Comprehensive Physiology最新文献_第9页

Extracellular Matrix Stiffness in Lung Health and Disease. 肺健康和疾病中的细胞外基质僵硬。

IF 5.8 2区医学

Comprehensive Physiology Pub Date : 2022-06-29 DOI: 10.1002/cphy.c210032

Ting Guo, Chao He, Aida Venado, Yong Zhou

{"title":"Extracellular Matrix Stiffness in Lung Health and Disease.","authors":"Ting Guo, Chao He, Aida Venado, Yong Zhou","doi":"10.1002/cphy.c210032","DOIUrl":"https://doi.org/10.1002/cphy.c210032","url":null,"abstract":"The extracellular matrix (ECM) provides structural support and imparts a wide variety of environmental cues to cells. In the past decade, a growing body of work revealed that the mechanical properties of the ECM, commonly known as matrix stiffness, regulate the fundamental cellular processes of the lung. There is growing appreciation that mechanical interplays between cells and associated ECM are essential to maintain lung homeostasis. Dysregulation of ECM-derived mechanical signaling via altered mechanosensing and mechanotransduction pathways is associated with many common lung diseases. Matrix stiffening is a hallmark of lung fibrosis. The stiffened ECM is not merely a sequelae of lung fibrosis but can actively drive the progression of fibrotic lung disease. In this article, we provide a comprehensive view on the role of matrix stiffness in lung health and disease. We begin by summarizing the effects of matrix stiffness on the function and behavior of various lung cell types and on regulation of biomolecule activity and key physiological processes, including host immune response and cellular metabolism. We discuss the potential mechanisms by which cells probe matrix stiffness and convert mechanical signals to regulate gene expression. We highlight the factors that govern matrix stiffness and outline the role of matrix stiffness in lung development and the pathogenesis of pulmonary fibrosis, pulmonary hypertension, asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. We envision targeting of deleterious matrix mechanical cues for treatment of fibrotic lung disease. Advances in technologies for matrix stiffness measurements and design of stiffness-tunable matrix substrates are also explored. © 2022 American Physiological Society. Compr Physiol 12:3523-3558, 2022.","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"12 3","pages":"3523-3558"},"PeriodicalIF":5.8,"publicationDate":"2022-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10088466/pdf/nihms-1883485.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10197880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

Endothelial Cells and the Cerebral Circulation. 内皮细胞与脑循环。

IF 5.8 2区医学

Comprehensive Physiology Pub Date : 2022-06-29 DOI: 10.1002/cphy.c210015

Theresa A Lansdell, Laura C Chambers, Anne M Dorrance

{"title":"Endothelial Cells and the Cerebral Circulation.","authors":"Theresa A Lansdell, Laura C Chambers, Anne M Dorrance","doi":"10.1002/cphy.c210015","DOIUrl":"https://doi.org/10.1002/cphy.c210015","url":null,"abstract":"Endothelial cells form the innermost layer of all blood vessels and are the only vascular component that remains throughout all vascular segments. The cerebral vasculature has several unique properties not found in the peripheral circulation; this requires that the cerebral endothelium be considered as a unique entity. Cerebral endothelial cells perform several functions vital for brain health. The cerebral vasculature is responsible for protecting the brain from external threats carried in the blood. The endothelial cells are central to this requirement as they form the basis of the blood-brain barrier. The endothelium also regulates fibrinolysis, thrombosis, platelet activation, vascular permeability, metabolism, catabolism, inflammation, and white cell trafficking. Endothelial cells regulate the changes in vascular structure caused by angiogenesis and artery remodeling. Further, the endothelium contributes to vascular tone, allowing proper perfusion of the brain which has high energy demands and no energy stores. In this article, we discuss the basic anatomy and physiology of the cerebral endothelium. Where appropriate, we discuss the detrimental effects of high blood pressure on the cerebral endothelium and the contribution of cerebrovascular disease endothelial dysfunction and dementia. © 2022 American Physiological Society. Compr Physiol 12:3449-3508, 2022.","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"12 3","pages":"3449-3508"},"PeriodicalIF":5.8,"publicationDate":"2022-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10197884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Paying the Iron Price: Liver Iron Homeostasis and Metabolic Disease. 付出铁的代价:肝铁稳态与代谢疾病。

