RESUMO
Rhabdomyosarcoma (RMS) is a rare type of soft tissue sarcoma most commonly found in pediatric patients. Despite progress, new and improved drug regimens are needed to increase survival rates. Citral, a natural product plant oil can induce cell death in cancer cells. Another compound, metformin, isolated originally from French lilac and used by diabetics, has been shown to reduce the incidence of cancer in these patients. Application of citral to RMS cells showed increase in cell death, and RD and RH30 cells showed half maximal inhibitory concentration (IC50 ) values as low as 36.28 µM and 62.37 µM, respectively. It was also shown that the citral initiated cell apoptosis through an increase in reactive oxygen species (ROS) and free calcium. In comparison, metformin only showed moderate cell death in RMS cell lines at a very high concentration (1,000 µM). Combinatorial experiments, however, indicated that citral and metformin worked antagonistically when used together. In particular, the ability of metformin to quench the ROS induced by citral could lead to the suppression of activity. These results clearly indicate that while clinical use of citral is a promising anti-tumor therapy, caution should be exercised in patients using metformin for diabetes.
Assuntos
Monoterpenos Acíclicos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Medicina Tradicional Chinesa/métodos , Metformina/uso terapêutico , Rabdomiossarcoma/tratamento farmacológico , Monoterpenos Acíclicos/farmacologia , Criança , Humanos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Rabdomiossarcoma/patologiaRESUMO
Coenzyme Q10 (CoQ10) is a lipophilic redox molecule that is present in membranes of almost all cells in human tissues. CoQ10 is, amongst other functions, essential for the respiratory transport chain and is a modulator of inflammatory processes and gene expression. Rare monogenetic CoQ10 deficiencies show noticeable symptoms in tissues (e.g. kidney) and cell types (e.g. neurons) with a high energy demand. To identify common genetic variants influencing serum CoQ10 levels, we performed a fixed effects meta-analysis in two independent cross-sectional Northern German cohorts comprising 1300 individuals in total. We identified two genome-wide significant susceptibility loci. The best associated single nucleotide polymorphism (SNP) was rs9952641 (P value = 1.31 × 10 -8, ß = 0.063, CI0.95 [0.041, 0.085]) within the COLEC12 gene on chromosome 18. The SNP rs933585 within the NRXN-1 gene on chromosome 2 also showed genome wide significance (P value = 3.64 × 10 -8, ß = -0.034, CI0.95 [-0.046, -0.022]). Both genes have been previously linked to neuronal diseases like Alzheimer's disease, autism and schizophrenia. Among our 'top-10' associated variants, four additional loci with known neuronal connections showed suggestive associations with CoQ10 levels. In summary, this study demonstrates that serum CoQ10 levels are associated with common genetic loci that are linked to neuronal diseases.
Assuntos
Degeneração Neural/genética , Ubiquinona/análogos & derivados , Adulto , Idoso , Ataxia/genética , Ataxia/metabolismo , Proteínas de Ligação ao Cálcio , Moléculas de Adesão Celular Neuronais/genética , Colectinas/genética , Estudos Transversais , Feminino , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Debilidade Muscular/genética , Debilidade Muscular/metabolismo , Degeneração Neural/etiologia , Proteínas do Tecido Nervoso/genética , Moléculas de Adesão de Célula Nervosa , Neurônios , Polimorfismo de Nucleotídeo Único/genética , Receptores Depuradores/genética , Ubiquinona/sangue , Ubiquinona/deficiência , Ubiquinona/genética , Ubiquinona/metabolismoRESUMO
Coenzyme Q10 (CoQ10) is synthesized in almost all human tissues and presumably involved in age-related alterations and diseases. Here, we examined the impact of aging and sex on the serum CoQ10 status in 860 European adults ranging in age from 18 to 82 years. We identified an inverse U-shaped relationship between CoQ10 concentration and age. Women showed lower cholesterol-adjusted CoQ10 levels than men, irrespective of age. As observed in both sexes, the decrease in CoQ10 concentration in older subjects was accompanied by a shift in the redox status in favour of the oxidized form. A strong positive correlation was found for total CoQ10 and cholesterol concentrations (Spearman's, p≤1E-74). We found strong negative correlations between total (Spearman's, p≤1E-07) and between cholesterol-adjusted CoQ10 concentration (Spearman's, p≤1E-14) and the proportion of the oxidized form of CoQ10. These correlations were not dependent on age and sex and were attenuated by supplementation with 150 mg/day reduced CoQ10 for 14 days. Overall, our results are useful to define risk groups with critical CoQ10 status in humans. In particular, older subjects were characterized by impaired CoQ10 status due to their lowered serum CoQ10 concentration and concomitant decrease of CoQ10 redox capacity.
