Role of mitochondrial complex I and protective effect of CoQ10 supplementation in propofol induced cytotoxicity.

Propofol (2,6-diisopropylphenol) is an anaesthetic widely used for human sedation. Due to its intrinsic antioxidant properties, rapid induction of anaesthesia and fast recovery, it is employed in paediatric anaesthesia and in the intensive care of premature infants. Recent studies have pointed out that exposure to anaesthesia in the early stage of life might be responsible of long-lasting cognitive impairment. The apoptotic neurodegeneration induced by general anaesthetics (GA) involves mitochondrial impairment due to the inhibition of the OXPHOS machinery. In the present work, we aim to identify the main mitochondrial respiratory chain target of propofol toxicity and to evaluate the possible protective effect of CoQ10 supplementation. The propofol effect on the mitochondrial functionality was assayed in isolated mitochondria and in two cell lines (HeLa and T67) by measuring oxygen consumption rate. The protective effect of CoQ10 was assessed by measuring cells viability, NADH-oxidase activity and ATP/ADP ratio in cells treated with propofol. Our results show that propofol reduces cellular oxygen consumption rate acting mainly on mitochondrial Complex I. The kinetic analysis of Complex I inhibition indicates that propofol interferes with the Q module acting as a non-competitive inhibitor with higher affinity for the free form of the enzyme. Cells supplemented with CoQ10 are more resistant to propofol toxicity. Propofol exposure induces cellular damages due to mitochondrial impairment. The site of propofol inhibition on Complex I is the Q module. CoQ10 supplementation protects cells against the loss of energy suggesting its possible therapeutic role to minimizing the detrimental effects of general anaesthesia.

Apontamentos acerca da Cadeia do Ser e o lugar dos negros na filosofia natural na Europa setecentista / Notes on the Chain of Being and the place of blacks in eighteenth-century European natural philosophy

Por meio da análise de obras acadêmicas produzidas por filósofos naturais no século XVIII, pretendemos discutir algumas ideias recorrentes acerca da Grande Cadeia do Ser. Para tal, analisamos as relações entre filosofia e teologia natural no período. Reavaliamos ainda alguns elementos da Cadeia do Ser, investigando autores que discorreram sobre o tema em seus escritos. Por fim, elencamos um ponto específico das discussões setecentistas sobre a scala naturae, qual seja, as diversas e nem sempre convergentes ideias de que, a partir de características específicas, haveria diferenças entre os homens, bem como seu consequente lugar na Cadeia do Ser.

This examination of academic works produced by eighteenth-century natural philosophers discusses some recurring ideas about the Chain of Being. To this end, the article analyzes the relations between natural philosophy and theology during the period. It also re-evaluates some elements of the Chain of Being through an exploration of authors who addressed the topic in their writings. Lastly, it identifies a specific element within eighteenth-century discussions of scala naturae, to wit, the various and not always convergent ideas about whether there are differences between humans based on specific characteristics and, consequently, about the places they occupy in the chain of being.

Prospects for neuroprotective therapies in prodromal Huntington's disease.

Huntington's disease (HD) is a prototypical dominantly inherited neurodegenerative disorder characterized by progressive cognitive deterioration, psychiatric disturbances, and a movement disorder. The genetic cause of the illness is a CAG repeat expansion in the huntingtin gene, which leads to a polyglutamine expansion in the huntingtin protein. The exact mechanism by which mutant huntingtin causes HD is unknown, but it causes abnormalities in gene transcription as well as both mitochondrial dysfunction and oxidative damage. Because the penetrance of HD is complete with CAG repeats greater than 39, patients can be diagnosed well before disease onset with genetic testing. Longitudinal studies of HD patients before disease onset have shown that subtle cognitive and motor deficits occur as much as 10 years before onset, as do reductions in glucose utilization and striatal atrophy. An increase in inflammation, as shown by elevated interleukin-6, occurs approximately 15 years before onset. Detection of these abnormalities may be useful in defining an optimal time for disease intervention to try to slow or halt the degenerative process. Although reducing gene expression with small interfering RNA or short hairpin RNA is an attractive approach, other approaches targeting energy metabolism, inflammation, and oxidative damage may be more easily and rapidly moved into the clinic. The recent PREQUEL study of coenzyme Q10 in presymptomatic gene carriers showed the feasibility of carrying out clinical trials to slow or halt onset of HD. We review both the earliest detectable clinical and laboratory manifestations of HD, as well as potential neuroprotective therapies that could be utilized in presymptomatic HD.

