Regulation of bile acid metabolism-related signaling pathways by gut microbiota in diseases / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Over the past decade, there has been increasing attention on the interaction between microbiota and bile acid metabolism. Bile acids are not only involved in the metabolism of nutrients, but are also important in signal transduction for the regulation of host physiological activities. Microbial-regulated bile acid metabolism has been proven to affect many diseases, but there have not been many studies of disease regulation by microbial receptor signaling pathways. This review considers findings of recent research on the core roles of farnesoid X receptor (FXR), G protein-coupled bile acid receptor (TGR5), and vitamin D receptor (VDR) signaling pathways in microbial-host interactions in health and disease. Studying the relationship between these pathways can help us understand the pathogenesis of human diseases, and lead to new solutions for their treatments.

Receptores nucleares y regulacion de la expresion génica por acidos grasos poliinsaturados: algo mas que produccion de energía y esencialidad / Nuclear receptors and regulation of gene expression by polyunsaturated fatty acids: something more than energy production and essentiality

Regulation of gene expression is controlled by many molecules which acting in concert may activate o repress a gene or a group of genes. The regulation requires of different nuclear receptors which as homodimers or heterodimers interact with DNA trough the so called DNA interaction domains. The DNA-receptor binding is determined by the presence of specific ligands. The final action of this complex is the activation or repression of gene expression. A number of molecules may act as ligands of nuclear receptors, being fatty acids and their derivatives one of the most important ligands of nutritional origin. Polyunsaturated fatty acids, acting as ligands of nuclear receptors may modulate a wide variety of molecular responses, such as adipocite differentiation, modifying insulin resistance, regulating vascular pressure, inducing apoptosis of tumor cells, modifying carbohydrate metabolism, etc. This new function of fatty acids as important modulators of gene expression goes beyond to the production of energy and essentiality. This work reviews the structure and function of nuclear receptors and the regulatory role of fatty acids in gene expression.

La regulación de la expresión de los genes está determinada por una serie de moléculas que en su conjunto modulan la activación o la represión de un gen o de un grupo de genes. Esta regulación requiere de diferentes receptores nucleares, que en la forma de homodímeros o heterodímeros interactúan con el DNA en lugares específicos denominados dominios de interacción del DNA. La unión del receptor al DNA es determinada por la presencia de ligandos específicos. El resultado final de este complejo proceso produce la activación o la represión de la expresión de un gen. Numerosas moléculas actúan como ligandos de receptores nucleares, siendo los ácidos grasos y sus derivados uno de los ligandos de origen nutricional más importantes. Los ácidos grasos poliinsaturados, al actuar como ligandos de receptores nucleares desencadenan una gran variedad de respuestas celulares; inducen la diferenciación de adipocitos, modifican la resistencia a la insulina, regulan la presión vascular, inducen la apoptósis de células tumorales, modifican el metabolismo de los carbohidratos, etc. Esta nueva función de los ácidos grasos los identifica como importantes reguladores de los genes, con lo cual actualmente se les relaciona con algo más que la producción de energía y la esencialidad. Este trabajo revisa la estructura y función de los receptores nucleares y el rol regulador de los ácidos grasos en la expresión de los genes.

Calcium-transporters in myocardial cells.

This is a concise review of important calcium-transporters on the sarcolemma and organellar membranes of myocardial cells, and their functional roles in cell physiology. It briefly addresses L and T type calcium channels, store-operated calcium channel (SOC), sodium-calcium exchanger (NCX), and the plasma membrane calcium ATPase (PMCA) on the sarcolemma, ryanodine receptor (RyR), IP3 receptor (IP3R) and the sarcoplasmic reticulum (SR) calcium ATPase (SAERCA) on the SR membrane and their contributions to contraction and rhythm-generation. Several agonists and blockers for every transporter that are commonly used in research, and those with therapeutic applications have also been discussed.

Estudo dos genes DAX1 e SF1 em pacientes portadores de distúrbios da determinação gonadal / DA and SF1 genes analysis in patientes with abnormal gonadal determinations

Com o objetivo de estudar a participação dos genes SF1 e DAX1 na etiologia dos distúrbios da determinação gonadal, analisamos uma casuística de 35 pacientes com sexo reverso 46,XY e 12 pacientes com sexo reverso 46,XX.. Estes pacientes foram estudados do ponto de vista clínico, hormonal, radiológico, anatomopatológico e molecular. Identificamos o primeiro paciente com uma mutação no gene SF1 associada a sexo reverso 46,XY sem insuficiência adrenal, e descrevemos o seu comportamento funcional in vitro. Identificamos também 9 variantes alélicas neste gene altamente conservado. /The aim of this study is to elucidate the participation of SF1 and DAX1 genes in the etiology of abnormal gonadal determination by analyzing 35 patients with 46,XY sex reversal and twelve 46,XX sex-reversed patients. All patients underwent clinical hormonal, radiological, anatomopathological and molecular evaluation. We identified the first case with a SF1 mutation associated to 46, XY sex reversal without adrenal insufficiency and characterized its transcriptional activity in vitro. We also identified 9 allelic variants in this highly conservative gene...

