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We investigated the associations of physical activity (PA), sedentary time (ST), and diet quality with biomarkers of inflammation in 390 children (192 girls, 198 boys) aged 6–8 years. PA energy expenditure (PAEE), light PA, moderate PA (MPA), vigorous PA (VPA), moderate-to-vigorous PA (MVPA), and ST were assessed by combined movement and heart rate sensor. Finnish Children Healthy Eating Index was calculated using data from 4 d food records. Body fat percentage (BF%) was measured by dual-energy X-ray absorptiometry. High-sensitivity C-reactive protein (Hs-CRP), leptin, interleukin-6 (IL-6), adiponectin, tumour necrosis factor-α, and glycoprotein acetyls were measured from fasting blood samples. PAEE, MPA, VPA, and MVPA were inversely associated with hs-CRP (β=−191 to −139, 95% CI=−0.294 to −0.024), leptin (β=−0.409 to −0.301, 95% CI=−0.499 to −0.107), IL-6 (β=−0.136 to −0.104, 95% CI=−0.240 to −0.001) and PAEE, MPA, and MVPA were inversely associated with glycoprotein acetyls (β=−0.117 to −0.103, 95% CI=−0.213 to −0.001). ST was directly associated with hs-CRP (β=0.170, 95% CI=0.070–0.269), leptin (β=0.355, 95% CI=0.265–0.445), and IL-6 (β=0.105, 95% CI=0.005–0.205). VPA was inversely associated with hs-CRP, leptin, and IL-6 in children with higher BF% (β=−0.344 to −0.181, 95% CI=−0.477 to −0.033) but not among children with lower BF% (β=−0.007–0.033, 95% CI=−0.183–0.184). In conclusion, PA was inversely and ST directly associated with circulating levels of biomarkers of inflammation among children. Furthermore, we observed that PA was inversely associated with these biomarkers for inflammation in children with a higher BF%. Highlights Systemic inflammation, as indicated by increased circulating concentrations of biomarkers for inflammation, may be important in causal pathways leading to insulin resistance, sub-clinical atherosclerosis, and eventually clinical manifestations of cardiovascular diseases. Higher levels of physical activity and lower levels of sedentary time were associated with more favourable inflammatory profile. Body fat percentage modified these associations and especially vigorous intensity physical activity was inversely associated with biomarkers of inflammation on children with higher body fat percentage but not in children with lower body fat percentage.

Irisin is a novel exercise-induced myokine that may be involved in regulating energy metabolism. We determined whether overtraining syndrome (OTS) and its biochemical markers are associated with plasma irisin levels in athletes. Seven severely overtrained athletes (OA) and 10 healthy control athletes (CA) were recruited and examined at the time of diagnosis (baseline) and after 6- and 12-months follow-up. Training volume and intensity were initially restricted but progressively increased in OA as OTS symptoms alleviated; CA continued their normal training routine. A maximal cycle ergometer test was performed with irisin analyzed before and after the test. Before the exercise test, irisin levels tended to be lower in OA than in CA at baseline (154.5 ± 28.5 vs. 171.7 ± 58.7 ng/mL). In both groups, at rest irisin levels changed only marginally during follow-up and were not affected by maximal exercise, nor were they associated with physical performance or body fat percentage. Irisin concentration at rest correlated positively with an oxidative stress marker, malondialdehyde (MDA) and negatively with an antioxidant protection marker, oxygen radical absorbance capacity (ORAC) in response to the exercise test in OA at baseline. Our findings help to clarify the possible contribution of irisin and its association with oxidative stress in the pathophysiology of OTS.

Background. Ornamental freshwater fish releases constitute a remarkable proportion of the 100 worst invasive species worldwide. Early detection and knowledge of likely introduction vectors and pathways of potentially invasive fishes into sensitive habitats are key for their proper management, hence rapid and correct identification of their occurrence is crucial. Therefore, we tested the hypothesis that a newly-discovered catfish population was that of Clarias batrachus (Linnaeus, 1758), and that this introduction might be of single origin released by aquarium pet fish owners. Materials and methods. In total, 45 specimens of C. batrachus were captured during two electrofishing surveys on 9 and 15 March 2016 by three operators for morphometric and molecular examination. Additionally, 28 specimens were collected for assessing gonadal maturity and sex. They were also measured for standard length and total length and weighed before being dissected. Results. Morphological and molecular analyses indicated that the examined specimens belong to C. batrachus, and that they were likely introduced by aquarium hobbyists. Successful reproduction and establishment of the species are demonstrated by the occurrence of ripe females and their young of the year and juvenile individuals in the catch. Conclusion. Our findings confirmed the presence of C. batrachus in a region with extraordinarily high biodiversity, including the first evidence to indicate the successful establishment of this species in Turkey. An initial first policy and management step would be to ban the importation and keeping of this species in Turkey, thus reducing the risk of further releases. Increased public awareness for the detrimental impacts of non-native fishes would serve to support the policy and field-based management practices to control, and hopefully eradicate this highly invasive species.