[Prodiabetic effect of statins--do we know the mechanisms of this phenomenon?]. / Procukrzycowe dzialanie statyn--czy znamy mechanizmy wyjasniajace to zjawisko?

Statins are drugs with the unquestionable effectiveness in the reduction of low density lipoprotein cholesterol (LDL-C) and the cardiovascular risk with the acceptable safety profile. On the basis of the above statins are the most common used drugs worldwide. The present review is aimed to discuss the potential mechanisms of statins leading to occurrence of glucose metabolism disturbances through the influence on insulin secretion by the beta-cells of pancreatic islets and the cells' sensitivity on insulin. It might be a results of disadvantageous statin properties connected to the intensification of inflammation and oxidation within the pancreatic islets, and the influence on adipokines secretion by the fat tissue cells. However, it should be emphasized that despite the recommendations of US Food and Drug Administration suggesting to keep caution in connection to potentially prodiabetic statins' properties, this data need to be confirmed in large multicenter clinical trials with properly designed main endpoints.

Alcohol depletes coenzyme-Q(10) associated with increased TNF-alpha secretion to induce cytotoxicity in HepG2 cells.

Alcohol consumption has been implicated to cause severe hepatic steatosis which is mediated by alcohol dehydrogenase (ADH) activity and CYP(450) 2E1 expression. In this context, the effect of ethanol was studied for its influence on lipogenesis in HepG2 cell which is deficient of ADH and does not express CYP(450) 2E1. The results showed that ethanol at 100mM concentration caused 40% cytotoxicity at 72h as determined by MTT assay. The incorporation of labeled [2-(14)C] acetate into triacylglycerol and phospholipid was increased by 40% and 26% respectively upon 24h incubation, whereas incorporation of labeled [2-(14)C] acetate into cholesterol was not significantly increased. Further, ethanol inhibited HMG-CoA reductase which is a rate-limiting enzyme in the cholesterol biosynthesis. It was observed that, HMG-CoA reductase inhibition was brought about by ethanol as a consequence of decreased cell viability, since incubation of HepG2 cells with mevalonate could not increase the cholesterol content and increase the cell viability. Addition of ethanol significantly increased TNF-alpha secretion and depleted mitochondrial coenzyme-Q(10) which is detrimental for cell viability. But vitamin E (10mM) could partially restore coenzyme-Q(10) and glutathione content with decreased TNF-alpha secretion in ethanol treated cells. Further, lipid peroxidation, glutathione peroxidase and superoxide dismutase enzyme activities remained unaffected. Ethanol decreased glutathione content while, GSH/GSSG ratio was significantly higher compared to other groups showing cellular pro-oxidant and antioxidant balance remained intact. Alanine amino transferase activity was increased by 4.85 folds in cells treated with ethanol confirming hepatocyte damage. Hence, it is inferred that ethanol induced cytotoxicity in HepG2 cells due to coenzyme-Q(10) depletion and increased TNF-alpha secretion.

Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock.

