Effects of acute beta-alanine supplementation on post-exertion rating of perceived exertion, heart rate, blood lactate, and physical performance on the 6-minute race test in middle-distance runners / Efectos de la suplementación aguda con beta-alanina sobre el índice de esfuerzo percibido, la frecuencia cardíaca y el lactato sanguíneo posesfuerzo, y el rendimiento físico en la prueba de carrera de 6 minutos en corredores de media distancia

Background: the use of beta-alanine (BA) to increase physical performance in the heavy-intensity domain zone (HIDZ) is widely documented. However, the effect of this amino acid on the post-exertion rating of perceived exertion (RPE), heart rate (HR), and blood lactate (BL) is still uncertain. Objectives: a) to determine the effect of acute BA supplementation on post-exertion RPE, HR, and BL in middle-distance athletes; and b) todetermine the effect of acute BA supplementation on physical performance on the 6-minute race test (6-MRT). Material and methods: the study included 12 male middle-distance athletes. The design was quasi-experimental, intrasubject, double-blind& crossover. It had two treatments (low-dose BA [30 mg·kg-1] and high-dose BA [45 mg·kg-1]) and a placebo, 72 hours apart. The effect of BA was evaluated at the end of the 6-MRT and post-exertion. The variables were RPE, HR and BL, and 6-MRT (m) distance. The statistical analysis included a repeated-measures ANOVA (p < 0.05). Results: the analysis evidenced no significant differences at the end of 6-MRT for all variables (p < 0.05). However, both doses of BA generated a lower post-exertion RPE. The high dose of BA caused significant increases in post-exertion BL (p < 0.05). Conclusion: acute supplementation with BA generated a lower post-exertion RPE. This decrease in RPE and the post-exertion BL increase could be related to an increase in physical performance in HIDZ. (AU)

Introducción: el uso de beta-alanina (BA) para aumentar el rendimiento físico en zonas con dominio de alta intensidad (HIDZ) está ampliamente documentado. Sin embargo, el efecto de este aminoácido sobre el índice de esfuerzo percibido (RPE), la frecuencia cardíaca (HR) y el lactato sanguíneo (BL) aún es incierto. Objetivos: a) determinar el efecto de la suplementación aguda de BA sobre el RPE, la HR y el BL posesfuerzo; y b) además del rendimiento en la prueba de carrera de 6 minutos (6-MRT), en atletas de media distancia. Material y métodos: el estudio incluyó a 12 atletas masculinos de media distancia. El diseño fue cuasiexperimental, intrasujeto, doble ciego y cruzado. Incluyó dos tratamientos (BA en dosis baja [30 mg·kg-1] y BA en dosis alta [45 mg·kg-1]) y placebo, con 72 horas de diferencia. El efecto de BA se evaluó al final de los 6-MRT y posesfuerzo. Las variables fueron RPE, HR y BL, y distancia en 6-MRT (m). El análisis estadístico incluyó un ANOVA de medidas repetidas (p < 0,05). Resultados: el análisis no evidenció diferencias significativas al final de los 6-MRT para todas las variables (p > 0,05). Sin embargo, ambasdosis de BA generaron un menor RPE posesfuerzo. La dosis alta de BA generó incrementos significativos en el BL posesfuerzo (p < 0,05). Conclusión: la suplementación aguda con BA generó un menor RPE posesfuerzo. Esta disminución del RPE y el aumento en el BL posesfuerzo podrían estar relacionados con un aumento del rendimiento físico en HIDZ. (AU)

