Coenzyme Q(10) and its effects in the treatment of neurodegenerative diseases

According to clinical and pre-clinical studies, oxidative stress and its consequences may be the cause or, at least, a contributing factor, to a large number of neurodegenerative diseases. These diseases include common and debilitating disorders, characterized by progressive and irreversible loss of neurons in specific regions of the brain. The most common neurodegenerative diseases are Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Coenzyme Q(10) (CoQ(10)) has been extensively studied since its discovery in 1957. It is a component of the electron transportation chain and participates in aerobic cellular respiration, generating energy in the form of adenosine triphosphate (ATP). The property of CoQ(10) to act as an antioxidant or a pro-oxidant, suggests that it also plays an important role in the modulation of redox cellular status under physiological and pathological conditions, also performing a role in the ageing process. In several animal models of neurodegenerative diseases, CoQ(10) has shown beneficial effects in reducing disease progression. However, further studies are needed to assess the outcome and effectiveness of CoQ(10) before exposing patients to unnecessary health risks at significant costs.

The Saccharomyces cerevisiae COQ10 gene encodes a START domain protein required for function of coenzyme Q in respiration

Deletion of the Saccharomyces cerevisiae gene YOL008W, here referred to as COQ10, elicits a respiratory defect as a result of the inability of the mutant to oxidize NADH and succinate. Both activities are restored by exogenous coenzyme Q(2). Respiration is also partially rescued by COQ2, COQ7, or COQ8/ABC1, when these genes are present in high copy. Unlike other coq mutants, all of which lack Q(6), the coq10 mutant has near normal amounts of Q(6) in mitochondria. Coq10p is widely distributed in bacteria and eukaryotes and is homologous to proteins of the aromatic-rich protein family Pfam03654 and to members of the START domain superfamily that have a hydrophobic tunnel implicated in binding lipophilic molecules such as cholesterol and polyketides. Analysis of coenzyme Q in polyhistidine-tagged Coq10p purified from mitochondria indicates the presence 0.032-0.034 mol of Q(6)/mol of protein. We propose that Coq10p is a Q(6)-binding protein and that in the coq10 mutant Q(6) it is not able to act as an electron carrier, possibly because of improper localization.

Distribution of neutral prilocaine in a phospholipid bilayer: Insights from molecular dynamics simulations

In this work, we report a 20-ns constant pressure molecular dynamics simulation of prilocaine (PLC), in amine-amide local anesthetic, in a hydrated liquid crystal bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine. The partition of PLC induces the lateral expansion of the bilayer and a concomitant contraction in its thickness. PLC molecules are preferentially found in the hydrophobic acyl chains region, with a maximum probability at similar to 12 angstrom from the center of the bilayer (between the C(4) and C(5) methylene groups). A decrease in the acyl chain segmental order parameter, vertical bar S-CD vertical bar, compared to neat bilayers, is found, in good agreement with experimental H-2-NMR studies. The decrease in vertical bar S-CD vertical bar induced by PLC is attributed to a larger accessible volume per lipid in the acyl chain region. (C) 2008 Wiley Periodicals, Inc.

Preferential location of prilocaine and etidocaine in phospholipid bilayers: A molecular dynamics study

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Co-feeding of live feed and inert diet from first-feeding affects Artemia lipid digestibility and retention in Senegalese sole (Solea senegalensis) larvae

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Growth hormone and heart failure: Oxidative stress and energetic metabolism in rats

Several evidences point for beneficial effects of growth hormone (GH) in heart failure (HF). Taking into account that HF is related with changes in myocardial oxidative stress and in energy generation from metabolic pathways, it is important to clarify whether GH increase or decrease myocardial oxidative stress and what is its effect on energetic metabolism in HF condition. Thus, this study investigated the effects of two different doses of GH on energetic metabolism and oxidative stress in myocardium of rats with HF. Male Wistar rats (n = 25) were submitted to aortic stenosis (AS). The HF was evidenced by tachypnea and echocardiographic criteria around 28 weeks of AS. The rats were then randomly divided into three groups: (HF) with HF, treated with saline (0.9% NaCl); (HF-GHI), treated with 1 mk/kg/day recombinant human growth hormone (rhGH), and (HF-GH2) treated with 2 mg/kg/day rhGH. GH was injected, subcutaneously, daily for 2 weeks. A control group (sham; n = 12), with the same age of the others rats was evaluated to confirm data for AS. HF had lower IGF-I (insulin-like growth factor-I) than sham-operated rats, and both GH treatments normalized IGF-I level. HF-GH1 animals had lower lipid hydroperoxide (LH), LH/total antioxidant substances (TAS) and glutathione-reductase than HF. Glutathione peroxidase (GSH-Px), hydroxyacyl coenzyme-A dehydrogenase, lactate dehydrogenase(LDH) were higher in HF-GH1 than in HF. HF-GH2 compared with HF, had increased LH/TAS ratio, as well as decreased oxidized glutathione and LDH activity. Comparing the two GH doses, GSH-Px, superoxide dismutase and LDH were lower in HF-GH2 than in HF-GHI. In conclusion, GH effects were dose-dependent and both tested doses did not aggravate the heart dysfunction. The higher GH dose, 2 mg/kg exerted detrimental effects related to energy metabolism and oxidative stress. The lower dose, 1 mg/kg GH exerted beneficial effects enhancing antioxidant defences, reducing oxidative stress and improving energy generation in myocardium of rats with heart failure. (c) 2007 Elsevier Ltd. All rights reserved.

