Connexins: Key Players in the Control of Vascular Plasticity and Function.
Abstract Of the 21 members of the connexin family, 4 (Cx37, Cx40, Cx43, and Cx45) are expressed in the endothelium and/or smooth muscle of intact blood vessels to a variable and dynamically regulated degree. Full-length connexins oligomerize and form channel structures connecting the cytosol of adjacent cells (gap junctions) or the cytosol with the extracellular space (hemichannels). The different connexins vary mainly with regard to length and sequence of their cytosolic COOH-terminal tails. These COOH-terminal parts, which in the case of Cx43 are also translated as independent short isoforms, are involved in var...
Source: Physiological Reviews - January 17, 2020 Category: Physiology Authors: Pohl U Tags: Physiol Rev Source Type: research

Are We meeting the Promise of Endotypes and Precision Medicine in Asthma.
Abstract While the term "asthma" has long been known to describe heterogeneous groupings of patients, only recently have data evolved which enable a molecular understanding of the clinical differences. The evolution of transcriptomics (and other 'omics platforms) and improved statistical analyses in combination with large clinical cohorts opened the door for molecular characterization of pathobiologic processes associated with a range of asthma patients. When linked with data from animal models and clinical trials of targeted biologic therapies emerging distinctions arose between patients with and withou...
Source: Physiological Reviews - January 9, 2020 Category: Physiology Authors: Ray A, Camiolo M, Fitzpatrick A, Gauthier M, Wenzel SE Tags: Physiol Rev Source Type: research

Regulation of the Renal NaCl Cotransporter and Its Role in Potassium Homeostasis.
Abstract Daily dietary potassium (K+) intake may be as large as the extracellular K+ pool. To avoid acute hyperkalemia, rapid removal of K+ from the extracellular space is essential. This is achieved by translocating K+ into cells and increasing urinary K+ excretion. Emerging data now indicate that the renal thiazide-sensitive NaCl cotransporter (NCC) is critically involved in this homeostatic kaliuretic response. This suggests that the early distal convoluted tubule (DCT) is a K+ sensor that can modify sodium (Na+) delivery to downstream segments to promote or limit K+ secretion. K+ sensing is mediated by the bas...
Source: Physiological Reviews - December 4, 2019 Category: Physiology Authors: Hoorn EJ, Gritter M, Cuevas CA, Fenton RA Tags: Physiol Rev Source Type: research

Stiffness Sensing in Cells and Tissues.
Abstract Physical stimuli are essential for the function of eukaryotic cells, and changes in physical signals are important elements in normal tissue development as well as in disease initiation and progression. The complexity of physical stimuli and the cellular signals they initiate are as complex as those triggered by chemical signals. One of the most important, and the focus of this review, is the effect of substrate mechanical properties on cell structure and function. The past decade has produced a nearly exponentially increasing number of mechanobiological studies to define how substrate stiffness alters ce...
Source: Physiological Reviews - November 21, 2019 Category: Physiology Authors: Janmey PA, Fletcher D, Reinhard King C Tags: Physiol Rev Source Type: research

Muscle Toxicity of Drugs: When Medication Turns Physiology into Pathophysiology.
Abstract Drugs are prescribed to manage or prevent symptoms and diseases, but may sometimes cause unexpected toxicity to muscles. The symptomatology and clinical manifestations of the myotoxic reaction can vary significantly between drugs and between patients on the same drug. This poses a challenge on how to recognize and prevent the occurrence of drug-induced muscle toxicity. The key to appropriate management of myotoxicity is prompt recognition that the symptoms of patients may be drug-related and to be aware that inter-individual differences in susceptibility to drug-induced toxicity exist. The most prevalent ...
Source: Physiological Reviews - November 21, 2019 Category: Physiology Authors: Janssen L, Allard N, Saris C, Keijer J, Hopman MTE, Timmers S Tags: Physiol Rev Source Type: research

mRNA Metabolism in Cardiac Development and Disease - Life After Transcription.
Abstract The central dogma of molecular biology illustrates the importance of messenger RNAs as critical mediators between genetic information encoded at the DNA level and proteomes/metabolomes at the cellular and organ levels. Although the total number of protein-producing (coding) genes in the mammalian genome is approximately 20,000, it is evident that the intricate processes of cardiac development and the highly regulated physiological regulation in the normal heart, as well as the complex manifestation of pathological remodeling in a diseased heart, would require a much higher degree of complexity at the tran...
Source: Physiological Reviews - November 21, 2019 Category: Physiology Authors: Gao C, Wang Y Tags: Physiol Rev Source Type: research

