Showing papers in "Physiology in 2014"
TL;DR: Melatonin is a small, highly conserved indole with numerous receptor-mediated and receptor-independent actions that relate to melatonin's ability to function in the detoxification of free radicals, thereby protecting critical molecules from the destructive effects of oxidative stress under conditions of ischemia/reperfusion injury, ionizing radiation, and drug toxicity.
Abstract: Melatonin is a small, highly conserved indole with numerous receptor-mediated and receptor-independent actions. Receptor-dependent functions include circadian rhythm regulation, sleep, and cancer inhibition. The receptor-independent actions relate to melatonin's ability to function in the detoxification of free radicals, thereby protecting critical molecules from the destructive effects of oxidative stress under conditions of ischemia/reperfusion injury (stroke, heart attack), ionizing radiation, and drug toxicity, among others. Melatonin has numerous applications in physiology and medicine.
431 citations
TL;DR: AMP-activated protein kinase appears to have evolved in single-celled eukaryotes as an adenine nucleotide sensor that maintains energy homeostasis at the cellular level but during evolution of more complex multicellular organisms, the system has adapted to interact with hormones so that it also plays a key role in balancing energy intake and expenditure at the whole body level.
Abstract: AMP-activated protein kinase appears to have evolved in single-celled eukaryotes as an adenine nucleotide sensor that maintains energy homeostasis at the cellular level. However, during evolution of more complex multicellular organisms, the system has adapted to interact with hormones so that it also plays a key role in balancing energy intake and expenditure at the whole body level.
238 citations
TL;DR: The cellular and circuit mechanisms generating the rhythm of breathing in mammals have been under intense investigation for decades and the key discoveries are integrated into an updated description of the basic neural processes generating respiratory rhythm under in vivo conditions.
Abstract: The cellular and circuit mechanisms generating the rhythm of breathing in mammals have been under intense investigation for decades. Here, we try to integrate the key discoveries into an updated description of the basic neural processes generating respiratory rhythm under in vivo conditions.
173 citations
TL;DR: Evidence is compiled showing that rodents used as preclinical models of human biology are cold-stressed, hypermetabolic, hypertensive, sleep-deprived, obesity-resistant, fever- resistant, aging-resistant and tumor-prone compared with mice housed at thermoneutrality.
Abstract: Does it matter that rodents used as preclinical models of human biology are routinely housed below their thermoneutral zone? We compile evidence showing that such rodents are cold-stressed, hypermetabolic, hypertensive, sleep-deprived, obesity-resistant, fever-resistant, aging-resistant, and tumor-prone compared with mice housed at thermoneutrality. The same genotype of mouse has a very different phenotype and response to physiological or pharmacological intervention when raised below or at thermoneutrality.
132 citations
TL;DR: The extent to which evolutionary pressure has refined the physiology of this high-altitude population is demonstrated and although many physiological differences between highlanders and lowlanders have been found, it also suggests many more potential avenues of investigation.
Abstract: Anecdotal evidence surrounding Tibetans' and Sherpas' exceptional tolerance to hypobaric hypoxia has been recorded since the beginning of high-altitude exploration. These populations have successfully lived and reproduced at high altitude for hundreds of generations with hypoxia as a constant evolutionary pressure. Consequently, they are likely to have undergone natural selection toward a genotype (and phenotype) tending to offer beneficial adaptation to sustained hypoxia. With the advent of translational human hypoxic research, in which genotype/phenotype studies of healthy individuals at high altitude may be of benefit to hypoxemic critically ill patients in a hospital setting, high-altitude natives may provide a valuable and intriguing model. The aim of this review is to provide a comprehensive summary of the scientific literature encompassing Tibetan and Sherpa physiological adaptations to a high-altitude residence. The review demonstrates the extent to which evolutionary pressure has refined the physiology of this high-altitude population. Furthermore, although many physiological differences between highlanders and lowlanders have been found, it also suggests many more potential avenues of investigation.