Diet compounds, glycemic index and obesity-related cardiac effects

Background: Diet compounds may influence obesity-related cardiac oxidative stress and metabolic sifting. Carbohydrate-rich diet may be disadvantageous from fat-rich diet to cardiac tissue and glycemic index rather than lipid profile may predict the obesity-related cardiac effects.Materials and methods: Male Wistar rats were divided into three groups (n=8/group): (C) receiving standard chow (3.0 kcal/g); (CRD) receiving carbohydrate-rich diet (4.0 kcal/g), and (FRD) receiving fat-rich diet (4.0 kcal/g). Rats were sacrificed after the oral glucose tolerance test (OGTT) at 60 days of dietary treatments. Lipid profile and oxidative stress parameters were determined in serum. Myocardial samples were used to determine oxidative stress, metabolic enzymes, glycogen and triacylglycerol.Results: FRD rats showed higher final body weight and body mass index than CRD and C. Serum cholesterol and low-density lipoprotein were higher in FRD than in CRD, while triacylglycerol and oxidized low-density lipoprotein cholesterol were higher in CRD than in FRD. CRD rats had the highest myocardial lipid hydroperoxide and diminished superoxide dismutase and catalase activities. Myocardial glycogen was lower and triacylglycerol was higher in CRD than in C and FRD rats. Although FRD rats had depressed myocardial-reducing power, no significant changes were observed in myocardial energy metabolism. Myocardial beta-hydroxyacyl coenzyme-A dehydrogenase and citrate synthase, as well as the enhanced lactate debydrogenase/citrate synthase ratio indicated that fatty acid degradation was decreased in CRD rats. Glycemic index was positively correlated with obesity-related cardiac effects.Conclusions: Isoenergetic carbohydrate-rich and fat-rich diets induced different degree of obesity and differently affected lipid profile. Carbohydrate-rich diet was deleterious relative to fat-rich diet in the heart enhancing lipoperoxidation and shifting the metabolic pathway for energy production. Glycemic index rather than dyslipidemic profile may predict the obesity effects on cardiac tissue. (C) 2007 Elsevier B.V. All rights reserved.

Pro-oxidant activity of apocynin radical

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Influence of different doses of retinoic acid on cardiac remodeling

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Effects of N-acetylcysteine on sucrose-rich diet-induced hyperglycaemia, dyslipidemia and oxidative stress in rats

This study examined whether sucrose-rich diet (SRD)-induced hyperglycaemia, dyslipidemia and oxidative stress may be inhibited by N-acetylcysteine (C5H9-NO3S), an organosulfur from Allium plants. Male Wistar 40 rats were divided into four groups (n = 10): (C) given standard chow and water; (N) receiving standard chow and 2 mg/l N-acetylcysteine in its drinking water; (SRD) given standard chow and 30% sucrose in its drinking water; and (SRD-N) receiving standard chow, 30% sucrose and N-acetylcysteine in its drinking water. After 30 days of treatment, SRD rats had obesity with increased abdominal circumference, hyperglycaemia, by dyslipidemia and hepatic triacylglycerol accumulation. These adverse effects were associated with oxidative stress and depressed lipid degradation in hepatic tissue. The SRD adverse effects were not observed in SDR-N rats. N-Acetylcysteine reduced the oxidative stress, enhancing glutathione-peroxidase activity, and normalizing lipid hydroperoxyde, reduced glutathione and superoxide dismutase in hepatic tissue of SRD-N rats. The beta-hydroxyacyl coenzyme-A dehydrogenase and citrate-synthase activities were increased in SRD-N rats, indicating enhanced lipid degradation in hepatic tissue as compared to SRD. SRD-N rats had reduced serum oxidative stress and diminished glucose, triacylglycerol, very-low-density lipoprotein (VLDL), oxidized low-density lipoprotein (alpha-LDL) and cholesterol/highdensity lipoprotein (HDL) ratio in relation to SRD. In conclusion, NAC offers promising therapeutic values in prevention of dyslipidemic profile and alleviation of hyperglycaemia in high-sucrose intake condition by improving antioxidant defences. N-Acetylcysteine had also effects preventing metabolic shifting in hepatic tissue, thus enhancing fat degradation and reducing body weight gain in conditions of excess sucrose intake. The application of this agent in food system via exogenous addition may be feasible and beneficial for antioxidant protection. (c) 2006 Elsevier B.V All rights reserved.

