ubiquinone-9 and Body-Weight

A single missense mutation at position 159 of coenzyme Q9 (COQ9) (G→A; rs109301586) has been associated with genetic variation in fertility in Holstein cattle, with the A allele associated with higher fertility. COQ9 is involved in the synthesis of coenzyme COQ10, a component of the electron transport system of the mitochondria. Here we tested whether reproductive phenotype is associated with the mutation and evaluated functional consequences for cellular oxygen metabolism, body weight changes, and ovarian function. The mutation in COQ9 modifies predicted tertiary protein structure and affected mitochondrial respiration of peripheral blood mononuclear cells. The A allele was associated with low resting oxygen consumption and high electron transport system capacity. Phenotypic measurements for fertility were evaluated for up to five lactations in a population of 2273 Holstein cows. There were additive effects of the mutation (P < 0.05) in favor of the A allele for pregnancy rate, interval from calving to conception, and services per conception. There was no association of genotype with milk production or body weight changes postpartum. The mutation in COQ9 affected ovarian function; the A allele was associated with increased mitochondrial DNA copy number in oocytes, and there were overdominance effects for COQ9 expression in oocytes, follicle number, and antimullerian hormone concentrations. Overall, results show how a gene involved in mitochondrial function is associated with overall fertility, possibly in part by affecting oocyte quality.

Topics: Animals; Anti-Mullerian Hormone; Blastocyst; Body Weight; Cattle; Cell Respiration; Cumulus Cells; Endometrium; Energy Metabolism; Female; Fertility; Lactation; Mitochondria; Mutation, Missense; Oocytes; Ovary; Pregnancy; Ubiquinone

Oxidative stress has been associated with many pathological disorders such as atherosclerosis, diabetes and cancer. Supplementation with exogenous antioxidants, including phenolic compounds from plant sources, may help to restore the pro-oxidative/antioxidative balance. To take into account effects of absorption, metabolisation, plasma protein binding, distribution, and elimination, antioxidative research should not be limited to in vitro assays but be extended to in vivo models.. In the present work a quantified 50% EtOH root extract of Pueraria lobata (Willd.) Ohwi (Fabaceae) was selected to determine its in vivo antioxidative activity in a diabetic rat model, where diabetes and the accompanying oxidative stress were induced by intraperitoneal administration of streptozotocin. This root extract was found to contain 10.42+/-0.15% puerarin as the main constituent and smaller amounts of the related isoflavonoids 3'-hydroxypuerarin, 3'-methoxypuerarin, 6''-xylosylpuerarin, daidzin, genistin, daidzein and genistein, as determined by a validated HPLC method. This extract was administered orally at a daily dose of 500 mg/kg root extract, corresponding to 50mg/kg puerarin, during 3 weeks. In addition the effect on the plasma concentration of some fat-soluble antioxidants (co-enzyme Q(9), alpha- and gamma-tocopherol) was evaluated.. The level of malondialdehyde (MDA) in plasma, used as a marker of oxidative damage to lipids, was reduced to the same level as in healthy control animals, and as in the positive control group treated daily with 50mg/kg alpha-tocopherol acetate. No obvious signs of toxicity were observed by administration of 10x the treatment dose.

Topics: alpha-Tocopherol; Animals; Antioxidants; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Drugs, Chinese Herbal; gamma-Tocopherol; Isoflavones; Lipid Peroxidation; Male; Malondialdehyde; Oxidative Stress; Plant Extracts; Plant Roots; Pueraria; Rats; Rats, Wistar; Ubiquinone

