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Zhou HY, Wang X, Li Y, Wang D, Zhou XZ, Xiao N, Li GX, Li G. Dynamic development of microglia and macrophages after spinal cord injury. Neural Regen Res 2025; 20:3606-3619. [PMID: 39101644 PMCID: PMC11974661 DOI: 10.4103/nrr.nrr-d-24-00063] [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: 01/17/2024] [Revised: 04/09/2024] [Accepted: 05/28/2024] [Indexed: 08/06/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202512000-00029/figure1/v/2025-01-31T122243Z/r/image-tiff Secondary injury following spinal cord injury is primarily characterized by a complex inflammatory response, with resident microglia and infiltrating macrophages playing pivotal roles. While previous studies have grouped these two cell types together based on similarities in structure and function, an increasing number of studies have demonstrated that microglia and macrophages exhibit differences in structure and function and have different effects on disease processes. In this study, we used single-cell RNA sequencing and spatial transcriptomics to identify the distinct evolutionary paths of microglia and macrophages following spinal cord injury. Our results showed that microglia were activated to a pro-inflammatory phenotype immediately after spinal cord injury, gradually transforming to an anti-inflammatory steady state phenotype as the disease progressed. Regarding macrophages, our findings highlighted abundant communication with other cells, including fibroblasts and neurons. Both pro-inflammatory and neuroprotective effects of macrophages were also identified; the pro-inflammatory effect may be related to integrin β2 ( Itgb2 ) and the neuroprotective effect may be related to the oncostatin M pathway. These findings were validated by in vivo experiments. This research underscores differences in the cellular dynamics of microglia and macrophages following spinal cord injury, and may offer new perspectives on inflammatory mechanisms and potential therapeutic targets.
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Affiliation(s)
- Hu-Yao Zhou
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
- Department of Rehabilitation, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, China
| | - Xia Wang
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
- Department of Rehabilitation, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, China
| | - Yi Li
- Department of Rehabilitation, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, China
| | - Duan Wang
- Department of Rehabilitation, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, China
| | - Xuan-Zi Zhou
- Department of Rehabilitation, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, China
| | - Nong Xiao
- Department of Rehabilitation, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, China
| | - Guo-Xing Li
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Gang Li
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, China
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Zhou Y, Dou L, Wang L, Chen J, Mao R, Zhu L, Liu D, Zheng K. Growth and differentiation factor 15: An emerging therapeutic target for brain diseases. Biosci Trends 2025; 19:72-86. [PMID: 39864834 DOI: 10.5582/bst.2024.01305] [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: 01/28/2025]
Abstract
Growth and differentiation factor 15 (GDF15), a member of the transforming growth factor-βsuperfamily, is considered a stress response factor and has garnered increasing attention in recent years due to its roles in neurological diseases. Although many studies have suggested that GDF15 expression is elevated in patients with neurodegenerative diseases (NDDs), glioma, and ischemic stroke, the effects of increased GDF15 expression and the potential underlying mechanisms remain unclear. Notably, many experimental studies have shown the multidimensional beneficial effects of GDF15 on NDDs, and GDF15 overexpression is able to rescue NDD-associated pathological changes and phenotypes. In glioma, GDF15 exerts opposite effects, it is both protumorigenic and antitumorigenic. The causes of these conflicting findings are not comprehensively clear, but inhibiting GDF15 is helpful for suppressing tumor progression. GDF15 is also regarded as a biomarker of poor clinical outcomes in ischemic stroke patients, and targeting GDF15 may help prevent this disease. Thus, we systematically reviewed the synthesis, transcriptional regulation, and biological functions of GDF15 and its related signaling pathways within the brain. Furthermore, we explored the potential of GDF15 as a therapeutic target and assessed its clinical applicability in interventions for brain diseases. By integrating the latest research findings, this study provides new insights into the future treatment of neurological diseases.
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Affiliation(s)
- Yingying Zhou
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lei Dou
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Luyao Wang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiajie Chen
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ruxue Mao
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lingqiang Zhu
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Dan Liu
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kai Zheng
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Isik FI, Thomson S, Cueto JF, Spathos J, Breit SN, Tsai VWW, Brown DA, Finney CA. A systematic review of the neuroprotective role and biomarker potential of GDF15 in neurodegeneration. Front Immunol 2024; 15:1514518. [PMID: 39737171 PMCID: PMC11682991 DOI: 10.3389/fimmu.2024.1514518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 11/25/2024] [Indexed: 01/01/2025] Open
Abstract
Neurodegeneration is characteristically multifaceted, with limited therapeutic options. One of the chief pathophysiological mechanisms driving these conditions is neuroinflammation, prompting increasing clinical interest in immunomodulatory agents. Growth differentiation factor 15 (GDF15; previously also called macrophage inhibitory cytokine-1 or MIC-1), an anti-inflammatory cytokine with established neurotrophic properties, has emerged as a promising therapeutic agent in recent decades. However, methodological challenges and the delayed identification of its specific receptor GFRAL have hindered research progress. This review systematically examines literature about GDF15 in neurodegenerative diseases and neurotrauma. The evidence collated in this review indicates that GDF15 expression is upregulated in response to neurodegenerative pathophysiology and increasing its levels in preclinical models typically improves outcomes. Key knowledge gaps are addressed for future investigations to foster a more comprehensive understanding of the neuroprotective effects elicited by GDF15.
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Affiliation(s)
- Finula I. Isik
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Shannon Thomson
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - John F. Cueto
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Jessica Spathos
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Samuel N. Breit
- St. Vincent’s Centre for Applied Medical Research, St. Vincent’s Hospital and Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Vicky W. W. Tsai
- St. Vincent’s Centre for Applied Medical Research, St. Vincent’s Hospital and Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - David A. Brown
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
- Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Western Sydney Local Health District, Institute for Clinical Pathology and Medical Research, NSW Health Pathology, Sydney, NSW, Australia
| | - Caitlin A. Finney
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
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Silva RCMC. The dichotomic role of cytokines in aging. Biogerontology 2024; 26:17. [PMID: 39621124 DOI: 10.1007/s10522-024-10152-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 10/30/2024] [Indexed: 12/11/2024]
Abstract
The chronic inflammation present in aged individuals is generally depicted as a detrimental player for longevity. Here, it is discussed several beneficial effects associated with the cytokines that are chronically elevated in inflammaging. These cytokines, such as IL-1β, type I interferons, IL-6 and TNF positively regulate macroautophagy, mitochondrial function, anti-tumor immune responses and skeletal muscle biogenesis, possibly contributing to longevity. On the other side, the detrimental and antagonistic role of these cytokines including the induction of sarcopenia, tissue damage and promotion of tumorigenesis are also discussed, underscoring the dichotomy associated with inflammaging and its players. In addition, it is discussed the role of the anti-inflammatory cytokine IL-10 and other cytokines that affect aging in a more linear way, such as IL-11, which promotes senescence, and IL-4 and IL-15, which promotes longevity. It is also discussed more specific regulators of aging that are downstream cytokines-mediated signaling.
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Wiens KR, Wasti N, Ulloa OO, Klegeris A. Diversity of Microglia-Derived Molecules with Neurotrophic Properties That Support Neurons in the Central Nervous System and Other Tissues. Molecules 2024; 29:5525. [PMID: 39683685 DOI: 10.3390/molecules29235525] [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: 10/02/2024] [Revised: 11/12/2024] [Accepted: 11/18/2024] [Indexed: 12/18/2024] Open
Abstract
Microglia, the brain immune cells, support neurons by producing several established neurotrophic molecules including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Modern analytical techniques have identified numerous phenotypic states of microglia, each associated with the secretion of a diverse set of substances, which likely include not only canonical neurotrophic factors but also other less-studied molecules that can interact with neurons and provide trophic support. In this review, we consider the following eight such candidate cytokines: oncostatin M (OSM), leukemia inhibitory factor (LIF), activin A, colony-stimulating factor (CSF)-1, interleukin (IL)-34, growth/differentiation factor (GDF)-15, fibroblast growth factor (FGF)-2, and insulin-like growth factor (IGF)-2. The available literature provides sufficient evidence demonstrating murine cells produce these cytokines and that they exhibit neurotrophic activity in at least one neuronal model. Several distinct types of neurotrophic activity are identified that only partially overlap among the cytokines considered, reflecting either their distinct intrinsic properties or lack of comprehensive studies covering the full spectrum of neurotrophic effects. The scarcity of human-specific studies is another significant knowledge gap revealed by this review. Further studies on these potential microglia-derived neurotrophic factors are warranted since they may be used as targeted treatments for diverse neurological disorders.
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Affiliation(s)
- Kennedy R Wiens
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia, Okanagan Campus, Kelowna, BC V1V 1V7, Canada
| | - Naved Wasti
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia, Okanagan Campus, Kelowna, BC V1V 1V7, Canada
| | - Omar Orlando Ulloa
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia, Okanagan Campus, Kelowna, BC V1V 1V7, Canada
| | - Andis Klegeris
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia, Okanagan Campus, Kelowna, BC V1V 1V7, Canada
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Beydoun MA, Noren Hooten N, Fanelli-Kuczmaski MT, Maino Vieytes CA, Georgescu MF, Beydoun HA, Freeman DW, Evans MK, Zonderman AB. Growth Differentiation Factor 15 and Diet Quality Trajectory Interact to Determine Frailty Incidence among Middle-Aged Urban Adults. J Nutr 2024; 154:1652-1664. [PMID: 38479650 PMCID: PMC11130674 DOI: 10.1016/j.tjnut.2024.03.006] [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: 01/30/2024] [Revised: 03/05/2024] [Accepted: 03/08/2024] [Indexed: 04/05/2024] Open
Abstract
BACKGROUND Elevated plasma growth differentiation factor 15 (GDF15) and poor diet quality may be associated with increased frailty incidence, although their interactive associations have not been assessed in urban middle-aged adults. OBJECTIVES We aimed to examine GDF15 and its interactive association with diet quality in relation to frailty incidence among a sample of middle-aged urban adults. METHODS The relationship between GDF15 and diet quality trajectories in relation to incident frailty was examined in a longitudinal study of participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (2004-2017). Serum GDF15 concentration and frailty incidence were primary exposure and outcome, respectively. Group-based trajectory models were used to assess diet quality trajectories (≤3 visits/participant, N = 945, N' = 2247 observations) using the Healthy Eating Index 2010 version (HEI-2010), Dietary Inflammatory Index, and mean adequacy ratio (MAR). Cox proportional hazards models were used, testing interactive associations of GDF15 and diet quality trajectories with frail/prefrail incidence (N = 400 frailty-free at first visit, N' = 604 observations, n = 168 incident frail/prefrail). RESULTS Both elevated GDF15 and lower diet quality trajectories were associated with a lower probability of remaining nonfrail (≤13 y follow-up). Among females, the "high diet quality" HEI-2010 trajectory had a hazard ratio (HR) of 0.15 [95% confidence interval (CI): 0.04, 0.54; P = 0.004; fully adjusted model] when compared with the "low diet quality" trajectory group. Among males only, there was an antagonistic interaction between lower HEI-2010 trajectory and elevated GDF15. Specifically, the HR for GDF15-frailty in the higher diet quality trajectory group (high/medium combined), and among males, was 2.69 (95% CI: 1.06, 6.62; P = 0.032), whereas among the lower diet quality trajectory group, the HR was 0.94 (95% CI: 0.49, 1.80; P = 0.86). Elevated GDF15 was independently associated with frailty among African American adults. CONCLUSIONS Pending replication, we found an antagonistic interaction between GDF15 and HEI-2010 trajectory in relation to frailty incidence among males.
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Affiliation(s)
- May A Beydoun
- Laboratory of Epidemiology and Population Sciences, NIA/NIH/IRP, Baltimore, MD, United States.
| | - Nicole Noren Hooten
- Laboratory of Epidemiology and Population Sciences, NIA/NIH/IRP, Baltimore, MD, United States
| | | | | | - Michael F Georgescu
- Laboratory of Epidemiology and Population Sciences, NIA/NIH/IRP, Baltimore, MD, United States
| | - Hind A Beydoun
- VA National Center on Homelessness Among Veterans, U.S. Department of Veterans Affairs, Washington, DC, United States; Department of Management, Policy, and Community Health, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - David W Freeman
- Department of Oncological Sciences, School of Medicine, University of Utah, Salt Lake City, UT, United States
| | - Michele K Evans
- Laboratory of Epidemiology and Population Sciences, NIA/NIH/IRP, Baltimore, MD, United States
| | - Alan B Zonderman
- Laboratory of Epidemiology and Population Sciences, NIA/NIH/IRP, Baltimore, MD, United States
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Fichtner K, Kalwa H, Lin MM, Gong Y, Müglitz A, Kluge M, Krügel U. GFRAL Is Widely Distributed in the Brain and Peripheral Tissues of Mice. Nutrients 2024; 16:734. [PMID: 38474863 DOI: 10.3390/nu16050734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
In 2017, four independent publications described the glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as receptor for the growth differentiation factor 15 (GDF15, also MIC-1, NAG-1) with an expression exclusively in the mice brainstem area postrema (AP) and nucleus tractus solitarii (NTS) where it mediates effects of GDF15 on reduction of food intake and body weight. GDF15 is a cell stress cytokine with a widespread expression and pleiotropic effects, which both seem to be in contrast to the reported highly specialized localization of its receptor. This discrepancy prompts us to re-evaluate the expression pattern of GFRAL in the brain and peripheral tissues of mice. In this detailed immunohistochemical study, we provide evidence for a more widespread distribution of this receptor. Apart from the AP/NTS region, GFRAL-immunoreactivity was found in the prefrontal cortex, hippocampus, nucleus arcuatus and peripheral tissues including liver, small intestine, fat, kidney and muscle tissues. This widespread receptor expression, not taken into consideration so far, may explain the multiple effects of GDF-15 that are not yet assigned to GFRAL. Furthermore, our results could be relevant for the development of novel pharmacological therapies for physical and mental disorders related to body image and food intake, such as eating disorders, cachexia and obesity.
