Showing papers in "Comprehensive Physiology in 2013"

Bile Acid Metabolism and Signaling

Abstract: Bile acids are important physiological agents for intestinal nutrient absorption and biliary secretion of lipids, toxic metabolites, and xenobiotics. Bile acids also are signaling molecules and metabolic regulators that activate nuclear receptors and G protein-coupled receptor (GPCR) signaling to regulate hepatic lipid, glucose, and energy homeostasis and maintain metabolic homeostasis. Conversion of cholesterol to bile acids is critical for maintaining cholesterol homeostasis and preventing accumulation of cholesterol, triglycerides, and toxic metabolites, and injury in the liver and other organs. Enterohepatic circulation of bile acids from the liver to intestine and back to the liver plays a central role in nutrient absorption and distribution, and metabolic regulation and homeostasis. This physiological process is regulated by a complex membrane transport system in the liver and intestine regulated by nuclear receptors. Toxic bile acids may cause inflammation, apoptosis, and cell death. On the other hand, bile acid-activated nuclear and GPCR signaling protects against inflammation in liver, intestine, and macrophages. Disorders in bile acid metabolism cause cholestatic liver diseases, dyslipidemia, fatty liver diseases, cardiovascular diseases, and diabetes. Bile acids, bile acid derivatives, and bile acid sequestrants are therapeutic agents for treating chronic liver diseases, obesity, and diabetes in humans.

Hepatic stellate cells and liver fibrosis.

Abstract: Hepatic stellate cells are resident perisinusoidal cells distributed throughout the liver, with a remarkable range of functions in normal and injured liver. Derived embryologically from septum transversum mesenchyme, their precursors include submesothelial cells that invade the liver parenchyma from the hepatic capsule. In normal adult liver, their most characteristic feature is the presence of cytoplasmic perinuclear droplets that are laden with retinyl (vitamin A) esters. Normal stellate cells display several patterns of intermediate filaments expression (e.g., desmin, vimentin, and/or glial fibrillary acidic protein) suggesting that there are subpopulations within this parental cell type. In the normal liver, stellate cells participate in retinoid storage, vasoregulation through endothelial cell interactions, extracellular matrix homeostasis, drug detoxification, immunotolerance, and possibly the preservation of hepatocyte mass through secretion of mitogens including hepatocyte growth factor. During liver injury, stellate cells activate into alpha smooth muscle actin-expressing contractile myofibroblasts, which contribute to vascular distortion and increased vascular resistance, thereby promoting portal hypertension. Other features of stellate cell activation include mitogen-mediated proliferation, increased fibrogenesis driven by connective tissue growth factor, and transforming growth factor beta 1, amplified inflammation and immunoregulation, and altered matrix degradation. Evolving areas of interest in stellate cell biology seek to understand mechanisms of their clearance during fibrosis resolution by either apoptosis, senescence, or reversion, and their contribution to hepatic stem cell amplification, regeneration, and hepatocellular cancer.

Bile formation and secretion.

Abstract: Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (∼1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions.

Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training

Abstract: Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity.

Kupffer cells in the liver.

Abstract: Kupffer cells are a critical component of the mononuclear phagocytic system and are central to both the hepatic and systemic response to pathogens Kupffer cells are reemerging as critical mediators of both liver injury and repair Kupffer cells exhibit a tremendous plasticity; depending on the local metabolic and immune environment, then can express a range of polarized phenotypes, from the proinflammatory M1 phenotype to the alternative/M2 phenotype Multiple M2 phenotypes can be distinguished, each involved in the resolution of inflammation and wound healing Here, we have provided an update on recent research that has contributed to the developing delineation of the contribution of Kupffer cells to different types of liver injury, with an emphasis on alcoholic and nonalcoholic liver diseases These recent advances in our understanding of Kupffer cell function and regulation will likely provide new insights into the potential for therapeutic manipulation of Kupffer cells to promote the resolution of inflammation and enhance wound healing in liver disease

