Regulation of iron homeostasis by microRNAs

Iron homeostasis is maintained at the cellular and systemic levels to assure adequate iron supply while preventing iron overload. The identification of genes mutated in patients with iron-related disorders or animal models with imbalances of iron homeostasis gave insight into the molecular mechanisms underlying processes critical for balancing iron levels, such as iron uptake, storage, export, and monitoring of available iron. MicroRNAs control genes involved in some of these processes adding an additional level of complexity to the regulation of iron metabolism. This review summarizes recent advances how miRNAs regulate iron homeostasis.     

Regulation of receptor function by cholesterol

Cholesterol influences many of the biophysical properties of membranes and is nonrandomly distributed between cellular organelles, subdomains of membranes, and leaflets of the membrane bilayer. In combination with the high dynamics of cholesterol distribution, this offers many possibilities for regulation of membrane-embedded receptors. Depending on the receptor, cholesterol can have a strong influence on the affinity state, on the binding capacity, and on signal transduction. Most important, cholesterol may stabilize receptors in defined conformations related to their biological functions. This may occur by direct molecular interaction between cholesterol and receptors. In this review, we discuss the functional dependence of the nicotinic acetylcholine receptor as well as different G protein-coupled receptors on the presence of cholesterol.     

Regulation of sodium and body fluid homeostasis during development: Implications for the pathogenesis of hypertension

The spontaneously hypertensive rat (SHR) is an important animal model of human essential hypertension. During the first month of life, increased retention of sodium is present in the SHR which appears to be mediated by the renin-angiotensin system. The present review will discuss the role that increased activity of the renin-angiotensin system plays in sodium/body fluid regulation during early development. It is hypothesized that disordered regulation of sodium/body fluid homeostasis during this stage leads to pathological cardiovascular regulation in adulthood. Through an understanding of the relationship between sodium/body fluid balance in the young and cardiovascular function in the adult insights may be gained into both the pathological state of hypertension and the critical role played by early development in shaping homeostatic mechanisms in adulthood.     

Regulation of sodium and body fluid homeostasis during development: implications for the pathogenesis of hypertension.

The spontaneously hypertensive rat (SHR) is an important animal model of human essential hypertension. During the first month of life, increased retention of sodium is present in the SHR which appears to be mediated by the renin-angiotensin system. The present review will discuss the role that increased activity of the renin-angiotensin system plays in sodium/body fluid regulation during early development. It is hypothesized that disordered regulation of sodium/body fluid homeostasis during this stage leads to pathological cardiovascular regulation in adulthood. Through an understanding of the relationship between sodium/body fluid balance in the young and cardiovascular function in the adult insights may be gained into both the pathological state of hypertension and the critical role played by early development in shaping homeostatic mechanisms in adulthood.     

Control of energy homeostasis by amylin

Amylin is an important control of nutrient fluxes because it reduces energy intake, modulates nutrient utilization by inhibiting postprandial glucagon secretion, and increases energy disposal by preventing compensatory decreases of energy expenditure in weight-reduced individuals. The best investigated function of amylin which is cosecreted with insulin is to reduce eating by promoting meal-ending satiation. This effect is thought to be mediated by a stimulation of specific amylin receptors in the area postrema. Secondary brain sites to mediate amylin action include the nucleus of the solitary tract and the lateral parabrachial nucleus, which convey the neural signal to the lateral hypothalamic area and other hypothalamic nuclei. Amylin may also signal adiposity because plasma levels of amylin are increased in adiposity and because higher amylin concentrations in the brain result in reduced body weight gain and adiposity, while amylin receptor antagonists increase body adiposity. The central mechanisms involved in amylin's effect on energy expenditure are much less known. A series of recent experiments in animals and humans indicate that amylin is a promising option for anti-obesity therapy especially in combination with other hormones. The most extensive dataset is available for the combination therapy of amylin and leptin. Ongoing research focuses on the mechanisms of these interactions.     

