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Coenzyme Q10 (CoQ10) is a naturally occurring component present in living cells. Its physiological function is to act as an essential cofactor for ATP production, and to perform important antioxidant activities in the body. In most countries, CoQ10 has been widely used as a dietary supplement for more than 20 years. Recently, the use of CoQ10 as a dietary supplement has grown with a corresponding increase in daily dosage. The present review describes the safety profile of CoQ10 on the basis of animal and human data. The published reports concerning safety studies indicate that CoQ10 has low toxicity and does not induce serious adverse effects in humans. The acceptable daily intake (ADI) is 12mg/kg/day, calculated from the no-observed-adverse-effect level (NOAEL) of 1200 mg/kg/day derived from a 52-week chronic toxicity study in rats, i.e., 720 mg/day for a person weighing 60 kg. Risk assessment for CoQ10 based on various clinical trial data indicates that the observed safety level (OSL) for CoQ10 is 1200 mg/day/person. Evidence from pharmacokinetic studies suggest that exogenous CoQ10 does not influence the biosynthesis of endogenous CoQ9/CoQ10 nor does it accumulate into plasma or tissues after cessation of supplementation. Overall, these data from preclinical and clinical studies indicate that CoQ10 is highly safe for use as a dietary supplement. Additionally, analysis of CoQ10 bioavailability or its pharmacokinetics provides the pertinent safety evaluation for CoQ10.

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Aim: The present study was conducted to define the relationship between the anti-aging effect of ubiquinol-10 supplementation and mitochondrial activation in senescence-accelerated mouse prone 1 (SAMP1) mice. Results: Here, we report that dietary supplementation with ubiquinol-10 prevents age-related decreases in the expression of sirtuin gene family members, which results in the activation of peroxisome proliferator-activated receptor c coactivator 1a (PGC-1a), a major factor that controls mitochondrial biogenesis and respiration, as well as superoxide dismutase 2 (SOD2) and isocitrate dehydrogenase 2 (IDH2), which are major mitochondrial antioxidant enzymes. Ubiquinol-10 supplementation can also increase mitochondrial complex I activity and decrease levels of oxidative stress markers, including protein carbonyls, apurinic/apyrimidinic sites, malondialdehydes, and increase the reduced glutathione/oxidized glutathione ratio. Furthermore, ubiquinol-10 may activate Sirt1 and PGC-1a by increasing cyclic adenosine monophosphate (cAMP) levels that, in turn, activate cAMP response element-binding protein (CREB) and AMP-activated protein kinase (AMPK). Innovation and Conclusion: These results show that ubiquinol-10 may enhance mitochondrial activity by increasing levels of SIRT1, PGC-1a, and SIRT3 that slow the rate of age-related hearing loss and protect against the progression of aging and symptoms of age-related diseases.

