus induces subcellular changes that may lead to neuronal cell death in the hippocampus. However, the mechanism of seizure-induced neuronal cell death remains unclear. The mitochondrial uncoupling protein 2 (UCP2) is expressed in selected regions of the brain and is emerged as an endogenous neuroprotective molecule in many neurological disorders. We evaluated the neuroprotective role of UCP2 against seizure-induced hippocampal neuronal cell death under experimental status epilepticus. Methods In Sprague–Dawley rats, kainic acid (KA) was microinjected unilaterally into the hippocampal CA3 subfield to induce prolonged bilateral seizure activity. Oxidized protein level, translocation of Bcl-2, Bax and cytochrome c between cytosol and mitochondria, and expression of peroxisome proliferator-activated receptors γ (PPARγ) and UCP2 were examined in the hippocampal CA3 subfield following KA-induced status epilepticus. The effects of microinjection bilaterally into CA3 area of a PPARγ agonist, rosiglitazone or a PPARγ antagonist, GW9662 on UCP2 expression, induced superoxide anion (O2· -) production, oxidized protein level, mitochondrial respiratory chain enzyme activities, translocation of Bcl-2, Bax and cytochrome c, and DNA fragmentation in bilateral CA3 subfields were examined. Results Increased oxidized proteins and mitochondrial or cytosol translocation of Bax or cytochrome c in the hippocampal CA3 subfield was observed 3–48 h after experimental status epilepticus. Expression of PPARγ and UCP2 increased 12–48 h after KA-induced status epilepticus. Pretreatment with rosiglitazone increased UCP2 expression, reduced protein oxidation, O2· - overproduction and dysfunction of mitochondrial Complex I, hindered the translocation of Bax and cytochrome c, and reduced DNA fragmentation in the CA3 subfield. Pretreatment with GW9662 produced opposite effects. Conclusions Activation of PPARγ upregulated mitochondrial UCP2 expression, which decreased overproduction of reactive oxygen species, improved mitochondrial Complex I dysfunction, inhibited mitochondrial translocation of Bax and prevented cytosolic release of cytochrome c by stabilizing the mitochondrial transmembrane potential, leading to amelioration of apoptotic neuronal cell death in the hippocampus following status epilepticus.
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Affiliation(s)
- Yao-Chung Chuang
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
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Abstract
Mitochondrial dysfunction contributes to the pathophysiology of acute neurologic disorders and neurodegenerative diseases. Bioenergetic failure is the primary cause of acute neuronal necrosis, and involves excitotoxicity-associated mitochondrial Ca(2+) overload, resulting in opening of the inner membrane permeability transition pore and inhibition of oxidative phosphorylation. Mitochondrial energy metabolism is also very sensitive to inhibition by reactive O(2) and nitrogen species, which modify many mitochondrial proteins, lipids, and DNA/RNA, thus impairing energy transduction and exacerbating free radical production. Oxidative stress and Ca(2+)-activated calpain protease activities also promote apoptosis and other forms of programmed cell death, primarily through modification of proteins and lipids present at the outer membrane, causing release of proapoptotic mitochondrial proteins, which initiate caspase-dependent and caspase-independent forms of cell death. This review focuses on three classifications of mitochondrial targets for neuroprotection. The first is mitochondrial quality control, maintained by the dynamic processes of mitochondrial fission and fusion and autophagy of abnormal mitochondria. The second includes targets amenable to ischemic preconditioning, e.g., electron transport chain components, ion channels, uncoupling proteins, and mitochondrial biogenesis. The third includes mitochondrial proteins and other molecules that defend against oxidative stress. Each class of targets exhibits excellent potential for translation to clinical neuroprotection.
