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1
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Dotto GP, Buckinx A, Özdemir BC, Simon C. Androgen receptor signalling in non-prostatic malignancies: challenges and opportunities. Nat Rev Cancer 2025; 25:93-108. [PMID: 39587300 PMCID: PMC11947662 DOI: 10.1038/s41568-024-00772-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/22/2024] [Indexed: 11/27/2024]
Abstract
The androgen receptor (AR) signalling pathway has been intensively studied in the context of prostate cancer, where androgen deprivation therapy is part of the standard of care for metastatic disease. By contrast, fewer studies have investigated the impact and translational potential of targeting AR in other cancer types where it is also expressed and functional. In this Review, we discuss the current understanding of AR in non-prostatic cancer types and summarize ongoing AR-directed clinical trials. While different androgen levels contribute to sexual dimorphism in cancer, targeting the AR system could benefit both sexes and help overcome resistance to targeted therapies. However, a bimodal function of AR signalling, which suppresses stromal changes associated with the early stages of cancer development, also needs to be considered. Future research is necessary to scrutinize cellular and molecular mechanisms of action of AR in cancer cells and the tumour microenvironment, to develop selective modulators of AR activity, and to identify patients with non-prostatic cancer who might benefit from targeting this pathway. AR-directed manipulation of host immune cells may offer a promising therapeutic approach for many types of cancers.
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Affiliation(s)
- G Paolo Dotto
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
- Service d'Oto-rhino-laryngologie et chirurgie cervical faciale, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne (UNIL), Lausanne, Switzerland.
- International Cancer Prevention Institute, Epalinges, Switzerland.
| | - An Buckinx
- International Cancer Prevention Institute, Epalinges, Switzerland
| | - Berna C Özdemir
- Department of Medical Oncology, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Christian Simon
- Service d'Oto-rhino-laryngologie et chirurgie cervical faciale, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne (UNIL), Lausanne, Switzerland
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2
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Wang X, Rong C, Niu P, Leng W, Wang G, He Z, Qi X, Zhao D, Li J. The neurotoxicity of iodoacetic acid, a byproduct of drinking water disinfection. FRONTIERS IN TOXICOLOGY 2025; 7:1543374. [PMID: 39931280 PMCID: PMC11808161 DOI: 10.3389/ftox.2025.1543374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 01/10/2025] [Indexed: 02/13/2025] Open
Abstract
IAA is a by-product of the water disinfection process and has been found to be neurotoxic. However, the role and mechanism of IAA neurotoxicity remain unclear. In this review, we comprehensively discuss the neurotoxic effects and mechanisms of IAA from the molecular level, cellular level and neurological manifestations. At the molecular level, IAA causes neurotoxicity by reducing mitochondrial membrane potential, aggravating oxidative stress and DNA damage. At the cellular level, IAA causes neurotoxicity by inducing BBB disruption, neuroinflammation, and apoptosis. In neurological manifestations, IAA can lead to neurotransmitter disorders, neurodevelopment dysfunction, and even neurodegenerative diseases. Taken together, our review provides insights into the mechanisms of IAA neurotoxicity that will contribute to future studies of IAA neurotoxicity and its protective strategies.
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Affiliation(s)
- Xu Wang
- Department of Encephalopathy, Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
- School of Public Health, Jilin University, Changchun, Jilin, China
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Chunshu Rong
- Department of Encephalopathy, Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Ping Niu
- Department of Encephalopathy, Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Wei Leng
- Department of Encephalopathy, Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Gaihua Wang
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Ziqiao He
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Xin Qi
- School of Public Health, Jilin University, Changchun, Jilin, China
| | - Dexi Zhao
- Department of Encephalopathy, Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Jinhua Li
- School of Public Health, Jilin University, Changchun, Jilin, China
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3
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Zadmajid V, Shahriar S, Gorelick DA. Testosterone acts through the membrane protein GPRC6A to cause cardiac edema in zebrafish embryos. Development 2024; 151:dev204390. [PMID: 39479956 PMCID: PMC11634029 DOI: 10.1242/dev.204390] [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: 09/18/2024] [Accepted: 10/06/2024] [Indexed: 11/02/2024]
Abstract
Androgens are classically thought to act through intracellular androgen receptors (AR/NR3C4), but they can also trigger non-genomic effects via membrane proteins. Although several membrane androgen receptors have been characterized in vitro, their functions in vivo remain unclear. Using a chemical-genetic screen in zebrafish, we found that GPRC6A, a G-protein-coupled receptor, mediates non-genomic androgen actions during embryonic development. Exposure to androgens (androstanedione, DHT and testosterone) caused cardiac edema or tail curvature in wild-type embryos, as well as in ar mutants, suggesting AR-independent pathways. We then mutated putative membrane androgen receptors [gprc6a, hcar1-4 and zip9 (slc39a9)] and found that only gprc6a mutants exhibited a significant reduction in cardiac edema after testosterone exposure. Additionally, co-treatment of wild-type embryos with testosterone and GPRC6A antagonists significantly suppressed the cardiac edema phenotype. Using RNA-seq and RNA rescue approaches, we found that testosterone and GPRC6A cause cardiac phenotypes by reducing Pak1 signaling. Our results indicate that testosterone induces cardiac edema in zebrafish embryos through GPRC6A, independent of nuclear androgen receptors, highlighting a previously unappreciated non-genomic androgen signaling pathway in embryonic development.
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MESH Headings
- Animals
- Zebrafish/embryology
- Zebrafish/metabolism
- Receptors, G-Protein-Coupled/metabolism
- Receptors, G-Protein-Coupled/genetics
- Testosterone/metabolism
- Testosterone/pharmacology
- Zebrafish Proteins/metabolism
- Zebrafish Proteins/genetics
- Edema, Cardiac/metabolism
- Edema, Cardiac/pathology
- Edema, Cardiac/genetics
- Embryo, Nonmammalian/metabolism
- Embryo, Nonmammalian/drug effects
- Receptors, Androgen/metabolism
- Receptors, Androgen/genetics
- Signal Transduction/drug effects
- Gene Expression Regulation, Developmental/drug effects
- Heart/embryology
- Heart/drug effects
- Androgens/pharmacology
- Androgens/metabolism
- Mutation/genetics
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Affiliation(s)
- Vahid Zadmajid
- Center for Precision Environmental Health, Department of Molecular & Cellular Biology, Baylor College of Medicine, One Baylor Plaza, BCM229, Houston, TX 77030, USA
| | - Shayan Shahriar
- Center for Precision Environmental Health, Department of Molecular & Cellular Biology, Baylor College of Medicine, One Baylor Plaza, BCM229, Houston, TX 77030, USA
| | - Daniel A. Gorelick
- Center for Precision Environmental Health, Department of Molecular & Cellular Biology, Baylor College of Medicine, One Baylor Plaza, BCM229, Houston, TX 77030, USA
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4
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Kim S, Kubelka NK, LaPorte HM, Krishnamoorthy VR, Singh M. Estradiol and 3β-diol protect female cortical astrocytes by regulating connexin 43 Gap Junctions. Mol Cell Endocrinol 2023; 578:112045. [PMID: 37595662 PMCID: PMC10592012 DOI: 10.1016/j.mce.2023.112045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 08/03/2023] [Accepted: 08/14/2023] [Indexed: 08/20/2023]
Abstract
While estrogens have been described to protect or preserve neuronal function in the face of insults such as oxidative stress, the prevailing mechanistic model would suggest that these steroids exert direct effects on the neurons. However, there is growing evidence that glial cells, such as astrocytes, are key cellular mediators of protection. Noting that connexin 43 (Cx43), a protein highly expressed in astrocytes, plays a key role in mediating inter-cellular communication, we hypothesized that Cx43 is a target of estradiol (E2), and the estrogenic metabolite of DHT, 3β-diol. Additionally, we sought to determine if either or both of these hormones attenuate oxidative stress-induced cytotoxicity by eliciting a reduction in Cx43 expression or inhibition of Cx43 channel permeability. Using primary cortical astrocytes, we found that E2 and 3β-diol were each protective against the mixed metabolic/oxidative insult, iodoacetic acid (IAA). Moreover, these effects were blocked by estrogen receptor antagonists. However, E2 and 3β-diol did not alter Cx43 mRNA levels in astrocytes but did inhibit IAA-induced Cx43 gap junction opening/permeability. Taken together, these data implicate astrocyte Cx43 gap junction as an understudied mediator of the cytoprotective effects of estrogens in the brain. Given the wide breadth of disease states associated with Cx43 function/dysfunction, further understanding the relationship between gonadal steroids and Cx43 channels may contribute to a better understanding of the biological basis for sex differences in various diseases.
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Affiliation(s)
- Seongcheol Kim
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, United States
| | - Nicholas Knesek Kubelka
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, United States
| | - Heather M LaPorte
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, United States
| | - Vignesh R Krishnamoorthy
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, United States
| | - Meharvan Singh
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, United States.
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5
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Tiberi J, Cesarini V, Stefanelli R, Canterini S, Fiorenza MT, Rosa PL. Sex differences in antioxidant defence and the regulation of redox homeostasis in physiology and pathology. Mech Ageing Dev 2023; 211:111802. [PMID: 36958540 DOI: 10.1016/j.mad.2023.111802] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/14/2023] [Accepted: 03/20/2023] [Indexed: 03/25/2023]
Abstract
Reactive oxygen species (ROS) is a term that defines a group of unstable compounds derived from exogenous sources or endogenous metabolism. Under physiological conditions, low levels of ROS play a key role in the regulation of signal transduction- or transcription-mediated cellular responses. In contrast, excessive and uncontrolled loading of ROS results in a pathological state known as oxidative stress (OS), a leading contributor to aging and a pivotal factor for the onset and progression of many disorders. Evolution has endowed cells with an antioxidant system involved in stabilizing ROS levels to a specific threshold, preserving ROS-induced signalling function and limiting negative side effects. In mammals, a great deal of evidence indicates that females defence against ROS is more proficient than males, determining a longer lifespan and lower incidence of most chronic diseases. In this review, we will summarize the most recent sex-related differences in the regulation of redox homeostasis. We will highlight the peculiar aspects of the antioxidant defence in sex-biased diseases whose onset or progression is driven by OS, and we will discuss the molecular, genetic, and evolutionary determinants of female proficiency to cope with ROS.
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Affiliation(s)
- Jessica Tiberi
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Rome, Italy; PhD program in Behavioral Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Valeriana Cesarini
- Department of Biomedicine Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, Italy
| | - Roberta Stefanelli
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Rome, Italy
| | - Sonia Canterini
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Rome, Italy; European Center for Brain Research, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Maria Teresa Fiorenza
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Rome, Italy; European Center for Brain Research, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Piergiorgio La Rosa
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Rome, Italy; European Center for Brain Research, IRCCS Fondazione Santa Lucia, Rome, Italy.
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6
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Galindez SM, Keightley A, Koulen P. Differential distribution of steroid hormone signaling networks in the human choroid-retinal pigment epithelial complex. BMC Ophthalmol 2022; 22:406. [PMID: 36266625 PMCID: PMC9583547 DOI: 10.1186/s12886-022-02585-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 08/22/2022] [Indexed: 11/10/2022] Open
Abstract
Background The retinal pigment epithelium (RPE), a layer of pigmented cells that lies between the neurosensory retina and the underlying choroid, plays a critical role in maintaining the functional integrity of photoreceptor cells and in mediating communication between the neurosensory retina and choroid. Prior studies have demonstrated neurotrophic effects of select steroids that mitigate the development and progression of retinal degenerative diseases via an array of distinct mechanisms of action. Methods Here, we identified major steroid hormone signaling pathways and their key functional protein constituents controlling steroid hormone signaling, which are potentially involved in the mitigation or propagation of retinal degenerative processes, from human proteome datasets with respect to their relative abundances in the retinal periphery, macula, and fovea. Results Androgen, glucocorticoid, and progesterone signaling networks were identified and displayed differential distribution patterns within these three anatomically distinct regions of the choroid-retinal pigment epithelial complex. Classical and non-classical estrogen and mineralocorticoid receptors were not identified. Conclusion Identified differential distribution patterns suggest both selective susceptibility to chronic neurodegenerative disease processes, as well as potential substrates for drug target discovery and novel drug development focused on steroid signaling pathways in the choroid-RPE.
