Showing papers in "Physiological Reviews in 2018"
TL;DR: This work aims to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response.
Abstract: The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have ma...
1,268 citations
TL;DR: Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.
Abstract: Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.
921 citations
TL;DR: This review describes historical milestones in the initial characterization of the KEAP1-NRF2 system and provides a comprehensive overview of the molecular mechanisms governing the functions ofKEAP1 and NRF2, as well as their roles in physiology and pathology.
Abstract: The Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (KEAP1-NRF2) system forms the major node of cellular and organismal defense against oxidative and electrophilic stresses of both exoge...
866 citations
TL;DR: This review highlights the current knowledge about the roles of ANG-(1–7) in physiology and disease, with particular emphasis on the brain.
Abstract: The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1-7)/MAS, whose end point is the metabolite ANG-(1-7). ACE2 and other enzymes can form ANG-(1-7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1-7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1-7) in physiology and disease, with particular emphasis on the brain.
682 citations
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TL;DR: Which forms of cell death occur in stroke and Alzheimer's disease are reassess, and why it has been so difficult to pinpoint the type of neuronal death involved is discussed.
Abstract: Neuronal cell death occurs extensively during development and pathology, where it is especially important because of the limited capacity of adult neurons to proliferate or be replaced. The concept of cell death used to be simple as there were just two or three types, so we just had to work out which type was involved in our particular pathology and then block it. However, we now know that there are at least a dozen ways for neurons to die, that blocking a particular mechanism of cell death may not prevent the cell from dying, and that non-neuronal cells also contribute to neuronal death. We review here the mechanisms of neuronal death by intrinsic and extrinsic apoptosis, oncosis, necroptosis, parthanatos, ferroptosis, sarmoptosis, autophagic cell death, autosis, autolysis, paraptosis, pyroptosis, phagoptosis, and mitochondrial permeability transition. We next explore the mechanisms of neuronal death during development, and those induced by axotomy, aberrant cell-cycle reentry, glutamate (excitoxicity and oxytosis), loss of connected neurons, aggregated proteins and the unfolded protein response, oxidants, inflammation, and microglia. We then reassess which forms of cell death occur in stroke and Alzheimer's disease, two of the most important pathologies involving neuronal cell death. We also discuss why it has been so difficult to pinpoint the type of neuronal death involved, if and why the mechanism of neuronal death matters, the molecular overlap and interplay between death subroutines, and the therapeutic implications of these multiple overlapping forms of neuronal death.
650 citations
TL;DR: It is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.
Abstract: The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG I...
618 citations
TL;DR: Understanding of this balance between long-range and short-range interactions between the immune system and the central nervous system has evolved over time, since the first demonstrations of immune influences on brain functions are shown.
Abstract: Because of the compartmentalization of disciplines that shaped the academic landscape of biology and biomedical sciences in the past, physiological systems have long been studied in isolation from ...
544 citations
TL;DR: The mechanisms of OXT expression and release, expression and binding of the OXTR in brain and periphery, OX TR-coupled signaling cascades, and their involvement in behavioral outcomes are discussed to assemble a comprehensive picture of the central and peripheral OXT system.
Abstract: The many facets of the oxytocin (OXT) system of the brain and periphery elicited nearly 25,000 publications since 1930 (see FIGURE 1, as listed in PubMed), which revealed central roles for OXT and ...
510 citations
TL;DR: The perineuronal net and how chondroitin sulfate proteoglycans deposited in both the glial scar and net impede axonal outgrowth at the level of the growth cone are discussed.
Abstract: Since no approved therapies to restore mobility and sensation following spinal cord injury (SCI) currently exist, a better understanding of the cellular and molecular mechanisms following SCI that compromise regeneration or neuroplasticity is needed to develop new strategies to promote axonal regrowth and restore function. Physical trauma to the spinal cord results in vascular disruption that, in turn, causes blood-spinal cord barrier rupture leading to hemorrhage and ischemia, followed by rampant local cell death. As subsequent edema and inflammation occur, neuronal and glial necrosis and apoptosis spread well beyond the initial site of impact, ultimately resolving into a cavity surrounded by glial/fibrotic scarring. The glial scar, which stabilizes the spread of secondary injury, also acts as a chronic, physical, and chemo-entrapping barrier that prevents axonal regeneration. Understanding the formative events in glial scarring helps guide strategies towards the development of potential therapies to enhance axon regeneration and functional recovery at both acute and chronic stages following SCI. This review will also discuss the perineuronal net and how chondroitin sulfate proteoglycans (CSPGs) deposited in both the glial scar and net impede axonal outgrowth at the level of the growth cone. We will end the review with a summary of current CSPG-targeting strategies that help to foster axonal regeneration, neuroplasticity/sprouting, and functional recovery following SCI.
