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1
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Darwish R, Alcibahy Y, Bucheeri S, Albishtawi A, Tama M, Shetty J, Butler AE. The Role of Hypothalamic Microglia in the Onset of Insulin Resistance and Type 2 Diabetes: A Neuro-Immune Perspective. Int J Mol Sci 2024; 25:13169. [PMID: 39684879 DOI: 10.3390/ijms252313169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/05/2024] [Accepted: 12/05/2024] [Indexed: 12/18/2024] Open
Abstract
Historically, microglial activation has been associated with diseases of a neurodegenerative and neuroinflammatory nature. Some, like Alzheimer's disease, Parkinson's disease, and multiple system atrophy, have been explored extensively, while others pertaining to metabolism not so much. However, emerging evidence points to hypothalamic inflammation mediated by microglia as a driver of metabolic dysregulations, particularly insulin resistance and type 2 diabetes mellitus. Here, we explore this connection further and examine pathways that underlie this relationship, including the IKKβ/NF-κβ, IRS-1/PI3K/Akt, mTOR-S6 Kinase, JAK/STAT, and PPAR-γ signaling pathways. We also investigate the role of non-coding RNAs, namely microRNAs and long non-coding RNAs, in insulin resistance related to neuroinflammation and their diagnostic and therapeutic potential. Finally, we explore therapeutics further, searching for both pharmacological and non-pharmacological interventions that can help mitigate microglial activation.
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Affiliation(s)
- Radwan Darwish
- School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain (RCSI-MUB), Busaiteen 228, Bahrain
| | - Yasmine Alcibahy
- School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain (RCSI-MUB), Busaiteen 228, Bahrain
| | - Shahd Bucheeri
- School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain (RCSI-MUB), Busaiteen 228, Bahrain
| | - Ashraf Albishtawi
- School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain (RCSI-MUB), Busaiteen 228, Bahrain
| | - Maya Tama
- School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain (RCSI-MUB), Busaiteen 228, Bahrain
| | - Jeevan Shetty
- Department of Biochemistry, Royal College of Surgeons in Ireland-Medical University of Bahrain (RCSI-MUB), Busaiteen 228, Bahrain
| | - Alexandra E Butler
- School of Postgraduate Studies and Research, Royal College of Surgeons in Ireland-Medical University of Bahrain (RCSI-MUB), Busaiteen 228, Bahrain
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2
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Zahoor I, Waters J, Ata N, Datta I, Pedersen TL, Cerghet M, Poisson L, Markovic-Plese S, Rattan R, Taha AY, Newman JW, Giri S. Blood-based targeted metabolipidomics reveals altered omega fatty acid-derived lipid mediators in relapsing-remitting multiple sclerosis patients. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.04.574253. [PMID: 38260401 PMCID: PMC10802284 DOI: 10.1101/2024.01.04.574253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Unresolved and uncontrolled inflammation is considered a hallmark of pathogenesis in chronic inflammatory diseases like multiple sclerosis (MS), suggesting a defective resolution process. Inflammatory resolution is an active process partially mediated by endogenous metabolites of dietary polyunsaturated fatty acids (PUFA), collectively termed specialized pro-resolving lipid mediators (SPMs). Altered levels of resolution mediators have been reported in several inflammatory diseases and may partly explain impaired inflammatory resolution. Performing LC-MS/MS-based targeted lipid mediator profiling, we observed distinct changes in fatty acid metabolites in serum from 30 relapsing-remitting MS (RRMS) patients relative to 30 matched healthy subjects (HS). Robust linear regression revealed 12 altered lipid mediators after adjusting for confounders (p <0.05). Of these, 15d-PGJ2, PGE3, and LTB5 were increased in MS while PGF2a, 8,9-DiHETrE, 5,6-DiHETrE, 20-HETE, 15-HETE, 12-HETE, 12-HEPE, 14-HDoHE, and DHEA were decreased in MS compared to HS. In addition, 12,13-DiHOME and 12,13-DiHODE were positively correlated with expanded disability status scale values (EDSS). Using Partial Least Squares, we identified several lipid mediators with high VIP scores (VIP > 1: 32% - 52%) of which POEA, PGE3, DHEA, LTB5, and 12-HETE were top predictors for distinguishing between RRMS and HS (AUC =0.75) based on the XGBoost Classifier algorithm. Collectively, these findings suggest an imbalance between inflammation and resolution. Altogether, lipid mediators appear to have potential as diagnostic and prognostic biomarkers for RRMS.
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Affiliation(s)
- Insha Zahoor
- Department of Neurology, Henry Ford Health, Detroit, 48202, USA
| | - Jeffrey Waters
- Department of Neurology, Henry Ford Health, Detroit, 48202, USA
| | - Nasar Ata
- Department of Neurology, Henry Ford Health, Detroit, 48202, USA
| | - Indrani Datta
- Department of Public Health Sciences, Henry Ford Health, Detroit, 48202, USA
| | | | - Mirela Cerghet
- Department of Neurology, Henry Ford Health, Detroit, 48202, USA
| | - Laila Poisson
- Department of Public Health Sciences, Henry Ford Health, Detroit, 48202, USA
| | - Silva Markovic-Plese
- Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Ramandeep Rattan
- Division of Gynaecology Oncology, Department of Women’s Health Services, Henry Ford Health, Detroit, 48202, USA
| | - Ameer Y. Taha
- Department of Food and Technology, University of California, Davis, USA
- West Coast Metabolomics Center, Genome Center, University of California-Davis, Davis, CA, 95616, USA
| | - John W. Newman
- United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, 95616, USA
- West Coast Metabolomics Center, Genome Center, University of California-Davis, Davis, CA, 95616, USA
- Department of Nutrition, University of California-Davis, Davis, CA, 95616, USA
| | - Shailendra Giri
- Department of Neurology, Henry Ford Health, Detroit, 48202, USA
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3
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Sheremeta CL, Yarlagadda S, Smythe ML, Noakes PG. Prostaglandins in the Inflamed Central Nervous System: Potential Therapeutic Targets. Curr Drug Targets 2024; 25:885-908. [PMID: 39177131 PMCID: PMC11774313 DOI: 10.2174/0113894501323980240815113851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 07/11/2024] [Accepted: 07/19/2024] [Indexed: 08/24/2024]
Abstract
The global burden of neurological disorders is evident, yet there remains limited efficacious therapeutics for their treatment. There is a growing recognition of the role of inflammation in diseases of the central nervous system (CNS); among the numerous inflammatory mediators involved, prostaglandins play a crucial role. Prostaglandins are small lipid mediators derived from arachidonic acid via multi-enzymatic pathways. The actions of prostaglandins are varied, with each prostaglandin having a specific role in maintaining homeostasis. In the CNS, prostaglandins can have neuroprotective or neurotoxic properties depending on their specific G-protein receptor. These G-protein receptors have varying subfamilies, tissue distribution, and signal transduction cascades. Further studies into the impact of prostaglandins in CNS-based diseases may contribute to the clarification of their actions, hopefully leading to the development of efficacious therapeutic strategies. This review focuses on the roles played by prostaglandins in neural degeneration, with a focus on Alzheimer's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis in both preclinical and clinical settings. We further discuss current prostaglandin-related agonists and antagonists concerning suggestions for their use as future therapeutics.
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Affiliation(s)
- Chynna-Loren Sheremeta
- Institute for Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia
- School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD 4072, Australia
| | - Sai Yarlagadda
- Institute for Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia
- School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD 4072, Australia
| | - Mark L. Smythe
- Institute for Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia
| | - Peter G. Noakes
- School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD 4072, Australia
- Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia
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4
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Javanbakht P, Yazdi FR, Taghizadeh F, Khadivi F, Hamidabadi HG, Kashani IR, Zarini D, Mojaverrostami S. Quercetin as a possible complementary therapy in multiple sclerosis: Anti-oxidative, anti-inflammatory and remyelination potential properties. Heliyon 2023; 9:e21741. [PMID: 37954351 PMCID: PMC10638059 DOI: 10.1016/j.heliyon.2023.e21741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 10/26/2023] [Accepted: 10/26/2023] [Indexed: 11/14/2023] Open
Abstract
Multiple sclerosis (MS) is a complex autoimmune disorder of the central nervous system (CNS) which causes various symptoms such as fatigue, dyscoordination weakness and visual weakness. The intricacy of the immune system and obscure etiology are the main reasons for the lack of a definite treatment for MS. Oxidative stress is one of the most important key factors in MS pathogenesis. It can enhance inflammation, neurodegeneration and autoimmune-mediated processes, which can lead to excessive demyelination and axonal disruption. Recently, promising effects of Quercetin as a non-pharmacological anti-oxidant therapy have been reported in preclinical studies of MS disease. In this review, we provide a compendium of preclinical and clinical studies that have investigated the effects of Quercetin on MS disease to evaluate its potential utility as a complementary therapy in MS. Quercetin treatment in MS disease not only protects the CNS against oxidative stress and neuroinflammation, but it also declines the demyelination process and promotes remyelination potential. The present study clarifies the reported knowledge on the beneficial effects of Quercetin against MS, with future implication as a neuroprotective complementary therapy.
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Affiliation(s)
- Parinaz Javanbakht
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzane Rezaei Yazdi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Taghizadeh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Farnaz Khadivi
- Department of Anatomy, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Hatef Ghasemi Hamidabadi
- Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Iraj Ragerdi Kashani
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Zarini
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sina Mojaverrostami
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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5
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Grajchen E, Loix M, Baeten P, Côrte-Real BF, Hamad I, Vanherle S, Haidar M, Dehairs J, Broos JY, Ntambi JM, Zimmermann R, Breinbauer R, Stinissen P, Hellings N, Verberk SGS, Kooij G, Giera M, Swinnen JV, Broux B, Kleinewietfeld M, Hendriks JJA, Bogie JFJ. Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity. Cell Mol Immunol 2023; 20:666-679. [PMID: 37041314 DOI: 10.1038/s41423-023-01011-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 03/23/2023] [Indexed: 04/13/2023] Open
Abstract
The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.
