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Yuan S, Guo J, Yang B, Huang AX, Hu S, Li Y, Chen J, Yuan B, Yang J. Liquiritigenin protects against cadmium-induced testis damage in mice by inhibiting apoptosis and activating androgen receptor. Biochem Biophys Res Commun 2025; 759:151642. [PMID: 40138758 DOI: 10.1016/j.bbrc.2025.151642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 02/23/2025] [Accepted: 03/14/2025] [Indexed: 03/29/2025]
Abstract
Cadmium (Cd) is a prevalent contaminant in both dietary and drinking water sources, posing harm to multiple tissues and disrupting reproductive function. Recent evidence indicates that natural products derived from plants may offer a mitigating Cd-induced tissue damage. However, the protective role of Liquiritigenin (LQ) and its underlying mechanism remain unclear. The present study was to investigate the protective effect of LQ against short-term, low-dose Cd-induced multi-organ damage. Notably, Cd exposure had no significant impact on body or tissue weight but did induce damage to the heart, liver, lungs, kidneys and testes of mice, while also reducing sperm quality. These adverse effects were reversed by LQ treatment, suggesting that LQ alleviates Cd toxicity. Mechanistically, LQ inhibited testicular apoptosis by modulating the protein levels of Bad, Caspase-3, Bax, Bcl-2, and NF-κB. Furthermore, molecular docking and molecular dynamics simulations provided insights into the interaction between LQ and the androgen receptor (AR). Further studies indicate that LQ increases AR level and further prevent testicular damage. Collectively, these findings support the potential of LQ in preventing Cd-induced tissue damage, particularly in the context of reproductive toxicity.
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Affiliation(s)
- Siyu Yuan
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, People's Republic of China
| | - Jun Guo
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, People's Republic of China
| | - Bijun Yang
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, People's Republic of China
| | - Aolin Xiao Huang
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, People's Republic of China
| | - Shuqi Hu
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, People's Republic of China
| | - Yingcan Li
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, People's Republic of China
| | - Jingxuan Chen
- The Xiyuan Campus of Hefei No. 50 East Middle School, Hefei, Anhui, 230031, People's Republic of China
| | - Bin Yuan
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, People's Republic of China.
| | - Jing Yang
- Experimental Teaching Center for Preventive Medicine, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, People's Republic of China.
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2
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Yao M, Rosario ER, Soper JC, Pike CJ. Androgens Regulate Tau Phosphorylation Through Phosphatidylinositol 3-Kinase-Protein Kinase B-Glycogen Synthase Kinase 3β Signaling. Neuroscience 2025; 568:503-518. [PMID: 35777535 PMCID: PMC9797620 DOI: 10.1016/j.neuroscience.2022.06.034] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/11/2022] [Accepted: 06/23/2022] [Indexed: 12/31/2022]
Abstract
Age-related testosterone depletion in men is a risk factor for Alzheimer's disease (AD). How testosterone modulates AD risk remains to be fully elucidated, although regulation of tau phosphorylation has been suggested as a contributing protective action. To investigate the relationship between testosterone and tau phosphorylation, we first evaluated the effect of androgen status on tau phosphorylation in 3xTg-AD mice. Depletion of endogenous androgens via gonadectomy resulted in increased tau phosphorylation that was prevented by acute testosterone treatment. Parallel alterations in the phosphorylation of both glycogen synthase kinase 3β (GSK3β) and protein kinase B (Akt) suggest possible components of the underlying signaling pathway. To further explore mechanism, primary cultured neurons were treated with a physiological concentration of testosterone or its active metabolite dihydrotestosterone (DHT). Results showed that testosterone and DHT induced significant decreases in phosphorylated tau and significant increases in phosphorylation of Akt and GSK3β. Pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K) effectively inhibited androgen-induced increases in Akt and GSK3β phosphorylation, and decreases in tau phosphorylation. In addition, androgen receptor (AR) knock-down by small interfering RNA prevented androgen-induced changes in the phosphorylation of Akt, GSK3β and tau, suggesting an AR-dependent mechanism. Additional experiments demonstrated androgen-induced changes in Akt, GSK3β and tau phosphorylation in AR-expressing PC12 cells but not in AR-negative PC12 cells. Together, these results suggest an AR-dependent pathway involving PI3K-Akt-GSK3β signaling through which androgens can reduce tau phosphorylation. These findings identify an additional protective mechanism of androgens that can improve neural health and inhibit development of AD.
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Affiliation(s)
- Mingzhong Yao
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
| | - Emily R Rosario
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
| | - Jenna Carroll Soper
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
| | - Christian J Pike
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
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Plumb AN, Lesnak JB, Rasmussen L, Sluka KA. Female specific interactions of serotonin and testosterone in the rostral ventromedial medulla after activity-induced muscle pain. THE JOURNAL OF PAIN 2025; 26:104723. [PMID: 39522853 DOI: 10.1016/j.jpain.2024.104723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 10/03/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024]
Abstract
Classical preclinical studies show that serotonin (5-HT) injected into the rostral ventromedial medulla (RVM) produces analgesia that is blocked by 5-HT2 receptor antagonists. One key modulator of 5-HT activity is the serotonin transporter (SERT) which reduces serotonergic signaling through reuptake into the presynaptic terminal. In the activity-induced muscle pain model, females show widespread pain and increased SERT expression in the RVM whereas males show localized pain and no changes in SERT expression. Since prior studies show testosterone protects from the development of widespread pain, and females have widespread pain in the activity-induced pain model, we hypothesized that testosterone modulates serotonin signaling to enhance analgesia in female mice with widespread pain. We showed that testosterone reduced the enhanced SERT protein expression and increased 5-HT2A receptor mRNA expression in the RVM normally observed in the activity-induced pain model in females, but not males. Inhibition of SERT in the RVM was analgesic in both female and male mice; this analgesia was blocked by co-administration of 5-HT2A antagonist. Next, using in situ hybridization, we demonstrated co-expression of SERT, 5-HT2A receptor, and androgen receptor mRNA in cells within the RVM in female mice. Lastly, activation of androgen receptors using dihydrotestosterone reduced hyperalgesia in female mice. These data therefore show for the first time expression of androgen receptors in the RVM in female mice, that activation of androgen receptors reduces nociceptive behaviors, and endogenous testosterone modulates SERT and 5-HT2 receptor expression. Thus, we show a sex-specific role for how testosterone modulates analgesia in mice. PERSPECTIVE: This article presents novel mechanisms testosterone's protection against muscle pain in female mice showing modulation of the serotonin system in the rostral ventromedial medulla. Understanding the relationship between testosterone and serotonin could lead to better treatment of individuals with muscle pain.
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Affiliation(s)
- Ashley N Plumb
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA 52242, USA
| | - Joseph B Lesnak
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA 52242, USA
| | - Lynn Rasmussen
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA 52242, USA
| | - Kathleen A Sluka
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA 52242, USA; Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA 52242, USA.
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4
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Peng J, Li Q, Liu L, Gao P, Xing L, Chen L, Liu H, Liu Z. Exploring the material basis and molecular targets of Changma Xifeng tablet in treating Tourette syndrome: an integrative approach of network pharmacology and miRNA analysis. Metab Brain Dis 2024; 39:1573-1590. [PMID: 39436634 DOI: 10.1007/s11011-024-01408-6] [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: 04/15/2024] [Accepted: 08/05/2024] [Indexed: 10/23/2024]
Abstract
This study was to investigate the mechanism of Changma Xifeng tablet, a traditional Chinese medicine in the treatment of Tourette syndrome. Network pharmacology was utilized to pinpoint blood-entering constituents of Changma Xifeng and explore their potential targets. Additionally, differential microRNA expression analysis was conducted to predict Tourette syndrome-associated targets, complemented by molecular docking and dynamics simulations to support the interactions of the active compounds with these targets. The study identified 98 common targets between Changma Xifeng and Tourette syndrome, which may be involved in the treatment process. A protein-protein interaction network and a drug-active ingredient-disease target network highlighted the formulation's multi-component, multi-target therapeutic approach. Eight pivotal targets-AR, GRM5, MET, RORA, HTR2A, CNR1, PDE4B, and TOP1-were identified at the intersection of microRNA and drug targets. Molecular docking revealed 12 complexes with favorable binding energies below - 7 kcal/mol, specifically: AR with Alfacalcidol, TOP1 with Albiflorin, GRM5 with Arachidic Acid, GRM5 with Palmitic Acid, AR with Arachidic Acid, AR with 2-Hydroxyoctadecanoic Acid, RORA with Pinellic Acid, RORA with Palmitic Acid, AR with Acoronene, AR with Epiacoronene, AR with 4,4'-Methylenediphenol, and HTR2A with Calycosin. Our molecular docking and molecular dynamics simulations suggest potential stable interactions between the formulation's active components and target proteins. These computational methods provide a preliminary theoretical framework that will guide our future experimental work. The study provides a scientific rationale for the use of traditional Chinese medicine in Tourette syndrome management and offers new insights for drug development.
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Affiliation(s)
- Jing Peng
- Department of Pharmacy, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 100 Xianggang Road, Jiang'an District, Wuhan, Hubei, 430016, China.
| | - Qiaoling Li
- Department of Pharmacy, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 100 Xianggang Road, Jiang'an District, Wuhan, Hubei, 430016, China
| | - Linhui Liu
- Department of Pharmacy, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 100 Xianggang Road, Jiang'an District, Wuhan, Hubei, 430016, China
| | - Ping Gao
- Department of Pharmacy, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 100 Xianggang Road, Jiang'an District, Wuhan, Hubei, 430016, China
| | - Lipeng Xing
- Department of Pharmacy, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 100 Xianggang Road, Jiang'an District, Wuhan, Hubei, 430016, China
| | - Li Chen
- Department of Pharmacy, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 100 Xianggang Road, Jiang'an District, Wuhan, Hubei, 430016, China
| | - Hui Liu
- Department of Pharmacy, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 100 Xianggang Road, Jiang'an District, Wuhan, Hubei, 430016, China
| | - Zhisheng Liu
- Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Hoyt KR, Horning P, Georgette Ang P, Karelina K, Obrietan K. Ribosomal S6 kinase signaling regulates neuronal viability during development and confers resistance to excitotoxic cell death in mature neurons. Neuroscience 2024; 558:1-10. [PMID: 39137868 DOI: 10.1016/j.neuroscience.2024.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 08/08/2024] [Indexed: 08/15/2024]
Abstract
The Ribosomal S6 Kinase (RSK) family of serine/threonine kinases function as key downstream effectors of the MAPK signaling cascade. In the nervous system, RSK signaling plays crucial roles in neuronal development and contributes to activity-dependent neuronal plasticity. This study examined the role of RSK signaling in cell viability during neuronal development and in neuroprotection in the mature nervous system. Using neuronal cell-culture-based profiling, we found that suppressing RSK signaling led to significant cell death in developing primary neuronal cultures. To this end, treatment with the RSK inhibitors BiD1870 or SL0101 on the first day of culturing resulted in over 80% cell death. In contrast, more mature cultures showed attenuated cell death upon RSK inhibition. Inhibition of RSK signaling during early neuronal development also disrupted neurite outgrowth and cell growth. In maturing hippocampal explant cultures, treatment with BiD1870 had minimal effects on cell viability, but led to a striking augmentation of NMDA-induced cell death. Finally, we used the endothelin 1 (ET-1) model of ischemia to examine the neuroprotective effects of RSK signaling in the mature hippocampus in vivo. Notably, in the absence of RSK inhibition, the granule cell layer (GCL) was resistant to the effects of ET-1; However, disruption of RSK signaling (via the microinjection of BiD1870) prior to ET-1 injection triggered cell death within the GCL, thus indicating a neuroprotective role for RSK signaling in the mature nervous system. Together these data reveal distinct, developmentally-defined, roles for RSK signaling in the nervous system.