129 citations
TL;DR: Intermittent hypoxia (IH) is most often thought of for its role in morbidity associated with sleep-disordered breathing, including central nervous system pathology as discussed by the authors.
Abstract: Intermittent hypoxia (IH) is most often thought of for its role in morbidity associated with sleep-disordered breathing, including central nervous system pathology. However, recent evidence suggest...
129 citations
TL;DR: The link between HIF and apoptosis is reviewed and it is shown that when oxygen levels decrease, HIF acts as a “spatially aggregating force” to trigger apoptosis.
Abstract: Eukaryotic life depends largely on molecular oxygen. During evolution, ingenious mechanisms have evolved that allow organisms to adapt when oxygen levels decrease. Many of these adaptional responses to low oxygen are orchestrated by the heterodimeric transcription factor hypoxia-inducible factor (HIF). Here, we review the link between HIF and apoptosis.
123 citations
TL;DR: In this paper, a nutraceutical compound that favorably modulates these pathways hold promise as a complementary approach for preserving endothelial health with aging, and healthy lifestyle behaviors preserve endothelial function with aging by inhibiting these mechanisms.
Abstract: Endothelial dysfunction develops with age and increases the risk of age-associated vascular disorders. Nitric oxide insufficiency, oxidative stress, and chronic low-grade inflammation, induced by upregulation of adverse cellular signaling processes and imbalances in stress resistance pathways, mediate endothelial dysfunction with aging. Healthy lifestyle behaviors preserve endothelial function with aging by inhibiting these mechanisms, and novel nutraceutical compounds that favorably modulate these pathways hold promise as a complementary approach for preserving endothelial health.
121 citations
TL;DR: Sex and age have important influences on sympathetic neural control of blood pressure in humans, and older men and women have higher sympathetic nerve activity and tighter coupling between SNA and blood pressure, contributing to the increased risk of hypertension with aging.
Abstract: Sex and age have important influences on sympathetic neural control of blood pressure in humans. Young women are relatively protected against risk of hypertension due to greater peripheral vasodilator influences compared with young men and older people. This protective effect is lost at menopause. Older men and women have higher sympathetic nerve activity and tighter coupling between SNA and blood pressure, contributing to the increased risk of hypertension with aging.
116 citations
TL;DR: This review summarizes the development of exercise-induced cardioprotection and the mechanisms responsible for this important adaptive response.
Abstract: Myocardial ischemia-reperfusion (IR) injury can cause ventricular cell death and is a major pathological event leading to morbidity and mortality in those with coronary artery disease. Interestingly, as few as five bouts of exercise on consecutive days can rapidly produce a cardiac phenotype that resists IR-induced myocardial injury. This review summarizes the development of exercise-induced cardioprotection and the mechanisms responsible for this important adaptive response.
115 citations
TL;DR: This review will highlight the pathways that endothelial cells and smooth muscle cells utilize to communicate during vessel formation and discuss how disruptions in these pathways contribute to disease.
Abstract: Blood vessels are composed of two primary cell types, endothelial cells and smooth muscle cells, each providing a unique contribution to vessel function. Signaling between these two cell types is essential for maintaining tone in mature vessels, and their communication is critical during development, and for repair and remodeling associated with blood vessel growth. This review will highlight the pathways that endothelial cells and smooth muscle cells utilize to communicate during vessel formation and discuss how disruptions in these pathways contribute to disease.
TL;DR: A hypothetical framework that regulates transport of germ cells across the seminiferous epithelium and its disruption causes infertility is provided and critically evaluate these findings.
Abstract: Transport of germ cells across the seminiferous epithelium is crucial to spermatogenesis. Its disruption causes infertility. Signaling molecules, such as focal adhesion kinase, c-Yes, c-Src, and intercellular adhesion molecules 1 and 2, are involved in these events by regulating actin-based cytoskeleton via their action on actin-regulating proteins, endocytic vesicle-mediated protein trafficking, and adhesion protein complexes. We critically evaluate these findings and provide a hypothetical framework that regulates these events.