Newly synthesized rifamycin derivatives, KRM-1648, KRM-1657, KRM-1668, KRM-1686, and KRM-1687, having the chemical structures of 3'-hydroxy-5'-(4-alkylpiperazinyl)-benzoxazinorifamycins (alkyl residues: isobutyl, propyl, sec-butyl, sec-butyl [R configuration], and sec-butyl [S configuration], respectively), were studied for their in vitro antimycobacterial activities. Representative (KRM-1648) MICs for 90% of the strains tested, determined by the agar dilution method on 7H11 medium, of various pathogenic mycobacteria (9 species, 174 strains) were as follows (in micrograms per milliliter): Mycobacterium tuberculosis (rifampin [RMP]-susceptible strains), <0.0125; M. tuberculosis (RMP-resistant strains), 12.5; M. kansasii, 0.05; M. marinum, .0.0125; M. scrofulaceum, 0.1; M. avium, 1.56; M. intracellulare, 0.1; M. fortuitum, >100; and M. chelonae subsp. abscessus and M. chelonae subsp. chelonae, >100. These values are more than 64 times lower than those of RMP, except for the values against RMP-resistant M. tuberculosis (8 times lower) and those against rapid growers, including M. fortuitum and M. chelonae (the same as those of RMP). The other derivatives had similar levels of in vitro activity against these mycobacteria. When murine peritoneal macrophages in which M. intracellulare was phagocytosed in vitro were cultured in the presence of the benzoxazinorifamycins (1 ,ug/ml), much more rapid killing of the organisms ingested in the macrophages was seen compared with when the same amount of RMP was added to the medium. The addition of benzoxazinorifamycins at the concentration of 0.05 ,ig/ml caused more marked suppression of intracellular growth of the organisms compared with addition of RMP. KRM-1648 and KRM-1657 inhibited intracellular growth of M. tuberculosis, and their efficacies were much greater than that of RMP.Rifampin (RMP), a rifamycin derivative, is highly active against a number of mycobacteria, especially slow growers such as Mycobacterium tuberculosis, M. kansasii, and M. marinum (3,22,23), and is used for the treatment of patients with tuberculosis and some atypical mycobacterial infections (4,8,17,21,27 (4,21,27) because of its considerably weak in vitro activity against the MAC (3, 22, 23), possibly because of the permeability barrier of the organisms (7,20). Although other types of rifamycin derivatives, e.g., rifabutin (RBT) (2), rifapentine (1), FCE22807 (6), CGP40/469A (6), CGP-7040 (10), and P-DEA (10), have been developed and although the drugs have higher in vitro antimycobacterial activities than RMP (2, 3, 5, 9, 23, 28), the drugs are generally not so active against MAC infection in humans, particularly immunocompromised hosts (12,14,29). Since MAC infections are increasing remarkably in immunocompromised hosts, particularly in AIDS patients (30), the need to develop new antimicrobial agents including rifamycin derivatives which have a strong activity against the MAC is urgent. In this study, we described the in vitro activities of newly synthesized benzoxazinorifamycins against various p...

Our present study reveals significant decelerating effects on senescence processes in middle-aged SAMP1 mice supplemented for 6 or 14 months with the reduced form (Q(10)H(2), 500 mg/kg BW/day) of coenzyme Q(10) (CoQ(10)). To unravel molecular mechanisms of these CoQ(10) effects, a genome-wide transcript profiling in liver, heart, brain and kidney of SAMP1 mice supplemented with the reduced (Q(10)H(2)) or oxidized form of CoQ(10) (Q(10)) was performed. Liver seems to be the main target tissue of CoQ(10) intervention, followed by kidney, heart and brain. Stringent evaluation of the resulting data revealed that Q(10)H(2) has a stronger impact on gene expression than Q(10), primarily due to differences in the bioavailability. Indeed, Q(10)H(2) supplementation was more effective than Q(10) to increase levels of CoQ(10) in the liver of SAMP1 mice. To identify functional and regulatory connections of the "top 50" (p<0.05) Q(10)H(2)-sensitive transcripts in liver, text mining analysis was used. Hereby, we identified Q(10)H(2)-sensitive genes which are regulated by peroxisome proliferator-activated receptor-alpha and are primarily involved in cholesterol synthesis (e.g. HMGCS1, HMGCL and HMGCR), fat assimilation (FABP5), lipoprotein metabolism (PLTP) and inflammation (STAT-1). These data may explain, at least in part, the decelerating effects on degenerative processes observed in Q(10)H(2)-supplemented SAMP1 mice.

Our recent studies revealed that supplementation with the reduced form of coenzyme Q10 (CoQ10H2) inhibits oxidative stress and slows the process of aging in senescence-accelerated mice. CoQ10H2 inhibits adipocyte differentiation and regulates lipid metabolism. In the present study, we show that dietary supplementation with CoQ10H2 significantly reduced white adipose tissue content and improved the function of brown adipose tissue by regulating expression of lipid metabolism-related factors in KKAy mice, a model of obesity and type 2 diabetes. In the liver, CoQ10H2 reduced cytoplasmic Ca2+ levels and consequently inhibited the phosphorylation of CaMKII. CoQ10H2 also regulated the activity of the transcription factor C-FOS and inhibited gene expression of PDE4, a cAMP-degrading enzyme, via the CaMKII-MEK1/2-ERK1/2 signaling pathway, thereby increasing intracellular cAMP. This increased cAMP activated AMPK, enhanced oxidative decomposition of lipids, and inhibited de novo synthesis of fatty acids, inhibiting the development and progression of obesity and type 2 diabetes. These results suggest that CoQ10H2 supplementation may be useful as a treatment for metabolic disorders associated with obesity.