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Esmaeili M, Nasr-Esfahani MH, Shoaraye Nejati A, Safaeinejad Z, Atefi A, L. Megraw T, Ghaedi K. PPARgamma dependent PEX11beta counteracts the suppressive role of SIRT1 on neural differentiation of HESCs. PLoS One 2024; 19:e0298274. [PMID: 38753762 PMCID: PMC11098471 DOI: 10.1371/journal.pone.0298274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 01/18/2024] [Indexed: 05/18/2024] Open
Abstract
The membrane peroxisomal proteins PEX11, play a crucial role in peroxisome proliferation by regulating elongation, membrane constriction, and fission of pre-existing peroxisomes. In this study, we evaluated the function of PEX11B gene in neural differentiation of human embryonic stem cell (hESC) by inducing shRNAi-mediated knockdown of PEX11B expression. Our results demonstrate that loss of PEX11B expression led to a significant decrease in the expression of peroxisomal-related genes including ACOX1, PMP70, PEX1, and PEX7, as well as neural tube-like structures and neuronal markers. Inhibition of SIRT1 using pharmacological agents counteracted the effects of PEX11B knockdown, resulting in a relative increase in PEX11B expression and an increase in differentiated neural tube-like structures. However, the neuroprotective effects of SIRT1 were eliminated by PPAR inhibition, indicating that PPARɣ may mediate the interaction between PEX11B and SIRT1. Our findings suggest that both SIRT1 and PPARɣ have neuroprotective effects, and also this study provides the first indication for a potential interaction between PEX11B, SIRT1, and PPARɣ during hESC neural differentiation.
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Affiliation(s)
- Maryam Esmaeili
- Department of Cellular Biotechnology, Royan Institute for Biotechnology, Cell Science Research Center, ACECR, Isfahan, Iran
| | - Mohammad Hossein Nasr-Esfahani
- Department of Cellular Biotechnology, Royan Institute for Biotechnology, Cell Science Research Center, ACECR, Isfahan, Iran
| | - Alireza Shoaraye Nejati
- Department of Cellular Biotechnology, Royan Institute for Biotechnology, Cell Science Research Center, ACECR, Isfahan, Iran
| | - Zahra Safaeinejad
- Department of Cellular Biotechnology, Royan Institute for Biotechnology, Cell Science Research Center, ACECR, Isfahan, Iran
| | - Atefeh Atefi
- Department of Cellular Biotechnology, Royan Institute for Biotechnology, Cell Science Research Center, ACECR, Isfahan, Iran
| | - Timothy L. Megraw
- Department of Biomedical Sciences, Florida State University College of Medicine, West Call Street, Tallahassee, FL, United States of America
| | - Kamran Ghaedi
- Department of Cellular Biotechnology, Royan Institute for Biotechnology, Cell Science Research Center, ACECR, Isfahan, Iran
- Faculty of Biological Science and Technology, Department of Cell and Molecular Biology and Microbiology, University of Isfahan, Isfahan, Iran
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Schroeder HT, De Lemos Muller CH, Heck TG, Krause M, Homem de Bittencourt PI. Heat shock response during the resolution of inflammation and its progressive suppression in chronic-degenerative inflammatory diseases. Cell Stress Chaperones 2024; 29:116-142. [PMID: 38244765 PMCID: PMC10939074 DOI: 10.1016/j.cstres.2024.01.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 01/22/2024] Open
Abstract
The heat shock response (HSR) is a crucial biochemical pathway that orchestrates the resolution of inflammation, primarily under proteotoxic stress conditions. This process hinges on the upregulation of heat shock proteins (HSPs) and other chaperones, notably the 70 kDa family of heat shock proteins, under the command of the heat shock transcription factor-1. However, in the context of chronic degenerative disorders characterized by persistent low-grade inflammation (such as insulin resistance, obesity, type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases) a gradual suppression of the HSR does occur. This work delves into the mechanisms behind this phenomenon. It explores how the Western diet and sedentary lifestyle, culminating in the endoplasmic reticulum stress within adipose tissue cells, trigger a cascade of events. This cascade includes the unfolded protein response and activation of the NOD-like receptor pyrin domain-containing protein-3 inflammasome, leading to the emergence of the senescence-associated secretory phenotype and the propagation of inflammation throughout the body. Notably, the activation of the NOD-like receptor pyrin domain-containing protein-3 inflammasome not only fuels inflammation but also sabotages the HSR by degrading human antigen R, a crucial mRNA-binding protein responsible for maintaining heat shock transcription factor-1 mRNA expression and stability on heat shock gene promoters. This paper underscores the imperative need to comprehend how chronic inflammation stifles the HSR and the clinical significance of evaluating the HSR using cost-effective and accessible tools. Such understanding is pivotal in the development of innovative strategies aimed at the prevention and treatment of these chronic inflammatory ailments, which continue to take a heavy toll on global health and well-being.
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Affiliation(s)
- Helena Trevisan Schroeder
- Laboratory of Cellular Physiology (FisCel), Department of Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Carlos Henrique De Lemos Muller
- Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX), Department of Physiology, ICBS, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil
| | - Thiago Gomes Heck
- Post Graduate Program in Integral Health Care (PPGAIS-UNIJUÍ/UNICRUZ/URI), Regional University of Northwestern Rio Grande Do Sul State (UNIJUI) and Post Graduate Program in Mathematical and Computational Modeling (PPGMMC), UNIJUI, Ijuí, Rio Grande do Sul, Brazil
| | - Mauricio Krause
- Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX), Department of Physiology, ICBS, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil
| | - Paulo Ivo Homem de Bittencourt
- Laboratory of Cellular Physiology (FisCel), Department of Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
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Castro E Costa AR, Mysore S, Paruchuri P, Chen KY, Liu AY. PolyQ-Expanded Mutant Huntingtin Forms Inclusion Body Following Transient Cold Shock in a Two-Step Aggregation Mechanism. ACS Chem Neurosci 2023; 14:277-288. [PMID: 36574489 DOI: 10.1021/acschemneuro.2c00585] [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] [Indexed: 12/28/2022] Open
Abstract
Age-dependent formation of insoluble protein aggregates is a hallmark of many neurodegenerative diseases. We are interested in the cell chemistry that drives the aggregation of polyQ-expanded mutant Huntingtin (mHtt) protein into insoluble inclusion bodies (IBs). Using an inducible cell model of Huntington's disease, we show that a transient cold shock (CS) at 4 °C followed by recovery incubation at temperatures of 25-37 °C strongly and rapidly induces the compaction of diffuse polyQ-expanded HuntingtinExon1-enhanced green fluorescent protein chimera protein (mHtt) into round, micron size, cytosolic IBs. This transient CS-induced mHtt IB formation is independent of microtubule integrity or de novo protein synthesis. The addition of millimolar concentrations of sodium chloride accelerates, whereas urea suppresses this transient CS-induced mHtt IB formation. These results suggest that the low temperature of CS constrains the conformation dynamics of the intrinsically disordered mHtt into labile intermediate structures to facilitate de-solvation and hydrophobic interaction for IB formation at the higher recovery temperature. This work, along with our previous observation of the effects of heat shock protein chaperones and osmolytes in driving mHtt IB formation, underscores the primacy of mHtt structuring and rigidification for H-bond-mediated cross-linking in a two-step mechanism of mHtt IB formation in living cells.