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Affiliation(s)
- Kari R Hoyt
- Division of Pharmaceutics and Pharmacology, Ohio State University, Columbus, OH, USA.
| | - Paul Horning
- Department of Neuroscience, Ohio State University, Columbus, OH, USA; Division of Pharmaceutics and Pharmacology, Ohio State University, Columbus, OH, USA
| | - Pia Georgette Ang
- Division of Pharmaceutics and Pharmacology, Ohio State University, Columbus, OH, USA
| | - Kate Karelina
- Department of Neuroscience, Ohio State University, Columbus, OH, USA
| | - Karl Obrietan
- Department of Neuroscience, Ohio State University, Columbus, OH, USA.
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Safi R, Wardell SE, Watkinson P, Qin X, Lee M, Park S, Krebs T, Dolan EL, Blattler A, Tsuji T, Nayak S, Khater M, Fontanillo C, Newlin MA, Kirkland ML, Xie Y, Long H, Fink EC, Fanning SW, Runyon S, Brown M, Xu S, Owzar K, Norris JD, McDonnell DP. Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells. Nat Commun 2024; 15:7675. [PMID: 39227594 PMCID: PMC11371910 DOI: 10.1038/s41467-024-52032-y] [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: 11/04/2023] [Accepted: 08/23/2024] [Indexed: 09/05/2024] Open
Abstract
Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the goal of current therapeutic approaches to treat prostate cancer (PCa). Paradoxically, high dose androgens also exhibit considerable efficacy as a treatment modality in patients with late-stage metastatic PCa. Here we show that low levels of androgens, functioning through an AR monomer, facilitate a non-genomic activation of the mTOR signaling pathway to drive proliferation. Conversely, high dose androgens facilitate the formation of AR dimers/oligomers to suppress c-MYC expression, inhibit proliferation and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR action in PCa and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies.
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Affiliation(s)
- Rachid Safi
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Suzanne E Wardell
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Paige Watkinson
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Xiaodi Qin
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
| | - Marissa Lee
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
| | - Sunghee Park
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Taylor Krebs
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Emma L Dolan
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Adam Blattler
- Oncogenesis Thematic Research Center, Bristol Myers Squibb, San Diego, CA, USA
| | - Toshiya Tsuji
- Oncogenesis Thematic Research Center, Bristol Myers Squibb, San Diego, CA, USA
| | - Surendra Nayak
- Oncogenesis Thematic Research Center, Bristol Myers Squibb, San Diego, CA, USA
| | - Marwa Khater
- Informatics and Predictive Sciences, Bristol Myers Squibb, San Diego, CA, USA
| | - Celia Fontanillo
- Informatics and Predictive Sciences, Bristol Myers Squibb, San Diego, CA, USA
| | - Madeline A Newlin
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Megan L Kirkland
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | | | - Henry Long
- Dana-Farber Cancer Institute, Boston, MA, USA
| | - Emma C Fink
- Department of Cancer Biology, Loyola University, Maywood, IL, USA
| | - Sean W Fanning
- Department of Cancer Biology, Loyola University, Maywood, IL, USA
| | - Scott Runyon
- RTI International, Research Triangle Park, NC, USA
| | - Myles Brown
- Dana-Farber Cancer Institute, Boston, MA, USA
| | - Shuichan Xu
- Oncogenesis Thematic Research Center, Bristol Myers Squibb, San Diego, CA, USA
| | - Kouros Owzar
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA
| | - John D Norris
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Donald P McDonnell
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
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Zacanti K, Park I, McNabb BR, Urbano TM, Maga EA, Nitta-Oda BJ, Rowe JD, Hennig SL, Ross P, Berger T. Gender disparity in survival of early porcine fetuses due to altered androgen receptor or associated U2 spliceosome component. Sci Rep 2023; 13:15072. [PMID: 37699945 PMCID: PMC10497509 DOI: 10.1038/s41598-023-41665-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 08/29/2023] [Indexed: 09/14/2023] Open
Abstract
A single locus on the X chromosome codes for androgen receptor (AR) although this gene is subject to alternative splicing. AR is expressed in multiple tissues in males and females and is essential for reproductive success in the male. Since male and female mice are viable following naturally occurring and engineered loss of function with male mice infertile as anticipated, functional deletion of AR in pigs was hypothesized to provide a genetic containment strategy for males with edited genomes. In addition, deletion of AR might be a method to manage boar taint, hence contributing to a perceived improvement in animal welfare. The CRISPR/Cas9 technology was used to edit either exon 2 or exon 5 of the pig AR gene. Although pregnancies were established following embryo transfer of edited embryos, they were not maintained beyond day 25. Furthermore, normal M:F sex ratios were present in edited blastocysts and 19-day fetuses, but all fetuses recovered on day 21 or later were female. The pig AR gene differs from the mouse in having a U2 spliceosome component encoded in the intronic region. Hence, the absence of fetal survival beyond day 25 may be due to interference with the U2 component rather than AR.
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Affiliation(s)
- Kelly Zacanti
- Department of Animal Science, University of California Davis, Davis, CA, USA
| | - Insung Park
- Department of Animal Science, University of California Davis, Davis, CA, USA
| | - Bret R McNabb
- Department of Population Health and Reproduction, University of California Davis, Davis, CA, USA
| | - Tara Marie Urbano
- Department of Population Health and Reproduction, University of California Davis, Davis, CA, USA
| | - Elizabeth A Maga
- Department of Animal Science, University of California Davis, Davis, CA, USA
| | | | - Joan D Rowe
- Department of Population Health and Reproduction, University of California Davis, Davis, CA, USA
| | - Sadie L Hennig
- Department of Animal Science, University of California Davis, Davis, CA, USA
| | - Pablo Ross
- Department of Animal Science, University of California Davis, Davis, CA, USA
| | - Trish Berger
- Department of Animal Science, University of California Davis, Davis, CA, USA.
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Dong B, Lu Y, He S, Li B, Li Y, Lai Q, Li W, Ji S, Chen Y, Dai L, Chen L. Multisite and multitimepoint proteomics reveal that patent foramen ovale closure improves migraine and epilepsy by reducing right-to-left shunt-induced hypoxia. MedComm (Beijing) 2023; 4:e334. [PMID: 37576864 PMCID: PMC10422075 DOI: 10.1002/mco2.334] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 03/02/2023] [Accepted: 03/12/2023] [Indexed: 08/15/2023] Open
Abstract
Patent foramen ovale (PFO) is a congenital defect in the partition between two atria, which may cause right-to-left shunt (RLS), leading to neurological chronic diseases with episodic manifestations (NCDEMs), such as migraine and epilepsy. However, whether PFO closure was effective in improving NCDEMs and the mechanism were unclear. Twenty-eight patients with migraine or epilepsy who underwent PFO closure were recruited. Notably, approximately half of patients received 50% or more reduction in seizure or headache attacks. Meanwhile, the postoperative blood oxygen partial pressure and oxygen saturation were elevated after PFO closure. Multisite (peripheral, right, and left atrial) and multitimepoint (before and after surgery) plasma proteomics from patients showed that the levels of free hemoglobin and cell adhesion molecules (CAMs) were significantly increased after PFO closure, which may be related to the relief of the hypoxic state. Furtherly, the omics data from multiple brain regions of mice revealed that a large number of proteins were differentially expressed in the occipital region in response to PFO, including redox molecules and CAMs, suggesting PFO-caused hypoxia may have great impacts on occipital region. Collectively, PFO may cause NCDEMs due to RLS-induced hypoxia, and PFO closure could prevent RLS to improve migraine and epilepsy.
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Affiliation(s)
- Bosi Dong
- Department of NeurologyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Ying Lu
- State Key Laboratory of BiotherapyNational Clinical Research Center for Geriatrics and Department of General PracticeWest China HospitalSichuan Universityand Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Siyu He
- State Key Laboratory of BiotherapyNational Clinical Research Center for Geriatrics and Department of General PracticeWest China HospitalSichuan Universityand Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Baichuan Li
- Department of NeurologyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Yajiao Li
- Department of CardiologyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Qi Lai
- Department of NeurologyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Wanling Li
- Department of NeurologyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Shuming Ji
- Department of Clinical Research ManagementWest China HospitalSichuan UniversityChengduSichuanChina
| | - Yucheng Chen
- Department of CardiologyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Lunzhi Dai
- State Key Laboratory of BiotherapyNational Clinical Research Center for Geriatrics and Department of General PracticeWest China HospitalSichuan Universityand Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Lei Chen
- Department of NeurologyWest China HospitalSichuan UniversityChengduSichuanChina
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9
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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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10
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Tan B, Yaşar A, Boz F, Dursun N, Süer C. Sex-related differences in somatic plasticity and possible role of ERK1/2: An in-vivo study of young-adult rats. Physiol Behav 2022; 255:113939. [PMID: 35961608 DOI: 10.1016/j.physbeh.2022.113939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 07/29/2022] [Accepted: 08/08/2022] [Indexed: 11/19/2022]
Abstract
The present study investigates sex differences in hippocampal functions in the context of synaptic plasticity, which is the cellular basis of learning and memory, and differences in the mitogen-activated protein kinase (MAPK) pathway that accompanies plasticity in young-adult rats. The long-term potentiation (LTP) and long-term depression (LTD) were induced by stimulating the perforant pathway (PP) and field potentials composed of the field excitatory post-synaptic potential (fEPSP) and population spike (PS) were recorded from the dentate gyrus (DG). Following the completion of the electrophysiological recordings, the hippocampi were removed bilaterally, and the protein and gene expression levels of the extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and P38-MAPK were determined by Western blot analysis and real-time PCR, respectively. No significant difference was found in synaptic and neuronal function before (basal) and after high-frequency stimulation between male and female rats. Nevertheless, female, but not male, rats were able to express long term depression at the PP - DG synapses, suggesting that sex differences in plasticity are stimulation paradigm specific. MAPK1 expression was higher in males and MAPK3 expression was higher in females, but these differences disappeared after induction of plasticity in both sexes. While the expression of MAPK8 is influenced by sex, independent of the induction of plasticity, MAPK14 expression was down regulated by plasticity induction in females, but not males. No effect of sex, HFS and LFS on total and phosphorylated levels of MAPKs was found except phosphorylated ERK1/2. Phosphorylation of ERK1/2 was up regulated after LFS in male rats but did not change in female rats. These findings indicate that LFS-induced plasticity is differentially modulated between sexes, probably as a result of increased activation of ERK1/2 in male rats.
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Affiliation(s)
- Burak Tan
- Faculty of Medicine, Department of Physiology, Erciyes University, Kayseri, Turkey.
| | - Aslınur Yaşar
- Faculty of Medicine, Department of Physiology, Erciyes University, Kayseri, Turkey.
| | - Fatma Boz
- Faculty of Medicine, Department of Physiology, Erciyes University, Kayseri, Turkey.
| | - Nurcan Dursun
- Faculty of Medicine, Department of Physiology, Erciyes University, Kayseri, Turkey.
| | - Cem Süer
- Faculty of Medicine, Department of Physiology, Erciyes University, Kayseri, Turkey.