The Influence of Exercise on Cognitive Abilities

Abstract: Scientific evidence based on neuroimaging approaches over the last decade has demonstrated the efficacy of physical activity improving cognitive health across the human lifespan. Aerobic fitness spares age-related loss of brain tissue during aging, and enhances functional aspects of higher order regions involved in the control of cognition. More active or higher fit individuals are capable of allocating greater attentional resources toward the environment and are able to process information more quickly. These data are suggestive that aerobic fitness enhances cognitive strategies enabling to respond effectively to an imposed challenge with a better yield in task performance. In turn, animal studies have shown that exercise has a benevolent action on health and plasticity of the nervous system. New evidence indicates that exercise exerts its effects on cognition by affecting molecular events related to the management of energy metabolism and synaptic plasticity. An important instigator in the molecular machinery stimulated by exercise is brain-derived neurotrophic factor, which acts at the interface of metabolism and plasticity. Recent studies show that exercise collaborates with other aspects of lifestyle to influence the molecular substrates of cognition. In particular, select dietary factors share similar mechanisms with exercise, and in some cases they can complement the action of exercise. Therefore, exercise and dietary management appear as a noninvasive and effective strategy to counteract neurological and cognitive disorders.

Muscle as a secretory organ.

Abstract: Skeletal muscle is the largest organ in the body. Skeletal muscles are primarily characterized by their mechanical activity required for posture, movement, and breathing, which depends on muscle fiber contractions. However, skeletal muscle is not just a component in our locomotor system. Recent evidence has identified skeletal muscle as a secretory organ. We have suggested that cytokines and other peptides that are produced, expressed, and released by muscle fibers and exert either autocrine, paracrine, or endocrine effects should be classified as “myokines.” The muscle secretome consists of several hundred secreted peptides. This finding provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs such as adipose tissue, liver, pancreas, bones, and brain. In addition, several myokines exert their effects within the muscle itself. Many proteins produced by skeletal muscle are dependent upon contraction. Therefore, it is likely that myokines may contribute in the mediation of the health benefits of exercise. © 2013 American Physiological Society. Compr Physiol 3:1337-1362, 2013.

Apoptosis and necrosis in the liver.

Abstract: Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor-mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor-induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of "programmed" necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article.

Molecular Mechanism of TRP Channels

Abstract: Transient receptor potential (TRP) channels are cellular sensors for a wide spectrum of physical and chemical stimuli. They are involved in the formation of sight, hearing, touch, smell, taste, temperature, and pain sensation. TRP channels also play fundamental roles in cell signaling and allow the host cell to respond to benign or harmful environmental changes. As TRP channel activation is controlled by very diverse processes and, in many cases, exhibits complex polymodal properties, understanding how each TRP channel responds to its unique forms of activation energy is both crucial and challenging. The past two decades witnessed significant advances in understanding the molecular mechanisms that underlie TRP channels activation. This review focuses on our current understanding of the molecular determinants for TRP channel activation.

Monocarboxylic Acid Transport

Abstract: Monocarboxylates such as lactate, pyruvate, and the ketone bodies play major roles in metabolism and must be transported across both the plasma membrane and mitochondrial inner membrane. A family of five proton-linked MonoCarboxylate Transporters (MCTs) is involved in the former and the mitochondrial pyruvate carrier (MPC) mediates the latter. In the intestine and kidney, two Sodium-coupled MonoCarboxylate Transporters (SMCTs) provide active transport of monocarboxylates across the apical membrane of the epithelial cells with MCTs on the basolateral membrane transporting the accumulated monocarboxylate into the blood. The kinetics and substrate and inhibitor specificities of MCTs, SMCTs, and the MPC have been well characterized and the molecular identity of the MCTs and SMCTs defined unequivocally. The identity of the MPC is less certain. The MCTs have been extensively studied and the three-dimensional structure of MCT1 has been modeled and a likely catalytic mechanism proposed. MCTs require the binding of a single transmembrane glycoprotein (either embigin or basigin) for activity. Regulation of MCT activity involves both transcriptional and posttranscriptional mechanisms, examples being upregulation of MCT1 by chronic exercise in red muscle (which oxidizes lactate) and in T-lymphocytes upon stimulation. MCT4 has properties that make it especially suited for lactic acid export by glycolytic cells and is upregulated by hypoxia. Some disease states are associated with modulation of plasma membrane and mitochondrial monocarboxylate transport and MCTs are promising drug targets for cancer chemotherapy. They may also be involved in drug uptake from the intestine and subsequent transport across the blood brain barrier.