IF 5.8 2区医学

Comprehensive Physiology Pub Date : 2022-06-29 DOI: 10.1002/cphy.c210039

Magdalene Ameka, Alyssa H Hasty

{"title":"Paying the Iron Price: Liver Iron Homeostasis and Metabolic Disease.","authors":"Magdalene Ameka, Alyssa H Hasty","doi":"10.1002/cphy.c210039","DOIUrl":"https://doi.org/10.1002/cphy.c210039","url":null,"abstract":"Iron is an essential metal element whose bioavailability is tightly regulated. Under normal conditions, systemic and cellular iron homeostases are synchronized for optimal function, based on the needs of each system. During metabolic dysfunction, this synchrony is lost, and markers of systemic iron homeostasis are no longer coupled to the iron status of key metabolic organs such as the liver and adipose tissue. The effects of dysmetabolic iron overload syndrome in the liver have been tied to hepatic insulin resistance, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. While the existence of a relationship between iron dysregulation and metabolic dysfunction has long been acknowledged, identifying correlative relationships is complicated by the prognostic reliance on systemic measures of iron homeostasis. What is lacking and perhaps more informative is an understanding of how cellular iron homeostasis changes with metabolic dysfunction. This article explores bidirectional relationships between different proteins involved in iron homeostasis and metabolic dysfunction in the liver. © 2022 American Physiological Society. Compr Physiol 12:3641-3663, 2022.","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"12 3","pages":"3641-3663"},"PeriodicalIF":5.8,"publicationDate":"2022-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10155403/pdf/nihms-1895393.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9839629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Remodeling of the Aged and Emphysematous Lungs: Roles of Microenvironmental Cues. 老年肺和气肿肺的重塑：微环境线索的作用

IF 4.2 2区医学

Comprehensive Physiology Pub Date : 2022-06-29 DOI: 10.1002/cphy.c210033

Béla Suki, Jason H T Bates, Erzsébet Bartolák-Suki

{"title":"Remodeling of the Aged and Emphysematous Lungs: Roles of Microenvironmental Cues.","authors":"Béla Suki, Jason H T Bates, Erzsébet Bartolák-Suki","doi":"10.1002/cphy.c210033","DOIUrl":"10.1002/cphy.c210033","url":null,"abstract":"Aging is a slow process that affects all organs, and the lung is no exception. At the alveolar level, aging increases the airspace size with thicker and stiffer septal walls and straighter and thickened collagen and elastic fibers. This creates a microenvironment that interferes with the ability of cells in the parenchyma to maintain normal homeostasis and respond to injury. These changes also make the lung more susceptible to disease such as emphysema. Emphysema is characterized by slow but progressive remodeling of the deep alveolar regions that leads to airspace enlargement and increased but disorganized elastin and collagen deposition. This remodeling has been attributed to ongoing inflammation that involves inflammatory cells and the cytokines they produce. Cellular senescence, another consequence of aging, weakens the ability of cells to properly respond to injury, something that also occurs in emphysema. These factors conspire to make alveolar walls more prone to mechanical failure, which can set emphysema in motion by driving inflammation through immune stimulation by protein fragments. Both aging and emphysema are influenced by microenvironmental conditions such as local inflammation, chemical makeup, tissue stiffness, and mechanical stresses. Although aging and emphysema are not equivalent, they have the potential to influence each other in synergistic ways; aging sets up the conditions for emphysema to develop, while emphysema may accelerate cellular senescence and thus aging itself. This article focuses on the similarities and differences between the remodeled microenvironment of the aging and emphysematous lung, with special emphasis on the alveolar septal wall. © 2022 American Physiological Society. Compr Physiol 12:3559-3574, 2022.","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"12 3","pages":"3559-3574"},"PeriodicalIF":4.2,"publicationDate":"2022-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10216373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Physiological Systems in Promoting Frailty. 促进衰弱的生理系统。