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11
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Saleki K, Banazadeh M, Saghazadeh A, Rezaei N. Aging, testosterone, and neuroplasticity: friend or foe? Rev Neurosci 2022; 34:247-273. [PMID: 36017670 DOI: 10.1515/revneuro-2022-0033] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 07/03/2022] [Indexed: 11/15/2022]
Abstract
Neuroplasticity or neural plasticity implicates the adaptive potential of the brain in response to extrinsic and intrinsic stimuli. The concept has been utilized in different contexts such as injury and neurological disease. Neuroplasticity mechanisms have been classified into neuroregenerative and function-restoring processes. In the context of injury, neuroplasticity has been defined in three post-injury epochs. Testosterone plays a key yet double-edged role in the regulation of several neuroplasticity alterations. Research has shown that testosterone levels are affected by numerous factors such as age, stress, surgical procedures on gonads, and pharmacological treatments. There is an ongoing debate for testosterone replacement therapy (TRT) in aging men; however, TRT is more useful in young individuals with testosterone deficit and more specific subgroups with cognitive dysfunction. Therefore, it is important to pay early attention to testosterone profile and precisely uncover its harms and benefits. In the present review, we discuss the influence of environmental factors, aging, and gender on testosterone-associated alterations in neuroplasticity, as well as the two-sided actions of testosterone in the nervous system. Finally, we provide practical insights for further study of pharmacological treatments for hormonal disorders focusing on restoring neuroplasticity.
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Affiliation(s)
- Kiarash Saleki
- Student Research Committee, Babol University of Medical Sciences, 47176 47745 Babol, Iran.,USERN Office, Babol University of Medical Sciences, 47176 47745 Babol, Iran.,Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), 14197 33151 Tehran, Iran
| | - Mohammad Banazadeh
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), 14197 33151 Tehran, Iran.,Pharmaceutical Sciences and Cosmetic Products Research Center, Kerman University of Medical Sciences, 76169 13555 Kerman, Iran
| | - Amene Saghazadeh
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), 14197 33151 Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, 14197 33151 Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, 14197 33151 Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 14176 13151 Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 14197 33151 Tehran, Iran
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12
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Bispo JMM, Melo JEC, Gois AM, Medeiros KAAL, Silva RS, Leal PC, Franco HS, Souza MF, Lins LCRF, Ribeiro AM, Silva RH, Santos JR. Testosterone propionate improves motor alterations and dopaminergic damage in the reserpine-induced progressive model of Parkinson's disease. Brain Res Bull 2022; 187:162-168. [PMID: 35781030 DOI: 10.1016/j.brainresbull.2022.06.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/27/2022] [Accepted: 06/29/2022] [Indexed: 11/16/2022]
Abstract
Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder with a higher susceptibility to occur in men. Studies suggest that this susceptibility is related to the hormonal differences observed between men and women, being a risk factor for PD. In addition, testosterone supplementation has shown controversial results in animal models of PD and parkinsonian patients. This study evaluated the effect of chronic administration of testosterone propionate (TP) on motor behavior and neurochemical parameters in the reserpine-induced rat model of parkinsonism. Male Wistar rats received 15 injections of reserpine (RES - 0.1 mg/kg) every other day and were concomitantly treated with different doses (0.1, 1.0, or 5.0 mg/kg) of daily TP for 30 days. The rats were euthanized 48 h after the 15th injection of RES or vehicle. Brains were removed and subjected to Tyrosine hydroxylase (TH) immunohistochemistry. TP at 1.0 mg/kg reduced the damages caused by reserpine in the vacuous chewing and tong protrusion behaviors and prevented dopaminergic damage in the SNpc, VTA, and Striatum. TP at 5.0 mg/kg reduced the damages caused by reserpine in the catalepsy and tong protrusion behaviors, prevented the weight loss, and prevented dopaminergic damage in the VTA. Our results suggest that chronic administration of TP has a protective effect in a rat model of parkinsonism, improving motor alterations and dopamine depletion induced by RES.
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Affiliation(s)
- José M M Bispo
- Behavioral and Evolutionary Neurobiology Laboratory, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil.
| | - João E C Melo
- Behavioral and Evolutionary Neurobiology Laboratory, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil.
| | - Auderlan M Gois
- Behavioral and Evolutionary Neurobiology Laboratory, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil.
| | - Katty A A L Medeiros
- Behavioral and Evolutionary Neurobiology Laboratory, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil.
| | - Rodolfo Santos Silva
- Behavioral and Evolutionary Neurobiology Laboratory, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil.
| | - Pollyana C Leal
- Behavioral and Evolutionary Neurobiology Laboratory, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil; Graduate Program in Dentistry / Federal University of Sergipe, Aracaju, SE, Brazil.
| | - Heitor S Franco
- Behavioral and Evolutionary Neurobiology Laboratory, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil.
| | - Marina F Souza
- Behavioral and Evolutionary Neurobiology Laboratory, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil.
| | - Lívia C R F Lins
- Department of Physiology, Federal University of Sergipe, São Cristóvão, SE, Brazil.
| | | | - Regina H Silva
- Department of Pharmacology, Federal University of São Paulo, São Paulo, SP, Brazil.
| | - José R Santos
- Behavioral and Evolutionary Neurobiology Laboratory, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil.
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13
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Magyar BP, Santi M, Sommer G, Nuoffer JM, Leichtle A, Grössl M, Flück CE. Short-term fasting attenuates overall steroid hormone biosynthesis in healthy young women. J Endocr Soc 2022; 6:bvac075. [PMID: 35668998 PMCID: PMC9154271 DOI: 10.1210/jendso/bvac075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Indexed: 11/19/2022] Open
Abstract
Context Fasting is stressful for the human body. It is managed by metabolic adaptations maintaining energy homeostasis and involves steroid hormone biosynthesis, but the exact interplay between energy and steroid metabolism remains elusive. Women with polycystic ovary syndrome (PCOS) suffer from disturbed metabolism and androgen excess, while in women with anorexia nervosa, cortisol and androgen production are decreased. By contrast, starvation of steroidogenic cells shifts adrenal steroid biosynthesis toward enhanced androgen production. Aim This study investigated the effect of fasting on steroid production in healthy women. Methods Twenty healthy young women fasted for 48 hours; steroid profiles from plasma and urine samples were assessed at baseline, after 24 hours, and 48 hours by liquid and gas chromatography–mass spectrometry. Results Fasting did not change overall steroidogenesis, although it increased progestogen production and lowered relative mineralocorticoid, glucocorticoid, and androgen production. The largest decrease in urine metabolites was seen for β-cortol, dehydroepiandrosterone, and androstenediol; higher levels were found for pregnanediol in urine and progesterone and aldosterone in serum. Activity of 17α-hydroxylase/17,20-lyase (CYP17A1), essential for androgen biosynthesis, was decreased after fasting in healthy women as were 21-hydroxylase (CYP21A2) and 5α-reductase activities. By contrast, hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) activity for cortisol inactivation seemed to increase with fasting. Conclusion Significant changes in steroid metabolism occurred after 48 hours of fasting in healthy women. In contrast to metabolic changes seen at baseline in PCOS women compared to healthy women, and after starving of steroidogenic cells, no androgen excess was observed after short-term fasting in healthy young women.
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Affiliation(s)
- Benjamin P Magyar
- Pediatric Endocrinology, Diabetology and Metabolism, Bern University Children’s Hospital, University of Bern, Bern, Switzerland
| | - Maristella Santi
- Pediatric Endocrinology, Diabetology and Metabolism, Bern University Children’s Hospital, University of Bern, Bern, Switzerland
| | - Grit Sommer
- Pediatric Endocrinology, Diabetology and Metabolism, Bern University Children’s Hospital, University of Bern, Bern, Switzerland
- Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Jean-Marc Nuoffer
- Pediatric Endocrinology, Diabetology and Metabolism, Bern University Children’s Hospital, University of Bern, Bern, Switzerland
- Department of Biomedical Research, University of Bern, Bern, Switzerland
- University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Alexander Leichtle
- University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
- Insel Data Science Center (IDSC), Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Michael Grössl
- Department of Biomedical Research, University of Bern, Bern, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Christa E Flück
- Pediatric Endocrinology, Diabetology and Metabolism, Bern University Children’s Hospital, University of Bern, Bern, Switzerland
- Department of Biomedical Research, University of Bern, Bern, Switzerland
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14
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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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15
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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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16
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Bjørnebekk A, Kaufmann T, Hauger LE, Klonteig S, Hullstein IR, Westlye LT. Long-term Anabolic-Androgenic Steroid Use Is Associated With Deviant Brain Aging. BIOLOGICAL PSYCHIATRY. COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2021; 6:579-589. [PMID: 33811018 DOI: 10.1016/j.bpsc.2021.01.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/02/2020] [Accepted: 01/04/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND High-dose long-term use of anabolic-androgenic steroids (AASs) may cause a range of adverse effects, including brain and cognitive abnormalities. We performed age prediction based on brain scans to test whether prolonged AAS use is associated with accentuated brain aging. METHODS T1-weighted magnetic resonance imaging (3D MPRAGE [magnetization-prepared rapid acquisition gradient-echo]) scans were obtained from male weightlifters with a history of prolonged AAS use (n = 130) or no AAS use (n = 99). We trained machine learning models on combinations of regional brain volumes, cortical thickness, and surface area in an independent training set of 1838 healthy male subjects (18-92 years of age) and predicted brain age for each participant in our study. Including cross-sectional and longitudinal (mean interval = 3.5 years, n = 76) magnetic resonance imaging data, we used linear mixed-effects models to compare the gap between chronological age and predicted brain age (the brain age gap [BAG]) for the two groups and tested for group differences in the rate of change in BAG. We tested for associations between apparent brain aging and AAS use duration, pattern of administration, and dependence. RESULTS AAS users had higher BAG compared with weightlifting control subjects, which was associated with dependency and longer history of use. Group differences in BAG could not be explained by other substance use, general cognitive abilities, or depression. While longitudinal analysis revealed no evidence of increased brain aging in the overall AAS group, accelerated brain aging was seen with longer AAS exposure. CONCLUSIONS The findings suggest that long-term high-dose AAS use may have adverse effects on brain aging, potentially linked to dependency and exaggerated use of AASs.
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Affiliation(s)
- Astrid Bjørnebekk
- Anabolic Androgenic Steroid Research Group, Section for Clinical Addiction Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
| | - Tobias Kaufmann
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
| | - Lisa E Hauger
- Anabolic Androgenic Steroid Research Group, Section for Clinical Addiction Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Sandra Klonteig
- Anabolic Androgenic Steroid Research Group, Section for Clinical Addiction Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Ingunn R Hullstein
- Norwegian Doping Control Laboratory, Oslo University Hospital, Oslo, Norway
| | - Lars T Westlye
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway; K.G. Jebsen Center for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway
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17
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Kövesdi E, Szabó-Meleg E, Abrahám IM. The Role of Estradiol in Traumatic Brain Injury: Mechanism and Treatment Potential. Int J Mol Sci 2020; 22:E11. [PMID: 33374952 PMCID: PMC7792596 DOI: 10.3390/ijms22010011] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/15/2020] [Accepted: 12/18/2020] [Indexed: 01/02/2023] Open
Abstract
Patients surviving traumatic brain injury (TBI) face numerous neurological and neuropsychological problems significantly affecting their quality of life. Extensive studies over the past decades have investigated pharmacological treatment options in different animal models, targeting various pathological consequences of TBI. Sex and gender are known to influence the outcome of TBI in animal models and in patients, respectively. Apart from its well-known effects on reproduction, 17β-estradiol (E2) has a neuroprotective role in brain injury. Hence, in this review, we focus on the effect of E2 in TBI in humans and animals. First, we discuss the clinical classification and pathomechanism of TBI, the research in animal models, and the neuroprotective role of E2. Based on the results of animal studies and clinical trials, we discuss possible E2 targets from early to late events in the pathomechanism of TBI, including neuroinflammation and possible disturbances of the endocrine system. Finally, the potential relevance of selective estrogenic compounds in the treatment of TBI will be discussed.