Funder: Opetus- ja Kulttuuriministeriö; doi: http://dx.doi.org/10.13039/501100003126, Funder: Sosiaali- ja Terveysministeriö; doi: http://dx.doi.org/10.13039/501100008487, Purpose: We studied the effects of a physical activity and dietary intervention on plasma lipids in a general population of children. We also investigated how lifestyle changes contributed to the intervention effects. Methods: We carried out a 2-year controlled, non-randomized lifestyle intervention study among 504 mainly prepubertal children aged 6–9 years at baseline. We assigned 306 children to the intervention group and 198 children to the control group. We assessed plasma concentrations of total, LDL, HDL, and VLDL cholesterol, triglycerides, HDL triglycerides, and VLDL triglycerides. We evaluated the consumption of foods using 4-day food records and physical activity using a movement and heart rate sensor. We analyzed data using linear mixed-effect models adjusted for age at baseline, sex, and pubertal stage at both time points. Furthermore, specific lifestyle variables were entered in these models. Results: Plasma LDL cholesterol decreased in the intervention group but did not change in the control group ( − 0.05 vs. 0.00 mmol/L, regression coefficient (β) = − 0.0385, p = 0.040 for group*time interaction). This effect was mainly explained by the changes in the consumption of high-fat vegetable oil-based spreads (β = − 0.0203, + 47% change in β) and butter-based spreads (β = − 0.0294, + 30% change in β), moderate-to-vigorous physical activity (β = − 0.0268, + 30% change in β), light physical activity (β = − 0.0274, + 29% change in β) and sedentary time (β = − 0.0270, + 30% change in β). The intervention had no effect on other plasma lipids. Conclusion: Lifestyle intervention resulted a small decrease in plasma LDL cholesterol concentration in children. The effect was explained by changes in quality and quantity of dietary fat and physical activity. Clinical Trial Registry Number: NCT01803776, ClinicalTrials.gov

(1) Objective: The aim of this study was to clarify the role of adipokines in the regulation of glucose metabolism in middle-aged obese subjects with impaired glucose tolerance in response to a long-term exercise and dietary intervention. (2) Methods: Skeletal muscle, plasma and serum samples were examined in 22 subjects from an exercise-diet intervention study aiming to prevent type 2 diabetes. The subjects were further divided into two subgroups (non-responders n = 9 and responders n = 13) based on their achievement in losing at least 3 kg. (3) Results: The two-year exercise-diet intervention reduced leptin levels and increased adiponectin levels in responders; the changes in leptin levels were significantly associated with changes in their weights (r = 0.662

Background: Mendelian randomization studies in adults suggest that abdominal adiposity is causally associated with increased risk of type 2 diabetes and coronary artery disease in adults, but its causal effect on cardiometabolic risk in children remains unclear.Objective: We aimed to study the causal relation of abdominal adiposity with cardiometabolic risk factors in children by applying Mendelian randomization.Methods: We constructed a genetic risk score (GRS) using variants previously associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI) and examined its associations with cardiometabolic factors by linear regression and Mendelian randomization in a meta-analysis of 6 cohorts, including 9895 European children and adolescents aged 3-17 y.Results: WHRadjBMI GRS was associated with higher WHRadjBMI (β = 0.021 SD/allele; 95% CI: 0.016, 0.026 SD/allele; P = 3 × 10-15) and with unfavorable concentrations of blood lipids (higher LDL cholesterol: β = 0.006 SD/allele; 95% CI: 0.001, 0.011 SD/allele; P = 0.025; lower HDL cholesterol: β = -0.007 SD/allele; 95% CI: -0.012, -0.002 SD/allele; P = 0.009; higher triglycerides: β = 0.007 SD/allele; 95% CI: 0.002, 0.012 SD/allele; P = 0.006). No differences were detected between prepubertal and pubertal/postpubertal children. The WHRadjBMI GRS had a stronger association with fasting insulin in children and adolescents with overweight/obesity (β = 0.016 SD/allele; 95% CI: 0.001, 0.032 SD/allele; P = 0.037) than in those with normal weight (β = -0.002 SD/allele; 95% CI: -0.010, 0.006 SD/allele; P = 0.605) (P for difference = 0.034). In a 2-stage least-squares regression analysis, each genetically instrumented 1-SD increase in WHRadjBMI increased circulating triglycerides by 0.17 mmol/L (0.35 SD, P = 0.040), suggesting that the relation between abdominal adiposity and circulating triglycerides may be causal.Conclusions: Abdominal adiposity may have a causal, unfavorable effect on plasma triglycerides and potentially other cardiometabolic risk factors starting in childhood. The results highlight the importance of early weight management through healthy dietary habits and physically active lifestyle among children with a tendency for abdominal adiposity.

Irisin is a myokine that is thought to be secreted in response to exercise that may help to prevent obesity and maintain normal glucose metabolism. In this study we investigated the associations between irisin and glucose homeostasis in middle-aged, overweight and obese men (n = 144) with impaired glucose regulation, and the impact of exercise training on these relationships. The participants underwent 12 weeks of resistance or aerobic (Nordic walking) exercise training three times per week, 60 minutes per session. Venous blood (n = 105) and skeletal muscle samples (n = 45) were obtained at baseline and post-intervention. Compared to controls, Nordic walking, but not resistance training, increased irisin levels in plasma (9.6 ± 4.2%, P = 0.014; 8.7 ± 4.9%, P = 0.087; respectively) compared to controls. When considering all subjects, baseline irisin correlated positively with atherogenic index of plasma (r = 0.244, P = 0.013) and 2-hour insulin levels (r = 0.214, P = 0.028), and negatively with age (r = -0.262, P = 0.007), adiponectin (r = -0.240, P = 0.014) and McAuley index (r = -0.259, P = 0.008). Training-induced FNDC5 mRNA changes were negatively correlated with HbA1c (r = -0.527, P = 0.030) in the resistance training group and with chemerin in the Nordic walking group (r = -0.615, P = 0.033). In conclusion, 12-weeks of Nordic walking was more effective than resistance training in elevating plasma irisin, in middle-aged men with impaired glucose tolerance. Thus, the change in irisin in response to exercise training varied by the type of exercise but showed limited association with improvements in glucose homeostasis.

