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Effects of coenzyme Q(10) administration on its tissue concentrations, mitochondrial oxidant generation, and oxidative stress in the rat

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Abstract

Coenzyme Q (CoQ(10)) is a component of the mitochondrial electron transport chain and also a constituent of various cellular membranes. It acts as an important in vivo antioxidant, but is also a primary source of O(2)(-*)/H(2)O(2) generation in cells. CoQ has been widely advocated to be a beneficial dietary adjuvant. However, it remains controversial whether oral administration of CoQ can significantly enhance its tissue levels and/or can modulate the level of oxidative stress in vivo. The objective of this study was to determine the effect of dietary CoQ supplementation on its content in various tissues and their mitochondria, and the resultant effect on the in vivo level of oxidative stress. Rats were administered CoQ(10) (150 mg/kg/d) in their diets for 4 and 13 weeks; thereafter, the amounts of CoQ(10) and CoQ(9) were determined by HPLC in the plasma, homogenates of the liver, kidney, heart, skeletal muscle, brain, and mitochondria of these tissues. Administration of CoQ(10) increased plasma and mitochondria levels of CoQ(10) as well as its predominant homologue CoQ(9). Generally, the magnitude of the increases was greater after 13 weeks than 4 weeks. The level of antioxidative defense enzymes in liver and skeletal muscle homogenates and the rate of hydrogen peroxide generation in heart, brain, and skeletal muscle mitochondria were not affected by CoQ supplementation. However, a reductive shift in plasma aminothiol status and a decrease in skeletal muscle mitochondrial protein carbonyls were apparent after 13 weeks of supplementation. Thus, CoQ supplementation resulted in an elevation of CoQ homologues in tissues and their mitochondria, a selective decrease in protein oxidative damage, and an increase in antioxidative potential in the rat.

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... The possibility of increasing CoQ10 levels in different organs or tissues through dietary supplementation has been widely explored in recent decades. Studies in rodents [153][154][155][156][157] suggest that CoQ10 administration is able to increase the amounts of CoQ10 in plasma and liver significantly, and in heart, kidney and skeletal muscle moderately. Similarly, different authors have reported increased systemic levels of CoQ10 in humans after supplementing with CoQ10 at different daily doses (100 to 2400 mg) and duration (20 days, 3 or even 16 months) in multiple trials [158][159][160][161][162]. Regarding the safety of CoQ10 supplements, different assessments in human and animals (reviewed by Hidaka et al. [163]) concluded that the endogenous biosynthesis of CoQ10 is not influenced by exogenous inputs. ...
... From a biochemical standpoint, CoQ10 benefits in relation to aging have been traditionally attributed to their antioxidant properties and to its role in MRC, which would influence mitochondrial functionality and ROS production. Supporting the protective role of CoQ10 against oxidative stress, some studies in animals have indicated that CoQ10 supplementation can reduce oxidative damage accumulation in certain tissues at least during some stages of the life [156,165]. In mice, 3 weeks of CoQ10 supplementation at a dose of 2.81 mg/g of diet was able to attenuate oxidative damage to proteins in liver in aged mice [165]. ...
... A similar effect on protein oxidative damage was found in skeletal muscle mitochondria of 14-week-old male rats after 13 weeks of CoQ10 supplementation. In the same study, a reductive shift was found in plasma aminothiol status [156]. This could imply an increase in the activity of antioxidant enzymes, higher levels of ROS scavengers or a decreased production of ROS. ...
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Coenzyme Q (CoQ) is an essential endogenously synthesized molecule that links different metabolic pathways to mitochondrial energy production thanks to its location in the mitochondrial inner membrane and its redox capacity, which also provide it with the capability to work as an antioxidant. Although defects in CoQ biosynthesis in human and mouse models cause CoQ deficiency syndrome, some animals models with particular defects in the CoQ biosynthetic pathway have shown an increase in life span, a fact that has been attributed to the concept of mitohormesis. Paradoxically, CoQ levels decline in some tissues in human and rodents during aging and coenzyme Q10 (CoQ10) supplementation has shown benefits as an anti-aging agent, especially under certain conditions associated with increased oxidative stress. Also, CoQ10 has shown therapeutic benefits in aging-related disorders, particularly in cardiovascular and metabolic diseases. Thus, we discuss the paradox of health benefits due to a defect in the CoQ biosynthetic pathway or exogenous supplementation of CoQ10.
... Heart and kidney have the largest concentrations and lower concentrations are found in liver, skeletal muscle, and brain. 139,140 It appears that exogenous CoQ 10 (dietary uptake) occurs when levels of endogenous CoQ 10 (biosynthesized) fall below a critical threshold. 141 With age and the onset of age-related disease, there appears to be a general decline in CoQ 10 levels in mammals. ...
... There is evidence that supplemental dietary CoQ 10 can enhance its mitochondrial localization and have an antioxidant effect in skeletal muscle. 139 Rats fed 150 mg/kg/day of CoQ 10 for 13 weeks showed increased mitochondrial levels of homologues CoQ 10 and CoQ 9 , as well as a reduction in skeletal muscle oxidative stress, specifically reduced mitochondrial protein oxidative damage. 139 Other studies confirm that mice fed supplemental CoQ 10 showed increased CoQ 10 in liver, heart, kidney, and skeletal muscle, 142 as well as the brain. ...
... 139 Rats fed 150 mg/kg/day of CoQ 10 for 13 weeks showed increased mitochondrial levels of homologues CoQ 10 and CoQ 9 , as well as a reduction in skeletal muscle oxidative stress, specifically reduced mitochondrial protein oxidative damage. 139 Other studies confirm that mice fed supplemental CoQ 10 showed increased CoQ 10 in liver, heart, kidney, and skeletal muscle, 142 as well as the brain. 143 These and other findings led to the synthesis of the mitochondria-targeted ubiquinone (MitoQ), which selectively targets mitochondria to increase the accumulation of CoQ 10 and reduce mitochondrial oxidative stress. ...
... CoQ10 is also known as ubiquinone. CoQ10, in its reduced form (ubiquinol) acts like a chain breaking antioxidant, acts as a potent free radical scavenger in lipid membranes, and reduces oxidative stress in subjects with diabetes (Kwong et al. 2002;Somayajulu et al. 2005;Quinzii et al. 2010). Also, CoQ10 treatment ameliorates cognitive deficits by modulating mitochondrial functions in surgically induced menopause (Sandhir et al. 2014). ...
... CoQ10 is also known as ubiquinone. CoQ10, in its reduced form (ubiquinol) acts like a chain breaking antioxidant, acts as a potent free radical scavenger in lipid membranes, and reduces oxidative stress in subjects with diabetes (Kwong et al. 2002;Somayajulu et al. 2005;Quinzii et al. 2010). ...
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The main objective of current work was to determine the effects of low and high dose supplementation with coenzyme Q10 (CoQ10) on spatial learning and memory in rats with streptozotocin (STZ)-induced diabetes. Male Wistar rats (weighing 220 ± 10) were randomly divided into six groups: (i) Control (Con, n = 8); (ii) Control+ Low dose of CoQ10 (100 mg/kg) (CLD, n = 10); (iii) Control+ high dose of CoQ10 (600 mg/kg) (CHD, n = 10); (iv) Diabetic (D, n = 10); (v) Diabetic + Low dose of CoQ10 (100 mg/kg) (DLD, n = 10); (vi) Diabetic + high dose of CoQ10 (600 mg/kg) (DHD, n = 10). Diabetes was induced by a single intraperitoneal injection of 50 mg/kg STZ. CoQ10 was administered intragastrically by gavage once a day for 90 days. After 90 days, Morris water maze (MWM) task was used to evaluate the spatial learning and memory in rats. Diabetic animals showed a slower rate of acquisition with respect to the control animals [F (1, 51) = 92.81, P < 0.0001, two-way ANOVA]. High dose (but no low dose) supplementation with CoQ10 could attenuate deteriorative effect of diabetes on memory acquisition. Diabetic animals which received CoQ10 (600 mg/kg) show a considerable decrease in escape latency and traveled distance compared to diabetic animals (p < 0.05, two-way ANOVA,). The present study has shown that low dose supplementation with CoQ10 in diabetic rats failed to improve deficits in cognitive function but high dose supplementation with CoQ10 reversed diabetes-related declines in spatial learning.
... Healthy human athletes have been found to develop CoQ 10 deficiencies, believed to be due to increased metabolic demand (Cooke et al., 2008;Kon et al., 2007;Orlando et al., 2018;Zhou et al., 2005). Deficiencies in skeletal muscle CoQ 10 are thought to result in less efficient energy transduction due to decreased ETC activity and suboptimal ATP production (Lenaz et al., 1999), resulting in reduced effective skeletal muscle contractile function and earlier onset of fatigue (Cooke et al., 2008;Kon et al., 2007;Kon et al., 2008;Kwong et al., 2002;Mizuno et al., 2008). Numerous studies have supported CoQ 10 supplementation in human athletes to improve exercise capacity, aerobic power and recovery after exercise (Alf et al., 2013;Bonetti et al., 2000;Cooke et al., 2008;Leelarungrayub et al., 2010;Mizuno et al., 2008). ...
... It has been hypothesised that increased skeletal muscle CoQ 10 should result in more efficient energy transduction (Lenaz et al., 1999). For horses in active training, this may lead to improvements in responses to exercise, delay in the onset of fatigue and enhanced recovery following intense work (Cooke et al., 2008;Kon et al., 2007;Kon et al., 2008;Kwong et al., 2002;Mizuno et al., 2008). During exercise, movement of plasma CoQ 10 into skeletal muscle may increase due to higher metabolic demand (Kon et al., 2007;Orlando et al., 2018). ...
Article
Coenzyme Q 10 (CoQ 10 ) is an essential component of the mitochondrial electron transport chain (ETC). Decreased skeletal muscle CoQ 10 content may result in decreased ETC activity and energy production. This study tested the hypotheses that supplementation with oral CoQ 10 will increase plasma CoQ 10 concentrations and that prolonged supplementation will increase skeletal muscle CoQ 10 content in young, healthy untrained Thoroughbreds. Nineteen Thoroughbreds (27.5±9.7 months old; 11 males, eight females) from one farm and maintained on a grass pasture with one grain meal per day were supplemented daily with 1.5 mg/kg body weight of an oral CoQ 10 -β-cyclodextrin inclusion complex. Whole-blood and skeletal muscle biopsies were collected before (T 0 ) and after (T 1 ) nine weeks of supplementation. Plasma CoQ 10 concentrations were determined via high-performance liquid chromatography. Skeletal muscle mitochondrial ETC combined complex I+III enzyme activity (indirect measurement of CoQ 10 content) was assessed spectrophotometrically and normalised to mitochondrial abundance. Horses accepted supplementation with no adverse effects. Plasma CoQ 10 concentration increased in all horses following supplementation, with mean plasma CoQ 10 concentration significantly increasing from T 0 to T 1 (0.13±0.02 vs 0.25±0.03 μg/ml; mean difference 0.12±0.03; P=0.004). However, variability in absorbance resulted in a 58% response rate (i.e. doubling of T 1 above T 0 values). The mean skeletal muscle complex I+III activity significantly increased from T 0 to T 1 (0.36±0.04 vs 0.59±0.05 pmol/min/mg of muscle, mean difference 0.23±0.05; P=0.0004), although T 1 values for three out of 19 horses decreased on average by 23% below T 0 values. In conclusion, oral supplementation with CoQ 10 in the diet of young, healthy untrained Thoroughbreds increased mean plasma CoQ 10 concentration by 99% with prolonged daily supplementation increasing mean skeletal muscle complex I+III activity by 65%. Additional research is warranted investigating training and exercise effects on skeletal muscle CoQ 10 content in CoQ 10 supplemented and un-supplemented Thoroughbreds.
... Especially because of the vital role of CoQ 10 in antioxidant defense system, it has been suggested that dietary CoQ 10 may protect against oxidative damage induced by reactive oxygen species (ROS), which is produced under certain physiological conditions [6,9]. In animal studies, CoQ 10 intake appeared to increase in antioxidative potential of tissues [10]. However, several studies insisted that the endogenous production level was enough to provide sufficient CoQ 10 to prevent deficiency in young healthy animals [11,12]. ...
... Rats that received a CoQ 10 supplemented diet (150 mg CoQ 10 /kg/d) showed an increased mitochondrial CoQ 10 level and antioxidant potential and decreased protein oxidative damage [10]. This study also demonstrated that 0.5% of a CoQ 10 supplement (equivalent to 100 mg/ day) had a potential antioxidant effect against cholesterol-induced oxidative stress in rats. ...
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A total of 24 SD rats were allotted to four treatment groups such as the control (CON), 1% of cholesterol diet (CHO), 0.5% of coenzyme Q10 (COQ) and 1% of cholesterol plus 0.5% of coenzyme Q10 (CHCQ) groups to determine the effects of coenzyme Q10 (CoQ10) on the antioxidant defense system in rats. The body weight, weight gain, liver weight and abdominal fat pads were unaffected by 0.5% of CoQ10 supplement in the rats. The level of triglyceride and HDL-cholesterol levels in the blood was significantly increased (p < 0.05) by the 1% of cholesterol supplement (CHO), whereas 0.5% of CoQ10 supplement (COQ) did not alter these blood lipid indices. In the mRNA expression, there was a significant effect (P < 0.05) of the CoQ10 supplement on the mRNA expression of superoxide dismutase (SOD), although the mRNA expression of glutathione peroxidase (GPX) and glutathione S-transferase (GST) was unaffected by cholesterol or the CoQ10 supplement. Similar to mRNA expression of SOD, its activity was also significantly increased (P < 0.05) by CoQ10, but not by the cholesterol supplement effect. The activities hepatic GPX and GST were unaffected by CoQ10 and cholesterol supplements in rats. Lipid peroxidation in the CHO group resulted in a significant (p < 0.05) increase compared with that in the other groups, indicating that the CoQ10 supplement to 1% of cholesterol-fed rats alleviated the production of lipid peroxidation in the liver. In conclusion, 0.5% of the CoQ10 supplement resulted in positive effects on the hepatic antioxidant defense system without affecting blood lipid indices in 1% of cholesterol fed rats.