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Affiliation(s)
- Erzsébet Kövesdi
- Molecular Neuroendocrinology Research Group, Institute of Physiology, Medical School, Center for Neuroscience, Szentágothai Research Center, University of Pécs, H-7624 Pecs, Hungary;
| | - Edina Szabó-Meleg
- Department of Biophysics, Medical School, University of Pécs, H-7624 Pecs, Hungary;
| | - István M. Abrahám
- Molecular Neuroendocrinology Research Group, Institute of Physiology, Medical School, Center for Neuroscience, Szentágothai Research Center, University of Pécs, H-7624 Pecs, Hungary;
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18
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Abstract
The testosterone decline is one of the potential causes of oxidative stress-induced anxiety and depressive behaviors, and cognitive impairment induces irreversible neuronal damage, which is not clearly understood. The orchidectomized rat model was used; the hippocampal neurons and anxiety behavior were analyzed. Adult male albino rats were divided into control and orchidectomy (ORX) groups, orchidectomy (ORX + T), and normal (Cont + T) groups. Testosterone propionate was used as a testosterone supplement. The anxiety and depressive-like behavior observed in ORX animals in the open field (OF) and elevated plus-maze experiments were effectively overturned in the ORX + T group. Studies on isolated hippocampus showed reduced antioxidant enzymes (SOD, CAT, and glutathione (GSH) compounds), increased lipid peroxidation (LPO), elevated caspase3, and reduced anti-apoptotic protein Bcl-2, and increased apoptotic nuclei in TUNEL staining of the hippocampus in the ORX rats. These observations indicate free radical-mediated neural damage. Testosterone presence promoted the antioxidant defense system and restored normal pyramidal neuron morphology in ORX + T. This study confirms that testosterone is indispensable in the normal adult hippocampus and deficiency seems to be a potential risk factor for neurodegenerative disorders. Besides, androgen appears to be a possible therapeutic strategy for treating depression/neurodegenerative diseases in aging men.
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Affiliation(s)
- Sakthi Jothi Muthu
- Department of Anatomy, Dr. Arcot Lakshmanasamy Mudaliar Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India
| | - Prakash Seppan
- Department of Anatomy, Dr. Arcot Lakshmanasamy Mudaliar Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India
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19
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Bianchi VE, Rizzi L, Bresciani E, Omeljaniuk RJ, Torsello A. Androgen Therapy in Neurodegenerative Diseases. J Endocr Soc 2020; 4:bvaa120. [PMID: 33094209 PMCID: PMC7568521 DOI: 10.1210/jendso/bvaa120] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 08/18/2020] [Indexed: 12/14/2022] Open
Abstract
Neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington disease, are characterized by the loss of neurons as well as neuronal function in multiple regions of the central and peripheral nervous systems. Several studies in animal models have shown that androgens have neuroprotective effects in the brain and stimulate axonal regeneration. The presence of neuronal androgen receptors in the peripheral and central nervous system suggests that androgen therapy might be useful in the treatment of neurodegenerative diseases. To illustrate, androgen therapy reduced inflammation, amyloid-β deposition, and cognitive impairment in patients with AD. As well, improvements in remyelination in MS have been reported; by comparison, only variable results are observed in androgen treatment of PD. In ALS, androgen administration stimulated motoneuron recovery from progressive damage and regenerated both axons and dendrites. Only a few clinical studies are available in human individuals despite the safety and low cost of androgen therapy. Clinical evaluations of the effects of androgen therapy on these devastating diseases using large populations of patients are strongly needed.
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Affiliation(s)
- Vittorio Emanuele Bianchi
- Department of Endocrinology and Metabolism, Clinical Center Stella Maris, Strada Rovereta, Falciano, San Marino
| | - Laura Rizzi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Elena Bresciani
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | | | - Antonio Torsello
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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20
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Forebrain Transcriptional Response to Transient Changes in Circulating Androgens in a Cichlid Fish. G3-GENES GENOMES GENETICS 2020; 10:1971-1982. [PMID: 32276961 PMCID: PMC7263668 DOI: 10.1534/g3.119.400947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
It has been hypothesized that androgens respond to the social interactions as a way to adjust the behavior of individuals to the challenges of the social environment in an adaptive manner. Therefore, it is expected that transient changes in circulating androgen levels within physiological scope should impact the state of the brain network that regulates social behavior, which should translate into adaptive behavioral changes. Here, we examined the effect that a transient peak in androgen circulating levels, which mimics socially driven changes in androgen levels, has on the forebrain state, which harbors most nuclei of the social decision-making network. For this purpose, we successfully induced transient changes in circulating androgen levels in an African cichlid fish (Mozambique tilapia, Oreochromis mossambicus) commonly used as a model in behavioral neuroendocrinology by injecting 11-ketotestosterone or testosterone, and compared the forebrain transcriptome of these individuals to control fish injected with vehicle. Forebrain samples were collected 30 min and 60 min after injection and analyzed using RNAseq. Our results showed that a transient peak in 11-ketotestosterone drives more accentuated changes in forebrain transcriptome than testosterone, and that transcriptomic impact was greater at the 30 min than at the 60 min post-androgen administration. Several genes involved in the regulation of translation, steroid metabolism, ion channel membrane receptors, and genes involved in epigenetic mechanisms were differentially expressed after 11-ketotestosterone or testosterone injection. In summary, this study identified specific candidate genes that may regulate socially driven changes in behavioral flexibility mediated by androgens.
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21
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Vegeto E, Villa A, Della Torre S, Crippa V, Rusmini P, Cristofani R, Galbiati M, Maggi A, Poletti A. The Role of Sex and Sex Hormones in Neurodegenerative Diseases. Endocr Rev 2020; 41:5572525. [PMID: 31544208 PMCID: PMC7156855 DOI: 10.1210/endrev/bnz005] [Citation(s) in RCA: 134] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 09/20/2019] [Indexed: 12/11/2022]
Abstract
Neurodegenerative diseases (NDs) are a wide class of disorders of the central nervous system (CNS) with unknown etiology. Several factors were hypothesized to be involved in the pathogenesis of these diseases, including genetic and environmental factors. Many of these diseases show a sex prevalence and sex steroids were shown to have a role in the progression of specific forms of neurodegeneration. Estrogens were reported to be neuroprotective through their action on cognate nuclear and membrane receptors, while adverse effects of male hormones have been described on neuronal cells, although some data also suggest neuroprotective activities. The response of the CNS to sex steroids is a complex and integrated process that depends on (i) the type and amount of the cognate steroid receptor and (ii) the target cell type-either neurons, glia, or microglia. Moreover, the levels of sex steroids in the CNS fluctuate due to gonadal activities and to local metabolism and synthesis. Importantly, biochemical processes involved in the pathogenesis of NDs are increasingly being recognized as different between the two sexes and as influenced by sex steroids. The aim of this review is to present current state-of-the-art understanding on the potential role of sex steroids and their receptors on the onset and progression of major neurodegenerative disorders, namely, Alzheimer's disease, Parkinson's diseases, amyotrophic lateral sclerosis, and the peculiar motoneuron disease spinal and bulbar muscular atrophy, in which hormonal therapy is potentially useful as disease modifier.
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Affiliation(s)
- Elisabetta Vegeto
- Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.,Dipartimento di Scienze Farmaceutiche (DiSFarm), Università degli Studi di Milano, Italy
| | - Alessandro Villa
- Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.,Dipartimento di Scienze della Salute (DiSS), Università degli Studi di Milano, Italy
| | - Sara Della Torre
- Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.,Dipartimento di Scienze Farmaceutiche (DiSFarm), Università degli Studi di Milano, Italy
| | - Valeria Crippa
- Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.,Dipartimento di Eccellenza di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, Italy
| | - Paola Rusmini
- Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.,Dipartimento di Eccellenza di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, Italy
| | - Riccardo Cristofani
- Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.,Dipartimento di Eccellenza di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, Italy
| | - Mariarita Galbiati
- Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.,Dipartimento di Eccellenza di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, Italy
| | - Adriana Maggi
- Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.,Dipartimento di Scienze Farmaceutiche (DiSFarm), Università degli Studi di Milano, Italy
| | - Angelo Poletti
- Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.,Dipartimento di Eccellenza di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, Italy
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22
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Spritzer MD, Roy EA. Testosterone and Adult Neurogenesis. Biomolecules 2020; 10:biom10020225. [PMID: 32028656 PMCID: PMC7072323 DOI: 10.3390/biom10020225] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/22/2020] [Accepted: 01/28/2020] [Indexed: 12/16/2022] Open
Abstract
It is now well established that neurogenesis occurs throughout adulthood in select brain regions, but the functional significance of adult neurogenesis remains unclear. There is considerable evidence that steroid hormones modulate various stages of adult neurogenesis, and this review provides a focused summary of the effects of testosterone on adult neurogenesis. Initial evidence came from field studies with birds and wild rodent populations. Subsequent experiments with laboratory rodents have tested the effects of testosterone and its steroid metabolites upon adult neurogenesis, as well as the functional consequences of induced changes in neurogenesis. These experiments have provided clear evidence that testosterone increases adult neurogenesis within the dentate gyrus region of the hippocampus through an androgen-dependent pathway. Most evidence indicates that androgens selectively enhance the survival of newly generated neurons, while having little effect on cell proliferation. Whether this is a result of androgens acting directly on receptors of new neurons remains unclear, and indirect routes involving brain-derived neurotrophic factor (BDNF) and glucocorticoids may be involved. In vitro experiments suggest that testosterone has broad-ranging neuroprotective effects, which will be briefly reviewed. A better understanding of the effects of testosterone upon adult neurogenesis could shed light on neurological diseases that show sex differences.
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Affiliation(s)
- Mark D. Spritzer
- Department of Biology, Middlebury College, Middlebury, VT 05753, USA
- Correspondence: ; Tel.: 802-443-5676
| | - Ethan A. Roy
- Graduate School of Education, Stanford University, Stanford, CA 94305, USA;
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23
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Lei Y, Renyuan Z. Effects of Androgens on the Amyloid-β Protein in Alzheimer's Disease. Endocrinology 2018; 159:3885-3894. [PMID: 30215697 DOI: 10.1210/en.2018-00660] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Accepted: 09/06/2018] [Indexed: 12/24/2022]
Abstract
Age-related androgen depletion has been implicated in compromised neuroprotection and is involved in the pathogenesis of neurodegenerative disease, including Alzheimer's disease (AD), the leading cause of dementia. Emerging data revealed that reduction of both serum and brain androgen levels in males is associated with increased amyloid-β (Aβ) accumulation, a putative cause of AD. It has been demonstrated that androgens can function as the endogenous negative regulators of Aβ. However, the mechanisms by which androgens regulate Aβ production, degradation, and clearance, as well as the Aβ-induced pathological process in AD, are still elusive. This review emphasizes the contributions of androgen to Aβ metabolism and toxicity in AD and thus may provide novel strategies for prevention and therapeutics.
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Affiliation(s)
- Yang Lei
- Department of Urology, Jing'an District Central Hospital, Fudan University, Shanghai, China
| | - Zhou Renyuan
- Department of Urology, Jing'an District Central Hospital, Fudan University, Shanghai, China
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24
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Mendell AL, MacLusky NJ. Neurosteroid Metabolites of Gonadal Steroid Hormones in Neuroprotection: Implications for Sex Differences in Neurodegenerative Disease. Front Mol Neurosci 2018; 11:359. [PMID: 30344476 PMCID: PMC6182082 DOI: 10.3389/fnmol.2018.00359] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 09/12/2018] [Indexed: 12/12/2022] Open
Abstract
Gonadal steroid hormones are neurotrophic and neuroprotective. These effects are modulated by local metabolism of the hormones within the brain. Such control is necessary to maintain normal function, as several signaling pathways that are activated by gonadal steroid hormones in the brain can also become dysregulated in disease. Metabolites of the gonadal steroid hormones—particularly 3α-hydroxy, 5α-reduced neurosteroids—are synthesized in the brain and can act through different mechanisms from their parent steroids. These metabolites may provide a mechanism for modulating the responses to their precursor hormones, thereby providing a regulatory influence on cellular responses. In addition, there is evidence that the 3α-hydroxy, 5α-reduced neurosteroids are neuroprotective in their own right, and therefore may contribute to the overall protection conferred by their precursors. In this review article, the rapidly growing body of evidence supporting a neuroprotective role for this class of neurosteroids will be considered, including a discussion of potential mechanisms that may be involved. In addition, we explore the hypothesis that differences between males and females in local neurosteroid production may contribute to sex differences in the development of neurodegenerative disease.