Brain and testicular metabonomics revealed the protective effects of Guilingji on senile sexual dysfunction rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Guilingji (GLJ), which has been used to treat male diseases in China for centuries, contains 28 Chinese herbs and was previously established as an effective treatment for male sexual dysfunction. However, its mechanism of action remains unclear. AIM OF THE STUDY: To explore the efficacy and mechanism of action of GLJ in improving senile sexual dysfunction (SSD) in aging rats. MATERIALS AND METHODS: An aging rat model of SSD was induced by the subcutaneous injection of d-galactose (300 mg⋅kg-1) and used to analyse the effects of GLJ (different concentrations of 37.5, 75, and 150 mg⋅kg-1) on the mating of aging rats. At the end of the 8th week, histopathological analysis of testicular tissues, assessment of the hypothalamic-pituitary-gonadal (HPG) axis hormone levels in serum or brain, and metabonomics analysis of the brain and testicular tissue with liquid chromatography-mass spectrometry was performed to explore the mechanism of action of GLJ. RESULT: After treatment with GLJ, the mount and ejaculation latency levels were increased in the treatment group than those in model group (P < 0.05), moreover, the testicular morphology was improved. Gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) levels in rats were also improved significant (P < 0.05) compared with those in the model group. Furthermore, the metabonomics results in the testicular and brain tissue showed that GLJ improved SSD by adjusting amino acid and lipid metabolism. CONCLUSION: This study integrated the complementary metabolic profiles of the target tissues. GLJ might affect SSD rats by regulating amino acid and lipid metabolism and may modulate sensitivity to the signaling pathway in the HPG axis. This study provides an essential basis for the broad clinical application of GLJ.

Induction of CTH expression in response to amino acid starvation confers resistance to anti-LAT1 therapy in MDA-MB-231 cells.

L type amino acid transporter 1 (LAT1) is an attractive molecular target for cancer therapy because of its overexpression in many cancer cells. JPH203, a selective LAT1 inhibitor, causes amino acid deprivation and suppresses cancer cell proliferation. However, several cancer cells showed resistance to amino acid deprivation. In this study, we aimed to elucidate the molecular mechanism of different sensitivity between 2 breast cancer cells to anti-LAT1 therapy. MDA-MB-231 cells were more resistant to growth suppression effect of JPH203 than T-47D cells (IC50 was 200 ± 12.5 µM for MDA-MB-231, and 5 ± 1.1 µM for T-47D cells; p < 0.05). Transcriptome and biochemical analysis were done in these cells in the presence/absence of JPH203. JPH203 induced intracellular amino acid deprivation stress in both cells, but it upregulated cystathionine γ lyase (CTH), an enzyme for synthesis of antioxidants, only in MDA-MB-231 cells. Moreover, siRNA-mediated CTH knockdown induced oxidative stress in response to JPH203 leading to decreased cell viability in MDA-MB-231 cells. These results suggest that activation of anti-oxidation pathways in response to amino acid deprivation confers resistance to anti-LAT1 therapy.

In vivo and in silico studies on the mechanisms of egg white peptides in relieving acute colitis symptoms.

Active peptides, as an alternative nutrition supplement, have been confirmed to have beneficial efficacy against acute colitis. Herein, egg white peptides (EWPs) were used as a nutritional supplement to relieve dextran sulfate sodium-induced acute colitis symptoms. The potential multi-component synergetic pharmacological intervention mechanism of EWPs was investigated on the basis of in silico pharmacology, bioinformatics analysis, and molecular docking. In vitro experiments demonstrated that the migration rate of HSF cells was enhanced 5.30-fold upon treatment with EWPs relative to the control group. After administration with EWPs, colitis symptoms were alleviated in a dose-dependent manner and the serum amino acid content was significantly enhanced, especially for Ala, Leu, Ser, Thr, and Met. Four peptides identified from EWPs showed a total of 52 acute colitis-related potential targets (Fit score >3.8) with network pharmacology analysis, and the targets participated in 31 signaling pathways (p < 0.001). Among these pathways, PI3K-Akt, VEGF, Ras, TNF, and MAPK signaling pathways may exert essential anti-inflammatory effects and accelerate repairing intestinal mucosa. Molecular docking showed that the majority binding energy of peptides-targets was between -10.35 kcal mol-1 and -18.72 kcal mol-1, and peptides mainly interacted with the core targets (Btk, Gstm1, and Rac1) by hydrogen-bonding interactions. The current study confirmed that EWPs as supplementary nutrition can alleviate acute colitis.

A metabolomics study: Reveals the protective effect and mechanism of Terminalia chebula Retz on the cardiotoxicity induced by radix Aconiti kusnezoffii Reichb.

