Sphingosine-1-phosphate-induced nociceptor excitation and ongoing pain behavior in mice and humans is largely mediated by S1P3 receptor

The biolipid sphingosine-1-phosphate (S1P) is an essential modulator of innate immunity, cell migration, and wound healing. It is released locally upon acute tissue injury from endothelial cells and activated thrombocytes and, therefore, may give rise to acute post-traumatic pain sensation via a yet elusive molecular mechanism. We have used an interdisciplinary approach to address this question, and we find that intradermal injection of S1P induced significant licking and flinching behavior in wild-type mice and a dose-dependent flare reaction in human skin as a sign of acute activation of nociceptive nerve terminals. Notably, S1P evoked a small excitatory ionic current that resulted in nociceptor depolarization and action potential firing. This ionic current was preserved in “cation-free” solution and blocked by the nonspecific Cl− channel inhibitor niflumic acid and by preincubation with the G-protein inhibitor GDP-β-S. Notably, S1P3 receptor was detected in virtually all neurons in human and mouse DRG. In line with this finding, S1P-induced neuronal responses and spontaneous pain behavior in vivo were substantially reduced in S1P3−/− mice, whereas in control S1P1 floxed (S1P1fl/fl) mice and mice with a nociceptor-specific deletion of S1P1−/− receptor (SNS-S1P1−/−), neither the S1P-induced responses in vitro nor the S1P-evoked pain-like behavior was altered. Therefore, these findings indicate that S1P evokes significant nociception via G-protein-dependent activation of an excitatory Cl− conductance that is largely mediated by S1P3 receptors present in nociceptors, and point to these receptors as valuable therapeutic targets for post-traumatic pain.The authors thank K. Braun, T. Martha, and M. Doblander for expert technical assistance. This work was supported by la Generalitat Valenciana and the Ministerio de Economia y Competitividad (A.V.F.M.), the Australian National Health and Medical Research Council Project Grant 535055 to R.V.H., the Intramural Research Programs of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases to R.L.P., and the Austrian Research Funding Agency FWF Project Grants P20562, P25345, and SPIN to M.K

Nutrition for the ageing brain: towards evidence for an optimal diet

As people age they become increasingly susceptible to chronic and extremely debilitating brain diseases. The precise cause of the neuronal degeneration underlying these disorders, and indeed normal brain ageing remains however elusive. Considering the limits of existing preventive methods, there is a desire to develop effective and safe strategies. Growing preclinical and clinical research in healthy individuals or at the early stage of cognitive decline has demonstrated the beneficial impact of nutrition on cognitive functions. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). The latest scientific advances specific to how dietary nutrients and non-nutrient may affect cognitive ageing are presented. Furthermore, several key points related to mechanisms contributing to brain ageing, pathological conditions affecting brain function, and brain biomarkers are also discussed. Overall, findings are inconsistent and fragmented and more research is warranted to determine the underlying mechanisms and to establish dose-response relationships for optimal brain maintenance in different population subgroups. Such approaches are likely to provide the necessary evidence to develop research portfolios that will inform about new dietary recommendations on how to prevent cognitive decline

Nutrition for the ageing brain: towards evidence for an optimal diet

As people age they become increasingly susceptible to chronic and extremely debilitating brain diseases. The precise cause of the neuronal degeneration underlying these disorders, and indeed normal brain ageing remains however elusive. Considering the limits of existing preventive methods, there is a desire to develop effective and safe strategies. Growing preclinical and clinical research in healthy individuals or at the early stage of cognitive decline has demonstrated the beneficial impact of nutrition on cognitive functions. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). The latest scientific advances specific to how dietary nutrients and non-nutrient may affect cognitive ageing are presented. Furthermore, several key points related to mechanisms contributing to brain ageing, pathological conditions affecting brain function, and brain biomarkers are also discussed. Overall, findings are inconsistent and fragmented and more research is warranted to determine the underlying mechanisms and to establish dose-response relationships for optimal brain maintenance in different population subgroups. Such approaches are likely to provide the necessary evidence to develop research portfolios that will inform about new dietary recommendations on how to prevent cognitive decline

Effect on an Oral Nutritional Supplement with β-Hydroxy-β-methylbutyrate and Vitamin D on Morphofunctional Aspects, Body Composition, and Phase Angle in Malnourished Patients

