Comprehensive Physiology最新文献

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.

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.

Reproduction, growth, stress, and metabolism are determined by endocrine/neuroendocrine systems that regulate circulating hormone concentrations. All these systems generate rhythms and changes in hormone pulsatility observed in a variety of pathophysiological states. Thus, the output of endocrine/neuroendocrine systems must be regulated within a narrow window of effective hormone concentrations but must also maintain a capacity for plasticity to respond to changing physiological demands. Remarkably most endocrinologists still have a "textbook" view of endocrine gland organization which has emanated from 20^th century histological studies on thin 2D tissue sections. However, 21^st -century technological advances, including in-depth 3D imaging of specific cell types have vastly changed our knowledge. We now know that various levels of multicellular organization can be found across different glands, that organizational motifs can vary between species and can be modified to enhance or decrease hormonal release. This article focuses on how the organization of cells regulates hormone output using three endocrine/neuroendocrine glands that present different levels of organization and complexity: the adrenal medulla, with a single neuroendocrine cell type; the anterior pituitary, with multiple intermingled cell types; and the pancreas with multiple intermingled cell types organized into distinct functional units. We give an overview of recent methodologies that allow the study of the different components within endocrine systems, particularly their temporal and spatial relationships. We believe the emerging findings about network organization, and its impact on hormone secretion, are crucial to understanding how homeostatic regulation of endocrine axes is carried out within endocrine organs themselves. © 2022 American Physiological Society. Compr Physiol 12:3371-3415, 2022.

Electronic cigarettes have gained widespread acceptance among adolescents and young adults. As a result of this popularity, there are concerns regarding the potential harm of primary, secondhand and thirdhand electronic cigarette exposures on fetal and postnatal development. In vitro studies have shown that constituents in electronic cigarette liquids, including nicotine, flavorings, and carrier agents can alter cellular processes and growth. Additionally, aerosolized electronic cigarette emissions have been shown to disrupt organ development and immune responses in preclinical studies. In clinical studies, an association between electronic cigarette use and frequent respiratory symptoms, greater asthma severity and impaired mucociliary clearance has been demonstrated with adolescent and young adult users of electronic cigarettes having twice the frequency of cough, mucus production, or bronchitis compared to nonusers. Along with the popularity of electronic cigarette use, secondhand electronic cigarette exposure has increased substantially; with almost one-fourth of middle and high school children reporting exposure to secondhand vapors. The health consequences of secondhand electronic cigarette exposure on children and other vulnerable populations are poorly understood but detectable levels of cotinine have been measured in nonusers. Pregnant women and their offspring are another vulnerable group at increased risk for health consequences from electronic cigarette exposure. Nicotine crosses the placenta and can disrupt brain and lung development in preclinical studies. This article will focus on the physiological and health effects associated with primary or secondhand exposure to electronic cigarettes. It is expected that with ongoing availability of electronic cigarettes as well as the accumulation of additional follow-up time for long-term outcomes, the risks associated with exposure will become better clarified. © 2022 American Physiological Society. Compr Physiol 12:3337-3346, 2022.

For centuries, regular exercise has been acknowledged as a potent stimulus to promote, maintain, and restore healthy functioning of nearly every physiological system of the human body. With advancing understanding of the complexity of human physiology, continually evolving methodological possibilities, and an increasingly dire public health situation, the study of exercise as a preventative or therapeutic treatment has never been more interdisciplinary, or more impactful. During the early stages of the NIH Common Fund Molecular Transducers of Physical Activity Consortium (MoTrPAC) Initiative, the field is well-positioned to build substantially upon the existing understanding of the mechanisms underlying benefits associated with exercise. Thus, we present a comprehensive body of the knowledge detailing the current literature basis surrounding the molecular adaptations to exercise in humans to provide a view of the state of the field at this critical juncture, as well as a resource for scientists bringing external expertise to the field of exercise physiology. In reviewing current literature related to molecular and cellular processes underlying exercise-induced benefits and adaptations, we also draw attention to existing knowledge gaps warranting continued research effort. © 2021 American Physiological Society. Compr Physiol 12:3193-3279, 2022.

Ca²⁺ homeostasis is essential for cell function and survival. As such, the cytosolic Ca²⁺ concentration is tightly controlled by a wide number of specialized Ca²⁺ handling proteins. One among them is the Na⁺ -Ca²⁺ exchanger (NCX), a ubiquitous plasma membrane transporter that exploits the electrochemical gradient of Na⁺ to drive Ca²⁺ out of the cell, against its concentration gradient. In this critical role, this secondary transporter guides vital physiological processes such as Ca²⁺ homeostasis, muscle contraction, bone formation, and memory to name a few. Herein, we review the progress made in recent years about the structure of the mammalian NCX and how it relates to function. Particular emphasis will be given to the mammalian cardiac isoform, NCX1.1, due to the extensive studies conducted on this protein. Given the degree of conservation among the eukaryotic exchangers, the information highlighted herein will provide a foundation for our understanding of this transporter family. We will discuss gene structure, alternative splicing, topology, regulatory mechanisms, and NCX's functional role on cardiac physiology. Throughout this article, we will attempt to highlight important milestones in the field and controversial topics where future studies are required. © 2021 American Physiological Society. Compr Physiol 12:1-37, 2021.