To reveal the protective effect of Terminalia chebula Retz (TCR) on cardiotoxicity induced by radix of Aconitum kusnezoffii Reichb (AKR). Control, AKR, AKR-TCR 1:3, AKR-TCR 1:1, AKR-TCR 3:1 and TCR-prepared AKR groups were set up. After treatment, the heart tissues were observed by H&E staining and transmission electron microscope. Serum myoglobin (MB) and troponin (cTn) were detected by ELISA. UPLC-Q Exactive/MS analysis was performed to detect the metabolic difference among the groups. ELISA results showed that the MB and cTn values of AKR group were significantly higher than Control group (P<0.05), while those of the other groups were lower than AKR group. TCR-prepared AKR group had similar MB and cTn contents to the Control group. Histopathological examination also indicated better detoxifying effects in the TCR-prepared AKR and AKR-TCR 1:1 group. The serum metabolomics analysis showed obvious distinction between the AKR and Control groups, while AKR-TCR combination reversed the metabolomics changes induced by AKR. Through multivariate statistical analysis, 9 metabolic markers related to energy, nucleic acid and amino acid metabolism were identified. Conclusively, AKR-induced cardiotoxicity may be related to energy, nucleic acid and amino acid metabolism, and TCR can reduce the cardiotoxicity by regulating the relative metabolism pathways.

Impact of ß-hydroxy-ß-methylbutyrate (HMB) on muscle loss and protein metabolism in critically ill patients: A RCT.

PURPOSE: Muscle wasting deteriorates life quality after critical illness and increases mortality. Wasting starts upon admission to intensive care unit (ICU). We aimed to determine whether ß-hydroxy-ß-methylbutyrate (HMB), a metabolite of leucine, can attenuate this process. METHODS: Prospective randomized, placebo-controlled double blind trial. INCLUSION CRITERIA: ICU patients depending on mechanical ventilation on day 3 having a functional gastrointestinal tract. They were randomized to HMB (3 g/day) or placebo (maltodextrin) from day 4 on for 30 days. PRIMARY OUTCOME: magnitude of loss of skeletal muscle area (SMA) of the quadriceps femoris measured by ultrasound at days 4 and 15. SECONDARY OUTCOMES: body composition, change in protein metabolism assessed by amino acids tracer pulse, and global health at 60 days. Data are mean [95% CI]. Statistics by ANCOVA with correction for confounders sex, age and/or BMI. RESULTS: Thirty patients completed the trial, aged 65 [59, 71] years, SAPS2 score 48 [43, 52] and SOFA 8.5 [7.4, 9.7]. The loss of total SMA was 11% between days 4 and 15 (p < 0.001), but not different between the groups (p = 0.86). In the HMB group, net protein breakdown (Δ Estimate HMB-Placebo: -153 [-242, -63]; p = 0.0021) and production of several amino acid was significantly reduced, while phase angle increased more (0.66 [0.09, 1.24]; p = 0.0247), and SF-12 global health improved more (Δ Estimate HMB-Placebo: 27.39 [1.594, 53.19], p = 0.04). CONCLUSION: HMB treatment did not significantly reduce muscle wasting over 10 days of observation (primary endpoint), but resulted in significantly improved amino acid metabolism, reduced net protein breakdown, a higher phase angle and better global health. CLINICALTRIALS. GOV IDENTIFIER: NCT03628365.

Effects of Vancomycin on Persistent Pain-Stimulated and Pain-Depressed Behaviors in Female Fischer Rats With or Without Voluntary Access to Running Wheels.

The present experiments determined the effects of the narrow-spectrum antibiotic vancomycin on inflammatory pain-stimulated and pain-depressed behaviors in rats. Persistent inflammatory pain was modeled using dilute formalin (0.5%). Two weeks of oral vancomycin administered in drinking water attenuated Phase II formalin pain-stimulated behavior, and prevented formalin pain-depressed wheel running. Fecal microbiota transplantation produced a non-significant trend toward reversal of the vancomycin effect on pain-stimulated behavior. Vancomycin depleted Firmicutes and Bacteroidetes populations in the gut while having a partial sparing effect on Lactobacillus species and Clostridiales. The vancomycin treatment effect was associated with an altered profile in amino acid concentrations in the gut with increases in arginine, glycine, alanine, proline, valine, leucine, and decreases in tyrosine and methionine. These results indicate that vancomycin may have therapeutic effects against persistent inflammatory pain conditions that are distal to the gut. PERSPECTIVE: The narrow-spectrum antibiotic vancomycin reduces pain-related behaviors in the formalin model of inflammatory pain. These data suggest that manipulation of the gut microbiome may be one method to attenuate inflammatory pain amplitude.

