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Ali NH, Al-Kuraishy HM, Al-Gareeb AI, Alnaaim SA, Alexiou A, Papadakis M, Saad HM, Batiha GES. Autophagy and autophagy signaling in Epilepsy: possible role of autophagy activator. Mol Med 2023; 29:142. [PMID: 37880579 PMCID: PMC10598971 DOI: 10.1186/s10020-023-00742-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 10/16/2023] [Indexed: 10/27/2023] Open
Abstract
Autophagy is an explicit cellular process to deliver dissimilar cytoplasmic misfolded proteins, lipids and damaged organelles to the lysosomes for degradation and elimination. The mechanistic target of rapamycin (mTOR) is the main negative regulator of autophagy. The mTOR pathway is involved in regulating neurogenesis, synaptic plasticity, neuronal development and excitability. Exaggerated mTOR activity is associated with the development of temporal lobe epilepsy, genetic and acquired epilepsy, and experimental epilepsy. In particular, mTOR complex 1 (mTORC1) is mainly involved in epileptogenesis. The investigation of autophagy's involvement in epilepsy has recently been conducted, focusing on the critical role of rapamycin, an autophagy inducer, in reducing the severity of induced seizures in animal model studies. The induction of autophagy could be an innovative therapeutic strategy in managing epilepsy. Despite the protective role of autophagy against epileptogenesis and epilepsy, its role in status epilepticus (SE) is perplexing and might be beneficial or detrimental. Therefore, the present review aims to revise the possible role of autophagy in epilepsy.
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Affiliation(s)
- Naif H Ali
- Department of Internal Medicine, Medical College, Najran university, Najran, Saudi Arabia
| | - Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, P.O. Box 14132, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, P.O. Box 14132, Baghdad, Iraq
| | - Saud A Alnaaim
- Clinical Neurosciences Department, College of Medicine, King Faisal University, Hofuf, Saudi Arabia
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW, 2770, Australia
- AFNP Med, Wien, 1030, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
| | - Hebatallah M Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Matrouh, Matrouh, 51744, Egypt.
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, AlBeheira, 22511, Egypt.
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Ma Q, Yao C, Wu Y, Wang H, Fan Q, Yang Q, Xu J, Dai H, Zhang Y, Xu F, Lu T, Dowling JK, Wang C. Neurological disorders after severe pneumonia are associated with translocation of endogenous bacteria from the lung to the brain. SCIENCE ADVANCES 2023; 9:eadi0699. [PMID: 37851811 PMCID: PMC10584344 DOI: 10.1126/sciadv.adi0699] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 09/15/2023] [Indexed: 10/20/2023]
Abstract
Neurological disorders are a common feature in patients who recover from severe acute pneumonia. However, the underlying mechanisms remain poorly understood. Here, we show that the neurological syndromes after severe acute pneumonia are partly attributed to the translocation of endogenous bacteria from the lung to the brain during pneumonia. Using principal components analysis, similarities were found between the brain's flora species and those of the lungs, indicating that the bacteria detected in the brain may originate from the lungs. We also observed impairment of both the lung-blood and brain-blood barriers, allowing endogenous lung bacteria to invade the brain during pneumonia. An elevated microglia and astrocyte activation signature via bacterial infection-related pathways was observed, indicating a bacterial-induced disruption of brain homeostasis. Collectively, we identify endogenous lung bacteria that play a role in altering brain homeostasis, which provides insight into the mechanism of neurological syndromes after severe pneumonia.
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Affiliation(s)
- Qingle Ma
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou 215123, China
| | - Chenlu Yao
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou 215123, China
| | - Yi Wu
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou 215123, China
| | - Heng Wang
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou 215123, China
| | - Qin Fan
- Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM) and School of Materials Science and Engineering, Nanjing University of Posts & Telecommunications, Nanjing, P. R. China
| | - Qianyu Yang
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou 215123, China
| | - Jialu Xu
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou 215123, China
| | - Huaxing Dai
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou 215123, China
| | - Yue Zhang
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou 215123, China
| | - Fang Xu
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou 215123, China
| | - Ting Lu
- Institute of Pharmacology, Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Disease, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
| | - Jennifer K. Dowling
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medical and Health Sciences, Dublin, Ireland
| | - Chao Wang
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou 215123, China
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Melanis K, Stefanou MI, Themistoklis KM, Papasilekas T. mTOR pathway - a potential therapeutic target in stroke. Ther Adv Neurol Disord 2023; 16:17562864231187770. [PMID: 37576547 PMCID: PMC10413897 DOI: 10.1177/17562864231187770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 06/27/2023] [Indexed: 08/15/2023] Open
Abstract
Stroke is ranked as the second leading cause of death worldwide and a major cause of long-term disability. A potential therapeutic target that could offer favorable outcomes in stroke is the mammalian target of rapamycin (mTOR) pathway. mTOR is a serine/threonine kinase that composes two protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), and is regulated by other proteins such as the tuberous sclerosis complex. Through a significant number of signaling pathways, the mTOR pathway can modulate the processes of post-ischemic inflammation and autophagy, both of which play an integral part in the pathophysiological cascade of stroke. Promoting or inhibiting such processes under ischemic conditions can lead to apoptosis or instead sustained viability of neurons. The purpose of this review is to examine the pathophysiological role of mTOR in acute ischemic stroke, while highlighting promising neuroprotective agents such as hamartin for therapeutic modulation of this pathway. The therapeutic potential of mTOR is also discussed, with emphasis on implicated molecules and pathway steps that warrant further elucidation in order for their neuroprotective properties to be efficiently tested in future clinical trials.
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Affiliation(s)
- Konstantinos Melanis
- Second Department of Neurology, School of Medicine and ‘Attikon’ University Hospital, National and Kapodistrian University of Athens, Rimini 1 Chaidari, Athens 12462, Greece
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Maria-Ioanna Stefanou
- Second Department of Neurology, School of Medicine and ‘Attikon’ University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos M. Themistoklis
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
- Department of Neurosurgery, ‘Korgialenio, Benakio, H.R.C’. General Hospital of Athens, Athens, Greece
| | - Themistoklis Papasilekas
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
- Department of Neurosurgery, ‘Korgialenio, Benakio, H.R.C’. General Hospital of Athens, Athens, Greece
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Zhao W, Xie C, Zhang X, Liu J, Liu J, Xia Z. Advances in the mTOR signaling pathway and its inhibitor rapamycin in epilepsy. Brain Behav 2023; 13:e2995. [PMID: 37221133 PMCID: PMC10275542 DOI: 10.1002/brb3.2995] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 03/15/2023] [Accepted: 03/22/2023] [Indexed: 05/25/2023] Open
Abstract
INTRODUCTION Epilepsy is one of the most common and serious brain syndromes and has adverse consequences on a patient's neurobiological, cognitive, psychological, and social wellbeing, thereby threatening their quality of life. Some patients with epilepsy experience poor treatment effects due to the unclear pathophysiological mechanisms of the syndrome. Dysregulation of the mammalian target of the rapamycin (mTOR) pathway is thought to play an important role in the onset and progression of some epilepsies. METHODS This review summarizes the role of the mTOR signaling pathway in the pathogenesis of epilepsy and the prospects for the use of mTOR inhibitors. RESULTS The mTOR pathway functions as a vital mediator in epilepsy development through diverse mechanisms, indicating that the it has great potential as an effective target for epilepsy therapy. The excessive activation of mTOR signaling pathway leads to structural changes in neurons, inhibits autophagy, exacerbates neuron damage, affects mossy fiber sprouting, enhances neuronal excitability, increases neuroinflammation, and is closely associated with tau upregulation in epilepsy. A growing number of studies have demonstrated that mTOR inhibitors exhibit significant antiepileptic effects in both clinical applications and animal models. Specifically, rapamycin, a specific inhibitor of TOR, reduces the intensity and frequency of seizures. Clinical studies in patients with tuberous sclerosis complex have shown that rapamycin has the function of reducing seizures and improving this disease. Everolimus, a chemically modified derivative of rapamycin, has been approved as an added treatment to other antiepileptic medicines. Further explorations are needed to evaluate the therapeutic efficacy and application value of mTOR inhibitors in epilepsy. CONCLUSIONS Targeting the mTOR signaling pathway provides a promising prospect for the treatment of epilepsy.
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Affiliation(s)
- Wei Zhao
- Department of GerontologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
| | - Cong Xie
- Department of GerontologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
| | - Xu Zhang
- Department of GerontologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
| | - Ju Liu
- Laboratory of Microvascular MedicineMedical Research CenterShandong Provincial Qianfoshan Hospital, Shandong UniversityJinanChina
| | - Jinzhi Liu
- Department of GerontologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
- Department of NeurologyLiaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical UniversityLiaochengChina
- Department of GerontologyCheeloo College of MedicineShandong Provincial Qianfoshan Hospital, Shandong UniversityJinanChina
- Department of Geriatric NeurologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
| | - Zhangyong Xia
- Department of NeurologyLiaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical UniversityLiaochengChina
- Department of NeurologyCheeloo College of MedicineLiaocheng People's Hospital, Shandong UniversityJinanChina
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Maiese K. Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System. Biomolecules 2023; 13:816. [PMID: 37238686 PMCID: PMC10216724 DOI: 10.3390/biom13050816] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/05/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer's disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY 10022, USA
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de la Monte SM. Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer's Disease (Type 3 Diabetes). J Alzheimers Dis 2023; 95:1301-1337. [PMID: 37718817 PMCID: PMC10896181 DOI: 10.3233/jad-230555] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/19/2023]
Abstract
Malignant brain aging corresponds to accelerated age-related declines in brain functions eventually derailing the self-sustaining forces that govern independent vitality. Malignant brain aging establishes the path toward dementing neurodegeneration, including Alzheimer's disease (AD). The full spectrum of AD includes progressive dysfunction of neurons, oligodendrocytes, astrocytes, microglia, and the microvascular systems, and is mechanistically driven by insulin and insulin-like growth factor (IGF) deficiencies and resistances with accompanying deficits in energy balance, increased cellular stress, inflammation, and impaired perfusion, mimicking the core features of diabetes mellitus. The underlying pathophysiological derangements result in mitochondrial dysfunction, abnormal protein aggregation, increased oxidative and endoplasmic reticulum stress, aberrant autophagy, and abnormal post-translational modification of proteins, all of which are signature features of both AD and dysregulated insulin/IGF-1-mechanistic target of rapamycin (mTOR) signaling. This article connects the dots from benign to malignant aging to neurodegeneration by reviewing the salient pathologies associated with initially adaptive and later dysfunctional mTOR signaling in the brain. Effective therapeutic and preventive measures must be two-pronged and designed to 1) address complex and shifting impairments in mTOR signaling through the re-purpose of effective anti-diabetes therapeutics that target the brain, and 2) minimize the impact of extrinsic mediators of benign to malignant aging transitions, e.g., inflammatory states, obesity, systemic insulin resistance diseases, and repeated bouts of general anesthesia, by minimizing exposures or implementing neuroprotective measures.