Alcoholism and alcohol abstinence: N-acetylcysteine to improve energy expenditure, myocardial oxidative stress, and energy metabolism in alcoholic heart disease

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Proteomic analysis of kidney in rats chronically exposed to fluoride

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Diets rich in saturated and polyunsaturated fatty acids: Metabolic shifting and cardiac health

OBJECTIVE: the aim of this study was to determine the effects of diets rich in saturated and polyunsaturated fatty acids on metabolic pathways and the relation of metabolic shifting to oxidative stress in cardiac tissue.METHODS: Male Wistar rats (age, 60 d; n = 10) were fed with a control low-fat diet, a diet rich in saturated fatty acids (SFAs), or a diet rich in polyunsaturated fatty acids (PUFAs). After 5 wk of treatment, sera were used for protein and lipid determinations. Protein, glycogen, triacylglycerol, lactate dehydrogenase, citrate synthase, beta-hydroxyacyl coenzyme-A dehydrogenase, catalase, glutathione peroxidase, superoxide dismutase, lipoperoxide, and lipid hydroperoxide were measured in cardiac tissue.RESULTS: the SFA group had higher triacylglycerol, cholesterol, low-density lipoprotein cholesterol, and atherogenic index (ratio of cholesterol to high-density lipoprotein) than did the PUFA and control groups. The PUFA group had low serum cholesterol, triacylglycerol, and low-density lipoprotein cholesterol as compared with the SFA group. SFA increased myocardial lipid hydroperoxide and diminished glutathione peroxidase. Despite the beneficial effects on serum lipids, the PUFA diet led to the highest levels of myocardial lipoperoxide and lipid hydroperoxide and diminished superoxide dismutase and catalase activities. The PUFA effects were related to increased feed efficiency, increased susceptibility to lipoperoxidation, and metabolic shifting in cardiac tissue. PUFA elevated triacylglycerol levels and decreased myocardial glycogen concentrations. The ratios of lactate dehydrogenase to citrate synthase and beta-hydroxyacyl coenzyme-A dehydrogenase to citrate synthase were increased, indicating myocardial reduction of tricarboxylic acid cycle.CONCLUSIONS: PUFAs have been recommended as a therapeutic measure in preventive medicine to lower serum cholesterol, but PUFAs increased oxidative stress in the heart by providing cardiac susceptibility to lipoperoxidation and shifting the metabolic pathway for energy production. The control diet, which was much lower in calories and fat, produced better overall clinical outcomes, better fat profiles, and less oxidative stress than did the diets rich in fatty acids.

Conformational analyses and docking studies of a series of 5-nitrofuran- and 5-nitrothiophen-semicarbazone derivatives in three possible binding sites of trypanothione and glutathione reductases

To explore three possible binding sites of trypanothione and glutathione reductase, namely, the active, the dimer interface and the coenzyme NADPH binding site, a series of eight compounds, nitrofurans and nitrothiophenes derivatives, were docked, using their crystallographic and modeled conformations. Docking results showed that, for both families and both enzymes, compounds are more likely to bind in the interface site, even though there is some probability of binding in the active site. These studies are in agreement with experimental data, which suggest that these class of compounds can act either as uncompetitive or mixed type inhibitors, and also with the finding that there is an alpha-helix which connects the active with the interface site, thus allowing charge transference between them. (c) 2005 Elsevier B.V. All rights reserved.

Reagentless biosensor for isocitrate using one step modified Pt-Ir microelectrode

The Pt-Ir microelectrode modified through one step, electropolymerization is proposed for the isocitrate amperometric biosensor construction. The enzyme (isocitrate dehydrogenase-ICDH), coenzyme (NADP(+)) and mediator (Meldola's Blue) were immobilized onto the microelectrode surface in one step from a PIPES buffer solution containing pyrrole. The optimized experimental conditions were 25 cycles of cyclic voltammetric in a solution containing 3.58 10(-5) mol l(-1) of mediator, 3.51 10(-4) mol l(-1) of coenzyme and 2.68 U ml(-1) of enzyme. In contrast to the biosensor for isocitrate reported in literature, just one enzyme was immobilized and no coenzyme addition in the solution of analysis was necessary. Catalytic currents were proportional to the isocitrate concentration between 7.7 10(-6) and 1.04 10(-4) mol l(-1), showing good repeatability. The detection limit of the proposed biosensor was 3.50 10(-6) mol l(-1), the response time was lower than 20 s, the lifetime was about 30 determinations and no significant interference of sugars and citric acid was verified. Orange juice samples were analysed by both methodology biosensor and spectrophotometric commercial kit, and the obtained results presented a good correlation. The data demonstrated that the developed biosensor is suitable for isocitrate determination in orange juice without matrix interferences. (C) 2001 Elsevier B.V. B.V. All rights reserved.