Overexpression of the Coq8 Kinase in Saccharomyces cerevisiae coq Null Mutants Allows for Accumulation of Diagnostic Intermediates of the Coenzyme Q6 Biosynthetic Pathway*

PubMed Central

Xie, Letian X.; Ozeir, Mohammad; Tang, Jeniffer Y.; Chen, Jia Y.; Jaquinod, Sylvie-Kieffer; Fontecave, Marc; Clarke, Catherine F.; Pierrel, Fabien

2012-01-01

Most of the Coq proteins involved in coenzyme Q (ubiquinone or Q) biosynthesis are interdependent within a multiprotein complex in the yeast Saccharomyces cerevisiae. Lack of only one Coq polypeptide, as in Δcoq strains, results in the degradation of several Coq proteins. Consequently, Δcoq strains accumulate the same early intermediate of the Q6 biosynthetic pathway; this intermediate is therefore not informative about the deficient biosynthetic step in a particular Δcoq strain. In this work, we report that the overexpression of the protein Coq8 in Δcoq strains restores steady state levels of the unstable Coq proteins. Coq8 has been proposed to be a kinase, and we provide evidence that the kinase activity is essential for the stabilizing effect of Coq8 in the Δcoq strains. This stabilization results in the accumulation of several novel Q6 biosynthetic intermediates. These Q intermediates identify chemical steps impaired in cells lacking Coq4 and Coq9 polypeptides, for which no function has been established to date. Several of the new intermediates contain a C4-amine and provide information on the deamination reaction that takes place when para-aminobenzoic acid is used as a ring precursor of Q6. Finally, we used synthetic analogues of 4-hydroxybenzoic acid to bypass deficient biosynthetic steps, and we show here that 2,4-dihydroxybenzoic acid is able to restore Q6 biosynthesis and respiratory growth in a Δcoq7 strain overexpressing Coq8. The overexpression of Coq8 and the use of 4-hydroxybenzoic acid analogues represent innovative tools to elucidate the Q biosynthetic pathway. PMID:22593570

Overexpression of the Coq8 kinase in Saccharomyces cerevisiae coq null mutants allows for accumulation of diagnostic intermediates of the coenzyme Q6 biosynthetic pathway.

PubMed

Xie, Letian X; Ozeir, Mohammad; Tang, Jeniffer Y; Chen, Jia Y; Jaquinod, Sylvie-Kieffer; Fontecave, Marc; Clarke, Catherine F; Pierrel, Fabien

2012-07-06

Most of the Coq proteins involved in coenzyme Q (ubiquinone or Q) biosynthesis are interdependent within a multiprotein complex in the yeast Saccharomyces cerevisiae. Lack of only one Coq polypeptide, as in Δcoq strains, results in the degradation of several Coq proteins. Consequently, Δcoq strains accumulate the same early intermediate of the Q(6) biosynthetic pathway; this intermediate is therefore not informative about the deficient biosynthetic step in a particular Δcoq strain. In this work, we report that the overexpression of the protein Coq8 in Δcoq strains restores steady state levels of the unstable Coq proteins. Coq8 has been proposed to be a kinase, and we provide evidence that the kinase activity is essential for the stabilizing effect of Coq8 in the Δcoq strains. This stabilization results in the accumulation of several novel Q(6) biosynthetic intermediates. These Q intermediates identify chemical steps impaired in cells lacking Coq4 and Coq9 polypeptides, for which no function has been established to date. Several of the new intermediates contain a C4-amine and provide information on the deamination reaction that takes place when para-aminobenzoic acid is used as a ring precursor of Q(6). Finally, we used synthetic analogues of 4-hydroxybenzoic acid to bypass deficient biosynthetic steps, and we show here that 2,4-dihydroxybenzoic acid is able to restore Q(6) biosynthesis and respiratory growth in a Δcoq7 strain overexpressing Coq8. The overexpression of Coq8 and the use of 4-hydroxybenzoic acid analogues represent innovative tools to elucidate the Q biosynthetic pathway.

Functional Conservation of Coenzyme Q Biosynthetic Genes among Yeasts, Plants, and Humans

PubMed Central

Hayashi, Kazuhiro; Ogiyama, Yuki; Yokomi, Kazumasa; Nakagawa, Tsuyoshi; Kaino, Tomohiro; Kawamukai, Makoto

2014-01-01

Coenzyme Q (CoQ) is an essential factor for aerobic growth and oxidative phosphorylation in the electron transport system. The biosynthetic pathway for CoQ has been proposed mainly from biochemical and genetic analyses of Escherichia coli and Saccharomyces cerevisiae; however, the biosynthetic pathway in higher eukaryotes has been explored in only a limited number of studies. We previously reported the roles of several genes involved in CoQ synthesis in the fission yeast Schizosaccharomyces pombe. Here, we expand these findings by identifying ten genes (dps1, dlp1, ppt1, and coq3–9) that are required for CoQ synthesis. CoQ10-deficient S. pombe coq deletion strains were generated and characterized. All mutant fission yeast strains were sensitive to oxidative stress, produced a large amount of sulfide, required an antioxidant to grow on minimal medium, and did not survive at the stationary phase. To compare the biosynthetic pathway of CoQ in fission yeast with that in higher eukaryotes, the ability of CoQ biosynthetic genes from humans and plants (Arabidopsis thaliana) to functionally complement the S. pombe coq deletion strains was determined. With the exception of COQ9, expression of all other human and plant COQ genes recovered CoQ10 production by the fission yeast coq deletion strains, although the addition of a mitochondrial targeting sequence was required for human COQ3 and COQ7, as well as A. thaliana COQ6. In summary, this study describes the functional conservation of CoQ biosynthetic genes between yeasts, humans, and plants. PMID:24911838

Mutations in COQ8B (ADCK4) found in patients with steroid-resistant nephrotic syndrome alter COQ8B function.

PubMed

Vazquez Fonseca, Luis; Doimo, Mara; Calderan, Cristina; Desbats, Maria Andrea; Acosta, Manuel J; Cerqua, Cristina; Cassina, Matteo; Ashraf, Shazia; Hildebrandt, Friedhelm; Sartori, Geppo; Navas, Placido; Trevisson, Eva; Salviati, Leonardo

2018-03-01

Mutations in COQ8B cause steroid-resistant nephrotic syndrome with variable neurological involvement. In yeast, COQ8 encodes a protein required for coenzyme Q (CoQ) biosynthesis, whose precise role is not clear. Humans harbor two paralog genes: COQ8A and COQ8B (previously termed ADCK3 and ADCK4). We have found that COQ8B is a mitochondrial matrix protein peripherally associated with the inner membrane. COQ8B can complement a ΔCOQ8 yeast strain when its mitochondrial targeting sequence (MTS) is replaced by a yeast MTS. This model was employed to validate COQ8B mutations, and to establish genotype-phenotype correlations. All mutations affected respiratory growth, but there was no correlation between mutation type and the severity of the phenotype. In fact, contrary to the case of COQ2, where residual CoQ biosynthesis correlates with clinical severity, patients harboring hypomorphic COQ8B alleles did not display a different phenotype compared with those with null mutations. These data also suggest that the system is redundant, and that other proteins (probably COQ8A) may partially compensate for the absence of COQ8B. Finally, a COQ8B polymorphism, present in 50% of the European population (NM_024876.3:c.521A > G, p.His174Arg), affects stability of the protein and could represent a risk factor for secondary CoQ deficiencies or for other complex traits. © 2017 The Authors. Human Mutation published by Wiley Periodicals, Inc.

Over-expression of COQ10 in Saccharomyces cerevisiae inhibits mitochondrial respiration.

PubMed

Zampol, Mariana A; Busso, Cleverson; Gomes, Fernando; Ferreira-Junior, Jose Ribamar; Tzagoloff, Alexander; Barros, Mario H

2010-11-05

COQ10 deletion in Saccharomyces cerevisiae elicits a defect in mitochondrial respiration correctable by addition of coenzyme Q(2). Rescue of respiration by Q(2) is a characteristic of mutants blocked in coenzyme Q(6) synthesis. Unlike Q(6) deficient mutants, mitochondria of the coq10 null mutant have wild-type concentrations of Q(6). The physiological significance of earlier observations that purified Coq10p contains bound Q(6) was examined in the present study by testing the in vivo effect of over-expression of Coq10p on respiration. Mitochondria with elevated levels of Coq10p display reduced respiration in the bc1 span of the electron transport chain, which can be restored with exogenous Q(2). This suggests that in vivo binding of Q(6) by excess Coq10p reduces the pool of this redox carrier available for its normal function in providing electrons to the bc1 complex. This is confirmed by observing that extra Coq8p relieves the inhibitory effect of excess Coq10p. Coq8p is a putative kinase, and a high-copy suppressor of the coq10 null mutant. As shown here, when over-produced in coq mutants, Coq8p counteracts turnover of Coq3p and Coq4p subunits of the Q-biosynthetic complex. This can account for the observed rescue by COQ8 of the respiratory defect in strains over-producing Coq10p. Copyright © 2010 Elsevier Inc. All rights reserved.

Preparation of coenzyme Q10 liposomes using supercritical anti-solvent technique.

PubMed

Xia, Fei; Jin, Heyang; Zhao, Yaping; Guo, Xinqiu

2012-01-01

Coenzyme Q(10) (CoQ(10)) proliposomes were prepared using the supercritical anti-solvent (SAS) technique to encapsulate CoQ(10). The mixture of cholesterol and soya bean phosphatidylcholine (PC) was chosen as wall materials. The effects of operation conditions (temperature, pressure and components) on the recovery of CoQ(10) and the CoQ(10) loading in CoQ(10) proliposomes were studied. At the optimum conditions of pressure of 8.0 MPa, temperature of 35°C, the weight ratio of 1/10 between CoQ(10) and PC, and the weight ratio of 1/3 between cholesterol and PC, the CoQ(10) loading reached 8.92%. CoQ(10) liposomes were obtained by hydrating CoQ(10) proliposomes and the entrapment efficiency of CoQ(10) reached 82.28%. The morphologies of CoQ(10) proliposomes were characterized by scanning electron microscope, and their solid states were characterized by X-ray diffractometer. The structures of CoQ(10) liposomes were characterized by transmission electron microscope. The particle size distribution of CoQ(10) liposomes was determined by dynamic light scattering instrument. The results indicate that CoQ(10) liposomes with particle sizes about 50 nm can be easily obtained from hydrating CoQ(10) proliposomes prepared by SAS technique.

Isolation and functional expression of human COQ2, a gene encoding a polyprenyl transferase involved in the synthesis of CoQ.

PubMed

Forsgren, Margareta; Attersand, Anneli; Lake, Staffan; Grünler, Jacob; Swiezewska, Ewa; Dallner, Gustav; Climent, Isabel

2004-09-01

The COQ2 gene in Saccharomyces cerevisiae encodes a Coq2 (p-hydroxybenzoate:polyprenyl transferase), which is required in the biosynthetic pathway of CoQ (ubiquinone). This enzyme catalyses the prenylation of p-hydroxybenzoate with an all-trans polyprenyl group. We have isolated cDNA which we believe encodes the human homologue of COQ2 from a human muscle and liver cDNA library. The clone contained an open reading frame of length 1263 bp, which encodes a polypeptide that has sequence homology with the Coq2 homologues in yeast, bacteria and mammals. The human COQ2 gene, when expressed in yeast Coq2 null mutant cells, rescued the growth of this yeast strain in the absence of a non-fermentable carbon source and restored CoQ biosynthesis. However, the rate of CoQ biosynthesis in the rescued cells was lower when compared with that in cells rescued with the yeast COQ2 gene. CoQ formed when cells were incubated with labelled decaprenyl pyrophosphate and nonaprenyl pyrophosphate, showing that the human enzyme is active and that it participates in the biosynthesis of CoQ.

The Regulation of Coenzyme Q Biosynthesis in Eukaryotic Cells: All That Yeast Can Tell Us

PubMed Central

González-Mariscal, Isabel; García-Testón, Elena; Padilla, Sergio; Martín-Montalvo, Alejandro; Pomares Viciana, Teresa; Vazquez-Fonseca, Luis; Gandolfo Domínguez, Pablo; Santos-Ocaña, Carlos

2014-01-01

Coenzyme Q (CoQ) is a mitochondrial lipid, which functions mainly as an electron carrier from complex I or II to complex III at the mitochondrial inner membrane, and also as antioxidant in cell membranes. CoQ is needed as electron acceptor in β-oxidation of fatty acids and pyridine nucleotide biosynthesis, and it is responsible for opening the mitochondrial permeability transition pore. The yeast model has been very useful to analyze the synthesis of CoQ, and therefore, most of the knowledge about its regulation was obtained from the Saccharomyces cerevisiae model. CoQ biosynthesis is regulated to support 2 processes: the bioenergetic metabolism and the antioxidant defense. Alterations of the carbon source in yeast, or in nutrient availability in yeasts or mammalian cells, upregulate genes encoding proteins involved in CoQ synthesis. Oxidative stress, generated by chemical or physical agents or by serum deprivation, modifies specifically the expression of some COQ genes by means of stress transcription factors such as Msn2/4p, Yap1p or Hsf1p. In general, the induction of COQ gene expression produced by metabolic changes or stress is modulated downstream by other regulatory mechanisms such as the protein import to mitochondria, the assembly of a multi-enzymatic complex composed by Coq proteins and also the existence of a phosphorylation cycle that regulates the last steps of CoQ biosynthesis. The CoQ biosynthetic complex assembly starts with the production of a nucleating lipid such as HHB by the action of the Coq2 protein. Then, the Coq4 protein recognizes the precursor HHB acting as the nucleus of the complex. The activity of Coq8p, probably as kinase, allows the formation of an initial pre-complex containing all Coq proteins with the exception of Coq7p. This pre-complex leads to the synthesis of 5-demethoxy-Q6 (DMQ6), the Coq7p substrate. When de novo CoQ biosynthesis is required, Coq7p becomes dephosphorylated by the action of Ptc7p increasing the synthesis rate of CoQ6. This critical model is needed for a better understanding of CoQ biosynthesis. Taking into account that patients with CoQ10 deficiency maintain to some extent the machinery to synthesize CoQ, new promising strategies for the treatment of CoQ10 deficiency will require a better understanding of the regulation of CoQ biosynthesis in the future. PMID:25126044

coq7/clk-1 regulates mitochondrial respiration and the generation of reactive oxygen species via coenzyme Q.

PubMed

Nakai, Daisuke; Shimizu, Takahiko; Nojiri, Hidetoshi; Uchiyama, Satoshi; Koike, Hideo; Takahashi, Mayumi; Hirokawa, Katsuiku; Shirasawa, Takuji

2004-10-01

coq7/clk-1 was isolated from a long-lived mutant of Caenorhabditis elegans, and shows sluggish behaviours and an extended lifespan. In C. elegans and Saccharomyces cerevisiae, coq7/clk-1 is required for the biosynthesis of coenzyme Q (CoQ), an essential co-factor in mitochondrial respiration. The clk-1 mutant contains dietary CoQ(8) from Escherichia coli and demethoxyubiquinone 9 (DMQ9) instead of CoQ(9). In a previous study, we generated COQ7-deficient mice by targeted disruption of the coq7 gene and reported that mouse coq7/clk-1 is also essential for CoQ synthesis, maintenance of mitochondrial integrity and neurogenesis. In the present study, we rescued COQ7-deficient mice from embryonic lethality and established a mouse model with decreased CoQ level by transgene expression of COQ7/CLK-1. A biochemical analysis showed a concomitant decrease in CoQ(9), mitochondrial respiratory enzyme activity and the generation of reactive oxygen species (ROS) in the mitochondria of CoQ-insufficient mice. This implied that the depressed activity of respiratory enzymes and the depressed production of ROS may play a physiological role in the control of lifespan in mammalian species and of C. elegans.

Dysfunctional Coq9 protein causes predominant encephalomyopathy associated with CoQ deficiency.

PubMed

García-Corzo, Laura; Luna-Sánchez, Marta; Doerrier, Carolina; García, José A; Guarás, Adela; Acín-Pérez, Rebeca; Bullejos-Peregrín, Javier; López, Ana; Escames, Germaine; Enríquez, José A; Acuña-Castroviejo, Darío; López, Luis C

2013-03-15

Coenzyme Q10 (CoQ(10)) or ubiquinone is a well-known component of the mitochondrial respiratory chain. In humans, CoQ(10) deficiency causes a mitochondrial syndrome with an unexplained variability in the clinical presentations. To try to understand this heterogeneity in the clinical phenotypes, we have generated a Coq9 Knockin (R239X) mouse model. The lack of a functional Coq9 protein in homozygous Coq9 mutant (Coq9(X/X)) mice causes a severe reduction in the Coq7 protein and, as consequence, a widespread CoQ deficiency and accumulation of demethoxyubiquinone. The deficit in CoQ induces a brain-specific impairment of mitochondrial bioenergetics performance, a reduction in respiratory control ratio, ATP levels and ATP/ADP ratio and specific loss of respiratory complex I. These effects lead to neuronal death and demyelinization with severe vacuolization and astrogliosis in the brain of Coq9(X/X) mice that consequently die between 3 and 6 months of age. These results suggest that the instability of mitochondrial complex I in the brain, as a primary event, triggers the development of mitochondrial encephalomyopathy associated with CoQ deficiency.

Coenzyme Q plays opposing roles on bacteria/fungi and viruses in Drosophila innate immunity.

PubMed

Cheng, W; Song, C; Anjum, K M; Chen, M; Li, D; Zhou, H; Wang, W; Chen, J

2011-08-01

Coenzyme Q (CoQ or ubiquinone) is a lipid-soluble component of virtually all types of cell membranes and has been shown to play multiple metabolic functions. Several clinical diseases including encephalomyopathy, cerebellar ataxia and isolated myopathy were shown to be associated with CoQ deficiency. However, the role of CoQ in immunity has not been defined. In the present study, we showed that flies defective in CoQ biosynthetic gene coq2 were more susceptible to bacterial and fungal infections, while were more resistant to viruses. We found that Drosophila contained both CoQ9 and CoQ10, and food supplement of CoQ10 could partially rescue the impaired immune functions of coq2 mutants. Surprisingly, wild-type flies fed CoQ10 became more susceptible to viral infection, which suggested that extra caution should be taken when using CoQ10 as a food supplement. We further showed that CoQ was essential for normal induction of anti-microbial peptides and amplification of viruses. Our work determined CoQ content in Drosophila and described its function in immunity for the first time. © 2011 Blackwell Publishing Ltd.

Respiratory-induced coenzyme Q biosynthesis is regulated by a phosphorylation cycle of Cat5p/Coq7p.

PubMed

Martín-Montalvo, Alejandro; González-Mariscal, Isabel; Padilla, Sergio; Ballesteros, Manuel; Brautigan, David L; Navas, Plácido; Santos-Ocaña, Carlos

2011-11-15

CoQ(6) (coenzyme Q(6)) biosynthesis in yeast is a well-regulated process that requires the final conversion of the late intermediate DMQ(6) (demethoxy-CoQ(6)) into CoQ(6) in order to support respiratory metabolism in yeast. The gene CAT5/COQ7 encodes the Cat5/Coq7 protein that catalyses the hydroxylation step of DMQ(6) conversion into CoQ(6). In the present study, we demonstrated that yeast Coq7 recombinant protein purified in bacteria can be phosphorylated in vitro using commercial PKA (protein kinase A) or PKC (protein kinase C) at the predicted amino acids Ser(20), Ser(28) and Thr(32). The total absence of phosphorylation in a Coq7p version containing alanine instead of these phospho-amino acids, the high extent of phosphorylation produced and the saturated conditions maintained in the phosphorylation assay indicate that probably no other putative amino acids are phosphorylated in Coq7p. Results from in vitro assays have been corroborated using phosphorylation assays performed in purified mitochondria without external or commercial kinases. Coq7p remains phosphorylated in fermentative conditions and becomes dephosphorylated when respiratory metabolism is induced. The substitution of phosphorylated residues to alanine dramatically increases CoQ(6) levels (256%). Conversely, substitution with negatively charged residues decreases CoQ(6) content (57%). These modifications produced in Coq7p also alter the ratio between DMQ(6) and CoQ(6) itself, indicating that the Coq7p phosphorylation state is a regulatory mechanism for CoQ(6) synthesis.

Biosynthesis of coenzyme Q in eukaryotes.

PubMed

Kawamukai, Makoto

2016-01-01

Coenzyme Q (CoQ) is a component of the electron transport chain that participates in aerobic cellular respiration to produce ATP. In addition, CoQ acts as an electron acceptor in several enzymatic reactions involving oxidation-reduction. Biosynthesis of CoQ has been investigated mainly in Escherichia coli and Saccharomyces cerevisiae, and the findings have been extended to various higher organisms, including plants and humans. Analyses in yeast have contributed greatly to current understanding of human diseases related to CoQ biosynthesis. To date, human genetic disorders related to mutations in eight COQ biosynthetic genes have been reported. In addition, the crystal structures of a number of proteins involved in CoQ synthesis have been solved, including those of IspB, UbiA, UbiD, UbiX, UbiI, Alr8543 (Coq4 homolog), Coq5, ADCK3, and COQ9. Over the last decade, knowledge of CoQ biosynthesis has accumulated, and striking advances in related human genetic disorders and the crystal structure of proteins required for CoQ synthesis have been made. This review focuses on the biosynthesis of CoQ in eukaryotes, with some comparisons to the process in prokaryotes.

Coenzyme Q1 redox metabolism during passage through the rat pulmonary circulation and the effect of hyperoxia

PubMed Central

Audi, Said H.; Merker, Marilyn P.; Krenz, Gary S.; Ahuja, Taniya; Roerig, David L.; Bongard, Robert D.

2008-01-01

The objective was to evaluate the pulmonary disposition of the ubiquinone homolog coenzyme Q1 (CoQ1) on passage through lungs of normoxic (exposed to room air) and hyperoxic (exposed to 85% O2 for 48 h) rats. CoQ1 or its hydroquinone (CoQ1H2) was infused into the arterial inflow of isolated, perfused lungs, and the venous efflux rates of CoQ1H2 and CoQ1 were measured. CoQ1H2 appeared in the venous effluent when CoQ1 was infused, and CoQ1 appeared when CoQ1H2 was infused. In normoxic lungs, CoQ1H2 efflux rates when CoQ1 was infused decreased by 58 and 33% in the presence of rotenone (mitochondrial complex I inhibitor) and dicumarol [NAD(P)H-quinone oxidoreductase 1 (NQO1) inhibitor], respectively. Inhibitor studies also revealed that lung CoQ1H2 oxidation was via mitochondrial complex III. In hyperoxic lungs, CoQ1H2 efflux rates when CoQ1 was infused decreased by 23% compared with normoxic lungs. Based on inhibitor effects and a kinetic model, the effect of hyperoxia could be attributed predominantly to 47% decrease in the capacity of complex I-mediated CoQ1 reduction, with no change in the other redox processes. Complex I activity in lung homogenates was also lower for hyperoxic than for normoxic lungs. These studies reveal that lung complexes I and III and NQO1 play a dominant role in determining the vascular concentration and redox status of CoQ1 during passage through the pulmonary circulation, and that exposure to hyperoxia decreases the overall capacity of the lung to reduce CoQ1 to CoQ1H2 due to a depression in complex I activity. PMID:18703762

Coenzyme Q1 redox metabolism during passage through the rat pulmonary circulation and the effect of hyperoxia.

PubMed

Audi, Said H; Merker, Marilyn P; Krenz, Gary S; Ahuja, Taniya; Roerig, David L; Bongard, Robert D

2008-10-01

The objective was to evaluate the pulmonary disposition of the ubiquinone homolog coenzyme Q(1) (CoQ(1)) on passage through lungs of normoxic (exposed to room air) and hyperoxic (exposed to 85% O(2) for 48 h) rats. CoQ(1) or its hydroquinone (CoQ(1)H(2)) was infused into the arterial inflow of isolated, perfused lungs, and the venous efflux rates of CoQ(1)H(2) and CoQ(1) were measured. CoQ(1)H(2) appeared in the venous effluent when CoQ(1) was infused, and CoQ(1) appeared when CoQ(1)H(2) was infused. In normoxic lungs, CoQ(1)H(2) efflux rates when CoQ(1) was infused decreased by 58 and 33% in the presence of rotenone (mitochondrial complex I inhibitor) and dicumarol [NAD(P)H-quinone oxidoreductase 1 (NQO1) inhibitor], respectively. Inhibitor studies also revealed that lung CoQ(1)H(2) oxidation was via mitochondrial complex III. In hyperoxic lungs, CoQ(1)H(2) efflux rates when CoQ(1) was infused decreased by 23% compared with normoxic lungs. Based on inhibitor effects and a kinetic model, the effect of hyperoxia could be attributed predominantly to 47% decrease in the capacity of complex I-mediated CoQ(1) reduction, with no change in the other redox processes. Complex I activity in lung homogenates was also lower for hyperoxic than for normoxic lungs. These studies reveal that lung complexes I and III and NQO1 play a dominant role in determining the vascular concentration and redox status of CoQ(1) during passage through the pulmonary circulation, and that exposure to hyperoxia decreases the overall capacity of the lung to reduce CoQ(1) to CoQ(1)H(2) due to a depression in complex I activity.

Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9.

PubMed

Danhauser, Katharina; Herebian, Diran; Haack, Tobias B; Rodenburg, Richard J; Strom, Tim M; Meitinger, Thomas; Klee, Dirk; Mayatepek, Ertan; Prokisch, Holger; Distelmaier, Felix

2016-03-01

Coenzyme Q10 (CoQ10) has an important role in mitochondrial energy metabolism by way of its functioning as an electron carrier in the respiratory chain. Genetic defects disrupting the endogenous biosynthesis pathway of CoQ10 may lead to severe metabolic disorders with onset in early childhood. Using exome sequencing in a child with fatal neonatal lactic acidosis and encephalopathy, we identified a homozygous loss-of-function variant in COQ9. Functional studies in patient fibroblasts showed that the absence of the COQ9 protein was concomitant with a strong reduction of COQ7, leading to a significant accumulation of the substrate of COQ7, 6-demethoxy ubiquinone10. At the same time, the total amount of CoQ10 was severely reduced, which was reflected in a significant decrease of mitochondrial respiratory chain succinate-cytochrome c oxidoreductase (complex II/III) activity. Lentiviral expression of COQ9 restored all these parameters, confirming the causal role of the variant. Our report on the second COQ9 patient expands the clinical spectrum associated with COQ9 variants, indicating the importance of COQ9 already during prenatal development. Moreover, the rescue of cellular CoQ10 levels and respiratory chain complex activities by CoQ10 supplementation points to the importance of an early diagnosis and immediate treatment.

Characterization of a Plasmodium falciparum Orthologue of the Yeast Ubiquinone-Binding Protein, Coq10p.

PubMed

Jenkins, Bethany J; Daly, Thomas M; Morrisey, Joanne M; Mather, Michael W; Vaidya, Akhil B; Bergman, Lawrence W

2016-01-01

Coenzyme Q (CoQ, ubiquinone) is a central electron carrier in mitochondrial respiration. CoQ is synthesized through multiple steps involving a number of different enzymes. The prevailing view that the CoQ used in respiration exists as a free pool that diffuses throughout the mitochondrial inner membrane bilayer has recently been challenged. In the yeast Saccharomyces cerevisiae, deletion of the gene encoding Coq10p results in respiration deficiency without inhibiting the synthesis of CoQ, suggesting that the Coq10 protein is critical for the delivery of CoQ to the site(s) of respiration. The precise mechanism by which this is achieved remains unknown at present. We have identified a Plasmodium orthologue of Coq10 (PfCoq10), which is predominantly expressed in trophozoite-stage parasites, and localizes to the parasite mitochondrion. Expression of PfCoq10 in the S. cerevisiae coq10 deletion strain restored the capability of the yeast to grow on respiratory substrates, suggesting a remarkable functional conservation of this protein over a vast evolutionary distance, and despite a relatively low level of amino acid sequence identity. As the antimalarial drug atovaquone acts as a competitive inhibitor of CoQ, we assessed whether over-expression of PfCoq10 altered the atovaquone sensitivity in parasites and in yeast mitochondria, but found no alteration of its activity.

Therapeutic Potential of Co-enzyme Q10 in Retinal Diseases.

PubMed

Zhang, Xun; Tohari, Ali Mohammad; Marcheggiani, Fabio; Zhou, Xinzhi; Reilly, James; Tiano, Luca; Shu, Xinhua

2017-01-01

Coenzyme Q10 (CoQ10) plays a critical role in mitochondrial oxidative phosphorylation by serving as an electron carrier in the respiratory electron transport chain. CoQ10 also functions as a lipid-soluble antioxidant by protecting lipids, proteins and DNA damaged by oxidative stress. CoQ10 deficiency has been associated with a number of human diseases in which CoQ10 supplementation therapy has been effective in slowing or reversing pathological changes. Oxidative stress is a major contributory factor in the process of retinal degeneration. The related literature was reviewed through searching PubMed using keywords: CoQ10, CoQ10 and oxidative stress, CoQ10 and retinal degeneration. The functions of CoQ10 were summarized and its use in the treatment of age-related macular degeneration and glaucoma highlighted. The therapeutic potential of CoQ10 for other retinal diseases was also discussed. CoQ10 has been applied in different types of neurodegeneration. CoQ10 is detectable in retina and declines with ageing. Early studies showed treatment of CoQ10 improved visual function in patients with age-related macular degeneration. In glaucomatous models, CoQ10 exposure protected ganglion cell death from environmental stress; in glaucoma patients, CoQ10 treatment demonstrated beneficial effects on function of inner retina and enhancement of visual cortical response. Since oxidative stress also plays a critical role in the pathogenesis of diabetic retinopathy and retinitis pigmentosa, CoQ10 is a therapeutic target for both conditions. A wide range of evidence supports a role of CoQ10 in retinal diseases through inhibiting production of reactive oxygen species and protecting neuroretinal cells from oxidative damage. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Antioxidant Effect of CoQ(10) on N-nitrosodiethylamine-induced Oxidative Stress in Mice.

PubMed

Song, Ho Sun; Kim, Hee Rae; Park, Tae Wook; Cho, Bong Jae; Choi, Mi Young; Kim, Chang Jong; Sohn, Uy Dong; Sim, Sang Soo

2009-08-01

The antioxidant effect of CoQ(10) on N-nitrosodiethylamine (NDEA)-induced oxidative stress was investigated in mice. Food intake and body weight were similar in both CoQ(10) and control groups during the 3-week experimental period. NDEA significantly increased the activities of typical marker enzymes of liver function (AST, ALT and ALP) both in control and CoQ(10) groups. However, the increase of plasma aminotransferase activity was significantly reduced in the CoQ(10) group. Lipid peroxidation in various tissues, such as heart, lung, liver, kidney, spleen and plasma, was significantly increased by NDEA, but this increase was significantly reduced by 100 mg/kg of CoQ(10). Superoxide dismutase activity increased significantly upon NDEA-induced oxidative stress in both the control and CoQ(10) groups with the effect being less in the CoQ(10) group. Catalase activity decreased significantly in both the control and CoQ(10) groups treated with NDEA, again with the effect being less in the CoQ(10) group. The lesser effect on superoxide dismutase and catalase in the NDEA-treated CoQ(10) group is indicative of the protective effect CoQ(10). Thus, CoQ(10) can offer useful protection against NDEA-induced oxidative stress.

Relative bioavailability and antioxidant potential of two coenzyme q10 preparations.

PubMed

Kurowska, Elzbieta M; Dresser, George; Deutsch, Luisa; Bassoo, Errol; Freeman, David J

2003-01-01

Coenzyme Q10 (CoQ10) is synthesized by the human body and found in certain foods. Daily supplementation of CoQ10 could protect against heart disease but the bioavailability of CoQ10 supplements depends on the formulation taken. We compared the bioavailability and antioxidant properties of two commercial CoQ10 formulations, a commercial grade CoQ10 powder (commercial grade CoQ) and a new BT-CoQ10 BIO-TRANSFORMED (BT-CoQ10) obtained by fermentation of a soy-based, CoQ10-rich media with baker's yeast. Eleven healthy individuals participated in a randomized two-way crossover trial, with a 3-week washout period. Capsules containing 300 mg of either BT-CoQ10 or commercial grade CoQ10 were given daily for 1 week and multiple blood samples were taken for CoQ10, glutathione and glutathione peroxidase (GPx) determination. In 3 subjects, baseline plasma CoQ10 levels were lower prior to BT than prior to commercial grade CoQ treatment. In the remaining participants, ingestion of BT vs. commercial grade CoQ significantly increased maximum plasma CoQ10 concentration (+126%, p = 0.04) and tended to increase CoQ10 area under the curve from 0 to 24 h (+160%, p = 0.07). One week of treatment with each formulation increased plasma CoQ10 but did not alter plasma glutathione or GPx activity. The enhanced bioavailability of the BT product might be due to its predominantly reduced, hydrophilic membrane-complex form. Copyright 2003 S. Karger AG, Basel

Clinical, biochemical and molecular aspects of cerebellar ataxia and Coenzyme Q10 deficiency.

PubMed

Montero, Raquel; Pineda, Mercé; Aracil, Asun; Vilaseca, Maria-Antonia; Briones, Paz; Sánchez-Alcázar, José-Antonio; Navas, Plácido; Artuch, Rafael

2007-01-01

Coenzyme Q(10) (CoQ) deficiency is an autosomal recessive disorder presenting five phenotypes: a myopathic form, a severe infantile neurological syndrome associated with nephritic syndrome, an ataxic variant, Leigh syndrome and a pure myopathic form. The third is the most common phenotype related with CoQ deficiency and it will be the focus of this review. This new syndrome presents muscle CoQ deficiency associated with cerebellar ataxia and cerebellar atrophy as the main neurological signs. Biochemically, the hallmark of CoQ deficiency syndrome is a decreased CoQ concentration in muscle and/or fibroblasts. There is no molecular evidence of the enzyme or gene involved in primary CoQ deficiencies associated with cerebellar ataxia, although recently a family has been reported with mutations at COQ2 gene who present a distinct phenotype. Patients with primary CoQ deficiency may benefit from CoQ supplementation, although the clinical response to this therapy varies even among patients with similar phenotypes. Some present an excellent response to CoQ while others show only a partial improvement of some symptoms and signs. CoQ deficiency is the mitochondrial encephalomyopathy with the best clinical response to CoQ supplementation, highlighting the importance of an early identification of this disorder.

Human neuronal coenzyme Q10 deficiency results in global loss of mitochondrial respiratory chain activity, increased mitochondrial oxidative stress and reversal of ATP synthase activity: implications for pathogenesis and treatment.

PubMed

Duberley, Kate E C; Abramov, Andrey Y; Chalasani, Annapurna; Heales, Simon J; Rahman, Shamima; Hargreaves, Iain P

2013-01-01

Disorders of coenzyme Q(10) (CoQ(10)) biosynthesis represent the most treatable subgroup of mitochondrial diseases. Neurological involvement is frequently observed in CoQ(10) deficiency, typically presenting as cerebellar ataxia and/or seizures. The aetiology of the neurological presentation of CoQ(10) deficiency has yet to be fully elucidated and therefore in order to investigate these phenomena we have established a neuronal cell model of CoQ(10) deficiency by treatment of neuronal SH-SY5Y cell line with para-aminobenzoic acid (PABA). PABA is a competitive inhibitor of the CoQ(10) biosynthetic pathway enzyme, COQ2. PABA treatment (1 mM) resulted in a 54 % decrease (46 % residual CoQ(10)) decrease in neuronal CoQ(10) status (p < 0.01). Reduction of neuronal CoQ(10) status was accompanied by a progressive decrease in mitochondrial respiratory chain enzyme activities, with a 67.5 % decrease in cellular ATP production at 46 % residual CoQ(10). Mitochondrial oxidative stress increased four-fold at 77 % and 46 % residual CoQ(10). A 40 % increase in mitochondrial membrane potential was detected at 46 % residual CoQ(10) with depolarisation following oligomycin treatment suggesting a reversal of complex V activity. This neuronal cell model provides insights into the effects of CoQ(10) deficiency on neuronal mitochondrial function and oxidative stress, and will be an important tool to evaluate candidate therapies for neurological conditions associated with CoQ(10) deficiency.

Coenzyme Q10 quantification in muscle, fibroblasts and cerebrospinal fluid by liquid chromatography/tandem mass spectrometry using a novel deuterated internal standard.

PubMed

Duberley, Kate E C; Hargreaves, Iain P; Chaiwatanasirikul, Korn-Anong; Heales, Simon J R; Land, John M; Rahman, Shamima; Mills, Kevin; Eaton, Simon

2013-05-15

Neurological dysfunction is common in primary coenzyme Q10 (2,3-dimethoxy, 5-methyl, 6-polyisoprene parabenzoquinone; CoQ10 ; ubiquinone) deficiencies, the most readily treatable subgroup of mitochondrial disorders. Therapeutic benefit from CoQ10 supplementation has also been noted in other neurodegenerative diseases. CoQ10 can be measured by high-performance liquid chromatography (HPLC) in plasma, muscle or leucocytes; however, there is no reliable method to quantify CoQ10 in cerebrospinal fluid (CSF). Additionally, many methods use CoQ9 , an endogenous ubiquinone in humans, as an internal standard. Deuterated CoQ10 (d6 -CoQ10 ) was synthesised by a novel, simple, method. Total CoQ10 was measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) using d6 -CoQ10 as internal standard and 5 mM methylamine as an ion-pairing reagent. Chromatography was performed using a Hypsersil GOLD C4 column (150 × 3 mm, 3 µm). CoQ10 levels were linear over a concentration range of 0-200 nM (R(2) = 0.9995). The lower limit of detection was 2 nM. The inter-assay coefficient of variation (CV) was 3.6% (10 nM) and 4.3% (20 nM), and intra-assay CV 3.4% (10 nM) and 3.6% (20 nM). Reference ranges were established for CoQ10 in CSF (5.7-8.7 nM; n = 17), fibroblasts (57.0-121.6 pmol/mg; n = 50) and muscle (187.3-430.1 pmol/mg; n = 15). Use of d6 -CoQ10 internal standard has enabled the development of a sensitive LC/MS/MS method to accurately determine total CoQ10 levels. Clinical applications of CSF CoQ10 determination include identification of patients with cerebral CoQ10 deficiency, and monitoring CSF CoQ10 levels following supplementation. Copyright © 2013 John Wiley & Sons, Ltd.

The Value of Coenzyme Q10 Determination in Mitochondrial Patients

PubMed Central

Yubero, Delia; Allen, George; Artuch, Rafael; Montero, Raquel

2017-01-01

Coenzyme Q10 (CoQ) is a lipid that is ubiquitously synthesized in tissues and has a key role in mitochondrial oxidative phosphorylation. Its biochemical determination provides insight into the CoQ status of tissues and may detect CoQ deficiency that can result from either an inherited primary deficiency of CoQ metabolism or may be secondary to different genetic and environmental conditions. Rapid identification of CoQ deficiency can also allow potentially beneficial treatment to be initiated as early as possible. CoQ may be measured in different specimens, including plasma, blood mononuclear cells, platelets, urine, muscle, and cultured skin fibroblasts. Blood and urinary CoQ also have good utility for CoQ treatment monitoring. PMID:28338638

Current state of coenzyme Q(10) production and its applications.