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Affiliation(s)
- Sydney M Galindez
- School of Medicine, Vision Research Center, Department of Ophthalmology, University of Missouri - Kansas City School of Medicine, 2411 Holmes St, Kansas City, MO, 64108, USA
| | - Andrew Keightley
- School of Medicine, Vision Research Center, Department of Ophthalmology, University of Missouri - Kansas City School of Medicine, 2411 Holmes St, Kansas City, MO, 64108, USA
| | - Peter Koulen
- School of Medicine, Vision Research Center, Department of Ophthalmology, University of Missouri - Kansas City School of Medicine, 2411 Holmes St, Kansas City, MO, 64108, USA. .,Department of Biomedical Sciences, University of Missouri - Kansas City School of Medicine, Kansas City, MO, USA.
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7
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Kuwahara N, Nicholson K, Isaacs L, MacLusky NJ. Androgen Effects on Neural Plasticity. ANDROGENS: CLINICAL RESEARCH AND THERAPEUTICS 2021; 2:216-230. [PMID: 35024693 PMCID: PMC8744448 DOI: 10.1089/andro.2021.0022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 10/24/2021] [Indexed: 12/20/2022]
Abstract
Androgens are synthesized in the brain, gonads, and adrenal glands, in both sexes, exerting physiologically important effects on the structure and function of the central nervous system. These effects may contribute to the incidence and progression of neurological disorders such as autism spectrum disorder, schizophrenia, and Alzheimer's disease, which occur at different rates in males and females. This review briefly summarizes the current state of knowledge with respect to the neuroplastic effects of androgens, with particular emphasis on the hippocampus, which has been the focus of much of the research in this field.
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Affiliation(s)
- Nariko Kuwahara
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Kate Nicholson
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Lauren Isaacs
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Neil J. MacLusky
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada
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8
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Blankers SA, Galea LA. Androgens and Adult Neurogenesis in the Hippocampus. ANDROGENS: CLINICAL RESEARCH AND THERAPEUTICS 2021; 2:203-215. [PMID: 35024692 PMCID: PMC8744005 DOI: 10.1089/andro.2021.0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 08/19/2021] [Indexed: 11/12/2022]
Abstract
Adult neurogenesis in the hippocampus is modulated by steroid hormones, including androgens, in male rodents. In this review, we summarize research showing that chronic exposure to androgens, such as testosterone and dihydrotestosterone, enhances the survival of new neurons in the dentate gyrus of male, but not female, rodents, via the androgen receptor. However, the neurogenesis promoting the effect of androgens in the dentate gyrus may be limited to younger adulthood as it is not evident in middle-aged male rodents. Although direct exposure to androgens in adult or middle age does not significantly influence neurogenesis in female rodents, the aromatase inhibitor letrozole enhances neurogenesis in the hippocampus of middle-aged female mice. Unlike other androgens, androgenic anabolic steroids reduce neurogenesis in the hippocampus of male rodents. Collectively, the research indicates that the ability of androgens to enhance hippocampal neurogenesis in adult rodents is dependent on dose, androgen type, sex, duration, and age. We discuss these findings and how androgens may be influencing neuroprotection, via neurogenesis in the hippocampus, in the context of health and disease.
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Affiliation(s)
- Samantha A. Blankers
- Graduate Program in Neuroscience, The University of British Columbia, Vancouver, Canada
- Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, Canada
| | - Liisa A.M. Galea
- Graduate Program in Neuroscience, The University of British Columbia, Vancouver, Canada
- Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, Canada
- Department of Psychology, The University of British Columbia, Vancouver, Canada
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9
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Zelleroth S, Nylander E, Örtenblad A, Stam F, Nyberg F, Grönbladh A, Hallberg M. Structurally different anabolic androgenic steroids reduce neurite outgrowth and neuronal viability in primary rat cortical cell cultures. J Steroid Biochem Mol Biol 2021; 210:105863. [PMID: 33677017 DOI: 10.1016/j.jsbmb.2021.105863] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/08/2021] [Accepted: 02/18/2021] [Indexed: 12/12/2022]
Abstract
The illicit use of anabolic androgenic steroids (AAS) among adolescents and young adults is a major concern due to the unknown and unpredictable impact of AAS on the developing brain and the consequences of this on mental health, cognitive function and behaviour. The present study aimed to investigate the effects of supra-physiological doses of four structurally different AAS (testosterone, nandrolone, stanozolol and trenbolone) on neurite development and cell viability using an in vitro model of immature primary rat cortical cell cultures. A high-throughput screening image-based approach, measuring the neurite length and number of neurons, was used for the analysis of neurite outgrowth. In addition, cell viability and expression of the Tubb3 gene (encoding the protein beta-III tubulin) were investigated. Testosterone, nandrolone, and trenbolone elicited adverse effects on neurite outgrowth as deduced from an observed reduced neurite length per neuron. Trenbolone was the only AAS that reduced the cell viability as indicated by a decreased number of neurons and declined mitochondrial function. Moreover, trenbolone downregulated the Tubb3 mRNA expression. The adverse impact on neurite development was neither inhibited nor supressed by the selective androgen receptor (AR) antagonist, flutamide, suggesting that the observed effects result from another mechanism or mechanisms of action that are operating apart from AR activation. The results demonstrate a possible AAS-induced detrimental effect on neuronal development and regenerative functions. An impact on these events, that are essential mechanisms for maintaining normal brain function, could possibly contribute to behavioural alterations seen in AAS users.
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Affiliation(s)
- Sofia Zelleroth
- The Beijer Laboratory, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, SE-751 24, Uppsala University, Sweden.
| | - Erik Nylander
- The Beijer Laboratory, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, SE-751 24, Uppsala University, Sweden.
| | - Axel Örtenblad
- The Beijer Laboratory, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, SE-751 24, Uppsala University, Sweden
| | - Frida Stam
- The Beijer Laboratory, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, SE-751 24, Uppsala University, Sweden.
| | - Fred Nyberg
- The Beijer Laboratory, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, SE-751 24, Uppsala University, Sweden.
| | - Alfhild Grönbladh
- The Beijer Laboratory, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, SE-751 24, Uppsala University, Sweden.
| | - Mathias Hallberg
- The Beijer Laboratory, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, SE-751 24, Uppsala University, Sweden.
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10
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Almaguer-Mederos LE, Aguilera-Rodríguez R, Almaguer-Gotay D, Hechavarría-Barzaga K, Álvarez-Sosa A, Chapman-Rodríguez Y, Silva-Ricardo Y, González-Zaldivar Y, Vázquez-Mojena Y, Cuello-Almarales D, Rodríguez-Estupiñán A. Testosterone Levels Are Decreased and Associated with Disease Duration in Male Spinocerebellar Ataxia Type 2 Patients. THE CEREBELLUM 2021; 19:597-604. [PMID: 32440846 DOI: 10.1007/s12311-020-01134-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder due to an unstable expansion of a CAG repeat in the ATXN2 gene. Despite clinical and experimental evidence indicating the relevance of the gonadotropic axis to the prognosis and therapeutics for several late-onset neurodegenerative disorders, its functioning and association with disease severity have not been previously explored in SCA2. To assess serum levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), and their clinical relevance in SCA2 patients. A case-control study involving 94 Cuban SCA2 patients and 101 gender- and age-matched healthy controls was conducted. Testosterone, LH, and FSH serum levels were determined by radioimmunoassay or immunoradiometric assay systems. Clinical outcomes included age at onset, disease duration, Scale for the Assessment and Rating of Ataxia (SARA) score, and progression rate. Univariate general linear models were generated. Testosterone, LH, and FSH serum levels were significantly reduced in male SCA2 patients relative to control individuals. On average, there was a 35% reduction in testosterone levels in male patients versus male control individuals. Testosterone levels were associated with disease duration (r = 0.383; p = 0.025) and age at onset (r = 0.414; p = 0.011) in male SCA2 patients, but no association was observed between testosterone and CAG expansion size, SARA score, or progression rate. Testosterone levels might be a biomarker of disease progression in male SCA2 patients. Further studies are needed to explore the effects of low testosterone levels on non-motor symptoms, and to assess the potential of testosterone replacement therapy in male SCA2 patients.
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Affiliation(s)
- Luis E Almaguer-Mederos
- Center for the Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguin, Cuba.
| | - Raúl Aguilera-Rodríguez
- Center for the Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguin, Cuba
| | - Dennis Almaguer-Gotay
- Center for the Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguin, Cuba
| | | | | | | | | | | | - Yaimé Vázquez-Mojena
- Center for the Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguin, Cuba
| | - Dany Cuello-Almarales
- Center for the Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguin, Cuba
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11
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van Weperen VYH, Littman RJ, Arneson DV, Contreras J, Yang X, Ajijola OA. Single-cell transcriptomic profiling of satellite glial cells in stellate ganglia reveals developmental and functional axial dynamics. Glia 2021; 69:1281-1291. [PMID: 33432730 DOI: 10.1002/glia.23965] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 12/30/2020] [Accepted: 12/31/2020] [Indexed: 12/31/2022]
Abstract
Stellate ganglion neurons, important mediators of cardiopulmonary neurotransmission, are surrounded by satellite glial cells (SGCs), which are essential for the function, maintenance, and development of neurons. However, it remains unknown whether SGCs in adult sympathetic ganglia exhibit any functional diversity, and what role this plays in modulating neurotransmission. We performed single-cell RNA sequencing of mouse stellate ganglia (n = 8 animals), focusing on SGCs (n = 11,595 cells). SGCs were identified by high expression of glial-specific transcripts, S100b and Fabp7. Microglia and Schwann cells were identified by expression of C1qa/C1qb/C1qc and Ncmap/Drp2, respectively, and excluded from further analysis. Dimensionality reduction and clustering of SGCs revealed six distinct transcriptomic subtypes, one of which was characterized the expression of pro-inflammatory markers and excluded from further analyses. The transcriptomic profiles and corresponding biochemical pathways of the remaining subtypes were analyzed and compared with published astrocytic transcriptomes. This revealed gradual shifts of developmental and functional pathways across the subtypes, originating from an immature and pluripotent subpopulation into two mature populations of SGCs, characterized by upregulated functional pathways such as cholesterol metabolism. As SGCs aged, these functional pathways were downregulated while genes and pathways associated with cellular stress responses were upregulated. These findings were confirmed and furthered by an unbiased pseudo-time analysis, which revealed two distinct trajectories involving the five subtypes that were studied. These findings demonstrate that SGCs in mouse stellate ganglia exhibit transcriptomic heterogeneity along maturation or differentiation axes. These subpopulations and their unique biochemical properties suggest dynamic physiological adaptations that modulate neuronal function.