This is a retrospective study of data from clinical practice to observe the effect of a high-calorie, high-protein oral nutritional supplement (ONS) with β-hydroxy-β-methylbutyrate (HMB) on nutritional status, body weight, and muscle-related parameters in 283 adult patients with or at risk of malnutrition under standard of care, 63% being cancer patients. They were recommended to increase physical activity and energy and protein intake from regular diet plus two servings per day of a specialized ONS enriched with HMB or standard ONS for up to 6 months. Dietary records, adherence and tolerance to ONS, nutritional status, body composition, handgrip strength, and blood analysis at the beginning and the end of the intervention were recorded. This program improved nutritional status from 100% malnourished or at risk of malnutrition at baseline to 80% well-nourished at final visit. It also increased body weight by 3.6-3.8 kg, fat-free mass by 0.9 to 1.3 kg, and handgrip strength by 4.7 to 6.2 kg. In a subgroup of patients (n = 43), phase angle (PhA), and body cell mass (BCM) increased only in the patients receiving the ONS enriched with HMB (0.95 (0.13) vs. -0.36 (0.4), and 2.98 (0.5) vs. -0.6 (1.5) kg, mean difference (SE) from baseline for PhA and BCM, respectively), suggesting the potential efficacy of this supplement on muscle health.I.C.-P. was the recipient of a postdoctoral grant (Río Hortega CM 17/00169) and is now the recipient of a postdoctoral grant (Juan Rodes JR 19/00054) from the Instituto de Salud Carlos III and cofounded by Fondo Europeo de Desarrollo Regional-FEDER. This study was a collaboration between the Institution and Abbott Laboratories. The company covered the publication cost.Ye

Maternal Diabetes and Cognitive Performance in the Offspring: A Systematic Review and Meta-Analysis.

Diabetes during gestation is one of the most common pregnancy complications associated with adverse health effects for the mother and the child. Maternal diabetes has been proposed to negatively affect the cognitive abilities of the child, but experimental research assessing its impact is conflicting. The main aim of our study was to compare the cognitive function in children of diabetic and healthy pregnant women.A systematic review and meta-analysis was conducted through a literature search using different electronic databases from the index date to January 31, 2015. We included studies that assessed the cognitive abilities in children (up to 14 years) of diabetic and non-diabetic mothers using standardized and validated neuropsychological tests.Of 7,698 references reviewed, 12 studies involving 6,140 infants met our inclusion criteria and contributed to meta-analysis. A random effect model was used to compute the standardized mean differences and 95% confidence interval (CI) were calculated. Infants (1-2 years) of diabetic mothers had significantly lower scores of mental and psychomotor development compared to control infants. The effect size for mental development was -0.41 (95% CI -0.59, -0.24; p<0.0001) and for psychomotor development was -0.31 (95% CI -0.55, -0.07; p = 0.0125) with non-significant heterogeneity. Diabetes during pregnancy could be associated with decreased intelligence quotient scores in school-age children, although studies showed significant heterogeneity.The association between maternal diabetes and deleterious effects on mental/psychomotor development and overall intellectual function in the offspring must be taken with caution. Results are based on observational cohorts and a direct causal influence of intrauterine hyperglycemia remains uncertain. Therefore, more trials that include larger populations are warranted to elucidate whether gestational diabetes mellitus (GDM) has a negative impact on offspring central nervous system (CNS)

Effect of pregnancy diabetes on the mental and psychomotor development and intelligence quotient.

<p>Forest plots comparing the difference in the (A) Mental Development Index and (B) Psychomotor Development Index subscales of the BSID between children of diabetic and non-diabetic mothers. (C) Forest plots comparing the difference in the intelligence quotient yielded by combined data from the Wechsler scales and the Stanford-Binet intelligence scale between children of diabetic and non-diabetic mothers.</p

Characteristics of the cohort studies included in the systematic review and meta-analysis (<i>n</i> = 12).

<p>Studies list is ordered by date and by type of outcome (Most recent studies and “support” are showed first).</p><p>ALSPAC, Avon Longitudinal Study of Parents and Children; ND, Not defined; GDM, Gestational Diabetes Mellitus; PGDM, Pre-gestational Diabetes Mellitus; Ctrl, Control; BMI, Body Mass Index; WISC-III/R, Wechsler Intelligence Scale for Children-3^rd Edition, R, revised; IQ, Intelligence Quotient; ADHD, Attention Deficit Hyperactivity Disorder; WPPSI-III/R, Wechsler Preschool and Primary Scale of Intelligence–3^rd Edition, R, Revised; SES, Socio Economic Status; T1DM, Type 1 Diabetes Mellitus; T2DM, Type 2 Diabetes Mellitus; BSID-I/II, Bayley Scales of Infant Development- 1^st/2^nd Edition; MDI, Mental Development Index; PDI, Psychomotor Development Index; OGTT, Oral Glucose Tolerance Test; DIEP, Diabetes in Early Pregnancy; FA, Fatty Acids.</p><p>Risk of bias classification (GRADE): L, Low; M, Medium; H, High.</p><p>Quality score (Newcastle-Ottawa): from 0 (lowest) to 9 (highest).</p><p>^† Number of children included in the studies.</p><p>*All values refer to mean (Standard Deviation), otherwise it is stated.</p><p>^§ Three references are related to the same subjects, so only the oldest study was included.</p><p>Characteristics of the cohort studies included in the systematic review and meta-analysis (<i>n</i> = 12).</p

Study flowchart showing the number of studies identified, screened, assessed for eligibility and included in the qualitative and quantitative analysis [17].

<p>*Further information regarding the excluded studies can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142583#pone.0142583.s010" target="_blank">S2 Text</a>.</p