The reproductive status determines tolerance and resistance to Mycobacterium marinum in Drosophila melanogaster.

Sex and reproductive status of the host have a major impact on the immune response against infection. Our aim was to understand their impact on host tolerance or resistance in the systemic Mycobacterium marinum infection of Drosophila melanogaster. We measured host survival and bacillary load at time of death, as well as expression by quantitative real-time polymerase chain reaction of immune genes (diptericin and drosomycin). We also assessed the impact of metabolic and hormonal regulation in the protection against infection by measuring expression of upd3, impl2 and ecR. Our data showed increased resistance in actively mating flies and in mated females, while reducing their tolerance to infection. Data suggests that Toll and immune deficiency (Imd) pathways determine tolerance and resistance, respectively, while higher basal levels of ecR favours the stimulation of the Imd pathway. A dual role has been found for upd3 expression, linked to increased/decreased mycobacterial load at the beginning and later in infection, respectively. Finally, impl2 expression has been related to increased resistance in non-actively mating males. These results allow further assessment on the differences between sexes and highlights the role of the reproductive status in D. melanogaster to face infections, demonstrating their importance to determine resistance and tolerance against M. marinum infection.

Endocrine disruptors in plastics alter ß-cell physiology and increase the risk of diabetes mellitus.

Plastic pollution breaks a planetary boundary threatening wildlife and humans through its physical and chemical effects. Of the latter, the release of endocrine disrupting chemicals (EDCs) has consequences on the prevalence of human diseases related to the endocrine system. Bisphenols (BPs) and phthalates are two groups of EDCs commonly found in plastics that migrate into the environment and make low-dose human exposure ubiquitous. Here we review epidemiological, animal, and cellular studies linking exposure to BPs and phthalates to altered glucose regulation, with emphasis on the role of pancreatic ß-cells. Epidemiological studies indicate that exposure to BPs and phthalates is associated with diabetes mellitus. Studies in animal models indicate that treatment with doses within the range of human exposure decreases insulin sensitivity and glucose tolerance, induces dyslipidemia, and modifies functional ß-cell mass and serum levels of insulin, leptin, and adiponectin. These studies reveal that disruption of ß-cell physiology by EDCs plays a key role in impairing glucose homeostasis by altering the mechanisms used by ß-cells to adapt to metabolic stress such as chronic nutrient excess. Studies at the cellular level demonstrate that BPs and phthalates modify the same biochemical pathways involved in adaptation to chronic excess fuel. These include changes in insulin biosynthesis and secretion, electrical activity, expression of key genes, and mitochondrial function. The data summarized here indicate that BPs and phthalates are important risk factors for diabetes mellitus and support a global effort to decrease plastic pollution and human exposure to EDCs.

Ozone use in the treatment of subclinical mastitis in dairy cows.

This research communication paper addresses the hypothesis that the use of therapeutic alternatives for mastitis, such as intramammary ozone, can cure the disease with lower costs and without harmful residues for human consumption and without formation of microbial resistance like the ones caused by indiscriminate use of antibiotics in dairy farms. The study was performed in 36 mammary quarters from 12 dairy cows with subclinical mastitis grade three. The experimental units were randomly assigned into four groups and each group received a treatment. Treatments comprised (a) 20 µg/ml ozone gas; (b) 40 µg/ml ozone gas; (c) negative control treatment of 12.5 µg/ml ozonated saline and (d) positive control treatment of 100 mg of cephalexin + 100 mg of neomycin + 10 mg of prednisolone, all by intramammary injection. In all quarters, milk was collected before and after the application of treatments for California mastitis test and evaluation of milk composition, somatic cell count, and bacterial cultures. The results indicated that the use of intramammary ozone did have a therapeutic effect, and whilst this was less than that of antibiotics, ozone does confer some advantages. Treated milk had a good composition, the treatment cost was low, milk withdrawal may not be necessary and there is no risk of antibiotic resistance.

