Distinct genetic control of parasite elimination, dissemination, and disease after Leishmania major infection

Elimination of pathogens is the basis of host resistance to infections; however, relationship between persisting pathogens and disease has not been clarified. Leishmania major infection in mice is an important model of host–pathogen relationship. Infected BALB/c mice exhibit high parasite numbers in lymph nodes and spleens, and a chronic disease with skin lesions, splenomegaly, and hepatomegaly, increased serum IgE levels and cytokine imbalance. Although numerous gene loci affecting these disease symptoms have been reported, genes controlling parasites’ elimination or dissemination have never been mapped. We therefore compared genetics of the clinical and immunologic symptomatology with parasite load in (BALB/c × CcS-11) F2 hybrids and mapped five loci, two of which control parasite elimination or dissemination. Lmr5 influences parasite loads in spleens (and skin lesions, splenomegaly, and serum IgE, IL-4, and IFNγ levels), and Lmr20 determines parasite numbers in draining lymph nodes (and serum levels of IgE and IFNγ), but no skin or visceral pathology. Three additional loci do not affect parasite numbers but influence significantly the disease phenotype—Lmr21: skin lesions and IFNγ levels, Lmr22: IL-4 levels, Lmr23: IFNγ levels, indicating that development of L. major-caused disease includes critical regulations additional to control of parasite spread

Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure

Arsenic (+3 oxidation state) methyltransferase (As3mt) is the key enzyme in the pathway for methylation of inorganic arsenic (iAs). Altered As3mt expression and AS3MT polymorphism have been linked to changes in iAs metabolism and in susceptibility to iAs toxicity in laboratory models and in humans. As3mt-knockout mice have been used to study the association between iAs metabolism and adverse effects of iAs exposure. However, little is known about systemic changes in metabolism of these mice and how these changes lead to their increased susceptibility to iAs toxicity. Here, we compared plasma and urinary metabolomes of male and female wild-type (WT) and As3mt-KO (KO) C57BL6 mice and examined metabolomic shifts associated with iAs exposure in drinking water. Surprisingly, exposure to 1 ppm As elicited only small changes in the metabolite profiles of either WT or KO mice. In contrast, comparisons of KO mice with WT mice revealed significant differences in plasma and urinary metabolites associated with lipid (phosphatidylcholines, cytidine, acyl-carnitine), amino acid (hippuric acid, acetylglycine, urea), and carbohydrate (L-sorbose, galactonic acid, gluconic acid) metabolism. Notably, most of these differences were sex-specific. Sex-specific differences were also found between WT and KO mice in plasma triglyceride and lipoprotein cholesterol levels. Some of the differentially changed metabolites (phosphatidylcholines, carnosine, and sarcosine) are substrates or products of reactions catalyzed by other methyltransferases. These results suggest that As3mt KO alters major metabolic pathways in a sex-specific manner, independent of iAs treatment, and that As3mt may be involved in other cellular processes beyond iAs methylation

SATB1 packages densely-looped, transciptionally-active chromatin for coordinated expression of cytokine genes

SATB1 is an important regulator of nuclear architecture that anchors specialized DNA sequences onto its cage-like network and recruits chromatin remodeling/modifying factors to control gene transcription. We studied the role of SATB1 in regulating the coordinated expression of Il5, Il4, and Il13 from the 200kb cytokine gene cluster region of mouse chromosome 11 during T-helper 2 (Th2)-cell activation. We show that upon cell activation, SATB1 is rapidly induced to form a unique transcriptionally-active chromatin structure that includes the cytokine gene region. Chromatin is folded into numerous small loops all anchored by SATB1, is histone H3 acetylated at lysine 9/14, and associated with Th2-specific factors, GATA3, STAT6, c-Maf, the chromatin-remodeling enzyme Brg-1, and RNA polymerase II across the 200kb region. Before activation, the chromatin displays some of these features, such as association with GATA3 and STAT6, but these were insufficient for cytokine gene expression. Using RNA interference (RNAi), we show that upon cell activation, SATB1 is not only required for chromatin folding into dense loops, but also for c-Maf induction and subsequently for Il4, Il5, and Il13 transcription. Our results show that SATB1 is an important determinant for chromatin architecture that constitutes a novel higher-order, transcriptionally-active chromatin structure upon Th2-cell activation