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Affiliation(s)
- Miguel A Perez-Pinzon
- Department of Neurology, Cerebral Vascular Disease Research Center, University of Miami Miller School of Medicine, Miami, FL, USA
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27
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Puddifoot C, Martel MA, Soriano FX, Camacho A, Vidal-Puig A, Wyllie DJA, Hardingham GE. PGC-1α negatively regulates extrasynaptic NMDAR activity and excitotoxicity. J Neurosci 2012; 32:6995-7000. [PMID: 22593067 PMCID: PMC3359835 DOI: 10.1523/jneurosci.6407-11.2012] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Revised: 03/30/2012] [Accepted: 04/01/2012] [Indexed: 11/21/2022] Open
Abstract
Underexpression of the transcriptional coactivator PGC-1α is causally linked to certain neurodegenerative disorders, including Huntington's Disease (HD). HD pathoprogression is also associated with aberrant NMDAR activity, in particular an imbalance between synaptic versus extrasynaptic (NMDAR(EX)) activity. Here we show that PGC-1α controls NMDAR(EX) activity in neurons and that its suppression contributes to mutant Huntingtin (mHtt)-induced increases in NMDAR(EX) activity and vulnerability to excitotoxic insults. We found that knock-down of endogenous PGC-1α increased NMDAR(EX) activity and vulnerability to excitotoxic insults in rat cortical neurons. In contrast, exogenous expression of PGC-1α resulted in a neuroprotective reduction of NMDAR(EX) currents without affecting synaptic NMDAR activity. Since HD models are associated with mHtt-mediated suppression of PGC-1α expression, as well as increased NMDAR(EX) activity, we investigated whether these two events were linked. Expression of mHtt (148Q) resulted in a selective increase in NMDAR(EX) activity, compared with wild-type Htt (18Q), and increased vulnerability to NMDA excitotoxicity. Importantly, we observed that the effects of mHtt and PGC-1α knockdown on NMDAR(EX) activity and vulnerability to excitotoxicity were nonadditive and occluded each other, consistent with a common mechanism. Moreover, exogenous expression of PGC-1α reversed mtHtt-mediated increases in NMDAR(EX) activity and protected neurons against excitotoxic cell death. The link between mHtt, PGC-1α, and NMDAR activity was also confirmed in rat striatal neurons. Thus, targeting levels of PGC-1α expression may help reduce aberrant NMDAR(EX) activity in disorders where PGC-1α is underexpressed.
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Affiliation(s)
- Clare Puddifoot
- Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, and
| | - Marc-Andre Martel
- Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, and
| | - Francesc X. Soriano
- Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, and
| | - Alberto Camacho
- University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Antonio Vidal-Puig
- University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
| | - David J. A. Wyllie
- Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, and
| | - Giles E. Hardingham
- Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, and
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Girnun GD. The diverse role of the PPARγ coactivator 1 family of transcriptional coactivators in cancer. Semin Cell Dev Biol 2012; 23:381-8. [PMID: 22285815 DOI: 10.1016/j.semcdb.2012.01.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Revised: 01/12/2012] [Accepted: 01/15/2012] [Indexed: 12/18/2022]
Abstract
The critical role that altered cellular metabolism plays in promoting and maintaining the cancer phenotype has received considerable attention in recent years. For many years it was believed that aerobic glycolysis, also known as the Warburg Effect, played an important role in cancer. However, recent studies highlight the requirement of mitochondrial function, oxidative phosphorylation and biosynthetic pathways in cancer. This has promoted interest into mechanisms controlling these metabolic pathways. The PPARγ coactivator (PGC)-1 family of transcriptional coactivators have emerged as key regulators of several metabolic pathways including oxidative metabolism, energy homeostasis and glucose and lipid metabolism. While PGC-1s have been implicated in a number of metabolic diseases, recent studies highlight an important role in cancer. Studies show that PGC-1s have both pro and anticancer functions and suggests a dynamic role for the PGC-1s in cancer. We discuss in this review the links between PGC-1s and cancer, with a focus on the most well studied family member, PGC-1α.
