A2B Adenosine Receptors and Sphingosine 1-Phosphate Signaling Cross-Talk in Oligodendrogliogenesis

Oligodendrocyte-formed myelin sheaths allow fast synaptic transmission in the brain. Impairments in the process of myelination, or demyelinating insults, might cause chronic diseases such as multiple sclerosis (MS). Under physiological conditions, remyelination is an ongoing process throughout adult life consisting in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs). During pathological events, this process fails due to unfavorable environment. Adenosine and sphingosine kinase/sphingosine 1-phosphate signaling axes (SphK/S1P) play important roles in remyelination processes. Remarkably, fingolimod (FTY720), a sphingosine analog recently approved for MS treatment, plays important roles in OPC maturation. We recently demonstrated that the selective stimulation of A(2)(B) adenosine receptors (A(2)(B)Rs) inhibit OPC differentiation in vitro and reduce voltage-dependent outward K(+) currents (I(K)) necessary to OPC maturation, whereas specific SphK1 or SphK2 inhibition exerts the opposite effect. During OPC differentiation A(2)(B)R expression increases, this effect being prevented by SphK1/2 blockade. Furthermore, selective silencing of A(2)(B)R in OPC cultures prompts maturation and, intriguingly, enhances the expression of S1P lyase, the enzyme responsible for irreversible S1P catabolism. Finally, the existence of an interplay between SphK1/S1P pathway and A(2)(B)Rs in OPCs was confirmed since acute stimulation of A(2)(B)Rs activates SphK1 by increasing its phosphorylation. Here the role of A(2)(B)R and SphK/S1P signaling during oligodendrogenesis is reviewed in detail, with the purpose to shed new light on the interaction between A(2)(B)Rs and S1P signaling, as eventual innovative targets for the treatment of demyelinating disorders

A2b adenosine receptors: When outsiders may become an attractive target to treat brain ischemia or demyelination

Adenosine is a signaling molecule, which, by activating its receptors, acts as an important player after cerebral ischemia. Here, we review data in the literature describing A2BR-mediated effects in models of cerebral ischemia obtained in vivo by the occlusion of the middle cerebral artery (MCAo) or in vitro by oxygen-glucose deprivation (OGD) in hippocampal slices. Adenosine plays an apparently contradictory role in this receptor subtype depending on whether it is activated on neuro-glial cells or peripheral blood vessels and/or inflammatory cells after ischemia. Indeed, A2BRs participate in the early glutamate-mediated excitotoxicity responsible for neuronal and synaptic loss in the CA1 hippocampus. On the contrary, later after ischemia, the same receptors have a protective role in tissue damage and functional impairments, reducing inflammatory cell infiltration and neuroinflammation by central and/or peripheral mechanisms. Of note, demyelination following brain ischemia, or autoimmune neuroinflammatory reactions, are also profoundly affected by A2BRs since they are expressed by oligodendroglia where their activation inhibits cell maturation and expression of myelin-related proteins. In conclusion, data in the literature indicate the A2BRs as putative therapeutic targets for the still unmet treatment of stroke or demyelinating diseases

Life course factors associated with metabolically healthy obesity: a protocol for the systematic review of longitudinal studies

Abstract Background There is heterogeneity among obese individuals, as some appear to have healthier metabolic profiles and decreased health risks. These individuals are defined as metabolically healthy obese (MHO), whilst those with unhealthy metabolic profiles are defined as metabolically unhealthy obese (MUO). To date, most research on MHO has been cross-sectional or focused on disease prognosis. However, longitudinal studies are required to provide greater insight into the life course factors that contribute to the development of MHO. This study aims to systematically review longitudinal studies investigating the association between life course exposures and future MHO status. Methods Electronic databases (MEDLINE, SCOPUS, and Web of Science) will be searched using a trialled search strategy. Studies will be included following a double-screening process according to inclusion criteria to assess eligibility. Studies eligible for inclusion will include those that have a longitudinal observational design where a life course exposure occurred or was measured at least 1 year before the outcome, investigate a human study population, are published in English after 1956, and investigate the association between ≥ 1 life course exposure and ≥ 1 outcome that reflects a measure of cardiometabolic resilience to obesity. Accepted life course exposures will include body size, body composition, pubertal development, smoking, diet, physical activity, sedentary behaviour, and psychosocial stress. The primary measure of cardiometabolic resilience to obesity will be MHO as an outcome (at follow-up). Studies investigating the development of cardiometabolic risk factors in an obese group without specifying MHO will also be accepted, such as the development of the metabolic syndrome (MetS) in an obese group. Key results of included studies will be tabulated, and a narrative synthesis will be conducted. Discussion This will be the first systematic review to summarise the literature on the life course correlates of MHO. Importantly, it may highlight which modifiable lifestyle factors could be targeted to delay the onset of cardiometabolic complications among the obese. Systematic review registration PROSPERO CRD4201705799

Evaluation by environmental monitoring of pesticide absorption in farm workers of 18 Italian tomato cultivations

Tornato cultivation farms of Soutbern Italy were investigated in order to evaluate tbe generai working conditions and tbe levels of exposure of farm workers to pesticides, during tbe mixinglloading and tbe application of pesticides on fields. Information on working modalities, personal protective equipment, etc. was collected using a questionnaire. Inbaling and cutaneous exposure levels were measured, and tbe estimated pesticide total absorbed dose was compared witb Admissible Daily Intakes (ADIs). Field treatments were mainly carried out by using sprayers witb open cab tractors, and, in 57 ~9% of cases, tbe pesticide mixture was manually prepared by mixing pesticides in a paU, often witbout using gloves (59.5%). Tbe estimated pesticides absorbed doses varied in tbe range 0.56-2630.31 mg (mean value, 46.9 mg), and 20% of tbe measured absorbed doses exceeded ADIs. Tbe findings obtained in tbe 18 examined farms sbow a worrying situation, suggesting tbe investigation of many more farms, so tbat a statistically significant picture of tornato cultivations in Soutbern Italy could be formed. Besides, tbe planning of training courses aimed to increase workers consciousness about bealtb risks and bow tbey can be prevented is advisable

Zinc inhibits calcium-mediated and nitric oxide-mediated ion secretion in human enterocytes

Zn2+ is effective in the treatment of acute diarrhea, but its mechanisms are not completely understood. We previously demonstrated that Zn2+ inhibits the secretory effect of cyclic adenosine monophosphate but not of cyclic guanosine monophosphate in human enterocytes. The aim of the present study was to investigate whether Zn2+ inhibits intestinal ion secretion mediated by the Ca2+ or nitric oxide pathways. To investigate ion transport we evaluated the effect of Zn2+ (35 μM) on electrical parameters of human intestinal epithelial cell monolayers (Caco2 cells) mounted in Ussing chambers and exposed to ligands that selectively increased intracellular Ca2+ (carbachol 10− 6 M) or nitric oxide (interferon-γ 300 UI/ml) concentrations. We also measured intracellular Ca2+ and nitric oxide concentrations. Zn2+ significantly reduced ion secretion elicited by carbachol (− 87%) or by interferon-γ (− 100%), and inhibited the increase of intracellular Ca2+ and nitric oxide concentrations. These data indicate that Zn2+ inhibits ion secretion elicited by Ca2+ and nitric oxide by directly interacting with the enterocyte. They also suggest that Zn2+ interferes with three of the four main intracellular pathways of intestinal ion secretion that are involved in acute diarrhe