Cellular maintenance of nuclear protein homeostasis

The accumulation and aggregation of misfolded proteins is the primary hallmark for more than 45 human degenerative diseases. These devastating disorders include Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. Over 15 degenerative diseases are associated with the aggregation of misfolded proteins specifically in the nucleus of cells. However, how the cell safeguards the nucleus from misfolded proteins is not entirely clear. In this review, we discuss what is currently known about the cellular mechanisms that maintain protein homeostasis in the nucleus and protect the nucleus from misfolded protein accumulation and aggregation. In particular, we focus on the chaperones found to localize to the nucleus during stress, the ubiquitin–proteasome components enriched in the nucleus, the signaling systems that might be present in the nucleus to coordinate folding and degradation, and the sites of misfolded protein deposition associated with the nucleus.     

Enzymology of NAD+ homeostasis in man

This review describes the enzymes involved in human pyridine nucleotide metabolism starting with a detailed consideration of their major kinetic, molecular and structural properties. The presentation encompasses all the reactions starting from the de novo pyridine ring formation and leading to nicotinamide adenine dinucleotide (NAD⁺) synthesis and utilization. The regulation of NAD⁺ homeostasis with respect to the physiological role played by the enzymes both utilizing NAD⁺ through the nonredox NAD⁺-dependent reactions and catalyzing the recycling of the common product, nicotinamide, is discussed. The salient features of other enzymes such as NAD⁺ pyrophosphatase, nicotinamide mononucleotide 5-nucleotidase, nicotinamide riboside kinase and nicotinamide riboside phosphorylase, described under miscellaneous, are likewise presented.Received 30 April 2003; received after revision 9 June 2003; accepted 20 June 2003     

Mechanisms of circulatory homeostasis and response inAplysia

This review concerns the organization and function of arterial vasculature inAplysia californica, especially the vasomotor reflexes that support circulatory homeostasis, and fixed patterns of response that may reroute blood flow during changes in behavioral state. The observations presented here raise three hypotheses for further study: 1)Arterial vasculature is functionally organized with precisely structured, independently regulated subdivisions; these are most evident for arterial systems serving digestive and reproductive processes; 2) arterial musculature is inherently responsive to local pressure changes, having both static and dynamic reflexes that promote efficient, evenly-distributed flow of blood; and 3) complex, long-lasting behaviors like egg laying have, as part of their makeup, equally prolonged and stereotypical changes in the pattern of circulation. Taken together, these observations support the view that maintenance and adjustment of blood flow in gastropod molluscs is an unexpectedly complex and highly integrated component of behavior.     

Establishment of intestinal homeostasis during the neonatal period

The intestinal mucosa faces the challenge of regulating the balance between immune tolerance towards commensal bacteria, environmental stimuli and food antigens on the one hand, and induction of efficient immune responses against invading pathogens on the other hand. This regulatory task is of critical importance to prevent inappropriate immune activation that may otherwise lead to chronic inflammation, tissue disruption and organ dysfunction. The most striking example for the efficacy of the adaptive nature of the intestinal mucosa is birth. Whereas the body surfaces are protected from environmental and microbial exposure during fetal life, bacterial colonization and contact with potent immunostimulatory substances start immediately after birth. In the present review, we summarize the current knowledge on the mechanisms underlying the transition of the intestinal mucosa during the neonatal period leading to the establishment of a stable, life-long host–microbial homeostasis. The environmental exposure and microbial colonization during the neonatal period, and also the influence of maternal milk on the immune protection of the mucosa and the role of antimicrobial peptides, are described. We further highlight the molecular mechanisms of innate immune tolerance in neonatal intestinal epithelium. Finally, we link the described immunoregulatory mechanisms to the increased susceptibility to inflammatory and infectious diseases during the neonatal period.     

Cellular communications in bone homeostasis and repair

Cellular communication between the bone component cells osteoblasts, osteocytes and (pre-)osteoclasts is essential for bone remodeling which maintains bone integrity. As in the remodeling of other organs, cell death is a trigger for remodeling of bone. During the systematic process of bone remodeling, direct or indirect cell–cell communication is indispensable. Thus, osteoblasts induce migration and differentiation of preosteoclasts, which is followed by bone resorption (by mature multinuclear osteoclasts). After completion of bone resorption, apoptosis of mature osteoclasts and differentiation of osteoblasts are initiated. At this time, the osteoblasts do not support osteoclast differentiation but do support bone formation. Finally, osteoblasts differentiate to osteocytes in bone or to bone lining cells on bone surfaces. In this way, old bone areas are regenerated as new bone. In this review the role of cell–cell communication in bone remodeling is discussed.     