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Affiliation(s)
- Ana Raquel Castro E Costa
- Department of Cell Biology and Neuroscience, Nelson Biology Laboratory, Rutgers State University of New Jersey, 604 Allison Road, Piscataway, New Jersey 08854, United States
| | - Sachin Mysore
- Department of Cell Biology and Neuroscience, Nelson Biology Laboratory, Rutgers State University of New Jersey, 604 Allison Road, Piscataway, New Jersey 08854, United States
| | - Praneet Paruchuri
- Department of Cell Biology and Neuroscience, Nelson Biology Laboratory, Rutgers State University of New Jersey, 604 Allison Road, Piscataway, New Jersey 08854, United States
| | - Kuang Yu Chen
- Department of Chemistry and Chemical Biology, Wright-Rieman Chemistry Laboratory, Rutgers State University of New Jersey, 610 Taylor Road, Piscataway, New Jersey 08854, United States
| | - Alice Y Liu
- Department of Cell Biology and Neuroscience, Nelson Biology Laboratory, Rutgers State University of New Jersey, 604 Allison Road, Piscataway, New Jersey 08854, United States
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Liu AY, Minetti CA, Remeta DP, Breslauer KJ, Chen KY. HSF1, Aging, and Neurodegeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1409:23-49. [PMID: 35995906 DOI: 10.1007/5584_2022_733] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Heat shock factor 1 (HSF1) is a master transcription regulator that mediates the induction of heat shock protein chaperones for quality control (QC) of the proteome and maintenance of proteostasis as a protective mechanism in response to stress. Research in this particular area has accelerated dramatically over the past three decades following successful isolation, cloning, and characterization of HSF1. The intricate multi-protein complexes and transcriptional activation orchestrated by HSF1 are fundamental processes within the cellular QC machinery. Our primary focus is on the regulation and function of HSF1 in aging and neurodegenerative diseases (ND) which represent physiological and pathological states of dysfunction in protein QC. This chapter presents an overview of HSF1 structural, functional, and energetic properties in healthy cells while addressing the deterioration of HSF1 function viz-à-viz age-dependent and neuron-specific vulnerability to ND. We discuss the structural domains of HSF1 with emphasis on the intrinsically disordered regions and note that disease proteins associated with ND are often structurally disordered and exquisitely sensitive to changes in cellular environment as may occur during aging. We propose a hypothesis that age-dependent changes of the intrinsically disordered proteome likely hold answers to understand many of the functional, structural, and organizational changes of proteins and signaling pathways in aging - dysfunction of HSF1 and accumulation of disease protein aggregates in ND included.Structured AbstractsIntroduction: Heat shock factor 1 (HSF1) is a master transcription regulator that mediates the induction of heat shock protein chaperones for quality control (QC) of the proteome as a cyto-protective mechanism in response to stress. There is cumulative evidence of age-related deterioration of this QC mechanism that contributes to disease vulnerability. OBJECTIVES Herein we discuss the regulation and function of HSF1 as they relate to the pathophysiological changes of protein quality control in aging and neurodegenerative diseases (ND). METHODS We present an overview of HSF1 structural, functional, and energetic properties in healthy cells while addressing the deterioration of HSF1 function vis-à-vis age-dependent and neuron-specific vulnerability to neurodegenerative diseases. RESULTS We examine the impact of intrinsically disordered regions on the function of HSF1 and note that proteins associated with neurodegeneration are natively unstructured and exquisitely sensitive to changes in cellular environment as may occur during aging. CONCLUSIONS We put forth a hypothesis that age-dependent changes of the intrinsically disordered proteome hold answers to understanding many of the functional, structural, and organizational changes of proteins - dysfunction of HSF1 in aging and appearance of disease protein aggregates in neurodegenerative diseases included.
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Affiliation(s)
- Alice Y Liu
- Department of Cell Biology and Neuroscience, Rutgers The State University of New Jersey, Piscataway, NJ, USA.
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.
| | - Conceição A Minetti
- Department of Chemistry and Chemical Biology, Rutgers The State University of New Jersey, Piscataway, NJ, USA
| | - David P Remeta
- Department of Chemistry and Chemical Biology, Rutgers The State University of New Jersey, Piscataway, NJ, USA
| | - Kenneth J Breslauer
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA
- Department of Chemistry and Chemical Biology, Rutgers The State University of New Jersey, Piscataway, NJ, USA
| | - Kuang Yu Chen
- Department of Chemistry and Chemical Biology, Rutgers The State University of New Jersey, Piscataway, NJ, USA
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Pérez MJ, Carden TR, Dos Santos Claro PA, Silberstein S, Páez PM, Cheli VT, Correale J, Pasquini JM. Transferrin Enhances Neuronal Differentiation. ASN Neuro 2023; 15:17590914231170703. [PMID: 37093743 PMCID: PMC10134178 DOI: 10.1177/17590914231170703] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023] Open
Abstract
Although transferrin (Tf) is a glycoprotein best known for its role in iron delivery, iron-independent functions have also been reported. Here, we assessed apoTf (aTf) treatment effects on Neuro-2a (N2a) cells, a mouse neuroblastoma cell line which, once differentiated, shares many properties with neurons, including process outgrowth, expression of selective neuronal markers, and electrical activity. We first examined the binding of Tf to its receptor (TfR) in our model and verified that, like neurons, N2a cells can internalize Tf from the culture medium. Next, studies on neuronal developmental parameters showed that Tf increases N2a survival through a decrease in apoptosis. Additionally, Tf accelerated the morphological development of N2a cells by promoting neurite outgrowth. These pro-differentiating effects were also observed in primary cultures of mouse cortical neurons treated with aTf, as neurons matured at a higher rate than controls and showed a decrease in the expression of early neuronal markers. Further experiments in iron-enriched and iron-deficient media showed that Tf preserved its pro-differentiation properties in N2a cells, with results hinting at a modulatory role for iron. Moreover, N2a-microglia co-cultures revealed an increase in IL-10 upon aTf treatment, which may be thought to favor N2a differentiation. Taken together, these findings suggest that Tf reduces cell death and favors the neuronal differentiation process, thus making Tf a promising candidate to be used in regenerative strategies for neurodegenerative diseases.
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Affiliation(s)
- María Julia Pérez
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | - Tomas Roberto Carden
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | - Paula Ayelen Dos Santos Claro
- Instituto de Investigación en Biomedicina de Buenos Aires (IBIoBA), CONICET-Partner Institute of The Max Plank Society, Buenos Aires, Argentina
| | - Susana Silberstein
- Instituto de Investigación en Biomedicina de Buenos Aires (IBIoBA), CONICET-Partner Institute of The Max Plank Society, Buenos Aires, Argentina
| | - Pablo Martin Páez
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, State University of New York at Buffalo, Buffalo, New York, USA
| | - Veronica Teresita Cheli
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, State University of New York at Buffalo, Buffalo, New York, USA
| | - Jorge Correale
- Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
- Departamento de Neurología, Fleni, Buenos Aires, Argentina
| | - Juana M Pasquini
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
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Park J, Lee K, Kim K, Yi SJ. The role of histone modifications: from neurodevelopment to neurodiseases. Signal Transduct Target Ther 2022; 7:217. [PMID: 35794091 PMCID: PMC9259618 DOI: 10.1038/s41392-022-01078-9] [Citation(s) in RCA: 130] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 06/11/2022] [Accepted: 06/21/2022] [Indexed: 12/24/2022] Open
Abstract
Epigenetic regulatory mechanisms, including DNA methylation, histone modification, chromatin remodeling, and microRNA expression, play critical roles in cell differentiation and organ development through spatial and temporal gene regulation. Neurogenesis is a sophisticated and complex process by which neural stem cells differentiate into specialized brain cell types at specific times and regions of the brain. A growing body of evidence suggests that epigenetic mechanisms, such as histone modifications, allow the fine-tuning and coordination of spatiotemporal gene expressions during neurogenesis. Aberrant histone modifications contribute to the development of neurodegenerative and neuropsychiatric diseases. Herein, recent progress in understanding histone modifications in regulating embryonic and adult neurogenesis is comprehensively reviewed. The histone modifications implicated in neurodegenerative and neuropsychiatric diseases are also covered, and future directions in this area are provided.