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Affiliation(s)
- Ari Loren Mendell
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Neil James MacLusky
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
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25
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Nikray N, Karimi I, Siavashhaghighi Z, Becker LA, Mofatteh MM. An effort toward molecular biology of food deprivation induced food hoarding in gonadectomized NMRI mouse model: focus on neural oxidative status. BMC Neurosci 2018; 19:59. [PMID: 30249177 PMCID: PMC6154416 DOI: 10.1186/s12868-018-0461-9] [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: 11/30/2017] [Accepted: 09/20/2018] [Indexed: 12/03/2022] Open
Abstract
Background Environmental uncertainty, such as food deprivation, may alter internal milieu of nervous system through various mechanisms. In combination with circumstances of stress or aging, high consumption of unsaturated fatty acids and oxygen can make neural tissues sensitive to oxidative stress (OS). For adult rats, diminished level of gonadal steroid hormones accelerates OS and may result in special behavioral manifestations. This study was aimed to partially answer the question whether OS mediates trade-off between food hoarding and food intake (fat hoarding) in environmental uncertainty (e.g., fluctuations in food resource) within gonadectomized mouse model in the presence of food deprivation-induced food hoarding behavior. Results Hoarding behavior was not uniformly expressed in all male mice that exposed to food deprivation. Extended phenotypes including hoarder and non-hoarder mice stored higher and lower amounts of food respectively as compared to that of low-hoarder mice (normal phenotype) after food deprivation. Results showed that neural oxidative status was not changed in the presence of hoarding behavior in gonadectomized mice regardless of tissue type, however, glutathione levels of brain tissues were increased in the presence of hoarding behavior. Decreased superoxide dismutase activity in brain and spinal cord tissues and increased malondialdehyde in brain tissues of gonadectomized mice were also seen. Conclusions Although, food deprivation-induced hoarding behavior is a strategic response to food shortage in mice, it did not induce the same amount of hoarding across all colony mates. Hoarding behavior, in this case, is a response to the environmental uncertainty of food shortage, therefore is not an abnormal behavior. Hoarding behavior induced neural OS with regard to an increase in brain glutathione levels but failed to show other markers of neural OS. Decreased superoxide dismutase activity in brain and spinal cord tissues and increased malondialdehyde levels in brain tissues of gonadectomized mice could be a hallmark of debilitated antioxidative defense and more lipid peroxidation due to reduced amount of gonadal steroid hormones during aging.
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Affiliation(s)
- Noushin Nikray
- Laboratory of Molecular and Cellular Biology 1214, Department of Basic Veterinary Sciences, School of Veterinary Medicine, Razi University, Kermanshah, Iran
| | - Isaac Karimi
- Laboratory of Molecular and Cellular Biology 1214, Department of Basic Veterinary Sciences, School of Veterinary Medicine, Razi University, Kermanshah, Iran. .,Department of Biology, Faculty of Science, Razi University, Kermanshah, 67149-67346, Iran.
| | | | - Lora A Becker
- Department of Psychology, University of Evansville, Evansville, IN, 47722, USA
| | - Mohammad Mehdi Mofatteh
- Department of Accounting, School of Economics and Accounting, Islamic Azad University South Tehran Branch, Tehran, Iran
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26
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Choi E, Yoo W, Park JH, Kim S. Simultaneous Delivery of Electrostatically Complexed Multiple Gene-Targeting siRNAs and an Anticancer Drug for Synergistically Enhanced Treatment of Prostate Cancer. Mol Pharm 2018; 15:3777-3785. [PMID: 30028622 DOI: 10.1021/acs.molpharmaceut.8b00227] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Simultaneous silencing of multiple apoptosis-related genes is an attractive approach to treat cancer. In this article, we present a multiple gene-targeting siRNA/drug delivery system for prostate cancer treatment with a high efficiency. Bcl-2, survivin, and androgen receptor genes involved in the cell apoptosis pathways were chosen as silencing targets with three different siRNAs. The colloidal nanocomplex delivery system (<10 nm in size) was formulated electrostatically between anionic siRNAs and a cationic drug (BZT), followed by encapsulation with the Pluronic F-68 polymer. The formulated nanocomplex system exhibited sufficient stability against nuclease-induced degradation, leading to successful intracellular delivery for the desired therapeutic performance. Silencing of targeted genes and apoptosis induction were evaluated in vitro on human prostate LNCaP-LN3 cancer cells by using various biological analysis tools (e.g., real-time PCR, MTT cell viability test, and flow cytometry). It was demonstrated that when the total loaded siRNA amounts were kept the same in the nanocomplexes, the simultaneous silencing of triple genes with co-loaded siRNAs (i.e., Bcl-2, survivin, and AR-targeting siRNAs) enhanced BZT-induced apoptosis of cancer cells more efficiently than the silencing of each single gene alone, offering a novel way of improving the efficacy of gene therapeutics including anticancer drug.
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Affiliation(s)
- Eunshil Choi
- Center for Theragnosis , Korea Institute of Science and Technology (KIST) , Seoul 136-791 , Korea
| | - Wonjae Yoo
- Center for Theragnosis , Korea Institute of Science and Technology (KIST) , Seoul 136-791 , Korea.,School of Chemical Engineering, College of Engineering , Sungkyunkwan Univeristy , Suwon 440-746 , Korea
| | - Jae Hyung Park
- School of Chemical Engineering, College of Engineering , Sungkyunkwan Univeristy , Suwon 440-746 , Korea
| | - Sehoon Kim
- Center for Theragnosis , Korea Institute of Science and Technology (KIST) , Seoul 136-791 , Korea.,Division of Bio-Medical Science & Technology, KIST School , Korea University of Science and Technology (UST) , Seoul 136-791 , Korea
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27
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The Dynamics of Neurosteroids and Sex-Related Hormones in the Pathogenesis of Alzheimer’s Disease. Neuromolecular Med 2018; 20:215-224. [DOI: 10.1007/s12017-018-8493-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 04/28/2018] [Indexed: 12/11/2022]
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28
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Choi YS, Horning P, Aten S, Karelina K, Alzate-Correa D, Arthur JSC, Hoyt KR, Obrietan K. Mitogen- and Stress-Activated Protein Kinase 1 Regulates Status Epilepticus-Evoked Cell Death in the Hippocampus. ASN Neuro 2018; 9:1759091417726607. [PMID: 28870089 PMCID: PMC5588809 DOI: 10.1177/1759091417726607] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Mitogen-activated protein kinase (MAPK) signaling has been implicated in a wide range of neuronal processes, including development, plasticity, and viability. One of the principal downstream targets of both the extracellular signal-regulated kinase/MAPK pathway and the p38 MAPK pathway is Mitogen- and Stress-activated protein Kinase 1 (MSK1). Here, we sought to understand the role that MSK1 plays in neuroprotection against excitotoxic stimulation in the hippocampus. To this end, we utilized immunohistochemical labeling, a MSK1 null mouse line, cell viability assays, and array-based profiling approaches. Initially, we show that MSK1 is broadly expressed within the major neuronal cell layers of the hippocampus and that status epilepticus drives acute induction of MSK1 activation. In response to the status epilepticus paradigm, MSK1 KO mice exhibited a striking increase in vulnerability to pilocarpine-evoked cell death within the CA1 and CA3 cell layers. Further, cultured MSK1 null neurons exhibited a heighted level of N-methyl-D-aspartate-evoked excitotoxicity relative to wild-type neurons, as assessed using the lactate dehydrogenase assay. Given these findings, we examined the hippocampal transcriptional profile of MSK1 null mice. Affymetrix array profiling revealed that MSK1 deletion led to the significant (>1.25-fold) downregulation of 130 genes and an upregulation of 145 genes. Notably, functional analysis indicated that a subset of these genes contribute to neuroprotective signaling networks. Together, these data provide important new insights into the mechanism by which the MAPK/MSK1 signaling cassette confers neuroprotection against excitotoxic insults. Approaches designed to upregulate or mimic the functional effects of MSK1 may prove beneficial against an array of degenerative processes resulting from excitotoxic insults.
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Affiliation(s)
- Yun-Sik Choi
- 1 Department of Pharmaceutical Science and Technology, Catholic University of Daegu, Gyeongbuk, Republic of Korea
| | - Paul Horning
- 2 Department of Neuroscience, 2647 Ohio State University , Columbus, OH, USA
| | - Sydney Aten
- 2 Department of Neuroscience, 2647 Ohio State University , Columbus, OH, USA
| | - Kate Karelina
- 2 Department of Neuroscience, 2647 Ohio State University , Columbus, OH, USA
| | | | - J Simon C Arthur
- 4 College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK
| | - Kari R Hoyt
- 3 Division of Pharmacology, 2647 Ohio State University , Columbus, OH, USA
| | - Karl Obrietan
- 2 Department of Neuroscience, 2647 Ohio State University , Columbus, OH, USA
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29
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Mendell AL, Chung BY, Creighton CE, Kalisch BE, Bailey CD, MacLusky NJ. Neurosteroid metabolites of testosterone and progesterone differentially inhibit ERK phosphorylation induced by amyloid β in SH-SY5Y cells and primary cortical neurons. Brain Res 2018; 1686:83-93. [DOI: 10.1016/j.brainres.2018.02.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 12/12/2017] [Accepted: 02/16/2018] [Indexed: 12/31/2022]
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30
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Soma M, Kim J, Kato A, Kawato S. Src Kinase Dependent Rapid Non-genomic Modulation of Hippocampal Spinogenesis Induced by Androgen and Estrogen. Front Neurosci 2018; 12:282. [PMID: 29765299 PMCID: PMC5938344 DOI: 10.3389/fnins.2018.00282] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 04/10/2018] [Indexed: 11/13/2022] Open
Abstract
Dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from an axon terminal at the synapse. Memories are stored in synapses which consist of spines and presynapses. Rapid modulations of dendritic spines induced by hippocampal sex steroids, including dihydrotestosterone (DHT), testosterone (T), and estradiol (E2), are essential for synaptic plasticity. Molecular mechanisms underlying the rapid non-genomic modulation through synaptic receptors of androgen (AR) and estrogen (ER) as well as its downstream kinase signaling, however, have not been well understood. We investigated the possible involvement of Src tyrosine kinase in rapid changes of dendritic spines in response to androgen and estrogen, including DHT, T, and E2, using hippocampal slices from adult male rats. We found that the treatments with DHT (10 nM), T (10 nM), and E2 (1 nM) increased the total density of spines by ~1.22 to 1.26-fold within 2 h using super resolution confocal imaging of Lucifer Yellow-injected CA1 pyramidal neurons. We examined also morphological changes of spines in order to clarify differences between three sex steroids. From spine head diameter analysis, DHT increased middle- and large-head spines, whereas T increased small- and middle-head spines, and E2 increased small-head spines. Upon application of Src tyrosine kinase inhibitor, the spine increases induced through DHT, T, and E2 treatments were completely blocked. These results imply that Src kinase is essentially involved in sex steroid-induced non-genomic modulation of the spine density and morphology. These results also suggest that rapid effects of exogenously applied androgen and estrogen can occur in steroid-depleted conditions, including “acute” hippocampal slices and the hippocampus of gonadectomized animals.