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Affiliation(s)
- Karoline Fichtner
- Rudolf Boehm Institute of Pharmacology and Toxicology, Faculty of Medicine, University of Leipzig, D-04103 Leipzig, Germany
| | - Hermann Kalwa
- Rudolf Boehm Institute of Pharmacology and Toxicology, Faculty of Medicine, University of Leipzig, D-04103 Leipzig, Germany
| | - Miao-Miao Lin
- Rudolf Boehm Institute of Pharmacology and Toxicology, Faculty of Medicine, University of Leipzig, D-04103 Leipzig, Germany
| | - Yuanyuan Gong
- Rudolf Boehm Institute of Pharmacology and Toxicology, Faculty of Medicine, University of Leipzig, D-04103 Leipzig, Germany
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Anne Müglitz
- Rudolf Boehm Institute of Pharmacology and Toxicology, Faculty of Medicine, University of Leipzig, D-04103 Leipzig, Germany
| | - Michael Kluge
- Department of Psychiatry and Psychotherapy, University of Leipzig, D-04103 Leipzig, Germany
- Department of Psychiatry, Rudolf-Virchow-Klinikum Glauchau, D-08371 Glauchau, Germany
| | - Ute Krügel
- Rudolf Boehm Institute of Pharmacology and Toxicology, Faculty of Medicine, University of Leipzig, D-04103 Leipzig, Germany
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Ahmad S, Kumar R. An update of new/potential cardiovascular markers: a narrative review. Mol Biol Rep 2024; 51:179. [PMID: 38252393 DOI: 10.1007/s11033-023-08978-1] [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: 08/17/2023] [Accepted: 11/07/2023] [Indexed: 01/23/2024]
Abstract
BACKGROUND Cardiovascular and their associated disease (CVD) is a leading cause of death worldwide, in developed and developing countries, and its prevalence has increased over the past few decades, due to changes in the lifestyle of people. Biomarkers are important tools for diagnosing, analyzing, and providing evidence of pathological conditions of CVD and their associated diseases. METHODS This study reviews historical cardiovascular biomarkers used to diagnose various diseases, their uses, and limitations, as well as the importance of new and emerging biomarkers. CONCLUSION sST2, GDF-15, CD-40, IL-6, and Micro-RNA. Initial studies of the future of cardiac biomarkers are promising, but more research is needed to demonstrate that they are more effective biomarkers of risk factors for CVD development. They also lack the analytical foundation needed for adoption in the medical industry. It is also necessary to determine whether these biomarkers can be used for diagnosis.
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Affiliation(s)
- Sharique Ahmad
- Department of Pathology, Era's Lucknow Medical College & Hospital, Era University, Lucknow, India
| | - Raushan Kumar
- Department of Pathology, Era's Lucknow Medical College & Hospital, Era University, Lucknow, India.
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Beydoun MA, Beydoun HA, Noren Hooten N, Meirelles O, Li Z, El-Hajj ZW, Weiss J, Maino Vieytes CA, Launer LJ, Evans MK, Zonderman AB. Hospital-treated prevalent infections, the plasma proteome and incident dementia among UK older adults. iScience 2023; 26:108526. [PMID: 38162022 PMCID: PMC10755048 DOI: 10.1016/j.isci.2023.108526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/18/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2024] Open
Abstract
The plasma proteome can mediate the association of hospital-treated infections with dementia incidence. We screened up to 37,269 UK Biobank participants aged 50-74 years for the presence of a prevalent hospital-treated infection, subsequently tested as a predictor for ≤1,463 plasma proteins and dementia incidence. Four-way decomposition models decomposed infection-dementia total effect into pure mediation, pure interaction, neither or both through the plasma proteome. Hospital-treated infections increased dementia two-fold. The strongest mediation effect was through the growth differentiation factor 15 (GDF15) protein. Top 17 proteomic mediators explained collectively 5% of the total effect, while pathway analysis of all mediators (k = 221 plasma proteins) revealed top pathways including the immune system, signal transduction, metabolism, disease and metabolism of proteins, with the GDF15 cluster reflecting most strongly the "transmembrane receptor protein tyrosine kinase signaling pathway". The association of hospital-treated infections with dementia was partially mediated through GDF15 and other plasma proteomic markers.
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Affiliation(s)
- May A. Beydoun
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Intramural Research Program, NIA/NIH/IRP, Baltimore, MD 21224, USA
| | - Hind A. Beydoun
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Intramural Research Program, NIA/NIH/IRP, Baltimore, MD 21224, USA
- AT Augusta Military Medical Center, Fort Belvoir, VA 22060, USA
| | - Nicole Noren Hooten
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Intramural Research Program, NIA/NIH/IRP, Baltimore, MD 21224, USA
| | - Osorio Meirelles
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Intramural Research Program, NIA/NIH/IRP, Baltimore, MD 21224, USA
| | - Zhiguang Li
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Intramural Research Program, NIA/NIH/IRP, Baltimore, MD 21224, USA
| | - Ziad W. El-Hajj
- Department of Biology, McGill University, Montreal, QC, Canada
| | - Jordan Weiss
- Stanford Center on Longevity, Stanford University, Palo Alto, CA 94305, USA
| | - Christian A. Maino Vieytes
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Intramural Research Program, NIA/NIH/IRP, Baltimore, MD 21224, USA
| | - Lenore J. Launer
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Intramural Research Program, NIA/NIH/IRP, Baltimore, MD 21224, USA
| | - Michele K. Evans
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Intramural Research Program, NIA/NIH/IRP, Baltimore, MD 21224, USA
| | - Alan B. Zonderman
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Intramural Research Program, NIA/NIH/IRP, Baltimore, MD 21224, USA
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Shen M, Zhang M, Mao N, Lin Z. Batokine in Central Nervous System Diseases. Mol Neurobiol 2023; 60:7021-7031. [PMID: 37526894 DOI: 10.1007/s12035-023-03490-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 07/06/2023] [Indexed: 08/02/2023]
Abstract
Brown adipose tissue (BAT) is a special type of fat tissue in mammals and is also a key endocrine organ in the human body. Batokine, the endocrine effector of BAT, plays a neuroprotective role and improves the prognosis by exerting anti-apoptotic and anti-inflammatory effects, as well as by improving vascular endothelial function and other mechanisms in nerve injury diseases. The present article briefly reviewed several types of batokines related to central nervous system (CNS) diseases. Following this, the potential therapeutic value and future research direction of batokines for CNS diseases were chiefly discussed from the aspects of protective mechanism and signaling pathway.
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Affiliation(s)
- Ming Shen
- Department of Neonatology, The Second Affiliated Hospital of Wenzhou Medical University and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang, China
- Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for Pediatric Disease, Wenzhou, Zhejiang, China
| | - Min Zhang
- Department of Neonatology, The Second Affiliated Hospital of Wenzhou Medical University and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang, China
- Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for Pediatric Disease, Wenzhou, Zhejiang, China
| | - Niping Mao
- Department of Neonatology, The Second Affiliated Hospital of Wenzhou Medical University and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang, China
- Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for Pediatric Disease, Wenzhou, Zhejiang, China
| | - Zhenlang Lin
- Department of Neonatology, The Second Affiliated Hospital of Wenzhou Medical University and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
- Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang, China.
- Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China.
- Zhejiang Provincial Clinical Research Center for Pediatric Disease, Wenzhou, Zhejiang, China.
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11
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Tasso M, Kageyama K, Iwasaki Y, Watanuki Y, Niioka K, Takayasu S, Daimon M. Growth differentiation factor-15 stimulates the synthesis of corticotropin-releasing factor in hypothalamic 4B cells. Peptides 2023; 170:171112. [PMID: 37918484 DOI: 10.1016/j.peptides.2023.171112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 10/11/2023] [Accepted: 10/27/2023] [Indexed: 11/04/2023]
Abstract
Growth differentiation factor-15 (GDF15) is a stress-activated cytokine that regulates cell growth and inflammatory and stress responses. We previously reported the role and regulation of GDF15 in pituitary corticotrophs. Dexamethasone increases Gdf15 gene expression levels and production. GDF15 suppresses adrenocorticotropic hormone synthesis in pituitary corticotrophs and subsequently mediates the negative feedback effect of glucocorticoids. Here, we analyzed corticotropin-releasing factor (Crf) promoter activity in hypothalamic 4B cells transfected with promoter-driven luciferase reporter constructs. The effects of time and GDF15 concentration on Crf mRNA levels were analyzed using quantitative real-time polymerase chain reaction. Glial cell-derived neurotrophic factor family receptor α-like (GFRAL) protein is expressed in 4B cells. GDF15 increased Crf promoter activity and Crf mRNA levels in 4B cells. The protein kinase A and C pathways also contributed to the GDF15-induced increase in Crf gene expression. GDF15 stimulates GFRAL, subsequently increasing the phosphorylation of AKT, an extracellular signal-related kinase, and the cAMP response element-binding protein. Therefore, GDF15-dependent pathways may be involved in regulating Crf expression under stressful conditions in hypothalamic cells.
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Affiliation(s)
- Mizuki Tasso
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Kazunori Kageyama
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
| | - Yasumasa Iwasaki
- Suzuka University of Medical Science, 1001-1 Kishioka-cho, Suzuka, Mie 510-0293, Japan
| | - Yutaka Watanuki
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Kanako Niioka
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Shinobu Takayasu
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Makoto Daimon
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
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12
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Miyaue N, Yabe H, Nagai M. Serum GDF-15 Levels in Patients with Parkinson's Disease, Progressive Supranuclear Palsy, and Multiple System Atrophy. Neurol Int 2023; 15:1044-1051. [PMID: 37755357 PMCID: PMC10535128 DOI: 10.3390/neurolint15030066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/28/2023] Open
Abstract
Serum growth differentiation factor 15 (GDF-15) levels are elevated in patients with Parkinson's disease (PD) and may help differentiate these patients from healthy individuals. We aimed to clarify whether serum GDF-15 levels can help differentiate PD from atypical parkinsonian syndromes and determine the association between serum GDF-15 levels and clinical parameters. We prospectively enrolled 46, 15, and 12 patients with PD, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA), respectively. The serum GDF-15 level in patients with PD (1394.67 ± 558.46 pg/mL) did not differ significantly from that in patients with PSP (1491.27 ± 620.78 pg/mL; p = 0.573) but was significantly higher than that in patients with MSA (978.42 ± 334.66 pg/mL; p = 0.017). Serum GDF-15 levels were positively correlated with age in patients with PD (r = 0.458; p = 0.001); PSP (r = 0.565; p = 0.028); and MSA (r = 0.708; p = 0.010). After accounting for age differences, serum GDF-15 levels did not differ significantly between patients with PD and MSA (p = 0.114). Thus, age has a strong influence on serum GDF-15 levels, which may not differ significantly between patients with PD and atypical parkinsonian syndromes such as PSP and MSA.
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Affiliation(s)
- Noriyuki Miyaue
- Department of Clinical Pharmacology and Therapeutics, Graduate School of Medicine, Ehime University, Tohon 791-0295, Ehime, Japan;
- Department of Neurology, Saiseikai Matsuyama Hospital, Matsuyama 791-8026, Ehime, Japan;
| | - Hayato Yabe
- Department of Neurology, Saiseikai Matsuyama Hospital, Matsuyama 791-8026, Ehime, Japan;
| | - Masahiro Nagai
- Department of Clinical Pharmacology and Therapeutics, Graduate School of Medicine, Ehime University, Tohon 791-0295, Ehime, Japan;
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13
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Hinojosa MG, Johansson Y, Cediel-Ulloa A, Ivanova E, Gabring N, Gliga A, Forsby A. Evaluation of mRNA markers in differentiating human SH-SY5Y cells for estimation of developmental neurotoxicity. Neurotoxicology 2023; 97:65-77. [PMID: 37210002 DOI: 10.1016/j.neuro.2023.05.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 05/05/2023] [Accepted: 05/17/2023] [Indexed: 05/22/2023]
Abstract
Current guidelines for developmental neurotoxicity (DNT) evaluation are based on animal models. These have limitations so more relevant, efficient and robust approaches for DNT assessment are needed. We have used the human SH-SY5Y neuroblastoma cell model to evaluate a panel of 93 mRNA markers that are frequent in Neuronal diseases and functional annotations and also differentially expressed during retinoic acid-induced differentiation in the cell model. Rotenone, valproic acid (VPA), acrylamide (ACR) and methylmercury chloride (MeHg) were used as DNT positive compounds. Tolbutamide, D-mannitol and clofibrate were used as DNT negative compounds. To determine concentrations for exposure for gene expression analysis, we developed a pipeline for neurite outgrowth assessment by live-cell imaging. In addition, cell viability was measured by the resazurin assay. Gene expression was analyzed by RT-qPCR after 6 days of exposure during differentiation to concentrations of the DNT positive compounds that affected neurite outgrowth, but with no or minimal effect on cell viability. Methylmercury affected cell viability at lower concentrations than neurite outgrowth, hence the cells were exposed with the highest non-cytotoxic concentration. Rotenone (7.3nM) induced 32 differentially expressed genes (DEGs), ACR (70µM) 8 DEGs, and VPA (75µM) 16 DEGs. No individual genes were significantly dysregulated by all 3 DNT positive compounds (p<0.05), but 9 genes were differentially expressed by 2 of them. Methylmercury (0.8nM) was used to validate the 9 DEGs. The expression of SEMA5A (encoding semaphorin 5A) and CHRNA7 (encoding nicotinic acetylcholine receptor subunit α7) was downregulated by all 4 DNT positive compounds. None of the DNT negative compounds dysregulated any of the 9 DEGs in common for the DNT positive compounds. We suggest that SEMA5A or CHRNA7 should be further evaluated as biomarkers for DNT studies in vitro since they also are involved in neurodevelopmental adverse outcomes in humans.