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Affiliation(s)
- Valerie Y H van Weperen
- UCLA Neurocardiology Research Center of Excellence, Los Angeles, California, USA.,UCLA Cardiac Arrhythmia Center, Los Angeles, California, USA
| | - Russell J Littman
- UCLA Bioinformatics Interdepartmental Program, Los Angeles, California, USA.,UCLA Integrative Biology and Physiology, Los Angeles, California, USA
| | - Douglas V Arneson
- UCLA Bioinformatics Interdepartmental Program, Los Angeles, California, USA.,UCLA Integrative Biology and Physiology, Los Angeles, California, USA.,UCSF Bakar Computational Health Sciences Institute, San Francisco, California, USA
| | - Jaime Contreras
- UCLA Neurocardiology Research Center of Excellence, Los Angeles, California, USA.,UCLA Cardiac Arrhythmia Center, Los Angeles, California, USA
| | - Xia Yang
- UCLA Bioinformatics Interdepartmental Program, Los Angeles, California, USA.,UCLA Integrative Biology and Physiology, Los Angeles, California, USA
| | - Olujimi A Ajijola
- UCLA Neurocardiology Research Center of Excellence, Los Angeles, California, USA.,UCLA Cardiac Arrhythmia Center, Los Angeles, California, USA
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12
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Kamińska A, Marek S, Pardyak L, Brzoskwinia M, Bilinska B, Hejmej A. Crosstalk between Androgen-ZIP9 Signaling and Notch Pathway in Rodent Sertoli Cells. Int J Mol Sci 2020; 21:ijms21218275. [PMID: 33167316 PMCID: PMC7663815 DOI: 10.3390/ijms21218275] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 11/02/2020] [Accepted: 11/02/2020] [Indexed: 12/24/2022] Open
Abstract
Our recent study demonstrated altered expression of Notch ligands, receptors, and effector genes in testes of pubertal rats following reduced androgen production or signaling. Herein we aimed to explore the role of nuclear androgen receptor (AR) and membrane androgen receptor (Zrt- and Irt-like protein 9; ZIP9) in the regulation of Notch pathway activation in rodent Sertoli cells. Experiments were performed using TM4 and 15P-1 Sertoli cell lines and rat primary Sertoli cells (PSC). We found that testosterone (10-8 M-10-6 M) increased the expression of Notch1 receptor, its active form Notch1 intracellular domain (N1ICD) (p < 0.05, p < 0.01, p < 0.001), and the effector genes Hey1 (p < 0.05, p < 0.01, p < 0.001) and Hes1 (p < 0.05, p < 0.001) in Sertoli cells. Knockdown of AR or ZIP9 as well as antiandrogen exposure experiments revealed that (i) action of androgens via both AR and ZIP9 controls Notch1/N1ICD expression and transcriptional activity of recombination signal binding protein (RBP-J), (ii) AR-dependent signaling regulates Hey1 expression, (iii) ZIP9-dependent pathway regulates Hes1 expression. Our findings indicate a crosstalk between androgen and Notch signaling in Sertoli cells and point to cooperation of classical and non-classical androgen signaling pathways in controlling Sertoli cell function.
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Affiliation(s)
- Alicja Kamińska
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Kraków, Poland; (A.K.); (S.M.); (L.P.); (M.B.); (B.B.)
| | - Sylwia Marek
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Kraków, Poland; (A.K.); (S.M.); (L.P.); (M.B.); (B.B.)
| | - Laura Pardyak
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Kraków, Poland; (A.K.); (S.M.); (L.P.); (M.B.); (B.B.)
- Center of Experimental and Innovative Medicine, University of Agriculture in Krakow, 30-248 Kraków, Poland
| | - Małgorzata Brzoskwinia
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Kraków, Poland; (A.K.); (S.M.); (L.P.); (M.B.); (B.B.)
| | - Barbara Bilinska
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Kraków, Poland; (A.K.); (S.M.); (L.P.); (M.B.); (B.B.)
| | - Anna Hejmej
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Kraków, Poland; (A.K.); (S.M.); (L.P.); (M.B.); (B.B.)
- Correspondence:
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13
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Morgunov LY, Denisova IA, Rozhkova TI, Stakhovskaya LV, Skvortsova VI. Hypogonadism and its treatment following ischaemic stroke in men with type 2 diabetes mellitus. Aging Male 2020; 23:71-80. [PMID: 30064273 DOI: 10.1080/13685538.2018.1487932] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Premature mortality in Russia is a major socio-economic problem, especially from acute cerebrovascular diseases which constitute 21.4% of the total mortality and is a considerable contributor to chronic disability. Risk of vascular catastrophe is higher in males than females, thought, in part, due to anti-atherosclerotic effects of oestrogens in females whilst an associated age-related deficiency of testosterone is observed in men. Clinical symptoms such as high blood pressure, changes in lipid profile, insulin resistance, obesity, and blood coagulation factors often accompany declining testosterone in males and reduced total testosterone is considered a cardiovascular risk factor. In the present study, the prevalence of hypogonadism in men who had suffered ischaemic stroke was evaluated along with the efficacy of testosterone undecanoate injections (TU) in patients with testosterone deficiency and type-2 diabetes (T2DM) in the acute phase of hemispheric ischaemic stroke. Hypogonadism was present in 66.3% of patients with ischaemic stroke, 50% with T2DM, and 26.3% without T2DM, respectively. TU treatment, at both the 2 and 5-year observation points, demonstrated significant improvements in biochemical, physical, and mental parameters. This supports that testosterone deficiency is a contributing factor in ischaemic events and that long-term testosterone therapy could play an important role in patient recovery.
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Affiliation(s)
- L Y Morgunov
- Ucebnyj centr innovacionnyh medicinskih tehnologij RNIMU imeni N I Pirogova, Moskva, Russian Federation
| | - I A Denisova
- Ucebnyj centr innovacionnyh medicinskih tehnologij RNIMU imeni N I Pirogova, Moskva, Russian Federation
| | - T I Rozhkova
- Ucebnyj centr innovacionnyh medicinskih tehnologij RNIMU imeni N I Pirogova, Moskva, Russian Federation
| | - L V Stakhovskaya
- Ucebnyj centr innovacionnyh medicinskih tehnologij RNIMU imeni N I Pirogova, Moskva, Russian Federation
| | - V I Skvortsova
- Ucebnyj centr innovacionnyh medicinskih tehnologij RNIMU imeni N I Pirogova, Moskva, Russian Federation
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Kollara A, Shathasivam P, Park S, Ringuette MJ, Brown TJ. Increased androgen receptor levels and signaling in ovarian cancer cells by VEPH1 associated with suppression of SMAD3 and AKT activation. J Steroid Biochem Mol Biol 2020; 196:105498. [PMID: 31614206 DOI: 10.1016/j.jsbmb.2019.105498] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 10/08/2019] [Accepted: 10/08/2019] [Indexed: 12/11/2022]
Abstract
Studies indicate androgens contribute to initiation or progression of epithelial ovarian cancer through poorly understood mechanisms. We provide evidence that the androgen receptor (AR) interacts in a ligand-independent manner with the putative armadillo repeat domain of ventricular zone expressed PH domain-containing 1 (VEPH1). This interaction was increased by mutation of the two nuclear receptor-interacting LxxLL motifs present within the VEPH1 armadillo repeat domain. Androgen treatment did not result in nuclear co-localization of VEPH1 with AR, suggesting that VEPH1 does not function as a nuclear co-regulatory protein. VEPH1 expression decreased SMAD3 and activated AKT levels in ovarian cancer cell lines and increased AR activity and protein levels, consistent with an impact on receptor stability. Treatment of cells with dihydrotestosterone (DHT) increased AR protein levels measured 24 h after treatment, an effect augmented in VEPH1-transfected cells, and inhibited by knock-down of endogenous VEPH1. SMAD3 overexpression decreased AR protein levels and prevented the VEPH1-dependent increase in AR; however, silencing of SMAD3 paradoxically also decreased AR levels. DHT treatment led to a rapid and sustained decrease in phosphorylated AKT (pAKT) levels that was enhanced by VEPH1 expression. Inhibition of PI3K resulted in increased AR protein levels. These studies indicate that VEPH1 acts to enhance AR activity in ovarian cancer cells by decreasing SMAD3 and pAKT levels, resulting in increased levels of AR protein.
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Affiliation(s)
- Alexandra Kollara
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, M5T 3L9, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, M5S 3G5, Canada
| | - Premalatha Shathasivam
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, M5T 3L9, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, M5S 3G5, Canada
| | - Soyeon Park
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, M5T 3L9, Canada
| | - Maurice J Ringuette
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, M5S 3G5, Canada
| | - Theodore J Brown
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, M5T 3L9, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, M5S 3G5, Canada.
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15
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Perez-Laso C, Cerdan S, Junque C, Gómez Á, Ortega E, Mora M, Avendaño C, Gómez-Gil E, Del Cerro MCR, Guillamon A. Effects of Adult Female Rat Androgenization on Brain Morphology and Metabolomic Profile. Cereb Cortex 2019; 28:2846-2853. [PMID: 29106544 DOI: 10.1093/cercor/bhx163] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Indexed: 11/14/2022] Open
Abstract
Androgenization in adult natal women, as in transsexual men (TM), affects brain cortical thickness and the volume of subcortical structures. In order to understand the mechanism underlying these changes we have developed an adult female rat model of androgenization. Magnetic resonance imaging and spectroscopy were used to monitor brain volume changes, white matter microstructure and ex vivo metabolic profiles over 32 days in androgenized and control subjects. Supraphysiological doses of testosterone prevents aging decrease of fractional anisotropy values, decreased general cortical volume and the relative concentrations of glutamine (Gln) and myo-Inositol (mI). An increase in the N-acetylaspartate (NAA)/mI ratio was detected d. Since mI and Gln are astrocyte markers and osmolytes, we suspect that the anabolic effects of testosterone change astrocyte osmolarity so as to extrude Mi and Gln from these cells in order to maintain osmotic homeostasis. This mechanism could explain the brain changes observed in TM and other individuals receiving androgenic anabolic steroids.
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Affiliation(s)
- Carmen Perez-Laso
- Departamento de Psicobiología, Facultad de Psicología, Universidad Nacional de Educación a Distancia, Madrid, Spain
| | - Sebastián Cerdan
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Carme Junque
- Departamento de Medicina, Facultad de Medicina, Universidad de Barcelona, Barcelona, Spain
| | - Ángel Gómez
- Departamento de Psicología Social y de las Organizaciones, Facultad de Psicología, Universidad Nacional de Educación a Distancia, Madrid, Spain
| | - Esperanza Ortega
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Granada, Granada, Spain
| | - Mireia Mora
- Departamento de Endocrinología, Hospital Clínic, Barcelona, Spain
| | - Carlos Avendaño
- Departamento de Anatomía y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Esther Gómez-Gil
- Unidad de Identidad de Género, Departamento de Psiquiatría, Hospital Clìnic, Barcelona, Spain
| | | | - Antonio Guillamon
- Departamento de Psicobiología, Facultad de Psicología, Universidad Nacional de Educación a Distancia, Madrid, Spain
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Kaidonis G, Rao AN, Ouyang YB, Stary CM. Elucidating sex differences in response to cerebral ischemia: immunoregulatory mechanisms and the role of microRNAs. Prog Neurobiol 2018; 176:73-85. [PMID: 30121237 DOI: 10.1016/j.pneurobio.2018.08.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 06/04/2018] [Accepted: 08/05/2018] [Indexed: 12/17/2022]
Abstract
Cerebral ischemia remains a major cause of death and disability worldwide, yet therapeutic options remain limited. Differences in sex and age play an important role in the final outcome in response to cerebral ischemia in both experimental and clinical studies: males have a higher risk and worse outcome than females at younger ages and this trend reverses in older ages. Although the molecular mechanisms underlying sex dimorphism are complex and are still not well understood, studies suggest steroid hormones, sex chromosomes, differential cell death and immune pathways, and sex-specific microRNAs may contribute to the outcome following cerebral ischemia. This review focuses on differential effects between males and females on cell death and immunological pathways in response to cerebral ischemia, the central role of innate sex differences in steroid hormone signaling, and upstreamregulation of sexually dimorphic gene expression by microRNAs.
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Affiliation(s)
- Georgia Kaidonis
- Stanford University School of Medicine, Department of Anesthesiology, Perioperative & Pain Medicine, United States; Stanford University School of Medicine, Department of Ophthalmology, United States
| | - Anand N Rao
- Stanford University School of Medicine, Department of Anesthesiology, Perioperative & Pain Medicine, United States
| | - Yi-Bing Ouyang
- Stanford University School of Medicine, Department of Anesthesiology, Perioperative & Pain Medicine, United States
| | - Creed M Stary
- Stanford University School of Medicine, Department of Anesthesiology, Perioperative & Pain Medicine, United States.