Aims/hypothesis We studied for the first time the long-term effects of a combined physical activity and dietary intervention on insulin resistance and fasting plasma glucose in a general population of predominantly normal-weight children. Methods We carried out a 2 year non-randomised controlled trial in a population sample of 504 children aged 6–9 years at baseline. The children were allocated to a combined physical activity and dietary intervention group (306 children at baseline, 261 children at 2-year follow-up) or a control group (198 children, 177 children) without blinding. We measured fasting insulin and fasting glucose, calculated HOMA-IR, assessed physical activity and sedentary time by combined heart rate and body movement monitoring, assessed dietary factors by a 4 day food record, used the Finnish Children Healthy Eating Index (FCHEI) as a measure of overall diet quality, and measured body fat percentage (BF%) and lean body mass by dual-energy x-ray absorptiometry. The intervention effects on insulin, glucose and HOMA-IR were analysed using the intention-to-treat principle and linear mixed-effects models after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The measures of physical activity, sedentary time, diet and body composition at baseline and 2 year follow-up were entered one-by-one as covariates into the models to study whether changes in these variables might partly explain the observed intervention effects. Results Compared with the control group, fasting insulin increased 4.65 pmol/l less (absolute change +8.96 vs +13.61 pmol/l) and HOMA-IR increased 0.18 units less (+0.31 vs +0.49 units) over 2 years in the combined physical activity and dietary intervention group. The intervention effects on fasting insulin (regression coefficient β for intervention effect −0.33 [95% CI −0.62, −0.04], p = 0.026) and HOMA-IR (β for intervention effect −0.084 [95% CI −0.156, −0.012], p = 0.023) were statistically significant after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The intervention had no effect on fasting glucose, BF% or lean body mass. Changes in total physical activity energy expenditure, light physical activity, moderate-to-vigorous physical activity, total sedentary time, the reported consumption of high-fat (≥60%) vegetable oil-based spreads, and FCHEI, but not a change in BF% or lean body mass, partly explained the intervention effects on fasting insulin and HOMA-IR. Conclusions/interpretation The combined physical activity and dietary intervention attenuated the increase in insulin resistance over 2 years in a general population of predominantly normal-weight children. This beneficial effect was partly mediated by changes in physical activity, sedentary time and diet but not changes in body composition. Trial registration ClinicalTrials.gov NCT01803776

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values, CP received funding from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. MMcC is a Wellcome Senior Investigator and an NIHR Senior Investigator. MMcC received funding from Wellcome (090532, 106130, 098381, 203141, 212259), NIDDK (U01DK105535), and NIHR (NF-SI-0617-10090). TGMV was supported by ZonMW (TOP 40-00812-9811010). DLC was supported by the American Diabetes Association Grant 1-17-PDF-077. SFAG is supported by the Daniel B. Burke Chair for Diabetes Research and NIH Grant R01 HD058886. NVT is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (2017 FI_B 00636), Generalitat de Catalunya -Fons Social Europeu. BK received personal funding from the European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG -no. 322605). BF was supported by an Oak Foundation Fellowship. RMF and RNB are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). ATH is supported by a Wellcome Trust Senior Investigator award (grant number 098395/Z/12/Z). DM is supported by a Canada Research Chair. DLC was supported by the American Diabetes Association Grant 1-17-PDF077. JTL was supported by the Finnish Cultural Foundation. DIB received a KNAW Academy Professor Award (PAH/6635). MH received PhD scholarship funding from TARGET (http://target.ku.dk), The Danish Diabetes Academy (http://danishdiabetesacademy.dk) and the Copenhagen Graduate School of Health and Medical Sciences. VWVJ received funding from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and the European Research Council (ERC-2014-CoG-648916). ISF was supported by the European Research Council, Wellcome Trust (098497/Z/12/Z), Medical Research Council (MRC_MC_UU_12012/5), the NIHR Cambridge Biomedical Research Centre, the Botnar Foundation, the Bernard Wolfe Health Neuroscience Endowment and the European Community's Seventh Framework Programme (FP7/2007-2013) project Beta-JUDO n degrees 279153. IB acknowledges funding from Wellcome (WT206194). ES works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). KC received funds from the French National Agency of Research, F-CRIN/FORCE. All funding for the studies that provided the underlying data for this manuscript can be found in S1 Text. The funders had no role in study design, data collection and analysis, data interpretation, decision to publish, or preparation of the manuscript.

Amino acids are thought to have a key role in the processes contributing to overreaching development through their metabolic properties and neuronal functions. In the present study, the effects of 10-week military training on the concentrations of 19 amino acids were investigated. Plasma amino acid concentrations were measured at rest from 53 healthy male conscripts on weeks 1, 4, 7, and 9 of their military service. Conscripts were classified as overreached and non-overreached. Overreaching classification was based on fulfilling at least three of five criteria: greater than 5% decrease in maximal oxygen uptake, increased rating perceived exertion (RPE), and decreased lactate-RPE ratio in submaximal marching test, admitting feeling overloaded and both increased scores in fatigue and decreased scores in vigor in the Profile of Mood States Adolescents. Eight conscripts (15%) were classified as overreached; their glutamine–glutamate ratio and alanine and arginine levels were significantly lower ( P Impact statement The diagnosis of overtraining syndrome and overreaching poses a great challenge. Military training aims at improving the physical performance of the conscripts, but an excessive training load could also lead to overreaching. This study of Finnish conscripts provides new insights into the pathophysiology of overreaching and overtraining through amino acids concentrations. In addition to confirming the possible use of plasma glutamine/glutamate concentration to indicate and predict overreaching, we made a novel finding, i.e. low alanine and arginine concentrations might have a role in performance decrement and fatigue related to overreaching. Moreover, this study is the first to show the possible association between amino acids with putative neuronal properties and overreaching. Thus, the present findings might help to detect and prevent overreaching and offer a reliable diagnostic approach. In order to avoid overreaching, military training should be planned more periodically and individually, especially during the first four weeks of military service.