RESUMO
Homozygosity for a premature stop codon at amino acid position 577 in the alpha-actinin-3 (ACTN3) gene leads to α-actinin-3 deficiency. This genotype is observed in approximately 18% of Caucasians. The ACTN3 R577X polymorphism has been previously associated with indicators of physical performance in several, but not all, studies. We examined the prevalence of R577X (rs1815739) and two additional haplotype tagging single nucleotide polymorphisms (htSNPs) of the ACTN3 gene (rs1791690 and rs2275998) in the Genathlete study comprising 316 male elite endurance athletes (VO2max 79.0+3.5 ml · kg(-1) · min(-1); mean +/- s) from North America, Finland, and Germany and 304 sedentary controls (VO2max 40.1+7.0 ml · kg(-1) · min(-1) matched by country of origin. The distribution of genotype and allele frequencies between the two groups was tested by Pearson chi-square and/or Fischer exact test. The prevalence of the 577X homozygote genotype was similar in endurance athletes and controls (20% and 17.5%, respectively). The resulting odds ratio for endurance performance in 577X homozygotes compared with 577R-allele carriers was 1.24 (95%CI 0.82-1.87, P = 0.3). The genotype distribution of the two htSNPs and haplotype frequencies did not differ significantly between athletes and controls. In conclusion, our findings indicate that ACTN3 R577X and other SNPs in ACTN3 are not genetic determinants of endurance performance in Caucasian males.
Assuntos
Actinina/genética , Atletas , Desempenho Atlético , Resistência Física/genética , Polimorfismo de Nucleotídeo Único , População Branca/genética , Finlândia , Frequência do Gene , Genótipo , Alemanha , Homozigoto , Humanos , Masculino , América do Norte , Razão de ChancesRESUMO
INTRODUCTION: Coenzyme Q10 (CoQ10) is a lipophilic endogenously synthesised antioxidant that is present in nearly all human tissues and plays an important role in mitochondrial energy production. It has been postulated that smoking has a consumptive effect on CoQ10. MATERIAL AND METHODS: To further define the relation between smoking and the serum CoQ10 status, 276 healthy volunteers aged 19 to 62 years were grouped into non-smokers (n = 113; 77 male, 36 female) and smokers (n = 163; 102 male, 61 female). Serum lipid profile was analysed by standard clinical chemistry. Coenzyme Q10 concentration and redox status were analysed by high-pressure liquid chromatography with electrochemical detection. RESULTS: Male smokers showed higher serum CoQ10 levels than female smokers. This sex-related difference was accounted for when CoQ10 was related to low-density lipoprotein (LDL) cholesterol as the main carrier of CoQ10 in the circulation. Neither LDL-adjusted CoQ10 concentration nor redox status significantly differed when smokers and non-smokers were compared. Regarding the smoking history, the number of cigarettes consumed per day did not significantly affect the CoQ10 status. Interestingly, with increasing time of smoking habit we observed increasing levels of LDL-adjusted serum CoQ10 concentration (Spearman's p < 0.002) and of the reduced form of CoQ10 (Spearman's p < 0.0001). CONCLUSIONS: As an adaptive response to oxidative stress in long-term smokers an increased demand for antioxidant capacity may be covered by increasing levels of LDL-adjusted CoQ10 serum concentrations and by a concomitantly increased availability of the reduced, active form of CoQ10, possibly by induction of enzymes that are involved in converting CoQ10ox to CoQ10red.