We recently reported insulin resistance in adult offspring of obese C57BL/6J mice. We have now evaluated whether parameters of skeletal muscle structure and function may play a role in insulin resistance in this model of developmental programming. Obesity was induced in female mice by feeding a highly palatable sugar and fat-rich diet for 6 wk prior to pregnancy, and during pregnancy and lactation. Offspring of obese dams were weaned onto standard laboratory chow. At 3 mo of age, skeletal muscle insulin signaling protein expression, mitochondrial electron transport chain activity (ETC), muscle fiber type, fiber density, and fiber cross-sectional area were compared with that of offspring of control dams weaned onto the chow diet. Female offspring of obese dams demonstrated decreased skeletal muscle expression of p110beta, the catalytic subunit of PI3K (P < 0.01), as well as reduced Akt phosphorylation at Serine residue 473 compared with control offspring. Male offspring of obese dams demonstrated increased skeletal muscle Akt2 and PKCzeta expression (P < 0.01; P < 0.001, respectively). A decrease in mitochondrial-linked complex II-III was observed in male offspring of obese dams (P < 0.01), which was unrelated to CoQ deficiency. This was not observed in females. There were no differences in muscle fiber density between offspring of obese dams and control offspring in either sex. Sex-related alterations in key insulin-signaling proteins and in mitochondrial ETC may contribute to a state of insulin resistance in offspring of obese mice.

Topics: Animal Nutritional Physiological Phenomena; Animals; Body Weight; Class I Phosphatidylinositol 3-Kinases; Disease Models, Animal; Electron Transport Complex II; Electron Transport Complex III; Female; Glucose Transporter Type 4; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Maternal Nutritional Physiological Phenomena; Mice; Mice, Inbred C57BL; Mitochondria, Muscle; Muscle Fibers, Skeletal; Obesity; Phosphatidylinositol 3-Kinases; Phosphorylation; Pregnancy; Prenatal Exposure Delayed Effects; Protein Kinase C; Proto-Oncogene Proteins c-akt; Quadriceps Muscle; Receptor, Insulin; Sex Factors; Signal Transduction; Ubiquinone

Coenzyme Q(10) (CoQ(10)) is widely consumed as a dietary supplement to enhance bioenergetic capacity and to ameliorate the debilitative effects of the aging process or certain pathological conditions. Our main purpose in this study was to determine whether CoQ(10) intake does indeed attenuate the age-associated losses in motor, sensory, and cognitive functions or decrease the rate of mortality in mice. Mice were fed a control nonpurified diet or that diet containing 0.68 mg/g (low dosage) or 2.6 mg/g (high dosage) CoQ(10), starting at 4 mo of age, and were tested for sensory, motor, and cognitive function at 7, 15, and 25 mo of age. Amounts of the ubiquinols CoQ(9)H(2) and CoQ(10)H(2) measured in a parallel study were augmented in the cerebral cortex but not in any other region of the brain. Intake of the low-CoQ(10) diet did not affect age-associated decrements in muscle strength, balance, coordinated running, or learning/memory, whereas intake at the higher amount increased spontaneous activity, worsened the age-related losses in acuity to auditory and shock stimuli, and impaired the spatial learning/memory of old mice. The CoQ(10) diets did not affect survivorship of mice through 25 mo of age. Our results suggest that prolonged intake of CoQ(10) in low amounts has no discernable impact on cognitive and motor functions whereas intake at higher amounts exacerbates cognitive and sensory impairments encountered in old mice. These findings do not support the notion that CoQ(10) is a fitness-enhancing or an "antiaging" substance under normal physiological conditions.

Topics: Aging; Animals; Body Weight; Brain; Brain Chemistry; Cognition; Dietary Supplements; Drug Administration Schedule; Eating; Male; Mice; Mice, Inbred C57BL; Ubiquinone