461 citations
TL;DR: Recent advances in understanding of the β-cell transcriptome, electrical activity, and insulin exocytosis are reviewed and models of how the different ion channels contribute to their electrical activity and insulin secretion are provided, and how these processes become perturbed in T2DM are discussed.
Abstract: The pancreatic β-cell plays a key role in glucose homeostasis by secreting insulin, the only hormone capable of lowering the blood glucose concentration. Impaired insulin secretion results in the chronic hyperglycemia that characterizes type 2 diabetes (T2DM), which currently afflicts >450 million people worldwide. The healthy β-cell acts as a glucose sensor matching its output to the circulating glucose concentration. It does so via metabolically induced changes in electrical activity, which culminate in an increase in the cytoplasmic Ca2+ concentration and initiation of Ca2+-dependent exocytosis of insulin-containing secretory granules. Here, we review recent advances in our understanding of the β-cell transcriptome, electrical activity, and insulin exocytosis. We highlight salient differences between mouse and human β-cells, provide models of how the different ion channels contribute to their electrical activity and insulin secretion, and conclude by discussing how these processes become perturbed in T2DM.
448 citations
TL;DR: An overview of current knowledge on adenosine receptors, including their characteristic structural features, molecular interactions and cellular functions, as well as their essential roles in pain, cancer, and neurodegenerative, inflammatory, and autoimmune diseases are offered.
Abstract: Adenosine is a ubiquitous endogenous autacoid whose effects are triggered through the enrollment of four G protein-coupled receptors: A1, A2A, A2B, and A3. Due to the rapid generation of adenosine ...
TL;DR: It is shown that maladaptation of EC metabolism contributes to vascular disorders, through EC dysfunction or excess angiogenesis, and presents new opportunities for anti-angiogenic strategies.
Abstract: Endothelial cells (ECs) are more than inert blood vessel lining material. Instead, they are active players in the formation of new blood vessels (angiogenesis) both in health and (life-threatening) diseases. Recently, a new concept arose by which EC metabolism drives angiogenesis in parallel to well-established angiogenic growth factors (e.g., vascular endothelial growth factor). 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3-driven glycolysis generates energy to sustain competitive behavior of the ECs at the tip of a growing vessel sprout, whereas carnitine palmitoyltransferase 1a-controlled fatty acid oxidation regulates nucleotide synthesis and proliferation of ECs in the stalk of the sprout. To maintain vascular homeostasis, ECs rely on an intricate metabolic wiring characterized by intracellular compartmentalization, use metabolites for epigenetic regulation of EC subtype differentiation, crosstalk through metabolite release with other cell types, and exhibit EC subtype-specific metabolic traits. Importantly, maladaptation of EC metabolism contributes to vascular disorders, through EC dysfunction or excess angiogenesis, and presents new opportunities for anti-angiogenic strategies. Here we provide a comprehensive overview of established as well as newly uncovered aspects of EC metabolism.
TL;DR: Arguments are provided to substantiate the relation of cancer hallmarks to ion channel dysfunction to channelopathies, as disease states causally linked with inherited mutations of ion channel genes that alter channel's biophysical properties in a broader context of the disease state.
Abstract: Genomic instability is a primary cause and fundamental feature of human cancer. However, all cancer cell genotypes generally translate into several common pathophysiological features, often referre...
TL;DR: Biophysical structure-function analysis identified residues involved in ion permeation, anion-proton coupling and gating and led to attractive biophysical models of mammalian CLCs and their role in disease.
Abstract: CLC anion transporters are found in all phyla and form a gene family of eight members in mammals. Two CLC proteins, each of which completely contains an ion translocation parthway, assemble to homo...
TL;DR: The involvement of arginase in diseases affecting the cardiovascular, renal, and central nervous system and cancer is reviewed and the value of therapies targeting the elevated activity of Arginase is discussed.
Abstract: The arginase enzyme developed in early life forms and was maintained during evolution. As the last step in the urea cycle, arginase cleaves l-arginine to form urea and l-ornithine. The urea cycle p...
TL;DR: The subcutaneous adipose tissue (SAT) is the largest and best storage site for excess lipids as discussed by the authors, however, it has a limited ability to expand by recruiting and/or differentiating available precursor cells.
Abstract: The subcutaneous adipose tissue (SAT) is the largest and best storage site for excess lipids. However, it has a limited ability to expand by recruiting and/or differentiating available precursor ce...