RESUMO
In the present study the relationship between the CoQ10 redox state (% oxidized form of CoQ10 ) and the serum level of c-reactive protein (CRP) was investigated in a large Caucasian study population (n = 1319). In order to evaluate independently the influence of the variables that predict the outcome of CRP, an analysis of covariance (ANCOVA) was performed with CRP as the dependent variable. Gender was taken as an independent factor and CoQ10 redox and BMI as independent covariates. Results were substantiated with findings from a human intervention study (n = 53), receiving 150 mg/day ubiquinol for 14 days. Spearman's correlation revealed a significant (P < 0.001) association between the CoQ10 redox state and CRP concentrations in the whole study population. Thus, higher CRP concentrations were found in subjects having more oxidized CoQ10 . Similar results were evident for further inflammatory markers (interleukin-6, number of leucocytes). The ANCOVA revealed a significant (P < 0.001) prediction of CRP concentrations by CoQ10 redox state, after controlling for the effect of BMI and separately for gender. In the intervention study it was further found that the oral intake of ubiquinol increased its proportion significantly (P < 0.001), with the highest increase in those persons having a low basal serum ubiquinol content (<92.3%). Here it was discovered that the ubiquinol status significantly correlated to the concentration of the inflammation marker monocyte chemotactic protein 1. It is concluded that CoQ10 redox state predicts the concentration of CRP. Persons at risk with lower ubiquinol status, higher BMI, and low grade inflammation may benefit from ubiquinol supplementation. © 2016 BioFactors, 42(3):268-276, 2016.
Assuntos
Proteína C-Reativa/metabolismo , Inflamação/dietoterapia , Ubiquinona/análogos & derivados , Adolescente , Adulto , Índice de Massa Corporal , Quimiocina CCL2/sangue , Suplementos Nutricionais , Humanos , Inflamação/sangue , Interleucina-6/biossíntese , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Oxirredução , Estatísticas não Paramétricas , Ubiquinona/administração & dosagem , Ubiquinona/sangueRESUMO
Aging is associated with sarcopenia, which is a loss of skeletal muscle mass and function. Coenzyme Q10 (CoQ10) is involved in several important functions that are related to bioenergetics and protection against oxidative damage; however, the role of CoQ10 as a determinant of muscular strength is not well documented. The aim of the present study was to evaluate the determinants of muscular strength by examining hand grip force in relation to CoQ10 status, gender, age and body mass index (BMI) in two independent cohorts (n = 334, n = 967). Furthermore, peak flow as a function of respiratory muscle force was assessed. Spearman's correlation revealed a significant positive association between CoQ10/cholesterol level and hand grip in the basic study population (p<0.01) as well as in the validation population (p<0.001). In the latter, we also found a negative correlation with the CoQ10 redox state (p<0.01), which represents a lower percentage of the reduced form of CoQ10 (ubiquinol) in subjects who exhibit a lower muscular strength. Furthermore, the age of the subjects showed a negative correlation with hand grip (p<0.001), whereas BMI was positively correlated with hand grip (p<0.01), although only in the normal weight subgroup (BMI <25 kg/m2). Analysis of the covariance (ANCOVA) with hand grip as the dependent variable revealed CoQ10/cholesterol as a determinant of muscular strength and gender as the strongest effector of hand grip. In conclusion, our data suggest that both a low CoQ10/cholesterol level and a low percentage of the reduced form of CoQ10 could be an indicator of an increased risk of sarcopenia in humans due to their negative associations to upper body muscle strength, peak flow and muscle mass.