Immune and Inflammatory Role in Renal Disease

Abstract: Chronic and acute renal diseases, irrespective of the initiating cause, have inflammation and immune system activation as a common underlying mechanism. The purpose of this review is to provide a broad overview of immune cells and inflammatory proteins that contribute to the pathogenesis of renal disease, and to discuss some of the physiological changes that occur in the kidney as a result of immune system activation. An overview of common forms of acute and chronic renal disease is provided, followed by a discussion of common therapies that have anti-inflammatory or immunosuppressive effects in the treatment of renal disease.

Comparative digestive physiology.

Abstract: In vertebrates and invertebrates, morphological and functional features of gastrointestinal (GI) tracts generally reflect food chemistry, such as content of carbohydrates, proteins, fats, and material(s) refractory to rapid digestion (e.g., cellulose). The expression of digestive enzymes and nutrient transporters approximately matches the dietary load of their respective substrates, with relatively modest excess capacity. Mechanisms explaining differences in hydrolase activity between populations and species include gene copy number variations and single-nucleotide polymorphisms. Transcriptional and posttranscriptional adjustments mediate phenotypic changes in the expression of hydrolases and transporters in response to dietary signals. Many species respond to higher food intake by flexibly increasing digestive compartment size. Fermentative processes by symbiotic microorganisms are important for cellulose degradation but are relatively slow, so animals that rely on those processes typically possess special enlarged compartment(s) to maintain a microbiota and other GI structures that slow digesta flow. The taxon richness of the gut microbiota, usually identified by 16S rRNA gene sequencing, is typically an order of magnitude greater in vertebrates than invertebrates, and the interspecific variation in microbial composition is strongly influenced by diet. Many of the nutrient transporters are orthologous across different animal phyla, though functional details may vary (e.g., glucose and amino acid transport with K+ rather than Na+ as a counter ion). Paracellular absorption is important in many birds. Natural toxins are ubiquitous in foods and may influence key features such as digesta transit, enzymatic breakdown, microbial fermentation, and absorption.

Principles of Liver Regeneration and Growth Homeostasis

Abstract: Liver regeneration is perhaps the most studied example of compensatory growth aimed to replace loss of tissue in an organ Hepatocytes, the main functional cells of the liver, manage to proliferate to restore mass and to simultaneously deliver all functions hepatic functions necessary to maintain body homeostasis They are the first cells to respond to regenerative stimuli triggered by mitogenic growth factor receptors MET (the hepatocyte growth factor receptor] and epidermal growth factor receptor and complemented by auxiliary mitogenic signals induced by other cytokines Termination of liver regeneration is a complex process affected by integrin mediated signaling and it restores the organ to its original mass as determined by the needs of the body (hepatostat function) When hepatocytes cannot proliferate, progenitor cells derived from the biliary epithelium transdifferentiate to restore the hepatocyte compartment In a reverse situation, hepatocytes can also transdifferentiate to restore the biliary compartment Several hormones and xenobiotics alter the hepatostat directly and induce an increase in liver to body weight ratio (augmentative hepatomegaly) The complex challenges of the liver toward body homeostasis are thus always preserved by complex but unfailing responses involving orchestrated signaling and affecting growth and differentiation of all hepatic cell types

Thermometry, calorimetry, and mean body temperature during heat stress.

Abstract: Heat balance in humans is maintained at near constant levels through the adjustment of physiological mechanisms that attain a balance between the heat produced within the body and the heat lost to the environment. Heat balance is easily disturbed during changes in metabolic heat production due to physical activity and/or exposure to a warmer environment. Under such conditions, elevations of skin blood flow and sweating occur via a hypothalamic negative feedback loop to maintain an enhanced rate of dry and evaporative heat loss. Body heat storage and changes in core temperature are a direct result of a thermal imbalance between the rate of heat production and the rate of total heat dissipation to the surrounding environment. The derivation of the change in body heat content is of fundamental importance to the physiologist assessing the exposure of the human body to environmental conditions that result in thermal imbalance. It is generally accepted that the concurrent measurement of the total heat generated by the body and the total heat dissipated to the ambient environment is the most accurate means whereby the change in body heat content can be attained. However, in the absence of calorimetric methods, thermometry is often used to estimate the change in body heat content. This review examines heat exchange during challenges to heat balance associated with progressive elevations in environmental heat load and metabolic rate during exercise. Further, we evaluate the physiological responses associated with heat stress and discuss the thermal and nonthermal influences on the body's ability to dissipate heat from a heat balance perspective.

