The fate of P2Y-related orphan receptors: GPR80/99 and GPR91 are receptors of dicarboxylic acids

Several orphan G protein-coupled receptors are structurally close to the family of P2Y nucleotide receptors: GPR80/99 and GPR91 are close to P2Y1/2/4/6/11 receptors, whereas GPR87, H963 and GPR34 are close to P2Y12/13/14. Over the years, several laboratories have attempted without success to identify the ligands of those receptors. In early 2004, two papers have been published: One claiming that GPR80/99 is an AMP receptor, called P2Y15, and the other one showing that GPR80/99 is a receptor for α-ketoglutarate, while GPR91 is a succinate receptor. The accompanying paper by Qi et al. entirely supports that GPR80/99 is an α-ketoglutarate receptor and not an AMP receptor. The closeness of dicarboxylic acid and P2Y nucleotide receptors might be linked to the negative charges of both types of ligands and the involvement of conserved Arg residues in their neutralization

Terpenoides de Caryopteris . clandonensis Simmonds (Lamiaceae), activités molluscicide et antiradicalaire

Des études préliminaires ont mis en évidence l'important potentiel de biosynthèse d'iridoïdes de Caryopteris . clandonensis et la présence de composés colorant ses racines en brun-rougeâtre. Notre recherche s'est inscrite dans la continuité de ces premiers résultats. Dans un premier chapitre, bibliographique, nous présentons la position systématique du genre Caryopteris et les principales caractéristiques botaniques de C. . clandonensis. Sont également abordées les études phytochimiques entreprises sur plusieurs espèces du genre. Les iridoîdes, molécules décrites chez plusieurs espèces de Caryopteris, font l'objet d'une attention plus particulière. L'étude phytochimique, exposée en deuxième partie, est consacrée à nos travaux sur la mise en évidence de terpénoïdes. Ainsi, grâce aux techniques spectrales actuelles (RMN 1D et 2D), nous avons identifié neuf iridoïdes de type harpagide. Sept de ces molécules sont de nouvelles structures naturelles. Furent également identifiées deux abiétanes quinones, la 15-déoxyfuerstione et la fuerstione et deux naphtoquinones prénylées, l'a-caryoptérone et la déhydro-a-lapachone. La troisième partie est consacrée à l'évaluation des potentialités biologiques de Caryopteris . clandonensis et de ses molécules. L'activité antiradicalaire de ces composés ainsi que de deux iridoïdes a été évaluée vis-à-vis du radical superoxyde.TOULOUSE-ENSAT-Documentation (315552324) / SudocTOULOUSE-ENSIACET (315552325) / SudocSudocFranceF

Obesity and access to kidney transplantation in patients starting dialysis: A prospective cohort study.

Obesity has been linked to poor access to medical care. Although scientific evidence suggest that kidney transplantation improves survival and quality of life in obese patients with end-stage renal disease (ESRD), few data exist on the impact of obesity on access to kidney transplantation in this population.We aimed to characterize the relationships between body mass index (BMI) at the start of dialysis, changes in BMI after the start of dialysis, and either access to kidney transplantation or overall mortality in dialysis or transplantation among ESRD patients.Between 2002 and 2011, 19524 dialysis patients with ESRD were included in the study via the French nationwide Renal Epidemiology and Information Network. Data on sociodemographic factors, comorbidities and laboratory test results were recorded upon entry into the registry. BMI were obtained at the start of dialysis and then yearly. Cubic spline regression analyses provided a graphic evaluation of the relationships between BMI at the start of dialysis and outcomes. Joint models were used to evaluate the association between the change over time in BMI and outcomes.During a median follow-up of 20.3 months, 6634 patients underwent kidney transplantation. A BMI >31 kg/m2 at the start of the dialysis was associated with a lower likelihood of receiving a kidney transplant, and the likelihood decreased even further with higher BMI values. For patients with BMI ≥30kg/m2 at the start of the dialysis, a 1 kg/m2 decrease in BMI during follow-up was associated with a 9% to 11% increase in the likelihood of receiving a transplant. There was an L-shaped relationship between BMI at the start of dialysis and overall mortality. We showed that obese patients with ESRD face barriers to the receipt of a kidney transplant without valid reasons.Greater attention to this issue would improve the fairness of the organ allocation process and might improve outcomes for obese patients with ESRD

Patient characteristics according to the BMI level at start of dialysis.

<p>Patient characteristics according to the BMI level at start of dialysis.</p

Flow chart for sample selection (RRT: Renal replacement therapy).

<p>Relative to the excluded patients, the included patients did not differ significantly in terms of gender and the prevalence of congestive heart failure but were older (+1 year, p<0.001), had a slight lower eGFR at initiation (-0.2ml/min, p = 0.03), were less likely to have diabetes (-2%, p<0.002) and had different patterns of initially treated conditions or primary renal disease (Table A in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176616#pone.0176616.s001" target="_blank">S1 File</a>).</p

Multivariate associations (hazard ratios and 95% confidence intervals derived from joint models) for access to transplantation for BMI in different multivariate joint models stratified on three levels of initial BMI with competing risk of death.

<p>Multivariate associations (hazard ratios and 95% confidence intervals derived from joint models) for access to transplantation for BMI in different multivariate joint models stratified on three levels of initial BMI with competing risk of death.</p

Multivariate associations between body mass index (BMI) at the start of dialysis and access to kidney transplantation.

<p>*Adjusted for gender, age, congestive heart failure, diabetes, chronic respiratory disease, coronary heart disease, cardiac dysrhythmia, peripheral vascular disease, active cancer disease and stroke.</p

Multivariate associations (hazard ratios and 95% confidence intervals derived from joint models) for overall mortality for BMI in different multivariate joint models stratified on three levels of initial BMI.

<p>Multivariate associations (hazard ratios and 95% confidence intervals derived from joint models) for overall mortality for BMI in different multivariate joint models stratified on three levels of initial BMI.</p

Oxysterols direct immune cell migration through EBI2

Epstein-Barr virus (EBV)-induced gene 2 (EBI2, aka GPR183) is a G protein-coupled receptor that is required for humoral immune responses and polymorphisms in the receptor have been associated with inflammatory autoimmune diseases1-3. The natural ligand for EBI2 has been unknown. Here we describe identification of 7, 25-dihydroxycholesterol (5-cholesten-3, 7, 25-triol; 7, 25-OHC) as a potent and selective agonist of EBI2. Functional activation of EBI2 by 7, 25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high affinity radioligand binding. Furthermore we find that 7, 25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A key enzyme required for the generation of 7, 25-OHC is cholesterol 25-hydroxylase (Ch25h)4. Similar to EBI2 receptor knockout mice, mice deficient in Ch25h fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that Ch25h generates EBI2 bioactivity in vivo and suggests that the EBI2 oxysterol signaling pathway plays an important role in the adaptive immune response