The Kale-Tavas sub-basin, which is the south-western part of the Lycian Molasse Basin, SW Turkey, hosts several coal seams of Late Oligocene, Early and Middle Miocene age within, respectively, the Mortuma, Yenidere, and Sekköy Formations. This study aims to determine coal rank, mineralogical, and geochemical features of the coal seams, and to ascertain factors controlling the mineralogical distribution and elemental enrichment. The distinct differences among the studied coal seams refer to mean random huminite/vitrinite reflectance (Rr). The highest Rr values (0.63–0.69%) are measured on the Late Oligocene Tavas coal, whereas the lowest Rr values (0.26–0.27%) were recorded in the Middle Miocene Narlı coal. Similar mineralogical assemblages were found in all the studied coal seams; however, aluminosilicate minerals are dominant to abundant phases in the coal from the Mortuma and Yenidere Formations, while carbonate minerals are the dominant phases in the coal from the Sekköy Formation. Accordingly, aluminosilicate-related elements (e.g. Al, K, Ti, and Li) display relatively higher concentrations in the studied coal seams from the Mortuma and Yenidere Formations, whereas relatively high-Ca concentrations and depletion of aluminosilicate-affiliated elements were recorded in the coal of the Sekköy Formation. Furthermore, Ni, Mo, and U are relatively enriched in all the studied seams, while relative B-enrichment is identified in the coal seams of the Mortuma and Yenidere Formations, and these seem to be related to possible marine influence of the palaeomires during Late Oligocene and Early Miocene and/or the occurrence of specific B-bearing aluminosilicate minerals. Also, U and Mo enrichments in the Narlı coal may be related with the development of anoxic conditions within the palaeomires during the Middle Miocene. Other indicators for anoxic conditions are framboidal pyrite grains and accessory Ni-bearing iron sulphides in all the studied samples. Although coal-bearing formations in the Kale-Tavas sub-basin deposited under different sedimentary environment, as the source areas for sediment supply of the coal seams remained the same during the Late Oligocene to Early Miocene, the mineralogical composition and elemental enrichment of the coal were mainly controlled by clastic inputs and redox conditions within the palaeomires; to a lesser extent a possible marine influence might have contributed to elemental enrichment., This study was partially supported by the Scientific and Technological Research Council of Turkey (TÜBİTAK) under a project (YDABCAG-117Y377) entitled “A multidisciplinary approach on palaeoenvironmental and palaeoclimate reconstruction of Kale-Kurbalık (Denizli) paralic coal basin” and by Hacettepe University, the Scientific Research Coordination Unit under the project number 05-01-602-002. The authors would like to thank Prof. Dr. Jim Hower for positive contributions, to Assoc. Prof. Dr. Mine Sezgül Kayseri-Özer for her contribuitons on geological age, and mining companies such as Azora, Bol, Özberil, As, and Emre for their permission for sampling and support during field studies. Special thanks go to mining engineer Mr. Ayhan Bircan for his assistance and support during sampling. Finally, the authors would like to thank Dr. Shifeng Dai, Editor-in-Chief of the Journal, and the anonymous reviewers for their comments and suggestions.

Increased sedentariness has been linked to the growing prevalence of obesity in children, but some longitudinal studies suggest that sedentariness may be a consequence rather than a cause of increased adiposity. We used Mendelian randomization to examine the causal relations between body mass index (BMI) and objectively assessed sedentary time and physical activity in 3–8 year-old children from one Finnish and two Danish cohorts [NTOTAL=679]. A genetic risk score (GRS) comprised of 15 independent genetic variants associated with childhood BMI was used as the instrumental variable to test causal effects of BMI on sedentary time, total physical activity, and moderate-to-vigorous physical activity (MVPA). In fixed effects meta-analyses, the GRS was associated with 0.05 SD/allele increase in sedentary time (P=0.019), but there was no significant association with total physical activity (beta=0.011 SD/allele, P=0.58) or MVPA (beta=0.001 SD/allele, P=0.96), adjusting for age, sex, monitor wear-time and first three genome-wide principal components. In two-stage least squares regression analyses, each genetically instrumented one unit increase in BMI z-score increased sedentary time by 0.47 SD (P=0.072). Childhood BMI may have a causal influence on sedentary time but not on total physical activity or MVPA in young children. Our results provide important insights into the regulation of movement behaviour in childhood., final draft, peerReviewed

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2–18 years old) and 15 599 controls (consistently

Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.