There is substantial evidence that a bioenergetic defect may play a role in the pathogenesis of Huntington's Disease (HD). A potential therapy for remediating defective energy metabolism is the mitochondrial cofactor, coenzyme Q10 (CoQ10). We have reported that CoQ10 is neuroprotective in the R6/2 transgenic mouse model of HD. Based upon the encouraging results of the CARE-HD trial and recent evidence that high-dose CoQ10 slows the progressive functional decline in Parkinson's disease, we performed a dose ranging study administering high levels of CoQ10 from two commercial sources in R6/2 mice to determine enhanced efficacy. High dose CoQ10 significantly extended survival in R6/2 mice, the degree of which was dose- and source-dependent. CoQ10 resulted in a marked improvement in motor performance and grip strength, with a reduction in weight loss, brain atrophy, and huntingtin inclusions in treated R6/2 mice. Brain levels of CoQ10 and CoQ9 were significantly lower in R6/2 mice, in comparison to wild type littermate control mice. Oral administration of CoQ10 elevated CoQ10 plasma levels and significantly increased brain levels of CoQ9, CoQ10, and ATP in R6/2 mice, while reducing 8-hydroxy-2-deoxyguanosine concentrations, a marker of oxidative damage. We demonstrate that high-dose administration of CoQ10 exerts a greater therapeutic benefit in a dose dependent manner in R6/2 mice than previously reported and suggest that clinical trials using high dose CoQ10 in HD patients are warranted.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenosine Triphosphate; Animals; Body Weight; Coenzymes; Deoxyguanosine; Disease Models, Animal; Dose-Response Relationship, Drug; Huntingtin Protein; Huntington Disease; Male; Mice; Mice, Transgenic; Neostriatum; Nerve Tissue Proteins; Neuroprotective Agents; Nuclear Proteins; Rotarod Performance Test; Treatment Outcome; Ubiquinone

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to prevent or reverse hypertrophy of the LV in several models of left ventricular hypertrophy. The aim of the present study was to determine whether treatment with simvastatin can prevent hypertension, reduction of tissue nitric oxide synthase activity and left ventricular (LV) remodeling in NG-nitro-L-arginine methyl ester(L-NAME)-induced hypertension. Four groups of rats were investigated: control, simvastatin (10 mg/kg), L-NAME (40 mg/kg) and L-NAME + simvastatin (in corresponding doses). Animals were sacrificed and studied after 6 weeks of treatment. The decrease of NO-synthase activity in the LV, kidney and brain was associated with hypertension, LV hypertrophy and fibrosis development and remodeling of the aorta in the L-NAME group. Simvastatin attenuated the inhibition of NO-synthase activity in kidney and brain, partly prevented hypertension development and reduced the concentration of coenzyme Q in the LV. Nevertheless, myocardial hypertrophy, fibrosis and enhancement of DNA concentration in the LV, and remodeling of the aorta were not prevented by simultaneous simvastatin treatment in the L-NAME treated animals. We conclude that the HMG-CoA reductase inhibitor simvastatin improved nitric oxide production and partially prevented hypertension development, without preventing remodeling of the left ventricle and aorta in NO-deficient hypertension.

Topics: Animals; Aorta; Blood Pressure; Body Weight; Coenzymes; DNA; Enzyme Inhibitors; Fibrosis; Hemodynamics; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Organ Size; Rats; Rats, Wistar; Simvastatin; Ubiquinone; Ventricular Remodeling

Consistent with the postulated role of oxidative stress in the etiology of late diabetic complications, pharmacological interventions based on biological antioxidants have been suggested. The aim of the present study was to investigate the effect of dietary supplementation with the pyridoindole antioxidant stobadine on the myocardial antioxidant status and ultrastructure of streptozotocin-diabetic rats. Diabetic male Wistar rats were fed for 32 weeks a standard diet or a diet supplemented with stobadine (0.05% w/w). Control rats received a standard diet or stobadine-supplemented diet (0.16% w/w). Plasma levels of glucose, cholesterol and triglycerides were increased significantly by diabetes. Activities of superoxide dismutase and catalase were markedly elevated in the diabetic myocardium. Myocardial levels of conjugated dienes increased after eight months of diabetes, in spite of significantly increased myocardial alpha-tocopherol and coenzyme Q9 content. The long-term treatment of diabetic animals with stobadine (i) reduced plasma cholesterol and triglyceride levels yet left the severe hyperglycemia unaffected, (ii) reduced oxidative damage of myocardial tissue as measured by conjugated dienes, (iii) reversed myocardial levels of alpha-tocopherol and coenzyme Q9 to near control values, (iv) reduced elevated activity of superoxide dismutase in the diabetic myocardium, and (v) attenuated angiopathic and atherogenic processes in the myocardium as assessed by electron microscopy examination. These results are in accordance with the postulated prooxidant role of chronic hyperglycemia and provide further evidence that development of pathological changes in diabetic myocardium is amenable to pharmacological intervention by biological antioxidants.