Ginkgolide B for Myocardial Ischemia/Reperfusion Injury: A Preclinical Systematic Review and Meta-Analysis.
Abstract Ginkgolide B (GB) is an extract of dried Ginkgo biloba leaves and possesses various pharmacological activities in the cardiovascular system. Herein, we aim to assess the available preclinical evidence and possible mechanisms of GB for myocardial ischemia/reperfusion injury. The study quality score was assessed using the CAMARADES 10-item checklist. Rev-Man 5.3 software was used for data analyses. Nineteen studies with total 437 animals were included for analysis. Meta-analyses indicated that GB interventions significantly reduce myocardial infarct size and cardiac markers when compared with control (P
Source: Physiological Reviews - November 6, 2019 Category: Physiology Authors: Zhu PC, Tong Q, Zhuang Z, Wang ZH, Deng LH, Zheng GQ, Wang Y Tags: Front Physiol Source Type: research

The physiology of the gastric parietal cell.
Abstract Parietal cells are responsible for gastric acid secretion, which aids in the digestion of food, absorption of minerals and control of harmful bacteria. However, a fine balance of activators and inhibitors of parietal cell mediated acid secretion is required to ensure proper digestion of food, while preventing damage to the gastric and duodenal mucosa. As a result, parietal cell secretion is highly regulated through numerous mechanisms including the vagus nerve, gastrin, histamine, ghrelin, somatostatin, GLP-1 and other agonists and antagonists. The tight regulation of parietal cells ensures the proper sec...
Source: Physiological Reviews - October 31, 2019 Category: Physiology Authors: Engevik AC, Kaji I, Goldenring JR Tags: Physiol Rev Source Type: research

Mammalian transient receptor potential TRPA1 channels: from structure to disease.
Abstract The Transient Receptor Potential Ankyrin TRPA channels are Ca2+-permeable non-selective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the N-terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may pr...
Source: Physiological Reviews - October 31, 2019 Category: Physiology Authors: Talavera K, Startek JB, Alvarez-Collazo J, Boonen B, Alpizar YA, Sanchez A, Naert R, Nilius B Tags: Physiol Rev Source Type: research

Origin and Evolution of the Neuroendocrine Control of Reproduction in Vertebrates, with Special Focus on Genome and Gene Duplications.
eau K Abstract In human, as in the other mammals, the neuroendocrine control of reproduction is ensured by the brain-pituitary gonadotropic axis. Multiple internal and environmental cues are integrated via brain neuronal networks, ultimately leading to the modulation of the activity of gonadotropin-releasing hormone (GnRH) neurons. The decapeptide GnRH is released into the hypothalamic-hypophyseal portal blood system, and stimulates the production of pituitary glycoprotein hormones, the two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). A novel actor, the neuropeptide Kiss, acting ...
Source: Physiological Reviews - October 18, 2019 Category: Physiology Authors: Dufour S, Quérat B, Tostivint H, Pasqualini C, Vaudry H, Rousseau K Tags: Physiol Rev Source Type: research

Pathogenesis of HIV-related lung disease: Immunity, infection, and inflammation.
Abstract Despite anti-retroviral therapy (ART), HIV-related pulmonary disease continues to be a major cause of morbidity and mortality for people living with HIV (PLWH). The spectrum of lung diseases has changed from acute opportunistic infections resulting in death to chronic lung diseases for those with access to ART. Chronic immune activation and suppression can result in impairment of innate immunity and progressive loss of T cell and B cell functionality with aberrant cytokine and chemokine responses systemically as well as in the lung. HIV can be detected in the lungs of PLWH and has profound effects on cell...
Source: Physiological Reviews - October 10, 2019 Category: Physiology Authors: Cribbs SK, Crothers K, Morris A Tags: Physiol Rev Source Type: research

The SLC9A-C Mammalian Na+/H+ Exchanger Family: Molecules, Mechanisms, and Physiology.
Abstract Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. They belong to an ancient family of highly evolutionarily conserved proteins, and they play essential physiological roles in all phyla. In this review, we focus on the mammalian Na+/H+ exchangers (NHEs), the solute carrier (SLC) 9 family. This family of electroneutral transporters constitutes three branches: SLC9A, -B, and -C. Within these, each isoform exhibits distinct tissue expression profiles, regulation, and physiological roles. Some of these tra...
Source: Physiological Reviews - September 13, 2019 Category: Physiology Authors: Pedersen SF, Counillon L Tags: Physiol Rev Source Type: research