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Tenkorang MA, Snyder B, Cunningham RL. Sex-related differences in oxidative stress and neurodegeneration. Steroids 2018; 133:21-27. [PMID: 29274405 PMCID: PMC5864532 DOI: 10.1016/j.steroids.2017.12.010] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 12/13/2017] [Accepted: 12/18/2017] [Indexed: 02/07/2023]
Abstract
Oxidative stress has been implicated in a number of neurodegenerative diseases spanning various fields of research. Reactive oxygen species can be beneficial or harmful, depending on their concentration. High levels of reactive oxygen species can lead to oxidative stress, which is an imbalance between free radicals and antioxidants. Increased oxidative stress can result in cell loss. Interestingly, sex differences have been observed in oxidative stress generation, which may underlie sex differences observed in neurodegenerative disorders. An enhanced knowledge of the role of sex hormones on oxidative stress signaling and cell loss can yield valuable information, leading to sex-based mechanistic approaches to neurodegeneration.
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Affiliation(s)
- Mavis A Tenkorang
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Brina Snyder
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Rebecca L Cunningham
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, United States.
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Schreihofer DA, Duong P, Cunningham RL. N-terminal truncations in sex steroid receptors and rapid steroid actions. Steroids 2018; 133:15-20. [PMID: 29104096 PMCID: PMC5864524 DOI: 10.1016/j.steroids.2017.10.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 10/27/2017] [Accepted: 10/30/2017] [Indexed: 01/14/2023]
Abstract
Sex steroid receptors act as ligand activated nuclear transcription factors throughout the body, including the brain. However, post-translational modification of these receptors can direct them to extranuclear sites, including the plasma membrane, where they are able to initiate rapid signaling. Because of the conserved domain structure of these receptors, alternative exon splicing can result in proteins with altered nuclear and extranuclear actions. Although much attention has focused on internal and C-terminal splice variants, both estrogen and androgen receptors undergo N-terminal truncations, as well. These truncated proteins not only influence the transcriptional activity of the full-length receptors, but also associate with caveolin and initiate signaling at the plasma membrane. Such actions may have important physiological consequences in neuronal, endothelial, and cancer signaling and cell survival.
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Affiliation(s)
- Derek A Schreihofer
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76244, USA
| | - Phong Duong
- Department of Physiology and Anatomy, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76244, USA
| | - Rebecca L Cunningham
- Department of Physiology and Anatomy, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76244, USA.
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Bojar I, Pinkas J, Gujski M, Owoc A, Raczkiewicz D, Gustaw-Rothenberg K. Postmenopausal cognitive changes and androgen levels in the context of apolipoprotein E polymorphism. Arch Med Sci 2017; 13:1148-1159. [PMID: 28883857 PMCID: PMC5575214 DOI: 10.5114/aoms.2016.62869] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 07/25/2016] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION The focus of this study was to assess cognitive functions in relation to androgens and specifically testosterone and dehydroepiandrosterone in postmenopausal women as well as the correlation between cognitive functions and these two androgens according to polymorphism of the apolipoprotein E gene (APOE). MATERIAL AND METHODS A group of 402 women was recruited to the study (minimum 2 years after the last menstruation, follicle-stimulating hormone (FSH) more than 30 U/ml and no dementia signs on Montreal Cognitive Assessment). The computerized battery of the Central Nervous System Vital Signs test was used to diagnose cognitive functions. APOE genotyping was performed by multiplex polymerase chain reaction (PCR). Testosterone (TTE) and dehydroepiandrosterone (DHEA) in the blood serum were assessed for further statistical correlations analysis. RESULTS In the group of postmenopausal women, higher testosterone concentration was associated with lower scores for Neurocognition Index (NCI) (p = 0.028), memory (p = 0.008) and psychomotor speed (p < 0.001). Presence of at least one APOE ε4 allele potentiated testosterone's negative influence on cognitive functions (p < 0.05). Woman with a high normal level of DHEA scored significantly better in verbal (p = 0.027) and visual memory (p < 0.001) than other participants. APOE polymorphism did not modify the relationship between DHEA concentration and scores for cognitive functions. CONCLUSIONS Hormonal balance variations after menopause may influence brain processes concerned with cognition, especially memory and psychomotor speed. The observed effects may be related to androgens' influence on higher cortical functions in the changed hormonal dynamics of the postmenopausal period.
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Affiliation(s)
- Iwona Bojar
- Department for Women Health, Institute of Rural Health, Lublin, Poland
| | - Jarosław Pinkas
- School of Public Health, Center of Postgraduate Medical Education, Warsaw, Poland
| | - Mariusz Gujski
- Department of Prevention of Environmental Hazards and Allergology, Medical University of Warsaw, Warsaw, Poland
| | - Alfred Owoc
- Center for Public Health and Health Promotion, Institute of Rural Health, Lublin, Poland
| | - Dorota Raczkiewicz
- Institute of Statistics and Demography, Warsaw School of Economics, Warsaw, Poland
| | - Kasia Gustaw-Rothenberg
- Lou Ruvo Brain Wellness Center, Neurological Institute, The Cleveland Clinic Foundation, Cleveland, OH, USA
- Department of Neurodegenerative Diseases, Institute of Rural Health, Lublin, Poland
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Huffman J, Hoffmann C, Taylor GT. Integrating insulin-like growth factor 1 and sex hormones into neuroprotection: Implications for diabetes. World J Diabetes 2017; 8:45-55. [PMID: 28265342 PMCID: PMC5320748 DOI: 10.4239/wjd.v8.i2.45] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 09/24/2016] [Accepted: 11/22/2016] [Indexed: 02/05/2023] Open
Abstract
Brain integrity and cognitive aptitude are often impaired in patients with diabetes mellitus, presumably a result of the metabolic complications inherent to the disease. However, an increasing body of evidence has demonstrated the central role of insulin-like growth factor 1 (IGF1) and its relation to sex hormones in many neuroprotective processes. Both male and female patients with diabetes display abnormal IGF1 and sex-hormone levels but the comparison of these fluctuations is seldom a topic of interest. It is interesting to note that both IGF1 and sex hormones have the ability to regulate phosphoinositide 3-kinase-Akt and mitogen-activated protein kinases-extracellular signal-related kinase signaling cascades in animal and cell culture models of neuroprotection. Additionally, there is considerable evidence demonstrating the neuroprotective coupling of IGF1 and estrogen. Androgens have also been implicated in many neuroprotective processes that operate on similar signaling cascades as the estrogen-IGF1 relation. Yet, androgens have not been directly linked to the brain IGF1 system and neuroprotection. Despite the sex-specific variations in brain integrity and hormone levels observed in diabetic patients, the IGF1-sex hormone relation in neuroprotection has yet to be fully substantiated in experimental models of diabetes. Taken together, there is a clear need for the comprehensive analysis of sex differences on brain integrity of diabetic patients and the relationship between IGF1 and sex hormones that may influence brain-health outcomes. As such, this review will briefly outline the basic relation of diabetes and IGF1 and its role in neuroprotection. We will also consider the findings on sex hormones and diabetes as a basis for separately analyzing males and females to identify possible hormone-induced brain abnormalities. Finally, we will introduce the neuroprotective interplay of IGF1 and estrogen and how androgen-derived neuroprotection operates through similar signaling cascades. Future research on both neuroprotection and diabetes should include androgens into the interplay of IGF1 and sex hormones.
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Song J, Jung C, Kim OY. The Novel Implication of Androgen in Diabetes-induced Alzheimer's Disease. J Lipid Atheroscler 2017. [DOI: 10.12997/jla.2017.6.2.66] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea
| | - Chaeyong Jung
- Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea
| | - Oh Yoen Kim
- Department of Food Science and Nutrition, Dong-A University, Busan, Korea
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22
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Gonadal hormone modulation of intracellular calcium as a mechanism of neuroprotection. Front Neuroendocrinol 2016; 42:40-52. [PMID: 26930421 DOI: 10.1016/j.yfrne.2016.02.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Revised: 02/22/2016] [Accepted: 02/26/2016] [Indexed: 12/28/2022]
Abstract
Hormones have wide-ranging effects throughout the nervous system, including the ability interact with and modulate many aspects of intracellular calcium regulation and calcium signaling. Indeed, these interactions specifically may help to explain the often opposing or paradoxical effects of hormones, such as their ability to both promote and prevent neuronal cell death during development, as well as reduce or exacerbate damage following an insult or injury in adulthood. Here, we review the basic mechanisms underlying intracellular calcium regulation-perhaps the most dynamic and flexible of all signaling molecules-and discuss how gonadal hormones might manipulate these mechanisms to coordinate diverse cellular responses and achieve disparate outcomes. Additional future research that specifically addresses questions of sex and hormone effects on calcium signaling at different ages will be critical to understanding hormone-mediated neuroprotection.
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23
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Holmes S, Singh M, Su C, Cunningham RL. Effects of Oxidative Stress and Testosterone on Pro-Inflammatory Signaling in a Female Rat Dopaminergic Neuronal Cell Line. Endocrinology 2016; 157:2824-35. [PMID: 27167771 PMCID: PMC4929547 DOI: 10.1210/en.2015-1738] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Parkinson's disease, a progressive neurodegenerative disorder, is associated with oxidative stress and neuroinflammation. These pathological markers can contribute to the loss of dopamine neurons in the midbrain. Interestingly, men have a 2-fold increased incidence for Parkinson's disease than women. Although the mechanisms underlying this sex difference remain elusive, we propose that the primary male sex hormone, testosterone, is involved. Our previous studies show that testosterone, through a putative membrane androgen receptor, can increase oxidative stress-induced neurotoxicity in dopamine neurons. Based on these results, this study examines the role of nuclear factor κ B (NF-κB), cyclooxygenase-2 (COX2), and apoptosis in the deleterious effects of androgens in an oxidative stress environment. We hypothesize, under oxidative stress environment, testosterone via a putative membrane androgen receptor will exacerbate oxidative stress-induced NF-κB/COX2 signaling in N27 dopaminergic neurons, leading to apoptosis. Our data show that testosterone increased the expression of COX2 and apoptosis in dopamine neurons. Inhibiting the NF-κB and COX2 pathway with CAPE and ibuprofen, respectively, blocked testosterone's negative effects on cell viability, indicating that NF-κB/COX2 cascade plays a role in the negative interaction between testosterone and oxidative stress on neuroinflammation. These data further support the role of testosterone mediating the loss of dopamine neurons under oxidative stress conditions, which may be a key mechanism contributing to the increased incidence of Parkinson's disease in men compared with women.
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Affiliation(s)
- Shaletha Holmes
- Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, Texas 76107
| | - Meharvan Singh
- Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, Texas 76107
| | - Chang Su
- Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, Texas 76107
| | - Rebecca L Cunningham
- Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, Texas 76107
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Cao Y, Risling M, Malm E, Sondén A, Bolling MF, Sköld MK. Cellular High-Energy Cavitation Trauma - Description of a Novel In Vitro Trauma Model in Three Different Cell Types. Front Neurol 2016; 7:10. [PMID: 26869990 PMCID: PMC4734234 DOI: 10.3389/fneur.2016.00010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 01/19/2016] [Indexed: 12/25/2022] Open
Abstract
The mechanisms involved in traumatic brain injury have yet to be fully characterized. One mechanism that, especially in high-energy trauma, could be of importance is cavitation. Cavitation can be described as a process of vaporization, bubble generation, and bubble implosion as a result of a decrease and subsequent increase in pressure. Cavitation as an injury mechanism is difficult to visualize and model due to its short duration and limited spatial distribution. One strategy to analyze the cellular response of cavitation is to employ suitable in vitro models. The flyer-plate model is an in vitro high-energy trauma model that includes cavitation as a trauma mechanism. A copper fragment is accelerated by means of a laser, hits the bottom of a cell culture well causing cavitation, and shock waves inside the well and cell medium. We have found the flyer-plate model to be efficient, reproducible, and easy to control. In this study, we have used the model to analyze the cellular response to microcavitation in SH-SY5Y neuroblastoma, Caco-2, and C6 glioma cell lines. Mitotic activity in neuroblastoma and glioma was investigated with BrdU staining, and cell numbers were calculated using automated time-lapse imaging. We found variations between cell types and between different zones surrounding the lesion with these methods. It was also shown that the injured cell cultures released S-100B in a dose-dependent manner. Using gene expression microarray, a number of gene families of potential interest were found to be strongly, but differently regulated in neuroblastoma and glioma at 24 h post trauma. The data from the gene expression arrays may be used to identify new candidates for biomarkers in cavitation trauma. We conclude that our model is useful for studies of trauma in vitro and that it could be applied in future treatment studies.
