Physiological reviews最新文献

{"title":"Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries.","authors":"Genesee J Martinez, Malik Appleton, Zachary A Kipp, Analia S Loria, Booki Min, Terry D Hinds","doi":"10.1152/physrev.00021.2023","DOIUrl":"10.1152/physrev.00021.2023","url":null,"abstract":"<p><p>The normal stress response in humans is governed by the hypothalamic-pituitary-adrenal (HPA) axis through heightened mechanisms during stress, raising blood levels of the glucocorticoid hormone cortisol. Glucocorticoids are quintessential compounds that balance the proper functioning of numerous systems in the mammalian body. They are also generated synthetically and are the preeminent therapy for inflammatory diseases. They act by binding to the nuclear receptor transcription factor glucocorticoid receptor (GR), which has two main isoforms (GRα and GRβ). Our classical understanding of glucocorticoid signaling is from the GRα isoform, which binds the hormone, whereas GRβ has no known ligands. With glucocorticoids being involved in many physiological and cellular processes, even small disruptions in their release via the HPA axis, or changes in GR isoform expression, can have dire ramifications on health. Long-term chronic glucocorticoid therapy can lead to a glucocorticoid-resistant state, and we deliberate how this impacts disease treatment. Chronic glucocorticoid treatment can lead to noticeable side effects such as weight gain, adiposity, diabetes, and others that we discuss in detail. There are sexually dimorphic responses to glucocorticoids, and women tend to have a more hyperresponsive HPA axis than men. This review summarizes our understanding of glucocorticoids and critically analyzes the GR isoforms and their beneficial and deleterious mechanisms and the sexual differences that cause a dichotomy in responses. We also discuss the future of glucocorticoid therapy and propose a new concept of dual GR isoform agonist and postulate why activating both isoforms may prevent glucocorticoid resistance.</p>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":" ","pages":"473-532"},"PeriodicalIF":29.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11281820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41125524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in blood pressure regulation and hypertension: renal, hemodynamic, and hormonal mechanisms.","authors":"Erika R Drury, Jing Wu, Joseph C Gigliotti, Thu H Le","doi":"10.1152/physrev.00041.2022","DOIUrl":"10.1152/physrev.00041.2022","url":null,"abstract":"<p><p>The teleology of sex differences has been argued since at least as early as Aristotle's controversial <i>Generation of Animals</i> more than 300 years BC, which reflects the sex bias of the time to contemporary readers. Although the question \"why are the sexes different\" remains a topic of debate in the present day in metaphysics, the recent emphasis on sex comparison in research studies has led to the question \"how are the sexes different\" being addressed in health science through numerous observational studies in both health and disease susceptibility, including blood pressure regulation and hypertension. These efforts have resulted in better understanding of differences in males and females at the molecular level that partially explain their differences in vascular function and renal sodium handling and hence blood pressure and the consequential cardiovascular and kidney disease risks in hypertension. This review focuses on clinical studies comparing differences between men and women in blood pressure over the life span and response to dietary sodium and highlights experimental models investigating sexual dimorphism in the renin-angiotensin-aldosterone, vascular, sympathetic nervous, and immune systems, endothelin, the major renal sodium transporters/exchangers/channels, and the impact of sex hormones on these systems in blood pressure homeostasis. Understanding the mechanisms governing sex differences in blood pressure regulation could guide novel therapeutic approaches in a sex-specific manner to lower cardiovascular risks in hypertension and advance personalized medicine.</p>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":" ","pages":"199-251"},"PeriodicalIF":29.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11281816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9867092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent insights into channelopathies.","authors":"Osama F Harraz, Eric Delpire","doi":"10.1152/physrev.00022.2023","DOIUrl":"10.1152/physrev.00022.2023","url":null,"abstract":"","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":" ","pages":"23-31"},"PeriodicalIF":33.