PubMed

Jeya, Marimuthu; Moon, Hee-Jung; Lee, Jeong-Lim; Kim, In-Won; Lee, Jung-Kul

2010-02-01

Coenzyme Q(10) (CoQ(10)), an obligatory cofactor in the aerobic respiratory electron transfer for energy generation, is formed from the conjugation of a benzoquinone ring with a hydrophobic isoprenoid chain. CoQ(10) is now used as a nutritional supplement because of its antioxidant properties and is beneficial in the treatment of several human diseases when administered orally. Bioprocesses have been developed for the commercial production of CoQ(10) because of its increased demand, and these bioprocesses depend on microbes that produce high levels of CoQ(10) naturally. However, as knowledge of the biosynthetic enzymes and the regulatory mechanisms modulating CoQ(10) production increases, approaches arise for the genetic engineering of CoQ(10) production in Escherichia coli and Agrobacterium tumefaciens. This review focused on approaches for CoQ(10) production, strategies used to engineer CoQ(10) production in microbes, and potential applications of CoQ(10).

Effect of mitochondrial dysfunction and oxidative stress on endogenous levels of coenzyme Q(10) in human cells.

PubMed

Yen, Hsiu-Chuan; Chen, Feng-Yuan; Chen, Shih-Wei; Huang, Yu-Hsiang; Chen, Yun-Ru; Chen, Chih-Wei

2011-01-01

Little is known about the regulation of endogenous CoQ(10) levels in response to mitochondrial dysfunction or oxidative stress although exogenous CoQ(10) has been extensively used in humans. In this study, we first demonstrated that acute treatment of antimycin A, an inhibitor of mitochondrial complex III, and the absence of mitochondrial DNA suppressed CoQ(10) levels in human 143B cells. Because these two conditions also enhanced formation of reactive oxygen species (ROS), we further investigated whether oxidative stress or mitochondrial dysfunction primarily contributed to the decrease of CoQ(10) levels. Results showed that H(2)O(2) augmented CoQ(10) levels, but carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), a chemical uncoupler, decreased CoQ(10) levels in 143B cells. However, H(2)O(2) and FCCP both increased mRNA levels of multiple COQ genes for biosynthesis of CoQ(10) . Our findings suggest that ROS induced CoQ(10) biosynthesis, whereas mitochondrial energy deficiency caused secondary suppression of CoQ(10) levels possibly due to impaired import of COQ proteins into mitochondria. Copyright © 2011 Wiley Periodicals, Inc.

RNA-binding proteins regulate cell respiration and coenzyme Q biosynthesis by post-transcriptional regulation of COQ7.

PubMed

Cascajo, María V; Abdelmohsen, Kotb; Noh, Ji Heon; Fernández-Ayala, Daniel J M; Willers, Imke M; Brea, Gloria; López-Lluch, Guillermo; Valenzuela-Villatoro, Marina; Cuezva, José M; Gorospe, Myriam; Siendones, Emilio; Navas, Plácido

2016-07-02

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain carrying electrons from complexes I and II to complex III and it is an intrinsic component of the respirasome. CoQ concentration is highly regulated in cells in order to adapt the metabolism of the cell to challenges of nutrient availability and stress stimuli. At least 10 proteins have been shown to be required for CoQ biosynthesis in a multi-peptide complex and COQ7 is a central regulatory factor of this pathway. We found that the first 765 bp of the 3'-untranslated region (UTR) of COQ7 mRNA contains cis-acting elements of interaction with RNA-binding proteins (RBPs) HuR and hnRNP C1/C2. Binding of hnRNP C1/C2 to COQ7 mRNA was found to require the presence of HuR, and hnRNP C1/C2 silencing appeared to stabilize COQ7 mRNA modestly. By contrast, lowering HuR levels by silencing or depriving cells of serum destabilized and reduced the half-life of COQ7 mRNA, thereby reducing COQ7 protein and CoQ biosynthesis rate. Accordingly, HuR knockdown decreased oxygen consumption rate and mitochondrial production of ATP, and increased lactate levels. Taken together, our results indicate that a reduction in COQ7 mRNA levels by HuR depletion causes mitochondrial dysfunction and a switch toward an enhanced aerobic glycolysis, the characteristic phenotype exhibited by primary deficiency of CoQ10. Thus HuR contributes to efficient oxidative phosphorylation by regulating of CoQ10 biosynthesis.

Amitriptyline down-regulates coenzyme Q10 biosynthesis in lung cancer cells.

PubMed

Ortiz, Tamara; Villanueva-Paz, Marina; Díaz-Parrado, Eduardo; Illanes, Matilde; Fernández-Rodríguez, Ana; Sánchez-Alcázar, José A; de Miguel, Manuel

2017-02-15

Amitriptyline, a tricyclic antidepressant, has been proposed as an antitumoral drug in oxidative therapy. Its pro-apoptotic effects, mediated by high reactive oxygen species generation, have been already described. In this study we analysed the effect of amitriptyline on the biosynthesis of coenzyme Q 10 (CoQ), an essential component for electron transport and a potent membrane antioxidant involved in redox signaling. We treated H460 cells, a non-small-cell lung cancer cell line, with amitriptyline and we analysed CoQ levels by HPLC and CoQ biosynthesis rate, as well as the enzymes involved in CoQ biosynthesis by real-time PCR and Western blot. Amitriptyline treatment induced a dose-dependent decrease in CoQ levels in tumor cells. CoQ decreased levels were associated with down-regulation of the expression of COQ4 gene, as well as decreased Coq4 and Coq6 protein levels. Our findings suggest that the effect of amitriptyline on CoQ biosynthesis highlights the potential of this drug for antitumoral oxidative therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Primary and secondary CoQ(10) deficiencies in humans.

PubMed

Quinzii, Catarina M; Hirano, Michio

2011-01-01

CoQ(10) deficiencies are clinically and genetically heterogeneous. This syndrome has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ(10) (primary CoQ(10) deficiencies) or in genes not directly related to CoQ(10) biosynthesis (secondary CoQ(10) deficiencies). Respiratory chain defects, ROS production, and apoptosis variably contribute to the pathogenesis of primary CoQ(10) deficiencies. Copyright © 2011 International Union of Biochemistry and Molecular Biology, Inc.

Coenzyme Q10 deficiencies in neuromuscular diseases.

PubMed

Artuch, Rafael; Salviati, Leonardo; Jackson, Sandra; Hirano, Michio; Navas, Plácido

2009-01-01

Coenzyme Q (CoQ) is an essential component of the respiratory chain but also participates in other mitochondrial functions such as regulation of the transition pore and uncoupling proteins. Furthermore, this compound is a specific substrate for enzymes of the fatty acids beta-oxidation pathway and pyrimidine nucleotide biosynthesis. Furthermore, CoQ is an antioxidant that acts in all cellular membranes and lipoproteins. A complex of at least ten nuclear (COQ) genes encoded proteins synthesizes CoQ but its regulation is unknown. Since 1989, a growing number of patients with multisystemic mitochondrial disorders and neuromuscular disorders showing deficiencies of CoQ have been identified. CoQ deficiency caused by mutation(s) in any of the COQ genes is designated primary deficiency. Other patients have displayed other genetic defects independent on the CoQ biosynthesis pathway, and are considered to have secondary deficiencies. This review updates the clinical and molecular aspects of both types of CoQ deficiencies and proposes new approaches to understanding their molecular bases.

Mitochondrial Ubiquinone Homologues, Superoxide Radical Generation, and Longevity in Different Mammalian Species*

PubMed Central

Lass, Achim; Agarwal, Sanjiv; Sohal, Rajindar S.

2010-01-01

Rates of mitochondrial superoxide anion radical ( O2·¯) 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 O2·¯ generation. The hypothesis that the relative amounts of the ubiquinones or coenzyme Q (CoQ) homologues, CoQ9 and CoQ10, are related with the rate of O2·¯ 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 O2·¯ 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 O2·¯ 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 O2·¯ 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 O2·¯ generation, followed by a plateau at high concentrations. Within the physiological range of CoQ concentrations, there were no differences in the rates of O2·¯ generation 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 O2·¯ generation than those obtained with CoQ10. These in vitro findings do not support the hypothesis that differences in the distribution of CoQ homologues are responsible for the variations in the rates of mitochondrial O2·¯ generation in different mammalian species. PMID:9235911

Characterisation and Skin Distribution of Lecithin-Based Coenzyme Q10-Loaded Lipid Nanocapsules

NASA Astrophysics Data System (ADS)

Zhou, Huafeng; Yue, Yang; Liu, Guanlan; Li, Yan; Zhang, Jing; Yan, Zemin; Duan, Mingxing

2010-10-01

The purpose of this study was to investigate the influence of the inner lipid ratio on the physicochemical properties and skin targeting of surfactant-free lecithin-based coenzyme Q10-loaded lipid nanocapsules (CoQ10-LNCs). The smaller particle size of CoQ10-LNCs was achieved by high pressure and a lower ratio of CoQ10/GTCC (Caprylic/capric triglyceride); however, the zeta potential of CoQ10-LNCs was above /- 60 mV/ with no distinct difference among them at different ratios of CoQ10/GTCC. Both the crystallisation point and the index decreased with the decreasing ratio of CoQ10/GTCC and smaller particle size; interestingly, the supercooled state of CoQ10-LNCs was observed at particle size below about 200 nm, as verified by differential scanning calorimetry (DSC) in one heating-cooling cycle. The lecithin monolayer sphere structure of CoQ10-LNCs was investigated by cryogenic transmission electron microscopy (Cryo-TEM). The skin penetration results revealed that the distribution of Nile red-loaded CoQ10-LNCs depended on the ratio of inner CoQ10/GTCC; moreover, epidermal targeting and superficial dermal targeting were achieved by the CoQ10-LNCs application. The highest fluorescence response was observed at a ratio of inner CoQ10/GTCC of 1:1. These observations suggest that lecithin-based LNCs could be used as a promising topical delivery vehicle for lipophilic compounds.

Coenzyme Q10 Supplementation in Aging and Disease

PubMed Central

Hernández-Camacho, Juan D.; Bernier, Michel; López-Lluch, Guillermo; Navas, Plácido

2018-01-01

Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an antioxidant in plasma membranes and lipoproteins. It is endogenously produced in all cells by a highly regulated pathway that involves a mitochondrial multiprotein complex. Defects in either the structural and/or regulatory components of CoQ complex or in non-CoQ biosynthetic mitochondrial proteins can result in a decrease in CoQ concentration and/or an increase in oxidative stress. Besides CoQ10 deficiency syndrome and aging, there are chronic diseases in which lower levels of CoQ10 are detected in tissues and organs providing the hypothesis that CoQ10 supplementation could alleviate aging symptoms and/or retard the onset of these diseases. Here, we review the current knowledge of CoQ10 biosynthesis and primary CoQ10 deficiency syndrome, and have collected published results from clinical trials based on CoQ10 supplementation. There is evidence that supplementation positively affects mitochondrial deficiency syndrome and the symptoms of aging based mainly on improvements in bioenergetics. Cardiovascular disease and inflammation are alleviated by the antioxidant effect of CoQ10. There is a need for further studies and clinical trials involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in metabolic syndrome and diabetes, neurodegenerative disorders, kidney diseases, and human fertility. PMID:29459830

Coenzyme Q(10) , endothelial function, and cardiovascular disease.

PubMed

Littarru, Gian Paolo; Tiano, Luca; Belardinelli, Romualdo; Watts, Gerald F

2011-01-01

Since the time a precise role of coenzyme Q(10) (CoQ(10) ) in myocardial bioenergetics was established, the involvement of CoQ in the pathophysiology of heart failure was hypothesized. This provided the rationale for numerous clinical trials of CoQ(10) as adjunctive treatment for heart failure. A mild hypotensive effect of CoQ was reported in the early years of clinical use of this compound. We review early human and animal studies on the vascular effects of CoQ. We then focus on endothelial dysfunction in type 2 diabetes and the possible impact on this condition of antioxidants and nutritional supplements, and in particular the therapeutic effects of CoQ. The effect of CoQ(10) on endothelial dysfunction in ischemic heart disease is also reviewed together with recent data highlighting that treatment with CoQ(10) increases extracellular SOD activity. Copyright © 2011 International Union of Biochemistry and Molecular Biology, Inc.

Coenzyme Q supplementation in pulmonary arterial hypertension

PubMed Central

Sharp, Jacqueline; Farha, Samar; Park, Margaret M.; Comhair, Suzy A.; Lundgrin, Erika L.; Tang, W.H. Wilson; Bongard, Robert D.; Merker, Marilyn P.; Erzurum, Serpil C.

2014-01-01

Mitochondrial dysfunction is a fundamental abnormality in the vascular endothelium and smooth muscle of patients with pulmonary arterial hypertension (PAH). Because coenzyme Q (CoQ) is essential for mitochondrial function and efficient oxygen utilization as the electron carrier in the inner mitochondrial membrane, we hypothesized that CoQ would improve mitochondrial function and benefit PAH patients. To test this, oxidized and reduced levels of CoQ, cardiac function by echocardiogram, mitochondrial functions of heme synthesis and cellular metabolism were evaluated in PAH patients (N=8) in comparison to healthy controls (N=7), at baseline and after 12 weeks oral CoQ supplementation. CoQ levels were similar among PAH and control individuals, and increased in all subjects with CoQ supplementation. PAH patients had higher CoQ levels than controls with supplementation, and a tendency to a higher reduced-to-oxidized CoQ ratio. Cardiac parameters improved with CoQ supplementation, although 6-minute walk distances and BNP levels did not significantly change. Consistent with improved mitochondrial synthetic function, hemoglobin increased and red cell distribution width (RDW) decreased in PAH patients with CoQ, while hemoglobin declined slightly and RDW did not change in healthy controls. In contrast, metabolic and redox parameters, including lactate, pyruvate and reduced or oxidized gluthathione, did not change in PAH patients with CoQ. In summary, CoQ improved hemoglobin and red cell maturation in PAH, but longer studies and/or higher doses with a randomized placebo-controlled controlled design are necessary to evaluate the clinical benefit of this simple nutritional supplement. PMID:25180165

Biosynthesis and bioproduction of coenzyme Q10 by yeasts and other organisms.

PubMed

Kawamukai, Makoto

2009-06-22

CoQ (coenzyme Q), an isoprenylated benzoquinone, is a well-known component of the electron-transfer system in eukaryotes. The main role of CoQ is to transfer electrons from NADH dehydrogenase and succinate dehydrogenase to CoQ:cytochrome c reductase in the respiratory chain. However, recent evidence indicates that an involvement in respiration is not the only role of CoQ. The second apparent role of CoQ is its anti-oxidation property, and other novel roles for CoQ, such as in disulfide-bond formation, sulfide oxidation and pyrimidine metabolism, have been reported. CoQ10, having ten isoprene units in the isoprenoid side chain, has been used as a medicine and is now commercially popular as a food supplement. Two yeast species, namely the budding yeast Saccharomyces cerevisiae, which produces CoQ6, and the fission yeast Schizosaccharomyces pombe, which produces CoQ10, are the main subjects of the present minireview because they have greatly contributed to our basic knowledge of CoQ biosynthesis among eukaryotes. The biosynthetic pathway that converts p-hydroxybenzoate into CoQ consists of eight steps in yeasts. The five enzymes involved in the biosynthetic pathway have been identified in both yeasts, yet the functions of three proteins were still not known. Analyses of the biosynthetic pathway in yeasts also contribute to the understanding of human genetic diseases related to CoQ deficiency. In the present minireview I focus on the biochemical and commercial aspects of CoQ in yeasts and in other organisms for comparison.

Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity.

PubMed

Stefely, Jonathan A; Licitra, Floriana; Laredj, Leila; Reidenbach, Andrew G; Kemmerer, Zachary A; Grangeray, Anais; Jaeg-Ehret, Tiphaine; Minogue, Catherine E; Ulbrich, Arne; Hutchins, Paul D; Wilkerson, Emily M; Ruan, Zheng; Aydin, Deniz; Hebert, Alexander S; Guo, Xiao; Freiberger, Elyse C; Reutenauer, Laurence; Jochem, Adam; Chergova, Maya; Johnson, Isabel E; Lohman, Danielle C; Rush, Matthew J P; Kwiecien, Nicholas W; Singh, Pankaj K; Schlagowski, Anna I; Floyd, Brendan J; Forsman, Ulrika; Sindelar, Pavel J; Westphall, Michael S; Pierrel, Fabien; Zoll, Joffrey; Dal Peraro, Matteo; Kannan, Natarajan; Bingman, Craig A; Coon, Joshua J; Isope, Philippe; Puccio, Hélène; Pagliarini, David J

2016-08-18

The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Coenzyme Q10 Therapy

PubMed Central

Garrido-Maraver, Juan; Cordero, Mario D.; Oropesa-Ávila, Manuel; Fernández Vega, Alejandro; de la Mata, Mario; Delgado Pavón, Ana; de Miguel, Manuel; Pérez Calero, Carmen; Villanueva Paz, Marina; Cotán, David; Sánchez-Alcázar, José A.

2014-01-01

For a number of years, coenzyme Q10 (CoQ10) was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in blood plasma, and extensively investigated its antioxidant role. These 2 functions constitute the basis for supporting the clinical use of CoQ10. Also, at the inner mitochondrial membrane level, CoQ10 is recognized as an obligatory cofactor for the function of uncoupling proteins and a modulator of the mitochondrial transition pore. Furthermore, recent data indicate that CoQ10 affects the expression of genes involved in human cell signaling, metabolism and transport, and some of the effects of CoQ10 supplementation may be due to this property. CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrial diseases, aging-related oxidative stress and carcinogenesis processes, and also statin treatment. Many neurodegenerative disorders, diabetes, cancer, and muscular and cardiovascular diseases have been associated with low CoQ10 levels as well as different ataxias and encephalomyopathies. CoQ10 treatment does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ10 absorption and tissue distribution. Oral administration of CoQ10 is a frequent antioxidant strategy in many diseases that may provide a significant symptomatic benefit. PMID:25126052

Photoionization of oxidized coenzyme Q in microemulsion: laser flash photolysis study in biomembrane-like system.

PubMed

Li, Kun; Wang, Mei; Wang, Jin; Zhu, Rongrong; Sun, Dongmei; Sun, Xiaoyu; Wang, Shi-Long

2013-01-01

Photoexcitation to generate triplet state has been proved to be the main photoreaction in homogeneous system for many benzoquinone derivatives, including oxidized coenzyme Q (CoQ) and its analogs. In the present study, microemulsion of CoQ, a heterogeneous system, is employed to mimic the distribution of CoQ in biomembrane. The photochemistry of CoQ(10) in microemulsion and cyclohexane is investigated and compared using laser flash photolysis and results show that CoQ(10) undergoes photoionization via a monophotonic process to generate radical cation of CoQ(10) in microemulsion and photoexcitation to generate excited triplet state in cyclohexane. Meanwhile, photoreactions of duroquinone (DQ) and CoQ(0) in microemulsion are also investigated to analyze the influence of molecular structure on the photochemistry of benzoquinone derivatives in microemulsion. Results suggest that photoexcitation, which is followed by excited state-involved hydrogen-abstraction reaction, is the main photoreaction for DQ and CoQ(0) in microemulsion. However, photoexcited CoQ(0) also leads to the formation of hydrated electrons. The isoprenoid side chain-involved high resonance stabilization is proposed to explain the difference in photoreactions of CoQ(0) and CoQ(10) in microemulsion. Considering that microemulsion is close to biomembrane system, its photoionization in microemulsion may be helpful to understand the real photochemistry of biological quinones in biomembrane system. © 2012 Tongji University. Photochemistry and Photobiology © 2012 The American Society of Photobiology.

Inhibition of Coenzyme Qs Accumulation in Engineered Escherichia coli by High Concentration of Farnesyl Diphosphate.

PubMed

Samoudi, Mojtaba; Omid Yeganeh, Negar; Shahbani Zahiri, Hossein; Shariati, Parvin; Hajhosseini, Reza

2015-01-01

Coenzyme Q 10 (CoQ 10 ) is an isoprenoid component used widely in nutraceutical industries. Farnesyl diphosphate synthase (FPPS) is a responsible enzyme for biosynthesis of farnesyl diphosphate (FPP), a key precursor for CoQs production. This research involved investigating the effect of FPPS over-expression on CoQs production in engineered CoQ 10 -producing Escherichia coli (E. coli). Two CoQ 10 -producing strains, as referred to E. coli Ba and E. coli Br, were transformed by the encoding gene for FPPS (ispA) under the control of either the trc or P BAD promoters. Over-expression of ispA under the control of P BAD promoter led to a relative increase in CoQ 10 production only in recombinant E. coli Br although induction by arabinose resulted in partial reduction of CoQ 10 production in both recombinant E. coli Ba and E. coli Br strains. Over-expression of ispA under the control of stronger trc promoter, however, led to a severe decrease in CoQ 10 production in both recombinant E. coli Ba and E. coli Br strains, as reflected by reductions from 629±40 to 30±13 and 564±28 to 80±14 μg/g Dried Cell Weight (DCW), respectively. The results showed high level of FPP reduces endogenous CoQ 8 production as well and that CoQs are produced in a complimentary manner, as the increase in production of one decreases the production of the other. The reduction in CoQ 10 production can be a result of Dds inhibition by high FPP concentration. Therefore, more effort is needed to verify the role of intermediate metabolite concentration and to optimize production of CoQ 10 .

Inhibition of Coenzyme Qs Accumulation in Engineered Escherichia coli by High Concentration of Farnesyl Diphosphate

PubMed Central

Samoudi, Mojtaba; Omid Yeganeh, Negar; Shahbani Zahiri, Hossein; Shariati, Parvin; Hajhosseini, Reza

2015-01-01

Background: Coenzyme Q 10 (CoQ 10 ) is an isoprenoid component used widely in nutraceutical industries. Farnesyl diphosphate synthase (FPPS) is a responsible enzyme for biosynthesis of farnesyl diphosphate (FPP), a key precursor for CoQs production. This research involved investigating the effect of FPPS over-expression on CoQs production in engineered CoQ 10 -producing Escherichia coli (E. coli). Methods: Two CoQ 10 -producing strains, as referred to E. coli Ba and E. coli Br, were transformed by the encoding gene for FPPS (ispA) under the control of either the trc or P BAD promoters. Results: Over-expression of ispA under the control of P BAD promoter led to a relative increase in CoQ 10 production only in recombinant E. coli Br although induction by arabinose resulted in partial reduction of CoQ 10 production in both recombinant E. coli Ba and E. coli Br strains. Over-expression of ispA under the control of stronger trc promoter, however, led to a severe decrease in CoQ 10 production in both recombinant E. coli Ba and E. coli Br strains, as reflected by reductions from 629±40 to 30±13 and 564±28 to 80±14 μg/g Dried Cell Weight (DCW), respectively. The results showed high level of FPP reduces endogenous CoQ 8 production as well and that CoQs are produced in a complimentary manner, as the increase in production of one decreases the production of the other. Conclusion: The reduction in CoQ 10 production can be a result of Dds inhibition by high FPP concentration. Therefore, more effort is needed to verify the role of intermediate metabolite concentration and to optimize production of CoQ 10 . PMID:26306151

Secondary coenzyme Q10 deficiency and oxidative stress in cultured fibroblasts from patients with riboflavin responsive multiple Acyl-CoA dehydrogenation deficiency.

PubMed

Cornelius, Nanna; Byron, Colleen; Hargreaves, Iain; Guerra, Paula Fernandez; Furdek, Andrea K; Land, John; Radford, Weston W; Frerman, Frank; Corydon, Thomas J; Gregersen, Niels; Olsen, Rikke K J

2013-10-01

Coenzyme Q10 (CoQ10) is essential for the energy production of the cells and as an electron transporter in the mitochondrial respiratory chain. CoQ10 links the mitochondrial fatty acid β-oxidation to the respiratory chain by accepting electrons from electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). Recently, it was shown that a group of patients with the riboflavin responsive form of multiple acyl-CoA dehydrogenation deficiency (RR-MADD) carrying inherited amino acid variations in ETF-QO also had secondary CoQ10 deficiency with beneficial effects of CoQ10 treatment, thus adding RR-MADD to an increasing number of diseases involving secondary CoQ10 deficiency. In this study, we show that moderately decreased CoQ10 levels in fibroblasts from six unrelated RR-MADD patients were associated with increased levels of mitochondrial reactive oxygen species (ROS). Treatment with CoQ10, but not with riboflavin, could normalize the CoQ10 level and decrease the level of ROS in the patient cells. Additionally, riboflavin-depleted control fibroblasts showed moderate CoQ10 deficiency, but not increased mitochondrial ROS, indicating that variant ETF-QO proteins and not CoQ10 deficiency are the causes of mitochondrial ROS production in the patient cells. Accordingly, the corresponding variant Rhodobacter sphaeroides ETF-QO proteins, when overexpressed in vitro, bind a CoQ10 pseudosubstrate, Q10Br, less tightly than the wild-type ETF-QO protein, suggesting that molecular oxygen can get access to the electrons in the misfolded ETF-QO protein, thereby generating superoxide and oxidative stress, which can be reversed by CoQ10 treatment.

Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency.

PubMed

Romero-Moya, Damià; Santos-Ocaña, Carlos; Castaño, Julio; Garrabou, Gloria; Rodríguez-Gómez, José A; Ruiz-Bonilla, Vanesa; Bueno, Clara; González-Rodríguez, Patricia; Giorgetti, Alessandra; Perdiguero, Eusebio; Prieto, Cristina; Moren-Nuñez, Constanza; Fernández-Ayala, Daniel J; Victoria Cascajo, Maria; Velasco, Iván; Canals, Josep Maria; Montero, Raquel; Yubero, Delia; Jou, Cristina; López-Barneo, José; Cardellach, Francesc; Muñoz-Cánoves, Pura; Artuch, Rafael; Navas, Plácido; Menendez, Pablo

2017-07-01

Coenzyme Q 10 (CoQ 10 ) plays a crucial role in mitochondria as an electron carrier within the mitochondrial respiratory chain (MRC) and is an essential antioxidant. Mutations in genes responsible for CoQ 10 biosynthesis (COQ genes) cause primary CoQ 10 deficiency, a rare and heterogeneous mitochondrial disorder with no clear genotype-phenotype association, mainly affecting tissues with high-energy demand including brain and skeletal muscle (SkM). Here, we report a four-year-old girl diagnosed with minor mental retardation and lethal rhabdomyolysis harboring a heterozygous mutation (c.483G > C (E161D)) in COQ4. The patient's fibroblasts showed a decrease in [CoQ 10 ], CoQ 10 biosynthesis, MRC activity affecting complexes I/II + III, and respiration defects. Bona fide induced pluripotent stem cell (iPSCs) lines carrying the COQ4 mutation (CQ4-iPSCs) were generated, characterized and genetically edited using the CRISPR-Cas9 system (CQ4 ed -iPSCs). Extensive differentiation and metabolic assays of control-iPSCs, CQ4-iPSCs and CQ4 ed -iPSCs demonstrated a genotype association, reproducing the disease phenotype. The COQ4 mutation in iPSC was associated with CoQ 10 deficiency, metabolic dysfunction, and respiration defects. iPSC differentiation into SkM was compromised, and the resulting SkM also displayed respiration defects. Remarkably, iPSC differentiation in dopaminergic or motor neurons was unaffected. This study offers an unprecedented iPSC model recapitulating CoQ 10 deficiency-associated functional and metabolic phenotypes caused by COQ4 mutation. Stem Cells 2017;35:1687-1703. © 2017 AlphaMed Press.

Coenzyme Q biosynthesis in health and disease.

PubMed

Acosta, Manuel Jesús; Vazquez Fonseca, Luis; Desbats, Maria Andrea; Cerqua, Cristina; Zordan, Roberta; Trevisson, Eva; Salviati, Leonardo

2016-08-01

Coenzyme Q (CoQ, or ubiquinone) is a remarkable lipid that plays an essential role in mitochondria as an electron shuttle between complexes I and II of the respiratory chain, and complex III. It is also a cofactor of other dehydrogenases, a modulator of the permeability transition pore and an essential antioxidant. CoQ is synthesized in mitochondria by a set of at least 12 proteins that form a multiprotein complex. The exact composition of this complex is still unclear. Most of the genes involved in CoQ biosynthesis (COQ genes) have been studied in yeast and have mammalian orthologues. Some of them encode enzymes involved in the modification of the quinone ring of CoQ, but for others the precise function is unknown. Two genes appear to have a regulatory role: COQ8 (and its human counterparts ADCK3 and ADCK4) encodes a putative kinase, while PTC7 encodes a phosphatase required for the activation of Coq7. Mutations in human COQ genes cause primary CoQ(10) deficiency, a clinically heterogeneous mitochondrial disorder with onset from birth to the seventh decade, and with clinical manifestation ranging from fatal multisystem disorders, to isolated encephalopathy or nephropathy. The pathogenesis of CoQ(10) deficiency involves deficient ATP production and excessive ROS formation, but possibly other aspects of CoQ(10) function are implicated. CoQ(10) deficiency is unique among mitochondrial disorders since an effective treatment is available. Many patients respond to oral CoQ(10) supplementation. Nevertheless, treatment is still problematic because of the low bioavailability of the compound, and novel pharmacological approaches are currently being investigated. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. Copyright © 2016. Published by Elsevier B.V.

The Role of Sulfide Oxidation Impairment in the Pathogenesis of Primary CoQ Deficiency.

PubMed

Quinzii, Catarina M; Luna-Sanchez, Marta; Ziosi, Marcello; Hidalgo-Gutierrez, Agustin; Kleiner, Giulio; Lopez, Luis C

2017-01-01

Coenzyme Q (CoQ) is a lipid present in all cell membranes. One of the multiple metabolic functions of CoQ is to transport electrons in the reaction catalyzed by sulfide:quinone oxidoreductase (SQOR), the first enzyme of the oxidation pathway of sulfides (hydrogen sulfide, H 2 S). Early evidence of a defect in the metabolism of H 2 S in primary CoQ deficiency came from yeast studies in Schizosaccharomyces pombe strains defective for dps1 and ppt1 (homologs of PDSS1 and COQ2 , respectively), which have H 2 S accumulation. Our recent studies in human skin fibroblasts and in murine models of primary CoQ deficiency show that, also in mammals, decreased CoQ levels cause impairment of H 2 S oxidation. Patient fibroblasts carrying different mutations in genes encoding proteins involved in CoQ biosynthesis show reduced SQOR activity and protein levels proportional to the levels of CoQ. In Pdss2 kd / kd mice, kidney, the only organ clinically affected, shows reduced SQOR levels and downstream enzymes, accumulation of H 2 S, and glutathione depletion. Pdss2 kd / kd mice have also low levels of thiosulfate in plasma and urine, and increased C4-C6 acylcarnitines in blood, due to inhibition of short-chain acyl-CoA dehydrogenase. Also in Coq9 R 239 X mice, the symptomatic organ, cerebrum, shows accumulation of H 2 S, reduced SQOR, increase in thiosulfate sulfurtransferase and sulfite oxidase, and reduction in the levels of glutathione and glutathione enzymes, leading to alteration of the biosynthetic pathways of glutamate, serotonin, and catecholamines. Coq9 R 239 X mice have also reduced blood pressure, possible consequence of H 2 S-induced vasorelaxation. Since liver is not clinically affected in Pdss2 and Coq9 mutant mice, the effects of the impairment of H 2 S oxidation in this organ were not investigated, despite its critical role in metabolism. In conclusion, in vitro and in vivo studies of CoQ deficient models provide evidence of tissue-specific H 2 S oxidation impairment, an additional pathomechanism that should be considered in the understanding and treatment of primary CoQ deficiency.

Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency.

PubMed

Di Giovanni, S; Mirabella, M; Spinazzola, A; Crociani, P; Silvestri, G; Broccolini, A; Tonali, P; Di Mauro, S; Servidei, S

2001-08-14

Two brothers with myopathic coenzyme Q10 (CoQ10) deficiency responded dramatically to CoQ10 supplementation. Muscle biopsies before therapy showed ragged-red fibers, lipid storage, and complex I + III and II + III deficiency. Approximately 30% of myofibers had multiple features of apoptosis. After 8 months of treatment, excessive lipid storage resolved, CoQ10 level normalized, mitochondrial enzymes increased, and proportion of fibers with TUNEL-positive nuclei decreased to 10%. The authors conclude that muscle CoQ10 deficiency can be corrected by supplementation of CoQ10, which appears to stimulate mitochondrial proliferation and to prevent apoptosis.

Protective effects of coenzyme q(10) on decreased oxidative stress resistance induced by simvastatin.

PubMed

Kettawan, Aikkarach; Takahashi, Takayuki; Kongkachuichai, Ratchanee; Charoenkiatkul, Somsri; Kishi, Takeo; Okamoto, Tadashi

2007-05-01

The effects of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), on oxidative stress resistance and the protective effects of coenzyme Q (CoQ) were investigated. When simvastatin was administered orally to mice, the levels of oxidized and reduced CoQ(9) and CoQ(10) in serum, liver, and heart, decreased significantly when compared to those of control. The levels of thiobarbituric acid reactive substances induced by Fe(2+)-ascorbate in liver and heart mitochondria also increased significantly with simvastatin. Furthermore, cultured cardiac myocytes treated with simvastatin exhibited less resistance to oxidative stress, decreased time to the cessation of spontaneous beating in response to H(2)O(2) addition, and decreased responsiveness to electrical field stimulation. These results suggested that oral administration of simvastatin suppresses the biosynthesis of CoQ, which shares the same biosynthesis pathway as cholesterol up to farnesyl pyrophosphate, thus compromising the physiological function of reduced CoQ, which possesses antioxidant activity. However, these undesirable effects induced by simvastatin were alleviated by coadministering CoQ(10) with simvastatin to mice. Simvastatin also reduced the activity of NADPH-CoQ reductase, a biological enzyme that converts oxidized CoQ to the corresponding reduced CoQ, while CoQ(10) administration improved it. These findings may also support the efficacy of coadministering CoQ(10) with statins.

Leigh Syndrome with Nephropathy and CoQ10 Deficiency Due to decaprenyl diphosphate synthase subunit 2 (PDSS2) Mutations

PubMed Central

López, Luis Carlos ; Schuelke, Markus ; Quinzii, Catarina M. ; Kanki, Tomotake ; Rodenburg, Richard J. T. ; Naini, Ali ; DiMauro, Salvatore ; Hirano, Michio 

2006-01-01

Coenzyme Q10 (CoQ10) is a vital lipophilic molecule that transfers electrons from mitochondrial respiratory chain complexes I and II to complex III. Deficiency of CoQ10 has been associated with diverse clinical phenotypes, but, in most patients, the molecular cause is unknown. The first defect in a CoQ10 biosynthetic gene, COQ2, was identified in a child with encephalomyopathy and nephrotic syndrome and in a younger sibling with only nephropathy. Here, we describe an infant with severe Leigh syndrome, nephrotic syndrome, and CoQ10 deficiency in muscle and fibroblasts and compound heterozygous mutations in the PDSS2 gene, which encodes a subunit of decaprenyl diphosphate synthase, the first enzyme of the CoQ10 biosynthetic pathway. Biochemical assays with radiolabeled substrates indicated a severe defect in decaprenyl diphosphate synthase in the patient’s fibroblasts. This is the first description of pathogenic mutations in PDSS2 and confirms the molecular and clinical heterogeneity of primary CoQ10 deficiency. PMID:17186472

ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption

PubMed Central

Ashraf, Shazia; Gee, Heon Yung; Woerner, Stephanie; Xie, Letian X.; Vega-Warner, Virginia; Lovric, Svjetlana; Fang, Humphrey; Song, Xuewen; Cattran, Daniel C.; Avila-Casado, Carmen; Paterson, Andrew D.; Nitschké, Patrick; Bole-Feysot, Christine; Cochat, Pierre; Esteve-Rudd, Julian; Haberberger, Birgit; Allen, Susan J.; Zhou, Weibin; Airik, Rannar; Otto, Edgar A.; Barua, Moumita; Al-Hamed, Mohamed H.; Kari, Jameela A.; Evans, Jonathan; Bierzynska, Agnieszka; Saleem, Moin A.; Böckenhauer, Detlef; Kleta, Robert; El Desoky, Sherif; Hacihamdioglu, Duygu O.; Gok, Faysal; Washburn, Joseph; Wiggins, Roger C.; Choi, Murim; Lifton, Richard P.; Levy, Shawn; Han, Zhe; Salviati, Leonardo; Prokisch, Holger; Williams, David S.; Pollak, Martin; Clarke, Catherine F.; Pei, York; Antignac, Corinne; Hildebrandt, Friedhelm

2013-01-01

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10. PMID:24270420

Involvement of a Broccoli COQ5 Methyltransferase in the Production of Volatile Selenium Compounds[C][OA

PubMed Central

Zhou, Xin; Yuan, Youxi; Yang, Yong; Rutzke, Michael; Thannhauser, Theodore W.; Kochian, Leon V.; Li, Li

2009-01-01

Selenium (Se) is an essential micronutrient for animals and humans but becomes toxic at high dosage. Biologically based Se volatilization, which converts Se into volatile compounds, provides an important means for cleanup of Se-polluted environments. To identify novel genes whose products are involved in Se volatilization from plants, a broccoli (Brassica oleracea var italica) cDNA encoding COQ5 methyltransferase (BoCOQ5-2) in the ubiquinone biosynthetic pathway was isolated. Its function was authenticated by complementing a yeast coq5 mutant and by detecting increased cellular ubiquinone levels in the BoCOQ5-2-transformed bacteria. BoCOQ5-2 was found to promote Se volatilization in both bacteria and transgenic Arabidopsis (Arabidopsis thaliana) plants. Bacteria expressing BoCOQ5-2 produced an over 160-fold increase in volatile Se compounds when they were exposed to selenate. Consequently, the BoCOQ5-2-transformed bacteria had dramatically enhanced tolerance to selenate and a reduced level of Se accumulation. Transgenic Arabidopsis expressing BoCOQ5-2 volatilized three times more Se than the vector-only control plants when treated with selenite and exhibited an increased tolerance to Se. In addition, the BoCOQ5-2 transgenic plants suppressed the generation of reactive oxygen species induced by selenite. BoCOQ5-2 represents, to our knowledge, the first plant enzyme that is not known to be directly involved in sulfur/Se metabolism yet was found to mediate Se volatilization. This discovery opens up new prospects regarding our understanding of the complete metabolism of Se and may lead to ways to modify Se-accumulator plants with increased efficiency for phytoremediation of Se-contaminated environments. PMID:19656903

Role of mitochondrial electron transport complex I in coenzyme Q1 reduction by intact pulmonary arterial endothelial cells and the effect of hyperoxia.

