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1
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Gaston-Breton R, Disdier C, Hagberg H, Mabondzo A. Hypoxia-ischemia and sexual dimorphism: modeling mitochondrial dysfunction using brain organoids. Cell Biosci 2025; 15:67. [PMID: 40413513 PMCID: PMC12103005 DOI: 10.1186/s13578-025-01402-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 04/27/2025] [Indexed: 05/27/2025] Open
Abstract
Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neurodevelopmental morbidities in full-term infants. There is strong evidence of sexual differences in hypoxic-ischemic (HI) injury where male neonates are at higher risk as they are subject to more pronounced neurological deficits and death than females. The cellular and molecular mechanisms underlying these sexual discrepancies in HI injury are poorly understood. Mitochondrial dysregulation has been increasingly explored in brain diseases and represents a major target during HI events. In this review, we discuss (1) different mitochondrial functions in the central nervous system (2), mitochondrial dysregulation in the context of HI injury (3), sex-dependent mitochondrial pathways in HIE and (4) modeling of mitochondrial dysfunction using human brain organoids. Gaining insight into these novel aspects of mitochondrial function will offer valuable understanding of brain development and neurological disorders such as HI injury, paving the way for the discovery and creation of new treatment approaches.
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Affiliation(s)
- Romane Gaston-Breton
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire & Innovation Thérapeutique (LENIT), Gif-sur-Yvette cedex, 91191, France
| | - Clémence Disdier
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire & Innovation Thérapeutique (LENIT), Gif-sur-Yvette cedex, 91191, France
| | | | - Aloïse Mabondzo
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire & Innovation Thérapeutique (LENIT), Gif-sur-Yvette cedex, 91191, France.
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Kobayashi H, Nishio M, Umetani M, Shigetomi H, Imanaka S, Hashimoto H. Endometrial Aging and Reproductive Decline: The Central Role of Mitochondrial Dysfunction. Int J Mol Sci 2025; 26:5060. [PMID: 40507871 PMCID: PMC12154470 DOI: 10.3390/ijms26115060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2025] [Revised: 05/18/2025] [Accepted: 05/21/2025] [Indexed: 06/16/2025] Open
Abstract
Socioeconomic factors have led an increasing number of women to postpone childbirth, thereby elevating the risks of reduced fertility, pregnancy complications, preterm birth, cesarean delivery, and chromosomal abnormalities. While diminished oocyte quality is a well-established contributor to age-related infertility, endometrial dysfunction also plays a pivotal role. Optimizing both oocyte quality and endometrial health is essential for enhancing reproductive outcomes. Although aging has been defined by twelve hallmarks, research specifically addressing age-related changes in endometrial function remains limited. This review examines the process of endometrial aging, with a particular emphasis on mitochondrial function. A comprehensive literature search was conducted using PubMed and Google Scholar to identify relevant studies published up to 31 January 2025. Endometrial aging is driven by multiple biological mechanisms, most notably the decline in endometrial receptivity. Key contributing factors include hormonal dysregulation, chronic inflammation, cell cycle arrest, genomic instability, epigenetic alterations, telomere attrition, and mitochondrial dysfunction. Among these, mitochondrial dysfunction emerges as a central driver of the aging process. Endometrial senescence, precipitated by irreversible mitochondrial impairment, may underlie the progressive decline in reproductive potential. Elucidating the role of mitochondrial dysfunction in aging provides critical insights into the molecular basis of fertility decline, particularly through its impact on endometrial receptivity.
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Affiliation(s)
- Hiroshi Kobayashi
- Department of Gynecology and Reproductive Medicine, Ms. Clinic MayOne, 871-1 Shijo-cho, Kashihara 634-0813, Japan; (M.N.); (M.U.); (S.I.); (H.H.)
- Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Japan;
| | - Miki Nishio
- Department of Gynecology and Reproductive Medicine, Ms. Clinic MayOne, 871-1 Shijo-cho, Kashihara 634-0813, Japan; (M.N.); (M.U.); (S.I.); (H.H.)
| | - Mai Umetani
- Department of Gynecology and Reproductive Medicine, Ms. Clinic MayOne, 871-1 Shijo-cho, Kashihara 634-0813, Japan; (M.N.); (M.U.); (S.I.); (H.H.)
| | - Hiroshi Shigetomi
- Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Japan;
- Department of Gynecology and Reproductive Medicine, Aska Ladies Clinic, 3-3-17 Kitatomigaoka-cho, Nara 634-0001, Japan
| | - Shogo Imanaka
- Department of Gynecology and Reproductive Medicine, Ms. Clinic MayOne, 871-1 Shijo-cho, Kashihara 634-0813, Japan; (M.N.); (M.U.); (S.I.); (H.H.)
- Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Japan;
| | - Hiratsugu Hashimoto
- Department of Gynecology and Reproductive Medicine, Ms. Clinic MayOne, 871-1 Shijo-cho, Kashihara 634-0813, Japan; (M.N.); (M.U.); (S.I.); (H.H.)
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Vona R, Cittadini C, Ortona E, Matarrese P. Sex Disparity in Cancer: Role of Autophagy and Estrogen Receptors. Cells 2025; 14:273. [PMID: 39996745 PMCID: PMC11854201 DOI: 10.3390/cells14040273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/24/2025] [Accepted: 02/07/2025] [Indexed: 02/26/2025] Open
Abstract
Autophagy, a cellular process essential for maintaining homeostasis, plays a fundamental role in recycling damaged components and in adapting to stress. The dysregulation of autophagy is implicated in numerous human diseases, including cancer, where it exhibits a dual role as both a suppressor and a promoter, depending on the context and the stage of tumor development. The significant sex differences observed in autophagic processes are determined by biological factors, such as genetic makeup and sex hormones. Estrogens, through their interaction with specific receptors, modulate autophagy and influence tumor progression, therapy resistance, and the immune response to tumors. In females, the escape from X inactivation and estrogen signaling may be responsible for the advantages, in terms of lower incidence and longer survival, observed in oncology. Women often show better responses to traditional chemotherapy, while men respond better to immunotherapy. The action of sex hormones on the immune system could contribute to these differences. However, women experience more severe adverse reactions to anticancer drugs. The estrogen/autophagy crosstalk-involved in multiple aspects of the tumor, i.e., development, progression and the response to therapy-deserves an in-depth study, as it could highlight sex-specific mechanisms useful for designing innovative and gender-tailored treatments from the perspective of precision medicine.
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Affiliation(s)
- Rosa Vona
- Center for Gender-Specific Medicine, National Institute of Health, 00161 Rome, Italy; (C.C.); (E.O.)
| | | | | | - Paola Matarrese
- Center for Gender-Specific Medicine, National Institute of Health, 00161 Rome, Italy; (C.C.); (E.O.)
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Fila M, Przyslo L, Derwich M, Pawlowska E, Blasiak J. Sexual Dimorphism in Migraine. Focus on Mitochondria. Curr Pain Headache Rep 2025; 29:11. [PMID: 39760955 DOI: 10.1007/s11916-024-01317-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/02/2024] [Indexed: 01/07/2025]
Abstract
PURPOSE OF REVIEW Migraine prevalence in females is up to 3 times higher than in males and females show higher frequency, longer duration, and increased severity of headache attacks, but the reason for that difference is not known. This narrative review presents the main aspects of sex dimorphism in migraine prevalence and discusses the role of sex-related differences in mitochondrial homeostasis in that dimorphism. The gender dimension is also shortly addressed. RECENT FINDINGS The imbalance between energy production and demand in the brain susceptible to migraine is an important element of migraine pathogenesis. Mitochondria are the main energy source in the brain and mitochondrial impairment is reported in both migraine patients and animal models of human migraine. However, it is not known whether the observed changes are consequences of primary disturbance of mitochondrial homeostasis or are secondary to the migraine-affected hyperexcitable brain. Sex hormones regulate mitochondrial homeostasis, and several reports suggest that the female hormones may act protectively against mitochondrial impairment, contributing to more effective energy production in females, which may be utilized in the mechanisms responsible for migraine progression. Migraine is characterized by several comorbidities that are characterized by sex dimorphism in their prevalence and impairments in mitochondrial functions. Mitochondria may play a major role in sexual dimorphism in migraine through the involvement in energy production, the dependence on sex hormones, and the involvement in sex-dependent comorbidities. Studies on the role of mitochondria in sex dimorphism in migraine may contribute to precise personal therapeutic strategies.
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Affiliation(s)
- Michal Fila
- Department of Developmental Neurology and Epileptology, Polish Mother's Memorial Hospital Research Institute, 93-338, Lodz, Poland
| | - Lukasz Przyslo
- Department of Developmental Neurology and Epileptology, Polish Mother's Memorial Hospital Research Institute, 93-338, Lodz, Poland
| | - Marcin Derwich
- Department of Developmental Dentistry, Medical University of Lodz, 90-647, Lodz, Poland
| | - Elzbieta Pawlowska
- Department of Developmental Dentistry, Medical University of Lodz, 90-647, Lodz, Poland
| | - Janusz Blasiak
- Faculty of Medicine, Collegium Medicum, Mazovian Academy in Plock, 09-420, Plock, Poland.
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Wang Y, Ji Q, Cao N, Ge G, Li X, Liu X, Mi Y. CYP19A1 regulates chemoresistance in colorectal cancer through modulation of estrogen biosynthesis and mitochondrial function. Cancer Metab 2024; 12:33. [PMID: 39468645 PMCID: PMC11520061 DOI: 10.1186/s40170-024-00360-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 10/20/2024] [Indexed: 10/30/2024] Open
Abstract
Chemoresistance remains a major challenge in the effective treatment of colorectal cancer (CRC), contributing to poor patient outcomes. While the molecular mechanisms underlying chemoresistance are complex and multifaceted, emerging evidence suggests that altered mitochondrial function and hormone signaling play crucial roles. In this study, we investigated the role of CYP19A1, a key enzyme in estrogen biosynthesis, in regulating chemoresistance in CRC. Using a combination of in vitro functional assays, transcriptomic analysis, and clinical data mining, we demonstrate that CYP19A1 expression is significantly upregulated in CRC cells and patient-derived samples compared to normal controls. Mechanistically, we found that CYP19A1 regulates chemoresistance through modulation of mitochondrial function and complex I activity, which is mediated by CYP19A1-dependent estrogen biosynthesis. Notably, targeted inhibition of CYP19A1 and complex I using specific inhibitors effectively reversed the chemoresistance of CRC cells to chemotherapeutic drugs. Moreover, analysis of the TCGA CRC dataset revealed that high CYP19A1 expression correlates with poor overall survival in chemotherapy-treated patients. Taken together, our findings uncover a novel role for CYP19A1 in regulating chemoresistance in CRC through modulation of mitochondrial function and estrogen signaling, and highlight the potential of targeting the CYP19A1/estrogen/complex I axis as a therapeutic strategy to overcome chemoresistance and improve patient outcomes.
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Affiliation(s)
- Yang Wang
- Department of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qiang Ji
- Department of Pharmacy, Sunshine Union Hospital, Weifang, Shandong, China
| | - Ning Cao
- Emergency General Surgery, Weifang People's Hospital, Shandong Second Medical University, Weifang, Shandong, China
| | - Guijie Ge
- Department of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaomin Li
- Department of Anesthesiology II Endoscopy Center, Weifang People's Hospital, Weifang, Shandong, China
| | - Xiangdong Liu
- Medical Center of gastrointestinal Surgery, Weifang People's Hospital, Weifang, Shandong, China
| | - Yanqi Mi
- Department of Pharmacy, Weifang People's Hospital, Weifang, Shandong, China.
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Kalimon OJ, Vekaria HJ, Prajapati P, Short SL, Hubbard WB, Sullivan PG. The Uncoupling Effect of 17β-Estradiol Underlies the Resilience of Female-Derived Mitochondria to Damage after Experimental TBI. Life (Basel) 2024; 14:961. [PMID: 39202703 PMCID: PMC11355196 DOI: 10.3390/life14080961] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 07/26/2024] [Accepted: 07/27/2024] [Indexed: 09/03/2024] Open
Abstract
Current literature finds females have improved outcomes over their male counterparts after severe traumatic brain injury (TBI), while the opposite seems to be true for mild TBI. This begs the question as to what may be driving these sex differences after TBI. Estrogen is thought to be neuroprotective in certain diseases, and its actions have been shown to influence mitochondrial function. Mitochondrial impairment is a major hallmark of TBI, and interestingly, this dysfunction has been shown to be more severe in males than females after brain injury. This suggests estrogen could be playing a role in promoting "mitoprotection" following TBI. Despite the existence of estrogen receptors in mitochondria, few studies have examined the direct role of estrogen on mitochondrial function, and no studies have explored this after TBI. We hypothesized ex vivo treatment of isolated mitochondria with 17β-estradiol (E2) would improve mitochondrial function after experimental TBI in mice. Total mitochondria from the ipsilateral (injured) and contralateral (control) cortices of male and female mice were isolated 24 h post-controlled severe cortical impact (CCI) and treated with vehicle, 2 nM E2, or 20 nM E2 immediately before measuring reactive oxygen species (ROS) production, bioenergetics, electron transport chain complex (ETC) activities, and β-oxidation of palmitoyl carnitine. Protein expression of oxidative phosphorylation (OXPHOS) complexes was also measured in these mitochondrial samples to determine whether this influenced functional outcomes with respect to sex or injury. While mitochondrial ROS production was affected by CCI in both sexes, there were other sex-specific patterns of mitochondrial injury 24 h following severe CCI. For instance, mitochondria from males were more susceptible to CCI-induced injury with respect to bioenergetics and ETC complex activities, whereas mitochondria from females showed only Complex II impairment and reduced β-oxidation after injury. Neither concentration of E2 influenced ETC complex activities themselves, but 20 nM E2 appeared to uncouple mitochondria isolated from the contralateral cortex in both sexes, as well as the injured ipsilateral cortex of females. These studies highlight the significance of measuring mitochondrial dysfunction in both sexes after TBI and also shed light on another potential neuroprotective mechanism in which E2 may attenuate mitochondrial dysfunction after TBI in vivo.