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Affiliation(s)
- Suzanne M. de la Monte
- Departments of Pathology and Laboratory Medicine, Medicine, Neurology and Neurosurgery, Rhode Island Hospital, Lifespan Academic Institutions, and the Warren Alpert Medical School of Brown University, Providence, RI, USA
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Maiese K. The Metabolic Basis for Nervous System Dysfunction in Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. Curr Neurovasc Res 2023; 20:314-333. [PMID: 37488757 PMCID: PMC10528135 DOI: 10.2174/1567202620666230721122957] [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: 05/04/2023] [Revised: 06/10/2023] [Accepted: 06/19/2023] [Indexed: 07/26/2023]
Abstract
Disorders of metabolism affect multiple systems throughout the body but may have the greatest impact on both central and peripheral nervous systems. Currently available treatments and behavior changes for disorders that include diabetes mellitus (DM) and nervous system diseases are limited and cannot reverse the disease burden. Greater access to healthcare and a longer lifespan have led to an increased prevalence of metabolic and neurodegenerative disorders. In light of these challenges, innovative studies into the underlying disease pathways offer new treatment perspectives for Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. Metabolic disorders are intimately tied to neurodegenerative diseases and can lead to debilitating outcomes, such as multi-nervous system disease, susceptibility to viral pathogens, and long-term cognitive disability. Novel strategies that can robustly address metabolic disease and neurodegenerative disorders involve a careful consideration of cellular metabolism, programmed cell death pathways, the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP-activated protein kinase (AMPK), growth factor signaling, and underlying risk factors such as the apolipoprotein E (APOE-ε4) gene. Yet, these complex pathways necessitate comprehensive understanding to achieve clinical outcomes that target disease susceptibility, onset, and progression.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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8
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Gonzalez-Alcocer A, Gopar-Cuevas Y, Soto-Dominguez A, Loera-Arias MDJ, Saucedo-Cardenas O, Montes de Oca-Luna R, Rodriguez-Rocha H, Garcia-Garcia A. Peripheral tissular analysis of rapamycin's effect as a neuroprotective agent in vivo. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:1239-1255. [PMID: 35895156 DOI: 10.1007/s00210-022-02276-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 07/15/2022] [Indexed: 10/16/2022]
Abstract
Rapamycin is the best-characterized autophagy inducer, which is related to its antiaging and neuroprotective effects. Although rapamycin is an FDA-approved drug for human use in organ transplantation and cancer therapy, its administration as an antiaging and neuroprotective agent is still controversial because of its immunosuppressive and reported side effects. Therefore, it is critical to determine whether the dose that exerts a neuroprotective effect, 35 times lower than that used as an immunosuppressant agent, harms peripheral organs. We validated the rapamycin neuroprotective dosage in a Parkinson's disease (PD) model induced with paraquat. C57BL/6 J mice were treated with intraperitoneal (IP) rapamycin (1 mg/kg) three times per week, followed by paraquat (10 mg/kg) twice per week for 6 weeks, along with rapamycin on alternate days. Rapamycin significantly decreased dopaminergic neuronal loss induced by paraquat. Since rapamycin's neuroprotective effect in a PD model was observed at 7 weeks of treatment; we evaluated its effect on the liver, kidney, pancreas, and spleen. In addition, we prolonged treatment with rapamycin for 14 weeks. Tissue sections were subjected to histochemical, immunodetection, and morphometric analysis. Chronic rapamycin administration does not affect bodyweight, survival, and liver or kidney morphology. Although the pancreas tissular architecture and cellular distribution in Langerhans islets are modified, they may be reversible. The spleen B lymphocyte and macrophage populations were decreased. Notably, the lymphocyte T population was not affected. Therefore, chronic administration of a rapamycin neuroprotective dose does not produce significant tissular alterations. Our findings support the therapeutic potential of rapamycin as a neuroprotective agent.
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Affiliation(s)
- Alfredo Gonzalez-Alcocer
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Yareth Gopar-Cuevas
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Adolfo Soto-Dominguez
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Maria de Jesus Loera-Arias
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Odila Saucedo-Cardenas
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Roberto Montes de Oca-Luna
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Humberto Rodriguez-Rocha
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Aracely Garcia-Garcia
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México.
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Maiese K. Biomarkers for Parkinson's Disease and Neurodegenerative Disorders: A Role for Non-coding RNAs. Curr Neurovasc Res 2022; 19:127-130. [PMID: 35657043 DOI: 10.2174/1567202619666220602125806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Twible C, Abdo R, Zhang Q. Astrocyte Role in Temporal Lobe Epilepsy and Development of Mossy Fiber Sprouting. Front Cell Neurosci 2021; 15:725693. [PMID: 34658792 PMCID: PMC8514632 DOI: 10.3389/fncel.2021.725693] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/02/2021] [Indexed: 11/13/2022] Open
Abstract
Epilepsy affects approximately 50 million people worldwide, with 60% of adult epilepsies presenting an onset of focal origin. The most common focal epilepsy is temporal lobe epilepsy (TLE). The role of astrocytes in the presentation and development of TLE has been increasingly studied and discussed within the literature. The most common histopathological diagnosis of TLE is hippocampal sclerosis. Hippocampal sclerosis is characterized by neuronal cell loss within the Cornu ammonis and reactive astrogliosis. In some cases, mossy fiber sprouting may be observed. Mossy fiber sprouting has been controversial in its contribution to epileptogenesis in TLE patients, and the mechanisms surrounding the phenomenon have yet to be elucidated. Several studies have reported that mossy fiber sprouting has an almost certain co-existence with reactive astrogliosis within the hippocampus under epileptic conditions. Astrocytes are known to play an important role in the survival and axonal outgrowth of central and peripheral nervous system neurons, pointing to a potential role of astrocytes in TLE and associated cellular alterations. Herein, we review the recent developments surrounding the role of astrocytes in the pathogenic process of TLE and mossy fiber sprouting, with a focus on proposed signaling pathways and cellular mechanisms, histological observations, and clinical correlations in human patients.
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Affiliation(s)
- Carolyn Twible
- Department of Pathology and Lab Medicine, Western University, London, ON, Canada
| | - Rober Abdo
- Department of Pathology and Lab Medicine, Western University, London, ON, Canada.,Department of Anatomy and Cell Biology, Western University, London, ON, Canada
| | - Qi Zhang
- Department of Pathology and Lab Medicine, Western University, London, ON, Canada.,Department of Pathology and Lab Medicine, London Health Sciences Centre, University Hospital, London, ON, Canada
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Maiese K. Neurodegeneration, memory loss, and dementia: the impact of biological clocks and circadian rhythm. FRONT BIOSCI-LANDMRK 2021; 26:614-627. [PMID: 34590471 PMCID: PMC8756734 DOI: 10.52586/4971] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/26/2021] [Accepted: 08/10/2021] [Indexed: 11/23/2022]
Abstract
Introduction: Dementia and cognitive loss impact a significant proportion of the global population and present almost insurmountable challenges for treatment since they stem from multifactorial etiologies. Innovative avenues for treatment are highly warranted. Methods and results: Novel work with biological clock genes that oversee circadian rhythm may meet this critical need by focusing upon the pathways of the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), the growth factor erythropoietin (EPO), and the wingless Wnt pathway. These pathways are complex in nature, intimately associated with autophagy that can maintain circadian rhythm, and have an intricate relationship that can lead to beneficial outcomes that may offer neuroprotection, metabolic homeostasis, and prevention of cognitive loss. However, biological clocks and alterations in circadian rhythm also have the potential to lead to devastating effects involving tumorigenesis in conjunction with pathways involving Wnt that oversee angiogenesis and stem cell proliferation. Conclusions: Current work with biological clocks and circadian rhythm pathways provide exciting possibilities for the treating dementia and cognitive loss, but also provide powerful arguments to further comprehend the intimate and complex relationship among these pathways to fully potentiate desired clinical outcomes.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY 10022, USA
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12
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Jayaraj RL, Beiram R, Azimullah S, M. F. NM, Ojha SK, Adem A, Jalal FY. Noscapine Prevents Rotenone-Induced Neurotoxicity: Involvement of Oxidative Stress, Neuroinflammation and Autophagy Pathways. Molecules 2021; 26:4627. [PMID: 34361780 PMCID: PMC8348109 DOI: 10.3390/molecules26154627] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 01/05/2023] Open
Abstract
Parkinson's disease is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) and the resultant loss of dopamine in the striatum. Various studies have shown that oxidative stress and neuroinflammation plays a major role in PD progression. In addition, the autophagy lysosome pathway (ALP) plays an important role in the degradation of aggregated proteins, abnormal cytoplasmic organelles and proteins for intracellular homeostasis. Dysfunction of ALP results in the accumulation of α-synuclein and the loss of dopaminergic neurons in PD. Thus, modulating ALP is becoming an appealing therapeutic intervention. In our current study, we wanted to evaluate the neuroprotective potency of noscapine in a rotenone-induced PD rat model. Rats were administered rotenone injections (2.5 mg/kg, i.p.,) daily followed by noscapine (10 mg/kg, i.p.,) for four weeks. Noscapine, an iso-qinulinin alkaloid found naturally in the Papaveraceae family, has traditionally been used in the treatment of cancer, stroke and fibrosis. However, the neuroprotective potency of noscapine has not been analyzed. Our study showed that administration of noscapine decreased the upregulation of pro-inflammatory factors, oxidative stress, and α-synuclein expression with a significant increase in antioxidant enzymes. In addition, noscapine prevented rotenone-induced activation of microglia and astrocytes. These neuroprotective mechanisms resulted in a decrease in dopaminergic neuron loss in SNpc and neuronal fibers in the striatum. Further, noscapine administration enhanced the mTOR-mediated p70S6K pathway as well as inhibited apoptosis. In addition to these mechanisms, noscapine prevented a rotenone-mediated increase in lysosomal degradation, resulting in a decrease in α-synuclein aggregation. However, further studies are needed to further develop noscapine as a potential therapeutic candidate for PD treatment.
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Affiliation(s)
- Richard L. Jayaraj
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, United Arab Emirates; (R.L.J.); (S.A.); (N.M.M.F.); (S.K.O.)
| | - Rami Beiram
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, United Arab Emirates; (R.L.J.); (S.A.); (N.M.M.F.); (S.K.O.)
| | - Sheikh Azimullah
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, United Arab Emirates; (R.L.J.); (S.A.); (N.M.M.F.); (S.K.O.)
| | - Nagoor Meeran M. F.
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, United Arab Emirates; (R.L.J.); (S.A.); (N.M.M.F.); (S.K.O.)
| | - Shreesh K. Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, United Arab Emirates; (R.L.J.); (S.A.); (N.M.M.F.); (S.K.O.)
| | - Abdu Adem
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi 127788, United Arab Emirates
| | - Fakhreya Yousuf Jalal
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, United Arab Emirates; (R.L.J.); (S.A.); (N.M.M.F.); (S.K.O.)
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Maiese K. Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways. Biomolecules 2021; 11:1002. [PMID: 34356626 PMCID: PMC8301848 DOI: 10.3390/biom11071002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/05/2021] [Accepted: 07/07/2021] [Indexed: 01/18/2023] Open
Abstract
Neurodegenerative disorders affect fifteen percent of the world's population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer's disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY 10022, USA
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14
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Luo L, Zang G, Liu B, Qin X, Zhang Y, Chen Y, Zhang H, Wu W, Wang G. Bioengineering CXCR4-overexpressing cell membrane functionalized ROS-responsive nanotherapeutics for targeting cerebral ischemia-reperfusion injury. Am J Cancer Res 2021; 11:8043-8056. [PMID: 34335979 PMCID: PMC8315061 DOI: 10.7150/thno.60785] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/28/2021] [Indexed: 12/14/2022] Open
Abstract
Rationale: As a potentially life-threatening disorder, cerebral ischemia-reperfusion (I/R) injury is associated with significantly high mortality, especially the irreversible brain tissue damage associated with increased reactive oxygen radical production and excessive inflammation. Currently, the insufficiency of targeted drug delivery and “on-demand” drug release remain the greatest challenges for cerebral I/R injury therapy. Bioengineered cell membrane-based nanotherapeutics mimic and enhance natural membrane functions and represent a potentially promising approach, relying on selective interactions between receptors and chemokines and increase nanomedicine delivery efficiency into the target tissues. Methods: We employed a systematic method to synthesize biomimetic smart nanoparticles. The CXCR4-overexpressing primary mouse thoracic aorta endothelial cell (PMTAEC) membranes and RAPA@HOP were extruded through a 200 nm polycarbonate porous membrane using a mini-extruder to harvest the RAPA@BMHOP. The bioengineered CXCR4-overexpressing cell membrane-functionalized ROS-responsive nanotherapeutics, loaded with rapamycin (RAPA), were fabricated to enhance the targeted delivery to lesions with pathological overexpression of SDF-1. Results: RAPA@BMHOP exhibited a three-fold higher rate of target delivery efficacy via the CXCR4/SDF-1 axis than its non-targeting counterpart in an in vivo model. Additionally, in response to the excessive pathological ROS, nanotherapeutics could be degraded to promote “on-demand” cargo release and balance the ROS level by p-hydroxy-benzyl alcohol degradation, thereby scavenging excessive ROS and suppressing the free radical-induced focal damage and local inflammation. Also, the stealth effect of cell membrane coating functionalization on the surface resulted in extended circulation time and high stability of nanoparticles. Conclusion: The biomimetic smart nanotherapeutics with active targeting, developed in this study, significantly improved the therapeutic efficacy and biosafety profiles. Thus, these nanoparticles could be a candidate for efficient therapy of cerebral I/R injury.