Oxidative stress resulting from decreased antioxidant protection and increased reactive oxygen and nitrogen species (RONS) production may contribute to muscle mass loss and dysfunction during aging. Curcumin is a phenolic compound shown to upregulate antioxidant defenses and directly quench RONS in vivo. This study determined the impact of prolonged dietary curcumin exposure on muscle mass and function of aged rats. Thirty-two-month-old male F344xBN rats were provided a diet with or without 0.2% curcumin for 4 months. The groups included: ad libitum control (CON, n = 18), 0.2% curcumin (CUR, and pair-fed (PAIR, n = 18) rats. CUR rats showed lower food intake compared to CON, making PAIR a suitable comparison group. CUR rats displayed larger plantaris mass and force production (vs. PAIR). Nuclear fraction levels of nuclear factor erythroid-2 related-factor-2 were greater, and oxidative macromolecule damage was lower in CUR (vs. PAIR). There were no significant differences in measures of antioxidant status between any of the groups. No difference in any measure was observed between CUR and CON rats. Thus, consumption of curcumin coupled with reduced food intake imparted beneficial effects on aged skeletal muscle. The benefit of curcumin on aging skeletal muscle should be explored further.

Excessive iron loading may cause skeletal muscle atrophy and weakness because of its free radical generating properties. To determine whether a clinically relevant degree of iron loading impairs skeletal muscle function, young male mice received injections of iron dextran (4 mg iron/200 µl) or 2 mM d-glucose (control) 5 days/week for 2 weeks ( n = 10/group). Systemic iron loading induced an approximate fourfold increase in the skeletal muscle nonheme iron concentration. Soleus specific tension (1, 30–250 Hz) was lower among iron-loaded animals compared with controls despite similar body mass and muscle mass. Soleus lipid peroxidation (4-hydroxynonenal adducts) and protein oxidation (protein carbonyls) levels were similar between groups. In gastrocnemius muscle, reduced glutathione (GSH) and glutathione peroxidase activity were similar but glutathione disulfide (GSSG) and the GSSG/GSH ratio were greater in iron-loaded muscle. A greater protein expression level of endogenous thiol antioxidant thioredoxin (TRX) was observed among iron-loaded muscle whereas its endogenous inhibitor thioredoxin-interacting protein (TXNip) and the TRX/TXNip ratio were similar. Glutaredoxin2, a thiol-disulfide oxidoreductase activated by GSSG-induced destabilization of its iron-sulfur [2Fe-2S] cluster, was lower following iron loading. Additionally, protein levels of α-actinin and αII-spectrin at 240 kDa were lower in the iron-loaded group. Ryanodine receptor stabilizing subunit calstabin1 was also lower following iron loading. In summary, the contractile dysfunction that resulted from moderate iron loading may be mediated by a disturbance in the muscle redox balance and from changes arising from an increased proteolytic response and aberrant sarcoplasmic reticulum Ca2+ release. NEW & NOTEWORTHY Although severe iron loading is known to cause muscle oxidative stress and dysfunction, the effects of a moderate degree of systemic iron loading on muscle contractile function and biochemical responses remain unclear. This study demonstrates that a pathophysiological elevation in the skeletal muscle iron load leads to force deficits that coincide with impaired redox status, structural integrity, and lower ryanodine receptor-associated calstabin1 in the absence of muscle mass changes or oxidative damage.

Background: Many of the activities associated with pepper fruits have been attributed to piperine, the most active compound present in these spices. Objective: This paper aims to provide an overview of the known properties of piperine, i.e. piperine’s chemistry, its physiological activity, documented interactions as a bioenhancer and reported data concerning its toxicity, antioxidant properties and anticancer activity. Discussion: It is known that piperine possesses several properties. In its interaction with other drugs, it can act as a bioavailability enhancer; this effect is also manifested in combination with other nutraceuticals, e.g. with curcumin, i.e. piperine can modify curcumin’s antioxidant, anti-inflammatory, antimicrobial and anticancer effects. Piperine displays significant immunomodulating, antioxidant, chemopreventive and anticancer activity; these effects have been shown to be dose-dependent and tissue-specific. However, the main limitation associated with piperine seems to be its low bioavailability, a disadvantage that innovative formulations are overcoming. Conclusion: It is predicted that an increasing number of studies will focus on piperine, especially those directed towards unraveling its properties at molecular level. The current knowledge about the action of piperine will form a foundation for ways to improve piperine’s bioavailability e.g. exploitation of different carrier systems. The therapeutical applications of this compound will be clarified, and piperine will be recognized as an important nutraceutical.

There are clear benefits of physical activity and especially exercise training on performance, including adaptation of muscle mass and strength. Maintenance of skeletal muscle mass is determined by a fine balance between protein synthesis and degradation. Loss of muscle mass ensues when degradation exceeds protein synthesis, which is observed in numerous conditions, including immobilization and age-related sarcopenia. Heat shock proteins (HSPs) are a family of highly conserved proteins that contribute to cellular protection, protein homeostasis, and survival against a variety of environmental and metabolic stresses. Some HSPs have been suggested for roles controlling skeletal muscle mass, and they may play a fundamental role in skeletal muscle function. Conversely, inability to induce individual HSPs could have deleterious effects on skeletal muscle protection and tolerance to external stressors. Both acute and chronic exercise induces HSP expression. As a physiological tool, physical exercise can be considered the safest strategy to enhance HSP levels in skeletal muscle. Studies on the modulation of skeletal muscle HSP levels using antioxidant and dietary supplementation strategies have provided contradictory results and warrant further investigation.