Particle Transport and Deposition: Basic Physics of Particle Kinetics

Abstract: The human body interacts with the environment in many different ways. The lungs interact with the external environment through breathing. The enormously large surface area of the lung with its extremely thin air-blood barrier is exposed to particles suspended in the inhaled air. The particle-lung interaction may cause deleterious effects on health if the inhaled pollutant aerosols are toxic. Conversely, this interaction can be beneficial for disease treatment if the inhaled particles are therapeutic aerosolized drugs. In either case, an accurate estimation of dose and sites of deposition in the respiratory tract is fundamental to understanding subsequent biological response, and the basic physics of particle motion and engineering knowledge needed to understand these subjects is the topic of this article. A large portion of this article deals with three fundamental areas necessary to the understanding of particle transport and deposition in the respiratory tract. These are: (i) the physical characteristics of particles, (ii) particle behavior in gas flow, and (iii) gas-flow patterns in the respiratory tract. Other areas, such as particle transport in the developing lung and in the diseased lung are also considered. The article concludes with a summary and a brief discussion of areas of future research.

Physiology of Cholangiocytes

Abstract: Cholangiocytes are epithelial cells that line the intra- and extrahepatic ducts of the biliary tree. The main physiologic function of cholangiocytes is modification of hepatocyte-derived bile, an intricate process regulated by hormones, peptides, nucleotides, neurotransmitters, and other molecules through intracellular signaling pathways and cascades. The mechanisms and regulation of bile modification are reviewed herein.

Mechanisms Modulating Skeletal Muscle Phenotype

Abstract: Mammalian skeletal muscles are composed of a variety of highly specialized fibers whose selective recruitment allows muscles to fulfill their diverse functional tasks. In addition, skeletal muscle fibers can change their structural and functional properties to perform new tasks or respond to new conditions. The adaptive changes of muscle fibers can occur in response to variations in the pattern of neural stimulation, loading conditions, availability of substrates, and hormonal signals. The new conditions can be detected by multiple sensors, from membrane receptors for hormones and cytokines, to metabolic sensors, which detect high-energy phosphate concentration, oxygen and oxygen free radicals, to calcium binding proteins, which sense variations in intracellular calcium induced by nerve activity, to load sensors located in the sarcomeric and sarcolemmal cytoskeleton. These sensors trigger cascades of signaling pathways which may ultimately lead to changes in fiber size and fiber type. Changes in fiber size reflect an imbalance in protein turnover with either protein accumulation, leading to muscle hypertrophy, or protein loss, with consequent muscle atrophy. Changes in fiber type reflect a reprogramming of gene transcription leading to a remodeling of fiber contractile properties (slow-fast transitions) or metabolic profile (glycolytic-oxidative transitions). While myonuclei are in postmitotic state, satellite cells represent a reserve of new nuclei and can be involved in the adaptive response.

Iron homeostasis in the liver.

Abstract: Iron is an essential nutrient that is tightly regulated. A principal function of the liver is the regulation of iron homeostasis. The liver senses changes in systemic iron requirements and can regulate iron concentrations in a robust and rapid manner. The last 10 years have led to the discovery of several regulatory mechanisms in the liver that control the production of iron regulatory genes, storage capacity, and iron mobilization. Dysregulation of these functions leads to an imbalance of iron, which is the primary cause of iron-related disorders. Anemia and iron overload are two of the most prevalent disorders worldwide and affect over a billion people. Several mutations in liver-derived genes have been identified, demonstrating the central role of the liver in iron homeostasis. During conditions of excess iron, the liver increases iron storage and protects other tissues, namely, the heart and pancreas from iron-induced cellular damage. However, a chronic increase in liver iron stores results in excess reactive oxygen species production and liver injury. Excess liver iron is one of the major mechanisms leading to increased steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma.