... Inhibition of mevalonate production by statin drugs lowered both myocardial (8) and serum CoQ10 (9) in dogs. CoQ10 disposal likely involves glucuronidation and excretion with bile and urine (10)(11)(12)(13). ...
... 30), increased degradation of both the absorbed hydroxylated (Note 8) and generated free-radical form should allow the development of a new steady state. The two forms may be converted into water-soluble glucuronides so that these compounds can be eliminated from the body in urine and bile (10)(11)(12)(13). Formation of glucuronic acid involves oxidation of glucose and yields NADH as reducing agent that might neutralize the free radical form of ubiquinol. ...
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Coenzyme Q10 in petfood Coenzyme Q10 (CoQ10) has two interconverting forms: its yellow, oxidized state (ubiquinone) and milky-white, reduced counterpart (ubiquinol). CoQ10 is ubiquitously present in mammalian tissues; origins are synthesis in the body and intestinal uptake from ingested foods. CoQ10 plays a significant role in energy production by the mitochondria, the powerhouses of body cells. Some supplements, treats and complete foods for dogs and cats feature CoQ10 as health-promoting ingredient (Notes 1-3). Among the various claimed effects of CoQ10, antioxidant capacity and support of heart and gum health are most common. As heart muscle has a high energy requirement, it is believed that extra CoQ10 enhances the organ's function. Because reduced CoQ10 can donate electrons, it is seen as neutralizer/scavenger of free radicals, thus fighting oxidative DNA damage and aging. As antioxidant and bioenergizer, CoQ10 is thought to suppress bacterial gum inflammation. For the claimed health effects of supplemental CoQ10 there is no scientific substantiation in the form of controlled experiments with dogs or cats. Moreover, there is no indirect evidence from which the health claims may be inferred. Admittedly, demonstrating that supplemental CoQ10 increases life span of dogs and cats is practically hardly possible, not least due to long duration, but studies in mice (1-3) do not support the anti-aging claim. CoQ10 is not recognized as an essential nutrient for dogs and cats (4), implying that body synthesis in normal animals is adequate. In addition to their own supply, dogs and cats also ingest CoQ10 with their regular food, but the actual quantities are unknown. In a dog study, supplemental CoQ10 did not increase antioxidant capacity of blood. CoQ10 might enhance canine and feline mitochondrial energy production under specific conditions (cf. 5, 6), but this remains to be shown. Function and metabolism CoQ10 is a lipophilic electron carrier, consisting of a quinone/quinol group and 10 isoprene units in the side chain. Successive uptake and release of two reducing equivalents (2 H + + 2 e-) transfers the quinone portion into quinol and back again. As such, CoQ10 is part of the mitochondrial electron transport chain of redox couples, producing a high energy state that powers ATP synthesis. All body cells may synthesize CoQ10 (7), inclusive of attaching the side chain to 4-hydroxybenzoate derived from tyrosine. The adjunct consists of isoprene units made from mevalonate as precursor. Inhibition of mevalonate production by statin drugs lowered both myocardial (8) and serum CoQ10 (9) in dogs. CoQ10 disposal likely involves glucuronidation and excretion with bile and urine (10-13). In mitochondrial electron transport, the CoQ10 redox couple acts as conduit for electrons, not as net electron donor or acceptor. For CoQ10 as free radical scavenger, the quinol form should donate electrons and the quinone generated should be disposed of by conjugation and excretion (Note 4). CoQ10 sources
... A decrease of CoQ10, or the reduced form of CoQ10, in SH-SY5Y neuroblastoma cells resulted in increased oxidative stress (58). In rats, oral administration of CoQ10 can significantly increase the CoQ10 level in plasma, cells, and mitochondria and decrease oxidative damage to proteins (107). Several trials in humans and in rats have validated the beneficial role of CoQ10 in neurodegenerative diseases, such as PD and motor dysfunction disorders (18,174). ...
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Significance: The thioredoxin (Trx) and glutathione (GSH) systems play important roles in maintaining the redox balance in the brain, a tissue that is prone to oxidative stress due to its high-energy demand. These two disulfide reductase systems are active in various areas of the brain and are considered to be critical antioxidant systems in the central nervous system (CNS). Various neuronal disorders have been characterized to have imbalanced redox homeostasis. Recent Advances: In addition to their detrimental effects, recent studies have highlighted that reactive oxygen species/reactive nitrogen species (ROS/RNS) act as critical signaling molecules by modifying thiols in proteins. The Trx and GSH systems, which reversibly regulate thiol modifications, regulate redox signaling involved in various biological events in the CNS. Critical Issues: In this review, we focus on the following: (i) how ROS/RNS are produced and mediate signaling in CNS; (ii) how Trx and GSH systems regulate redox signaling by catalyzing reversible thiol modifications; (iii) how dysfunction of the Trx and GSH systems causes alterations of cellular redox signaling in human neuronal diseases; and (iv) the effects of certain small molecules that target thiol-based signaling pathways in the CNS. Future Directions: Further study on the roles of thiol-dependent redox systems in the CNS will improve our understanding of the pathogenesis of many human neuronal disorders and also help to develop novel protective and therapeutic strategies against neuronal diseases. Antioxid. Redox Signal. 27, 989-1010.
... Reahal demonstrated that also different routes of CoQ10 administration (oral and intraperitoneal) in rats did not impact its myocardial accumulation [47]. On the contrary, Kwong et al. reported an increase of CoQ9 (i.e. the major endogenous CoQ form in rodents) in whole homogenates from heart and in mitochondrial fraction following 4 weeks of treatment with 150 mg/kg/day CoQ10 in rats [50]. Probably, the accumulation of CoQ10 into the heart, differently from other organs, is limited and triggered by specific physiological conditions like increased energy demand, CoQ10 deficiency, or increased mitochondrial biogenesis. ...
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Epidemiological data show a rise in the mean age of patients affected by heart disease undergoing cardiac surgery. Senescent myocardium reduces the tolerance to ischemic stress and there are indications about age-associated deficit in post-operative cardiac performance. Coenzyme Q10 (CoQ10), and more specifically its reduced form ubiquinol (QH), improve several conditions related to bioenergetic deficit or increased exposure to oxidative stress. This trial (Eudra-CT 2009-015826-13) evaluated the clinical and biochemical effects of ubiquinol in 50 elderly patients affected by severe aortic stenosis undergoing aortic valve replacement and randomized to either placebo or 400 mg/day ubiquinol from 7 days before to 5 days after surgery. Plasma and cardiac tissue CoQ10 levels and oxidative status, circulating troponin I, CK-MB (primary endpoints), IL-6 and S100B were assessed. Moreover, main cardiac adverse effects, NYHA class, contractility and myocardial hypertrophy (secondary endpoints) were evaluated during a 6-month follow-up visit. Ubiquinol treatment counteracted the post-operative plasma CoQ10 decline (p<0.0001) and oxidation (p=0.038) and curbed the post-operative increase in troponin I (QH, 1.90 [1.47-2.48] ng/dL; placebo, 4.03 [2.45-6.63] ng/dL; p=0.007) related to cardiac surgery. Moreover, ubiquinol prevented the adverse outcomes that might have been associated with defective left ventricular ejection fraction recovery in elderly patients.
... In vivo studies also confirm that long-term supplementation of CoQ10 is more effective in stabilizing inflammatory and oxidative balance [46]. In addition, stratified results by doses demonstrated that more than 200 mg/day CoQ10 increased TAC significantly Fig. 6 Forest plot detailing standard mean difference and 95% confidence intervals for the impact of CoQ10 supplementation on SOD activity (U/mg) compared to less than 200 mg/day. ...
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PurposeOxidative stress (OS) is associated with several chronic complications and diseases. The use of coenzyme Q10 (CoQ10) as an adjuvant treatment with routine clinical therapy against metabolic diseases has shown to be beneficial. However, the impact of CoQ10 as a preventive agent against OS has not been systematically investigated.MethodsA systematic literature search was performed using the PubMed, SCOPUS, EMBASE, and Cochrane Library databases to identify randomized clinical trials evaluating the efficacy of CoQ10 supplementation on OS parameters. Standard mean differences and 95% confidence intervals were calculated for net changes in OS parameters using a random-effects model.ResultsSeventeen randomized clinical trials met the eligibility criteria to be included in the meta-analysis. Overall, CoQ10 supplementation was associated with a statistically significant decrease in malondialdehyde (MDA) (SMD − 0.94; 95% CI − 1.46, − 0.41; I2 = 87.7%) and a significant increase in total antioxidant capacity (TAC) (SMD 0.67; 95% CI 0.28, 1.07; I2 = 74.9%) and superoxide dismutase (SOD) activity (SMD 0.40; 95% CI 1.12, 0.67; I2 = 9.6%). The meta-analysis found no statistically significant impact of CoQ10 supplementation on nitric oxide (NO) (SMD − 1.40; 95% CI − 0.12, 1.93; I2 = 92.6%), glutathione (GSH) levels (SMD 0.41; 95% CI − 0.09, 0.91; I2 = 70.0%), catalase (CAT) activity (SMD 0.36; 95% CI − 0.46, 1.18; I2 = 90.0%), or glutathione peroxidase (GPx) activities (SMD − 1.40; 95% CI: − 0.12, 1.93; I2 = 92.6%).Conclusion CoQ10 supplementation, in the tested range of doses, was shown to reduce MDA concentrations, and increase TAC and antioxidant defense system enzymes. However, there were no significant effects of CoQ10 on NO, GSH concentrations, or CAT activity.
... Our results are in agreement with those reported by Annaházi et al. and Mohamed et al. [9,15] Furthermore, our results showed that CoQ10 improved memory and learning, cell viability and decreased oxidant level Compared to untreated 2VO group. Our findings are in accordance with those demonstrated by Kwong et al. and Hashemzadeh et al. [34,35] Importantly, we showed for the first time that the combination of Vit E with CoQ10 improved memory and learning and cell viability and decreased oxidant level compared to untreated 2VO group. There was no statistically significant difference in memory and learning, number of hippocampal viable pyramidal cell and oxidant levels between CoQ10-Vit E treated group and Vit E treated group, CoQ10 treated group and Sham operated group. ...
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Alzheimer's disease (AD) is the most common type of neurodegenerative diseases. Currently, there is no prevention or cure for AD. The potential use of natural antioxidants for prevention and treatment of AD has attracted considerable attention. Here, we used combination of the antioxidants coenzyme Q10 (CoQ10) and vitamin-E (Vit E) for the protection against AD. The current study assessed the neuroprotective effects of combination of CoQ10 with Vit E in Chronic Cerebral Hypoperfusion-induced neurodegeneration (CCH-ND) rat model. After acclimatization, 27 Sprague Dawley rats weighing 220-250 g were divided into six groups; sham control, 2-vessel occlusion (2VO), 2VO+E (treated daily with Vit E, 100 mg/kg, orally following 2VO), CoQ10 (treated daily with CoQ10, 200 mg/kg, orally following 2VO), CoQ10+E (treated with combination of CoQ10 and Vit E, orally following 2VO) and last group was treated with coconut-oil as a vehicle control. On the 8th week, all rats were tested by Morris water maze cognitive test and then euthanized and the hippocampi were isolated. Viable neuronal cell count in the hippocampal region was estimated. The Isoprostane F2 (F2-IsoPs) levels were assessed in the brain homogenates to quantify the oxidative stress status. There was significant difference in neuronal cell death, memory and learning, and F2-Iso level in untreated 2VO group compared to the treated and sham groups. However, there was no statistically significant difference in neuroprotective effects of combination of Vit E with CoQ10 and each one alone. To conclude, combination of the antioxidants (Vit E and CoQ10) improves memory, neuronal cell viability and decreases antioxidant level, same as each antioxidant alone.
... It has been reported that oral CoQ10 supplementation lead to significant increase in CoQ10 levels in various tissues and/or tissue mitochondria such as brain, skeletal muscle, liver, heart and kidney in mice or rats [13][14][15][16] and mitochondria in human myocardial tissue [17] as well as in human plasma or serum levels [18][19][20]. ...
Article
Background: Coenzyme Q10 (CoQ10) is the electron transporter in oxidative phosphorylation and an endogenous antioxidant. Recent researches have indicated that doses of 200-300 mg/day are needed to recognize effects to prevent oxidative damage in athletes, and the reduced form of CoQ10, ubiquinol-10, is more bioavailable than its oxidized form. Therefore, we hypothesized that higher doses of ubiquinol-10 could elevate plasma CoQ10 levels rapidly and exert physiological benefits in athletes. Therefore, a placebo controlled, double blinded test was carried out to determine the effects of ubiquinol-10 on the extravasate enzymes and fatigue levels of distance runners. Methods: Sixteen male collegiate distance runners were allocated to two groups receiving 300 mg/day of ubiquinol-10 (19.8 ± 1.7 years) or a placebo (20.1 ± 1.6 years) for 12 days during summer training that comprised 25- and 40-km runs on days 7 and 9, respectively. Results: Ubiquinol-10 elevated plasma CoQ10 concentration to 5.62 μg/mL and significantly decreased activities of the serum extravasate enzymes, CK, ALT, LDH (P < 0.01), and AST (P < 0.05) on day 6. Subjective fatigue status was significantly elevated on day 10 (the day after the 45-km run) in the placebo group (P < 0.001), but did not significantly change in the group given ubiquinol-10. Therefore, ubiquinol-10 could mitigate tissue damage and alleviate fatigue status in distance runners during summer training. Conclusions: Ubiquinol-10 (300 mg/day) supplementation elevated plasma CoQ10 concentrations almost to plateau levels, decreased extravasate enzymes within six days, and suppressed the subjective fatigue in male distance runners.