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Affiliation(s)
- Geoffrey D Girnun
- Department of Biochemistry and Molecular Biology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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Cheng A, Wan R, Yang JL, Kamimura N, Son TG, Ouyang X, Luo Y, Okun E, Mattson MP. Involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines. Nat Commun 2012; 3:1250. [PMID: 23212379 PMCID: PMC4091730 DOI: 10.1038/ncomms2238] [Citation(s) in RCA: 312] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Accepted: 10/31/2012] [Indexed: 12/13/2022] Open
Abstract
The formation, maintenance and reorganization of synapses are critical for brain development and the responses of neuronal circuits to environmental challenges. Here we describe a novel role for peroxisome proliferator-activated receptor γ co-activator 1α, a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, proliferator-activated receptor γ co-activator 1α overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of proliferator-activated receptor γ co-activator 1α inhibits spinogenesis and synaptogenesis. Proliferator-activated receptor γ co-activator 1α knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor stimulates proliferator-activated receptor γ co-activator-1α-dependent mitochondrial biogenesis by activating extracellular signal-regulated kinases and cyclic AMP response element-binding protein. Proliferator-activated receptor γ co-activator-1α knockdown inhibits brain-derived neurotrophic factor-induced dendritic spine formation without affecting expression and activation of the brain-derived neurotrophic factor receptor tyrosine receptor kinase B. Our findings suggest that proliferator-activated receptor γ co-activator-1α and mitochondrial biogenesis have important roles in the formation and maintenance of hippocampal dendritic spines and synapses.
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Affiliation(s)
- Aiwu Cheng
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
| | - Ruiqian Wan
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
| | - Jenq-Lin Yang
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
- Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
| | - Naomi Kamimura
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
- Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki-city, 211-8533 Japan
| | - Tae Gen Son
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
| | - Xin Ouyang
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
| | - Yongquan Luo
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
| | - Eitan Okun
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
| | - Mark P. Mattson
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
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Mai S, Muster B, Bereiter-Hahn J, Jendrach M. Autophagy proteins LC3B, ATG5 and ATG12 participate in quality control after mitochondrial damage and influence lifespan. Autophagy 2012; 8:47-62. [PMID: 22170153 DOI: 10.4161/auto.8.1.18174] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Mitochondrial health is maintained by the quality control mechanisms of mitochondrial dynamics (fission and fusion) and mitophagy. Decline of these processes is thought to contribute to aging and neurodegenerative diseases. To investigate the role of mitochondrial quality control in aging on the cellular level, human umbilical vein endothelial cells (HUVEC) were subjected to mitochondria-targeted damage by combining staining of mitochondria and irradiation. This treatment induced a short boost of reactive oxygen species, which resulted in transient fragmentation of mitochondria followed by mitophagy, while mitochondrial dynamics were impaired. Furthermore, targeted mitochondrial damage upregulated autophagy factors LC3B, ATG5 and ATG12. Consequently these proteins were overexpressed in HUVEC as an in vitro aging model, which significantly enhanced the replicative life span up to 150% and the number of population doublings up to 200%, whereas overexpression of LAMP-1 did not alter the life span. Overexpression of LC3B, ATG5 and ATG12 resulted in an improved mitochondrial membrane potential, enhanced ATP production and generated anti-apoptotic effects, while ROS levels remained unchanged and the amount of oxidized proteins increased. Taken together, these data relate LC3B, ATG5 and ATG12 to mitochondrial quality control after oxidative damage, and to cellular longevity.
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Affiliation(s)
- Sören Mai
- Kinematic Cell Research Group; Institute for Cell Biology and Neuroscience, Center of Excellence Frankfurt-Macromolecular Complexes, Goethe University, Frankfurt/Main, Germany
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Chen SD, Yang DI, Lin TK, Shaw FZ, Liou CW, Chuang YC. Roles of oxidative stress, apoptosis, PGC-1α and mitochondrial biogenesis in cerebral ischemia. Int J Mol Sci 2011; 12:7199-215. [PMID: 22072942 PMCID: PMC3211033 DOI: 10.3390/ijms12107199] [Citation(s) in RCA: 275] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Revised: 10/12/2011] [Accepted: 10/19/2011] [Indexed: 12/12/2022] Open
Abstract
The primary physiological function of mitochondria is to generate adenosine triphosphate through oxidative phosphorylation via the electron transport chain. Overproduction of reactive oxygen species (ROS) as byproducts generated from mitochondria have been implicated in acute brain injuries such as stroke from cerebral ischemia. It was well-documented that mitochondria-dependent apoptotic pathway involves pro- and anti-apoptotic protein binding, release of cytochrome c, leading ultimately to neuronal death. On the other hand, mitochondria also play a role to counteract the detrimental effects elicited by excessive oxidative stress. Recent studies have revealed that oxidative stress and the redox state of ischemic neurons are also implicated in the signaling pathway that involves peroxisome proliferative activated receptor-γ (PPARγ) co-activator 1α (PGC1-α). PGC1-α is a master regulator of ROS scavenging enzymes including manganese superoxide dismutase 2 and the uncoupling protein 2, both are mitochondrial proteins, and may contribute to neuronal survival. PGC1-α is also involved in mitochondrial biogenesis that is vital for cell survival. Experimental evidence supports the roles of mitochondrial dysfunction and oxidative stress as determinants of neuronal death as well as endogenous protective mechanisms after stroke. This review aims to summarize the current knowledge focusing on the molecular mechanisms underlying cerebral ischemia involving ROS, mitochondrial dysfunction, apoptosis, mitochondrial proteins capable of ROS scavenging, and mitochondrial biogenesis.