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Affiliation(s)
- Yuli Cao
- Department of Neuroscience, Karolinska Institutet , Stockholm , Sweden
| | - Mårten Risling
- Department of Neuroscience, Karolinska Institutet , Stockholm , Sweden
| | - Elisabeth Malm
- Department of Neuroscience, Karolinska Institutet , Stockholm , Sweden
| | - Anders Sondén
- Section of Surgery, Department of Clinical Science and Education, Karolinska Institutet at Södersjukhuset , Stockholm , Sweden
| | - Magnus Frödin Bolling
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Mattias K Sköld
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neurosurgery, Uppsala University Hospital, Uppsala, Sweden
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Pace M, Baracchi F, Gao B, Bassetti C. Identification of Sleep-Modulated Pathways Involved in Neuroprotection from Stroke. Sleep 2015; 38:1707-18. [PMID: 26085290 DOI: 10.5665/sleep.5148] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 04/13/2015] [Indexed: 12/21/2022] Open
Abstract
STUDY OBJECTIVES Sleep deprivation (SDp) performed before stroke induces an ischemic tolerance state as observed in other forms of preconditioning. As the mechanisms underlying this effect are not well understood, we used DNA oligonucleotide microarray analysis to identify the genes and the gene-pathways underlying SDp preconditioning effects. DESIGN Gene expression was analyzed 3 days after stroke in 4 experimental groups: (i) SDp performed before focal cerebral ischemia (IS) induction; (ii) SDp performed before sham surgery; (iii) IS without SDp; and (iv) sham surgery without SDp. SDp was performed by gentle handling during the last 6 h of the light period, and ischemia was induced immediately after. SETTINGS Basic sleep research laboratory. MEASUREMENTS AND RESULTS Stroke induced a massive alteration in gene expression both in sleep deprived and non-sleep deprived animals. However, compared to animals that underwent ischemia alone, SDp induced a general reduction in transcriptional changes with a reduction in the upregulation of genes involved in cell cycle regulation and immune response. Moreover, an upregulation of a new neuroendocrine pathway which included melanin concentrating hormone, glycoprotein hormones-α-polypeptide and hypocretin was observed exclusively in rats sleep deprived before stroke. CONCLUSION Our data indicate that sleep deprivation before stroke reprogrammed the signaling response to injury. The inhibition of cell cycle regulation and inflammation are neuroprotective mechanisms reported also for other forms of preconditioning treatment, whereas the implication of the neuroendocrine function is novel and has never been described before. These results therefore provide new insights into neuroprotective mechanisms involved in ischemic tolerance mechanisms.
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Affiliation(s)
- Marta Pace
- ZEN - Zentrum für Experimentelle Neurologie, Inselspital, Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Francesca Baracchi
- ZEN - Zentrum für Experimentelle Neurologie, Inselspital, Bern, Switzerland
| | - Bo Gao
- ZEN - Zentrum für Experimentelle Neurologie, Inselspital, Bern, Switzerland
| | - Claudio Bassetti
- ZEN - Zentrum für Experimentelle Neurologie, Inselspital, Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
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Li S, Kang L, Zhang Y, Feng B, Du J, Cui H. Detecting the presence of hippocampus membrane androgen receptors in male SAMP8 mice and their induced synaptic plasticity. Mol Cell Endocrinol 2015; 414:82-90. [PMID: 26164088 DOI: 10.1016/j.mce.2015.07.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 07/03/2015] [Accepted: 07/05/2015] [Indexed: 12/14/2022]
Abstract
Testosterone (T), the principal androgen, and its metabolite, dihydrotestosterone (DHT), are known to mediate their effects through binding to intracellular androgen receptors (iARs). In addition to their well-known genomic effects, androgens rapidly alter neuronal excitability through a non-genomic pathway mediated by membrane androgen receptors (mARs). The existence and specificity of mARs in the hippocampus were investigated in SAMP8 mice. Using T-BSA-FITC, we detected plasma membrane labeling by flow cytometry analysis for the presence of mARs. The specificity of binding was examined with iAR antagonist or anti-iAR antibody. Flow cytometry analysis showed that pretreatment with iAR antagonist, flutamide (F), failed to completely prevent the coupling action of the T-BSA-FITC membrane binding. In addition, we found classical iARs did not localize to the membrane of hippocampal neurons. These data indicate that these mARs might be not identical to classical iARs. Modulation of hippocampal synaptic plasticity by androgen has been attracting much attention. To identify the functional consequences induced by mARs, we analyzed the rapid effects of T on the density of dendritic spines using Golgi staining. The application of 50 μg/5 μl T and 30 μg/5 μl DHT induced a rapid increase in the dendritic spines within 2 h. Almost no difference was observed between T and T-BSA in the effect on thorn density. Next, we explored the protective mechanism and found that T and DHT altered the expression of synaptophysin (SYN) and postsynaptic dense material 95 (PSD95), which play crucial roles in cognitive function and synaptic plasticity.
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Affiliation(s)
- Sha Li
- Department of Human Anatomy, Hebei Medical University, Hebei, PR China; Hebei Key Laboratory for Brain Aging and Cognitive Neuroscience, Hebei, PR China
| | - Lin Kang
- Department of Human Anatomy, Hebei Medical University, Hebei, PR China
| | - Yizhou Zhang
- Department of Human Anatomy, Hebei Medical University, Hebei, PR China
| | - Baofeng Feng
- Department of Human Anatomy, Hebei Medical University, Hebei, PR China
| | - Juan Du
- Department of Human Anatomy, Hebei Medical University, Hebei, PR China
| | - Huixian Cui
- Department of Human Anatomy, Hebei Medical University, Hebei, PR China; Hebei Key Laboratory for Brain Aging and Cognitive Neuroscience, Hebei, PR China.
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Takemoto T, Ishihara Y, Ishida A, Yamazaki T. Neuroprotection elicited by nerve growth factor and brain-derived neurotrophic factor released from astrocytes in response to methylmercury. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2015; 40:199-205. [PMID: 26143513 DOI: 10.1016/j.etap.2015.06.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 06/05/2015] [Accepted: 06/06/2015] [Indexed: 06/04/2023]
Abstract
The protective roles of astrocytes in neurotoxicity induced by environmental chemicals, such as methylmercury (MeHg), are largely unknown. We found that conditioned medium of MeHg-treated astrocytes (MCM) attenuated neuronal cell death induced by MeHg, suggesting that astrocytes-released factors can protect neuronal cells. The increased expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) was observed in MeHg-treated astrocytes. NGF and BDNF were detected in culture media as homodimers, which are able to bind specific tyrosine kinase receptors, tropomyosin related kinase (Trk) A and TrkB, respectively. The TrkA antagonist and TrkB antagonist abolished the protective effects of MCM in neuronal cell death induced by MeHg. Taken together, astrocytes synthesize and release NGF and BDNF in response to MeHg to protect neurons from MeHg toxicity. This study is considered to show a novel defense mechanism against MeHg-induced neurotoxicity.
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Affiliation(s)
- Takuya Takemoto
- Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan
| | - Yasuhiro Ishihara
- Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan.
| | - Atsuhiko Ishida
- Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan
| | - Takeshi Yamazaki
- Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan
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Pesaresi M, Soon-Shiong R, French L, Kaplan DR, Miller FD, Paus T. Axon diameter and axonal transport: In vivo and in vitro effects of androgens. Neuroimage 2015; 115:191-201. [PMID: 25956809 DOI: 10.1016/j.neuroimage.2015.04.048] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 04/23/2015] [Accepted: 04/24/2015] [Indexed: 01/05/2023] Open
Abstract
Testosterone is a sex hormone involved in brain maturation via multiple molecular mechanisms. Previous human studies described age-related changes in the overall volume and structural properties of white matter during male puberty. Based on this work, we have proposed that testosterone may induce a radial growth of the axon and, possibly, modulate axonal transport. In order to determine whether this is the case we have used two different experimental approaches. With electron microscopy, we have evaluated sex differences in the structural properties of axons in the corpus callosum (splenium) of young rats, and tested consequences of castration carried out after weaning. Then we examined in vitro the effect of the non-aromatizable androgen Mibolerone on the structure and bidirectional transport of wheat-germ agglutinin vesicles in the axons of cultured sympathetic neurons. With electron microscopy, we found robust sex differences in axonal diameter (males>females) and g ratio (males>females). Removal of endogenous testosterone by castration was associated with lower axon diameter and lower g ratio in castrated (vs. intact) males. In vitro, Mibolerone influenced the axonal transport in a time- and dose-dependent manner, and increased the axon caliber as compared with vehicle-treated neurons. These findings are consistent with the role of testosterone in shaping the axon by regulating its radial growth, as predicted by the initial human studies.
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Affiliation(s)
- M Pesaresi
- Rotman Research Institute, University of Toronto, 3560 Bathurst Street, Toronto, Ontario M6A 2E1, Canada
| | - R Soon-Shiong
- Rotman Research Institute, University of Toronto, 3560 Bathurst Street, Toronto, Ontario M6A 2E1, Canada
| | - L French
- Rotman Research Institute, University of Toronto, 3560 Bathurst Street, Toronto, Ontario M6A 2E1, Canada
| | - D R Kaplan
- Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
| | - F D Miller
- Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
| | - T Paus
- Rotman Research Institute, University of Toronto, 3560 Bathurst Street, Toronto, Ontario M6A 2E1, Canada.
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Shores MM, Arnold AM, Biggs ML, Longstreth W, Smith NL, Kizer JR, Cappola AR, Hirsch CH, Marck BT, Matsumoto AM. Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study. Clin Endocrinol (Oxf) 2014; 81:746-53. [PMID: 24645738 PMCID: PMC4169352 DOI: 10.1111/cen.12452] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Revised: 12/10/2013] [Accepted: 03/12/2014] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Ischaemic stroke is a major cause of morbidity and mortality in elderly men. Our main objective was to examine whether testosterone (T) or dihydrotestosterone (DHT) was associated with incident ischaemic stroke in elderly men. DESIGN Cohort study. PARTICIPANTS Elderly men in the Cardiovascular Health Study who had no history of stroke, heart disease or prostate cancer as of 1994 and were followed until December 2010. MEASUREMENTS Adjudicated ischaemic stroke. RESULTS Among 1032 men (mean age 76, range 66-97), followed for a median of 10 years, 114 had an incident ischaemic stroke. Total T and free T were not significantly associated with stroke risk, while DHT had a nonlinear association with incident stroke (P = 0·006) in analyses adjusted for stroke risk factors. The lowest risk of stroke was at DHT levels of 50-75 ng/dl, with greater risk of stroke at DHT levels above 75 ng/dl or below 50 ng/dl. Results were unchanged when SHBG was added to the model. Calculated free DHT had an inverse linear association with incident ischaemic stroke with HR 0·77 (95% CI, 0·61, 0·98) per standard deviation in analyses adjusted for stroke risk factors. CONCLUSIONS Dihydrotestosterone had a nonlinear association with stroke risk in which there was an optimal DHT level associated with the lowest stroke risk. Further studies are needed to confirm these results and to clarify whether there is an optimal androgen range associated with the least risk of adverse outcomes in elderly men.