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15
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Guden DS, Temiz-Resitoglu M, Senol SP, Kibar D, Yilmaz SN, Tunctan B, Malik KU, Sahan-Firat S. mTOR inhibition as a possible pharmacological target in the management of systemic inflammatory response and associated neuroinflammation by lipopolysaccharide challenge in rats. Can J Physiol Pharmacol 2021; 99:921-934. [PMID: 33641344 DOI: 10.1139/cjpp-2020-0487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Neuroinflammation plays a critical role during sepsis triggered by microglial activation. Mammalian target of rapamycin (mTOR) has gained attraction in neuroinflammation, however, the mechanism remains unclear. Our goal was to assess the effects of mTOR inhibition by rapamycin on inflammation, microglial activation, oxidative stress, and apoptosis associated with the changes in the inhibitor-κB (IκB)-α/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α) pathway activity following a systemic challenge with lipopolysaccharide (LPS). Rats received saline (10 mL/kg), LPS (10 mg/kg), and (or) rapamycin (1 mg/kg) intraperitoneally. Inhibition of mTOR by rapamycin blocked phosphorylated form of ribosomal protein S6, NF-κB p65 activity by increasing degradation of IκB-α in parallel with HIF-1α expression increased by LPS in the kidney, heart, lung, and brain tissues. Rapamycin attenuated the increment in the expression of tumor necrosis factor-α and interleukin-1β, the inducible nitric oxide synthase, gp91phox, and p47phox in addition to nitrite levels elicited by LPS in tissues or sera. Concomitantly, rapamycin treatment reduced microglial activation, brain expression of caspase-3, and Bcl-2-associated X protein while it increased expression of B cell lymphoma 2 induced by LPS. Overall, this study supports the hypothesis that mTOR contributes to the detrimental effect of LPS-induced systemic inflammatory response associated with neuroinflammation via IκB-α/NF-κB/HIF-1α signaling pathway.
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Affiliation(s)
- Demet Sinem Guden
- Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | | | - Sefika Pinar Senol
- Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Deniz Kibar
- Department of Histology and Embryology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Sakir Necat Yilmaz
- Department of Histology and Embryology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Bahar Tunctan
- Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Kafait U Malik
- Department of Pharmacology, College of Medicine, University of Tennessee, Department of Pharmacology, College of Medicine, Memphis, TN, USA
| | - Seyhan Sahan-Firat
- Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
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16
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Maiese K. Nicotinamide as a Foundation for Treating Neurodegenerative Disease and Metabolic Disorders. Curr Neurovasc Res 2021; 18:134-149. [PMID: 33397266 PMCID: PMC8254823 DOI: 10.2174/1567202617999210104220334] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 02/06/2023]
Abstract
Neurodegenerative disorders impact more than one billion individuals worldwide and are intimately tied to metabolic disease that can affect another nine hundred individuals throughout the globe. Nicotinamide is a critical agent that may offer fruitful prospects for neurodegenerative diseases and metabolic disorders, such as diabetes mellitus. Nicotinamide protects against multiple toxic environments that include reactive oxygen species exposure, anoxia, excitotoxicity, ethanolinduced neuronal injury, amyloid (Aß) toxicity, age-related vascular disease, mitochondrial dysfunction, insulin resistance, excess lactate production, and loss of glucose homeostasis with pancreatic β-cell dysfunction. However, nicotinamide offers cellular protection in a specific concentration range, with dosing outside of this range leading to detrimental effects. The underlying biological pathways of nicotinamide that involve the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and mammalian forkhead transcription factors (FoxOs) may offer insight for the clinical translation of nicotinamide into a safe and efficacious therapy through the modulation of oxidative stress, apoptosis, and autophagy. Nicotinamide is a highly promising target for the development of innovative strategies for neurodegenerative disorders and metabolic disease, but the benefits of this foundation depend greatly on gaining a further understanding of nicotinamide's complex biology.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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17
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Jayaraj RL, Beiram R, Azimullah S, MF NM, Ojha SK, Adem A, Jalal FY. Valeric Acid Protects Dopaminergic Neurons by Suppressing Oxidative Stress, Neuroinflammation and Modulating Autophagy Pathways. Int J Mol Sci 2020; 21:ijms21207670. [PMID: 33081327 PMCID: PMC7589299 DOI: 10.3390/ijms21207670] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 02/07/2023] Open
Abstract
Parkinson's disease, the second common neurodegenerative disease is clinically characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) with upregulation of neuroinflammatory markers and oxidative stress. Autophagy lysosome pathway (ALP) plays a major role in degradation of damaged organelles and proteins for energy balance and intracellular homeostasis. However, dysfunction of ALP results in impairment of α-synuclein clearance which hastens dopaminergic neurons loss. In this study, we wanted to understand the neuroprotective efficacy of Val in rotenone induced PD rat model. Animals received intraperitoneal injections (2.5 mg/kg) of rotenone daily followed by Val (40 mg/kg, i.p) for four weeks. Valeric acid, a straight chain alkyl carboxylic acid found naturally in Valeriana officianilis have been used in the treatment of neurological disorders. However, their neuroprotective efficacy has not yet been studied. In our study, we found that Val prevented rotenone induced upregulation of pro-inflammatory cytokine oxidative stress, and α-synuclein expression with subsequent increase in vital antioxidant enzymes. Moreover, Val mitigated rotenone induced hyperactivation of microglia and astrocytes. These protective mechanisms prevented rotenone induced dopaminergic neuron loss in SNpc and neuronal fibers in the striatum. Additionally, Val treatment prevented rotenone blocked mTOR-mediated p70S6K pathway as well as apoptosis. Moreover, Val prevented rotenone mediated autophagic vacuole accumulation and increased lysosomal degradation. Hence, Val could be further developed as a potential therapeutic candidate for treatment of PD.
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Affiliation(s)
- Richard L. Jayaraj
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE; (R.L.J.); (S.A.); (N.M.M.); (S.K.O.); (F.Y.J.)
| | - Rami Beiram
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE; (R.L.J.); (S.A.); (N.M.M.); (S.K.O.); (F.Y.J.)
- Correspondence: (R.B.); (A.A.); Tel.: +971-37137521 (R.B.); +971-504482894 (A.A.)
| | - Sheikh Azimullah
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE; (R.L.J.); (S.A.); (N.M.M.); (S.K.O.); (F.Y.J.)
| | - Nagoor Meeran MF
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE; (R.L.J.); (S.A.); (N.M.M.); (S.K.O.); (F.Y.J.)
| | - Shreesh K. Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE; (R.L.J.); (S.A.); (N.M.M.); (S.K.O.); (F.Y.J.)
| | - Abdu Adem
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE; (R.L.J.); (S.A.); (N.M.M.); (S.K.O.); (F.Y.J.)
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi 127788, UAE
- Correspondence: (R.B.); (A.A.); Tel.: +971-37137521 (R.B.); +971-504482894 (A.A.)
| | - Fakhreya Yousuf Jalal
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE; (R.L.J.); (S.A.); (N.M.M.); (S.K.O.); (F.Y.J.)
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18
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Wang H, Li Q, Sun S, Chen S. Neuroprotective Effects of Salidroside in a Mouse Model of Alzheimer's Disease. Cell Mol Neurobiol 2020; 40:1133-1142. [PMID: 32002777 PMCID: PMC11448871 DOI: 10.1007/s10571-020-00801-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 01/22/2020] [Indexed: 01/25/2023]
Abstract
Alzheimer's disease (AD), the most common form of dementia worldwide, is characterized by pathological hallmarks like β-amyloid peptide (Aβ) and clinical manifestations including cognitive impairment, psychiatry disorders, and behavioral changes. Salidroside (Sal) extracted from Rhodiola rosea L. showed protective effects against Aβ-induced neurotoxicity in a Drosophila AD model in our previous research. In the present study, daily doses of Sal were administered to APP/PS1 mice, a mouse model of AD, and several parameters were tested, including behavioral performance, Aβ status, levels of synapse-related proteins, and levels of PI3K/Akt targets of mTOR cell signaling pathway proteins. The behavioral testing showed an improvement in locomotor activity in the APP/PS1 mice after the administration of Sal. Treatment with Sal decreased both the soluble and insoluble Aβ levels and increased the expression of PSD95, NMDAR1, and calmodulin-dependent protein kinase II. The phosphatidylinositide PI3K/Akt/mTOR signaling was upregulated, which was in accordance with the above improvements from Sal treatment. Our findings suggested that Sal may protect the damaged synapses of the neurons in the APP/PS1 mice.
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Affiliation(s)
- Hualong Wang
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Neurology, The First Hospital of Hebei Medical University; Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Shijiazhuang, Hebei, China
| | - Qiongqiong Li
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Suya Sun
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Shengdi Chen
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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Maiese K. Dysregulation of metabolic flexibility: The impact of mTOR on autophagy in neurodegenerative disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 155:1-35. [PMID: 32854851 DOI: 10.1016/bs.irn.2020.01.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Non-communicable diseases (NCDs) that involve neurodegenerative disorders and metabolic disease impact over 400 million individuals globally. Interestingly, metabolic disorders, such as diabetes mellitus, are significant risk factors for the development of neurodegenerative diseases. Given that current therapies for these NCDs address symptomatic care, new avenues of discovery are required to offer treatments that affect disease progression. Innovative strategies that fill this void involve the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), AMP activated protein kinase (AMPK), trophic factors that include erythropoietin (EPO), and the programmed cell death pathways of autophagy and apoptosis. These pathways are intriguing in their potential to provide effective care for metabolic and neurodegenerative disorders. Yet, future work is necessary to fully comprehend the entire breadth of the mTOR pathways that can effectively and safely translate treatments to clinical medicine without the development of unexpected clinical disabilities.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY, United States.