Assuntos
Envelhecimento/metabolismo , Colesterol/sangue , Metabolismo Energético/fisiologia , Força da Mão/fisiologia , Músculo Esquelético/metabolismo , Ubiquinona/análogos & derivados , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos de Coortes , Creatina Quinase/sangue , Creatinina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Fatores Sexuais , Ubiquinona/sangueRESUMO
BACKGROUND: Leptin has been considered a starvation hormone, but its role in malnourished patients is unknown. OBJECTIVE: We aimed to characterize the role of leptin in metabolic adaptation in women with anorexia nervosa (AN). DESIGN: In a cross-sectional study, 57 women with AN [mean (+/-SD) body mass index (kg/m(2)) on admission: 15.2 +/- 1.5] were compared with 49 healthy, normal-weight women (mean body mass index: 22.3 +/- 2.3). Nineteen patients were reinvestigated during weight gain 43 and 84 d after baseline. We measured serum concentrations of leptin, soluble leptin receptor, insulin, ghrelin, and thyroid hormones [thyrotropin, triiodothyronine (T(3)), and thyroxine]; fat mass (FM) and fat-free mass (FFM); resting energy expenditure (REE); energy intake; and eating behavior. RESULTS: Compared with values in the control women, leptin, T(3), REE, FM, and FFM were lower in the women with AN, but the leptin secretion rate was not significantly different. Leptin correlated with FM (r = 0.83, P < 0.001), T(3) (r = 0.68, P < 0.001), respiratory quotient (r = -0.47, P < 0.001), and REE (r = 0.58, P < 0.001). The association with REE weakened after adjustment for FFM and disappeared after further adjustment for T(3). Hunger and appetite had positive, whereas satiety and restraint had negative, associations with leptin. During weight gain (9.0 +/- 3.3 kg in 84 d), serum leptin and the leptin secretion rate increased. Changes in leptin secretion were associated with energy intake and REE. The initial changes in the leptin secretion rate (ie, the difference between baseline and 43 d) were negatively associated with changes in body weight from 43 to 84 d. CONCLUSIONS: Leptin contributes to metabolic adaptation in women with AN. The leptin response is associated with weight gain.
Assuntos
Anorexia Nervosa/metabolismo , Índice de Massa Corporal , Peso Corporal , Leptina/sangue , Adolescente , Adulto , Anorexia Nervosa/terapia , Metabolismo Basal , Estudos de Casos e Controles , Estudos Transversais , Ingestão de Alimentos/psicologia , Ingestão de Energia , Metabolismo Energético , Feminino , Humanos , Pessoa de Meia-Idade , Estado NutricionalRESUMO
OBJECTIVE: We aimed to define the effect of L-3,5,3'-tri-iodothyronine (T(3)) on metabolic adaptation in underweight patients with anorexia nervosa (AN) as well as during weight gain. METHODS: This involved clinical investigation of 28 underweight patients with AN, who were compared with 49 normal-weight controls. A subgroup of 17 patients was followed during weight gain. Resting energy expenditure was measured by indirect calorimetry. Body composition was measured by anthropometry as well as bioelectrical impedance analysis. Energy intake (EI) was assessed by a 3-day dietary record. Plasma concentrations of thyroid hormones (thyroxine (T(4)), T(3) and thyrotropin (TSH)) were analyzed by enzyme immunoassays. RESULTS: When compared with normal-weight women, underweight patients with AN had reduced fat mass (FM) (-71.3%), fat-free mass (FFM) (-13.1%), resting energy expenditure (REE) (-21.8%), T(3)- (-33.4%) and T(4)-concentrations (-19.8%) at unchanged TSH. REE remained reduced after adjustment for FFM (-24.6%). T(3) showed a close association with REE. This association remained after adjustment of REE for FFM. Treatment of underweight AN patients resulted in a mean weight gain of 8.3 kg. This was mainly explained by an increase in FM with small or no changes in FFM. REE and T(3) also increased (+9.3% and +33.3% respectively) at unchanged TSH and T(4). There was a highly significant association between weight gain-induced changes in T(3) and changes in adjusted REE (r = 0.78, P < 0.001, based on Pearson's correlation). An increase in plasma T(3) concentrations of 1.8 pmol/l could explain an increase in REE of 0.6 MJ/day (that is, a 32% increase in T(3) was associated with a 13% increase in REE). CONCLUSIONS: Our data provide evidence that the low T(3) concentrations add to metabolic adaptation in underweight patients with AN. During weight gain, increases in T(3) are associated with increases in REE, which is independent of FFM. Both results are evidence for a physiologic role of T(3) in modulation of energy expenditure in humans.