IF 4.2 2区医学

Comprehensive Physiology Pub Date : 2022-04-26 DOI: 10.1002/cphy.c210034

Laís R Perazza, Holly M Brown-Borg, LaDora V Thompson

{"title":"Physiological Systems in Promoting Frailty.","authors":"Laís R Perazza, Holly M Brown-Borg, LaDora V Thompson","doi":"10.1002/cphy.c210034","DOIUrl":"10.1002/cphy.c210034","url":null,"abstract":"Frailty is a complex syndrome affecting a growing sector of the global population as medical developments have advanced human mortality rates across the world. Our current understanding of frailty is derived from studies conducted in the laboratory as well as the clinic, which have generated largely phenotypic information. Far fewer studies have uncovered biological underpinnings driving the onset and progression of frailty, but the stage is set to advance the field with preclinical and clinical assessment tools, multiomics approaches together with physiological and biochemical methodologies. In this article, we provide comprehensive coverage of topics regarding frailty assessment, preclinical models, interventions, and challenges as well as clinical frameworks and prevalence. We also identify central biological mechanisms that may be at play including mitochondrial dysfunction, epigenetic alterations, and oxidative stress that in turn, affect metabolism, stress responses, and endocrine and neuromuscular systems. We review the role of metabolic syndrome, insulin resistance and visceral obesity, focusing on glucose homeostasis, adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and nicotinamide adenine dinucleotide (NAD+ ) as critical players influencing the age-related loss of health. We further focus on how immunometabolic dysfunction associates with oxidative stress in promoting sarcopenia, a key contributor to slowness, weakness, and fatigue. We explore the biological mechanisms involved in stem cell exhaustion that affect regeneration and may contribute to the frailty-associated decline in resilience and adaptation to stress. Together, an overview of the interplay of aging biology with genetic, lifestyle, and environmental factors that contribute to frailty, as well as potential therapeutic targets to lower risk and slow the progression of ongoing disease is covered. © 2022 American Physiological Society. Compr Physiol 12:1-46, 2022.","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"12 3","pages":"3575-3620"},"PeriodicalIF":4.2,"publicationDate":"2022-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531553/pdf/nihms-1839399.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9839934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Respiratory-Cardiovascular Interactions During Mechanical Ventilation: Physiology and Clinical Implications. 机械通气期间呼吸-心血管相互作用:生理学和临床意义。

IF 5.8 2区医学

Comprehensive Physiology Pub Date : 2022-04-26 DOI: 10.1002/cphy.c210003

John Kreit

{"title":"Respiratory-Cardiovascular Interactions During Mechanical Ventilation: Physiology and Clinical Implications.","authors":"John Kreit","doi":"10.1002/cphy.c210003","DOIUrl":"https://doi.org/10.1002/cphy.c210003","url":null,"abstract":"Positive-pressure inspiration and positive end-expiratory pressure (PEEP) increase pleural, alveolar, lung transmural, and intra-abdominal pressure, which decrease right and left ventricular (RV; LV) preload and LV afterload and increase RV afterload. The magnitude and clinical significance of the resulting changes in ventricular function are determined by the delivered tidal volume, the total level of PEEP, the compliance of the lungs and chest wall, intravascular volume, baseline RV and LV function, and intra-abdominal pressure. In mechanically ventilated patients, the most important, adverse consequences of respiratory-cardiovascular interactions are a PEEP-induced reduction in cardiac output, systemic oxygen delivery, and blood pressure; RV dysfunction in patients with ARDS; and acute hemodynamic collapse in patients with pulmonary hypertension. On the other hand, the hemodynamic changes produced by respiratory-cardiovascular interactions can be beneficial when used to assess volume responsiveness in hypotensive patients and by reducing dyspnea and improving hypoxemia in patients with cardiogenic pulmonary edema. Thus, a thorough understanding of the physiological principles underlying respiratory-cardiovascular interactions is essential if critical care practitioners are to anticipate, recognize, manage, and utilize their hemodynamic effects. © 2022 American Physiological Society. Compr Physiol 12:1-24, 2022.","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"12 3","pages":"3425-3448"},"PeriodicalIF":5.8,"publicationDate":"2022-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9894221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Molecular Modeling is an Enabling Approach to Complement and Enhance Channelopathy Research. 分子模型是补充和加强通道病研究的一种有利方法。