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Affiliation(s)
- Jisu Park
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyubin Lee
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyunghwan Kim
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
| | - Sun-Ju Yi
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
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Kurop MK, Huyen CM, Kelly JH, Blagg BSJ. The heat shock response and small molecule regulators. Eur J Med Chem 2021; 226:113846. [PMID: 34563965 PMCID: PMC8608735 DOI: 10.1016/j.ejmech.2021.113846] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 09/07/2021] [Accepted: 09/07/2021] [Indexed: 01/09/2023]
Abstract
The heat shock response (HSR) is a highly conserved cellular pathway that is responsible for stress relief and the refolding of denatured proteins [1]. When a host cell is exposed to conditions such as heat shock, ischemia, or toxic substances, heat shock factor-1 (HSF-1), a transcription factor, activates the genes that encode for the heat shock proteins (Hsps), which are a family of proteins that work alongside other chaperones to relieve stress and refold proteins that have been denatured (Burdon, 1986) [2]. Along with the refolding of denatured proteins, Hsps facilitate the removal of misfolded proteins by escorting them to degradation pathways, thereby preventing the accumulation of misfolded proteins [3]. Research has indicated that many pathological conditions, such as diabetes, cancer, neuropathy, cardiovascular disease, and aging have a negative impact on HSR function and are commonly associated with misfolded protein aggregation [4,5]. Studies indicate an interplay between mitochondrial homeostasis and HSF-1 levels can impact stress resistance, proteostasis, and malignant cell growth, which further support the role of Hsps in pathological and metabolic functions [6]. On the other hand, Hsp activation by specific small molecules can induce the heat shock response, which can afford neuroprotection and other benefits [7]. This review will focus on the modulation of Hsps and the HSR as therapeutic options to treat these conditions.
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Affiliation(s)
- Margaret K Kurop
- Warren Center for Drug Discovery, Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA
| | - Cormac M Huyen
- Warren Center for Drug Discovery, Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA
| | - John H Kelly
- Warren Center for Drug Discovery, Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA
| | - Brian S J Blagg
- Warren Center for Drug Discovery, Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA.
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8
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Challagundla N, Agrawal-Rajput R. microRNAs (miR 9, 124, 155 and 224) transdifferentiate mouse macrophages to neurons. Exp Cell Res 2021; 402:112563. [PMID: 33757809 DOI: 10.1016/j.yexcr.2021.112563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 03/06/2021] [Accepted: 03/09/2021] [Indexed: 11/30/2022]
Abstract
Development is an irreversible process of differentiating the undifferentiated cells to functional cells. Brain development involves generation of cells with varied phenotype and functions, which is limited during adulthood, stress, damage/degeneration. Cellular reprogramming makes differentiation reversible process with reprogramming somatic/stem cells to alternative fate with/without stem cells. Exogenously expressed transcription factors or small molecule inhibitors have driven reprogramming of stem/somatic cells to neurons providing alternative approach for pre-clinical/clinical testing and therapeutics. Here in, we report a novel approach of microRNA (miR)- induced trans-differentiation of macrophages (CD11b high) to induced neuronal cells (iNCs) (neuronal markershigh- Nestin, Nurr1, Map2, NSE, Tubb3 and Mash1) without exogenous use of transcription factors. miR 9, 124, 155 and 224 successfully transdifferentiated macrophages to neurons with transient stem cell-like phenotype. We report trans differentiation efficacy 18% and 21% with miR 124 and miR 155. in silico(String 10.0, miR gator, mESAdb, TargetScan 7.0) and experimental analysis indicate that the reprogramming involves alteration of pluripotencygenes like Oct4, Sox2, Klf4, Nanog and pluripotency miR, miR 302. iNCs also shifted to G0 phase indicating manipulation of cell cycle by these miRs. Further, CD133+ intermediate cells obtained during current protocol could be differentiated to iNCs using miRs. The syanpsin+ neurons were functionally active and displayed intracellular Ca+2 evoke on activation. miRs could also transdifferentiate bone marrow-derived macrophages and peripheral blood mononuclear cells to neuronal cells. The current protocol could be employed for direct in vivo reprogramming of macrophages to neurons without teratoma formation for transplantation and clinical studies.
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Affiliation(s)
- Naveen Challagundla
- Immunology Lab,Indian Institute of Advanced Research [IIAR], Gandhinagar, Gujarat, 382427, India.
| | - Reena Agrawal-Rajput
- Immunology Lab,Indian Institute of Advanced Research [IIAR], Gandhinagar, Gujarat, 382427, India.
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Maiese K. Cognitive impairment with diabetes mellitus and metabolic disease: innovative insights with the mechanistic target of rapamycin and circadian clock gene pathways. Expert Rev Clin Pharmacol 2020; 13:23-34. [PMID: 31794280 PMCID: PMC6959472 DOI: 10.1080/17512433.2020.1698288] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/25/2019] [Indexed: 12/18/2022]
Abstract
Introduction: Dementia is the 7th leading cause of death that imposes a significant financial and service burden on the global population. Presently, only symptomatic care exists for cognitive loss, such as Alzheimer's disease.Areas covered: Given the advancing age of the global population, it becomes imperative to develop innovative therapeutic strategies for cognitive loss. New studies provide insight to the association of cognitive loss with metabolic disorders, such as diabetes mellitus.Expert opinion: Diabetes mellitus is increasing in incidence throughout the world and affects 350 million individuals. Treatment strategies identifying novel pathways that oversee metabolic and neurodegenerative disorders offer exciting prospects to treat dementia. The mechanistic target of rapamycin (mTOR) and circadian clock gene pathways that include AMP activated protein kinase (AMPK), Wnt1 inducible signaling pathway protein 1 (WISP1), erythropoietin (EPO), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) provide novel strategies to treat cognitive loss that has its basis in metabolic cellular dysfunction. However, these pathways are complex and require precise regulation to maximize treatment efficacy and minimize any potential clinical disability. Further investigations hold great promise to treat both the onset and progression of cognitive loss that is associated with metabolic disease.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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10
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Miller DJ, Fort PE. Heat Shock Proteins Regulatory Role in Neurodevelopment. Front Neurosci 2018; 12:821. [PMID: 30483047 PMCID: PMC6244093 DOI: 10.3389/fnins.2018.00821] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 10/22/2018] [Indexed: 01/20/2023] Open
Abstract
Heat shock proteins (Hsps) are a large family of molecular chaperones that are well-known for their roles in protein maturation, re-folding and degradation. While some Hsps are constitutively expressed in certain regions, others are rapidly upregulated in the presence of stressful stimuli. Numerous stressors, including hyperthermia and hypoxia, can induce the expression of Hsps, which, in turn, interact with client proteins and co-chaperones to regulate cell growth and survival. Such interactions must be tightly regulated, especially at critical points during embryonic and postnatal development. Hsps exhibit specific patterns of expression consistent with a spatio-temporally regulated role in neurodevelopment. There is also growing evidence that Hsps may promote or inhibit neurodevelopment through specific pathways regulating cell differentiation, neurite outgrowth, cell migration, or angiogenesis. This review will examine the regulatory role that these individual chaperones may play in neurodevelopment, and will focus specifically on the signaling pathways involved in the maturation of neuronal and glial cells as well as the underlying vascular network.