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Affiliation(s)
- Molly M. Shores
- VA Puget Sound Health Care System, Seattle, WA
- Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA
| | - Alice M. Arnold
- Department of Biostatistics, University of Washington, Seattle, WA
| | - Mary L. Biggs
- Department of Biostatistics, University of Washington, Seattle, WA
| | - W.T. Longstreth
- Department of Neurology, University of Washington, Seattle, WA
- Department of Epidemiology, University of Washington, Seattle, WA
| | - Nicholas L. Smith
- VA Puget Sound Health Care System, Seattle, WA
- Department of Epidemiology, University of Washington, Seattle, WA
- VA Epidemiologic Research and Information Center (ERIC), Department of Veterans Affairs Office of Research and Development, Seattle, WA
- Group Health Research Institute, Group Health Cooperative, Seattle, WA
| | - Jorge R. Kizer
- Department of Medicine, and Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY
| | - Anne R. Cappola
- Department of Internal Medicine, Division of Endocrinology Diabetes and Metabolism, University of Pennsylvania, Philadelphia, PA
| | - Calvin H. Hirsch
- Department of Internal Medicine, Geriatric Medicine, University of California-Davis, Davis, CA
| | - Brett T. Marck
- VA Puget Sound Health Care System, Seattle, WA
- Geriatric Research, Education and Clinical Care (GRECC), VA Puget Sound Health Care System
| | - Alvin M. Matsumoto
- VA Puget Sound Health Care System, Seattle, WA
- Geriatric Research, Education and Clinical Care (GRECC), VA Puget Sound Health Care System
- Department of Medicine, Division of Gerontology & Geriatric Medicine, University of Washington, Seattle WA
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Bing L, Wu J, Zhang J, Chen Y, Hong Z, Zu H. DHT inhibits the Aβ25-35-induced apoptosis by regulation of seladin-1, survivin, XIAP, bax, and bcl-xl expression through a rapid PI3-K/Akt signaling in C6 glial cell lines. Neurochem Res 2014; 40:41-8. [PMID: 25347962 DOI: 10.1007/s11064-014-1463-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 10/15/2014] [Accepted: 10/23/2014] [Indexed: 11/28/2022]
Abstract
Previous evidences indicate that androgen is neuroprotective in the brain. However, the underling mechanisms remain to be fully elucidated. Moreover, it is controversial whether dihydrotestosterone (DHT) modulates the expression of apoptosis-related effectors, such as survivin, XIAP, bax, and bcl-xl proteins mediated by the PI3-K/Akt pathway, which contributes to androgen neuroprotection. In this study using a C6 glial cell model, apoptotic cells were detected by flow cytometry. Akt, seladin-1, survivin, XIAP, bcl-xl, and bax protein expression is investigated by Western blot. After amyloid β-protein fragment (Aβ25-35) treatment, apoptotic cells at early (annexin V+, PI-) and late (annexin V+, PI+) stages were significantly increased. Apoptosis at early and late was obviously inhibited in the presence of DHT. The effect of DHT was markedly blocked by PI3-K inhibitor LY294002.To elicit the mechanism of DHT protection, the expression of seladin-1, survivin, XIAP, bax, and bcl-xl protein was determined in C6 cells treated with Aβ25-35, DHT, or LY294002. Aβ25-35 significantly downregulated the expression of seladin-1, survivin, XIAP, bcl-xl protein and upregulated the expression of bax protein. DHT significantly inhibited the expression of bax, seladin-1, survivin, XIAP, and bcl-xl protein induced by Aβ25-35. Further, we found the effect of DHT was significantly inhibited by LY294002. Collectively, in a C6 glial cell model, we firstly found that DHT inhibits Aβ25-35-induced apoptosis by a rapid nongenic PI-3K/Akt activation as well as regulation of seladin-1, survivin, XIAP, bcl-xl, and bax proteins.
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Affiliation(s)
- Lelin Bing
- Department of Neurology, Jinshan Hospital Affiliated to Fudan University, No. 1508 Longhang Road, Jinshan District, Shanghai, 201508, China
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Wu YC, Du X, van den Buuse M, Hill RA. Sex differences in the adolescent developmental trajectory of parvalbumin interneurons in the hippocampus: a role for estradiol. Psychoneuroendocrinology 2014; 45:167-78. [PMID: 24845187 DOI: 10.1016/j.psyneuen.2014.03.016] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Revised: 03/25/2014] [Accepted: 03/27/2014] [Indexed: 11/18/2022]
Abstract
OBJECTIVE Gender differences in the neurodevelopmental disorder, schizophrenia, have been described for nearly all features of the illness. Reduced hippocampal expression of the GABAergic interneuron marker, parvalbumin (PV), and GABA synthesizing enzyme, GAD67, are consistently reported in schizophrenia. However, little is known of the expression patterns of hippocampal PV and GAD67 during adolescence and their interaction with sex steroid hormones during adolescent development. This study examined the effects of altered sex steroid hormone levels during adolescence on protein levels of PV, GAD67 and estrogen receptors (ERα/β) in the hippocampus of mice. METHODS Protein expression of PV and GAD67 was measured in the dorsal (DHP) and ventral (VHP) hippocampus of female and male C57Bl/6 mice by Western blot in a week by week analysis from pre-pubescence to adulthood (week 3-12). Fluorescent immunohistochemistry (IHC) was used to investigate the relationship between ERs and PV(+) cells in the hippocampus of female mice at young adulthood (week 10-11). To further examine the role of sex steroid hormones on PV and GAD67 expression, gonadectomy and hormone replacement was done at 5 weeks of age. RESULTS Female mice showed a significant gradual increase in PV expression from 3 to 12 weeks of age in the DHP and VHP which correlated with serum 17β-estradiol levels. Fluorescent IHC showed approximately 30-50% co-localization of ER-α in PV(+) cells in the female DHP and VHP (dentate gryus/hilus and CA1-CA3). Adolescent ovariectomy significantly reduced PV expression in the DHP but not VHP of female mice, while 17β-estradiol replacement prevented this deficit in DHP PV levels. ER-α expression, but not ER-β, was also reduced in the DHP following ovariectomy with no significant effect of 17β-estradiol replacement. In contrast to female mice, male mice did not show any significant changes in hippocampal PV/GAD67 expression throughout adolescent development. Furthermore, adolescent castration and treatment with testosterone or dihydrotestosterone produced no changes in PV/GAD67 expression. CONCLUSIONS Our data suggest a differential developmental trajectory of PV expression between the sexes and manipulating circulating levels of sex steroid hormones by ovariectomy alters this trajectory in a region-dependent manner. This may be mediated via ER-α signaling as this receptor was found to be co-localized with PV(+) cells in the female mouse hippocampus. Alternative mechanisms of 17β-estradiol-induced regulation of PV expression are also discussed herein. Together, results from the present study may offer more insight into neurodevelopmental disorders, including schizophrenia, where sex steroid hormones and GABAergic markers are implicated in the pathophysiology of the illness.
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Affiliation(s)
- YeeWen Candace Wu
- Behavioural Neuroscience Laboratory, Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Australia; Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia
| | - Xin Du
- Behavioural Neuroscience Laboratory, Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Australia
| | - Maarten van den Buuse
- Behavioural Neuroscience Laboratory, Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Australia; Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia; School of Psychological Science, La Trobe University, Melbourne, Australia
| | - Rachel A Hill
- Behavioural Neuroscience Laboratory, Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Australia.
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Calabrese D, Giatti S, Romano S, Porretta-Serapiglia C, Bianchi R, Milanese M, Bonanno G, Caruso D, Viviani B, Gardoni F, Garcia-Segura LM, Melcangi RC. Diabetic neuropathic pain: a role for testosterone metabolites. J Endocrinol 2014; 221:1-13. [PMID: 24424289 DOI: 10.1530/joe-13-0541] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Diabetic neuropathy is associated with neuropathic pain in about 50% of diabetic subjects. Clinical management of neuropathic pain is complex and so far unsatisfactory. In this study, we analyzed the effects of the testosterone metabolites, dihydrotestosterone (DHT), and 3α-diol, on nociceptive and allodynia thresholds and on molecular and functional parameters related to pain modulation in the dorsal horns of the spinal cord and in the dorsal root ganglia of rats rendered diabetic by streptozotocin injection. Furthermore, the levels of DHT and 3α-diol were analyzed in the spinal cord. Diabetes resulted in a significant decrease in DHT levels in the spinal cord that was reverted by DHT or 3α-diol treatments. In addition, 3α-diol treatment resulted in a significant increase in 3α-diol in the spinal cord compared with control values. Both steroids showed analgesic properties on diabetic neuropathic pain, affecting different pain parameters and possibly by different mechanisms of action. Indeed, DHT counteracted the effect of diabetes on the mechanical nociceptive threshold, pre- and post-synaptic components, glutamate release, astrocyte immunoreactivity, and expression of interleukin-1β (IL1β), while 3α-diol was effective on tactile allodynia threshold, glutamate release, astrocyte immunoreactivity and the expression of substance P, toll-like receptor 4, tumor necrosis factor-α, transforming growth factor β-1, IL1β, and translocator protein. These results indicate that testosterone metabolites are potential agents for the treatment of diabetic neuropathic pain.
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Affiliation(s)
- Donato Calabrese
- Section of Biomedicine and Endocrinology, Department of Pharmacological and Biomolecular Sciences, Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy Neuromuscular Disease Unit, IRCCS 'Carlo Besta' Neurological Institute, Milan, Italy Department of Pharmacy and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy Instituto Cajal, C.S.I.C., Madrid, Spain
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Handa RJ, Weiser MJ. Gonadal steroid hormones and the hypothalamo-pituitary-adrenal axis. Front Neuroendocrinol 2014; 35:197-220. [PMID: 24246855 PMCID: PMC5802971 DOI: 10.1016/j.yfrne.2013.11.001] [Citation(s) in RCA: 308] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2013] [Revised: 10/04/2013] [Accepted: 11/07/2013] [Indexed: 12/17/2022]
Abstract
The hypothalamo-pituitary-adrenal (HPA) axis represents a complex neuroendocrine feedback loop controlling the secretion of adrenal glucocorticoid hormones. Central to its function is the paraventricular nucleus of the hypothalamus (PVN) where neurons expressing corticotropin releasing factor reside. These HPA motor neurons are a primary site of integration leading to graded endocrine responses to physical and psychological stressors. An important regulatory factor that must be considered, prior to generating an appropriate response is the animal's reproductive status. Thus, PVN neurons express androgen and estrogen receptors and receive input from sites that also express these receptors. Consequently, changes in reproduction and gonadal steroid levels modulate the stress response and this underlies sex differences in HPA axis function. This review examines the make up of the HPA axis and hypothalamo-pituitary-gonadal (HPG) axis and the interactions between the two that should be considered when exploring normal and pathological responses to environmental stressors.
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Affiliation(s)
- Robert J Handa
- Department of Basic Medical Science, The University of Arizona College of Medicine, Phoenix, AZ 85004, United States.
| | - Michael J Weiser
- DSM Nutritional Products Ltd., R&D Human Nutrition and Health, Boulder, CO 80301, United States
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Quillinan N, Deng G, Grewal H, Herson PS. Androgens and stroke: good, bad or indifferent? Exp Neurol 2014; 259:10-5. [PMID: 24512750 DOI: 10.1016/j.expneurol.2014.02.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 01/28/2014] [Accepted: 02/02/2014] [Indexed: 12/16/2022]
Abstract
Cerebral ischemia caused by loss of blood supply to the brain during cardiac arrest or stroke are major causes of death and disability. Biological sex is an important factor in predicting vulnerability of the brain to an ischemic insult, with males being at higher risk for cardio-cerebrovascular events than females of the same age. However, relative incidence of stroke between the genders appears to normalize at advanced ages. Therefore, many scientists have focused on the mechanisms of sex differences in outcome following brain ischemic injury, with a particular emphasis on the role of sex steroids. The majority of studies indicate that female sex steroids, such as estrogen and progesterone, play important roles in the relative neuroprotection following cerebral ischemia observed in females. However, less is known about male sex steroids and brain damage. This review describes the state of our knowledge of androgen-related contributions to neurological injury and recovery following cerebral ischemia that occurs following stroke. Experimental studies examining the effects of castration, androgenic agonists and antagonists and aging provide valuable insights into the role of androgens in clinical outcome following cerebrovascular events.
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Affiliation(s)
- Nidia Quillinan
- Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, 12800 E. 19th Ave., Aurora, CO 80045, USA
| | - Guiying Deng
- Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, 12800 E. 19th Ave., Aurora, CO 80045, USA
| | - Himmat Grewal
- Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, 12800 E. 19th Ave., Aurora, CO 80045, USA
| | - Paco S Herson
- Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, 12800 E. 19th Ave., Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, 12800 E. 19th Ave., Aurora, CO 80045, USA.