Assuntos
Anorexia Nervosa/metabolismo , Metabolismo Basal/fisiologia , Tri-Iodotironina/análogos & derivados , Tri-Iodotironina/sangue , Aumento de Peso/fisiologia , Adaptação Fisiológica/fisiologia , Adolescente , Adulto , Anorexia Nervosa/fisiopatologia , Peso Corporal/fisiologia , Calorimetria Indireta , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Descanso/fisiologiaRESUMO
Ubiquinone and ubiquinol represent the oxidized and reduced forms of Coenzyme Q10 (CoQ10). CoQ10 is present in membranes of almost all human tissues and organs, with highest concentration in the heart. In patients with heart failure, serum levels of the N-terminal pro-brain natriuretic peptide (NT-proBNP) are an indicator of disease severity. Here, we investigated the relationship between serum levels of CoQ10 and NT-proBNP in healthy volunteers of an elderly study population (mean age 52 years, n = 871). We found a negative association between serum levels of ubiquinol and NT-proBNP (P < 0.001). Accordingly, the CoQ10 redox state (% oxidized form of CoQ10) is positively associated with serum NT-proBNP level (P < 0.001). Compared to patients who survived a myocardial infarction (n = 21), healthy subjects have lower NT-proBNP level (500.39 ± 631.28 pg/ml vs. 76.90 ± 120.27 pg/ml, P < 0.001), higher ubiquinol serum level (0.43 ± 0.19 µmol/L vs. 0.71 ± 0.32 µmol/L; P < 0.001), and a lower CoQ10 redox state (27.6 ± 13.8% vs. 17.6 ± 10.1%; P < 0.001). Interestingly, ubiquinol supplementation (150 mg/day; 14 day; n = 53) slightly reduces the expression of CLCN6, a gene related to NT-proBNP level. In summary, higher serum levels of ubiquinol are associated with lower serum NT-proBNP levels in healthy elderly subjects. However, to what extent a high serum level of ubiquinol is a protective factor for heart failure remains to be elucidated in prospective studies.
Assuntos
Infarto do Miocárdio/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Ubiquinona/análogos & derivados , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Canais de Cloreto/sangue , Canais de Cloreto/genética , HDL-Colesterol/sangue , Suplementos Nutricionais , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Peptídeo Natriurético Encefálico/genética , Fragmentos de Peptídeos/genética , Triglicerídeos/sangue , Ubiquinona/administração & dosagem , Ubiquinona/sangueRESUMO
Dietary restriction (DR) is a robust intervention that extends both health span and life span in many organisms. Ubiquinol and ubiquinone represent the reduced and oxidized forms of coenzyme Q (CoQ). CoQ plays a central role in energy metabolism and functions in several cellular processes including gene expression. Here we used the model organism Caenorhabditis elegans to determine level and redox state of CoQ and expression of genes in response to DR. We found that DR down-regulates the steady-state expression levels of several evolutionary conserved genes (i.e. coq-1) that encode key enzymes of the mevalonate and CoQ-synthesizing pathways. In line with this, DR decreases the levels of total CoQ and ubiquinol. This CoQ-reducing effect of DR is obvious in adult worms but not in L4 larvae and is also evident in the eat-2 mutant, a genetic model of DR. In conclusion, we propose that DR reduces the level of CoQ and ubiquinol via gene expression in the model organism C. elegans.
Assuntos
Envelhecimento/metabolismo , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Restrição Calórica , Ubiquinona/análogos & derivados , Ubiquinona/metabolismo , Envelhecimento/genética , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Metabolismo Energético/genética , Regulação da Expressão Gênica , Longevidade/genética , Anotação de Sequência Molecular , Oxirredução , Transdução de SinaisRESUMO
Coenzyme Q10 (CoQ10 ) exists in a reduced (ubiquinol) and an oxidized (ubiquinone) form in all human tissues and functions, amongst others, in the respiratory chain, redox-cycles, and gene expression. As the status of CoQ10 is an important risk factor for several diseases, here we determined the CoQ10 status (ubiquinol, ubiquinone) in a large Caucasian study population (n = 1,911). The study population covers a wide age range (age: 18-83 years, 43.4% men), has information available on more than 10 measured clinical phenotypes, more than 30 diseases (presence vs. absence), about 30 biomarkers, and comprehensive genetic information including whole-genome SNP typing (>891,000 SNPs). The major aim of this long-term resource in CoQ10 research is the comprehensive analysis of the CoQ10 status with respect to integrated health parameters (i.e., fat metabolism, inflammation), disease-related biomarkers (i.e., liver enzymes, marker for heart failure), common diseases (i.e., neuropathy, myocardial infarction), and genetic risk in humans. Based on disease status, biomarkers, and genetic variants, our cohort is also useful to perform Mendelian randomisation approaches. In conclusion, the present study population is a promising resource to gain deeper insight into CoQ10 status in human health and disease.