PubMed

Merker, Marilyn P; Audi, Said H; Lindemer, Brian J; Krenz, Gary S; Bongard, Robert D

2007-09-01

The objective was to determine the impact of intact normoxic and hyperoxia-exposed (95% O(2) for 48 h) bovine pulmonary arterial endothelial cells in culture on the redox status of the coenzyme Q(10) homolog coenzyme Q(1) (CoQ(1)). When CoQ(1) (50 microM) was incubated with the cells for 30 min, its concentration in the medium decreased over time, reaching a lower level for normoxic than hyperoxia-exposed cells. The decreases in CoQ(1) concentration were associated with generation of CoQ(1) hydroquinone (CoQ(1)H(2)), wherein 3.4 times more CoQ(1)H(2) was produced in the normoxic than hyperoxia-exposed cell medium (8.2 +/- 0.3 and 2.4 +/- 0.4 microM, means +/- SE, respectively) after 30 min. The maximum CoQ(1) reduction rate for the hyperoxia-exposed cells, measured using the cell membrane-impermeant redox indicator potassium ferricyanide, was about one-half that of normoxic cells (11.4 and 24.1 nmol x min(-1) x mg(-1) cell protein, respectively). The mitochondrial electron transport complex I inhibitor rotenone decreased the CoQ(1) reduction rate by 85% in the normoxic cells and 44% in the hyperoxia-exposed cells. There was little or no inhibitory effect of NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors on CoQ(1) reduction. Intact cell oxygen consumption rates and complex I activities in mitochondria-enriched fractions were also lower for hyperoxia-exposed than normoxic cells. The implication is that intact pulmonary endothelial cells influence the redox status of CoQ(1) via complex I-mediated reduction to CoQ(1)H(2), which appears in the extracellular medium, and that the hyperoxic exposure decreases the overall CoQ(1) reduction capacity via a depression in complex I activity.

Effects of dietary L-carnitine and coenzyme Q10 supplementation on performance and ascites mortality of broilers.

PubMed

Geng, Ailian; Guo, Yuming; Yuan, Jianmin

2004-12-01

The study was conducted to determine the effects of dietary L-carnitine and coenzyme Q10 (CoQ10) supplementation on growth performance and ascites mortality of broilers. A 3 x 3 factorial arrangement was employed with three levels (0, 75 and 150 mg/kg) of L-carnitine and three levels of CoQ10 (0, 20 and 40 mg/kg) supplementation during the experiment. Five hundred and forty one-day-old Arbor Acre male broiler chicks were randomly allocated into nine groups with six replicates each. All birds were fed with the basal diets from day 1 to 7 and changed to the experimental diets from day 8. During day 15 to 21 all the birds were exposed to low ambient temperature (15-18 degrees C) to induce ascites. The results showed that under this condition, growth performance of broilers were not significantly affected by CoQ10 or L-carnitine + CoQ10 supplementation during week 0-3 and 0-6, but body weight gain (BWG) of broilers was significantly reduced by 150 mg/ kg L-carnitine during week 0-6. Packed cell volume (PCV) of broilers was significantly decreased by L-carnitine and L-carnitine + CoQ10 supplementation (P < 0.05). Erythrocyte osmotic fragility (EOF), ascites heart index (AHI) and ascites mortality of broilers were significantly decreased by L-carnitine, CoQ10 and L-carnitine + CoQ10 supplementation. Though no significant changes were observed in total antioxidative capability (T-AOC), total superoxide dismutase (T-SOD) was increased by L-carnitine, CoQ10 and L-carnitine + CoQ10 supplementation (P < 0.05). Malonaldehyde (MDA) content was significantly decreased by CoQ10 and L-carnitine + CoQ10 supplementation. The results indicate that dietary L-carnitine and CoQ10 supplementation reduce ascites mortality of broilers; the reason may be partially associated with their antioxidative effects.

Coenzyme Q(1) as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type and Nqo1-null mouse lung.

PubMed

Bongard, Robert D; Myers, Charles R; Lindemer, Brian J; Baumgardt, Shelley; Gonzalez, Frank J; Merker, Marilyn P

2012-05-01

Previous studies showed that coenzyme Q(1) (CoQ(1)) reduction on passage through the rat pulmonary circulation was catalyzed by NAD(P)H:quinone oxidoreductase 1 (NQO1) and mitochondrial complex I, but that NQO1 genotype was not a factor in CoQ(1) reduction on passage through the mouse lung. The aim of the present study was to evaluate the complex I contribution to CoQ(1) reduction in the isolated perfused wild-type (NQO1(+/+)) and Nqo1-null (NQO1(-)/(-)) mouse lung. CoQ(1) reduction was measured as the steady-state pulmonary venous CoQ(1) hydroquinone (CoQ(1)H(2)) efflux rate during infusion of CoQ(1) into the pulmonary arterial inflow. CoQ(1)H(2) efflux rates during infusion of 50 μM CoQ(1) were not significantly different for NQO1(+/+) and NQO1(-/-) lungs (0.80 ± 0.03 and 0.68 ± 0.07 μmol·min(-1)·g lung dry wt(-1), respectively, P > 0.05). The mitochondrial complex I inhibitor rotenone depressed CoQ(1)H(2) efflux rates for both genotypes (0.19 ± 0.08 and 0.08 ± 0.04 μmol·min(-1)·g lung dry wt(-1) for NQO1(+/+) and NQO1(-/-), respectively, P < 0.05). Exposure of mice to 100% O(2) for 48 h also depressed CoQ(1)H(2) efflux rates in NQO1(+/+) and NQO1(-/-) lungs (0.43 ± 0.03 and 0.11 ± 0.04 μmol·min(-1)·g lung dry wt(-1), respectively, P < 0.05 by ANOVA). The impact of rotenone or hyperoxia on CoQ(1) redox metabolism could not be attributed to effects on lung wet-to-dry weight ratios, perfusion pressures, perfused surface areas, or total venous effluent CoQ(1) recoveries, the latter measured by spectrophotometry or mass spectrometry. Complex I activity in mitochondria-enriched lung fractions was depressed in hyperoxia-exposed lungs for both genotypes. This study provides new evidence for the potential utility of CoQ(1) as a nondestructive indicator of the impact of pharmacological or pathological exposures on complex I activity in the intact perfused mouse lung.

The Role of Sulfide Oxidation Impairment in the Pathogenesis of Primary CoQ Deficiency

PubMed Central

Quinzii, Catarina M.; Luna-Sanchez, Marta; Ziosi, Marcello; Hidalgo-Gutierrez, Agustin; Kleiner, Giulio; Lopez, Luis C.

2017-01-01

Coenzyme Q (CoQ) is a lipid present in all cell membranes. One of the multiple metabolic functions of CoQ is to transport electrons in the reaction catalyzed by sulfide:quinone oxidoreductase (SQOR), the first enzyme of the oxidation pathway of sulfides (hydrogen sulfide, H2S). Early evidence of a defect in the metabolism of H2S in primary CoQ deficiency came from yeast studies in Schizosaccharomyces pombe strains defective for dps1 and ppt1 (homologs of PDSS1 and COQ2, respectively), which have H2S accumulation. Our recent studies in human skin fibroblasts and in murine models of primary CoQ deficiency show that, also in mammals, decreased CoQ levels cause impairment of H2S oxidation. Patient fibroblasts carrying different mutations in genes encoding proteins involved in CoQ biosynthesis show reduced SQOR activity and protein levels proportional to the levels of CoQ. In Pdss2kd/kd mice, kidney, the only organ clinically affected, shows reduced SQOR levels and downstream enzymes, accumulation of H2S, and glutathione depletion. Pdss2kd/kd mice have also low levels of thiosulfate in plasma and urine, and increased C4–C6 acylcarnitines in blood, due to inhibition of short-chain acyl-CoA dehydrogenase. Also in Coq9R239X mice, the symptomatic organ, cerebrum, shows accumulation of H2S, reduced SQOR, increase in thiosulfate sulfurtransferase and sulfite oxidase, and reduction in the levels of glutathione and glutathione enzymes, leading to alteration of the biosynthetic pathways of glutamate, serotonin, and catecholamines. Coq9R239X mice have also reduced blood pressure, possible consequence of H2S-induced vasorelaxation. Since liver is not clinically affected in Pdss2 and Coq9 mutant mice, the effects of the impairment of H2S oxidation in this organ were not investigated, despite its critical role in metabolism. In conclusion, in vitro and in vivo studies of CoQ deficient models provide evidence of tissue-specific H2S oxidation impairment, an additional pathomechanism that should be considered in the understanding and treatment of primary CoQ deficiency. PMID:28790927

Restoring de novo Coenzyme Q biosynthesis in Caenorhabditis elegans coq-3 mutants yields profound rescue compared to exogenous Coenzyme Q supplementation

PubMed Central

Gomez, Fernando; Saiki, Ryoichi; Chin, Randall; Srinivasan, Chandra; Clarke, Catherine F.

2012-01-01

Coenzyme Q (ubiquinone or Q) is an essential lipid component of the mitochondrial electron transport chain. In Caenorhabditis elegans Q biosynthesis involves at least nine steps, including the hydroxylation of the hydroquinone ring by CLK-1 and two O-methylation steps mediated by COQ-3. We characterize two C. elegans coq-3 deletion mutants, and show that while each has defects in Q synthesis, their phenotypes are distinct. First generation homozygous coq-3(ok506) mutants are fertile when fed the standard lab diet of Q-replete OP50 E. coli, but their second generation homozygous progeny do not reproduce. In contrast, the coq-3(qm188) deletion mutant remains sterile when fed Q-replete OP50. Quantitative PCR analyses suggest that the longer qm188 deletion may alter expression of the flanking nuo-3 and gdi-1 genes, located 5′ and 3′, respectively of coq-3 within an operon. We surmise that variable expression of nuo-3, a subunit of complex I, or of gdi-1, a guanine nucleotide dissociation inhibitor, may act in combination with defects in Q biosynthesis to produce a more severe phenotype. The phenotypes of both coq-3 mutants are more drastic as compared to the C. elegans clk-1 mutants. When fed OP50, clk-1 mutants reproduce for many generations, but show reduced fertility, slow behaviors, and enhanced life span. The coq-3 and clk-1 mutants all show arrested development and are sterile when fed the Q-deficient E. coli strain GD1 (harboring a mutation in the ubiG gene). However, unlike clk-1 mutant worms, neither coq-3 mutant strain responded to dietary supplementation with purified exogenous Q10. Here we show that the Q9 content can be determined in lipid extracts from just 200 individual worms, enabling the determination of Q content in the coq-3 mutants unable to reproduce. An extra-chromosomal array expressing wild-type C. elegans coq-3 rescued fertility of both coq-3 mutants and partially restored steady-state levels of COQ-3 polypeptide and Q9 content, indicating that primary defect in both is limited to coq-3. The limited response of the coq-3 mutants to dietary supplementation with Q provides a powerful model to probe the effectiveness of exogenous Q supplementation as compared to restoration of de novo Q biosynthesis. PMID:22735617

Restoring de novo coenzyme Q biosynthesis in Caenorhabditis elegans coq-3 mutants yields profound rescue compared to exogenous coenzyme Q supplementation.

PubMed

Gomez, Fernando; Saiki, Ryoichi; Chin, Randall; Srinivasan, Chandra; Clarke, Catherine F

2012-09-10

Coenzyme Q (ubiquinone or Q) is an essential lipid component of the mitochondrial electron transport chain. In Caenorhabditis elegans Q biosynthesis involves at least nine steps, including the hydroxylation of the hydroquinone ring by CLK-1 and two O-methylation steps mediated by COQ-3. We characterize two C. elegans coq-3 deletion mutants, and show that while each has defects in Q synthesis, their phenotypes are distinct. First generation homozygous coq-3(ok506) mutants are fertile when fed the standard lab diet of Q-replete OP50 Escherichia coli, but their second generation homozygous progeny does not reproduce. In contrast, the coq-3(qm188) deletion mutant remains sterile when fed Q-replete OP50. Quantitative PCR analyses suggest that the longer qm188 deletion may alter expression of the flanking nuo-3 and gdi-1 genes, located 5' and 3', respectively of coq-3 within an operon. We surmise that variable expression of nuo-3, a subunit of complex I, or of gdi-1, a guanine nucleotide dissociation inhibitor, may act in combination with defects in Q biosynthesis to produce a more severe phenotype. The phenotypes of both coq-3 mutants are more drastic as compared to the C. elegans clk-1 mutants. When fed OP50, clk-1 mutants reproduce for many generations, but show reduced fertility, slow behaviors, and enhanced life span. The coq-3 and clk-1 mutants all show arrested development and are sterile when fed the Q-deficient E. coli strain GD1 (harboring a mutation in the ubiG gene). However, unlike clk-1 mutant worms, neither coq-3 mutant strain responded to dietary supplementation with purified exogenous Q(10). Here we show that the Q(9) content can be determined in lipid extracts from just 200 individual worms, enabling the determination of Q content in the coq-3 mutants unable to reproduce. An extra-chromosomal array expressing wild-type C. elegans coq-3 rescued fertility of both coq-3 mutants and partially restored steady-state levels of COQ-3 polypeptide and Q(9) content, indicating that primary defect in both is limited to coq-3. The limited response of the coq-3 mutants to dietary supplementation with Q provides a powerful model to probe the effectiveness of exogenous Q supplementation as compared to restoration of de novo Q biosynthesis. Copyright © 2012 Elsevier B.V. All rights reserved.

Olive oil supplemented with Coenzyme Q(10): effect on plasma and lipoprotein oxidative status.

PubMed

Brugè, Francesca; Bacchetti, Tiziana; Principi, Federica; Scarpa, Emanuele-Salvatore; Littarru, Gian Paolo; Tiano, Luca

2012-01-01

Olive oil consumption is associated with protective cardiovascular properties, including some beneficial modifications in lipoprotein profile and composition. Coenzyme Q(10) (CoQ(10)) exerts a protective effect on plasma lipoproteins. Aim of the study was to investigate whether extra virgin (EV) olive oil enriched with CoQ(10) affects CoQ(10) levels and oxidative status in plasma and in isolated lipoproteins. Twelve subjects were administered 20 mL olive oil per day for 2 weeks, followed by 2 weeks of olive oil enriched with 20 mg and 2 more weeks with 40 mg of CoQ(10). Plasma and isolated lipoproteins were collected in each phase of the study and subsequently analyzed to assess lipid profile, CoQ10 levels, ORAC assay, resistance of lipoproteins to peroxidation and paroxonase 1 activity. Plasma CoQ(10) levels significantly increased with the 20 mg (+73%) and 40 mg dose (+170%), while the percentage of oxidized CoQ(10) decreased. A significant inverse correlation was found in plasma between percentage of oxidized CoQ(10) and total antioxidant capacity. A lower susceptibility of LDL to peroxidation was also found. Finally, a positive correlation was observed between concentration of CoQ(10) in HDL and paraoxonase-1 activity. EV olive oil enriched with both doses of CoQ(10) significantly affects its bioavailability and plasma redox status. These changes are associated with a decreased susceptibility of plasma lipoproteins to peroxidation associated with a chain-breaking antioxidant activity of the formulation. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

Impact of Oral Ubiquinol on Blood Oxidative Stress and Exercise Performance

PubMed Central

Bloomer, Richard J.; Canale, Robert E.; McCarthy, Cameron G.; Farney, Tyler M.

2012-01-01

Coenzyme Q10 (CoQ10) plays an important role in bioenergetic processes and has antioxidant activity. Fifteen exercise-trained individuals (10 men and 5 women; 30–65 years) received reduced CoQ10 (Kaneka QH ubiquinol; 300 mg per day) or a placebo for four weeks in a random order, double blind, cross-over design (3 week washout). After each four-week period, a graded exercise treadmill test and a repeated cycle sprint test were performed (separated by 48 hours). Blood samples were collected before and immediately following both exercise tests and analyzed for lactate, malondialdehyde, and hydrogen peroxide. Resting blood samples were analyzed for CoQ10 (ubiquinone and ubiquinol) profile before and after each treatment period. Treatment with CoQ10 resulted in a significant increase in total blood CoQ10 (138%; P = 0.02) and reduced blood CoQ10 (168%; P = 0.02), but did not improve exercise performance (with the exception of selected individuals) or impact oxidative stress. The relationship between the percentage change in total blood CoQ10 and the cycle sprint total work (R2 = 0.6009) was noted to be moderate to strong. We conclude that treatment with CoQ10 in healthy, exercise-trained subjects increases total and reduced blood CoQ10, but this increase does not translate into improved exercise performance or decreased oxidative stress. PMID:22966414

Improving coenzyme Q8 production in Escherichia coli employing multiple strategies.

PubMed

Xu, Wen; Yang, Shuiyun; Zhao, Junchao; Su, Tingting; Zhao, Liangrui; Liu, Jiankang

2014-08-01

Coenzyme Q (CoQ) is a medically valuable compound and a high yielding strain for CoQ will have several benefits for the industrial production of CoQ. To increase the CoQ(8) content of E. coli, we blocked the pathway for the synthesis of menaquinone by deleting the menA gene. The blocking of menaquinone pathway increased the CoQ(8) content by 81 % in E. coli (ΔmenA). To study the CoQ producing potential of E. coli, we employed previous known increasing strategies for systematic metabolic engineering. These include the supplementation with substrate precursors and the co-expression of rate-limiting genes. The co-expression of dxs-ubiA and the supplementation with substrate precursors such as pyruvate (PYR) and parahydroxybenzoic acid (pHBA) increased the content of CoQ(8) in E. coli (ΔmenA) by 125 and 59 %, respectively. Moreover, a 180 % increase in the CoQ(8) content in E. coli (ΔmenA) was realized by the combination of the co-expression of dxs-ubiA and the supplementation with PYR and pHBA. All in all, CoQ(8) content in E. coli increased 4.06 times by blocking the menaquinone pathway, dxs-ubiA co-expression and the addition of sodium pyruvate and parahydroxybenzoic acid to the medium. Results suggested a synergistic effect among different metabolic engineering strategies.

A germline missense mutation in COQ6 is associated with susceptibility to familial schwannomatosis

PubMed Central

Zhang, Keqiang; Lin, Jia-Wei; Wang, Jinhui; Wu, Xiwei; Gao, Hanlin; Hsieh, Yi-Chen; Hwu, Peter; Liu, Yun-Ru; Su, Leila; Chiou, Hung-Yi; Wang, Daidong; Yuan, Yate-Ching; Whang-Peng, Jacqueline; Chiu, Wen-Ta; Yen, Yun

2014-01-01

Purpose: Schwannomatosis, a subtype of neurofibromatosis, is characterized by multiple benign, nonvestibular, nonintradermal schwannomas. Although the tumor suppressor SMARCB1 gene has been frequently identified as the underlying genetic cause of half of familial and ~10% of sporadic schwannomatosis, for most other cases, further causative genes remain to be discovered. Herein, we characterize the genome of a schwannomatosis family without constitutional inactivation of the SMARCB1 gene to explore novel genomic alterations predisposing individuals to the familial disease. Methods: We performed whole-genome/exome sequencing on genomic DNA of both schwannomatosis-affected and normal members of the family. Results: We identified a novel missense mutation (p.Asp208His; c.622G>C) in the coenzyme Q10 (CoQ10) biosynthesis monooxygenase 6 gene (COQ6) in schwannomatosis-affected members. The deleterious effects of the COQ6 mutations were validated by their lack of complementation in a coq6-deficient yeast mutant. Our study further indicated that the resultant haploinsufficiency of COQ6 might lead to CoQ10 deficiency and chronic overproduction of reactive oxygen species in Schwann cells. Conclusion: Although the exact oncogenetic mechanisms in this schwannomatosis family remain to be elucidated, our data strongly indicate a probable role of COQ6 mutation and CoQ10 deficiency in the development of familial schwannomatosis. PMID:24763291

A germline missense mutation in COQ6 is associated with susceptibility to familial schwannomatosis.

PubMed

Zhang, Keqiang; Lin, Jia-Wei; Wang, Jinhui; Wu, Xiwei; Gao, Hanlin; Hsieh, Yi-Chen; Hwu, Peter; Liu, Yun-Ru; Su, Leila; Chiou, Hung-Yi; Wang, Daidong; Yuan, Yate-Ching; Whang-Peng, Jacqueline; Chiu, Wen-Ta; Yen, Yun

2014-10-01

Schwannomatosis, a subtype of neurofibromatosis, is characterized by multiple benign, nonvestibular, nonintradermal schwannomas. Although the tumor suppressor SMARCB1 gene has been frequently identified as the underlying genetic cause of half of familial and ~10% of sporadic schwannomatosis, for most other cases, further causative genes remain to be discovered. Herein, we characterize the genome of a schwannomatosis family without constitutional inactivation of the SMARCB1 gene to explore novel genomic alterations predisposing individuals to the familial disease. We performed whole-genome/exome sequencing on genomic DNA of both schwannomatosis-affected and normal members of the family. We identified a novel missense mutation (p.Asp208His; c.622G>C) in the coenzyme Q10 (CoQ10) biosynthesis monooxygenase 6 gene (COQ6) in schwannomatosis-affected members. The deleterious effects of the COQ6 mutations were validated by their lack of complementation in a coq6-deficient yeast mutant. Our study further indicated that the resultant haploinsufficiency of COQ6 might lead to CoQ10 deficiency and chronic overproduction of reactive oxygen species in Schwann cells. Although the exact oncogenetic mechanisms in this schwannomatosis family remain to be elucidated, our data strongly indicate a probable role of COQ6 mutation and CoQ10 deficiency in the development of familial schwannomatosis.Genet Med 16 10, 787-792.

A single nucleotide polymorphism in COQ9 affects mitochondrial and ovarian function and fertility in Holstein cows

USDA-ARS?s Scientific Manuscript database

A single missense mutation at position 159 of COQ9 (GàA) has been associated with genetic variation in fertility in Holstein cattle, with the A allele associated with higher fertility. COQ9 is involved in the synthesis of coenzyme COQ10, a component of the electron transport system of the mitochondr...

Coenzyme Q(10) enhances dermal elastin expression, inhibits IL-1α production and melanin synthesis in vitro.

PubMed

Zhang, M; Dang, L; Guo, F; Wang, X; Zhao, W; Zhao, R

2012-06-01

Coenzyme Q(10) (CoQ(10) ) is a well-known antioxidant and has been used in many skincare products for anti-ageing purpose. However, the molecular mechanisms of CoQ(10) function in skin cells are not fully understood. In this paper, we compared the effects of CoQ(10) on primary human dermal fibroblasts from three individuals, including adult. We demonstrated that CoQ(10) treatment promoted proliferation of fibroblasts, increased type IV collagen expression and reduced UVR-induced matrix metalloproteinases-1 (MMP-1) level in embryonic and adult cells. In addition, CoQ(10) treatment increased elastin gene expression in cultured fibroblasts and significantly decreased UVR-induced IL-1α production in HaCat cells. Taken together, CoQ(10) presented anti-ageing benefits against intrinsic ageing as well as photo damage. Interestingly, CoQ(10) was able to inhibit tyrosinase activity, resulting in reduced melanin content in B16 cells. Thus, CoQ(10) may have potential depigmentation effects for skincare. © 2012 Space Biology Research & Technology Center, CASC. ICS © 2012 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Multi-omics Reveal Specific Targets of the RNA-Binding Protein Puf3p and Its Orchestration of Mitochondrial Biogenesis.

PubMed

Lapointe, Christopher P; Stefely, Jonathan A; Jochem, Adam; Hutchins, Paul D; Wilson, Gary M; Kwiecien, Nicholas W; Coon, Joshua J; Wickens, Marvin; Pagliarini, David J

2018-01-24

Coenzyme Q (CoQ) is a redox-active lipid required for mitochondrial oxidative phosphorylation (OxPhos). How CoQ biosynthesis is coordinated with the biogenesis of OxPhos protein complexes is unclear. Here, we show that the Saccharomyces cerevisiae RNA-binding protein (RBP) Puf3p regulates CoQ biosynthesis. To establish the mechanism for this regulation, we employed a multi-omic strategy to identify mRNAs that not only bind Puf3p but also are regulated by Puf3p in vivo. The CoQ biosynthesis enzyme Coq5p is a critical Puf3p target: Puf3p regulates the abundance of Coq5p and prevents its detrimental hyperaccumulation, thereby enabling efficient CoQ production. More broadly, Puf3p represses a specific set of proteins involved in mitochondrial protein import, translation, and OxPhos complex assembly (pathways essential to prime mitochondrial biogenesis). Our data reveal a mechanism for post-transcriptionally coordinating CoQ production with OxPhos biogenesis, and they demonstrate the power of multi-omics for defining genuine targets of RBPs. Copyright © 2017 Elsevier Inc. All rights reserved.

Primary coenzyme Q10 (CoQ 10) deficiencies and related nephropathies.

PubMed

Ozaltin, Fatih

2014-06-01

Oxidative phosphorylation (OXPHOS) is a metabolic pathway that uses energy released by the oxidation of nutrients to generate adenosine triphosphate (ATP). Coenzyme Q10 (CoQ10), also known as ubiquinone, plays an essential role in the human body not only by generating ATP in the mitochondrial respiratory chain but also by providing protection from reactive oxygen species (ROS) and functioning in the activation of many mitochondrial dehydrogenases and enzymes required in pyrimidine nucleoside biosynthesis. The presentations of primary CoQ10 deficiencies caused by genetic mutations are very heterogeneous. The phenotypes related to energy depletion or ROS production may depend on the content of CoQ10 in the cell, which is determined by the severity of the mutation. Primary CoQ10 deficiency is unique among mitochondrial disorders because early supplementation with CoQ10 can prevent the onset of neurological and renal manifestations. In this review I summarize primary CoQ10 deficiencies caused by various genetic abnormalities, emphasizing its nephropathic form.

Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance

PubMed Central

Fazakerley, Daniel J; Chaudhuri, Rima; Yang, Pengyi; Maghzal, Ghassan J; Thomas, Kristen C; Krycer, James R; Humphrey, Sean J; Parker, Benjamin L; Fisher-Wellman, Kelsey H; Meoli, Christopher C; Hoffman, Nolan J; Diskin, Ciana; Burchfield, James G; Cowley, Mark J; Kaplan, Warren; Modrusan, Zora; Kolumam, Ganesh; Yang, Jean YH; Chen, Daniel L; Samocha-Bonet, Dorit; Greenfield, Jerry R; Hoehn, Kyle L

2018-01-01

Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance. PMID:29402381

Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ 10).

PubMed

Horvath, Rita

2012-07-01

Riboflavin and ubiquinone (Coenzyme Q(10), CoQ(10)) deficiencies are heterogeneous groups of autosomal recessive conditions affecting both children and adults. Riboflavin (vitamin B(2))-derived cofactors are essential for the function of numerous dehydrogenases. Genetic defects of the riboflavin transport have been detected in Brown-Vialetto-Van Laere and Fazio-Londe syndromes (C20orf54), and haploinsufficiency of GPR172B has been proposed in one patient to cause persistent riboflavin deficiency. Mutations in the electron tranferring fravoprotein genes (ETFA/ETFB) and its dehydrogenase (ETFDH) are causative for multiple acyl-CoA dehydrogenase deficiency. Mutations in ACAD9, encoding the acyl-CoA dehydrogenase 9 protein were recently reported in mitochondrial disease with respiratory chain complex I deficiency. All these conditions may respond to riboflavin therapy. CoQ(10) is a lipid-soluble component of the cell membranes, where it functions as a mobile electron and proton carrier, but also participates in other cellular processes as a potent antioxidant, and by influencing pyrimidine metabolism. The increasing number of molecular defects in enzymes of the CoQ(10) biosynthetic pathways (PDSS1, PDSS2, COQ2, COQ6, COQ9, CABC1/ADCK3) underlies the importance of these conditions. The clinical heterogeneity may reflect blocks at different levels in the complex biosynthetic pathway. Despite the identification of several primary CoQ(10) deficiency genes, the number of reported patients is still low, and no true genotype-phenotype correlations are known which makes the genetic diagnosis still difficult. Additionally to primary CoQ(10) deficiencies, where the mutation impairs a protein directly involved in CoQ(10) biosynthesis, we can differentiate secondary deficiencies. CoQ(10) supplementation may be beneficial in both primary and secondary deficiencies and therefore the early recognition of these diseases is of utmost importance.

Coenzyme Q0 Enhances Ultraviolet B-Induced Apoptosis in Human Estrogen Receptor-Positive Breast (MCF-7) Cancer Cells.

PubMed

Wang, Hui-Min; Yang, Hsin-Ling; Thiyagarajan, Varadharajan; Huang, Tzu-Hsiang; Huang, Pei-Jane; Chen, Ssu-Ching; Liu, Jer-Yuh; Hsu, Li-Sung; Chang, Hsueh-Wei; Hseu, You-Cheng

2017-09-01

Coenzyme Q 0 (CoQ 0 ; 2,3-dimethoxy-5-methyl-1,4-benzoquinone), a major active constituent of Antrodia camphorata, has been shown to inhibit human triple-negative breast cancer (MDA-MB-231) cells through induction of apoptosis and cell-cycle arrest. Ecological studies have suggested a possible association between ultraviolet B (UVB) radiation and reduction in the risk of breast cancer. However, the underlying mechanism of the combination of CoQ 0 and UVB in human estrogen receptor-positive breast cancer (MCF-7) remains unclear. In this study, the possible effect of CoQ 0 on inducing apoptosis in MCF-7 cells under exposure to low-dose UVB (0.05 J/cm 2 ) has been investigated. CoQ 0 treatment (0-35 µM, for 24-72 hours) inhibits moderately the growth of breast cancer MCF-7 cells, and the cell viability was significantly decreased when the cells were pretreated with UVB irradiation. It was noted that there was a remarkable accumulation of subploid cells, the so-called sub-G1 peak, in CoQ 0 -treated cells by using flow cytometric analysis, which suggests that the viability reduction observed after treatment may result from apoptosis induction in MCF-7 cells. CoQ 0 caused an elevation of reactive oxygen species, as indicated by dichlorofluorescein fluorescence, and UVB pretreatment significantly increased CoQ 0 -induced reactive oxygen species generation in MCF-7 cells. In addition, cells were exposed to CoQ 0 , and the induction of DNA damage was evaluated by single-cell gel electrophoresis (comet assay). CoQ 0 -induced DNA damage was remarkably enhanced by UVB pretreatment. Furthermore, CoQ 0 induced apoptosis in MCF-7 cells, which was associated with PARP degradation, Bcl-2/Bax dysregulation, and p53 expression as shown by western blot. Collectively, these findings suggest that CoQ 0 might be an important supplemental agent for treating patients with breast cancer.

Modeling Monogenic Human Nephrotic Syndrome in the Drosophila Garland Cell Nephrocyte.

PubMed

Hermle, Tobias; Braun, Daniela A; Helmstädter, Martin; Huber, Tobias B; Hildebrandt, Friedhelm

2017-05-01

Steroid-resistant nephrotic syndrome is characterized by podocyte dysfunction. Drosophila garland cell nephrocytes are podocyte-like cells and thus provide a potential in vivo model in which to study the pathogenesis of nephrotic syndrome. However, relevant pathomechanisms of nephrotic syndrome have not been studied in nephrocytes. Here, we discovered that two Drosophila slit diaphragm proteins, orthologs of the human genes encoding nephrin and nephrin-like protein 1, colocalize within a fingerprint-like staining pattern that correlates with ultrastructural morphology. Using RNAi and conditional CRISPR/Cas9 in nephrocytes, we found this pattern depends on the expression of both orthologs. Tracer endocytosis by nephrocytes required Cubilin and reflected size selectivity analogous to that of glomerular function. Using RNAi and tracer endocytosis as a functional read-out, we screened Drosophila orthologs of human monogenic causes of nephrotic syndrome and observed conservation of the central pathogenetic alterations. We focused on the coenzyme Q 10 (CoQ 10 ) biosynthesis gene Coq2 , the silencing of which disrupted slit diaphragm morphology. Restoration of CoQ 10 synthesis by vanillic acid partially rescued the phenotypic and functional alterations induced by Coq2 -RNAi. Notably, Coq2 colocalized with mitochondria, and Coq2 silencing increased the formation of reactive oxygen species (ROS). Silencing of ND75 , a subunit of the mitochondrial respiratory chain that controls ROS formation independently of CoQ 10 , phenocopied the effect of Coq2 -RNAi. Moreover, the ROS scavenger glutathione partially rescued the effects of Coq2 -RNAi. In conclusion, Drosophila garland cell nephrocytes provide a model with which to study the pathogenesis of nephrotic syndrome, and ROS formation may be a pathomechanism of COQ2 -nephropathy. Copyright © 2017 by the American Society of Nephrology.

Protective effects of coenzyme Q10 nanoparticles on dichlorvos-induced hepatotoxicity and mitochondrial/lysosomal injury.

PubMed

Eftekhari, Aziz; Ahmadian, Elham; Azami, Aida; Johari-Ahar, Mohammad; Eghbal, Mohammad Ali

2018-02-01

Development of biocompatible antioxidant nanoparticles for xenobiotic-induced liver disease treatment by oral or parenteral administration is of great interest in medicine. In the current study, we demonstrate the protective effects of coenzyme Q10 nanoparticles (CoQ10-NPs) on hepatotoxicity induced by dichlorvos (DDVP) as an organophosphate. Although CoQ10 is an efficient antioxidant, its poor bioavailability has limited the applications of this useful agent. First, CoQ10-NPs were prepared then characterized using dynamic light scattering (DLS) and transmission electron microscopy (TEM). In DDVP-treated and non-treated hepatocytes in the presence of CoQ10-NPs, cell viability, the level of reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial membrane potential (MMP), lysosome membrane integrity, and cellular glutathione (GSH) content were measured. The prepared CoQ10-NPs were mono-dispersed and had narrow size distribution with average diameter of 54 nm. In the in vivo study, we evaluated the enzymes, which are involved in the antioxidant system for maintenance of normal liver function. In comparison to nonparticulate CoQ10, the CoQ10-NPs efficiently decreased the ROS formation, lipid peroxidation and cell death. Also, particulate form of CoQ10 improved MMP, GSH level and lysosome membrane integrity. In the in vivo, study, we revealed that CoQ10-NPs were better hepatoprotective than its nonparticulate form (P < .05). Altogether, we propose that the CoQ10-NPs have potential capability to be used as a therapeutic and prophylactic agent for poisoning that is induced by organophosphate agents, especially in the case of DDVP. Furthermore, these positive remarks make this nanoparticle amenable for the treatment of xenobiotic-induced liver diseases. © 2017 Wiley Periodicals, Inc.

CoQ(10) deficiencies and MNGIE: two treatable mitochondrial disorders.

PubMed

Hirano, Michio; Garone, Caterina; Quinzii, Catarina M

2012-05-01

Although causative mutations have been identified for numerous mitochondrial disorders, few disease-modifying treatments are available. Two examples of treatable mitochondrial disorders are coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Here, we describe clinical and molecular features of CoQ(10) deficiencies and MNGIE and explain how understanding their pathomechanisms have led to rationale therapies. Primary CoQ(10) deficiencies, due to mutations in genes required for ubiquinone biosynthesis, and secondary deficiencies, caused by genetic defects not directly related to CoQ(10) biosynthesis, often improve with CoQ(10) supplementation. In vitro and in vivo studies of CoQ(10) deficiencies have revealed biochemical alterations that may account for phenotypic differences among patients and variable responses to therapy. In contrast to the heterogeneous CoQ(10) deficiencies, MNGIE is a single autosomal recessive disease due to mutations in the TYMP gene encoding thymidine phosphorylase (TP). In MNGIE, loss of TP activity causes toxic accumulations of the nucleosides thymidine and deoxyuridine that are incorporated by the mitochondrial pyrimidine salvage pathway and cause deoxynucleoside triphosphate pool imbalances, which, in turn cause mtDNA instability. Allogeneic hematopoetic stem cell transplantation to restore TP activity and eliminate toxic metabolites is a promising therapy for MNGIE. CoQ(10) deficiencies and MNGIE demonstrate the feasibility of treating specific mitochondrial disorders through replacement of deficient metabolites or via elimination of excessive toxic molecules. Studies of CoQ(10) deficiencies and MNGIE illustrate how understanding the pathogenic mechanisms of mitochondrial diseases can lead to meaningful therapies. This article is part of a Special Issue entitled: Biochemistry of Mitochondria, Life and Intervention 2010. Copyright © 2012 Elsevier B.V. All rights reserved.

A Conserved START Domain Coenzyme Q-binding Polypeptide is Required for Efficient Q Biosynthesis, Respiratory Electron Transport, and Antioxidant Function in Saccharomyces cerevisiae

PubMed Central

Morvaridi, Susan; Saiki, Ryoichi; Johnson, Jarrett S.; Liau, Wei-Siang; Hirano, Kathleen; Kawashima, Tadashi; Ji, Ziming; Loo, Joseph A.; Shepherd, Jennifer N.; Clarke, Catherine F.

2014-01-01

Coenzyme Qn (ubiquinone or Qn) is a redox active lipid composed of a fully substituted benzoquinone ring and a polyisoprenoid tail of n isoprene units. Saccharomyces cerevisiae coq1-coq9 mutants have defects in Q biosynthesis, lack Q6, are respiratory defective, and sensitive to stress imposed by polyunsaturated fatty acids. The hallmark phenotype of the Q-less yeast coq mutants is that respiration in isolated mitochondria can be rescued by the addition of Q2, a soluble Q analog. Yeast coq10 mutants share each of these phenotypes, with the surprising exception that they continue to produce Q6. Structure determination of the Caulobacter crescentus Coq10 homolog (CC1736) revealed a steroidogenic acute regulatory protein-related lipid transfer (START) domain, a hydrophobic tunnel known to bind specific lipids in other START domain family members. Here we show that purified CC1736 binds Q2, Q3, Q10, or demethoxy-Q3 in an equimolar ratio, but fails to bind 3-farnesyl-4-hydroxybenzoic acid, a farnesylated analog of an early Q-intermediate. Over-expression of C. crescentus CC1736 or COQ8 restores respiratory electron transport and antioxidant function of Q6 in the yeast coq10 null mutant. Studies with stable isotope ring precursors of Q reveal that early Q-biosynthetic intermediates accumulate in the coq10 mutant and de novo Q-biosynthesis is less efficient than in the wild-type yeast or rescued coq10 mutant. The results suggest that the Coq10 polypeptide:Q (protein:ligand) complex may serve essential functions in facilitating de novo Q biosynthesis and in delivering newly synthesized Q to one or more complexes of the respiratory electron transport chain. PMID:23270816

Polyisoprenoid epoxides stimulate the biosynthesis of coenzyme Q and inhibit cholesterol synthesis.

PubMed

Bentinger, Magnus; Tekle, Michael; Brismar, Kerstin; Chojnacki, Tadeusz; Swiezewska, Ewa; Dallner, Gustav

2008-05-23

In our search for compounds that up-regulate the biosynthesis of coenzyme Q (CoQ), we discovered that irradiation of CoQ with ultraviolet light results in the formation of a number of compounds that influence the synthesis of mevalonate pathway lipids by HepG2 cells. Among the compounds that potently stimulated CoQ synthesis while inhibiting cholesterol synthesis, derivatives of CoQ containing 1-4 epoxide moieties in their polyisoprenoid side chains were identified. Subsequently, chemical epoxidation of all-trans-polyprenols of different lengths revealed that the shorter farnesol and geranylgeraniol derivatives were without effect, whereas the longer derivatives of solanesol enhanced CoQ and markedly reduced cholesterol biosynthesis. In contrast, none of the modified trans-trans-poly-cis-polyprenols exerted noticeable effects. Tocotrienol epoxides were especially potent in our system; those with one epoxide moiety in the side-chain generally up-regulated CoQ biosynthesis by 200-300%, whereas those with two such moieties also decreased cholesterol synthesis by 50-90%. Prolonged treatment of HepG2 cells with tocotrienol epoxides for 26 days elevated their content of CoQ by 30%. In addition, the levels of mRNA encoding enzymes involved in CoQ biosynthesis were also elevated by the tocotrienol epoxides. The site of inhibition of cholesterol synthesis was shown to be oxidosqualene cyclase. In conclusion, epoxide derivatives of certain all-trans-polyisoprenoids cause pronounced stimulation of CoQ synthesis and, in some cases, simultaneous reduction of cholesterol biosynthesis by HepG2 cells.