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10046282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ca²⁺ dynamics in interstitial cells: foundational mechanisms for the motor patterns in the gastrointestinal tract.","authors":"Kenton M Sanders, Bernard T Drumm, Caroline A Cobine, Salah A Baker","doi":"10.1152/physrev.00036.2022","DOIUrl":"10.1152/physrev.00036.2022","url":null,"abstract":"<p><p>The gastrointestinal (GI) tract displays multiple motor patterns that move nutrients and wastes through the body. Smooth muscle cells (SMCs) provide the forces necessary for GI motility, but interstitial cells, electrically coupled to SMCs, tune SMC excitability, transduce inputs from enteric motor neurons, and generate pacemaker activity that underlies major motor patterns, such as peristalsis and segmentation. The interstitial cells regulating SMCs are interstitial cells of Cajal (ICC) and PDGF receptor (PDGFR)α⁺ cells. Together these cells form the SIP syncytium. ICC and PDGFRα⁺ cells express signature Ca²⁺-dependent conductances: ICC express Ca²⁺-activated Cl^- channels, encoded by <i>Ano1</i>, that generate inward current, and PDGFRα⁺ cells express Ca²⁺-activated K⁺ channels, encoded by <i>Kcnn3</i>, that generate outward current. The open probabilities of interstitial cell conductances are controlled by Ca²⁺ release from the endoplasmic reticulum. The resulting Ca²⁺ transients occur spontaneously in a stochastic manner. Ca²⁺ transients in ICC induce spontaneous transient inward currents and spontaneous transient depolarizations (STDs). Neurotransmission increases or decreases Ca²⁺ transients, and the resulting depolarizing or hyperpolarizing responses conduct to other cells in the SIP syncytium. In pacemaker ICC, STDs activate voltage-dependent Ca²⁺ influx, which initiates a cluster of Ca²⁺ transients and sustains activation of ANO1 channels and depolarization during slow waves. Regulation of GI motility has traditionally been described as neurogenic and myogenic. Recent advances in understanding Ca²⁺ handling mechanisms in interstitial cells and how these mechanisms influence motor patterns of the GI tract suggest that the term \"myogenic\" should be replaced by the term \"SIPgenic,\" as this review discusses.</p>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":" ","pages":"329-398"},"PeriodicalIF":29.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11281822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10005435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sympathetic circuits regulating hepatic glucose metabolism: where we stand.","authors":"Andrea Zsombok, Lucie D Desmoulins, Andrei V Derbenev","doi":"10.1152/physrev.00005.2023","DOIUrl":"10.1152/physrev.00005.2023","url":null,"abstract":"<p><p>The prevalence of metabolic disorders, including type 2 diabetes mellitus, continues to increase worldwide. Although newer and more advanced therapies are available, current treatments are still inadequate and the search for solutions remains. The regulation of energy homeostasis, including glucose metabolism, involves an exchange of information between the nervous systems and peripheral organs and tissues; therefore, developing treatments to alter central and/or peripheral neural pathways could be an alternative solution to modulate whole body metabolism. Liver glucose production and storage are major mechanisms controlling glycemia, and the autonomic nervous system plays an important role in the regulation of hepatic functions. Autonomic nervous system imbalance contributes to excessive hepatic glucose production and thus to the development and progression of type 2 diabetes mellitus. At cellular levels, change in neuronal activity is one of the underlying mechanisms of autonomic imbalance; therefore, modulation of the excitability of neurons involved in autonomic outflow governance has the potential to improve glycemic status. Tissue-specific subsets of preautonomic neurons differentially control autonomic outflow; therefore, detailed information about neural circuits and properties of liver-related neurons is necessary for the development of strategies to regulate liver functions via the autonomic nerves. This review provides an overview of our current understanding of the hypothalamus-ventral brainstem-liver pathway involved in the sympathetic regulation of the liver, outlines strategies to identify organ-related neurons, and summarizes neuronal plasticity during diabetic conditions with a particular focus on liver-related neurons in the paraventricular nucleus.</p>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":" ","pages":"85-101"},"PeriodicalIF":29.