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Affiliation(s)
- M G Hinojosa
- Department of Biochemistry and Biophysics, Stockholm University, 106 91, Stockholm, Sweden
| | - Y Johansson
- Department of Biochemistry and Biophysics, Stockholm University, 106 91, Stockholm, Sweden
| | - A Cediel-Ulloa
- Department of Organismal Biology, Environmental Toxicology, Uppsala University, 752 36, Uppsala, Sweden
| | - E Ivanova
- Department of Biochemistry and Biophysics, Stockholm University, 106 91, Stockholm, Sweden
| | - N Gabring
- Department of Biochemistry and Biophysics, Stockholm University, 106 91, Stockholm, Sweden
| | - A Gliga
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, 171 77, Sweden
| | - A Forsby
- Department of Biochemistry and Biophysics, Stockholm University, 106 91, Stockholm, Sweden
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14
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He J, Zhou M, Zhao F, Cheng H, Huang H, Xu X, Han J, Hong W, Wang F, Xiao Y, Xia J, Liu K. FGF-21 and GDF-15 are increased in migraine and associated with the severity of migraine-related disability. J Headache Pain 2023; 24:28. [PMID: 36935492 PMCID: PMC10026504 DOI: 10.1186/s10194-023-01563-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 03/09/2023] [Indexed: 03/21/2023] Open
Abstract
BACKGROUND Migraine is a prevalent disorder with significant socioeconomic impact. The impairment of metabolic homeostasis in migraine warrants further investigation. Changes in serum levels of Fibroblast-growth-factor 21 (FGF-21) and Growth-differentiation-factor 15 (GDF-15) are characteristic of some metabolic and mitochondrial diseases. This study aimed to assess whether the presence of migraine affects serum levels of FGF-21 and GDF-15, and taking metabolic disorders into account as potential confounding factors. METHODS We collected serum samples from 221 migraine patients (153 episodic migraineurs and 68 chronic migraineurs) and 124 healthy controls. The serum concentrations of FGF-21 and GDF-15 were measured using an enzyme-linked immunosorbent assay (ELISA) based approach. Clinical variables, including monthly headache days, peak headache pain intensity, the 6-item Headache Impact Test (HIT-6), and the Migraine Disability Assessment (MIDAS), were also addressed. The associations between the clinical variables of migraine patients and serum levels of FGF-21 and GDF-15 were studied. RESULTS In the multiple regression that corrected for age, we found that the serum levels of FGF-21 and GDF-15 were significantly higher in migraine sufferers than in healthy controls. A significant elevation in serum concentration of FGF-21, but not GDF-15, was observed in patients with chronic migraine (CM) compared to those with episodic migraine (EM). Regarding migraine-related disability, higher scores on the HIT-6 and MIDAS were associated with higher levels of FGF-21 and GDF-15. For the receiver operating characteristic (ROC) analysis, the diagnosis of migraine using GDF-15 showed that the area under the ROC curve (AUC) was 0.801 and the AUC of chronic migraine was 0.880. CONCLUSION Serum GDF-15 and FGF-21 levels are increased in patients with migraine and associated with the severity of migraine-related disability.
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Affiliation(s)
- Jiahui He
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No 88 Jiefang Road, Hangzhou, Zhejiang, China
| | - Mengting Zhou
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No 88 Jiefang Road, Hangzhou, Zhejiang, China
| | - Fanglin Zhao
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No 88 Jiefang Road, Hangzhou, Zhejiang, China
| | - Hongrong Cheng
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No 88 Jiefang Road, Hangzhou, Zhejiang, China
| | - Hao Huang
- Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No 88 Jiefang Road, Hangzhou, Zhejiang, China
| | - Xiaopei Xu
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No 88 Jiefang Road, Hangzhou, Zhejiang, China
| | - Jian Han
- Department of Neurology, Affiliated Hospital of Shaoxing University, No 999 Zhongxingnan Road, Shaoxing, Zhejiang, China
| | - Wenwu Hong
- Department of Neurology, Tiantai People's Hospital of Zhejiang Province, No 1 Kangning Middle Road, Taizhou, Zhejiang, China
| | - Faming Wang
- Department of Neurology, Tiantai People's Hospital of Zhejiang Province, No 1 Kangning Middle Road, Taizhou, Zhejiang, China
| | - Yujin Xiao
- Zhejiang Chinese Medical University Affiliated Jiaxing TCM Hospital, 1501 East Zhongshan Road, Jiaxing, Zhejiang, China
| | - Jinjin Xia
- Department of Neurology, Changxing People's Hospital of Zhejiang Province, No 66 Taihu Middle Road, Changxing, Huzhou, Zhejiang, China
| | - Kaiming Liu
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No 88 Jiefang Road, Hangzhou, Zhejiang, China.
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15
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Al‐kuraishy HM, Al‐Gareeb AI, Alexiou A, Papadakis M, Nadwa EH, Albogami SM, Alorabi M, Saad HM, Batiha GE. Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: A hidden treasure. J Diabetes 2022; 14:806-814. [PMID: 36444166 PMCID: PMC9789395 DOI: 10.1111/1753-0407.13334] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/03/2022] [Accepted: 11/03/2022] [Indexed: 11/30/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic endocrine disorder due to the reduction of insulin sensitivity and relative deficiency of insulin secretion. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor beta (TGF-β) superfamily and was initially identified as macrophage inhibitory cytokine-1 (MIC-1). GDF15 is considered a cytokine with an anti-inflammatory effect and increases insulin sensitivity, reduces body weight, and improves clinical outcomes in diabetic patients. GDF15 acts through stimulation of glial-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), which is highly expressed in the brain stem to induce taste aversion. Metformin belongs to the group of biguanides that are derived from the plant Galega officinalis. It is interesting to note that metformin is an insulin-sensitizing agent used as a first-line therapy for T2DM that has been shown to increase the circulating level of GDF15. Thus, the present review aims to determine the critical association of the GDF15 biomarker in T2DM and how metformin agents affect it. This review illustrates that metformin activates GDF15 expression, which reduces appetite and leads to weight loss in both diabetic and nondiabetic patients. However, the present review cannot give a conclusion in this regard. Therefore, experimental, preclinical, and clinical studies are warranted to confirm the potential role of GDF15 in T2DM patients.
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Affiliation(s)
- Hayder M. Al‐kuraishy
- Department of Clinical Pharmacology and Medicine, College of MedicineAL‐Mustansiriyah UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Department of Clinical Pharmacology and Medicine, College of MedicineAL‐Mustansiriyah UniversityBaghdadIraq
| | - Athanasios Alexiou
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamAustralia
- AFNP MedWienAustria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten‐Herdecke, Heusnerstrasse 40WuppertalGermany
| | - Eman Hassan Nadwa
- Department of Pharmacology and TherapeuticsCollege of Medicine, Jouf UniversitySakakahSaudi Arabia
- Department of Medical Pharmacology, Faculty of MedicineCairo UniversityGizaEgypt
| | - Sarah M. Albogami
- Department of BiotechnologyCollege of Science, Taif UniversityTaifSaudi Arabia
| | - Mohammed Alorabi
- Department of BiotechnologyCollege of Science, Taif UniversityTaifSaudi Arabia
| | - Hebatallah M. Saad
- Department of Pathology, Faculty of Veterinary MedicineMatrouh UniversityMarsa MatruhEgypt
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhour UniversityDamanhourEgypt
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16
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Kageyama K, Iwasaki Y, Watanuki Y, Murasawa S, Niioka K, Tasso M, Kosugi A, Daimon M. Growth differentiation factor-15 modulates adrenocorticotropic hormone synthesis in murine AtT-20 corticotroph cells. Peptides 2022; 155:170841. [PMID: 35868568 DOI: 10.1016/j.peptides.2022.170841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/12/2022] [Accepted: 07/16/2022] [Indexed: 12/01/2022]
Abstract
Growth differentiation factor-15 (GDF15) is a stress-responsive cytokine that plays important roles in regulation of inflammatory responses, cell growth, and cell differentiation. However, the nature of these roles remains unclear. Here, we aimed to examine the regulatory effects of dexamethasone on Gdf15 expression in murine AtT-20 corticotroph cells. Human Gdf15 promoter-driven luciferase reporter constructs were transfected into corticotroph cells to analyze their promoter activity. The effects of time and concentration of dexamethasone on Gdf15 and proopiomelanocortin (Pomc) mRNA levels were assessed using quantitative real-time polymerase chain reaction. Dexamethasone induced Gdf15 transcription and mRNA levels as well as GDF15 production in transfected cells, whereas reduced the Pomc mRNA levels. GDF15 modulated adrenocorticotropic hormone (ACTH) synthesis, and the dexamethasone-mediated reduction in Pomc mRNA levels were partially relieved upon Gdf15 knockdown. We concluded that GDF15 modulated ACTH production in pituitary corticotrophs in an autocrine manner by suppressing Pomc expression and subsequently mediating the negative feedback effect of glucocorticoids, thereby contributing to pituitary stress response and homeostasis.
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Affiliation(s)
- Kazunori Kageyama
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
| | - Yasumasa Iwasaki
- Suzuka University of Medical Science, 1001-1 Kishioka-cho, Suzuka, Mie 510-0293, Japan
| | - Yutaka Watanuki
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Shingo Murasawa
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Kanako Niioka
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Mizuki Tasso
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Ai Kosugi
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Makoto Daimon
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
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17
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The promise of the TGF-β superfamily as a therapeutic target for Parkinson's disease. Neurobiol Dis 2022; 171:105805. [PMID: 35764291 DOI: 10.1016/j.nbd.2022.105805] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 11/20/2022] Open
Abstract
A large body of evidence underscore the regulatory role of TGF-β superfamily in the central nervous system. Components of the TGF-β superfamily modulate key events during embryonic brain development and adult brain tissue injury repair. With respect to Parkinson's disease (PD), TGF-ß signaling pathways are implicated in the differentiation, maintenance and synaptic function of the dopaminergic neurons, as well as in processes related to the activation state of astrocytes and microglia. In vitro and in vivo studies using toxin models, have interrogated on the dopaminotrophic and protective role of the TGF-β superfamily members. The evolution of genetic and animal models of PD that more closely recapitulate the disease condition has made possible the dissection of intracellular pathways in response to TGF-ß treatment. Although the first clinical trials using GDNF did not meet their primary endpoints, substantial work has been carried out to reappraise the TGF-β superfamily's clinical benefit.
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18
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Circulating Growth Differentiation Factor 15 Is Associated with Diabetic Neuropathy. J Clin Med 2022; 11:jcm11113033. [PMID: 35683420 PMCID: PMC9180959 DOI: 10.3390/jcm11113033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/19/2022] [Accepted: 05/25/2022] [Indexed: 12/04/2022] Open
Abstract
Background: Growth differentiation factor (GDF15) is a superfamily of transforming growth factor-beta which has been suggested to be correlated with various pathological conditions. The current study aimed to investigate the predicted role of circulating GDF15 in diabetic metabolism characteristics and diabetic neuropathy. Methods: 241 diabetic patients and 42 non-diabetic subjects were included to participate in the study. The plasma GDF15 levels were measured using ELISA. Chronic kidney disease and albuminuria were defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline. The nerve conductive study (NCS) was performed with measurement of distal latency, amplitude, nerve conduction velocity (NCV), H-reflex, and F-wave studies. Results: The diabetic group had a significantly higher prevalence of chronic kidney disease and higher plasma GDF15 level. After adjusting for age and BMI, GDF15 was significantly positively correlated with waist circumference (r = 0.332, p = <0.001), hip circumference (r = 0.339, p < 0.001), HbA1c (r = 0.302, p < 0.001), serum creatine (r = 0.146, p = 0.017), urine albumin/creatinine ratio (r = 0.126, p = 0.040), and HOMA-IR (r = 0.166, p = 0.007). As to NCS, GDF15 was significantly correlated with all latency and amplitude of sensory and motor nerves, as well as F-wave and H-reflex latencies. The area under the curve (AUC) in predicting tibial motor nerve neuropathy (MNCV) in all subjects and in the diabetic group for GDF15 was 0.646 (p = 0.001) and 0.610 (p = 0.012), respectively; for HbA1c was 0.639 (p = 0.001) and 0.604 (p = 0.018), respectively. Predicting ulnar sensory nerve neuropathy for GDF15 was 0.639 (p = 0.001) and 0.658 (p = 0.001), respectively; for HbA1c was 0.545 (p = 0.307) and 0.545 (p = 0.335), respectively. Predicting median sensory nerve neuropathy for GDF15 was 0.633 (p = 0.007) and 0.611 (p = 0.032), respectively; for HbA1c was 0.631 (p = 0.008) and 0.607 (p = 0.038), respectively. Predicting CKD for GDF15 was 0.709 (95% CI, 0.648−0.771), p < 0.001) and 0.676 (95% CI, 0.605−0.746), p < 0.001), respectively; for HbA1c was 0.560 (95% CI, 0.493−0.627); p = 0.080) and 0.515 (95% CI, 0.441−0.588); p = 0.697), respectively. Conclusions: We suggest that there is a significant association between the increased serum GDF-15 level and metabolic parameters and diabetic neuropathy. Plasma GDF15 may be an independent predictor of diabetic neuropathy.