Identification of Coq11, a New Coenzyme Q Biosynthetic Protein in the CoQ-Synthome in Saccharomyces cerevisiae*

PubMed Central

Allan, Christopher M.; Awad, Agape M.; Johnson, Jarrett S.; Shirasaki, Dyna I.; Wang, Charles; Blaby-Haas, Crysten E.; Merchant, Sabeeha S.; Loo, Joseph A.; Clarke, Catherine F.

2015-01-01

Coenzyme Q (Q or ubiquinone) is a redox active lipid composed of a fully substituted benzoquinone ring and a polyisoprenoid tail and is required for mitochondrial electron transport. In the yeast Saccharomyces cerevisiae, Q is synthesized by the products of 11 known genes, COQ1–COQ9, YAH1, and ARH1. The function of some of the Coq proteins remains unknown, and several steps in the Q biosynthetic pathway are not fully characterized. Several of the Coq proteins are associated in a macromolecular complex on the matrix face of the inner mitochondrial membrane, and this complex is required for efficient Q synthesis. Here, we further characterize this complex via immunoblotting and proteomic analysis of tandem affinity-purified tagged Coq proteins. We show that Coq8, a putative kinase required for the stability of the Q biosynthetic complex, is associated with a Coq6-containing complex. Additionally Q6 and late stage Q biosynthetic intermediates were also found to co-purify with the complex. A mitochondrial protein of unknown function, encoded by the YLR290C open reading frame, is also identified as a constituent of the complex and is shown to be required for efficient de novo Q biosynthesis. Given its effect on Q synthesis and its association with the biosynthetic complex, we propose that the open reading frame YLR290C be designated COQ11. PMID:25631044

Identification of Coq11, a New Coenzyme Q Biosynthetic Protein in the CoQ-Synthome in Saccharomyces cerevisiae

DOE PAGES

Allan, Christopher M.; Awad, Agape M.; Johnson, Jarrett S.; ...

2015-01-28

Coenzyme Q (Q or ubiquinone) is a redox active lipid composed of a fully substituted benzoquinone ring and a polyisoprenoid tail and is required for mitochondrial electron transport. In the yeast Saccharomyces cerevisiae, Q is synthesized by the products of 11 known genes, COQ1–COQ9, YAH1, and ARH1. The function of some of the Coq proteins remains unknown, and several steps in the Q biosynthetic pathway are not fully characterized. Several of the Coq proteins are associated in a macromolecular complex on the matrix face of the inner mitochondrial membrane, and this complex is required for efficient Q synthesis. In thismore » paper, we further characterize this complex via immunoblotting and proteomic analysis of tandem affinity-purified tagged Coq proteins. We show that Coq8, a putative kinase required for the stability of the Q biosynthetic complex, is associated with a Coq6-containing complex. Additionally Q 6 and late stage Q biosynthetic intermediates were also found to co-purify with the complex. A mitochondrial protein of unknown function, encoded by the YLR290C open reading frame, is also identified as a constituent of the complex and is shown to be required for efficient de novo Q biosynthesis. Finally, given its effect on Q synthesis and its association with the biosynthetic complex, we propose that the open reading frame YLR290C be designated COQ11.« less

Does Coenzyme Q10 Supplementation Mitigate Statin-Associated Muscle Symptoms? Pharmacological and Methodological Considerations.

PubMed

Taylor, Beth A

2018-04-01

Statin drugs markedly reduce low-density lipoprotein cholesterol and consequently the incidence of cardiac events. In approximately 5-10% of adults, these drugs are associated with a range of muscle side effects such as muscle pain, cramping and weakness. Reduction in mitochondrial coenzyme Q10 (CoQ10), or ubiquinone, has been proposed as a mechanism for these statin-associated muscle symptoms (SAMS), and thus various formulations of CoQ10 are marketed and consumed for the prevention and treatment of SAMS. However, data supporting the efficacy of CoQ10 are equivocal, with some studies showing that CoQ10 supplementation reduces the incidence and severity of SAMS and others finding no beneficial effects of supplementation. Methodological and pharmacological issues may confound interpretation of data on this topic. For example, many patients who report SAMS, such as those who have been enrolled in previous CoQ10 studies, may be experiencing non-specific (non-statin-associated) muscle pain. In addition, the effectiveness of oral CoQ10 supplementation to increase mitochondrial CoQ10 in human skeletal muscle is not well established. This manuscript will critically evaluate the published data on the efficacy of CoQ10 supplements in the prevention and treatment of SAMS.

Coenzyme Q10 protects hair cells against aminoglycoside.

PubMed

Sugahara, Kazuma; Hirose, Yoshinobu; Mikuriya, Takefumi; Hashimoto, Makoto; Kanagawa, Eiju; Hara, Hirotaka; Shimogori, Hiroaki; Yamashita, Hiroshi

2014-01-01

It is well known that the production of free radicals is associated with sensory cell death induced by an aminoglycoside. Many researchers have reported that antioxidant reagents protect sensory cells in the inner ear, and coenzyme Q10 (CoQ10) is an antioxidant that is consumed as a health food in many countries. The purpose of this study was to investigate the role of CoQ10 in mammalian vestibular hair cell death induced by aminoglycoside. Cultured utricles of CBA/CaN mice were divided into three groups (control group, neomycin group, and neomycin + CoQ10 group). In the neomycin group, utricles were cultured with neomycin (1 mM) to induce hair cell death. In the neomycin + CoQ10 group, utricles were cultured with neomycin and water-soluble CoQ10 (30-0.3 µM). Twenty-four hours after exposure to neomycin, the cultured tissues were fixed, and vestibular hair cells were labeled using an anti-calmodulin antibody. Significantly more hair cells survived in the neomycin + CoQ10 group than in the neomycin group. These data indicate that CoQ10 protects sensory hair cells against neomycin-induced death in the mammalian vestibular epithelium; therefore, CoQ10 may be useful as a protective drug in the inner ear.

Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway.

PubMed

Ziosi, Marcello; Di Meo, Ivano; Kleiner, Giulio; Gao, Xing-Huang; Barca, Emanuele; Sanchez-Quintero, Maria J; Tadesse, Saba; Jiang, Hongfeng; Qiao, Changhong; Rodenburg, Richard J; Scalais, Emmanuel; Schuelke, Markus; Willard, Belinda; Hatzoglou, Maria; Tiranti, Valeria; Quinzii, Catarina M

2017-01-01

Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Here, we show that lack of CoQ in human skin fibroblasts causes impairment of hydrogen sulfide oxidation, proportional to the residual levels of CoQ. Biochemical and molecular abnormalities are rescued by CoQ supplementation in vitro and recapitulated by pharmacological inhibition of CoQ biosynthesis in skin fibroblasts and ADCK3 depletion in HeLa cells. Kidneys of Pdss2 kd/kd mice, which only have ~15% residual CoQ concentrations and are clinically affected, showed (i) reduced protein levels of SQR and downstream enzymes, (ii) accumulation of hydrogen sulfides, and (iii) glutathione depletion. These abnormalities were not present in brain, which maintains ~30% residual CoQ and is clinically unaffected. In Pdss2 kd/kd mice, we also observed low levels of plasma and urine thiosulfate and increased blood C4-C6 acylcarnitines. We propose that impairment of the sulfide oxidation pathway induced by decreased levels of CoQ causes accumulation of sulfides and consequent inhibition of short-chain acyl-CoA dehydrogenase and glutathione depletion, which contributes to increased oxidative stress and kidney failure. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Enhancement of solubility and dissolution of coenzyme Q10 using solid dispersion formulation.

PubMed

Nepal, Pushp R; Han, Hyo-Kyung; Choi, Hoo-Kyun

2010-01-04

This study aimed to develop a stable solid dispersion of Coenzyme Q(10) (CoQ(10)) with high aqueous solubility and dissolution rate. Among various carriers screened, poloxamer 407 was most effective to form a superior solid dispersion of CoQ(10) having significantly enhanced solubility. Particularly, solid dispersion of CoQ(10) with poloxamer 407 in the weight ratio of 1:5 prepared by melting method enhanced the solubility of CoQ(10) to the greatest extent. However, it exhibited poor stability and hence Aerosil 200 (colloidal silicon dioxide) was incorporated into the solid dispersion as an adsorbent to inhibit the recrystallization process. The solid dispersion of CoQ(10), poloxamer 407 and Aerosil 200 in the weight ratio of 1:5:6 exhibited improved stability with no significant change in solubility during the 1-month stability test. Moreover, the solid dispersion formulation containing Aerosil 200 significantly enhanced the extent of drug release (approx. 75% release) as well as the dissolution rate of CoQ(10). In conclusion, the present study has developed the stable solid dispersion formulation of CoQ(10) with poloxamer 407 and Aerosil 200 for the enhanced solubility and dissolution of CoQ(10), which could also offer some additional advantages including ease of preparation, good flowability and cost-effectiveness.

Coenzyme Q as an antiadipogenic factor.

PubMed

Bour, Sandy; Carmona, Maria-Carmen; Galinier, Anne; Caspar-Bauguil, Sylvie; Van Gaal, Luc; Staels, Bart; Pénicaud, Luc; Casteilla, Louis

2011-02-01

Coenzyme Q (CoQ) is not only the single antioxidant synthesized in humans but also an obligatory element of mitochondrial functions. We have previously reported CoQ deficiency in white adipose tissue of ob/ob mice. We sought to determine (i) whether this deficit exists in all species and its relevance in human obesity and (ii) to what extent CoQ could be involved in adipocyte differentiation. Here we identified in rodents as well as in humans a specific very strong nonlinear negative correlation between CoQ content in subcutaneous adipose tissue and obesity indexes. This striking correlation reveals a threshold value similar in both species. This relative deficit in CoQ content in adipose tissue rapidly took place during the time course of high-fat-diet-induced obesity in mice. Adipocyte differentiation was assessed in vitro using the preadipocyte 3T3-F442A cell line. When CoQ synthesis was inhibited by a pharmacological approach using chlorobenzoic acid, this strongly triggered adipose differentiation. In contrast, adipogenesis was strongly inhibited when a long-term increase in CoQ content was obtained by overexpressing human 4-hydroxy benzoate acid polyprenyltransferase gene. Altogether, these data suggest that a strict level of CoQ remains essential for adipocyte differentiation, and its impairment is associated with obesity.

Plasma levels of coenzyme Q10 in children with hyperthyroidism.

PubMed

Menke, Thomas; Niklowitz, Petra; Reinehr, Thomas; de Sousa, Gideon John; Andler, Werner

2004-01-01

In hyperthyroidism, increased oxygen consumption and free radical production in the stimulated respiratory chain leads to oxidative stress. Apart from its antioxidative function, coenzyme Q10 (CoQ10) is involved in electron transport in the respiratory chain. The aim of this study was to determine whether there is a correlation between an increased respiratory chain activity and the state of CoQ10 in children with hyperthyroidism. The CoQ10 plasma concentration was measured by high-performance liquid chromatography in 12 children with hyperthyroidism before and after treatment. In the hyperthyroid state, the plasma level of CoQ10 was significantly decreased in comparison with the level in the euthyroid state. The correction of the hyperthyroid state resulted in a normalization of the CoQ10 level. Plasma CoQ10 deficiency appears to be related to the stimulated respiratory chain activity in children with hyperthyroidism. Copyright 2004 S. Karger AG, Basel

Detergent-dependent kinetics of truncated Plasmodium falciparum dihydroorotate dehydrogenase.

PubMed

Malmquist, Nicholas A; Baldwin, Jeffrey; Phillips, Margaret A

2007-04-27

The survival of the malaria parasite Plasmodium falciparum is dependent upon the de novo biosynthesis of pyrimidines. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the fourth step in this pathway in an FMN-dependent reaction. The full-length enzyme is associated with the inner mitochondrial membrane, where ubiquinone (CoQ) serves as the terminal electron acceptor. The lipophilic nature of the co-substrate suggests that electron transfer to CoQ occurs at the two-dimensional lipid-solution interface. Here we show that PfDHODH associates with liposomes even in the absence of the N-terminal transmembrane-spanning domain. The association of a series of ubiquinone substrates with detergent micelles was studied by isothermal titration calorimetry, and the data reveal that CoQ analogs with long decyl (CoQ(D)) or geranyl (CoQ(2)) tails partition into detergent micelles, whereas that with a short prenyl tail (CoQ(1)) remains in solution. PfDHODH-catalyzed reduction of CoQ(D) and CoQ(2), but not CoQ(1), is stimulated as detergent concentrations (Tween 80 or Triton X-100) are increased up to their critical micelle concentrations, beyond which activity declines. Steady-state kinetic data acquired for the reaction with CoQ(D) and CoQ(2) in substrate-detergent mixed micelles fit well to a surface dilution kinetic model. In contrast, the data for CoQ(1) as a substrate were well described by solution steady-state kinetics. Our results suggest that the partitioning of lipophilic ubiquinone analogues into detergent micelles needs to be an important consideration in the kinetic analysis of enzymes that utilize these substrates.

AarF Domain Containing Kinase 3 (ADCK3) Mutant Cells Display Signs of Oxidative Stress, Defects in Mitochondrial Homeostasis and Lysosomal Accumulation

PubMed Central

Cullen, Jason K.; Abdul Murad, Norazian; Yeo, Abrey; McKenzie, Matthew; Ward, Micheal; Chong, Kok Leong; Schieber, Nicole L.; Parton, Robert G.; Lim, Yi Chieh; Wolvetang, Ernst; Maghzal, Ghassan J.; Stocker, Roland; Lavin, Martin F.

2016-01-01

Autosomal recessive ataxias are a clinically diverse group of syndromes that in some cases are caused by mutations in genes with roles in the DNA damage response, transcriptional regulation or mitochondrial function. One of these ataxias, known as Autosomal Recessive Cerebellar Ataxia Type-2 (ARCA-2, also known as SCAR9/COQ10D4; OMIM: #612016), arises due to mutations in the ADCK3 gene. The product of this gene (ADCK3) is an atypical kinase that is thought to play a regulatory role in coenzyme Q10 (CoQ10) biosynthesis. Although much work has been performed on the S. cerevisiae orthologue of ADCK3, the cellular and biochemical role of its mammalian counterpart, and why mutations in this gene lead to human disease is poorly understood. Here, we demonstrate that ADCK3 localises to mitochondrial cristae and is targeted to this organelle via the presence of an N-terminal localisation signal. Consistent with a role in CoQ10 biosynthesis, ADCK3 deficiency decreased cellular CoQ10 content. In addition, endogenous ADCK3 was found to associate in vitro with recombinant Coq3, Coq5, Coq7 and Coq9, components of the CoQ10 biosynthetic machinery. Furthermore, cell lines derived from ARCA-2 patients display signs of oxidative stress, defects in mitochondrial homeostasis and increases in lysosomal content. Together, these data shed light on the possible molecular role of ADCK3 and provide insight into the cellular pathways affected in ARCA-2 patients. PMID:26866375

Determination of Coenzyme Q10 Content in Raw Materials and Dietary Supplements by High-Performance Liquid Chromatography-UV: Collaborative Study

PubMed Central

Lunetta, Steven; Roman, Mark

2008-01-01

An international collaborative study was conducted of a high-performance liquid chromatographic (HPLC)-UV method for the determination of coenzyme Q10 (CoQ10, ubidecarenone) in raw materials and dietary supplements. Ten collaborating laboratories determined the total CoQ10 content in 8 blind duplicate samples. Sample materials included CoQ10 raw material and 4 finished product dietary supplements representing softgels, hardshell gelatin capsules, and chewable wafers. In addition, collaborating laboratories received a negative control and negative control spiked with CoQ10 at low and high levels to determine recovery. Materials were extracted with an acetonitrile–tetrahydrofuran–water mixture. Ferric chloride was added to the test solutions to ensure all CoQ10 was in the oxidized form. The HPLC analyses were performed on a C18 column using UV detection at 275 nm. Repeatability relative standard deviations (RSDr) ranged from 0.94 to 5.05%. Reproducibility relative standard deviations (RSDR) ranged from 3.08 to 17.1%, with HorRat values ranging from 1.26 to 5.17. Recoveries ranged from 74.0 to 115%. Based on these results, the method is recommended for Official First Action for determination of CoQ10 in raw materials and dietary supplement finished products containing CoQ10 at a concentration of >100 mg CoQ10/g test material. PMID:18727527

Tissue-specific oxidative stress and loss of mitochondria in CoQ-deficient Pdss2 mutant mice.

PubMed

Quinzii, Catarina M; Garone, Caterina; Emmanuele, Valentina; Tadesse, Saba; Krishna, Sindu; Dorado, Beatriz; Hirano, Michio

2013-02-01

Primary human CoQ(10) deficiencies are clinically heterogeneous diseases caused by mutations in PDSS2 and other genes required for CoQ(10) biosynthesis. Our in vitro studies of PDSS2 mutant fibroblasts, with <20% CoQ(10) of control cells, revealed reduced activity of CoQ(10)-dependent complex II+III and ATP synthesis, without amplification of reactive oxygen species (ROS), markers of oxidative damage, or antioxidant defenses. In contrast, COQ2 and ADCK3 mutant fibroblasts, with 30-50% CoQ(10) of controls, showed milder bioenergetic defects but significantly increased ROS and oxidation of lipids and proteins. We hypothesized that absence of oxidative stress markers and cell death in PDSS2 mutant fibroblasts were due to the extreme severity of CoQ(10) deficiency. Here, we have investigated in vivo effects of Pdss2 deficiency in affected and unaffected organs of CBA/Pdss2(kd/kd) mice at presymptomatic, phenotypic-onset, and end-stages of the disease. Although Pdss2 mutant mice manifest widespread CoQ(9) deficiency and mitochondrial respiratory chain abnormalities, only affected organs show increased ROS production, oxidative stress, mitochondrial DNA depletion, and reduced citrate synthase activity, an index of mitochondrial mass. Our data indicate that kidney-specific loss of mitochondria triggered by oxidative stress may be the cause of renal failure in Pdss2(kd/kd) mice.

NADPH-dependent coenzyme Q reductase is the main enzyme responsible for the reduction of non-mitochondrial CoQ in cells.

PubMed

Takahashi, Takayuki; Okuno, Masaaki; Okamoto, Tadashi; Kishi, Takeo

2008-01-01

We purified an NADPH-dependent coenzyme Q reductase (NADPH-CoQ reductase) in rat liver cytosol and compared its enzymatic properties with those of the other CoQ10 reductases such as NADPH: quinone acceptor oxidoreductase 1 (NQO1), lipoamide dehydrogenase, thioredoxine reductase and glutathione reductase. NADPH-CoQ reductase was the only enzyme that preferred NADPH to NADH as an electron donor and was also different from the other CoQ10 reductases in the sensitivities to its inhibitors and stimulators. Especially, Zn2+ was the most powerful inhibitor for NADPH-CoQ reductase, but CoQ10 reduction by the other CoQ10 reductases could not be inhibited by Zn2+. Furthermore, the reduction of the CoQ9 incorporated into HeLa cells was also inhibited by Zn2+ in the presence of pyrithione, a zinc ionophore. Moreover, NQO1 gene silencing in HeLa cells by transfection of a small interfering RNA resulted in lowering of both the NQO1 protein level and the NQO1 activity by about 75%. However, this transfection did not affect the NADPH-CoQ reductase activity and the reduction of CoQ9 incorporated into the cells. These results suggest that the NADPH-CoQ reductase located in cytosol may be the main enzyme responsible for the reduction of non-mitochondrial CoQ in cells.

Coenzyme Q10 and vitamin E deficiency in Friedreich's ataxia: predictor of efficacy of vitamin E and coenzyme Q10 therapy.

PubMed

Cooper, J M; Korlipara, L V P; Hart, P E; Bradley, J L; Schapira, A H V

2008-12-01

A pilot study of high dose coenzyme Q(10) (CoQ(10))/vitamin E therapy in Friedreich's ataxia (FRDA) patients resulted in significant clinical improvements in most patients. This study investigated the potential for this treatment to modify clinical progression in FRDA in a randomized double blind trial. Fifty FRDA patients were randomly divided into high or low dose CoQ(10)/ vitamin E groups. The change in International Co-operative Ataxia Ratings Scale (ICARS) was assessed over 2 years as the primary end-point. A post hoc analysis was made using cross-sectional data. At baseline serum CoQ(10) and vitamin E levels were significantly decreased in the FRDA patients (P < 0.001). During the trial CoQ(10) and vitamin E levels significantly increased in both groups (P < 0.01). The primary and secondary end-points were not significantly different between the therapy groups. When compared to cross-sectional data 49% of all patients demonstrated improved ICARS scores. This responder group had significantly lower baseline serum CoQ(10) levels. A high proportion of FRDA patients have a decreased serum CoQ(10) level which was the best predictor of a positive clinical response to CoQ(10)/vitamin E therapy. Low and high dose CoQ(10)/vitamin E therapies were equally effective in improving ICARS scores.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allan, Christopher M.; Awad, Agape M.; Johnson, Jarrett S.

Coenzyme Q (Q or ubiquinone) is a redox active lipid composed of a fully substituted benzoquinone ring and a polyisoprenoid tail and is required for mitochondrial electron transport. In the yeast Saccharomyces cerevisiae, Q is synthesized by the products of 11 known genes, COQ1–COQ9, YAH1, and ARH1. The function of some of the Coq proteins remains unknown, and several steps in the Q biosynthetic pathway are not fully characterized. Several of the Coq proteins are associated in a macromolecular complex on the matrix face of the inner mitochondrial membrane, and this complex is required for efficient Q synthesis. In thismore » paper, we further characterize this complex via immunoblotting and proteomic analysis of tandem affinity-purified tagged Coq proteins. We show that Coq8, a putative kinase required for the stability of the Q biosynthetic complex, is associated with a Coq6-containing complex. Additionally Q 6 and late stage Q biosynthetic intermediates were also found to co-purify with the complex. A mitochondrial protein of unknown function, encoded by the YLR290C open reading frame, is also identified as a constituent of the complex and is shown to be required for efficient de novo Q biosynthesis. Finally, given its effect on Q synthesis and its association with the biosynthetic complex, we propose that the open reading frame YLR290C be designated COQ11.« less

Determination of coenzyme Q10 content in raw materials and dietary supplements by high-performance liquid chromatography-UV: collaborative study.

PubMed

Lunetta, Steven; Roman, Mark

2008-01-01

An international collaborative study was conducted of a high-performance liquid chromatographic (HPLC)-UV method for the determination of coenzyme Q10 (CoQ10, ubidecarenone) in raw materials and dietary supplements. Ten collaborating laboratories determined the total CoQ10 content in 8 blind duplicate samples. Sample materials included CoQ10 raw material and 4 finished product dietary supplements representing softgels, hardshell gelatin capsules, and chewable wafers. In addition, collaborating laboratories received a negative control and negative control spiked with CoQ10 at low and high levels to determine recovery. Materials were extracted with an acetonitrile-tetrahydrofuran-water mixture. Ferric chloride was added to the test solutions to ensure all CoQ10 was in the oxidized form. The HPLC analyses were performed on a C18 column using UV detection at 275 nm. Repeatability relative standard deviations (RSDr) ranged from 0.94 to 5.05%. Reproducibility relative standard deviations (RSDR) ranged from 3.08 to 17.1%, with HorRat values ranging from 1.26 to 5.17. Recoveries ranged from 74.0 to 115%. Based on these results, the method is recommended for Official First Action for determination of CoQ10 in raw materials and dietary supplement finished products containing CoQ10 at a concentration of >100 mg CoQ10/g test material.

Opposite and tissue-specific effects of coenzyme Q2 on mPTP opening and ROS production between heart and liver mitochondria: role of complex I.

PubMed

Gharib, Abdallah; De Paulis, Damien; Li, Bo; Augeul, Lionel; Couture-Lepetit, Elisabeth; Gomez, Ludovic; Angoulvant, Denis; Ovize, Michel

2012-05-01

Coenzyme Q(2) (CoQ(2)) is known to inhibit mitochondrial permeability transition pore (mPTP) opening in isolated rat liver mitochondria. In this study, we investigated and compared the effects of CoQ(2) on mPTP opening and ROS production in isolated rabbit heart and rat liver mitochondria. Mitochondria were isolated from New Zealand White rabbit hearts and Wistar rat livers. Oxygen consumption, Ca(2+)-induced mPTP opening, ROS production and NADH DUb-reductase activity were measured. Rotenone was used to investigate the effect of CoQ(2) on respiratory complex I activity. CoQ(2) (23 μM) reduced the respiratory control index by 32% and 57% (p<0.01) in heart and liver mitochondria respectively, mainly through an increased oxygen consumption in state 4. CoQ(2) induced a 60% (p<0.05) decrease of calcium retention capacity (CRC) in heart mitochondria and inversely a 46% (p<0.05) increase in liver mitochondria. In basal condition, CoQ(2) induced a 170% (p<0.05) increase of H(2)O(2) production in heart mitochondria and 21% (ns) decrease of H(2)O(2) production in liver mitochondria. Because rotenone, a complex I inhibitor, increases H(2)O(2) production in heart but not in liver mitochondria we investigated the CoQ(2) effect in a dose-response assay of complex I inhibition by rotenone in both mitochondria. CoQ(2) antagonized the effect of rotenone on respiratory complex I activity in liver but not in heart mitochondria. CoQ(2) significantly reduced NADH DUb-reductase activity in liver (-47%) and heart (-37%) mitochondria. In conclusion, our data showed that on the contrary to what was observed in liver mitochondria, CoQ(2) favors mPTP opening and ROS production in heart mitochondria through an opposite effect on respiratory complex I activity. Copyright © 2012 Elsevier Ltd. All rights reserved.

A conserved START domain coenzyme Q-binding polypeptide is required for efficient Q biosynthesis, respiratory electron transport, and antioxidant function in Saccharomyces cerevisiae.

PubMed

Allan, Christopher M; Hill, Shauna; Morvaridi, Susan; Saiki, Ryoichi; Johnson, Jarrett S; Liau, Wei-Siang; Hirano, Kathleen; Kawashima, Tadashi; Ji, Ziming; Loo, Joseph A; Shepherd, Jennifer N; Clarke, Catherine F

2013-04-01

Coenzyme Qn (ubiquinone or Qn) is a redox active lipid composed of a fully substituted benzoquinone ring and a polyisoprenoid tail of n isoprene units. Saccharomyces cerevisiae coq1-coq9 mutants have defects in Q biosynthesis, lack Q6, are respiratory defective, and sensitive to stress imposed by polyunsaturated fatty acids. The hallmark phenotype of the Q-less yeast coq mutants is that respiration in isolated mitochondria can be rescued by the addition of Q2, a soluble Q analog. Yeast coq10 mutants share each of these phenotypes, with the surprising exception that they continue to produce Q6. Structure determination of the Caulobacter crescentus Coq10 homolog (CC1736) revealed a steroidogenic acute regulatory protein-related lipid transfer (START) domain, a hydrophobic tunnel known to bind specific lipids in other START domain family members. Here we show that purified CC1736 binds Q2, Q3, Q10, or demethoxy-Q3 in an equimolar ratio, but fails to bind 3-farnesyl-4-hydroxybenzoic acid, a farnesylated analog of an early Q-intermediate. Over-expression of C. crescentus CC1736 or COQ8 restores respiratory electron transport and antioxidant function of Q6 in the yeast coq10 null mutant. Studies with stable isotope ring precursors of Q reveal that early Q-biosynthetic intermediates accumulate in the coq10 mutant and de novo Q-biosynthesis is less efficient than in the wild-type yeast or rescued coq10 mutant. The results suggest that the Coq10 polypeptide:Q (protein:ligand) complex may serve essential functions in facilitating de novo Q biosynthesis and in delivering newly synthesized Q to one or more complexes of the respiratory electron transport chain. Copyright © 2012 Elsevier B.V. All rights reserved.

CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome.

PubMed

Luna-Sánchez, Marta; Hidalgo-Gutiérrez, Agustín; Hildebrandt, Tatjana M; Chaves-Serrano, Julio; Barriocanal-Casado, Eliana; Santos-Fandila, Ángela; Romero, Miguel; Sayed, Ramy Ka; Duarte, Juan; Prokisch, Holger; Schuelke, Markus; Distelmaier, Felix; Escames, Germaine; Acuña-Castroviejo, Darío; López, Luis C

2017-01-01

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. Therefore, SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism. In cerebrum of Coq9 R239X mice, the deficit in SQR induces an increase in thiosulfate sulfurtransferase and sulfite oxidase, as well as modifications in the levels of thiols. As a result, biosynthetic pathways of glutamate, serotonin, and catecholamines were altered in the cerebrum, and the blood pressure was reduced. Therefore, this study reveals the reduction in SQR activity as one of the pathomechanisms associated with CoQ deficiency syndrome. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Self-Nanoemulsifying Drug Delivery System of Coenzyme (Q10) with Improved Dissolution, Bioavailability, and Protective Efficiency on Liver Fibrosis.

PubMed

Khattab, Abeer; Hassanin, Lobna; Zaki, Nashwah

2017-07-01

The aim of our investigation is to develop and characterize self-nanoemulsifying drug delivery systems (SNEDDS) of CoQ 10 to improve its water solubility, dissolution rate, and bioavailability, and then evaluate its biochemical and physiological effect on liver cirrhosis in rats compared with CoQ 10 powder. SNEDDS are isotropic and thermodynamically stable mixture of oil, surfactant, co-surfactant, and drug that form an oil/water nanoemulsion when added to aqueous phases with soft agitation. Upon administration, self-nanoemulsifying system becomes in contact with gastrointestinal fluid and forms o/w nanoemulsion by the aid of gastrointestinal motility. When the nanoemulsion is formed in the gastrointestinal tract, it presents the drug in a solubilized form inside small nano-sized droplets that provide a large surface area for enhancing the drug release and absorption. Solubility of CoQ 10 in various oils, surfactants, and co-surfactants were studied to identify the components of SNEDDS; pseudo-ternary phase diagrams were plotted to identify the efficient self-emulsifying regions. CoQ 10 -loaded SNEDDS were prepared using isopropyl myristate as oil; Cremophor El, Labrasol, or Tween80 as surfactant; and Transcutol as co-surfactant. The amount of CoQ 10 in each vehicle was 3%. The formulations that passed thermostability evaluation test were assessed for particle size analysis, morphological characterization, refractive index, zeta potential, viscosity, electroconductivity, drug release profile, as well as ex vivo permeability. Pharmacokinetics and hepatoprotective efficiency of the optimized SNEDDS of CoQ 10 compared with CoQ 10 suspension were performed. Results showed that all optimized formulae have the ability to form a good and stable nanoemulsion when diluted with water; the mean droplet size of all formulae was in the nanometric range (11.7-13.5 nm) with optimum polydispersity index values (0.2-0.21). All formulae showed negative zeta potential (-11.3 to -17.2), and maximum drug loading efficiency. One hundred percent of CoQ 10 was released from most formulae within 30 min. One hundred percent of CoQ 10 was permeated from all formulae through 10 h. The pharmacokinetic study in rabbits revealed a significant increase in bioavailability of CoQ 10 SNEDDS to 2.1-fold compared with CoQ 10 suspension after oral administration. Comparative effect of the optimized formulae on acute liver injury compared with CoQ 10 powder was also studied; it was found that all the liver biochemical markers as alanine transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP), total protein (TP), and albumin were significantly improved at p < 0.05. Also, histochemical and histopthological studies confirm the biochemical results. Our results suggest the potential use of SNEDDS to increase the solubility of liphophilic drug as poorly water-soluble CoQ 10 and improve its oral absorption, so it can be more efficient to improve liver damage compared to CoQ 10 powder. These results demonstrated that CoQ 10 SNEDDS inhibited thioacetamide (TAA)-induced liver fibrosis mainly through suppression of collagen production.

CINRG pilot trial of coenzyme Q10 in steroid-treated Duchenne muscular dystrophy.

PubMed

Spurney, Christopher F; Rocha, Carolina Tesi; Henricson, Erik; Florence, Julaine; Mayhew, Jill; Gorni, Ksenija; Pasquali, Livia; Pestronk, Alan; Martin, Gerard R; Hu, Fengming; Nie, Lei; Connolly, Anne M; Escolar, Diana M

2011-08-01

Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin-deficient muscle. We performed an open-label, "add-on" pilot study of CoQ10 in thirteen 5-10-year-old DMD patients on steroids. The primary outcome measure was the total quantitative muscle testing (QMT) score. Twelve of 16 children (mean age 8.03 ± 1.64 years) completed the trial. Target serum levels of CoQ10 (≥2.5 μg/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in an 8.5% increase in muscle strength (P = 0.03). Addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD. Copyright © 2011 Wiley Periodicals, Inc.

Knockdown of the coenzyme Q synthesis gene Smed-dlp1 affects planarian regeneration and tissue homeostasis

PubMed Central

Shiobara, Yumiko; Harada, Chiaki; Shiota, Takeshi; Sakamoto, Kimitoshi; Kita, Kiyoshi; Tanaka, Saeko; Tabata, Kenta; Sekie, Kiyoteru; Yamamoto, Yorihiro; Sugiyama, Tomoyasu

2015-01-01

The freshwater planarian is a model organism used to study tissue regeneration that occupies an important position among multicellular organisms. Planarian genomic databases have led to the identification of genes that are required for regeneration, with implications for their roles in its underlying mechanism. Coenzyme Q (CoQ) is a fundamental lipophilic molecule that is synthesized and expressed in every cell of every organism. Furthermore, CoQ levels affect development, life span, disease and aging in nematodes and mice. Because CoQ can be ingested in food, it has been used in preventive nutrition. In this study, we investigated the role of CoQ in planarian regeneration. Planarians synthesize both CoQ9 and rhodoquinone 9 (RQ9). Knockdown of Smed-dlp1, a trans-prenyltransferase gene that encodes an enzyme that synthesizes the CoQ side chain, led to a decrease in CoQ9 and RQ9 levels. However, ATP levels did not consistently decrease in these animals. Knockdown animals exhibited tissue regression and curling. The number of mitotic cells decreased in Smed-dlp1 (RNAi) animals. These results suggested a failure in physiological cell turnover and stem cell function. Accordingly, regenerating planarians died from lysis or exhibited delayed regeneration. Interestingly, the observed phenotypes were partially rescued by ingesting food supplemented with α-tocopherol. Taken together, our results suggest that oxidative stress induced by reduced CoQ9 levels affects planarian regeneration and tissue homeostasis. PMID:26516985

Nutritional programming of coenzyme Q: potential for prevention and intervention?

PubMed

Tarry-Adkins, Jane L; Fernandez-Twinn, Denise S; Chen, Jian-Hua; Hargreaves, Iain P; Martin-Gronert, Malgorzata S; McConnell, Josie M; Ozanne, Susan E

2014-12-01

Low birth weight and rapid postnatal growth increases risk of cardiovascular-disease (CVD); however, underlying mechanisms are poorly understood. Previously, we demonstrated that rats exposed to a low-protein diet in utero that underwent postnatal catch-up growth (recuperated) have a programmed deficit in cardiac coenzyme Q (CoQ) that was associated with accelerated cardiac aging. It is unknown whether this deficit occurs in all tissues, including those that are clinically accessible. We investigated whether aortic and white blood cell (WBC) CoQ is programmed by suboptimal early nutrition and whether postweaning dietary supplementation with CoQ could prevent programmed accelerated aging. Recuperated male rats had reduced aortic CoQ [22 d (35±8.4%; P<0.05); 12 m (53±8.8%; P<0.05)], accelerated aortic telomere shortening (P<0.01), increased DNA damage (79±13% increase in nei-endonucleaseVIII-like-1), increased oxidative stress (458±67% increase in NAPDH-oxidase-4; P<0.001), and decreased mitochondrial complex II-III activity (P<0.05). Postweaning dietary supplementation with CoQ prevented these detrimental programming effects. Recuperated WBCs also had reduced CoQ (74±5.8%; P<0.05). Notably, WBC CoQ levels correlated with aortic telomere-length (P<0.0001) suggesting its potential as a diagnostic marker of vascular aging. We conclude that early intervention with CoQ in at-risk individuals may be a cost-effective and safe way of reducing the global burden of CVDs. © FASEB.

Coenzyme Q10-Loaded Fish Oil-Based Bigel System: Probing the Delivery Across Porcine Skin and Possible Interaction with Fish Oil Fatty Acids.

PubMed

Zulfakar, Mohd Hanif; Chan, Lee Mei; Rehman, Khurram; Wai, Lam Kok; Heard, Charles M

2018-04-01

Coenzyme Q10 (CoQ10) is a vitamin-like oil-soluble molecule that has anti-oxidant and anti-ageing effects. To determine the most optimal CoQ10 delivery vehicle, CoQ10 was solubilised in both water and fish oil, and formulated into hydrogel, oleogel and bigel. Permeability of CoQ10 from each formulation across porcine ear skin was then evaluated. Furthermore, the effects of the omega-3 fatty eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids from fish oil on skin permeation were investigated by means of nuclear magnetic resonance (NMR) and computerised molecular modelling docking experiments. The highest drug permeation was achieved with the bigel formulation that proved to be the most effective vehicle in delivering CoQ10 across the skin membrane due to a combination of its adhesive, viscous and lipophilic properties. Furthermore, the interactions between CoQ10 and fatty acids revealed by NMR and molecular modelling experiments likely accounted for skin permeability of CoQ10. NMR data showed dose-dependent changes in proton chemical shifts in EPA and DHA. Molecular modelling revealed complex formation and large binding energies between fatty acids and CoQ10. This study advances the knowledge about bigels as drug delivery vehicles and highlights the use of NMR and molecular docking studies for the prediction of the influence of drug-excipient relationships at the molecular level.

The effect of coenzyme Q10 included by γ-cyclodextrin on the growth of fission yeast studied by microscope Raman spectroscopy

NASA Astrophysics Data System (ADS)

Nishida, Tatsuro; Kaino, Tomohiro; Ikarashi, Ryo; Nakata, Daisuke; Terao, Keiji; Ando, Masahiro; Hamaguchi, Hiro-o.; Kawamukai, Makoto; Yamamoto, Tatsuyuki

2013-09-01

The inclusion complex of coenzyme Q10 (CoQ10) by γ-cyclodextrin (γ-CD), CoQ10-CD complex, was recently developed. The addition of the CoQ10-CD complex recovered the growth of a fission yeast mutant strain, Δdps1, which otherwise cannot grow well due to the lack of coenzyme Q producing ability. However, the oxygen consumption rate of this strain was not restored by the addition of the CoQ10-CD complex. The addition of two other anti-oxidative reagents, glutathione and ascorbic acid, also recovered the growth of the Δdps1 strain as well. These results indicated that the recovery of the growth of Δdps1 was brought about by the anti-oxidative property of CoQ10. The intensity of Raman spectra of Δdps1 at 1602 cm-1, which is prominently observed for the wild type of the fission yeast, was compared between before and after addition of the CoQ10-CD complex. The signal was very weakly observed for Δdps1 and did not increase in intensity by the addition of the CoQ10-CD complex. These results suggested the recovery of the growth of Δdps1 was brought about not by the restoration of respiration function of Δdps1 but by the anti-oxidative property of CoQ10 to result in the decrease in the oxidative stress.