Effect of Lactic Fermentation Products on Human Epidermal Cell Differentiation, Ceramide Content, and Amino Acid Production.

INTRODUCTION: Lactic fermentation products (LFPs) are thought to affect "good" bacteria in the gut. We previously reported that oral administration of LFPs has beneficial therapeutic effects in a mouse model of atopic dermatitis. However, it is unclear how LFPs affect human epidermal cell differentiation, ceramide (Cer), and amino acid production. OBJECTIVE: The aim of this study was to determine the effects of LFPs on epidermal cell differentiation, by assessing amino acid and Cer production. METHODS: A 3-dimensional cultured human epidermis model and normal human epidermal keratinocytes were used. Cytotoxicity tests were performed using alamar Blue. Transepidermal water loss (TEWL) was used as an index to assess barrier function. Keratin 1 (K1), keratin 5 (K5), keratin 10 (K10), involucrin (INV), calpain 1, and transglutaminase (TGase) (markers of differentiation) and profilaggrin (proFLG) and bleomycin hydrolase (amino acid synthesis-related genes) expression levels were quantified by RT-PCR. In addition, TGase protein levels were measured by Western blotting. The intercellular lipid content of the stratum corneum was measured by high-performance thin-layer chromatography. Amino acids were quantified using an amino acid analyzer. Finally, bound water content in the stratum corneum was measured by differential scanning calorimetry. RESULTS: Cell viability did not change, but TEWL was significantly decreased in the cells treated with LFPs compared with the control cells. Treatment with LFPs significantly increased expression of the late-differentiation markers INV and TGase at the RNA level. Furthermore, TGase protein expression was significantly increased by treatment with LFPs. Treating a 3-dimensional cultured epidermis model with LFPs significantly increased the intercellular lipid content of the stratum corneum and production of the amino acid arginine (Arg). The amount of bound water in the stratum corneum was increased significantly in the LFP application group. CONCLUSION: Treatment with LFPs promotes human epidermal cell differentiation and increases the intercellular content of the free fatty acid, Chol, Cer [NS], Cer [AS], and Cer [AP]. This may result in improved skin barrier function. The increased amount of Arg observed in keratinocytes may help improve water retention.

Effects of low and high doses of fenofibrate on protein, amino acid, and energy metabolism in rat.

A feared adverse effect of dyslipidaemia therapy by fibrates is myopathy. We examined the effect of fenofibrate (FF) on protein and amino acid metabolism. Rats received a low (50 mg/kg, LFFD) or high (300 mg/kg, HFFD) dose of FF or vehicle daily by oral gavage. Blood plasma, liver, and soleus and extensor digitorum longus muscles were analysed after 10 days. The FF-treated rats developed hepatomegaly associated with increased hepatic carnitine and ATP and AMP concentrations, decreased protein breakdown, and decreased concentrations of DNA and triglycerides. HFFD increased plasma ALT and AST activities. The weight and protein content of muscles in the HFFD group were lower compared with controls. In muscles of the LFFD group there were increased ATP and decreased AMP concentrations; in the HFFD group AMP was increased. In both FF-treated groups there were increased glycine, phenylalanine, and citrulline and decreased arginine and branched-chain keto acids (BCKA) in blood plasma. After HFFD there were decreased levels of branched-chain amino acids (BCAA; valine, leucine and isoleucine), methionine, and lysine and increased homocysteine. Decreased arginine and increased glycine concentrations were found in both muscles in FF-treated animals; in HFFD-treated animals lysine, methionine, and BCAA were decreased. We conclude that FF exerts protein-anabolic effects on the liver and catabolic effects on muscles. HFFD causes signs of hepatotoxicity, impairs energy and protein balance in muscles, and decreases BCAA, methionine, and lysine. It is suggested that increased glycine and decreased lysine and methionine levels are due to activated carnitine synthesis; decreased BCAA and BCKA levels are due to increased BCAA oxidation.

Prebiotic properties of different polysaccharide fractions from Artemisia sphaerocephala Krasch seeds evaluated by simulated digestion and in vitro fermentation by human fecal microbiota.