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Affiliation(s)
- David J Miller
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United States.,Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Patrice E Fort
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United States.,Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
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11
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Chen JY, Parekh M, Seliman H, Bakshinskaya D, Dai W, Kwan K, Chen KY, Liu AYC. Heat shock promotes inclusion body formation of mutant huntingtin (mHtt) and alleviates mHtt-induced transcription factor dysfunction. J Biol Chem 2018; 293:15581-15593. [PMID: 30143534 PMCID: PMC6177601 DOI: 10.1074/jbc.ra118.002933] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 08/22/2018] [Indexed: 01/08/2023] Open
Abstract
PolyQ-expanded huntingtin (mHtt) variants form aggregates, termed inclusion bodies (IBs), in individuals with and models of Huntington's disease (HD). The role of IB versus diffusible mHtt in neurotoxicity remains unclear. Using a ponasterone (PA)-inducible cell model of HD, here we evaluated the effects of heat shock on the appearance and functional outcome of Htt103QExon1-EGFP expression. Quantitative image analysis indicated that 80-90% of this mHtt protein initially appears as "diffuse" signals in the cytosol, with IBs forming at high mHtt expression. A 2-h heat shock during the PA induction reduced the diffuse signal, but greatly increased mHtt IB formation in both cytosol and nucleus. Dose- and time-dependent mHtt expression suggested that nucleated polymerization drives IB formation. RNA-mediated knockdown of heat shock protein 70 (HSP70) and heat shock cognate 70 protein (HSC70) provided evidence for their involvement in promoting diffuse mHtt to form IBs. Reporter gene assays assessing the impacts of diffuse versus IB mHtt showed concordance of diffuse mHtt expression with the repression of heat shock factor 1, cAMP-responsive element-binding protein (CREB), and NF-κB activity. CREB repression was reversed by heat shock coinciding with mHtt IB formation. In an embryonic striatal neuron-derived HD model, the chemical chaperone sorbitol similarly promoted the structuring of diffuse mHtt into IBs and supported cell survival under stress. Our results provide evidence that mHtt IB formation is a chaperone-supported cellular coping mechanism that depletes diffusible mHtt conformers, alleviates transcription factor dysfunction, and promotes neuron survival.
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Affiliation(s)
- Justin Y Chen
- From the Department of Cell Biology and Neuroscience and
| | - Miloni Parekh
- From the Department of Cell Biology and Neuroscience and
| | - Hadear Seliman
- From the Department of Cell Biology and Neuroscience and
| | | | - Wei Dai
- From the Department of Cell Biology and Neuroscience and
| | - Kelvin Kwan
- From the Department of Cell Biology and Neuroscience and
| | - Kuang Yu Chen
- Department of Chemistry and Chemical Biology, Rutgers State University of New Jersey, Piscataway, New Jersey 08854
| | - Alice Y C Liu
- From the Department of Cell Biology and Neuroscience and
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Brunquell J, Raynes R, Bowers P, Morris S, Snyder A, Lugano D, Deonarine A, Westerheide SD. CCAR-1 is a negative regulator of the heat-shock response in Caenorhabditis elegans. Aging Cell 2018; 17:e12813. [PMID: 30003683 PMCID: PMC6156500 DOI: 10.1111/acel.12813] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 06/07/2018] [Accepted: 06/13/2018] [Indexed: 12/31/2022] Open
Abstract
Defects in protein quality control during aging are central to many human diseases, and strategies are needed to better understand mechanisms of controlling the quality of the proteome. The heat-shock response (HSR) is a conserved survival mechanism mediated by the transcription factor HSF1 which functions to maintain proteostasis. In mammalian cells, HSF1 is regulated by a variety of factors including the prolongevity factor SIRT1. SIRT1 promotes the DNA-bound state of HSF1 through deacetylation of the DNA-binding domain of HSF1, thereby enhancing the HSR. SIRT1 is also regulated by various factors, including negative regulation by the cell-cycle and apoptosis regulator CCAR2. CCAR2 negatively regulates the HSR, possibly through its inhibitory interaction with SIRT1. We were interested in studying conservation of the SIRT1/CCAR2 regulatory interaction in Caenorhabditis elegans, and in utilizing this model organism to observe the effects of modulating sirtuin activity on the HSR, longevity, and proteostasis. The HSR is highly conserved in C. elegans and is mediated by the HSF1 homolog, HSF-1. We have uncovered that negative regulation of the HSR by CCAR2 is conserved in C. elegans and is mediated by the CCAR2 ortholog, CCAR-1. This negative regulation requires the SIRT1 homolog SIR-2.1. In addition, knockdown of CCAR-1 via ccar-1 RNAi works through SIR-2.1 to enhance stress resistance, motility, longevity, and proteostasis. This work therefore highlights the benefits of enhancing sirtuin activity to promote the HSR at the level of the whole organism.
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Affiliation(s)
- Jessica Brunquell
- Cell Biology, Microbiology and Molecular BiologyUniversity of South FloridaTampaFloridaUSA
| | - Rachel Raynes
- Cell Biology, Microbiology and Molecular BiologyUniversity of South FloridaTampaFloridaUSA
| | - Philip Bowers
- Cell Biology, Microbiology and Molecular BiologyUniversity of South FloridaTampaFloridaUSA
| | - Stephanie Morris
- Cell Biology, Microbiology and Molecular BiologyUniversity of South FloridaTampaFloridaUSA
| | - Alana Snyder
- Cell Biology, Microbiology and Molecular BiologyUniversity of South FloridaTampaFloridaUSA
| | - Doreen Lugano
- Cell Biology, Microbiology and Molecular BiologyUniversity of South FloridaTampaFloridaUSA
| | - Andrew Deonarine
- Cell Biology, Microbiology and Molecular BiologyUniversity of South FloridaTampaFloridaUSA
| | - Sandy D. Westerheide
- Cell Biology, Microbiology and Molecular BiologyUniversity of South FloridaTampaFloridaUSA
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13
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Li Z, Wang F, Zha S, Cao Q, Sheng J, Chen S. SIRT1 inhibits TGF‐β‐induced endothelial‐mesenchymal transition in human endothelial cells with Smad4 deacetylation. J Cell Physiol 2018; 233:9007-9014. [PMID: 29856490 DOI: 10.1002/jcp.26846] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 05/10/2018] [Indexed: 12/24/2022]
Affiliation(s)
- Zhen Li
- Department of Geriatrics, Xinhua Hospital, School of Medicine Shanghai Jiao Tong University Shanghai China
| | - Fei Wang
- Department of Geriatrics, Xinhua Hospital, School of Medicine Shanghai Jiao Tong University Shanghai China
| | - Siyuan Zha
- Department of Geriatrics, Xinhua Hospital, School of Medicine Shanghai Jiao Tong University Shanghai China
| | - Qing Cao
- Department of Geriatrics, Xinhua Hospital, School of Medicine Shanghai Jiao Tong University Shanghai China
| | - Jing Sheng
- Department of Geriatrics Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Shuyan Chen
- Department of Geriatrics, Xinhua Hospital, School of Medicine Shanghai Jiao Tong University Shanghai China
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Shi X, Pi L, Zhou S, Li X, Min F, Wang S, Liu Z, Wu J. Activation of Sirtuin 1 Attenuates High Glucose-Induced Neuronal Apoptosis by Deacetylating p53. Front Endocrinol (Lausanne) 2018; 9:274. [PMID: 29892266 PMCID: PMC5985296 DOI: 10.3389/fendo.2018.00274] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Accepted: 05/09/2018] [Indexed: 12/04/2022] Open
Abstract
Diabetes mellitus (DM) has been proven to be a key risk factor for cognitive impairment. Previous studies have implicated hippocampal neuronal apoptosis in diabetes-related cognitive impairment. However, the underlying mechanism remains unknown. Sirtuin 1 (SIRT1) is a protein deacetylase depended on nicotinamide adenine dinucleotide. Furthermore, it is indispensable in normal learning and memory. Whether SIRT1 is taken part in diabetes-induced neuronal apoptosis and thus involve in the development of diabetic cognitive impairment is still not clear. To address this issue, we examined the possible role of SIRT1 in hippocampal neuronal apoptosis in streptozotocin-induced diabetic mice. Furthermore, the possible mechanism was investigated in high glucose-induced SH-SY5Y cells. We found that downregulation of the activity and expression of SIRT1 was associated with increased hippocampal neuronal apoptosis in mice. In vitro, cell apoptosis induced by high glucose which was accompanied by a downregulation of SIRT1 and an increased acetylation of p53. On the contrary, activation of SIRT1 using its agonist resveratrol ameliorated cell apoptosis via deacetylating p53. Our data suggest that high concentration of glucose can induce neuronal apoptosis through downregulation of SIRT1 and increased acetylation of p53, which likely contribute to the development of cognitive impairment in diabetes.