Identification of Unknown Substances in Ambient Air (PM10), Profiles and Differences between Rural, Urban and Industrial Areas.

A fast and automated strategy has been developed for identifying unknown substances in the atmosphere (concretely, in the particulate matter, PM10) using LC-HRMS (MS3). A total of 15 samples were collected in three different areas (rural, urban and industrial). A sampling flow rate of 30 m3 h-1 was applied for 24 h, sampling a total volume of around 720 m3. A total of 49 compounds were tentatively identified using very restrictive criteria regarding exact mass, retention time, isotopic profile and both MS2 and MS3 spectra. Pesticides, pharmaceutical active compounds, drugs, plasticizers and metabolites were the most identified compounds. To verify whether the developed methodology was suitable, 11 substances were checked with their analytical standards and all of them were confirmed. Different profiles for industrial, rural and urban areas were examined. The Principal Component Analysis (PCA) model allowed us to separate the obtained data of the three assessed area. When the profiles obtained in the three evaluated areas were compared using a Volcano plot (the rural area was taken as reference), 11 compounds were confirmed as being discriminant: three of them (3-hydroxy-2-methylpyridine, 3-methyladenine and nicotine) were more likely to be found in industrial sites; ten compounds (3-hydroxy-2-methylpyridine, 3-methyladenine, azoxystrobin, cocaine, cotinine, ethoprophos, imidacloprid, metalaxyl-M, nicotine and pyrimethanil) were more probable in the case of urban sites; finally, triisopropanolamine was more likely to be detected in rural locations.

Indoor Air Quality including Respiratory Viruses.

The detection of SARS-CoV-2 in indoor environments is a cause of increasing concern. In this study, three sampling methodologies have been used in order to collect SARS-CoV-2 and 17 other respiratory viruses in indoor air, combined with a new analytical process to analyze respiratory viruses. Different areas of an ophthalmological hospital were investigated for the presence of these airborne viruses. Moreover, indoor air quality (IAQ) parameters (carbon dioxide, CO2; carbon monoxide, CO; nitrogen dioxide, NO2; volatile organic compounds, VOCs; formaldehyde, HCHO; and particulate matter, PM) have been examined to study the relationship between IAQ and airborne viruses. All indoor air and surface samples assessed were found to be negative for SARS-CoV-2. Nevertheless, another airborne respiratory virus (HRV/ENV) was detected, illustrating that the methodology set out here is a suitable one. Regarding the results for the IAQ, chemical parameters studied in the hall and waiting room of the hospital presented acceptable values. However, in the doctor's consultation room VOCs and HCHO show some instantaneous levels higher than the recommended guide values. The methodological approach described in this paper, integrating conventional IAQ and the assessment of bioaerosols, can be used in research and control programs aimed at promoting a healthy indoor environment.

Resilience and coping strategies in relation to mental health outcomes in people with cancer.

Considering the importance of psychological variables on health-related processes, this study investigated the role of resilience and coping strategies in relation to health. The aim of this research was to explore the underlying association between these aspects for the better understanding of the effect of psychosocial variables on mental health in cancer. This information could lead to the design of adapted psychological interventions in cancer. Participants with different diagnosis of cancer were recruited (N = 170). They came from the Spanish Association Against Cancer of Biscay. Resilience was measured with the 10 items Connor-Davidson Resilience Scale, coping with the Cognitive Emotion Regulation Questionnaire and mental health was measured as a global indicator through the SF-12 and the GHQ-12. A structural equation model (SEM) was conducted to test the effects between the constructs. Results showed that resilience and coping were significantly associated. Results reflected an absence of significant correlation between adaptive and disadaptive coping strategies. Resilience was the factor that most correlated with health outcomes (ß = -.45, p < .001). However, disadaptive coping strategies did not correlate with resilience or mental health indicators. Findings in this study underscore the positive contribution of high levels of resilience and an adaptive coping on participants´ level of health. Disadaptive coping strategies did not reflect any positive relation with resilience or health indicators. Thus, promoting resilience and adaptive coping could be a significant goal for psychosocial and educational interventions in people with cancer.