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Affiliation(s)
- Olivia J. Kalimon
- Department of Neuroscience, University of Kentucky, Lexington, KY 40508, USA;
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA; (H.J.V.); (P.P.); (S.L.S.); (W.B.H.)
- Lexington Veterans Affairs Healthcare System, Lexington, KY 40502, USA
| | - Hemendra J. Vekaria
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA; (H.J.V.); (P.P.); (S.L.S.); (W.B.H.)
- Lexington Veterans Affairs Healthcare System, Lexington, KY 40502, USA
| | - Paresh Prajapati
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA; (H.J.V.); (P.P.); (S.L.S.); (W.B.H.)
- Lexington Veterans Affairs Healthcare System, Lexington, KY 40502, USA
| | - Sydney L. Short
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA; (H.J.V.); (P.P.); (S.L.S.); (W.B.H.)
| | - W. Brad Hubbard
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA; (H.J.V.); (P.P.); (S.L.S.); (W.B.H.)
- Lexington Veterans Affairs Healthcare System, Lexington, KY 40502, USA
- Department of Physiology, University of Kentucky, Lexington, KY 40508, USA
| | - Patrick G. Sullivan
- Department of Neuroscience, University of Kentucky, Lexington, KY 40508, USA;
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA; (H.J.V.); (P.P.); (S.L.S.); (W.B.H.)
- Lexington Veterans Affairs Healthcare System, Lexington, KY 40502, USA
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Merzel Šabović EK, Kocjan T, Zalaudek I. Treatment of menopausal skin - A narrative review of existing treatments, controversies, and future perspectives. Post Reprod Health 2024; 30:85-94. [PMID: 38379168 DOI: 10.1177/20533691241233440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2024]
Abstract
Menopause is a state of estrogen deficiency that affects numerous estrogen-dependent tissues in the female body. Skin is one of the most affected organs. Many consider menopausal skin changes to be merely an aesthetic problem; however, they can significantly affect women's quality of life. Currently, there are no approved effective treatments to prevent or alleviate skin changes associated with estrogen deficiency. Standard systemic hormone replacement therapy used to treat menopausal symptoms may be effective to some degree for skin treatment. In addition, compounded bioidentical hormone replacement therapy, selective estrogen receptor modulators, and phytoestrogens could also be used for skin treatment, although this is only hypothetical due to lack of data. Many questions therefore remain unanswered. On the other hand, topical, low-dose estrogen that would act only on the skin without systemic effects could be a possible option, as could be skin-only acting topical phytoestrogens. Such topical products without systemic effects could play a role in the treatment of menopausal skin. However, they are not currently approved because there is insufficient data on their safety and efficacy. A healthy lifestyle could have a positive effect on the menopausal skin. In this review, we provide an overview of the characteristics of menopausal skin, an outlook on the future treatment of menopausal skin with estrogens and other approaches, and the associated controversies and speculations. Overall, the importance of menopausal skin changes should not be neglected, and high-quality research is needed to gain new insights into the treatment of menopausal skin.
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Affiliation(s)
- Eva K Merzel Šabović
- Department of Dermatology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tomaž Kocjan
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Iris Zalaudek
- Department of Dermatology, Maggiore Hospital, University of Trieste, Trieste, Italy
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Kleis-Olsen AS, Farlov JE, Petersen EA, Schmücker M, Flensted-Jensen M, Blom I, Ingersen A, Hansen M, Helge JW, Dela F, Larsen S. Metabolic flexibility in postmenopausal women: Hormone replacement therapy is associated with higher mitochondrial content, respiratory capacity, and lower total fat mass. Acta Physiol (Oxf) 2024; 240:e14117. [PMID: 38404156 DOI: 10.1111/apha.14117] [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: 11/28/2023] [Revised: 01/24/2024] [Accepted: 02/07/2024] [Indexed: 02/27/2024]
Abstract
AIM To investigate effects of hormone replacement therapy in postmenopausal women on factors associated with metabolic flexibility related to whole-body parameters including fat oxidation, resting energy expenditure, body composition and plasma concentrations of fatty acids, glucose, insulin, cortisol, and lipids, and for the mitochondrial level, including mitochondrial content, respiratory capacity, efficiency, and hydrogen peroxide emission. METHODS 22 postmenopausal women were included. 11 were undergoing estradiol and progestin treatment (HT), and 11 were matched non-treated controls (CONT). Peak oxygen consumption, maximal fat oxidation, glycated hemoglobin, body composition, and resting energy expenditure were measured. Blood samples were collected at rest and during 45 min of ergometer exercise (65% VO2peak). Muscle biopsies were obtained at rest and immediately post-exercise. Mitochondrial respiratory capacity, efficiency, and hydrogen peroxide emission in permeabilized fibers and isolated mitochondria were measured, and citrate synthase (CS) and 3-hydroxyacyl-CoA dehydrogenase (HAD) activity were assessed. RESULTS HT showed higher absolute mitochondrial respiratory capacity and post-exercise hydrogen peroxide emission in permeabilized fibers and higher CS and HAD activities. All respiration normalized to CS activity showed no significant group differences in permeabilized fibers or isolated mitochondria. There were no differences in resting energy expenditure, maximal, and resting fat oxidation or plasma markers. HT had significantly lower visceral and total fat mass compared to CONT. CONCLUSION Use of hormone therapy is associated with higher mitochondrial content and respiratory capacity and a lower visceral and total fat mass. Resting energy expenditure and fat oxidation did not differ between HT and CONT.
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Affiliation(s)
- A S Kleis-Olsen
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - J E Farlov
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - E A Petersen
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - M Schmücker
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - M Flensted-Jensen
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - I Blom
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - A Ingersen
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - M Hansen
- Department of Public Health, Section of Sport Science, Aarhus University, Aarhus N, Denmark
| | - J W Helge
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - F Dela
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Geriatrics, Bispebjerg-Frederiksberg University Hospital, Copenhagen, Denmark
- Department of Human Physiology and Biochemistry, Riga Stradiņš University, Riga, Latvia
| | - S Larsen
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
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Miao C, Zhao Y, Chen Y, Wang R, Ren N, Liu Q, Dou X, Zhang Q. He 's Yangchao recipe improves premature ovarian insufficiency by regulating mitochondrial biogenesis of granulose cells via ER β/PGC1 α/TFAM pathway. Zhejiang Da Xue Xue Bao Yi Xue Ban 2024; 53:358-367. [PMID: 39188182 PMCID: PMC11348690 DOI: 10.3724/zdxbyxb-2023-0521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/14/2024] [Indexed: 08/28/2024]
Abstract
OBJECTIVES To investigate the effect of Chinese medicine He's Yangchao recipe on premature ovarian insufficiency (POI) and its relationship with mitochondrial function of ovarian granulose cells in an animal model. METHODS Thirty-six female C57BL/6J mice were randomly divided into blank control group, model group, low-, medium- and high-dose He's Yangchao recipe treatment group and coenzyme Q10 (Q10) treatment group (positive control). The POI model was induced by a single intraperitoneal injection of cyclophosphamide (90 mg/kg). The animals were sacrificed after 21 days. Primary granulose cells were obtained from POI mice and treated with He's Yangchao recipe, ERβ inhibitor PHTPP, and He's Yangchao recipe+PHTPP in vitro for 24 h, respectively. Ovarian histopathological changes were observed by hematoxylin-eosin (HE) staining, ATP levels were detected by luciferase assay, mtDNA copy numbers were detected by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), mitochondrial structure changes were observed by transmission electron microscopy, protein and mRNA expression levels of estrogen receptor β (ERβ), peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), mitochondrial transcription factor A (TFAM), and superoxide dismutase 2 (SOD2) were detected by Western blotting and qRT-PCR. RESULTS The ovarian tissue in model group exhibited few secondary and tertiary follicles, whereas the He's Yangchao recipe groups and Q10 group had abundant secondary and tertiary follicles. Compared with the blank control group, ATP and mtDNA levels in model group decreased (P<0.01), mitochondrial crista disappeared or abnormal vacuolated structure increased; the protein and mRNA levels of ERβ, PGC1α, TFAM, and SOD2 decreased (all P<0.01). ATP production increased in granulose cells of high-dose He's Yangchao recipe group and Q10 group; mtDNA copy numbers increased (P<0.05 or P<0.01); abnormal mitochondrial structure was reduced; the protein and mRNA expressions of ERβ, PGC1α, TFAM, and SOD2 increased (P<0.05 or P<0.01). Compared with the PHTPP intervention group, the proportion of normal mitochondrial structure in the granulose cells of He's Yangchao recipe + PHTPP group was higher; ATP content increased (P<0.05 or P<0.01); mtDNA copy numbers increased (P<0.05 or P<0.01); the protein and mRNA expression of ERβ, PGC1α, TFAM and SOD2 increased (P<0.05 or P<0.01). CONCLUSIONS He's Yangchao recipe can regulate mitochondrial biogenesis through ERβ/PGC1α/TFAM pathway to improve ovarian function in POI mice.
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Affiliation(s)
- Chenyun Miao
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Ying Zhao
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yun Chen
- Department of TCM Gynecology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310007, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou 310016, China
| | - Ruye Wang
- Department of TCM Gynecology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310007, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou 310016, China
| | - Ning Ren
- Department of TCM Gynecology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310007, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou 310016, China
| | - Qing Liu
- Department of TCM Gynecology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310007, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou 310016, China
| | - Xiaobing Dou
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Qin Zhang
- Department of TCM Gynecology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310007, China.
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou 310016, China.
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Bhat MA, Dhaneshwar S. Neurodegenerative Diseases: New Hopes and Perspectives. Curr Mol Med 2024; 24:1004-1032. [PMID: 37691199 DOI: 10.2174/1566524023666230907093451] [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: 05/29/2023] [Revised: 07/10/2023] [Accepted: 07/27/2023] [Indexed: 09/12/2023]
Abstract
Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and Friedrich ataxia are all incurable neurodegenerative diseases defined by the continuous progressive loss of distinct neuronal subtypes. Despite their rising prevalence among the world's ageing population, fewer advances have been made in the concurrent massive efforts to develop newer drugs. Recently, there has been a shift in research focus towards the discovery of new therapeutic agents for neurodegenerative diseases. In this review, we have summarized the recently developed therapies and their status in the management of neurodegenerative diseases.
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Affiliation(s)
- Mohammad Aadil Bhat
- Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, Noida, UP, India
| | - Suneela Dhaneshwar
- Amity Institute of Pharmacy, Amity University Maharashtra, Mumbai, Maharashtra, India
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11
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Fliegner D, Ellieva A, Angelov A, Petrov G, Regitz-Zagrosek V. Sex differences and estrogen effects in cardiac mitochondria in human aortic stenosis and in the mouse heart. Front Endocrinol (Lausanne) 2023; 14:1181044. [PMID: 37916152 PMCID: PMC10617023 DOI: 10.3389/fendo.2023.1181044] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 09/22/2023] [Indexed: 11/03/2023] Open
Abstract
Introduction Sex differences in the adaptation to pressure overload have been described in humans, as well as animal models, and have been related to sex-specific expression of mitochondrial genes. We therefore tested whether sex differences in cardiac mitochondrial respiration exist in humans with aortic stenosis (AS). We also examined whether these potential differences may be at least partially due to sex hormones by testing if mitochondrial respiration is affected by estrogen (17ß-estradiol (E2)). Methods Consecutive patients undergoing transapical aortic valve implantation (TAVI) (women, n = 7; men, n = 10) were included. Cardiac biopsies were obtained during TAVI and used directly for mitochondrial function measurements. Male and female C57BL/6J mice (n = 8/group) underwent sham surgery or gonadectomy (GDX) at the age of 2 months. After 14 days, mice were treated once with intraperitoneally injected vehicle (placebo), 17ß-estradiol (E2), estrogen receptor alpha (ERα) agonist [propyl pyrazole triol (PPT)], or ER beta (ERβ) agonist (BAY-1214257). Thereafter, mitochondrial measurements were performed directly in cardiac skinned fibers from isolated left ventricles and musculus solei. Results Mitochondrial State-3 respiration was higher in female than that in male human heart biopsies (15.0 ± 2.30 vs. 10.3 ± 2.05 nmol/mL/min/mg, p< 0.05). In the mouse model, mitochondrial State-3 respiration decreased significantly after GDX in female (27.6 ± 1.55 vs. 21.4 ± 1.71 nmol/mL/min/mg; p< 0.05) and male hearts (30.7 ± 1,48 vs. 23.7 ± 2,23 nmol/mL/min/mg; p< 0.05). In ovariectomized female mice, E2 and ERβ-agonist treatment restored the State-3 respiration to intact placebo level, whereas ERα-agonist treatment did not modulate State-3 respiration. The treatment with E2, ERα-, or ERβ-agonist did not modulate the State-3 respiration in GDX male mice. Conclusion We identified sex differences in mitochondrial respiration in the diseased human heart. This is in alignment with known sex differences in the gene expression and proteome level at the functional level. E2 and ERβ affect cardiac mitochondrial function in the mouse model, suggesting that they may also contribute to the sex differences in the human heart. Their roles should be further investigated.