... Contrary to previous meta-analysis, 63 we found that longer intervention duration can be beneficial in the reduction of the blood glucose level, because our review contained additional studies with longer duration that were published since that prior reviews. What's more, some animal experiments 64,65 found that chronic ingestion of CoQ10 has been shown to increase the concentration of CoQ10 in plasma in rodent models. In addition, a study 66 found that the average blood CoQ10 concentration increased by times after 90mg CoQ10 supplementation for 3 and 9 months in healthy subjects. ...
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Background: Previous reviews reported that the effects of CoQ10 on glycemic control were inconsistent. There is no review exploring the optimal intake of CoQ10 for glycemic control. We aimed to investigate the efficacy of CoQ10 on glycemic control and evaluate the dose–response relationship via integrating the existing evidence from randomized control trials (RCTs). Methods: Databases (PubMed, Embase, and Cochrane Library) were searched to identify RCTs for investigating the efficacy of CoQ10 on fasting glucose, fasting insulin, HbA1c, and HOMA-IR up to March 12, 2022. We performed a meta-analysis on 40 RCTs of CoQ10. Weighted mean difference (WMD) and 95% confidence intervals (CIs) were calculated for net changes. Evidence certainty was assessed using GRADE. Dose-response relationships were evaluated using 1-stage restricted cubic spline regression model. The protocol was registered in PROSPERO (CRD42021252933). Findings: Forty studies (n = 2,424 participants) were included in this meta-analysis. CoQ10 significantly reduced fasting glucose (WMD: -5.22 [95% CI: -8.33, -2.11] mg/dl; P
... Oxidatively damaged mitochondria, observed early in AD, often do not contain intact ETCs as many enzymes involved with oxidative phosphorylation become irreversibly damaged; thus, CoQ 10 administration to cells with mitochondria exhibiting early stages of dysfunction is ineffective [Lass et al. 1999]. In addition, oral administration of CoQ 10 did not significantly increase the protein levels of CoQ 10 in the brain [Kwong et al. 2002]. This finding suggests that the current formulation of CoQ 10 lacks the ability to penetrate the blood—brain barrier (BBB). ...
Chapter
Alzheimer's disease (AD) is a progressive neurodegenerative disease which begins with insidious deterioration of higher cognition and progresses to severe dementia. Clinical symptoms typically involve impairment of memory and at least one other cognitive domain. Owing to the exponential increase in the incidence of AD with age, the aging population across the world has seen a congruous increase in AD, emphasizing the importance of disease-altering therapy. Current therapeutics on the market, including cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, provide symptomatic relief but do not alter progression of the disease. Therefore, progress in the areas of prevention and disease modification may be of critical interest. In this review, we summarize novel AD therapeutics that are currently being explored, and also mechanisms of action of specific drugs within the context of current knowledge of AD pathologic pathways.
... CoQ10 to some extent, reduced the harmful effects of CPZ and elevated the level of SOD and TAC. CoQ10's protective effect is due to inhibition of lipid peroxidation in the inner layer of mitochondria and its ability to regeneration other powerful antioxidants like α-tocopherol and ascorbate (Kwong et al. 2002). In addition, Doll et al. have demonstrated that CoQ10 prevents ferroptosis through, ferroptosis suppressor protein 1 (FSP1)-CoQ 10 -NAD (P) H pathway (Doll et al. 2019), so it seems that CoQ10 prevents the death of OLGs by suppressing apoptosis and ferroptosis, simultaneously. ...
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Multiple Sclerosis (MS) is a chronic, progressive demyelinating disease of the central nervous system that causes the most disability in young people, besides trauma. Coenzyme Q10 (CoQ10)—also known as ubiquinone—is an endogenous lipid-soluble antioxidant in the mitochondrial oxidative respiratory chain which can reduce oxidative stress and inflammation, the processes associated with demyelination in MS. Cuprizone (CPZ) intoxication is a well-established model of inducing MS, best for studying demyelination—remyelination. In this study, we examined for the first time the role of CoQ10 in preventing demyelination and induction of remyelination in the chronic CPZ model of MS. 40 male mice were divided into four groups. 3 group chewed CPZ-containing food for 12 weeks to induce MS. After 4 weeks, one group were treated with CoQ10 (150 mg/kg/day) by daily gavage until the end of the experiment, while CPZ poisoning continued. At the end of 12 weeks, tail suspension test (TST) and open field test (OFT) was taken and animals were sacrificed to assess myelin basic protein (MBP), oligodendrocyte transcription factor-1 (Olig1), tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) by real-time polymerase chain reaction (real-time PCR) and total antioxidant capacity (TAC) and superoxide dismutase (SOD) by Elisa test. Luxol fast blue (LFB) staining was used to evaluate histological changes. CoQ10 administration promoted remyelination in histological findings. MBP and Olig-1 expression were increased significantly in CoQ10 treated group compare to the CPZ-intoxicated group. CoQ10 treatment alleviated stress oxidative status induced by CPZ and dramatically suppress inflammatory biomarkers. CPZ ingestion made no significant difference between normal control group and the CPZ-intoxicated group in TST and OFT. CoQ10 can enhance remyelination in the CPZ model and potentially might have same effects in MS patients.
... In a rat model for AD, CoQ10 prevented the cognitive decline (Dehghani Dolatabadi et al., 2012). Still, due to a low bioavailability in the brain (Kwong et al., 2002), CoQ10 has never been successful in humans. To overcome this issue, the mitoquinone mesylate (MitoQ) was optimized. ...
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Alzheimer disease (AD) is a progressive and deleterious neurodegenerative disorder that affects mostly the elderly population. At the moment, no effective treatments are available in the market, making the whole situation a compelling challenge for societies worldwide. Recently, novel mechanisms have been proposed to explain the etiology of this disease leading to the new concept that AD is a multifactor pathology. Among others, the function of mitochondria has been considered as one of the intracellular processes severely compromised in AD since the early stages and likely represents a common feature of many neurodegenerative diseases. Many mitochondrial parameters decline already during the aging, reaching an extensive functional failure concomitant with the onset of neurodegenerative conditions, although the exact timeline of these events is still unclear. Thereby, it is not surprising that mitochondria have been already considered as therapeutic targets in neurodegenerative diseases including AD. Together with an overview of the role of mitochondrial dysfunction, this review examines the pros and cons of the tested therapeutic approaches targeting mitochondria in the context of AD. Since mitochondrial therapies in AD have shown different degrees of progress, it is imperative to perform a detailed analysis of the significance of mitochondrial deterioration in AD and of a pharmacological treatment at this level. This step would be very important for the field, as an effective drug treatment in AD is still missing and new therapeutic concepts are urgently needed.
... Many studies have stated the benefits of CoQ10 in the prevention and management of ischemia in animals' stroke models. It has been shown that CoQ10 administration leads to elevation of endogenous CoQ10 content in rat brain [67][68][69][70]. Recent experimental results indicate that CoQ10 could be used as a primary medication in the acute phase of stroke [71] since it exhibited beneficial effects against experimental cerebral ischemia/reperfusion (I/R) injury [72][73][74], and was also reported by many studies to decrease size of cerebral ischemic or infarction zones [71,75,76], resulting in improvement of both functional and morphological indices of brain damage [71], thus improving neurological and neurobehavioral outcomes [48]. ...
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Many neurodegenerative diseases share the same pathophysiology and etiologies, this led us to search for a product that may fit in the treatment of most of diseases, including neurological, cardiovascular, cancers, etc. Coenzyme Q10 is a natural product found in many kinds of beings like fish, beef, organ meat (liver, heart), whole grains, etc. Many studies on different animal models have concluded that coenzyme Q10 has neuroprotective effects against neurological disorders, improves mitochondrial functions, prevents oxidative stress and cellular death, stimulates cell growth, inhibits inflammation, and enhances neurogenesis. In addition, it decreases cerebral infarct size, inhibits platelet aggregation and blood thrombosis, and improves endothelial dysfunction. Coenzyme Q10 has important roles in different body systems ranging from cardioprotection, hepatoprotection, gastroprotection and nephroprotection to a documented function in slowing the aging processes. This article aims to summarize and discuss up-to-date experimental findings related to the mechanisms by which coenzyme Q10 and its analogs assist in treatment and thus improvement of many conditions in animals and human.
... Many studies have stated the benefits of CoQ10 in the prevention and management of ischemia in animals' stroke models. It has been shown that CoQ10 administration leads to elevation of endogenous CoQ10 content in rat brain [67][68][69][70]. Recent experimental results indicate that CoQ10 could be used as a primary medication in the acute phase of stroke [71] since it exhibited beneficial effects against experimental cerebral ischemia/reperfusion (I/R) injury [72][73][74], and was also reported by many studies to decrease size of cerebral ischemic or infarction zones [71,75,76], resulting in improvement of both functional and morphological indices of brain damage [71], thus improving neurological and neurobehavioral outcomes [48]. ...
Article
Full-text available
Many neurodegenerative diseases share the same pathophysiology and etiologies, this led us to search for a product that may fit in the treatment of most of diseases, including neurological, cardiovascular, cancers, etc. Coenzyme Q10 is a natural product found in many kinds of beings like fish, beef, organ meat (liver, heart), whole grains, etc. Many studies on different animal models have concluded that coenzyme Q10 has neuroprotective effects against neurological disorders, improves mitochondrial functions, prevents oxidative stress and cellular death, stimulates cell growth, inhibits inflammation, and enhances neurogenesis. In addition, it decreases cerebral infarct size, inhibits platelet aggregation and blood thrombosis, and improves endothelial dysfunction. Coenzyme Q10 has important roles in different body systems ranging from cardioprotection, hepatoprotection, gastroprotection and nephroprotection to a documented function in slowing the aging processes. This article aims to summarize and discuss up-to-date experimental findings related to the mechanisms by which coenzyme Q10 and its analogs assist in treatment and thus improvement of many conditions in animals and human.
... However, there is some evidence that chronic administration can increase tissue levels [53]. In a study where rats were chronically fed a large dose of 150 mg/kg/day of CoQ 10 for 13 weeks, small but significant increases in both CoQ 9 and CoQ 10 were found in all tissues measured [54]. No such data exist for young or aged human tissues; however, the accumulated evidence of benefit of CoQ 10 therapy in human disease states does suggest that tissue levels can be increased by oral administration. ...
Article
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The aging process includes impairment in mitochondrial function, a reduction in anti-oxidant activity, and an increase in oxidative stress, marked by an increase in reactive oxygen species (ROS) production. Oxidative damage to macromolecules including DNA and electron transport proteins likely increases ROS production resulting in further damage. This oxidative theory of cell aging is supported by the fact that diseases associated with the aging process are marked by increased oxidative stress. Coenzyme Q10 (CoQ10) levels fall with aging in the human but this is not seen in all species or all tissues. It is unknown whether lower CoQ10 levels have a part to play in aging and disease or whether it is an inconsequential cellular response to aging. Despite the current lay public interest in supplementing with CoQ10, there is currently not enough evidence to recommend CoQ10 supplementation as an anti-aging anti-oxidant therapy.
... Likewise, other interesting physiological roles related to these activities have been suggested for this molecule (19,20). Levels of this molecule in blood and different tissues (21)(22)(23)(24)(25) have been reported to change in response to dietary intake. Therefore, CoQ 10 supplements could prove to be particularly interesting for aging. ...
Article
Extending life by delaying the aging process have proven to be the most effective way to fight multiple chronic diseases in elderly adults. Evidence suggests that longevity is inversely related to unsaturation of membrane phospholipids. The present study investigated how different unsaturated dietary fats affect lifespan and cause death in male Wistar rats fed diets based on virgin olive oil (V), sunflower oil (S) or fish oil (F), which were supplemented or not with Coenzyme Q10 (CoQ 10). Previous results suggest that individual longevity and survival probability at different ages may be modulated by an appropriate dietary fat treatment. Lifelong feeding with V or F diets would reduce death probability compared to feeding with S diet at certain ages, although the effects of V diet would be maintained for most of life. Furthermore, the addition of lower amounts of CoQ 10 reduced mortality associated with S diet, but CoQ 10 had no effect on survival when combined with virgin olive oil or fish oil. Supplementation with low doses of CoQ 10 failed to increase the maximum lifespan potential of rats fed a V or F diet. No clear evidence showing that MUFA, n-3 PUFA or CoQ 10 exerted the observed effects by modulating the rate of aging has been found.
... However, it also warns us that an increase in plasma does not necessarily correlate with an increase in muscle tissue. It is possible that sufficient treatment time or higher dosage may be required, as it occurs in animal models where it is shown that chronic ingestion of relatively large doses of CoQ 10 in the diet is able to increase the CoQ 10 concentrations, especially in the mitochondrial fractions of the heart [113]. It is therefore worth remembering that the use of the same dose of Ubiquinone, or Ubiquinol, taken orally by athletes with different body compositions, leads to different intakes of CoQ 10 per kg of body weight [32]. ...