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11281813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9764341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT7: the seventh key to unlocking the mystery of aging.","authors":"Umar Raza, Xiaolong Tang, Zuojun Liu, Baohua Liu","doi":"10.1152/physrev.00044.2022","DOIUrl":"10.1152/physrev.00044.2022","url":null,"abstract":"<p><p>Aging is a chronic yet natural physiological decline of the body. Throughout life, humans are continuously exposed to a variety of exogenous and endogenous stresses, which engender various counteractive responses at the cellular, tissue, organ, as well as organismal levels. The compromised cellular and tissue functions that occur because of genetic factors or prolonged stress (or even the stress response) may accelerate aging. Over the last two decades, the sirtuin (SIRT) family of lysine deacylases has emerged as a key regulator of longevity in a variety of organisms. SIRT7, the most recently identified member of the SIRTs, maintains physiological homeostasis and provides protection against aging by functioning as a watchdog of genomic integrity, a dynamic sensor and modulator of stresses. SIRT7 decline disrupts metabolic homeostasis, accelerates aging, and increases the risk of age-related pathologies including cardiovascular and neurodegenerative diseases, pulmonary and renal disorders, inflammatory diseases, and cancer, etc. Here, we present SIRT7 as the seventh key to unlock the mystery of aging, and its specific manipulation holds great potential to ensure healthiness and longevity.</p>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":" ","pages":"253-280"},"PeriodicalIF":29.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11281815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10161831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative damage in neurodegeneration: roles in the pathogenesis and progression of Alzheimer disease.","authors":"Marzia Perluigi, Fabio Di Domenico, D Allan Butterfield","doi":"10.1152/physrev.00030.2022","DOIUrl":"10.1152/physrev.00030.2022","url":null,"abstract":"<p><p>Alzheimer disease (AD) is associated with multiple etiologies and pathological mechanisms, among which oxidative stress (OS) appears as a major determinant. Intriguingly, OS arises in various pathways regulating brain functions, and it seems to link different hypotheses and mechanisms of AD neuropathology with high fidelity. The brain is particularly vulnerable to oxidative damage, mainly because of its unique lipid composition, resulting in an amplified cascade of redox reactions that target several cellular components/functions ultimately leading to neurodegeneration. The present review highlights the \"OS hypothesis of AD,\" including amyloid beta-peptide-associated mechanisms, the role of lipid and protein oxidation unraveled by redox proteomics, and the antioxidant strategies that have been investigated to modulate the progression of AD. Collected studies from our groups and others have contributed to unraveling the close relationships between perturbation of redox homeostasis in the brain and AD neuropathology by elucidating redox-regulated events potentially involved in both the pathogenesis and progression of AD. However, the complexity of AD pathological mechanisms requires an in-depth understanding of several major intracellular pathways affecting redox homeostasis and relevant for brain functions. This understanding is crucial to developing pharmacological strategies targeting OS-mediated toxicity that may potentially contribute to slow AD progression as well as improve the quality of life of persons with this severe dementing disorder.</p>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"104 1","pages":"103-197"},"PeriodicalIF":29.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11281823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN.","authors":"Arnaud Monteil, Nathalie C Guérineau, Antonio Gil-Nagel, Paloma Parra-Diaz, Philippe Lory, Adriano Senatore","doi":"10.1152/physrev.00014.2022","DOIUrl":"10.1152/physrev.00014.2022","url":null,"abstract":"<p><p>Cell excitability and its modulation by hormones and neurotransmitters involve the concerted action of a large repertoire of membrane proteins, especially ion channels. Unique complements of coexpressed ion channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that are tailored for diverse physiological contributions, and dysfunction of any component may induce a disease state. A crucial parameter controlling cell excitability is the resting membrane potential (RMP) set by extra- and intracellular concentrations of ions, mainly Na⁺, K⁺, and Cl^-, and their passive permeation across the cell membrane through leak ion channels. Indeed, dysregulation of RMP causes significant effects on cellular excitability. This review describes the molecular and physiological properties of the Na⁺ leak channel NALCN, which associates with its accessory subunits