Artemisia sphaerocephala Krasch polysaccharide (ASKP) and its two fractions-60P (branched xylan) and 60S (branched glucomannan), were subjected to simulated gastrointestinal digestion and in vitro fermentation by human fecal microbiota. The results showed that all polysaccharide fractions could transit through gastrointestinal tract without dramatic degradation and be utilized by gut microbiota. ASKP exhibited the highest depletion rate and highest capability to decrease the pH than its fractions. Meanwhile, 60S showed the stronger capability to increase the production of propionic acid and reduce the ratio of acetic acid to propionic acid. At the phylum level, all polysaccharides efficiently reduced the Firmicutes/Bacteroidetes ratio and relative abundance of Proteobacteria, with ASKP being the most capable to suppress the proliferation of Proteobacteria. At the genus level, ASKP and 60P markedly promoted the growth of Bacteroidetes, and 60S promoted the growth of Parabacteroides and Collinsella. Prediction on metabolic function revealed that polysaccharide administration could dramatically change the metabolic profile of bacteria compared with fructooligosaccharides. Besides, all the polysaccharides dramatically promoted the bile acid metabolism. Compared with 60S, ASKP and 60P showed stronger ability to suppress the metabolisms on carbohydrate and amino acid. In summary, both ASKP and its two fractions showed the prebiotic potentials.

Synergism between SLC6A14 blockade and gemcitabine in pancreactic cancer: a 1H-NMR-based metabolomic study in pancreatic cancer cells.

Gemcitabine is the first-line chemotherapy for pancreatic cancer. To overcome the often-acquired gemcitabine resistance, other drugs are used in combination with gemcitabine. It is well-known that cancer cells reprogram cellular metabolism, coupled with the up-regulation of selective nutrient transporters to feed into the altered metabolic pathways. Our previous studies have demonstrated that the amino acid transporter SLC6A14 is markedly up-regulated in pancreatic cancer and that it is a viable therapeutic target. α-Methyltryptophan (α-MT) is a blocker of SLC6A14 and is effective against pancreatic cancer in vitro and in vivo. In the present study, we tested the hypothesis that α-MT could synergize with gemcitabine in the treatment of pancreatic cancer. We investigated the effects of combination of α-MT and gemcitabine on proliferation, migration, and apoptosis in a human pancreatic cancer cell line, and examined the underlying mechanisms using 1H-NMR-based metabolomic analysis. These studies examined the intracellular metabolite profile and the extracellular metabolite profile separately. Combination of α-MT with gemcitabine elicited marked changes in a wide variety of metabolic pathways, particularly amino acid metabolism with notable alterations in pathways involving tryptophan, branched-chain amino acids, ketone bodies, and membrane phospholipids. The metabolomic profiles of untreated control cells and cells treated with gemcitabine or α-MT were distinctly separable, and the combination regimen showed a certain extent of overlap with the individual α-MT and gemcitabine groups. This represents the first study detailing the metabolomic basis of the anticancer efficacy of gemcitabine, α-MT and their combination.

Maternal supplementation with citrulline or arginine during gestation impacts fetal amino acid availability in a model of intrauterine growth restriction (IUGR).