TL;DR: Theoretical models show how a combination of angiogenesis, remodeling, and pruning in response to hemodynamic and metabolic stimuli, termed "angioadaptation," generates well organized, functional networks.
Abstract: The adequate and efficient functioning of the microcirculation requires not only numerous vessels providing a large surface area for transport but also a structure that provides short diffusion distances from capillaries to tissue and efficient distribution of convective blood flow. Theoretical models show how a combination of angiogenesis, remodeling, and pruning in response to hemodynamic and metabolic stimuli, termed “angioadaptation,” generates well organized, functional networks.
TL;DR: Despite largely unchanged metabolism and perfusion, repeated exposures to altered hemodynamics and hormonal milieu produced by acute exercise, long-term exercise training appears to be capable of inducing effects also in tissues other than muscles that may yield health benefits.
Abstract: Virtually all tissues in the human body rely on aerobic metabolism for energy production and are therefore critically dependent on continuous supply of oxygen. Oxygen is provided by blood flow, and, in essence, changes in organ perfusion are also closely associated with alterations in tissue metabolism. In response to acute exercise, blood flow is markedly increased in contracting skeletal muscles and myocardium, but perfusion in other organs (brain and bone) is only slightly enhanced or is even reduced (visceral organs). Despite largely unchanged metabolism and perfusion, repeated exposures to altered hemodynamics and hormonal milieu produced by acute exercise, long-term exercise training appears to be capable of inducing effects also in tissues other than muscles that may yield health benefits. However, the physiological adaptations and driving-force mechanisms in organs such as brain, liver, pancreas, gut, bone, and adipose tissue, remain largely obscure in humans. Along these lines, this review integrates current information on physiological responses to acute exercise and to long-term physical training in major metabolically active human organs. Knowledge is mostly provided based on the state-of-the-art, noninvasive human imaging studies, and directions for future novel research are proposed throughout the review.
TL;DR: The role of TRP channels, particularly endothelial TRPV4 and smooth muscle TRPC6 and TRPM4 channels, in vascular mechanosensing circuits is explored, placing their putative mechanosensitivity in context with other proposed upstream and downstream signaling pathways.
Abstract: Endothelial cells and smooth muscle cells of resistance arteries mediate opposing responses to mechanical forces acting on the vasculature, promoting dilation in response to flow and constriction in response to pressure, respectively. In this review, we explore the role of TRP channels, particularly endothelial TRPV4 and smooth muscle TRPC6 and TRPM4 channels, in vascular mechanosensing circuits, placing their putative mechanosensitivity in context with other proposed upstream and downstream signaling pathways.
TL;DR: The frequent occurrence of alcohol use disorders in the adult population and the significant and widespread detrimental organ system effects highlight the importance of recognizing and further investigating the pathophysiological mechanisms underlying alcohol-induced tissue and organ injury.
Abstract: Alcohol abuse; the most common and costly form of drug abuse, is a major contributing factor to many disease categories. The alcohol-attributable disease burden is closely related to the average volume of alcohol consumption, with dose-dependent relationships between amount and duration of alcohol consumption and the incidence of diabetes mellitus, hypertension, cardiovascular disease, stroke, and pneumonia. The frequent occurrence of alcohol use disorders in the adult population and the significant and widespread detrimental organ system effects highlight the importance of recognizing and further investigating the pathophysiological mechanisms underlying alcohol-induced tissue and organ injury.
TL;DR: There is now evidence that the myoendothelial junction serves as a signaling microdomain to organize proteins used to facilitate vascular heterocellular communication.
Abstract: A vast amount of investigation has centered on how the endothelium and smooth muscle communicate. From this evidence, myoendothelial junctions have emerged as critical anatomical structures to regulate heterocellular cross talk. Indeed, there is now evidence that the myoendothelial junction serves as a signaling microdomain to organize proteins used to facilitate vascular heterocellular communication. This review highlights the evolving role of myoendothelial junctions in the context of vascular cell-cell communication.