Article
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Evidence exists to suggest that ROS induce muscular injury with a subsequent decrease in physical performance. Supplementation with certain antioxidants is important for physically active individuals to hasten recovery from fatigue and to prevent exercise damage. The use of nutritional supplements associated with exercise, with the aim of improving health, optimizing training or improving sports performance, is a scientific concern that not only drives many research projects but also generates great expectations in the field of their application in pathology. Since its discovery in the 1970s, coenzyme Q10 (CoQ10) has been one of the most controversial molecules. The interest in determining its true value as a bioenergetic supplement in muscle contraction, antioxidant or in the inflammatory process as a muscle protector in relation to exercise has been studied at different population levels of age, level of physical fitness or sporting aptitude, using different methodologies of effort and with the contribution of data corresponding to very diverse variables. Overall, in the papers reviewed, although the data are inconclusive, they suggest that CoQ10 supplementation may be an interesting molecule in health or disease in individuals without a pathological deficiency and when used for optimising exercise performance. Considering the results observed in the literature, and as a conclusion of this systematic review, we could say that it is an interesting molecule in sports performance. However, clear approaches should be considered when conducting future research.
... Atorvastatin calcium (Borg pharmaceuticals, Alexandria, Egypt) and coenzyme Q10 (Selleckchem, Houston, USA) were both suspended in 0.5% caboxymethylcellulose (CMC). Rats were randomized into three groups (n = 7): control group received CMC, Atorvastatin group received atorvastatin in a dose of 100 mg/kg and Protected group received both atorvastatin (100 mg/kg) and coenzyme Q10 (100 mg/kg) (Kwong et al., 2002). All drugs were administrated by oral gavage for 21 days. ...
Article
Myopathy is a well-known adverse effect of statins, affecting a large sector of statins users. The reported experimental data emphasized on mechanistic study of statin myopathy on large muscles. Clinically, both large muscles and respiratory muscles are reported to be involved in the myotoxic profile of statins. However, the experimental data investigating the myopathic mechanism on respiratory muscles are still lacking. The present work aimed to study the effect of atorvastatin treatment on respiratory muscles using rat isolated hemidiaphragm in normoxic & hypoxic conditions. The contractile activity of isolated hemidiaphragm in rats treated with atorvastatin for 21 days was investigated using nerve stimulated technique. Muscle twitches, train of four and tetanic stimulation was measured in normoxic, hypoxic and reoxygenation conditions. Atorvastatin significantly increased the tetanic fade, a measure of muscle fatigability, in hypoxic conditions. Upon reoxygenation, rat hemidiaphragm regains its normal contractile profile. Co-treatment with coenzyme Q10 showed significant improvement in defective diaphragmatic contractility in hypoxic conditions. This work showed that atorvastatin treatment rapidly deteriorates diaphragmatic activity in low oxygen environment. The mitochondrial respiratory dysfunction is probably the mechanism behind such finding. This was supported by the improvement of muscle contractile activity following CoQ10 co-treatment.
... Other compounds in use are antioxidants such as CoQ10 and its derivatives idebenone, and EPI-743. Idebenone is taken up more readily by the cells and has been suggested as a replacement for CoQ10 (Kwong et al., 2002). Although idebenone has been used mainly as a treatment for Leber's hereditary optic neuropathy (LHON), it is now being tested as a treatment option for LS (Haginoya et al., 2009;Carelli et al., 2011;Barboni et al., 2013). ...
Article
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Leigh syndrome is a rare, complex, and incurable early onset (typically infant or early childhood) mitochondrial disorder with both phenotypic and genetic heterogeneity. The heterogeneous nature of this disorder, based in part on the complexity of mitochondrial genetics, and the significant interactions between the nuclear and mitochondrial genomes has made it particularly challenging to research and develop therapies. This review article discusses some of the advances that have been made in the field to date. While the prognosis is poor with no current substantial treatment options, multiple studies are underway to understand the etiology, pathogenesis, and pathophysiology of Leigh syndrome. With advances in available research tools leading to a better understanding of the mitochondria in health and disease, there is hope for novel treatment options in the future.
... A Previous study confirmed the antioxidant effect of CoQ10 in vitro and in vivo. They were able to show a shift in plasma redox status toward a more antioxidative environment by increasing the reduced/oxidized glutathione ratio and decreasing cysteinyl glycine and homocysteine levels (Kwong et al., 2002;Wadsworth, Bishop, Pappu, Woltjer & Quinn, 2008). Our data showed the antioxidant and anti-inflammatory effects of VE &Se in AD rats. ...
Article
Alzheimer's disease (AD) is one of such diseases that represent the most prominent cause of dementia in elderly people. To explore the possible neuroprotective effect as well as mechanism of action of Vinpocetine either alone or in combination with EGCG, CoQ10, or VE & Se in ameliorating aluminium chloride-induced AD in rats. Rats were received AlCl3 (70 mg/kg) intraperitoneal daily dose for 30 days along with EGCG (10 mg/kg, I.P), CoQ10 (200 mg/kg, P.O), VE (100 mg/kg, P.O) & Se (1 mg/kg, P.O) as well as Vinpocetine (20 mg/kg, P.O) either alone or in combination. Results revealed that the combination of Vinpocetine with EGCG showed the best neuroprotection. This protection in the brain was indicated by the significant decrease in Aβ and ACHE. The same pattern of results were shown in the levels of monoamines and BDNF. In addition, the combination of Vinpocetine with EGCG showed more pronounced anti-inflammatory (TNF-α, IL-1β) and antioxidant (MDA, SOD, TAC) effects in comparison to other combinations. These results were confirmed using histopathological examinations as well as DNA fragmentation assays. Vinpocetine with EGCG showed pronounced protection on neurons against AD induced by AlCl3 in rats.
... Some of the antioxidants can also act as pro-oxidants under deleterious conditions, and thus, they may potentiate oxidative stress and thus their antioxidant activity remains questionable in these conditions [380]. Consistent with these findings, some of the agents (e.g., CoQ) which has been suggested and speculated to confer therapeutic benefits in AD patients cannot cross the BBB and failed to produce any change in the cognitive functions in AD patients [381,382]. For CoQ, it has been reported that to exert its therapeutic effect, CoQ must be retained in the mitochondrial ETC. ...
Article
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Alzheimer’s disease (AD) is considered the sixth leading cause of death in elderly patients and is characterized by progressive neuronal degeneration and impairment in memory, language, etc. AD is characterized by the deposition of senile plaque, accumulation of fibrils, and neurofibrillary tangles (NFTs) which are responsible for neuronal degeneration. Amyloid-β (Aβ) plays a key role in the process of neuronal degeneration in the case of AD. It has been reported that Aβ is responsible for the production of reactive oxygen species (ROS), depletion of endogenous antioxidants, increase in intracellular Ca²⁺ which further increases mitochondria dysfunctions, oxidative stress, release of pro-apoptotic factors, neuronal apoptosis, etc. Thus, oxidative stress plays a key role in the pathogenesis of AD. Antioxidants are compounds that have the ability to counteract the oxidative damage conferred by ROS. Therefore, the antioxidant therapy may provide benefits and halt the progress of AD to advance stages by counteracting neuronal degeneration. However, despite the beneficial effects imposed by the antioxidants, the findings from the clinical studies suggested inconsistent results which might be due to poor study design, selection of the wrong antioxidant, inability of the molecule to cross the blood–brain barrier (BBB), treatment in the advanced state of disease, etc. The present review insights into the neuroprotective effects and limitations of the antioxidant therapy for the treatment of AD by targeting mitochondrial-derived ROS. This particular article will certainly help the researchers to search new avenues for the treatment of AD by utilizing mitochondrial-derived ROS-targeted antioxidant therapies. Graphical abstract
... Some of the antioxidants can also act as pro-oxidants under deleterious conditions, and thus, they may potentiate oxidative stress and thus their antioxidant activity remains questionable in these conditions [380]. Consistent with these findings, some of the agents (e.g., CoQ) which has been suggested and speculated to confer therapeutic benefits in AD patients cannot cross the BBB and failed to produce any change in the cognitive functions in AD patients [381,382]. For CoQ, it has been reported that to exert its therapeutic effect, CoQ must be retained in the mitochondrial ETC. ...
Article
Alzheimer’s disease (AD) is considered the sixth leading cause of death in elderly patients and is characterized by progressive neuronal degeneration and impairment in memory, language, etc. AD is characterized by the deposition of senile plaque, accumulation of fibrils, and neurofibrillary tangles (NFTs) which are responsible for neuronal degeneration. Amyloid-β (Aβ) plays a key role in the process of neuronal degeneration in the case of AD. It has been reported that Aβ is responsible for the production of reactive oxygen species (ROS), depletion of endogenous antioxidants, increase in intracellular Ca2+ which further increases mitochondria dysfunctions, oxidative stress, release of pro-apoptotic factors, neuronal apoptosis, etc. Thus, oxidative stress plays a key role in the pathogenesis of AD. Antioxidants are compounds that have the ability to counteract the oxidative damage conferred by ROS. Therefore, the antioxidant therapy may provide benefits and halt the progress of AD to advance stages by counteracting neuronal degeneration. However, despite the beneficial effects imposed by the antioxidants, the findings from the clinical studies suggested inconsistent results which might be due to poor study design, selection of the wrong antioxidant, inability of the molecule to cross the blood–brain barrier (BBB), treatment in the advanced state of disease, etc. The present review insights into the neuroprotective effects and limitations of the antioxidant therapy for the treatment of AD by targeting mitochondrial-derived ROS. This particular article will certainly help the researchers to search new avenues for the treatment of AD by utilizing mitochondrial-derived ROS-targeted antioxidant therapies.
... It performs this function by acting as a coenzyme of three mitochondrial enzymes (complex I, II, III) (Littarru & Tiano, 2010). Furthermore, the quinol form of CoQ10 plays a potential antioxidant role by directly suppressing free radicals in the inner membrane of the mitochondria or by reducing the αtocopherol radical (Kwong et al., 2002). Paunovid et al (2017) report that CoQ10 administration strengthens erythrocyte antioxidant capacity by clearing ROS of the toxic effects of cadmium and interrupting lipid peroxidation (Paunovid et al., 2017). ...
... On the other hand, in a study in mice receiving daily 148 or 654 mg CoQ 10 per kg body weight for eleven weeks both CoQ 9 and CoQ 10 were increased in homogenates and in mitochondria of liver, skeletal muscle and heart, in addition to mitochondria of the brain (Kamzalov et al., 2003). In rats, doses of 150 mg/kg/day or higher can lead to raised levels of total CoQ 10 in the heart and muscles, indicating that peripheral tissues may accumulate CoQ 10 when present in high concentrations in the plasma (Kwong et al., 2002). Conflicting results has also been reported in humans receiving supplemental CoQ 10 regarding its entry into skeletal muscle (Paredes-Fuentes et al., 2020). ...
Article
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Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial electron transport chain. It is also an antioxidant in cellular membranes and lipoproteins. All cells produce CoQ10 by a specialized cytoplasmatic-mitochondrial pathway. CoQ10 deficiency can result from genetic failure or ageing. Some drugs including statins, widely used by inter alia elderly, may inhibit endogenous CoQ10 synthesis. There are also chronic diseases with lower levels of CoQ10 in tissues and organs. High doses of CoQ10 may increase both circulating and intracellular levels, but there are conflicting results regarding bioavailability. Here, we review the current knowledge of CoQ10 biosynthesis and primary and acquired CoQ10 deficiency, and results from clinical trials based on CoQ10 supplementation. There are indications that supplementation positively affects mitochondrial deficiency syndrome and some of the symptoms of ageing. Cardiovascular disease and inflammation appear to be alleviated by the antioxidant effect of CoQ10. There is a need for further studies and well-designed clinical trials, with CoQ10 in a formulation of proven bioavailability, involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in neurodegenerative disorders, as well as in metabolic syndrome and its complications.
... These results came in accordance with stated that CoQ10 acts as a potent natural antioxidant, oxygen-derived free radical scavenger and as membrane stabilizer . In addition, CoQ10 exerts inhibiting character on mitochondrial ROS generation and inner mitochondrial depolarization (Kwong et al., 2002). Moreover, CoQ10 supplementation protects plasma membrane against oxidative stress (Gómez-Díaz et al., 2003).The above mentioned effects of CoQ10 permit this coenzyme to exhibit an improvement in each of the oxidative stress markers as investigated in the present study. ...
... The coenzyme Q10 (CoQ10) is a cancer preventive agent coordinated to mitochondria and consisting of quinone structure and is a part of the mitochondrial respiratory chain content. In AD rodent model, the coenzyme CoQ10 has been tried to prevent the cognitive decline [141] but due to its decreased brain absorption [142] it has not been considered successful for patients with AD. Therefore, to rule-over, mitoquinone mesylate (MitoQ) was modified and recuperated as a cancer preventive agent comprising consolidated ubiquinone along with triphenyl phosphonium (TPP) where TPP emphasizes and targets the MitoQ to the mitochondria as it aids in crossing the lipid bilayer which accumulates on the negative site of mitochondrial membrane [143][144]. ...
Article
Mitochondria play a crucial role in expediting the energy homeostasis under varying environmental conditions. As mitochondria are controllers of both energy production and apoptotic pathways, they are also distinctively involved in controlling the neuronal cell survival and/or death. Numerous factors are responsible for mitochondria to get degraded with aging and huge functional failures in mitochondria are also found to be associated with the commencement of numerous neurodegenerative conditions, including Alzheimer's disease (AD). A large number of existing literatures promote the pivotal role of mitochondrial damage and oxidative impairment in the pathogenesis of AD. Numerous mitochondria associated processes such as mitochondrial biogenesis, fission, fusion, mitophagy, transportation and bioenergetics are crucial for proper functioning of mitochondria but are reported to be defective in AD patients. Though, the knowledge on the precise and in-depth mechanisms of these actions is still in infancy. Based upon the outcome of various significant studies, mitochondria are also being considered as therapeutic targets for AD. Here, we review the current status of mitochondrial defects in AD and also summarize the possible role of these defects in the pathogenesis of AD. The various approaches for developing the mitochondria-targeted therapies are also discussed here in detail. Consequently, it is suggested that improving mitochondrial activity via pharmacological and/or non-pharmacological interventions could postpone the onset and slow the development of AD. Further research and consequences of ongoing clinical trials should extend our understanding and help to validate conclusions regarding the causation of AD.
