Showing papers in "Physiology in 2017"

Modeling Physiological Events in 2D vs. 3D Cell Culture.

Abstract: Cell culture has become an indispensable tool to help uncover fundamental biophysical and biomolecular mechanisms by which cells assemble into tissues and organs, how these tissues function, and how that function becomes disrupted in disease. Cell culture is now widely used in biomedical research, tissue engineering, regenerative medicine, and industrial practices. Although flat, two-dimensional (2D) cell culture has predominated, recent research has shifted toward culture using three-dimensional (3D) structures, and more realistic biochemical and biomechanical microenvironments. Nevertheless, in 3D cell culture, many challenges remain, including the tissue-tissue interface, the mechanical microenvironment, and the spatiotemporal distributions of oxygen, nutrients, and metabolic wastes. Here, we review 2D and 3D cell culture methods, discuss advantages and limitations of these techniques in modeling physiologically and pathologically relevant processes, and suggest directions for future research.

New Concepts and Mechanisms of Platelet Activation Signaling.

Abstract: Upon blood vessel injury, platelets are exposed to adhesive proteins in the vascular wall and soluble agonists, which initiate platelet activation, leading to formation of hemostatic thrombi. Pathological activation of platelets can induce occlusive thrombosis, resulting in ischemic events such as heart attack and stroke, which are leading causes of death globally. Platelet activation requires intracellular signal transduction initiated by platelet receptors for adhesion proteins and soluble agonists. Whereas many platelet activation signaling pathways have been established for many years, significant recent progress reveals much more complex and sophisticated signaling and amplification networks. With the discovery of new receptor signaling pathways and regulatory networks, some of the long-standing concepts of platelet signaling have been challenged. This review provides an overview of the new developments and concepts in platelet activation signaling.

Sleep Neurophysiological Dynamics Through the Lens of Multitaper Spectral Analysis.

Abstract: During sleep, cortical and subcortical structures within the brain engage in highly structured oscillatory dynamics that can be observed in the electroencephalogram (EEG). The ability to accurately...

Lactic Acid: No Longer an Inert and End-Product of Glycolysis.

Abstract: For decades, lactic acid has been considered a dead-end product of glycolysis. Research in the last 20+ years has shown otherwise. Through its transporters (MCTs) and receptor (GPR81), lactic acid plays a key role in multiple cellular processes, including energy regulation, immune tolerance, memory formation, wound healing, ischemic tissue injury, and cancer growth and metastasis. We summarize key findings of lactic acid signaling, functions, and many remaining questions.

Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty

Abstract: Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age.

Physical Activity, Aging, and Physiological Function

Abstract: Human evolution suggests that the default position for health is to be physically active. Inactivity, by contrast, has serious negative effects on health across the lifespan. Therefore, only in physically active people can the inherent aging process proceed unaffected by disuse complications. In such individuals, although the relationship between age and physiological function remains complex, function is generally superior with health, well being, and the aging process optimized.

In vitro models to study human lung development, disease and homeostasis

Abstract: The main function of the lung is to support gas exchange, and defects in lung development or diseases affecting the structure and function of the lung can have fatal consequences. Most of what we currently understand about human lung development and disease has come from animal models. However, animal models are not always fully able to recapitulate human lung development and disease, highlighting an area where in vitro models of the human lung can compliment animal models to further understanding of critical developmental and pathological mechanisms. This review will discuss current advances in generating in vitro human lung models using primary human tissue, cell lines, and human pluripotent stem cell derived lung tissue, and will discuss crucial next steps in the field.

The Hypertension Pandemic: An Evolutionary Perspective.

Abstract: Hypertension affects over 1.2 billion individuals worldwide and has become the most critical and expensive public health problem. Hypertension is a multifactorial disease involving environmental and genetic factors together with risk-conferring behaviors. The cause of the disease is identified in ∼10% of the cases (secondary hypertension), but in 90% of the cases no etiology is found (primary or essential hypertension). For this reason, a better understanding of the mechanisms controlling blood pressure in normal and hypertensive patients is the aim of very active experimental and clinical research. In this article, we review the importance of the renin-angiotensin-aldosterone system (RAAS) for the control of blood pressure, focusing on the evolution of the system and its critical importance for adaptation of vertebrates to a terrestrial and dry environment. The evolution of blood pressure control during the evolution of primates, hominins, and humans is discussed, together with the role of common genetic factors and the possible causes of the current hypertension pandemic in the light of evolutionary medicine.