Assuntos
Insuficiência Cardíaca/sangue , Infarto do Miocárdio/sangue , Neoplasias/sangue , Doenças Neurodegenerativas/sangue , Dor/sangue , Doenças do Sistema Nervoso Periférico/sangue , Ubiquinona/análogos & derivados , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Inflamação , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Ubiquinona/sangueRESUMO
Holocarboxylase synthetase (HLCS) is the sole protein-biotin ligase in the human proteome. HLCS has key regulatory functions in intermediary metabolism, including fatty acid metabolism, and in gene repression through epigenetic mechanisms. The objective of this study was to identify food-borne inhibitors of HLCS that alter HLCS-dependent pathways in metabolism and gene regulation. When libraries of extracts from natural products and chemically pure compounds were screened for HLCS inhibitor activity, resveratrol compounds in grape materials caused an HLCS inhibition of >98% in vitro. The potency of these compounds was piceatannol>resveratrol>piceid. Grape-borne compounds other than resveratrol metabolites also contributed toward HLCS inhibition, e.g., p-coumaric acid and cyanidin chloride. HLCS inhibitors had meaningful effects on body fat mass. When Drosophila melanogaster brummer mutants, which are genetically predisposed to storing excess amounts of lipids, were fed diets enriched with grape leaf extracts and piceid, body fat mass decreased by more than 30% in males and females. However, Drosophila responded to inhibitor treatment with an increase in the expression of HLCS, which elicited an increase in the abundance of biotinylated carboxylases in vivo. We conclude that mechanisms other than inhibition of HLCS cause body fat loss in flies. We propose that the primary candidate is the inhibition of the insulin receptor/Akt signaling pathway.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Carbono-Nitrogênio Ligases/antagonistas & inibidores , Drosophila melanogaster/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Estilbenos/farmacologia , Animais , Biotinilação/efeitos dos fármacos , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Lipase/genética , Masculino , Extratos Vegetais/farmacologia , Resveratrol , Estilbenos/metabolismo , Vitis/químicaRESUMO
BACKGROUND: The reduced form of Coenzyme Q10 (CoQ10), ubiquinol (Q10H2), serves as a potent antioxidant in mitochondria and lipid membranes. There is evidence that Q10H2 protects against oxidative events in lipids, proteins and DNA. Serum gamma-glutamyltransferase (GGT) activity is associated with cardiovascular diseases. In a physiological range, activity of GGT is a potential early and sensitive marker of inflammation and oxidative stress.In this study, we first examined the relationship between CoQ10 status and serum GGT activity in 416 healthy participants between 19 and 62 years of age in a cross-sectional study (cohort I). In the second step, 53 healthy males (21-48 years of age; cohort II) underwent a 14-day Q10H2 supplementation (150 mg/d) to evaluate the effect of Q10H2 supplementation on serum GGT activity and GGT1 gene expression. FINDINGS: There was a strong positive association between CoQ10 status and serum GGT activity in cohort I. However, a gender-specific examination revealed differences between male and female volunteers regarding the association between CoQ10 status and serum GGT activity. Q10H2 supplementation (cohort II) caused a significant decrease in serum GGT activity from T0 to T14 (p < 0.001). GGT1 mRNA levels declined 1.49-fold after Q10H2 supplementation. Of note, other liver enzymes (i.e., aspartate aminotransferase, AST) were not affected by Q10H2 supplementation. CONCLUSIONS: CoQ10 level is positively associated with serum GGT activity. Supplementation with Q10H2 reduces serum GGT activity. This effect might be caused by gene expression. Overall, we provide preliminary evidence that higher Q10H2 levels improve oxidative stress via reduction of serum GGT activity in humans. TRIAL REGISTRATION: Current Controlled Trials ISRCTN26780329.