Bisphenol A Regulates Sodium Ramp Currents in Mouse Dorsal Root Ganglion Neurons and Increases Nociception.

17ß-Estradiol mediates the sensitivity to pain and is involved in sex differences in nociception. The widespread environmental disrupting chemical bisphenol A (BPA) has estrogenic activity, but its implications in pain are mostly unknown. Here we show that treatment of male mice with BPA (50 µg/kg/day) during 8 days, decreases the latency to pain behavior in response to heat, suggesting increased pain sensitivity. We demonstrate that incubation of dissociated dorsal root ganglia (DRG) nociceptors with 1 nM BPA increases the frequency of action potential firing. SCN9A encodes the voltage-gated sodium channel Nav1.7, which is present in DRG nociceptors and is essential in pain signaling. Nav1.7 and other voltage-gated sodium channels in mouse DRG are considered threshold channels because they produce ramp currents, amplifying small depolarizations and enhancing electrical activity. BPA increased Nav-mediated ramp currents elicited with slow depolarizations. Experiments using pharmacological tools as well as DRG from ERß-/- mice indicate that this BPA effect involves ERα and phosphoinositide 3-kinase. The mRNA expression and biophysical properties other than ramp currents of Nav channels, were unchanged by BPA. Our data suggest that BPA at environmentally relevant doses affects the ability to detect noxious stimuli and therefore should be considered when studying the etiology of pain conditions.

Hacia una intervención psicosomática a medida / Pour une intervention psychosomatique sur mesure / Moving towards a tailor-made psychosomatic approach

En este texto se presentan la síntesis y las conclusiones de un trabajo psicoterapéutico realizado en equipo con pacientes oncológicos y sus familiares. Utilizando las herramientas, que son básicamente la psicosomática de la Escuela de París y la experiencia del trabajo en grupos, el equipo muestra la originalidad de organizar las psicoterapias de grupo y las sesiones individuales adaptadas a las capacidades del funcionamiento mental de cada paciente. (AU)

In this text, we present the synthesis and conclusions of a psychotherapeutic work done by a team with oncological patients and their relatives. Using tools that are basically the Psychosomatics of the Scof Paris and the experience of working in groups, the team demonstrates the originality of organizing group psychotherapies and individual sessions that are adapted to the capacities of the mental functioning of each patient. (AU)

Dans ce texte sont présentées la synthèse et les conclusions d’un travail psychothérapeutique mené en équipe avec des patients oncologiques et leurs proches. Utilisant les outils, qui sont essentiellement la psychosomatique de l’École de Paris et l’expérience du travail en groupe. L’équipe montre l’originalité de l’organisation de psychothérapies de groupe et des séances individuelles adaptées aux capacités du fonctionnement mental de chaque patient. (AU)

Timing of Exposure and Bisphenol-A: Implications for Diabetes Development.

Bisphenol-A (BPA) is one of the most widespread endocrine disrupting chemicals (EDCs). It is used as the base compound in the production of polycarbonate and other plastics present in many consumer products. It is also used as a building block in epoxy can coating and the thermal paper of cash register receipts. Humans are consistently exposed to BPA and, in consequence, this compound has been detected in the majority of individuals examined. Over the last decade, an enlarging body of evidence has provided a strong support for the role of BPA in the etiology of diabetes and other metabolic disorders. Timing of exposure to EDCs results crucial since it has important implications on the resulting adverse effects. It is now well established that the developing organisms are particularly sensitive to environmental influences. Exposure to EDCs during early life may result in permanent adverse consequences, which increases the risk of developing chronic diseases like diabetes in adult life. In addition to that, developmental abnormalities can be transmitted from one generation to the next, thus affecting future generations. More recently, it has been proposed that gestational environment may also program long-term susceptibility to metabolic disorders in the mother. In the present review, we will comment and discuss the contributing role of BPA in the etiology of diabetes. We will address the metabolic consequences of BPA exposure at different stages of life and comment on the final phenotype observed in different whole-animal models of study.