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Jeon H, Kim HJ, Doo HM, Chang EH, Kwak G, Mo WM, Jang SY, Lee MW, Choi BO, Hong YB. Cytokines secreted by mesenchymal stem cells reduce demyelination in an animal model of Charcot-Marie-Tooth disease. Biochem Biophys Res Commun 2022; 597:1-7. [PMID: 35121177 DOI: 10.1016/j.bbrc.2022.01.098] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 01/25/2022] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Demyelinating Charcot-Marie-Tooth disease (CMT) is caused by mutations in the genes that encode myelinating proteins or their transcription factors. Our study thus sought to assess the therapeutic effects of cytokines secreted from mesenchymal stem cells (MSCs) on this disease. METHODS The therapeutic potential of Wharton's jelly MSCs (WJ-MSCs) and cytokines secreted by WJ-MSCs was evaluated on Schwann cells (SCs) exhibiting demyelination features, as well as a mouse model of demyelinating CMT. RESULTS Co-culture with WJ-MSC protected PMP22-overexpressing SCs from apoptotic cell death. Using a cytokine array, the secretion of growth differentiation factor-15 (GDF-15) and amphiregulin (AREG) was found to be elevated in WJ-MSCs when co-incubated with the PMP22-overexpressing SCs. Administration of both cytokines into trembler-J (Tr-J) mice, an animal model of CMT, significantly enhanced motor nerve conduction velocity compared to the control group. More importantly, this treatment alleviated the demyelinating phenotype of Tr-J mice, as demonstrated by an improvement in the mean diameter and g-ratio of the myelinated axons. CONCLUSIONS Our findings demonstrated that WJ-MSCs alleviate the demyelinating phenotype of CMT via the secretion of several cytokines. Further elucidation of the underlying mechanisms of GDF-15 and AREG in myelination might provide a robust basis for the development of effective therapies against demyelinating CMT.
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Affiliation(s)
- Hyeonjin Jeon
- Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, South Korea
| | - Hye Jin Kim
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, South Korea
| | - Hyun Myung Doo
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, South Korea
| | - Eun Hyuk Chang
- Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Co, Ltd, Seoul, 06351, South Korea
| | - Geon Kwak
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, South Korea
| | - Won Min Mo
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, South Korea
| | - So Young Jang
- Department of Biochemistry, College of Medicine, Dong-A University, Busan, 49201, South Korea
| | | | - Byung-Ok Choi
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, South Korea; Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, South Korea.
| | - Young Bin Hong
- Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, South Korea; Department of Biochemistry, College of Medicine, Dong-A University, Busan, 49201, South Korea.
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20
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Xue XH, Tao LL, Su DQ, Guo CJ, Liu H. Diagnostic utility of GDF15 in neurodegenerative diseases: A systematic review and meta-analysis. Brain Behav 2022; 12:e2502. [PMID: 35068064 PMCID: PMC8865151 DOI: 10.1002/brb3.2502] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 11/29/2021] [Accepted: 01/02/2022] [Indexed: 12/29/2022] Open
Abstract
INTRODUCTION GDF15 may be a potential biomarker for neurodegenerative diseases. In this analysis, we aimed to quantitative analysis the levels of GDF15 in patients with neurological diseases and in health control, and then to determine its potential diagnostic utility. METHODS Two researchers separately conducted a systematic search of the relevant studies up to January 2021 in Embase, PubMed, and Web of Science. Effect sizes were estimated to use the standardized mean difference (SMD) with 95% confidence interval (CI). Sensitivity and specificity were calculated by the summary receiver operating characteristics curve (SROC) method. The sensitivity analysis was performed by the "one-in/one-out" approach. Considering the considerable heterogeneity among studies, random-effects model was used for the meta-analysis investigation. RESULTS A total of eight articles were included in this meta-analysis and systematic review. The pooled results of the random effect model indicated GDF15 levels were significantly higher in patients with neurodegenerative disease than healthy people (SMD = 0.92, 95% CI: 0.44-1.40, Z = 3.75, p < 0.001). Sensitivity and specificity of biomarker of GDF15 were 0.90 (95% CI: 0.75-0.97), 0.77 (95% CI: 0.67-0.65), and AUC = 0.87 (95% CI: 0.84-0.90), respectively. CONCLUSIONS GDF15 levels were higher in patients with neurodegenerative disease than healthy people. And serum levels of GDF15 were a better marker for diagnostic utility of neurodegenerative disease.
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Affiliation(s)
- Xin-Hong Xue
- Department of Neurology, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng People's Hospital, Liaocheng, China
| | - Lin-Lin Tao
- Department of Neurology, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng People's Hospital, Liaocheng, China
| | - Dao-Qing Su
- Department of Neurosurgery, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng People's Hospital, Liaocheng, China
| | - Cun-Ju Guo
- Department of Neurology, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng People's Hospital, Liaocheng, China
| | - Hong Liu
- Department of Neurology, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng People's Hospital, Liaocheng, China
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21
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Saarma M. To celebrate the 80th birthday of Klaus Unsicker: discovery of a new growth factor and studies on the effects of growth factors on adrenal chromaffin cells and neurons. Cell Tissue Res 2022; 387:9-12. [PMID: 34978591 DOI: 10.1007/s00441-021-03571-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Mart Saarma
- Institute of Biotechnology, HiLIFE, University of Helsinki, P.O. Box 56 (Viikinkaari 5D), 00014, Helsinki, Finland.
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22
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Negishi K, Hoshide S, Shimpo M, Kanegae H, Kario K. Growth Differentiation Factor-15 Predicts Death and Stroke Event in Outpatients With Cardiovascular Risk Factors: The J-HOP Study. J Am Heart Assoc 2021; 10:e022601. [PMID: 34889104 PMCID: PMC9075247 DOI: 10.1161/jaha.121.022601] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background Growth differentiation factor-15 (GDF-15) has emerged as a novel biomarker to predict all-cause death in community-dwelling individuals and patients with cardiovascular disease. We evaluated the prognostic value of GDF-15 in outpatients with cardiovascular risk factors. Methods and Results GDF-15 levels were measured in 3562 outpatients with cardiovascular risk factors in the J-HOP (Japan Morning Surge-Home Blood Pressure) study, a nationwide prospective study. Participants were stratified according to tertiles of GDF-15 and followed up for all-cause death and cardiovascular disease. During a mean follow-up period of 6.6 years, there were 155 all-cause deaths, 81 stroke events including cerebral infarction and intracranial hemorrhage, and 141 cardiac events including cardiac artery disease and heart failure. Patients with higher GDF-15 levels were associated with risks of all-cause death and stroke events (except for cardiac events) after adjustment for traditional risk factors and other prognostic biomarkers (NT-proBNP [N-terminal pro-B-type natriuretic peptide], high-sensitivity troponin T; all-cause death, hazard ratio, 2.38; 95% CI, 1.26-4.48; P=0.007; stroke events, hazard ratio, 2.93; 95% CI, 1.31-6.56, P=0.009; compared with the lowest tertile). Furthermore, incorporating GDF-15 to the predictive models for all-cause death improved discrimination and reclassification significantly. For stroke events, GDF-15 showed similar diagnostic accuracy to NT-proBNP and high-sensitivity troponin T. Conclusions In Japanese outpatients with cardiovascular risk factors, GDF-15 improves risk stratification for all-cause death when compared with NT-proBNP and high-sensitivity troponin T. GDF-15 was associated with increased risks of stroke events beyond conventional risk factors and other prognostic markers; however, the predictive ability for stroke events was equivalent to NT-proBNP and high-sensitivity troponin T. Registration URL: http://www.umin.ac.jp/ctr.; Unique identifier: UMIN000000894.
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Affiliation(s)
- Keita Negishi
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University Tochigi Japan
| | - Satoshi Hoshide
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University Tochigi Japan
| | - Masahisa Shimpo
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University Tochigi Japan
| | - Hiroshi Kanegae
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University Tochigi Japan.,Genki Plaza Medical Center for Health Care Tokyo Japan
| | - Kazuomi Kario
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University Tochigi Japan
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23
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Jiang WW, Zhang ZZ, He PP, Jiang LP, Chen JZ, Zhang XT, Hu M, Zhang YK, Ouyang XP. Emerging roles of growth differentiation factor-15 in brain disorders (Review). Exp Ther Med 2021; 22:1270. [PMID: 34594407 PMCID: PMC8456456 DOI: 10.3892/etm.2021.10705] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 08/06/2021] [Indexed: 12/14/2022] Open
Abstract
Brain disorders, such as Alzheimer's and Parkinson's disease and cerebral stroke, are an important contributor to mortality and disability worldwide, where their pathogenesis is currently a topic of intense research. The mechanisms underlying the development of brain disorders are complex and vary widely, including aberrant protein aggregation, ischemic cell necrosis and neuronal dysfunction. Previous studies have found that the expression and function of growth differentiation factor-15 (GDF15) is closely associated with the incidence of brain disorders. GDF15 is a member of the TGFβ superfamily, which is a dimer-structured stress-response protein. The expression of GDF15 is regulated by a number of proteins upstream, including p53, early growth response-1, non-coding RNAs and hormones. In particular, GDF15 has been reported to serve an important role in regulating angiogenesis, apoptosis, lipid metabolism and inflammation. For example, GDF15 can promote angiogenesis by promoting the proliferation of human umbilical vein endothelial cells, apoptosis of prostate cancer cells and fat metabolism in fasted mice, and GDF15 can decrease the inflammatory response of lipopolysaccharide-treated mice. The present article reviews the structure and biosynthesis of GDF15, in addition to the possible roles of GDF15 in Alzheimer's disease, cerebral stroke and Parkinson's disease. The purpose of the present review is to summarize the mechanism underlying the role of GDF15 in various brain disorders, which hopes to provide evidence and guide the prevention and treatment of these debilitating conditions.
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Affiliation(s)
- Wei-Wei Jiang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Zi-Zhen Zhang
- Department of Medical Humanities, School of Medicine, Hunan Polytechnic of Environment and Biology, Hengyang, Hunan 421001, P.R. China
| | - Ping-Ping He
- Hunan Province Cooperative Innovation Centre for Molecular Target New Drug Study, Nursing School, University of South China, Hengyang, Hunan 421001, P.R. China.,Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Li-Ping Jiang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China.,Department of Critical Care Medicine, Hunan Taihe Hospital, Changsha, Hunan 410004, P.R. China
| | - Jin-Zhi Chen
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xing-Ting Zhang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Mi Hu
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yang-Kai Zhang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xin-Ping Ouyang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China.,Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
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24
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Xiong WP, Yao WQ, Wang B, Liu K. BMSCs-exosomes containing GDF-15 alleviated SH-SY5Y cell injury model of Alzheimer's disease via AKT/GSK-3β/β-catenin. Brain Res Bull 2021; 177:92-102. [PMID: 34536520 DOI: 10.1016/j.brainresbull.2021.09.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 08/27/2021] [Accepted: 09/12/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) therapy has great potential for Alzheimer's disease (AD) treatment. Here, we investigated the roles of BMSCs-exosomes containing growth differentiation factor-15 (GDF-15) in regulating SH-SY5Y cell injury in AD. METHODS The SH-SY5Y cell injury model was constructed by treating SH-SY5Y cells with 10 μM Aβ42. GDF-15 expression was assessed using qRT-PCR and western blot. CCK8 assay and flow cytometry assay were employed to elevate cell proliferation and apoptosis, respectively. The expression levels of inflammatory factors (IL-6, IL-1β, TNFα and IL-8) and Aβ42 were detected using ELISA. Besides, the levels of apoptosis-related proteins and AKT pathway-related proteins were determined using western blot. RESULTS Our results displayed that BMSCs-EVs treatment elevated cell viability, while suppressed cell apoptosis and inflammation in Aβ42-treated SH-SY5Y cells. Exosomes secreted by BMSCs after GDF-15 silence lost the ability to restore Aβ42-induced SH-SY5Y cell damage. GDF-15 treatment restored Aβ42-induced SH-SY5Y cell damage, while it was eliminated by AKT pathway inhibition. BMSCs-exosomes containing GDF-15 upregulated NEP and IDE via activation of AKT/GSK-3β/β-catenin pathway, thereby degrading Aβ42 protein to relieve SH-SY5Y cell damage. CONCLUSION BMSCs-exosomes containing GDF-15 alleviated SH-SY5Y cell damage via AKT/GSK-3β/β-catenin. Our work confers a promising therapeutic strategy for AD.