BACKGROUND: Supplementing maternal diet with citrulline or arginine during gestation was shown to enhance fetal growth in a model of IUGR induced by maternal dietary protein restriction in the rat. OBJECTIVE: The aims of this study were to determine in the same model whether maternal supplementation with citrulline or arginine would increase 1) citrulline and arginine concentration in fetal circulation; 2) the expression of placental amino acid transporters, and 3) the fetal availability of essential amino acids. METHODS: Pregnant rats (n = 8 per group) were fed either an isocaloric control (20% protein, NP) or a low protein (LP, 4% protein) diet, either alone or supplemented with 2 g/kg/d of l-citrulline (LP + CIT) or isonitrogenous Arginine (LP + ARG) in drinking water throughout gestation. Fetuses were extracted by C-section on the 21st day of gestation. The gene expression of system A (Slc38a1, Slc38a2, and Slc38a4) and L (Slc7a2, Slc7a5, Slc7a8) amino acid transporters was measured in placenta and amino acid concentrations determined in maternal and fetal plasma. RESULTS: Maternal LP diet decreased fetal (4.01 ± 0.03 vs. 5.45 ± 0.07 g, p < 0.0001) and placental weight (0.617 ± 0.01 vs. 0.392 ± 0.04 g, p < 0.001), by 26 and 36% respectively, compared with NP diet. Supplementation with either CIT or ARG increased fetal birth weight by ≈ 5 or 11%, respectively (4.21 ± 0.05 and 4.48 ± 0.05 g vs. 4.01 ± 0.03 g, p < 0.05). CIT supplementation produced a 5- and 2-fold increase in fetal plasma citrulline and arginine, respectively, whereas ARG supplementation only increased fetal arginine concentration. LP diet led to lower placental SNAT 4 mRNA, and higher LAT2 and SNAT1 expression, compared with NP. SNAT4, 4hFC, LAT2 mRNA were up-regulated in LP + CIT and LP + ARG group compared with the un-supplemented LP group. Higher level of LAT1 mRNA was also observed in the LP + CIT group than in the LP group (p < 0.01). SNAT2 expression was unchanged in response to CIT or ARG supplementation. Fetal amino acid concentrations were decreased by LP diet, and were not restored by CIT or ARG supplementation. CONCLUSIONS: The current findings confirm supplementation with citrulline or arginine enhances fetal growth in a rat model of IUGR. They further suggest that: 1) citrulline and arginine administered orally to the pregnant mother may reach fetal circulation; 2) citrulline effectively raises fetal arginine availability; and 3) although it failed to increase the concentrations of essential amino acids in fetal plasma, citrulline or arginine supplementation upregulates the gene expression of several placental amino acid transporters.

Citrus polymethoxyflavones attenuate metabolic syndrome by regulating gut microbiome and amino acid metabolism.

Metabolic syndrome (MetS) is intricately linked to dysregulation of gut microbiota and host metabolomes. Here, we first find that a purified citrus polymethoxyflavone-rich extract (PMFE) potently ameliorates high-fat diet (HFD)-induced MetS, alleviates gut dysbiosis, and regulates branched-chain amino acid (BCAA) metabolism using 16S rDNA amplicon sequencing and metabolomic profiling. The metabolic protective effects of PMFE are gut microbiota dependent, as demonstrated by antibiotic treatment and fecal microbiome transplantation (FMT). The modulation of gut microbiota altered BCAA levels in the host serum and feces, which were significantly associated with metabolic features and actively responsive to therapeutic interventions with PMFE. Notably, PMFE greatly enriched the commensal bacterium Bacteroides ovatus, and gavage with B. ovatus reduced BCAA concentrations and alleviated MetS in HFD mice. PMFE may be used as a prebiotic agent to attenuate MetS, and target-specific microbial species may have unique therapeutic promise for metabolic diseases.

Serum metabonomics analysis of quercetin against the toxicity induced by cadmium in rats.

This study aimed to investigate the protective effect of quercetin against the toxicity induced by chronic exposure to low levels of cadmium in rats by an ultra performance liquid chromatography mass spectrometer. Rats were randomly divided into six groups as follows: control group (C), low dose of quercetin group (Q1: 10 mg/kg·bw), high dose of quercetin group (Q2: 50 mg/kg·bw), cadmium chloride group (D), low dose of quercetin plus cadmium chloride group (DQ1), and high dose of quercetin plus cadmium chloride group (DQ2). Cadmium chloride (CdCl2 ) was administered to rats by drinking water ad libitum in a concentration of 40 mg/L. The final amount of CdCl2 ingested was estimated from the water consumption data to be 4.85, 4.91, and 4.89 mg/kg·bw/day, for D, DQ1, and DQ2 groups, respectively. After a 12-week treatment, the serum samples of rats were collected for metabonomics analysis. Ten potential biomarkers were identified for which intensities were significantly increased or reduced as a result of the treatment. These metabolites included isorhamnetin 4'-O-glucuronide, 3-indolepropionic acid, tetracosahexaenoic acid, lysophosphatidylcholine (LysoPC) (20:5), lysoPC (18:3), lysophosphatidylethanolamine (LysoPE) (20:5/0:0), bicyclo-prostaglandin E2, sulpholithocholylglycine, lithocholyltaurine, and glycocholic acid. Results indicated that quercetin exerted a protective effect against cadmium-induced toxicity by regulating lipid and amino acid metabolism, enhancing the antioxidant defense system and protecting liver and kidney function.

