Autophagy–physiology and pathophysiology

“Autophagy” is a highly conserved pathway for degradation, by which wasted intracellular macromolecules are delivered to lysosomes, where they are degraded into biologically active monomers such as amino acids that are subsequently re-used to maintain cellular metabolic turnover and homeostasis. Recent genetic studies have shown that mice lacking an autophagy-related gene (Atg5 or Atg7) cannot survive longer than 12 h after birth because of nutrient shortage. Moreover, tissue-specific impairment of autophagy in central nervous system tissue causes massive loss of neurons, resulting in neurodegeneration, while impaired autophagy in liver tissue causes accumulation of wasted organelles, leading to hepatomegaly. Although autophagy generally prevents cell death, our recent study using conditional Atg7-deficient mice in CNS tissue has demonstrated the presence of autophagic neuron death in the hippocampus after neonatal hypoxic/ischemic brain injury. Thus, recent genetic studies have shown that autophagy is involved in various cellular functions. In this review, we introduce physiological and pathophysiological roles of autophagy.     

Confronting physiology: how do infected flies die?

Fruit fly immunology is on the verge of an exciting new path. The fruit fly has served as a strong model for innate immune responses; the field is now expanding to use the fruit fly to study pathogenesis. We argue here that, to understand pathogenesis in the fly, we need to understand pathology - and to understand pathology, we need to confront physiology with molecular tools. When flies are infected with a pathogen, they get sick. We group the events following infection into three categories: innate immune responses (defence mechanisms by which the fly attempts to kill or neutralize the microbe, some of which can themselves cause harm to the fly); microbial virulence (mechanisms by which the microbe evades the immune response); and host pathology (physiologies adversely affected by either the immune response or microbial virulence). We divide this review into sections mirroring these categories. The molecular study of infection in the fruit fly has focused on the first category, has begun to explore the second, and has yet to tap the full potential of the fly regarding the third.     

FSH and bone – important physiology or not?

For many years, osteoporosis in women was equated with estrogen deficiency. The recent articles by Zaidi and colleagues offer a new challenge to the estrogen-deficiency-osteoporosis hypothesis by showing that follicle-stimulating hormone (FSH) stimulates osteoclastic bone resorption perhaps through tumor necrosis factor-alpha (TNF-alpha). These authors, however, neglected to mention bone abnormalities and high testosterone levels that were previously shown in FSH-receptor knockout and other modified mice. It is also possible that they have overemphasized potential relationships of these new data with human bone loss. Despite these fascinating data, the paradigm of FSH causing hypogonadal bone loss is not yet ready to displace the estrogen-deficiency-osteoporosis paradigm, although that model already faces considerable challenge.     

How to help students understand physiology? Emphasize general models

Students generally approach topics in physiology as a series of unrelated phenomena that share few underlying principles. In many students' view, the Fick equation for cardiac output is fundamentally different from a renal clearance equation. If, however, students recognize that these apparently different situations can be viewed as examples of the same general conceptual model (e.g., conservation of mass), they may gain a more unified understanding of physiological systems. An understanding of as few as seven general models can provide students with an initial conceptual framework for analyzing most physiological systems. The general models deal with control systems, conservation of mass, mass and heat flow, elastic properties of tissues, transport across membranes, cell-to-cell communication, and molecular interaction.     

Lessons from the past—human and animal thermal physiology

(1) Primordial lesioning and stimulation experiments established a thermoregulatory centre in the rostral brain stem at the end of the 19th century. (2) A major landmark in understanding how deep-body temperature (T_c) is sensed, came in 1912 when Barbour found that changing rostral brain stem temperature inversely raised or lowered T_c, ultimately leading to a mono-centric concept of hypothalamic thermoregulation, prevailing for about 50 years. (3) The discovery of extrahypothalamic sites of temperature signal generation in the 1960s led to the multiple-input, multiple-controller concept of thermoregulation. (4) During the last 40 years, concepts concerning thermosensory specificity have radically changed from viewing bimodal peripheral thermoreceptors and hypothalamic thermoreceptors as the only relevant signal generators towards a complex picture including monomodality of peripheral warm and cold thermoreceptors and multimodality of deep-body thermosensors.     