Holes in the Plasma Membrane Mimic Torso-Like Perforin in Torso Tyrosine Kinase Receptor Activation in the Drosophila Embryo.

Receptor tyrosine kinase (RTK) pathways play central roles in development, and, when abnormally activated, they can lead to pathological conditions, including oncogenesis. Thus, RTK activation, mediated by ligand binding, is under tight control, a critical step being the conversion of an inactive precursor into the active form of the ligand. A variety of mechanisms have been shown to be involved in this conversion; however, little attention has been paid to how mechanical phenomena may impinge on this process. Here we address this issue by studying Torso, an RTK activated at both poles of the Drosophila embryo at the blastoderm stage. Torso activation is induced by a cleaved form of Trunk, a growth factor-like protein, but it also requires the accumulation of the Torso-like (Tsl) protein at both ends of the blastoderm. Tsl is the only known protein in Drosophila bearing a membrane attack complex/perforin (MACPF) domain-a motif present in proteins involved in pore formation at cell membranes. However, while different hypotheses have been put forward to account for the function of Tsl in Torso receptor activation, little is known about its molecular role and whether it indeed contributes to membrane pore formation. Here, we show that mechanically induced holes in the Drosophila embryo can substitute for Tsl function. These results suggest that Tsl is required for an exchange between the interior of the Drosophila embryo and its surrounding milieu and that mechanically induced cell injuries may contribute to abnormal RTK activation.

Extranuclear-initiated estrogenic actions of endocrine disrupting chemicals: Is there toxicology beyond paracelsus?

Endocrine Disrupting Chemicals (EDCs), including bisphenol-A (BPA) do not act as traditional toxic chemicals inducing massive cell damage or death in an unspecific manner. EDCs can work upon binding to hormone receptors, acting as agonists, antagonists or modulators. Bisphenol-A displays estrogenic activity and, for many years it has been classified as a weak estrogen, based on the classic transcriptional action of estrogen receptors serving as transcription factors. However, during the last two decades our knowledge about estrogen signaling has advanced considerably. It is now accepted that estrogen receptors ERα and ERß activate signaling pathways outside the nucleus which may or may not involve transcription. In addition, a new membrane estrogen receptor, GPER, has been proposed. Pharmacological and molecular evidence, along with results obtained in genetically modified mice, demonstrated that BPA, and its substitute BPS, are potent estrogens acting at nanomolar concentrations via extranuclear ERα, ERß, and GPER. The different signaling pathways activated by BPA and BPS explain the well-known estrogenic effects of low doses of EDCs as well as non-monotonic dose-response relationships. These signaling pathways may help to explain the actions of EDCs with estrogenic activity in the etiology of different pathologies, including type-2 diabetes and obesity.

Effects of Bisphenol A on ion channels: Experimental evidence and molecular mechanisms.

Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) produced in huge quantities in the manufacture of polycarbonate plastics and epoxy resins. It is present in most humans in developed countries, acting as a xenoestrogen and it is considered an environmental risk factor associated to several diseases. Among the whole array of identified mechanisms by which BPA can interfere with physiological processes in living organisms, changes on ion channel activity is one of the most poorly understood. There is still little evidence about BPA regulation of ion channel expression and function. However, this information is key to understand how BPA disrupts excitable and non-excitable cells, including neurons, endocrine cells and muscle cells. This report is the result of a comprehensive literature review on the effects of BPA on ion channels. We conclude that there is evidence to say that these important molecules may be key end-points for EDCs acting as xenoestrogens. However, more research on channel-mediated BPA effects is needed. Particularly, mechanistic studies to unravel the pathophysiological actions of BPA on ion channels at environmentally relevant doses.

Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes.