The Neuroscience of Drug Reward and Addiction.
Abstract Drug consumption is driven by a drug's pharmacological effects, which are experienced as rewarding, and is influenced by genetic, developmental, and psychosocial factors that mediate drug accessibility, norms, and social support systems or lack thereof. The reinforcing effects of drugs mostly depend on dopamine signaling in the nucleus accumbens, and chronic drug exposure triggers glutamatergic-mediated neuroadaptations in dopamine striato-thalamo-cortical (predominantly in prefrontal cortical regions including orbitofrontal cortex and anterior cingulate cortex) and limbic pathways (amygdala and hippocamp...
Source: Physiological Reviews - September 13, 2019 Category: Physiology Authors: Volkow ND, Michaelides M, Baler R Tags: Physiol Rev Source Type: research

The Microbiota-Gut-Brain Axis.
ra JS, Peterson VL, Rea K, Ritz NL, Sherwin E, Spichak S, Teichman EM, van de Wouw M, Ventura-Silva AP, Wallace-Fitzsimons SE, Hyland N, Clarke G, Dinan TG Abstract The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological b...
Source: Physiological Reviews - August 29, 2019 Category: Physiology Authors: Cryan JF, O'Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, Guzzetta KE, Jaggar M, Long-Smith CM, Lyte JM, Martin JA, Molinero-Perez A, Moloney G, Morelli E, Morillas E, O'Connor R, Cruz-Pere Tags: Physiol Rev Source Type: research

Metabolomics for Investigating Physiological and Pathophysiological Processes.
Abstract Metabolomics uses advanced analytical chemistry techniques to enable the high-throughput characterization of metabolites from cells, organs, tissues, or biofluids. The rapid growth in metabolomics is leading to a renewed interest in metabolism and the role that small molecule metabolites play in many biological processes. As a result, traditional views of metabolites as being simply the "bricks and mortar" of cells or just the fuel for cellular energetics are being upended. Indeed, metabolites appear to have much more varied and far more important roles as signaling molecules, immune modulators,...
Source: Physiological Reviews - August 24, 2019 Category: Physiology Authors: Wishart DS Tags: Physiol Rev Source Type: research

Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease.
Abstract Twelve regulated cell death programs have been described. We review in detail the basic biology of nine including death receptor-mediated apoptosis, death receptor-mediated necrosis (necroptosis), mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, autophagy-dependent cell death, ferroptosis, pyroptosis, parthanatos, and immunogenic cell death. This is followed by a dissection of the roles of these cell death programs in the major cardiac syndromes: myocardial infarction and heart failure. The most important conclusion relevant to heart disease is that regulated forms of cardiomyocyte death...
Source: Physiological Reviews - August 2, 2019 Category: Physiology Authors: Del Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN Tags: Physiol Rev Source Type: research

Mechanistic Links Between Obesity, Diabetes, and Blood Pressure: Role of Perivascular Adipose Tissue.
Abstract Obesity is increasingly prevalent and is associated with substantial cardiovascular risk. Adipose tissue distribution and morphology play a key role in determining the degree of adverse effects, and a key factor in the disease process appears to be the inflammatory cell population in adipose tissue. Healthy adipose tissue secretes a number of vasoactive adipokines and anti-inflammatory cytokines, and changes to this secretory profile will contribute to pathogenesis in obesity. In this review, we discuss the links between adipokine dysregulation and the development of hypertension and diabetes and explore ...
Source: Physiological Reviews - July 26, 2019 Category: Physiology Authors: Saxton SN, Clark BJ, Withers SB, Eringa EC, Heagerty AM Tags: Physiol Rev Source Type: research

Cell Adhesion by Integrins.
r B Abstract Integrins are heterodimeric cell surface receptors ensuring the mechanical connection between cells and the extracellular matrix. In addition to the anchorage of cells to the extracellular matrix, these receptors have critical functions in intracellular signaling, but are also taking center stage in many physiological and pathological conditions. In this review, we provide some historical, structural, and physiological notes so that the diverse functions of these receptors can be appreciated and put into the context of the emerging field of mechanobiology. We propose that the exciting journey of the e...
Source: Physiological Reviews - July 19, 2019 Category: Physiology Authors: Bachmann M, Kukkurainen S, Hytönen VP, Wehrle-Haller B Tags: Physiol Rev Source Type: research

Learning Physiology From Inherited Kidney Disorders.
Abstract The identification of genes causing inherited kidney diseases yielded crucial insights in the molecular basis of disease and improved our understanding of physiological processes that operate in the kidney. Monogenic kidney disorders are caused by mutations in genes coding for a large variety of proteins including receptors, channels and transporters, enzymes, transcription factors, and structural components, operating in specialized cell types that perform highly regulated homeostatic functions. Common variants in some of these genes are also associated with complex traits, as evidenced by genome-wide as...
Source: Physiological Reviews - June 20, 2019 Category: Physiology Authors: van der Wijst J, Belge H, Bindels RJM, Devuyst O Tags: Physiol Rev Source Type: research