Central Sleep Apnea

Abstract: Neurophysiologically, central apnea is due to a temporary failure in the pontomedullary pacemaker generating breathing rhythm. As a polysomnographic finding, central apneas occur in many pathophysiological conditions. Depending on the cause or mechanism, central apneas may not be clinically significant, for example, those that occur normally at sleep onset. In contrast, central apneas occur in a number of disorders and result in pathophysiological consequences. Central apneas occur commonly in high-altitude sojourn, disrupt sleep, and cause desaturation. Central sleep apnea also occurs in number of disorders across all age groups and both genders. Common causes of central sleep apnea in adults are congestive heart failure and chronic use of opioids to treat pain. Under such circumstances, diagnosis and treatment of central sleep apnea may improve quality of life, morbidity, and perhaps mortality. The mechanisms of central sleep apnea have been best studied in congestive heart failure and hypoxic conditions when there is increased CO2 sensitivity below eupnea resulting in lowering eupneic PCO2 below apneic threshold causing cessation of breathing until the PCO2 rises above the apneic threshold when breathing resumes. In many other disorders, the mechanism of central sleep apnea (CSA) remains to be investigated.

Evolution of air breathing: oxygen homeostasis and the transitions from water to land and sky.

Abstract: Life originated in anoxia, but many organisms came to depend upon oxygen for survival, independently evolving diverse respiratory systems for acquiring oxygen from the environment. Ambient oxygen tension (PO2) fluctuated through the ages in correlation with biodiversity and body size, enabling organisms to migrate from water to land and air and sometimes in the opposite direction. Habitat expansion compels the use of different gas exchangers, for example, skin, gills, tracheae, lungs, and their intermediate stages, that may coexist within the same species; coexistence may be temporally disjunct (e.g., larval gills vs. adult lungs) or simultaneous (e.g., skin, gills, and lungs in some salamanders). Disparate systems exhibit similar directions of adaptation: toward larger diffusion interfaces, thinner barriers, finer dynamic regulation, and reduced cost of breathing. Efficient respiratory gas exchange, coupled to downstream convective and diffusive resistances, comprise the "oxygen cascade"-step-down of PO2 that balances supply against toxicity. Here, we review the origin of oxygen homeostasis, a primal selection factor for all respiratory systems, which in turn function as gatekeepers of the cascade. Within an organism's lifespan, the respiratory apparatus adapts in various ways to upregulate oxygen uptake in hypoxia and restrict uptake in hyperoxia. In an evolutionary context, certain species also become adapted to environmental conditions or habitual organismic demands. We, therefore, survey the comparative anatomy and physiology of respiratory systems from invertebrates to vertebrates, water to air breathers, and terrestrial to aerial inhabitants. Through the evolutionary directions and variety of gas exchangers, their shared features and individual compromises may be appreciated.

Molecular Biology of Freezing Tolerance

Abstract: Winter survival for many kinds of animals involves freeze tolerance, the ability to endure the conversion of about 65% of total body water into extracellular ice and the consequences that freezing imposes including interruption of vital processes (e.g., heartbeat and breathing), cell shrinkage, elevated osmolality, anoxia/ischemia, and potential physical damage from ice. Freeze-tolerant animals include various terrestrially hibernating amphibians and reptiles, many species of insects, and numerous other invertebrates inhabiting both terrestrial and intertidal environments. Well-known strategies of freezing survival include accumulation of low molecular mass carbohydrate cryoprotectants (e.g., glycerol), use of ice nucleating agents/proteins for controlled triggering of ice growth and of antifreeze proteins that inhibit ice recrystallization, and good tolerance of anoxia and dehydration. The present article focuses on more recent advances in our knowledge of the genes and proteins that support freeze tolerance and the metabolic regulatory mechanisms involved. Important roles have been identified for aquaporins and transmembrane channels that move cryoprotectants, heat shock proteins and other chaperones, antioxidant defenses, and metabolic rate depression. Genome and proteome screening has revealed many new potential targets that respond to freezing, in particular implicating cytoskeleton remodeling as a necessary facet of low temperature and/or cell volume adaptation. Key regulatory mechanisms include reversible phosphorylation control of metabolic enzymes and microRNA control of gene transcript expression. These help to remodel metabolism to preserve core functions while suppressing energy expensive metabolic activities such as the cell cycle. All of these advances are providing a much more complete picture of life in the frozen state.