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Affiliation(s)
- Daniela Fliegner
- Institute of Gender in Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
- Medical Affairs Internal Medicine, Pfizer Pharma GmbH, Berlin, Germany
| | - Alexandra Ellieva
- Institute of Gender in Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Anja Angelov
- Institute of Gender in Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | | | - Vera Regitz-Zagrosek
- Institute of Gender in Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
- Clinic for Cardiology, University Hospital Zürich, Zürich, Switzerland
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Helman TJ, Headrick JP, Stapelberg NJC, Braidy N. The sex-dependent response to psychosocial stress and ischaemic heart disease. Front Cardiovasc Med 2023; 10:1072042. [PMID: 37153459 PMCID: PMC10160413 DOI: 10.3389/fcvm.2023.1072042] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 04/03/2023] [Indexed: 05/09/2023] Open
Abstract
Stress is an important risk factor for modern chronic diseases, with distinct influences in males and females. The sex specificity of the mammalian stress response contributes to the sex-dependent development and impacts of coronary artery disease (CAD). Compared to men, women appear to have greater susceptibility to chronic forms of psychosocial stress, extending beyond an increased incidence of mood disorders to include a 2- to 4-fold higher risk of stress-dependent myocardial infarction in women, and up to 10-fold higher risk of Takotsubo syndrome-a stress-dependent coronary-myocardial disorder most prevalent in post-menopausal women. Sex differences arise at all levels of the stress response: from initial perception of stress to behavioural, cognitive, and affective responses and longer-term disease outcomes. These fundamental differences involve interactions between chromosomal and gonadal determinants, (mal)adaptive epigenetic modulation across the lifespan (particularly in early life), and the extrinsic influences of socio-cultural, economic, and environmental factors. Pre-clinical investigations of biological mechanisms support distinct early life programming and a heightened corticolimbic-noradrenaline-neuroinflammatory reactivity in females vs. males, among implicated determinants of the chronic stress response. Unravelling the intrinsic molecular, cellular and systems biological basis of these differences, and their interactions with external lifestyle/socio-cultural determinants, can guide preventative and therapeutic strategies to better target coronary heart disease in a tailored sex-specific manner.
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Affiliation(s)
- Tessa J. Helman
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, NSW, Sydney, Australia
- Correspondence: Tessa J. Helman
| | - John P. Headrick
- Schoolof Pharmacy and Medical Sciences, Griffith University, Southport, QLD, Australia
| | | | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, NSW, Sydney, Australia
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Queathem ED, Fitzgerald M, Welly R, Rowles CC, Schaller K, Bukhary S, Baines CP, Rector RS, Padilla J, Manrique-Acevedo C, Lubahn DB, Vieira-Potter VJ. Suppression of estrogen receptor beta classical genomic activity enhances systemic and adipose-specific response to chronic beta-3 adrenergic receptor (β3AR) stimulation. Front Physiol 2022; 13:920675. [PMID: 36213237 PMCID: PMC9534559 DOI: 10.3389/fphys.2022.920675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 08/15/2022] [Indexed: 11/23/2022] Open
Abstract
White adipose tissue (WAT) dysfunction independently predicts cardiometabolic disease, yet there is a lack of effective adipocyte-targeting therapeutics. B3AR agonists enhance adipocyte mitochondrial function and hold potential in this regard. Based on enhanced sensitivity to B3AR-mediated browning in estrogen receptor (ER)alpha-null mice, we hypothesized that ERβ may enhance the WAT response to the B3AR ligand, CL316,243 (CL). Methods: Male and female wild-type (WT) and ERβ DNA binding domain knock-out (ERβDBDKO) mice fed high-fat diet (HFD) to induce obesity were administered CL (1 mg/kg) daily for 2 weeks. Systemic physiological assessments of body composition (EchoMRI), bioenergetics (metabolic chambers), adipocyte mitochondrial respiration (oroboros) and glucose tolerance were performed, alongside perigonadal (PGAT), subcutaneous (SQAT) and brown adipose tissue (BAT) protein expression assessment (Western blot). Mechanisms were tested in vitro using primary adipocytes isolated from WT mice, and from Esr2-floxed mice in which ERβ was knocked down. Statistical analyses were performed using 2 × 2 analysis of variance (ANOVA) for main effects of genotype (G) and treatment (T), as well as GxT interactions; t-tests were used to determine differences between in vitro treatment conditions (SPSS V24). Results: There were no genotype differences in HFD-induced obesity or systemic rescue effects of CL, yet ERβDBDKO females were more sensitive to CL-induced increases in energy expenditure and WAT UCP1 induction (GxT, p < 0.05), which coincided with greater WAT B3AR protein content among the KO (G, p < 0.05). Among males, who were more insulin resistant to begin with (no genotype differences before treatment), tended to be more sensitive to CL-mediated reduction in insulin resistance. With sexes combined, basal WAT mitochondrial respiration trended toward being lower in the ERβDBDKO mice, but this was completely rescued by CL (p < 0.05). Confirming prior work, CL increased adipose tissue ERβ protein (T, p < 0.05, all), an effect that was enhanced in WAT and BAT the female KO (GxT, p < 0.01). In vitro experiments indicated that an inhibitor of ERβ genomic function (PHTPP) synergized with CL to further increase UCP1 mRNA (p = 0.043), whereas full ERβ protein was required for UCP1 expression (p = 0.042). Conclusion: Full ERβ activity appears requisite and stimulatory for UCP1 expression via a mechanism involving non-classical ERβ signaling. This novel discovery about the role of ERβ in adipocyte metabolism may have important clinical applications.
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Affiliation(s)
- Eric D. Queathem
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
- Department of Biochemistry, University of Missouri, Columbia, MO, United States
| | - Maggie Fitzgerald
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
| | - Rebecca Welly
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
| | - Candace C. Rowles
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
| | - Kylie Schaller
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
- Department of Biochemistry, University of Missouri, Columbia, MO, United States
| | - Shahad Bukhary
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
| | - Christopher P. Baines
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, United States
- Department of Biomedical Sciences, University of Missouri, Columbia, MO, United States
| | - R. Scott Rector
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
- Internal Medicine-Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO, United States
- Research Service, Truman VA Memorial Hospital, Columbia, MO, United States
| | - Jaume Padilla
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, United States
| | - Camila Manrique-Acevedo
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri Columbia School of Medicine, Columbia, MO, United States
| | - Dennis B. Lubahn
- Department of Biochemistry, University of Missouri, Columbia, MO, United States
| | - Victoria J. Vieira-Potter
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
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14
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Sex Steroid Receptors in Polycystic Ovary Syndrome and Endometriosis: Insights from Laboratory Studies to Clinical Trials. Biomedicines 2022; 10:biomedicines10071705. [PMID: 35885010 PMCID: PMC9312843 DOI: 10.3390/biomedicines10071705] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 07/12/2022] [Accepted: 07/13/2022] [Indexed: 12/13/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) and endometriosis are reproductive disorders that may cause infertility. The pathology of both diseases has been suggested to be associated with sex steroid hormone receptors, including oestrogen receptors (ER), progesterone receptors (PRs) and androgen receptors (ARs). Therefore, with this review, we aim to provide an update on the available knowledge of these receptors and how their interactions contribute to the pathogenesis of PCOS and endometriosis. One of the main PCOS-related medical conditions is abnormal folliculogenesis, which is associated with the downregulation of ER and AR expression in the ovaries. In addition, metabolic disorders in PCOS are caused by dysregulation of sex steroid hormone receptor expression. Furthermore, endometriosis is related to the upregulation of ER and the downregulation of PR expression. These receptors may serve as therapeutic targets for the treatment of PCOS-related disorders and endometriosis, considering their pathophysiological roles. Receptor agonists may be applied to increase the expression of a specific receptor and treat endometriosis or metabolic disorders. In contrast, receptor antagonist functions to reduce receptor expression and can be used to treat endometriosis and induce ovulation. Understanding PCOS and the pathological roles of endometriosis sex steroid receptors is crucial for developing potential therapeutic strategies to treat infertility in both conditions. Therefore, research should be continued to fill the knowledge gap regarding the subject.
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Yang K, Cao F, Xue Y, Tao L, Zhu Y. Three Classes of Antioxidant Defense Systems and the Development of Postmenopausal Osteoporosis. Front Physiol 2022; 13:840293. [PMID: 35309045 PMCID: PMC8927967 DOI: 10.3389/fphys.2022.840293] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 01/25/2022] [Indexed: 01/04/2023] Open
Abstract
Osteoporosis is a common bone imbalance disease that threatens the health of postmenopausal women. Estrogen deficiency accelerates the aging of women. Oxidative stress damage is regarded as the main pathogenesis of postmenopausal osteoporosis. The accumulation of reactive oxygen species in the bone microenvironment plays a role in osteoblast and osteoclast apoptosis. Improving the oxidative state is essential for the prevention and treatment of postmenopausal osteoporosis. There are three classes of antioxidant defense systems in the body to eliminate free radicals and peroxides including antioxidant substances, antioxidant enzymes, and repair enzymes. In our review, we demonstrated the mechanism of antioxidants and their effect on bone metabolism in detail. We concluded that glutathione/oxidized glutathione (GSH/GSSG) conversion involved the PI3K/Akt-Nrf2/HO-1 signaling pathway and that the antioxidant enzyme-mediated mitochondrial apoptosis pathway of osteoblasts was necessary for the development of postmenopausal osteoporosis. Since the current therapeutic effects of targeting bone cells are not significant, improving the systemic peroxidation state and then regulating bone homeostasis will be a new method for the treatment of postmenopausal osteoporosis.
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Affiliation(s)
- Keda Yang
- Department of Orthopedics, First Hospital of China Medical University, Shenyang, China
| | - Fangming Cao
- Department of Orthopedics, First Hospital of China Medical University, Shenyang, China
| | - Yuchuan Xue
- The First Department of Clinical Medicine, China Medical University, Shenyang, China
| | - Lin Tao
- Department of Orthopedics, First Hospital of China Medical University, Shenyang, China
- *Correspondence: Lin Tao,
| | - Yue Zhu
- Department of Orthopedics, First Hospital of China Medical University, Shenyang, China
- Yue Zhu,
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16
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Chung JK, Ahn YM, Kim SA, Joo EJ. Differences in mitochondrial DNA copy number between patients with bipolar I and II disorders. J Psychiatr Res 2022; 145:325-333. [PMID: 33190840 DOI: 10.1016/j.jpsychires.2020.11.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 10/08/2020] [Accepted: 11/05/2020] [Indexed: 02/01/2023]
Abstract
Mitochondria play a critical role in energy metabolism. Genetic, postmortem brain, and brain imaging studies of bipolar disorder (BD) patients indicated that mitochondrial dysfunction might explain BD pathophysiology. Mitochondrial function can be indirectly evaluated by measuring mitochondrial DNA (mtDNA) copy numbers. We recruited 186 bipolar I disorder (BD1) and 95 bipolar II disorder (BD2) patients, and age- and sex-matched controls. MtDNA copy numbers in peripheral blood cells were measured via quantitative polymerase chain reaction. We explored parameters (including age and clinical features) that might affect mtDNA copy numbers. We found that BD1 patients had a lower mtDNA copy number than controls and that mtDNA copy number was negatively associated with the number of mood episodes. BD2 patients had a higher mtDNA copy number than controls. Thus, changes in mitochondrial function may influence BD pathophysiology. The opposite directions of the association with mtDNA copy number in BD1 and BD2 patients suggests that the difference in pathophysiology may be associated with mitochondrial function.