Passing the Vascular Barrier: Endothelial Signaling Processes Controlling Extravasation.
Abstract A central function of the vascular endothelium is to serve as a barrier between the blood and the surrounding tissue of the body. At the same time, solutes and cells have to pass the endothelium to leave or to enter the bloodstream to maintain homeostasis. Under pathological conditions, for example, inflammation, permeability for fluid and cells is largely increased in the affected area, thereby facilitating host defense. To appropriately function as a regulated permeability filter, the endothelium uses various mechanisms to allow solutes and cells to pass the endothelial layer. These include transcellula...
Source: Physiological Reviews - May 30, 2019 Category: Physiology Authors: Wettschureck N, Strilic B, Offermanns S Tags: Physiol Rev Source Type: research

Diverse Cell Types, Circuits, and Mechanisms for Color Vision in the Vertebrate Retina.
Abstract Synaptic interactions to extract information about wavelength, and thus color, begin in the vertebrate retina with three classes of light-sensitive cells: rod photoreceptors at low light levels, multiple types of cone photoreceptors that vary in spectral sensitivity, and intrinsically photosensitive ganglion cells that contain the photopigment melanopsin. When isolated from its neighbors, a photoreceptor confounds photon flux with wavelength and so by itself provides no information about color. The retina has evolved elaborate color opponent circuitry for extracting wavelength information by comparing the...
Source: Physiological Reviews - May 30, 2019 Category: Physiology Authors: Thoreson WB, Dacey DM Tags: Physiol Rev Source Type: research

FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications.
d L Abstract FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed almost exclusively in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of FLT3 leads to its autophosphorylation and initiation of several signal transduction cascades. Signaling is initiated by the recruitment of signal transduction molecules to activated FLT3 through binding to specific phosphorylated tyrosine residues in the intracellular region of FLT3. Activation of FLT3 mediates cell survival, cell proliferation, an...
Source: Physiological Reviews - May 10, 2019 Category: Physiology Authors: Kazi JU, Rönnstrand L Tags: Physiol Rev Source Type: research

Myelin in the Central Nervous System: Structure, Function, and Pathology.
Abstract Oligodendrocytes generate multiple layers of myelin membrane around axons of the central nervous system to enable fast and efficient nerve conduction. Until recently, saltatory nerve conduction was considered the only purpose of myelin, but it is now clear that myelin has more functions. In fact, myelinating oligodendrocytes are embedded in a vast network of interconnected glial and neuronal cells, and increasing evidence supports an active role of oligodendrocytes within this assembly, for example, by providing metabolic support to neurons, by regulating ion and water homeostasis, and by adapting to acti...
Source: Physiological Reviews - May 10, 2019 Category: Physiology Authors: Stadelmann C, Timmler S, Barrantes-Freer A, Simons M Tags: Physiol Rev Source Type: research

The Sleep-Immune Crosstalk in Health and Disease.
Abstract Sleep and immunity are bidirectionally linked. Immune system activation alters sleep, and sleep in turn affects the innate and adaptive arm of our body's defense system. Stimulation of the immune system by microbial challenges triggers an inflammatory response, which, depending on its magnitude and time course, can induce an increase in sleep duration and intensity, but also a disruption of sleep. Enhancement of sleep during an infection is assumed to feedback to the immune system to promote host defense. Indeed, sleep affects various immune parameters, is associated with a reduced infection risk, and can...
Source: Physiological Reviews - March 30, 2019 Category: Physiology Authors: Besedovsky L, Lange T, Haack M Tags: Physiol Rev Source Type: research

The Orphan Nuclear Receptors Steroidogenic Factor-1 and Liver Receptor Homolog-1: Structure, Regulation, and Essential Roles in Mammalian Reproduction.
In conclusion, the NR5A orphan nuclear receptors are nonredundant factors that are crucial regulators of a panoply of biological processes, across multiple reproductive tissues. PMID: 30810078 [PubMed - in process] (Source: Physiological Reviews)
Source: Physiological Reviews - February 28, 2019 Category: Physiology Authors: Meinsohn MC, Smith OE, Bertolin K, Murphy BD Tags: Physiol Rev Source Type: research

The Neutrophil's Role During Health and Disease.
Abstract Neutrophils have always been considered as uncomplicated front-line troopers of the innate immune system equipped with limited proinflammatory duties. Yet recently, the role of the neutrophil has been undergoing a rejuvenation of sorts. Neutrophils are now considered complex cells capable of a significant array of specialized functions, and as an effector of the innate immune response, they are able to regulate many processes such as acute injury and repair, cancer, autoimmunity, and chronic inflammatory processes. Furthermore, evidence exists to indicate that neutrophils also contribute to adaptive immun...
Source: Physiological Reviews - February 15, 2019 Category: Physiology Authors: Liew PX, Kubes P Tags: Physiol Rev Source Type: research