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Affiliation(s)
- Wen-Ping Xiong
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No.169, East Lake Road, Wuhan 430071, Hubei Province, PR China
| | - Wei-Qi Yao
- Department of Hematology, Union Hospital, Huazhong University of Science and Technology, Hubei Engineering Research Center for Human Stem Cell Preparation and Application and Resource Conservation, Wuhan 430071, Hubei Province, PR China
| | - Bei Wang
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No.169, East Lake Road, Wuhan 430071, Hubei Province, PR China
| | - Kui Liu
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No.169, East Lake Road, Wuhan 430071, Hubei Province, PR China.
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25
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Lin W, Zhang WW, Lyu N, Cao H, Xu WD, Zhang YQ. Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons. Neurosci Bull 2021; 37:1289-1302. [PMID: 34076854 PMCID: PMC8423960 DOI: 10.1007/s12264-021-00709-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/10/2021] [Indexed: 01/01/2023] Open
Abstract
Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β superfamily. It is widely distributed in the central and peripheral nervous systems. Whether and how GDF-15 modulates nociceptive signaling remains unclear. Behaviorally, we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats. Electrophysiologically, we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia (DRG) neurons. Furthermore, GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents, and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction. GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels, suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel. Immunohistochemistry results showed that activin receptor-like kinase-2 (ALK2) was widely expressed in DRG medium- and small-diameter neurons, and some of them were Nav1.8-positive. Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors. Inhibition of PKA and ERK, but not PKC, blocked the inhibitory effect of GDF-15 on Nav1.8 currents. These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK, which mediate the peripheral analgesia of GDF-15.
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Affiliation(s)
- Wei Lin
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China
| | - Wen-Wen Zhang
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China
| | - Ning Lyu
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
| | - Hong Cao
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China
| | - Wen-Dong Xu
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
- Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Yu-Qiu Zhang
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
- Department of Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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26
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Kawada T. Serum N-terminal pro-B-type natriuretic peptide, macrophage inhibitor cytokine-1, and cognitive functions in hemodialysis patients. Semin Dial 2021; 34:331. [PMID: 34291835 DOI: 10.1111/sdi.13003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/17/2021] [Accepted: 07/01/2021] [Indexed: 11/27/2022]
Affiliation(s)
- Tomoyuki Kawada
- Department of Hygiene and Public Health, Nippon Medical School, Tokyo, Japan
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27
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Townsend LK, MacPherson REK, Wright DC. New Horizon: Exercise and a Focus on Tissue-Brain Crosstalk. J Clin Endocrinol Metab 2021; 106:2147-2163. [PMID: 33982072 DOI: 10.1210/clinem/dgab333] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Indexed: 01/03/2023]
Abstract
The world population is aging, leading to increased rates of neurodegenerative disorders. Exercise has countless health benefits and has consistently been shown to improve brain health and cognitive function. The purpose of this review is to provide an overview of exercise-induced adaptations in the brain with a focus on crosstalk between peripheral tissues and the brain. We highlight recent investigations into exercise-induced circulating factors, or exerkines, including irisin, cathepsin B, GPLD1, and ketones and the mechanisms mediating their effects in the brain.
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Affiliation(s)
- Logan K Townsend
- Department of Medicine, McMaster University, Hamilton, L8S 4L8, Canada
- Department of Human Health and Nutritional Science, University of Guelph, Guelph, N1G 2W1, Canada
| | - Rebecca E K MacPherson
- Department of Health Sciences and Centre for Neuroscience, Brock University, St. Catharines, L2S 3A1, Canada
| | - David C Wright
- Department of Human Health and Nutritional Science, University of Guelph, Guelph, N1G 2W1, Canada
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28
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Andersson-Hall U, Svedin P, Mallard C, Blennow K, Zetterberg H, Holmäng A. Growth differentiation factor 15 increases in both cerebrospinal fluid and serum during pregnancy. PLoS One 2021; 16:e0248980. [PMID: 34043633 PMCID: PMC8158880 DOI: 10.1371/journal.pone.0248980] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 05/14/2021] [Indexed: 12/14/2022] Open
Abstract
Aim Growth differentiation factor 15 (GDF15) increases in serum during pregnancy to levels not seen in any other physiological state and is suggested to be involved in pregnancy-induced nausea, weight regulation and glucose metabolism. The main action of GDF15 is regulated through a receptor of the brainstem, i.e., through exposure of GDF15 in both blood and cerebrospinal fluid (CSF). The aim of the current study was to measure GDF15 in both CSF and serum during pregnancy, and to compare it longitudinally to non-pregnant levels. Methods Women were sampled at elective caesarean section (n = 45, BMI = 28.1±5.0) and were followed up 5 years after pregnancy (n = 25). GDF15, insulin and leptin were measured in CSF and serum. Additional measurements included plasma glucose, and serum adiponectin and Hs-CRP. Results GDF15 levels were higher during pregnancy compared with follow-up in both CSF (385±128 vs. 115±32 ng/l, P<0.001) and serum (73789±29198 vs. 404±102 ng/l, P<0.001). CSF levels correlated with serum levels during pregnancy (P<0.001), but not in the non-pregnant state (P = 0.98). Both CSF and serum GDF15 were highest in women carrying a female fetus (P<0.001). Serum GDF15 correlated with the homeostatic model assessment for beta-cell function and placental weight, and CSF GDF15 correlated inversely with CSF insulin levels. Conclusion This, the first study to measure CSF GDF15 during pregnancy, demonstrated increased GDF15 levels in both serum and CSF during pregnancy. The results suggest that effects of GDF15 during pregnancy can be mediated by increases in both CSF and serum levels.
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Affiliation(s)
- Ulrika Andersson-Hall
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
- * E-mail:
| | - Pernilla Svedin
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Carina Mallard
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Kaj Blennow
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
| | - Henrik Zetterberg
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
- UK Dementia Research Institute at UCL, London, United Kingdom
| | - Agneta Holmäng
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
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29
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Salikhova D, Bukharova T, Cherkashova E, Namestnikova D, Leonov G, Nikitina M, Gubskiy I, Akopyan G, Elchaninov A, Midiber K, Bulatenco N, Mokrousova V, Makarov A, Yarygin K, Chekhonin V, Mikhaleva L, Fatkhudinov T, Goldshtein D. Therapeutic Effects of hiPSC-Derived Glial and Neuronal Progenitor Cells-Conditioned Medium in Experimental Ischemic Stroke in Rats. Int J Mol Sci 2021; 22:4694. [PMID: 33946667 PMCID: PMC8125106 DOI: 10.3390/ijms22094694] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/12/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023] Open
Abstract
Transplantation of various types of stem cells as a possible therapy for stroke has been tested for years, and the results are promising. Recent investigations have shown that the administration of the conditioned media obtained after stem cell cultivation can also be effective in the therapy of the central nervous system pathology (hypothesis of their paracrine action). The aim of this study was to evaluate the therapeutic effects of the conditioned medium of hiPSC-derived glial and neuronal progenitor cells in the rat middle cerebral artery occlusion model of the ischemic stroke. Secretory activity of the cultured neuronal and glial progenitor cells was evaluated by proteomic and immunosorbent-based approaches. Therapeutic effects were assessed by overall survival, neurologic deficit and infarct volume dynamics, as well as by the end-point values of the apoptosis- and inflammation-related gene expression levels, the extent of microglia/macrophage infiltration and the numbers of formed blood vessels in the affected area of the brain. As a result, 31% of the protein species discovered in glial progenitor cells-conditioned medium and 45% in neuronal progenitor cells-conditioned medium were cell type specific. The glial progenitor cell-conditioned media showed a higher content of neurotrophins (BDNF, GDNF, CNTF and NGF). We showed that intra-arterial administration of glial progenitor cells-conditioned medium promoted a faster decrease in neurological deficit compared to the control group, reduced microglia/macrophage infiltration, reduced expression of pro-apoptotic gene Bax and pro-inflammatory cytokine gene Tnf, increased expression of anti-inflammatory cytokine genes (Il4, Il10, Il13) and promoted the formation of blood vessels within the damaged area. None of these effects were exerted by the neuronal progenitor cell-conditioned media. The results indicate pronounced cytoprotective, anti-inflammatory and angiogenic properties of soluble factors secreted by glial progenitor cells.
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Affiliation(s)
- Diana Salikhova
- Research Centre for Medical Genetics, 115522 Moscow, Russia; (T.B.); (G.L.); (N.B.); (V.M.); (D.G.)
- Research Institute of Human Morphology, 117418 Moscow, Russia; (M.N.); (A.E.); (K.M.); (L.M.); (T.F.)
| | - Tatiana Bukharova
- Research Centre for Medical Genetics, 115522 Moscow, Russia; (T.B.); (G.L.); (N.B.); (V.M.); (D.G.)
| | - Elvira Cherkashova
- Department of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (E.C.); (D.N.); (I.G.); (A.M.); (V.C.)
- Radiology and Clinical Physiology Scientific Research Center, Federal State Budgetary Institution “Federal Center of Brain Research and Neurotechnologies of the Federal Medical Biological Agency”, 117997 Moscow, Russia;
| | - Daria Namestnikova
- Department of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (E.C.); (D.N.); (I.G.); (A.M.); (V.C.)
- Radiology and Clinical Physiology Scientific Research Center, Federal State Budgetary Institution “Federal Center of Brain Research and Neurotechnologies of the Federal Medical Biological Agency”, 117997 Moscow, Russia;
| | - Georgy Leonov
- Research Centre for Medical Genetics, 115522 Moscow, Russia; (T.B.); (G.L.); (N.B.); (V.M.); (D.G.)
| | - Maria Nikitina
- Research Institute of Human Morphology, 117418 Moscow, Russia; (M.N.); (A.E.); (K.M.); (L.M.); (T.F.)
| | - Ilya Gubskiy
- Department of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (E.C.); (D.N.); (I.G.); (A.M.); (V.C.)
- Radiology and Clinical Physiology Scientific Research Center, Federal State Budgetary Institution “Federal Center of Brain Research and Neurotechnologies of the Federal Medical Biological Agency”, 117997 Moscow, Russia;
| | - Gevorg Akopyan
- Radiology and Clinical Physiology Scientific Research Center, Federal State Budgetary Institution “Federal Center of Brain Research and Neurotechnologies of the Federal Medical Biological Agency”, 117997 Moscow, Russia;
| | - Andrey Elchaninov
- Research Institute of Human Morphology, 117418 Moscow, Russia; (M.N.); (A.E.); (K.M.); (L.M.); (T.F.)
| | - Konstantin Midiber
- Research Institute of Human Morphology, 117418 Moscow, Russia; (M.N.); (A.E.); (K.M.); (L.M.); (T.F.)
| | - Natalia Bulatenco
- Research Centre for Medical Genetics, 115522 Moscow, Russia; (T.B.); (G.L.); (N.B.); (V.M.); (D.G.)
| | - Victoria Mokrousova
- Research Centre for Medical Genetics, 115522 Moscow, Russia; (T.B.); (G.L.); (N.B.); (V.M.); (D.G.)
| | - Andrey Makarov
- Department of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (E.C.); (D.N.); (I.G.); (A.M.); (V.C.)
| | - Konstantin Yarygin
- Institute of Biomedical Chemistry, 119121 Moscow, Russia;
- Russian Medical Academy of Continuous Professional Education, 125993 Moscow, Russia
| | - Vladimir Chekhonin
- Department of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (E.C.); (D.N.); (I.G.); (A.M.); (V.C.)
| | - Liudmila Mikhaleva
- Research Institute of Human Morphology, 117418 Moscow, Russia; (M.N.); (A.E.); (K.M.); (L.M.); (T.F.)
| | - Timur Fatkhudinov
- Research Institute of Human Morphology, 117418 Moscow, Russia; (M.N.); (A.E.); (K.M.); (L.M.); (T.F.)
- Department of Histology, Cytology and Embryology, Peoples’ Friendship University of Russia, 117198 Moscow, Russia
| | - Dmitry Goldshtein
- Research Centre for Medical Genetics, 115522 Moscow, Russia; (T.B.); (G.L.); (N.B.); (V.M.); (D.G.)
- Department of Histology, Cytology and Embryology, Peoples’ Friendship University of Russia, 117198 Moscow, Russia
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Hasanpour Segherlou Z, Nouri-Vaskeh M, Noroozi Guilandehi S, Baghbanzadeh A, Zand R, Baradaran B, Zarei M. GDF-15: Diagnostic, prognostic, and therapeutic significance in glioblastoma multiforme. J Cell Physiol 2021; 236:5564-5581. [PMID: 33580506 DOI: 10.1002/jcp.30289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 12/16/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022]
Abstract
Glioblastoma multiforme (GBM) is the commonest primary malignant brain tumor and has a remarkably weak prognosis. According to the aggressive form of GBM, understanding the accurate molecular mechanism associated with GBM pathogenesis is essential. Growth differentiation factor 15 (GDF-15) belongs to transforming growth factor-β superfamily with important roles to control biological processes. It affects cancer growth and progression, drug resistance, and metastasis. It also can promote stemness in many cancers, and also can stress reactions control, bone generation, hematopoietic growth, adipose tissue performance, and body growth, and contributes to cardiovascular disorders. The role GDF-15 to develop and progress cancer is complicated and remains unclear. GDF-15 possesses tumor suppressor properties, as well as an oncogenic effect. GDF-15 antitumorigenic and protumorigenic impacts on tumor development are linked to the cancer type and stage. However, the GDF-15 signaling and mechanism have not yet been completely identified because of no recognized cognate receptor.