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Affiliation(s)
- Elien Grajchen
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- University MS Center Hasselt, Pelt, Belgium
| | - Melanie Loix
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- University MS Center Hasselt, Pelt, Belgium
| | - Paulien Baeten
- University MS Center Hasselt, Pelt, Belgium
- Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Beatriz F Côrte-Real
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- University MS Center Hasselt, Pelt, Belgium
- VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research, Hasselt University, Diepenbeek, Belgium
| | - Ibrahim Hamad
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- University MS Center Hasselt, Pelt, Belgium
- VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research, Hasselt University, Diepenbeek, Belgium
| | - Sam Vanherle
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- University MS Center Hasselt, Pelt, Belgium
| | - Mansour Haidar
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- University MS Center Hasselt, Pelt, Belgium
| | - Jonas Dehairs
- Department of Oncology, Laboratory of Lipid Metabolism and Cancer, LKI - Leuven Cancer Institute, KU Leuven - University of Leuven, Leuven, Belgium
| | - Jelle Y Broos
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam, The Netherlands
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - James M Ntambi
- Department of Biochemistry, Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, USA
| | - Robert Zimmermann
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
- BioTechMed-Graz, Graz, Austria
| | - Rolf Breinbauer
- BioTechMed-Graz, Graz, Austria
- Institute of Organic Chemistry, Graz University of Technology, Graz, Austria
| | - Piet Stinissen
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- University MS Center Hasselt, Pelt, Belgium
| | - Niels Hellings
- University MS Center Hasselt, Pelt, Belgium
- Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Sanne G S Verberk
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- University MS Center Hasselt, Pelt, Belgium
| | - Gijs Kooij
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam, The Netherlands
| | - Martin Giera
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Johannes V Swinnen
- Department of Oncology, Laboratory of Lipid Metabolism and Cancer, LKI - Leuven Cancer Institute, KU Leuven - University of Leuven, Leuven, Belgium
| | - Bieke Broux
- University MS Center Hasselt, Pelt, Belgium
- Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- Cardiovascular Research Institute Maastricht, Department of Internal Medicine, Maastricht University, Maastricht, The Netherlands
| | - Markus Kleinewietfeld
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- University MS Center Hasselt, Pelt, Belgium
- VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research, Hasselt University, Diepenbeek, Belgium
| | - Jerome J A Hendriks
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- University MS Center Hasselt, Pelt, Belgium
| | - Jeroen F J Bogie
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
- University MS Center Hasselt, Pelt, Belgium.
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6
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Drake SS, Zaman A, Simas T, Fournier AE. Comparing RNA-sequencing datasets from astrocytes, oligodendrocytes, and microglia in multiple sclerosis identifies novel dysregulated genes relevant to inflammation and myelination. WIREs Mech Dis 2023; 15:e1594. [PMID: 36600404 DOI: 10.1002/wsbm.1594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 09/25/2022] [Accepted: 12/14/2022] [Indexed: 01/06/2023]
Abstract
Central nervous system (CNS) inflammation is a key factor in multiple sclerosis (MS). Invasion of peripheral immune cells into the CNS resulting from an unknown signal or combination of signals results in activation of resident immune cells and the hallmark feature of the disease: demyelinating lesions. These lesion sites are an amalgam of reactive peripheral and central immune cells, astrocytes, damaged and dying oligodendrocytes, and injured neurons and axons. Sustained inflammation affects cells directly located within the lesion site and further abnormalities are apparent diffusely throughout normal-appearing white matter and grey matter. It is only relatively recently, using animal models, new tissue sampling techniques, and next-generation sequencing, that molecular changes occurring in CNS resident cells have been broadly captured. Advances in cell isolation through Fluorescence Activated Cell Sorting (FACS) and laser-capture microdissection together with the emergence of single-cell sequencing have enabled researchers to investigate changes in gene expression in astrocytes, microglia, and oligodendrocytes derived from animal models of MS as well as from primary patient tissue. The contribution of some dysregulated pathways has been followed up in individual studies; however, corroborating results often go unreported between sequencing studies. To this end, we have consolidated results from numerous RNA-sequencing studies to identify and review novel patterns of differentially regulated genes and pathways occurring within CNS glial cells in MS. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
- Sienna S Drake
- McGill University, Montreal Neurological Institute, Montreal, Quebec, Canada
| | - Aliyah Zaman
- McGill University, Montreal Neurological Institute, Montreal, Quebec, Canada
| | - Tristan Simas
- McGill University, Montreal Neurological Institute, Montreal, Quebec, Canada
| | - Alyson E Fournier
- McGill University, Montreal Neurological Institute, Montreal, Quebec, Canada
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7
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Erra Diaz F, Mazzitelli I, Bleichmar L, Melucci C, Thibodeau A, Dalotto Moreno T, Marches R, Rabinovich GA, Ucar D, Geffner J. Concomitant inhibition of PPARγ and mTORC1 induces the differentiation of human monocytes into highly immunogenic dendritic cells. Cell Rep 2023; 42:112156. [PMID: 36842088 DOI: 10.1016/j.celrep.2023.112156] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/29/2022] [Accepted: 02/08/2023] [Indexed: 02/27/2023] Open
Abstract
Monocytes can differentiate into macrophages (Mo-Macs) or dendritic cells (Mo-DCs). The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the differentiation of monocytes into Mo-Macs, while the combination of GM-CSF/interleukin (IL)-4 is widely used to generate Mo-DCs for clinical applications and to study human DC biology. Here, we report that pharmacological inhibition of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) in the presence of GM-CSF and the absence of IL-4 induces monocyte differentiation into Mo-DCs. Remarkably, we find that simultaneous inhibition of PPARγ and the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) induces the differentiation of Mo-DCs with stronger phenotypic stability, superior immunogenicity, and a transcriptional profile characterized by a strong type I interferon (IFN) signature, a lower expression of a large set of tolerogenic genes, and the differential expression of several transcription factors compared with GM-CSF/IL-4 Mo-DCs. Our findings uncover a pathway that tailors Mo-DC differentiation with potential implications in the fields of DC vaccination and cancer immunotherapy.
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Affiliation(s)
- Fernando Erra Diaz
- Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina
| | - Ignacio Mazzitelli
- Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina
| | - Lucía Bleichmar
- Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina
| | - Claudia Melucci
- Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina
| | - Asa Thibodeau
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
| | - Tomás Dalotto Moreno
- Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Radu Marches
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
| | - Gabriel A Rabinovich
- Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Duygu Ucar
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06030, USA; Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT 06030, USA.
| | - Jorge Geffner
- Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina.
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8
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Salsinha AS, Socodato R, Relvas JB, Pintado M. The pro- and antiinflammatory activity of fatty acids. BIOACTIVE LIPIDS 2023:51-75. [DOI: 10.1016/b978-0-12-824043-4.00002-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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9
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Salsinha AS, Rodríguez-Alcalá LM, Pimentel LL, Pintado M. Role of bioactive lipids in obesity. BIOACTIVE LIPIDS 2023:133-167. [DOI: 10.1016/b978-0-12-824043-4.00012-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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10
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Zorrilla Veloz RI, McKenzie T, Palacios BE, Hu J. Nuclear hormone receptors in demyelinating diseases. J Neuroendocrinol 2022; 34:e13171. [PMID: 35734821 PMCID: PMC9339486 DOI: 10.1111/jne.13171] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 04/20/2022] [Accepted: 05/27/2022] [Indexed: 11/28/2022]
Abstract
Demyelination results from the pathological loss of myelin and is a hallmark of many neurodegenerative diseases. Despite the prevalence of demyelinating diseases, there are no disease modifying therapies that prevent the loss of myelin or promote remyelination. This review aims to summarize studies in the field that highlight the importance of nuclear hormone receptors in the promotion and maintenance of myelination and the relevance of nuclear hormone receptors as potential therapeutic targets for demyelinating diseases. These nuclear hormone receptors include the estrogen receptor, progesterone receptor, androgen receptor, vitamin D receptor, thyroid hormone receptor, peroxisome proliferator-activated receptor, liver X receptor, and retinoid X receptor. Pre-clinical studies in well-established animal models of demyelination have shown a prominent role of these nuclear hormone receptors in myelination through their promotion of oligodendrocyte maturation and development. The activation of the nuclear hormone receptors by their ligands also promotes the synthesis of myelin proteins and lipids in mouse models of demyelination. There are limited clinical studies that focus on how the activation of these nuclear hormone receptors could alleviate demyelination in patients with diseases such as multiple sclerosis (MS). However, the completed clinical trials have reported improved clinical outcome in MS patients treated with the ligands of some of these nuclear hormone receptors. Together, the positive results from both clinical and pre-clinical studies point to nuclear hormone receptors as promising therapeutic targets to counter demyelination.
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Affiliation(s)
- Rocío I Zorrilla Veloz
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Cancer Biology Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Takese McKenzie
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Neuroscience Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Bridgitte E Palacios
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Cancer Biology Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
- Neuroscience Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Jian Hu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Cancer Biology Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
- Neuroscience Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
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11
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Inhibition effect of PPAR-γ signaling on mast cell-mediated allergic inflammation through down-regulation of PAK1/ NF-κB activation. Int Immunopharmacol 2022; 108:108692. [DOI: 10.1016/j.intimp.2022.108692] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/17/2022] [Accepted: 03/07/2022] [Indexed: 12/14/2022]
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12
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Role of JAK-STAT and PPAR-Gamma Signalling Modulators in the Prevention of Autism and Neurological Dysfunctions. Mol Neurobiol 2022; 59:3888-3912. [PMID: 35437700 DOI: 10.1007/s12035-022-02819-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 03/23/2022] [Indexed: 01/10/2023]
Abstract
The Janus-kinase (JAK) and signal transducer activator of transcription (STAT) signalling pathways regulate gene expression and control various factors involved in normal physiological functions such as cell proliferation, neuronal development, and cell survival. JAK activation phosphorylates STAT3 in astrocytes and microglia, and this phosphorylation has been linked to mitochondrial damage, apoptosis, neuroinflammation, reactive astrogliosis, and genetic mutations. As a regulator, peroxisome proliferator-activated receptor gamma (PPAR-gamma), in relation to JAK-STAT signalling, prevents this phosphorylation and aids in the treatment of the above-mentioned neurocomplications. Changes in cellular signalling may also contribute to the onset and progression of autism. Thus, PPAR-gamma agonist upregulation may be associated with JAK-STAT signal transduction downregulation. It may also be responsible for attenuating neuropathological changes by stimulating SOCS3 or involving RXR or SMRT, thereby reducing transcription of the various cytokine proteins and genes involved in neuronal damage. Along with JAK-STAT inhibitors, PPAR-gamma agonists could be used as target therapeutic interventions for autism. This research-based review explores the potential involvement and mutual regulation of JAK-STAT and PPAR-gamma signalling in controlling multiple pathological factors associated with autism.
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Role of Phytoconstituents as PPAR Agonists: Implications for Neurodegenerative Disorders. Biomedicines 2021; 9:biomedicines9121914. [PMID: 34944727 PMCID: PMC8698906 DOI: 10.3390/biomedicines9121914] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/09/2021] [Accepted: 12/11/2021] [Indexed: 12/16/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPAR-γ, PPAR-α, and PPAR-β/δ) are ligand-dependent nuclear receptors that play a critical role in the regulation of hundreds of genes through their activation. Their expression and targeted activation play an important role in the treatment of a variety of diseases, including neurodegenerative, cardiovascular, diabetes, and cancer. In recent years, several reviews have been published describing the therapeutic potential of PPAR agonists (natural or synthetic) in the disorders listed above; however, no comprehensive report defining the role of naturally derived phytoconstituents as PPAR agonists targeting neurodegenerative diseases has been published. This review will focus on the role of phytoconstituents as PPAR agonists and the relevant preclinical studies and mechanistic insights into their neuroprotective effects. Exemplary research includes flavonoids, fatty acids, cannabinoids, curcumin, genistein, capsaicin, and piperine, all of which have been shown to be PPAR agonists either directly or indirectly. Additionally, a few studies have demonstrated the use of clinical samples in in vitro investigations. The role of the fruit fly Drosophila melanogaster as a potential model for studying neurodegenerative diseases has also been highlighted.