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Affiliation(s)
- Jae Kyung Chung
- Department of Psychiatry, Eumsung-somang Hospital, Eumsung, Republic of Korea
| | - Yong Min Ahn
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea; Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human Behavioral Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Soon Ae Kim
- Department of Pharmacology, School of Medicine, Eulji University, Daejeon, Republic of Korea.
| | - Eun-Jeong Joo
- Department of Neuropsychiatry, School of Medicine, Eulji University, Daejeon, Republic of Korea; Department of Psychiatry, Nowon Eulji Medical Center, Eulji University, Seoul, Republic of Korea.
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17
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Fotesko K, Thomsen BSV, Kolko M, Vohra R. Girl Power in Glaucoma: The Role of Estrogen in Primary Open Angle Glaucoma. Cell Mol Neurobiol 2022; 42:41-57. [PMID: 33040237 PMCID: PMC11441221 DOI: 10.1007/s10571-020-00965-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 09/22/2020] [Indexed: 12/24/2022]
Abstract
Estrogen is essential in maintaining various physiological features in women, and a decline in estrogen levels are known to give rise to numerous unfortunate symptoms associated with menopause. To alleviate these symptoms hormone replacement therapy with estrogen is often used, and has been shown to be fruitful in improving quality of life in women suffering from postmenopausal discomforts. An often forgotten condition associated with menopause is the optic nerve disorder, glaucoma. Thus, estrogen may also have an impact in maintaining the retinal ganglion cells (RGCs), which make up the optic nerve, thereby preventing glaucomatous neurodegeneration. This review aims to provide an overview of possible associations of estrogen and the glaucoma subtype, primary open-angle glaucoma (POAG), by evaluating the current literature through a PubMed-based literature search. Multiple in vitro and in vivo studies of RGC protection, as well as clinical and epidemiological data concerning the well-defined retinal neurodegenerative disorder POAG have been reviewed. Over all, deficiencies in retinal estrogen may potentially instigate RGC loss, visual disability, and eventual blindness. Estrogen replacement therapy may therefore be a beneficial future treatment. However, more studies are needed to confirm the relevance of estrogen in glaucoma prevention.
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Affiliation(s)
- Kyrylo Fotesko
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | | | - Miriam Kolko
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
- Department of Ophthalmology, Rigshospitalet-Glostrup, Glostrup, Denmark.
| | - Rupali Vohra
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark.
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18
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Maharjan CK, Mo J, Wang L, Kim MC, Wang S, Borcherding N, Vikas P, Zhang W. Natural and Synthetic Estrogens in Chronic Inflammation and Breast Cancer. Cancers (Basel) 2021; 14:cancers14010206. [PMID: 35008370 PMCID: PMC8744660 DOI: 10.3390/cancers14010206] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/17/2021] [Accepted: 12/19/2021] [Indexed: 12/17/2022] Open
Abstract
The oncogenic role of estrogen receptor (ER) signaling in breast cancer has long been established. Interaction of estrogen with estrogen receptor (ER) in the nucleus activates genomic pathways of estrogen signaling. In contrast, estrogen interaction with the cell membrane-bound G-protein-coupled estrogen receptor (GPER) activates the rapid receptor-mediated signaling transduction cascades. Aberrant estrogen signaling enhances mammary epithelial cell proliferation, survival, and angiogenesis, hence is an important step towards breast cancer initiation and progression. Meanwhile, a growing number of studies also provide evidence for estrogen's pro- or anti-inflammatory roles. As other articles in this issue cover classic ER and GPER signaling mediated by estrogen, this review will discuss the crucial mechanisms by which estrogen signaling influences chronic inflammation and how that is involved in breast cancer. Xenoestrogens acquired from plant diet or exposure to industrial products constantly interact with and alter innate estrogen signaling at various levels. As such, they can modulate chronic inflammation and breast cancer development. Natural xenoestrogens generally have anti-inflammatory properties, which is consistent with their chemoprotective role in breast cancer. In contrast, synthetic xenoestrogens are proinflammatory and carcinogenic compounds that can increase the risk of breast cancer. This article also highlights important xenoestrogens with a particular focus on their role in inflammation and breast cancer. Improved understanding of the complex relationship between estrogens, inflammation, and breast cancer will guide clinical research on agents that could advance breast cancer prevention and therapy.
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Affiliation(s)
- Chandra K. Maharjan
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA; (C.K.M.); (J.M.); (L.W.); (M.-C.K.)
| | - Jiao Mo
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA; (C.K.M.); (J.M.); (L.W.); (M.-C.K.)
| | - Lei Wang
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA; (C.K.M.); (J.M.); (L.W.); (M.-C.K.)
| | - Myung-Chul Kim
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA; (C.K.M.); (J.M.); (L.W.); (M.-C.K.)
| | - Sameul Wang
- Canyonoak Consulting LLC, San Diego, CA 92127, USA;
| | - Nicholas Borcherding
- Department of Pathology and Immunology, School of Medicine, Washington University, St. Louis, MO 63110, USA;
| | - Praveen Vikas
- Department of Internal Medicine, Carver College of Medicine, Iowa City, IA 52242, USA;
| | - Weizhou Zhang
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA; (C.K.M.); (J.M.); (L.W.); (M.-C.K.)
- Mechanism of Oncogenesis Program, University of Florida Health Cancer Center, University of Florida, Gainesville, FL 32610, USA
- Correspondence: to: ; Tel.: +1-352-273-6748
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Shaw GA. Mitochondria as the target for disease related hormonal dysregulation. Brain Behav Immun Health 2021; 18:100350. [PMID: 34746877 PMCID: PMC8554460 DOI: 10.1016/j.bbih.2021.100350] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 09/12/2021] [Accepted: 09/17/2021] [Indexed: 12/13/2022] Open
Abstract
Mitochondria play an important role in the synthesis of steroid hormones, including the sex hormone estrogen. Sex-specific regulation of these hormones is important for phenotypic development and downstream, sex-specific activational effects in both brain and behavior. First, mitochondrial contribution to the synthesis of estrogen, followed by a discussion of the signaling interactions between estrogen and the mitochondria will be reviewed. Next, disorders with an established sex difference related to aging, mood, and cognition will be examined. Finally, review of mitochondria as a biomarker of disease and data supporting efforts in targeting mitochondria as a therapeutic target for the amelioration of these disorders will be discussed. Taken together, this review aims to assess the influence of E2 on mitochondrial function within the brain via exploration of E2-ER interactions within neural mitochondria and how they may act to influence the development and presentation of neurodegenerative and neurocognitive diseases with known sex differences.
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Affiliation(s)
- Gladys A. Shaw
- Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, USA
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Peng G, Zheng H, Wu C, Wu C, Ma X, Xiong J, Hou J, Zhang L, Yang L, Pan H. Intranasal administration of DHED protects against exhaustive exercise-induced brain injury in rats. Brain Res 2021; 1772:147665. [PMID: 34562473 DOI: 10.1016/j.brainres.2021.147665] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 09/07/2021] [Accepted: 09/18/2021] [Indexed: 11/24/2022]
Abstract
DHED (10β,17β-dihydroxyestra-1,4-dien-3-one) is a brain-selective prodrug of 17β-estradiol and has been reported to have a strong neuroprotective effect. In this study, the exhaustive swimming rat model was used to investigate the therapeutic effects and mechanisms of intranasal DHED treatment. Male eight-week-old healthy Sprague Dawley rats were randomly divided into three groups: control group (Cont), exhaustive swimming (ES), and DHED + exhaustive swimming (DHED). The open-field test and beam-walking test were performed to measure exploratory behavior and general activity in rats. Immunofluorescence staining, western blotting, ELISA analysis and related assay kits were applied to measure brain damage, inflammatory cytokines, and apoptosis pathways. Behavioral data shows that DHED intranasal administration can prevent neurobehavioral impairment caused by exhaustive swimming. Using a series of bioanalytical assays, we demonstrated that DHED markedly abated neuronal injury compared to the exhaustive swimming group, as evidenced by the reduced expression of apoptosis-regulated proteins, the improvement of neural survival, and the prevention of myelin loss. In addition, mitochondrial fission was attenuated distinctly, and a dynamic equilibrium was restored. Intranasal administration of DHED likewise significantly suppressed reactive gliosis and the release of inflammatory cytokines in the rat cerebral motor cortex. Consistent with previous reports, DHED treatment ameliorated changes of excitatory neurotransmitters. These results provide strong support for the promising therapeutic effects of DHED on neuroprotection during exhaustive swimming. The underlying mechanisms may rely on mitochondrial dynamics, neuroinflammation, and the balance of neurotransmitters.
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Affiliation(s)
- Guangcong Peng
- Cognitive & Sports Neuroscience Laboratory, National Demonstration Center for Experimental Sports Science Education, College of Physical Education and Sports Science, South China Normal University, Guangzhou, Guangdong 510006, China
| | - Huaping Zheng
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, Guilin 541001, China
| | - Chunyi Wu
- Cognitive & Sports Neuroscience Laboratory, National Demonstration Center for Experimental Sports Science Education, College of Physical Education and Sports Science, South China Normal University, Guangzhou, Guangdong 510006, China
| | - Chongyun Wu
- Cognitive & Sports Neuroscience Laboratory, National Demonstration Center for Experimental Sports Science Education, College of Physical Education and Sports Science, South China Normal University, Guangzhou, Guangdong 510006, China
| | - Xu Ma
- Cognitive & Sports Neuroscience Laboratory, National Demonstration Center for Experimental Sports Science Education, College of Physical Education and Sports Science, South China Normal University, Guangzhou, Guangdong 510006, China
| | - Jing Xiong
- Cognitive & Sports Neuroscience Laboratory, National Demonstration Center for Experimental Sports Science Education, College of Physical Education and Sports Science, South China Normal University, Guangzhou, Guangdong 510006, China
| | - Jun Hou
- Cognitive & Sports Neuroscience Laboratory, National Demonstration Center for Experimental Sports Science Education, College of Physical Education and Sports Science, South China Normal University, Guangzhou, Guangdong 510006, China
| | - Limei Zhang
- Cognitive & Sports Neuroscience Laboratory, National Demonstration Center for Experimental Sports Science Education, College of Physical Education and Sports Science, South China Normal University, Guangzhou, Guangdong 510006, China
| | - Luodan Yang
- Cognitive & Sports Neuroscience Laboratory, National Demonstration Center for Experimental Sports Science Education, College of Physical Education and Sports Science, South China Normal University, Guangzhou, Guangdong 510006, China.
| | - Hongying Pan
- Cognitive & Sports Neuroscience Laboratory, National Demonstration Center for Experimental Sports Science Education, College of Physical Education and Sports Science, South China Normal University, Guangzhou, Guangdong 510006, China.
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Burgos-Aceves MA, Migliaccio V, Di Gregorio I, Paolella G, Lepretti M, Faggio C, Lionetti L. 1,1,1-trichloro-2,2-bis (p-chlorophenyl)-ethane (DDT) and 1,1-Dichloro-2,2-bis (p, p'-chlorophenyl) ethylene (DDE) as endocrine disruptors in human and wildlife: A possible implication of mitochondria. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2021; 87:103684. [PMID: 34052433 DOI: 10.1016/j.etap.2021.103684] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 04/14/2021] [Accepted: 05/25/2021] [Indexed: 06/12/2023]
Abstract
1,1,1-trichloro-2,2-bis (p-chlorophenyl)-ethane (DDT) and its main metabolite 1,1-Dichloro-2,2-bis (p, p'-chlorophenyl) ethylene (DDE) act as endocrine disruptors in humans and wildlife. Immunomodulatory functions have also been attributed to both xenobiotics. DDT was banned in the 1970s due to its toxicity, but it is still produced and used for indoor residual spraying with disease vector control purposes. Due to their persistence and lipophilic properties, DDT and DDE can bioaccumulate through the food chain, being stored in organisms' adipose depots. Their endocrine disruptor function is mediated by agonist or antagonist interaction with nuclear receptors. Present review aimed to provide an overview of how DDT and DDE exposure impacts reproductive and immune systems with estrogen-disrupting action in humans and wildlife. Studies showing DDT and DDE impact on mitochondrial function and apoptosis pathway will also be reviewed, suggesting the hypothesis of direct action on mitochondrial steroid receptors.
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Affiliation(s)
- Mario Alberto Burgos-Aceves
- Department of Chemistry and Biology, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, SA, Italy
| | - Vincenzo Migliaccio
- Department of Chemistry and Biology, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, SA, Italy
| | - Ilaria Di Gregorio
- Department of Chemistry and Biology, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, SA, Italy
| | - Gaetana Paolella
- Department of Chemistry and Biology, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, SA, Italy
| | - Marilena Lepretti
- Department of Chemistry and Biology, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, SA, Italy
| | - Caterina Faggio
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres, 31, 98166 Messina, Italy
| | - Lillà Lionetti
- Department of Chemistry and Biology, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, SA, Italy.