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20
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Abstract
Metabolic disorders, such as diabetes mellitus (DM), are increasingly becoming significant risk factors for the health of the global population and consume substantial portions of the gross domestic product of all nations. Although conventional therapies that include early diagnosis, nutritional modification of diet, and pharmacological treatments may limit disease progression, tight serum glucose control cannot prevent the onset of future disease complications. With these concerns, novel strategies for the treatment of metabolic disorders that involve the vitamin nicotinamide, the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and the cellular pathways of autophagy and apoptosis offer exceptional promise to provide new avenues of treatment. Oversight of these pathways can promote cellular energy homeostasis, maintain mitochondrial function, improve glucose utilization, and preserve pancreatic beta-cell function. Yet, the interplay among mTOR, AMPK, and autophagy pathways can be complex and affect desired clinical outcomes, necessitating further investigations to provide efficacious treatment strategies for metabolic dysfunction and DM.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022,
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21
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Pan YR, Song JY, Fan B, Wang Y, Che L, Zhang SM, Chang YX, He C, Li GY. mTOR may interact with PARP-1 to regulate visible light-induced parthanatos in photoreceptors. Cell Commun Signal 2020; 18:27. [PMID: 32066462 PMCID: PMC7025415 DOI: 10.1186/s12964-019-0498-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 12/16/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Excessive light exposure is a detrimental environmental factor that plays a critical role in the pathogenesis of retinal degeneration. However, the mechanism of light-induced death of retina/photoreceptor cells remains unclear. The mammalian/mechanistic target of rapamycin (mTOR) and Poly (ADP-ribose) polymerase-1 (PARP-1) have become the primary targets for treating many neurodegenerative disorders. The aim of this study was to elucidate the mechanisms underlying light-induced photoreceptor cell death and whether the neuroprotective effects of mTOR and PARP-1 inhibition against death are mediated through apoptosis-inducing factor (AIF). METHODS Propidium iodide (PI)/Hoechst staining, lentiviral-mediated short hairpin RNA (shRNA), Western blot analysis, cellular fraction separation, plasmid transient transfection, laser confocal microscopy, a mice model, electroretinography (ERG), and hematoxylin-eosin (H & E) staining were employed to explore the mechanisms by which rapamycin/3-Aminobenzamide (3AB) exert neuroprotective effects of mTOR/PARP-1 inhibition in light-injured retinas. RESULTS A parthanatos-like death mechanism was evaluated in light-injured 661 W cells that are an immortalized photoreceptor-like cell line that exhibit cellular and biochemical feature characteristics of cone photoreceptor cells. The death process featured over-activation of PARP-1 and AIF nuclear translocation. Either PARP-1 or AIF knockdown played a significantly protective role for light-damaged photoreceptors. More importantly, crosstalk was observed between mTOR and PARP-1 signaling and mTOR could have regulated parthanatos via the intermediate factor sirtuin 1 (SIRT1). The parthanatos-like injury was also verified in vivo, wherein either PARP-1 or mTOR inhibition provided significant neuroprotection against light-induced injury, which is evinced by both structural and functional retinal analysis. Overall, these results elucidate the mTOR-regulated parthanatos death mechanism in light-injured photoreceptors/retinas and may facilitate the development of novel neuroprotective therapies for retinal degeneration diseases. CONCLUSIONS Our results demonstrate that inhibition of the mTOR/PARP-1 axis exerts protective effects on photoreceptors against visible-light-induced parthanatos. These protective effects are conducted by regulating the downstream factors of AIF, while mTOR possibly interacts with PARP-1 via SIRT1 to regulate parthanatos. Video Abstract Schematic diagram of mTOR interacting with PARP-1 to regulate visible light-induced parthanatos. Increased ROS caused by light exposure penetrates the nuclear membrane and causes nuclear DNA strand breaks. PARP-1 detects DNA breaks and synthesizes PAR polymers to initiate the DNA repair system that consumes a large amount of cellular NAD+. Over-production of PAR polymers prompts the release of AIF from the mitochondria and translocation to the nucleus, which leads to parthanatos. Activated mTOR may interact with PARP-1 via SIRT1 to regulate visible light-induced parthanatos.
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Affiliation(s)
- Yi-Ran Pan
- Department of Ophthalmology, Second Hospital of JiLin University, No.218 Zi-Qiang St, ChangChun, 130041 China
| | - Jing-Yao Song
- Department of Ophthalmology, Second Hospital of JiLin University, No.218 Zi-Qiang St, ChangChun, 130041 China
| | - Bin Fan
- Department of Ophthalmology, Second Hospital of JiLin University, No.218 Zi-Qiang St, ChangChun, 130041 China
| | - Ying Wang
- Department of Hemooncolog, Second Hospital of JiLin University, ChangChun, 130041 China
| | - Lin Che
- Department of Ophthalmology, Second Hospital of JiLin University, No.218 Zi-Qiang St, ChangChun, 130041 China
| | - Si-Ming Zhang
- Department of Ophthalmology, Second Hospital of JiLin University, No.218 Zi-Qiang St, ChangChun, 130041 China
| | - Yu-Xin Chang
- Department of Orthopedics, Second Hospital of JiLin University, ChangChun, 130041 China
| | - Chang He
- Department of Genetics,Basic, Medical College of Jilin University, ChangChun, 130041 China
| | - Guang-Yu Li
- Department of Ophthalmology, Second Hospital of JiLin University, No.218 Zi-Qiang St, ChangChun, 130041 China
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Maiese K. Cognitive impairment with diabetes mellitus and metabolic disease: innovative insights with the mechanistic target of rapamycin and circadian clock gene pathways. Expert Rev Clin Pharmacol 2020; 13:23-34. [PMID: 31794280 PMCID: PMC6959472 DOI: 10.1080/17512433.2020.1698288] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/25/2019] [Indexed: 12/18/2022]
Abstract
Introduction: Dementia is the 7th leading cause of death that imposes a significant financial and service burden on the global population. Presently, only symptomatic care exists for cognitive loss, such as Alzheimer's disease.Areas covered: Given the advancing age of the global population, it becomes imperative to develop innovative therapeutic strategies for cognitive loss. New studies provide insight to the association of cognitive loss with metabolic disorders, such as diabetes mellitus.Expert opinion: Diabetes mellitus is increasing in incidence throughout the world and affects 350 million individuals. Treatment strategies identifying novel pathways that oversee metabolic and neurodegenerative disorders offer exciting prospects to treat dementia. The mechanistic target of rapamycin (mTOR) and circadian clock gene pathways that include AMP activated protein kinase (AMPK), Wnt1 inducible signaling pathway protein 1 (WISP1), erythropoietin (EPO), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) provide novel strategies to treat cognitive loss that has its basis in metabolic cellular dysfunction. However, these pathways are complex and require precise regulation to maximize treatment efficacy and minimize any potential clinical disability. Further investigations hold great promise to treat both the onset and progression of cognitive loss that is associated with metabolic disease.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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23
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Maiese K. Nicotinamide: Oversight of Metabolic Dysfunction Through SIRT1, mTOR, and Clock Genes. Curr Neurovasc Res 2020; 17:765-783. [PMID: 33183203 PMCID: PMC7914159 DOI: 10.2174/1567202617999201111195232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/24/2020] [Accepted: 10/27/2020] [Indexed: 12/13/2022]
Abstract
Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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Farmer K, Abd-Elrahman KS, Derksen A, Rowe EM, Thompson AM, Rudyk CA, Prowse NA, Dwyer Z, Bureau SC, Fortin T, Ferguson SSG, Hayley S. mGluR5 Allosteric Modulation Promotes Neurorecovery in a 6-OHDA-Toxicant Model of Parkinson's Disease. Mol Neurobiol 2019; 57:1418-1431. [PMID: 31754998 DOI: 10.1007/s12035-019-01818-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 10/14/2019] [Indexed: 10/25/2022]
Abstract
Parkinson's disease is a neurodegenerative disease characterized by a loss of dopaminergic substantia nigra neurons and depletion of dopamine. To date, current therapeutic approaches focus on managing motor symptoms and trying to slow neurodegeneration, with minimal capacity to promote neurorecovery. mGluR5 plays a key role in neuroplasticity, and altered mGluR5 signaling contributes to synucleinopathy and dyskinesia in patients with Parkinson's disease. Here, we tested whether the mGluR5-negative allosteric modulator, (2-chloro-4-[2[2,5-dimethyl-1-[4-(trifluoromethoxy) phenyl] imidazol-4-yl] ethynyl] pyridine (CTEP), would be effective in improving motor deficits and promoting neural recovery in a 6-hydroxydopamine (6-OHDA) mouse model. Lesions were induced by 6-ODHA striatal infusion, and 30 days later treatment with CTEP (2 mg/kg) or vehicle commenced for either 1 or 12 weeks. Animals were subjected to behavioral, pathological, and molecular analyses. We also assessed how long the effects of CTEP persisted, and finally, using rapamycin, determined the role of the mTOR pathway. CTEP treatment induced a duration-dependent improvement in apomorphine-induced rotation and performance on rotarod in lesioned mice. Moreover, CTEP promoted a recovery of striatal tyrosine hydroxylase-positive fibers and normalized FosB levels in lesioned mice. The beneficial effects of CTEP were paralleled by an activation of mammalian target of rapamycin (mTOR) pathway and elevated brain-derived neurotrophic factor levels in the striatum of lesioned mice. The mTOR inhibitor, rapamycin (sirolimus), abolished CTEP-induced neurorecovery and rescue of motor deficits. Our findings indicate that mTOR pathway is a useful target to promote recovery and that mGluR5 allosteric regulators may potentially be repurposed to selectively target this pathway to enhance neuroplasticity in patients with Parkinson's disease.
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Affiliation(s)
- Kyle Farmer
- Department of Neuroscience, Carleton University, Ottawa, Ontario, K1S 5B6, Canada
| | - Khaled S Abd-Elrahman
- University of Ottawa Brain and Mind Institute, Ottawa, Ontario, K1H 8M5, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada
| | - Alexa Derksen
- Department of Neuroscience, Carleton University, Ottawa, Ontario, K1S 5B6, Canada
| | - Elyn M Rowe
- Department of Neuroscience, Carleton University, Ottawa, Ontario, K1S 5B6, Canada
| | - Ashley M Thompson
- Department of Neuroscience, Carleton University, Ottawa, Ontario, K1S 5B6, Canada
| | - Christopher A Rudyk
- Department of Neuroscience, Carleton University, Ottawa, Ontario, K1S 5B6, Canada
| | - Natalie A Prowse
- Department of Neuroscience, Carleton University, Ottawa, Ontario, K1S 5B6, Canada
| | - Zachary Dwyer
- Department of Neuroscience, Carleton University, Ottawa, Ontario, K1S 5B6, Canada
| | - Samantha C Bureau
- Department of Neuroscience, Carleton University, Ottawa, Ontario, K1S 5B6, Canada
| | - Teresa Fortin
- Department of Neuroscience, Carleton University, Ottawa, Ontario, K1S 5B6, Canada
| | - Stephen S G Ferguson
- University of Ottawa Brain and Mind Institute, Ottawa, Ontario, K1H 8M5, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada
| | - Shawn Hayley
- Department of Neuroscience, Carleton University, Ottawa, Ontario, K1S 5B6, Canada.
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25
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Zheng Z, Wu Y, Li Z, Ye L, Lu Q, Zhou Y, Yuan Y, Jiang T, Xie L, Liu Y, Chen D, Ye J, Nimlamool W, Zhang H, Xiao J. Valproic acid affects neuronal fate and microglial function via enhancing autophagic flux in mice after traumatic brain injury. J Neurochem 2019; 154:284-300. [PMID: 31602651 DOI: 10.1111/jnc.14892] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 10/05/2019] [Accepted: 10/09/2019] [Indexed: 12/11/2022]
Abstract
In recent years, many studies have focused on autophagy, an evolutionarily conserved mechanism that relies on lysosomes to achieve cellular metabolic requirements and organelle turnover, and revealed its important role in animal models of traumatic injury. Autophagy is a double-edged sword. Appropriate levels of autophagy can promote the removal of abnormal proteins or damaged organelles, while hyperactivated autophagy can induce autophagic apoptosis. However, recent studies suggest that autophagic flux seems to be blocked after traumatic brain injury (TBI), which contributes to the apoptosis of brain cells. In this study, valproic acid (VPA), which was clinically used for epilepsy treatment, was used to treat TBI. The Morris water maze test, hematoxylin & eosin staining and Nissl staining were first conducted to confirm that VPA treatment had a therapeutic effect on mice after TBI. Western blotting, enzyme-linked immunosorbent assay and immunofluorescence staining were then performed to reveal that VPA treatment reversed TBI-induced blockade of autophagic flux, which was accompanied by a reduced inflammatory response. In addition, the variations in activation and phenotypic polarization of microglia were observed after VPA treatment. Nevertheless, the use of the autophagy inhibitor 3-methyladenine partially abolished VPA-induced neuroprotection and the regulation of microglial function after TBI, resulting in the deterioration of the central nervous system microenvironment and neurological function. Collectively, VPA treatment reversed the TBI-induced blockade of autophagic flux in the mouse brain cortex, subsequently inhibiting brain cell apoptosis and affecting microglial function to achieve the promotion of functional recovery in mice after TBI. Cover Image for this issue: doi: 10.1111/jnc.14755.