Glucose homeostasis is precisely regulated by glucagon and insulin, which are released by pancreatic α- and ß-cells, respectively. While ß-cells have been the focus of intense research, less is known about α-cell function and the actions of glucagon. In recent years, the study of this endocrine cell type has experienced a renewed drive. The present review contains a summary of established concepts as well as new information about the regulation of α-cells by glucose, amino acids, fatty acids and other nutrients, focusing especially on glucagon release, glucagon synthesis and α-cell survival. We have also discussed the role of glucagon in glucose homeostasis and in energy and lipid metabolism as well as its potential as a modulator of food intake and body weight. In addition to the well-established action on the liver, we discuss the effects of glucagon in other organs, where the glucagon receptor is expressed. These tissues include the heart, kidneys, adipose tissue, brain, small intestine and the gustatory epithelium. Alterations in α-cell function and abnormal glucagon concentrations are present in diabetes and are thought to aggravate the hyperglycaemic state of diabetic patients. In this respect, several experimental approaches in diabetic models have shown important beneficial results in improving hyperglycaemia after the modulation of glucagon secretion or action. Moreover, glucagon receptor agonism has also been used as a therapeutic strategy to treat obesity.

Bisphenol-A acts as a potent estrogen via non-classical estrogen triggered pathways.

Bisphenol-A (BPA) is an estrogenic monomer commonly used in the manufacture of numerous consumer products such as food and beverage containers. Widespread human exposure to significant doses of this compound has been reported. Traditionally, BPA has been considered a weak estrogen, based on its lower binding affinity to the nuclear estrogen receptors (ERs) compared to 17-ß estradiol (E2) as well as its low transcriptional activity after ERs activation. However, in vivo animal studies have demonstrated that it can interfere with endocrine signaling pathways at low doses during fetal, neonatal or perinatal periods as well as in adulthood. In addition, mounting evidence suggests a variety of pathways through which BPA can elicit cellular responses at very low concentrations with the same or even higher efficiency than E2. Thus, the purpose of the present review is to analyze with substantiated scientific evidence the strong estrogenic activity of BPA when it acts through alternative mechanisms of action at least in certain cell types.

Regulation of K(ATP) channel by 17ß-estradiol in pancreatic ß-cells.

ATP-sensitive potassium channels (K(ATP)) regulate electrical activity and insulin secretion in pancreatic ß-cells. When glucose concentration increases, the [ATP]/[ADP] ratio rises closing K(ATP) channels, and the membrane potential depolarizes, triggering insulin secretion. This pivotal role of K(ATP) channels is used not only by glucose but also by neurotransmitters, hormones and other physiological agents to modulate electrical and secretory ß-cell response. In recent years, it has been demonstrated that estrogens and estrogen receptors are involved in glucose homeostasis, and that they can modulate the electrical activity and insulin secretion of pancreatic ß-cells. The hormone 17ß-estradiol (E2), at physiological levels, is implicated in maintaining normal insulin sensitivity for ß-cell function. Long term exposure to E2 increases insulin content, insulin gene expression and insulin release via the estrogen receptor α (ERα), while rapid responses to E2 can regulate K(ATP) channels increasing cGMP levels through the estrogen receptor ß (ERß) and type A guanylate cyclase receptor (GC-A). This review summarizes the main actions of 17ß-estradiol on K(ATP) channels and the subsequent insulin release in pancreatic ß-cells.

Role of estrogen receptors alpha, beta and GPER1/GPR30 in pancreatic beta-cells.

Estrogen receptors (ER) are emerging as important molecules involved in the adaptation of beta-cells to insulin resistance. The onset of type 2 diabetes is marked by insulin secretory dysfunction and decreased beta-cell mass. During pregnancy, puberty and obesity there is increased metabolic demand and insulin resistance is developed. This metabolic state increases the demand on beta-cells to augment insulin biosynthesis and release. In this respect, ERalpha is directly implicated in the E2-regulation of insulin content and secretion, while ERbeta is in the E2-potentiation of glucose-induced insulin release. Both receptors develop their actions within the physiological range of E2. In addition, the G protein-coupled estrogen receptor (GPER1/GPR30) seems to be implicated in the E2-regulation of stimulus-secretion coupling in the three cell types of the islet. The increased demand of insulin production for long time may lead to beta-cell stress and apoptosis. ERalpha, ERbeta and GPER1/GPR30 are involved in preventing beta-cell apoptosis, impeding the loss of critical beta-cell mass. Therefore, estrogen receptors may play an essential role in the adaptation of the pancreas to insulin resistant periods.