IF 5.8 2区医学

Comprehensive Physiology Pub Date : 2022-03-29 DOI: 10.1002/cphy.c190047

Michael T Zimmermann

{"title":"Molecular Modeling is an Enabling Approach to Complement and Enhance Channelopathy Research.","authors":"Michael T Zimmermann","doi":"10.1002/cphy.c190047","DOIUrl":"https://doi.org/10.1002/cphy.c190047","url":null,"abstract":"Hundreds of human membrane proteins form channels that transport necessary ions and compounds, including drugs and metabolites, yet details of their normal function or how function is altered by genetic variants to cause diseases are often unknown. Without this knowledge, researchers are less equipped to develop approaches to diagnose and treat channelopathies. High-resolution computational approaches such as molecular modeling enable researchers to investigate channelopathy protein function, facilitate detailed hypothesis generation, and produce data that is difficult to gather experimentally. Molecular modeling can be tailored to each physiologic context that a protein may act within, some of which may currently be difficult or impossible to assay experimentally. Because many genomic variants are observed in channelopathy proteins from high-throughput sequencing studies, methods with mechanistic value are needed to interpret their effects. The eminent field of structural bioinformatics integrates techniques from multiple disciplines including molecular modeling, computational chemistry, biophysics, and biochemistry, to develop mechanistic hypotheses and enhance the information available for understanding function. Molecular modeling and simulation access 3D and time-dependent information, not currently predictable from sequence. Thus, molecular modeling is valuable for increasing the resolution with which the natural function of protein channels can be investigated, and for interpreting how genomic variants alter them to produce physiologic changes that manifest as channelopathies. © 2022 American Physiological Society. Compr Physiol 12:3141-3166, 2022.","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"12 2","pages":"3141-3166"},"PeriodicalIF":5.8,"publicationDate":"2022-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10191168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases. 肝脏疾病病理生理学中的氧化应激和氧化还原信号转导。

IF 5.8 2区医学

Comprehensive Physiology Pub Date : 2022-03-29 DOI: 10.1002/cphy.c200021

Raja Gopal Reddy Mooli, Dhanunjay Mukhi, Sadeesh K Ramakrishnan

{"title":"Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases.","authors":"Raja Gopal Reddy Mooli, Dhanunjay Mukhi, Sadeesh K Ramakrishnan","doi":"10.1002/cphy.c200021","DOIUrl":"10.1002/cphy.c200021","url":null,"abstract":"The increased production of derivatives of molecular oxygen and nitrogen in the form of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to molecular damage called oxidative stress. Under normal physiological conditions, the ROS generation is tightly regulated in different cells and cellular compartments. Any disturbance in the balance between the cellular generation of ROS and antioxidant balance leads to oxidative stress. In this article, we discuss the sources of ROS (endogenous and exogenous) and antioxidant mechanisms. We also focus on the pathophysiological significance of oxidative stress in various cell types of the liver. Oxidative stress is implicated in the development and progression of various liver diseases. We narrate the master regulators of ROS-mediated signaling and their contribution to liver diseases. Nonalcoholic fatty liver diseases (NAFLD) are influenced by a \"multiple parallel-hit model\" in which oxidative stress plays a central role. We highlight the recent findings on the role of oxidative stress in the spectrum of NAFLD, including fibrosis and liver cancer. Finally, we provide a brief overview of oxidative stress biomarkers and their therapeutic applications in various liver-related disorders. Overall, the article sheds light on the significance of oxidative stress in the pathophysiology of the liver. © 2022 American Physiological Society. Compr Physiol 12:3167-3192, 2022.","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"12 2","pages":"3167-3192"},"PeriodicalIF":5.8,"publicationDate":"2022-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10074426/pdf/nihms-1880813.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9887959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Computational and Experimental Analysis of Genetic Variants. 遗传变异的计算与实验分析。

IF 5.8 2区医学

Comprehensive Physiology Pub Date : 2022-03-29 DOI: 10.1002/cphy.c210012

Jeremy W Prokop, Vladislav Jdanov, Lane Savage, Michele Morris, Neil Lamb, Elizabeth VanSickle, Cynthia L Stenger, Surender Rajasekaran, Caleb P Bupp