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14
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Du M, Yang L, Liu B, Yang L, Mao X, Liang M, Huang K. Inhibition of NFAT suppresses foam cell formation and the development of diet-induced atherosclerosis. FASEB J 2021; 35:e21951. [PMID: 34551141 DOI: 10.1096/fj.202100947r] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 09/02/2021] [Accepted: 09/09/2021] [Indexed: 11/11/2022]
Abstract
Deciphering the molecular and cellular processes involved in foam cell formation is critical for us to understand the pathogenesis of atherosclerosis. Nuclear factor of activated T cells (NFAT) is a transcription factor originally identified as a key player in the differentiation of T cells and maturation of immune system. Nowadays it has been brought into attention that NFAT also regulates multiple pathophysiological processes and targeted intervention in NFAT may be effective in the treatment of some cardiovascular diseases. However, whether NFAT is involved in foam cell formation remains elusive. NFAT in human monocyte-derived macrophage was activated by ox-LDL and translocated from the cytoplasm to the nucleus. NFAT then directly bound to peroxisome proliferator-activated receptor γ (PPARγ) in the nucleus and negatively regulated its transcriptional activity. NFATc2 knockdown or NFAT inhibitor 11R-VIVIT increased cholesterol efflux (by activating PPARγ-LXRα-ABCA1 cascade) and reduced the uptake of modified lipoprotein (in a PPARγ-independent way) in macrophage, thus prevented foam cell formation. Besides, 11R-VIVIT also exerted a protective role in the development of atherosclerosis in western diet-fed ApoE-/- mice. These results suggest NFAT inhibition as a potential therapeutic strategy in atherosclerosis.
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Affiliation(s)
- Meng Du
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Liyuan Cardiovascular Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liu Yang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bing Liu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liuye Yang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoxiang Mao
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Minglu Liang
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Huang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Liyuan Cardiovascular Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Matsumoto R, Takahashi D, Watanabe M, Nakatani S, Takamura Y, Kurosaki Y, Kakuta H, Hase K. A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice. Front Pharmacol 2021; 12:715752. [PMID: 34475823 PMCID: PMC8406631 DOI: 10.3389/fphar.2021.715752] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/29/2021] [Indexed: 11/30/2022] Open
Abstract
Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RBhighCD4+ T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-γ-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs.
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Affiliation(s)
- Ryohtaroh Matsumoto
- Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Daisuke Takahashi
- Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Masaki Watanabe
- Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Shunsuke Nakatani
- Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yuta Takamura
- Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yuji Kurosaki
- Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Hiroki Kakuta
- Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Koji Hase
- Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University, Tokyo, Japan.,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo, Japan
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16
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Sandi D, Fricska-Nagy Z, Bencsik K, Vécsei L. Neurodegeneration in Multiple Sclerosis: Symptoms of Silent Progression, Biomarkers and Neuroprotective Therapy-Kynurenines Are Important Players. Molecules 2021; 26:molecules26113423. [PMID: 34198750 PMCID: PMC8201043 DOI: 10.3390/molecules26113423] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/01/2021] [Accepted: 06/03/2021] [Indexed: 12/17/2022] Open
Abstract
Neurodegeneration is one of the driving forces behind the pathogenesis of multiple sclerosis (MS). Progression without activity, pathopsychological disturbances (cognitive impairment, depression, fatigue) and even optic neuropathy seems to be mainly routed in this mechanism. In this article, we aim to give a comprehensive review of the clinical aspects and symptomology, radiological and molecular markers and potential therapeutic targets of neurodegeneration in connection with MS. As the kynurenine pathway (KP) was evidenced to play an important role in the pathogenesis of other neurodegenerative conditions (even implied to have a causative role in some of these diseases) and more and more recent evidence suggest the same central role in the neurodegenerative processes of MS as well, we pay special attention to the KP. Metabolites of the pathway are researched as biomarkers of the disease and new, promising data arising from clinical evaluations show the possible therapeutic capability of KP metabolites as neuroprotective drugs in MS. Our conclusion is that the kynurenine pathway is a highly important route of research both for diagnostic and for therapeutic values and is expected to yield concrete results for everyday medicine in the future.
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Affiliation(s)
- Dániel Sandi
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, H-6725 Szeged, Hungary; (D.S.); (Z.F.-N.); (K.B.)
| | - Zsanett Fricska-Nagy
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, H-6725 Szeged, Hungary; (D.S.); (Z.F.-N.); (K.B.)
| | - Krisztina Bencsik
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, H-6725 Szeged, Hungary; (D.S.); (Z.F.-N.); (K.B.)
| | - László Vécsei
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, H-6725 Szeged, Hungary; (D.S.); (Z.F.-N.); (K.B.)
- MTA-SZTE Neuroscience Research Group, University of Szeged, H-6725 Szeged, Hungary
- Interdisciplinary Excellence Centre, University of Szeged, H-6725 Szeged, Hungary
- Correspondence: ; Tel.: +36-62-545-384; Fax: +36-62-545-597
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17
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Fatty acids role on obesity induced hypothalamus inflammation: From problem to solution – A review. Trends Food Sci Technol 2021. [DOI: 10.1016/j.tifs.2021.03.042] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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18
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Loving BA, Tang M, Neal MC, Gorkhali S, Murphy R, Eckel RH, Bruce KD. Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation. Cells 2021; 10:cells10020198. [PMID: 33498265 PMCID: PMC7909280 DOI: 10.3390/cells10020198] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/12/2021] [Accepted: 01/15/2021] [Indexed: 12/18/2022] Open
Abstract
Microglia become increasingly dysfunctional with aging and contribute to the onset of neurodegenerative disease (NDs) through defective phagocytosis, attenuated cholesterol efflux, and excessive secretion of pro-inflammatory cytokines. Dysfunctional microglia also accumulate lipid droplets (LDs); however, the mechanism underlying increased LD load is unknown. We have previously shown that microglia lacking lipoprotein lipase (LPL KD) are polarized to a pro-inflammatory state and have impaired lipid uptake and reduced fatty acid oxidation (FAO). Here, we also show that LPL KD microglia show excessive accumulation of LD-like structures. Moreover, LPL KD microglia display a pro-inflammatory lipidomic profile, increased cholesterol ester (CE) content, and reduced cholesterol efflux at baseline. We also show reduced expression of genes within the canonical cholesterol efflux pathway. Importantly, PPAR agonists (rosiglitazone and bezafibrate) rescued the LD-associated phenotype in LPL KD microglia. These data suggest that microglial-LPL is associated with lipid uptake, which may drive PPAR signaling and cholesterol efflux to prevent inflammatory lipid distribution and LD accumulation. Moreover, PPAR agonists can reverse LD accumulation, and therefore may be beneficial in aging and in the treatment of NDs.
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Affiliation(s)
- Bailey A. Loving
- Department of Radiation Oncology, Oakland University William Beaumont School of Medicine, Royal Oak, MI 48309, USA;
| | - Maoping Tang
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; (M.T.); (M.C.N.); (S.G.); (R.H.E.)
| | - Mikaela C. Neal
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; (M.T.); (M.C.N.); (S.G.); (R.H.E.)
| | - Sachi Gorkhali
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; (M.T.); (M.C.N.); (S.G.); (R.H.E.)
| | - Robert Murphy
- Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Robert H. Eckel
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; (M.T.); (M.C.N.); (S.G.); (R.H.E.)
| | - Kimberley D. Bruce
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; (M.T.); (M.C.N.); (S.G.); (R.H.E.)
- Correspondence:
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Kahroba H, Ramezani B, Maadi H, Sadeghi MR, Jaberie H, Ramezani F. The role of Nrf2 in neural stem/progenitors cells: From maintaining stemness and self-renewal to promoting differentiation capability and facilitating therapeutic application in neurodegenerative disease. Ageing Res Rev 2021; 65:101211. [PMID: 33186670 DOI: 10.1016/j.arr.2020.101211] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 11/05/2020] [Accepted: 11/07/2020] [Indexed: 02/07/2023]
Abstract
Neurodegenerative diseases (NDs) cause progressive loss of neurons in nervous system. NDs are categorized as acute NDs such as stroke and head injury, besides chronic NDs including Alzheimer's, Parkinson's, Huntington's diseases, Friedreich's Ataxia, Multiple Sclerosis. The exact etiology of NDs is not understood but oxidative stress, inflammation and synaptic dysfunction are main hallmarks. Oxidative stress leads to free radical attack on neural cells which contributes to protein misfolding, glia cell activation, mitochondrial dysfunction, impairment of DNA repair system and subsequently cellular death. Neural stem cells (NSCs) support adult neurogenesis in nervous system during injuries which is limited to certain regions in brain. NSCs can differentiate into the neurons, astrocytes or oligodendrocytes. Impaired neurogenesis and inadequate induction of neurogenesis are the main obstacles in treatment of NDs. Protection of neural cells from oxidative damages and supporting neurogenesis are promising strategies to treat NDs. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a transcriptional master regulator that maintains the redox homeostasis in cells by provoking expression of antioxidant, anti-inflammatory and cytoprotective genes. Nrf2 can strongly influence the NSCs function and fate determination by reducing levels of reactive oxygen species in benefit of NSC survival and neurogenesis. In this review we will summarize the role of Nrf2 in NSC function, and exogenous and endogenous therapeutic strategies in treatment of NDs.