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Affiliation(s)
- Shang-Der Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
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Manzanero S, Gelderblom M, Magnus T, Arumugam TV. Calorie restriction and stroke. EXPERIMENTAL & TRANSLATIONAL STROKE MEDICINE 2011; 3:8. [PMID: 21910904 PMCID: PMC3179731 DOI: 10.1186/2040-7378-3-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2011] [Accepted: 09/12/2011] [Indexed: 12/15/2022]
Abstract
Stroke, a major cause of disability and mortality in the elderly, occurs when a cerebral blood vessel is occluded or ruptured, resulting in ischemic damage and death of brain cells. The injury mechanism involves metabolic and oxidative stress, excitotoxicity, apoptosis and inflammatory processes, including activation of glial cells and infiltration of leukocytes. In animal models, dietary energy restriction, by daily calorie reduction (CR) or intermittent fasting (IF), extends lifespan and decreases the development of age-related diseases. Dietary energy restriction may also benefit neurons, as suggested by experimental evidence showing that CR and IF protect neurons against degeneration in animal models. Recent findings by our group and others suggest the possibility that dietary energy restriction may protect against stroke induced brain injury, in part by inducing the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF); protein chaperones, including heat shock protein 70 (Hsp70) and glucose regulated protein 78 (GRP78); antioxidant enzymes, such as superoxide dismutases (SOD) and heme oxygenase-1 (HO-1), silent information regulator T1 (SIRT1), uncoupling proteins and anti-inflammatory cytokines. This article discusses the protective mechanisms activated by dietary energy restriction in ischemic stroke.
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Affiliation(s)
- Silvia Manzanero
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia.
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Geng T, Li P, Yin X, Yan Z. PGC-1α promotes nitric oxide antioxidant defenses and inhibits FOXO signaling against cardiac cachexia in mice. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 178:1738-48. [PMID: 21435455 DOI: 10.1016/j.ajpath.2011.01.005] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Revised: 12/03/2010] [Accepted: 01/04/2011] [Indexed: 12/21/2022]
Abstract
Chronic heart failure often results in catabolic muscle wasting, exercise intolerance, and death. Oxidative muscles, which have greater expression of the metabolic master gene peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and its target genes, are more resistant to catabolic wasting than are glycolytic muscles; however, the underlying mechanism is unknown. To determine the functional role of PGC-1α in oxidative phenotype-associated protection, skeletal muscle-specific PGC-1α transgenic mice were crossbred with cardiac-specific calsequestrin transgenic mice, a genetic model of chronic heart failure. PGC-1α overexpression in glycolytic muscles significantly attenuated catabolic muscle wasting induced by chronic heart failure. In addition to inactivation of forkhead transcription factor signaling through enhanced Akt/protein kinase B expression, in glycolytic muscles, PGC-1α overexpression led to enhanced expression of inducible nitric oxide synthase and endothelial nitric oxide synthase, production of nitric oxide, and expression of antioxidant enzyme including superoxide dismutases (SOD1, SOD2, and SOD3) and catalase, and reduced oxidative stress. These findings suggest that PGC-1α protects muscle from catabolic wasting in chronic heart failure through enhanced nitric oxide antioxidant defenses and inhibition of the forkhead transcription factor signaling pathways.