Metabolomic analysis reveals metabolic alterations of human peripheral blood lymphocytes by perfluorooctanoic acid.

Perfluorooctanoic acid (PFOA) is a dispersive persistent organic pollutant in the environment. Accumulating reports suggest that PFOA is toxic to human lymphocytes; however, the toxicological effects of PFOA on these cells remain largely unclear. In this study, ultra-performance liquid chromatography (UPLC)-based metabolomic analysis was employed to identify metabolites in human peripheral blood lymphocytes and to assess the metabolic alterations caused by PFOA exposure. Our comparative metabolomic analysis results demonstrated that PFOA treatment could increase the level of organic acids and reduce the level of lipid molecules. Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation further highlighted the fact that the PFOA treatment interfered with the metabolism of amino acids, carbohydrates and lipids, which may lead to disruption of the immune system.

Short-Term Effects of Growth Hormone on Lipolysis, Glucose and Amino Acid Metabolism Assessed in Serum and Microdialysate of Healthy Young Men.

OBJECTIVE: We investigated direct effects of a therapeutic growth hormone dose on lipolysis, glucose and amino acid metabolism. METHODS: This crossover microdialysis trial involved six healthy male volunteers receiving single subcutaneous injections of both growth hormone (0.035 mg/kg) and placebo (0.9% sodium chloride). The investigation comprised three test days with standard diet. The first day served for adaptation, the second and third one for determining study data during 9 night hours with or without growth hormone. Abdominal subcutaneous microdialysate and blood were continuously collected and forwarded to a separate room next door where hourly taken samples were centrifuged and frozen until analysed. RESULTS: Growth hormone achieved the peak serum level after 3 h followed by a plateau-like course for the next 6 h. Glycerol in microdialysate started to rise 2 h following growth hormone injection achieving significance compared to placebo after 9 h (P<0.05). Serum glycerol increased 4 h after growth hormone administration achieving significance after 6 h (P<0.05). Glucose and amino acid concentrations showed neither in microdialysate nor in serum significant differences between growth hormone and placebo. Serum values of insulin and C-peptide revealed no significant difference between growth hormone and placebo. SUMMARY AND CONCLUSION: As the result of a high single subcutaneous dose of GH, persistent lipolysis can be shown in continuously collected microdialysate and blood, but no indication for gluconeogenesis or protein anabolism.

No evidence of attenuation of placental insulin-stimulated Akt phosphorylation and amino acid transport in maternal obesity and gestational diabetes mellitus.

Pregnancies complicated by obesity and/or gestational diabetes (GDM) are associated with peripheral insulin resistance; however, the insulin responsiveness of the placenta in these pregnancy complications remains largely unknown. We tested the hypothesis that primary human trophoblast cells and placental villous explants will be insulin responsive, characterized by amino acid transport, Akt and Erk activity with maternal obesity, and/or GDM. We evaluated term placentas from women with normal body mass index (BMI) (normal; n = 15), obesity (OB; n = 11), normal BMI with GDM (N-GDM; n = 11), and obesity with GDM (OB-GDM; n = 11). In a subgroup, primary human trophoblast cells (PHT) were isolated, and in an independent subgroup placental villous explants were exposed to varying concentrations of insulin. Amino acid transport capacity and insulin signaling activity were determined. Insulin significantly increased amino acid transport activity to a similar degree in PHT cells isolated from normal (+21%), N-GDM (+38%), OB (+37%), and OB-GDM (+35%) pregnancies. Insulin increased Akt and Erk phosphorylation in PHT cells (3-fold) and in villous explants (2-fold) in all groups to a similar degree. In contrast to the peripheral maternal insulin resistance commonly associated with obesity and/or GDM, we found that the placenta is insulin sensitive in these pregnancy complications. We suggest that elevated maternal insulin levels in pregnancies complicated by obesity and/or GDM promote critical placental functions, including amino acid transport. Insulin-stimulated placental nutrient delivery may contribute to the increased risk of fetal overgrowth and adiposity in these pregnancies. Moreover, our findings may inform efforts to optimize insulin regimens for women with GDM.

Effects of maternal alpha-ketoglutarate supplementation during lactation on the performance of lactating sows and suckling piglets.