The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms.
Abstract UDP-glycosyltransferases (UGTs) catalyze the covalent addition of sugars to a broad range of lipophilic molecules. This biotransformation plays a critical role in elimination of a broad range of exogenous chemicals and by-products of endogenous metabolism, and also controls the levels and distribution of many endogenous signaling molecules. In mammals, the superfamily comprises four families: UGT1, UGT2, UGT3, and UGT8. UGT1 and UGT2 enzymes have important roles in pharmacology and toxicology including contributing to interindividual differences in drug disposition as well as to cancer risk. These UGTs ar...
Source: Physiological Reviews - February 8, 2019 Category: Physiology Authors: Meech R, Hu DG, McKinnon RA, Mubarokah SN, Haines AZ, Nair PC, Rowland A, Mackenzie PI Tags: Physiol Rev Source Type: research

The Role of Voltage-Gated Sodium Channels in Pain Signaling.
Abstract Acute pain signaling has a key protective role and is highly evolutionarily conserved. Chronic pain, however, is maladaptive, occurring as a consequence of injury and disease, and is associated with sensitization of the somatosensory nervous system. Primary sensory neurons are involved in both of these processes, and the recent advances in understanding sensory transduction and human genetics are the focus of this review. Voltage-gated sodium channels (VGSCs) are important determinants of sensory neuron excitability: they are essential for the initial transduction of sensory stimuli, the electrogenesis of...
Source: Physiological Reviews - January 25, 2019 Category: Physiology Authors: Bennett DL, Clark AJ, Huang J, Waxman SG, Dib-Hajj SD Tags: Physiol Rev Source Type: research

Clock Gene Expression is Altered in Veterans with Sleep Apnea.
Abstract Clock gene dysregulation has been shown to underlie various sleep disorders and may lead to negative cardio-metabolic outcomes. However, the association between sleep apnea(SA) and core clock gene expression is unclear. We performed a cross-sectional analysis of 49 Veterans enrolled in a study of SA outcomes in Veterans with chronic kidney disease, not selected for SA or sleep complaints. All participants underwent full polysomnography and next morning whole blood collection for clock gene expression. We defined SA as an apnea-hypopnea index (AHI)≥15 events/hour; nocturnal hypoxemia(NH) was defined as ...
Source: Physiological Reviews - January 18, 2019 Category: Physiology Authors: Canales MT, Holzworth MR, Bozorgmehri S, Ishani A, Weiner ID, Berry RB, Beyth RJ, Gumz ML Tags: Physiol Genomics Source Type: research

Plasma neuronal exosomes serve as biomarkers of cognitive impairment in HIV infection and Alzheimer's disease.
In this report, we call the vesicles exosomes, since they are the predominant vesicles in our preparations. They are involved in cell-to-cell communication in normal homeostasis and can be carriers of toxic proteins (Aβ, tau) (Sardar Sinha et al., Acta Neuropathol 136: 41-56, 2018) shed by cells as waste or actively secreted in a degenerative process (review Gupta and Pulliam, J Neuroinflammation 11: 68, 2014). The idea that exosomes originating from a specific cell can be recovered in the plasma using cellular surface markers of interest is intriguing. Neuron derived exosomes (NDEs) were first described in 2015 and i...
Source: Physiological Reviews - January 4, 2019 Category: Physiology Authors: Pulliam L, Sun B, Mustapic M, Chawla S, Kapogiannis D Tags: J Neurovirol Source Type: research

Brain Glucose Metabolism: Integration of Energetics with Function.
Abstract Glucose is the long-established, obligatory fuel for brain that fulfills many critical functions, including ATP production, oxidative stress management, and synthesis of neurotransmitters, neuromodulators, and structural components. Neuronal glucose oxidation exceeds that in astrocytes, but both rates increase in direct proportion to excitatory neurotransmission; signaling and metabolism are closely coupled at the local level. Exact details of neuron-astrocyte glutamate-glutamine cycling remain to be established, and the specific roles of glucose and lactate in the cellular energetics of these processes a...
Source: Physiological Reviews - December 20, 2018 Category: Physiology Authors: Dienel GA Tags: Physiol Rev Source Type: research

Innate Immune Signaling and Its Role in Metabolic and Cardiovascular Diseases.
Abstract The innate immune system is an evolutionarily conserved system that senses and defends against infection and irritation. Innate immune signaling is a complex cascade that quickly recognizes infectious threats through multiple germline-encoded cell surface or cytoplasmic receptors and transmits signals for the deployment of proper countermeasures through adaptors, kinases, and transcription factors, resulting in the production of cytokines. As the first response of the innate immune system to pathogenic signals, inflammatory responses must be rapid and specific to establish a physical barrier against the s...
Source: Physiological Reviews - December 20, 2018 Category: Physiology Authors: Xu M, Liu PP, Li H Tags: Physiol Rev Source Type: research