... CoQ10 can stimulate ATPase content and participates in ATP production [80]. In addition, it is able to inhibit mitochondrial ROS generation and inner mitochondrial depolarization [81]. Moreover, plasma membrane protection against oxidative stress is increased due to CoQ10 supplementation [82]. ...
... On the other hand, higher supplementations of coenzyme Q10 reaching up to 150 mg/kg/day could result in a significant increase in tissue levels particularly within the heart and skeletal muscle tissues. This suggests that improved peripheral tissues uptake is associated with higher plasma coenzyme Q10 concentrations [15]. Because of the ease of sample collection and providing valuable pathophysiological and therapeutic information, plasma coenzyme Q10 concentrations ranging from 0.40 to 1.91 μmol/l are usually used for the assessment of its status in humans [14]. ...
Article
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Results from investigations about the effect of coenzyme Q10 supplementation on diabetes mellitus and its related complicationshave varied and are slightly inconsistent. This review study aims at highlighting key points in several clinical trials, the potentialeffect of coenzyme Q10 on glycaemic biomarkers in diabetes mellitus alongside its complications while spotting out severalsimilarities and differenceswithin clinical trials. Twenty-six articles from well-known databases that provided details on clinicaltrials between 1999 and 2020were reviewed. In summarized tables, the articles provided information on the effects of coenzymeQ10 supplementation on glycaemic control ofdiabetes mellitus and its complications. Four of thirteen studies reported no significantchanges in metabolic parameters of diabetes mellitus; three results from these studies reported that there might be improvedglycaemic control especially when coenzyme Q10 is taken in combination with conventional antidiabetic medicines. Results fromthe other thirteen clinical studies on main outcomes of diabetic complications also varied. Eight of these clinicaltrials revealed thatcoenzyme Q10 improved endothelial function thereby reducing vasculopathy and nephropathy of diabetes mellitus complications,while two double-blind placebo-controlled clinical trial showed significant improvement in neuropathy and retinopathy symptomsof diabetes mellitus, respectively. It was observed that the clinicaltrials with the lowest population sizes concluded that coenzymeQ10 may contribute to potential long-term benefits in the treatment of type 2 diabetic patients and its complications; however, morerandomized and large-sample-size trials of coenzyme Q10 for type 2 diabetes mellitus are needed in the nearby future.
... On the other hand, higher supplementations of coenzyme Q10 reaching up to 150 mg/kg/day could result in a significant increase in tissue levels particularly within the heart and skeletal muscle tissues. This suggests that improved peripheral tissues uptake is associated with higher plasma coenzyme Q10 concentrations [15]. Because of the ease of sample collection and providing valuable pathophysiological and therapeutic information, plasma coenzyme Q10 concentrations ranging from 0.40 to 1.91 μmol/l are usually used for the assessment of its status in humans [14]. ...
Article
Full-text available
Results from investigations about the effect of coenzyme Q10 supplementation on diabetes mellitus and its related complications have varied and are slightly inconsistent. This review study aims at highlighting key points in several clinical trials, the potential effect of coenzyme Q10 on glycaemic biomarkers in diabetes mellitus alongside its complications while spotting out several similarities and differences within clinical trials. Twenty-six articles from well-known databases that provided details on clinical trials between 1999 and 2020were reviewed. In summarized tables, the articles provided information on the effects of coenzyme Q10 supplementation on glycaemic control of diabetes mellitus and its complications. Four of thirteen studies reported no significant changes in metabolic parameters of diabetes mellitus; three results from these studies reported that there might be improved glycaemic control especially when coenzyme Q10 is taken in combination with conventional antidiabetic medicines. Results from the other thirteen clinical studies on main outcomes of diabetic complications also varied. Eight of these clinical trials revealed that coenzyme Q10 improved endothelial function thereby reducing vasculopathy and nephropathy of diabetes mellitus complications, while two double-blind placebo-controlled clinical trial showed significant improvement in neuropathy and retinopathy symptoms of diabetes mellitus, respectively. It was observed that the clinical trials with the lowest population sizes concluded that coenzyme Q10 may contribute to potential long-term benefits in the treatment of type 2 diabetic patients and its complications; however, more randomized and large-sample-size trials of coenzyme Q10 for type 2 diabetes mellitus are needed in the nearby future.
... Coenzyme Q10 (CoQ10) or ubiquinone is a lipid-soluble molecule that is often regarded as a naturally occurring antioxidant vitamin in the human body. CoQ10 also acts as a cofactor in mitochondrial energy production, particularly in the production of adenosine triphosphate (ATP) (Kwong et al. 2002;Littarru and Tiano 2007). Thus, coupled with its ability to easily cross the blood-brain barrier, CoQ10 neuroprotective properties have been implicated in improving a range of brain diseases (Mancuso et al. 2010), including epilepsy. ...
Article
Aim: This study aimed to determine the effect of exercise training alone and in combination with coenzyme Q10 (Q10) supplementation on the Q10 level, oxidative damage, and antioxidant defense markers in blood and skeletal muscle tissue in young and aged rats. Methods: The study included 4-month old (young) and 20-month old (aged) rats. Each group was further divided into control, exercise training, Q10 supplementation, and Q10 supplementation plus exercise training groups. The exercise training program consisted of swimming for 8 weeks, and Q10 or vehicle during the same period. Results: The Q10 concentration in plasma (P < 0.05), but not in skeletal muscle (P > 0.05) increased significantly following Q10 supplementation in both the young and aged rats. Plasma SOD and CAT activity were significantly higher in the aged rats in the Q10 and Q10 plus exercise training groups than in the other groups (P < 0.05); however, there was no significant difference between the groups in skeletal muscle (P > 0.05). Additionally, plasma and skeletal GSH levels did not differ between the groups (P > 0.05). Conclusion: The present findings indicate that Q10 supplementation increased the Q10 concentration in blood but not in skeletal muscle tissue. On the other hand, Q10 administration alone and in combination with exercise challenge improved antioxidant enzyme capacity especially in the aged rats.
Article
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Due to large increases in the elderly populations across the world, age-related diseases are expected to increase dramatically in the coming years. Among these, neurodegenerative diseases will be among the most devastating in terms of their emotional and economic impact on patients, their families, and associated subsidized health costs. There is no currently available cure or rescue for dying brain cells. Viable therapeutics for any of these disorders would be a breakthrough and provide relief for the large number of affected patients and their families. Neurodegeneration is accompanied by elevated oxidative damage and inflammation. While natural antioxidants have largely failed in clinical trials, preclinical phenotyping of the properties of the unnatural, mitochondrial targeted nitroxide, XJB-5-131, bodes well for further translational development in advanced animal models or in humans. Here we consider the usefulness of synthetic antioxidants for the treatment of Huntington’s disease. The mitochondrial targeting properties of XJB-5-131 have great promise. It is both an electron scavenger and an antioxidant, reducing both somatic expansion and toxicity simultaneously through the same redox mechanism. By quenching reactive oxygen species, XJB-5-131 breaks the cycle between the rise in oxidative damage during disease progression and the somatic growth of the CAG repeat which depends on oxidation.
Article
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Coenzyme Q10 (CoQ10), a lipophilic substituted benzoquinone, is present in animal and plant cells. It is endogenously synthetized in every cell and involved in a variety of cellular processes. CoQ10 is an obligatory component of the respiratory chain in inner mitochondrial membrane. In addition, the presence of CoQ10 in all cellular membranes and in blood. It is the only endogenous lipid antioxidant. Moreover, it is an essential factor for uncoupling protein and controls the permeability transition pore in mitochondria. It also participates in extramitochondrial electron transport and controls membrane physicochemical properties. CoQ10 effects on gene expression might affect the overall metabolism. Primary changes in the energetic and antioxidant functions can explain its remedial effects. CoQ10 supplementation is safe and well-tolerated, even at high doses. CoQ10 does not cause any serious adverse effects in humans or experimental animals. New preparations of CoQ10 that are less hydrophobic and structural derivatives, like idebenone and MitoQ, are being developed to increase absorption and tissue distribution. The review aims to summarize clinical and experimental effects of CoQ10 supplementations in some neurological diseases such as migraine, Parkinson´s disease, Huntington´s disease, Alzheimer´s disease, amyotrophic lateral sclerosis, Friedreich´s ataxia or multiple sclerosis. Cardiovascular hypertension was included because of its central mechanisms controlling blood pressure in the brainstem rostral ventrolateral medulla and hypothalamic paraventricular nucleus. In conclusion, it seems reasonable to recommend CoQ10 as adjunct to conventional therapy in some cases. However, sometimes CoQ10 supplementations are more efficient in animal models of diseases than in human patients (e.g. Parkinson´s disease) or rather vague (e.g. Friedreich´s ataxia or amyotrophic lateral sclerosis).
Article
Extending life by delaying the aging process have proven to be the most effective way to fight multiple chronic diseases in elderly adults. Evidence suggests that longevity is inversely related to unsaturation of membrane phospholipids. The present study investigated how different unsaturated dietary fats affect lifespan and cause death in male Wistar rats fed diets based on virgin olive oil (V), sunflower oil (S) or fish oil (F), which were supplemented or not with Coenzyme Q10 (CoQ10). Previous results suggest that individual longevity and survival probability at different ages may be modulated by an appropriate dietary fat treatment. Lifelong feeding with V or F diets would reduce death probability compared to feeding with S diet at certain ages, although the effects of V diet would be maintained for most of life. Furthermore, the addition of lower amounts of CoQ10 reduced mortality associated with S diet, but CoQ10 had no effect on survival when combined with virgin olive oil or fish oil. Supplementation with low doses of CoQ10 failed to increase the maximum lifespan potential of rats fed a V or F diet. No clear evidence showing that MUFA, n-3 PUFA or CoQ10 exerted the observed effects by modulating the rate of aging has been found.
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The aim of the study was to determine the effects of immobilization on the gross morphology of rats’ intervertebral disc (IVD) and observe the ameliorating effects of Omega 3 fatty acids and Co-enzyme Q 10 (CoQ10). Forty Sprague Dawley rats weighing 250-300 g were procured from NIH Islamabad. The animals were randomly selected and were divided into four groups of 10 animals in each. Group-A rats served as control group. Each rat of Group B was disc immobilized by using an Illizarov-type apparatus, which was applied for 60 days. Group-C and -D rats after disc immobilization were administrated with Omega 3 fatty acids (260 mg/kg/day) and CoQ10 (150mg/kg/day) through oral gavage respectively. Gross examination of IVD was done using the Thompson grading scale and the disc alterations were scored from grade 1 to 5 in increasing order of IVD alterations. Gross examination of the sections of IVD’s of the control group showed normal healthy morphology, falling in Thompson grade I degeneration. The frequency of disc alteration was statistically significant in disc-immobilized group B when compared to control group A (p-value=0.000), group C (p-value=0.000) and group D (p value=0.002). Group C in which n-3 fatty acid was given along with disc immobilization, showed significant improvement in disc degenerative changes. On comparison with group B, p-value<0.001 was statistically significant. In experimental Group D, where CoQ10 was given along with disc immobilization, the degenerative changes were significantly reduced as compared to Group B (p = 0.002). In this study, gross morphological changes were induced by immobilization in IVDs of the experimental rats and its reversal by omega 3 and CoQ10 was proven. Co-administration of Omega 3 and CoQ10 significantly minimized degenerative changes in IVDs induced by immobilization.
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Coenzyme Q (CoQ) is a ubiquitous lipid serving essential cellular functions. It is the only component of the mitochondrial respiratory chain that can be exogenously absorbed. Here, we provide an overview of current knowledge, controversies, and open questions about CoQ intracellular and tissue distribution, in particular in brain and skeletal muscle. We discuss human neurological diseases and mouse models associated with secondary CoQ deficiency in these tissues and highlight pharmacokinetic and anatomical challenges in exogenous CoQ biodistribution, recent improvements in CoQ formulations and imaging, as well as alternative therapeutical strategies to CoQ supplementation. The last section proposes possible mechanisms underlying secondary CoQ deficiency in human diseases with emphasis on neurological and neuromuscular disorders.
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Harmful effects of heat stress on organisms are a matter of concern for environmental health and global warming. High ambient temperature, whether it is ‘acute' or ‘chronic' in nature, constitutes a significant hindrance to the growth of animals. Heat-induced reactive oxygen species (ROS) formation may be a factor that causes molecular changes in DNA, proteins, lipids and other biological molecules. To create a method for nutritional regulation of ROS production and protein degradation of skeletal muscle in heat-stressed chickens, we focused on elucidating underlying effects of heat stress on ROS production of skeletal muscle with two models to identify conditions for making broiler chickens more tolerant to heat stress. ‘Acute' heat stress in broiler chickens under 34 °C conditions induces increased mitochondrial ROS production via increased β-oxidation and downregulation of the avian form of mitochondrial uncoupling protein (avUCP), resulting in higher oxidative damage to mitochondrial proteins and lipids. Similarly, ‘chronic' heat stress induces increased ROS production in skeletal muscle mitochondria, probably via elevation of the membrane potential DY in state 4, resulting from enhanced oxygen consumption in the initial stage of heat exposure. However, animals can become acclimatized to environmental heat stress. Muscle protein degradation can occur after a short time (3 d) after heat exposure and this may be due to the activation of ubiquitination by atrogin-1 involved with mitochondrial ROS production. Nutritional regulation of ROS production and protein degradation, such as via enhanced avUCP gene expression, are important for making broiler chickens more tolerant to heat stress.