This study reports the effects of Q10, coenzyme Q10 or ubiquinone, a component of the electron transport chain in mitochondria, on nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), inhibitors of kappa B (IκB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and hemeoxygenase 1 (HO-1) in rats after chronic exercise training for 6 weeks. 8-week old male Wistar rats were assigned randomly to one of four treatments planned in a 2 x 2 factorial arrangement of two condition (sedentary vs. exercise training), and two coenzyme Q10 levels (0 and 300 mg/kg per day for 6 weeks). The expression levels of the target proteins were determined in the heart, liver and muscle, and biochemical parameters including creatinine, urea, glucose and lipid profile were investigated in plasma. When compared with sedentary group, significant decreases in heart, liver and muscle NFκB levels by 45%, 26% and 44% were observed in Q10 supplemented rats after exercise training, respectively, while the inhibitory protein IκB increased by 179%, 111% and 127% in heart, liver and muscle tissues. Q10 supplementation caused an increase in Nrf2 (167%, 165% and 90%) and HO-1 (107%, 156% and 114%) after exercise training in heart, liver and muscle tissues (p < 0.05). No significant change was observed in any of the parameters associated with protein, carbohydrate and lipid metabolism, except that exercise caused a decrease in plasma triglyceride, which was further decreased by Q10. In conclusion, these results suggest that Q10 modulates the expression of NFκB, IκB, Nrf2 and HO-1 in exercise training, indicating an anti-inflammatory effect of Q10 and emphasizes its role in antioxidant defense.

The 167K allele in the TM6SF2 gene has been suggested to protect against cardiovascular disease at the cost of developing nonalcoholic fatty liver disease in adults.We performed a cross-sectional study in a population sample of 462 Caucasian children aged 6-9 y, genotyped the polymorphism using HumanCoreExome BeadChip, and assessed several cardiometabolic risk factors.The 51 (11%) carriers of the 167K allele had higher plasma alanine aminotransferase (ALT) (20.8 vs. 18.4 U/l, P = 0.011) but lower plasma triglycerides (0.54 vs. 0.61 mmol/l, P = 0.024), total cholesterol (4.08 vs. 4.30 mmol/l, P = 0.016), and low-density lipoprotein (LDL) cholesterol (2.22 vs. 2.38 mmol/l, P = 0.012) than the 411 noncarriers. In factor analysis, the first factor was heavily loaded by plasma ALT (factor loading 0.63), triglycerides (-0.82), LDL cholesterol (-0.71), and waist circumference (0.61) in the carriers but not in the noncarriers.The carriers of the 167K allele have higher plasma ALT but lower plasma triglycerides and total and LDL cholesterol than the noncarriers already in childhood.

Background Most obese children show cardiometabolic impairments, such as insulin resistance, dyslipidemia, and hypertension. Yet some obese children retain a normal cardiometabolic profile. The mechanisms underlying this variability remain largely unknown. We examined whether genetic loci associated with increased insulin sensitivity and relatively higher fat storage on the hip than on the waist in adults are associated with a normal cardiometabolic profile despite higher adiposity in children. Methods We constructed a genetic score using variants previously linked to increased insulin sensitivity and/or decreased waist–hip ratio adjusted for body mass index (BMI), and examined the associations of this genetic score with adiposity and cardiometabolic impairments in a meta-analysis of six cohorts, including 7391 European children aged 3–18 years. Results The genetic score was significantly associated with increased degree of obesity (higher BMI-SDS beta = 0.009 SD/allele, SE = 0.003, P = 0.003; higher body fat mass beta = 0.009, SE = 0.004, P = 0.031), yet improved body fat distribution (lower WHRadjBMI beta = −0.014 SD/allele, SE = 0.006, P = 0.016), and favorable concentrations of blood lipids (higher HDL cholesterol: beta = 0.010 SD/allele, SE = 0.003, P = 0.002; lower triglycerides: beta = −0.011 SD/allele, SE = 0.003, P = 0.001) adjusted for age, sex, and puberty. No differences were detected between prepubertal and pubertal/postpubertal children. The genetic score predicted a normal cardiometabolic profile, defined by the presence of normal glucose and lipid concentrations, among obese children (OR = 1.07 CI 95% 1.01–1.13, P = 0.012, n = 536). Conclusions Genetic predisposition to higher body fat yet lower cardiometabolic risk exerts its influence before puberty.

The current study examined the effect of aging and long-term wheel-running on the expression of heat shock protein (HSP), redox regulation, and endoplasmic reticulum (ER) stress markers in tibialis anterior (T.A.) and soleus muscle of mice. Male mice were divided into young (Y, 3-month-old), old-sedentary (OS, 24-month-old), and old-exercise (OE, 24-month-old) groups. The OE group started voluntary wheel-running at 3 months and continued until 24 months of age. Aging was associated with a higher thioredoxin-interacting protein (TxNiP) level, lower thioredoxin-1 (TRX-1) to TxNiP ratio—a determinant of redox regulation and increased CHOP, an indicator of ER stress-related apoptosis signaling in both muscles. Notably, GRP78, a key indicator of ER stress, was selectively elevated in T.A. Long-term exercise decreased TxNiP in T.A. and soleus muscles and increased the TRX-1/TxNiP ratio in soleus muscle of aged mice. Inducible HSP70 and constituent HSC70 were upregulated, whereas CHOP was reduced after exercise in soleus muscle. Thus, our data demonstrated that aging induced oxidative stress and activated ER stress-related apoptosis signaling in skeletal muscle, whereas long-term wheel-running improved redox regulation, ER stress adaptation and attenuated ER stress-related apoptosis signaling. These findings suggest that life-long exercise can protect against age-related cellular stress.