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis.

PubMed

Stefely, Jonathan A; Pagliarini, David J

2017-10-01

Coenzyme Q (CoQ, ubiquinone) is a redox-active lipid produced across all domains of life that functions in electron transport and oxidative phosphorylation and whose deficiency causes human diseases. Yet, CoQ biosynthesis has not been fully defined in any organism. Several proteins with unclear molecular functions facilitate CoQ biosynthesis through unknown means, and multiple steps in the pathway are catalyzed by currently unidentified enzymes. Here we highlight recent progress toward filling these knowledge gaps through both traditional biochemistry and cutting-edge 'omics' approaches. To help fill the remaining gaps, we present questions framed by the recently discovered CoQ biosynthetic complex and by putative biophysical barriers. Mapping CoQ biosynthesis, metabolism, and transport pathways has great potential to enhance treatment of numerous human diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Coq6 Is Responsible for the C4-deamination Reaction in Coenzyme Q Biosynthesis in Saccharomyces cerevisiae*

PubMed Central

Ozeir, Mohammad; Pelosi, Ludovic; Ismail, Alexandre; Mellot-Draznieks, Caroline; Fontecave, Marc; Pierrel, Fabien

2015-01-01

The yeast Saccharomyces cerevisiae is able to use para-aminobenzoic acid (pABA) in addition to 4-hydroxybenzoic acid as a precursor of coenzyme Q, a redox lipid essential to the function of the mitochondrial respiratory chain. The biosynthesis of coenzyme Q from pABA requires a deamination reaction at position C4 of the benzene ring to substitute the amino group with an hydroxyl group. We show here that the FAD-dependent monooxygenase Coq6, which is known to hydroxylate position C5, also deaminates position C4 in a reaction implicating molecular oxygen, as demonstrated with labeling experiments. We identify mutations in Coq6 that abrogate the C4-deamination activity, whereas preserving the C5-hydroxylation activity. Several results support that the deletion of Coq9 impacts Coq6, thus explaining the C4-deamination defect observed in Δcoq9 cells. The vast majority of flavin monooxygenases catalyze hydroxylation reactions on a single position of their substrate. Coq6 is thus a rare example of a flavin monooxygenase that is able to act on two different carbon atoms of its C4-aminated substrate, allowing its deamination and ultimately its conversion into coenzyme Q by the other proteins constituting the coenzyme Q biosynthetic pathway. PMID:26260787

Coenzyme Q10 inhibits the release of glutamate in rat cerebrocortical nerve terminals by suppression of voltage-dependent calcium influx and mitogen-activated protein kinase signaling pathway.

PubMed

Chang, Yi; Huang, Shu-Kuei; Wang, Su-Jane

2012-12-05

This study investigates the effects and possible mechanism of coenzyme Q10 (CoQ10) on endogenous glutamate release in the cerebral cortex nerve terminals of rats. CoQ10 inhibited the release of glutamate evoked by the K+ channel blocker 4-aminopyridine (4-AP). CoQ10 reduced the depolarization-induced increase in cytosolic [Ca2+]c but did not alter the 4-AP-mediated depolarization. The effect of CoQ10 on evoked glutamate release was abolished by blocking the Cav2.2 (N-type) and Cav2.1 (P/Q-type) Ca2+ channels and mitogen-activated protein kinase kinase (MEK). In addition, CoQ10 decreased the 4-AP-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and synaptic vesicle-associated protein synapsin I, a major presynaptic substrate for ERK. Moreover, the inhibition of glutamate release by CoQ10 was strongly attenuated in mice without synapsin I. These results suggest that CoQ10 inhibits glutamate release from cortical synaptosomes in rats through the suppression of the presynaptic voltage-dependent Ca2+ entry and ERK/synapsin I signaling pathway.

Highly sensitive and selective determination of redox states of coenzymes Q9 and Q10 in mice tissues: Application of orbitrap mass spectrometry.

PubMed

Pandey, Renu; Riley, Christopher L; Mills, Edward M; Tiziani, Stefano

2018-06-29

Coenzyme Q (CoQ) is a redox active molecule that plays a fundamental role in mitochondrial energy generation and functions as a potent endogenous antioxidant. Redox ratio of CoQ has been suggested as a good marker of mitochondrial dysfunction and oxidative stress. Nevertheless, simultaneous measurement of redox states of CoQ is challenging owing to its hydrophobicity and instability of the reduced form. In order to improve the analytical methodology, paying special attention to this instability, we developed a highly sensitive and selective high-resolution/accurate-mass (HR/AM) UHPLC-MS/MS method for the rapid determination of redox states of CoQ 9 and CoQ 10 by ultra-performance liquid chromatography-hybrid quadrupole-Orbitrap mass spectrometry. CoQs were extracted using hexane with the addition of butylated hydroxytoluene to limit oxidation during sample preparation. Chromatographic separation of the analytes was achieved on a Kinetex C 18 column with the isocratic elution of 5 mM ammonium formate in 2-propanol/methanol (60:40) within 4 min. A full MS/all ion fragmentation (AIF) acquisition mode with mass accuracy < 5 ppm was used for detection and determination of redox states of CoQ 9 and CoQ 10 in healthy mice tissues using reduced and oxidized CoQ 4 as internal standards. The validated method showed good linearity (r 2  ≥ 0.9991), intraday, inter-day precision (CVs ≤ 11.9%) and accuracy (RE ≤±15.2%). In contrast to existing methods, the current method offers enhanced sensitivity (up to 52 fold) with LOD and LOQ ranged from 0.01 to 0.49 ng mL -1 and 0.04-1.48 ng mL -1 , respectively. Moreover, we evaluated various diluents to investigate bench top stability (at 4 °C) of targeted analytes in tissue samples during LC-MS assay up to 24 h. Ethanol was determined to be an optimum diluent without any significant oxidation of reduced CoQ up to 24 h. The developed method offers a rapid, highly sensitive and selective strategy for the measurement of redox states of CoQs in clinical studies. Copyright © 2018 Elsevier B.V. All rights reserved.

Effects of dietary L-carnitine and coenzyme Q10 at different supplemental ages on growth performance and some immune response in ascites-susceptible broilers.

PubMed

Geng, Ailian; Li, Baoming; Guo, Yuming

2007-02-01

Effects of dietary L-carnitine and coenzyme Q10 (CoQ10) at different supplemental ages on performance and some immune response were investigated in ascites-susceptible broilers. A 3 x 2 x 2 factorial design was used consisting of L-carnitine supplementation (0, 75, and 100 mg/kg), CoQ10 supplementation (0 and 40 mg/kg) and different supplemental ages (from day 1 on and from day 10 on). A total of 480 one-day-old Arbor Acre male broiler chicks were randomly allocated to 12 groups, every group had five replicates, each with eight birds. The birds were fed a corn-soybean based diet for six weeks. From day 10-21, all the birds were exposed to a low ambient temperature (12-15 degrees C) to increase the susceptibility to ascites. No significant effects were observed on growth performance by L-carnitine, CoQ10 supplementation, and different supplemental ages. Packed cell volume was significantly decreased by L-carnitine supplementation alone, and ascites heart index and ascites mortality were decreased by L-carnitine, CoQ10 supplementation alone, and L-carnitine + CoQ10 supplementation together (p < 0.05). Heart index of broilers was significantly improved by L-carnitine, CoQ10 supplementation alone during 0-3 week. Serum IgG content was improved by L-carnitine supplementation alone (p < 0.05), but lysozyme activity was increased by L-carnitine + CoQ10 supplementation together (p < 0.05). A significant L-carnitine by supplemental age interaction was observed in lysozyme activity. L-carnitine supplementation alone had no effects on the peripheral blood lymphocyte (PBL) proliferation in response to concanavalin A (ConA) and lipopolysaccharide, but supplemental CoQ10 alone and L-carnitine+ CoQ10 together decreased the PBL proliferation in response to ConA (p < 0.05). The present study suggested that L-carnitine + CoQ10 supplementation together had positive effects on some immune response of ascites-susceptible broilers, which might benefit for the reduction of broilers' susceptibility to ascites.

Invertebrate Models for Coenzyme Q10 Deficiency

PubMed Central

Fernández-Ayala, Daniel J.M.; Jiménez-Gancedo, Sandra; Guerra, Ignacio; Navas, Plácido

2014-01-01

The human syndrome of coenzyme Q (CoQ) deficiency is a heterogeneous mitochondrial disease characterized by a diminution of CoQ content in cells and tissues that affects all the electron transport processes CoQ is responsible for, like the electron transference in mitochondria for respiration and ATP production and the antioxidant capacity that it exerts in membranes and lipoproteins. Supplementation with external CoQ is the main attempt to address these pathologies, but quite variable results have been obtained ranging from little response to a dramatic recovery. Here, we present the importance of modeling human CoQ deficiencies in animal models to understand the genetics and the pathology of this disease, although the election of an organism is crucial and can sometimes be controversial. Bacteria and yeast harboring mutations that lead to CoQ deficiency are unable to grow if they have to respire but develop without any problems on media with fermentable carbon sources. The complete lack of CoQ in mammals causes embryonic lethality, whereas other mutations produce tissue-specific diseases as in humans. However, working with transgenic mammals is time and cost intensive, with no assurance of obtaining results. Caenorhabditis elegans and Drosophila melanogaster have been used for years as organisms to study embryonic development, biogenesis, degenerative pathologies, and aging because of the genetic facilities and the speed of working with these animal models. In this review, we summarize several attempts to model reliable human CoQ deficiencies in invertebrates, focusing on mutant phenotypes pretty similar to those observed in human patients. PMID:25126050

Knockdown of the coenzyme Q synthesis gene Smed-dlp1 affects planarian regeneration and tissue homeostasis.

PubMed

Shiobara, Yumiko; Harada, Chiaki; Shiota, Takeshi; Sakamoto, Kimitoshi; Kita, Kiyoshi; Tanaka, Saeko; Tabata, Kenta; Sekie, Kiyoteru; Yamamoto, Yorihiro; Sugiyama, Tomoyasu

2015-12-01

The freshwater planarian is a model organism used to study tissue regeneration that occupies an important position among multicellular organisms. Planarian genomic databases have led to the identification of genes that are required for regeneration, with implications for their roles in its underlying mechanism. Coenzyme Q (CoQ) is a fundamental lipophilic molecule that is synthesized and expressed in every cell of every organism. Furthermore, CoQ levels affect development, life span, disease and aging in nematodes and mice. Because CoQ can be ingested in food, it has been used in preventive nutrition. In this study, we investigated the role of CoQ in planarian regeneration. Planarians synthesize both CoQ9 and rhodoquinone 9 (RQ9). Knockdown of Smed-dlp1, a trans-prenyltransferase gene that encodes an enzyme that synthesizes the CoQ side chain, led to a decrease in CoQ9 and RQ9 levels. However, ATP levels did not consistently decrease in these animals. Knockdown animals exhibited tissue regression and curling. The number of mitotic cells decreased in Smed-dlp1 (RNAi) animals. These results suggested a failure in physiological cell turnover and stem cell function. Accordingly, regenerating planarians died from lysis or exhibited delayed regeneration. Interestingly, the observed phenotypes were partially rescued by ingesting food supplemented with α-tocopherol. Taken together, our results suggest that oxidative stress induced by reduced CoQ9 levels affects planarian regeneration and tissue homeostasis. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Reduction of ascites mortality in broilers by coenzyme Q10.

PubMed

Geng, A L; Guo, Y M; Yang, Y

2004-09-01

Effects of coenzyme Q10 (CoQ10) supplementation on growth performance and ascites were studied in broilers. One hundred eighty 1-d-old Arbor Acre male broiler chicks were randomly allocated into 3 groups with 6 replicates each. From d 8, the diets were supplemented with CoQ10 at levels of 0, 20, and 40 mg/kg, respectively. From d 15 to 21, all the chicks were exposed to low ambient temperature (15 to 18 degrees C) to induce ascites. Average feed intake, BW gain, and feed conversion ratio of the broilers during 0 to 3 wk, 3 to 6 wk, and 0 to 6 wk were measured. The results showed that there were no influences observed on broilers' growth performance, but the mortality due to ascites was reduced by CoQ10 supplementation (P < or = 0.05). Erythrocyte osmotic fragility (EOF) was significantly decreased by 40 mg/kg CoQ10 compared with the control, but no significant changes were observed on blood packed cell volume (PCV) among the treatments. Pulmonary arterial diastolic pressure was significantly decreased on d 36, but no significant changes were observed on right ventricular pressure (RVP), pulmonary arterial systolic pressure, and the maximum change ratio of right intraventricular pressure (+/- dp/ dtmax). Ascites heart index (AHI) was significantly decreased by 40 mg/kg CoQ10 supplementation (P < or = 0.05). The results of this study suggested that CoQ10 has a beneficial effect in reducing ascites mortality in broilers, and 40 mg/kg CoQ10 seems to be more effective than 20 mg/ kg CoQ10.

Effect of cooking and in vitro digestion on the stability of co-enzyme Q10 in processed meat products.

PubMed

Tobin, Brian D; O'Sullivan, Maurice G; Hamill, Ruth; Kerry, Joseph P

2014-05-01

The use of CoQ10 fortification in the production of a functional food has been demonstrated in the past but primarily for dairy products. This study aimed to determine the bio-accessibility of CoQ10 in processed meat products, beef patties and pork breakfast sausages, fortified with CoQ10. Both the patties and sausages were fortified with a micellarized form of CoQ10 to enhance solubility to a concentration of 1mg/g of sample (NovaSolQ®). An assay was developed combining in vitro digestion and HPLC analysis to quantify the CoQ10 present in fortified products (100mg/g). The cooking retention level of CoQ10 in the products was found to be 74±1.42% for patties and 79.69±0.75% for sausages. The digestibility for both products ranged between 93% and 95%, sausages did have a higher digestibility level than patties but this was not found to be significant (P<0.01). Copyright © 2013 Elsevier Ltd. All rights reserved.

Improved brain and muscle mitochondrial respiration with CoQ. An in vivo study by 31P-MR spectroscopy in patients with mitochondrial cytopathies.

PubMed

Barbiroli, B; Iotti, S; Lodi, R

1999-01-01

We used in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) to study the effect of CoQ10 on the efficiency of brain and skeletal muscle mitochondrial respiration in ten patients with mitochondrial cytopathies. Before CoQ, brain [PCr] was remarkably lower in patients than in controls, while [Pi] and [ADP] were higher. Brain cytosolic free [Mg2+] and delta G of ATP hydrolysis were also abnormal in all patients. MRS also revealed abnormal mitochondrial function in the skeletal muscles of all patients, as shown by a decreased rate of PCr recovery from exercise. After six-months of treatment with CoQ (150 mg/day), all brain MRS-measurable variables as well as the rate of muscle mitochondrial respiration were remarkably improved in all patients. These in vivo findings show that treatment with CoQ in patients with mitochondrial cytopathies improves mitochondrial respiration in both brain and skeletal muscles, and are consistent with Lenaz's view that increased CoQ concentration in the mitochondrial membrane increases the efficiency of oxidative phosphorylation independently of enzyme deficit.

The CoQH2/CoQ Ratio Serves as a Sensor of Respiratory Chain Efficiency.

PubMed

Guarás, Adela; Perales-Clemente, Ester; Calvo, Enrique; Acín-Pérez, Rebeca; Loureiro-Lopez, Marta; Pujol, Claire; Martínez-Carrascoso, Isabel; Nuñez, Estefanía; García-Marqués, Fernando; Rodríguez-Hernández, María Angeles; Cortés, Ana; Diaz, Francisca; Pérez-Martos, Acisclo; Moraes, Carlos T; Fernández-Silva, Patricio; Trifunovic, Aleksandra; Navas, Plácido; Vazquez, Jesús; Enríquez, Jose A

2016-04-05

Electrons feed into the mitochondrial electron transport chain (mETC) from NAD- or FAD-dependent enzymes. A shift from glucose to fatty acids increases electron flux through FAD, which can saturate the oxidation capacity of the dedicated coenzyme Q (CoQ) pool and result in the generation of reactive oxygen species. To prevent this, the mETC superstructure can be reconfigured through the degradation of respiratory complex I, liberating associated complex III to increase electron flux via FAD at the expense of NAD. Here, we demonstrate that this adaptation is driven by the ratio of reduced to oxidized CoQ. Saturation of CoQ oxidation capacity induces reverse electron transport from reduced CoQ to complex I, and the resulting local generation of superoxide oxidizes specific complex I proteins, triggering their degradation and the disintegration of the complex. Thus, CoQ redox status acts as a metabolic sensor that fine-tunes mETC configuration in order to match the prevailing substrate profile. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Multi-omic Mitoprotease Profiling Defines a Role for Oct1p in Coenzyme Q Production.

PubMed

Veling, Mike T; Reidenbach, Andrew G; Freiberger, Elyse C; Kwiecien, Nicholas W; Hutchins, Paul D; Drahnak, Michael J; Jochem, Adam; Ulbrich, Arne; Rush, Matthew J P; Russell, Jason D; Coon, Joshua J; Pagliarini, David J

2017-12-07

Mitoproteases are becoming recognized as key regulators of diverse mitochondrial functions, although their direct substrates are often difficult to discern. Through multi-omic profiling of diverse Saccharomyces cerevisiae mitoprotease deletion strains, we predicted numerous associations between mitoproteases and distinct mitochondrial processes. These include a strong association between the mitochondrial matrix octapeptidase Oct1p and coenzyme Q (CoQ) biosynthesis-a pathway essential for mitochondrial respiration. Through Edman sequencing and in vitro and in vivo biochemistry, we demonstrated that Oct1p directly processes the N terminus of the CoQ-related methyltransferase, Coq5p, which markedly improves its stability. A single mutation to the Oct1p recognition motif in Coq5p disrupted its processing in vivo, leading to CoQ deficiency and respiratory incompetence. This work defines the Oct1p processing of Coq5p as an essential post-translational event for proper CoQ production. Additionally, our data visualization tool enables efficient exploration of mitoprotease profiles that can serve as the basis for future mechanistic investigations. Copyright © 2017 Elsevier Inc. All rights reserved.

Micropygomyia (Coquillettimyia) nahua sp. nov., a new Phlebotominae sand fly from Mexico (Diptera, Psychodidae).

PubMed

Ibáñez-Bernal, Sergio; García-Torres, Carlos Roberto; Vásquez-Márquez, Mario

2017-11-10

Micropygomyia (Coquillettimyia) nahua sp. nov., is described and illustrated based on male and female characteristics. Specimens were collected in the Municipality of Naolinco, state of Veracruz, Mexico. This new species of phlebotomine sand fly has characteristics corresponding to the series vexator Fairchild of Galati, with male similar to Micropygomyia (Coquillettimyia) apache (Young & Perkins), Mi. (Coq.) oppidana (Dampf) and Mi. (Coq.) vexator (Coquillett), but recognized by the male paramere structure and simple apex of aedeagal ducts in the male, the later exception for this species series. Female can be confused with Mi. (Coq.) vexator, Mi. (Coq.) oppidana and Mi. (Coq.) apache, but is distinguishable by the cibarial armature combined with the long and very slender individual spermathecal ducts. Keys for male and female species of Micropygomyia (Coquillettimyia) are provided.

Coenzyme Q10 and oxidative stress, the association with peripheral sensory neuropathy and cardiovascular disease in type 2 diabetes mellitus.

PubMed

Forsberg, Elisabete; Xu, Cheng; Grünler, Jacob; Frostegård, Johan; Tekle, Michael; Brismar, Kerstin; Kärvestedt, Lars

2015-01-01

Our study aimed to explore associations between metabolic control, oxidative stress and coenzyme Q10 (CoQ10) in relation to diabetes complications in a representative population of type 2 diabetes. A geographic cohort of 156 subjects was recruited. Serum concentrations of CoQ10 and vitamin E were measured by HPLC. ROS was determined by free oxygen radicals testing (FORT). Glutaredoxin (Grx) activity, oxidized LDL cholesterol (oxLDLc), high sensitive CRP (hsCRP), HbA1c, urine albumin, serum creatinine, serum cystatin C, and plasma lipids were assayed with routine laboratory protocols. Serum CoQ10 was higher than in nondiabetics. HbA1c, fP-glucose, hyperlipidemia, inflammation (hsCRP), and increased BMI were associated with signs of oxidative stress as increased levels of FORT, Grx activity and/or increased levels of oxLDLc Oxidative stress was found to be strongly correlated with prevalence of cardiovascular disease (CVD) and peripheral sensory neuropathy (PSN). In both gender groups there were positive correlations between CoQ10 and oxLDLc, and between BMI and the ratio CoQ10/chol. Grx activity was inversely correlated to oxLDLc and CoQ10. Women with CVD and PSN had higher waist index, oxLDLc, and FORT levels compared to men but lower CoQ10 levels. Men had worse kidney function and lower vitamin E. Multiple regression analysis showed increased levels of CoQ10 to be significantly correlated with increased levels of cholesterol, triglycerides, vitamin E, fB-glucose and BMI. Hyperlipidemia, hyperglycemia and inflammation were associated with oxidative stress, which was correlated to the prevalence of diabetes complications. CoQ10 was increased in response to oxidative stress. There were gender differences in the risk factors associated with diabetes complications. Copyright © 2015 Elsevier Inc. All rights reserved.

Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110α) signaling.

PubMed

De Blasio, Miles J; Huynh, Karina; Qin, Chengxue; Rosli, Sarah; Kiriazis, Helen; Ayer, Anita; Cemerlang, Nelly; Stocker, Roland; Du, Xiao-Jun; McMullen, Julie R; Ritchie, Rebecca H

2015-10-01

Diabetes-induced cardiac complications include left ventricular (LV) dysfunction and heart failure. We previously demonstrated that LV phosphoinositide 3-kinase p110α (PI3K) protects the heart against diabetic cardiomyopathy, associated with reduced NADPH oxidase expression and activity. Conversely, in dominant negative PI3K(p110α) transgenic mice (dnPI3K), reduced cardiac PI3K signaling exaggerated diabetes-induced cardiomyopathy, associated with upregulated NADPH oxidase. The goal was to examine whether chronic supplementation with the antioxidant coenzyme Q(10) (CoQ(10)) could attenuate LV superoxide and diabetic cardiomyopathy in a setting of impaired PI3K signaling. Diabetes was induced in 6-week-old nontransgenic and dnPI3K male mice via streptozotocin. After 4 weeks of diabetes, CoQ(10) supplementation commenced (10 mg/kg ip, 3 times/week, 8 weeks). At study end (12 weeks of diabetes), markers of LV function, cardiomyocyte hypertrophy, collagen deposition, NADPH oxidase, oxidative stress (3-nitrotyrosine), and concentrations of CoQ(9) and CoQ(10) were determined. LV NADPH oxidase (Nox2 gene expression and activity, and lucigenin-enhanced chemiluminescence), as well as oxidative stress, were increased by diabetes, exaggerated in diabetic dnPI3K mice, and attenuated by CoQ(10). Diabetes-induced LV diastolic dysfunction (prolonged deceleration time, elevated end-diastolic pressure, impaired E/A ratio), cardiomyocyte hypertrophy and fibrosis, expression of atrial natriuretic peptide, connective tissue growth factor, and β-myosin heavy chain were all attenuated by CoQ(10). Chronic CoQ(10) supplementation attenuates aspects of diabetic cardiomyopathy, even in a setting of reduced cardiac PI3K protective signaling. Given that CoQ(10) supplementation has been suggested to have positive outcomes in heart failure patients, chronic CoQ(10) supplementation may be an attractive adjunct therapy for diabetic heart failure. Copyright © 2015 Elsevier Inc. All rights reserved.

Coenzyme Q10 as a potent compound that inhibits Cdt1-geminin interaction.

PubMed

Mizushina, Yoshiyuki; Takeuchi, Toshifumi; Takakusagi, Yoichi; Yonezawa, Yuko; Mizuno, Takeshi; Yanagi, Ken-Ichiro; Imamoto, Naoko; Sugawara, Fumio; Sakaguchi, Kengo; Yoshida, Hiromi; Fujita, Masatoshi

2008-02-01

A human replication initiation protein Cdt1 is a very central player in the cell cycle regulation of DNA replication, and geminin down-regulates Cdt1 function by directly binding to it. It has been demonstrated that Cdt1 hyperfunction resulting from Cdt1-geminin imbalance, for example by geminin silencing with siRNA, induces DNA re-replication and eventual cell death in some cancer-derived cell lines. In the present study, we first established a high throughput screening system based on modified ELISA (enzyme linked immunosorbent assay) to identify compounds that interfere with human Cdt1-geminin binding. Using this system, we found that coenzyme Q(10) (CoQ(10)) can inhibit Cdt1-geminin interaction in vitro. CoQ compound is an isoprenoid quinine that functions as an electron carrier in the mitochondrial respiratory chain in eukaryotes. CoQ(10), having a longer isoprenoid chain, was the strongest inhibitor of Cdt1-geminin binding in the tested CoQs, with 50% inhibition observed at concentrations of 16.2 muM. Surface plasmon resonance analysis demonstrated that CoQ(10) bound selectively to Cdt1, but did not interact with geminin. Moreover, CoQ(10) had no influence on the interaction between Cdt1 and mini-chromosome maintenance (MCM)4/6/7 complexes. These results suggested that CoQ(10) inhibits Cdt1-geminin complex formation by binding to Cdt1 and thereby could liberate Cdt1 from inhibition by geminin. Using three-dimensional computer modeling analysis, CoQ(10) was considered to interact with the geminin interaction interface on Cdt1, and was assumed to make hydrogen bonds with the residue of Arg243 of Cdt1. CoQ(10) could prevent the growth of human cancer cells, although only at high concentrations, and it remains unclear whether such an inhibitory effect is associated with the interference with Cdt1-geminin binding. The application of inhibitors for the formation of Cdt1-geminin complex is discussed.

Additive enhancement of wound healing in diabetic mice by low level light and topical CoQ10.

PubMed

Mao, Zhigang; Wu, Jeffrey H; Dong, Tingting; Wu, Mei X

2016-02-02

Diabetes, a highly prevalent disease that affects 9.3% of Americans, often leads to severe complications and slow wound healing. Preclinical studies have suggested that low level light therapy (LLLT) can accelerate wound healing in diabetic subjects, but significant improvements must be made to overcome the absence of persuasive evidence for its clinical use. We demonstrate here that LLLT can be combined with topical Coenzyme Q10 (CoQ10) to heal wounds in diabetic mice significantly faster than LLLT alone, CoQ10 alone, or controls. LLLT followed by topical CoQ10 enhanced wound healing by 68~103% in diabetic mice in the first week and more than 24% in the second week compared with untreated controls. All wounds were fully healed in two weeks following the dual treatment, in contrast to only 50% wounds or a fewer being fully healed for single or sham treatment. The accelerated healing was corroborated by at least 50% higher hydroxyproline levels, and tripling cell proliferation rates in LLLT and CoQ10 treated wounds over controls. The beneficial effects on wound healing were probably attributed to additive enhancement of ATP production by LLLT and CoQ10 treatment. The combination of LLLT and topical CoQ10 is safe and convenient, and merits further clinical study.

Additive enhancement of wound healing in diabetic mice by low level light and topical CoQ10

NASA Astrophysics Data System (ADS)

Mao, Zhigang; Wu, Jeffrey H.; Dong, Tingting; Wu, Mei X.

2016-02-01

Diabetes, a highly prevalent disease that affects 9.3% of Americans, often leads to severe complications and slow wound healing. Preclinical studies have suggested that low level light therapy (LLLT) can accelerate wound healing in diabetic subjects, but significant improvements must be made to overcome the absence of persuasive evidence for its clinical use. We demonstrate here that LLLT can be combined with topical Coenzyme Q10 (CoQ10) to heal wounds in diabetic mice significantly faster than LLLT alone, CoQ10 alone, or controls. LLLT followed by topical CoQ10 enhanced wound healing by 68~103% in diabetic mice in the first week and more than 24% in the second week compared with untreated controls. All wounds were fully healed in two weeks following the dual treatment, in contrast to only 50% wounds or a fewer being fully healed for single or sham treatment. The accelerated healing was corroborated by at least 50% higher hydroxyproline levels, and tripling cell proliferation rates in LLLT and CoQ10 treated wounds over controls. The beneficial effects on wound healing were probably attributed to additive enhancement of ATP production by LLLT and CoQ10 treatment. The combination of LLLT and topical CoQ10 is safe and convenient, and merits further clinical study.

Additive enhancement of wound healing in diabetic mice by low level light and topical CoQ10

PubMed Central

Mao, Zhigang; Wu, Jeffrey H.; Dong, Tingting; Wu, Mei X.

2016-01-01

Diabetes, a highly prevalent disease that affects 9.3% of Americans, often leads to severe complications and slow wound healing. Preclinical studies have suggested that low level light therapy (LLLT) can accelerate wound healing in diabetic subjects, but significant improvements must be made to overcome the absence of persuasive evidence for its clinical use. We demonstrate here that LLLT can be combined with topical Coenzyme Q10 (CoQ10) to heal wounds in diabetic mice significantly faster than LLLT alone, CoQ10 alone, or controls. LLLT followed by topical CoQ10 enhanced wound healing by 68~103% in diabetic mice in the first week and more than 24% in the second week compared with untreated controls. All wounds were fully healed in two weeks following the dual treatment, in contrast to only 50% wounds or a fewer being fully healed for single or sham treatment. The accelerated healing was corroborated by at least 50% higher hydroxyproline levels, and tripling cell proliferation rates in LLLT and CoQ10 treated wounds over controls. The beneficial effects on wound healing were probably attributed to additive enhancement of ATP production by LLLT and CoQ10 treatment. The combination of LLLT and topical CoQ10 is safe and convenient, and merits further clinical study. PMID:26830658

A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy.

PubMed

Taylor, Beth A; Lorson, Lindsay; White, C Michael; Thompson, Paul D

2015-02-01

Coenzyme Q10 (CoQ10) supplementation is the most popular therapy for statin myalgia among both physicians and patients despite limited and conflicting evidence of its efficacy. This study examined the effect of coenzyme Q10 (CoQ10) supplementation on simvastatin-associated muscle pain, muscle strength and aerobic performance in patients with confirmed statin myalgia. Statin myalgia was confirmed in 120 patients with prior symptoms of statin myalgia using an 8-week randomized, double-blind crossover trial of simvastatin 20 mg/d and placebo. Forty-one subjects developed muscle pain with simvastatin but not with placebo and were randomized to simvastatin 20 mg/d combined with CoQ10 (600 mg/d ubiquinol) or placebo for 8 weeks. Muscle pain (Brief Pain Inventory [BPI]), time to pain onset, arm and leg muscle strength, and maximal oxygen uptake (VO2max) were measured before and after each treatment. Serum CoQ10 increased from 1.3 ± 0.4 to 5.2 ± 2.3 mcg/mL with simvastatin and CoQ10, but did not increase with simvastatin and placebo (1.3 ± 0.3 to 0.8 ± 0.2) (p < 0.05). BPI pain severity and interference scores increased with simvastatin therapy (both p < 0.01), irrespective of CoQ10 assignment (p = 0.53 and 0.56). There were no changes in muscle strength or VO2max with simvastatin with or without CoQ10 (all p > 0.10). Marginally more subjects reported pain with CoQ10 (14 of 20 vs 7 of 18; p = 0.05). There was no difference in time to pain onset in the CoQ10 (3.0 ± 2.0 weeks) vs. placebo (2.4 ± 2.1 wks) groups (p = 0.55). A similar lack of CoQ10 effect was observed in 24 subjects who were then crossed over to the alternative treatment. Only 36% of patients complaining of statin myalgia develop symptoms during a randomized, double-blind crossover of statin vs placebo. CoQ10 supplementation does not reduce muscle pain in patients with statin myalgia. Trial RegistrationNCT01140308; www.clinicaltrials.gov. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Coenzyme Q10 instilled as eye drops on the cornea reaches the retina and protects retinal layers from apoptosis in a mouse model of kainate-induced retinal damage.

PubMed

Lulli, Matteo; Witort, Ewa; Papucci, Laura; Torre, Eugenio; Schipani, Christian; Bergamini, Christian; Dal Monte, Massimo; Capaccioli, Sergio

2012-12-17

To evaluate if coenzyme Q10 (CoQ10) can protect retinal ganglion cells (RGCs) from apoptosis and, when instilled as eye drops on the cornea, if it can reach the retina and exert its antiapoptotic activity in this area in a mouse model of kainate (KA)-induced retinal damage. Rat primary or cultured RGCs were subjected to glutamate (50 μM) or chemical hypoxia (Antimycin A, 200 μM) or serum withdrawal (FBS, 0.5%) in the presence or absence of CoQ10 (10 μM). Cell viability was evaluated by light microscopy and fluorescence-activated cell sorting analyses. Apoptosis was evaluated by caspase 3/7 activity and mitochondrion depolarization tetramethylrhodamine ethyl ester analysis. CoQ10 transfer to the retina following its instillation as eye drops on the cornea was quantified by HPLC. Retinal protection by CoQ10 (10 μM) eye drops instilled on the cornea was then evaluated in a mouse model of KA-induced excitotoxic retinal cell apoptosis by cleaved caspase 3 immunohistofluorescence, caspase 3/7 activity assays, and quantification of inhibition of RGC loss. CoQ10 significantly increased viable cells by preventing RGC apoptosis. Furthermore, when topically applied as eye drops to the cornea, it reached the retina, thus substantially increasing local CoQ10 concentration and protecting retinal layers from apoptosis. The ability of CoQ10 eye drops to protect retinal cells from apoptosis in the mouse model of KA-induced retinal damage suggests that topical CoQ10 may be evaluated in designing therapies for treating apoptosis-driven retinopathies.

The effects of coenzyme Q10 treatment on maternally inherited diabetes mellitus and deafness, and mitochondrial DNA 3243 (A to G) mutation.

PubMed

Suzuki, S; Hinokio, Y; Ohtomo, M; Hirai, M; Hirai, A; Chiba, M; Kasuga, S; Satoh, Y; Akai, H; Toyota, T

1998-05-01

The characteristic clinical features of diabetes mellitus with mitochondrial DNA (mtDNA) 3243(A-G) mutation are progressive insulin secretory defect, neurosensory deafness and maternal inheritance, referred to as maternally inherited diabetes mellitus and deafness (MIDD). A treatment for MIDD to improve insulin secretory defects and reduce deafness has not been established. The effects of coenzyme Q10 (CoQ10) treatment on insulin secretory response, hearing capacity and clinical symptoms of MIDD were investigated. 28 MIDD patients (CoQ10-DM), 7 mutant subjects with impaired glucose tolerance (IGT), and 15 mutant subjects with normal glucose tolerance (NGT) were treated daily with oral administration of 150 mg of CoQ10 for 3 years. Insulin secretory response, blood lactate after exercise, hearing capacity and other laboratory examinations were investigated every year. In the same way we evaluated 16 MIDD patients (control-DM), 5 mutant IGT and 5 mutant NGT subjects in yearly examinations. The insulin secretory response assessed by glucagon-induced C-peptide secretion and 24 h urinary C-peptide excretion after 3 years in the CoQ10-DM group was significantly higher than that in the control-DM group. CoQ10 therapy prevented progressive hearing loss and improved blood lactate after exercise in the MIDD patients. CoQ10 treatment did not affect the diabetic complications or other clinical symptoms of MIDD patients. CoQ10 treatment did not affect the insulin secretory capacity of the mutant IGT and NGT subjects. There were no side effects during therapy. This is the first report demonstrating the therapeutic usefulness of CoQ10 on MIDD.

Coenzyme Q10 for the treatment of heart failure: a review of the literature

PubMed Central

DiNicolantonio, James J; Bhutani, Jaikrit; McCarty, Mark F; O'Keefe, James H

2015-01-01

Coenzyme Q10 (CoQ10) is an endogenously synthesised and diet-supplied lipid-soluble cofactor that functions in the mitochondrial inner membrane to transfer electrons from complexes I and II to complex III. In addition, its redox activity enables CoQ10 to act as a membrane antioxidant. In patients with congestive heart failure, myocardial CoQ10 content tends to decline as the degree of heart failure worsens. A number of controlled pilot trials with supplemental CoQ10 in heart failure found improvements in functional parameters such as ejection fraction, stroke volume and cardiac output, without side effects. Subsequent meta-analyses have confirmed these findings, although the magnitude of benefit tends to be less notable in patients with severe heart failure, or within the context of ACE inhibitor therapy. The multicentre randomised placebo-controlled Q-SYMBIO trial has assessed the impact of supplemental CoQ10 on hard endpoints in heart failure. A total of 420 patients received either CoQ10 (100 mg three times daily) or placebo and were followed for 2 years. Although short-term functional endpoints were not statistically different in the two groups, CoQ10 significantly reduced the primary long-term endpoint—a major adverse cardiovascular event—which was observed in 15% of the treated participants compared to 26% of those receiving placebo (HR=0.50, CI 0.32 to 0.80, p=0.003). Particularly in light of the excellent tolerance and affordability of this natural physiological compound, supplemental CoQ10 has emerged as an attractive option in the management of heart failure, and merits evaluation in additional large studies. PMID:26512330

Inhibition of liver fibrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-beta1 expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Hoo-Kyun; Pokharel, Yuba Raj; Lim, Sung Chul

2009-11-01

Coenzyme Q10 (CoQ10), an endogenous antioxidant, is important in oxidative phosphorylation in mitochondria. It has anti-diabetic and anti-cardiovascular disease effects, but its ability to protect against liver fibrosis has not been studied. Here, we assessed the ability of solubilized CoQ10 to improve dimethylnitrosamine (DMN)-induced liver fibrogenesis in mice. DMN treatments for 3 weeks produced a marked liver fibrosis as assessed by histopathological examination and tissue 4-hydroxyproline content. Solubilized CoQ10 (10 and 30 mg/kg) significantly inhibited both the increases in fibrosis score and 4-hydroxyproline content induced by DMN. Reverse transcription-polymerase chain reaction and Western blot analyses revealed that solubilized CoQ10 inhibitedmore » increases in the transforming growth factor-beta1 (TGF-beta1) mRNA and alpha-smooth muscle actin (alpha-SMA) protein by DMN. Interestingly, hepatic glutamate-cysteine ligase (GCL) and glutathione S-transferase A2 (GSTA2) were up-regulated in mice treated with CoQ10. Solubilized CoQ10 also up-regulated antioxidant enzymes such as catalytic subunits of GCL and GSTA2 via activating NF-E2 related factor2 (Nrf2)/antioxidant response element (ARE) in H4IIE hepatoma cells. Moreover, CoQ10's inhibition of alpha-SMA and TGF-beta1 expressions disappeared in Nrf2-null MEF cells. In contrast, Nrf2 overexpression significantly decreased the basal expression levels of alpha-SMA and TGF-beta1 in Nrf2-null MEF cells. These results demonstrated that solubilized CoQ10 inhibited DMN-induced liver fibrosis through suppression of TGF-beta1 expression via Nrf2/ARE activation.« less

Coenzyme Q10 and statins: biochemical and clinical implications.