TL;DR: This review aims to summarize recent advances in epithelial transport and barrier function and to highlight how bile acids are now emerging as exciting new targets for disease intervention.
Abstract: Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid t...
TL;DR: Evidence thus reviewed supports that chronic, mildly elevated intracranial pressure in space (as opposed to more variable ICP with posture and activity on Earth) is largely accounted for by loss of hydrostatic pressures and altered hemodynamics in the intrac Cranial circulation and the cerebrospinal fluid system.
Abstract: Visual impairment intracranial pressure (VIIP) syndrome is considered an unexplained major risk for future long-duration spaceflight. NASA recently redefined this syndrome as Spaceflight-Associated Neuro-ocular Syndrome (SANS). Evidence thus reviewed supports that chronic, mildly elevated intracranial pressure (ICP) in space (as opposed to more variable ICP with posture and activity on Earth) is largely accounted for by loss of hydrostatic pressures and altered hemodynamics in the intracranial circulation and the cerebrospinal fluid system. In space, an elevated pressure gradient across the lamina cribrosa, caused by a chronic but mildly elevated ICP, likely elicits adaptations of multiple structures and fluid systems in the eye which manifest themselves as the VIIP syndrome. A chronic mismatch between ICP and intraocular pressure (IOP) in space may acclimate the optic nerve head, lamina cribrosa, and optic nerve subarachnoid space to a condition that is maladaptive to Earth, all contributing to the pathogenesis of space VIIP syndrome. Relevant findings help to evaluate whether artificial gravity is an appropriate countermeasure to prevent this seemingly adverse effect of long-duration spaceflight.
TL;DR: This review focuses on the physiology of CRF-related peptides and their cognate receptors and describes the major molecular features covering aspects of gene expression and regulation, structural properties, and molecular interactions, as well as mechanisms of signal transduction and their surveillance.
Abstract: The physiological stress response is responsible for the maintenance of homeostasis in the presence of real or perceived challenges. In this function, the brain activates adaptive responses that involve numerous neural circuits and effector molecules to adapt to the current and future demands. A maladaptive stress response has been linked to the etiology of a variety of disorders, such as anxiety and mood disorders, eating disorders, and the metabolic syndrome. The neuropeptide corticotropin-releasing factor (CRF) and its relatives, the urocortins 1-3, in concert with their receptors (CRFR1, CRFR2), have emerged as central components of the physiological stress response. This central peptidergic system impinges on a broad spectrum of physiological processes that are the basis for successful adaptation and concomitantly integrate autonomic, neuroendocrine, and behavioral stress responses. This review focuses on the physiology of CRF-related peptides and their cognate receptors with the aim of providing a comprehensive up-to-date overview of the field. We describe the major molecular features covering aspects of gene expression and regulation, structural properties, and molecular interactions, as well as mechanisms of signal transduction and their surveillance. In addition, we discuss the large body of published experimental studies focusing on state-of-the-art genetic approaches with high temporal and spatial precision, which collectively aimed to dissect the contribution of CRF-related ligands and receptors to different levels of the stress response. We discuss the controversies in the field and unravel knowledge gaps that might pave the way for future research directions and open up novel opportunities for therapeutic intervention.
TL;DR: The goal is to present recent findings concerning novel inhibitory proteins or the regulation of the actin branched junction and place these in the context of what was previously known to provide a global overview of how the Arp2/3 complex is regulated in human cells.
Abstract: The Arp2/3 complex is an evolutionary conserved molecular machine that generates branched actin networks. When activated, the Arp2/3 complex contributes the actin branched junction and thus cross-links the polymerizing actin filaments in a network that exerts a pushing force. The different activators initiate branched actin networks at the cytosolic surface of different cellular membranes to promote their protrusion, movement, or scission in cell migration and membrane traffic. Here we review the structure, function, and regulation of all the direct regulators of the Arp2/3 complex that induce or inhibit the initiation of a branched actin network and that controls the stability of its branched junctions. Our goal is to present recent findings concerning novel inhibitory proteins or the regulation of the actin branched junction and place these in the context of what was previously known to provide a global overview of how the Arp2/3 complex is regulated in human cells. We focus on the human set of Arp2/3 regulators to compare normal Arp2/3 regulation in untransformed cells to the deregulation of the Arp2/3 system observed in patients affected by various cancers. In many cases, these deregulations promote cancer progression and have a direct impact on patient survival.