The Link Between Adipose Tissue Renin-Angiotensin- Aldosterone System Signaling and Obesity-Associated Hypertension

Abstract: Obese individuals frequently develop hypertension, which is for an important part attributable to renin-angiotensin-aldosterone system (RAAS) overactivity. This review summarizes preclinical and clinical evidence on the involvement of dysfunctional adipose tissue in RAAS activation and on the renal, central, and vascular mechanisms linking RAAS components to obesity-associated hypertension.

Potassium Homeostasis: The Knowns, the Unknowns, and the Health Benefits

Abstract: Potassium homeostasis has a very high priority because of its importance for membrane potential. Although extracellular K+ is only 2% of total body K+, our physiology was evolutionarily tuned for a high-K+, low-Na+ diet. We review how multiple systems interface to accomplish fine K+ balance and the consequences for health and disease.

Running Changes the Brain: the Long and the Short of It

Abstract: Exercise is a simple intervention that profoundly benefits cognition. In rodents, running increases neurogenesis in the hippocampus, a brain area important for memory. We describe the dynamic changes in new neuron number and afferent connections throughout their maturation. We highlight the effects of exercise on the neurotransmitter systems involved, with a focus on the role of glutamate and acetylcholine in the initial development of new neurons in the adult brain.

ORAI Calcium Channels

Abstract: In this review article, we discuss the different gene products and translational variants of ORAI proteins and their contribution to the makeup of different native calcium-conducting channels with distinct compositions and modes of activation. We also review the different modes of regulation of these distinct calcium channels and their impact on downstream cellular signaling controlling important physiological functions.

Central Role of Metabolism in Endothelial Cell Function and Vascular Disease.

Abstract: The importance of endothelial cell (EC) metabolism and its regulatory role in the angiogenic behavior of ECs during vessel formation and in the function of different EC subtypes determined by different vascular beds has been recognized only in the last few years. Even more importantly, apart from a role of nitric oxide and reactive oxygen species in EC dysfunction, deregulations of EC metabolism in disease only recently received increasing attention. Although comprehensive metabolic characterization of ECs still needs further investigation, the concept of targeting EC metabolism to treat vascular disease is emerging. In this overview, we summarize EC-specific metabolic pathways, describe the current knowledge on their deregulation in vascular diseases, and give an outlook on how vascular endothelial metabolism can serve as a target to normalize deregulated endothelium.

Stem Cells in Repair of Gastrointestinal Epithelia

Abstract: Among the endodermal tissues of adult mammals, the gastrointestinal (GI) epithelium exhibits the highest turnover rate. As the ingested food moves along the GI tract, gastric acid, digestive enzymes, and gut resident microbes aid digestion as well as nutrient and mineral absorption. Due to the harsh luminal environment, replenishment of new epithelial cells is essential to maintain organ structure and function during routine turnover and injury repair. Tissue-specific adult stem cells in the GI tract serve as a continuous source for this immense regenerative activity. Tissue homeostasis is achieved by a delicate balance between gain and loss of cells. In homeostasis, temporal tissue damage is rapidly restored by well-balanced tissue regeneration, whereas prolonged imbalance may result in diverse pathologies of homeostasis and injury repair. Starting with a summary of the current knowledge of GI tract homeostasis, we continue with providing models of acute injury and chronic diseases. Finally, we will discuss how primary organoid cultures allow new insights into the mechanisms of homeostasis, injury repair, and disease, and how this novel 3D culture system has the potential to translate into the clinic.

Therapeutic Stimulation for Restoration of Function After Spinal Cord Injury

Abstract: Paralysis due to spinal cord injury can severely limit motor function and independence. This review summarizes different approaches to electrical stimulation of the spinal cord designed to restore motor function, with a brief discussion of their origins and the current understanding of their mechanisms of action. Spinal stimulation leads to impressive improvements in motor function along with some benefits to autonomic functions such as bladder control. Nonetheless, the precise mechanisms underlying these improvements and the optimal spinal stimulation approaches for restoration of motor function are largely unknown. Finally, spinal stimulation may augment other therapies that address the molecular and cellular environment of the injured spinal cord. The fact that several stimulation approaches are now leading to substantial and durable improvements in function following spinal cord injury provides a new perspectives on the previously “incurable” condition of paralysis.