Topics: Animals; Anti-Arrhythmia Agents; Antioxidants; Blood Glucose; Body Weight; Carbolines; Cardiomyopathies; Catalase; Cholesterol; Diabetes Mellitus, Experimental; Drinking; Eating; Glutathione Peroxidase; Heart; Male; Myocardium; Oxidation-Reduction; Random Allocation; Rats; Rats, Wistar; Superoxide Dismutase; Triglycerides; Ubiquinone; Vitamin E

The aim of this study was to investigate if feeding with carbonyl iron would facilitate the development of preneoplastic lesions initiated by diethylnitrosamine (DEN) and promoted by CCl4-induced liver cirrhosis.. Male Wistar rats were fed a diet with 1.25%-2.5% carbonyl iron for 23 weeks and received intragastric injections of CCl4 (1.0 or 2.0 ml/kg per week) for 13 weeks, followed by one i.p. injection of DEN (200 mg/kg), after which CCl4 was administered for 8 additional weeks. Animals were killed 48 h after the first CCl4 injection to evaluate liver necrosis, 8 weeks later to evaluate fibrosis, and 9 weeks after DEN to determine formation of glutathione S-transferase 7,7 (GST-7,7) positive foci.. Treatment with iron counteracted the increased serum alanine aminotransferase levels and liver necrosis following CCl4 administration. Hepatic levels of reduced Q9 and alpha-tocopherol were elevated in rats treated with CCl4 and decreased in rats treated with iron compared to the controls. Fibrogenesis was not altered by iron treatment. Nine weeks after DEN initiation, the number and volume density of GST-7,7-positive foci in rats treated with CCl4 were significantly increased as compared with controls, but co-treatment with iron inhibited this increase. Apoptotic index was increased in iron-loaded livers, and labelling index (the fraction of S-phase hepatocytes) was decreased by co-treatment with iron in livers exposed to CCl4.. Carbonyl iron depleted hepatic levels of antioxidants, it decreased CCl4-induced necrosis and cell proliferation, it enhanced apoptosis and did not facilitate fibrogenesis. These effects together may explain the suppression of CCl4-induced promotion after DEN initiation exerted by carbonyl iron in the present study.

Topics: Animals; Antioxidants; Apoptosis; Body Weight; Carbon Tetrachloride; Carcinogens; Cell Division; Diet; Diethylnitrosamine; Iron; Kupffer Cells; Liver; Liver Neoplasms, Experimental; Male; Necrosis; Organ Size; Rats; Rats, Wistar; Ubiquinone; Vitamin E