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Affiliation(s)
- Houman Kahroba
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Bahman Ramezani
- Department of Chemistry, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Hamid Maadi
- Department of Medical Genetics, and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Mohammad Reza Sadeghi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hajar Jaberie
- Department of Biochemistry, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Fatemeh Ramezani
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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20
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Thomas G, Frederick E, Thompson L, Bar-Or R, Mulugeta Y, Hausburg M, Roshon M, Mains C, Bar-Or D. LMWF5A suppresses cytokine release by modulating select inflammatory transcription factor activity in stimulated PBMC. J Transl Med 2020; 18:452. [PMID: 33256749 PMCID: PMC7702209 DOI: 10.1186/s12967-020-02626-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 11/19/2020] [Indexed: 12/24/2022] Open
Abstract
Background Dysregulation of transcription and cytokine expression has been implicated in the pathogenesis of a variety inflammatory diseases. The resulting imbalance between inflammatory and resolving transcriptional programs can cause an overabundance of pro-inflammatory, classically activated macrophage type 1 (M1) and/or helper T cell type 1 (Th1) products, such as IFNγ, TNFα, IL1-β, and IL12, that prevent immune switching to resolution and healing. The low molecular weight fraction of human serum albumin (LMWF5A) is a novel biologic drug that is currently under clinical investigation for the treatment of osteoarthritis and the hyper-inflammatory response associated with COVID-19. This study aims to elucidate transcriptional mechanisms of action involved with the ability of LMWF5A to reduce pro-inflammatory cytokine release. Methods ELISA arrays were used to identify cytokines and chemokines influenced by LMWF5A treatment of LPS-stimulated peripheral blood mononuclear cells (PBMC). The resulting profiles were analyzed by gene enrichment to gain mechanistic insight into the biologic processes and transcription factors (TFs) underlying the identified differentially expressed cytokines. DNA-binding ELISAs, luciferase reporter assays, and TNFα or IL-1β relative potency were then employed to confirm the involvement of enriched pathways and TFs. Results LMWF5A was found to significantly inhibit a distinct set of pro-inflammatory cytokines (TNFα, IL-1β, IL-12, CXCL9, CXCL10, and CXCL11) associated with pro-inflammatory M1/Th1 immune profiles. Gene enrichment analysis also suggests these cytokines are, in part, regulated by NF-κB and STAT transcription factors. Data from DNA-binding and reporter assays support this with LMWF5A inhibition of STAT1α DNA-binding activity as well as a reduction in overall NF-κB-driven luciferase expression. Experiments using antagonists specific for the immunomodulatory and NF-κB/STAT-repressing transcription factors, peroxisome proliferator-activated receptor (PPAR)γ and aryl hydrocarbon receptor (AhR), indicate these pathways are involved in the LMWF5A mechanisms of action by reducing LMWF5A drug potency as measured by TNFα and IL-1β release. Conclusion In this report, we provide evidence that LMWF5A reduces pro-inflammatory cytokine release by activating the immunoregulatory transcription factors PPARγ and AhR. In addition, our data indicate that LMWF5A suppresses NF-κB and STAT1α pro-inflammatory pathways. This suggests that LMWF5A acts through these mechanisms to decrease pro-inflammatory transcription factor activity and subsequent inflammatory cytokine production.
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Affiliation(s)
- Gregory Thomas
- Ampio Pharmaceuticals Inc, 373 Inverness Parkway Suite 200, Englewood, CO, 80122, USA
| | - Elizabeth Frederick
- Ampio Pharmaceuticals Inc, 373 Inverness Parkway Suite 200, Englewood, CO, 80122, USA
| | - Lisa Thompson
- Ampio Pharmaceuticals Inc, 373 Inverness Parkway Suite 200, Englewood, CO, 80122, USA
| | - Raphael Bar-Or
- Ampio Pharmaceuticals Inc, 373 Inverness Parkway Suite 200, Englewood, CO, 80122, USA.,Trauma Research Department, Swedish Medical Center, 501 E. Hampden Ave. Rm 4-454, Englewood, CO, 80113, USA.,Trauma Research Department, St. Anthony Hospital, 11600 W 2nd Pl, Lakewood, CO, 80228, USA.,Trauma Research Department, Penrose Hospital, 2222 N Nevada Ave, Colorado Springs, CO, 80907, USA.,Centura Health Systems, 9100 E. Mineral Cir, Centennial, CO, 80112, USA
| | - Yetti Mulugeta
- Ampio Pharmaceuticals Inc, 373 Inverness Parkway Suite 200, Englewood, CO, 80122, USA
| | - Melissa Hausburg
- Trauma Research Department, Swedish Medical Center, 501 E. Hampden Ave. Rm 4-454, Englewood, CO, 80113, USA.,Trauma Research Department, St. Anthony Hospital, 11600 W 2nd Pl, Lakewood, CO, 80228, USA.,Trauma Research Department, Penrose Hospital, 2222 N Nevada Ave, Colorado Springs, CO, 80907, USA.,Centura Health Systems, 9100 E. Mineral Cir, Centennial, CO, 80112, USA
| | - Michael Roshon
- Trauma Research Department, Penrose Hospital, 2222 N Nevada Ave, Colorado Springs, CO, 80907, USA
| | - Charles Mains
- Centura Health Systems, 9100 E. Mineral Cir, Centennial, CO, 80112, USA
| | - David Bar-Or
- Trauma Research Department, Swedish Medical Center, 501 E. Hampden Ave. Rm 4-454, Englewood, CO, 80113, USA. .,Trauma Research Department, St. Anthony Hospital, 11600 W 2nd Pl, Lakewood, CO, 80228, USA. .,Trauma Research Department, Penrose Hospital, 2222 N Nevada Ave, Colorado Springs, CO, 80907, USA. .,Centura Health Systems, 9100 E. Mineral Cir, Centennial, CO, 80112, USA. .,Department of Molecular Biology, Rocky Vista University, 8401 S Chambers Rd, Parker, CO, 80134, USA.
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Dysregulation of metabolic pathways by carnitine palmitoyl-transferase 1 plays a key role in central nervous system disorders: experimental evidence based on animal models. Sci Rep 2020; 10:15583. [PMID: 32973137 PMCID: PMC7519132 DOI: 10.1038/s41598-020-72638-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
The etiology of CNS diseases including multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis remains elusive despite decades of research resulting in treatments with only symptomatic effects. In this study, we provide evidence that a metabolic shift from glucose to lipid is a key mechanism in neurodegeneration. We show that, by downregulating the metabolism of lipids through the key molecule carnitine palmitoyl transferase 1 (CPT1), it is possible to reverse or slowdown disease progression in experimental models of autoimmune encephalomyelitis-, SOD1G93A and rotenone models, mimicking these CNS diseases in humans. The effect was seen both when applying a CPT1 blocker or by using a Cpt1a P479L mutant mouse strain. Furthermore, we show that diet, epigenetics, and microbiota are key elements in this metabolic shift. Finally, we present a systemic model for understanding the complex etiology of neurodegeneration and how different regulatory systems are interconnected through a central metabolic pathway that becomes deregulated under specific conditions.
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22
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Liu Y, Wang J, Luo S, Zhan Y, Lu Q. The roles of PPARγ and its agonists in autoimmune diseases: A comprehensive review. J Autoimmun 2020; 113:102510. [PMID: 32622513 PMCID: PMC7327470 DOI: 10.1016/j.jaut.2020.102510] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/18/2020] [Accepted: 06/20/2020] [Indexed: 01/10/2023]
Abstract
Autoimmune diseases are common diseases of the immune system that are characterized by the loss of self-tolerance and the production of autoantibodies; the breakdown of immune tolerance and the prolonged inflammatory reaction are undisputedly core steps in the initiation and maintenance of autoimmunity. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that belong to the nuclear hormone receptor family and act as ligand-activated transcription factors. There are three different isotypes of PPARs: PPARα, PPARγ, and PPARβ/δ. PPARγ is an established regulator of glucose homeostasis and lipid metabolism. Recent studies have demonstrated that PPARγ exhibits anti-inflammatory and anti-fibrotic effects in multiple disease models. PPARγ can also modulate the activation and polarization of macrophages, regulate the function of dendritic cells and mediate T cell survival, activation, and differentiation. In this review, we summarize the signaling pathways and biological functions of PPARγ and focus on how PPARγ and its agonists play protective roles in autoimmune diseases, including autoimmune thyroid diseases, multiple sclerosis, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, primary Sjogren syndrome and primary biliary cirrhosis.
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Affiliation(s)
- Yu Liu
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenetics, Changsha, Hunan, 410011, PR China
| | - Jiayu Wang
- Xiangya Medical School, Central South University, #176 Tongzipo Rd, Changsha, Hunan, 410013, PR China
| | - Shuangyan Luo
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenetics, Changsha, Hunan, 410011, PR China
| | - Yi Zhan
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenetics, Changsha, Hunan, 410011, PR China
| | - Qianjin Lu
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenetics, Changsha, Hunan, 410011, PR China.
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Hoxha M, Spahiu E, Prendi E, Zappacosta B. A Systematic Review on the Role of Arachidonic Acid Pathway in Multiple Sclerosis. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2020; 21:160-187. [PMID: 32842948 DOI: 10.2174/1871527319666200825164123] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 06/28/2020] [Accepted: 07/17/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND & OBJECTIVE Multiple sclerosis (MS) is an inflammatory neurodegenerative disease characterized by destruction of oligodendrocytes, immune cell infiltration and demyelination. Inflammation plays a significant role in MS, and the inflammatory mediators such as eicosanoids, leukotrienes, superoxide radicals are involved in pro-inflammatory responses in MS. In this systematic review we tried to define and discuss all the findings of in vivo animal studies and human clinical trials on the potential association between arachidonic acid (AA) pathway and multiple sclerosis. METHODS A systematic literature search across Pubmed, Scopus, Embase and Cochrane database was conducted. This systematic review was performed according to PRISMA guidelines. RESULTS A total of 146 studies were included, of which 34 were conducted in animals, 58 in humans, and 60 studies reported the role of different compounds that target AA mediators or their corresponding enzymes/ receptors, and can have a therapeutic effect in MS. These results suggest that eicosanoids have significant roles in experimental autoimmune encephalomyelitis (EAE) and MS. The data from animal and human studies elucidated that PGI2, PGF2α, PGD2, isoprostanes, PGE2, PLA2, LTs are increased in MS. PLA2 inhibition modulates the progression of the disease. PGE1 analogues can be a useful option in the treatment of MS. CONCLUSIONS All studies reported the beneficial effects of COX and LOX inhibitors in MS. The hybrid compounds, such as COX-2 inhibitors/TP antagonists and 5-LOX inhibitors can be an innovative approach for multiple sclerosis treatment. Future work in MS should shed light in synthesizing new compounds targeting arachidonic acid pathway.
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Affiliation(s)
- Malvina Hoxha
- Department of Chemical-Toxicological and Pharmacological Evaluations of Drugs, Faculty of Pharmacy, Catholic University Our Lady of Good Counsel, Rruga Dritan Hoxha, Tirana. Albania
| | | | - Emanuela Prendi
- Catholic University Our Lady of Good Counsel, Department of Biomedical Sciences, Rruga Dritan Hoxha, Tirana. Albania
| | - Bruno Zappacosta
- Department of Chemical-Toxicological and Pharmacological Evaluations of Drugs, Faculty of Pharmacy, Catholic University Our Lady of Good Counsel, Rruga Dritan Hoxha, Tirana. Albania
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Famitafreshi H, Karimian M. Prostaglandins as the Agents That Modulate the Course of Brain Disorders. Degener Neurol Neuromuscul Dis 2020; 10:1-13. [PMID: 32021549 PMCID: PMC6970614 DOI: 10.2147/dnnd.s240800] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 12/30/2019] [Indexed: 12/14/2022] Open
Abstract
Neurologic and neuropsychiatric diseases are associated with great morbidity and mortality. Prostaglandins (PGs) are formed by sequential oxygenation of arachidonic acid in physiologic and pathologic conditions. For the production of PGs cyclooxygenase is a necessary enzyme that has two isoforms, that are named COX-1 and COX-2. COX-1 produces type 1 prostaglandins and on the other hand, COX-2 produces type 2 prostaglandins. Recent studies suggest PGs abnormalities are present in a variety of neurologic and psychiatric disorders. In a disease state, type 2 prostaglandins are mostly responsible and type 1 PGs are not so important in the disease state. In this review, the importance of prostaglandins especially type 2 in brain diseases has been discussed and their possible role in the initiation and outcome of brain diseases has been assessed. Overall the studies suggest prostaglandins are the agents that modulate the course of brain diseases in a positive or negative manner. Here in this review article, the various aspects of PGs in the disease state have discussed. It appears more studies must be done to understand the exact role of these agents in the pathophysiology of brain diseases. However, the suppression of prostaglandin production may confer the alleviation of some brain diseases.