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Affiliation(s)
- Zhilong Zheng
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yanqing Wu
- The Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang, China
| | - Zhengmao Li
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Luxia Ye
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qi Lu
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yajiao Zhou
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuan Yuan
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ting Jiang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ling Xie
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yanlong Liu
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Daqing Chen
- Department of Emergency, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Junming Ye
- Department of Anesthesia, The First Affiliated Hospital, Gangnan Medical University Ganzhou, Jiangxi, China
| | - Wutigri Nimlamool
- Department of Pharmacology, Faculty of medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Hongyu Zhang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jian Xiao
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
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26
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Zhang Y, Guo H, Guo X, Ge D, Shi Y, Lu X, Lu J, Chen J, Ding F, Zhang Q. Involvement of Akt/mTOR in the Neurotoxicity of Rotenone-Induced Parkinson's Disease Models. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16203811. [PMID: 31658620 PMCID: PMC6843606 DOI: 10.3390/ijerph16203811] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/03/2019] [Accepted: 10/05/2019] [Indexed: 12/31/2022]
Abstract
Rotenone has recently been widely used to establish Parkinson’s disease (PD) models to replicate the features of PD. However, the mechanisms involved in rotenone neurotoxicity have not been elucidated. The aim of the present study was to identify the neurotoxicity of rotenone through intraperitoneal injection in mice and to investigate the global changes of phosphorylation proteomic profiles in rotenone-injured SH-SY5Y cells through a label-free proteomic analysis using a PTMScan with LC–MS/MS. ICR (Institute of Cancer Research) mice were intraperitoneally injected with different dosages of rotenone (1 mg/kg/d or 3 mg/kg/d) daily for 21 consecutive days. Rotenone caused a dose-dependent decrease in locomotor activities and a decrease in the number of Nissl-positive and tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra pars compacta (SNpc). Here, 194 phosphopeptides on 174 proteins were detected in SH-SY5Y cells, and 37 phosphosites on 33 proteins displayed statistically significant changes in expression after rotenone injury. The downregulation of phosphorylated Akt and mTOR was further confirmed by western blot analysis. A specific Akt activator, SC79, could protect cell viability and induce autophagy in rotenone-injured SH-SY5Y cells. This study indicates the involvement of the Akt/mTOR (mammalian target of rapamycin) signaling pathway in rotenone-injured SH-SY5Y cells and provides molecular information for the neurotoxicity of rotenone.
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Affiliation(s)
- Yu Zhang
- School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, China.
| | - Hui Guo
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, China.
| | - Xinyu Guo
- School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, China.
| | - Denfeng Ge
- School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, China.
| | - Yue Shi
- School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, China.
| | - Xiyu Lu
- School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, China.
| | - Jinli Lu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, China.
| | - Juan Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, China.
| | - Fei Ding
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, China.
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, 20 Xisi Road, Nantong 226001, China.
| | - Qi Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, China.
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, 20 Xisi Road, Nantong 226001, China.
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27
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Lu Y, Li C, Chen Q, Liu P, Guo Q, Zhang Y, Chen X, Zhang Y, Zhou W, Liang D, Zhang Y, Sun T, Lu W, Jiang C. Microthrombus-Targeting Micelles for Neurovascular Remodeling and Enhanced Microcirculatory Perfusion in Acute Ischemic Stroke. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1808361. [PMID: 30957932 DOI: 10.1002/adma.201808361] [Citation(s) in RCA: 113] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 03/13/2019] [Indexed: 06/09/2023]
Abstract
Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, and brain vascular impairment occur within neurovascular units, leading to microthrombus formation and ultimate neuron death. In this work, a multitarget micelle system is developed to simultaneously modulate various cell types involved in these events. Briefly, rapamycin is encapsulated in self-assembled micelles that are consisted of reactive oxygen species (ROS)-responsive and fibrin-binding polymers to achieve micelle retention and controlled drug release within the ischemic lesion. Neuron survival is reinforced by the combination of micelle facilitated ROS elimination and antistress signaling pathway interference under ischemia conditions. In vivo results demonstrate an overall remodeling of neurovascular unit through micelle polarized M2 microglia repair and blood-brain barrier preservation, leading to enhanced neuroprotection and blood perfusion. This strategy gives a proof of concept that neurovascular units can serve as an integrated target for ischemic stroke treatment with nanomedicines.
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Affiliation(s)
- Yifei Lu
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
- National Pharmaceutical Engineering and Research Center, China State Institute of Pharmaceutical Industry, Shanghai, 201203, China
| | - Chao Li
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Qinjun Chen
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Peixin Liu
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Qin Guo
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Yu Zhang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Xinli Chen
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Yujie Zhang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Wenxi Zhou
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Donghui Liang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Yiwen Zhang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Tao Sun
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Weigen Lu
- National Pharmaceutical Engineering and Research Center, China State Institute of Pharmaceutical Industry, Shanghai, 201203, China
| | - Chen Jiang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China
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28
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Garza-Lombó C, Petrosyan P, Tapia-Rodríguez M, Valdovinos-Flores C, Gonsebatt ME. Systemic L-buthionine-S-R-sulfoximine administration modulates glutathione homeostasis via NGF/TrkA and mTOR signaling in the cerebellum. Neurochem Int 2018; 121:8-18. [PMID: 30300680 DOI: 10.1016/j.neuint.2018.10.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 10/02/2018] [Accepted: 10/03/2018] [Indexed: 12/11/2022]
Abstract
Glutathione (GSH) is an essential component of intracellular antioxidant systems that plays a primordial role in the protection of cells against oxidative stress, maintaining redox homeostasis and xenobiotic detoxification. GSH synthesis in the brain is limited by the availability of cysteine and glutamate. Cystine, the disulfide form of cysteine is transported into endothelial cells of the blood-brain barrier (BBB) and astrocytes via the system xc-, which is composed of xCT and the heavy chain of 4F2 cell surface antigen (4F2hc). Cystine is reduced inside the cells and the L-type amino acid transporter 1 (LAT1) transports cysteine from the endothelial cells into the brain, cysteine is transported into the neurons through the excitatory amino acid transporter 3 (EAAT3), also known as excitatory amino acid carrier 1 (EAAC1). The mechanistic/mammalian target of rapamycin (mTOR) and neurotrophins can activate signaling pathways that modulate amino acid transporters for GSH synthesis. The present study found that systemic L-buthionine-S-R-sulfoximine (BSO) administration selectively altered GSH homeostasis and EAAT3 levels in the mice cerebellum. Intraperitoneal treatment of mice with 6 mmol/kg of BSO depleted GSH and GSSG in the liver at 2 h of treatment. The cerebellum, but not other brain regions, exhibited a redox response. The mTOR and the neuronal growth factor (NGF)/tropomyosin receptor kinase A (TrkA) signaling pathways were activated and lead to an increase in the protein levels of the EAAT3 transporter, which was linked to an increase in the GSH/GSSG ratio and GSH concentration in the cerebellum at 0.5 and 2 h, respectively. Therefore, the cerebellum responds to peripheral GSH depletion via activation of the mTOR and NGF/TrkA pathways, which increase the transport of cysteine for GSH synthesis.
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Affiliation(s)
- Carla Garza-Lombó
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
| | - Pavel Petrosyan
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
| | - Miguel Tapia-Rodríguez
- Unidad de Microscopía, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
| | - Cesar Valdovinos-Flores
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
| | - María E Gonsebatt
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
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29
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Pharmacological reactivation of inactive X-linked Mecp2 in cerebral cortical neurons of living mice. Proc Natl Acad Sci U S A 2018; 115:7991-7996. [PMID: 30012595 DOI: 10.1073/pnas.1803792115] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Rett syndrome (RTT) is a genetic disorder resulting from a loss-of-function mutation in one copy of the X-linked gene methyl-CpG-binding protein 2 (MECP2). Typical RTT patients are females and, due to random X chromosome inactivation (XCI), ∼50% of cells express mutant MECP2 and the other ∼50% express wild-type MECP2. Cells expressing mutant MECP2 retain a wild-type copy of MECP2 on the inactive X chromosome (Xi), the reactivation of which represents a potential therapeutic approach for RTT. Previous studies have demonstrated reactivation of Xi-linked MECP2 in cultured cells by biological or pharmacological inhibition of factors that promote XCI (called "XCI factors" or "XCIFs"). Whether XCIF inhibitors in living animals can reactivate Xi-linked MECP2 in cerebral cortical neurons, the cell type most therapeutically relevant to RTT, remains to be determined. Here, we show that pharmacological inhibitors targeting XCIFs in the PI3K/AKT and bone morphogenetic protein signaling pathways reactivate Xi-linked MECP2 in cultured mouse fibroblasts and human induced pluripotent stem cell-derived postmitotic RTT neurons. Notably, reactivation of Xi-linked MECP2 corrects characteristic defects of human RTT neurons including reduced soma size and branch points. Most importantly, we show that intracerebroventricular injection of the XCIF inhibitors reactivates Xi-linked Mecp2 in cerebral cortical neurons of adult living mice. In support of these pharmacological results, we also demonstrate genetic reactivation of Xi-linked Mecp2 in cerebral cortical neurons of living mice bearing a homozygous XCIF deletion. Collectively, our results further establish the feasibility of pharmacological reactivation of Xi-linked MECP2 as a therapeutic approach for RTT.
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30
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Maiese K. Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer. Curr Neurovasc Res 2018; 14:299-304. [PMID: 28721811 DOI: 10.2174/1567202614666170718092010] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 06/22/2017] [Accepted: 07/06/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND The mammalian circadian clock and its associated clock genes are increasingly been recognized as critical components for a number of physiological and disease processes that extend beyond hormone release, thermal regulation, and sleep-wake cycles. New evidence suggests that clinical behavior disruptions that involve prolonged shift work and even space travel may negatively impact circadian rhythm and lead to multi-system disease. METHODS In light of the significant role circadian rhythm can hold over the body's normal physiology as well as disease processes, we examined and discussed the impact circadian rhythm and clock genes hold over lifespan, neurodegenerative disorders, and tumorigenesis. RESULTS In experimental models, lifespan is significantly reduced with the introduction of arrhythmic mutants and leads to an increase in oxidative stress exposure. Interestingly, patients with Alzheimer's disease and Parkinson's disease may suffer disease onset or progression as a result of alterations in the DNA methylation of clock genes as well as prolonged pharmacological treatment for these disorders that may lead to impairment of circadian rhythm function. Tumorigenesis also can occur with the loss of a maintained circadian rhythm and lead to an increased risk for nasopharyngeal carcinoma, breast cancer, and metastatic colorectal cancer. Interestingly, the circadian clock system relies upon the regulation of the critical pathways of autophagy, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) as well as proliferative mechanisms that involve the wingless pathway of Wnt/β-catenin pathway to foster cell survival during injury and block tumor cell growth. CONCLUSION Future targeting of the pathways of autophagy, mTOR, SIRT1, and Wnt that control mammalian circadian rhythm may hold the key for the development of novel and effective therapies against aging- related disorders, neurodegenerative disease, and tumorigenesis.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, NY. United States
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31
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Ko PY, Yang CC, Kuo YL, Su FC, Hsu TI, Tu YK, Jou IM. Schwann-Cell Autophagy, Functional Recovery, and Scar Reduction After Peripheral Nerve Repair. J Mol Neurosci 2018; 64:601-610. [PMID: 29644600 DOI: 10.1007/s12031-018-1056-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 03/06/2018] [Indexed: 12/24/2022]
Abstract
The functional outcome after peripheral nerve repair is often unpredictable for many reasons, e.g., the severity of neuronal death and scarring. Axonal degeneration significantly affects outcomes. Post-injury axonal degeneration in peripheral nerves is accompanied by myelin degradation initiated by Schwann cells (SCs), which activate autophagy, a ubiquitous cytoprotective process essential for degrading and recycling cellular constituents. Scar formation occurs concomitantly with nerve insult and axonal degeneration. The association between SC autophagy and the mechanisms of nerve scar formation is still unknown. A rat model of peripheral nerve lesions induced by sciatic nerve transection injuries was used to examine the function of autophagy in fibrosis reduction during the early phase of nerve repair. Rats were treated with rapamycin (autophagy inducer) or 3-methyladenine (autophagy inhibitor). One week after the nerve damage, fibrosis was potently inhibited in rapamycin-treated rats and, based on gait analysis, yielded a better functional outcome. Immunohistochemistry showed that the autophagic activity of SCs and the accumulation of neurofilaments were upregulated in rapamycin-treated rats. A deficiency of SC autophagic activity might be an early event in nerve scar formation, and modulating autophagy might be a powerful pharmacological approach for improving functional outcomes.