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Affiliation(s)
- Xiajie Shi
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, China
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Linhua Pi
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, China
| | - Shanlei Zhou
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, China
| | - Xin Li
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Fangyuan Min
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Shan Wang
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Zhenqi Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA, United States
| | - Jing Wu
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, China
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15
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Kaszubowska L, Foerster J, Kaczor JJ, Schetz D, Ślebioda TJ, Kmieć Z. NK cells of the oldest seniors represent constant and resistant to stimulation high expression of cellular protective proteins SIRT1 and HSP70. IMMUNITY & AGEING 2018. [PMID: 29541147 PMCID: PMC5840822 DOI: 10.1186/s12979-018-0115-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Background Natural killer cells (NK cells) are cytotoxic lymphocytes of innate immunity that reveal some immunoregulatory properties, however, their role in the process of ageing is not completely understood. The study aimed to analyze the expression of proteins involved in cellular stress response: sirtuin 1 (SIRT1), heat shock protein 70 (HSP70) and manganese superoxide dismutase (SOD2) in human NK cells with reference to the process of ageing. Non-stimulated and stimulated with IL-2, LPS or PMA with ionomycin cells originated from peripheral blood samples of: seniors aged over 85 (‘the oldest’; n = 25; 88.5 ± 0.5 years, mean ± SEM), seniors aged under 85 (‘the old’; n = 30; 75.6 ± 0.9 years) and the young (n = 31; 20.9 ± 0.3 years). The relationships between the levels of expression of cellular protective proteins in the studied population were also analyzed. The concentrations of carbonyl groups and 8-isoprostanes, markers of oxidative stress, in both stimulated and non-stimulated cultured NK cells were measured to assess the level of the oxidative stress in the cells. Results The oldest seniors varied from the other age groups by significantly higher expression of SIRT1 and HSP70 both in non-stimulated and stimulated NK cells. These cells also appeared to be resistant to further stimulations with IL-2, LPS or PMA with ionomycin. Highly positive correlations between SIRT1 and intracellular HSP70 in both stimulated and non-stimulated NK cells were observed. SOD2 presented low expression in non-stimulated cells, whereas its sensitivity to stimulation increased with age of donors. High positive correlations between SOD2 and surface HSP70 were observed. We found that the markers of oxidative stress in NK cells did not change with ageing. Conclusions The oldest seniors revealed well developed adaptive stress response in NK cells with increased, constant levels of SIRT1 and intracellular HSP70. They presented also very high positive correlations between expression of these cellular protective proteins both in stimulated and non-stimulated cells. These phenomena may contribute to the long lifespan of this group of elderly. Interestingly, in NK cells SOD2 revealed a distinct role in cellular stress response since it showed sensitivity to stimulation increasing with age of participants. These observations provide novel data concerning the role of NK cells in the process of ageing.
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Affiliation(s)
- Lucyna Kaszubowska
- 1Department of Histology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Jerzy Foerster
- 2Department of Social and Clinical Gerontology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Jan Jacek Kaczor
- 3Department of Bioenergetics and Physiology of Exercise, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Daria Schetz
- 4Department of Pharmacology, Medical University of Gdańsk, Dębowa 23, 80-204 Gdańsk, Poland
| | - Tomasz Jerzy Ślebioda
- 1Department of Histology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Zbigniew Kmieć
- 1Department of Histology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
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16
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Gomez-Pastor R, Burchfiel ET, Thiele DJ. Regulation of heat shock transcription factors and their roles in physiology and disease. Nat Rev Mol Cell Biol 2017; 19:4-19. [PMID: 28852220 DOI: 10.1038/nrm.2017.73] [Citation(s) in RCA: 537] [Impact Index Per Article: 67.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The heat shock transcription factors (HSFs) were discovered over 30 years ago as direct transcriptional activators of genes regulated by thermal stress, encoding heat shock proteins. The accepted paradigm posited that HSFs exclusively activate the expression of protein chaperones in response to conditions that cause protein misfolding by recognizing a simple promoter binding site referred to as a heat shock element. However, we now realize that the mammalian family of HSFs comprises proteins that independently or in concert drive combinatorial gene regulation events that activate or repress transcription in different contexts. Advances in our understanding of HSF structure, post-translational modifications and the breadth of HSF-regulated target genes have revealed exciting new mechanisms that modulate HSFs and shed new light on their roles in physiology and pathology. For example, the ability of HSF1 to protect cells from proteotoxicity and cell death is impaired in neurodegenerative diseases but can be exploited by cancer cells to support their growth, survival and metastasis. These new insights into HSF structure, function and regulation should facilitate the development tof new disease therapeutics to manipulate this transcription factor family.
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Affiliation(s)
- Rocio Gomez-Pastor
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine
| | | | - Dennis J Thiele
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine.,Department of Biochemistry, Duke University School of Medicine.,Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina 27710, USA
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17
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Calapre L, Gray ES, Kurdykowski S, David A, Descargues P, Ziman M. SIRT1 activation mediates heat-induced survival of UVB damaged Keratinocytes. BMC DERMATOLOGY 2017; 17:8. [PMID: 28601088 PMCID: PMC5466784 DOI: 10.1186/s12895-017-0060-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 06/02/2017] [Indexed: 11/10/2022]
Abstract
Background Exposure to heat stress after UVB irradiation induces a reduction of apoptosis, resulting in survival of DNA damaged human keratinocytes. This heat-mediated evasion of apoptosis appears to be mediated by activation of SIRT1 and inactivation of p53 signalling. In this study, we assessed the role of SIRT1 in the inactivation of p53 signalling and impairment of DNA damage response in UVB plus heat exposed keratinocytes. Results Activation of SIRT1 after multiple UVB plus heat exposures resulted in increased p53 deacetylation at K382, which is known to affect its binding to specific target genes. Accordingly, we noted decreased apoptosis and down regulation of the p53 targeted pro-apoptotic gene BAX and the DNA repair genes ERCC1 and XPC after UVB plus heat treatments. In addition, UVB plus heat induced increased expression of the cell survival gene Survivin and the proliferation marker Ki67. Notably, keratinocytes exposed to UVB plus heat in the presence of the SIRT1 inhibitor, Ex-527, showed a similar phenotype to those exposed to UV alone; i.e. an increase in p53 acetylation, increased apoptosis and low levels of Survivin. Conclusion This study demonstrate that heat-induced SIRT1 activation mediates survival of DNA damaged keratinocytes through deacetylation of p53 after exposure to UVB plus heat Electronic supplementary material The online version of this article (doi:10.1186/s12895-017-0060-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Leslie Calapre
- School of Medical Science, Edith Cowan University, 270 Joondalup Drive, Joondalup, Perth, WA, 6027, Australia
| | - Elin S Gray
- School of Medical Science, Edith Cowan University, 270 Joondalup Drive, Joondalup, Perth, WA, 6027, Australia
| | | | - Anthony David
- GENOSKIN Centre Pierre Potier, Oncopole, Toulouse, France
| | | | - Mel Ziman
- School of Medical Science, Edith Cowan University, 270 Joondalup Drive, Joondalup, Perth, WA, 6027, Australia. .,School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia.
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18
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Jeong WY, Kim JB, Kim HJ, Kim CW. Extremely low-frequency electromagnetic field promotes astrocytic differentiation of human bone marrow mesenchymal stem cells by modulating SIRT1 expression. Biosci Biotechnol Biochem 2017; 81:1356-1362. [PMID: 28351214 DOI: 10.1080/09168451.2017.1308243] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
It has been shown that extremely low-frequency electromagnetic fields (ELFMF) affect regulation of cell fate and differentiation. Thus, the aim of this study was to investigate the role of ELFMFs in the enhancement of astrocytic differentiation. ELFMF exposure reduced the rate of proliferation and enhanced astrocytic differentiation. The ELFMF-treated cells showed increased levels of the astrocyte marker (GFAP), while those of the early neuronal marker (Nestin) and stemness marker (OCT3/4) were downregulated. The reactive oxygen species (ROS) level was observed to be significantly elevated after ELFMF exposure, which strengthens the modulatory role of SIRT1 and SIRT1 downstream molecules (TLE1, HES1, and MASH1) during astrocytic differentiation. After nicotinamide (5 mM) mediated inhibition of SIRT1, levels of TLE1, HES1, and MASH1 were examined; TLE1 was significantly upregulated and MASH1 was downregulated. These results suggest that ELFMFs induce astrocytic differentiation through activation of SIRT1 and SIRT1 downstream molecules.