Assuntos
Antioxidantes/metabolismo , Suplementos Nutricionais , Mitocôndrias/efeitos dos fármacos , Ubiquinona/análogos & derivados , gama-Glutamiltransferase/sangue , Adulto , Antioxidantes/administração & dosagem , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Estresse Oxidativo , Fatores de Risco , Ubiquinona/administração & dosagem , Ubiquinona/sangueRESUMO
Coenzyme Q derivatives (CoQ) are lipid soluble antioxidants that are synthesized endogenously in almost all species and function as an obligatory cofactor of the respiratory chain. There is evidence that CoQ status is altered by age in several species. Here we determined level and redox-state of CoQ in different age groups of pigs, mice and Caenorhabditis elegans. Since these species are very different with respect to lifespan, reproduction and physiology, our approach could provide some general tendencies of CoQ status in ageing organisms. We found that CoQ level decreases with age in pigs and mice, whereas CoQ content increases in older worms. As observed in all three species, ubiquinone, the oxidized form of CoQ, increases with age. Additionally, we were able to show that supplementation of ubiquinol-10, the reduced form of human CoQ10 , slightly increases lifespan of post-reproductive worms. In conclusion, the percentage of the oxidized form of CoQ increases with age indicating higher oxidative stress or rather a decreased anti-oxidative capacity of aged animals.
Assuntos
Envelhecimento/metabolismo , Estresse Oxidativo , Ubiquinona/metabolismo , Animais , Caenorhabditis elegans , Feminino , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Especificidade da Espécie , Sus scrofaRESUMO
BACKGROUND: Coenzyme Q10 is an essential cofactor in the respiratory chain and serves in its reduced form, ubiquinol, as a potent antioxidant. Studies in vitro and in vivo provide evidence that ubiquinol reduces inflammatory processes via gene expression. Here we investigate the putative link between expression and DNA methylation of ubiquinol sensitive genes in monocytes obtained from human volunteers supplemented with 150 mg/ day ubiquinol for 14 days. FINDINGS: Ubiquinol decreases the expression of the pro-inflammatory chemokine (C-X-C motif) ligand 2 gene (CXCL2) more than 10-fold. Bisulfite-/ MALDI-TOF-based analysis of regulatory regions of the CXCL2 gene identified six adjacent CpG islands which showed a 3.4-fold decrease of methylation status after ubiquinol supplementation. This effect seems to be rather gene specific, because ubiquinol reduced the expression of two other pro-inflammatory genes (PMAIP1, MMD) without changing the methylation pattern of the respective gene. CONCLUSION: In conclusion, ubiquinol decreases monocytic expression and DNA methylation of the pro-inflammatory CXCL2 gene in humans. Current Controlled Trials ISRCTN26780329.
Assuntos
Quimiocina CXCL2/metabolismo , Metilação de DNA/efeitos dos fármacos , Suplementos Nutricionais , Mediadores da Inflamação/metabolismo , Monócitos/efeitos dos fármacos , Ubiquinona/análogos & derivados , Adulto , Quimiocina CXCL2/genética , Ilhas de CpG/efeitos dos fármacos , Regulação para Baixo , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , RNA Mensageiro/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Ubiquinona/farmacologia , Adulto JovemAssuntos
Envelhecimento/patologia , Envelhecimento/fisiologia , Distúrbios Nutricionais/epidemiologia , Estado Nutricional , Idoso , Idoso de 80 Anos ou mais , Composição Corporal/fisiologia , Peso Corporal/fisiologia , Metabolismo Energético/fisiologia , Feminino , Avaliação Geriátrica , Humanos , MasculinoRESUMO
Hypoxia-inducible factor-1alpha (HIF1A) is a transcription factor regulating several genes in response to hypoxic stimuli. HIF1A target genes code for proteins involved in oxygen transport, glycolytic enzymes, and glucose transporters. We investigated whether single-nucleotide polymorphisms and haplotypes in the HIF1A gene are associated with endurance performance in the Genathlete cohort, which includes 316 Caucasian male elite endurance athletes (EEA) with a maximal oxygen uptake of 79.0+/-3.5 ml.kg(-1).min(-1) (mean+/-SD) and 304 Caucasian male sedentary controls with a maximal oxygen uptake of 40.1+/-7.0 ml.kg(-1).min(-1). Six single-nucleotide polymorphisms (rs1951795, rs11158358, rs2301113, rs11549465, rs115494657, rs17099207) were genotyped with the TaqMan system. We found a nominal significant tendency for a difference between the two groups for HIF1A Pro582Ser (rs11549465) genotype distributions (Pchi2=0.017). Homozygotes of the Pro genotype were slightly more frequent in athletes than in controls (84 vs. 75%). Compared with Ser carriers, the odds ratio (OR) of being an EEA in Pro/Pro homozygotes was 1.77 [95% confidence interval (CI): 1.18-2.67, P=0.006] compared with the other genotypes. A common HIF1A haplotype (frequency: 15%), including the rs11549465 Pro allele and the minor A allele of rs17099207 in the 3' flanking region of the gene, showed a significant association with EEA status (OR: 2.37, 95% CI: 1.21-4.66, P=0.012), whereas the most prevalent haplotype (frequency: 59%) comprising the rs11549465 Pro allele and the major G allele of rs1709920 showed no association with EEA status (OR: 0.93, 95% CI: 0.58-1.50, P=0.769). We found preliminary evidence that the HIF1A Pro582Ser polymorphism and a common haplotype of the HIF1A gene may be associated with EEA status in Caucasian men.