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22
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Xu J, Zhou Y, Yan C, Wang X, Lou J, Luo Y, Gao S, Wang J, Wu L, Gao X, Shao A. Neurosteroids: A novel promise for the treatment of stroke and post-stroke complications. J Neurochem 2021; 160:113-127. [PMID: 34482541 DOI: 10.1111/jnc.15503] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 08/22/2021] [Accepted: 08/23/2021] [Indexed: 01/14/2023]
Abstract
Stroke is the primary reason for death and disability worldwide, with few treatment strategies to date. Neurosteroids, which are natural molecules in the brain, have aroused great interest in the field of stroke. Neurosteroids are a kind of steroid that acts on the nervous system, and are synthesized in the mitochondria of neurons or glial cells using cholesterol or other steroidal precursors. Neurosteroids mainly include estrogen, progesterone (PROG), allopregnanolone, dehydroepiandrosterone (DHEA), and vitamin D (VD). Most of the preclinical studies have confirmed that neurosteroids can decrease the risk of stroke, and improve stroke outcomes. In the meantime, neurosteroids have been shown to have a positive therapeutic significance in some post-stroke complications, such as epilepsy, depression, anxiety, cardiac complications, movement disorders, and post-stroke pain. In this review, we report the historical background, modulatory mechanisms of neurosteroids in stroke and post-stroke complications, and emphasize on the application prospect of neurosteroids in stroke therapy.
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Affiliation(s)
- Jiawei Xu
- The First Affiliated Hospital of Zhejiang, Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yunxiang Zhou
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Caochong Yan
- The Key Laboratory of Reproductive Genetics, Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaoyu Wang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianyao Lou
- Department of General Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yi Luo
- The Second Affiliated Hospital of Zhejiang University School of Medicine (Changxing Branch), Changxing, Huzhou, Zhejiang, China
| | - Shiqi Gao
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Junjie Wang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liang Wu
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiangfu Gao
- The First Affiliated Hospital of Zhejiang, Chinese Medical University, Hangzhou, Zhejiang, China
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Anti-Apoptotic and Antioxidant Activities of the Mitochondrial Estrogen Receptor Beta in N2A Neuroblastoma Cells. Int J Mol Sci 2021; 22:ijms22147620. [PMID: 34299239 PMCID: PMC8306648 DOI: 10.3390/ijms22147620] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/05/2021] [Accepted: 07/13/2021] [Indexed: 12/11/2022] Open
Abstract
Estrogens are steroid hormones that play a crucial role in the regulation of the reproductive and non-reproductive system physiology. Among non-reproductive systems, the nervous system is mainly affected by estrogens due to their antioxidant, anti-apoptotic, and anti-inflammatory activities, which are mediated by membranous and nuclear estrogen receptors, and also by non-estrogen receptor-associated estrogen actions. Neuronal viability and functionality are also associated with the maintenance of mitochondrial functions. Recently, the localization of estrogen receptors, especially estrogen receptor beta, in the mitochondria of many types of neuronal cells is documented, indicating the direct involvement of the mitochondrial estrogen receptor beta (mtERβ) in the maintenance of neuronal physiology. In this study, cell lines of N2A cells stably overexpressing a mitochondrial-targeted estrogen receptor beta were generated and further analyzed to study the direct involvement of mtERβ in estrogen neuroprotective antioxidant and anti-apoptotic actions. Results from this study revealed that the presence of estrogen receptor beta in mitochondria render N2A cells more resistant to staurosporine- and H2O2-induced apoptotic stimuli, as indicated by the reduced activation of caspase-9 and -3, the increased cell viability, the increased ATP production, and the increased resistance to mitochondrial impairment in the presence or absence of 17-β estradiol (E2). Thus, the direct involvement of mtERβ in antioxidant and anti-apoptotic activities is documented, rendering mtERβ a promising therapeutic target for mitochondrial dysfunction-associated degenerative diseases.
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24
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Lephart ED, Naftolin F. Menopause and the Skin: Old Favorites and New Innovations in Cosmeceuticals for Estrogen-Deficient Skin. Dermatol Ther (Heidelb) 2021; 11:53-69. [PMID: 33242128 PMCID: PMC7859014 DOI: 10.1007/s13555-020-00468-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Indexed: 12/14/2022] Open
Abstract
Estrogen is a pivotal signaling molecule; its production is regulated by the expression of the aromatase (CYP19A1) gene from ovarian and peripheral tissue sites, and it is transmitted via estrogen receptors to influence many important biological functions. However, the narrative for this overview focuses on the decline of 17β-estradiol levels from ovarian sites after menopause. This estrogen-deficient condition is associated with a dramatic reduction in skin health and wellness by negatively impacting dermal cellular and homeostatic mechanisms, as well as other important biological functions. The changes include loss of collagen, elastin, fibroblast function, vascularity, and increased matrix metalloproteinase(s) enzymatic activities, resulting in cellular and extracellular degradation that leads to dryness, wrinkles, atrophy, impaired wound healing/barrier function, decreased antioxidant capacity [i.e., defense against reactive oxygen species (ROS) and oxidative stress], decreased attractiveness and psychological health, and increased perception of aging. While topical estrogen may reverse these changes, the effects of today's low-dose systemic hormone treatments are not well established, raising the need for more concentrated local administration of hormones or newer cosmeceutical agents such as selective estrogen receptor modulators (SERMs), including phytoestrogens that have become major active ingredients for skin care products, especially when addressing estrogen-deficient skin. Two example compounds are presented, an analog of resveratrol (i.e., 4'-acetoxy resveratrol) and the isoflavonoid equol, both of which are involved in a variety of biochemical/molecular actions and mechanisms, as demonstrated via in vitro and clinical studies that enhance human dermal health, especially in estrogen-deficient skin.
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Affiliation(s)
- Edwin D Lephart
- Department of Physiology, Developmental Biology and The Neuroscience Center, College of Life Sciences, Brigham Young University, Provo, UT, USA.
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25
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Yin L, Luo M, Wang R, Ye J, Wang X. Mitochondria in Sex Hormone-Induced Disorder of Energy Metabolism in Males and Females. Front Endocrinol (Lausanne) 2021; 12:749451. [PMID: 34987473 PMCID: PMC8721233 DOI: 10.3389/fendo.2021.749451] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 11/24/2021] [Indexed: 01/01/2023] Open
Abstract
Androgens have a complex role in the regulation of insulin sensitivity in the pathogenesis of type 2 diabetes. In male subjects, a reduction in androgens increases the risk for insulin resistance, which is improved by androgen injections. However, in female subjects with polycystic ovary syndrome (PCOS), androgen excess becomes a risk factor for insulin resistance. The exact mechanism underlying the complex activities of androgens remains unknown. In this review, a hormone synergy-based view is proposed for understanding this complexity. Mitochondrial overactivation by substrate influx is a mechanism of insulin resistance in obesity. This concept may apply to the androgen-induced insulin resistance in PCOS. Androgens and estrogens both exhibit activities in the induction of mitochondrial oxidative phosphorylation. The two hormones may synergize in mitochondria to induce overproduction of ATP. ATP surplus in the pancreatic β-cells and α-cells causes excess secretion of insulin and glucagon, respectively, leading to peripheral insulin resistance in the early phase of type 2 diabetes. In the skeletal muscle and liver, the ATP surplus contributes to insulin resistance through suppression of AMPK and activation of mTOR. Consistent ATP surplus leads to mitochondrial dysfunction as a consequence of mitophagy inhibition, which provides a potential mechanism for mitochondrial dysfunction in β-cells and brown adipocytes in PCOS. The hormone synergy-based view provides a basis for the overactivation and dysfunction of mitochondria in PCOS-associated type 2 diabetes. The molecular mechanism for the synergy is discussed in this review with a focus on transcriptional regulation. This view suggests a unifying mechanism for the distinct metabolic roles of androgens in the control of insulin action in men with hypogonadism and women with PCOS.
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Affiliation(s)
- Lijun Yin
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Man Luo
- Metabolism Research Center, Zhengzhou University Affiliated Zhengzhou Central Hospital, Zhengzhou, China
| | - Ru Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Jianping Ye
- Metabolism Research Center, Zhengzhou University Affiliated Zhengzhou Central Hospital, Zhengzhou, China
- Center for Advanced Medicine, College of Medicine, Zhengzhou University, Zhengzhou, China
- Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- *Correspondence: Jianping Ye, ; Xiaohui Wang,
| | - Xiaohui Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
- *Correspondence: Jianping Ye, ; Xiaohui Wang,
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26
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Mahboobifard F, Dargahi L, Jorjani M, Ramezani Tehrani F, Pourgholami MH. The role of ERα36 in cell type-specific functions of estrogen and cancer development. Pharmacol Res 2021; 163:105307. [PMID: 33246174 DOI: 10.1016/j.phrs.2020.105307] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/05/2020] [Accepted: 11/09/2020] [Indexed: 02/07/2023]
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27
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McCarthy M, Raval AP. The peri-menopause in a woman's life: a systemic inflammatory phase that enables later neurodegenerative disease. J Neuroinflammation 2020; 17:317. [PMID: 33097048 PMCID: PMC7585188 DOI: 10.1186/s12974-020-01998-9] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/14/2020] [Indexed: 02/08/2023] Open
Abstract
The peri-menopause or menopausal transition—the time period that surrounds the final years of a woman’s reproductive life—is associated with profound reproductive and hormonal changes in a woman’s body and exponentially increases a woman’s risk of cerebral ischemia and Alzheimer’s disease. Although our understanding of the exact timeline or definition of peri-menopause is limited, it is clear that there are two stages to the peri-menopause. These are the early menopausal transition, where menstrual cycles are mostly regular, with relatively few interruptions, and the late transition, where amenorrhea becomes more prolonged and lasts for at least 60 days, up to the final menstrual period. Emerging evidence is showing that peri-menopause is pro-inflammatory and disrupts estrogen-regulated neurological systems. Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-β). Estrogen receptor-beta has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function. This review will present an overview of the menopausal transition as an inflammatory event, with associated systemic and central nervous system inflammation, plus regulation of the innate immune response by ER-β-mediated mechanisms.
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Affiliation(s)
- Micheline McCarthy
- Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Ami P Raval
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Leonard M. Miller School of Medicine, University of Miami, 1420 NW 9th Avenue, Neurology Research Building, Room # 203H, Miami, FL, 33136, USA. .,Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
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28
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Sellitto A, D’Agostino Y, Alexandrova E, Lamberti J, Pecoraro G, Memoli D, Rocco D, Coviello E, Giurato G, Nassa G, Tarallo R, Weisz A, Rizzo F. Insights into the Role of Estrogen Receptor β in Triple-Negative Breast Cancer. Cancers (Basel) 2020; 12:cancers12061477. [PMID: 32516978 PMCID: PMC7353068 DOI: 10.3390/cancers12061477] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/01/2020] [Accepted: 06/03/2020] [Indexed: 12/12/2022] Open
Abstract
Estrogen receptors (ERα and ERβ) are ligand-activated transcription factors that play different roles in gene regulation and show both overlapping and specific tissue distribution patterns. ERβ, contrary to the oncogenic ERα, has been shown to act as an oncosuppressor in several instances. However, while the tumor-promoting actions of ERα are well-known, the exact role of ERβ in carcinogenesis and tumor progression is not yet fully understood. Indeed, to date, highly variable and even opposite effects have been ascribed to ERβ in cancer, including for example both proliferative and growth-inhibitory actions. Recently ERβ has been proposed as a potential target for cancer therapy, since it is expressed in a variety of breast cancers (BCs), including triple-negative ones (TNBCs). Because of the dependence of TNBCs on active cellular signaling, numerous studies have attempted to unravel the mechanism(s) behind ERβ-regulated gene expression programs but the scenario has not been fully revealed. We comprehensively reviewed the current state of knowledge concerning ERβ role in TNBC biology, focusing on the different signaling pathways and cellular processes regulated by this transcription factor, as they could be useful in identifying new diagnostic and therapeutic approaches for TNBC.
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Affiliation(s)
- Assunta Sellitto
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Ylenia D’Agostino
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Elena Alexandrova
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Jessica Lamberti
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Giovanni Pecoraro
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Domenico Memoli
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Domenico Rocco
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Elena Coviello
- Genomix4Life, via S. Allende 43/L, 84081 Baronissi (SA), Italy;
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Alessandro Weisz
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
- CRGS (Genome Research Center for Health), University of Salerno Campus of Medicine, 84081 Baronissi (SA), Italy
- Correspondence: (A.W.); (F.R.); Tel.: (39+)-089-965043 (A.W.); Tel.: (39+)-089-965221 (F.R.)
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
- CRGS (Genome Research Center for Health), University of Salerno Campus of Medicine, 84081 Baronissi (SA), Italy
- Correspondence: (A.W.); (F.R.); Tel.: (39+)-089-965043 (A.W.); Tel.: (39+)-089-965221 (F.R.)