Porphyrin and Heme Metabolism and the Porphyrias

Abstract: Porphyrins and metalloporphyrins are the key pigments of life on earth as we know it, because they include chlorophyll (a magnesium-containing metalloporphyrin) and heme (iron protoporphyrin). In eukaryotes, porphyrins and heme are synthesized by a multistep pathway that involves eight enzymes. The first and rate-controlling step is the formation of delta-aminolevulinic acid (ALA) from glycine plus succinyl CoA, catalyzed by ALA synthase. Intermediate steps occur in the cytoplasm, with formation of the monopyrrole porphobilinogen and the tetrapyrroles hydroxymethylbilane and a series of porphyrinogens, which are serially decarboxylated. Heme is utilized chiefly for the formation of hemoglobin in erythrocytes, myoglobin in muscle cells, cytochromes P-450 and mitochondrial cytochromes, and other hemoproteins in hepatocytes. The rate-controlling step of heme breakdown is catalyzed by heme oxygenase (HMOX), of which there are two isoforms, called HMOX1 and HMOX2. HMOX breaks down heme to form biliverdin, carbon monoxide, and iron. The porphyrias are a group of disorders, mainly inherited, in which there are defects in normal porphyrin and heme synthesis. The cardinal clinical features are cutaneous (due to the skin-damaging effects of excess deposited porphyrins) or neurovisceral attacks of pain, sometimes with weakness, delirium, seizures, and the like (probably due mainly to neurotoxic effects of ALA). The treatment of choice for the acute hepatic porphyrias is intravenous heme therapy, which repletes a critical regulatory heme pool in hepatocytes and leads to downregulation of hepatic ALA synthase, which is a biochemical hallmark of all forms of acute porphyria in relapse.

Renal ammonia metabolism and transport.

Abstract: Renal ammonia metabolism and transport mediates a central role in acid-base homeostasis. In contrast to most renal solutes, the majority of renal ammonia excretion derives from intrarenal production, not from glomerular filtration. Renal ammoniagenesis predominantly results from glutamine metabolism, which produces 2 NH4(+) and 2 HCO3(-) for each glutamine metabolized. The proximal tubule is the primary site for ammoniagenesis, but there is evidence for ammoniagenesis by most renal epithelial cells. Ammonia produced in the kidney is either excreted into the urine or returned to the systemic circulation through the renal veins. Ammonia excreted in the urine promotes acid excretion; ammonia returned to the systemic circulation is metabolized in the liver in a HCO3(-)-consuming process, resulting in no net benefit to acid-base homeostasis. Highly regulated ammonia transport by renal epithelial cells determines the proportion of ammonia excreted in the urine versus returned to the systemic circulation. The traditional paradigm of ammonia transport involving passive NH3 diffusion, protonation in the lumen and NH4(+) trapping due to an inability to cross plasma membranes is being replaced by the recognition of limited plasma membrane NH3 permeability in combination with the presence of specific NH3-transporting and NH4(+)-transporting proteins in specific renal epithelial cells. Ammonia production and transport are regulated by a variety of factors, including extracellular pH and K(+), and by several hormones, such as mineralocorticoids, glucocorticoids and angiotensin II. This coordinated process of regulated ammonia production and transport is critical for the effective maintenance of acid-base homeostasis.

Reactive oxygen species in pulmonary vascular remodeling.