In order to examine whether iron and alcohol act synergistically during tumor initiation in vivo, we investigated the effects of dietary iron overload and a liquid ethanol-containing diet on the initiation phase of the Solt & Farber model of chemical hepatocarcinogenesis.. Following dietary supplementation with carbonyl iron for 8 weeks and ethanol pair-feeding according to Lieber deCarli for 5 weeks, animals were subjected to partial hepatectomy in order to induce regenerative cell proliferation and thereby "fix" putative DNA lesions. Levels of malondialdehyde, reduced and oxidized ubiquinone-9, alpha-tocopherol and 8-oxo-2'-deoxyguanosine were analyzed in liver tissue removed at the time of partial hepatectomy, and blood was collected for determination of alanine amino-transferase activities. Following a 2-week recovery period, promotion was achieved with 0.02% dietary 2-acetylaminofluorene and carbon tetrachloride. Two weeks after the completion of promotion, animals were sacrificed and the number of preneoplastic, glutathione S-transferase 7,7-positive lesions counted. Animals initiated with diethylnitrosamine served as a positive control group.. Serum aminotransferase activities were significantly increased, and hepatic contents of ubiquinol-9 (reduced ubiquinone-9) were significantly decreased in animals exposed to the combination of iron and ethanol in comparison to the other groups. Livers from iron-treated animals had decreased levels of alpha-tocopherol and increased contents of malondialdehyde, whereas treatment with ethanol did not further enhance these alterations. Levels of 8-oxo-2'-deoxyguanosine were not significantly different in animals treated with iron, ethanol or iron + ethanol as compared with controls. The number of preneoplastic foci at the time of sacrifice was not increased in livers exposed to iron and/or ethanol as compared with those from control animals. As expected, the number of foci was significantly increased in positive controls which were initiated with diethylnitrosamine.. Iron potentiated the cytotoxic effects of ethanol, resulting in increased serum aminotransferase activities and decreased hepatic contents of ubiquinol. However, the combination of iron and ethanol did not exert genotoxic effects detectable as enhanced hepatic levels of 8-oxo-2'-deoxyguanosine, or increased formation of preneoplastic, glutathione S-transferase 7,7-positive lesions in the Solt & Farber model of chemical hepatocarcinogenesis.

Topics: Alanine Transaminase; Animals; Antioxidants; Body Weight; Disease Models, Animal; Ethanol; Iron Overload; Liver; Liver Neoplasms, Experimental; Male; Malondialdehyde; Rats; Rats, Sprague-Dawley; Rats, Wistar; Ubiquinone; Vitamin E

Alcohol metabolism may result in oxidant stress and free radical injury through a variety of mechanisms. Lovastatin may also produce oxidant stress by reducing levels of an endogenous antioxidant, coenzyme Q (CoQ). The separate and combined effects of ethanol, 20 EN% in a total liquid diet, and lovastatin, 67 mg/kg diet, on alpha-tocopherol, retinol palmitate, CoQ9 and thiobarbituric acid reactive (TBAR) material in liver from rats were determined. The effect of exogenous CoQ10 on these treatment groups was also determined. Food consumption, weight gain, liver lipid and TBAR material were similar between treatment groups. Compared to control animals, ethanol reduced retinol palmitate significantly, from 143 to 90 micrograms/g wet weight. Lovastatin had no effect on retinal palmitate nor did it act additively with ethanol. Ethanol decreased liver alpha-tocopherol from 28 to 12 micrograms/g wet weight and lovastatin diminished it to 12 micrograms; no additive effect was evident. Ethanol had no effect, but lovastatin decreased CoQ9 from 83 to 55 micrograms/g wet weight. Supplementation with CoQ10 did not modulate the effect of ethanol on retinal palmitate, but it did reverse the effect of lovastatin on CoQ9. Supplementary CoQ10 did not alter control levels of alpha-tocopherol, but it appeared to reverse most of the decrease in alpha-tocopherol attributable to ethanol or lovastatin separately. It only partially reversed the effect of ethanol and lovastatin combined on alpha-tocopherol, however. As expected, lovastatin had no effect on CoQ10 levels in supplemented animals. Ethanol, either separately or in combination with lovastatin, diminished liver stores of CoQ10 by almost 40%. We conclude that 20 EN% ethanol given in a liquid diet for 5 weeks is sufficient to lower retinol palmitate and that lovastatin reduces CoQ9. Both diminish alpha-tocopherol, an effect largely overcome by CoQ10 supplementation with either drug alone, but not with the combination. Since many individuals chronically consume the levels of ethanol represented by this experiment, and since a certain number of those also take lovastatin, further research into the possible clinical significance of these observations is warranted.

Topics: Animals; Antioxidants; Body Weight; Coenzymes; Diet; Diterpenes; Drug Evaluation, Preclinical; Ethanol; Liver; Liver Diseases, Alcoholic; Lovastatin; Organ Size; Oxidative Stress; Rats; Rats, Sprague-Dawley; Retinyl Esters; Thiobarbituric Acid Reactive Substances; Ubiquinone; Vitamin A; Vitamin E