The aim of the study was to investigate if dietary alpha-ketoglutarate (AKG) supplementation may improve the performance of lactating sows and their suckling piglets. After farrowing, 24 lactating sows (Large White × Landrace) with similar body weight (BW) were assigned to the control and AKG groups based on parity, and their lactation diets were supplemented with 0.00 or 0.25% AKG, respectively. It was found that supplementing the diet of lactating sows with 0.25% AKG enhanced growth performance of the suckling piglets from d 7 to d 21 of the lactation period, improved villus height of ileum and tended (p = 0.085) to increase mean volumetric bone mineral density of femur in the weanling piglets. In the lactating sows, dietary supplementation of AKG decreased plasma urea level on d 14 of lactation, decreased plasma calcium (Ca) concentrations from d 7 to d 21 of lactation and increased lactose and Ca levels in ordinary milk. Thus, it was proposed that AKG supplementation stimulates the capacity for lactose synthesis and Ca uptake in the mammary gland, thereby altering the composition of the ordinary milk which might be associated with the enhanced performance of piglets during the suckling period. These findings could lead to a better application of AKG in lactating nutrition, and therefore, promoting pork production.

Role of mitochondria in diabetic peripheral neuropathy: Influencing the NAD+-dependent SIRT1-PGC-1α-TFAM pathway.

Survival of human peripheral nervous system neurons and associated distal axons is highly dependent on energy. Diabetes invokes a maladaptation in glucose and lipid energy metabolism in adult sensory neurons, axons and Schwann cells. Mitochondrial (Mt) dysfunction has been implicated as an etiological factor in failure of energy homeostasis that results in a low intrinsic aerobic capacity within the neuron. Over time, this energy failure can lead to neuronal and axonal degeneration and results in increased oxidative injury in the neuron and axon. One of the key pathways that is impaired in diabetic peripheral neuropathy (DPN) is the energy sensing pathway comprising the nicotinamide-adenine dinucleotide (NAD+)-dependent Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α)/Mt transcription factor A (TFAM or mtTFA) signaling pathway. Knockout of PGC-1α exacerbates DPN, whereas overexpression of human TFAM is protective. LY379268, a selective metabolomic glutamate receptor 2/3 (mGluR2/3) receptor agonist, also upregulates the SIRT1/PGC-1α/TFAM signaling pathway and prevents DPN through glutamate recycling in Schwann/satellite glial (SG) cells and by improving dorsal root ganglion (DRG) neuronal Mt function. Furthermore, administration of nicotinamide riboside (NR), a precursor of NAD+, prevents and reverses DPN, in part by increasing NAD+ levels and SIRT1 activity. In summary, we review the role of NAD+, mitochondria and the SIRT1-PGC-1α-TFAM pathway both from the perspective of pathogenesis and therapy in DPN.

Amino Acid-Modified Conjugated Oligomer Self-Assembly Hydrogel for Efficient Capture and Specific Killing of Antibiotic-Resistant Bacteria.

Bacterial infection is one of main causes that threaten global human health. Especially, antibiotic-resistant bacteria like methicillin-resistant Staphylococcus aureus (MRSA) lead to high mortality rate and more expensive treatment cost. Here, a novel amino-acid-modified conjugated oligomer OTE-d-Phe was synthesized by modifying the side chain of conjugated oligo(thiophene ethynylene) with d-phenylalanine. By mixing 9-fluorenylmethyloxycarbonyl-l-phenylalanin (Fmoc-l-Phe) with OTE-d-Phe, a new and biocompatible low-molecular weight hydrogel (HG-2) was prepared through self-assembly. In solution, HG-2 can effectively capture bacteria spontaneously, such as Escherichia coli and MRSA. Most importantly, the hydrogel has specific and strong antibacterial activity against MRSA over methicillin-susceptible S. aureus, Staphylococcus epidermidis, and E. coli. Interestingly, when the hydrogel was put on a model surface, a piece of cloth, it also is able to selectively kill MRSA with low cell cytotoxicity. The antibacterial mechanism was investigated, and it demonstrated that the HG-2 interacts with and physically breaks the cell wall and membrane, which leads to MRSA death. Therefore, this new conjugated oligomer-based hydrogel provides promising applications in disinfection and therapy of MRSA in hospital and in community.