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Adenosine monophosphate-activated protein kinase (AMPK) has a crucial role in neuroprotection. It phosphorylates serine/threonine kinase (Akt) Substrate inhibiting the inflammatory responses induced by the nuclear factor-κB (NF-κB). Exposure to chromium VI dust among workers has been reported and induced brain injury, as the absorption of chromium through the nasal membrane has been found to deliver it directly to the brain. The study aimed to investigate the influence of administration of L-carnitine or/and Co Q10 as theraputic agents against potassium dichromate (PD)-induced brain injury via AMPK/AKT/NF-κβ signaling pathway. Brain injury was induced by PD intranasally as a single dose of 2 mg/kg, 24 h latter rats received L-carnitine (100 mg/kg; orally), Co Q10 (50 mg/kg; orally) and L-carnitine (50 mg/kg; orally) + Co Q10 (25 mg/kg; orally) respectively for 3 days. Locomotor activity was assessed before and at the end of the experiment, then, biochemical and histopathological investigations were assessed in brain homogenate. The exposure of rats to PD promoted oxidative stress and inflammation via an increase in MDA and a decrease in GSH serum contents with an increase in brain contents of TNF-α, IL-6, and NF-kβ and reduced AMPK and AKT brain contents as compared to the control group. Treatment with L-carnitine + Co Q10 ameliorated cognitive impairment and oxidative stress, decreased the brain contents of inflammatory mediators; TNF-α, IL-6, and NF-κβ elevated AMPK and AKT, as compared to each drug. Also, L-carnitine + Co Q10 administration restored morphological changes as degenerated neurons and necrosis. L-carnitine + Co Q10 play important role in AMPK/AKT/NF-κβ pathway that responsible for their antioxidant and anti-inflammatory effects against PD-induced brain injury in rats.
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Objective The aim of this study was to investigate the effect of coenzyme Q10 (CoQ10) supplementation on oxidative stress engendered from hypoxia in population live at high altitude. Methods This is an intervention study in which 50 females of volunteers population-36 of them who live at high altitude compared with the placebo group (14 from the total population that live at sea level). Blood samples were collected in -anticoagulant tubes from control and high altitude before and after CoQ10 supplementation (150 mg/day for 2, 4 and 8 weeks). Plasma was separated and used for the determination of malondialdehyde (MDA), nitric oxide (NOx), total antioxidant capacity (TAC), paraoxonase (PON1) by spectrophotometer, CoQ10 and vitamin E by high performance liquid chromatography (HPLC). Results Our results appeared that TAC, PON1, vitamin E and CoQ10 concentrations were significantly decreased in population at high altitude at base line compared to placebo group population at sea level. Whereas, administration of CoQ10 attenuated all measured parameters especially after eight weeks of administration. Conclusion We concluded that coenzyme Q10 supplement at a dose of 150 mg/day has a powerful effect in oxidative stress parameters and increased antioxidant parameters included vitamin E in population with hypoxia after 4 and 8 weeks. So that supplementation positively affects oxidative stress and is recommended CoQ10 supplementation in population who live at high altitude.
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The aim of this study was to investigated anti-proliferative and anti-apoptotic effects of coenzyme Q10 (CoQ10) in the prevention of radioiodine-131 (RAI) (I131) induced kidney damage. A total of 24 Wistar albino rats were seperated into equal three groups (n = 8/group): Group 1 (control): untreated group; Group 2 (RAI): 3 mCi/kg RAI oral route; Group 3 (RAI+CoQ10): 3 mCi/kg RAI oral route and intraperitoneally 30 mg/kg/day CoQ10. CoQ10 treatment was started two days before RAI administration and was continued five days once daily after RAI. Pathomorphological parameters of kidneys were measured using hematoxylin–eosin and Masson’s trichrome staining. Immunohistochemically; proliferating cell nuclear antigen (PCNA), caspase 8, caspase 9 and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling (TUNEL) were used to determine proliferation and apoptosis. With the exception of the control group, varying degrees of inflammation, degeneration, necrosis, and interstitial/perivascular fibrosis were detected in the kidneys of all rats. This histopathological damage was found to be significantly less in CoQ10 group versus RAI group (p < 0.05). The all immunohistochemical examinations demonstrated that administration of CoQ10 has reduced proliferation and apoptosis (p < 0.05). The results of kidney histopathology and immunohistochemistry of this study demonstrated that administration of CoQ10 has reduced inflammation, proliferation, and apoptosis. This findings show that CoQ10 can play an important role in radioprotection of kidney against RAI-induced damage.
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Primary coenzyme Q10 (CoQ10) deficiency encompasses a subset of mitochondrial diseases caused by mutations affecting proteins involved in the CoQ10 biosynthetic pathway. One of the most frequent clinical syndromes associated with primary CoQ10 deficiency is the severe infantile multisystemic form, which, until recently, was underdiagnosed. In the last few years, the availability of genetic screening through whole exome sequencing and whole genome sequencing has enabled molecular diagnosis in a growing number of patients with this syndrome and has revealed new disease phenotypes and molecular defects in CoQ10 biosynthetic pathway genes. Early genetic screening can rapidly and non-invasively diagnose primary CoQ10 deficiencies. Early diagnosis is particularly important in cases of CoQ10 deficient steroid-resistant nephrotic syndrome, which frequently improves with treatment. In contrast, the infantile multisystemic forms of CoQ10 deficiency, particularly when manifesting with encephalopathy, present therapeutic challenges, due to poor responses to CoQ10 supplementation. Administration of CoQ10 biosynthetic intermediate compounds is a promising alternative to CoQ10; however, further pre-clinical studies are needed to establish their safety and efficacy, as well as to elucidate the mechanism of actions of the intermediates. Here, we review the molecular defects causes of the multisystemic infantile phenotype of primary CoQ10 deficiency, genotype-phenotype correlations, and recent therapeutic advances. Keywords: Coenzyme Q10, coenzyme Q10 deficiency, coenzyme Q biosynthesis, nephrotic syndrome, cardiopathy, encephalopathy
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Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy specific liver disease characterized by pruritus, elevated serum bile acids and abnormal liver function that may be associated with severe adverse pregnancy outcomes. We previously reported that plasma coenzyme Q10 (CoQ10) is decreased in women with ICP as it is its analogue coenzyme Q9 (CoQ9) in rats with ethinyl estradiol (EE)-induced cholestasis. The aim of the present study was to evaluate the possible therapeutic role of CoQ10 in experimental hepatocellular cholestasis and to compare it with ursodeoxycholic acid (UDCA) supplementation. Bile acids, CoQ9, CoQ10, transaminases, alkaline phosphatase, retinol, α-tocopherol, ascorbic acid, thiobarbituric acid, carbonyls, glutathione, superoxide dismutase and catalase were assessed in plasma, liver and/or hepatic mitochondria in control and cholestatic rats supplemented with CoQ10 (250 mg/kg) administered alone or combined with UDCA (25 mg/kg). CoQ10 supplementation prevented bile flow decline (P < 0.05) and the increase in serum alkaline phosphatase and bile acids, particularly lithocholic acid (P < 0.05) in cholestatic rats. Furthermore, it also improved oxidative stress parameters in the liver, increased both CoQ10 and CoQ9 plasma levels and partially prevented the fall in α-tocopherol (P < 0.05). UDCA also prevented cholestasis, but it was less efficient than CoQ10 to improve the liver redox environment. Combined administration of CoQ10 and UDCA resulted in additive effects. In conclusion, present findings show that CoQ10 supplementation attenuated EE-induced cholestasis by promoting a favorable redox environment in the liver, and further suggest that it may represent an alternative therapeutic option for ICP.
Chapter
Coenzyme Q is a very old molecule in evolutionary terms that has accumulated numerous functions in the cellular metabolism beyond its primordial function, the electron transport. In all organisms, coenzyme Q maintains a highly conserved structure allowing a localization inside cell membranes in a hydrophobic environment thanks to having an isoprenoid tail, and at the same time allows the polar ring benzene to interact with acceptors and electron donors. Coenzyme Q deficiency constitutes a group of mitochondrial diseases. Affected patients suffer mainly a decrease in energy production that induces dysfunctions in most organs and body systems. Current therapeutic alternatives are based on increasing coenzyme Q levels either through induction of endogenous mechanisms or exogenous supplementation. This chapter includes both aspects, the mechanisms associated with the coenzyme Q supplementation and the regulatory mechanisms of coenzyme Q biosynthesis. In terms of synthesis, the structure of coenzyme Q is complicated since it requires the participation of two well-differentiated pathways that must be carefully regulated. The synthesis is carried out through the participation of a multienzyme complex located in the inner mitochondrial membrane and controlled by different levels of regulation that at this time are not well-known.
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Ethnopharmacological relevance: The consumption of khat (Catha Edulis, Forsk) is on the rise despite the much publicized associated deleterious health effects. How chemicals present in khat, affect various physiological and biochemical processes requires further scrutiny. A clear understanding of these processes will provide an avenue for countering khat-driven negative effects using appropriate pharmacological and/or nutritional interventions. Aim of the study: The current study investigated the effect of khat on vital physiological and biochemical processes such as oxidative stress, inflammation and immune responses and the role of Coenzyme-Q10 (CoQ10), a potent antioxidant and anti-inflammatory, in modulating any negative effects due to khat exposure. Methodology: Three (3) weeks old forty (40) Swiss albino mice were randomly assigned into four treatment groups (n = 10). The first group was the control that was not administered with khat or CoQ10. The second group received 200 mg/kg body weight (b/w) of CoQ10, while the third group received 1500 mg/kg b/w of khat extract and finally the forth group was co-treated with 200 mg/kg b/w of CoQ10 and 1500 mg/kg b/w of khat extract. The experiment was conducted for 90 days after which samples were collected for physiological and biochemical analyses. Results: The effects of khat and CoQ10 on the weights of brain, liver, kidney and spleen was determined. Administration of khat decreased the levels of RBCs and its subtypes (MCV, MCH, RDW-SD and RDW-CV), a clear indicator of khat-induced normochromic microcytic anemia. White blood cells (lymphocytes, monocytes, neutrophils and eosinophil) which are vital in responding to infections were markedly elevated by khat. Moreover, these results provide evidence for khat-induced liver and kidney injury as shown by increased biomarkers; AST, ALT, GGT and creatinine respectively. Standard histopathological analysis confirmed this finding for khat-driven liver and kidney injury. Further studies showed evidence for khat-induced inflammation and oxidative stress as depicted by increased levels of the pro-inflammatory cytokine TNF-alpha and elevation of GSH in the brain, liver and spleen. Remarkably, this is the first study to demonstrate the potential of CoQ10 in ameliorating khat-induced negative effects as outlined. CoQ10 supplementation restored the khat-induced reduction in RBC subtypes, and was protective against liver and kidney injury as shown by the appropriate biomarkers and standard histopathology analysis. The other significant finding was the CoQ10-driven normalization of GSH and TNF-α levels, indicating a protective effect from khat-driven oxidative stress and inflammation respectively. Conclusion: From this study, we conclude that CoQ10 may be useful in nullifying khat-driven deleterious events among chronic khat users.
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Coenzyme Q (CoQ, ubiquinone/ubiquinol) is a ubiquitous and unique molecule that drives electrons in mitochondrial respiratory chain and an obligatory step for multiple metabolic pathways in aerobic metabolism. Alteration of CoQ biosynthesis or its redox stage are causing mitochondrial dysfunctions as hallmark of heterogeneous disorders as mitochondrial/metabolic, cardiovascular, and age-associated diseases. Regulation of CoQ biosynthesis pathway is demonstrated to affect all steps of proteins production of this pathway, posttranslational modifications and protein-protein-lipid interactions inside mitochondria. There is a bi-directional relationship between CoQ and the epigenome in which not only the CoQ status determines the epigenetic regulation of many genes, but CoQ biosynthesis is also a target for epigenetic regulation, which adds another layer of complexity to the many pathways by which CoQ levels are regulated by environmental and developmental signals to fulfill its functions in eukaryotic aerobic metabolism.
Chapter
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During the course of measuring superoxide dismutase (SOD) activity in rat breast tissue, interferences in the nitroblue tetrazolium (NBT) and cytochrome c assay systems were noted. These interferences inhibit accurate measurement of SOD activity in breast tissues, necessitating the development of a new NBT-based assay that includes compounds capable of inhibiting tissue specific interferences. The most effective compounds were metal chelators that were also electron transport chain inhibitors. Bathocuproine sulfonate (BCS) was the most effective of these compounds. The inclusion of BCS in the NBT assay system was shown to make the accurate measurement of SOD activity in tissues with interferences possible.
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Under normal physiological conditions, the use of oxygen by cells of aerobic organisms generates potentially deleterious reactive oxygen metabolites. A chronic state of oxidative stress exists in cells because of an imbalance between prooxidants and antioxidants. The amount of oxidative damage increases as an organism ages and is postulated to be a major causal factor of senescence. Support for this hypothesis includes the following observations: (i) Overexpression of antioxidative enzymes retards the age-related accrual of oxidative damage and extends the maximum life-span of transgenic Drosophila melanogaster. (ii) Variations in longevity among different species inversely correlate with the rates of mitochondrial generation of the superoxide anion radical (O·−2) and hydrogen peroxide. (iii) Restriction of caloric intake lowers steady-state levels of oxidative stress and damage, retards age-associated changes, and extends the maximum life-span in mammals.