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Affiliation(s)
| | - Morteza Karimian
- Physiology Department, Tehran University of Medical Sciences, Tehran, Iran
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25
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Uddin MS, Kabir MT, Jakaria M, Mamun AA, Niaz K, Amran MS, Barreto GE, Ashraf GM. Endothelial PPARγ Is Crucial for Averting Age-Related Vascular Dysfunction by Stalling Oxidative Stress and ROCK. Neurotox Res 2019; 36:583-601. [PMID: 31055770 DOI: 10.1007/s12640-019-00047-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 04/01/2019] [Accepted: 04/11/2019] [Indexed: 02/07/2023]
Abstract
Aging plays a significant role in the progression of vascular diseases and vascular dysfunction. Activation of the ADP-ribosylation factor 6 and small GTPases by inflammatory signals may cause vascular permeability and endothelial leakage. Pro-inflammatory molecules have a significant effect on smooth muscle cells (SMC). The migration and proliferation of SMC can be promoted by tumor necrosis factor alpha (TNF-α). TNF-α can also increase oxidative stress in SMCs, which has been identified to persuade DNA damage resulting in apoptosis and cellular senescence. Peroxisome proliferator-activated receptor (PPAR) acts as a ligand-dependent transcription factor and a member of the nuclear receptor superfamily. They play key roles in a wide range of biological processes, including cell differentiation and proliferation, bone formation, cell metabolism, tissue remodeling, insulin sensitivity, and eicosanoid signaling. The PPARγ activation regulates inflammatory responses, which can exert protective effects in the vasculature. In addition, loss of function of PPARγ enhances cardiovascular events and atherosclerosis in the vascular endothelium. This appraisal, therefore, discusses the critical linkage of PPARγ in the inflammatory process and highlights a crucial defensive role for endothelial PPARγ in vascular dysfunction and disease, as well as therapy for vascular aging.
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Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh.
| | | | - Md Jakaria
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju, South Korea
| | | | - Kamal Niaz
- Department of Pharmacology and Toxicology, Faculty of Bio-Sciences, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
| | - Md Shah Amran
- Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka, Bangladesh
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, DC, Colombia.,Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. .,Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
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Fakan B, Szalardy L, Vecsei L. Exploiting the Therapeutic Potential of Endogenous Immunomodulatory Systems in Multiple Sclerosis-Special Focus on the Peroxisome Proliferator-Activated Receptors (PPARs) and the Kynurenines. Int J Mol Sci 2019; 20:ijms20020426. [PMID: 30669473 PMCID: PMC6358998 DOI: 10.3390/ijms20020426] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 01/13/2019] [Accepted: 01/15/2019] [Indexed: 01/20/2023] Open
Abstract
Multiple sclerosis (MS) is a progressive neurodegenerative disease, characterized by autoimmune central nervous system (CNS) demyelination attributable to a disturbed balance between encephalitic T helper 1 (Th1) and T helper 17 (Th17) and immunomodulatory regulatory T cell (Treg) and T helper 2 (Th2) cells, and an alternatively activated macrophage (M2) excess. Endogenous molecular systems regulating these inflammatory processes have recently been investigated to identify molecules that can potentially influence the course of the disease. These include the peroxisome proliferator-activated receptors (PPARs), PPARγ coactivator-1alpha (PGC-1α), and kynurenine pathway metabolites. Although all PPARs ameliorate experimental autoimmune encephalomyelitis (EAE), recent evidence suggests that PPARα, PPARβ/δ agonists have less pronounced immunomodulatory effects and, along with PGC-1α, are not biomarkers of neuroinflammation in contrast to PPARγ. Small clinical trials with PPARγ agonists have been published with positive results. Proposed as immunomodulatory and neuroprotective, the therapeutic use of PGC-1α activation needs to be assessed in EAE/MS. The activation of indolamine 2,3-dioxygenase (IDO), the rate-limiting step of the kynurenine pathway of tryptophan (Trp) metabolism, plays crucial immunomodulatory roles. Indeed, Trp metabolites have therapeutic relevance in EAE and drugs with structural analogy to kynurenines, such as teriflunomide, are already approved for MS. Further studies are required to gain deeper knowledge of such endogenous immunomodulatory pathways with potential therapeutic implications in MS.
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Affiliation(s)
- Bernadett Fakan
- Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, H-6725 Szeged, Semmelweis u. 6, Hungary.
| | - Levente Szalardy
- Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, H-6725 Szeged, Semmelweis u. 6, Hungary.
| | - Laszlo Vecsei
- Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, H-6725 Szeged, Semmelweis u. 6, Hungary.
- MTA-SZTE Neuroscience Research Group, H-6725 Szeged, Semmelweis u. 6, Hungary.
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Vallée A, Vallée JN, Guillevin R, Lecarpentier Y. Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis. Cell Mol Neurobiol 2018; 38:783-795. [PMID: 28905149 PMCID: PMC11482031 DOI: 10.1007/s10571-017-0550-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 09/09/2017] [Indexed: 12/13/2022]
Abstract
Multiple sclerosis (MS) is marked by neuroinflammation and demyelination with loss of oligodendrocytes in the central nervous system. The immune response is regulated by WNT/beta-catenin pathway in MS. Activated NF-kappaB, a major effector of neuroinflammation, and upregulated canonical WNT/beta-catenin pathway positively regulate each other. Demyelinating events present an upregulation of WNT/beta-catenin pathway, whereas proper myelinating phases show a downregulation of WNT/beta-catenin pathway essential for the promotion of oligodendrocytes precursors cells proliferation and differentiation. The activation of WNT/beta-catenin pathway results in differentiation failure and impairment in remyelination. However, PI3K/Akt pathway and TCF7L2, two downstream targets of WNT/beta-catenin pathway, are upregulated and promote proper remyelination. The interactions of these signaling pathways remain unclear. PPAR gamma activation can inhibit NF-kappaB, and can also downregulate the WNT/beta-catenin pathway. PPAR gamma and canonical WNT/beta-catenin pathway act in an opposite manner. PPAR gamma agonists appear as a promising treatment for the inhibition of demyelination and the promotion of proper remyelination through the control of both NF-kappaB activity and canonical WNT/beta-catenin pathway.
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Affiliation(s)
- Alexandre Vallée
- Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France.
- Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France.
| | - Jean-Noël Vallée
- Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France
- CHU Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France
| | - Rémy Guillevin
- DACTIM, UMR CNRS 7348, University of Poitiers et CHU de Poitiers, Poitiers, France
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France
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Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches. Int J Mol Sci 2018; 19:ijms19041212. [PMID: 29659554 PMCID: PMC5979570 DOI: 10.3390/ijms19041212] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 04/09/2018] [Accepted: 04/11/2018] [Indexed: 12/20/2022] Open
Abstract
Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/β-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4+ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/β-catenin pathway. Upregulation of WNT/β-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/β-catenin signaling and demyelinating processes by inducing dysfunction of CD4+ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4+ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/β-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions.
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Affiliation(s)
- Alexandre Vallée
- Délégation à la Recherche Clinique et à l'Innovation (DRCI), Hôpital Foch, 92150 Suresnes, France.
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), 77100 Meaux, France.
| | - Rémy Guillevin
- Data Analysis and Computations Through Imaging Modeling-Mathématiques (DACTIM), Unité mixte de recherche (UMR), Centre National de la Recherche Scientifique (CNRS) 7348 (Laboratoire de Mathématiques et Application), University of Poitiers, Centre Hospitalier Universitaire (CHU) de Poitiers, 86000 Poitiers, France.
| | - Jean-Noël Vallée
- Centre Hospitalier Universitaire (CHU) Amiens Picardie, University of Picardie Jules Verne (UPJV), 80000 Amiens, France.
- LMA (Laboratoire de Mathématiques et Applications), Unité mixte de recherche (UMR), Centre National de la Recherche Scientifique (CNRS) 7348, Université de Poitiers, 86000 Poitiers, France.
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Bi J, Sun K, Wu H, Chen X, Tang H, Mao J. PPARγ alleviated hepatocyte steatosis through reducing SOCS3 by inhibiting JAK2/STAT3 pathway. Biochem Biophys Res Commun 2018; 498:1037-1044. [PMID: 29550470 DOI: 10.1016/j.bbrc.2018.03.110] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 03/13/2018] [Indexed: 01/22/2023]
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) participates in the process of insulin resistance (IR), a crucial pathophysiology in non-alcoholic fatty liver disease (NAFLD). Meanwhile, suppressor of cytokine signaling3 (SOCS3) also regulates IR in NAFLD. Both PPARγ and SOCS3 play a role in NAFLD through regulating IR, while it is unclear whether these two proteins interact to regulate hepatic steatosis. PPARγ, SOCS3 and its associated JAK2/STAT3 pathway were analyzed using Kuppfer cells (KCs) treatment with LPS and BRL-3A cells treatment with palmitic acid, KC-conditioned medium (KCCM), PPARγ agonist rosiglitazone (ROZ) or JAK2 inhibitor AG490 to demonstrate the role of PPARγ and SOCS3 in hepatocytes steatosis. As LPS concentration increasing, phagocytosis activity of KCs decreased; but releasing of TNF-α and IL-6 increased. After treatment with KCCM, mRNA level of SOCS3, JAK2 and STAT3 as well as protein expression of SOCS3, p-JAK2 and p-STAT3 in steatosis BRL-3A cells increased significantly, which were inhibited by AG490 or ROZ treatment. Taken together, these results indicated that KCCM attributed to KCs dysfunction facilitated hepatocyte steatosis through promoting expressing SOCS3; but PPARγ agonist ROZ alleviated steatosis through reducing SOCS3 expression by inhibiting JAK2/STAT3 in hepatocytes.