PubMed

Littarru, Gian Paolo; Langsjoen, Peter

2007-06-01

Statins are drugs of known and undisputed efficacy in the treatment of hypercholesterolemia, usually well tolerated by most patients. In some cases treatment with statins produces skeletal muscle complaints, and/or mild serum CK elevation; the incidence of rhabdomyolysis is very low. As a result of the common biosynthetic pathway Coenzyme Q (ubiquinone) and dolichol levels are also affected, to a certain degree, by the treatment with these HMG-CoA reductase inhibitors. Plasma levels of CoQ10 are lowered in the course of statin treatment. This could be related to the fact that statins lower plasma LDL levels, and CoQ10 is mainly transported by LDL, but a decrease is also found in platelets and in lymphocytes of statin treated patients, therefore it could truly depend on inhibition of CoQ10 synthesis. There are also some indications that statin treatment affects muscle ubiquinone levels, although it is not yet clear to which extent this depends on some effect on mitochondrial biogenesis. Some papers indicate that CoQ10 depletion during statin therapy might be associated with subclinical cardiomyopathy and this situation is reversed upon CoQ10 treatment. We can reasonably hypothesize that in some conditions where other CoQ10 depleting situations exist treatment with statins may seriously impair plasma and possible tissue levels of coenzyme Q10. While waiting for a large scale clinical trial where patients treated with statins are also monitored for their CoQ10 status, with a group also being given CoQ10, physicians should be aware of this drug-nutrient interaction and be vigilant to the possibility that statin drugs may, in some cases, impair skeletal muscle and myocardial bioenergetics.

Design and Evaluation of Multi-functional Nanocarriers for Selective Delivery of Coenzyme Q10 to Mitochondria

PubMed Central

Sharma, Anjali; Soliman, Ghareb M.; Al-Hajaj, Noura; Sharma, Rishi; Maysinger, Dusica; Kakkar, Ashok

2016-01-01

Impairments of mitochondrial functions have been associated with failure of cellular functions in different tissues leading to various pathologies. We report here a mitochondria–targeted nanodelivery system for coenzyme Q10 (CoQ10) which can reach mitochondria, and deliver CoQ10 in adequate quantities. Multifunctional nanocarriers based on ABC miktoarm polymers (A= PEG, B = polycaprolactone (PCL) and C = triphenylphosphonium bromide (TPPBr)) were synthesized using a combination of click chemistry with ring opening polymerization, self-assembled into nano-sized micelles, and were employed for CoQ10-loading. Drug loading capacity (60 weight%), micelle size (25–60 nm) and stability were determined using a variety of techniques. The micelles had a small critical association concentration, and were colloidally stable in solution for more than 3 months. The extraordinarily high CoQ10 loading capacity in the micelles is attributed to good compatibility between CoQ10 and PCL, as indicated by low Flory-Huggins interaction parameter. Confocal microscopy studies of fluorescently labeled polymer analog together with the mitochondria-specific vital dye label, indicated that the carrier did indeed reach mitochondria. The high CoQ10 loading efficiency allowed testing of micelles within a broad concentration range, and provided evidence for CoQ10 effectiveness in two different experimental paradigms: oxidative stress and inflammation. Combined results from chemical, analytical and biological experiments suggest that the new miktoarm-based carrier provides a suitable means of CoQ10 delivery to mitochondria without loss of drug effectiveness. The versatility of the click chemistry used to prepare this new mitochondria-targeting nanocarrier offers a widely applicable, simple and easily reproducible procedure to deliver drugs to mitochondria or other intracellular organelles. PMID:22148549

Coenzyme Q biosynthesis and its role in the respiratory chain structure.

PubMed

Alcázar-Fabra, María; Navas, Plácido; Brea-Calvo, Gloria

2016-08-01

Coenzyme Q (CoQ) is a unique electron carrier in the mitochondrial respiratory chain, which is synthesized on-site by a nuclear encoded multiprotein complex. CoQ receives electrons from different redox pathways, mainly NADH and FADH2 from tricarboxylic acid pathway, dihydroorotate dehydrogenase, electron transfer flavoprotein dehydrogenase and glycerol-3-phosphate dehydrogenase that support key aspects of the metabolism. Here we explore some lines of evidence supporting the idea of the interaction of CoQ with the respiratory chain complexes, contributing to their superassembly, including respirasome, and its role in reactive oxygen species production in the mitochondrial inner membrane. We also review the current knowledge about the involvement of mitochondrial genome defects and electron transfer flavoprotein dehydrogenase mutations in the induction of secondary CoQ deficiency. This mechanism would imply specific interactions coupling CoQ itself or the CoQ-biosynthetic apparatus with the respiratory chain components. These interactions would regulate mitochondrial CoQ steady-state levels and function. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. Copyright © 2016 Elsevier B.V. All rights reserved.

Dietary restriction decreases coenzyme Q and ubiquinol potentially via changes in gene expression in the model organism C. elegans.

PubMed

Fischer, Alexandra; Klapper, Maja; Onur, Simone; Menke, Thomas; Niklowitz, Petra; Döring, Frank

2015-05-06

Dietary restriction (DR) is a robust intervention that extends both health span and life span in many organisms. Ubiquinol and ubiquinone represent the reduced and oxidized forms of coenzyme Q (CoQ). CoQ plays a central role in energy metabolism and functions in several cellular processes including gene expression. Here we used the model organism Caenorhabditis elegans to determine level and redox state of CoQ and expression of genes in response to DR. We found that DR down-regulates the steady-state expression levels of several evolutionary conserved genes (i.e. coq-1) that encode key enzymes of the mevalonate and CoQ-synthesizing pathways. In line with this, DR decreases the levels of total CoQ and ubiquinol. This CoQ-reducing effect of DR is obvious in adult worms but not in L4 larvae and is also evident in the eat-2 mutant, a genetic model of DR. In conclusion, we propose that DR reduces the level of CoQ and ubiquinol via gene expression in the model organism C. elegans. © 2015 International Union of Biochemistry and Molecular Biology.

Effects of coenzyme Q10 on semen cryopreservation of stallions classified as having good or bad semen freezing ability.

PubMed

Carneiro, Joao A M; Canisso, Igor F; Bandeira, R S; Scheeren, V F C; Freitas-Dell'Aqua, Camila P; Alvarenga, Marco A; Papa, Frederico O; Dell'Aqua, Jose A

2018-05-01

This study aimed to evaluate the antioxidant properties of coenzyme Q10 (CoQ10) during cryopreservation of semen obtained from stallions having good and bad semen freezing ability (GFA vs. BFA, respectively). Forty ejaculates (n = 20 stallions) were split into five centrifugation and five freezing extenders containing different concentrations of CoQ10 (0, 25, 50, 75 and 100 μmols/L). If CoQ10 was added to the centrifugation extender, the freezing extender had no CoQ10 added; similarly, if CoQ10 was added to the freezing extender, the centrifugation extender had no CoQ10. Semen cryopreserved on extenders containing no CoQ10 served as the control. After post-thaw total sperm motility (TM) assessments, the stallions were classified as GFA (i.e., decrease of ≤25% in TM, n = 7) or BFA (i.e., decrease of ≥40% in TM, n = 5). Stallions not fitting (n = 8) this enrollment criteria had samples discarded. After that, two straws for each extender were thawed at 37 °C for 30 s; one straw was immediately used for evaluation of sperm kinetics, plasma membrane integrity, non-capacitated spermatozoa, reactive oxygen species production, mitochondrial activity and lipid peroxidation. The second straw was kept at 37 °C for 30 min and subjected to the same assessments. Expectedly, sperm motility parameters were significantly lower for stallions with BFA. There were no effects of CoQ10 concentration or time for all parameters evaluated in the group with GFA when compared with the control extender (p > 0.05), except lipid peroxidation (p < 0.05). However, stallions with BFA had improved sperm parameters for samples processed with extenders containing CoQ10 (particularly 75 μmols/L) (p < 0.05), except for the reactive oxygen species production and mitochondrial potential (T0) in which there were no differences between the groups (p > 0.05). In summary, 75 μmols/L appears to be the optimal dose of Co-Q10, particularly, when added to the centrifugation extender. Copyright © 2018 Elsevier B.V. All rights reserved.

Combined coenzyme Q10 and clomiphene citrate for ovulation induction in clomiphene-citrate-resistant polycystic ovary syndrome.

PubMed

El Refaeey, Abdelaziz; Selem, Amal; Badawy, Ahmed

2014-07-01

This prospective randomized controlled trial evaluated the effect of combined oral coenzyme Q10 (CoQ10) and clomiphene citrate for ovulation induction in clomiphene-citrate-resistant polycystic ovary syndrome (PCOS). A total of 101 infertile women with PCOS resistant to clomiphene citrate were randomized either to combined CoQ10 and clomiphene citrate (51 patients, 82 cycles) or to clomiphene citrate alone (50 patients, 71 cycles). The outcome measures were number of follicles, serum oestradiol, serum progesterone, endometrial thickness and ovulation, clinical pregnancy and miscarriage rates. Numbers of follicles >14 mm and ≥18 mm were significantly higher in the CoQ10 group. Endometrial thickness on the day of human chorionic gonadotrophin was significantly greater in the CoQ10 group (8.82 ± 0.27 mm versus 7.03 ± 0.74 mm). Ovulation occurred in 54/82 cycles (65.9%) in the CoQ10 group and 11/71 cycles (15.5%) in the control group. Clinical pregnancy rate was significantly higher in the CoQ10 group (19/51, 37.3%) versus the control group (3/50, 6.0%). Combination of CoQ10 and clomiphene citrate in the treatment of clomiphene-citrate-resistant PCOS patients improves ovulation and clinical pregnancy rates. It is an effective and safe option and can be considered before gonadotrophin therapy or laparoscopic ovarian drilling. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Coenzyme Q10 Protects Human Endothelial Cells from β-Amyloid Uptake and Oxidative Stress-Induced Injury

PubMed Central

Durán-Prado, Mario; Frontiñán, Javier; Santiago-Mora, Raquel; Peinado, Juan Ramón; Parrado-Fernández, Cristina; Gómez-Almagro, María Victoria; Moreno, María; López-Domínguez, José Alberto; Villalba, José Manuel; Alcaín, Francisco J.

2014-01-01

Neuropathological symptoms of Alzheimer's disease appear in advances stages, once neuronal damage arises. Nevertheless, recent studies demonstrate that in early asymptomatic stages, ß-amyloid peptide damages the cerebral microvasculature through mechanisms that involve an increase in reactive oxygen species and calcium, which induces necrosis and apoptosis of endothelial cells, leading to cerebrovascular dysfunction. The goal of our work is to study the potential preventive effect of the lipophilic antioxidant coenzyme Q (CoQ) against ß-amyloid-induced damage on human endothelial cells. We analyzed the protective effect of CoQ against Aβ-induced injury in human umbilical vein endothelial cells (HUVECs) using fluorescence and confocal microscopy, biochemical techniques and RMN-based metabolomics. Our results show that CoQ pretreatment of HUVECs delayed Aβ incorporation into the plasma membrane and mitochondria. Moreover, CoQ reduced the influx of extracellular Ca2+, and Ca2+ release from mitochondria due to opening the mitochondrial transition pore after β-amyloid administration, in addition to decreasing O2 .− and H2O2 levels. Pretreatment with CoQ also prevented ß-amyloid-induced HUVECs necrosis and apoptosis, restored their ability to proliferate, migrate and form tube-like structures in vitro, which is mirrored by a restoration of the cell metabolic profile to control levels. CoQ protected endothelial cells from Aβ-induced injury at physiological concentrations in human plasma after oral CoQ supplementation and thus could be a promising molecule to protect endothelial cells against amyloid angiopathy. PMID:25272163

Identification of bottlenecks in Escherichia coli engineered for the production of CoQ(10).

PubMed

Cluis, Corinne P; Ekins, Andrew; Narcross, Lauren; Jiang, Heng; Gold, Nicholas D; Burja, Adam M; Martin, Vincent J J

2011-11-01

In this work, Escherichia coli was engineered to produce a medically valuable cofactor, coenzyme Q(10) (CoQ(10)), by removing the endogenous octaprenyl diphosphate synthase gene and functionally replacing it with a decaprenyl diphosphate synthase gene from Sphingomonas baekryungensis. In addition, by over-expressing genes coding for rate-limiting enzymes of the aromatic pathway, biosynthesis of the CoQ(10) precursor para-hydroxybenzoate (PHB) was increased. The production of isoprenoid precursors of CoQ(10) was also improved by the heterologous expression of a synthetic mevalonate operon, which permits the conversion of exogenously supplied mevalonate to farnesyl diphosphate. The over-expression of these precursors in the CoQ(10)-producing E. coli strain resulted in an increase in CoQ(10) content, as well as in the accumulation of an intermediate of the ubiquinone pathway, decaprenylphenol (10P-Ph). In addition, the over-expression of a PHB decaprenyl transferase (UbiA) encoded by a gene from Erythrobacter sp. NAP1 was introduced to direct the flux of DPP and PHB towards the ubiquinone pathway. This further increased CoQ(10) content in engineered E. coli, but decreased the accumulation of 10P-Ph. Finally, we report that the combined over-production of isoprenoid precursors and over-expression of UbiA results in the decaprenylation of para-aminobenzoate, a biosynthetic precursor of folate, which is structurally similar to PHB. Copyright © 2011 Elsevier Inc. All rights reserved.

Coenzyme Q10 Attenuates High Glucose-Induced Endothelial Progenitor Cell Dysfunction through AMP-Activated Protein Kinase Pathways

PubMed Central

Tsai, Hsiao-Ya; Lin, Chih-Pei; Huang, Po-Hsun; Li, Szu-Yuan; Chen, Jia-Shiong; Lin, Feng-Yen; Chen, Jaw-Wen; Lin, Shing-Jong

2016-01-01

Coenzyme Q10 (CoQ10), an antiapoptosis enzyme, is stored in the mitochondria of cells. We investigated whether CoQ10 can attenuate high glucose-induced endothelial progenitor cell (EPC) apoptosis and clarified its mechanism. EPCs were incubated with normal glucose (5 mM) or high glucose (25 mM) enviroment for 3 days, followed by treatment with CoQ10 (10 μM) for 24 hr. Cell proliferation, nitric oxide (NO) production, and JC-1 assay were examined. The specific signal pathways of AMP-activated protein kinase (AMPK), eNOS/Akt, and heme oxygenase-1 (HO-1) were also assessed. High glucose reduced EPC functional activities, including proliferation and migration. Additionally, Akt/eNOS activity and NO production were downregulated in high glucose-stimulated EPCs. Administration of CoQ10 ameliorated high glucose-induced EPC apoptosis, including downregulation of caspase 3, upregulation of Bcl-2, and increase in mitochondrial membrane potential. Furthermore, treatment with CoQ10 reduced reactive oxygen species, enhanced eNOS/Akt activity, and increased HO-1 expression in high glucose-treated EPCs. These effects were negated by administration of AMPK inhibitor. Transplantation of CoQ10-treated EPCs under high glucose conditions into ischemic hindlimbs improved blood flow recovery. CoQ10 reduced high glucose-induced EPC apoptosis and dysfunction through upregulation of eNOS, HO-1 through the AMPK pathway. Our findings provide a potential treatment strategy targeting dysfunctional EPC in diabetic patients. PMID:26682233

Role of Mitochondria in Prostate Cancer

DTIC Science & Technology

2005-12-01

outer surface of the inner mitochondrial membrane. This enzyme acts in concert with the cytoplasmic NAD-linked glycerophosphate dehydrogenase (cGPDH...dependent ROS production (Fig. 4). This observation may be attributable to the absence of a CoQ -binding protein in mGPDH. This CoQ -binding protein...evidently has a natural protection of ubisemiquinone formed during CoQ reduction by succinate dehydrogenase [28]. Evaluation of cell proliferation

Targeting Oxidative Stress, Cytokines and Serotonin Interactions Via Indoleamine 2, 3 Dioxygenase by Coenzyme Q10: Role in Suppressing Depressive Like Behavior in Rats.

PubMed

Abuelezz, Sally A; Hendawy, Nevien; Magdy, Yosra

2017-06-01

Depression is a major health problem in which oxidative stress and inflammation are inextricably connected in its pathophysiology. Coenzyme Q10 (CoQ10) is an important anti-oxidant compound with anti-inflammatory and neuro-protective properties. This study was designed to investigate the hypothesis that CoQ10 by its anti-oxidant and anti-inflammatory potentials can alleviate depressive- like behavior by restoring the balance of the tryptophan catabolites kynurenine/serotonin toward the serotonin pathway by down-regulation of hippocampal indoleamine 2,3-dioxygenase 1 (IDO-1). Depressive-like behavior was induced by chronic unpredictable mild stress (CUMS) protocol including food or water deprivation, cage tilting, reversed light cycle etc. Male Wistar rats were randomly divided into five groups; Control, CUMS, CUMS and CoQ10 (50,100 and 200 mg/kg/day i.p. respectively) groups. CoQ10 effects on different behavioral and biochemical tests were analyzed. CoQ10 showed significant antidepressant efficacy, as evidenced by significantly decreased stress induced changes to forced swimming challenge and open field test, as well as attenuating raised corticosterone level and adrenal glands weight. The anti-oxidant effect of CoQ10 was exhibited by its ability to significantly reduce hippocampal elevated malondialdehyde and 4-hydroxynonenal levels and elevate the reduced glutathione and catalase levels. CoQ10 significantly reduced different pro-inflammatory cytokines levels including interleukin (IL)-1β, IL-2, IL-6 and tumor necrosis factor-α. It suppressed hippocampal IDO-1 and subsequent production of kynurenine and enhanced the hippocampal contents of tryptophan and serotonin. Immunohistochemical analysis revealed that CoQ10 was able to attenuate the elevated microglial CD68 and elevate the astrocyte glial fibrillary acidic protein compared to CUMS group. CoQ10 exhibited antidepressant-like effects on rats exposed to CUMS. This could be attributed to its ability to reduce IDO-1 leading to shift the balance of the Kynurenine/ serotonin toward the serotonin pathway.

Neonatal liver failure and Leigh syndrome possibly due to CoQ-responsive OXPHOS deficiency.

PubMed

Leshinsky-Silver, E; Levine, A; Nissenkorn, A; Barash, V; Perach, M; Buzhaker, E; Shahmurov, M; Polak-Charcon, S; Lev, D; Lerman-Sagie, T

2003-08-01

CoQ transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There are very few reports on human CoQ deficiency. The clinical presentation is usually characterized by: epilepsy, muscle weakness, ataxia, cerebellar atrophy, migraine, myogloblinuria and developmental delay. We describe a patient who presented with neonatal liver and pancreatic insufficiency, tyrosinemia and hyperammonemia and later developed sensorineural hearing loss and Leigh syndrome. Liver biopsy revealed markedly reduced complex I+III and II+III. Addition of CoQ to the liver homogenate restored the activities, suggesting CoQ depletion. Histological staining showed prominent bridging; septal fibrosis and widening of portal spaces with prominent mixed inflammatory infiltrate, associated with interface hepatitis, bile duct proliferation with numerous bile plugs. Electron microscopy revealed a large number of mitochondria, which were altered in shape and size, widened and disordered intercristal spaces. This may be the first case of Leigh syndrome with liver and pancreas insufficiency, possibly caused by CoQ responsive oxphos deficiency.

Modeling of process parameters for enhanced production of coenzyme Q10 from Rhodotorula glutinis.

PubMed

Balakumaran, Palanisamy Athiyaman; Meenakshisundaram, Sankaranarayanan

2015-01-01

Coenzyme Q10 (CoQ10) plays an indispensable role in ATP generation through oxidative phosphorylation and helps in scavenging superoxides generated during electron transfer reactions. It finds extensive applications specifically related to oxidative damage and metabolic dysfunctions. This article reports the use of a statistical approach to optimize the concentration of key variables for the enhanced production of CoQ10 by Rhodotorula glutinis in a lab-scale fermenter. The culture conditions that promote optimum growth and CoQ10 production were optimized and the interaction of significant variables para-hydroxybenzoic acid (PHB, 819.34 mg/L) and soybean oil (7.78% [v/v]) was studied using response surface methodology (RSM). CoQ10 production increased considerably from 10 mg/L (in control) to 39.2 mg/L in batch mode with RSM-optimized precursor concentration. In the fed-batch mode, PHB and soybean oil feeding strategy enhanced CoQ10 production to 78.2 mg/L.

Topical Coenzyme Q10 demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension.

PubMed

Davis, Benjamin Michael; Tian, Kailin; Pahlitzsch, Milena; Brenton, Jonathan; Ravindran, Nivedita; Butt, Gibran; Malaguarnera, Giulia; Normando, Eduardo M; Guo, Li; Cordeiro, M Francesca

2017-09-01

Coenzyme Q10 (CoQ10) is a mitochondrial-targeted antioxidant with known neuroprotective activity. Its ocular effects when co-solubilised with α-tocopherol polyethylene glycol succinate (TPGS) were evaluated. In vitro studies confirmed that CoQ10 was significantly protective in different retinal ganglion cell (RGC) models. In vivo studies in Adult Dark Agouti (DA) rats with unilateral surgically-induced ocular hypertension (OHT) treated with either CoQ10/TPGS micelles or TPGS vehicle twice daily for three weeks were performed, following which retinal cell health was assessed in vivo using DARC (Detection of Apoptotic Retinal Cells) and post-mortem with Brn3a histological assessment on whole retinal mounts. CoQ10/TPGS showed a significant neuroprotective effect compared to control with DARC (p<0.05) and Brn3 (p<0.01). Topical CoQ10 appears an effective therapy preventing RGC apoptosis and loss in glaucoma-related models. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Ubiad1 Is an Antioxidant Enzyme that Regulates eNOS Activity by CoQ10 Synthesis

PubMed Central

Mugoni, Vera; Postel, Ruben; Catanzaro, Valeria; De Luca, Elisa; Turco, Emilia; Digilio, Giuseppe; Silengo, Lorenzo; Murphy, Michael P.; Medana, Claudio; Stainier, Didier Y.R.; Bakkers, Jeroen; Santoro, Massimo M.

2013-01-01

Summary Protection against oxidative damage caused by excessive reactive oxygen species (ROS) by an antioxidant network is essential for the health of tissues, especially in the cardiovascular system. Here, we identified a gene with important antioxidant features by analyzing a null allele of zebrafish ubiad1, called barolo (bar). bar mutants show specific cardiovascular failure due to oxidative stress and ROS-mediated cellular damage. Human UBIAD1 is a nonmitochondrial prenyltransferase that synthesizes CoQ10 in the Golgi membrane compartment. Loss of UBIAD1 reduces the cytosolic pool of the antioxidant CoQ10 and leads to ROS-mediated lipid peroxidation in vascular cells. Surprisingly, inhibition of eNOS prevents Ubiad1-dependent cardiovascular oxidative damage, suggesting a crucial role for this enzyme and nonmitochondrial CoQ10 in NO signaling. These findings identify UBIAD1 as a nonmitochondrial CoQ10-forming enzyme with specific cardiovascular protective function via the modulation of eNOS activity. PMID:23374346

High-fat diet-induced met-hemoglobin formation in rats prone (WOKW) or resistant (DA) to the metabolic syndrome: effect of CoQ10 supplementation.

PubMed

Orlando, Patrick; Silvestri, Sonia; Brugè, Francesca; Tiano, Luca; Kloting, Ingrid; Falcioni, Giancarlo; Polidori, Carlo

2014-01-01

The aim of this study was to evaluate the effects of a high-fat diet (HFD) on oxidative indexes in WistarOttawaKarlsburg W (WOKW) rats used as a model of metabolic syndrome in comparison with Dark Agouti (DA) rats used as a control strain. This syndrome is defined by the occurrence of two or more risk factors including obesity, hypertension, dyslipidemia, and insulin resistance. Forty rats were used in the study and the effect of HFD was evaluated in terms of body weight and both hemoglobin and CoQ oxidative status. Moreover, 16 rats (8 of each strain) were supplemented with 3 mg/100 g b.w. of CoQ10 for 1 month in view of its beneficial properties in cardiovascular disease due to its antioxidant activity in the lipid environment. HFD promoted an increase in body weight, in particular in WOKW males, and in the methemoglobin (met-Hb) index in both strains. Moreover, HFD promoted endogenous CoQ10 oxidation. CoQ10 supplementation was able to efficiently counteract the HFD pro-oxidant effects, preventing met-Hb formation and CoQ oxidation. © 2014 International Union of Biochemistry and Molecular Biology.

Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice.

PubMed

Falk, Marni J; Polyak, Erzsebet; Zhang, Zhe; Peng, Min; King, Rhonda; Maltzman, Jonathan S; Okwuego, Ezinne; Horyn, Oksana; Nakamaru-Ogiso, Eiko; Ostrovsky, Julian; Xie, Letian X; Chen, Jia Yan; Marbois, Beth; Nissim, Itzhak; Clarke, Catherine F; Gasser, David L

2011-07-01

Therapy of mitochondrial respiratory chain diseases is complicated by limited understanding of cellular mechanisms that cause the widely variable clinical findings. Here, we show that focal segmental glomerulopathy-like kidney disease in Pdss2 mutant animals with primary coenzyme Q (CoQ) deficiency is significantly ameliorated by oral treatment with probucol (1% w/w). Preventative effects in missense mutant mice are similar whether fed probucol from weaning or for 3 weeks prior to typical nephritis onset. Furthermore, treating symptomatic animals for 2 weeks with probucol significantly reduces albuminuria. Probucol has a more pronounced health benefit than high-dose CoQ(10) supplementation and uniquely restores CoQ(9) content in mutant kidney. Probucol substantially mitigates transcriptional alterations across many intermediary metabolic domains, including peroxisome proliferator-activated receptor (PPAR) pathway signaling. Probucol's beneficial effects on the renal and metabolic manifestations of Pdss2 disease occur despite modest induction of oxidant stress and appear independent of its hypolipidemic effects. Rather, decreased CoQ(9) content and altered PPAR pathway signaling appear, respectively, to orchestrate the glomerular and global metabolic consequences of primary CoQ deficiency, which are both preventable and treatable with oral probucol therapy. Copyright © 2011 EMBO Molecular Medicine.

Novel Lipid-Free Nanoformulation for Improving Oral Bioavailability of Coenzyme Q10

PubMed Central

Zhou, Huafeng; Liu, Guoqing; Zhang, Jing; Sun, Ning; Duan, Mingxing; Yan, Zemin; Xia, Qiang

2014-01-01

To improve the bioavailability of orally administered lipophilic coenzyme Q10 (CoQ10), we formulated a novel lipid-free nano-CoQ10 system stabilized by various surfactants. Nano-CoQ10s, composed of 2.5% (w/w) CoQ10, 1.67% (w/w) surfactant, and 41.67% (w/w) glycerol, were prepared by hot high-pressure homogenization. The resulting formulations were characterized by particle size, zeta potential, differential scanning calorimetry, and cryogenic transmission electron microscopy. We found that the mean particle size of all nano-CoQ10s ranged from 66.3 ± 1.5 nm to 92.7 ± 1.5 nm and the zeta potential ranged from −12.8 ± 1.4 mV to −41.6 ± 1.4 mV. The CoQ10 in nano-CoQ10s likely existed in a supercooled state, and nano-CoQ10s stored in a brown sealed bottle were stable for 180 days at 25°C. The bioavailability of CoQ10 was evaluated following oral administration of CoQ10 formulations in Sprague-Dawley rats. Compared to the values observed following administration of CoQ10-Suspension, nano-CoQ10 modified with various surfactants significantly increased the maximum plasma concentration and the area under the plasma concentration-time curve. Thus, the lipid-free system of a nano-CoQ10 stabilized with a surfactant may be an effective vehicle for improving oral bioavailability of CoQ10. PMID:24995328

Effects of dietary coenzyme Q10 supplementation on hepatic mitochondrial function and the activities of respiratory chain-related enzymes in ascitic broiler chickens.

PubMed

Geng, A L; Guo, Y M

2005-10-01

1. One hundred and sixty 1-d-old Arbor Acre male broiler chicks were fed with maize-soybean based diets for 6 weeks in a 2 x 2 factorial experiment. The factors were CoQ10 supplementation (0 or 40 mg/kg) and Escherichia coli lipopolysaccharide (LPS) challenge (LPS or saline). 2. CoQ10 was supplemented from d 1. From d 18, the chickens received three weekly i.p. injections of LPS (1.0 mg/kg BW) or an equivalent amount of sterile saline as control. From d 10 on, all chickens were exposed to low ambient temperature (12 to 15 degrees C) to induce ascites. 3. The blood packed cell volume and ascites heart index of broiler chickens were reduced by dietary CoQ10 supplementation. Mitochondrial State 3 and State 4 respiration, respiratory control ratio and phosphate oxygen ratio were not changed, but H+/site stoichiometry of complex II + III was elevated by dietary CoQ10 supplementation. 4. Cytochrome c oxidase and H+-ATPase activity were increased by CoQ10 supplementation, whereas NADH cytochrome c reductase and succinate cytochrome c reductase were not influenced. Mitochondrial anti-ROS capability was increased and malondialdehyde content was decreased by CoQ10 supplementation. 5. The work suggested that dietary CoQ10 supplementation could reduce broiler chickens' susceptibility to ascites, which might be the result of improving hepatic mitochondrial function, some respiratory chain-related enzymes activities and mitochondrial antioxidative capability.

Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials.

PubMed

Banach, Maciej; Serban, Corina; Sahebkar, Amirhossein; Ursoniu, Sorin; Rysz, Jacek; Muntner, Paul; Toth, Peter P; Jones, Steven R; Rizzo, Manfredi; Glasser, Stephen P; Lip, Gregory Y H; Dragan, Simona; Mikhailidis, Dimitri P

2015-01-01

To evaluate the efficacy of coenzyme Q10 (CoQ10) supplementation on statin-induced myopathy. We searched the MEDLINE, Cochrane Library, Scopus, and EMBASE databases (November 1, 1987, to May 1, 2014) to identify randomized controlled trials investigating the impact of CoQ10 on muscle pain and plasma creatine kinase (CK) activity as 2 measures of statin-induced myalgia. Two independent reviewers extracted data on study characteristics, methods, and outcomes. We included 6 studies with 302 patients receiving statin therapy: 5 studies with 226 participants evaluated the effect of CoQ10 supplementation on plasma CK activity, and 5 studies (4 used in the CK analysis and 1 other study) with 253 participants were included to assess the effect of CoQ10 supplementation on muscle pain. Compared with the control group, plasma CK activity was increased after CoQ10 supplementation, but this change was not significant (mean difference, 11.69 U/L [to convert to μkat/L, multiply by 0.0167]; 95% CI, -14.25 to 37.63 U/L; P=.38). Likewise, CoQ10 supplementation had no significant effect on muscle pain despite a trend toward a decrease (standardized mean difference, -0.53; 95% CI, -1.33 to 0.28; P=.20). No dose-effect association between changes in plasma CK activity (slope, -0.001; 95% CI, -0.004 to 0.001; P=.33) or in the indices of muscle pain (slope, 0.002; 95% CI, -0.005 to 0.010; P=.67) and administered doses of CoQ10 were observed. The results of this meta-analysis of available randomized controlled trials do not suggest any significant benefit of CoQ10 supplementation in improving statin-induced myopathy. Larger, well-designed trials are necessary to confirm the findings from this meta-analysis. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Can didactic continuing education improve clinical decision making and reduce cost of quality? Evidence from a case study.

PubMed

Vuković, Mira; Gvozdenović, Branislav S; Ranković, Milena; McCormick, Bryan P; Vuković, Danica D; Gvozdenović, Biljana D; Kastratović, Dragana A; Marković, Srdjan Z; Ilić, Miodrag; Jakovljević, Mihajlo B

2015-01-01

Administration of human serum albumin (HSA) solutions for the resuscitation of critically ill patients remains controversial. The objective of this study was to assess the effect of continuing medical education (CME) on health care professionals' clinical decision making with regard to HSA administration and the costs of quality (COQ). A quasi-experimental study of time series association of CME intervention with COQ and use of HSA solution was conducted at the Surgery Department of the Hospital Valjevo, Serbia. The CME contained evidence-based criteria for HSA solution administration in surgical patients. The preintervention period was defined as January 2009 to May 2011. CME was provided in June 2011, with the postintervention period June 2011 to May 2012. Total mortality rate, the rate of nonsurgical mortality, the rate of surgical mortality, the rate of sepsis patient mortality, index of irrational use of HSA solutions, and number of hospital days per hospitalized patient were collected for each month as quality indicators. Statistical analysis was performed by multivariate autoregressive integrated moving average (MARIMA) modeling. The specification of the COQ was performed according to a traditional COQ model. The CME intervention resulted in an average monthly reduction of the hospital days per hospitalized patient, the rate of sepsis patient mortality, index of irrational use of HSA solutions, and COQ for $593,890.77 per year. Didactic CME presenting evidence-based criteria for HSA administration was associated with improvements in clinical decisions and COQ. In addition, this study demonstrates that models combining MARIMA and traditional COQ models can be useful in the evaluation of CME interventions aimed at reducing COQ. © 2015 The Alliance for Continuing Education in the Health Professions, the Society for Academic Continuing Medical Education, and the Council on Continuing Medical Education, Association for Hospital Medical Education.

Analysis of flavin oxidation and electron-transfer inhibition in Plasmodium falciparum dihydroorotate dehydrogenase.

PubMed

Malmquist, Nicholas A; Gujjar, Ramesh; Rathod, Pradipsinh K; Phillips, Margaret A

2008-02-26

Plasmodium falciparum dihydroorotate dehydrogenase (pfDHODH) is a flavin-dependent mitochondrial enzyme that provides the only route to pyrimidine biosynthesis in the parasite. Clinically significant inhibitors of human DHODH (e.g., A77 1726) bind to a pocket on the opposite face of the flavin cofactor from dihydroorotate (DHO). This pocket demonstrates considerable sequence variability, which has allowed species-specific inhibitors of the malarial enzyme to be identified. Ubiquinone (CoQ), the physiological oxidant in the reaction, has been postulated to bind this site despite a lack of structural evidence. To more clearly define the residues involved in CoQ binding and catalysis, we undertook site-directed mutagenesis of seven residues in the structurally defined A77 1726 binding site, which we term the species-selective inhibitor site. Mutation of several of these residues (H185, F188, and F227) to Ala substantially decreased the affinity of pfDHODH-specific inhibitors (40-240-fold). In contrast, only a modest increase in the Kmapp for CoQ was observed, although mutation of Y528 in particular caused a substantial reduction in kcat (40-100-fold decrease). Pre-steady-state kinetic analysis by single wavelength stopped-flow spectroscopy showed that the mutations had no effect on the rate of the DHO-dependent reductive half-reaction, but most reduced the rate of the CoQ-dependent flavin oxidation step (3-20-fold decrease), while not significantly altering the Kdox for CoQ. As with the mutants, inhibitors that bind this site block the CoQ-dependent oxidative half-reaction without affecting the DHO-dependent step. These results identify residues involved in inhibitor binding and electron transfer to CoQ. Importantly, the data provide compelling evidence that the binding sites for CoQ and species-selective site inhibitors do not overlap, and they suggest instead that inhibitors act either by blocking the electron path between flavin and CoQ or by stabilizing a conformation that excludes CoQ binding.

Existence of compensatory defense mechanisms against oxidative stress and hypertension in preeclampsia.

PubMed

Roland, L; Gagné, A; Bélanger, M-C; Boutet, M; Berthiaume, L; Fraser, W D; Julien, P; Bilodeau, J-F

2010-01-01

Preeclampsia is a complex obstetrical syndrome characterized by hypertension and proteinuria. This syndrome is associated with oxidative stress, antioxidant imbalance and impaired production of vasoactive eicosanoids such as thromboxane A(2) (TXA(2)), a potent vasoconstrictor, and prostacyclin (PGI(2)), a well-known vasodilator. We hypothesized that there was a relationship between antioxidant vitamins, such as vitamin E and coenzyme Q(10) (CoQ(10)), and the production of vasoactive eicosanoids- PGI(2) and TXA(2)-potentially regulated by pro-oxidants and antioxidants in preeclampsia. Therefore, the plasma levels of vitamin E, CoQ(10), TXA(2) and PGI(2) in normotensive (n = 30) and preeclamptic (n = 29) pregnancies were evaluated. Reduced and oxidized forms of vitamin E and CoQ(10) in blood were measured using a HPLC coupled to electrochemical detection. The levels of TXB(2) and 6-keto-PGF(1alpha), stable metabolites of TXA(2) and PGI(2) respectively, were measured by ELISA. The CoQ(10) oxidized/reduced ratio was significantly higher in preeclamptic compared to normotensive pregnancies (p = 0.04). A strong correlation between plasma levels of reduced vitamin E and CoQ(10), corrected for apolipoprotein B, was observed only in preeclampsia (r = 0.69, p < 0.0001). The 6-keto-PGF(1alpha)/TXB(2) ratio was higher in preeclampsia than in controls (p = 0.02), and this ratio was correlated to the oxidized/reduced ratio of both, vitamin E and CoQ(10) in all pregnancies (p <0.023). The data indicated that CoQ(10) is a sensitive marker of oxidative stress in preeclampsia. The correlation between vitamin E and CoQ(10) suggested a coordinated defense mechanism against oxidation. Furthermore, the higher 6-keto-PGF(1alpha)/TXB(2) ratio that strongly correlated with oxidative stress markers, suggests a mechanism developed by the maternal cardiovascular system to counteract hypertension during preeclampsia.

Synergistic cosolubilization of omega-3 fatty acid esters and CoQ10 in dilutable microemulsions.

PubMed

Deutch-Kolevzon, Rivka; Aserin, Abraham; Garti, Nissim

2011-10-01

Water-dilutable microemulsions were prepared and loaded with two types of omega-3 fatty acid esters (omega-3 ethyl esters, OEE; and omega-3 triacylglycerides, OTG), each separately and together with ubiquinone (CoQ(10)). The microemulsions showed high and synergistic loading capabilities. The linear fatty acid ester (OEE) solubilization capacity was greater than that of the bulky and robust OTG. The location of the guest molecules within the microemulsions at any dilution point were determined by electrical conductivity, viscosity, DSC, SAXS, cryo-TEM, SD-NMR, and DLS. We found that OEE molecules pack well within the surfactant tails to form reverse micelles that gradually, upon water dilution, invert into bicontinuous phase and finally into O/W droplets. The CoQ(10) increases the stabilization and solubilization of the omega-3 fatty acid esters because it functions as a kosmotropic agent in the micellar system. The hydrophobic and bulky OTG molecule strongly interferes with the tail packing and spaces them significantly - mainly in the low and medium range water dilutions. When added to the micellar system, CoQ(10) forms some reverse hexagonal mesophases. The inversion into direct micelles is more difficult in comparison to the OEE system and requires additional water dilution. The OTG with or without CoQ(10) destabilizes the structures and decreases the solubilization capacity since it acts as a chaotropic agent to the micellar system and as a kosmotropic agent to hexagonal packing. These results explain the differences in the behavior of these molecules with vehicles that solubilize them in aqueous phases. Temperature disorders the bicontinuous structures and reduces the supersaturation of the system containing OEE with CoQ(10); as a result CoQ(10) crystallization is retarded. Copyright © 2011. Published by Elsevier Ireland Ltd.