Novel and Unexpected Functions of SGLTs

Abstract: It has been 30 years since the intestinal sodium glucose cotransporter SGLT1 was cloned, and, in the intervening years, there have been many advances that have influenced physiology and medicine. A...

Expression and Processing of Amyloid Precursor Protein in Vascular Endothelium.

Abstract: Amyloid precursor protein (APP) is evolutionary conserved protein expressed in endothelial cells of cerebral and peripheral arteries. In this review, we discuss mechanisms responsible for expression and proteolytic cleavage of APP in endothelial cells. We focus on physiological and pathological implications of APP expression in vascular endothelium.

Extracellular Acid-Base Balance and Ion Transport Between Body Fluid Compartments

Abstract: Clinical assessment of acid-base disorders depends on measurements made in the blood, part of the extracellular compartment. Yet much of the metabolic importance of these disorders concerns intracellular events. Intracellular and interstitial compartment acid-base balance is complex and heterogeneous. This review considers the determinants of the extracellular fluid pH related to the ion transport processes at the interface of cells and the interstitial fluid, and between epithelial cells lining the transcellular contents of the gastrointestinal and urinary tracts that open to the external environment. The generation of acid-base disorders and the associated disruption of electrolyte balance are considered in the context of these membrane transporters. This review suggests a process of internal and external balance for pH regulation, similar to that of potassium. The role of secretory gastrointestinal epithelia and renal epithelia with respect to normal pH homeostasis and clinical disorders are considered. Electroneutrality of electrolytes in the ECF is discussed in the context of reciprocal changes in Cl- or non Cl- anions and [Formula: see text].

Pathophysiology of Aortic Valve Stenosis: Is It Both Fibrocalcific and Sex Specific?

Abstract: Our understanding of the fundamental biology and identification of efficacious therapeutic targets in aortic valve stenosis has lagged far behind the fields of atherosclerosis and heart failure. In this review, we highlight the most clinically relevant problems facing men and women with fibrocalcific aortic valve stenosis, discuss the fundamental biology underlying valve calcification and fibrosis, and identify key molecular points of intersection with sex hormone signaling.

Metabolic Regulation of Angiogenesis in Diabetes and Aging

Abstract: Impaired angiogenesis and endothelial dysfunction are hallmarks of diabetes and aging. Clinical efforts at promoting angiogenesis have largely focused on growth factor pathways, with mixed results. Recently, a new repertoire of endothelial intracellular molecules critical to endothelial metabolism has emerged as playing an important role in regulating angiogenesis. This review thus focuses on the emerging importance and therapeutic potential of these proteins and of endothelial bioenergetics in diabetes and aging.

Thyroid Hormone Regulation and Insulin Resistance: Insights From Animals Naturally Adapted to Fasting.

Abstract: The contribution of thyroidal status in insulin signaling and glucose homeostasis has been implicated as a potential pathophysiological factor in humans, but the specific mechanisms remain largely elusive. Fasting induces changes in both thyroid hormone secretion and insulin signaling. Here, we explore how mammals that undergo natural, prolonged bouts of fasting provide unique insight into evolved physiological adaptations that allow them to tolerate such conditions despite intermittent states of reversible insulin resistance. Such insights from nature may provide clues to better understand the basis of thyroidal involvement in insulin dysregulation in humans.

Feeding Your Baby In Utero: How the Uteroplacental Circulation Impacts Pregnancy.

Abstract: The utero-placental circulation links the maternal and fetal circulations during pregnancy, ensuring adequate gas and nutrient exchange, and consequently fetal growth. However, our understanding of this circulatory system remains incomplete. Here, we discuss how the utero-placental circulation is established, how it changes dynamically during pregnancy, and how this may impact on pregnancy success, highlighting how we may address knowledge gaps through advances in imaging and computational modeling approaches.

Right Ventricular-Pulmonary Vascular Interactions.

Abstract: Accurate and comprehensive evaluation of right ventricular (RV)-pulmonary vascular (PV) interactions is critical to the assessment of cardiopulmonary function, dysfunction, and failure. Here, we review methods of quantifying RV-PV interactions and experimental results from clinical trials as well as large- and small-animal models based on pressure-volume analysis. We conclude by outlining critical gaps in knowledge that should drive future studies.

Microbiotal-Host Interactions and Hypertension.