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Affiliation(s)
- Jian Bi
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Kang Sun
- Department of GI Endoscopy, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Hao Wu
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Xiuli Chen
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Haiying Tang
- Department of Respiratory and Critical Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
| | - Jingwei Mao
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
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Liu Y, Gibson SA, Benveniste EN, Qin H. Opportunities for Translation from the Bench: Therapeutic Intervention of the JAK/STAT Pathway in Neuroinflammatory Diseases. Crit Rev Immunol 2018; 35:505-27. [PMID: 27279046 DOI: 10.1615/critrevimmunol.2016015517] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Pathogenic CD4+ T cells and myeloid cells play critical roles in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. These immune cells secrete aberrantly high levels of pro-inflammatory cytokines that pathogenically bridge the innate and adaptive immune systems and damage neurons and oligodendrocytes. These cytokines include interleukin-2 (IL-2), IL-6, IL-12, IL-21, IL-23, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon-γ (IFN-γ). It is, therefore, not surprising that both the dysregulated expression of these cytokines and the subsequent activation of their downstream signaling cascades is a common feature in MS/EAE. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is utilized by numerous cytokines for signal transduction and is essential for the development and regulation of immune responses. Unbridled activation of the JAK/STAT pathway by pro-inflammatory cytokines has been demonstrated to be critically involved in the pathogenesis of MS/EAE. In this review, we discuss recent advancements in our understanding of the involvement of the JAK/STAT signaling pathway in the pathogenesis of MS/EAE, with a particular focus on therapeutic approaches to target the JAK/STAT pathway.
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Affiliation(s)
- Yudong Liu
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, 35294; Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Sara A Gibson
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, 35294
| | - Etty N Benveniste
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, 35294
| | - Hongwei Qin
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, 35294
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31
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Vignali PDA, Barbi J, Pan F. Metabolic Regulation of T Cell Immunity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1011:87-130. [DOI: 10.1007/978-94-024-1170-6_2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Szalardy L, Zadori D, Bencsik K, Vecsei L, Klivenyi P. Unlike PPARgamma, neither other PPARs nor PGC-1alpha is elevated in the cerebrospinal fluid of patients with multiple sclerosis. Neurosci Lett 2017; 651:128-133. [PMID: 28483651 DOI: 10.1016/j.neulet.2017.05.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 05/05/2017] [Accepted: 05/05/2017] [Indexed: 02/06/2023]
Abstract
Corroborating with prior experimental findings, we recently reported the pronounced elevation of peroxisome proliferator-activated receptor gamma (PPARγ) protein concentration in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS), in association with neuroinflammatory markers and clinical severity. Based on subsequent reports on the possible involvement of other PPARs and PPARγ coactivator-1alpha (PGC-1α) in neuroinflammation in MS, we analyzed the protein levels of PPARα, PPARβ/δ, and PGC-1α in a subset of CSF samples from the same cohort of relapsing-remitting MS patients. Unlike PPARγ, none of these proteins were found elevated in MS patients (n=25) compared to non-inflammatory controls (n=16), with the levels of PPARα and PPARβ/δ found generally below the limit of detection, and that of PGC-1α being detectable but comparable in both groups. The clinical and laboratory associations previously reported with PPARγ were however significant even in this smaller subset. The potential underlying causes of these differential alterations are discussed. The findings suggest that despite their proposed involvement in the regulation of inflammatory processes in MS, PPARα, PPARβ/δ, and PGC-1α proteins are not potential biomarkers of neuroinflammation in MS, and indicate a preferential role of PPARγ in the endogenous regulation of autoimmune response in the human CNS within its receptor family.
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Affiliation(s)
- Levente Szalardy
- Department of Neurology, University of Szeged, H-6725, Szeged, Semmelweis u. 6, Hungary
| | - Denes Zadori
- Department of Neurology, University of Szeged, H-6725, Szeged, Semmelweis u. 6, Hungary
| | - Krisztina Bencsik
- Department of Neurology, University of Szeged, H-6725, Szeged, Semmelweis u. 6, Hungary
| | - Laszlo Vecsei
- Department of Neurology, University of Szeged, H-6725, Szeged, Semmelweis u. 6, Hungary; MTA-SZTE Neuroscience Research Group, H-6725, Szeged, Semmelweis u. 6, Hungary
| | - Peter Klivenyi
- Department of Neurology, University of Szeged, H-6725, Szeged, Semmelweis u. 6, Hungary.
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Fiander MD, Stifani N, Nichols M, Akay T, Robertson GS. Kinematic gait parameters are highly sensitive measures of motor deficits and spinal cord injury in mice subjected to experimental autoimmune encephalomyelitis. Behav Brain Res 2017; 317:95-108. [DOI: 10.1016/j.bbr.2016.09.034] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 09/12/2016] [Accepted: 09/14/2016] [Indexed: 12/13/2022]
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Multiple Sclerosis and Obesity: Possible Roles of Adipokines. Mediators Inflamm 2016; 2016:4036232. [PMID: 27721574 PMCID: PMC5046034 DOI: 10.1155/2016/4036232] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 07/22/2016] [Accepted: 08/08/2016] [Indexed: 12/21/2022] Open
Abstract
Multiple Sclerosis (MS) is an autoimmune disorder of the Central Nervous System that has been associated with several environmental factors, such as diet and obesity. The possible link between MS and obesity has become more interesting in recent years since the discovery of the remarkable properties of adipose tissue. Once MS is initiated, obesity can contribute to increased disease severity by negatively influencing disease progress and treatment response, but, also, obesity in early life is highly relevant as a susceptibility factor and causally related risk for late MS development. The aim of this review was to discuss recent evidence about the link between obesity, as a chronic inflammatory state, and the pathogenesis of MS as a chronic autoimmune and inflammatory disease. First, we describe the main cells involved in MS pathogenesis, both from neural tissue and from the immune system, and including a new participant, the adipocyte, focusing on their roles in MS. Second, we concentrate on the role of several adipokines that are able to participate in the mediation of the immune response in MS and on the possible cross talk between the latter. Finally, we explore recent therapy that involves the transplantation of adipocyte precursor cells for the treatment of MS.
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Ackermann JA, Hofheinz K, Zaiss MM, Krönke G. The double-edged role of 12/15-lipoxygenase during inflammation and immunity. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1862:371-381. [PMID: 27480217 DOI: 10.1016/j.bbalip.2016.07.014] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 07/01/2016] [Accepted: 07/28/2016] [Indexed: 01/18/2023]
Abstract
12/15-Lipoxygenase (12/15-LOX) mediates the enzymatic oxidation of polyunsaturated fatty acids, thereby contributing to the generation of various bioactive lipid mediators. Although 12/15-LOX has been implicated in the pathogenesis of multiple chronic inflammatory diseases, its physiologic functions seem to include potent immune modulatory properties that physiologically contribute to the resolution of inflammation and the clearance of inflammation-associated tissue damage. This review aims to give a comprehensive overview about our current knowledge on the role of this enzyme during the regulation of inflammation and immunity. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder.
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Affiliation(s)
- Jochen A Ackermann
- Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany; Nikolaus Fiebiger Center of Molecular Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Katharina Hofheinz
- Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany; Nikolaus Fiebiger Center of Molecular Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Mario M Zaiss
- Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany
| | - Gerhard Krönke
- Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany; Nikolaus Fiebiger Center of Molecular Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany.
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Sandoval-Hernández A, Contreras MJ, Jaramillo J, Arboleda G. Regulation of Oligodendrocyte Differentiation and Myelination by Nuclear Receptors: Role in Neurodegenerative Disorders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 949:287-310. [DOI: 10.1007/978-3-319-40764-7_14] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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PPARγ and the Innate Immune System Mediate the Resolution of Inflammation. PPAR Res 2015; 2015:549691. [PMID: 26713087 PMCID: PMC4680113 DOI: 10.1155/2015/549691] [Citation(s) in RCA: 398] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 10/15/2015] [Indexed: 11/18/2022] Open
Abstract
The resolution of inflammation is an active and dynamic process, mediated in large part by the innate immune system. Resolution represents not only an increase in anti-inflammatory actions, but also a paradigm shift in immune cell function to restore homeostasis. PPARγ, a ligand activated transcription factor, has long been studied for its anti-inflammatory actions, but an emerging body of literature is investigating the role of PPARγ and its ligands (including thiazolidinediones, prostaglandins, and oleanolic acids) in all phases of resolution. PPARγ can shift production from pro- to anti-inflammatory mediators by neutrophils, platelets, and macrophages. PPARγ and its ligands further modulate platelet and neutrophil function, decreasing trafficking, promoting neutrophil apoptosis, and preventing platelet-leukocyte interactions. PPARγ alters macrophage trafficking, increases efferocytosis and phagocytosis, and promotes alternative M2 macrophage activation. There are also roles for this receptor in the adaptive immune response, particularly regarding B cells. These effects contribute towards the attenuation of multiple disease states, including COPD, colitis, Alzheimer's disease, and obesity in animal models. Finally, novel specialized proresolving mediators-eicosanoids with critical roles in resolution-may act through PPARγ modulation to promote resolution, providing another exciting area of therapeutic potential for this receptor.
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Tuncer S, Banerjee S. Eicosanoid pathway in colorectal cancer: Recent updates. World J Gastroenterol 2015; 21:11748-11766. [PMID: 26557000 PMCID: PMC4631974 DOI: 10.3748/wjg.v21.i41.11748] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/25/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Enzymatic metabolism of the 20C polyunsaturated fatty acid (PUFA) arachidonic acid (AA) occurs via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, and leads to the production of various bioactive lipids termed eicosanoids. These eicosanoids have a variety of functions, including stimulation of homeostatic responses in the cardiovascular system, induction and resolution of inflammation, and modulation of immune responses against diseases associated with chronic inflammation, such as cancer. Because chronic inflammation is essential for the development of colorectal cancer (CRC), it is not surprising that many eicosanoids are implicated in CRC. Oftentimes, these autacoids work in an antagonistic and highly temporal manner in inflammation; therefore, inhibition of the pro-inflammatory COX-2 or 5-LOX enzymes may subsequently inhibit the formation of their essential products, or shunt substrates from one pathway to another, leading to undesirable side-effects. A better understanding of these different enzymes and their products is essential not only for understanding the importance of eicosanoids, but also for designing more effective drugs that solely target the inflammatory molecules found in both chronic inflammation and cancer. In this review, we have evaluated the cancer promoting and anti-cancer roles of different eicosanoids in CRC, and highlighted the most recent literature which describes how those molecules affect not only tumor tissue, but also the tumor microenvironment. Additionally, we have attempted to delineate the roles that eicosanoids with opposing functions play in neoplastic transformation in CRC through their effects on proliferation, apoptosis, motility, metastasis, and angiogenesis.