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Affiliation(s)
- Po-Yen Ko
- Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.,Department of Orthopedics, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Cheng-Chang Yang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yao-Lung Kuo
- Department of Plastic Surgeon, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Fong-Chin Su
- Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan
| | - Tai-I Hsu
- Department of Orthopedics, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Yuan-Kun Tu
- Department of Orthopedics, E-Da Hospital, Kaohsiung, Taiwan.
| | - I-Ming Jou
- Department of Orthopedics, E-Da Hospital, Kaohsiung, Taiwan.
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32
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The mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (SIRT1): oversight for neurodegenerative disorders. Biochem Soc Trans 2018. [PMID: 29523769 DOI: 10.1042/bst20170121] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
As a result of the advancing age of the global population and the progressive increase in lifespan, neurodegenerative disorders continue to increase in incidence throughout the world. New strategies for neurodegenerative disorders involve the novel pathways of the mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) that can modulate pathways of apoptosis and autophagy. The pathways of mTOR and SIRT1 are closely integrated. mTOR forms the complexes mTOR Complex 1 and mTOR Complex 2 and can impact multiple neurodegenerative disorders that include Alzheimer's disease, Huntington's disease, and Parkinson's disease. SIRT1 can control stem cell proliferation, block neuronal injury through limiting programmed cell death, drive vascular cell survival, and control clinical disorders that include dementia and retinopathy. It is important to recognize that oversight of programmed cell death by mTOR and SIRT1 requires a fine degree of precision to prevent the progression of neurodegenerative disorders. Additional investigations and insights into these pathways should offer effective and safe treatments for neurodegenerative disorders.
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33
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Qu Z, D'Mello SR. Proteomic analysis identifies NPTX1 and HIP1R as potential targets of histone deacetylase-3-mediated neurodegeneration. Exp Biol Med (Maywood) 2018; 243:627-638. [PMID: 29486577 DOI: 10.1177/1535370218761149] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
A defining feature of neurodegenerative diseases is the abnormal and excessive loss of neurons. One molecule that is particularly important in promoting neuronal death in a variety of cell culture and in vivo models of neurodegeneration is histone deacetylase-3 (HDAC3), a member of the histone deacetylase family of proteins. As a step towards understanding how HDAC3 promotes neuronal death, we conducted a proteomic screen aimed at identifying proteins that were regulated by HDAC3. HDAC3 was overexpressed in cultured rat cerebellar granule neurons (CGNs) and protein lysates were analyzed by mass spectrometry. Of over 3000 proteins identified in the screen, only 21 proteins displayed a significant alteration in expression. Of these, 12 proteins were downregulated whereas 9 proteins were upregulated. The altered expression of five of these proteins, TEX10, NPTX1, TFG, TSC1, and NFL, along with another protein that was downregulated in the proteomic screen, HIP1R, was confirmed using Western blots and commercially available antibodies. Because antibodies were not available for some of the proteins and since HDAC3 is a transcriptional regulator of gene expression, we conducted RT-PCR analysis to confirm expression changes. In separate analyses, we also included other proteins that are known to regulate neurodegeneration, including HDAC9, HSF1, huntingtin, GAPDH, FUS, and p65/RELA. Based on our proteomic screen and candidate protein approach, we identify three genes, Nptx1, Hip1r, and Hdac9, all known to regulate neurodegeneration that are robustly regulated by HDAC3. Given their suggested roles in regulating neuronal death, these genes are likely to be involved in regulating HDAC3-mediated neurotoxicity. Impact statement Neurodegenerative diseases are a major medical, social, and economic problem. Recent studies by several laboratories have indicated that histone deacetylase-3 (HDAC3) plays a key role in promoting neuronal death. But the downstream mediators of HDAC3 neurotoxicity have yet to be identified. We conducted a proteomic screen to identify HDAC3 targets the results of which have been described in this report. Briefly, we identify Nptx1, Hip1r, and Hdac9 as genes whose expression is altered by HDAC3. Investigating how these genes are involved in HDAC3 neurotoxicity could shed valuable insight into neurodegenerative disease and identify molecules that can be targeted to treat these devastating disorders.
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Affiliation(s)
- Zhe Qu
- Department of Biological Sciences, Southern Methodist University, Dallas, TX 75275, USA
| | - Santosh R D'Mello
- Department of Biological Sciences, Southern Methodist University, Dallas, TX 75275, USA
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Role of Forkhead Box O (FOXO) transcription factor in aging and diseases. Gene 2018; 648:97-105. [PMID: 29428128 DOI: 10.1016/j.gene.2018.01.051] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 12/26/2017] [Accepted: 01/14/2018] [Indexed: 12/21/2022]
Abstract
Fork head box O (FOXO) transcription factor is a key player in an evolutionarily conserved pathway. The mammalian FOXO family consists of FOXO1, 3, 4 and 6, are highly similar in their structure, function and regulation. To maintain optimum body function, the organisms have developed complex mechanisms for homeostasis. Importantly, it is well known that when these mechanisms dysregulate it results in the development of age-related disease. FOXO proteins are involved in a diverse cellular function and also have clinical significance including cell cycle arrest, cell differentiation, tumour suppression, DNA repair, longevity, diabetic complications, immunity, wound healing, regulation of metabolism and thus treatment of several types of diseases. By the combinations of post-translational modifications FOXO's serve as a 'molecular code' to sense external stimuli and recruit it as to specific regions of the genome and provide an integrated cellular response to changing physiological conditions. Akt/Protein kinase B a signaling pathway as a main regulator of FOXO to perform a diverse function in organisms. The present review summarizes the molecular and clinical aspects of FOXO transcription factor. And also elaborate the interaction of FOXO with the nucleosome remodelling complex to target genes, which is essential to cellular homeostasis.
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Maiese K. Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors. Curr Neurovasc Res 2018; 15:81-91. [PMID: 29557749 PMCID: PMC6021214 DOI: 10.2174/1567202615666180319151244] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 01/23/2018] [Accepted: 02/07/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND With the global increase in lifespan expectancy, neurodegenerative disorders continue to affect an ever-increasing number of individuals throughout the world. New treatment strategies for neurodegenerative diseases are desperately required given the lack of current treatment modalities. METHODS Here, we examine novel strategies for neurodegenerative disorders that include circadian clock genes, non-coding Ribonucleic Acids (RNAs), and the mammalian forkhead transcription factors of the O class (FoxOs). RESULTS Circadian clock genes, non-coding RNAs, and FoxOs offer exciting prospects to potentially limit or remove the significant disability and death associated with neurodegenerative disorders. Each of these pathways has an intimate relationship with the programmed death pathways of autophagy and apoptosis and share a common link to the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and the mechanistic target of rapamycin (mTOR). Circadian clock genes are necessary to modulate autophagy, limit cognitive loss, and prevent neuronal injury. Non-coding RNAs can control neuronal stem cell development and neuronal differentiation and offer protection against vascular disease such as atherosclerosis. FoxOs provide exciting prospects to block neuronal apoptotic death and to activate pathways of autophagy to remove toxic accumulations in neurons that can lead to neurodegenerative disorders. CONCLUSION Continued work with circadian clock genes, non-coding RNAs, and FoxOs can offer new prospects and hope for the development of vital strategies for the treatment of neurodegenerative diseases. These innovative investigative avenues have the potential to significantly limit disability and death from these devastating disorders.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101
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Wu M, Zhang H, Kai J, Zhu F, Dong J, Xu Z, Wong M, Zeng LH. Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats. Ann Clin Transl Neurol 2017; 5:138-146. [PMID: 29468175 PMCID: PMC5817831 DOI: 10.1002/acn3.507] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 10/31/2017] [Accepted: 11/01/2017] [Indexed: 12/13/2022] Open
Abstract
Objective Whether activation or inhibition of the mTOR pathway is beneficial to ischemic injury remains controversial. It may result from the different reaction of ischemic penumbra and core to modulation of mTOR pathway after cerebral ischemia-reperfusion injury in rats. Methods Longa's middle cerebral artery occlusion (MCAO) method was conducted to induce the focal cerebral ischemia-reperfusion. Western blot analysis was used to examine the protein expression involving mTOR pathway, apoptosis, and autophagy-related proteins. TTC staining and Fluoro-Jade B staining was conducted to detect the infarct volume and cell apoptosis, respectively. Neurological function was measured by modified neurological severity score and left-biased swing. Results mTOR signaling pathway was activated in ischemic penumbra and decreased in ischemic core after ischemia and ischemia-reperfusion. Ischemia-reperfusion injury induced the increase in cleaved caspase 9 and caspase 3 both in ischemic penumbra and in ischemic core, whereas the expression of phosphorylated ULK1, Beclin 1 and LC3-II was decreased. Rapamycin pre or postadministration inhibited the overactivation of mTOR pathway in ischemic penumbra. Ameliorated neurological function and reduced infarct volume were observed after pre or postrapamycin treatment. Rapamycin markedly decreased the number of FJB-positive cells and the expression of cleaved caspase-3 and cleaved caspase-9 proteins as well as increased the activation of autophagy reflected by ULK1, Beclin-1 and LC3. Interpretation mTOR signaling pathway was activated in ischemic penumbra after cerebral ischemia-reperfusion injury in rats. mTOR inhibitor rapamycin significantly decreased the mTOR activation and infarct volume and subsequently improved neurological function. These results may relate to inhibition of neuron apoptosis and activation of autophagy.
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Affiliation(s)
- Meiling Wu
- Department of Pharmacology School of Medicine Zhejiang University City College Hangzhou Zhejiang 310015 China
| | - Huadan Zhang
- Department of Pharmacology School of Medicine Zhejiang University City College Hangzhou Zhejiang 310015 China
| | - Jiejing Kai
- Department of Pharmacology School of Medicine Zhejiang University City College Hangzhou Zhejiang 310015 China
| | - Feng Zhu
- Department of Pharmacology School of Medicine Zhejiang University City College Hangzhou Zhejiang 310015 China
| | - Jingyin Dong
- Department of Pharmacology School of Medicine Zhejiang University City College Hangzhou Zhejiang 310015 China
| | - Ziwei Xu
- Department of Pharmacology School of Medicine Zhejiang University City College Hangzhou Zhejiang 310015 China
| | - Michael Wong
- Department of Neurology School of Medicine Washington University in St. Louis Saint Louis Missouri 63110
| | - Ling-Hui Zeng
- Department of Pharmacology School of Medicine Zhejiang University City College Hangzhou Zhejiang 310015 China
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Anilkumar U, Weisova P, Schmid J, Bernas T, Huber HJ, Düssmann H, Connolly NMC, Prehn JHM. Defining external factors that determine neuronal survival, apoptosis and necrosis during excitotoxic injury using a high content screening imaging platform. PLoS One 2017; 12:e0188343. [PMID: 29145487 PMCID: PMC5690623 DOI: 10.1371/journal.pone.0188343] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 11/06/2017] [Indexed: 12/27/2022] Open
Abstract
Cell death induced by excessive glutamate receptor overactivation, excitotoxicity, has been implicated in several acute and chronic neurological disorders. While numerous studies have demonstrated the contribution of biochemically and genetically activated cell death pathways in excitotoxic injury, the factors mediating passive, excitotoxic necrosis are less thoroughly investigated. To address this question, we developed a high content screening (HCS) based assay to collect high volumes of quantitative cellular imaging data and elucidated the effects of intrinsic and external factors on excitotoxic necrosis and apoptosis. The analysis workflow consisted of robust nuclei segmentation, tracking and a classification algorithm, which enabled automated analysis of large amounts of data to identify and quantify viable, apoptotic and necrotic neuronal populations. We show that mouse cerebellar granule neurons plated at low or high density underwent significantly increased necrosis compared to neurons seeded at medium density. Increased extracellular Ca2+ sensitized neurons to glutamate-induced excitotoxicity, but surprisingly potentiated cell death mainly through apoptosis. We also demonstrate that inhibition of various cell death signaling pathways (including inhibition of calpain, PARP and AMPK activation) primarily reduced excitotoxic apoptosis. Excitotoxic necrosis instead increased with low extracellular glucose availability. Our study is the first of its kind to establish and implement a HCS based assay to investigate the contribution of external and intrinsic factors to excitotoxic apoptosis and necrosis.