Abstract: The pathogenesis of pulmonary hypertension is a complex multifactorial process that involves the remodeling of pulmonary arteries. This remodeling process encompasses concentric medial thickening of small arterioles, neomuscularization of previously nonmuscular capillary-like vessels, and structural wall changes in larger pulmonary arteries. The pulmonary arterial muscularization is characterized by vascular smooth muscle cell hyperplasia and hypertrophy. In addition, in uncontrolled pulmonary hypertension, the clonal expansion of apoptosis-resistant endothelial cells leads to the formation of plexiform lesions. Based upon a large number of studies in animal models, the three major stimuli that drive the vascular remodeling process are inflammation, shear stress, and hypoxia. Although, the precise mechanisms by which these stimuli impair pulmonary vascular function and structure are unknown, reactive oxygen species (ROS)-mediated oxidative damage appears to play an important role. ROS are highly reactive due to their unpaired valence shell electron. Oxidative damage occurs when the production of ROS exceeds the quenching capacity of the antioxidant mechanisms of the cell. ROS can be produced from complexes in the cell membrane (nicotinamide adenine dinucleotide phosphate-oxidase), cellular organelles (peroxisomes and mitochondria), and in the cytoplasm (xanthine oxidase). Furthermore, low levels of tetrahydrobiopterin (BH4) and L-arginine the rate limiting cofactor and substrate for endothelial nitric oxide synthase (eNOS), can cause the uncoupling of eNOS, resulting in decreased NO production and increased ROS production. This review will focus on the ROS generation systems, scavenger antioxidants, and oxidative stress associated alterations in vascular remodeling in pulmonary hypertension.

Hepatic Nervous System and Neurobiology of the Liver

Abstract: The liver has a nervous system containing both afferent and efferent neurons that are involved in a number of processes. The afferent arm includes the sensation of lipids, glucose, and metabolites (after eating and drinking) and triggers the nervous system to make appropriate physiological changes. The efferent arm is essential for metabolic regulation, modulation of fibrosis and biliary function and the control of a number of other processes. Experimental models have helped us to establish how: (i) the liver is innervated by the autonomic nervous system; and (ii) the cell types that are involved in these processes. Thus, the liver acts as both a sensor and effector that is influenced by neurological signals and ablation. Understanding these processes hold significant implications in disease processes such as diabetes and obesity, which are influenced by appetite and hormonal signals.

Exercise and type 1 diabetes (T1DM).

Abstract: Physical exercise is firmly incorporated in the management of type 1 diabetes (T1DM), due to multiple recognized beneficial health effects (cardiovascular disease prevention being preeminent). When glycemic values are not excessively low or high at the time of exercise, few absolute contraindications exist; practical guidelines regarding amount, type, and duration of age-appropriate exercise are regularly updated by entities such as the American Diabetes Association and the International Society for Pediatric and Adolescent Diabetes. Practical implementation of exercise regimens, however, may at times be problematic. In the poorly controlled patient, specific structural changes may occur within skeletal muscle fiber, which is considered by some to be a disease-specific myopathy. Further, even in well-controlled patients, several homeostatic mechanisms regulating carbohydrate metabolism often become impaired, causing hypo- or hyperglycemia during and/or after exercise. Some altered responses may be related to inappropriate exogenous insulin administration, but are often also partly caused by the "metabolic memory" of prior glycemic events. In this context, prior hyperglycemia correlates with increased inflammatory and oxidative stress responses, possibly modulating key exercise-associated cardio-protective pathways. Similarly, prior hypoglycemia correlates with impaired glucose counterregulation, resulting in greater likelihood of further hypoglycemia to develop. Additional exercise responses that may be altered in T1DM include growth factor release, which may be especially important in children and adolescents. These multiple alterations in the exercise response should not discourage physical activity in patients with T1DM, but rather should stimulate the quest for the identification of the exercise formats that maximize beneficial health effects.

Renal Vascular Structure and Rarefaction

Abstract: An intact microcirculation is vital for diffusion of oxygen and nutrients and for removal of toxins of every organ and system in the human body. The functional and/or anatomical loss of microvessels is known as rarefaction, which can compromise the normal organ function and have been suggested as a possible starting point of several diseases. The purpose of this overview is to discuss the potential underlying mechanisms leading to renal microvascular rarefaction, and the potential consequences on renal function and on the progression of renal damage. Although the kidney is a special organ that receives much more blood than its metabolic needs, experimental and clinical evidence indicates that renal microvascular rarefaction is associated to prevalent cardiovascular diseases such as diabetes, hypertension, and atherosclerosis, either as cause or consequence. On the other hand, emerging experimental evidence using progenitor cells or angiogenic cytokines supports the feasibility of therapeutic interventions capable of modifying the progressive nature of microvascular rarefaction in the kidney. This overview will also attempt to discuss the potential renoprotective mechanisms of the therapeutic targeting of the renal microcirculation.