UNC-79, UNC-80, and NLF-1/FAM155 to conduct depolarizing background Na⁺ currents in various excitable cell types, especially neurons. Studies of animal models clearly demonstrate that NALCN contributes to fundamental physiological processes in the nervous system including the control of respiratory rhythm, circadian rhythm, sleep, and locomotor behavior. Furthermore, dysfunction of NALCN and its subunits is associated with severe pathological states in humans. The critical involvement of NALCN in physiology is now well established, but its study has been hampered by the lack of specific drugs that can block or agonize NALCN currents in vitro and in vivo. Molecular tools and animal models are now available to accelerate our understanding of how NALCN contributes to key physiological functions and the development of novel therapies for NALCN channelopathies.</p>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":" ","pages":"399-472"},"PeriodicalIF":33.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10426886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The conducted vasomotor response and the principles of electrical communication in resistance arteries.","authors":"Galina Yu Mironova,&nbsp;Paulina M Kowalewska,&nbsp;Mohammed El-Lakany,&nbsp;Cam Ha T Tran,&nbsp;Maria Sancho,&nbsp;Anil Zechariah,&nbsp;William F Jackson,&nbsp;Donald G Welsh","doi":"10.1152/physrev.00035.2022","DOIUrl":"10.1152/physrev.00035.2022","url":null,"abstract":"<p><p>Biological tissues are fed by arterial networks whose task is to set blood flow delivery in accordance with energetic demand. Coordinating vasomotor activity among hundreds of neighboring segments is an essential process, one dependent upon electrical information spreading among smooth muscle and endothelial cells. The \"conducted vasomotor response\" is a functional expression of electrical spread, and it is this process that lies at the heart of this critical review. Written in a narrative format, this review first highlights historical manuscripts and then characterizes the conducted response across a range of preparations. Trends are highlighted and used to guide subsequent sections, focused on cellular foundations, biophysical underpinnings, and regulation in health and disease. Key information has been tabulated; figures reinforce grounding concepts and reveal a framework within which theoretical and experimental work can be rationalized. This summative review highlights that despite 30 years of concerted experimentation, key aspects of the conducted response remain ill defined. Of note is the need to rationalize the regulation and deterioration of conduction in pathobiological settings. New quantitative tools, along with transgenic technology, are discussed as a means of propelling this investigative field forward.</p>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":" ","pages":"33-84"},"PeriodicalIF":33.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9755683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Making a good egg: human oocyte health, aging, and in vitro development.","authors":"Evelyn E Telfer, Johanne Grosbois, Yvonne L Odey, Roseanne Rosario, Richard A Anderson","doi":"10.1152/physrev.00032.2022","DOIUrl":"10.1152/physrev.00032.2022","url":null,"abstract":"<p><p>Mammalian eggs (oocytes) are formed during fetal life and establish associations with somatic cells to form primordial follicles that create a store of germ cells (the primordial pool). The size of this pool is influenced by key events during the formation of germ cells and by factors that influence the subsequent activation of follicle growth. These regulatory pathways must ensure that the reserve of oocytes within primordial follicles in humans lasts for up to 50 years, yet only approximately 0.1% will ever be ovulated with the rest undergoing degeneration. This review outlines the mechanisms and regulatory pathways that govern the processes of oocyte and follicle formation and later growth, within the ovarian stroma, through to ovulation with particular reference to human oocytes/follicles. In addition, the effects of aging on female reproductive capacity through changes in oocyte number and quality are emphasized, with both the cellular mechanisms and clinical implications discussed. Finally, the details of current developments in culture systems that support all stages of follicle growth to generate mature oocytes in vitro and emerging prospects for making new oocytes from stem cells are outlined.</p>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"103 4","pages":"2623-2677"},"PeriodicalIF":33.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10625843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9930226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}