Inositol 1, 4, 5-trisphosphate receptors in the heart

Inositol 1,4,5-trisphosphate (InsP3) is an established calcium-mobilizing messenger, which is well-known to activate Ca2+ signaling in many cell types. Contractile cardiomyocytes express hormone receptors that are coupled to the production of InsP3. Such cardioactive hormones, including endothelin, may have profound inotropic and arrhythmogenic actions, but it is unclear whether InsP3 underlies any of these effects. We have examined the expression and localization of InsP3 receptors (InsP3Rs), and the potential role of InsP3 in modulating cardiac excitation-contraction coupling (EC coupling). Stimulation of electrically-paced atrial and ventricular myocytes with a membrane-permeant InsP3 ester was found to evoke an increase in the amplitudes of action potential-evoked Ca2+ transients and to cause pro-arrhythmic diastolic Ca2+ transients. All the effects of the InsP3 ester could be blocked using a membrane-permeant antagonist of InsP3Rs (2-aminoethoxydiphenyl borate; 2-APB). Furthermore, 2-APB blocked arrhythmias evoked by endothelin and delayed the onset of positive inotropic responses. Our data indicate that atrial and ventricular cardiomyocytes express functional InsP3Rs, and these channels have the potential to influence EC coupling.

Melatonin, biological rhythm disorders and phototherapy.

Biological rhythms are endogenous in nature and are generated by self sustained oscillators present in the living organisms themselves. Of these, circadian rhythms are the most thoroughly studied and are driven by the suprachiasmatic (SCN) of hypothalamus. The recent discovery of high affinity melatonin receptors ML1, ML2 in SCN suggests that melatonin is involved in the control of circadian rhythm generation. The fact that biological rhythm disorders like delayed sleep phase syndrome (DSPS), Jet lag, shift-work disorders, seasonal effective disorder (SAD) respond well either to phototherapy or melatonin adds further support to the concept that melatonin is involved in the pathogenesis of these conditions. Indeed altered melatonin rhythms have bee documented in MDP, shift work disorder, endogenous depression etc. In addition to functioning as a rhythm regulator, melatonin is also involved in the control of sleep, regulation of body temperature, reproduction, and as a free radical scavanger and antioxidant protecting the cells and tissues of our body against oxidative damage. Low levels of melatonin in cancer patients and patients with coronary heart disease indicate that melatonin may be involved in these disorders also.

Melatonin: a master hormone and a candidate for universal panacea.

The molecule of melatonin seems to have been evolutionarily conserved. Its presence has been demonstrated in almost all groups of organisms, from plants, protozoa to people. During evolution, melatonin is claimed to have mediated dark adaptation. The universal presence of melatonin may be because it is lipophilic in nature which enables it to cross all biological (lipid membrane) barriers and to diffuse into every compartment of the cell, and because it serves as an antioxidant and is used as a free radical scavenger. In vertebrates, the pineal gland is the single largest source of melatonin production although, especially in non-mammalian vertebrates, other organs (e.g. retina, harderian gland etc.) may contribute significantly to the blood melatonin levels. In invertebrates, on the other hand, the pineal gland is absent and, therefore, melatonin secretion is clearly derived from another source(s). Regardless of the site of synthesis and the nature of organisms (diurnal, nocturnal or crepuscular), melatonin is secreted in the night and melatonin biosynthetic pathway remains essentially the same. Tryptophan, an amino acid derived from dietary sources, undergoes a series of enzymatic reactions to produce melatonin. The rhythm in melatonin secretion is generated endogenously by the circadian pacemaker(s) in the suprachiasmatic nuclei (SCN), and regulated by environmental light:dark cycle. Melatonin through its action on the SCN synchronizes disrupted or free-running circadian rhythms, and regulates a variety of daily and seasonal changes in the physiology and behaviour of animals. Emerging scientific evidence for the role of melatonin as therapeutic agent in the treatment of circadian rhythm-associated sleep disorders in persons having normal social working hours and shift workers, in jet lag, in immunological functions etc. have considerably increased interest in this hormone molecule. The role of melatonin in organisms physiology has now been widely recognized, and the wealth of information accumulated in the past two decades indicate it to be the best hormone candidate to be investigated for a universal panacea.