The effects of six weeks of supplementation with multi-ingredient performance supplements and resistance training on anabolic hormones, body composition, strength, and power in resistance-trained men

<p>Abstract</p> <p>Background</p> <p>Resistance training (RT) enhances muscle protein synthesis and hypertrophy while increasing strength and power. Some multi-ingredient performance supplements (MIPS) have been shown to augment the physiological improvements associated with RT. The purpose of this study was to investigate the impact of specific pre- and post-workout MIPS on anabolic hormones, body composition, muscle strength, and power in resistance-trained men participating in a periodized RT program.</p> <p>Methods</p> <p>Twenty-four ( mean ± SE; 24.0 ± 0.9 years; 180.5 ± 5.8 cm; 83.7 ± 0.5 kg) resistance-trained men completed 6 wks of periodized RT (3x/wk). Participants were assigned to one of two groups based upon maximal voluntary contraction of the quadriceps (Biodex) to lean mass (LM) ratio. Group 1 (n = 13; MIPS) consumed one serving of NO-Shotgun® (whey protein, casein protein, branched-chain amino acids, creatine, beta alanine, and caffeine) before each workout and one serving of NO-Synthesize® (whey protein, casein protein, branched-chain amino acids, creatine, and beta alanine; Vital Pharmaceuticals, Inc., Davie, FL) immediately after each workout and on non-RT days. Group 2 (n = 11; Placebo; PLA) consumed a flavor-matched isocaloric maltodextrin placebo. Serum insulin-like growth factor 1, human growth hormone, testosterone, body composition (DXA), circumferences, 1-repetition maximal strength (1RM) of the upper (chest press) and lower body (leg press), and anaerobic power (Wingate test) were assessed before and after the intervention. Statistical analysis included a 2 × 2 (group x time) ANOVA with repeated measures. Tukey LSD post hoc tests were used to examine pairwise differences. Significance was set at p < 0.05.</p> <p>Results</p> <p>There was a main time effect (p = 0.035) for testosterone to increase, but no differences between groups were observed. There were no differences in the other blood hormones. Group x time interactions were observed for LM (MIPS: PRE, 62.9 ± 2.1 to POST, 65.7 ± 2.0 vs. PLA: PRE, 63.5 ± 2.3 to POST, 64.8 ± 2.5 kg; p = 0.017). Only a main effect of time was noted for circumference measures. Both groups increased upper and lower body 1RM strength to a similar degree. MIPS significantly increased peak anaerobic power (PRE, 932.7 ± 172.5 W vs. POST, 1119.2 ± 183.8 W, p = 0.002) while PLA remained unchanged (PRE, 974.4 ± 44.1 W vs. POST, 1033.7 ± 48.6 W, p = 0.166).</p> <p>Conclusion</p> <p>Consumption of MIPS during the course of a periodized RT program facilitated training-induced improvement in LM in trained males, whereas the consumption of PLA did not. MIPS improved measures of anaerobic power while PLA did not.</p

Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males

BACKGROUND: The purpose of this study was to examine whether ingesting a pre-workout dietary supplement (PWS) with and without synephrine (S) during training affects training responses in resistance-trained males. METHODS: Resistance-trained males (N = 80) were randomly assigned to supplement their diet in a double-blind manner with either a flavored placebo (PLA); a PWS containing beta-alanine (3 g), creatine nitrate as a salt (2 g), arginine alpha-ketoglutarate (2 g), N-Acetyl-L-Tyrosine (300 mg), caffeine (284 mg), Mucuna pruiriens extract standardized for 15% L-Dopa (15 mg), Vitamin C as Ascorbic Acid (500 mg), niacin (60 mg), folate as folic acid (50 mg), and Vitamin B12 as Methylcobalamin (70 mg); or, the PWS supplement with Citrus aurantium extract containing 20 mg of synephrine (PWS + S) once per day for 8-weeks during training. Participants donated a fasting blood sample and had body composition (DXA), resting heart rate and blood pressure, cognitive function (Stroop Test), readiness to perform, bench and leg press 1 RM, and Wingate anaerobic capacity assessments determined a 0, 4, and 8-weeks of standardized training. Data were analyzed by MANOVA with repeated measures. Performance and cognitive function data were analyzed using baseline values as covariates as well as mean changes from baseline with 95% confidence intervals (CI). Blood chemistry data were also analyzed using Chi-square analysis. RESULTS: Although significant time effects were seen, no statistically significant overall MANOVA Wilks’ Lambda interactions were observed among groups for body composition, resting heart and blood pressure, readiness to perform questions, 1RM strength, anaerobic sprint capacity, or blood chemistry panels. MANOVA univariate analysis and analysis of changes from baseline with 95% CI revealed some evidence that cognitive function and 1RM strength were increased to a greater degree in the PWS and/or PWS + S groups after 4- and/or 8-weeks compared to PLA responses. However, there was no evidence that PWS + S promoted greater overall training adaptations compared to the PWS group. Dietary supplementation of PWS and PWS + S did not increase the incidence of reported side effects or significantly affect the number of blood values above clinical norms compared to PLA. CONCLUSION: Results provide some evidence that 4-weeks of PWS and/or PWS + S supplementation can improve some indices of cognitive function and exercise performance during resistance-training without significant side effects in apparently health males. However, these effects were similar to PLA responses after 8-weeks of supplementation and inclusion of synephrine did not promote additive benefits. TRIAL REGISTRATION: This trial (NCT02999581) was retrospectively registered on December 16th 2016

Effects of acute ingestion of a pre-workout dietary supplement with and without p-synephrine on resting energy expenditure, cognitive function and exercise performance

Background The purpose of this study was to examine the effects of acute ingestion of a pre-workout dietary supplement (PWS) with and without p-synephrine (S) on perceptions of readiness to perform, cognitive function, exercise performance, and markers of safety. Methods In a randomized, double-blind, and counterbalanced manner; 25 healthy and recreationally active male and female participants ingested a flavored maltodextrin placebo (PLA), a PWS containing beta-alanine (3 g), creatine nitrate as a salt (2 g), arginine alpha-ketoglutarate (2 g), N-Acetyl-L-Tyrosine (300 mg), caffeine (284 mg), Mucuna pruiriens extract standardized for 15% L-Dopa (15 mg), Vitamin C as Ascorbic Acid (500 mg), niacin (60 mg), folate as folic acid (50 mg), and Vitamin B12 as Methylcobalamin (70 mg) with 2 g of maltodextrin and flavoring; or, the PWS with Citrus aurantium (PWS + S) extract standardized for 30% p-synephrine (20 mg). Participants had heart rate (HR), blood pressure, resting energy expenditure (REE), 12-lead electrocardiograms (ECG), perceptions about readiness to perform, cognitive function (Stroop Color-Word test), bench and leg press performance (2 sets of 10 repetitions at 70% of 1RM and 1 set to failure), and Wingate anaerobic capacity (WAC) sprint performance determined as well as donated blood samples prior to and/or following exercise/supplementation. Data were analyzed by MANOVA with repeated measures as well as mean changes from baseline with 95% confidence intervals (CI). Results No clinically significant differences were observed among treatments in HR, blood pressure, ECG, or general clinical blood panels. There was evidence that PWS and PWS + S ingestion promoted greater changes in REE responses. Participants reported higher perception of optimism about performance and vigor and energy with PWS and PWS + S ingestion and there was evidence that PWS and PWS + S improved changes in cognitive function scores from baseline to a greater degree than PLA after 1 or 2 h. However, the scores in the PWS + S treatment did not exceed PLA or PWS responses at any data point. No statistically significant differences were observed among treatments in total bench press lifting volume, leg press lifting volume or WAC sprint performance. Conclusions Within the confines of this study, ingestion of PWS and/or PWS + S prior to exercise appears to be well-tolerated when consumed by young, healthy individuals. The primary effects appear to be to increase REE responses and improve perceptions about readiness to perform and cognitive function with limited to no effects on muscular endurance and WAC. The addition of 20 mg of p-synephrine to the PWS provided limited to no additive benefits. Trial registration This trial (NCT02952014) was retrospectively registered on September 13th 2016