INTRODUCTION: Mitochondrial dysfunction is associated with increased mortality in septic shock. Coenzyme Q10 (CoQ10) is a key cofactor in the mitochondrial respiratory chain, but whether CoQ10 is depleted in septic shock remains unknown. Moreover, statin therapy may decrease CoQ10 levels, but whether this occurs acutely remains unknown. We measured CoQ10 levels in septic shock patients enrolled in a randomized trial of simvastatin versus placebo. METHODS: We conducted a post hoc analysis of a prospective, randomized trial of simvastatin versus placebo in patients with septic shock (ClinicalTrials.gov ID: NCT00676897). Adult patients with suspected or confirmed infection and the need for vasopressor support were included in the initial trial. For the current analysis, blood specimens were analyzed for plasma CoQ10 and low-density lipoprotein (LDL) levels. The relationship between CoQ10 levels and inflammatory and vascular endothelial biomarkers was assessed using either the Pearson or Spearman correlation coefficient. RESULTS: We analyzed 28 samples from 14 patients. CoQ10 levels were low, with a median of 0.49 (interquartile range 0.26 to 0.62) compared to levels in healthy control patients (CoQ10 = 0.95 µmol/L ± 0.29; P < 0.0001). Statin therapy had no effect on plasma CoQ10 levels over time (P = 0.13). There was a statistically significant relationship between plasma CoQ10 levels and levels of vascular cell adhesion molecule (VCAM) (r2 = 0.2; P = 0.008), TNF-α (r2 = 0.28; P = 0.004), IL-8 (r2 = 0.21; P = 0.015), IL-10 (r2 = 0.18; P = 0.025), E-selectin (r2 = 0.17; P = -0.03), IL-1ra (r2 = 0.21; P = 0.014), IL-6 (r2 = 0.17; P = 0.029) and IL-2 (r2 = 0.23; P = 0.009). After adjusting for LDL levels, there was a statistically significant inverse relationship between plasma CoQ10 levels and levels of VCAM (r2 = 0.24; P = 0.01) (Figure 3) and IL-10 (r2 = 0.24; P = 0.02). CONCLUSIONS: CoQ10 levels are significantly lower in septic shock patients than in healthy controls. CoQ10 is negatively associated with vascular endothelial markers and inflammatory molecules, though this association diminishes after adjusting for LDL levels.

Amitriptyline induces coenzyme Q deficiency and oxidative damage in mouse lung and liver.

Amitriptyline is a tricyclic antidepressant commonly prescribed for the treatment of several neuropathic and inflammatory illnesses. We have already reported that amitriptyline has cytotoxic effect in human cell cultures, increasing oxidative stress, and decreasing growth rate and mitochondrial activity. Coenzyme Q (CoQ), a component of the respiratory chain and a potent antioxidant, has been proposed as a mitochondrial dysfunction marker. In the present work we evaluated lipid peroxidation, a consequence of oxidative stress, and CoQ level in liver, lung, kidney, brain, heart, skeletal muscle, and serum of mice treated with amitriptyline for two weeks. Lipid peroxidation was increased in a dose-dependent manner in all tissues analyzed. CoQ levels were increased in brain, heart, skeletal muscle, and serum, and strongly decreased in liver and lung. The relation between amitriptyline, CoQ, and oxidative stress is discussed.

Rosuvastatin lowers coenzyme Q10 levels, but not mitochondrial adenosine triphosphate synthesis, in children with familial hypercholesterolemia.

OBJECTIVE: To investigate whether statin therapy affects coenzyme Q10 (CoQ10) status in children with heterozygous familial hypercholesterolemia (FH). STUDY DESIGN: Samples were obtained at baseline (treatment naïve) and after dose titration with rosuvastatin, aiming for a low-density lipoprotein cholesterol level of 110 mg/dL. Twenty-nine patients were treated with 5, 10, or 20 mg of rosuvastatin for a mean period of 29 weeks. RESULTS: We found a significant (32%) decrease in peripheral blood mononuclear cell (PBMC) CoQ10 level (P = .02), but no change in PBMC adenosine triphosphate synthesis (P = .60). Uncorrected plasma CoQ10 values were decreased significantly, by 45% (P < .01). In contrast, ratios of plasma CoQ10/total cholesterol and CoQ10/low-density lipoprotein cholesterol remained equal during treatment. CONCLUSIONS: In children with FH, rosuvastatin causes a significant decrease in cellular PBMC CoQ10 status but does not affect mitochondrial adenosine triphosphate synthesis in children with FH. Further studies should address whether (rare) side effects of statin therapy could be explained by a deterioration in CoQ10 status.

Effect of beer consumption on levels of complex I and complex IV liver and heart mitochondrial enzymes and coenzymes Q9 and Q10 in adriamycin-treated rats.