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Affiliation(s)
- Tuoyu Geng
- Department of Medicine-Cardiovascular Medicine, University of Virginia, Charlottesville, VA 22908, USA
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Soriano FX, Léveillé F, Papadia S, Bell KFS, Puddifoot C, Hardingham GE. Neuronal activity controls the antagonistic balance between peroxisome proliferator-activated receptor-γ coactivator-1α and silencing mediator of retinoic acid and thyroid hormone receptors in regulating antioxidant defenses. Antioxid Redox Signal 2011; 14:1425-36. [PMID: 20849372 PMCID: PMC3044457 DOI: 10.1089/ars.2010.3568] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2010] [Accepted: 09/19/2010] [Indexed: 12/21/2022]
Abstract
Transcriptional coactivators and corepressors often have multiple targets and can have opposing actions on transcription and downstream physiological events. The coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is under-expressed in Huntington's disease and is a regulator of antioxidant defenses and mitochondrial biogenesis. We show that in primary cortical neurons, expression of PGC-1α strongly promotes resistance to excitotoxic and oxidative stress in a cell autonomous manner, whereas knockdown increases sensitivity. In contrast, the transcriptional corepressor silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) specifically antagonizes PGC-1α-mediated antioxidant effects. The antagonistic balance between PGC-1α and SMRT is upset in favor of PGC-1α by synaptic activity. Synaptic activity triggers nuclear export of SMRT reliant on multiple regions of the protein. Concomitantly, synaptic activity post-translationally enhances the transactivating potential of PGC-1α in a p38-dependent manner, as well as upregulating cyclic-AMP response element binding protein-dependent PGC-1α transcription. Activity-dependent targeting of PGC-1α results in enhanced gene expression mediated by the thyroid hormone receptor, a prototypical transcription factor coactivated by PGC-1α and repressed by SMRT. As a consequence of these events, SMRT is unable to antagonize PGC-1α-mediated resistance to oxidative stress in synaptically active neurons. Thus, PGC-1α and SMRT are antagonistic regulators of neuronal vulnerability to oxidative stress. Further, this coactivator-corepressor antagonism is regulated by the activity status of the cell, with implications for neuronal viability.
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Affiliation(s)
- Francesc X Soriano
- Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
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Morris KC, Lin HW, Thompson JW, Perez-Pinzon MA. Pathways for ischemic cytoprotection: role of sirtuins in caloric restriction, resveratrol, and ischemic preconditioning. J Cereb Blood Flow Metab 2011; 31:1003-19. [PMID: 21224864 PMCID: PMC3070983 DOI: 10.1038/jcbfm.2010.229] [Citation(s) in RCA: 110] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2010] [Revised: 11/11/2010] [Accepted: 12/01/2010] [Indexed: 01/11/2023]
Abstract
Caloric restriction (CR), resveratrol, and ischemic preconditioning (IPC) have been shown to promote protection against ischemic injury in the heart and brain, as well as in other tissues. The activity of sirtuins, which are enzymes that modulate diverse biologic processes, seems to be vital in the ability of these therapeutic modalities to prevent against cellular dysfunction and death. The protective mechanisms of the yeast Sir2 and the mammalian homolog sirtuin 1 have been extensively studied, but the involvement of other sirtuins in ischemic protection is not yet clear. We examine the roles of mammalian sirtuins in modulating protective pathways against oxidative stress, energy depletion, excitotoxicity, inflammation, DNA damage, and apoptosis. Although many of these sirtuins have not been directly implicated in ischemic protection, they may have unique roles in enhancing function and preventing against stress-mediated cellular damage and death. This review will include in-depth analyses of the roles of CR, resveratrol, and IPC in activating sirtuins and in mediating protection against ischemic damage in the heart and brain.
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Affiliation(s)
- Kahlilia C Morris
- Department of Neurology, Cerebral Vascular Disease Research Center, University of Miami, Miller School of Medicine, Miami, Florida, USA
| | - Hung Wen Lin
- Department of Neurology, Cerebral Vascular Disease Research Center, University of Miami, Miller School of Medicine, Miami, Florida, USA
| | - John W Thompson
- Department of Neurology, Cerebral Vascular Disease Research Center, University of Miami, Miller School of Medicine, Miami, Florida, USA
| | - Miguel A Perez-Pinzon
- Department of Neurology, Cerebral Vascular Disease Research Center, University of Miami, Miller School of Medicine, Miami, Florida, USA
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