Assuntos
Haplótipos/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Músculo Esquelético/fisiologia , Resistência Física/genética , Polimorfismo de Nucleotídeo Único/genética , Esportes/fisiologia , Humanos , Masculino , Adulto JovemRESUMO
Current anthropometric indices for health risk assessment are indirect measures of total or visceral body fat mass that do not consider the inverse relationship of lean body mass to metabolic risk as well as the non-linear relationship between central obesity and insulin resistance. We examined a new anthropometric index that reflects the relationship of waist circumference (WC) as a risk factor to fat-free mass (FFM) as a protective parameter of body composition. In a population of 335 adults (191 females and 144 males; mean age 53 (SD 13.9) years) with a high prevalence of obesity (27%) and metabolic syndrome (30%) we derived FFM:WC(3) from the best fit of the relationship with metabolic risk factors (plasma triacylglycerol levels and insulin resistance by homeostasis model assessment index). Because FFM is known to be proportional to the cube of height, FFM was subsequently replaced by height(3) yielding height(3):WC(3) as an easily applicable anthropometric index. Significant inverse relationships of height(3):WC(3) to metabolic risk factors were observed for both sexes. They slightly exceeded those of conventional anthropometric indices such as BMI, WC or WC:hip ratio in women but not in men. The exponential character of the denominator WC(3) implies that at a given FFM with gradually increasing WC the increase in metabolic risk is lower than proportional. Further studies are needed to evaluate height(3):WC(3) as an anthropometric index for health risk assessment.
Assuntos
Antropometria/métodos , Doenças Cardiovasculares/patologia , Síndrome Metabólica/patologia , Gordura Abdominal/patologia , Adulto , Idoso , Composição Corporal , Constituição Corporal , Estatura , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco/métodos , Sensibilidade e Especificidade , Relação Cintura-QuadrilRESUMO
Air-displacement plethysmography (ADP) is now widely used for body composition measurement in pediatric populations. However, the manufacturer's software developed for adults leaves a potential bias for application in children and adolescents, and recent publications do not consistently use child-specific corrections. Therefore we analyzed child-specific ADP corrections with respect to quantity and etiology of bias compared with adult formulas. An optimal correction protocol is provided giving step-by-step instructions for calculations. In this study, 258 children and adolescents (143 girls and 115 boys ranging from 5 to 18 y) with a high prevalence of overweight or obesity (28.0% in girls and 22.6% in boys) were examined by ADP applying the manufacturer's software as well as published equations for child-specific corrections for surface area artifact (SAA), thoracic gas volume (TGV), and density of fat-free mass (FFM). Compared with child-specific equations for SAA, TGV, and density of FFM, the mean overestimation of the percentage of fat mass using the manufacturer's software was 10% in children and adolescents. Half of the bias derived from the use of Siri's equation not corrected for age-dependent differences in FFM density. An additional 3 and 2% of bias resulted from the application of adult equations for prediction of SAA and TGV, respectively. Different child-specific equations used to predict TGV did not differ in the percentage of fat mass. We conclude that there is a need for child-specific equations in ADP raw data analysis considering SAA, TGV, and density of FFM.