Abstract: Hypertension, or elevated blood pressure (BP), has been extensively researched over decades and clearly demonstrated to be caused due to a combination of host genetic and environmental factors. Although much research remains to be conducted to pin-point the precise genetic elements on the host genome that control BP, new lines of evidence are emerging to indicate that, besides the host genome, the genomes of all indigenous commensal micro-organisms, collectively referred to as the microbial metagenome or microbiome, are important, but largely understudied, determinants of BP. Unlike the rigid host genome, the microbiome or the "second genome" can be altered by diet or microbiotal transplantation in the host. This possibility is attractive from the perspective of exploiting the microbiotal composition for clinical management of inherited hypertension. Thus, focusing on the limited current literature supporting a role for the microbiome in BP regulation, this review highlights the need to further explore the role of the co-existence of host and the microbiota as an organized biological unit called the "holobiont" in the context of BP regulation.

Reprogramming Interferon Regulatory Factor Signaling in Cardiometabolic Diseases

Abstract: Interferon regulatory factors (IRFs) are evolutionarily conserved proteins expressed not only in immune cells but also in other tissues and organs outside the immune system. In this review, we discuss mechanisms responsible for IRF-mediated innate immune responses and the function and mechanism of IRFs in cardiometabolic diseases. We focus on the role of IRFs in innate immunity and cardiometabolic homeostasis, and highlight reprogrammed IRF signaling.

Lymphatic Endothelial Cell Plasticity in Development and Disease

Abstract: The lymphatic vasculature is crucial for maintaining tissue-fluid homeostasis, providing immune surveillance and mediating lipid absorption. The lymphatic vasculature is tightly associated with the blood vasculature, although it exhibits distinct morphological and functional features. Endothelial cells (ECs) lineage fate specification is determined during embryonic development; however, accumulating evidence suggests that differentiated ECs exhibit remarkable heterogeneity and plasticity. In this review, we provide an overview of the molecular mechanisms promoting lymphatic cell fate specification in the mammalian embryo. We also summarize available data suggesting that lymphatic EC fate is reprogrammable in normal and pathological settings. We further discuss the possible advantages of cell fate manipulation to treat certain disorders associated with lymphatic dysfunction.

Cardiometabolic Features of Polycystic Ovary Syndrome: Role of Androgens.

Abstract: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder that affects reproductive-age women. Hyperandrogenemia is present in a significant fraction (~80%) of women with PCOS. Increased prevalence of cardiometabolic risk factors is frequently observed in PCOS women. The present review aims to highlight the key role of androgens in mediating the negative cardiometabolic profile observed in PCOS women.

Chloride Channels Take Center Stage in Acute Regulation of Excitability in Skeletal Muscle: Implications for Fatigue.

Abstract: Initiation and propagation of action potentials in muscle fibers is a key element in the transmission of activating motor input from the central nervous system to their contractile apparatus, and maintenance of excitability is therefore paramount for their endurance during work. Here, we review current knowledge about the acute regulation of ClC-1 channels in active muscles and its importance for muscle excitability, function, and fatigue.

Mitochondria and Reactive Oxygen Species Contribute to Neurogenic Hypertension.

Abstract: Beyond its primary role as fuel generators, mitochondria are engaged in a variety of cellular processes, including redox homeostasis. Mitochondrial dysfunction, therefore, may have a profound impact on high-energy-demanding organs such as the brain. Here, we review the roles of mitochondrial biogenesis and bioenergetics, and their associated signaling in cellular redox homeostasis, and illustrate their contributions to the oxidative stress-related neural mechanism of hypertension, focusing on specific brain areas that are involved in the generation or modulation of sympathetic outflows to the cardiovascular system. We also highlight future challenges of research on mitochondrial physiology and pathophysiology.

Both Ways at Once: Keeping Small Airways Clean

Abstract: The small airways of the lungs are under constant assault from the pathogens and debris in the air that they must conduct to alveoli. Although hygiene is of paramount importance for respiratory health, the underlying principles of airway clearance have not been well integrated or established. Newly emerging concepts of simultaneous absorption and secretion of airway surface liquid (ASL) and the role of [Formula: see text] in the maturation of mucins have advanced from experimental evidence as well as observations from the congenital disease cystic fibrosis (CF) to present a novel model that integrates microanatomy with organ physiology to meet the constant challenge of cleaning small airways.