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This mini-review describes the role of different mitochondrial components in the formation of reactive oxygen species under normal and pathological conditions and the effect of inhibitors and uncouplers on superoxide formation.
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Rates of mitochondrial superoxide anion radical (O·̄2) generation are known to be inversely correlated with the maximum life span potential of different mammalian species. The objective of this study was to understand the possible mechanism(s) underlying such variations in the rate of O·̄2 generation. The hypothesis that the relative amounts of the ubiquinones or coenzyme Q (CoQ) homologues, CoQ9 and CoQ10, are related with the rate of O·̄2 generation was tested. A comparison of nine different mammalian species, namely mouse, rat, guinea pig, rabbit, pig, goat, sheep, cow, and horse, which vary from 3.5 to 46 years in their maximum longevity, indicated that the rate of O·̄2 generation in cardiac submitochondrial particles (SMPs) was directly related to the relative amount of CoQ9 and inversely related to the amount of CoQ10, extractable from their cardiac mitochondria. To directly test the relationship between CoQ homologues and the rate of O·̄2 generation, rat heart SMPs, naturally containing mainly CoQ9 and cow heart SMPs, with high natural CoQ10 content, were chosen for depletion/reconstitution experiments. Repeated extractions of rat heart SMPs with pentane exponentially depleted both CoQ homologues while the corresponding rates of O·̄2 generation and oxygen consumption were lowered linearly. Reconstitution of both rat and cow heart SMPs with different amounts of CoQ9 or CoQ10 caused an initial increase in the rates of O·̄2 generation, followed by a plateau at high concentrations. Within the physiological range of CoQ concentrations, there were no differences in the rates of O·̄2generation between SMPs reconstituted with CoQ9 or CoQ10. Only at concentrations that were considerably higher than the physiological level, the SMPs reconstituted with CoQ9 exhibited higher rates of O·̄2 generation than those obtained with CoQ10. These in vitrofindings do not support the hypothesis that differences in the distribution of CoQ homologues are responsible for the variations in the rates of mitochondrial O·̄2 generation in different mammalian species.
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With phosphorus magnetic resonance spectroscopy (31P-MRS) we studied in vivo the effect of six-month coenzyme Q10 treatment on the efficiency of brain and skeletal muscle mitochondrial respiration in six patients with different mitochondrial cytopathies. Before CoQ we found a low phosphocreatine content (average of 25% decrease from controls) in the occipital lobes of all patients. Calculated [ADP] and the relative rate of ATP synthesis were high (as an average, 57% and 16% above control group respectively), whereas the cytosolic phosphorylation potential was low (as an average, 60% of control value). 31P-MRS also revealed an average of 29% reduction of the mitochondrial function in the skeletal muscle of patients compared with controls. After a six-month treatment with 150 mg CoQ10/day all brain variables were remarkably improved in all patients, returning within the control range in all cases. Treatment with CoQ also improved the muscle mitochondrial functionality enough to reduce the average deficit to 56% of the control group. These in vivo findings show the beneficial effect of CoQ in patients with mitochondrial cytopathies, and are consistent with the view that increased CoQ concentration in the mitochondrial membrane increases the efficiency of oxidative phosphorylation independently of enzyme deficit.
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Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q10 increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats administration of coenzyme Q10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q10. Oral administration of coenzyme Q10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.
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The effects of coenzyme Q(10) (CoQ(10)) and alpha-tocopherol on the rate of mitochondrial superoxide anion radical (O2(./-)) generation were examined in skeletal muscle, liver, and kidney of 24-month-old mice. Mice were orally administered alpha-tocopherol (200 mg.kg(-1).day(-1)) alone, CoQ(10) (123 mg.kg(-1).day(-1)) alone, or the two together for 13 wk. Administration of alpha-tocopherol resulted in an approximately sevenfold elevation of mitochondrial alpha-tocopherol content. Intake of CoQ(10) alone caused an approximately fivefold increase in CoQ content (CoQ(9) and/or CoQ(10)) and alpha-tocopherol of mitochondria. The rate of (O2(./-)) generation by submitochondrial particles (SMPs) was inversely related to their alpha-tocopherol content but unrelated to CoQ content. Experimental in vitro augmentation of SMPs with varying amounts of alpha-tocopherol caused an up to approximately 50% decrease in the rate of O2(./-) generation. Similar in vitro augmentations of SMPs with CoQ(10) had previously been found to have no effect on the rate of O2(./-) generation The CoQ(10)-induced elevation of alpha-tocopherol in the present study was inferred to be due to a 'sparing/regeneration' by CoQ. Results indicate the involvement of alpha-tocopherol in the elimination of mitochondrially generated O2(./-)
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Vitamin E (VE) and coenzyme Q (CQ) are essential for maintaining functions and integrity of mitochondria, and high concentrations of these compounds are found in their inner membranes. This study was conducted to examine the interaction between exogenously administered CQ10 and VE in rats. Male Sprague-Dawley rats (12 mo old) were fed a basal diet (10 IU VE or 6.7 mg RRR-alpha-tocopherol equivalent) supplemented with either 0 or 500 mg CQ10, and 0, 100 or 1310 IU VE/kg diet for 14 or 28 d. Liver, spleen, heart, kidney, skeletal muscle, brain and serum were analyzed for the levels of CQ10, CQ9 and VE. CQ10 supplementation significantly (P: < 0.05) increased CQ10 concentration in the liver and spleen (total and mitochondria) and serum, but not in other organs. Interestingly, rats supplemented with CQ10 plus 100 IU VE/kg diet had significantly higher CQ10 levels in the liver and spleen, whereas those supplemented with CQ10 plus 1310 IU VE/kg diet had lower levels, compared with those supplemented with CQ10 alone. As expected, dietary VE increased VE content in all of the organs analyzed in a dose-dependent manner. However, rats fed the basal diet supplemented with CQ10 had significantly higher VE levels in liver (total and mitochondria) than those not receiving CQ10 supplementation. CQ9 levels were higher in the liver and spleen, lower in skeletal muscle and unaltered in brain, serum, heart and kidney of rats supplemented with CQ10 compared with the controls. These data provide direct evidence for an interactive effect between exogenously administered VE and CQ10 in terms of tissue uptake and retention, and for a sparing effect of CQ10 on VE. Data also suggest that dietary VE plays a key role in determining tissue retention of exogenous CQ10.
Chapter
This chapter examines the stability and preparation of catalase. Catalase combines rapidly with H2O2 or alkyl hydroperoxides. The rate constant for the reaction catalase + H2O2 is of the order of 10⁷ s⁻¹ X mole⁻¹. With the alkyl hydroperoxides, the constant decreases with increasing chain length. In comparison to the formation of the primary compound the back reaction can be disregarded. The turnover number for the decomposition of hydrogen peroxide is 2.5 × 10⁶ to 5 × 10⁶ moles/min. The maximum rise in temperature after the start of the reaction can serve as an approximate measure of the activity. The manometric method is considerably more accurate than the volumetric measurement of oxygen with the Katalaser. The paper disk method is rapid and easy to carry out but is not so accurate. In this method the enzyme activity is measured by the rate at which a filter paper disk soaked in the sample solution is carried to the surface of a H2O2 solution by the oxygen liberated. The temperature coefficient for the decomposition of H2O2 is about 5% per degree between 0 and + 10°C.
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Endogenous proteins are highly susceptible to modification by ROS produced as byproducts of normal metabolic processes, or upon exposure to oxidative stress and atmospheric pollutants. The ROS-mediated modification of proteins may lead to loss of biological function and to conversion of the proteins to forms that are rapidly degraded by endogenous proteases, especially by the multicatalytic protease. One of many different kinds of protein modification elicited by ROS is the oxidation of some amino acid side chains to carbonyl derivatives. The carbonyl content of protein is therefore a convenient marker of ROS-mediated protein damage. By means of highly sensitive methods for the detection and quantitation of protein carbonyl groups, it has been established in several different animal models that there is an exponential increase in the level of oxidized protein during aging and that elevated levels of oxidized proteins are associated with a number of diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, diabetes, muscular dystrophy, and cataractogenesis, to name a few. Although protein oxidation probably contributes to the biological dysfunction associated with these diseases, a causal relationship between protein oxidation and the etiology or progression of a disease has not been established. Nevertheless, in the case of some neurological disorders, there is a positive correlation between the loss of a particular biological function and an elevation of the level of oxidized protein in the brain (153) and in specific regions of the brain that control that function (154). Finally, because oxidized proteins are readily degraded by endogenous proteases, the steady state intracellular level of oxidized proteins is a complex function of a multiplicity of factors that govern the generation of ROS, the antioxidant systems that scavenge ROS, the susceptibility of proteins to oxidative modification, and the activities of the proteases that degrade oxidized proteins. Accordingly, the accumulation of oxidized protein that occurs during aging and in various diseases is likely attributable to the accumulated genetic damage (ROS-mediated mutations?) that affects one or more of the numerous factors that determine the balance between protein oxidation on the one hand and the degradation of oxidized proteins on the other.
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: The oxidative modification of proteins by reactive species, especially reactive oxygen species, is implicated in the etiology or progression of a panoply of disorders and diseases. These reactive species form through a large number of physiological and non-physiological reactions. An increase in the rate of their production or a decrease in their rate of scavenging will increase the oxidative modification of cellular molecules, including proteins. For the most part, oxidatively modified proteins are not repaired and must be removed by proteolytic degradation, and a decrease in the efficiency of proteolysis will cause an increase in the cellular content of oxidatively modified proteins. The level of these modified molecules can be quantitated by measurement of the protein carbonyl content, which has been shown to increase in a variety of diseases and processes, most notably during aging. Accumulation of modified proteins disrupts cellular function either by loss of catalytic and structural integrity or by interruption of regulatory pathways.
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Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport chain as well as an important antioxidant. Previous studies have suggested that it may exert therapeutic effects in patients with known mitochondrial disorders. We investigated whether it can exert neuroprotective effects in a variety of animal models. We have demonstrated that CoQ10 can protect against striatal lesions produced by both malonate and 3-nitropropionic acid. It also protects against MPTP toxicity in mice. It extended survival in a transgenic mouse model of amyotrophic lateral sclerosis. We demonstrated that oral administration can increase plasma levels in patients with Parkinson's disease. Oral administration of CoQ10 significantly decreased elevated lactate levels in patients with Huntington's disease. These studies therefore raise the prospect that administration of CoQ10 may be useful for the treatment of neurodegenerative diseases.
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The clinical experience in cardiology with CoQ10 includes studies on congestive heart failure, ischemic heart disease, hypertensive heart disease, diastolic dysfunction of the left ventricle, and reperfusion injury as it relates to coronary artery bypass graft surgery. The CoQ10-lowering effect of HMG-CoA reductase inhibitors and the potential adverse consequences are of growing concern. Supplemental CoQ10 alters the natural history of cardiovascular illnesses and has the potential for prevention of cardiovascular disease through the inhibition of LDL cholesterol oxidation and by the maintenance of optimal cellular and mitochondrial function throughout the ravages of time and internal and external stresses. The attainment of higher blood levels of CoQ10 (>3.5 μg/ml) with the use of higher doses of CoQ10 appears to enhance both the magnitude and rate of clinical improvement. In this communication, 34 controlled trials and several open-label and long-term studies on the clinical effects of CoQ10 in cardiovascular diseases are reviewed.
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Antimycin-inhibited bovine heart submitochondrial particles generate O2- and H2O2 with succinate as electron donor. H2O2 generation involves the action of the mitochondrial superoxide dismutase, in accordance with the McCord & Fridovich [(1969) j. biol. Chem. 244, 6049-6055] reaction mechanism. Removal of ubiquinone by acetone treatment decreases the ability of mitochondrial preparations to generate O2- and H2O2, whereas supplementation of the depleted membranes with ubiquinone enhances the peroxide-generating activity in the reconstituted membranes. Addition of superoxide dismutase to ubiquinone-reconstituted membranes is essential in order to obtain maximal rates of H2O2 generation since the acetone treatment of the membranes apparently inactivates (or removes) the mitochondrial superoxide dismutase. Parallel measurements of H2O2 production, succinate dehydrogenase and succinate-cytochrome c reductase activities show that peroxide generation by ubiquinone-supplemented membranes is a monotonous function of the reducible ubiquinone content, whereas the other two measured activities reach saturation at relatively low concentrations of reducible quinone. Alkaline treatment of submitochondrial particles causes a significant decrease in succinate dehydrogenase activity and succinate-dependent H2O2 production, which contrasts with the increase of peroxide production by the same particles with NADH as electron donor. Solubilized succinate dehydrogenase generates H2O2 at a much lower rate than the parent submitochondrial particles. It is postulated that ubisemiquinone (and ubiquinol) are chiefly responsible for the succinate-dependent peroxide production by the mitochondrial inner membrane.
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Daily oral or ip administration of coenzyme Q10 to rats for time periods of 2 to 10 weeks leads to its accumulation in liver, concentrating in the soluble fraction of the liver cells. No uptake of coenzyme Q10 can be detected in the heart or kidney. Intraperitoneal administration also results in the accumulation of coenzyme Q10 in the spleen. It is concluded that the normal endogenous levels of quinone in the rat heart and kidney cannot be supplemented over the long term by administration of exogenous quinone.