Lower Body Negative Pressure: Physiological Effects, Applications, and Implementation.
Abstract This review presents lower body negative pressure (LBNP) as a unique tool to investigate the physiology of integrated systemic compensatory responses to altered hemodynamic patterns during conditions of central hypovolemia in humans. An early review published in Physiological Reviews over 40 yr ago (Wolthuis et al. Physiol Rev 54: 566-595, 1974) focused on the use of LBNP as a tool to study effects of central hypovolemia, while more than a decade ago a review appeared that focused on LBNP as a model of hemorrhagic shock (Cooke et al. J Appl Physiol (1985) 96: 1249-1261, 2004). Since then there has been a ...
Source: Physiological Reviews - December 13, 2018 Category: Physiology Authors: Goswami N, Blaber AP, Hinghofer-Szalkay H, Convertino VA Tags: Physiol Rev Source Type: research

Evolving and Expanding the Roles of Mitophagy as a Homeostatic and Pathogenic Process.
n GW Abstract The central functions fulfilled by mitochondria as both energy generators essential for tissue homeostasis and gateways to programmed apoptotic and necrotic cell death mandate tight control over the quality and quantity of these ubiquitous endosymbiotic organelles. Mitophagy, the targeted engulfment and destruction of mitochondria by the cellular autophagy apparatus, has conventionally been considered as the mechanism primarily responsible for mitochondrial quality control. However, our understanding of how, why, and under what specific conditions mitophagy is activated has grown tremendously over th...
Source: Physiological Reviews - December 13, 2018 Category: Physiology Authors: Gustafsson ÅB, Dorn GW Tags: Physiol Rev Source Type: research

The Activity of Peptides of the Calcitonin Family in Bone.
Abstract Calcitonin was discovered over 50 yr ago as a new hormone that rapidly lowers circulating calcium levels. This effect is caused by the inhibition of calcium efflux from bone, as calcitonin is a potent inhibitor of bone resorption. Calcitonin has been in clinical use for conditions of accelerated bone turnover, including Paget's disease and osteoporosis; although in recent years, with the development of drugs that are more potent inhibitors of bone resorption, its use has declined. A number of peptides that are structurally similar to calcitonin form the calcitonin family, which currently includes calciton...
Source: Physiological Reviews - December 13, 2018 Category: Physiology Authors: Naot D, Musson DS, Cornish J Tags: Physiol Rev Source Type: research

Activin A in Mammalian Physiology.
Abstract Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. Activins were discovered in 1986 following the isolation of inhibins from porcine follicular fluid, and were characterized as ovarian hormones that stimulate follicle stimulating hormone (FSH) release by the pituitary gland. In particular, activin A was shown to be the isoform of greater physiological importance in humans. The current understanding of activin A surpasses the reproductive system...
Source: Physiological Reviews - December 13, 2018 Category: Physiology Authors: Bloise E, Ciarmela P, Dela Cruz C, Luisi S, Petraglia F, Reis FM Tags: Physiol Rev Source Type: research

Structure, gating, and regulation of the cftr anion channel.
STRUCTURE, GATING, AND REGULATION OF THE CFTR ANION CHANNEL. Physiol Rev. 2019 Jan 01;99(1):707-738 Authors: Csanády L, Vergani P, Gadsby DC Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) belongs to the ATP binding cassette (ABC) transporter superfamily but functions as an anion channel crucial for salt and water transport across epithelial cells. CFTR dysfunction, because of mutations, causes cystic fibrosis (CF). The anion-selective pore of the CFTR protein is formed by its two transmembrane domains (TMDs) and regulated by its cytosolic domains: two nucleotide binding...
Source: Physiological Reviews - December 7, 2018 Category: Physiology Authors: Csanády L, Vergani P, Gadsby DC Tags: Physiol Rev Source Type: research

Wound Healing: A Cellular Perspective.
Abstract Wound healing is one of the most complex processes in the human body. It involves the spatial and temporal synchronization of a variety of cell types with distinct roles in the phases of hemostasis, inflammation, growth, re-epithelialization, and remodeling. With the evolution of single cell technologies, it has been possible to uncover phenotypic and functional heterogeneity within several of these cell types. There have also been discoveries of rare, stem cell subsets within the skin, which are unipotent in the uninjured state, but become multipotent following skin injury. Unraveling the roles of each o...
Source: Physiological Reviews - November 27, 2018 Category: Physiology Authors: Rodrigues M, Kosaric N, Bonham CA, Gurtner GC Tags: Physiol Rev Source Type: research