Do microRNAs regulate bone marrow stem cell niche physiology?

The adult bone marrow, situated within the bone cavity, comprises three distinct stem cell populations: hematopoietic stem cells (HSCs), mesenchymal stromal/stem cells (MSCs) and endothelial progenitor/stem cells (EPCs). HSCs are a well-characterized population of self-renewing cells that give rise to all blood cells. The definition of MSCs is more complex due to the limited understanding of MSC properties. In general, MSCs are considered multipotent stromal cells that are able to differentiate into various cell types, including osteoblasts, chondrocytes and adipocytes. Compared to HSCs and MSCs, EPCs are a newly discovered population of stem/progenitor cells with the capacity to differentiate into endothelial cells, the cells forming the inner lining of a blood vessel.     

RANKL/RANK – From bone physiology to breast cancer

RANK and its ligand RANKL are key molecules in bone metabolism and are critically involved in pathologic bone disorders. Deregulation of the RANK/RANKL system is for example a main reason for the development of postmenopausal osteoporosis, which affects millions of women worldwide. Another essential function of RANK and RANKL is the development of a functional lactating mammary gland during pregnancy. Sex hormones, in particular progesterone, induce RANKL expression resulting in proliferation of mammary epithelial cells. Moreover, RANK and RANKL have been shown to regulate mammary epithelial stem cells. RANK and RANKL were also identified as critical mechanism in the development of hormone-induced breast cancer and metastatic spread to bone. In this review, we will focus on the various RANK/RANKL functions ranging from bone physiology, immune regulation, and initiation of breast cancer.     

Is physiology the locus of health/health promotion?

A current trend in physiology education involves the use of clinical vignettes to demonstrate the importance of knowing normal physiology to appreciate pathophysiology. Although laudable, in effect, such tactics promote the so-called "disease" model of medicine while at the same time suggesting that the only utility for the knowledge of physiology is to understand pathophysiology. This would seem to be at odds with health professions and institutions, who maintain their goal is to promote health. Yet, a search for the locus of "health" education in typical curricula is not easily found. Given the developing interest in biological systems as well as aging, it is suggested that these topics may provide a basis for locating physiology as the locus for understanding "health."     

Does the fetal genotype affect maternal physiology during pregnancy?

Conventional wisdom states that associations between fetal growth and diseases in pregnancy, such as pregnancy-induced hypertension (PIH) and gestational diabetes (GDM), result from effects of the mother's genotype or environment acting on her physiology which subsequently affect the fetus. However, recent evidence from human mothers carrying macrosomic offspring with Beckwith Wiedemann syndrome and pregnant mice carrying p57(kip2)-null offspring suggest that variation in the fetal genome can modify maternal physiology to increase fetal nutrient delivery and optimise growth. These are some of the first documented examples of such effects, whereby the genome of one individual directly affects the physiology of another related individual from the same species. We propose that this mechanism is involved in the aetiology of PIH and GDM.     

Transforming growth factor-β receptors: Role in physiology and disease

Transforming growth factor- (TGF-) plays a pivotal role in numerous vital cellular activities, most significantly the regulation of cellular proliferation and differentiation and synthesis of extracellular matrix components. Its ubiquitous presence in different tissues and strict conservation of nucleotide sequence down through the most primitive vertebrate organisms underscore the essential nature of this family of molecules. The effects of TGF- are mediated by a family of dedicated receptors, the TGF- types I, II, and III receptors. It is now known that a wide variety of human pathology can be caused by aberrant expression and function of these receptors or their cognate ligands. The coding sequence of the human type II receptor appears to render it uniquely susceptible to DNA replication errors in the course of normal cell division. There are now substantial data suggesting that TGF- type II receptor should be considered a tumor suppressor gene. High levels of mutation in the TGF- type II receptor gene have been observed in a wide variety of primarily epithelial malignancies, including colon, gastric, and hepatic cancer. It appears likely that mutation of the TGF- type II receptor gene represents a very critical step in the pathway of carcinogenesis.     