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Ventura-Clapier R, Piquereau J, Garnier A, Mericskay M, Lemaire C, Crozatier B. Gender issues in cardiovascular diseases. Focus on energy metabolism. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165722. [DOI: 10.1016/j.bbadis.2020.165722] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 01/20/2020] [Accepted: 02/07/2020] [Indexed: 12/12/2022]
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30
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Varkuti BH, Liu Z, Kepiro M, Pacifico R, Gai Y, Kamenecka T, Davis RL. High-Throughput Small Molecule Screen Identifies Modulators of Mitochondrial Function in Neurons. iScience 2020; 23:100931. [PMID: 32146326 PMCID: PMC7063260 DOI: 10.1016/j.isci.2020.100931] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 01/16/2020] [Accepted: 02/17/2020] [Indexed: 12/20/2022] Open
Abstract
We developed a high-throughput assay for modulators of mitochondrial function in neurons measuring inner mitochondrial membrane potential (ΔΨm) and ATP production. The assay was used to screen a library of small molecules, which led to the identification of structural/functional classes of mitochondrial modulators such as local anesthetics, isoflavones, COXII inhibitors, adrenergic receptor blockers, and neurotransmitter system effectors. Our results show that some of the isolated compounds promote mitochondrial health, enhance oxygen consumption rate, and protect neurons against toxic insults found in the cellular environment of Alzheimer disease. These studies offer a set of compounds that may provide efficacy in protecting the mitochondrial system in neurodegenerative disorders.
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Affiliation(s)
- Boglarka H Varkuti
- Department of Neuroscience, Scripps Research Institute Florida, Jupiter, FL 33458, USA
| | - Ze Liu
- Department of Neuroscience, Scripps Research Institute Florida, Jupiter, FL 33458, USA
| | - Miklos Kepiro
- Department of Neuroscience, Scripps Research Institute Florida, Jupiter, FL 33458, USA
| | - Rodrigo Pacifico
- Department of Neuroscience, Scripps Research Institute Florida, Jupiter, FL 33458, USA
| | - Yunchao Gai
- Department of Neuroscience, Scripps Research Institute Florida, Jupiter, FL 33458, USA
| | - Ted Kamenecka
- Department of Molecular Medicine, Scripps Research Institute Florida, Jupiter, FL 33458, USA
| | - Ronald L Davis
- Department of Neuroscience, Scripps Research Institute Florida, Jupiter, FL 33458, USA.
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31
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Kondakova IV, Shashova EE, Sidenko EA, Astakhova TM, Zakharova LA, Sharova NP. Estrogen Receptors and Ubiquitin Proteasome System: Mutual Regulation. Biomolecules 2020; 10:biom10040500. [PMID: 32224970 PMCID: PMC7226411 DOI: 10.3390/biom10040500] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/21/2020] [Accepted: 03/25/2020] [Indexed: 12/11/2022] Open
Abstract
This review provides information on the structure of estrogen receptors (ERs), their localization and functions in mammalian cells. Additionally, the structure of proteasomes and mechanisms of protein ubiquitination and cleavage are described. According to the modern concept, the ubiquitin proteasome system (UPS) is involved in the regulation of the activity of ERs in several ways. First, UPS performs the ubiquitination of ERs with a change in their functional activity. Second, UPS degrades ERs and their transcriptional regulators. Third, UPS affects the expression of ER genes. In addition, the opportunity of the regulation of proteasome functioning by ERs—in particular, the expression of immune proteasomes—is discussed. Understanding the complex mechanisms underlying the regulation of ERs and proteasomes has great prospects for the development of new therapeutic agents that can make a significant contribution to the treatment of diseases associated with the impaired function of these biomolecules.
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Affiliation(s)
- Irina V. Kondakova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, 634009 Tomsk, Russia; (I.V.K.); (E.E.S.); (E.A.S.)
| | - Elena E. Shashova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, 634009 Tomsk, Russia; (I.V.K.); (E.E.S.); (E.A.S.)
| | - Evgenia A. Sidenko
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, 634009 Tomsk, Russia; (I.V.K.); (E.E.S.); (E.A.S.)
| | - Tatiana M. Astakhova
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, Russia; (T.M.A.); (L.A.Z.)
| | - Liudmila A. Zakharova
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, Russia; (T.M.A.); (L.A.Z.)
| | - Natalia P. Sharova
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, Russia; (T.M.A.); (L.A.Z.)
- Correspondence: ; Tel.: +7-499-135-7674; Fax: +7-499-135-3322
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32
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Tsialtas I, Gorgogietas VA, Michalopoulou M, Komninou A, Liakou E, Georgantopoulos A, Kalousi FD, Karra AG, Protopapa E, Psarra AMG. Neurotoxic effects of aluminum are associated with its interference with estrogen receptors signaling. Neurotoxicology 2020; 77:114-126. [PMID: 31945389 DOI: 10.1016/j.neuro.2020.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 01/10/2020] [Accepted: 01/12/2020] [Indexed: 12/20/2022]
Abstract
Aluminum compounds have been observed in various brain regions, and their accumulation has been associated with many neurodegenerative disorders. Neurotoxic effects of aluminum are attributed to reactive oxygen species generation, induction of apoptosis and inflammatory reactions activation. Metalloestrogen activity of aluminum has also been linked to breast cancer progression and metastasis. In this study, taking into account the anti-apoptotic and anti-oxidant activities of estrogens in neuronal cells, which are mediated by estrogen receptors, the possible estrogenic activity of aluminum in SH-SY5Y neuroblastoma cells was studied. Our results showed that aluminum in the form of aluminum chlorohydrate (ACH) exhibited no effect on estrogen receptors transcriptional activation, and differential effect on estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) protein levels. ACH caused reduction in ERβ protein levels, and increase in its mitochondrial localization. ACH-induced reduction in ERβ protein level may be linked, at least in part, to the ACH-induced increase in ERα protein level. This statement is based on our observations showing aluminum-induced reduction in the E2-induced increase in ERα S118 phosphorylation, in MCF-7 and SH-SH5Y cells. Phosphorylation at S118 residue is known to be associated with inhibition of the ubiquitin-induced proteolytic degradation of ERα, leading to its accumulation. Since it is known that ERα negatively regulate ERβ expression, increase in ERα, may contribute to reduction in ERβ levels and subsequent weakening of its anti-apoptotic and anti-oxidant activity, justified by the observed reduction in procaspase 9, mitochondrial cytochrome c, Bcl-2, Bcl-xL and mitochondrial thioredoxin protein level, as well as by the increase in proapoptotic BAX level, in ACH treated SH-SY5Y cells. In addition, increase in mitochondrial ERβ localization may also trigger mitochondrial metabolism, suppress biosynthetic process of gluconeogenesis, as indicated by the observed reduction in the phosphoenolpyruvate carboxykinase protein level, and eventually lead to increase in reactive oxygen species (ROS) generation, known to be implicated in aluminum induced neurodegeneration. This statement was verified by the observed ACH-induced increase in ERβ mitochondrial localization, induction of the mitochondrial membrane depolarization and increase in ROS production, in neuronal-like differentiated SH-SY5Y cells.
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Affiliation(s)
- Ioannis Tsialtas
- Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece
| | - Vyron A Gorgogietas
- Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece
| | - Maria Michalopoulou
- Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece
| | - Aggeliki Komninou
- Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece
| | - Eleni Liakou
- Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece
| | | | - Foteini D Kalousi
- Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece
| | - Aikaterini G Karra
- Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece
| | - Evagelia Protopapa
- Department of Aesthetics and Cosmetology, Faculty of Health & Caring Professions, University of West Attica, Egaleo, Greece
| | - Anna-Maria G Psarra
- Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece.
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Guercio G, Saraco N, Costanzo M, Marino R, Ramirez P, Berensztein E, Rivarola MA, Belgorosky A. Estrogens in Human Male Gonadotropin Secretion and Testicular Physiology From Infancy to Late Puberty. Front Endocrinol (Lausanne) 2020; 11:72. [PMID: 32158430 PMCID: PMC7051936 DOI: 10.3389/fendo.2020.00072] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 02/03/2020] [Indexed: 12/13/2022] Open
Abstract
Several reports in humans as well as transgenic mouse models have shown that estrogens play an important role in male reproduction and fertility. Estrogen receptor alpha (ERα) and beta (ERβ) are expressed in different male tissues including the brain. The estradiol-binding protein GPER1 also mediates estrogen action in target tissues. In human testes a minimal ERα expression during prepuberty along with a marked pubertal up-regulation in germ cells has been reported. ERβ expression was detected mostly in spermatogonia, primary spermatocytes, and immature spermatids. In Sertoli cells ERβ expression increases with age. The aromatase enzyme (cP450arom), which converts androgens to estrogens, is widely expressed in human tissues (including gonads and hypothalamus), even during fetal life, suggesting that estrogens are also involved in human fetal physiology. Moreover, cP450arom is expressed in the early postnatal testicular Leydig cells and spermatogonia. Even though the aromatase complex is required for estrogen synthesis, its biological relevance is also related to the regulation of the balance between androgens and estrogens in different tissues. Knockout mouse models of aromatase (ArKO) and estrogen receptors (ERKOα, ERKOβ, and ERKOαβ) provide an important tool to study the effects of estrogens on the male reproductive physiology including the gonadal axis. High basal serum FSH levels were reported in adult aromatase-deficient men, suggesting that estrogens are involved in the negative regulatory gonadotropin feedback. However, normal serum gonadotropin levels were observed in an aromatase-deficient boy, suggesting a maturational pattern role of estrogen in the regulation of gonadotropin secretion. Nevertheless, the role of estrogens in primate testis development and function is controversial and poorly understood. This review addresses the role of estrogens in gonadotropin secretion and testicular physiology in male humans especially during childhood and puberty.
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Affiliation(s)
- Gabriela Guercio
- Endocrinology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
- Research Institute Garrahan-CONICET, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
| | - Nora Saraco
- Endocrinology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
- Research Institute Garrahan-CONICET, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
| | - Mariana Costanzo
- Endocrinology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
| | - Roxana Marino
- Endocrinology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
| | - Pablo Ramirez
- Endocrinology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
| | - Esperanza Berensztein
- Endocrinology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
- Facultad de Medicina, Department of Cellular Biology and Histology, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Marco A. Rivarola
- Endocrinology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
- Research Institute Garrahan-CONICET, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
| | - Alicia Belgorosky
- Endocrinology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
- Research Institute Garrahan-CONICET, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina
- *Correspondence: Alicia Belgorosky
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Zolezzi JM, Villaseca P, Inestrosa NC. Toward an integrative understanding of the neuroinflammatory molecular milieu in Alzheimer disease neurodegeneration. GENETICS, NEUROLOGY, BEHAVIOR, AND DIET IN DEMENTIA 2020:163-176. [DOI: 10.1016/b978-0-12-815868-5.00011-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Chen YH, Wang V, Huang EYK, Chou YC, Kuo TT, Olson L, Hoffer BJ. Delayed Dopamine Dysfunction and Motor Deficits in Female Parkinson Model Mice. Int J Mol Sci 2019; 20:ijms20246251. [PMID: 31835787 PMCID: PMC6940785 DOI: 10.3390/ijms20246251] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/22/2019] [Accepted: 12/04/2019] [Indexed: 12/21/2022] Open
Abstract
This study analyzed gender differences in the progressive dopamine (DA) deficiency phenotype in the MitoPark (MP) mouse model of Parkinson’s disease (PD) with progressive loss of DA release and reuptake in midbrain DA pathways. We found that the progressive loss of these DA presynaptic parameters begins significantly earlier in male than female MP mice. This was correlated with behavioral gender differences of both forced and spontaneous motor behavior. The degeneration of the nigrostriatal DA system in MP mice is earlier and more marked than that of the mesolimbic DA system, with male MP mice again being more strongly affected than female MP mice. After ovariectomy, DA presynaptic and behavioral changes in female mice become very similar to those of male animals. Our results suggest that estrogen, either directly or indirectly, is neuroprotective in the midbrain DA system. Our results are compatible with epidemiological data on incidence and symptom progression in PD, showing that men are more strongly affected than women at early ages.
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Affiliation(s)
- Yuan-Hao Chen
- Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
- Correspondence: (Y.-H.C.); (B.J.H.)
| | - Vicki Wang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Eagle Yi-Kung Huang
- Department of Pharmacology, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Yu-Ching Chou
- School of Public Health, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Tung-Tai Kuo
- Graduate Institute of Computer and Communication Engineering, National Taipei University of Technology, Taipei 10608, Taiwan;
| | - Lars Olson
- Department of Neuroscience, Karolinska Institute, 17177 Stockholm, Sweden;
| | - Barry J. Hoffer
- Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Correspondence: (Y.-H.C.); (B.J.H.)