Impaired expression of heat shock proteins (HSPs) and increased oxidative stress may contribute to the pathophysiology of diabetes by disrupted tissue protection. Acute exercise induces oxidative stress, whereas exercise training up-regulates endogenous antioxidant defenses and HSP expression. Although diabetic nephropathy is a major contributor to diabetic morbidity, information regarding the effect of HSPs on kidney protection is limited. This study evaluated the effects of eight-week exercise training on kidney HSP expression and markers of oxidative stress at rest and after acute exercise in rats with or without streptozotocin-induced diabetes. Induction of diabetes increased DNA-binding activity of heat shock factor-1, but decreased the expression of HSP72, HSP60, and HSP90. The inflammatory markers IL-6 and TNF-alpha were increased in the kidney tissue of diabetic animals. Both exercise training and acute exercise increased HSP72 and HSP90 protein levels only in non-diabetic rats. On the other hand, exercise training appeared to reverse the diabetes-induced histological changes together with decreased expression of TGF-beta as a key inducer of glomerulosclerosis, and decreased levels of IL-6 and TNF-alpha. Notably, HSP72 and TGF-beta were negatively correlated. In conclusion, impaired HSP defense seems to contribute to kidney injury vulnerability in diabetes and exercise training does not up-regulate kidney HSP expression despite the improvements in histopathological and inflammatory markers.

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Trace elements can participate in the catalysis of group-transfer reactions and can serve as their structural components. However, most of them including zinc and selenium have multifunctional roles in biological environments such as antioxidant and/or pro-oxidant effects, as concentration-dependent manner. Although it has been demonstrated the antioxidant actions of either selenium or zinc compounds, there are several documents pointing out their pro-oxidant/oxidant roles in biological systems. Here we have used ELISA-based immuno-spin trapping, a method for detection of free radical formation, to detect whether or not a zinc compound, Zn3(PO4)2, or a selenium compound, Na2SeO3, has antioxidant and/or pro-oxidant effect on 5,5-Dimethyl-1-Pyrroline-N-Oxide (DMPO)-DNA nitrone adducts induced with Cu(II)-H2O2-oxidizing system in in vitro preparations. Second, we examined whether this technique is capable to demonstrate the different DMPO-protein nitrone adduct productions in isolated protein crude of hearts from normal rats (CON) or rats with metabolic syndrome (MetS). Our data demonstrated that either Zn(2+) (100 µM) or SeO3(-2) (50 nM) has very strong antioxidant action against 200 µM H2O2-induced DMPO-DNA nitrone adduct production, whereas their higher concentrations have apparent pro-oxidant actions. We also used verification by Western blotting analysis whether immuno-spin trapping can be used to assess H2O2-induced DMPO-protein nitrone adducts in heart protein crudes. Our Western blot data further confirmed the ELISA-data from proteins and demonstrated how Zn(2+) or SeO3(-2) are dual-functioning ions such as antioxidant at lower concentrations while pro-oxidant at higher concentrations. Particularly, our present data with SeO3(-2) in DMPO-protein nitrone adducts, being in line with our previous observation on its dual-actions in ischemia/reperfusion-induced damaged heart, have shown that this ion has higher pro-oxidant actions over 50 nM in MetS-group compared to that of CON group.

Protein carbonyls are widely analysed as a measure of protein oxidation. Several different methods exist for their determination. A previous study had described orders of magnitude variance that existed when protein carbonyls were analysed in a single laboratory by ELISA using different commercial kits. We have further explored the potential causes of variance in carbonyl analysis in a ring study. A soluble protein fraction was prepared from rat liver and exposed to 0, 5 and 15 min of UV irradiation. Lyophilised preparations were distributed to six different laboratories that routinely undertook protein carbonyl analysis across Europe. ELISA and Western blotting techniques detected an increase in protein carbonyl formation between 0 and 5 min of UV irradiation irrespective of method used. After irradiation for 15 min, less oxidation was detected by half of the laboratories than after 5 min irradiation. Three of the four ELISA carbonyl results fell within 95% confidence intervals. Likely errors in calculating absolute carbonyl values may be attributed to differences in standardisation. Out of up to 88 proteins identified as containing carbonyl groups after tryptic cleavage of irradiated and control liver proteins, only seven were common in all three liver preparations. Lysine and arginine residues modified by carbonyls are likely to be resistant to tryptic proteolysis. Use of a cocktail of proteases may increase the recovery of oxidised peptides. In conclusion, standardisation is critical for carbonyl analysis and heavily oxidised proteins may not be effectively analysed by any existing technique., Graphical abstract, Highlights • ELISA of protein carbonyls is sensitive and robust to detect moderate oxidation. • Western blot for protein carbonyls offers a robust semi-quantitative alternative. • Improved standardisation is needed for protein carbonyl analysis methods. • Mass spectrometry is suitable for protein oxidation target discovery. • Fewer carbonyls are detected in heavily-relative to moderately-oxidised proteins.