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Affiliation(s)
- Mika Soma
- Department of Cognitive Neuroscience, Faculty of Pharma-Science, Teikyo University, Itabashi, Japan
| | - Jonghyuk Kim
- Department of Cognitive Neuroscience, Faculty of Pharma-Science, Teikyo University, Itabashi, Japan
| | - Asami Kato
- Department of Cognitive Neuroscience, Faculty of Pharma-Science, Teikyo University, Itabashi, Japan
| | - Suguru Kawato
- Department of Cognitive Neuroscience, Faculty of Pharma-Science, Teikyo University, Itabashi, Japan.,Department of Urology, Graduate School of Medicine, Juntendo University, Hongo, Japan.,Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Meguro, Japan
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31
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Akinola OB, Gabriel MO. Neuroanatomical and molecular correlates of cognitive and behavioural outcomes in hypogonadal males. Metab Brain Dis 2018; 33:491-505. [PMID: 29230619 DOI: 10.1007/s11011-017-0163-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 11/28/2017] [Indexed: 12/18/2022]
Abstract
Robust epidemiological, clinical and laboratory evidence supports emerging roles for the sex steroids in such domains as neurodevelopment, behaviour, learning and cognition. Regions of the mammalian brain that are involved in cognitive development and memory do not only express the classical nuclear androgen receptor, but also the non-genomic membrane receptor, which is a G protein-coupled receptor that mediates some rapid effects of the androgens on neurogenesis and synaptic plasticity. Under physiological conditions, hippocampal neurons do express the enzyme aromatase, and therefore actively aromatize testosterone to oestradiol. Although glial expression of the aromatase enzyme is minimal, increased expression following injury suggests a role for sex steroids in neuroprotection. It is therefore plausible to deduce that low levels of circulating androgens in males would perturb neuronal functions in relation to cognition and memory, as well as neural repair following injury. The present review is an overview of some roles of the sex steroids on cognitive function in males, and the neuroanatomical and molecular underpinnings of some behavioural and cognitive deficits characteristic of such genetic disorders noted for low androgen levels, including Klinefelter syndrome, Bardet-Biedl syndrome, Kallman syndrome and Prader-Willi syndrome. Recent literature in relation to some behavioural and cognitive changes secondary to surgical and pharmacological castration are also appraised.
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Affiliation(s)
- O B Akinola
- Division of Endocrinology, Department of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.
| | - M O Gabriel
- Division of Endocrinology, Department of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
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32
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Farajdokht F, Farhoudi M, Majdi A, Zamanlu M, Sadigh-Eteghad S, Vahedi S, Mahmoudi J. Testosterone May Hold Therapeutic Promise for the Treatment of Ischemic Stroke in Aging: A Closer Look at Laboratory Findings. Adv Pharm Bull 2018; 9:48-55. [PMID: 31011557 PMCID: PMC6468219 DOI: 10.15171/apb.2019.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 12/20/2018] [Accepted: 12/22/2018] [Indexed: 12/22/2022] Open
Abstract
Male sex is more prone to cerebrovascular disorders, yet the exact role of androgens in cerebral
ischemia remains unclear. Here we reviewed current understanding of testosterone (TES)
neuroprotective activity against ischemic stroke and mechanisms underlying these effects in
aging. TES may exert a neuroprotective effect in aging through pathways including inhibition of
oxidant molecules production, enhancing the enzymatic antioxidant capacity of the brain and
modulation of apoptotic cell death. Given this, a better understanding of the neuroprotective
roles of TES may propose an effective therapeutic strategy to improve the quality of life and
decrease androgen-related cerebrovascular problems in the aging men.
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Affiliation(s)
- Fereshteh Farajdokht
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Farhoudi
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Majdi
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Masumeh Zamanlu
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Sadigh-Eteghad
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shabnam Vahedi
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Mahmoudi
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
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33
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Massa MG, David C, Jörg S, Berg J, Gisevius B, Hirschberg S, Linker RA, Gold R, Haghikia A. Testosterone Differentially Affects T Cells and Neurons in Murine and Human Models of Neuroinflammation and Neurodegeneration. THE AMERICAN JOURNAL OF PATHOLOGY 2017. [PMID: 28634006 DOI: 10.1016/j.ajpath.2017.03.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The high female-to-male sex ratio of multiple sclerosis (MS) prevalence has continuously confounded researchers, especially in light of male patients' accelerated disease course at later stages of MS. Although multiple studies have concentrated on estrogenic mechanisms of disease modulation, fairly little attention has been paid to androgenic effects in a female system, and even fewer studies have attempted to dissociate hormonal effects on the neurodegenerative and neuroinflammatory processes of MS. Herein, we demonstrate the differential effects of hormone treatment on the acute inflammatory and chronic neurodegenerative phases of murine experimental autoimmune encephalomyelitis. Although s.c. treatment with testosterone and aromatase inhibitor applied beginning on the day of immunization ameliorated initial course of disease, similar treatment administered therapeutically exacerbated chronic disease course. Spinal cord analyses of axonal densities reflected the clinical scores of the chronic phase. In vitro, testosterone treatment not only decreased Th1 and Th17 differentiation in an aromatase-independent fashion, but also exacerbated cell death in induced pluripotent stem cell-derived primary human neurons under oxidative stress conditions in an aromatase inhibitor-dependent manner. Thus, through the alleviation of inflammatory processes and the exacerbation of neurodegenerative processes, androgens may contribute to the epidemiologic sex differentials observed in MS prevalence and course.
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Affiliation(s)
- Megan G Massa
- Department of Neurology, Ruhr University-Bochum, Bochum, Germany
| | - Christina David
- Department of Neurology, Ruhr University-Bochum, Bochum, Germany
| | - Stefanie Jörg
- Department of Neurology, Friedrich-Alexander University-Erlangen-Nuremberg, Erlangen, Germany
| | - Johannes Berg
- Department of Neurology, Ruhr University-Bochum, Bochum, Germany
| | - Barbara Gisevius
- Department of Neurology, Ruhr University-Bochum, Bochum, Germany
| | - Sarah Hirschberg
- Department of Neurology, Ruhr University-Bochum, Bochum, Germany
| | - Ralf A Linker
- Department of Neurology, Friedrich-Alexander University-Erlangen-Nuremberg, Erlangen, Germany
| | - Ralf Gold
- Department of Neurology, Ruhr University-Bochum, Bochum, Germany
| | - Aiden Haghikia
- Department of Neurology, Ruhr University-Bochum, Bochum, Germany.
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34
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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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Martínez-Rivera FJ, Pérez-Laspiur J, Santiago-Gascot ME, Alemán-Reyes AG, García-Santiago E, Rodríguez-Pérez Y, Calo-Guadalupe C, Otero-Pagán I, Ayala-Pagán RN, Martínez M, Cantres-Rosario YM, Meléndez LM, Barreto-Estrada JL. Differential protein expression profile in the hypothalamic GT1-7 cell line after exposure to anabolic androgenic steroids. PLoS One 2017; 12:e0180409. [PMID: 28719635 PMCID: PMC5515402 DOI: 10.1371/journal.pone.0180409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Accepted: 06/15/2017] [Indexed: 11/19/2022] Open
Abstract
The abuse of anabolic androgenic steroids (AAS) has been considered a major public health problem during decades. Supraphysiological doses of AAS may lead to a variety of neuroendocrine problems. Precisely, the hypothalamic-pituitary-gonadal (HPG) axis is one of the body systems that is mainly influenced by steroidal hormones. Fluctuations of the hormonal milieu result in alterations of reproductive function, which are made through changes in hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH). In fact, previous studies have shown that AAS modulate the activity of these neurons through steroid-sensitive afferents. To increase knowledge about the cellular mechanisms induced by AAS in GnRH neurons, we performed proteomic analyses of the murine hypothalamic GT1-7 cell line after exposure to 17α-methyltestosterone (17α-meT; 1 μM). These cells represent a good model for studying regulatory processes because they exhibit the typical characteristics of GnRH neurons, and respond to compounds that modulate GnRH in vivo. Two-dimensional difference in gel electrophoresis (2D-DIGE) and mass spectrometry analyses identified a total of 17 different proteins that were significantly affected by supraphysiological levels of AAS. Furthermore, pathway analyses showed that modulated proteins were mainly associated to glucose metabolism, drug detoxification, stress response and cell cycle. Validation of many of these proteins, such as GSTM1, ERH, GAPDH, PEBP1 and PDIA6, were confirmed by western blotting. We further demonstrated that AAS exposure decreased expression of estrogen receptors and GnRH, while two important signaling pathway proteins p-ERK, and p-p38, were modulated. Our results suggest that steroids have the capacity to directly affect the neuroendocrine system by modulating key cellular processes for the control of reproductive function.
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Affiliation(s)
- Freddyson J. Martínez-Rivera
- Department of Anatomy and Neurobiology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Juliana Pérez-Laspiur
- Translational Proteomics Center-RCMI, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - María E. Santiago-Gascot
- Department of Anatomy and Neurobiology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Abner G. Alemán-Reyes
- Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico, United States of America
| | - Emanuel García-Santiago
- Department of Biotechnology, Universidad del Este, Carolina, Puerto Rico, United States of America
| | - Yolanda Rodríguez-Pérez
- Translational Proteomics Center-RCMI, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Cristhian Calo-Guadalupe
- Department of Biotechnology, Universidad del Este, Carolina, Puerto Rico, United States of America
| | - Inelia Otero-Pagán
- Department of Anatomy and Neurobiology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Roxsana N. Ayala-Pagán
- Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico, United States of America
| | - Magdiel Martínez
- Department of Physiology and Biophysics, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Yisel M. Cantres-Rosario
- Department of Microbiology and Medical Zoology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Loyda M. Meléndez
- Translational Proteomics Center-RCMI, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
- Department of Microbiology and Medical Zoology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Jennifer L. Barreto-Estrada
- Department of Anatomy and Neurobiology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
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Boese AC, Kim SC, Yin KJ, Lee JP, Hamblin MH. Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease. Am J Physiol Heart Circ Physiol 2017. [PMID: 28626075 DOI: 10.1152/ajpheart.00217.2016] [Citation(s) in RCA: 144] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Sex differences between women and men are often overlooked and underappreciated when studying the cardiovascular system. It has been long assumed that men and women are physiologically similar, and this notion has resulted in women being clinically evaluated and treated for cardiovascular pathophysiological complications as men. Currently, there is increased recognition of fundamental sex differences in cardiovascular function, anatomy, cell signaling, and pathophysiology. The National Institutes of Health have enacted guidelines expressly to gain knowledge about ways the sexes differ in both normal function and diseases at the various research levels (molecular, cellular, tissue, and organ system). Greater understanding of these sex differences will be used to steer future directions in the biomedical sciences and translational and clinical research. This review describes sex-based differences in the physiology and pathophysiology of the vasculature, with a special emphasis on sex steroid receptor (estrogen and androgen receptor) signaling and their potential impact on vascular function in health and diseases (e.g., atherosclerosis, hypertension, peripheral artery disease, abdominal aortic aneurysms, cerebral aneurysms, and stroke).