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Affiliation(s)
| | - Masoud Nouri-Vaskeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | | | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Zand
- Department of Neurology, Geisinger Health System, Danville, Pennsylvania, USA
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Zarei
- Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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31
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Mitochondrial stress and GDF15 in the pathophysiology of sepsis. Arch Biochem Biophys 2020; 696:108668. [PMID: 33188737 DOI: 10.1016/j.abb.2020.108668] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 02/07/2023]
Abstract
Mitochondria are multifunctional organelles that regulate diverse cellular processes. Mitochondrial stress, including stress generated by electron transport chain defects and impaired mitochondrial proteostasis, is intimately involved in various diseases and pathological conditions. Sepsis is a life-threatening condition that occurs when an imbalanced host response to infection leads to organ dysfunction. Metabolic disturbances and impaired immune responses are implicated in the pathogenesis and development of sepsis. Given that mitochondria play central roles in cellular metabolism, mitochondrial stress is predicted to be involved in the pathological mechanism of sepsis. Under mitochondrial stress, cells activate stress response systems to maintain homeostasis. This mitochondrial stress response transcriptionally activates genes involved in cell survival and death. Mitochondrial stress also induces the release of distinctive secretory proteins from cells. Recently, we showed that growth differentiation factor 15 (GDF15) is a major secretory protein induced by mitochondrial dysfunction. In this article, we provide a brief overview of mitochondrial stress response and GDF15, and discuss the potential role of GDF15 in the pathophysiology of sepsis.
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32
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Mahato AK, Sidorova YA. Glial cell line-derived neurotrophic factors (GFLs) and small molecules targeting RET receptor for the treatment of pain and Parkinson's disease. Cell Tissue Res 2020; 382:147-160. [PMID: 32556722 PMCID: PMC7529621 DOI: 10.1007/s00441-020-03227-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023]
Abstract
Rearranged during transfection (RET), in complex with glial cell line-derived (GDNF) family receptor alpha (GFRα), is the canonical signaling receptor for GDNF family ligands (GFLs) expressed in both central and peripheral parts of the nervous system and also in non-neuronal tissues. RET-dependent signaling elicited by GFLs has an important role in the development, maintenance and survival of dopamine and sensory neurons. Both Parkinson's disease and neuropathic pain are devastating disorders without an available cure, and at the moment are only treated symptomatically. GFLs have been studied extensively in animal models of Parkinson's disease and neuropathic pain with remarkable outcomes. However, clinical trials with recombinant or viral vector-encoded GFL proteins have produced inconclusive results. GFL proteins are not drug-like; they have poor pharmacokinetic properties and activate multiple receptors. Targeting RET and/or GFRα with small molecules may resolve the problems associated with using GFLs as drugs and can result in the development of therapeutics for disease-modifying treatments against Parkinson's disease and neuropathic pain.
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Affiliation(s)
- Arun Kumar Mahato
- Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, 00014, Helsinki, Finland
| | - Yulia A Sidorova
- Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, 00014, Helsinki, Finland.
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33
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GDF15, an update of the physiological and pathological roles it plays: a review. Pflugers Arch 2020; 472:1535-1546. [PMID: 32936319 DOI: 10.1007/s00424-020-02459-1] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 08/06/2020] [Accepted: 09/02/2020] [Indexed: 02/07/2023]
Abstract
Growth differentiation factor 15 (GDF15) is a peptide hormone, and a divergent member of the transforming growth factor beta (TGFβ) superfamily. In normal physiology, GDF15 is expressed in multiple tissues at a low concentration. GDF15 is overexpressed during and following many pathological conditions such as tissue injury and inflammation in order to play a protective role. However, GDF15 appears to promote tumour growth in the later stages of malignant cancer. The recently identified endogenous receptor for GDF15, GDNF family receptor a-like (GFRAL), has allowed elucidation of a physiological pathway in which GDF15 regulates energy homeostasis and body weight, primarily via appetite suppression. The anorectic effect of GDF15 provides some therapeutic potential in management of cancer-related anorexia/cachexia and obesity. Despite the identification of GFRAL as a GDF15 receptor, there appears to be other signalling mechanisms utilized by GDF15 that further increase the possibility of development of therapeutic treatments, should these pathways be fully characterized. In this review, GDF15 function in both physiological and pathological conditions in various tissues will be discussed.
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34
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Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration. Int J Mol Sci 2020; 21:ijms21186575. [PMID: 32911810 PMCID: PMC7554781 DOI: 10.3390/ijms21186575] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/31/2020] [Accepted: 09/06/2020] [Indexed: 12/14/2022] Open
Abstract
Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are able to promote the survival of multiple neuronal populations in the body and, therefore, hold considerable promise for disease-modifying treatments of diseases and conditions caused by neurodegeneration. Available data reveal the potential of GFLs for the therapy of Parkinson's disease, neuropathic pain and diseases caused by retinal degeneration but, also, amyotrophic lateral sclerosis and, possibly, Alzheimer's disease. Despite promising data collected in preclinical models, clinical translation of GFLs is yet to be conducted. The main reasons for the limited success of GFLs clinical development are the poor pharmacological characteristics of GFL proteins, such as the inability of GFLs to cross tissue barriers, poor diffusion in tissues, biphasic dose-response and activation of several receptors in the organism in different cell types, along with ethical limitations on patients' selection in clinical trials. The development of small molecules selectively targeting particular GFL receptors with improved pharmacokinetic properties can overcome many of the difficulties and limitations associated with the clinical use of GFL proteins. The current review lists several strategies to target the GFL receptor complex with drug-like molecules, discusses their advantages, provides an overview of available chemical scaffolds and peptides able to activate GFL receptors and describes the effects of these molecules in cultured cells and animal models.
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35
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Nichterwitz S, Nijssen J, Storvall H, Schweingruber C, Comley LH, Allodi I, Lee MVD, Deng Q, Sandberg R, Hedlund E. LCM-seq reveals unique transcriptional adaptation mechanisms of resistant neurons and identifies protective pathways in spinal muscular atrophy. Genome Res 2020; 30:1083-1096. [PMID: 32820007 PMCID: PMC7462070 DOI: 10.1101/gr.265017.120] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 07/10/2020] [Indexed: 11/25/2022]
Abstract
Somatic motor neurons are selectively vulnerable in spinal muscular atrophy (SMA), which is caused by a deficiency of the ubiquitously expressed survival of motor neuron protein. However, some motor neuron groups, including oculomotor and trochlear (ocular), which innervate eye muscles, are for unknown reasons spared. To reveal mechanisms of vulnerability and resistance in SMA, we investigate the transcriptional dynamics in discrete neuronal populations using laser capture microdissection coupled with RNA sequencing (LCM-seq). Using gene correlation network analysis, we reveal a TRP53-mediated stress response that is intrinsic to all somatic motor neurons independent of their vulnerability, but absent in relatively resistant red nucleus and visceral motor neurons. However, the temporal and spatial expression analysis across neuron types shows that the majority of SMA-induced modulations are cell type-specific. Using Gene Ontology and protein network analyses, we show that ocular motor neurons present unique disease-adaptation mechanisms that could explain their resilience. Specifically, ocular motor neurons up-regulate (1) Syt1, Syt5, and Cplx2, which modulate neurotransmitter release; (2) the neuronal survival factors Gdf15, Chl1, and Lif; (3) Aldh4, that protects cells from oxidative stress; and (4) the caspase inhibitor Pak4. Finally, we show that GDF15 can rescue vulnerable human spinal motor neurons from degeneration. This confirms that adaptation mechanisms identified in resilient neurons can be used to reduce susceptibility of vulnerable neurons. In conclusion, this in-depth longitudinal transcriptomics analysis in SMA reveals novel cell type-specific changes that, alone and combined, present compelling targets, including Gdf15, for future gene therapy studies aimed toward preserving vulnerable motor neurons.
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Affiliation(s)
| | - Jik Nijssen
- Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Helena Storvall
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
- Ludwig Institute for Cancer Research, Karolinska Institutet, 171 77 Stockholm, Sweden
| | | | - Laura Helen Comley
- Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Ilary Allodi
- Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Mirjam van der Lee
- Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Qiaolin Deng
- Ludwig Institute for Cancer Research, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Rickard Sandberg
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
- Ludwig Institute for Cancer Research, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Eva Hedlund
- Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
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36
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Yue T, Lu H, Yao XM, Du X, Wang LL, Guo DD, Liu YM. Elevated serum growth differentiation factor 15 in multiple system atrophy patients: A case control study. World J Clin Cases 2020; 8:2473-2483. [PMID: 32607324 PMCID: PMC7322433 DOI: 10.12998/wjcc.v8.i12.2473] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 05/09/2020] [Accepted: 05/12/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Multiple system atrophy (MSA) is a serious progressive neurodegenerative disease. Early diagnosis of MSA is very difficult, and diagnostic biomarkers are limited. Growth differentiation factor 15 (GDF15) is involved in the differentiation and progression of the central nervous system, and is widely distributed in peripheral blood, which may be a novel biomarker for MSA.
AIM To determine serum GDF15 levels, related factors and their potential diagnostic value in MSA patients, compared with Parkinson’s disease (PD) patients and healthy controls.
METHODS A case-control study was conducted, including 49 MSA patients, 50 PD patients and 50 healthy controls. Serum GDF15 levels were measured by human enzyme-linked immunosorbent assay, and the differences between the MSA, PD and control groups were analyzed. Further investigations were performed in different MSA subgroups according to age of onset, sex, clinical subtypes, diagnostic criteria, and disease duration. Receiver-operating characteristic curve analysis was used to evaluate the diagnostic value of GDF15, especially for the differential diagnosis between MSA and PD.
RESULTS Serum GDF15 levels were significantly higher in MSA patients than in PD patients and healthy controls (P = 0.000). Males and those with a disease duration of more than three years showed higher serum GDF15 levels (P = 0.043 and 0.000; respectively). Serum GDF15 levels may be a potential diagnostic biomarker for MSA patients compared with healthy controls and PD patients (cutoff: 470.42 pg/mL, sensitivity: 85.7%, specificity: 88.0%; cutoff: 1075.91 pg/mL, sensitivity: 51.0%, specificity: 96.0%; respectively).
CONCLUSION Serum GDF15 levels are significantly higher in MSA patients and provide suggestions on the etiology of MSA.
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Affiliation(s)
- Tao Yue
- Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
- Department of Gerontology, Zibo Central Hospital, Zibo 255036, Shandong Province, China
| | - Hui Lu
- Department of Ophthalmology, Zibo Central Hospital, Zibo 255036, Shandong Province, China
| | - Xiao-Mei Yao
- Department of Gerontology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250013, Shandong Province, China
| | - Xia Du
- Department of Neurology, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, Shandong Province, China
| | - Ling-Ling Wang
- Department of Neurology, Yantaishan Hospital, Yantai 264001, Shandong Province, China
| | - Dan-Dan Guo
- Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Yi-Ming Liu
- Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
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37
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Verhamme FM, Freeman CM, Brusselle GG, Bracke KR, Curtis JL. GDF-15 in Pulmonary and Critical Care Medicine. Am J Respir Cell Mol Biol 2020; 60:621-628. [PMID: 30633545 DOI: 10.1165/rcmb.2018-0379tr] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
GDF-15 (growth differentiation factor 15) acts both as a stress-induced cytokine with diverse actions at different body sites and as a cell-autonomous regulator linked to cellular senescence and apoptosis. For multiple reasons, this divergent transforming growth factor-β molecular superfamily member should be better known to pulmonary researchers and clinicians. In ambulatory individuals, GDF-15 concentrations in peripheral blood are an established predictive biomarker of all-cause mortality and of adverse cardiovascular events. Concentrations upon admission of critically ill patients (without or with sepsis) correlate with organ dysfunction and independently predict short- and long-term mortality risk. GDF-15 is a major downstream mediator of p53 activation, but it can also be induced independently of p53, notably by nonsteroidal antiinflammatory agents. GDF-15 blood concentrations are markedly elevated in adults and children with pulmonary hypertension. Concentrations are also increased in chronic obstructive pulmonary disease, in which they contribute to mucus hypersecretion, airway epithelial cell senescence, and impaired antiviral defenses, which together with murine data support a role for GDF-15 in chronic obstructive pulmonary disease pathogenesis and progression. This review summarizes biological and clinical data on GDF-15 relevant to pulmonary and critical care medicine. We highlight the recent discovery of a central nervous system receptor for GDF-15, GFRAL (glial cell line-derived neurotrophic factor family receptor-α-like), an important advance with potential for novel treatments for obesity and cachexia. We also describe limitations and controversies in the existing literature, and we delineate research questions that must be addressed to determine whether GDF-15 can be therapeutically manipulated in other clinical settings.