[Professional dance: an appraisal from the occupational health]. / Danza profesional: una revisión desde la salud laboral.

BACKGROUND: Dance is essentially an artistic discipline, with the dancer being exposed, as in any other occupation, to occupational risk factors. This document aims at identifying the characteristics about Professional Dance and its impact on the dancer's health. METHODS: Bibliographical review of all the material indexed at: Medline, Embase, Cochrane Library, Lilacs, Cinhal and IME. Using the keywords: dancing, professional ballet, danza (dance), danza profesional (professional dance), bailarín/a/es (dancer(s)) y zapateado (tap dance). RESULTS: 893 articles were identified: 76 were included in the bibliographical review. 40 of them are focused on the study of traumatic lesions and accidents. 40% are related to rehearsing and 70% affect the lower limbs. 36 articles analyze eating, menstrual, and bone density disorders. 50% describe low weight problems for women dancers, 58% identify delayed menarche and menstrual disorders, while 14% explore the beneficial/harmful effect of intensive dancing on bone mass. 62% are cross-sectional studies. CONCLUSIONS: Scientific production gets us closer to the health condition of dance professionals, but doesn't provide an insight on the cause-effect relationship of this profession's pathologies because most studies are merely descriptive. These studies underline the need of a deeper research on nutrition training, its stand before lesions, social and working conditions, and the training of dedicated professionals on occupational health in professional dance.

Danza profesional: una revisión desde la salud laboral / Professional dance: an appraisal from the occupational health

Fundamentos: La danza es una disciplina artística ycomo en cualquier ocupación los bailarines están expuestos afactores de riesgo laborales. El objetivo de este trabajo es analizarlas características de la evidencia empírica existentesobre la danza profesional y su repercusión en la salud.Métodos: Revisión bibliográfica de todos los artículosindexados en: Medline, Embase, Cochrane Library, Lilacs,Cinhal e IME. Utilizando como palabras claves: dancing, professionalballet, danza, danza profesional, bailarín/a/es y zapateadoResultados: Se identificaron 893 artículos: 76 fueronincluidos en la revisión bibliográfica. De ellos 40 tienen comoobjeto de estudio las lesiones traumáticas y accidentes. El 40%relacionados con los ensayos y en el 70% localizadas en elmiembro inferior. Los 36 artículos restantes analizan los trastornosde la alimentación, menstruación y densidad ósea eneste colectivo profesional. El 50%, describe problemas de bajopeso en las bailarinas, el 58% identifica menarquia tardía ytrastornos menstruales y el 14% explora, con resultados contradictorios,el efecto protector o de riesgo del baile intenso enla masa ósea. El 62% son estudios transversales.Conclusiones: La producción científica nos aproxima a lasituación de salud de profesionales de la danza, pero no proporcionauna dirección de causalidad relacionada a las patologíasde esta profesión, pues se trata mayoritariamente de estudiosdescriptivos. Los estudios apuntan a la necesidad deprofundizar en la investigación sobre la formación nutricional,su actitud ante las lesiones, condiciones sociolaborales y tambiénla necesidad de formación de profesionales especializadosen riesgos laborales de la danza profesional(AU)