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Elkabes S, Nicot AB. Sex steroids and neuroprotection in spinal cord injury: a review of preclinical investigations. Exp Neurol 2014; 259:28-37. [PMID: 24440641 DOI: 10.1016/j.expneurol.2014.01.008] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 12/25/2013] [Accepted: 01/04/2014] [Indexed: 11/30/2022]
Abstract
Spinal cord injury (SCI) is a debilitating condition that affects motor, sensory and autonomic functions. Subsequent to the first mechanical trauma, secondary events, which include inflammation and glial activation, exacerbate tissue damage and worsen functional deficits. Although these secondary injury mechanisms are amenable to therapeutic interventions, the efficacy of current approaches is inadequate. Further investigations are necessary to implement new therapies that can protect neural cells and attenuate some of the detrimental effects of inflammation while promoting regeneration. Studies on different animal models of SCI indicated that sex steroids, especially 17β-estradiol and progesterone, exert neuroprotective, anti-apoptotic and anti-inflammatory effects, ameliorate tissue sparing and improve functional deficits in SCI. As sex steroid receptors are expressed in a variety of cells including neurons, glia and immune system-related cells which infiltrate the injury epicenter, sex steroids could impact multiple processes simultaneously and in doing so, influence the outcomes of SCI. However, the translation of these pre-clinical findings into the clinical setting presents challenges such as the narrow therapeutic time window of sex steroid administration, the diversity of treatment regimens that have been employed in animal studies and the lack of sufficient information regarding the persistence of the effects in chronic SCI. The current review will summarize some of the major findings in this field and will discuss the challenges associated with the implementation of sex steroids as a promising treatment in human SCI.
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Affiliation(s)
- Stella Elkabes
- The Reynolds Family Spine Laboratory, Department of Neurological Surgery, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
| | - Arnaud B Nicot
- UMR 1064, INSERM, Nantes, France; Faculté de Médecine, Université de Nantes, France; ITUN, CHU de Nantes, France
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Holmes S, Abbassi B, Su C, Singh M, Cunningham RL. Oxidative stress defines the neuroprotective or neurotoxic properties of androgens in immortalized female rat dopaminergic neuronal cells. Endocrinology 2013; 154:4281-92. [PMID: 23959938 PMCID: PMC3800758 DOI: 10.1210/en.2013-1242] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Males have a higher risk for developing Parkinson's disease and parkinsonism after ischemic stroke than females. Although estrogens have been shown to play a neuroprotective role in Parkinson's disease, there is little information on androgens' actions on dopamine neurons. In this study, we examined the effects of androgens under conditions of oxidative stress to determine whether androgens play a neuroprotective or neurotoxic role in dopamine neuronal function. Mitochondrial function, cell viability, intracellular calcium levels, and mitochondrial calcium influx were examined in response to androgens under both nonoxidative and oxidative stress conditions. Briefly, N27 dopaminergic cells were exposed to the oxidative stressor, hydrogen peroxide, and physiologically relevant levels of testosterone or dihydrotestosterone, applied either before or after oxidative stress exposure. Androgens, alone, increased mitochondrial function via a calcium-dependent mechanism. Androgen pretreatment protected cells from oxidative stress-induced cell death. However, treatment with androgens after the oxidative insult increased cell death, and these effects were, in part, mediated by calcium influx into the mitochondria. Interestingly, the negative effects of androgens were not blocked by either androgen or estrogen receptor antagonists. Instead, a putative membrane-associated androgen receptor was implicated. Overall, our results indicate that androgens are neuroprotective when oxidative stress levels are minimal, but when oxidative stress levels are elevated, androgens exacerbate oxidative stress damage.
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Affiliation(s)
- Shaletha Holmes
- PhD, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3400 Camp Bowie Boulevard, Fort Worth, Texas 76107-2699.
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Liu X, Busby J, John C, Wei J, Yuan X, Lu ML. Direct interaction between AR and PAK6 in androgen-stimulated PAK6 activation. PLoS One 2013; 8:e77367. [PMID: 24130878 PMCID: PMC3795072 DOI: 10.1371/journal.pone.0077367] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2013] [Accepted: 09/02/2013] [Indexed: 01/14/2023] Open
Abstract
A p21-activated kinase 6 (PAK6) was previously identified to be an androgen receptor (AR) interacting protein through a yeast two-hybrid screening. We used hormone responsive prostate cancer LAPC4 and LNCap cell lines as models to study the signaling events associated with androgen stimulation and PAK6. An androgen-stimulated PAK6 kinase activation was observed in LAPC4 cells expressing endogenous PAK6 and in LNCap cells ectopically expressing a wild type PAK6. This activation was likely mediated through a direct interaction between AR and PAK6 since siRNA knock-down of AR in LAPC4 cells downregulated androgen-stimulated PAK6 activation. In addition, LNCap cells expressing a non-AR-interacting PAK6 mutant exhibited dampened androgen-stimulated kinase activation. As a consequence of androgen-stimulated activation, PAK6 was phosphorylated at multiple serine/threonine residues including the AR-interacting domain of PAK6. Furthermore, androgen-stimulation promoted prostate cancer cell motility and invasion were demonstrated in LNCap cells ectopically expressing PAK6-WT. In contrast, LNCap expressing non-AR-interacting mutant PAK6 did not respond to androgen stimulation with increased cell motility and invasion. Our results demonstrate that androgen-stimulated PAK6 activation is mediated through a direct interaction between AR and PAK6 and PAK6 activation promotes prostate cancer cells motility and invasion.
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Affiliation(s)
- Xia Liu
- Urologic Research, Brigham and Women's Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Jennifer Busby
- Department of Molecular Therapeutics, Scripps South Florida, Jupiter, Florida, United States of America
| | - Ciny John
- Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida, United States of America
| | - Jianning Wei
- Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida, United States of America
| | - Xin Yuan
- Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Michael L. Lu
- Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida, United States of America
- * E-mail:
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Lang F, Alevizopoulos K, Stournaras C. Targeting membrane androgen receptors in tumors. Expert Opin Ther Targets 2013; 17:951-63. [PMID: 23746222 DOI: 10.1517/14728222.2013.806491] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION In the last decade androgen actions that are originated from non-genomic, rapid signaling have been described in a large number of cell models and tissues. These effects are initiated through the stimulation of membrane androgen-binding sites or receptors (mAR). Although the molecular identity of mARs remains elusive, their activation is known to trigger multiple non-genomic signaling cascades and to regulate numerous cell responses. In recent years specific interest is being paid to the role of mARs in tumors. Specifically, it was demonstrated that mAR activation by non-permeable testosterone conjugates induced potent anti-tumorigenic responses in prostate, breast, colon and glial tumors. In addition, in vivo animal studies further emphasized the potential clinical importance of these receptors. AREAS COVERED This review will summarize the current knowledge on the mAR-induced non-genomic, rapid androgen actions. It will focus on the molecular signaling pathways governed by mAR activation, discuss latest attempts to elucidate the molecular identity of mAR, address the plethora of cell responses initiated by mAR and evaluate the potential role of mAR and mAR-specific signaling as possible therapeutic targets in tumors. EXPERT OPINION mAR and mAR-induced specific signaling may represent novel therapeutic targets in tumors through the development of specific testosterone analogs.
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Affiliation(s)
- Florian Lang
- University of Tübingen, Department of Physiology, Gmelin Str. 5, Tübingen, 72076, Germany
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Zuo W, Zhang W, Chen NH. Sexual dimorphism in cerebral ischemia injury. Eur J Pharmacol 2013; 711:73-9. [PMID: 23652162 DOI: 10.1016/j.ejphar.2013.04.024] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2013] [Revised: 04/24/2013] [Accepted: 04/26/2013] [Indexed: 12/19/2022]
Abstract
Stroke is a leading cause of permanent disability and death. A complex series of biochemical and molecular mechanisms (e.g. the release of ROS/NOS, proapoptotic proteins and proinflammatory cytokine; neuronal depolarization, Ca2+ accumulation and so on) impair the neurologic functions of cerebral ischemia and stroke. We have known for some time that the epidemiology of human stroke is sexually dimorphic until late in life, well beyond the years of reproductive senescence and menopause. The principal mammalian estrogen (17β estradiol or E2) is neuroprotective in many types of brain injury and has been the major focus of investigation over the past several decades. However the incidence of stroke in women is lower than in men until decades past menopause, suggesting that factors beyond sex hormone contribute to these epidemiological sex differences. So a new concept is emerging: both sex steroids and biologic sex are important factors in clinical and experimental strokes. In this review, we will address sex steroids and gender differences in influencing the mechanisms and outcomes of brain ischemia stroke. These sex differences need to be identified which could help future translation to human neuroprotection.
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Affiliation(s)
- Wei Zuo
- Key Laboratory of Bioactive Substances and Resources Utilization, Ministry of Education, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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Wilson ME. Stroke: understanding the differences between males and females. Pflugers Arch 2013; 465:595-600. [PMID: 23503729 DOI: 10.1007/s00424-013-1260-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Revised: 03/01/2013] [Accepted: 03/01/2013] [Indexed: 01/09/2023]
Abstract
Stroke is a significant cause of death and long-term disability in the USA. The incidence, mortality, and outcomes of stroke are significantly different between men and women. As with many diseases that affect men and women differently, an understanding on the reasons underlying those differences is critical to effective diagnosis and treatment. This review will examine the sex differences in stroke in both humans and animal models of stroke and review what is known about potential mechanisms underlying these differences. It is clear that there is a complex interaction between hormonal, genetic, and unknown factors at play in generating the sex differences in stroke.
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Affiliation(s)
- Melinda E Wilson
- Department of Physiology, University of Kentucky, MS508 800 Rose St., Lexington, KY 40536, USA.
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Jung S, Verdicchio M, Kiefer J, Von Hoff D, Berens M, Bittner M, Kim S. Learning contextual gene set interaction networks of cancer with condition specificity. BMC Genomics 2013; 14:110. [PMID: 23418942 PMCID: PMC3644282 DOI: 10.1186/1471-2164-14-110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Accepted: 01/29/2013] [Indexed: 12/01/2022] Open
Abstract
Background Identifying similarities and differences in the molecular constitutions of various types of cancer is one of the key challenges in cancer research. The appearances of a cancer depend on complex molecular interactions, including gene regulatory networks and gene-environment interactions. This complexity makes it challenging to decipher the molecular origin of the cancer. In recent years, many studies reported methods to uncover heterogeneous depictions of complex cancers, which are often categorized into different subtypes. The challenge is to identify diverse molecular contexts within a cancer, to relate them to different subtypes, and to learn underlying molecular interactions specific to molecular contexts so that we can recommend context-specific treatment to patients. Results In this study, we describe a novel method to discern molecular interactions specific to certain molecular contexts. Unlike conventional approaches to build modular networks of individual genes, our focus is to identify cancer-generic and subtype-specific interactions between contextual gene sets, of which each gene set share coherent transcriptional patterns across a subset of samples, termed contextual gene set. We then apply a novel formulation for quantitating the effect of the samples from each subtype on the calculated strength of interactions observed. Two cancer data sets were analyzed to support the validity of condition-specificity of identified interactions. When compared to an existing approach, the proposed method was much more sensitive in identifying condition-specific interactions even in heterogeneous data set. The results also revealed that network components specific to different types of cancer are related to different biological functions than cancer-generic network components. We found not only the results that are consistent with previous studies, but also new hypotheses on the biological mechanisms specific to certain cancer types that warrant further investigations. Conclusions The analysis on the contextual gene sets and characterization of networks of interaction composed of these sets discovered distinct functional differences underlying various types of cancer. The results show that our method successfully reveals many subtype-specific regions in the identified maps of biological contexts, which well represent biological functions that can be connected to specific subtypes.