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Affiliation(s)
- Fien M Verhamme
- 1 Department of Respiratory Medicine, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Ghent University Hospital, Ghent, Belgium
| | - Christine M Freeman
- 2 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and.,3 Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan.,4 VA Ann Arbor Healthcare System, Ann Arbor, Michigan; and
| | - Guy G Brusselle
- 1 Department of Respiratory Medicine, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Ghent University Hospital, Ghent, Belgium.,5 Department of Epidemiology and.,6 Department of Respiratory Medicine, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Ken R Bracke
- 1 Department of Respiratory Medicine, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Ghent University Hospital, Ghent, Belgium
| | - Jeffrey L Curtis
- 2 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and.,3 Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan.,4 VA Ann Arbor Healthcare System, Ann Arbor, Michigan; and
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38
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Rueda F, Cediel G, García-García C, Aranyó J, González-Lopera M, Aranda Nevado MC, Serra Gregori J, Oliveras T, Labata C, Ferrer M, El Ouaddi N, Bayés-Genís A. Growth differentiation factor 15 and early prognosis after out-of-hospital cardiac arrest. Ann Intensive Care 2019; 9:119. [PMID: 31624933 PMCID: PMC6797678 DOI: 10.1186/s13613-019-0593-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 10/05/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Growth differentiation factor 15 (GDF-15) is an inflammatory cytokine released in response to tissue injury. It has prognostic value in cardiovascular diseases and other acute and chronic conditions. Here, we explored the value of GDF-15 as an early predictor of neurologic outcome after an out-of-hospital cardiac arrest (OHCA). METHODS Prospective registry study of patients in coma after an OHCA, admitted in the intensive cardiac care unit from a single university center. Serum levels of GDF-15 were measured on admission. Neurologic status was evaluated according to the cerebral performance category (CPC) scale. The relationship between GDF-15 levels and poor neurologic outcome at 6 months was analyzed. RESULTS Among 62 patients included, 32 (51.6%) presented poor outcome (CPC 3-5). Patients with CPC 3-5 exhibited significantly higher GDF-15 levels (median, 17.1 [IQR, 11.1-20.4] ng/mL) compared to those with CPC 1-2 (7.6 [IQR, 4.1-13.1] ng/mL; p = 0.004). Multivariable logistic regression analyses showed that age (OR, 1.09; 95% CI 1.01-1.17; p = 0.020), home setting arrest (OR, 8.07; 95% CI 1.61-40.42; p = 0.011), no bystander cardiopulmonary resuscitation (OR, 7.91; 95% CI 1.84-34.01; p = 0.005), and GDF-15 levels (OR, 3.74; 95% CI 1.32-10.60; p = 0.013) were independent predictors of poor outcome. The addition of GDF-15 in a dichotomous manner (≥ 10.8 vs. < 10.8 ng/mL) to the resulting clinical model improved discrimination; it increased the area under the curve from 0.867 to 0.917, and the associated continuous net reclassification improvement was 0.90 (95% CI 0.48-1.44), which allowed reclassification of 37.1% of patients. CONCLUSIONS After an OHCA, increased GDF-15 levels were an independent, early predictor of poor neurologic outcome. Furthermore, when added to the most common clinical factors, GDF-15 improved discrimination and allowed patient reclassification.
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Affiliation(s)
- Ferran Rueda
- Heart Institute, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain.,PhD Program in Internal Medicine, Autonomous University of Barcelona, Barcelona, Spain
| | - Germán Cediel
- Heart Institute, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Cosme García-García
- Heart Institute, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Júlia Aranyó
- Heart Institute, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Marta González-Lopera
- Heart Institute, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - M Cruz Aranda Nevado
- Heart Institute, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Judith Serra Gregori
- Heart Institute, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Teresa Oliveras
- Heart Institute, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Carlos Labata
- Heart Institute, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Marc Ferrer
- Heart Institute, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Nabil El Ouaddi
- Heart Institute, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Antoni Bayés-Genís
- Heart Institute, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain. .,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain.
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Richter B, Uray T, Krychtiuk KA, Schriefl C, Lenz M, Nürnberger A, Kastl SP, Wojta J, Heinz G, Schwameis M, Speidl WS. Growth differentiation factor-15 predicts poor survival after cardiac arrest. Resuscitation 2019; 143:22-28. [PMID: 31394153 DOI: 10.1016/j.resuscitation.2019.07.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 07/08/2019] [Accepted: 07/26/2019] [Indexed: 12/30/2022]
Abstract
BACKGROUND Early prognostication in post-cardiac arrest (CA) patients remains challenging and biomarkers have evolved as helpful tools in risk assessment. The stress-response cytokine growth differentiation factor-15 (GDF-15) is dramatically up-regulated during various kinds of tissue injury and predicts outcome in many pathological conditions. We aimed to assess the predictive value of circulating GDF-15 in post-CA patients. METHODS This prospective observational study included 128 consecutive patients (median age 60.3 years, 75.8% male) with return of spontaneous circulation after in- or out-of-hospital CA who were treated at a tertiary university hospital. GDF-15 serum levels were determined at admission. RESULTS A total of 52 patients (40.6%) died during the 6-month follow-up. Median GDF-15 levels were significantly lower in survivors (1601 ng/L (interquartile range: 1114-2983 ng/L) than in non-survivors (3172 ng/L (1927-8340 ng/L); p < 0.001). GDF-15 levels were also significantly lower in patients with favourable neurological 6-month outcome (cerebral performance category (CPC) 1-2) than in those with poor neurological outcome (CPC 3-5; p < 0.001). GDF-15 significantly predicted 6-month mortality in univariate Cox regression analysis (hazard ratio (HR) per 1-standard deviation increase 1.76 [95% confidence interval (CI) 1.35-2.31; p < 0.001] and remained significant after multivariable adjustment (HR 1.57 [95% CI 1.19-2.07; p = 0.001]). Subgroup analysis revealed that the association between GDF-15 and 6-month outcome was present both in patients with in- and out-of-hospital CA. CONCLUSIONS GDF-15 predicts poor survival and neurological outcome in post-CA patients. GDF-15 may reflect the extent of hypoxic injury to the brain and other organs and might help to improve early risk stratification after CA.
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Affiliation(s)
- Bernhard Richter
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Thomas Uray
- Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
| | - Konstantin A Krychtiuk
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Christoph Schriefl
- Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
| | - Max Lenz
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
| | | | - Stefan P Kastl
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Johann Wojta
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria; Core Facilities, Medical University of Vienna, Vienna, Austria
| | - Gottfried Heinz
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Michael Schwameis
- Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria.
| | - Walter S Speidl
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
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40
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Hassanpour Golakani M, Mohammad MG, Li H, Gamble J, Breit SN, Ruitenberg MJ, Brown DA. MIC-1/GDF15 Overexpression Is Associated with Increased Functional Recovery in Traumatic Spinal Cord Injury. J Neurotrauma 2019; 36:3410-3421. [PMID: 31232176 DOI: 10.1089/neu.2019.6421] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Spinal cord injury (SCI) has devastating consequences, with limited therapeutic options; therefore, improving its functional outcome is a major goal. The outcome of SCI is contributed to by neuroinflammation, which may be a target for improved recovery and quality of life after injury. Macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15) has been identified as a potential novel therapy for central nervous system (CNS) injury because it is an immune regulatory cytokine with neurotrophic properties. Here we used MIC-1/GDF15 knockout (KO) and overexpressing/transgenic (Tg) and wild type (WT) animals to explore its putative therapeutic benefits in a mouse model of contusive SCI. MIC-1/GDF15 Tg mice had superior locomotor recovery and reduced secondary tissue loss at 28 days compared with their KO and WT counterparts. Overexpression of MIC-1/GDF15 coincided with increased expression of monocyte chemoattractant protein-1 (MCP-1)/C-C Motif Chemokine Ligand 2 (CCL2) at the lesion site (28 days post-SCI) and enhanced recruitment of inflammatory cells to the injured spinal cord. This inflammatory cellular infiltrate included an increased frequency of macrophages and dendritic cells (DCs) that mostly preceded recruitment of cluster of differentiation (CD)4+ and CD8+ T cells. Collectively, our findings suggest hat MIC-1/GDF15 is associated with beneficial changes in the clinical course of SCI that are characterized by altered post-injury inflammation and improved functional outcome. Further investigation of MIC-1/GDF15 as a novel therapeutic target for traumatic SCI appears warranted.
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Affiliation(s)
- Masoud Hassanpour Golakani
- St. Vincent's Centre for Applied Medical Research (AMR), St Vincent's Hospital and University of New South Wales (UNSW), Sydney, New South Wales, Australia.,The Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
| | - Mohammad G Mohammad
- Department of Medical Laboratory Sciences, College of Health Sciences and Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates. Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
| | - Hui Li
- St. Vincent's Centre for Applied Medical Research (AMR), St Vincent's Hospital and University of New South Wales (UNSW), Sydney, New South Wales, Australia.,The Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
| | - Joanne Gamble
- The Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
| | - Samuel N Breit
- St. Vincent's Centre for Applied Medical Research (AMR), St Vincent's Hospital and University of New South Wales (UNSW), Sydney, New South Wales, Australia
| | - Marc J Ruitenberg
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
| | - David A Brown
- St. Vincent's Centre for Applied Medical Research (AMR), St Vincent's Hospital and University of New South Wales (UNSW), Sydney, New South Wales, Australia.,The Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.,Department of Immunopathology, Institute for Clinical Pathology and Medical Research-New South Wales Health Pathology, Westmead Hospital, Sydney, New South Wales, Australia
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41
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Adaptive adipose tissue stromal plasticity in response to cold stress and antibody-based metabolic therapy. Sci Rep 2019; 9:8833. [PMID: 31222070 PMCID: PMC6586812 DOI: 10.1038/s41598-019-45354-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 05/29/2019] [Indexed: 01/09/2023] Open
Abstract
In response to environmental and nutrient stress, adipose tissues must establish a new homeostatic state. Here we show that cold exposure of obese mice triggers an adaptive tissue remodeling in visceral adipose tissue (VAT) that involves extracellular matrix deposition, angiogenesis, sympathetic innervation, and adipose tissue browning. Obese VAT is predominated by pro-inflammatory M1 macrophages; cold exposure induces an M1-to-M2 shift in macrophage composition and dramatic changes in macrophage gene expression in both M1 and M2 macrophages. Antibody-mediated CSF1R blocking prevented the cold-induced recruitment of adipose tissue M2 macrophages, suggesting the role of CSF1R signaling in the process. These cold-induced effects in obese VAT are phenocopied by an administration of the FGF21-mimetic antibody, consistent with its action to stimulate sympathetic nerves. Collectively, these studies illuminate adaptive visceral adipose tissue plasticity in obese mice in response to cold stress and antibody-based metabolic therapy.
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42
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Sidorova YA, Volcho KP, Salakhutdinov NF. Neuroregeneration in Parkinson's Disease: From Proteins to Small Molecules. Curr Neuropharmacol 2019; 17:268-287. [PMID: 30182859 PMCID: PMC6425072 DOI: 10.2174/1570159x16666180905094123] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 08/16/2018] [Accepted: 08/30/2018] [Indexed: 01/07/2023] Open
Abstract
Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, the lifetime risk of developing this disease is 1.5%. Motor diagnostic symptoms of PD are caused by degeneration of nigrostria-tal dopamine neurons. There is no cure for PD and current therapy is limited to supportive care that partially alleviates dis-ease signs and symptoms. As diagnostic symptoms of PD result from progressive degeneration of dopamine neurons, drugs restoring these neurons may significantly improve treatment of PD. Method: A literature search was performed using the PubMed, Web of Science and Scopus databases to discuss the pro-gress achieved in the development of neuroregenerative agents for PD. Papers published before early 2018 were taken into account. Results: Here, we review several groups of potential agents capable of protecting and restoring dopamine neurons in cul-tures or animal models of PD including neurotrophic factors and small molecular weight compounds. Conclusion: Despite the promising results of in vitro and in vivo experiments, none of the found agents have yet shown conclusive neurorestorative properties in PD patients. Meanwhile, a few promising biologicals and small molecules have been identified. Their further clinical development can eventually give rise to disease-modifying drugs for PD. Thus, inten-sive research in the field is justified.
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Affiliation(s)
- Yulia A Sidorova
- Laboratory of Molecular Neuroscience, Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Konstantin P Volcho
- Novosibirsk Institute of Organic Chemistry, Novosibirsk, Russian Federation.,Novosibirsk State University, Novosibirsk, Russian Federation
| | - Nariman F Salakhutdinov
- Novosibirsk Institute of Organic Chemistry, Novosibirsk, Russian Federation.,Novosibirsk State University, Novosibirsk, Russian Federation
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43
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Kostuk EW, Cai J, Iacovitti L. Subregional differences in astrocytes underlie selective neurodegeneration or protection in Parkinson's disease models in culture. Glia 2019; 67:1542-1557. [PMID: 31025779 DOI: 10.1002/glia.23627] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/20/2019] [Accepted: 04/04/2019] [Indexed: 12/19/2022]
Abstract
Parkinson's disease (PD) is characterized by the selective degeneration of dopamine (DA) neurons of the substantia nigra pars compacta (SN), while the neighboring ventral tegmental area (VTA) is relatively spared. The mechanisms underlying this selectivity are not fully understood. Here, we demonstrate a vital role for subregional astrocytes in the protection of VTA DA neurons. We found that elimination of astrocytes in vitro exposes a novel vulnerability of presumably protected VTA DA neurons to the PD mimetic toxin MPP+ , as well as exacerbation of SN DA neuron vulnerability. Conversely, VTA astrocytes protected both VTA and SN DA neurons from MPP+ toxicity in a dose dependent manner, and this protection was mediated via a secreted molecule. RNAseq analysis of isolated VTA and SN astrocytes demonstrated a vast array of transcriptional differences between these two closely related populations demonstrating regional heterogeneity of midbrain astrocytes. We found that GDF15, a member of the TGFβ superfamily which is expressed 230-fold higher in VTA astrocytes than SN, recapitulates neuroprotection of both rat midbrain and iPSC-derived DA neurons, whereas its knockdown conversely diminished this effect. Neuroprotection was likely mediated through the GRFAL receptor expressed on DA neurons. Together; these results suggest that subregional differences in astrocytes underlie the selective degeneration or protection of DA neurons in PD.