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Riera Leal A, Ortiz-Lazareno PC, Jave-Suárez LF, Ramírez De Arellano A, Aguilar-Lemarroy A, Ortiz-García YM, Barrón-Gallardo CA, Solís-Martínez R, Luquin De Anda S, Muñoz-Valle JF, Pereira-Suárez AL. 17β‑estradiol‑induced mitochondrial dysfunction and Warburg effect in cervical cancer cells allow cell survival under metabolic stress. Int J Oncol 2019; 56:33-46. [PMID: 31746421 PMCID: PMC6910176 DOI: 10.3892/ijo.2019.4912] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 08/19/2019] [Indexed: 02/07/2023] Open
Abstract
Mitochondria from different types of cancer show bioenergetics and dysfunction that favor cell proliferation. The mechanistic understanding of estrogen in cervical cancer is poorly understood. Therefore, the objective of this study was to determine how 17β-estradiol (E2) affects mitochondrial function and the Warburg effect in SiHa, HeLa and C33A cervical cancer cells. Mitochondrial compromise was evaluated measuring changes in the membrane permeability by immunofluorescence, calcium concentration, redox status, iron and ferritin reserves. Glucose consumption and lactic acid assays were used to detect the metabolic activity. Results were confirmed at molecular level by analysis of the differential gene expression using RNA sequencing. E2 modified the mitochondrial permeability and produced an alteration in the calcium signaling pathway. In HeLa and SiHa, there was a significant decrease in nitric oxide levels and lipid peroxidation, and an increase in glucose consumption and lactic acid levels when stimulated with E2. Intracellular iron or ferritin reserves were not affected by the E2 treatment. Genes differentially modulated by E2 were involved in the mitochondrial electron transport chain, oxidative phosphorylation system, glycolysis, pentose phosphate pathway and the regulation of metabolic signaling pathways. Herein, we provide evidence for a primary effect of estrogen on mitochondrial function and the Warburg effect, favoring the metabolic adaptation of the cervical cancer cell lines and their survival.
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Affiliation(s)
- Annie Riera Leal
- Laboratory of Immunology, Department of Physiology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Pablo César Ortiz-Lazareno
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
| | - Luis Felipe Jave-Suárez
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
| | - Adrián Ramírez De Arellano
- Research Institute in Biomedical Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Adriana Aguilar-Lemarroy
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
| | - Yveth Marlene Ortiz-García
- Laboratory of Immunology, Department of Physiology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Carlos Alfredo Barrón-Gallardo
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
| | - Raúl Solís-Martínez
- Diagnostic Laboratory, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Sonia Luquin De Anda
- Department of Neurosciences, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - José Francisco Muñoz-Valle
- Research Institute in Biomedical Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Ana Laura Pereira-Suárez
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
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Tobore TO. Towards a comprehensive etiopathogenetic and pathophysiological theory of multiple sclerosis. Int J Neurosci 2019; 130:279-300. [PMID: 31588832 DOI: 10.1080/00207454.2019.1677648] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background: Multiple sclerosis (MS) is a neurodegenerative disease caused by dysfunction of the immune system that affects the central nervous system (CNS). It is characterized by demyelination, chronic inflammation, neuronal and oligodendrocyte loss and reactive astrogliosis. It can result in physical disability and acute neurological and cognitive problems. Despite the gains in knowledge of immunology, cell biology, and genetics in the last five decades, the ultimate etiology or specific elements that trigger MS remain unknown. The objective of this review is to propose a theoretical basis for MS etiopathogenesis.Methods: Search was done by accessing PubMed/Medline, EBSCO, and PsycINFO databases. The search string used was "(multiple sclerosis* OR EAE) AND (pathophysiology* OR etiopathogenesis)". The electronic databases were searched for titles or abstracts containing these terms in all published articles between January 1, 1960, and June 30, 2019. The search was filtered down to 362 articles which were included in this review.Results: A framework to better understand the etiopathogenesis and pathophysiology of MS can be derived from four essential factors; mitochondria dysfunction (MtD) & oxidative stress (OS), vitamin D (VD), sex hormones and thyroid hormones. These factors play a direct role in MS etiopathogenesis and have a modulatory effect on many other factors involved in the disease.Conclusions: For better MS prevention and treatment outcomes, efforts should be geared towards treating thyroid problems, sex hormone alterations, VD deficiency, sleep problems and melatonin alterations. MS patients should be encouraged to engage in activities that boost total antioxidant capacity (TAC) including diet and regular exercise and discouraged from activities that promote OS including smoking and alcohol consumption.
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Tobore TO. On elucidation of the role of mitochondria dysfunction and oxidative stress in multiple sclerosis. ACTA ACUST UNITED AC 2019. [DOI: 10.1111/ncn3.12335] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Kandasamy M, Radhakrishnan RK, Poornimai Abirami GP, Roshan SA, Yesudhas A, Balamuthu K, Prahalathan C, Shanmugaapriya S, Moorthy A, Essa MM, Anusuyadevi M. Possible Existence of the Hypothalamic-Pituitary-Hippocampal (HPH) Axis: A Reciprocal Relationship Between Hippocampal Specific Neuroestradiol Synthesis and Neuroblastosis in Ageing Brains with Special Reference to Menopause and Neurocognitive Disorders. Neurochem Res 2019; 44:1781-1795. [PMID: 31254250 DOI: 10.1007/s11064-019-02833-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 05/13/2019] [Accepted: 06/19/2019] [Indexed: 12/18/2022]
Abstract
The hippocampus-derived neuroestradiol plays a major role in neuroplasticity, independent of circulating estradiol that originates from gonads. The response of hypothalamus-pituitary regions towards the synthesis of neuroestradiol in the hippocampus is an emerging scientific concept in cognitive neuroscience. Hippocampal plasticity has been proposed to be regulated via neuroblasts, a major cellular determinant of functional neurogenesis in the adult brain. Defects in differentiation, integration and survival of neuroblasts in the hippocampus appear to be an underlying cause of neurocognitive disorders. Gonadotropin receptors and steroidogenic enzymes have been found to be expressed in neuroblasts in the hippocampus of the brain. However, the reciprocal relationship between hippocampal-specific neuroestradiol synthesis along neuroblastosis and response of pituitary based feedback regulation towards regulation of estradiol level in the hippocampus have not completely been ascertained. Therefore, this conceptual article revisits (1) the cellular basis of neuroestradiol synthesis (2) a potential relationship between neuroestradiol synthesis and neuroblastosis in the hippocampus (3) the possible involvement of aberrant neuroestradiol production with mitochondrial dysfunctions and dyslipidemia in menopause and adult-onset neurodegenerative disorders and (4) provides a hypothesis for the possible existence of the hypothalamic-pituitary-hippocampal (HPH) axis in the adult brain. Eventually, understanding the regulation of hippocampal neurogenesis by abnormal levels of neuroestradiol concentration in association with the feedback regulation of HPH axis might provide additional cues to establish a neuroregenerative therapeutic management for mood swings, depression and cognitive decline in menopause and neurocognitive disorders.
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Affiliation(s)
- Mahesh Kandasamy
- Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India.
- Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India.
- School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India.
- Faculty Recharge Programme, University Grants Commission(UGC-FRP), New Delhi, India.
| | - Risna Kanjirassery Radhakrishnan
- Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India
- Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India
| | - G P Poornimai Abirami
- School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India
| | - Syed Aasish Roshan
- Molecular Gerontology Laboratory, Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India
- Department of Biochemistry, Bharathidasan University, Tiruchirappalli, 620024, India
| | - Ajisha Yesudhas
- Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India
- Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India
| | - Kadalmani Balamuthu
- Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India
- School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India
| | - Chidambaram Prahalathan
- School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India
- Department of Biochemistry, Bharathidasan University, Tiruchirappalli, 620024, India
| | | | - Anbalagan Moorthy
- Department of Integrative Biology, School of Bioscience and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Musthafa Mohamed Essa
- Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Muscat, Oman
- Ageing and Dementia Research Group, Sultan Qaboos University, Muscat, Oman
| | - Muthuswamy Anusuyadevi
- School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India
- Molecular Gerontology Laboratory, Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India
- Department of Biochemistry, Bharathidasan University, Tiruchirappalli, 620024, India
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Turkson S, Kloster A, Hamilton PJ, Neigh GN. Neuroendocrine drivers of risk and resilience: The influence of metabolism & mitochondria. Front Neuroendocrinol 2019; 54:100770. [PMID: 31288042 PMCID: PMC6886586 DOI: 10.1016/j.yfrne.2019.100770] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/20/2019] [Accepted: 07/03/2019] [Indexed: 02/07/2023]
Abstract
The manifestation of risk versus resilience has been considered from varying perspectives including genetics, epigenetics, early life experiences, and type and intensity of the challenge with which the organism is faced. Although all of these factors are central to determining risk and resilience, the current review focuses on what may be a final common pathway: metabolism. When an organism is faced with a perturbation to the environment, whether internal or external, appropriate energy allocation is essential to resolving the divergence from equilibrium. This review examines the potential role of metabolism in the manifestation of stress-induced neural compromise. In addition, this review details the current state of knowledge on neuroendocrine factors which are poised to set the tone of the metabolic response to a systemic challenge. The goal is to provide an essential framework for understanding stress in a metabolic context and appreciation for key neuroendocrine signals.
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Affiliation(s)
- Susie Turkson
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States
| | - Alix Kloster
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States
| | - Peter J Hamilton
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States
| | - Gretchen N Neigh
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States.
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Sex differences and the neurobiology of affective disorders. Neuropsychopharmacology 2019; 44:111-128. [PMID: 30061743 PMCID: PMC6235863 DOI: 10.1038/s41386-018-0148-z] [Citation(s) in RCA: 173] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 05/14/2018] [Accepted: 06/25/2018] [Indexed: 12/11/2022]
Abstract
Observations of the disproportionate incidence of depression in women compared with men have long preceded the recent explosion of interest in sex differences. Nonetheless, the source and implications of this epidemiologic sex difference remain unclear, as does the practical significance of the multitude of sex differences that have been reported in brain structure and function. In this article, we attempt to provide a framework for thinking about how sex and reproductive hormones (particularly estradiol as an example) might contribute to affective illness. After briefly reviewing some observed sex differences in depression, we discuss how sex might alter brain function through hormonal effects (both organizational (programmed) and activational (acute)), sex chromosome effects, and the interaction of sex with the environment. We next review sex differences in the brain at the structural, cellular, and network levels. We then focus on how sex and reproductive hormones regulate systems implicated in the pathophysiology of depression, including neuroplasticity, genetic and neural networks, the stress axis, and immune function. Finally, we suggest several models that might explain a sex-dependent differential regulation of affect and susceptibility to affective illness. As a disclaimer, the studies cited in this review are not intended to be comprehensive but rather serve as examples of the multitude of levels at which sex and reproductive hormones regulate brain structure and function. As such and despite our current ignorance regarding both the ontogeny of affective illness and the impact of sex on that ontogeny, sex differences may provide a lens through which we may better view the mechanisms underlying affective regulation and dysfunction.
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Ventura-Clapier R, Piquereau J, Veksler V, Garnier A. Estrogens, Estrogen Receptors Effects on Cardiac and Skeletal Muscle Mitochondria. Front Endocrinol (Lausanne) 2019; 10:557. [PMID: 31474941 PMCID: PMC6702264 DOI: 10.3389/fendo.2019.00557] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 07/29/2019] [Indexed: 12/27/2022] Open
Abstract
Mitochondria are unique organelles present in almost all cell types. They are involved not only in the supply of energy to the host cell, but also in multiple biochemical and biological processes like calcium homeostasis, production, and regulation of reactive oxygen species (ROS), pH control, or cell death. The importance of mitochondria in cell biology and pathology is increasingly recognized. Being maternally inherited, mitochondria exhibit a tissue-specificity, because most of the mitochondrial proteins are encoded by the nuclear genome. This renders them exquisitely well-adapted to the physiology of the host cell. It is thus not surprising that mitochondria show a sexual dimorphism and that they are also prone to the influence of sex chromosomes and sex hormones. Estrogens affect mitochondria through multiple processes involving membrane and nuclear estrogen receptors (ERs) as well as more direct effects. Moreover, estrogen receptors have been identified within mitochondria. The effects of estrogens on mitochondria comprise protein content and specific activity of mitochondrial proteins, phospholipid content of membranes, oxidant and anti-oxidant capacities, oxidative phosphorylation, and calcium retention capacities. Herein we will briefly review the life cycle and functions of mitochondria, the importance of estrogen receptors and the effects of estrogens on heart and skeletal muscle mitochondria.
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Martin-Jiménez C, Gaitán-Vaca DM, Areiza N, Echeverria V, Ashraf GM, González J, Sahebkar A, Garcia-Segura LM, Barreto GE. Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury. Neuroendocrinology 2019; 108:142-160. [PMID: 30391959 DOI: 10.1159/000495078] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 11/02/2018] [Indexed: 11/19/2022]
Abstract
Traumatic brain injury (TBI) is a serious public health problem. It may result in severe neurological disabilities and in a variety of cellular metabolic alterations for which available therapeutic strategies are limited. In the last decade, the use of estrogenic compounds, which activate protective mechanisms in astrocytes, has been explored as a potential experimental therapeutic approach. Previous works have suggested estradiol (E2) as a neuroprotective hormone that acts in the brain by binding to estrogen receptors (ERs). Several steroidal and nonsteroidal estrogenic compounds can imitate the effects of estradiol on ERs. These include hormonal estrogens, phytoestrogens and synthetic estrogens, such as selective ER modulators or tibolone. Current evidence of the role of astrocytes in mediating protective actions of estrogenic compounds after TBI is reviewed in this paper. We conclude that the use of estrogenic compounds to modulate astrocytic properties is a promising therapeutic approach for the treatment of TBI.