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Affiliation(s)
- Won-Yong Jeong
- a College of Life Sciences and Biotechnology , Korea University , Seoul , Korea
| | - Jun-Beom Kim
- a College of Life Sciences and Biotechnology , Korea University , Seoul , Korea
| | - Hyun-Jung Kim
- a College of Life Sciences and Biotechnology , Korea University , Seoul , Korea
| | - Chan-Wha Kim
- a College of Life Sciences and Biotechnology , Korea University , Seoul , Korea
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19
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Correia M, Perestrelo T, Rodrigues AS, Ribeiro MF, Pereira SL, Sousa MI, Ramalho-Santos J. Sirtuins in metabolism, stemness and differentiation. Biochim Biophys Acta Gen Subj 2017; 1861:3444-3455. [DOI: 10.1016/j.bbagen.2016.09.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 08/16/2016] [Accepted: 09/06/2016] [Indexed: 12/20/2022]
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20
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Leite JSM, Cruzat VF, Krause M, Homem de Bittencourt PI. Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions. ACTA ACUST UNITED AC 2016. [DOI: 10.1186/s41110-016-0021-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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21
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A potent and selective small molecule inhibitor of sirtuin 1 promotes differentiation of pluripotent P19 cells into functional neurons. Sci Rep 2016; 6:34324. [PMID: 27680533 PMCID: PMC5041152 DOI: 10.1038/srep34324] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 09/12/2016] [Indexed: 12/20/2022] Open
Abstract
Sirtuin 1 (SIRT1) is known to suppress differentiation of pluripotent/multipotent cells and neural progenitor cells into neurons by blocking activation of transcription factors critical for neurogenesis. EX-527 is a highly selective and potent inhibitor against SIRT1 and has been used as a chemical probe that modulates SIRT1-associated biological processes. However, the effect of EX-527 on neuronal differentiation in pluripotent cells has not been well elucidated. Here, we report an examination of EX-527 effects on neurogenesis of pluripotent P19 cells. The results showed that EX-527 greatly accelerated differentiation of P19 cells into neurons without generation of cardiac cells and astrocytes. Importantly, neurons derived from P19 cells treated with EX-527 generated voltage-dependent sodium currents and depolarization-induced action potentials. The findings indicate that the differentiated cells have electrophysiological properties. The present study suggests that the selective SIRT1 inhibitor could have the potential of being employed as a chemical inducer to generate functionally active neurons.
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22
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Karvinen S, Silvennoinen M, Vainio P, Sistonen L, Koch LG, Britton SL, Kainulainen H. Effects of intrinsic aerobic capacity, aging and voluntary running on skeletal muscle sirtuins and heat shock proteins. Exp Gerontol 2016; 79:46-54. [DOI: 10.1016/j.exger.2016.03.015] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 03/03/2016] [Accepted: 03/23/2016] [Indexed: 11/25/2022]
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23
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Piri N, Kwong JMK, Gu L, Caprioli J. Heat shock proteins in the retina: Focus on HSP70 and alpha crystallins in ganglion cell survival. Prog Retin Eye Res 2016; 52:22-46. [PMID: 27017896 PMCID: PMC4842330 DOI: 10.1016/j.preteyeres.2016.03.001] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Revised: 03/14/2016] [Accepted: 03/22/2016] [Indexed: 10/22/2022]
Abstract
Heat shock proteins (HSPs) belong to a superfamily of stress proteins that are critical constituents of a complex defense mechanism that enhances cell survival under adverse environmental conditions. Cell protective roles of HSPs are related to their chaperone functions, antiapoptotic and antinecrotic effects. HSPs' anti-apoptotic and cytoprotective characteristics, their ability to protect cells from a variety of stressful stimuli, and the possibility of their pharmacological induction in cells under pathological stress make these proteins an attractive therapeutic target for various neurodegenerative diseases; these include Alzheimer's, Parkinson's, Huntington's, prion disease, and others. This review discusses the possible roles of HSPs, particularly HSP70 and small HSPs (alpha A and alpha B crystallins) in enhancing the survival of retinal ganglion cells (RGCs) in optic neuropathies such as glaucoma, which is characterized by progressive loss of vision caused by degeneration of RGCs and their axons in the optic nerve. Studies in animal models of RGC degeneration induced by ocular hypertension, optic nerve crush and axotomy show that upregulation of HSP70 expression by hyperthermia, zinc, geranyl-geranyl acetone, 17-AAG (a HSP90 inhibitor), or through transfection of retinal cells with AAV2-HSP70 effectively supports the survival of injured RGCs. RGCs survival was also stimulated by overexpression of alpha A and alpha B crystallins. These findings provide support for translating the HSP70- and alpha crystallin-based cell survival strategy into therapy to protect and rescue injured RGCs from degeneration associated with glaucomatous and other optic neuropathies.
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Affiliation(s)
- Natik Piri
- Stein Eye Institute, University of California, Los Angeles, CA 90095, USA; Brain Research Institute, University of California, Los Angeles, CA 90095, USA.
| | - Jacky M K Kwong
- Stein Eye Institute, University of California, Los Angeles, CA 90095, USA
| | - Lei Gu
- Stein Eye Institute, University of California, Los Angeles, CA 90095, USA
| | - Joseph Caprioli
- Stein Eye Institute, University of California, Los Angeles, CA 90095, USA; Brain Research Institute, University of California, Los Angeles, CA 90095, USA
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24
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Maiese K. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Neural Regen Res 2016; 11:372-85. [PMID: 27127460 PMCID: PMC4828986 DOI: 10.4103/1673-5374.179032] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Throughout the globe, diabetes mellitus (DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder. DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy. The mechanistic target of rapamycin (mTOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM. mTOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis, insulin resistance, insulin secretion, stem cell proliferation and differentiation, pancreatic β-cell function, and programmed cell death with apoptosis and autophagy. mTOR is central element for the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), and growth factors. As a result, mTOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease. Future studies directed to elucidate the delicate balance mTOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.
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25
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Abstract
Globally, greater than 30 million individuals are afflicted with disorders of the nervous system accompanied by tens of thousands of new cases annually with limited, if any, treatment options. Erythropoietin (EPO) offers an exciting and novel therapeutic strategy to address both acute and chronic neurodegenerative disorders. EPO governs a number of critical protective and regenerative mechanisms that can impact apoptotic and autophagic programmed cell death pathways through protein kinase B (Akt), sirtuins, mammalian forkhead transcription factors, and wingless signaling. Translation of the cytoprotective pathways of EPO into clinically effective treatments for some neurodegenerative disorders has been promising, but additional work is necessary. In particular, development of new treatments with erythropoiesis-stimulating agents such as EPO brings several important challenges that involve detrimental vascular outcomes and tumorigenesis. Future work that can effectively and safely harness the complexity of the signaling pathways of EPO will be vital for the fruitful treatment of disorders of the nervous system.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101
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26
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Dattilo S, Mancuso C, Koverech G, Di Mauro P, Ontario ML, Petralia CC, Petralia A, Maiolino L, Serra A, Calabrese EJ, Calabrese V. Heat shock proteins and hormesis in the diagnosis and treatment of neurodegenerative diseases. Immun Ageing 2015; 12:20. [PMID: 26543490 PMCID: PMC4634585 DOI: 10.1186/s12979-015-0046-8] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 10/15/2015] [Indexed: 12/16/2022]
Abstract
Modulation of endogenous cellular defense mechanisms via the vitagene system represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. The possibility of high-throughoutput screening using proteomic techniques, particularly redox proteomics, provide more comprehensive overview of the interaction of proteins, as well as the interplay among processes involved in neuroprotection. Here by introducing the hormetic dose response concept, the mechanistic foundations and applications to the field of neuroprotection, we discuss the emerging role of heat shock protein as prominent member of vitagene network in neuroprotection and redox proteomics as a tool for investigating redox modulation of stress responsive vitagenes. Hormetic mechanisms are reviewed as possibility of targeted therapeutic manipulation in a cell-, tissue- and/or pathway-specific manner at appropriate points in the neurodegenerative disease process.
