The common diabetes drug metformin can diminish the action of citral against Rhabdomyosarcoma cells in vitro.

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.

Coenzyme Q10 redox state predicts the concentration of c-reactive protein in a large caucasian cohort.

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.

Resveratrol compounds inhibit human holocarboxylase synthetase and cause a lean phenotype in Drosophila melanogaster.

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.

Determination of the coenzyme Q10 status in a large Caucasian study population.

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.

Association between serum level of ubiquinol and NT-proBNP, a marker for chronic heart failure, in healthy elderly subjects.

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.

Ubiquinol reduces gamma glutamyltransferase as a marker of oxidative stress in humans.

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.

A comparative study into alterations of coenzyme Q redox status in ageing pigs, mice, and worms.

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.

Ubiquinol decreases monocytic expression and DNA methylation of the pro-inflammatory chemokine ligand 2 gene in humans.

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.