Coenzyme Q10 and Pyridoxal Phosphate Deficiency Is a Common Feature in Mucopolysaccharidosis Type III.

PubMed

Yubero, Dèlia; Montero, Raquel; O'Callaghan, Mar; Pineda, Mercè; Meavilla, Silvia; Delgadillo, Veronica; Sierra, Cristina; Altimira, Laura; Navas, Plácido; Pope, Simon; Oppenheim, Marcus; Neergheen, Viruna; Ghosh, Arunabha; Mills, Phillipa; Clayton, Peter; Footitt, Emma; Cleary, Maureen; Hargreaves, Iain; Jones, Simon A; Heales, Simon; Artuch, Rafael

2016-01-01

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiencies of lysosomal enzymes catalyzing degradation of glycosaminoglycans (GAGs). Previously, we reported a secondary plasma coenzyme Q 10 (CoQ) deficiency in MPS patients. For this study, nine MPS patients were recruited in the Hospital Sant Joan de Déu (HSJD, Barcelona) and two patients in the Neurometabolic Unit, National Hospital (NMU, London), to explore the nutritional status of MPS type III patients by analyzing several vitamins and micronutrients in blood and in cerebrospinal fluid. Plasma CoQ and plasma and cerebrospinal fluid pyridoxal phosphate (PLP) content were analyzed by high-pressure liquid chromatography (HPLC) with electrochemical and fluorescence detection, respectively. We found that most MPS-III patients disclosed low plasma pyridoxal phosphate (PLP) values (seven out of nine) and also low plasma CoQ concentrations (eight out of nine). We observed significantly lower median values of PLP, tocopherol, and CoQ (Mann-Whitney U test, p = 0.006, p = 0.004, and p = 0.001, respectively) in MPS patients when compared with age-matched controls. Chi-square test showed a significant association between the fact of having low plasma PLP and CoQ values in the whole cohort of patients. Cerebrospinal fluid PLP values were clearly deficient in the two patients studied. In conclusion, we report a combined CoQ and PLP deficiency in MPS-III patients. These observations could be related to the complexity of the physiopathology of the disease. If our results are confirmed in larger series of patients, CoQ and PLP therapy could be trialed as coadjuvant therapy with the current MPS treatments.

Effect of coenzyme Q10 supplementation on heart failure: a meta-analysis123

PubMed Central

Thompson-Paul, Angela M; Bazzano, Lydia A

2013-01-01

Background: Coenzyme Q10 (CoQ10; also called ubiquinone) is an antioxidant that has been postulated to improve functional status in congestive heart failure (CHF). Several randomized controlled trials have examined the effects of CoQ10 on CHF with inconclusive results. Objective: The objective of this meta-analysis was to evaluate the impact of CoQ10 supplementation on the ejection fraction (EF) and New York Heart Association (NYHA) functional classification in patients with CHF. Design: A systematic review of the literature was conducted by using databases including MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and manual examination of references from selected studies. Studies included were randomized controlled trials of CoQ10 supplementation that reported the EF or NYHA functional class as a primary outcome. Information on participant characteristics, trial design and duration, treatment, dose, control, EF, and NYHA classification were extracted by using a standardized protocol. Results: Supplementation with CoQ10 resulted in a pooled mean net change of 3.67% (95% CI: 1.60%, 5.74%) in the EF and −0.30 (95% CI: −0.66, 0.06) in the NYHA functional class. Subgroup analyses showed significant improvement in EF for crossover trials, trials with treatment duration ≤12 wk in length, studies published before 1994, and studies with a dose ≤100 mg CoQ10/d and in patients with less severe CHF. These subgroup analyses should be interpreted cautiously because of the small number of studies and patients included in each subgroup. Conclusions: Pooled analyses of available randomized controlled trials suggest that CoQ10 may improve the EF in patients with CHF. Additional well-designed studies that include more diverse populations are needed. PMID:23221577

A single nucleotide polymorphism in COQ9 affects mitochondrial and ovarian function and fertility in Holstein cows.

PubMed

Ortega, M Sofia; Wohlgemuth, Stephanie; Tribulo, Paula; Siqueira, Luiz G B; Cole, John B; Hansen, Peter J

2017-03-01

A single missense mutation at position 159 of coenzyme Q9 (COQ9) (G→A; rs109301586) has been associated with genetic variation in fertility in Holstein cattle, with the A allele associated with higher fertility. COQ9 is involved in the synthesis of coenzyme COQ10, a component of the electron transport system of the mitochondria. Here we tested whether reproductive phenotype is associated with the mutation and evaluated functional consequences for cellular oxygen metabolism, body weight changes, and ovarian function. The mutation in COQ9 modifies predicted tertiary protein structure and affected mitochondrial respiration of peripheral blood mononuclear cells. The A allele was associated with low resting oxygen consumption and high electron transport system capacity. Phenotypic measurements for fertility were evaluated for up to five lactations in a population of 2273 Holstein cows. There were additive effects of the mutation (P < 0.05) in favor of the A allele for pregnancy rate, interval from calving to conception, and services per conception. There was no association of genotype with milk production or body weight changes postpartum. The mutation in COQ9 affected ovarian function; the A allele was associated with increased mitochondrial DNA copy number in oocytes, and there were overdominance effects for COQ9 expression in oocytes, follicle number, and antimullerian hormone concentrations. Overall, results show how a gene involved in mitochondrial function is associated with overall fertility, possibly in part by affecting oocyte quality. © The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardioprotective Effect of Coenzyme Q10 on Apoptotic Myocardial Cell Death by Regulation of Bcl-2 Gene Expression

PubMed Central

Khan, Najam Ali; Abid, M.; Ahmad, Aftab; Abuzinadah, Mohammed F.; Basheikh, Mohammed; Kishore, Kamal

2017-01-01

Objectives: To investigate the effect of coenzyme Q10 (CoQ10) on apoptotic myocardial cell death in rat model of heart ischemia and reperfusion I/R injury. Materials and Methods: Eighteen rats (200–250 g) were divided into three groups of 6 rats in each. Group I (sham-operated control group): this is the control group. The animals received the surgical procedure without IR injury or any drug treatment. Group II (I/R group): ischemia was accomplished by the occlusion of coronary artery for 30 min followed by reperfusion for 45 min and Group-III (Coenzyme Q10 treated group): Treated with CoQ10 at a dose of 1 mg/kg, postoperative for 7 days before induction of IR injury. Results: The study revealed that pretreatment with CoQ10 has shown protective effect on apoptotic rat heart and agreed with earlier reports that CoQ10 significantly protects from oxidative stress and cytopathological changes caused by cardiac ischemia followed by reperfusion and attenuated decrease of antioxidant enzymes. Nitric oxide production in the heart of ischemic rats was significantly increased by the pretreatment with CoQ10 in comparison with IR group. Conclusions: CoQ10 protects against cardiac apoptosis induced by IR injury by significantly decreasing the apoptotic DNA and regulating the expression of Bcl-2 gene. PMID:29081620

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

PubMed

Beal, M Flint; Oakes, David; Shoulson, Ira; Henchcliffe, Claire; Galpern, Wendy R; Haas, Richard; Juncos, Jorge L; Nutt, John G; Voss, Tiffini Smith; Ravina, Bernard; Shults, Clifford M; Helles, Karen; Snively, Victoria; Lew, Mark F; Griebner, Brian; Watts, Arthur; Gao, Shan; Pourcher, Emmanuelle; Bond, Louisette; Kompoliti, Katie; Agarwal, Pinky; Sia, Cherissa; Jog, Mandar; Cole, Linda; Sultana, Munira; Kurlan, Roger; Richard, Irene; Deeley, Cheryl; Waters, Cheryl H; Figueroa, Angel; Arkun, Ani; Brodsky, Matthew; Ondo, William G; Hunter, Christine B; Jimenez-Shahed, Joohi; Palao, Alicia; Miyasaki, Janis M; So, Julie; Tetrud, James; Reys, Liza; Smith, Katharine; Singer, Carlos; Blenke, Anita; Russell, David S; Cotto, Candace; Friedman, Joseph H; Lannon, Margaret; Zhang, Lin; Drasby, Edward; Kumar, Rajeev; Subramanian, Thyagarajan; Ford, Donna Stuppy; Grimes, David A; Cote, Diane; Conway, Jennifer; Siderowf, Andrew D; Evatt, Marian Leslie; Sommerfeld, Barbara; Lieberman, Abraham N; Okun, Michael S; Rodriguez, Ramon L; Merritt, Stacy; Swartz, Camille Louise; Martin, W R Wayne; King, Pamela; Stover, Natividad; Guthrie, Stephanie; Watts, Ray L; Ahmed, Anwar; Fernandez, Hubert H; Winters, Adrienna; Mari, Zoltan; Dawson, Ted M; Dunlop, Becky; Feigin, Andrew S; Shannon, Barbara; Nirenberg, Melissa Jill; Ogg, Mattson; Ellias, Samuel A; Thomas, Cathi-Ann; Frei, Karen; Bodis-Wollner, Ivan; Glazman, Sofya; Mayer, Thomas; Hauser, Robert A; Pahwa, Rajesh; Langhammer, April; Ranawaya, Ranjit; Derwent, Lorelei; Sethi, Kapil D; Farrow, Buff; Prakash, Rajan; Litvan, Irene; Robinson, Annette; Sahay, Alok; Gartner, Maureen; Hinson, Vanessa K; Markind, Samuel; Pelikan, Melisa; Perlmutter, Joel S; Hartlein, Johanna; Molho, Eric; Evans, Sharon; Adler, Charles H; Duffy, Amy; Lind, Marlene; Elmer, Lawrence; Davis, Kathy; Spears, Julia; Wilson, Stephanie; Leehey, Maureen A; Hermanowicz, Neal; Niswonger, Shari; Shill, Holly A; Obradov, Sanja; Rajput, Alex; Cowper, Marilyn; Lessig, Stephanie; Song, David; Fontaine, Deborah; Zadikoff, Cindy; Williams, Karen; Blindauer, Karen A; Bergholte, Jo; Propsom, Clara Schindler; Stacy, Mark A; Field, Joanne; Mihaila, Dragos; Chilton, Mark; Uc, Ergun Y; Sieren, Jeri; Simon, David K; Kraics, Lauren; Silver, Althea; Boyd, James T; Hamill, Robert W; Ingvoldstad, Christopher; Young, Jennifer; Thomas, Karen; Kostyk, Sandra K; Wojcieszek, Joanne; Pfeiffer, Ronald F; Panisset, Michel; Beland, Monica; Reich, Stephen G; Cines, Michelle; Zappala, Nancy; Rivest, Jean; Zweig, Richard; Lumina, L Pepper; Hilliard, Colette Lynn; Grill, Stephen; Kellermann, Marye; Tuite, Paul; Rolandelli, Susan; Kang, Un Jung; Young, Joan; Rao, Jayaraman; Cook, Maureen M; Severt, Lawrence; Boyar, Karyn

2014-05-01

Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. To examine whether CoQ10 could slow disease progression in early PD. A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit. clinicaltrials.gov Identifier: NCT00740714.

Efficiency of emulsifier-free emulsions and emulsions containing rapeseed lecithin as delivery systems for vectorization and release of coenzyme Q10: physico-chemical properties and in vitro evaluation.

PubMed

Kaci, M; Arab-Tehrany, E; Dostert, G; Desjardins, I; Velot, E; Desobry, S

2016-11-01

To improve the encapsulation and release of coenzyme Q10 (CoQ10), emulsifier-free-emulsions were developed with a new emulsification process using high-frequency ultrasound (HFU) at 1.7MHz. Nano-emulsions containing CoQ10 were prepared with or without rapeseed lecithin as an emulsifier. The emulsions prepared with HFU were compared with an emulsion of CoQ10 containing emulsifier prepared with the same emulsification technique as well as with emulsions prepared with low-frequency ultrasound coupled with high-pressure homogenization (LFU+HPH). The physico-chemical properties of the emulsions were determined by average droplet size measurement with nano-droplet tracking analysis, droplet surface charge with ζ potential measurement, surface tension and rheological behaviour. Emulsions made by LFU+HPH with an emulsifier showed lower droplet sizes due to cavitation generated by the HFU process. Surface tension results showed that there was no significant difference between emulsions containing lecithin emulsifier regardless of the preparation process or the inclusion of CoQ10. In vitro biocompatibility tests were performed on human mesenchymal stem cells in order to show the cytotoxicity of various formulations and the efficiency of CoQ10-loaded emulsions. In vitro tests proved that the vectors were not toxic. Furthermore, CoQ10 facilitated a high rate of cell proliferation and metabolic activity especially when in an emulsifier-free formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Reducing exercise-induced muscular injury in kendo athletes with supplementation of coenzyme Q10.

PubMed

Kon, Michihiro; Tanabe, Kai; Akimoto, Takayuki; Kimura, Fuminori; Tanimura, Yuko; Shimizu, Kazuhiro; Okamoto, Tadashi; Kono, Ichiro

2008-10-01

Intensive physical exercise may cause muscular injury and increase oxidative stress. The purpose of this study was to examine the effect of an antioxidant, coenzyme Q10 (CoQ10), on muscular injury and oxidative stress during exercise training. Eighteen male students, all elite Japanese kendo athletes, were randomly assigned to either a CoQ10 group (n 10) or a placebo group (n 8) in a double-blind manner. Subjects in the CoQ10 group took 300 mg CoQ10 per d for 20 d, while subjects in the placebo group took the same dosage of a placebo. All subjects practised kendo 5.5 h per d for 6 d during the experimental period. Blood samples were taken 2 weeks before, during (1 d, 3 d, 5 d) and 1 week after the training. Serum creatine kinase (CK) activity and myoglobin (Mb) concentration significantly increased in both groups (at 3 d and 5 d). Serum CK (at 3 d), Mb (at 3 d) and lipid peroxide (at 3 d and 5 d) of the CoQ10 group were lower than those of the placebo group. The leucocyte counts in the placebo group significantly increased (at 3 d) and neutrophils significantly increased in both groups (at 3 d and 5 d). Serum scavenging activity against superoxide anion did not change in either group. These results indicate that CoQ10 supplementation reduced exercise-induced muscular injury in athletes.

Coenzyme Q10 ameliorates pain and cartilage degradation in a rat model of osteoarthritis by regulating nitric oxide and inflammatory cytokines.

PubMed

Lee, Jennifer; Hong, Yeon Sik; Jeong, Jeong Hee; Yang, Eun Ji; Jhun, Joo Yeon; Park, Mi Kyoung; Jung, Young Ok; Min, Jun Ki; Kim, Ho Youn; Park, Sung Hwan; Cho, Mi-La

2013-01-01

To investigate the effect of CoenzymeQ10 (CoQ10) on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA). OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration of CoQ10 was initiated on day 4 after MIA injection. Pain severity was assessed by measuring secondary tactile allodynia using the von Frey assessment test. The degree of cartilage degradation was determined by measuring cartilage thickness and the amount of proteoglycan. The mankin scoring system was also used. Expressions of matrix metalloproteinase-13 (MMP-13), interleukin-1β (IL-1β), IL-6, IL-15, inducible nitric oxide synthase (iNOS), nitrotyrosine and receptor for advanced glycation end products (RAGE) were analyzed using immunohistochemistry. Treatment with CoQ10 demonstrated an antinociceptive effect in the OA animal model. The reduction in secondary tactile allodynia was shown by an increased pain withdrawal latency and pain withdrawal threshold. CoQ10 also attenuated cartilage degeneration in the osteoarthritic joints. MMP-13, IL-1β, IL-6, IL-15, iNOS, nitrotyrosine and RAGE expressions were upregulated in OA joints and significantly reduced with CoQ10 treatment. CoQ10 exerts a therapeutic effect on OA via pain suppression and cartilage degeneration by inhibiting inflammatory mediators, which play a vital role in OA pathogenesis.

Primary Coenzyme Q Deficiency in Pdss2 Mutant Mice Causes Isolated Renal Disease

PubMed Central

Haase, Volker H.; King, Rhonda; Polyak, Erzsebet; Selak, Mary; Yudkoff, Marc; Hancock, Wayne W.; Meade, Ray; Saiki, Ryoichi; Lunceford, Adam L.; Clarke, Catherine F.; Gasser, David L.

2008-01-01

Coenzyme Q (CoQ) is an essential electron carrier in the respiratory chain whose deficiency has been implicated in a wide variety of human mitochondrial disease manifestations. Its multi-step biosynthesis involves production of polyisoprenoid diphosphate in a reaction that requires the enzymes be encoded by PDSS1 and PDSS2. Homozygous mutations in either of these genes, in humans, lead to severe neuromuscular disease, with nephrotic syndrome seen in PDSS2 deficiency. We now show that a presumed autoimmune kidney disease in mice with the missense Pdss2kd/kd genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2kd/kd mutants were significantly lower than those in B6 control mice. Disease manifestations originate specifically in glomerular podocytes, as renal disease is seen in Podocin/cre,Pdss2loxP/loxP knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes. Liver-conditional B6.Alb/cre,Pdss2loxP/loxP knockout mice have no overt disease despite demonstration that their livers have undetectable CoQ9 levels, impaired respiratory capacity, and significantly altered intermediary metabolism as evidenced by transcriptional profiling and amino acid quantitation. These data suggest that disease manifestations of CoQ deficiency relate to tissue-specific respiratory capacity thresholds, with glomerular podocytes displaying the greatest sensitivity to Pdss2 impairment. PMID:18437205

Calcium binding and transport by coenzyme Q.

PubMed

Bogeski, Ivan; Gulaboski, Rubin; Kappl, Reinhard; Mirceski, Valentin; Stefova, Marina; Petreska, Jasmina; Hoth, Markus

2011-06-22

Coenzyme Q10 (CoQ10) is one of the essential components of the mitochondrial electron-transport chain (ETC) with the primary function to transfer electrons along and protons across the inner mitochondrial membrane (IMM). The concomitant proton gradient across the IMM is essential for the process of oxidative phosphorylation and consequently ATP production. Cytochrome P450 (CYP450) monoxygenase enzymes are known to induce structural changes in a variety of compounds and are expressed in the IMM. However, it is unknown if CYP450 interacts with CoQ10 and how such an interaction would affect mitochondrial function. Using voltammetry, UV-vis spectrometry, electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), fluorescence microscopy and high performance liquid chromatography-mass spectrometry (HPLC-MS), we show that both CoQ10 and its analogue CoQ1, when exposed to CYP450 or alkaline media, undergo structural changes through a complex reaction pathway and form quinone structures with distinct properties. Hereby, one or both methoxy groups at positions 2 and 3 on the quinone ring are replaced by hydroxyl groups in a time-dependent manner. In comparison with the native forms, the electrochemically reduced forms of the new hydroxylated CoQs have higher antioxidative potential and are also now able to bind and transport Ca(2+) across artificial biomimetic membranes. Our results open new perspectives on the physiological importance of CoQ10 and its analogues, not only as electron and proton transporters, but also as potential regulators of mitochondrial Ca(2+) and redox homeostasis.

Coenzyme Q10 protects neural stem cells against hypoxia by enhancing survival signals.

PubMed

Park, Jinse; Park, Hyun-Hee; Choi, Hojin; Kim, Young Seo; Yu, Hyun-Jeung; Lee, Kyu-Yong; Lee, Young Joo; Kim, Seung Hyun; Koh, Seong-Ho

2012-10-10

Recanalization and secondary prevention are the main therapeutic strategies for acute ischemic stroke. Neuroprotective therapies have also been investigated despite unsuccessful clinical results. Coenzyme Q10 (CoQ10), which is an essential cofactor for electron transport in mitochondria, is known to have an antioxidant effect. We investigated the protective effects of CoQ10 against hypoxia in neural stem cells (NSCs). We measured cell viability and levels of intracellular signaling proteins after treatment with several concentrations of CoQ10 under hypoxia-reperfusion. CoQ10 protected NSCs against hypoxia-reperfusion in a concentration-dependent manner by reducing growth inhibition and inhibiting free radical formation. It increased the expression of a number of survival-related proteins such as phosphorylated Akt (pAkt), phosphorylated glycogen synthase kinase 3-β (pGSK3-β), and B-cell lymphoma 2 (Bcl-2) in NSCs injured by hypoxia-reperfusion and reduced the expression of death-related proteins such as cleaved caspase-3. We conclude that CoQ10 has effects against hypoxia-reperfusion induced damage to NSCs by enhancing survival signals and decreasing death signals. Copyright © 2012 Elsevier B.V. All rights reserved.

44 CFR 75.3 - Burden of proof.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Burden of proof. 75.3 Section 75.3 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND... PROPERTIES UNDER SELF-INSURANCE PLAN General § 75.3 Burden of proof. In any application made by a State to...

44 CFR 75.3 - Burden of proof.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 44 Emergency Management and Assistance 1 2014-10-01 2014-10-01 false Burden of proof. 75.3 Section 75.3 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND... PROPERTIES UNDER SELF-INSURANCE PLAN General § 75.3 Burden of proof. In any application made by a State to...

The effect of short-term coenzyme Q10 supplementation and pre-cooling strategy on cardiac damage markers in elite swimmers.

PubMed

Emami, Ali; Tofighi, Asghar; Asri-Rezaei, Siamak; Bazargani-Gilani, Behnaz

2018-02-01

Strenuous physical exercise and hyperthermia may paradoxically induce oxidative stress and adverse effects on myocardial function. The purpose of this study was to investigate the effect of 14-d coenzyme Q10 (CoQ10) supplementation and pre-cooling on serum creatine kinase-MB (CK-MB), cardiac Troponin I (cTnI), myoglobin (Mb), lactate dehydrogenase (LD), total antioxidant capacity (TAC), lipid peroxidation (LPO) and CoQ10 concentration in elite swimmers. In total, thirty-six healthy males (mean age 17 (sd 1) years) were randomly selected and divided into four groups of supplementation, supplementation with pre-cooling, pre-cooling and control. During an eighteen-session protocol in the morning and evening, subjects attended speed and endurance swimming training sessions for 5 km in each session. Blood sampling was done before (two stages) and after (two stages) administration of CoQ10 and pre-cooling. ANCOVA and repeated measurement tests with Bonferroni post hoc test were used for the statistical analysis of the data. There was no significant statistical difference among groups for the levels of CK-MB, cTnI, Mb, LD, TAC, LPO and CoQ10 at the presampling (stages 1 and 2) (P>0·05). However, pre-cooling and control groups show a significant increase in the levels of CK-MB, cTnI, Mb, LD and LPO compared with the supplementation and supplementation with pre-cooling groups in the post-sampling (stages 1 and 2) (P<0·05), except for the TAC and CoQ10. Consequently, CoQ10 supplementation prevents adverse changes of myocardial damage and oxidative stress during swimming competition phase. Meanwhile, the pre-cooling strategy individually has no desired effect on the levels of CK-MB, cTnI, Mb, LD, LPO, TAC and CoQ10.

CoQ10 plasmatic levels in breast-fed infants compared to formula-fed infants.

PubMed

Compagnoni, G; Giuffrè, B; Lista, G; Mosca, F; Marini, A

2004-01-01

Coenzyme Q10 has been recognized as an important antioxidant factor besides its main role in bioenergetic metabolism. CoQ10 tissue levels depend both on exogenous dietetic intake and on endogenous biosynthesis, as this compound can be partly synthesized in human cells. Q10 plasma levels reflect the tissue content of the coenzyme and can be used to evaluate the presence of this compound in the human organism. Aim of the study was to measure CoQ10 plasmatic levels in a newborn breast-fed population and to compare them to CoQ10 levels in a newborn formula-fed population in order to verify whether changes in CoQ10 plasmatic contents could be related to a different dietetic intakes. We measured CoQ10 plasmatic levels in 25 healthy term neonates with different dietetic intakes: 15 breast-fed and 10 bottle-fed with a common infant formula. These infants were evaluated prospectively during the first month of life. The analyses were performed on the mothers' blood samples and cord blood samples at the time of delivery, then on infants at 4 and 28 days of age. Our results showed markedly reduced Q10 levels in cord blood samples compared to maternal Q10 plasmatic levels at the time of delivery, suggesting placental impermeability towards this molecule or increased fetal utilization during labor and delivery. At 4 days of age Q10 levels had increased in both groups of neonates, but significantly more in breast-fed infants compared to formula-fed babies (p <0.05). At 4 weeks of age no significant changes occurred in breast-fed infants, while values increased significantly in formula-fed infants (p <0.05). The content of Q10 in breast milk samples was lower than in infant formula. The results of this study show that CoQ10 plasmatic levels are at least partly influenced by the exogenous dietetic supply.

Obesity-induced oocyte mitochondrial defects are partially prevented and rescued by supplementation with co-enzyme Q10 in a mouse model

PubMed Central

Boots, C.E.; Boudoures, A.; Zhang, W.; Drury, A.; Moley, K.H.

2016-01-01

STUDY QUESTION Does supplementation with co-enzyme Q10 (CoQ10) improve the oocyte mitochondrial abnormalities associated with obesity in mice? SUMMARY ANSWER In an obese mouse model, CoQ10 improves the mitochondrial function of oocytes. WHAT IS KNOWN ALREADY Obesity impairs oocyte quality. Oocytes from mice fed a high-fat/high-sugar (HF/HS) diet have abnormalities in mitochondrial distribution and function and in meiotic progression. STUDY DESIGN, SIZE, DURATION Mice were randomly assigned to a normal, chow diet or an isocaloric HF/HS diet for 12 weeks. After 6 weeks on the diet, half of the mice receiving a normal diet and half of the mice receiving a HF/HS diet were randomly assigned to receive CoQ10 supplementation injections for the remaining 6 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS Dietary intervention was initiated on C57Bl6 female mice at 4 weeks of age, CoQ10 versus vehicle injections were assigned at 10 weeks, and assays were conducted at 16 weeks of age. Mice were super-ovulated, and oocytes were collected and stained to assess mitochondrial distribution, quantify reactive oxygen species (ROS), assess meiotic spindle formation, and measure metabolites. In vitro fertilization was performed, and blastocyst embryos were transferred into control mice. Oocyte number, fertilization rate, blastulation rate and implantation rate were compared between the four cohorts. Bivariate statistics were performed appropriately. MAIN RESULTS AND THE ROLE OF CHANCE HF/HS mice weighed significantly more than normal diet mice (29 versus 22 g, P< 0.001). CoQ10 supplementation did not influence weight. Levels of ATP, citrate, and phosphocreatine were lower and ROS levels were higher in HF/HS mice than in controls (P< 0.001). CoQ10 supplementation significantly increased the levels of metabolites and decreased ROS levels in oocytes from normal diet mice but not in oocytes from HF/HS mice. However, CoQ10 completely prevented the mitochondrial distribution abnormalities observed in the HF/HS mice. Overall, CoQ10 supplementation significantly increased the percentage of normal spindle and chromosome alignment (92.3 versus 80.2%, P= 0.039). In the sub-analysis by diet, the difference did not reach statistical significance. When undergoing IVF, there were no statistically significant differences in the number of mature oocytes, the fertilization rate, blastocyst formation rates, implantation rates, resorption rates or litter size between HF/HS mice receiving CoQ10 or vehicle injections. LIMITATIONS, REASONS FOR CAUTION Experiments were limited to one species and strain of mice. The majority of experiments were performed after ovulation induction, which may not represent natural cycle fertility. WIDER IMPLICATIONS OF THE FINDINGS Improvement in oocyte mitochondrial distribution and function of normal, chow-fed mice and HF/HS-fed mice demonstrates the importance of CoQ10 and the efficiency of the mitochondrial respiratory chain in oocyte competence. Clinical studies are now needed to evaluate the therapeutic potential of CoQ10 in women's reproductive health. STUDY FUNDING/COMPETING INTEREST(S) C.E.B. received support from the National Research Training Program in Reproductive Medicine sponsored by the National Institute of Health (T32 HD040135-13) and the Scientific Advisory Board of Vivere Health. K.H.M received support from the American Diabetes Association and the National Institute of Health (R01 HD083895). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER This study is not a clinical trial. PMID:27432748

Low-cost and disposable sensors for the simultaneous determination of coenzyme Q10 and α-lipoic acid using manganese (IV) oxide-modified screen-printed graphene electrodes.

PubMed

Charoenkitamorn, Kanokwan; Chaiyo, Sudkate; Chailapakul, Orawon; Siangproh, Weena

2018-04-03

In this work, for the first time, manganese (IV) oxide-modified screen-printed graphene electrodes (MnO 2 /SPGEs) were developed for the simultaneous electrochemical detection of coenzyme Q10 (CoQ10) and α-lipoic acid (ALA). This sensor exhibits attractive benefits such as simplicity, low production costs, and disposability. Cyclic voltammetry (CV) was used to characterize the electrochemical behavior of the analyte and investigate the capacitance and electroactive surface area of the unmodified and modified electrode surfaces. The electrochemical behavior of CoQ10 and ALA on MnO 2 /SPGEs was also discussed. Additionally, square wave anodic stripping voltammetry (SWASV) was used for the quantitative determination of CoQ10 and ALA. Under optimal conditions, the obtained signals are linear in the concentration range from 2.0 to 75.0 μg mL -1 for CoQ10 and 0.3-25.0 μg mL -1 for ALA. The low limits of detection (LODs) were found to be 0.56 μg mL -1 and 0.088 μg mL -1 for CoQ10 and ALA, respectively. Moreover, we demonstrated the utility and applicability of the MnO 2 /SPGE sensor through simultaneous measurements of CoQ10 and ALA in dietary supplements. The sensor provides high accuracy measurements, exhibiting its high potential for practical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Genome-wide association study of serum coenzyme Q10 levels identifies susceptibility loci linked to neuronal diseases.

PubMed

Degenhardt, Frauke; Niklowitz, Petra; Szymczak, Silke; Jacobs, Gunnar; Lieb, Wolfgang; Menke, Thomas; Laudes, Matthias; Esko, Tõnu; Weidinger, Stephan; Franke, Andre; Döring, Frank; Onur, Simone

2016-07-01

Coenzyme Q 10 (CoQ 10 ) is a lipophilic redox molecule that is present in membranes of almost all cells in human tissues. CoQ 10 is, amongst other functions, essential for the respiratory transport chain and is a modulator of inflammatory processes and gene expression. Rare monogenetic CoQ 10 deficiencies show noticeable symptoms in tissues (e.g. kidney) and cell types (e.g. neurons) with a high energy demand. To identify common genetic variants influencing serum CoQ 10 levels, we performed a fixed effects meta-analysis in two independent cross-sectional Northern German cohorts comprising 1300 individuals in total. We identified two genome-wide significant susceptibility loci. The best associated single nucleotide polymorphism (SNP) was rs9952641 (P value = 1.31 × 10 - 8 , β = 0.063, CI 0.95 [0.041, 0.085]) within the COLEC12 gene on chromosome 18. The SNP rs933585 within the NRXN-1 gene on chromosome 2 also showed genome wide significance (P value = 3.64 × 10 - 8 , β = -0.034, CI 0.95 [-0.046, -0.022]). Both genes have been previously linked to neuronal diseases like Alzheimer's disease, autism and schizophrenia. Among our 'top-10' associated variants, four additional loci with known neuronal connections showed suggestive associations with CoQ 10 levels. In summary, this study demonstrates that serum CoQ 10 levels are associated with common genetic loci that are linked to neuronal diseases. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The evidence basis for coenzyme Q therapy in oxidative phosphorylation disease.

PubMed

Haas, Richard H

2007-06-01

The evidence supporting a treatment benefit for coenzyme Q10 (CoQ10) in primary mitochondrial disease (mitochondrial disease) whilst positive is limited. Mitochondrial disease in this context is defined as genetic disease causing an impairment in mitochondrial oxidative phosphorylation (OXPHOS). There are no treatment trials achieving the highest Level I evidence designation. Reasons for this include the relative rarity of mitochondrial disease, the heterogeneity of mitochondrial disease, the natural cofactor status and easy 'over the counter availability' of CoQ10 all of which make funding for the necessary large blinded clinical trials unlikely. At this time the best evidence for efficacy comes from controlled trials in common cardiovascular and neurodegenerative diseases with mitochondrial and OXPHOS dysfunction the etiology of which is most likely multifactorial with environmental factors playing on a background of genetic predisposition. There remain questions about dosing, bioavailability, tissue penetration and intracellular distribution of orally administered CoQ10, a compound which is endogenously produced within the mitochondria of all cells. In some mitochondrial diseases and other commoner disorders such as cardiac disease and Parkinson's disease low mitochondrial or tissue levels of CoQ10 have been demonstrated providing an obvious rationale for supplementation. This paper discusses the current state of the evidence supporting the use of CoQ10 in mitochondrial disease.

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease.

PubMed

McGarry, Andrew; McDermott, Michael; Kieburtz, Karl; de Blieck, Elisabeth A; Beal, Flint; Marder, Karen; Ross, Christopher; Shoulson, Ira; Gilbert, Peter; Mallonee, William M; Guttman, Mark; Wojcieszek, Joanne; Kumar, Rajeev; LeDoux, Mark S; Jenkins, Mary; Rosas, H Diana; Nance, Martha; Biglan, Kevin; Como, Peter; Dubinsky, Richard M; Shannon, Kathleen M; O'Suilleabhain, Padraig; Chou, Kelvin; Walker, Francis; Martin, Wayne; Wheelock, Vicki L; McCusker, Elizabeth; Jankovic, Joseph; Singer, Carlos; Sanchez-Ramos, Juan; Scott, Burton; Suchowersky, Oksana; Factor, Stewart A; Higgins, Donald S; Molho, Eric; Revilla, Fredy; Caviness, John N; Friedman, Joseph H; Perlmutter, Joel S; Feigin, Andrew; Anderson, Karen; Rodriguez, Ramon; McFarland, Nikolaus R; Margolis, Russell L; Farbman, Eric S; Raymond, Lynn A; Suski, Valerie; Kostyk, Sandra; Colcher, Amy; Seeberger, Lauren; Epping, Eric; Esmail, Sherali; Diaz, Nancy; Fung, Wai Lun Alan; Diamond, Alan; Frank, Samuel; Hanna, Philip; Hermanowicz, Neal; Dure, Leon S; Cudkowicz, Merit

2017-01-10

To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. These data do not justify use of CoQ as a treatment to slow functional decline in HD. NCT00608881. This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD. © 2016 American Academy of Neurology.

The Emerging Role of Disturbed CoQ Metabolism in Nonalcoholic Fatty Liver Disease Development and Progression

PubMed Central

Botham, Kathleen M.; Napolitano, Mariarosaria; Bravo, Elena

2015-01-01

Although non-alcoholic fatty liver disease (NAFLD), characterised by the accumulation of triacylglycerol in the liver, is the most common liver disorder, the causes of its development and progression to the more serious non-alcoholic steatohepatitis (NASH) remain incompletely understood. Oxidative stress has been implicated as a key factor in both these processes, and mitochondrial dysfunction and inflammation are also believed to play a part. Coenzyme Q (CoQ) is a powerful antioxidant found in all cell membranes which has an essential role in mitochondrial respiration and also has anti-inflammatory properties. NAFLD has been shown to be associated with disturbances in plasma and liver CoQ concentrations, but the relationship between these changes and disease development and progression is not yet clear. Dietary supplementation with CoQ has been found to be hepatoprotective and to reduce oxidative stress and inflammation as well as improving mitochondrial dysfunction, suggesting that it may be beneficial in NAFLD. However, studies using animal models or patients with NAFLD have given inconclusive results. Overall, evidence is now emerging to indicate that disturbances in CoQ metabolism are involved in NAFLD development and progression to NASH, and this highlights the need for further studies with human subjects to fully clarify its role. PMID:26633474

Prophylactic role of coenzyme Q10 and Cynara scolymus L on doxorubicin-induced toxicity in rats: Biochemical and immunohistochemical study.

PubMed

Mustafa, Hesham N; El Awdan, Sally A; Hegazy, Gehan A; Abdel Jaleel, Gehad A

2015-01-01

The study aims to evaluate the protective effects of coenzyme Q10 (CoQ10) and Cynara scolymus L (CS) on doxorubicin (dox)-induced toxicity. Sixty male rats were divided into six groups. Group 1 as a control. Group 2 received dox (10 mg/kg) intraperitoneally. Group 3 received CoQ10 (200 mg/kg). Group 4 received CS (500 mg/kg). Group 5 received CoQ10 (200 mg/kg) and dox (10 mg/kg). Group 6 received CS (500 mg/kg) and dox (10 mg/kg). The rats were then evaluated biochemically and immunohistochemically. Dox produced a significant deterioration of hepatic and renal functional parameters. Moreover, an upsurge of oxidative stress and nitrosative stress markers. The expression of alpha-smooth muscle actin (α-SMA) was increased and proliferating cell nuclear antigen (PCNA) expression was decreased. Administration of CoQ10 and CS resulted in a significant improvement of hepatic and renal functional parameters, and an improvement of both α-SMA and PCNA. It is concluded that pretreatment with CoQ10 and CS is associated with up-regulation of favorable protective enzymes and down-regulation of oxidative stress. That can be advised as a supplement to dox-treated patients.

Prophylactic role of coenzyme Q10 and Cynara scolymus L on doxorubicin-induced toxicity in rats: Biochemical and immunohistochemical study

PubMed Central

Mustafa, Hesham N.; El Awdan, Sally A.; Hegazy, Gehan A.; Abdel Jaleel, Gehad A.

2015-01-01

Objective: The study aims to evaluate the protective effects of coenzyme Q10 (CoQ10) and Cynara scolymus L (CS) on doxorubicin (dox)-induced toxicity. Materials and Methods: Sixty male rats were divided into six groups. Group 1 as a control. Group 2 received dox (10 mg/kg) intraperitoneally. Group 3 received CoQ10 (200 mg/kg). Group 4 received CS (500 mg/kg). Group 5 received CoQ10 (200 mg/kg) and dox (10 mg/kg). Group 6 received CS (500 mg/kg) and dox (10 mg/kg). The rats were then evaluated biochemically and immunohistochemically. Results: Dox produced a significant deterioration of hepatic and renal functional parameters. Moreover, an upsurge of oxidative stress and nitrosative stress markers. The expression of alpha-smooth muscle actin (α-SMA) was increased and proliferating cell nuclear antigen (PCNA) expression was decreased. Administration of CoQ10 and CS resulted in a significant improvement of hepatic and renal functional parameters, and an improvement of both α-SMA and PCNA. Conclusion: It is concluded that pretreatment with CoQ10 and CS is associated with up-regulation of favorable protective enzymes and down-regulation of oxidative stress. That can be advised as a supplement to dox-treated patients. PMID:26729958

Vitamin K2 biosynthetic enzyme, UBIAD1 is essential for embryonic development of mice.