The Functional and Neurobiological Properties of Bad Taste.
Abstract The gustatory system serves as a critical line of defense against ingesting harmful substances. Technological advances have fostered the characterization of peripheral receptors and have created opportunities for more selective manipulations of the nervous system, yet the neurobiological mechanisms underlying taste-based avoidance and aversion remain poorly understood. One conceptual obstacle stems from a lack of recognition that taste signals subserve several behavioral and physiological functions which likely engage partially segregated neural circuits. Moreover, although the gustatory system evolved to...
Source: Physiological Reviews - November 27, 2018 Category: Physiology Authors: Schier LA, Spector AC Tags: Physiol Rev Source Type: research

Homocysteine Modification in Protein Structure/Function and Human Disease.
Abstract Epidemiological studies established that elevated homocysteine, an important intermediate in folate, vitamin B12, and one carbon metabolism, is associated with poor health, including heart and brain diseases. Earlier studies show that patients with severe hyperhomocysteinemia, first identified in the 1960s, exhibit neurological and cardiovascular abnormalities and premature death due to vascular complications. Although homocysteine is considered to be a nonprotein amino acid, studies over the past 2 decades have led to discoveries of protein-related homocysteine metabolism and mechanisms by which homocyst...
Source: Physiological Reviews - November 16, 2018 Category: Physiology Authors: Jakubowski H Tags: Physiol Rev Source Type: research

Building and Regenerating the Lung Cell by Cell.
Abstract The unique architecture of the mammalian lung is required for adaptation to air breathing at birth and thereafter. Understanding the cellular and molecular mechanisms controlling its morphogenesis provides the framework for understanding the pathogenesis of acute and chronic lung diseases. Recent single-cell RNA sequencing data and high-resolution imaging identify the remarkable heterogeneity of pulmonary cell types and provides cell selective gene expression underlying lung development. We will address fundamental issues related to the diversity of pulmonary cells, to the formation and function of the ma...
Source: Physiological Reviews - November 16, 2018 Category: Physiology Authors: Whitsett JA, Kalin TV, Xu Y, Kalinichenko VV Tags: Physiol Rev Source Type: research

Sarcopenia: Aging-Related Loss of Muscle Mass and Function.
Abstract Sarcopenia is a loss of muscle mass and function in the elderly that reduces mobility, diminishes quality of life, and can lead to fall-related injuries, which require costly hospitalization and extended rehabilitation. This review focuses on the aging-related structural changes and mechanisms at cellular and subcellular levels underlying changes in the individual motor unit: specifically, the perikaryon of the α-motoneuron, its neuromuscular junction(s), and the muscle fibers that it innervates. Loss of muscle mass with aging, which is largely due to the progressive loss of motoneurons, is associat...
Source: Physiological Reviews - November 16, 2018 Category: Physiology Authors: Larsson L, Degens H, Li M, Salviati L, Lee YI, Thompson W, Kirkland JL, Sandri M Tags: Physiol Rev Source Type: research

Cardiac Disorders and Pathophysiology of Sarcomeric Proteins.
Abstract The sarcomeric proteins represent the structural building blocks of heart muscle, which are essential for contraction and relaxation. During recent years, it has become evident that posttranslational modifications of sarcomeric proteins, in particular phosphorylation, tune cardiac pump function at rest and during exercise. This delicate, orchestrated interaction is also influenced by mutations, predominantly in sarcomeric proteins, which cause hypertrophic or dilated cardiomyopathy. In this review, we follow a bottom-up approach starting from a description of the basic components of cardiac muscle at the ...
Source: Physiological Reviews - November 3, 2018 Category: Physiology Authors: van der Velden J, Stienen GJM Tags: Physiol Rev Source Type: research

The TNF Family of Ligands and Receptors: Communication Modules in the Immune System and Beyond.
Abstract The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies (TNFSF/TNFRSF) include 19 ligands and 29 receptors that play important roles in the modulation of cellular functions. The communication pathways mediated by TNFSF/TNFRSF are essential for numerous developmental, homeostatic, and stimulus-responsive processes in vivo. TNFSF/TNFRSF members regulate cellular differentiation, survival, and programmed death, but their most critical functions pertain to the immune system. Both innate and adaptive immune cells are controlled by TNFSF/TNFRSF members in a manner that is crucial for the coordinat...
Source: Physiological Reviews - October 27, 2018 Category: Physiology Authors: Dostert C, Grusdat M, Letellier E, Brenner D Tags: Physiol Rev Source Type: research