{"title":"Computational and Experimental Analysis of Genetic Variants.","authors":"Jeremy W Prokop, Vladislav Jdanov, Lane Savage, Michele Morris, Neil Lamb, Elizabeth VanSickle, Cynthia L Stenger, Surender Rajasekaran, Caleb P Bupp","doi":"10.1002/cphy.c210012","DOIUrl":"https://doi.org/10.1002/cphy.c210012","url":null,"abstract":"Genomics has grown exponentially over the last decade. Common variants are associated with physiological changes through statistical strategies such as Genome-Wide Association Studies (GWAS) and quantitative trail loci (QTL). Rare variants are associated with diseases through extensive filtering tools, including population genomics and trio-based sequencing (parents and probands). However, the genomic associations require follow-up analyses to narrow causal variants, identify genes that are influenced, and to determine the physiological changes. Large quantities of data exist that can be used to connect variants to gene changes, cell types, protein pathways, clinical phenotypes, and animal models that establish physiological genomics. This data combined with bioinformatics including evolutionary analysis, structural insights, and gene regulation can yield testable hypotheses for mechanisms of genomic variants. Molecular biology, biochemistry, cell culture, CRISPR editing, and animal models can test the hypotheses to give molecular variant mechanisms. Variant characterizations can be a significant component of educating future professionals at the undergraduate, graduate, or medical training programs through teaching the basic concepts and terminology of genetics while learning independent research hypothesis design. This article goes through the computational and experimental analysis strategies of variant characterization and provides examples of these tools applied in publications. © 2022 American Physiological Society. Compr Physiol 12:3303-3336, 2022.","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"12 2","pages":"3303-3336"},"PeriodicalIF":5.8,"publicationDate":"2022-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9887964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Polycystic Ovary Syndrome and the Neuroendocrine Consequences of Androgen Excess. 多囊卵巢综合征和雄激素过量的神经内分泌后果。

IF 5.8 2区医学

Comprehensive Physiology Pub Date : 2022-03-29 DOI: 10.1002/cphy.c210025

Mauro S B Silva, Rebecca E Campbell

{"title":"Polycystic Ovary Syndrome and the Neuroendocrine Consequences of Androgen Excess.","authors":"Mauro S B Silva, Rebecca E Campbell","doi":"10.1002/cphy.c210025","DOIUrl":"https://doi.org/10.1002/cphy.c210025","url":null,"abstract":"Polycystic ovary syndrome (PCOS) is a major endocrine disorder strongly associated with androgen excess and frequently leading to female infertility. Although classically considered an ovarian disease, altered neuroendocrine control of gonadotropin-releasing hormone (GnRH) neurons in the brain and abnormal gonadotropin secretion may underpin PCOS presentation. Defective regulation of GnRH pulse generation in PCOS promotes high luteinizing hormone (LH) pulsatile secretion, which in turn overstimulates ovarian androgen production. Early and emerging evidence from preclinical models suggests that maternal androgen excess programs abnormalities in developing neuroendocrine circuits that are associated with PCOS pathology, and that these abnormalities are sustained by postpubertal elevation of endogenous androgen levels. This article will discuss experimental evidence, from the clinic and in preclinical animal models, that has significantly contributed to our understanding of how androgen excess influences the assembly and maintenance of neuroendocrine impairments in the female brain. Abnormal central gamma-aminobutyric acid (GABA) signaling has been identified in both patients and preclinical models as a possible link between androgen excess and elevated GnRH/LH secretion. Enhanced GABAergic innervation and drive to GnRH neurons is suspected to contribute to the pathogenesis and early manifestation of neuroendocrine derangement in PCOS. Accordingly, this article also provides an overview of GABA regulation of GnRH neuron function from prenatal development to adulthood to discuss possible avenues for future discovery research and therapeutic interventions. © 2022 American Physiological Society. Compr Physiol 12:3347-3369, 2022.","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"12 2","pages":"3347-3369"},"PeriodicalIF":5.8,"publicationDate":"2022-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9833238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4