Background: Dance is essentially an artistic discipline,with the dancer being exposed, as in any other occupation, toocuppational risk factors. This document aims at identifyingthe characteristics about Professional Dance and its impact onthe dancer’s health.Methods: Bibliographical review of all the materialindexed at: Medline, Embase, Cochrane Library, Lilacs,Cinhal and IME. Using the keywords: dancing, professionalballet, danza (dance), danza profesional (professional dance),bailarín/a/es (dancer(s)) y zapateado (tap dance).Results: 893 articles were identified: 76 were included inthe bibliographical review. 40 of them are focused on the studyof traumatic lesions and accidents. 40% are related torehearsing and 70% affect the lower limbs. 36 articles analyzeeating, menstrual, and bone density disorders. 50% describelow weight problems for women dancers, 58% identifydelayed menarche and menstrual disorders, while 14% explorethe beneficial/harmful effect of intensive dancing on bonemass. 62% are cross-sectional studies.Conclusions: Scientific production gets us closer to thehealth condition of dance professionals, but doesn’t provide aninsight on the cause-effect relationship of this profession’spathologies because most studies are merely descriptive. Thisstudies underline the need of a deeper research on nutritiontraining, its stand before lesions, social and workingconditions, and the training of dedicated professionals onoccupational health in professional dance(AU)

Lysophosphatidic acid induces Ca2+ mobilization and c-Myc expression in mouse embryonic stem cells via the phospholipase C pathway.

Embryonic stem cells (ESC) are pluripotent and could be maintained in vitro in a self-renewing state indefinitely, at the same time preserving their potential to differentiate towards more specific lineages. Despite the progress in the field, the complex network of signalling cascades involved in the maintenance of the self-renewing and pluripotent state remains not fully understood. In the present study, we have investigated the role of lysophosphatidic acid (LPA), a potent mitogen present in serum, in Ca(2+) signalling and early gene activation in mouse ESC (mESC). In these cells, we detected the expression of the G-protein coupled LPA receptor subtypes LPA(1), LPA(2) and LPA(3). Using fluorescence Ca(2+) imaging techniques, we showed that LPA induced an increase in intracellular Ca(2+) concentration. This increase was also observed in the absence of extracellular Ca(2+), suggesting the involvement of internal stores. Pre-treatment with BAPTA-AM, thapsigargin or U-73122 efficiently blocked this Ca(2+) release, indicating that LPA was evoking Ca(2+) mobilization from the endoplasmic reticulum via the phospholipase C (PLC) pathway. Interestingly, this signalling cascade initiated by LPA was involved in inducing the expression of the Ca(2+)-dependent early response gene c-myc, a key gene implicated in ESC self-renewal and pluripotency. Additionally, LPA increased the proliferation rate of mESC. Our findings therefore outline the physiological role of LPA in mESC.

Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPAR alpha ligands in mouse pancreatic islets of Langerhans.

PPAR alpha is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. PPAR alpha is involved in the regulation of in vivo triglyceride levels, presumably through its effects on fatty acid and lipoprotein metabolism. Some nuclear receptors have been involved in rapid effects mediated by non-genomic mechanisms. In this paper, we report the rapid non-genomic effects of PPAR alpha ligands on the intracellular calcium concentration ([Ca2+]i), mitochondrial function, reactive oxygen species (ROS) generation, and secretion of insulin in freshly isolated mouse islets of Langerhans. The hypolipidemic fibrate PPAR alpha agonist WY-14 643 decreased the glucose-induced calcium oscillations in intact islets. This effect was mimicked by the synthetic agonist GW7647 and the endogenous agonist oleylethanolamide. The WY-14 643 action was rapid in onset (5 min) and was still produced in the presence of protein and mRNA synthesis inhibitors, cycloheximide, and actinomycin-d. This suggests that it is independent of gene transcription. In addition, WY-14 623 impaired mitochondrial function, increased ROS formation and decreased insulin release. PPAR alpha is present in beta-cells, mainly in the cytosol and nucleus, with a small subpopulation localized in the plasma membrane. However, the presence of the PPAR alpha ligand effects in mice bearing a disrupted Ppar alpha gene raises the possibility that the rapid effects of the agonists in pancreatic beta-cells are independent of the receptor. We conclude that PPAR alpha agonists produce a decrease in glucose-induced [Ca2+]i signals and insulin secretion in beta-cells through a rapid, non-genomic mechanism.