Defining Physiological Normoxia for Improved Translation of Cell Physiology to Animal Models and Humans.
Abstract The extensive oxygen gradient between the air we breathe (Po2 ~21 kPa) and its ultimate distribution within mitochondria (as low as ~0.5-1 kPa) is testament to the efforts expended in limiting its inherent toxicity. It has long been recognized that cell culture undertaken under room air conditions falls short of replicating this protection in vitro. Despite this, difficulty in accurately determining the appropriate O2 levels in which to culture cells, coupled with a lack of the technology to replicate and maintain a physiological O2 environment in vitro, has hindered addressing this issue thus far. In thi...
Source: Physiological Reviews - October 27, 2018 Category: Physiology Authors: Keeley TP, Mann GE Tags: Physiol Rev Source Type: research

Thick Ascending Limb Sodium Transport in the Pathogenesis of Hypertension.
Abstract The thick ascending limb plays a key role in maintaining water and electrolyte balance. The importance of this segment in regulating blood pressure is evidenced by the effect of loop diuretics or local genetic defects on this parameter. Hormones and factors produced by thick ascending limbs have both autocrine and paracrine effects, which can extend prohypertensive signaling to other structures of the nephron. In this review, we discuss the role of the thick ascending limb in the development of hypertension, not as a sole participant, but one that works within the rich biological context of the renal medu...
Source: Physiological Reviews - October 27, 2018 Category: Physiology Authors: Gonzalez-Vicente A, Saez F, Monzon CM, Asirwatham J, Garvin JL Tags: Physiol Rev Source Type: research

Induced Pluripotent Stem Cells and Their Use in Human Models of Disease and Development.
Abstract The discovery of somatic cell nuclear transfer proved that somatic cells can carry the same genetic code as the zygote, and that activating parts of this code are sufficient to reprogram the cell to an early developmental state. The discovery of induced pluripotent stem cells (iPSCs) nearly half a century later provided a molecular mechanism for the reprogramming. The initial creation of iPSCs was accomplished by the ectopic expression of four specific genes (OCT4, KLF4, SOX2, and c-Myc; OSKM). iPSCs have since been acquired from a wide range of cell types and a wide range of species, suggesting a univers...
Source: Physiological Reviews - October 18, 2018 Category: Physiology Authors: Karagiannis P, Takahashi K, Saito M, Yoshida Y, Okita K, Watanabe A, Inoue H, Yamashita JK, Todani M, Nakagawa M, Osawa M, Yashiro Y, Yamanaka S, Osafune K Tags: Physiol Rev Source Type: research

Blood-Brain Barrier: From Physiology to Disease and Back.
Abstract The blood-brain barrier (BBB) prevents neurotoxic plasma components, blood cells, and pathogens from entering the brain. At the same time, the BBB regulates transport of molecules into and out of the central nervous system (CNS), which maintains tightly controlled chemical composition of the neuronal milieu that is required for proper neuronal functioning. In this review, we first examine molecular and cellular mechanisms underlying the establishment of the BBB. Then, we focus on BBB transport physiology, endothelial and pericyte transporters, and perivascular and paravascular transport. Next, we discuss ...
Source: Physiological Reviews - October 4, 2018 Category: Physiology Authors: Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV Tags: Physiol Rev Source Type: research

Melanosomes: Biogenesis, Properties, and Evolution of an Ancient Organelle.
Abstract Melanosomes are organelles that produce and store melanin, a widespread biological pigment with a unique suite of properties including high refractive index, semiconducting capabilities, material stiffness, and high fossilization potential. They are involved in numerous critical biological functions in organisms across the tree of life. Individual components such as melanin chemistry and melanosome development have recently been addressed, but a broad synthesis is needed. Here, we review the hierarchical structure, development, functions, and evolution of melanosomes. We highlight variation in melanin che...
Source: Physiological Reviews - September 27, 2018 Category: Physiology Authors: D'Alba L, Shawkey MD Tags: Physiol Rev Source Type: research

From Molecules to Mechanisms: Functional Proteomics and Its Application to Renal Tubule Physiology.
Abstract Classical physiological studies using electrophysiological, biophysical, biochemical, and molecular techniques have created a detailed picture of molecular transport, bioenergetics, contractility and movement, and growth, as well as the regulation of these processes by external stimuli in cells and organisms. Newer systems biology approaches are beginning to provide deeper and broader understanding of these complex biological processes and their dynamic responses to a variety of environmental cues. In the past decade, advances in mass spectrometry-based proteomic technologies have provided invaluable tool...
Source: Physiological Reviews - September 7, 2018 Category: Physiology Authors: Rinschen MM, Limbutara K, Knepper MA, Payne DM, Pisitkun T Tags: Physiol Rev Source Type: research