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Affiliation(s)
- Sandro Dattilo
- />Department of Biomedical and Biotechnological Sciences, University of Catania, Via Andrea Doria, 95100 Catania, Italy
| | - Cesare Mancuso
- />Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy
| | - Guido Koverech
- />Department of Biomedical and Biotechnological Sciences, University of Catania, Via Andrea Doria, 95100 Catania, Italy
| | - Paola Di Mauro
- />Department of Medical and Surgery Specialties, University of Catania, Catania, Italy
| | - Maria Laura Ontario
- />Department of Biomedical and Biotechnological Sciences, University of Catania, Via Andrea Doria, 95100 Catania, Italy
| | | | - Antonino Petralia
- />Department of Clinical and Experimental Medicine, School of Medicine, University of Catania, Catania, Italy
| | - Luigi Maiolino
- />Department of Medical and Surgery Specialties, University of Catania, Catania, Italy
| | - Agostino Serra
- />Department of Medical and Surgery Specialties, University of Catania, Catania, Italy
| | - Edward J. Calabrese
- />Environmental Health Sciences Division, School of Public Health, University of Massachusetts, Amherst, MA USA
| | - Vittorio Calabrese
- />Department of Biomedical and Biotechnological Sciences, University of Catania, Via Andrea Doria, 95100 Catania, Italy
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27
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Kim HW, Kim SA, Ahn SG. Sirtuin inhibitors, EX527 and AGK2, suppress cell migration by inhibiting HSF1 protein stability. Oncol Rep 2015; 35:235-42. [PMID: 26530275 DOI: 10.3892/or.2015.4381] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 09/17/2015] [Indexed: 11/05/2022] Open
Abstract
The histone deacetylases (HDACs), Sirtuin 1 (Sirt1) and Sirt2, play crucial roles in many biological processes, including cell proliferation, differentiation and apoptosis. HDAC inhibitors have been considered as a potential therapeutic approach for various types of cancers. Here, we demonstrated that the Sirt1 and Sirt2 inhibitors EX527 and AGK2 suppressed cell growth and caused G1 phase arrest by inhibiting the expression of Cdk6 and/or Cdk4. An agar colony formation assay revealed that EX527 and AGK2 decreased colony formation in soft agar. Furthermore, EX527 and AGK2 pretreatment inhibited the expression of HSF1 and HSP27 and induced HSF1 ubiquitination. Sirt1 overexpression increased HSF1 expression and/or stabilization and induced cell migration in a scratch assay. Overall, these results indicate that EX527 and AGK2 suppress cell growth and migration by inhibiting HSF1 protein stability.
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Affiliation(s)
- Hyun-Woo Kim
- Department of Pathology, School of Dentistry, Chosun University, Gwangju 501-759, Republic of Korea
| | - Soo-A Kim
- Department of Biochemistry, College of Oriental Medicine, Dongguk University, Gyeongju 780-714, Republic of Korea
| | - Sang-Gun Ahn
- Department of Pathology, School of Dentistry, Chosun University, Gwangju 501-759, Republic of Korea
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Krause M, Bock PM, Takahashi HK, Homem De Bittencourt PI, Newsholme P. The regulatory roles of NADPH oxidase, intra- and extra-cellular HSP70 in pancreatic islet function, dysfunction and diabetes. Clin Sci (Lond) 2015; 128:789-803. [PMID: 25881670 DOI: 10.1042/cs20140695] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
The 70 kDa heat-shock protein (HSP70) family is important for a dynamic range of cellular processes that include protection against cell stress, modulation of cell signalling, gene expression, protein synthesis, protein folding and inflammation. Within this family, the inducible 72 kDa and the cognate 73 kDa forms are found at the highest level. HSP70 has dual functions depending on location. For example, intracellular HSP70 (iHSP70) is anti-inflammatory whereas extracellular HSP70 (eHSP70) has a pro-inflammatory function, resulting in local and systemic inflammation. We have recently identified a divergence in the levels of eHSP70 and iHSP70 in subjects with diabetes compared with healthy subjects and also reported that eHSP70 was correlated with insulin resistance and pancreatic β-cell dysfunction/death. In the present review, we describe possible mechanisms by which HSP70 participates in cell function/dysfunction, including the activation of NADPH oxidase isoforms leading to oxidative stress, focusing on the possible role of HSPs and signalling in pancreatic islet α- and β-cell physiological function in health and Type 2 diabetes mellitus.
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Affiliation(s)
- Mauricio Krause
- *Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Patricia Martins Bock
- *Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Hilton Kenji Takahashi
- *Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Paulo Ivo Homem De Bittencourt
- *Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Philip Newsholme
- ‡School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, Western Australia
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New Insights for Oxidative Stress and Diabetes Mellitus. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:875961. [PMID: 26064426 PMCID: PMC4443788 DOI: 10.1155/2015/875961] [Citation(s) in RCA: 149] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 04/15/2015] [Indexed: 12/12/2022]
Abstract
The release of reactive oxygen species (ROS) and the generation of oxidative stress are considered critical factors for the pathogenesis of diabetes mellitus (DM), a disorder that is growing in prevalence and results in significant economic loss. New therapeutic directions that address the detrimental effects of oxidative stress may be especially warranted to develop effective care for the millions of individuals that currently suffer from DM. The mechanistic target of rapamycin (mTOR), silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), and Wnt1 inducible signaling pathway protein 1 (WISP1) are especially justified to be considered treatment targets for DM since these pathways can address the complex relationship between stem cells, trophic factors, impaired glucose tolerance, programmed cell death pathways of apoptosis and autophagy, tissue remodeling, cellular energy homeostasis, and vascular biology that greatly impact the biology and disease progression of DM. The translation and development of these pathways into viable therapies will require detailed understanding of their proliferative nature to maximize clinical efficacy and limit adverse effects that have the potential to lead to unintended consequences.
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Chen PY, Wu MJ, Chang HY, Tai MH, Ho CT, Yen JH. Up-Regulation of miR-34a Expression in Response to the Luteolin-Induced Neurite Outgrowth of PC12 Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:4148-4159. [PMID: 25865700 DOI: 10.1021/acs.jafc.5b01005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Luteolin (3',4',5,7-tetrahydroxyflavone), a flavonoid found in several vegetables and fruits, has been reported to possess neurotrophic activities that are associated with its capacity to promote neuronal survival and differentiation. In the present study, we report for the first time a genomewide screen for microRNAs (miRNAs) regulated during the luteolin-mediated neurite outgrowth of PC12 cells. We found that after luteolin treatment, the abundance of 16 miRNAs was markedly up-regulated and that of 3 miRNAs was down-regulated in PC12 cells. The induction of miR-34a by luteolin was the most pronounced among these differentially expressed miRNAs. The correlation between miR-34a down-regulation and decreased luteolin-mediated neurite outgrowth may indicate a mechanism by which miR-34a may act as a modulator of neuronal differentiation. Furthermore, we found that luteolin enhanced the phosphorylation of p53 at Ser15, which was associated with the promotion of miR-34a transcription and neurite outgrowth. Moreover, the level of sirtuin 1 (SIRT1), a known miR-34a target, was reduced during luteolin-induced neurite outgrowth. In turn, the level of acetylated p53, a substrate of SIRT1, was correspondingly increased in luteolin-treated PC12 cells. In addition to p53 activation, we further identified that luteolin-induced miR-34a transcription and neurite outgrowth involved the activation of the JNK and p38 MAPK pathways. However, the inhibition of JNK and p38 MAPK activation did not block luteolin-induced p53 activation in PC12 cells. Our findings suggested that the activation of both p53-dependent and p53-independent miR-34a/SIRT1 pathways plays a critical role in the mechanisms underlying luteolin-induced neuritogenesis.