BACKGROUND: There is increasing evidence indicating that the dietary intake of food with high antioxidant capacity may protect mitochondria from damage and exert positive effects on different pathogenic processes. AIM OF THE STUDY: The present study was designed to evaluate the possible protective effect of alcohol-free beer intake on chain components dysfunction of liver and heart mitochondria, and to compare with the effect of alcohol beer intake. METHODS: The study was carried out in rat heart and liver mitochondria by inducing with Adriamycin the dysfunction of the respiratory chain. Heart and liver mitochondria were isolated from rats and subjected to oxidative stress with two doses of Adriamycin (5 mg/Kg) 7 days from the beginning of consumption of both alcohol-free and alcohol beer during 31 days. Complexes I and IV and the levels of coenzymes Q(9) and Q(10) were evaluated and compared with a control group. RESULTS: Liver and heart mitochondria isolated from rats treated with Adryamicin showed a decrease in levels of complex I and complex IV enzymatic activity and in levels of coenzymes Q(9) and Q(10). Beer intake for itself does not affect any of the studied parameters. Therefore, the consumption of both alcohol and alcohol-free beer by rats treated with Adriamycin prevents the inhibition of enzymatic activities of complexes I and IV and the oxidation of coenzymes Q(9) and Q(10) in rat heart and liver mitochondria. CONCLUSIONS: These results indicate that alcohol-free beer prevents adriamycin-induced damage to mitochondrial chain components and, therefore, helps to prevent mitochondrial dysfunction.

Atorvastatin-induced changes in plasma coenzyme q10 and brain natriuretic peptide in patients with coronary artery disease.

The beneficial effects of statins in patients with coronary artery disease (CAD) may be balanced by concerns that statins can depress production of ubiquinone (CoQ10), which serves as a component of mitochondrial energy production and an antioxidant. Accordingly, the effects of atorvastatin (ATO)-induced changes in plasma CoQ10 on BNP and oxidative stress were investigated. In 29 patients with CAD, the plasma levels of CoQ10 and BNP and urinary excretion of 8-iso-prostaglandin F2alpha (8-iso-PGF) were determined before and after 3-month treatment with ATO. Ten patients had received pravastatin and 10 patients fluvastatin, while 9 patients had not received any statin before ATO. There was a linear correlation between ATO-induced changes in total cholesterol and CoQ10 (r = 0.632, P < 0.01), and an inverse correlation between ATO-induced changes in CoQ10 and BNP (r = -0.497, P < 0.01). There was no significant correlation between ATO-induced changes in CoQ10 and 8-iso-PGF. Multivariate analysis revealed that ATO-induced decreases in plasma CoQ10 were significantly associated with increasing BNP levels. In conclusion, long-term treatment with ATO might increase plasma levels of BNP in patients with CAD when it is accompanied by a greater reduction in plasma CoQ10. However, ATO-induced decreases in CoQ10 might not increase oxidative stress.

Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy.

Over the past 2 decades our understanding of the pathologic mechanisms that lead to heart failure (HF) has evolved from simplistic hemodynamic models to more complex models that have implicated neurohormonal activation and adverse cardiac remodeling as important mechanisms of disease progression. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have become a standard part of the armamentarium in the prevention and treatment of coronary artery disease. Apart from their lipid-lowering capabilities, statins seem to have non-lipid-lowering effects that impact neurohormonal activation and cardiac remodeling. This review will examine the potential benefits of statins in HF patients with ischemic and nonischemic cardiomyopathy as well as potential concerns regarding the use of statins in these patients.

Effect of carni Q-gel (ubiquinol and carnitine) on cytokines in patients with heart failure in the Tishcon study.