Cholesterol sulfate in human physiology: what's it all about?

Cholesterol sulfate is quantitatively the most important known sterol sulfate in human plasma, where it is present in a concentration that overlaps that of the other abundant circulating steroid sulfate, dehydroepiandrosterone (DHEA) sulfate. Although these sulfolipids have similar production and metabolic clearance rates, they arise from distinct sources and are metabolized by different pathways. While the function of DHEA sulfate remains an enigma, cholesterol sulfate has emerged as an important regulatory molecule. Cholesterol sulfate is a component of cell membranes where it has a stabilizing role, e.g., protecting erythrocytes from osmotic lysis and regulating sperm capacitation. It is present in platelet membranes where it supports platelet adhesion. Cholesterol sulfate can regulate the activity of serine proteases, e.g., those involved in blood clotting, fibrinolysis, and epidermal cell adhesion. As a result of its ability to regulate the activity of selective protein kinase C isoforms and modulate the specificity of phosphatidylinositol 3-kinase, cholesterol sulfate is involved in signal transduction. Cholesterol sulfate functions in keratinocyte differentiation, inducing genes that encode for key components involved in development of the barrier.The accumulating evidence demonstrating a regulatory function for cholesterol sulfate appears solid; the challenge now is to work out the molecular mechanisms whereby this interesting molecule carries out its various roles.     

Microbiology and physiology of Cachaça (Aguardente) fermentations

Cachaça (aguardente) is a rum-style spirit made from sugar cane juice by artisanal methods in Brazil. A study was made of the production, biochemistry and microbiology of the process in fifteen distilleries in Sul de Minas. Identification of 443 yeasts showed Saccharomyces cerevisiae to be the predominant yeast but Rhodotorula glutinis and Candida maltosa were predominant in three cases. Bacterial infection is a potential problem, particularly in older wooden vats, when the ratio of yeasts:bacteria can be 10:1 or less. A study of daily batch fermentations in one distillery over one season in which 739 yeasts were identified revealed that S. cerevisiae was the predominant yeast. Six other yeast species showed a daily succession: Kluyveromyces marxianus, Pichia heimii and Hanseniaspora uvarum were present only at the beginning, Pichia subpelliculosa and Debaryomyces hansenii were detected from mid to the end of fermentation, and Pichia methanolica appeared briefly after the cessation of fermentation. Despite a steady influx of yeasts from nature, the species population in the fermenter was stable for at least four months suggesting strong physiological and ecological pressure for its maintenance. Cell densities during the fermentation were: yeasts – 4 × 10⁸/ml; lactic acid bacteria – 4 × 10⁵/ml; and bacilli – 5 × 10⁴/ml. Some acetic acid bacteria and enterobacteriaceae appeared at the end. Sucrose was immediately hydrolysed to fructose and glucose. The main fermentation was complete after 12 hours but not all fructose was utilised when harvesting after 24 hours.     

Roles of insulin-like growth factor Ⅱ in regulating female reproductive physiology

The number of growth factors involved in female fertility has been extensively studied, but reluctance to add essential growth factors in culture media has limited progress in optimizing embryonic growth and implantation outcomes, a situation that has ultimately led to reduced pregnancy outcomes. Insulin-like growth factor Ⅱ(IGF-Ⅱ) is the most intricately regulated of all known reproduction-related growth factors characterized to date, and is perhaps the predominant growth factor in human ovarian follicles. This review aims to concisely summarize what is known about the role of IGF-Ⅱ in follicular development, oocyte maturation, embryonic development, implantation success, placentation, fetal growth, and in reducing placental cell apoptosis, as well as present strategies that use growth factors in culture systems to improve the developmental potential of oocytes and embryos in different species. Synthesizing the present knowledge about the physiological roles of IGF-Ⅱ in follicular development, oocyte maturation, and early embryonic development should, on the one hand, deepen our overall understanding of the potential beneficial effects of growth factors in female reproduction and on the other hand support development(optimization) of improved outcomes for assisted reproductive technologies.     