Na,K-ATPase is an ubiquitous enzyme actively transporting Na-ions out of the cell in exchange for K-ions, thereby maintaining their concentration gradients across the cell membrane. Since its discovery more than six decades ago the Na-pump has been studied extensively and its vital physiological role in essentially every cell has been established. This article aims at providing an overview of well-established biochemical properties with a focus on Na,K-ATPase isoforms, its transport mechanism and principle conformations, inhibitors, and insights gained from crystal structures. © 2021 American Physiological Society. Compr Physiol 11:1-21, 2021.

When animals walk overground, mechanical stimuli activate various receptors located in muscles, joints, and skin. Afferents from these mechanoreceptors project to neuronal networks controlling locomotion in the spinal cord and brain. The dynamic interactions between the control systems at different levels of the neuraxis ensure that locomotion adjusts to its environment and meets task demands. In this article, we describe and discuss the essential contribution of somatosensory feedback to locomotion. We start with a discussion of how biomechanical properties of the body affect somatosensory feedback. We follow with the different types of mechanoreceptors and somatosensory afferents and their activity during locomotion. We then describe central projections to locomotor networks and the modulation of somatosensory feedback during locomotion and its mechanisms. We then discuss experimental approaches and animal models used to investigate the control of locomotion by somatosensory feedback before providing an overview of the different functional roles of somatosensory feedback for locomotion. Lastly, we briefly describe the role of somatosensory feedback in the recovery of locomotion after neurological injury. We highlight the fact that somatosensory feedback is an essential component of a highly integrated system for locomotor control. © 2021 American Physiological Society. Compr Physiol 11:1-71, 2021.

Epithelial oxalate transport is fundamental to the role occupied by the gastrointestinal (GI) tract in oxalate homeostasis. The absorption of dietary oxalate, together with its secretion into the intestine, and degradation by the gut microbiota, can all influence the excretion of this nonfunctional terminal metabolite in the urine. Knowledge of the transport mechanisms is relevant to understanding the pathophysiology of hyperoxaluria, a risk factor in kidney stone formation, for which the intestine also offers a potential means of treatment. The following discussion presents an expansive review of intestinal oxalate transport. We begin with an overview of the fate of oxalate, focusing on the sources, rates, and locations of absorption and secretion along the GI tract. We then consider the mechanisms and pathways of transport across the epithelial barrier, discussing the transcellular, and paracellular components. There is an emphasis on the membrane-bound anion transporters, in particular, those belonging to the large multifunctional Slc26 gene family, many of which are expressed throughout the GI tract, and we summarize what is currently known about their participation in oxalate transport. In the final section, we examine the physiological stimuli proposed to be involved in regulating some of these pathways, encompassing intestinal adaptations in response to chronic kidney disease, metabolic acid-base disorders, obesity, and following gastric bypass surgery. There is also an update on research into the probiotic, Oxalobacter formigenes, and the basis of its unique interaction with the gut epithelium. © 2021 American Physiological Society. Compr Physiol 11:1-41, 2021.

Numerous conceptual models are used to describe the dynamic responsiveness of physiological systems to environmental pressures, originating with Claude Bernard's milieu intérieur and extending to more recent models such as allostasis. The impact of stress and anxiety upon these regulatory processes has both basic science and clinical relevance, extending from the pioneering work of Hans Selye who advanced the concept that stress can significantly impact physiological health and function. Of particular interest within the current article, anxiety is independently associated with cardiovascular risk, yet mechanisms underlying these associations remain equivocal. This link between anxiety and cardiovascular risk is relevant given the high prevalence of anxiety in the general population, as well as its early age of onset. Chronically anxious populations, such as those with anxiety disorders (i.e., generalized anxiety disorder, panic disorder, specific phobias, etc.) offer a human model that interrogates the deleterious effects that chronic stress and allostatic load can have on the nervous system and cardiovascular function. Further, while many of these disorders do not appear to exhibit baseline alterations in sympathetic neural activity, reactivity to mental stress offers insights into applicable, real-world scenarios in which heightened sympathetic reactivity may predispose those individuals to elevated cardiovascular risk. This article also assesses behavioral and lifestyle modifications that have been shown to concurrently improve anxiety symptoms, as well as sympathetic control. Lastly, future directions of research will be discussed, with a focus on better integration of psychological factors within physiological studies examining anxiety and neural cardiovascular health. © 2022 American Physiological Society. Compr Physiol 12:1-33, 2022.