Calcium Signaling in the Liver

Abstract: Intracellular free Ca2+ ([Ca2+]i) is a highly versatile second messenger that regulates a wide range of functions in every type of cell and tissue. To achieve this versatility, the Ca2+ signaling system operates in a variety of ways to regulate cellular processes that function over a wide dynamic range. This is particularly well exemplified for Ca2+ signals in the liver, which modulate diverse and specialized functions such as bile secretion, glucose metabolism, cell proliferation, and apoptosis. These Ca2+ signals are organized to control distinct cellular processes through tight spatial and temporal coordination of [Ca2+]i signals, both within and between cells. This article will review the machinery responsible for the formation of Ca2+ signals in the liver, the types of subcellular, cellular, and intercellular signals that occur, the physiological role of Ca2+ signaling in the liver, and the role of Ca2+ signaling in liver disease. © 2013 American Physiological Society. Compr Physiol 3:515-539, 2013.

Mechanical properties of respiratory muscles.

Abstract: Striated respiratory muscles are necessary for lung ventilation and to maintain the patency of the upper airway. The basic structural and functional properties of respiratory muscles are similar to those of other striated muscles (both skeletal and cardiac). The sarcomere is the fundamental organizational unit of striated muscles and sarcomeric proteins underlie the passive and active mechanical properties of muscle fibers. In this respect, the functional categorization of different fiber types provides a conceptual framework to understand the physiological properties of respiratory muscles. Within the sarcomere, the interaction between the thick and thin filaments at the level of cross-bridges provides the elementary unit of force generation and contraction. Key to an understanding of the unique functional differences across muscle fiber types are differences in cross-bridge recruitment and cycling that relate to the expression of different myosin heavy chain isoforms in the thick filament. The active mechanical properties of muscle fibers are characterized by the relationship between myoplasmic Ca2+ and cross-bridge recruitment, force generation and sarcomere length (also cross-bridge recruitment), external load and shortening velocity (cross-bridge cycling rate), and cross-bridge cycling rate and ATP consumption. Passive mechanical properties are also important reflecting viscoelastic elements within sarcomeres as well as the extracellular matrix. Conditions that affect respiratory muscle performance may have a range of underlying pathophysiological causes, but their manifestations will depend on their impact on these basic elemental structures.

Pulmonary gas exchange and acid-base balance during exercise.

Abstract: As the first step in the oxygen-transport chain, the lung has a critical task: optimizing the exchange of respiratory gases to maintain delivery of oxygen and the elimination of carbon dioxide. In healthy subjects, gas exchange, as evaluated by the alveolar-to-arterial PO2 difference (A-aDO2), worsens with incremental exercise, and typically reaches an A-aDO2 of approximately 25 mmHg at peak exercise. While there is great individual variability, A-aDO2 is generally largest at peak exercise in subjects with the highest peak oxygen consumption. Inert gas data has shown that the increase in A-aDO2 is explained by decreased ventilation-perfusion matching, and the development of a diffusion limitation for oxygen. Gas exchange data does not indicate the presence of right-to-left intrapulmonary shunt developing with exercise, despite recent data suggesting that large-diameter arteriovenous shunt vessels may be recruited with exercise. At the same time, multisystem mechanisms regulate systemic acid-base balance in integrative processes that involve gas exchange between tissues and the environment and simultaneous net changes in the concentrations of strong and weak ions within, and transfer between, extracellular and intracellular fluids. The physicochemical approach to acid-base balance is used to understand the contributions from independent acid-base variables to measured acid-base disturbances within contracting skeletal muscle, erythrocytes and noncontracting tissues. In muscle, the magnitude of the disturbance is proportional to the concentrations of dissociated weak acids, the rate at which acid equivalents (strong acid) accumulate and the rate at which strong base cations are added to or removed from muscle.