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Affiliation(s)
- Pei-Yi Chen
- †Center of Medical Genetics, Buddhist Tzu Chi General Hospital, Hualien 970, Taiwan
| | - Ming-Jiuan Wu
- ‡Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | | | | | - Chi-Tang Ho
- #Department of Food Science, Rutgers University, 65 Dudley Road, New Brunswick, New Jersey 08901-8520, United States
| | - Jui-Hung Yen
- ∥Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan
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Abstract
During the development of the central nervous system (CNS), neurons and glia are derived from multipotent neural stem cells (NSCs) undergoing self-renewal. NSC commitment and differentiation are tightly controlled by intrinsic and external regulatory mechanisms in space- and time-related fashions. SIRT1, a silent information regulator 2 (Sir2) ortholog, is expressed in several areas of the brain and has been reported to be involved in the self-renewal, multipotency, and fate determination of NSCs. Recent studies have highlighted the role of the deacetylase activity of SIRT1 in the determination of the final fate of NSCs. This review summarizes the roles of SIRT1 in the expansion and differentiation of NSCs, specification of neuronal subtypes and glial cells, and reprogramming of functional neurons from embryonic stem cells and fibroblasts. This review also discusses potential signaling pathways through which SIRT1 can exhibit versatile functions in NSCs to regulate the cell fate decisions of neurons and glia.
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Maiese K. SIRT1 and stem cells: In the forefront with cardiovascular disease, neurodegeneration and cancer. World J Stem Cells 2015; 7:235-242. [PMID: 25815111 PMCID: PMC4369483 DOI: 10.4252/wjsc.v7.i2.235] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Revised: 12/10/2014] [Accepted: 01/19/2015] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular disease, nervous system disorders, and cancer in association with other diseases such as diabetes mellitus result in greater than sixty percent of the global annual deaths. These noncommunicable diseases also affect at least one-third of the population in low and middle-income countries and lead to hypertension, elevated cholesterol, malignancy, and neurodegenerative disorders such as Alzheimer’s disease and stroke. With the climbing lifespan of the world’s population, increased prevalence of these disorders is expected requiring the development of new therapeutic strategies against these disabling disease entities. Targeting stem cell proliferation for cardiac disease, vascular disorders, cancer, and neurodegenerative disorders is receiving great enthusiasm, especially those that focus upon SIRT1, a mammalian homologue of the yeast silent information regulator-2. Modulation of the cellular activity of SIRT1 can involve oversight by nicotinamide/nicotinic acid mononucleotide adenylyltransferase, mammalian forkhead transcription factors, mechanistic of rapamycin pathways, and cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma over-expressed gene family members that can impact cytoprotective outcomes. Ultimately, the ability of SIRT1 to control the programmed cell death pathways of apoptosis and autophagy can determine not only cardiac, vascular, and neuronal stem cell development and longevity, but also the onset of tumorigenesis and the resistance against chemotherapy. SIRT1 therefore has a critical role and holds exciting prospects for new therapeutic strategies that can offer reparative processes for cardiac, vascular, and nervous system degenerative disorders as well as targeted control of aberrant cell growth during cancer.
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Ng F, Wijaya L, Tang BL. SIRT1 in the brain-connections with aging-associated disorders and lifespan. Front Cell Neurosci 2015; 9:64. [PMID: 25805970 PMCID: PMC4353374 DOI: 10.3389/fncel.2015.00064] [Citation(s) in RCA: 131] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 02/11/2015] [Indexed: 01/23/2023] Open
Abstract
The silent mating type information regulation 2 proteins (sirtuins) 1 of class III histone deacetylases (HDACs) have been associated with health span and longevity. SIRT1, the best studied member of the mammalian sirtuins, has a myriad of roles in multiple tissues and organs. However, a significant part of SIRT1's role that impinges on aging and lifespan may lie in its activities in the central nervous system (CNS) neurons. Systemically, SIRT1 influences energy metabolism and circadian rhythm through its activity in the hypothalamic nuclei. From a cell biological perspective, SIRT1 is a crucial component of multiple interconnected regulatory networks that modulate dendritic and axonal growth, as well as survival against stress. This neuronal cell autonomous activity of SIRT1 is also important for neuronal plasticity, cognitive functions, as well as protection against aging-associated neuronal degeneration and cognitive decline. We discuss recent findings that have shed light on the various activities of SIRT1 in the brain, which collectively impinge on aging-associated disorders and lifespan.
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Affiliation(s)
- Fanny Ng
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System Singapore, Singapore
| | - Laura Wijaya
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System Singapore, Singapore
| | - Bor Luen Tang
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System Singapore, Singapore ; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore Singapore, Singapore
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Oxygen-dependent acetylation and dimerization of the corepressor CtBP2 in neural stem cells. Exp Cell Res 2015; 332:128-35. [DOI: 10.1016/j.yexcr.2014.10.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 10/15/2014] [Indexed: 11/21/2022]
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Maiese K. Programming apoptosis and autophagy with novel approaches for diabetes mellitus. Curr Neurovasc Res 2015; 12:173-88. [PMID: 25742566 PMCID: PMC4380829 DOI: 10.2174/1567202612666150305110929] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 02/16/2015] [Accepted: 02/19/2015] [Indexed: 12/13/2022]
Abstract
According to the World Health Organization, diabetes mellitus (DM) in the year 2030 will be ranked the seventh leading cause of death in the world. DM impacts all systems of the body with oxidant stress controlling cell fate through endoplasmic reticulum stress, mitochondrial dysfunction, alterations in uncoupling proteins, and the induction of apoptosis and autophagy. Multiple treatment approaches are being entertained for DM with Wnt1 inducible signaling pathway protein 1 (WISP1), mechanistic target of rapamycin (mTOR), and silent mating type information regulation 2 homolog) 1 (S. cerevisiae) (SIRT1) generating significant interest as target pathways that can address maintenance of glucose homeostasis as well as prevention of cellular pathology by controlling insulin resistance, stem cell proliferation, and the programmed cell death pathways of apoptosis and autophagy. WISP1, mTOR, and SIRT1 can rely upon similar pathways such as AMP activated protein kinase as well as govern cellular metabolism through cytokines such as EPO and oral hypoglycemics such as metformin. Yet, these pathways require precise biological control to exclude potentially detrimental clinical outcomes. Further elucidation of the ability to translate the roles of WISP1, mTOR, and SIRT1 into effective clinical avenues offers compelling prospects for new therapies against DM that can benefit hundreds of millions of individuals throughout the globe.
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Affiliation(s)
- Kenneth Maiese
- MD, Cellular and Molecular Signaling, Newark, New Jersey 07101, USA.
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36
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Bosch-Presegué L, Vaquero A. Sirtuin-dependent epigenetic regulation in the maintenance of genome integrity. FEBS J 2014; 282:1745-67. [DOI: 10.1111/febs.13053] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 09/09/2014] [Accepted: 09/12/2014] [Indexed: 12/12/2022]
Affiliation(s)
- Laia Bosch-Presegué
- Chromatin Biology Laboratory; Cancer Epigenetics and Biology Program; Institut d'Investigació Biomèdica de Bellvitge; Barcelona Spain
| | - Alejandro Vaquero
- Chromatin Biology Laboratory; Cancer Epigenetics and Biology Program; Institut d'Investigació Biomèdica de Bellvitge; Barcelona Spain
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