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Affiliation(s)
- Cynthia Martin-Jiménez
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Diana Milena Gaitán-Vaca
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Natalia Areiza
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Valentina Echeverria
- Universidad San Sebastián, Fac. Cs de la Salud, Concepción, Chile
- Research and Development Service, Bay Pines VA Healthcare System, Bay Pines, Florida, USA
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Janneth González
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Luis Miguel Garcia-Segura
- Instituto Cajal, CSIC, Madrid, Spain
- Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias Pontificia Universidad Javeriana, Bogotá, Colombia,
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Cabas I, Chaves-Pozo E, Mulero V, García-Ayala A. Role of estrogens in fish immunity with special emphasis on GPER1. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2018; 89:102-110. [PMID: 30092317 DOI: 10.1016/j.dci.2018.08.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/03/2018] [Accepted: 08/03/2018] [Indexed: 06/08/2023]
Abstract
It is well accepted that estrogens, the primary female sex hormones, play a key role in modulating different aspects of the immune response. Moreover, estrogens have been linked with the sexual dimorphism observed in some immune disorders, such as chronic inflammatory and autoimmune diseases. Nevertheless, their effects are often controversial and depend on several factors, such as the pool of estrogen receptors (ERs) involved in the response. Their classical mode of action is through nuclear ERs, which act as transcription factors, promoting the regulation of target genes. However, it has long been noted that some of the estrogen-mediated effects cannot be explained by these classical receptors, since they are rapid and mediated by non-genomic signaling pathways. Hence, the interest in membrane ERs, especially in G protein-coupled estrogen receptor 1 (GPER1), has grown in recent years. Although the presence of nuclear ERs, and ER signaling, in immune cells in mammals and fish has been well documented, information on membrane ERs is much scarcer. In this context, the present manuscript aims to review our knowledge concerning the effect of estrogens on fish immunity, with special emphasis on GPER1. For example, the numerous tools developed over recent years allowed us to report for the first time that the regulation of fish granulocyte functions by estrogens through GPER1 predates the split of fish and tetrapods more than 450 million years ago, pointing to the relevance of estrogens as modulators of the immune responses, and the pivotal role of GPER1 in immunity.
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Affiliation(s)
- Isabel Cabas
- Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, IMIB-Arrixaca, Murcia, Spain.
| | - Elena Chaves-Pozo
- Centro Oceanográfico de Murcia, Instituto Español de Oceanografía (IEO), Murcia, Spain
| | - Victoriano Mulero
- Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, IMIB-Arrixaca, Murcia, Spain
| | - Alfonsa García-Ayala
- Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, IMIB-Arrixaca, Murcia, Spain
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Abstract
Estrogens coordinate and integrate cellular metabolism and mitochondrial activities by direct and indirect mechanisms mediated by differential expression and localization of estrogen receptors (ER) in a cell-specific manner. Estrogens regulate transcription and cell signaling pathways that converge to stimulate mitochondrial function- including mitochondrial bioenergetics, mitochondrial fusion and fission, calcium homeostasis, and antioxidant defense against free radicals. Estrogens regulate nuclear gene transcription by binding and activating the classical genomic estrogen receptors α and β (ERα and ERβ) and by activating plasma membrane-associated mERα, mERβ, and G-protein coupled ER (GPER, GPER1). Localization of ERα and ERβ within mitochondria and in the mitochondrial membrane provides additional mechanisms of regulation. Here we review the mechanisms of rapid and longer-term effects of estrogens and selective ER modulators (SERMs, e.g., tamoxifen (TAM)) on mitochondrial biogenesis, morphology, and function including regulation of Nuclear Respiratory Factor-1 (NRF-1, NRF1) transcription. NRF-1 is a nuclear transcription factor that promotes transcription of mitochondrial transcription factor TFAM (mtDNA maintenance factorFA) which then regulates mtDNA-encoded genes. The nuclear effects of estrogens on gene expression directly controlling mitochondrial biogenesis, oxygen consumption, mtDNA transcription, and apoptosis are reviewed.
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Elsaed WM, Bedeer RF, Eladl MA. Ameliorative effect of vitamin B12 on seminiferous epithelium of cimetidine-treated rats: a histopathological, immunohistochemical and ultrastructural study. Anat Cell Biol 2018; 51:52-61. [PMID: 29644110 PMCID: PMC5890017 DOI: 10.5115/acb.2018.51.1.52] [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: 11/27/2017] [Revised: 01/08/2018] [Accepted: 01/10/2018] [Indexed: 12/27/2022] Open
Abstract
Cimetidine is an H2 receptor antagonist that has an antiandrogenic effect. It intervenes with the conversion of testosterone into estrogen in the Sertoli cells with accompanying testicular structural changes. In the present study, the microscopic and the ultrastructural changes induced by cimetidine and the effect of vitamin B12 as a protective agent on rat testes were studied. Immunoexpression of estrogen receptor β (ERβ) in testes was evaluated. Twenty-four adult male rats were divided into four groups: control, cimetidine-treated, vitamin B12 treated, and combined cimetidine and vitamin B12 treated. The experimental rats were administered with cimetidine and/or vitamin B12 for 52 days. Group II rats showed marked atrophy of the seminiferous tubules with a significant increase in tubular diameter and decrease in the tubular luminal and epithelial areas. Ultrastructure of this group showed irregular Sertoli cells with basal cytoplasmic vacuolation and significantly thickened basement membrane. ERβ immunoexpression was similar to controls. Group III rats showed near normal seminiferous tubular structures with minimal cellular alterations and the immunoreactivity of the testicular sections was very close to normal. However, group IV rats showed markedly immunopositive detached cells, spermatids, and primary spermatocytes. Cimetidine interferes with the control of spermatogenesis as evidenced by microscopic and ultrastructural studies and affection of ERβ receptors and vitamin B12 has a protective action against this harmful effect.
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Affiliation(s)
- Wael M Elsaed
- Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.,Department of Anatomy and Embryology, Faculty of Medicine, Taibah University, Madinah, Saudi Arabia
| | - Raouf Fekry Bedeer
- Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mohamed Ahmed Eladl
- Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.,Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, UAE
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Nemeth VL, Must A, Horvath S, Király A, Kincses ZT, Vécsei L. Gender-Specific Degeneration of Dementia-Related Subcortical Structures Throughout the Lifespan. J Alzheimers Dis 2018; 55:865-880. [PMID: 27792015 DOI: 10.3233/jad-160812] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Age-related changes in brain structure are a question of interest to a broad field of research. Structural decline has been consistently, but not unambiguously, linked to functional consequences, including cognitive impairment and dementia. One of the areas considered of crucial importance throughout this process is the medial temporal lobe, and primarily the hippocampal region. Gender also has a considerable effect on volume deterioration of subcortical grey matter (GM) structures, such as the hippocampus. The influence of age×gender interaction on disproportionate GM volume changes might be mediated by hormonal effects on the brain. Hippocampal volume loss appears to become accelerated in the postmenopausal period. This decline might have significant influences on neuroplasticity in the CA1 region of the hippocampus highly vulnerable to pathological influences. Additionally, menopause has been associated with critical pathobiochemical changes involved in neurodegeneration. The micro- and macrostructural alterations and consequent functional deterioration of critical hippocampal regions might result in clinical cognitive impairment-especially if there already is a decline in the cognitive reserve capacity. Several lines of potential vulnerability factors appear to interact in the menopausal period eventually leading to cognitive decline, mild cognitive impairment, or Alzheimer's disease. This focused review aims to delineate the influence of unmodifiable risk factors of neurodegenerative processes, i.e., age and gender, on critical subcortical GM structures in the light of brain derived estrogen effects. The menopausal period appears to be of key importance for the risk of cognitive decline representing a time of special vulnerability for molecular, structural, and functional influences and offering only a narrow window for potential protective effects.
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Affiliation(s)
- Viola Luca Nemeth
- Department of Neurology, Albert Szent-Györgyi Clinical Center, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Anita Must
- Department of Neurology, Albert Szent-Györgyi Clinical Center, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Szatmar Horvath
- Department of Psychiatry, Albert Szent-Györgyi Clinical Center, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Andras Király
- Department of Neurology, Albert Szent-Györgyi Clinical Center, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Zsigmond Tamas Kincses
- Department of Neurology, Albert Szent-Györgyi Clinical Center, Faculty of Medicine, University of Szeged, Szeged, Hungary.,International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
| | - László Vécsei
- Department of Neurology, Albert Szent-Györgyi Clinical Center, Faculty of Medicine, University of Szeged, Szeged, Hungary.,MTA-SZTE Neuroscience Research Group, Szeged, Hungary
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Zárate S, Stevnsner T, Gredilla R. Role of Estrogen and Other Sex Hormones in Brain Aging. Neuroprotection and DNA Repair. Front Aging Neurosci 2018. [PMID: 29311911 DOI: 10.3389/fnagi.2017.00430/xml/nlm] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023] Open
Abstract
Aging is an inevitable biological process characterized by a progressive decline in physiological function and increased susceptibility to disease. The detrimental effects of aging are observed in all tissues, the brain being the most important one due to its main role in the homeostasis of the organism. As our knowledge about the underlying mechanisms of brain aging increases, potential approaches to preserve brain function rise significantly. Accumulating evidence suggests that loss of genomic maintenance may contribute to aging, especially in the central nervous system (CNS) owing to its low DNA repair capacity. Sex hormones, particularly estrogens, possess potent antioxidant properties and play important roles in maintaining normal reproductive and non-reproductive functions. They exert neuroprotective actions and their loss during aging and natural or surgical menopause is associated with mitochondrial dysfunction, neuroinflammation, synaptic decline, cognitive impairment and increased risk of age-related disorders. Moreover, loss of sex hormones has been suggested to promote an accelerated aging phenotype eventually leading to the development of brain hypometabolism, a feature often observed in menopausal women and prodromal Alzheimer's disease (AD). Although data on the relation between sex hormones and DNA repair mechanisms in the brain is still limited, various investigations have linked sex hormone levels with different DNA repair enzymes. Here, we review estrogen anti-aging and neuroprotective mechanisms, which are currently an area of intense study, together with the effect they may have on the DNA repair capacity in the brain.
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Affiliation(s)
- Sandra Zárate
- Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Departamento de Histología, Embriología, Biología Celular y Genética, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Tinna Stevnsner
- Danish Center for Molecular Gerontology and Danish Aging Research Center, Department of Molecular Biology and Genetics, University of Aarhus, Aarhus, Denmark
| | - Ricardo Gredilla
- Department of Physiology, Faculty of Medicine, Complutense University, Madrid, Spain
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50
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Zárate S, Stevnsner T, Gredilla R. Role of Estrogen and Other Sex Hormones in Brain Aging. Neuroprotection and DNA Repair. Front Aging Neurosci 2017; 9:430. [PMID: 29311911 PMCID: PMC5743731 DOI: 10.3389/fnagi.2017.00430] [Citation(s) in RCA: 188] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 12/14/2017] [Indexed: 12/13/2022] Open
Abstract
Aging is an inevitable biological process characterized by a progressive decline in physiological function and increased susceptibility to disease. The detrimental effects of aging are observed in all tissues, the brain being the most important one due to its main role in the homeostasis of the organism. As our knowledge about the underlying mechanisms of brain aging increases, potential approaches to preserve brain function rise significantly. Accumulating evidence suggests that loss of genomic maintenance may contribute to aging, especially in the central nervous system (CNS) owing to its low DNA repair capacity. Sex hormones, particularly estrogens, possess potent antioxidant properties and play important roles in maintaining normal reproductive and non-reproductive functions. They exert neuroprotective actions and their loss during aging and natural or surgical menopause is associated with mitochondrial dysfunction, neuroinflammation, synaptic decline, cognitive impairment and increased risk of age-related disorders. Moreover, loss of sex hormones has been suggested to promote an accelerated aging phenotype eventually leading to the development of brain hypometabolism, a feature often observed in menopausal women and prodromal Alzheimer's disease (AD). Although data on the relation between sex hormones and DNA repair mechanisms in the brain is still limited, various investigations have linked sex hormone levels with different DNA repair enzymes. Here, we review estrogen anti-aging and neuroprotective mechanisms, which are currently an area of intense study, together with the effect they may have on the DNA repair capacity in the brain.
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Affiliation(s)
- Sandra Zárate
- Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
- Departamento de Histología, Embriología, Biología Celular y Genética, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Tinna Stevnsner
- Danish Center for Molecular Gerontology and Danish Aging Research Center, Department of Molecular Biology and Genetics, University of Aarhus, Aarhus, Denmark
| | - Ricardo Gredilla
- Department of Physiology, Faculty of Medicine, Complutense University, Madrid, Spain
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