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Affiliation(s)
- Austin C Boese
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Seong C Kim
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Ke-Jie Yin
- Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jean-Pyo Lee
- Department of Neurology, Tulane University School of Medicine, New Orleans, Louisiana; and.,Center for Stem Cell Research and Regenerative Medicine, New Orleans, Louisiana
| | - Milton H Hamblin
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana;
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Jean A, Trouillet AC, Andrianarivelo NA, Mhaouty-Kodja S, Hardin-Pouzet H. Phospho-ERK and sex steroids in the mPOA: involvement in male mouse sexual behaviour. J Endocrinol 2017; 233:257-267. [PMID: 28356400 DOI: 10.1530/joe-17-0025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 03/29/2017] [Indexed: 12/20/2022]
Abstract
This paper aimed to investigate the mechanisms triggering ERK phosphorylation and its functional role in male sexual behaviour. ERK1/2-phosphorylated form was detected in the medial preoptic area of the hypothalamus (mPOA) during the sexual stimulation of naive and sexually experienced males who were killed 5 min after the first intromission. This mating-induced ERK phosphorylation was increased in sexually experienced males compared to that in naive mice. The functional role of the ERK1/2 pathway activation during sexual behaviour was explored with the administration of a MEK inhibitor, SL-327 (30 mg/kg, i.p.), 45 min before the contact with a receptive female. Inhibition of ERK phosphorylation was found to decrease sexual motivation in both naive and experienced males without altering their copulatory ability. The mechanisms potentially involved in this rapid ERK1/2 pathway activation were specified ex vivo on hypothalamic slices. A thirty-minute incubation with 100 nM of testosterone (T), dihydrotestosterone (DHT) or oestradiol (E2) led to ERK phosphorylation. No changes were observed after incubation with testosterone 3-(O-carboxymethyl)oxime-BSA (T-BSA), an impermeable to the plasma membrane form of testosterone. All these results indicate that ERK phosphorylation within the mPOA could be a key player in the motivational signalling pathway and considered as an index of sexual motivation. They also demonstrate the involvement of oestrogen receptor (ER) and androgen receptor (AR) transduction pathways in steroid-dependent ERK activation.
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Affiliation(s)
- Arnaud Jean
- Sorbonne UniversitésUPMC Univ Paris 06, INSERM, CNRS, Neuroscience Paris - Seine; Institut de Biologie Paris Seine, Paris, France
| | - Anne-Charlotte Trouillet
- Sorbonne UniversitésUPMC Univ Paris 06, INSERM, CNRS, Neuroscience Paris - Seine; Institut de Biologie Paris Seine, Paris, France
| | - Njiva Andry Andrianarivelo
- Sorbonne UniversitésUPMC Univ Paris 06, INSERM, CNRS, Neuroscience Paris - Seine; Institut de Biologie Paris Seine, Paris, France
| | - Sakina Mhaouty-Kodja
- Sorbonne UniversitésUPMC Univ Paris 06, INSERM, CNRS, Neuroscience Paris - Seine; Institut de Biologie Paris Seine, Paris, France
| | - Hélène Hardin-Pouzet
- Sorbonne UniversitésUPMC Univ Paris 06, INSERM, CNRS, Neuroscience Paris - Seine; Institut de Biologie Paris Seine, Paris, France
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Koushyar S, Economides G, Zaat S, Jiang W, Bevan CL, Dart DA. The prohibitin-repressive interaction with E2F1 is rapidly inhibited by androgen signalling in prostate cancer cells. Oncogenesis 2017; 6:e333. [PMID: 28504694 PMCID: PMC5523065 DOI: 10.1038/oncsis.2017.32] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 02/16/2017] [Accepted: 03/27/2017] [Indexed: 12/20/2022] Open
Abstract
Prohibitin (PHB) is a tumour suppressor molecule with pleiotropic activities across several cellular compartments including mitochondria, cell membrane and the nucleus. PHB and the steroid-activated androgen receptor (AR) have an interplay where AR downregulates PHB, and PHB represses AR. Additionally, their cellular locations and chromatin interactions are in dynamic opposition. We investigated the mechanisms of cell cycle inhibition by PHB and how this is modulated by AR in prostate cancer. Using a prostate cancer cell line overexpressing PHB, we analysed the gene expression changes associated with PHB-mediated cell cycle arrest. Over 1000 gene expression changes were found to be significant and gene ontology analysis confirmed PHB-mediated repression of genes essential for DNA replication and synthesis, for example, MCMs and TK1, via an E2F1 regulated pathway—agreeing with its G1/S cell cycle arrest activity. PHB is known to inhibit E2F1-mediated transcription, and the PHB:E2F1 interaction was seen in LNCaP nuclear extracts, which was then reduced by androgen treatment. Upon two-dimensional western blot analysis, the PHB protein itself showed androgen-mediated charge differentiation (only in AR-positive cells), indicating a potential dephosphorylation event. Kinexus phosphoprotein array analysis indicated that Src kinase was the main interacting intracellular signalling hub in androgen-treated LNCaP cells, and that Src inhibition could reduce this AR-mediated charge differentiation. PHB charge change may be associated with rapid dissociation from chromatin and E2F1, allowing the cell cycle to proceed. The AR and androgens may deactivate the repressive functions of PHB upon E2F1 leading to cell cycle progression, and indicates a role for AR in DNA replication licensing.
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Affiliation(s)
- S Koushyar
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, UK
| | - G Economides
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, UK
| | - S Zaat
- Androgen Signalling Laboratory, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK
| | - W Jiang
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, UK
| | - C L Bevan
- Androgen Signalling Laboratory, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK
| | - D A Dart
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, UK
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Crawford ED, Schally AV, Pinthus JH, Block NL, Rick FG, Garnick MB, Eckel RH, Keane TE, Shore ND, Dahdal DN, Beveridge TJR, Marshall DC. The potential role of follicle-stimulating hormone in the cardiovascular, metabolic, skeletal, and cognitive effects associated with androgen deprivation therapy. Urol Oncol 2017; 35:183-191. [PMID: 28325650 DOI: 10.1016/j.urolonc.2017.01.025] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 01/20/2017] [Accepted: 01/24/2017] [Indexed: 11/25/2022]
Abstract
PURPOSE To explore how follicle-stimulating hormone (FSH) may contribute to cardiovascular, metabolic, skeletal, and cognitive events in men treated for prostate cancer, with various forms of androgen deprivation therapy (ADT). MATERIALS AND METHODS A colloquium of prostate cancer experts was convened in May 2015, to discuss the role of FSH in the development of unwanted effects associated with ADT. Subsequently, a literature review (Medline, PubMed, and relevant congress abstract databases) was performed to further explore and evaluate the collected evidence. RESULTS It has become evident that, in the setting of ADT, FSH can promote the development of atherosclerotic plaque formation, metabolic syndrome, and insulin resistance. Data also suggest that FSH is an important mediator of bone remodeling, particularly bone resorption, and thereby increases the risk for bone fracture. Additional evidence implicates a role for FSH in bone metastasis as well. The influence of FSH on ADT-induced cognitive deficits awaits further elucidation; however, the possibility that FSH may be involved therein cannot be ruled out. CONCLUSIONS The widespread molecular and physiological consequences of FSH system activation in normal and pathological conditions are becoming better understood. Progress in this area has been achieved by the development of additional investigative and clinical measures to better evaluate specific adverse effects. More research is needed on FSH function in the development of cancer as well as its association with cardiovascular, metabolic, musculoskeletal, and cognitive effects in ADT.
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Affiliation(s)
- E David Crawford
- Department of Urologic Oncology, School of Medicine, University of Colorado, Denver, Denver, CO.
| | - Andrew V Schally
- Endocrine, Polypeptide and Cancer Institute, Miami Veterans Affairs Medical Center, Miami, FL; Department of Pathology, University of Miami School of Medicine, Miami, FL; Department of Medicine, University of Miami School of Medicine, Miami, FL
| | - Jehonathan H Pinthus
- Department of Surgery, Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada
| | - Norman L Block
- Endocrine, Polypeptide and Cancer Institute, Miami Veterans Affairs Medical Center, Miami, FL; Department of Pathology, University of Miami School of Medicine, Miami, FL; Department of Medicine, University of Miami School of Medicine, Miami, FL
| | - Ferenc G Rick
- Endocrine, Polypeptide and Cancer Institute, Miami Veterans Affairs Medical Center, Miami, FL; Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL
| | - Marc B Garnick
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Robert H Eckel
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado, Denver, CO
| | - Thomas E Keane
- Department of Urology, Medical University of South Carolina, Charleston, SC
| | - Neal D Shore
- Carolina Urologic Research Center, Myrtle Beach, SC
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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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Mendell AL, Creighton CE, Kalisch BE, MacLusky NJ. 5α-Androstane-3α,17β-Diol Inhibits Neurotoxicity in SH-SY5Y Human Neuroblastoma Cells and Mouse Primary Cortical Neurons. Endocrinology 2016; 157:4570-4578. [PMID: 27754784 DOI: 10.1210/en.2016-1508] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Low free T levels in men are associated with age-related cognitive decline and increased risk for neurotoxicity, resulting in disease. The mechanisms underlying these observations remain poorly defined. Although rapid, androgen receptor-dependent activation of ERK has been postulated as a neurotrophic and neuroprotective mechanism, actions of T metabolites such as 5α-androstane-3α,17β-diol (3α-diol) may also be involved. We investigated the influence of 3α-diol on the induction of ERK phosphorylation in SH-SY5Y human female neuroblastoma cells and primary cortical neurons from male and female mice. In SH-SY5Y cells, ERK phosphorylation was induced by 10 nM DHT, epidermal growth factor, hydrogen peroxide (H2O2), and acetylcholine. The addition of 10 nM 3α-diol, which did not itself activate ERK, significantly inhibited ERK phosphorylation induced by DHT, epidermal growth factor, or H2O2, but not acetylcholine. In both SH-SY5Y cells and primary cortical neurons, prolonged ERK phosphorylation and caspase-3 cleavage resulting from amyloid β-peptide 1-42 (Aβ42) exposure were inhibited by cotreatment with 3α-diol. 3α-diol also reduced the loss in cellular viability induced by Aβ42 or H2O2 in SH-SY5Y cells. These data suggest that T-mediated neuroprotection may occur via two distinct but complementary mechanisms: an initial rapid activation of ERK phosphorylation, followed by modulation via 3α-diol of the potentially adverse consequences of prolonged ERK activation.
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Affiliation(s)
- A L Mendell
- Department of Biomedical Sciences (A.L.M., C.E.C., B.E.K., N.J.M.), Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada, N1G 2W1
| | - C E Creighton
- Department of Biomedical Sciences (A.L.M., C.E.C., B.E.K., N.J.M.), Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada, N1G 2W1
| | - B E Kalisch
- Department of Biomedical Sciences (A.L.M., C.E.C., B.E.K., N.J.M.), Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada, N1G 2W1
| | - Neil J MacLusky
- Department of Biomedical Sciences (A.L.M., C.E.C., B.E.K., N.J.M.), Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada, N1G 2W1
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Duarte AC, Hrynchak MV, Gonçalves I, Quintela T, Santos CRA. Sex Hormone Decline and Amyloid β Synthesis, Transport and Clearance in the Brain. J Neuroendocrinol 2016; 28. [PMID: 27632792 DOI: 10.1111/jne.12432] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 09/12/2016] [Accepted: 09/12/2016] [Indexed: 12/15/2022]
Abstract
Sex hormones (SH) are essential regulators of the central nervous system. The decline in SH levels along with ageing may contribute to compromised neuroprotection and set the grounds for neurodegeneration and cognitive impairments. In Alzheimer's disease, besides other pathological features, there is an imbalance between amyloid β (Aβ) production and clearance, leading to its accumulation in the brain of older subjects. Aβ accumulation is a primary cause for brain inflammation and degeneration, as well as concomitant cognitive decline. There is mounting evidence that SH modulate Aβ production, transport and clearance. Importantly, SH regulate most of the molecules involved in the amyloidogenic pathway, their transport across brain barriers for elimination, and their degradation in the brain interstitial fluid. This review brings together data on the regulation of Aβ production, metabolism, degradation and clearance by SH.