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Affiliation(s)
- Ujval Anilkumar
- Department of Physiology and Medical Physics and RCSI Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Petronela Weisova
- Department of Physiology and Medical Physics and RCSI Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jasmin Schmid
- Department of Physiology and Medical Physics and RCSI Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Tytus Bernas
- Department of Physiology and Medical Physics and RCSI Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Heinrich J. Huber
- Department of Physiology and Medical Physics and RCSI Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Heiko Düssmann
- Department of Physiology and Medical Physics and RCSI Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Niamh M. C. Connolly
- Department of Physiology and Medical Physics and RCSI Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jochen H. M. Prehn
- Department of Physiology and Medical Physics and RCSI Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- * E-mail:
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Maiese K. Forkhead Transcription Factors: Formulating a FOXO Target for Cognitive Loss. Curr Neurovasc Res 2017; 14:415-420. [PMID: 29149835 PMCID: PMC5792363 DOI: 10.2174/1567202614666171116102911] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 10/22/2017] [Accepted: 10/30/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND With almost 47 million individuals worldwide suffering from some aspect of dementia, it is clear that cognitive loss impacts a significant proportion of the global population. Unfortunately, definitive treatments to resolve or prevent the onset of cognitive loss are limited. In most cases such care is currently non-existent prompting the need for novel treatment strategies. METHODS Mammalian forkhead transcription factors of the O class (FoxO) are one such avenue of investigation that offer an exciting potential to bring new treatments forward for disorders that involve cognitive loss. Here we examine the background, structure, expression, and function of FoxO transcription factors and their role in cognitive loss, programmed cell death in the nervous system with apoptosis and autophagy, and areas to target FoxOs for dementia and specific disorders such as Alzheimer's disease. RESULTS FoxO proteins work in concert with a number of other cell survival pathways that involve growth factors, such as erythropoietin and neurotrophins, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), Wnt signaling, and cancer-related pathways. FoxO transcription factors oversee proinflammatory pathways, affect nervous system amyloid (Aβ) production and toxicity, lead to mitochondrial dysfunction, foster neuronal apoptotic cell death, and accelerate the progression of degenerative disease. However, under some scenarios such as those involving autophagy, FoxOs also can offer protection in the nervous system and reduce toxic intracellular protein accumulations and potentially limit Aβ toxicity. CONCLUSION Given the ability of FoxOs to not only promote apoptotic cell death in the nervous system, but also through the induction of autophagy offer protection against degenerative disease that can lead to dementia, a fine balance in the activity of FoxOs may be required to target cognitive loss in individuals. Future work should yield exciting new prospects for FoxO proteins as new targets to treat the onset and progression of cognitive loss and dementia.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101
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Maiese K. Harnessing the Power of SIRT1 and Non-coding RNAs in Vascular Disease. Curr Neurovasc Res 2017; 14:82-88. [PMID: 27897112 PMCID: PMC5383524 DOI: 10.2174/1567202613666161129112822] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 10/31/2016] [Accepted: 11/14/2016] [Indexed: 02/06/2023]
Abstract
Noncommunicable diseases (NCDs) contribute to a significant amount of disability and death in the world. Of these disorders, vascular disease is ranked high, falls within the five leading causes of death, and impacts multiple other disease entities such as those of the cardiac system, nervous system, and metabolic disease. Targeting the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) pathway and the modulation of micro ribonucleic acids (miRNAs) may hold great promise for the development of novel strategies for the treatment of vascular disease since each of these pathways are highly relevant to cardiac and nervous system disorders as well as to metabolic dysfunction. SIRT1 is vital in determining the course of stem cell development and the survival, metabolism, and life span of differentiated cells that are overseen by both autophagy and apoptosis. SIRT1 interfaces with a number of pathways that involve forkhead transcription factors, mechanistic of rapamycin (mTOR), AMP activated protein kinase (AMPK) and Wnt1 inducible signaling pathway protein 1 (WISP1) such that the level of activity of SIRT1 can become a critical determinant for biological and clinical outcomes. The essential fine control of SIRT1 is directly tied to the world of non-coding RNAs that ultimately oversee SIRT1 activity to either extend or end cellular survival. Future studies that can further elucidate the crosstalk between SIRT1 and non-coding RNAs should serve well our ability to harness the power of SIRT1 and non-coding RNAs for the treatment of vascular disorders.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101
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Park YS, Park JH, Ko J, Shin IC, Koh HC. mTOR inhibition by rapamycin protects against deltamethrin-induced apoptosis in PC12 Cells. ENVIRONMENTAL TOXICOLOGY 2017; 32:109-121. [PMID: 26588882 DOI: 10.1002/tox.22216] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Revised: 10/21/2015] [Accepted: 11/01/2015] [Indexed: 06/05/2023]
Abstract
The autophagy pathway can be induced and upregulated in response to intracellular reactive oxygen species (ROS). In this study, we explored a novel pharmacotherapeutic approach involving the regulation of autophagy to prevent deltamethrin (DLM) neurotoxicity. We found that DLM-induced apoptosis in PC12 cells, as demonstrated by the activation of caspase-3 and -9 and by nuclear condensation. DLM treatment significantly decreased dopamine (DA) levels in PC12 cells. In addition, we observed that cells treated with DLM underwent autophagic cell death, by monitoring the expression of LC3-II, p62, and Beclin-1. Exposure of PC12 cells to DLM led to the production of ROS. Treatment with N-acetyl cysteine (NAC) effectively blocked both apoptosis and autophagy. In addition, mitogen-activated protein kinase (MAPK) inhibitors attenuated apoptosis as well as autophagic cell death. We also investigated the modulation of DLM-induced apoptosis in response to autophagy regulation. Pretreatment with the autophagy inducer, rapamycin, significantly enhanced the viability of DLM-exposed cells, and this enhancement of cell viability was partially due to alleviation of DLM-induced apoptosis via a decrease in levels of cleaved caspase-3. However, pretreatment of cells with the autophagy inhibitor, 3-methyladenine (3MA), significantly increased DLM toxicity in these cells. Our results suggest that DLM-induced cytotoxicity is modified by autophagy regulation and that rapamycin protects against DLM-induced apoptosis by enhancing autophagy. Pharmacologic induction of autophagy by rapamycin may be a useful treatment strategy in neurodegenerative disorders. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 109-121, 2017.
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Affiliation(s)
- Yun Sun Park
- Department of Pharmacology, College of Medicine, Hanyang University, Korea
- Hanyang Biomedical Research Institute, Seoul, Republic of Korea
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea
| | - Jae Hyeon Park
- Department of Pharmacology, College of Medicine, Hanyang University, Korea
- Hanyang Biomedical Research Institute, Seoul, Republic of Korea
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea
| | - Juyeon Ko
- Department of Pharmacology, College of Medicine, Hanyang University, Korea
- Hanyang Biomedical Research Institute, Seoul, Republic of Korea
| | - In Chul Shin
- Department of Pharmacology, College of Medicine, Hanyang University, Korea
- Hanyang Biomedical Research Institute, Seoul, Republic of Korea
| | - Hyun Chul Koh
- Department of Pharmacology, College of Medicine, Hanyang University, Korea
- Hanyang Biomedical Research Institute, Seoul, Republic of Korea
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea
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Santulli C, Brizi C, Micucci M, Del Genio A, De Cristofaro A, Bracco F, Pepe GL, di Perna I, Budriesi R, Chiarini A, Frosini M. Castanea sativa Mill. Bark Extract Protects U-373 MG Cells and Rat Brain Slices Against Ischemia and Reperfusion Injury. J Cell Biochem 2016; 118:839-850. [PMID: 27739104 DOI: 10.1002/jcb.25760] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 10/10/2016] [Indexed: 12/26/2022]
Abstract
Ischemic brain injury is one of the most important causes of death worldwide. The use of one-drug-multi-target agents based on natural compounds is a promising therapeutic option for cerebral ischemia due to their pleiotropic properties. This study assessed the neuroprotective properties of Castanea sativa Mill. bark extract (ENC) in human astrocytoma U-373 MG cells subjected to oxygen-glucose deprivation and reperfusion and rat cortical slices subjected to ischemia-like conditions or treated with glutamate or hydrogen peroxide. Neuroprotective effects were determined by assessing cells or slices viability (MTT assay), ROS formation (DCFH-DA assay), apoptosis (sub G0/G1 peak), nuclear fragmentation and chromatin condensation (DAPI staining) as well as changes in lysosomes and mitochondria morphology (Acridine Orange and Rhodamine123 staining, respectively). ENC treatment before injury on U-373 MG cells (5-50 μg/ml) and cortical slices (50-100 μg/ml) provided neuroprotection, while lower or higher concentrations (100 μg/ml U-373 MG cells, 200 μg/ml brain slices) were ineffective. ENC addition during reperfusion or after the injury was not found to be effective. The results suggest that ENC might hold potential as preventive neuroprotective agent, and indicate the importance of further studies exploring its mechanism of action. J. Cell. Biochem. 118: 839-850, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Chiara Santulli
- Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro 2-53100, Siena, Italy
| | - Claudia Brizi
- Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro 2-53100, Siena, Italy
| | - Matteo Micucci
- Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Belmeloro 6-40126, Bologna, Italy
| | - Ambra Del Genio
- Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro 2-53100, Siena, Italy
| | - Assunta De Cristofaro
- Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro 2-53100, Siena, Italy
| | - Federica Bracco
- Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro 2-53100, Siena, Italy
| | - Giuseppina Lucia Pepe
- Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro 2-53100, Siena, Italy
| | - Ilaria di Perna
- Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro 2-53100, Siena, Italy
| | - Roberta Budriesi
- Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Belmeloro 6-40126, Bologna, Italy
| | - Alberto Chiarini
- Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Belmeloro 6-40126, Bologna, Italy
| | - Maria Frosini
- Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro 2-53100, Siena, Italy
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Kim D, Hwang HY, Kim JY, Lee JY, Yoo JS, Marko-Varga G, Kwon HJ. FK506, an Immunosuppressive Drug, Induces Autophagy by Binding to the V-ATPase Catalytic Subunit A in Neuronal Cells. J Proteome Res 2016; 16:55-64. [PMID: 28056508 DOI: 10.1021/acs.jproteome.6b00638] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The drug FK506 (tacrolimus, fujimycin) exerts its immunosuppressive effects by regulating the nuclear factor of the activated T-cell (NFAT) family of transcription factors. However, FK506 also exhibits neuroprotective effects, but its direct target proteins that mediate these effects have not been determined. To identify the target proteins responsible for FK506's neuroprotective effects, the drug affinity responsive target stability (DARTS) method was performed using label-free FK506, and LC-MS/MS analysis of the FK506-treated proteome was also performed. Using DARTS and LC-MS/MS analyses in combination with reference studies, V-ATPase catalytic subunit A (ATP6V1A) was identified as a new target protein of FK506. The biological relevance of ATP6V1A in mediating the neuroprotective effects of FK506 was validated by analyzing FK506 activity with respect to autophagy via acridine orange staining and transcription factor EB (TFEB) translocation assay. These analyses demonstrated that the binding of FK506 with ATP6V1A induces autophagy by activating the translocation of TFEB from the cytosol into the nucleus. Because autophagy has been identified as a mechanism for treating neurodegenerative diseases and because we have demonstrated that FK506 induces autophagy, this study demonstrates that FK506 is a possible new therapy for treating neurodegenerative diseases.