Background: Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG. Participants and methods: A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight). Results: Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10−8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG. Conclusions: We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG., published version, peerReviewed

Lean body mass (LM) has been positively associated with bone mineral density (BMD) in children and adolescents, but the relationship between body fat mass (FM) and BMD remains controversial. Several biomarkers secreted by adipose tissue, skeletal muscle, or bone may affect bone metabolism and BMD. We investigated the associations of LM, FM, and such biomarkers with BMD in children. We studied a population sample of 472 prepubertal Finnish children (227 girls, 245 boys) aged 6–8 years. We assessed BMD, LM, and FM using whole-body dual-energy x-ray absorptiometry and analysed several biomarkers from fasting blood samples. We studied the associations of LM, FM, and the biomarkers with BMD of the whole body excluding the head using linear regression analysis. LM (standardized regression coefficient β = 0.708, p, final draft, peerReviewed

Retinal pigment epithelium (RPE) plays a major role in the maintenance of photoreceptors, and degeneration of RPE results in the development of age-related macular degeneration (AMD). Accumulation of intracellular protein aggregates, increased oxidative stress, and chronic inflammation are all factors damaging the functionality of aged RPE cells. Here, we report that inhibition of proteasomal degradation with MG-132 and autophagy with bafilomycin A1 resulted in the release of IL-1β but not that of IL-18 in human ARPE-19 cells. NLRP3 receptor became upregulated, and caspase-1, the functional component of an inflammasome complex, was activated. In addition to accumulating intracellular protein aggregates, inhibition of degradation systems induced oxidative stress which was demonstrated by elevated amounts of intracellular 4-hydroxynonenal (HNE)-protein adducts. Along with IL-1β, exposure to MG-132 and bafilomycin A1 resulted in the secretion of IL-8. A low concentration (1pg/ml) of IL-1β was capable of triggering significant IL-8 production which also became attenuated by treatment with a specific caspase-1 inhibitor. These results suggest that decline in intracellular degradation systems results not only in increased amounts of intracellular protein aggregates and oxidative stress but also in the activation of NLRP3 inflammasomes, arisen as a result of elevated production of biologically active IL-1β.

Summary Objectives PNPLA3 I148M polymorphism (rs738409) has been strongly associated with liver fat content and plasma alanine aminotransferase (ALT) levels in obese adults and children, but little is known about these relationships in normal weight individuals. We studied the associations and interactions of overweight and the PNPLA3 I148M polymorphism with plasma ALT levels during 2-year follow-up in children. Methods Subjects were a population sample of 481 Caucasian children aged 6–8 years examined at baseline and 419 children re-examined after 2-year follow-up. Altogether, 58 (12%) of 481 children at baseline and 71 (17%) of 419 children after 2-year follow-up were overweight. We assessed plasma ALT levels and other cardiometabolic risk factors and genotyped the PNPLA3 I148M polymorphism. Results Being overweight and carrying PNPLA3 148M allele were associated with increased ALT levels at baseline (P = 0.002; P = 0.033) and after 2-year follow-up (P

To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413

In diabetes, the endogenous defence systems are overwhelmed, causing various types of stress in tissues. In this study, newly diagnosed or diet-treated type 2 diabetics (T2D) (n=10) were compared with subjects with impaired glucose tolerance (IGT) (n=8). In both groups, at resting conditions, blood samples were drawn for assessing metabolic indices and skeletal muscle samples (m. vastus lateralis) were taken for the measurements of cellular defence markers: thioredoxin-1 (TRX-1) and stress proteins HSP72, HSP90. The protein level of TRX-1 was 36.1% lower (P=0.031) and HSP90 was 380% higher (P<0.001) in the T2D than in the IGT subjects, with no significant changes in HSP72. However, after the adjustment of both analyses with HOMA-IR only HSP90 difference remained significant. In conclusion, level of TRX-1 in skeletal muscle tissue was lower while that of HSP90 was higher in T2D than in IGT subjects. This may impair antioxidant defence and lead to disruptions of protein homoeostasis and redox regulation of cellular defences. Because HSP90 may be involved in sustaining functional insulin signalling pathway in type 2 diabetic muscles and higher HSP90 levels can be a consequence of type 2 diabetes, our results are potentially important for the diabetes research.

Indirect evidence suggests the increased production of reactive oxygen species (ROS) in migraine pathophysiology. In the current study we measured lipid peroxidation product in the rat cortex, trigeminal ganglia and meninges after the induction of cortical spreading depression (CSD), a phenomenon known to be associated with migraine aura, and tested nociceptive firing triggered by ROS in trigeminal nerves ex vivo. Application of KCl to dura mater in anesthetized rats induced several waves of CSD recorded by an extracellular electrode in the cortex. Following CSD, samples of cortex (affected regions were identified with blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI)), meninges from left and right hemispheres and trigeminal ganglia were taken for biochemical analysis. We found that CSD increased the level of the lipid peroxidation product malondialdehyde (MDA) in the ipsilateral cerebral cortex and meninges, but also in both ipsi- and contralateral trigeminal ganglia. In order to test the pro-nociceptive action of ROS, we applied the mild oxidant hydrogen peroxide to isolated rat hemiskull preparations including preserved trigeminal innervations. Application of hydrogen peroxide to meninges transiently enhanced electrical spiking activity of trigeminal nerves showing a pro-nociceptive action of ROS. In the presence of hydrogen peroxide trigeminal nerves still responded to capsaicin by burst of spiking activity indicating integrity of neuronal structures. The action of hydrogen peroxide was mediated by TRPA1 receptors as it was abolished by the specific TRPA1 antagonist TCS-5861528. Using dorsal root ganglion sensory neurons as test system we found that hydrogen peroxide promoted the release of the migraine mediator calcitonin gene-related peptide (CGRP), which we previously identified as a trigger of delayed sensitization of trigeminal neurons. Our data suggest that, after CSD, oxidative stress spreads downstream within the trigeminal nociceptive system and could be involved in the coupling of CSD with the activation of trigeminovascular system in migraine pathology. © 2013 IBRO.