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Affiliation(s)
- A C Duarte
- Health Sciences Research Centre - CICS-UBI, University of Beira Interior, Covilhã, Portugal
| | - M V Hrynchak
- Health Sciences Research Centre - CICS-UBI, University of Beira Interior, Covilhã, Portugal
| | - I Gonçalves
- Health Sciences Research Centre - CICS-UBI, University of Beira Interior, Covilhã, Portugal
| | - T Quintela
- Health Sciences Research Centre - CICS-UBI, University of Beira Interior, Covilhã, Portugal
| | - C R A Santos
- Health Sciences Research Centre - CICS-UBI, University of Beira Interior, Covilhã, Portugal
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Snyder HM, Asthana S, Bain L, Brinton R, Craft S, Dubal DB, Espeland MA, Gatz M, Mielke MM, Raber J, Rapp PR, Yaffe K, Carrillo MC. Sex biology contributions to vulnerability to Alzheimer's disease: A think tank convened by the Women's Alzheimer's Research Initiative. Alzheimers Dement 2016; 12:1186-1196. [PMID: 27692800 DOI: 10.1016/j.jalz.2016.08.004] [Citation(s) in RCA: 177] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 08/17/2016] [Indexed: 01/29/2023]
Abstract
More than 5 million Americans are living with Alzheimer's disease (AD) today, and nearly two-thirds of Americans with AD are women. This sex difference may be due to the higher longevity women generally experience; however, increasing evidence suggests that longevity alone is not a sufficient explanation and there may be other factors at play. The Alzheimer's Association convened an expert think tank to focus on the state of the science and level of evidence around gender and biological sex differences for AD, including the knowledge gaps and areas of science that need to be more fully addressed. This article summarizes the think tank discussion, moving forward a research agenda and funding program to better understand the biological underpinnings of sex- and gender-related disparities of risk for AD.
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Affiliation(s)
- Heather M Snyder
- Division of Medical & Scientific Relations, Alzheimer's Association, Chicago, IL, USA.
| | - Sanjay Asthana
- Department of Medicine, University of Wisconsin School of Medicine, Madison, WI, USA
| | - Lisa Bain
- Independent Science Writer, Philadelphia, PA, USA
| | - Roberta Brinton
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA; Department of Neurology, University of Southern California, Los Angeles, CA, USA
| | - Suzanne Craft
- Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Dena B Dubal
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
| | - Mark A Espeland
- Department of Biostatistical Science, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Margaret Gatz
- Department of Psychology, University of Southern California, Los Angeles, CA, USA
| | - Michelle M Mielke
- Division of Epidemiology, Department of Health Sciences Research and Neurology, Mayo Clinic, Rochester, MN, USA
| | - Jacob Raber
- Departments of Behavioral Neuroscience, Neurology, and Radiation Medicine, Oregon Health & Science University, Portland, OR, USA; Division of Neuroscience, ONPRC, Oregon Health & Science University, Portland, OR, USA
| | - Peter R Rapp
- Laboratory of Behavioral Neuroscience, Neurocognitive Aging Section, National Institute on Aging Intramural Research Program, Baltimore, MD, USA
| | - Kristine Yaffe
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
| | - Maria C Carrillo
- Division of Medical & Scientific Relations, Alzheimer's Association, Chicago, IL, USA
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Grönbladh A, Nylander E, Hallberg M. The neurobiology and addiction potential of anabolic androgenic steroids and the effects of growth hormone. Brain Res Bull 2016; 126:127-137. [DOI: 10.1016/j.brainresbull.2016.05.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 05/03/2016] [Accepted: 05/04/2016] [Indexed: 12/30/2022]
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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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Braden BB, Andrews MG, Acosta JI, Mennenga SE, Lavery C, Bimonte-Nelson HA. A comparison of progestins within three classes: Differential effects on learning and memory in the aging surgically menopausal rat. Behav Brain Res 2016; 322:258-268. [PMID: 27368418 DOI: 10.1016/j.bbr.2016.06.053] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 06/03/2016] [Accepted: 06/27/2016] [Indexed: 10/21/2022]
Abstract
INTRODUCTION For decades, progestins have been included in hormone therapies (HT) prescribed to women to offset the risk of unopposed estrogen-induced endometrial hyperplasia. However, the potential effects on cognition of subcategories of clinically used progestins have been largely unexplored. METHODS In two studies, the present investigation evaluated the cognitive effects of norethindrone acetate (NETA), levonorgestrel (LEVO), and medroxyprogesterone acetate (MPA) on the water radial-arm maze (WRAM) and Morris water maze (MM) in middle-aged ovariectomized rats. RESULTS In Study 1, six-weeks of a high-dose NETA treatment impaired learning and delayed retention on the WRAM, and impaired reference memory on the MM. Low-dose NETA treatment impaired delayed retention on the WRAM. In Study 2, high-dose NETA treatment was reduced to four-weeks and compared to MPA and LEVO. As previously shown, MPA impaired working memory performance during the lattermost portion of testing, at the highest working memory load, impaired delayed retention on the WRAM, and impaired reference memory on the MM. NETA also impaired performance on these WRAM and MM measures. Interestingly, LEVO did not impair performance, but instead enhanced learning on the WRAM. CONCLUSIONS The current study corroborates previous evidence that the most commonly prescribed FDA-approved progestin for HT, MPA, impairs learning and memory in the ovariectomized middle-aged rat. When progestins from two different additional subcategories were investigated, NETA impaired learning and memory similarly to MPA, but LEVO enhanced learning. Future research is warranted to determine LEVO's potential as an ideal progestin for optimal health in women, including for cognition.
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Affiliation(s)
- B Blair Braden
- Department of Psychology, Arizona State University, Tempe, AZ, United States; Arizona Alzheimer's Consortium, United States
| | - Madeline G Andrews
- Department of Psychology, Arizona State University, Tempe, AZ, United States
| | - Jazmin I Acosta
- Department of Psychology, Arizona State University, Tempe, AZ, United States
| | - Sarah E Mennenga
- Department of Psychology, Arizona State University, Tempe, AZ, United States
| | - Courtney Lavery
- Department of Psychology, Arizona State University, Tempe, AZ, United States
| | - Heather A Bimonte-Nelson
- Department of Psychology, Arizona State University, Tempe, AZ, United States; Arizona Alzheimer's Consortium, United States.
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Toro-Urrego N, Garcia-Segura LM, Echeverria V, Barreto GE. Testosterone Protects Mitochondrial Function and Regulates Neuroglobin Expression in Astrocytic Cells Exposed to Glucose Deprivation. Front Aging Neurosci 2016; 8:152. [PMID: 27445795 PMCID: PMC4921852 DOI: 10.3389/fnagi.2016.00152] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 06/13/2016] [Indexed: 12/11/2022] Open
Abstract
Testosterone is a hormone that has been shown to confer neuroprotection from different insults affecting the central nervous system (CNS). Testosterone induces this protection by different mechanisms that include the activation of anti-apoptotic pathways that are directly implicated in neuronal survival. However, little attention has been devoted to its actions on glial cells. In the present study, we have assessed whether testosterone exerts protection in a human astrocyte cell model, the T98G cells. Our results indicate that testosterone improves cell survival and mitochondrial membrane potential and reduces nuclear fragmentation and reactive oxygen species (ROS) generation. These effects were accompanied by a positive regulation of neuroglobin, an oxygen-binding and sensor protein, which may serve as a regulator of ROS and nitrogen reactive species (NOS), and these protective effects of testosterone may be at least in part mediated by estradiol and DHT. In conclusion, these findings suggest that astroglia may mediate some of the protective actions of testosterone in the brain upon pathological conditions.
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Affiliation(s)
- Nicolas Toro-Urrego
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad JaverianaBogotá, Colombia
| | | | | | - George E. Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad JaverianaBogotá, Colombia
- Instituto de Ciencias Biomédicas, Universidad Autónoma de ChileSantiago, Chile
- Universidad Científica del SurLima, Perú
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49
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Chen C, Dienhart JA, Bolton EC. Androgen-Sensitized Apoptosis of HPr-1AR Human Prostate Epithelial Cells. PLoS One 2016; 11:e0156145. [PMID: 27203692 PMCID: PMC4874596 DOI: 10.1371/journal.pone.0156145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 05/10/2016] [Indexed: 01/27/2023] Open
Abstract
Androgen receptor (AR) signaling is crucial to the development and homeostasis of the prostate gland, and its dysregulation mediates common prostate pathologies. The mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells have been investigated in human and rodent adult prostate. However, the cellular stress response of human prostate epithelial cells is not well understood, though it is central to prostate health and pathology. Here, we report that androgen sensitizes HPr-1AR and RWPE-AR human prostate epithelial cells to cell stress agents and apoptotic cell death. Although 5α-dihydrotestosterone (DHT) treatment alone did not induce cell death, co-treatment of HPr-1AR cells with DHT and an apoptosis inducer, such as staurosporine (STS), TNFt, or hydrogen peroxide, synergistically increased cell death in comparison to treatment with each apoptosis inducer by itself. We found that the synergy between DHT and apoptosis inducer led to activation of the intrinsic/mitochondrial apoptotic pathway, which is supported by robust cleavage activation of caspase-9 and caspase-3. Further, the dramatic depolarization of the mitochondrial membrane potential that we observed upon co-treatment with DHT and STS is consistent with increased mitochondrial outer membrane permeabilization (MOMP) in the pro-apoptotic mechanism. Interestingly, the synergy between DHT and apoptosis inducer was abolished by AR antagonists and inhibitors of transcription and protein synthesis, suggesting that AR mediates pro-apoptotic synergy through transcriptional regulation of MOMP genes. Expression analysis revealed that pro-apoptotic genes (BCL2L11/BIM and AIFM2) were DHT-induced, whereas pro-survival genes (BCL2L1/BCL-XL and MCL1) were DHT-repressed. Hence, we propose that the net effect of these AR-mediated expression changes shifts the balance of BCL2-family proteins, such that androgen signaling sensitizes mitochondria to apoptotic signaling, thus rendering HPr-1AR more vulnerable to cell death signals. Our study offers insight into AR-mediated regulation of prostate epithelial cell death signaling.
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Affiliation(s)
- Congcong Chen
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Jason A. Dienhart
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Eric C. Bolton
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
- * E-mail:
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Siddiqui AN, Siddiqui N, Khan RA, Kalam A, Jabir NR, Kamal MA, Firoz CK, Tabrez S. Neuroprotective Role of Steroidal Sex Hormones: An Overview. CNS Neurosci Ther 2016; 22:342-50. [PMID: 27012165 PMCID: PMC6492877 DOI: 10.1111/cns.12538] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Revised: 02/21/2016] [Accepted: 02/21/2016] [Indexed: 12/11/2022] Open
Abstract
Progesterone, estrogens, and testosterone are the well-known steroidal sex hormones, which have been reported to have "nonreproductive "effects in the brain, specifically in the neuroprotection and neurotrophy. In the last one decade, there has been a surge in the research on the role of these hormones in neuroprotection and their positive impact on different brain injuries. The said interest has been sparked by a desire to understand the action and mechanisms of these steroidal sex hormones throughout the body. The aim of this article was to highlight the potential outcome of the steroidal hormones, viz. progesterone, estrogens, and testosterone in terms of their role in neuroprotection and other brain injuries. Their possible mechanism of action at both genomic and nongenomic level will be also discussed. As far as our knowledge goes, we are for the first time reporting neuroprotective effect and possible mechanism of action of these hormones in a single article.
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Affiliation(s)
- Ali Nasir Siddiqui
- Department of Pharmaceutical Medicine, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India
| | - Nahida Siddiqui
- Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India
| | - Rashid Ali Khan
- Department of Pharmaceutical Medicine, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India
| | - Abul Kalam
- Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India
| | - Nasimudeen R Jabir
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Enzymoics, 7 Peterlee Place, Hebersham, NSW, Australia
| | | | - Shams Tabrez
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
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