INTRODUCTION: There is evidence that both carnitine and coenzyme Q 10 (Co Q), which are important for the functioning of myocardial mitochondria, are deficient in patients with congestive heart failure, in association with increased pro-inflammatory cytokines. It is possible that supplementation with ubiquinol and L-carnitine may protect these patients by decreasing inflammation. SUBJECTS AND METHODS: In a randomized, double-blind, placebo-controlled trial, the effects of carni Q-gel (2250 mg/d L-carnitine and 270 mg/d hydrosoluble ubiquinol) were examined for 12 weeks. Thirty-one patients with heart failure received intervention (group A) and another 31 patients served as controls (group B). Serum levels of interleukin (IL)-6, tumour necrosis factor (TNF)-alpha and IL-10 could be studied among 29 patients in each group. Statistical analysis was conducted by analysis of variance and chi square test. RESULTS: Echocardiographic ejection fractions were lower at baseline (38.8 + 7.6 vs. 39.3 + 6.7% in the intervention and control groups, respectively) among both group of patients, indicating class II-IV heart failure. Serum concentration of interleukin-6 (IL-6), a pro-inflammatory cytokine, was high (18.7 +/- 5.8 vs. 15.0 +/- 3.3 pg/ml, normal 0.0-3.9) and IL-10 (anti-inflammatory) was normal (3.4 +/- 1.5 vs. 2.9 +/- 1.0 pg/ml, the normal range is 1.5-3.1 pg/ml) in both groups at baseline. After 12 weeks, there was a marked reduction in IL-6 in the intervention group without such changes in the control group (7.6 +/- 1.5 vs. 11.4 +/- 2.5 pg/ml, P < 0.01. IL-10 showed only the non-significant decrease in both groups from the baseline levels (3.2 +/- 1.0 vs. 2.8 +/- 0.9 pg/ml). TNF-alpha, which was comparable at baseline (17.6 +/- 4.3 vs. 20.0 +/- 5.3 pg/ml), also showed a greater decline in the carni Q-gel group compared to the placebo group (12.5 +/- 3.3 vs. 17.2 +/- 3.2 pg/ml, P < 0.05). Baseline serum CoQ levels (0.21 +/- 0.11 vs. 0.19 +/- 0.10 microg/ml) were low; however, after 12 weeks, serum CoQ showed a significant increase in the carni Q-gel group as compared to the control group (2.7 +/- 1.2 and 0.76 +/- 0.14 microg/ml, respectively). After 12 weeks of treatment, the quality of life visual analogous scale revealed that dyspnoea, palpitation and fatigue, (NYHA class II-III-IV), which were present at rest in all patients at baseline, showed beneficial effects in the intervention group compared to the placebo group. The six-minute walk test showed that there was a significant greater benefit in walking, from the baseline distance in the intervention group (208 +/- 15.8 vs. 281 +/- 20.6 metres, P < 0.02) compared to the placebo group (218.4 +/- 17.6 vs. 260.7 +/- 19.3 metres, P < 0.05). The symptom scale indicated that the majority of patients showed improvement in the intervention group compared to the control group (28 vs. 16 patients, respectively, P < 0.05). Three patients in the intervention group had nausea and vomiting, which were controlled with symptomatic treatment. CONCLUSIONS: These findings indicate that treatment with ubiquinol + L-carnitine can cause a significant reduction in the pro-inflammatory cytokines that are neurohumoural precursors related to sympathetic and parasympathetic activity, which is impaired in patients with heart failure. There was no adverse effect on IL-10. There was a significant improvement in quality of life as well as decrease in NYHA-defined heart failure.

[Statin drugs decrease the plasma level of coenzyme Q10 (ubiquinone) in the organism]. / A statinok csökkentik a plazma koenzim-Q10-szintjét a szervezetben.

In this paper the authors review the relationship and the possible interaction between the HMG-CoA reductase inhibitors (statins) and the CoQ10 (ubiquinone) based on the current literature. The statins are widely used in the clinical practice. Inhibiting the synthesis of mevalonic acid they decrease the plasma cholesterol level. Since mevalonic acid is also required for ubiquinone synthesis statins could influence ubiquinone metabolism. Many studies confirmed the relationship between statin therapy and lower plasma ubiquinone level. Much less data are available about the tissue concentration changes of ubiquinone during statin therapy. The authors try to summarise the consequences of the interaction between statin therapy and ubiquinone metabolism.

Effects of CoQ10 supplementation on plasma lipoprotein lipid, CoQ10 and liver and muscle enzyme levels in hypercholesterolemic patients treated with atorvastatin: a randomized double-blind study.