The roles of O-linked β-N-acetylglucosamine in cardiovascular physiology and disease

More than 1,000 proteins of the nucleus, cytoplasm, and mitochondria are dynamically modified by O-linked β-N-acetylglucosamine (O-GlcNAc), an essential post-translational modification of metazoans. O-GlcNAc, which modifies Ser/Thr residues, is thought to regulate protein function in a manner analogous to protein phosphorylation and, on a subset of proteins, appears to have a reciprocal relationship with phosphorylation. Like phosphorylation, O-GlcNAc levels change dynamically in response to numerous signals including hyperglycemia and cellular injury. Recent data suggests that O-GlcNAc appears to be a key regulator of the cellular stress response, the augmentation of which is protective in models of acute vascular injury, trauma hemorrhage, and ischemia-reperfusion injury. In contrast to these studies, O-GlcNAc has also been implicated in the development of hypertension and type II diabetes, leading to vascular and cardiac dysfunction. Here we summarize the current understanding of the roles of O-GlcNAc in the heart and vasculature.     

Isoprostanes: an emerging role in vascular physiology and disease?

Among the isoprostanes, the 15-series F2-isoprostanes and 15-E2t-IsoP mediate vasoconstriction in different vascular beds and species. In addition, 15-F2t-IsoP induces smooth muscle cells mitogenesis and monocyte adhesion to endothelial cells. In clinical studies, 15-F2t-IsoP levels are increased in some vascular disorders involving atherosclerosis, ischemia-reperfusion and inflammation. Whether the same effects observed in vitro are observed consistently in vivo at physiological concentrations and whether these effects contribute to pathological states in vivo is still debated.     

Structure,ecology and physiology of root clusters – a review

Hairy rootlets, aggregated in longitudinal rows to form distinct clusters, are a major part of the root system in some species. These root clusters are almost universal (1600 species) in the family Proteaceae (proteoid roots), with fewer species in another seven families. There may be 10–1000 rootlets per cm length of parent root in 2–7 rows. Proteoid roots may increase the surface area by over 140× and soil volume explored by 300× that per length of an equivalent non-proteoid root. This greatly enhances exudation of carboxylates, phenolics and water, solubilisation of mineral and organic nutrients and uptake of inorganic nutrients, amino acids and water per unit root mass. Root cluster production peaks at soil nutrient levels (P, N, Fe) suboptimal for growth of the rest of the root system, and may cease when shoot mass peaks. As with other root types, root cluster production is controlled by the interplay between external and internal nutrient levels, and mediated by auxin and other hormones to which the process is particularly sensitive. Proteoid roots are concentrated in the humus-rich surface soil horizons, by 800× in Banksia scrub-heath. Compared with an equal mass of the B horizon, the A₁ horizon has much higher levels of N, P, K and Ca in soils where species with proteoid root clusters are prominent, and the concentration of root clusters in that region ensures that uptake is optimal where supply is maximal. Both proteoid and non-proteoid root growth are promoted wherever the humus-rich layer is located in the soil profile, with 4× more proteoid roots per root length in Hakea laurina. Proteoid root production near the soil surface is favoured among hakeas, even in uniform soil, but to a lesser extent, while addition of dilute N or P solutions in split-root system studies promotes non-proteoid, but inhibits proteoid, root production. Local or seasonal applications of water to hakeas initiate non-proteoid, then proteoid, root production, while waterlogging inhibits non-proteoid, but promotes proteoid, root production near the soil surface. A chemical stimulus, probably of bacterial origin, may be associated with root cluster initiation, but most experiments have alternative interpretations. It is possible that the bacterial component of soil pockets rich in organic matter, rather than their nutrient component, could be responsible for the proliferation of proteoid roots there, but much more research on root cluster microbiology is needed.