TL;DR: A review will highlight the potential mechanisms that contribute to the etiology of sex differences in the developmental programming of cardiovascular disease.
Abstract: The Developmental Origins of Health and Disease (DOHaD) proposes that adverse events during early life program an increased risk for cardiovascular disease. Experimental models provide proof of concept but also indicate that insults during early life program sex differences in adult blood pressure and cardiovascular risk. This review will highlight the potential mechanisms that contribute to the etiology of sex differences in the developmental programming of cardiovascular disease.
TL;DR: The potential impact of obesity-related changes in gut and visceral adipose tissue biology on the development of insulin resistance and Type 2 diabetes is reviewed.
Abstract: Obesity is associated with altered gut microbiota composition and impaired gut barrier function. These changes, together with interrelated mesenteric adipose tissue inflammation, result in increased release of pro-inflammatory cytokines, bacteria-derived factors, and lipids into the portal circulation, promoting the development of (hepatic) insulin resistance. Herein, the potential impact of obesity-related changes in gut and visceral adipose tissue biology on the development of insulin resistance and Type 2 diabetes is reviewed.
TL;DR: How SR recruitment relates to the structural organization of the cardiomyocyte to provide new insight into the evolution of cardiac design and function in vertebrates is discussed.
Abstract: The sarcoplasmic reticulum (SR) is crucial for contraction and relaxation of the mammalian cardiomyocyte, but its role in other vertebrate classes is equivocal. Recent evidence suggests differences in SR function across species may have an underlying structural basis. Here, we discuss how SR recruitment relates to the structural organization of the cardiomyocyte to provide new insight into the evolution of cardiac design and function in vertebrates.
TL;DR: It is shown how the physiological capacity of large mammals to cope with hotter and drier arid-zone habitats likely with climate change can be better understood.
Abstract: Although laboratory studies of large mammals have revealed valuable information on thermoregulation, such studies cannot predict accurately how animals respond in their natural habitats. Through insights obtained on thermoregulatory behavior, body temperature variability, and selective brain cooling in free-living mammals, we show here how we can better understand the physiological capacity of large mammals to cope with hotter and drier arid-zone habitats likely with climate change.
TL;DR: This review examines the various glucose sensory loci involved in hypoglycemic detection, with a particular emphasis on peripheral glucose sensory Loci and their contribution to hypoglycemia counterregulation.
Abstract: Hypoglycemia poses a serious threat to the integrity of the brain, owing to its reliance on blood glucose as a fuel. Protecting against hypoglycemia is an extended network of glucose sensors located within the brain and in the periphery that serve to mediate responses restoring euglycemia, i.e., counterregulatory responses. This review examines the various glucose sensory loci involved in hypoglycemic detection, with a particular emphasis on peripheral glucose sensory loci and their contribution to hypoglycemic counterregulation.
TL;DR: Electrical stimulation and exercise are treatments to enhance recovery from peripheral nerve injuries and brain-derived neurotrophic factor and androgen receptor signaling are requirements for the effectiveness of these treatments.
Abstract: Electrical stimulation and exercise are treatments to enhance recovery from peripheral nerve injuries Brain-derived neurotrophic factor and androgen receptor signaling are requirements for the effectiveness of these treatments Increased neuronal activity is adequate to promote regeneration in injured nerves, but the dosing of activity and its relationship to neurotrophins and sex steroid hormones is less clear Translation of these therapies will require principles associated with their cellular mechanisms
TL;DR: The hypothesis that, in neurosecretory cells, fusion pore formation is directly accomplished by a conformational change in the SNARE complex via movement of the transmembrane domains is discussed.
Abstract: The SNARE (Soluble NSF Attachment protein REceptor) complex, which in mammalian neurosecretory cells is composed of the proteins synaptobrevin 2 (also called VAMP2), syntaxin, and SNAP-25, plays a key role in vesicle fusion. In this review, we discuss the hypothesis that, in neurosecretory cells, fusion pore formation is directly accomplished by a conformational change in the SNARE complex via movement of the transmembrane domains.