The long-term efficacy and safety of HMG-CoA reductase inhibitors (statins) have been established in large multicenter trials. Inhibition of this enzyme, however, results in decreased synthesis of cholesterol and other products downstream of mevalonate, such as CoQ10 or dolichol. This was a randomized double-blind, placebo-controlled study that examined the effects of CoQ10 and placebo in hypercholesterolemic patients treated by atorvastatin. Eligible patients were given 10mg/day of atorvastatin for 16 weeks. Half of the patients (n=24) were supplemented with 100mg/day of CoQ10, while the other half (n=25) were given the placebo. Serum LDL-C levels in the CoQ10 group decreased by 43%, while in the placebo group by 49%. The HDL-C increment was more striking in the CoQ10 group than in the placebo group. All patients showed definite reductions of plasma CoQ10 levels in the placebo group, by 42%. All patients supplemented with CoQ10 showed striking increases in plasma CoQ10 by 127%. In conclusion atorvastatin definitely decreased plasma CoQ10 levels and supplementation with CoQ10 increased their levels. These changes in plasma CoQ10 levels showed no relation to the changes in serum AST, ALT and CK levels. Further studies are needed, however, for the evaluation of CoQ10 supplementation in statin therapy.

The role of coenzyme Q10 in statin-associated myopathy: a systematic review.

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are currently the most effective medications for reducing low-density lipoprotein cholesterol concentrations. Although generally safe, they have been associated with a variety of myopathic complaints. Statins block production of farnesyl pyrophosphate, an intermediate in the synthesis of ubiquinone or coenzyme Q10 (CoQ10). This fact, plus the role of CoQ10 in mitochondrial energy production, has prompted the hypothesis that statin-induced CoQ10 deficiency is involved in the pathogenesis of statin myopathy. We identified English language articles relating statin treatment and CoQ10 levels via a PubMed search through August 2006. Abstracts were reviewed and articles addressing the relationship between statin treatment and CoQ10 levels were examined in detail. Statin treatment reduces circulating levels of CoQ10. The effect of statin therapy on intramuscular levels of CoQ10 is not clear, and data on intramuscular CoQ10 levels in symptomatic patients with statin-associated myopathy are scarce. Mitochondrial function may be impaired by statin therapy, and this effect may be exacerbated by exercise. Supplementation can raise the circulating levels of CoQ10, but data on the effect of CoQ10 supplementation on myopathic symptoms are scarce and contradictory. We conclude that there is insufficient evidence to prove the etiologic role of CoQ10 deficiency in statin-associated myopathy and that large, well-designed clinical trials are required to address this issue. The routine use of CoQ10 cannot be recommended in statin-treated patients. Nevertheless, there are no known risks to this supplement and there is some anecdotal and preliminary trial evidence of its effectiveness. Consequently, CoQ10 can be tested in patients requiring statin treatment, who develop statin myalgia, and who cannot be satisfactorily treated with other agents. Some patients may respond, if only via a placebo effect.

Effect of coenzyme q10 on myopathic symptoms in patients treated with statins.

Treatment of hypercholesterolemia with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) is effective in the primary and secondary prevention of cardiovascular disease. However, statin use is often associated with a variety of muscle-related symptoms or myopathies. Myopathy may be related in part to statin inhibition of the endogenous synthesis of coenzyme Q10, an essential cofactor for mitochondrial energy production. The aim of this study is to determine whether coenzyme Q10 supplementation would reduce the degree of muscle pain associated with statin treatment. Patients with myopathic symptoms were randomly assigned in a double-blinded protocol to treatment with coenzyme Q10 (100 mg/day, n = 18) or vitamin E (400 IU/day, n = 14) for 30 days. Muscle pain and pain interference with daily activities were assessed before and after treatment. After a 30-day intervention, pain severity decreased by 40% (p <0.001) and pain interference with daily activities decreased by 38% (p <0.02) in the group treated with coenzyme Q10. In contrast, no changes in pain severity (+9%, p = NS) or pain interference with daily activities (-11%, p = NS) was observed in the group treated with vitamin E. In conclusion, results suggest that coenzyme Q10 supplementation may decrease muscle pain associated with statin treatment. Thus, coenzyme Q10 supplementation may offer an alternative to stopping treatment with these vital drugs.