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Affiliation(s)
- Sungwon Jung
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona, USA
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Vest RS, Pike CJ. Gender, sex steroid hormones, and Alzheimer's disease. Horm Behav 2013; 63:301-7. [PMID: 22554955 PMCID: PMC3413783 DOI: 10.1016/j.yhbeh.2012.04.006] [Citation(s) in RCA: 164] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2012] [Revised: 03/24/2012] [Accepted: 04/11/2012] [Indexed: 02/07/2023]
Abstract
Age-related loss of sex steroid hormones is a established risk factor for the development of Alzheimer's disease (AD) in women and men. While the relationships between the sex steroid hormones and AD are not fully understood, findings from both human and experimental paradigms indicate that depletion of estrogens in women and androgens in men increases vulnerability of the aging brain to AD pathogenesis. We review evidence of a wide range of beneficial neural actions of sex steroid hormones that may contribute to their hypothesized protective roles against AD. Both estrogens and androgens exert general neuroprotective actions relevant to a several neurodegenerative conditions, some in a sex-specific manner, including protection from neuron death and promotion of select aspects of neural plasticity. In addition, estrogens and androgens regulate key processes implicated in AD pathogenesis, in particular the accumulation of β-amyloid protein. We discuss evidence of hormone-specific mechanisms related to the regulation of the production and clearance of β-amyloid as critical protective pathways. Continued elucidation of these pathways promises to yield effective hormone-based strategies to delay development of AD.
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Affiliation(s)
- Rebekah S Vest
- USC Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
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Flutamide Enhances Neuroprotective Effects of Testosterone during Experimental Cerebral Ischemia in Male Rats. ISRN NEUROLOGY 2012; 2013:592398. [PMID: 23401794 PMCID: PMC3562684 DOI: 10.1155/2013/592398] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2012] [Accepted: 12/18/2012] [Indexed: 12/30/2022]
Abstract
Testosterone has been shown to worsen histological and neurological impairment during cerebral ischemia in animal models. Cell culture studies revealed that testosterone is implicated in protecting neural and glial cells against insults, and they started to elucidate testosterone pathways that underlie these protective effects. These studies support the hypothesis that testosterone can be neuroprotective throughout an episode of cerebral ischemia. Therefore, we evaluated the mechanisms underlying the shift between testosterone protective and deleterious effects via block testosterone aromatization and androgen receptors in rats subjected to 60-minute middle cerebral artery occlusion. Fifty rats were divided into five equal groups: gonadally intact male; castrated male; intact male + flutamide; intact male + letrozole; intact male + combination flutamide and letrozole. Our results indicated that castration has the ability to reduce histological damage and to improve neurological score 24 hours after middle cerebral artery occlusion. Moreover, flutamide improved histologic and neurological impairment better than castration. Letrozole induced increases in striatal infarct volume and seizures in gonadally intact rats. Combination of flutamide and letrozole showed that letrozole can reverse beneficial effects of flutamide. In conclusion, it seems that the beneficial effects of flutamide are the prevention of the deleterious effects and enhancement of neuroprotective effects of testosterone during cerebral ischemia.
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Johnson RT, Schneider A, DonCarlos LL, Breedlove SM, Jordan CL. Astrocytes in the rat medial amygdala are responsive to adult androgens. J Comp Neurol 2012; 520:2531-44. [PMID: 22581688 PMCID: PMC4209966 DOI: 10.1002/cne.23061] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The posterodorsal medial amygdala (MePD) exhibits numerous sex differences including differences in volume and in the number and morphology of neurons and astroctyes. In adulthood, gonadal hormones, including both androgens and estrogens, have been shown to play a role in maintaining the masculine character of many of these sex differences, but whether adult gonadal hormones maintain the increased number and complexity of astrocytes in the male MePD was unknown. To answer this question we examined astrocytes in the MePD of male and female Long Evans rats that were gonadectomized as adults and treated for 30 days with either testosterone or a control treatment. At the end of treatment brains were collected and immunostained for glial fibrillary acidic protein. Stereological analysis revealed that adult androgen levels influenced the number and complexity of astrocytes in the MePD of both sexes, but the specific effects of androgens were different in males and females. However, sex differences in the number and complexity of adult astrocytes persisted even in the absence of gonadal hormones in adulthood, suggesting that androgens also act earlier in life to determine these adult sex differences. Using immunofluorescence and confocal microscopy, we found robust androgen receptor immunostaining in a subpopulation of MePD astrocytes, suggesting that testosterone may act directly on MePD astrocytes to influence their structure and function.
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Affiliation(s)
- Ryan T Johnson
- Neuroscience Program, Michigan State University, East Lansing, Michigan 48824-1101, USA.
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45
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Schindler M, Fabre C, de Weille J, Carreau S, Mersel M, Bakalara N. Disruption of nongenomic testosterone signaling in a model of spinal and bulbar muscular atrophy. Mol Endocrinol 2012; 26:1102-16. [PMID: 22570336 DOI: 10.1210/me.2011-1367] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
As one of the nine hereditary neurodegenerative polyQ disorders, spinal and bulbar muscular atrophy (SBMA) results from a polyQ tract expansion in androgen receptor (AR). Although protein aggregates are the pathological hallmark of many neurodegenerative diseases, their direct role in the neurodegeneration is more and more questioned. To determine the early molecular mechanisms causing motor neuron degeneration in SBMA, we established an in vitro system based on the tetracycline-inducible expression of normal (AR20Q), the mutated, 51 glutamine-extended (AR51Q), or polyQ-deleted (AR0Q) AR in NSC34, a motor neuron-like cell line lacking endogenous AR. Although no intracellular aggregates were formed, the expression of the AR51Q leads to a loss of function characterized by reduced neurite outgrowth and to a toxic gain of function resulting in decreased cell viability. In this study, we show that both AR20Q and AR51Q are recruited to lipid rafts in response to testosterone stimulation. However, whereas testosterone induces the activation of the c-jun N-terminal kinase/c-jun pathway via membrane-associated AR20Q, it does not so in NSC34 expressing AR51Q. Phosphorylation of c-jun N-terminal kinase plays a crucial role in AR20Q-dependent survival and differentiation of NSC34. Moreover, c-jun protein levels decrease more slowly in AR20Q- than in AR51Q-expressing NSC34 cells. This is due to a rapid and transient inhibition of glycogen synthase kinase 3α occurring in a phosphatidylinositol 3-kinase-independent manner. Our results demonstrate that the deregulation of nongenomic AR signaling may be involved in SBMA establishment, opening new therapeutic perspectives.
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Affiliation(s)
- Mathilde Schindler
- Institut des Neurosciences de Montpellier, Institut National de la Santé et de la Recherche Médicale Unité 1051, 34295 Montpellier, France
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Zu H, Wu J, Zhang J, Yu M, Hong Z. Testosterone up-regulates seladin-1 expression by iAR and PI3-K/Akt signaling pathway in C6 cells. Neurosci Lett 2012; 514:122-6. [PMID: 22405892 DOI: 10.1016/j.neulet.2012.02.072] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Revised: 02/11/2012] [Accepted: 02/14/2012] [Indexed: 11/25/2022]
Abstract
The previous study indicated that DHCR24/seladin-1 was an important neuroprotective effector. However, the molecular mechanisms that androgen modulates the expression of seladin-1 remain incompletely defined. In this paper, we showed that the expression of seladin-1 was significantly increased by testosterone at all concentrations tested at the protein and mRNA levels in C6 cells, the selective AR antagonist flutamide obviously inhibited the effect in a concentration-dependent manner. Furthermore, we found that testosterone significantly increased the phosphorylation level of V-akt murine thymoma viral oncogene (Akt), a key effector of the phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway, while a specific PI3-K inhibitor LY294002 obviously prevented the activation of Akt phosphorylation. In addition, the PI3-K inhibitor LY294002 also markedly blocked the up-regulation expression of seladin-1 gene induced by testosterone at the protein and mRNA levels. Collectively, the above results suggested that testosterone regulated the expression of seladin-1 by the intracellular androgen receptor (iAR)-mediated genomic signaling pathway and the non-genomic PI3-K/Akt signaling pathway in C6 glial cells.
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Affiliation(s)
- Hengbing Zu
- Department of Neurology, Jinshan Hospital Affiliated to Fudan University, Shanghai 200540, China.
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Cunningham RL, Lumia AR, McGinnis MY. Androgen receptors, sex behavior, and aggression. Neuroendocrinology 2012; 96:131-40. [PMID: 22414851 PMCID: PMC3474193 DOI: 10.1159/000337663] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2011] [Accepted: 02/28/2012] [Indexed: 11/19/2022]
Abstract
Androgens are intricately involved in reproductive and aggressive behaviors, but the role of the androgen receptor in mediating these behaviors is less defined. Further, activity of the hypothalamic-pituitary-gonadal axis and hypothalamic-pituitary-adrenal axis can influence each other at the level of the androgen receptor. Knowledge of the mechanisms for androgens' effects on behaviors through the androgen receptor will guide future studies in elucidating male reproductive and aggressive behavior repertoires.
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Affiliation(s)
- Rebecca L Cunningham
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Centre at Fort Worth, Fort Worth, TX 76107, USA.
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Alabarse PV, Salomon TB, Medeiros TM, Hackenhaar FS, Schüller AK, Ehrenbrink G, Benfato MS. Oxidative stress in the kidney of reproductive male rats during aging. Exp Gerontol 2011; 46:773-80. [DOI: 10.1016/j.exger.2011.05.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2010] [Revised: 04/06/2011] [Accepted: 05/12/2011] [Indexed: 01/05/2023]
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Dziennis S, Akiyoshi K, Subramanian S, Offner H, Hurn PD. Role of dihydrotestosterone in post-stroke peripheral immunosuppression after cerebral ischemia. Brain Behav Immun 2011; 25:685-95. [PMID: 21262338 PMCID: PMC3081425 DOI: 10.1016/j.bbi.2011.01.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Revised: 01/04/2011] [Accepted: 01/16/2011] [Indexed: 12/15/2022] Open
Abstract
Stroke is a sexually dimorphic disease with male gender considered a disadvantage in terms of risk and disease outcome. In intact males, stroke induces peripheral immunosuppression, characterized by decreased splenocyte numbers and proliferation and altered percentages of viable T, B, and CD11b+ cells. To investigate whether the potent androgen and known immunomodulator, dihydrotestosterone (DHT), exacerbates post-stroke immunosuppression in castrated male mice after focal stroke, we evaluated the effect of middle cerebral artery occlusion (MCAO) on peripheral and central nervous system (CNS) immune responses in castrated mice with or without controlled levels of DHT. MCAO reduced spleen cell numbers in both groups, but altered T cell and B cell percentages in remaining splenocytes and concomitantly increased the percentage of CD11b+ blood cells solely in DHT-replaced animals at 24 h. Furthermore, DHT-replacement reduced splenocyte proliferation which was accompanied by an increased percentage of immunosuppressive regulatory T cells relative to castrates 96 h post-MCAO. In brain, the percentages of immune cell populations in the ischemic hemisphere relative to the non-ischemic hemisphere were similar between castrated and DHT-replaced mice after MCAO. These data suggest DHT modulates peripheral immunosuppression after MCAO but with relatively little effect on early immune response of the recovering CNS.
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Affiliation(s)
- Suzan Dziennis
- Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, 97123
| | - Kozaburo Akiyoshi
- Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, 97123
| | - Sandhya Subramanian
- Neuroimmunology Research, Veterans Affairs Medical Center; Portland, Oregon, 97239
| | - Halina Offner
- Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, 97123, Department of Neurology, Oregon Health & Science University, Portland, OR, 97123, Neuroimmunology Research, Veterans Affairs Medical Center; Portland, Oregon, 97239
| | - Patricia D. Hurn
- Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, 97123
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50
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Alabarse PVG, Hackenhaar FS, Medeiros TM, Mendes MFA, Viacava PR, Schüller ÁK, Salomon TB, Ehrenbrink G, Benfato MS. Oxidative stress in the brain of reproductive male rats during aging. Exp Gerontol 2011; 46:241-8. [DOI: 10.1016/j.exger.2010.10.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 08/26/2010] [Accepted: 10/13/2010] [Indexed: 12/31/2022]
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