TL;DR: A novel classification of DAMPs is introduced in this review to help detect the relative contribution of each RN-pathway to certain physiological and pathophysiological conditions of necroinflammation.
Abstract: When cells undergo necrotic cell death in either physiological or pathophysiological settings in vivo, they release highly immunogenic intracellular molecules and organelles into the interstitium a...
TL;DR: Cell-specific and organ-specific roles in the integrated physiological response to acute lung infection, and the mechanisms by which intercellular and interorgan signaling contribute to host defense and healthy respiratory physiology or to acute lungs injury, chronic pulmonary disease, and adverse extrapulmonary sequelae are discussed.
Abstract: Pneumonia is a type of acute lower respiratory infection that is common and severe. The outcome of lower respiratory infection is determined by the degrees to which immunity is protective and infla...
TL;DR: This review comprehensively covers EPAC protein functions at the molecular, cellular, physiological, and pathophysiological levels; and in turn, the applications of employing EPAC-based biosensors as detection tools for dissecting cAMP signaling and the implications for targeting EPAC proteins for therapeutic development are discussed.
Abstract: This review focuses on one family of the known cAMP receptors, the exchange proteins directly activated by cAMP (EPACs), also known as the cAMP-regulated guanine nucleotide exchange factors (cAMP-G...
TL;DR: In this review, the existing data concerning the expression, as well as the physiological and pathophysiological functions, of ORs outside of the nose are highlighted to provide insights into future lines of research.
Abstract: Olfactory receptors (ORs) are not exclusively expressed in the olfactory sensory neurons; they are also observed outside of the olfactory system in all other human tissues tested to date, including the testis, lung, intestine, skin, heart, and blood. Within these tissues, certain ORs have been determined to be exclusively expressed in only one tissue, whereas other ORs are more widely distributed in many different tissues throughout the human body. For most of the ectopically expressed ORs, limited data are available for their functional roles. They have been shown to be involved in the modulation of cell-cell recognition, migration, proliferation, the apoptotic cycle, exocytosis, and pathfinding processes. Additionally, there is a growing body of evidence that they have the potential to serve as diagnostic and therapeutic tools, as ORs are highly expressed in different cancer tissues. Interestingly, in addition to the canonical signaling pathways activated by ORs in olfactory sensory neurons, alternative...
TL;DR: The metabolic crosstalk in humans, which regulates insulin sensitivity and energy homeostasis in the main insulin-sensitive tissues, skeletal muscle, liver, and adipose tissue, is focused on.
Abstract: Excessive energy intake and reduced energy expenditure drive the development of insulin resistance and metabolic diseases such as obesity and type 2 diabetes mellitus. Metabolic signals derived fro...
TL;DR: This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonaryDevelopment, and the hypothalamic-pituitary-adrenal axis and adipose tissue.
Abstract: Hypoxia is one of the most common and severe challenges to the maintenance of homeostasis. Oxygen sensing is a property of all tissues, and the response to hypoxia is multidimensional involving com...
TL;DR: Evidence suggests that PTX3 is a key homeostatic component at the crossroad of innate immunity, inflammation, tissue repair, and cancer.
Abstract: Innate immunity includes a cellular and a humoral arm PTX3 is a fluid-phase pattern recognition molecule conserved in evolution which acts as a key component of humoral innate immunity in infectio
TL;DR: This work reviews the proposed mechanisms governing changes in eating behavior, food intake, and body weight after bariatric surgery and suggests that additive or synergistic effects of both conditioned and unconditioned factors likely account for the complete picture of changes in Eating behavior.
Abstract: Obesity is an escalating global chronic disease. Bariatric surgery is a very efficacious treatment for obesity and its comorbidities. Alterations to gastrointestinal anatomy during bariatric surger...
TL;DR: This review provides a comprehensive overview of the intricacies of the BMP pathway and its inhibitors in bone development, homeostasis, and disease and proposes two major areas of need of future study by the field: greater resolution of the gene regulatory network downstream of BMP signaling in the skeleton, and an expanded repertoire of reagents to reliably and specifically inhibit individual B MP pathway components.
Abstract: Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor-β family of ligands BMPs exhibit widespread utility and pleiotropic, context-dependent effec
TL;DR: This review examines the variability in the individual peptides produced in different tissues and the impact of the simultaneous presence of their precursors or fragments and suggests that this comprehensive view of POMC processing is a necessity for all involved in studying this fascinating physiological regulatory phenomenon.
Abstract: Pro-opiomelanocortin (POMC) is the archetypal polypeptide precursor of hormones and neuropeptides. In this review, we examine the variability in the individual peptides produced in different tissue...