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Black LL, Srivastava R, Schoeb TR, Moore RD, Barnes S, Kabarowski JH. Cholesterol-Independent Suppression of Lymphocyte Activation, Autoimmunity, and Glomerulonephritis by Apolipoprotein A-I in Normocholesterolemic Lupus-Prone Mice. THE JOURNAL OF IMMUNOLOGY 2015; 195:4685-98. [PMID: 26466956 DOI: 10.4049/jimmunol.1500806] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 09/21/2015] [Indexed: 11/19/2022]
Abstract
Apolipoprotein (Apo)A-I, the major lipid-binding protein of high-density lipoprotein, can prevent autoimmunity and suppress inflammation in hypercholesterolemic mice by attenuating lymphocyte cholesterol accumulation and removing tissue-oxidized lipids. However, whether ApoA-I mediates immune-suppressive or anti-inflammatory effects under normocholesterolemic conditions and the mechanisms involved remain unresolved. We transferred bone marrow from systemic lupus erythematosus (SLE)-prone Sle123 mice into normal, ApoA-I-knockout (ApoA-I(-/-)) and ApoA-I-transgenic (ApoA-I(tg)) mice. Increased ApoA-I in ApoA-I(tg) mice suppressed CD4(+) T and B cell activation without changing lymphocyte cholesterol levels or reducing major ApoA-I-binding oxidized fatty acids. Unexpectedly, oxidized fatty acid peroxisome proliferator-activated receptor γ ligands 13- and 9-hydroxyoctadecadienoic acid were increased in lymphocytes of autoimmune ApoA-I(tg) mice. ApoA-I reduced Th1 cells independently of changes in CD4(+)Foxp3(+) regulatory T cells or CD11c(+) dendritic cell activation and migration. Follicular helper T cells, germinal center B cells, and autoantibodies were also lower in ApoA-I(tg) mice. Transgenic ApoA-I also improved SLE-mediated glomerulonephritis. However, ApoA-I deficiency did not have the opposite effects on autoimmunity or glomerulonephritis, possibly as the result of compensatory increases in ApoE on high-density lipoprotein. We conclude that, although compensatory mechanisms prevent the proinflammatory effects of ApoA-I deficiency in normocholesterolemic mice, increasing ApoA-I can attenuate lymphocyte activation and autoimmunity in SLE independently of cholesterol transport, possibly through oxidized fatty acid peroxisome proliferator-activated receptor γ ligands, and it can reduce renal inflammation in glomerulonephritis.
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Affiliation(s)
- Leland L Black
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Roshni Srivastava
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Trenton R Schoeb
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294; and
| | - Ray D Moore
- Department of Pharmacology and Toxicology, Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Stephen Barnes
- Department of Pharmacology and Toxicology, Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Janusz H Kabarowski
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294;
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40
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Zhang ZG, Li Y, Ng CT, Song YQ. Inflammation in Alzheimer's Disease and Molecular Genetics: Recent Update. Arch Immunol Ther Exp (Warsz) 2015; 63:333-44. [PMID: 26232392 DOI: 10.1007/s00005-015-0351-0] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 03/03/2015] [Indexed: 01/01/2023]
Abstract
Alzheimer's disease (AD) is a complex age-related neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE ε4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.
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Affiliation(s)
- Zhi-Gang Zhang
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, People's Republic of China
| | - Yan Li
- Energy Research Institute of Shandong Academy of Sciences, Jinan, Shandong, People's Republic of China
| | - Cheung Toa Ng
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, People's Republic of China
| | - You-Qiang Song
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, People's Republic of China. .,State Key Laboratory for Cognitive and Brain Sciences, The University of Hong Kong, Pokfulam, Hong Kong, People's Republic of China.
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Benveniste EN, Liu Y, McFarland BC, Qin H. Involvement of the janus kinase/signal transducer and activator of transcription signaling pathway in multiple sclerosis and the animal model of experimental autoimmune encephalomyelitis. J Interferon Cytokine Res 2015; 34:577-88. [PMID: 25084174 DOI: 10.1089/jir.2014.0012] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Multiple sclerosis (MS) and its animal model of experimental autoimmune encephalomyelitis (EAE) are characterized by focal inflammatory infiltrates into the central nervous system, demyelinating lesions, axonal damage, and abundant production of cytokines that activate immune cells and damage neurons and oligodendrocytes, including interleukin-12 (IL-12), IL-6, IL-17, IL-21, IL-23, granulocyte macrophage-colony stimulating factor, and interferon-gamma. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway mediates the biological activities of these cytokines and is essential for the development and regulation of immune responses. Dysregulation of the JAK/STAT pathway contributes to numerous autoimmune diseases, including MS/EAE. The JAK/STAT pathway is aberrantly activated in MS/EAE because of excessive production of cytokines, loss of expression of negative regulators such as suppressors of cytokine signaling proteins, and significant enrichment of genes encoding components of the JAK/STAT pathway, including STAT3. Specific JAK/STAT inhibitors have been used in numerous preclinical models of MS and demonstrate beneficial effects on the clinical course of disease and attenuation of innate and adaptive immune responses. In addition, other drugs such as statins, glatiramer acetate, laquinimod, and fumarates have beneficial effects that involve inhibition of the JAK/STAT pathway. We conclude by discussing the feasibility of the JAK/STAT pathway as a target for neuroinflammatory diseases.
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Affiliation(s)
- Etty N Benveniste
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham , Birmingham, Alabama
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42
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Chang CZ, Wu SC, Kwan AL. Glycyrrhizin Attenuates Proinflammatory Cytokines through a Peroxisome Proliferator-Activated Receptor-γ-Dependent Mechanism and Experimental Vasospasm in a Rat Model. J Vasc Res 2015; 52:12-21. [PMID: 25896311 DOI: 10.1159/000381099] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 02/15/2015] [Indexed: 11/19/2022] Open
Abstract
The peroxisome proliferator-activated receptor (PPAR) is downregulated in the cortex of experimental subarachnoid hemorrhage (SAH) animals. This study is to examine the effect of glycyrrhizin on the alternation of PPARs and proinflammatory cytokines in a rodent SAH model. CSF cytokines were evaluated by RT-PCR. Basilar arteries (BAs) were harvested to examine PPARs (RT-PCR and Western blot), and a morphological examination was conducted. Deformed endothelium and tortuous elastic lamina were observed in the BAs of the SAH groups, but they were absent in the glycyrrhizin groups or the healthy controls. The PPAR-γ and -δ protein levels were reduced in the SAH groups (p < 0.01). Glycyrrhizin significantly increased the expressed PPAR-γ protein and mRNA (preconditioning) and PPAR-δ mRNA (both treatment and preconditioning), which corresponded to the reduced IL-1β and TNF-α levels. The administration of a PPAR-γ inhibitor, BADGE, halted the reduction of IL-1β and TNF-α in the glycyrrhizin groups. Conclusively, glycyrrhizin exerts anti-inflammatory effects on SAH-induced vasospasm and attenuates the expression of PPARs, especially PPAR-γ, which corresponds to the severity of SAH-related inflammation. These findings also offer credit to the antivasospastic effect of glycyrrhizin and its vasculoprotective effect in animals subjected to SAH.
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MESH Headings
- Animals
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology
- Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
- Basilar Artery/metabolism
- Cytokines/biosynthesis
- Cytokines/cerebrospinal fluid
- Cytokines/genetics
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Endothelium, Vascular/pathology
- Gene Expression Regulation/drug effects
- Glycyrrhizic Acid/pharmacology
- Glycyrrhizic Acid/therapeutic use
- Inflammation
- Infusion Pumps
- Male
- PPAR delta/biosynthesis
- PPAR delta/genetics
- PPAR gamma/antagonists & inhibitors
- PPAR gamma/biosynthesis
- PPAR gamma/genetics
- PPAR gamma/physiology
- Phytotherapy
- Premedication
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Random Allocation
- Rats
- Rats, Sprague-Dawley
- Single-Blind Method
- Subarachnoid Hemorrhage/complications
- Subarachnoid Hemorrhage/drug therapy
- Subarachnoid Hemorrhage/genetics
- Vasospasm, Intracranial/etiology
- Vasospasm, Intracranial/physiopathology
- Vasospasm, Intracranial/prevention & control
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Affiliation(s)
- Chih-Zen Chang
- Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
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Wright MB, Bortolini M, Tadayyon M, Bopst M. Minireview: Challenges and opportunities in development of PPAR agonists. Mol Endocrinol 2014; 28:1756-68. [PMID: 25148456 PMCID: PMC5414793 DOI: 10.1210/me.2013-1427] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Accepted: 08/08/2014] [Indexed: 01/06/2023] Open
Abstract
The clinical impact of the fibrate and thiazolidinedione drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here we review concepts used to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and nongenomic regulation. We briefly describe the recently discovered non-PPAR protein targets of thiazolidinediones, mitoNEET, and mTOT. Finally, we summarize the contributions of on- and off-target actions to select therapeutic and side effects of PPAR ligands including insulin sensitivity, cardiovascular actions, inflammation, and carcinogenicity.
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Affiliation(s)
- Matthew B Wright
- F. Hoffmann-La Roche Pharmaceuticals (M.B.W., M.Bor., M.Bop.), CH-4070 Basel, Switzerland; and MediTech Media (M.T.), London EC1V 9AZ, United Kingdom
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Chen K, Li J, Wang J, Xia Y, Dai W, Wang F, Shen M, Cheng P, Zhang Y, Wang C, Yang J, Zhu R, Zhang H, Zheng Y, Lu J, Fan Z, Zhou Y, Guo C. 15-Deoxy- γ 12,14-prostaglandin J2 Reduces Liver Impairment in a Model of ConA-Induced Acute Hepatic Inflammation by Activation of PPAR γ and Reduction in NF- κ B Activity. PPAR Res 2014; 2014:215631. [PMID: 25120564 PMCID: PMC4121249 DOI: 10.1155/2014/215631] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 06/22/2014] [Accepted: 06/23/2014] [Indexed: 11/17/2022] Open
Abstract
Objective. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) reduces inflammation and has been identified as an anti-inflammatory prostaglandin in numerous animal models. In this study, we investigated both effects of 15d-PGJ2 and its protection mechanism in concanavalin A- (ConA-) induced autoimmune hepatitis in mice. Materials and Methods. In vivo, Balb/C mice were injected with ConA (25 mg/kg) to induce acute autoimmune hepatitis, and 15d-PGJ2 (10 μg or 25 μg) was administered 1 h before the ConA injection. The histological grade, proinflammatory cytokine levels, and NF-κB and PPARγ activity were determined 6, 12, and 24 h after the ConA injection. In vitro, LO2 cells and RAW264.7 cells were pretreated with 15d-PGJ2 (2 μM) 1 h before the stimulation with ConA (30 μg/mL). The NF-κB and PPARγ activity were determined 30 min after the ConA administration. Results. Pretreatment with 15d-PGJ2 reduced the pathological effects of ConA-induced autoimmune hepatitis and significantly reduced the levels of cytokines after injection. 15d-PGJ2 activated PPARγ, blocked the degradation of IκBα, and inhibited the translocation of NF-κB into the nucleus. Conclusion. These results indicate that 15d-PGJ2 protects against ConA-induced autoimmune hepatitis by reducing proinflammatory cytokines. This reduction in inflammation may correlate with the activation of PPARγ and the reduction in NF-κB activity.