Neuronal ciliary signaling in homeostasis and disease

Primary cilia are a class of cilia that are typically solitary, immotile appendages present on nearly every mammalian cell type. Primary cilia are believed to perform specialized sensory and signaling functions that are important for normal development and cellular homeostasis. Indeed, primary cilia dysfunction is now linked to numerous human diseases and genetic disorders. Collectively, primary cilia disorders are termed as ciliopathies and present with a wide range of clinical features, including cystic kidney disease, retinal degeneration, obesity, polydactyly, anosmia, intellectual disability, and brain malformations. Although significant progress has been made in elucidating the functions of primary cilia on some cell types, the precise functions of most primary cilia remain unknown. This is particularly true for primary cilia on neurons throughout the mammalian brain. This review will introduce primary cilia and ciliary signaling pathways with a focus on neuronal cilia and their putative functions and roles in human diseases.     

Acid-base homeostasis and the thyro-parathyroid glands]

Chronic metabolic acidosis entails hyperparathyroidism and osteopathy. In order to elucidate the role of the thyroparathyroids in this bone lesion production the effects of acidic diet for 7 weeks were studied in parathyroidectomized (PTX), thyroparathyroidectomized (TPTX) and shamoperated (Sh-O) growing rats. In all animals urinary excretion of calcium, phosphate, ammonium and titrable acidity was similarly increased. The rise in hydroxyproline excretion and urinary 85-sr (that was injected previous to acidic feeding) was more marked in PTX and TPTX rats. Moreover, in these animals the serum calcium level was increased, the blood pH was decreased. According to these data, an acidic diet intake that is not sufficient to elicit a fall in blood pH of normal young rats can induce severe acidosis in chronically parathyroidectomized or thyroparathyroidectomized animals; moreover the bone resorption appears more marked. It is concluded that parathyroids are involved in the extra-cellular fluid defense mechanism against acidosis by a no bone resorptive mechanism. We hypothesize that the parathyroids permit the necessary and adequate supply of bicarbonates by the bone to maintain blood pH homeostasis.     

Distribution of tritium inWilzbach treated cholesterol

Zusammenfassung Es wird gezeigt, dass Cholesterin-H³, nach Behandlung von besonders gereinigtem Handelscholesterin mit Tritium entsprechend der Vorschrift vonWilzbach, bei sechsmal wiederholter Bromierung nachFieser frei von Cholestanol-H³ erhalten wird. In so gereinigtem Cholesterin-H³ ist der schwere Wasserstoff gleichmässig über alle wasserstofftragenden Kohlenstoffatome verteilt.

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This work was supported by an Institutional Grant No. P-108A of the American Cancer Society and by a Grant No. G-7477 of the National Science Foundation. The authors are grateful to Dr.M. Gut of this Institute for theWilzbach treatment of cholesterol.     

Mechanisms of circulatory homeostasis and response in Aplysia.

This review concerns the organization and function of arterial vasculature in Aplysia californica, especially the vasomotor reflexes that support circulatory homeostasis, and fixed patterns of response that may reroute blood flow during changes in behavioral state. The observations presented here raise three hypotheses for further study: 1) Arterial vasculature is functionally organized with precisely structured, independently regulated subdivisions; these are most evident for arterial systems serving digestive and reproductive processes; 2) arterial musculature is inherently responsive to local pressure changes, having both static and dynamic reflexes that promote efficient, evenly-distributed flow of blood; and 3) complex, long-lasting behaviors like egg laying have, as part of their makeup, equally prolonged and stereotypical changes in the pattern of circulation. Taken together, these observations support the view that maintenance and adjustment of blood flow in gastropod molluscs is an unexpectedly complex and highly integrated component of behavior.