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Affiliation(s)
- Eric Wildon Kostuk
- Department of Neuroscience, Thomas Jefferson University, Farber Institute for Neurosciences, Philadelphia, Pennsylvania
| | - Jingli Cai
- Department of Neuroscience, Thomas Jefferson University, Farber Institute for Neurosciences, Philadelphia, Pennsylvania
| | - Lorraine Iacovitti
- Department of Neuroscience, Thomas Jefferson University, Farber Institute for Neurosciences, Philadelphia, Pennsylvania.,Department of Neurology, Thomas Jefferson University, Farber Institute for Neurosciences, Philadelphia, Pennsylvania.,Department of Neurosurgery, Thomas Jefferson University, Farber Institute for Neurosciences, Philadelphia, Pennsylvania
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44
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Liu H, Liu J, Si L, Guo C, Liu W, Liu Y. GDF-15 promotes mitochondrial function and proliferation in neuronal HT22 cells. J Cell Biochem 2019; 120:10530-10547. [PMID: 30635935 DOI: 10.1002/jcb.28339] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 12/11/2018] [Indexed: 01/21/2023]
Abstract
The neuronal cell line HT22 is an excellent model for studying Parkinson's disease. Growth differentiation factor 15 (GDF15) plays a critical role in Parkinson's disease, but the molecular mechanism involved are not well understood. We constructed the GDF15 overexpression HT22 cells and detected the effects of overexpression of GDF15 on the viability, oxygen consumption, mitochondrial membrane potential of oligomycin-treated HT22 cells. In addition, we used a high-throughput RNA-sequencing to study the lncRNA and mRNA expression profiling and obtained key lncRNAs, mRNA, gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway. The expression of selected DElncRNAs was validated by quantitative real-time PCR (qRT-PCR). Our results showed that overexpression of GDF15 significantly reversed the cells viability, oxygen consumption, and mitochondrial membrane potential effect caused by oligomycin in HT22 cells. The 1093 DEmRNAs and 395 DElncRNAs in HT22 cells between GDF15-oligomycin non-intervention group and a normal control-oligomycin un-intervention group were obtained, and 394 DEmRNAs and 271 DElncRNAs in HT22 cells between GDF15-oligomycin intervention group and normal control-oligomycin intervention group were identified. Base on the GO and KEGG enrichment analysis of between GDF15-oligomycin intervention group and normal control-oligomycin intervention group, positive regulation of cell proliferation was most significantly enriched GO terms, and Cav1 was enriched in positive regulation of cell proliferation pathway. PI3K-Akt signaling pathway was one significantly enriched pathway in GDF15-oligomycin intervention group. The qRT-PCR results were consistent with RNA-sequencing, generally. GDF15 might promote mitochondrial function and proliferation of HT22 cells by regulating PI3K/Akt signaling pathway. Our study may be helpful in understanding the potential molecular mechanism of GDF15 in Parkinson's disease.
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Affiliation(s)
- Hong Liu
- Department of Neurology, Qilu Hospital of Shandong University, Jinan, Shandong, China.,Department of Neurology, People's Hospital of Liaocheng Affiliated to Taishan Medical College, Liaocheng, Shandong, China
| | - Jiahui Liu
- Department of Neurology, Baotou Central Hospital, Baotou, Inner Mongolia, China
| | - Lei Si
- Department of Precision, People's Hospital of Liaocheng Affiliated to Taishan Medical College, Liaocheng, Shandong, China
| | - Cunju Guo
- Department of Neurology, People's Hospital of Liaocheng Affiliated to Taishan Medical College, Liaocheng, Shandong, China
| | - Wei Liu
- Department of Central Laboratory, People's Hospital of Liaocheng Affiliated to Taishan Medical College, Liaocheng, Shandong, China
| | - Yiming Liu
- Department of Neurology, Qilu Hospital of Shandong University, Jinan, Shandong, China
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45
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Duan J, Göring HHH, Sanders AR, Moy W, Freda J, Drigalenko EI, Kos M, He D, Gejman PV. Transcriptomic signatures of schizophrenia revealed by dopamine perturbation in an ex vivo model. Transl Psychiatry 2018; 8:158. [PMID: 30115913 PMCID: PMC6095865 DOI: 10.1038/s41398-018-0216-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The dopaminergic hypothesis of schizophrenia (SZ) postulates that dopaminergic over activity causes psychosis, a central feature of SZ, based on the observation that blocking dopamine (DA) improves psychotic symptoms. DA is known to have both receptor- and non-receptor-mediated effects, including oxidative mechanisms that lead to apoptosis. The role of DA-mediated oxidative processes in SZ has been little studied. Here, we have used a cell perturbation approach and measured transcriptomic profiles by RNAseq to study the effect of DA exposure on transcription in B-cell transformed lymphoblastoid cell lines (LCLs) from 514 SZ cases and 690 controls. We found that DA had widespread effects on both cell growth and gene expression in LCLs. Overall, 1455 genes showed statistically significant differential DA response in SZ cases and controls. This set of differentially expressed genes is enriched for brain expression and for functions related to immune processes and apoptosis, suggesting that DA may play a role in SZ pathogenesis through modulating those systems. Moreover, we observed a non-significant enrichment of genes near genome-wide significant SZ loci and with genes spanned by SZ-associated copy number variants (CNVs), which suggests convergent pathogenic mechanisms detected by both genetic association and gene expression. The study suggests a novel role of DA in the biological processes of immune and apoptosis that may be relevant to SZ pathogenesis. Furthermore, our results show the utility of pathophysiologically relevant perturbation experiments to investigate the biology of complex mental disorders.
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Affiliation(s)
- Jubao Duan
- Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
| | - Harald H H Göring
- South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, San Antonio, TX, USA
| | - Alan R Sanders
- Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA
| | - Winton Moy
- Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA
| | - Jessica Freda
- Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA
| | - Eugene I Drigalenko
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Mark Kos
- South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, San Antonio, TX, USA
| | - Deli He
- Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA
| | - Pablo V Gejman
- Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
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46
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Jiang J, Thalamuthu A, Ho JE, Mahajan A, Ek WE, Brown DA, Breit SN, Wang TJ, Gyllensten U, Chen MH, Enroth S, Januzzi JL, Lind L, Armstrong NJ, Kwok JB, Schofield PR, Wen W, Trollor JN, Johansson Å, Morris AP, Vasan RS, Sachdev PS, Mather KA. A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood. Front Genet 2018; 9:97. [PMID: 29628937 PMCID: PMC5876753 DOI: 10.3389/fgene.2018.00097] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Accepted: 03/08/2018] [Indexed: 01/12/2023] Open
Abstract
Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of ∼5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 × 10-35), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the“COPI-mediated anterograde transport” gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels.
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Affiliation(s)
- Jiyang Jiang
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
| | - Anbupalam Thalamuthu
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
| | - Jennifer E Ho
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, United States.,Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
| | - Anubha Mahajan
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Weronica E Ek
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - David A Brown
- St. Vincent's Centre for Applied Medical Research, St. Vincent's Hospital, Darlinghurst, NSW, Australia.,Westmead Institute for Medical Research, The Institute for Clinical Pathology and Medical Research and Westmead Hospital, Westmead, NSW, Australia
| | - Samuel N Breit
- St. Vincent's Centre for Applied Medical Research, St. Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Thomas J Wang
- Division of Cardiology, Department of Medicine, Vanderbilt University, Nashville, TN, United States
| | - Ulf Gyllensten
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Ming-Huei Chen
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA, United States.,The Framingham Heart Study, Framingham, MA, United States
| | - Stefan Enroth
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - James L Januzzi
- Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
| | - Lars Lind
- Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden
| | - Nicola J Armstrong
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.,Mathematics and Statistics, Murdoch University, Perth, WA, Australia
| | - John B Kwok
- Neuroscience Research Australia, Randwick, NSW, Australia.,School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Peter R Schofield
- Neuroscience Research Australia, Randwick, NSW, Australia.,School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Wei Wen
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.,Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, NSW, Australia
| | - Julian N Trollor
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.,Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
| | - Åsa Johansson
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Andrew P Morris
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.,Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom
| | - Ramachandran S Vasan
- Sections of Preventive Medicine and Epidemiology and Cardiology, Department of Medicine, Boston University School of Medicine, and Department of Epidemiology, Boston University School of Public Health, Boston, MA, United States.,National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Boston University, Boston, MA, United States
| | - Perminder S Sachdev
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.,Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, NSW, Australia
| | - Karen A Mather
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
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48
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Wang S, Li M, Zhang W, Hua H, Wang N, Zhao J, Ge J, Jiang X, Zhang Z, Ye D, Yang C. Growth differentiation factor 15 promotes blood vessel growth by stimulating cell cycle progression in repair of critical-sized calvarial defect. Sci Rep 2017; 7:9027. [PMID: 28831101 PMCID: PMC5567281 DOI: 10.1038/s41598-017-09210-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 07/21/2017] [Indexed: 11/24/2022] Open
Abstract
Repair of large bone defects remains a challenge for surgeons, tissue engineering represents a promising approach. However, the use of this technique is limited by delayed vascularization in central regions of the scaffold. Growth differentiation factor 15(GDF15) has recently been reported to be a potential angiogenic cytokine and has an ability to promote the proliferation of human umbilical vein endothelial cells(HUVECs). Whether it can be applied for promoting vascularized bone regeneration is still unknown. In this study, we demonstrated that GDF15 augmented the expression of cyclins D1 and E, induced Rb phosphorylation and E2F-1 nuclear translocation, as well as increased HUVECs proliferation. Furthermore, we also observed that GDF15 promoted the formation of functional vessels at an artificially-induced angiogenic site, and remarkably improved the healing in the repair of critical-sized calvarial defects. Our results confirm the essential role of GDF15 in angiogenesis and suggest its potential beneficial use in regenerative medicine.
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Affiliation(s)
- Shaoyi Wang
- Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China
| | - Mengyu Li
- Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China
| | - Wenjie Zhang
- Department of Prosthodontics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China.,Oral Bioengineering Lab/Regenerative Medicine Lab, Shanghai Research Institute of Stomatology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China
| | - Hongfei Hua
- Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China
| | - Ningtao Wang
- Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China
| | - Jun Zhao
- Department of Orthodontics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China
| | - Jing Ge
- Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China
| | - Xinquan Jiang
- Department of Prosthodontics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China.,Oral Bioengineering Lab/Regenerative Medicine Lab, Shanghai Research Institute of Stomatology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China
| | - Zhiyuan Zhang
- Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China.
| | - Dongxia Ye
- Shanghai Research Institute of Stomatology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China.
| | - Chi Yang
- Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China.
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49
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Kumar P, Millischer V, Villaescusa JC, Nilsson IAK, Östenson CG, Schalling M, Ösby U, Lavebratt C. Plasma GDF15 level is elevated in psychosis and inversely correlated with severity. Sci Rep 2017; 7:7906. [PMID: 28801589 PMCID: PMC5554200 DOI: 10.1038/s41598-017-07503-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 06/27/2017] [Indexed: 12/20/2022] Open
Abstract
Accumulating evidence suggests that GDF15 is a biomarker for ageing and morbidity of many somatic disorders such as cancer and inflammatory disorders. Recently, elevated serum GDF15 level was proposed as a marker for mood disorder. However, psychosis severity was not investigated in relation to plasma GDF15 levels. In the present study we measured GDF15 levels in plasma of 120 psychosis patients compared to 120 age and gender matched healthy controls. Within the patient cohort GDF15 levels were evaluated for association with age, gender, lifestyle factors, C-reactive protein levels, psychosis severity and metabolic disorder. Psychosis patients had elevated GDF15 levels compared to controls (medianPsychosis = 744 ng/mL, mediancontrols = 516 ng/mL, p < 0.001). Within the psychosis cohort, GDF15 levels, when corrected for age, metabolic health and lifestyle factors, were negatively correlated with psychosis severity (β = −0.218, p = 0.012). While GDF15 levels were elevated in patients versus healthy controls, the negative correlation between psychosis severity and GDF15 suggests a loss of anti-inflammatory GDF15 mediated functionality in severe psychosis. Study replication in larger cohorts will be necessary to assess the potential of GDF15 as a prognostic biomarker in psychosis.
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Affiliation(s)
- Parvin Kumar
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. .,Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
| | - Vincent Millischer
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - J Carlos Villaescusa
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Ida A K Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Claes-Göran Östenson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Martin Schalling
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Urban Ösby
- Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.,Department of Adult Psychiatry, PRIMA Barn och Vuxenpsykiatri AB, Stockholm, Sweden.,Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Catharina Lavebratt
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. .,Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
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50
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Suzuki A, Yoshida H, van Heeringen SJ, Takebayashi-Suzuki K, Veenstra GJC, Taira M. Genomic organization and modulation of gene expression of the TGF-β and FGF pathways in the allotetraploid frog Xenopus laevis. Dev Biol 2017; 426:336-359. [DOI: 10.1016/j.ydbio.2016.09.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 06/10/2016] [Accepted: 09/19/2016] [Indexed: 12/13/2022]
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