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Affiliation(s)
- Kan Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Junshan Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Weiqi Dai
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Fan Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Miao Shen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ping Cheng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yan Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Chengfen Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jing Yang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Rong Zhu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Huawei Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yuanyuan Zheng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Zhuoyi Fan
- Tongji University School of Medicine, Shanghai 200092, China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
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Dentesano G, Serratosa J, Tusell JM, Ramón P, Valente T, Saura J, Solà C. CD200R1 and CD200 expression are regulated by PPAR-γ in activated glial cells. Glia 2014; 62:982-98. [PMID: 24639050 DOI: 10.1002/glia.22656] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 02/25/2014] [Accepted: 02/25/2014] [Indexed: 12/18/2022]
Abstract
The mechanisms that control microglial activation are of interest, since neuroinflammation, which involves reactive microglia, may be an additional target in the search for therapeutic strategies to treat neurodegenerative diseases. Neuron-microglia interaction through contact-dependent or independent mechanisms is involved in the regulation of the microglial phenotype in both physiological and pathological conditions. The interaction between CD200, which is mainly present in neurons but also in astrocytes, and CD200R1, which is mainly present in microglia, is one of the mechanisms involved in keeping the microglial proinflammatory phenotype under control in physiological conditions. Alterations in the expression of CD200 and CD200R1 have been described in neurodegenerative diseases, but little is known about the mechanism of regulation of these proteins under physiological or pathological conditions. The aim of this work was to study the modulation of CD200 and CD200R1 expression by peroxisome proliferator-activated receptor gamma (PPAR-γ), a transcription factor involved in the control of the inflammatory response. Mouse primary neuronal and glial cultures and neuron-microglia cocultures were treated with the PPAR-γ endogenous ligand 15-deoxy-Δ(12, 14) -prostaglandin J2 (15d-PGJ2 ) in the presence and absence of lipopolysaccharide plus interferon-γ (LPS/IFN-γ)-induced glial activation. We show that 15d-PGJ2 inhibits the pro-inflammatory response and prevents both CD200R1 downregulation and CD200 upregulation in reactive glial cells. In addition, 15d-PGJ2 abrogates reactive-microglia induced neurotoxicity in neuron-microglia cultures through a CD200-CD200R1 dependent mechanism. These results suggest that PPAR-γ modulates CD200 and CD200R1 gene expression and that CD200-CD200R1 interaction is involved in the anti-inflammatory and neuroprotective action of PPAR-γ agonists.
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Affiliation(s)
- Guido Dentesano
- Department of Cerebral Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas (CSIC), Institut d'Investigacions Biomèdiques August-Pi i Sunyer (IDIBAPS), Barcelona, Spain
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Utreras E, Hamada R, Prochazkova M, Terse A, Takahashi S, Ohshima T, Kulkarni AB. Suppression of neuroinflammation in forebrain-specific Cdk5 conditional knockout mice by PPARγ agonist improves neuronal loss and early lethality. J Neuroinflammation 2014; 11:28. [PMID: 24495352 PMCID: PMC3931315 DOI: 10.1186/1742-2094-11-28] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 01/21/2014] [Indexed: 01/04/2023] Open
Abstract
Background Cyclin-dependent kinase 5 (Cdk5) is essential for brain development and function, and its deregulated expression is implicated in some of neurodegenerative diseases. We reported earlier that the forebrain-specific Cdk5 conditional knockout (cKO) mice displayed an early lethality associated with neuroinflammation, increased expression of the neuronal tissue-type plasminogen activator (tPA), and neuronal migration defects. Methods In order to suppress neuroinflammation in the cKO mice, we first treated these mice with pioglitazone, a PPARγ agonist, and analyzed its effects on neuronal loss and longevity. In a second approach, to delineate the precise role of tPA in neuroinflammation in these mice, we generated Cdk5 cKO; tPA double knockout (dKO) mice. Results We found that pioglitazone treatment significantly reduced astrogliosis, microgliosis, neuronal loss and behavioral deficit in Cdk5 cKO mice. Interestingly, the dKO mice displayed a partial reversal in astrogliosis, but they still died at early age, suggesting that the increased expression of tPA in the cKO mice does not contribute significantly to the pathological process leading to neuroinflammation, neuronal loss and early lethality. Conclusion The suppression of neuroinflammation in Cdk5 cKO mice ameliorates gliosis and neuronal loss, thus suggesting the potential beneficial effects of the PPARγ agonist pioglitazone for the treatment for neurodegenerative diseases.
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Affiliation(s)
| | | | | | | | | | - Toshio Ohshima
- Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
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Liu Y, Holdbrooks AT, De Sarno P, Rowse AL, Yanagisawa LL, McFarland BC, Harrington LE, Raman C, Sabbaj S, Benveniste EN, Qin H. Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis. THE JOURNAL OF IMMUNOLOGY 2013; 192:59-72. [PMID: 24323580 DOI: 10.4049/jimmunol.1301513] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Pathogenic Th cells and myeloid cells are involved in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The JAK/STAT pathway is used by numerous cytokines for signaling and is critical for development, regulation, and termination of immune responses. Dysregulation of the JAK/STAT pathway has pathological implications in autoimmune and neuroinflammatory diseases. Many of the cytokines involved in MS/EAE, including IL-6, IL-12, IL-23, IFN-γ, and GM-CSF, use the JAK/STAT pathway to induce biological responses. Thus, targeting JAKs has implications for treating autoimmune inflammation of the brain. We have used AZD1480, a JAK1/2 inhibitor, to investigate the therapeutic potential of inhibiting the JAK/STAT pathway in models of EAE. AZD1480 treatment inhibits disease severity in myelin oligodendrocyte glycoprotein-induced classical and atypical EAE models by preventing entry of immune cells into the brain, suppressing differentiation of Th1 and Th17 cells, deactivating myeloid cells, inhibiting STAT activation in the brain, and reducing expression of proinflammatory cytokines and chemokines. Treatment of SJL/J mice with AZD1480 delays disease onset of PLP-induced relapsing-remitting disease, reduces relapses and diminishes clinical severity. AZD1480 treatment was also effective in reducing ongoing paralysis induced by adoptive transfer of either pathogenic Th1 or Th17 cells. In vivo AZD1480 treatment impairs both the priming and expansion of T cells and attenuates Ag presentation functions of myeloid cells. Inhibition of the JAK/STAT pathway has clinical efficacy in multiple preclinical models of MS, suggesting the feasibility of the JAK/STAT pathway as a target for neuroinflammatory diseases.
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Affiliation(s)
- Yudong Liu
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294
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Promoting return of function in multiple sclerosis: An integrated approach. Mult Scler Relat Disord 2013; 2:S2211-0348(13)00044-8. [PMID: 24363985 DOI: 10.1016/j.msard.2013.04.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Multiple sclerosis is a disease characterized by inflammatory demyelination, axonal degeneration and progressive brain atrophy. Most of the currently available disease modifying agents proved to be very effective in managing the relapse rate, however progressive neuronal damage continues to occur and leads to progressive accumulation of irreversible disability. For this reason, any therapeutic strategy aimed at restoration of function must take into account not only immunomodulation, but also axonal protection and new myelin formation. We further highlight the importance of an holistic approach, which considers the variability of therapeutic responsiveness as the result of the interplay between genetic differences and the epigenome, which is in turn affected by gender, age and differences in life style including diet, exercise, smoking and social interaction.
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49
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Szalardy L, Zadori D, Tanczos E, Simu M, Bencsik K, Vecsei L, Klivenyi P. Elevated levels of PPAR-gamma in the cerebrospinal fluid of patients with multiple sclerosis. Neurosci Lett 2013; 554:131-4. [PMID: 24021801 DOI: 10.1016/j.neulet.2013.08.069] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 07/21/2013] [Accepted: 08/28/2013] [Indexed: 11/19/2022]
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcriptional factor involved in the regulation of glucose and lipid metabolism, has gained interest as a potential therapeutic target in multiple sclerosis (MS) due to its potent immunoregulatory properties and the therapeutic efficacy of its ligands in experimental autoimmune encephalitis (EAE). Elevated expression of PPARγ has been observed in the spinal cord of EAE mice and in an in vitro model of antigen-induced demyelination; however, no reports have yet been available on the PPARγ status in the central nervous system of human individuals with MS. Aiming to identify a possible alteration, the present study assessed the levels of PPARγ protein in the cerebrospinal fluid (CSF) of MS patients via ELISA technique. We report a pronounced elevation in the CSF levels of PPARγ in MS patients (n=35) compared to non-inflammatory controls (n=22). This elevation was independent of blood-CSF barrier integrity, but correlated with CSF white blood cell count and IgG index, associating the observed elevation with neuroinflammation. Controlling for potential confounders, the CSF levels of PPARγ further displayed a moderate but significant association with clinical severity. Corroborating with prior experimental findings, these results may contribute to our understanding about the role of PPARγ in MS, and may implicate this protein as a potential CSF biomarker of the disease.
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Affiliation(s)
- Levente Szalardy
- Department of Neurology, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
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Huxlin KR, Hindman HB, Jeon KI, Bühren J, MacRae S, DeMagistris M, Ciufo D, Sime PJ, Phipps RP. Topical rosiglitazone is an effective anti-scarring agent in the cornea. PLoS One 2013; 8:e70785. [PMID: 23940641 PMCID: PMC3733781 DOI: 10.1371/journal.pone.0070785] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2012] [Accepted: 06/25/2013] [Indexed: 12/12/2022] Open
Abstract
Corneal scarring remains a major cause of blindness world-wide, with limited treatment options, all of which have side-effects. Here, we tested the hypothesis that topical application of Rosiglitazone, a Thiazolidinedione and ligand of peroxisome proliferator activated receptor gamma (PPARγ), can effectively block scar formation in a cat model of corneal damage. Adult cats underwent bilateral epithelial debridement followed by excimer laser ablation of the central corneal stroma to a depth of ~160 µm as a means of experimentally inducing a reproducible wound. Eyes were then left untreated, or received 50 µl of either 10 µM Rosiglitazone in DMSO/Celluvisc, DMSO/Celluvisc vehicle or Celluvisc vehicle twice daily for 2 weeks. Cellular aspects of corneal wound healing were evaluated with in vivo confocal imaging and post-mortem immunohistochemistry for alpha smooth muscle actin (αSMA). Impacts of the wound and treatments on optical quality were assessed using wavefront sensing and optical coherence tomography at 2, 4, 8 and 12 weeks post-operatively. In parallel, cat corneal fibroblasts were cultured to assess the effects of Rosiglitazone on TGFβ-induced αSMA expression. Topical application of Rosiglitazone to cat eyes after injury decreased αSMA expression and haze, as well as the induction of lower-order and residual, higher-order wavefront aberrations compared to vehicle-treated eyes. Rosiglitazone also inhibited TGFβ-induced αSMA expression in cultured corneal fibroblasts. In conclusion, Rosiglitazone effectively controlled corneal fibrosis in vivo and in vitro, while restoring corneal thickness and optics. Its topical application may represent an effective, new avenue for the prevention of corneal scarring with distinct advantages for pathologically thin corneas.
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Affiliation(s)
- Krystel R Huxlin
- Flaum Eye Institute, University of Rochester, Rochester, New York, United States of America.
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