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Ubiquinones and tocopherols (vitamin E) are intrinsic lipid components which have a stabilizing function in many membranes attributed to their antioxidant activity. The antioxidant effects of tocopherols are due to direct radical scavenging. Although ubiquinones also exert antioxidant properties the specific molecular mechanisms of their antioxidant activity may be due to: (i) direct reaction with lipid radicals or (ii) interaction with chromanoxyl radicals resulting in regeneration of vitamin E. Lipid peroxidation results have now shown that tocopherols are much stronger membrane antioxidants than naturally occurring ubiquinols (ubiquinones). Thus direct radical scavenging effects of ubiquinols (ubiquinones) might be negligible in the presence of comparable or higher concentrations of tocopherols. In support of this our ESR findings show that ubiquinones synergistically enhance enzymic NADH- and NADPH-dependent recycling of tocopherols by electron transport in mitochondria and microsomes. If ubiquinols were direct radical scavengers their consumption would be expected. Further proving our conclusion HPLC measurements demonstrated that ubiquinone-dependent sparing of tocopherols was not accompanied by ubiquinone consumption.
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The general objective of this study was to examine the relationship between oxygen free radicals and the aging process. The rate of superoxide anion radical (O2.-) generation was measured in liver sub-mitochondrial particles from mouse, rat, rabbit, pig and cow, and in flight muscle sub-mitochondrial particles from the housefly. The rate of O2.- generation was determined as superoxide dismutase inhibitable reduction of ferricytochrome c in the presence of antimycin A and KCN. O2.- generation was inversely related to maximum species life span potential (MLSP) (r = -0.92). A 24-fold difference in the rate of O2.- production was observed between the cow and the fly while a 6-fold difference existed among the mammals. The results are interpreted to indicate that under identical conditions, mitochondria from organisms with low MLSP have a relatively greater propensity to generate O2.-. This may be suggestive of innate differences in the molecular organization of the inner mitochondrial membrane among different species.
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Oxidatively modified proteins have been implicated in a variety of physiologic and pathologic processes. Oxidative modification typically causes inactivation of enzymes and also the introduction of carbonyl groups into amino acid side chains of the protein. We describe a method to quantify oxidatively modified proteins through reduction of these carbonyl groups with tritiated borohydride. The technique was applied to purified, oxidatively modified glutamine synthetase and to bronchoalveolar lavage fluid from dogs and from humans. Since the protein content of lung lavage fluid is low, a very sensitive method was required to measure the oxidized residues. Reduction of the carbonyl group generated during oxidation of proteins with tritiated borohydride provided excellent sensitivity. Incorporation of tritium was directly proportional to the amount of protein with a range from 10 to 1000 micrograms. Should moieties other than amino acids be labeled, they are easily removed by rapid benchtop hydrolysis of the protein followed by chromatography on Dowex 50.
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Much evidence indicates that superoxide is generated from O2 in a cyanide-sensitive reaction involving a reduced component of complex III of the mitochondrial respiratory chain, particularly when antimycin A is present. Although it is generally believed that ubisemiquinone is the electron donor to O2, little experimental evidence supporting this view has been reported. Experiments with succinate as electron donor in the presence of antimycin A in intact rat heart mitochondria, which contain much superoxide dismutase but little catalase, showed that myxothiazol, which inhibits reduction of the Rieske iron-sulfur center, prevented formation of hydrogen peroxide, determined spectrophotometrically as the H2O2-peroxidase complex. Similarly, depletion of the mitochondria of their cytochrome c also inhibited formation of H2O2, which was restored by addition of cytochrome c. These observations indicate that factors preventing the formation of ubisemiquinone also prevent H2O2 formation. They also exclude ubiquinol, which remains reduced under these conditions, as the reductant of O2. Since cytochrome b also remains fully reduced when myxothiazol is added to succinate- and antimycin A-supplemented mitochondria, reduced cytochrome b may also be excluded as the reductant of O2. These observations, which are consistent with the Q-cycle reactions, by exclusion of other possibilities leave ubisemiquinone as the only reduced electron carrier in complex III capable of reducing O2 to O2-.
Article
The electron-microscopic morphology, mitochondrial respiratory rates and respiratory control ratios, and the histochemical distribution of mitochondrial enzymes were studied in the ventricular myocardium of young female rats during the time-course of repeated exercise by swimming. Following swimming between a total of 140 and 180 hours (at the rate of 6 hours a day, 6 days a week) there was a large increase in mitochondrial mass. The respiratory rate of these mitochondria showed no change with α-ketoglutarate, succinate, or pyruvate, and slight increase with glutamate. With only the latter substrate, however, a considerable increase of the mitochondrial respiratory control ratio was observed. Already at this stage of exercising, which represented an optimum physical condition of the animals, some scattered degenerative foci in the myocardium were noted showing fusion, swelling, clumping and reduction of mitochondrial cristae, and disoriented indistinct myofilaments in which the sarcomere bands could not be seen. These foci showed decrease of histochemically detectable succinic dehydrogenase and β-hydroxybutyric dehydrogenase.
Article
1. Pigeon heart mitochondria produce H(2)O(2) at a maximal rate of about 20nmol/min per mg of protein. 2. Succinate-glutamate and malate-glutamate are substrates which are able to support maximal H(2)O(2) production rates. With malate-glutamate, H(2)O(2) formation is sensitive to rotenone. Endogenous substrate, octanoate, stearoyl-CoA and palmitoyl-carnitine are by far less efficient substrates. 3. Antimycin A exerts a very pronounced effect in enhancing H(2)O(2) production in pigeon heart mitochondria; 0.26nmol of antimycin A/mg of protein and the addition of an uncoupler are required for maximal H(2)O(2) formation. 4. In the presence of endogenous substrate and of antimycin A, ATP decreases and uncoupler restores the rates of H(2)O(2) formation. 5. Reincorporation of ubiquinone-10 and ubiquinone-3 to ubiquinone-depleted pigeon heart mitochondria gives a system in which H(2)O(2) production is linearly related to the incorporated ubiquinone. 6. The generation of H(2)O(2) by pigeon heart mitochondria in the presence of succinate-glutamate and in metabolic state 4 has an optimum pH value of 7.5. In states 1 and 3u, and in the presence of antimycin A and uncoupler, the optimum pH value is shifted towards more alkaline values. 7. With increase of the partial pressure of O(2) to the hyperbaric region the formation of H(2)O(2) is markedly increased in pigeon heart mitochondria and in rat liver mitochondria. With rat liver mitochondria and succinate as substrate in state 4, an increase in the pO(2) up to 1.97MPa (19.5atm) increases H(2)O(2) formation 10-15-fold. Similar pO(2) profiles were observed when rat liver mitochondria were supplemented either with antimycin A or with antimycin A and uncoupler. No saturation of the system with O(2) was observed up to 1.97MPa (19.5atm). By increasing the pO(2) to 1.97MPa (19.5atm), H(2)O(2) formation in pigeon heart mitochondria with succinate as substrate increased fourfold in metabolic state 4, with antimycin A added the increase was threefold and with antimycin A and uncoupler it was 2.5-fold. In the last two saturation of the system with oxygen was observed, with an apparent K(m) of about 71kPa (0.7-0.8atm) and a V(max.) of 12 and 20nmol of H(2)O(2)/min per mg of protein. 8. It is postulated that in addition to the well-known flavin reaction, formation of H(2)O(2) may be due to interaction with an energy-dependent component of the respiratory chain at the cytochrome b level.
Article
A fluorimetric assay for the indirect determination of superoxide production during the respiratory burst of stimulated polymorphonuclear leukocytes was described. The method allowed the determination of submicromolar concentrations of superoxide, and was sufficiently sensitive that first-derivative kinetic analysis of the respiratory burst could be quickly analyzed. Conditions for the simultaneous fluorimetric analysis of superoxide production and intracellular calcium fluxes were described.
Article
Quantitative analyses of individual ubiquinones (Q) homologs in biological samples have been performed by high-performance liquid chromatography (HPLC) combined with an ultraviolet spectrometric detector (UVD) or by mass spectrometry (MS). An electrochemical detector (ECD) for HPLC was confirmed to be simple and sensitive for the determination of Q. However, only Q was determined by these methods. For the determination of QH2 (ubiquinol) and Q in mitochondria, submitochondrial particle and cell-free bacterial homogenates, the dual-wavelength spectrometric method has been generally used. The method, however, cannot simultaneously measure the amounts of QH2 and Q in whole tissues owing to the presence of vitamin A and other interfering compounds, which have an absorbance in the same spectral region as Q and undergo an absorption change by chemical reduction. The dual-wavelength spectrometric method cannot separately determine individual Q homologs. The analytical procedure described was developed to provide a rapid, sensitive, and direct assay method for QH2 and Q in biological samples. This method is based on extraction from tissues, mitochondria, microsomal fractions, or plasma with organic solvents, followed by quantitation by means of reversed-phase chromatography with UVD and ECD.
Article
A method of high performance liquid chromatography with both of a UV detector and an electrochemical detector for the simultaneous determination of ubiquinone and ubiquinol was established. This method could sensitively and specifically measure the redox state of ubiquinone in mitochondria and tissues.
Article
This presentation is a brief review of current knowledge concerning some biochemical, physiological and medical aspects of the function of ubiquinone (coenzyme Q) in mammalian organisms. In addition to its well-established function as a component of the mitochondrial respiratory chain, ubiquinone has in recent years acquired increasing attention with regard to its function in the reduced form (ubiquinol) as an antioxidant. Ubiquinone, partly in the reduced form, occurs in all cellular membranes as well as in blood serum and in serum lipoproteins. Ubiquinol efficiently protects membrane phospholipids and serum low-density lipoprotein from lipid peroxidation, and, as recent data indicate, also mitochondrial membrane proteins and DNA from free-radical induced oxidative damage. These effects of ubiquinol are independent of those of exogenous antioxidants, such as vitamin E, although ubiquinol can also potentiate the effect of vitamin E by regenerating it from its oxidized form. Tissue ubiquinone levels are regulated through the mevalonate pathway, increasing upon various forms of oxidative stress, and decreasing during aging. Drugs inhibiting cholesterol biosynthesis via the mevalonate pathway may inhibit or stimulate ubiquinone biosynthesis, depending on their site of action. Administration of ubiquinone as a dietary supplement seems to lead primarily to increased serum levels, which may account for most of the reported beneficial effects of ubiquinone intake in various instances of experimental and clinical medicine.
Article
Coenzyme Q is an important mitochondrial redox component and the only endogenously produced lipid-soluble antioxidant. Its tissue concentration decreases with aging and in a number of diseases; dietary supplementation of this lipid would fulfill important functions by counteracting coenzyme Q depletion. To investigate possible uptake, rats were administered 12 mumol coenzyme Q10/100 g body wt once daily by gastric intubation. The appearance of coenzyme Q10 in various tissues and blood after 6 h, 4 d or 8 d was studied. The control group of rats received rapeseed-soybean oil (the vehicle in the experimental group). Lipids were extracted with petroleum ethermethanol, and the reduced and oxidized forms of coenzyme Q9 and Q10 were separated and quantified by reversed-phase HPLC. In the plasma, the total coenzyme Q concentration was doubled after 4 d of treatment. Coenzyme Q10 was also recovered in liver homogenates, where, as in the plasma, it was largely in the reduced form. Uptake into the spleen could be to a large extent accounted for by the blood content of this organ. No dietary coenzyme Q10 was recovered in the heart or kidney. The uptake in the whole body was 2-3% of the total dose. Coenzyme Q10 found in the liver was located mainly in the lysosomes. Dietary coenzyme Q10 did not influence the endogenous biosynthesis of coenzyme Q9. This is in contrast to dietary cholesterol, which down-regulates cholesterol biosynthesis. The dietary coenzyme Q10 level in the plasma decreased to approximately 50% after 4 d. These results suggest that dietary coenzyme Q10 may play a role primarily in the blood and that no appreciable uptake occurs into tissues.
Article
This study was conducted in order to test the concept that oxidative damage is associated with aging and may be a factor in the modulation of life span in response to variations in caloric intake. Mice fed a diet that was 40% lower in calories (DR) than the ad libitum fed (AL) animals exhibited a 43% extension in average life span and a 61% prolongation in mortality rate doubling time. A comparison of AL and DR mice at 9, 17 and 23 months of age indicated that the protein carbonyl content in the brain, heart and kidney increased with age and was significantly greater in the AL than DR group in each organ at each of the three ages. Mitochondrial state 4 or resting respiratory rate increased with age in the AL, but not the DR group, and was also relatively higher in the former. The rates of mitochondrial superoxide and hydrogen peroxide generation increased with age and were higher in the AL than DR mice in all the three organs at each age. In contrast, there was no clear-cut overall pattern of age-related or dietary-related changes in antioxidant defenses provided by superoxide dismutase, catalase and glutathione peroxidase. Results suggest that mechanisms of aging and life span shortening by enhanced caloric intake are associated with oxidative damage arising from corresponding changes in mitochondrial oxidant production. Protein carbonyl content, and mitochondrial O2.- and H2O2 generation may act as indices of aging.
Article
This article is a study of the relationship between lipid peroxidation and protein modification in beef heart submitochondrial particles, and the protective effect of endogenous ubiquinol (reduced coenzyme Q) against these effects. ADP-Fe3+ and ascorbate were used to initiate lipid peroxidation and protein modification, which were monitored by measuring TBARS and protein carbonylation, respectively. Endogenous ubiquinone was reduced by the addition of succinate and antimycin. The parameters investigated included extraction and reincorporation of ubiquinone, and comparison of the effect of ubiquinol with those of various antioxidant compounds and enzymes, as well as the iron chelator EDTA. Under all conditions employed there was a close correlation between lipid peroxidation and protein carbonylation, and the inhibition of these effects by endogenous ubiquinol. SDS-PAGE analysis revealed a differential effect on individual protein components and its prevention by ubiquinol. Conceivable mechanisms behind the observed oxidative modifications of membrane phospholipids and proteins and of the role of ubiquinol in preventing these effects are considered.