TL;DR: This review highlights the importance of neural mechanisms capable of protecting the heart against lethal ischemia/reperfusion injury and suggests that activation of autonomic reflex pathways contributes to powerful innate mechanisms of cardioprotection underlying the remote ischemic conditioning phenomena.
Abstract: This review highlights the importance of neural mechanisms capable of protecting the heart against lethal ischemia/reperfusion injury. Increased parasympathetic (vagal) activity limits myocardial infarction, and recent data suggest that activation of autonomic reflex pathways contributes to powerful innate mechanisms of cardioprotection underlying the remote ischemic conditioning phenomena.
TL;DR: Current understanding of hypoxia-dependent production of gasotransmitters, how they regulate ion channels in the carotid body, and how this impacts carotids body function is reviewed.
Abstract: Carotid bodies detect hypoxia in arterial blood, translating this stimulus into physiological responses via the CNS. It is long established that ion channels are critical to this process. More recent evidence indicates that gasotransmitters exert powerful influences on O2 sensing by the carotid body. Here, we review current understanding of hypoxia-dependent production of gasotransmitters, how they regulate ion channels in the carotid body, and how this impacts carotid body function.
TL;DR: Human obesity can potentially be understood in an evolutionary context as due to drift in the upper intervention point following release from predation 2 million years ago combined with a stimulus in modern society to overconsume calories.
Abstract: Life involves a continuous use of energy, but food intake, which supplies that energy, is episodic. Feeding is switched on and off by a complex array of predominantly gut-derived peptides (and pote...
TL;DR: Technological advances have made it possible to evaluate genome-wide epigenetic changes (epigenomics) in diseases of lung remodeling, clarifying existing pathophysiological paradigms and uncovering novel mechanisms of disease.
Abstract: The lung develops from a very simple outpouching of the foregut into a highly complex, finely structured organ with multiple specialized cell types that are required for its normal physiological function. During both the development of the lung and its remodeling in the context of disease or response to injury, gene expression must be activated and silenced in a coordinated manner to achieve the tremendous phenotypic heterogeneity of cell types required for homeostasis and pathogenesis. Epigenetic mechanisms, consisting of DNA base modifications such as methylation, alteration of histones resulting in chromatin modification, and the action of noncoding RNA, control the regulation of information “beyond the genome” required for both lung modeling and remodeling. Epigenetic regulation is subject to modification by environmental stimuli, such as oxidative stress, infection, and aging, and is thus critically important in chronic remodeling disorders such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD), and pulmonary hypertension (PH). Technological advances have made it possible to evaluate genome-wide epigenetic changes (epigenomics) in diseases of lung remodeling, clarifying existing pathophysiological paradigms and uncovering novel mechanisms of disease. Many of these represent new therapeutic targets. Advances in epigenomic technology will accelerate our understanding of lung development and remodeling, and lead to novel treatments for chronic lung diseases.
TL;DR: The concept of compartmentalization is guiding the search for therapies that have the potential to offer greater efficacy and tolerability compared with current treatments.
Abstract: Novel technological advances have improved our understanding of how cyclic nucleotides are able to convey signals faithfully between cellular compartments. Phosphodiesterases play a crucial role in shaping these signals in health and disease. The concept of compartmentalization is guiding the search for therapies that have the potential to offer greater efficacy and tolerability compared with current treatments.
TL;DR: The role of the brain melanocortin system in causing increased sympathetic activity in obesity and other forms of hypertension is discussed and potential mechanisms by which the brain sunscreen system modulates metabolic and cardiovascular functions are highlighted.
Abstract: Excess weight gain is the most significant, preventable cause of increased blood pressure (BP) in patients with primary (essential) hypertension and increases the risk for cardiovascular and renal diseases In this review, we discuss the role of the brain melanocortin system in causing increased sympathetic activity in obesity and other forms of hypertension In addition, we highlight potential mechanisms by which the brain melanocortin system modulates metabolic and cardiovascular functions