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Affiliation(s)
- Dongyoung Kim
- Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University , Seoul 120-749, Korea
| | - Hui-Yun Hwang
- Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University , Seoul 120-749, Korea
| | - Jin Young Kim
- Biomedical Omics Group, Korea Basic Science Institute , Ochang, Chungbuk 28119, Korea
| | - Ju Yeon Lee
- Biomedical Omics Group, Korea Basic Science Institute , Ochang, Chungbuk 28119, Korea
| | - Jong Shin Yoo
- Biomedical Omics Group, Korea Basic Science Institute , Ochang, Chungbuk 28119, Korea
| | - György Marko-Varga
- Clinical Protein Science & Imaging, Biomedical Center, Department of Biomedical Engineering, Lund University , BMC D13, SE-221 84 Lund, Sweden
| | - Ho Jeong Kwon
- Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University , Seoul 120-749, Korea.,Department of Internal Medicine, College of Medicine, Yonsei University , Seoul 120-752, Korea
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Maiese K. Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders. Br J Clin Pharmacol 2016; 82:1245-1266. [PMID: 26469771 PMCID: PMC5061806 DOI: 10.1111/bcp.12804] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Revised: 10/11/2015] [Accepted: 10/13/2015] [Indexed: 12/14/2022] Open
Abstract
Neurodegenerative disorders are significantly increasing in incidence as the age of the global population continues to climb with improved life expectancy. At present, more than 30 million individuals throughout the world are impacted by acute and chronic neurodegenerative disorders with limited treatment strategies. The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin, is a 289 kDa serine/threonine protein kinase that offers exciting possibilities for novel treatment strategies for a host of neurodegenerative diseases that include Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, stroke and trauma. mTOR governs the programmed cell death pathways of apoptosis and autophagy that can determine neuronal stem cell development, precursor cell differentiation, cell senescence, cell survival and ultimate cell fate. Coupled to the cellular biology of mTOR are a number of considerations for the development of novel treatments involving the fine control of mTOR signalling, tumourigenesis, complexity of the apoptosis and autophagy relationship, functional outcome in the nervous system, and the intimately linked pathways of growth factors, phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation two homologue one (Saccharomyces cerevisiae) (SIRT1) and others. Effective clinical translation of the cellular signalling mechanisms of mTOR offers provocative avenues for new drug development in the nervous system tempered only by the need to elucidate further the intricacies of the mTOR pathway.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey, 07101, USA.
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Autophagy Promoted the Degradation of Mutant ATXN3 in Neurally Differentiated Spinocerebellar Ataxia-3 Human Induced Pluripotent Stem Cells. BIOMED RESEARCH INTERNATIONAL 2016; 2016:6701793. [PMID: 27847820 PMCID: PMC5099487 DOI: 10.1155/2016/6701793] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 08/30/2016] [Accepted: 09/18/2016] [Indexed: 11/18/2022]
Abstract
Spinocerebellar ataxia-3 (SCA3) is the most common dominant inherited ataxia worldwide and is caused by an unstable CAG trinucleotide expansion mutation within the ATXN3 gene, resulting in an expanded polyglutamine tract within the ATXN3 protein. Many in vitro studies have examined the role of autophagy in neurodegenerative disorders, including SCA3, using transfection models with expression of pathogenic proteins in normal cells. In the current study, we aimed to develop an improved model for studying SCA3 in vitro using patient-derived cells. The patient-derived iPS cells presented a phenotype similar to that of human embryonic stem cells and could be differentiated into neurons. Additionally, these cells expressed abnormal ATXN3 protein without changes in the CAG repeat length during culture for at least 35 passages as iPS cells, up to 3 passages as neural stem cells, and after 4 weeks of neural differentiation. Furthermore, we demonstrated that neural differentiation in these iPS cells was accompanied by autophagy and that rapamycin promoted autophagy through degradation of mutant ATXN3 proteins in neurally differentiated spinocerebellar ataxia-3 human induced pluripotent stem cells (p < 0.05). In conclusion, patient-derived iPS cells are a good model for studying the mechanisms of SCA3 and may provide a tool for drug discovery in vitro.
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Sulforaphane protects against rotenone-induced neurotoxicity in vivo: Involvement of the mTOR, Nrf2, and autophagy pathways. Sci Rep 2016; 6:32206. [PMID: 27553905 PMCID: PMC4995453 DOI: 10.1038/srep32206] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 08/03/2016] [Indexed: 02/06/2023] Open
Abstract
Sulforaphane, a naturally occurring compound found in cruciferous vegetables, has been shown to be neuroprotective in several neurological disorders. In this study, we sought to investigate the potential protective effects and associated molecular mechanisms of sulforaphane in an in vivo Parkinson's disease (PD) model, based on rotenone-mediated neurotoxicity. Our results showed that sulforaphane inhibited rotenone-induced locomotor activity deficiency and dopaminergic neuronal loss. Additionally, sulforaphane treatment inhibited the rotenone-induced reactive oxygen species production, malondialdehyde (MDA) accumulation, and resulted in an increased level of total glutathione and reduced glutathione (GSH): oxidized glutathione (GSSG) in the brain. Western blot analysis illustrated that sulforaphane increased the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase (NQO1), the latter two of which are anti-oxidative enzymes. Moreover, sulforaphane treatment significantly attenuated rotenone-inhibited mTOR-mediated p70S6K and 4E-BP1 signalling pathway, as well as neuronal apoptosis. In addition, sulforaphane rescued rotenone-inhibited autophagy, as detected by LC3-II. Collectively, these findings demonstrated that sulforaphane exert neuroprotective effect involving Nrf2-dependent reductions in oxidative stress, mTOR-dependent inhibition of neuronal apoptosis, and the restoration of normal autophagy. Sulforaphane appears to be a promising compound with neuroprotective properties that may play an important role in preventing PD.
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Liu P, Yang X, Hei C, Meli Y, Niu J, Sun T, Li PA. Rapamycin Reduced Ischemic Brain Damage in Diabetic Animals Is Associated with Suppressions of mTOR and ERK1/2 Signaling. Int J Biol Sci 2016; 12:1032-40. [PMID: 27489506 PMCID: PMC4971741 DOI: 10.7150/ijbs.15624] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 05/28/2016] [Indexed: 12/17/2022] Open
Abstract
The objectives of the present study are to investigate the activation of mTOR and ERK1/2 signaling after cerebral ischemia in diabetic rats and to examine the neuroprotective effects of rapamycin. Ten minutes transient global cerebral ischemia was induced in straptozotocin-induced diabetic hyperglycemic rats and non-diabetic, euglycemic rats. Brain samples were harvested after 16 h of reperfusion. Rapamycin or vehicle was injected 1 month prior to the induction of ischemia. The results showed that diabetes increased ischemic neuronal cell death and associated with elevations of p-P70S6K and Ras/ERK1/2 and suppression of p-AMPKα. Rapamycin ameliorated diabetes-enhanced ischemic brain damage and suppressed phosphorylation of P70S6K and ERK1/2. It is concluded that diabetes activates mTOR and ERK1/2 signaling pathways in rats subjected to transient cerebral ischemia and inhibition of mTOR by rapamycin reduces ischemic brain damage and suppresses the mTOR and ERK1/2 signaling in diabetic settings.
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Affiliation(s)
- Ping Liu
- 1. Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan 750004, China
- 2. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USA
| | - Xiao Yang
- 2. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USA
- 3. Neuroscience Center, General Hospital of Ningcia Medical University, and Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Yinchuan 750004, China
| | - Changchun Hei
- 2. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USA
- 4. Department of Human Anatomy, Histology and Embryology, Ningxia Medical University, Yinchuan 75004, China
| | - Yvonne Meli
- 2. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USA
| | - Jianguo Niu
- 4. Department of Human Anatomy, Histology and Embryology, Ningxia Medical University, Yinchuan 75004, China
| | - Tao Sun
- 4. Department of Human Anatomy, Histology and Embryology, Ningxia Medical University, Yinchuan 75004, China
| | - P. Andy Li
- 2. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USA
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Ilex paraguariensis hydroalcoholic extract exerts antidepressant-like and neuroprotective effects: involvement of the NMDA receptor and the l-arginine-NO pathway. Behav Pharmacol 2016; 27:384-92. [DOI: 10.1097/fbp.0000000000000211] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Maiese K. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Neural Regen Res 2016; 11:372-85. [PMID: 27127460 PMCID: PMC4828986 DOI: 10.4103/1673-5374.179032] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Throughout the globe, diabetes mellitus (DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder. DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy. The mechanistic target of rapamycin (mTOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM. mTOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis, insulin resistance, insulin secretion, stem cell proliferation and differentiation, pancreatic β-cell function, and programmed cell death with apoptosis and autophagy. mTOR is central element for the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), and growth factors. As a result, mTOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease. Future studies directed to elucidate the delicate balance mTOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.
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Busse S, Steiner J, Glorius S, Dobrowolny H, Greiner-Bohl S, Mawrin C, Bommhardt U, Hartig R, Bogerts B, Busse M. VGF expression by T lymphocytes in patients with Alzheimer's disease. Oncotarget 2016; 6:14843-51. [PMID: 26142708 PMCID: PMC4558119 DOI: 10.18632/oncotarget.3569] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 02/22/2015] [Indexed: 12/21/2022] Open
Abstract
Secretion of VGF is increased in cerebrospinal fluid and blood in neurodegenerative disorders like Alzheimer's disease (AD) and VGF is a potential biomarker for these disorders. We have shown that VGF is expressed in peripheral T cells and is correlated with T cell survival and cytokine secretion. The frequency of VGF+CD3+ T cells increases with normal aging. We found an increased number of VGF-expressing T cells in patients with AD compared to aged healthy controls, which was associated with enhanced HbA1c levels in blood. Upon treatment with rivastigmine, T cell proliferation and VGF expression in AD patients decreased to the level found in controls. Moreover, rapamycin treatment in vitro reduced the number of VGF+CD3+ cells in AD patients to control levels.
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Affiliation(s)
- Stefan Busse
- Department of Psychiatry, University of Magdeburg, Magdeburg, Germany
| | - Johann Steiner
- Department of Psychiatry, University of Magdeburg, Magdeburg, Germany.,Center for Behavioral Brain Sciences, University of Magdeburg, Magdeburg, Germany
| | - Sarah Glorius
- Department of Psychiatry, University of Magdeburg, Magdeburg, Germany
| | - Henrik Dobrowolny
- Department of Psychiatry, University of Magdeburg, Magdeburg, Germany
| | | | - Christian Mawrin
- Department of Neuropathology, University of Magdeburg, Magdeburg, Germany
| | - Ursula Bommhardt
- Institute of Molecular and Clinical Immunology, University of Magdeburg, Magdeburg, Germany
| | - Roland Hartig
- Institute of Molecular and Clinical Immunology, University of Magdeburg, Magdeburg, Germany
| | - Bernhard Bogerts
- Department of Psychiatry, University of Magdeburg, Magdeburg, Germany.,Center for Behavioral Brain Sciences, University of Magdeburg, Magdeburg, Germany
| | - Mandy Busse
- Department of Pediatric Pulmonology, Allergology & Neonatology, Medical University of Hannover, Hannover, Germany
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Zhang B, Wang Y, Li H, Xiong R, Zhao Z, Chu X, Li Q, Sun S, Chen S. Neuroprotective effects of salidroside through PI3K/Akt pathway activation in Alzheimer's disease models. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:1335-43. [PMID: 27103787 PMCID: PMC4827895 DOI: 10.2147/dddt.s99958] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by deposits of aggregated amyloid-β (Aβ) peptide and neurofibrillary tangles in the brain parenchyma. Despite considerable research to elucidate the pathological mechanisms and identify therapeutic strategies for AD, effective treatments are still lacking. In the present study, we found that salidroside (Sal), a phenylpropanoid glycoside isolated from Rhodiola rosea L., can protect against Aβ-induced neurotoxicity in four transgenic Drosophila AD models. Both longevity and locomotor activity were improved in Sal-fed Drosophila. Sal also decreased Aβ levels and Aβ deposition in brain and ameliorated toxicity in Aβ-treated primary neuronal culture. The neuroprotective effect of Sal was associated with upregulated phosphatidylinositide 3-kinase (PI3K)/Akt signaling. Our findings identify a compound that may possess potential therapeutic benefits for AD and other forms of neurodegeneration.
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Affiliation(s)
- Bei Zhang
- Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; Laboratory of Neurodegenerative Diseases, The Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Ying Wang
- Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Hui Li
- Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Ran Xiong
- Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Zongbo Zhao
- Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xingkun Chu
- Laboratory of Neurodegenerative Diseases, The Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Qiongqiong Li
- Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Suya Sun
- Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Shengdi Chen
- Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; Laboratory of Neurodegenerative Diseases, The Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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