PubMed

Nakagawa, Kimie; Sawada, Natsumi; Hirota, Yoshihisa; Uchino, Yuri; Suhara, Yoshitomo; Hasegawa, Tomoka; Amizuka, Norio; Okamoto, Tadashi; Tsugawa, Naoko; Kamao, Maya; Funahashi, Nobuaki; Okano, Toshio

2014-01-01

UbiA prenyltransferase domain containing 1 (UBIAD1) is a novel vitamin K2 biosynthetic enzyme screened and identified from the human genome database. UBIAD1 has recently been shown to catalyse the biosynthesis of Coenzyme Q10 (CoQ10) in zebrafish and human cells. To investigate the function of UBIAD1 in vivo, we attempted to generate mice lacking Ubiad1, a homolog of human UBIAD1, by gene targeting. Ubiad1-deficient (Ubiad1(-/-)) mouse embryos failed to survive beyond embryonic day 7.5, exhibiting small-sized body and gastrulation arrest. Ubiad1(-/-) embryonic stem (ES) cells failed to synthesize vitamin K2 but were able to synthesize CoQ9, similar to wild-type ES cells. Ubiad1(+/-) mice developed normally, exhibiting normal growth and fertility. Vitamin K2 tissue levels and synthesis activity were approximately half of those in the wild-type, whereas CoQ9 tissue levels and synthesis activity were similar to those in the wild-type. Similarly, UBIAD1 expression and vitamin K2 synthesis activity of mouse embryonic fibroblasts prepared from Ubiad1(+/-) E15.5 embryos were approximately half of those in the wild-type, whereas CoQ9 levels and synthesis activity were similar to those in the wild-type. Ubiad1(-/-) mouse embryos failed to be rescued, but their embryonic lifespans were extended to term by oral administration of MK-4 or CoQ10 to pregnant Ubiad1(+/-) mice. These results suggest that UBIAD1 is responsible for vitamin K2 synthesis but may not be responsible for CoQ9 synthesis in mice. We propose that UBIAD1 plays a pivotal role in embryonic development by synthesizing vitamin K2, but may have additional functions beyond the biosynthesis of vitamin K2.

Phase II trial of CoQ10 for ALS finds insufficient evidence to justify Phase III

PubMed Central

Kaufmann, Petra; Thompson, John L.P.; Levy, Gilberto; Buchsbaum, Richard; Shefner, Jeremy; Krivickas, Lisa S.; Katz, Jonathan; Rollins, Yvonne; Barohn, Richard J.; Jackson, Carlayne E.; Tiryaki, Ezgi; Lomen-Hoerth, Catherine; Armon, Carmel; Tandan, Rup; Rudnicki, Stacy A.; Rezania, Kourosh; Sufit, Robert; Pestronk, Alan; Novella, Steven P.; Heiman-Patterson, Terry; Kasarskis, Edward J.; Pioro, Erik P.; Montes, Jacqueline; Arbing, Rachel; Vecchio, Darleen; Barsdorf, Alexandra; Mitsumoto, Hiroshi; Levin, Bruce

2010-01-01

Objective Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial. Methods We designed and implemented a multi-center trial with an adaptive, two-stage, bias-adjusted, randomized, placebo-controlled, double-blind, Phase II design (n=185). The primary outcome in both stages was decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo. Results Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an accompanying pre-specified sensitivity test, and further supplementary analyses. Pre-specified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns. Interpretation CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial. PMID:19743457

Water-soluble Coenzyme Q10 formulation (Q-ter) promotes outer hair cell survival in a guinea pig model of noise induced hearing loss (NIHL).

PubMed

Fetoni, Anna Rita; Piacentini, Roberto; Fiorita, Antonella; Paludetti, Gaetano; Troiani, Diana

2009-02-27

The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS) also in noise induced hearing loss (NIHL) and anti-oxidants and free-radicals scavengers have been shown to attenuate the damage. Coenzyme Q(10) (CoQ(10)) or ubiquinone has a bioenergetic role as a component of the mithocondrial respiratory chain, it inhibits mitochondrial lipid peroxidation, inducing ATP production and it is involved in ROS removal and prevention of oxidative stress-induced apoptosis. However the therapeutic application of CoQ(10) is limited by the lack of solubility and poor bio- availability, therefore it is a challenge to improve its water solubility in order to ameliorate the efficacy in tissues and fluids. This study was conducted in a model of acoustic trauma in the guinea pig where the effectiveness of CoQ(10) was compared with a soluble formulation of CoQ(10) (multicomposite CoQ(10) Terclatrate, Q-ter) given intraperitoneally 1 h before and once daily for 3 days after pure tone noise exposure (6 kHz for 1 h at 120 dB SPL). Functional and morphological studies were carried out by measuring auditory brainstem responses, scanning electron microscopy for hair cell loss count, active caspase 3 staining and terminal deoxynucleotidyl transferase-mediated dUTP labelling assay in order to identify initial signs of apoptosis. Treatments decreased active caspase 3 expression and the number of apoptotic cells, but animals injected with Q-ter showed a greater degree of activity in preventing apoptosis and thus in improving hearing. These data confirm that solubility of Coenzyme Q(10) improves the ability of CoQ(10) in preventing oxidative injuries that result from mitochondrial dysfunction.

Antioxidant vitamins C, E and coenzyme Q10 vs Dexamethasone: comparisons of their effects in pulmonary contusion model

PubMed Central

2012-01-01

Background The goal of our study is to evaluate the effects of antioxidant vitamins (vitamin C and E), Coenzyme Q10 (CoQ10) and dexamethasone (Dxm) in experimental rat models with pulmonary contusion (PC). Methods Rats were randomly divided into six groups. Except for the control, all subgroups had a moderate pulmonary contusion. Animals in the group I and group II received intraperitoneal saline, group III received 10mg.kg-1 CoQ10 group IV received 100mg.kg-1 vitamin C, group V received 150mg.kg-1 vitamin E, and group VI received 10mg.kg-1 Dxm. Blood gas analysis, serum nitric oxide (NO) and malondialdehyde (MDA) levels as well as superoxide dismutase (SOD) activity assays, bronchoalveolar lavage (BAL) fluid and histopathological examination were performed. Results Administration of CoQ10 resulted in a significant increase in PaO2 values compared with the group I (p = 0.004). Levels of plasma MDA in group II were significantly higher than those in the group I (p = 0.01). Early administration of vitamin C, CoQ10, and Dxm significantly decreased the levels of MDA (p = 0.01). Lung contusion due to blunt trauma significantly decreased SOD activities in rat lung tissue compared with group I (p = 0.01). SOD levels were significantly elevated in animals treated with CoQ10, Vitamin E, or Dxm compared with group II (p = 0.01). Conclusions In our study, CoQ10, vitamin C, vitamin E and Dxm had a protective effect on the biochemical and histopathological outcome of PC after experimental blunt thorax trauma. PMID:23013526

Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial.

PubMed

Dai, Yuk-Ling; Luk, Ting-Hin; Yiu, Kai-Hang; Wang, Mei; Yip, Pandora M C; Lee, Stephen W L; Li, Sheung-Wai; Tam, Sidney; Fong, Bonnie; Lau, Chu-Pak; Siu, Chung-Wah; Tse, Hung-Fat

2011-06-01

Coronary artery disease (CAD) is associated with endothelial dysfunction and mitochondrial dysfunction (MD). The aim of this study was to investigate whether co-enzyme Q10 (CoQ) supplementation, which is an obligatory coenzyme in the mitochondrial respiratory transport chain, can reverse MD and improve endothelial function in patients with ischaemic left ventricular systolic dysfunction (LVSD). We performed a randomized, double-blind, placebo-controlled trial to determine the effects of CoQ supplement (300 mg/day, n=28) vs. placebo (controls, n=28) for 8 weeks on brachial flow-mediated dilation (FMD) in patients with ischaemic LVSD(left ventricular ejection fraction <45%). Mitochondrial function was determined by plasma lactate/pyruvate ratio (LP ratio). After 8 weeks, CoQ-treated patients had significant increases in plasma CoQ concentration (treatment effect 2.20 μg/mL, P<0.001) and FMD (treatment effect 1.51%, P=0.03); and decrease in LP ratio (treatment effect -2.46, P=0.03) compared with controls. However, CoQ treatment did not alter nitroglycerin-mediated dilation, blood pressure, blood levels of fasting glucose, haemoglobin A1c, lipid profile, high-sensitivity C-reactive protein and oxidative stress as determined by serum superoxide dismutase and 8-isoprostane (all P>0.05). Furthermore, the reduction in LP ratio significantly correlated with improvement in FMD (r=-0.29, P=0.047). In patients with ischaemic LVSD, 8 weeks supplement of CoQ improved mitochondrial function and FMD; and the improvement of FMD correlated with the change in mitochondrial function, suggesting that CoQ improved endothelial function via reversal of mitochondrial dysfunction in patients with ischaemic LVSD. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

CoQ10 and L-carnitine for statin myalgia?

PubMed

DiNicolantonio, James J

2012-10-01

Statins are a standard of care in many clinical settings such as acute myocardial infarction and for patients having or at risk of cardiovascular (CV) disease. This is based on a plethora of data showing reductions in CV events and mortality. The CV benefit of statins can be partly explained by their ability to inhibit of HMG-CoA reductase, which subsequently lowers cholesterol and decreases the formation of mevalonate. However, the inhibition of the mevalonate pathway decreases the formation of coenzyme Q10 (CoQ10) within the body. It has been a long-standing theory that statin-associated muscle pain (myalgia) is caused, or at least partly contributed by, a reduction in CoQ10 levels in muscle mitochondria. One of the main side effects of statins is myalgia, which causes the patient to either stop their statin or significantly reduce the dose of their statin. The question of whether CoQ10 can help treat statin myopathy is a common one encountered by clinicians in current day practice.

Bioavailability enhancement of coenzyme Q10: an extensive review of patents.

PubMed

Beg, Sarwar; Javed, Shamama; Kohli, Kanchan

2010-11-01

Coenzyme Q10 (CoQ10) is a major antioxidant principle found in human body which plays a vital role in maintaining several biochemical pathways of body. It acts as a potential mediator in transferring electrons in oxidoreductive reactions of electron transport chain. Chemically, it is a basic quinone containing moiety having a large and high molecular weight structure. Deficiency of this in body leads to several potential disorders like dysfunctions in cellular energetics, neurological degeneration, higher oxidative stress induced damage, breast cancer etc. The high molecular weight and lipophilicity of CoQ10 makes it poorly water soluble and consequently leads to low systemic availability. Several advancements have been made to enhance the bioavailability of CoQ10 using various approaches like size reduction, solubility enhancement (by solid dispersion, prodrug, complexation, ionization) and use of novel drug carriers such as liposomes, microspheres, nanoparticles, nanoemulsions and self-emulsifying system. The primary objective of the present review is to assemble patents representing the various approaches used for enhancement of CoQ10 bioavailability.

Effect of Coenzyme Q10 on ischemia and neuronal damage in an experimental traumatic brain-injury model in rats

PubMed Central

2011-01-01

Background Head trauma is one of the most important clinical issues that not only can be fatal and disabling, requiring long-term treatment and care, but also can cause heavy financial burden. Formation or distribution of free oxygen radicals should be decreased to enable fixing of poor neurological outcomes and to prevent neuronal damage secondary to ischemia after trauma. Coenzyme Q10 (CoQ10), a component of the mitochondrial electron transport chain, is a strong antioxidant that plays a role in membrane stabilization. In this study, the role of CoQ10 in the treatment of head trauma is researched by analyzing the histopathological and biochemical effects of CoQ10 administered after experimental traumatic brain injury in rats. A traumatic brain-injury model was created in all rats. Trauma was inflicted on rats by the free fall of an object of 450 g weight from a height of 70 cm on the frontoparietal midline onto a metal disc fixed between the coronal and the lambdoid sutures after a midline incision was carried out. Results In the biochemical tests, tissue malondialdehyde (MDA) levels were significantly higher in the traumatic brain-injury group compared to the sham group (p < 0.05). Administration of CoQ10 after trauma was shown to be protective because it significantly lowered the increased MDA levels (p < 0.05). Comparing the superoxide dismutase (SOD) levels of the four groups, trauma + CoQ10 group had SOD levels ranging between those of sham group and traumatic brain-injury group, and no statistically significant increase was detected. Histopathological results showed a statistically significant difference between the CoQ10 and the other trauma-subjected groups with reference to vascular congestion, neuronal loss, nuclear pyknosis, nuclear hyperchromasia, cytoplasmic eosinophilia, and axonal edema (p < 0.05). Conclusion Neuronal degenerative findings and the secondary brain damage and ischemia caused by oxidative stress are decreased by CoQ10 use in rats with traumatic brain injury. PMID:21801363

Examining intentions to use CoQ10 amongst breast cancer patients.

PubMed

Hill, Gina Jarman; Shriver, Brent J; Arnett, Dennis B

2006-01-01

To determine factors that influence breast cancer patients' intentions to supplement with CoQ10. A survey based upon the expanded rational expectations intentions model was completed by breast cancer outpatients (N=160). A significantly positive relationship existed between referent other (the influence specific people have in terms of an individual's behavior) and subjective norm (subject's perception of how people view a behavior). Beliefs, referent other, attitude, and subjective norm did have a significant effect on intention to use CoQ10. Health practitioners may address supplementation with breast cancer patients with a better understanding of what factors impact supplement use.

Non-Invasive Evaluation of Cephalic Blood Flow in the +Gz Environment

DTIC Science & Technology

1988-09-25

and the center frequency, COQ , is set by R3 and C1. The transfer function for this BPF is given by: K co„s/Q H(s)=-^ eq.5 S + S(OQ/Q -I- CO...0 where 0 = 20,1.4 < K < 8.6, COQ = 613.2 x 103 rad/s (97.6 kHz), Vout = output voltage, Vin = input voltage, and bandwidth = 7 kHz. To choose the...values of R1 - R4 and C1, these factors were first normalized: COQ = 1 rad/s, C1 = 1F, and R4 = lil. Then R1 = Q/K, R2 = Q, and R3 = 1i^. To denor

A Program Certification Assistant Based on Fully Automated Theorem Provers

NASA Technical Reports Server (NTRS)

Denney, Ewen; Fischer, Bernd

2005-01-01

We describe a certification assistant to support formal safety proofs for programs. It is based on a graphical user interface that hides the low-level details of first-order automated theorem provers while supporting limited interactivity: it allows users to customize and control the proof process on a high level, manages the auxiliary artifacts produced during this process, and provides traceability between the proof obligations and the relevant parts of the program. The certification assistant is part of a larger program synthesis system and is intended to support the deployment of automatically generated code in safety-critical applications.

Sunflower Oil but Not Fish Oil Resembles Positive Effects of Virgin Olive Oil on Aged Pancreas after Life-Long Coenzyme Q Addition

PubMed Central

González-Alonso, Adrián; Ramírez-Tortosa, César L.; Varela-López, Alfonso; Roche, Enrique; Arribas, María I.; Ramírez-Tortosa, M. Carmen; Giampieri, Francesca; Ochoa, Julio J.; Quiles, José L.

2015-01-01

An adequate pancreatic structure is necessary for optimal organ function. Structural changes are critical in the development of age-related pancreatic disorders. In this context, it has been reported that different pancreatic compartments from rats were affected according to the fat composition consumed. Since there is a close relationship between mitochondria, oxidative stress and aging, an experimental approach has been developed to gain more insight into this process in the pancreas. A low dosage of coenzyme Q was administered life-long in rats in order to try to prevent pancreatic aging-related alterations associated to some dietary fat sources. According to that, three groups of rats were fed normocaloric diets containing Coenzyme Q (CoQ) for two years, where virgin olive, sunflower, or fish oil was included as unique fat source. Pancreatic samples for microscopy and blood samples were collected at the moment of euthanasia. The main finding is that CoQ supplementation gives different results according to fat used in diet. When sunflower oil was the main fat in the diet, CoQ supplementation seems to improve endocrine pancreas structure and in particular β-cell mass resembling positive effects of virgin olive oil. Conversely, CoQ intake does not seem to improve the structural alterations of exocrine compartment previously observed in fish oil fed rats. Therefore CoQ may improve pancreatic alterations associated to the chronic intake of some dietary fat sources. PMID:26426013

Oxidative Stress Correlates with Headache Symptoms in Fibromyalgia: Coenzyme Q10 Effect on Clinical Improvement

PubMed Central

Cordero, Mario D.; Cano-García, Francisco Javier; Alcocer-Gómez, Elísabet; De Miguel, Manuel; Sánchez-Alcázar, José Antonio

2012-01-01

Background Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology and a wide spectrum of symptoms such as allodynia, debilitating fatigue, joint stiffness and migraine. Recent studies have shown some evidences demonstrating that oxidative stress is associated to clinical symptoms in FM of fibromyalgia. We examined oxidative stress and bioenergetic status in blood mononuclear cells (BMCs) and its association to headache symptoms in FM patients. The effects of oral coenzyme Q10 (CoQ10) supplementation on biochemical markers and clinical improvement were also evaluated. Methods We studied 20 FM patients and 15 healthy controls. Clinical parameters were evaluated using the Fibromyalgia Impact Questionnaire (FIQ), visual analogues scales (VAS), and the Headache Impact Test (HIT-6). Oxidative stress was determined by measuring CoQ10, catalase and lipid peroxidation (LPO) levels in BMCs. Bioenergetic status was assessed by measuring ATP levels in BMCs. Results We found decreased CoQ10, catalase and ATP levels in BMCs from FM patients as compared to normal control (P<0.05 and P<0.001, respectively) We also found increased level of LPO in BMCs from FM patients as compared to normal control (P<0.001). Significant negative correlations between CoQ10 or catalase levels in BMCs and headache parameters were observed (r = −0.59, P<0.05; r = −0.68, P<0.05, respectively). Furthermore, LPO levels showed a significant positive correlation with HIT-6 (r = 0.33, P<0.05). Oral CoQ10 supplementation restored biochemical parameters and induced a significant improvement in clinical and headache symptoms (P<0.001). Discussion The results of this study suggest a role for mitochondrial dysfunction and oxidative stress in the headache symptoms associated with FM. CoQ10 supplementation should be examined in a larger placebo controlled trial as a possible treatment in FM. PMID:22532869

Coenzyme Q10 supplementation downregulates the increase of monocytes expressing toll-like receptor 4 in response to 6-day intensive training in kendo athletes.

PubMed

Shimizu, Kazuhiro; Kon, Michihiro; Tanimura, Yuko; Hanaoka, Yukichi; Kimura, Fuminori; Akama, Takao; Kono, Ichiro

2015-06-01

This study examined changes in toll-like receptor 4 (TLR-4)-expressing monocytes and lymphocyte subpopulations in response to continuous intensive exercise training in athletes, as well as the effect of coenzyme Q10 (CoQ10) supplementation on these changes. Eighteen male elite kendo athletes in Japan were randomly assigned to a CoQ10-supplementation group (n = 9) or a placebo-supplementation group (n = 9) using a double-blind method. Subjects in the CoQ10 group took 300 mg CoQ10 per day for 20 days. Subjects in the placebo group took the same dosage of placebo. All subjects practiced kendo 5.5 h per day for 6 consecutive days during the study period. Blood samples were collected 2 weeks before training, on the first day (day 1), third day (day 3), and fifth day of training (day 5), and 1 week after the training period (post-training) to ascertain TLR-4(+)/CD14(+) monocyte and lymphocyte subpopulations (CD3(+), CD4(+), CD8(+), CD28(+)/CD4(+), CD28(+)/CD8(+), and CD56(+)/CD3(-) cells) using flow cytometry analysis. The group × time interaction for TLR-4(+)/CD14(+) cells did not reach significance (p = 0.08). Within the CoQ10 group, the absolute number of TLR-4(+)/CD14(+) cells was significantly higher only at day 5. The placebo group showed a significant increase in the absolute number of TLR-4(+)/CD14(+) cells at day 3, day 5, and post-training (p < 0.05). There was no significant group × time interaction for any lymphocyte subpopulation. CD3(+), CD8(+), and CD56(+)/CD3(-) cells were significantly reduced at day 3 in both groups (p < 0.05). In conclusion, CoQ10 supplementation might downregulate the increase of TLR-4-expressing monocytes in response to continuous strenuous exercise training in kendo athletes.

Oxidative stress correlates with headache symptoms in fibromyalgia: coenzyme Q₁₀ effect on clinical improvement.

PubMed

Cordero, Mario D; Cano-García, Francisco Javier; Alcocer-Gómez, Elísabet; De Miguel, Manuel; Sánchez-Alcázar, José Antonio

2012-01-01

Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology and a wide spectrum of symptoms such as allodynia, debilitating fatigue, joint stiffness and migraine. Recent studies have shown some evidences demonstrating that oxidative stress is associated to clinical symptoms in FM of fibromyalgia. We examined oxidative stress and bioenergetic status in blood mononuclear cells (BMCs) and its association to headache symptoms in FM patients. The effects of oral coenzyme Q(10) (CoQ(10)) supplementation on biochemical markers and clinical improvement were also evaluated. We studied 20 FM patients and 15 healthy controls. Clinical parameters were evaluated using the Fibromyalgia Impact Questionnaire (FIQ), visual analogues scales (VAS), and the Headache Impact Test (HIT-6). Oxidative stress was determined by measuring CoQ(10), catalase and lipid peroxidation (LPO) levels in BMCs. Bioenergetic status was assessed by measuring ATP levels in BMCs. We found decreased CoQ(10), catalase and ATP levels in BMCs from FM patients as compared to normal control (P < 0.05 and P < 0.001, respectively) We also found increased level of LPO in BMCs from FM patients as compared to normal control (P < 0.001). Significant negative correlations between CoQ(10) or catalase levels in BMCs and headache parameters were observed (r  = -0.59, P < 0.05; r  =  -0.68, P < 0.05, respectively). Furthermore, LPO levels showed a significant positive correlation with HIT-6 (r = 0.33, P<0.05). Oral CoQ(10) supplementation restored biochemical parameters and induced a significant improvement in clinical and headache symptoms (P < 0.001). The results of this study suggest a role for mitochondrial dysfunction and oxidative stress in the headache symptoms associated with FM. CoQ10 supplementation should be examined in a larger placebo controlled trial as a possible treatment in FM.

The relationships between clinical outcome and the levels of total antioxidant capacity (TAC) and coenzyme Q (CoQ 10) in children with pandemic influenza (H 1 N1) and seasonal flu.

PubMed

Kelekçi, S; Evliyaoğlu, O; Sen, V; Yolbaş, I; Uluca, U; Tan, I; Gürkan, M F

2012-08-01

This study was planned to evaluate the relationships between the levels of total antioxidant capacity (TAC) and Coenzyme Q (CoQ10) and clinical outcome in hospitalized children with pandemic influenza (H1N1). Serum copper (Cu) and zinc (Zn) levels were also determined to evaluate the changings of oxidative stress's enzyme activities depending on their cofactor concentrations. Children with suspected H1N1 virus infection were hospitalized and nasal swabs were sent to laboratory for confirmation of H1N1 by rRT-PCR assay. Age and sex matched 31 healthy children were included as Control Group. Total antioxidant capacity and CoQ10 were determined by spectrophotometry and HPLC, respectively, and Cu and Zn were determined using atomic absorption spectrometer. Totally 28 children had H1N1 and 37 children had seasonal influenza (SI). TAC, CoQ10 and Zn levels were found to be significantly decreased in H1N1 patients (1.01 +/- 0.19, 752.2 +/- 163, 69 +/- 27, respectively) compared to Control Group (1.64 +/- 0.36, 934 +/- 21, 92 +/- 4, respectively). Seasonal Influenza group had significantly decreased TAC and Zn levels (1.31 +/- 0.27, 78 +/- 34 respectively) compared with control group (1.64 +/- 0.36, 92 +/-41, respectively). CoQ10 levels were also found as decreased in H1N1 compared to seasonal influenza (752.2 +/- 163 vs 1022 +/- 199, p = 0.003). There was a significant correlation between CoQ10 levels of sera and chest radiographic findings of patients with H1N1 pneumonia. No significant differences were found in serum Cu levels between patients with H1N1 and SI or control group (150 +/- 45 vs 127 +/- 37, p = 0.215). CONCLUSIONS, Pandemic influenza infection had increased oxidative stress compared to the seasonal influenza.

Uptake of exogenous coenzyme Q and transport to mitochondria is required for bc1 complex stability in yeast coq mutants.

PubMed

Santos-Ocaña, Carlos; Do, Thai Q; Padilla, Sergio; Navas, Placido; Clarke, Catherine F

2002-03-29

Coenzyme Q (Q) is an essential component of the mitochondrial respiratory chain in eukaryotic cells but also is present in other cellular membranes where it acts as an antioxidant. Because Q synthesis machinery in Saccharomyces cerevisiae is located in the mitochondria, the intracellular distribution of Q indicates the existence of intracellular Q transport. In this study, the uptake of exogenous Q(6) by yeast and its transport from the plasma membrane to mitochondria was assessed in both wild-type and in Q-less coq7 mutants derived from four distinct laboratory yeast strains. Q(6) supplementation of medium containing ethanol, a non-fermentable carbon source, rescued growth in only two of the four coq7 mutant strains. Following culture in medium containing dextrose, the added Q(6) was detected in the plasma membrane of each of four coq7 mutants tested. This detection of Q(6) in the plasma membrane was corroborated by measuring ascorbate stabilization activity, as catalyzed by NADH-ascorbate free radical reductase, a transmembrane redox activity that provides a functional assay of plasma membrane Q(6). These assays indicate that each of the four coq7 mutant strains assimilate exogenous Q(6) into the plasma membrane. The two coq7 mutant strains rescued by Q(6) supplementation for growth on ethanol contained mitochondrial Q(6) levels similar to wild type. However, the content of Q(6) in mitochondria from the non-rescued strains was only 35 and 8%, respectively, of that present in the corresponding wild-type parental strains. In yeast strains rescued by exogenous Q(6), succinate-cytochrome c reductase activity was partially restored, whereas non-rescued strains contained very low levels of activity. There was a strong correlation between mitochondrial Q(6) content, succinate-cytochrome c reductase activity, and steady state levels of the cytochrome c(1) polypeptide. These studies show that transport of extracellular Q(6) to the mitochondria operates in yeast but is strain-dependent. When Q biosynthesis is disrupted in yeast strains with defects in the intracellular transport of exogenous Q, the bc(1) complex is unstable. These results indicate that delivery of exogenous Q(6) to mitochondria is required fore activity and stability of the bc(1) complex in yeast coq mutants.

Revealing the hidden structures of an historical bridge by high resolution geophysical methods : A case study of Pont de Coq, France

NASA Astrophysics Data System (ADS)

Antoine, R.; Fauchard, C.

2012-04-01

In the last decades, public institutions have shown an increased interest in heritage conservation and monuments protection. Geophysical methods have been used for 20 years as powerful tools to assist in the curation of buildings. Ancient masonry bridges usually exhibit a complex structure/geometry. This complexity makes the use of combined geophysical methods highly necessary to obtain a meaningful model of the internal structure of such constructions and their environment. A high resolution geophysical survey was carried out at a stone arch bridge called Pont de Coq and located near Menerval, Normandy (France) in 2011. This decameter-sized bridge was built 400 years ago and crosses the Epte river, which is a tributary of the Seine river. The main objective of this work was to evaluate the structural state of the bridge and its vicinities. Two complementary methods were used : Electrical Resistivity tomography (ERT) and Ground Penetrating radar (GPR). Several profiles were realized along the road crossing the bridge and transversally to the construction, as well as on the two banks of the Epte river. High resolution electrical resistivity data were obtained both in the horizontal and vertical direction up to 8 meter-depth by two ERT methods (Wenner/Schlumberger and dipole-dipole). The GPR was used with shielded antennas at three different frequencies (200 MHz, 400 MHz and 1.5 GHz). This approach lead to the investigation of the subsurface up to approximately 6 meters-depth, with a resolution in the range of 0.04 m-0.40m. An excellent correlation is obtained between the ERT and the GPR methods, allowing us to propose a precise structural model of the Pont de Coq and to characterize the soil under the building. Several anomalies are observed within the roadway of the bridge at 50 cm-depth, as well as within the vaulting, corresponding to the presence of voids and a root network which lead to the slow destruction of the structure.

Tactics for mechanized reasoning: a commentary on Milner (1984) ‘The use of machines to assist in rigorous proof’

PubMed Central

Gordon, M. J. C.

2015-01-01

Robin Milner's paper, ‘The use of machines to assist in rigorous proof’, introduces methods for automating mathematical reasoning that are a milestone in the development of computer-assisted theorem proving. His ideas, particularly his theory of tactics, revolutionized the architecture of proof assistants. His methodology for automating rigorous proof soundly, particularly his theory of type polymorphism in programing, led to major contributions to the theory and design of programing languages. His citation for the 1991 ACM A.M. Turing award, the most prestigious award in computer science, credits him with, among other achievements, ‘probably the first theoretically based yet practical tool for machine assisted proof construction’. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society. PMID:25750147

Nano-encapsulation of coenzyme Q10 using octenyl succinic anhydride modified starch

USDA-ARS?s Scientific Manuscript database

Octenyl succinic anhydride modified starch (OSA-ST) was used to encapsulate Coenzyme Q10 (CoQ10). CoQ10 was dissolved in rice bran oil (RBO), and incorporated into an aqueous OSA-ST solution. High pressure homogenization (HPH) of the mixture was conducted at 170 MPa for 5-6 cycles. The resulting ...

[Modulation of oxidative stresses in human aging skin].

PubMed

Blatt, T; Mundt, C; Mummert, C; Maksiuk, T; Wolber, R; Keyhani, R; Schreiner, V; Hoppe, U; Schachtschabel, D O; Stäb, F

1999-04-01

Oxidative stress (UV irradiation, free radicals) plays a significant role in aging. Coenzyme Q10 (CoQ10) and exogenously applied antioxidants can significantly reduce the formation of oxidative stress with increasing age. In our in vitro and in vivo experiments concerning the parameters of ultraweak photon emission (UPE), intracellular thiol status, mitochondrial membrane potential and cell vitality, we demonstrated a diminished resistance in keratinocytes of old donors against UV irradiation. This reduced epidermal resistance against oxidative stressors, i.e. UV irradiation, can be improved by topical application of CoQ10 and antioxidants like alpha-glucosylrutin (15). Furthermore, our in vivo investigations show that wrinkles around the region of the eyes ("crow feet") could be reduced by long-term application of CoQ10.

Coq Tacticals and PVS Strategies: A Small Step Semantics

NASA Technical Reports Server (NTRS)

Kirchner, Florent

2003-01-01

The need for a small step semantics and more generally for a thorough documentation and understanding of Coq's tacticals and PVS's strategies arise with their growing use and the progressive uncovering of their subtleties. The purpose of the following study is to provide a simple and clear formal framework to describe their detailed semantics, and highlight their differences and similarities.

Supplementing Rhodobacter sphaeroides in the diet of lactating Holstein cows may naturally produce coenzyme Q10-enriched milk

PubMed Central

Bae, Gui-Seck; Choi, Ahreum; Yeo, Joon Mo; Kim, Jong Nam; Song, Jaeyong; Kim, Eun Joong; Chang, Moon Baek

2018-01-01

Objective To examine the effects of Rhodobacter sphaeroides (R. sphaeroides) supplementation as a direct-fed microbial (DFM) on rumen fermentation in dairy cows and on coenzyme Q10 (CoQ10) transition into milk, an in vitro rumen simulation batch culture and an in vivo dairy cow experiment were conducted. Methods The characteristics of in vitro ruminal fermentation were investigated using rumen fluids from six cannulated Holstein dairy cows at 2 h post-afternoon feeding. A control treatment was included in the experiments based on a typified total mixed ration (TMR) for lactating dairy cows, which was identical to the one used in the in vivo study, plus R. sphaeroides at 0.1%, 0.3%, and 0.5% TMR dry matter. The in vivo study employed six ruminally cannulated lactating Holstein cows randomly allotted to either the control TMR (C-TMR) treatment or to a diet supplemented with a 0.5% R. sphaeroides culture (S-TMR, dry matter basis) ad libitum. The presence of R. sphaeroides was verified using denaturing gradient gel electrophoresis (DGGE) applied to the bacterial samples obtained from the in vivo study. The concentration of CoQ10 in milk and in the supernatant from the in vitro study was determined using high performance liquid chromatography. Results The results of the in vitro batch culture and DGGE showed that the concentration of CoQ10 significantly increased after 2 h of R. sphaeroides supplementation above 0.1%. When supplemented to the diet of lactating cows at the level of 0.5%, R. sphaeroides did not present any adverse effect on dry matter intake and milk yield. However, the concentration of CoQ10 in milk dramatically increased, with treated cows producing 70.9% more CoQ10 than control cows. Conclusion The CoQ10 concentration in milk increased via the use of a novel DFM, and R. sphaeroides might be used for producing value-added milk and dairy products in the future. PMID:28427254

Why did high-dose rosuvastatin not improve cardiac remodeling in chronic heart failure? Mechanistic insights from the UNIVERSE study.

PubMed

Ashton, Emma; Windebank, Emma; Skiba, Marina; Reid, Christopher; Schneider, Hans; Rosenfeldt, Franklin; Tonkin, Andrew; Krum, Henry

2011-02-03

Statins are often prescribed for prevention of atherosclerotic outcomes in patients who have chronic heart failure (CHF), if this has an ischaemic etiology. These agents may also possess additional properties, independent of effects on blood lipid levels, which may have an effect on cardiac remodeling. However, beneficial effects were not observed in the recent UNIVERSE trial. We prospectively planned a sub-study of UNIVERSE to explore relevant mechanistic effects of rosuvastatin, including effects on collagen turnover and plasma coenzyme Q10 (CoQ) levels. Additionally, CoQ levels in CHF patients receiving chronic statin therapy were measured. CoQ levels were significantly reduced after 26 weeks of rosuvastatin statin therapy (n = 32), compared to placebo (n = 37) in CHF patients in UNIVERSE trial. Patients with CHF (n = 56) matched for age, gender and severity of disease who had been taking statins for 12 months or longer had CoQ levels of 847 ± 344 nmol/L, significantly lower than 1065.4 ± 394 nmol/L in UNIVERSE patients at baseline (p = 0.0001). Serum types I and III N-terminal procollagen peptide (PINP and PIIINP), measures of collagen turnover which can contribute to cardiac fibrosis were significantly increased in the rosuvastatin group compared to baseline in UNIVERSE patients (PINP: p = 0.03, PIIINP: p = 0.001). In conclusion putative beneficial effects of statin therapy on cardiac remodeling in UNIVERSE may have been negated by increases in collagen turnover markers as well as a reduction in plasma CoQ levels in these patients with CHF. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: A double blind randomized clinical trial.

PubMed

Sanoobar, Meisam; Dehghan, Parvin; Khalili, Mohammad; Azimi, Amirreza; Seifar, Fatemeh

2016-01-01

Multiple sclerosis (MS) is the chronic inflammatory and demyelinating disorder of central nervous system which is accompanied with disability and negative life style changes such as fatigue and depression. The aim of this study is to investigate the effect of coenzyme Q10 (CoQ10) supplementation on fatigue and depression in patients with MS. We performed a randomized, double-blinded, placebo-controlled trial to determine the effect of CoQ10 supplement (500 mg/day) vs. placebo for 12 weeks. Fatigue symptoms were quantified by means of fatigue severity scale (FSS) and the Beck depression inventory (BDI) was used to assess depressive symptoms. A significant decrease of FSS was observed in CoQ10 group during the intervention (P = 0.001) and significant increase of FSS change was observed within placebo group (P = 0.001). Repeated measure analysis of variance showed a significant time-by-treatment interaction for FSS (baseline 41.5 ± 15.6 vs. endpoint 45 ± 13.6; F1,45 = 55.23, P < 0.001, η(2) = 0.56) and BDI (baseline 17.8 ± 12.2 vs. endpoint 20.4 ± 11.4; F1,45 = 40.3, P < 0.001, η(2) = 0.48), indicating significant decrease of FSS and BDI in CoQ10 group compared to placebo group. Our study suggests that CoQ10 supplementation (500 mg/day) can improve fatigue and depression in patients with multiple sclerosis.

POTENTIAL ADMINISTRATION OF LIPOIC ACID AND COENZYME Q AGAINST ADIPOGENSIS: TARGET FOR WEIGHT REDUCTION.

PubMed

Al-Ghamdi, Maryam A; Choudhry, Hani; Al-Doghather, Huda A; Huwait, Etimad H; Kumosani, Taha A; Moselhy, Said S

2017-01-01

Body overweight and obesity were considered as a risk factor for many systemic diseases as diabetic hypertension, cardiovascular diseases, and some cancers. The lipoic acid and Co Q are considered as coenzymes needed for enhancement metabolic rate. The goal of this study is to evaluate the anti-obese effect of lipoic acid alone or combined with Co-Q in rats. Ninety male albino rats (100-150g) were used in this study, divided into six groups (15 each). Group I: Normal rats fed normal diet. Group II: Rats fed high fat diet (HFD). Group III: Rats fed HFD were given lipoic acid (10 μg/kg b w/day) intra-gastric by stomach tube. Group IV: Rats fed HFD were given Co-Q (10 μg/kg b.w/day) intra-gastric. Group V: Rats fed HFD were given lipoic acid (50 mg/kg b w/day) and Co-Q (10 μg/kg b. w/day). Group VI: Rats were given orlistat intra-gastric (10 mg/kg b w/day) as positive control for 6 weeks. Serum was subjected for determination of lipid profile, liver function tests atherogenic factor and lipoprotein lipase. It was found that treatment with lipoic acid or Co-Q or combined showed increase in the activity of lipoprotein lipase ( P < 0.001) and reduction of atherogenic effect and obesity index ( P <0.001). The effect of combined gives good results than orlistat or individual treatment. lipoic acid combined with Co-Q increase fat oxidation and prevent fat accumulation. The consumption of lipoic acid daily promotes fat oxidation and prevents its accumulation in visceral tissues. Further studies should be carried out to examine the mechanistic signals of these nutrients that helps in weight management.

POTENTIAL ADMINISTRATION OF LIPOIC ACID AND COENZYME Q AGAINST ADIPOGENSIS: TARGET FOR WEIGHT REDUCTION

PubMed Central

AL-Ghamdi, Maryam A.; Choudhry, Hani; AL-Doghather, Huda A.; Huwait, Etimad H.; Kumosani, Taha A; Moselhy, Said S

2017-01-01

Background: Body overweight and obesity were considered as a risk factor for many systemic diseases as diabetic hypertension, cardiovascular diseases, and some cancers. The lipoic acid and Co Q are considered as coenzymes needed for enhancement metabolic rate. The goal of this study is to evaluate the anti-obese effect of lipoic acid alone or combined with Co-Q in rats. Materials and Methods: Ninety male albino rats (100-150g) were used in this study, divided into six groups (15 each). Group I: Normal rats fed normal diet. Group II: Rats fed high fat diet (HFD). Group III: Rats fed HFD were given lipoic acid (10 μg/kg b w/day) intra-gastric by stomach tube. Group IV: Rats fed HFD were given Co-Q (10 μg/kg b.w/day) intra-gastric. Group V: Rats fed HFD were given lipoic acid (50 mg/kg b w/day) and Co-Q (10 μg/kg b. w/day). Group VI: Rats were given orlistat intra-gastric (10 mg/kg b w/day) as positive control for 6 weeks. Serum was subjected for determination of lipid profile, liver function tests atherogenic factor and lipoprotein lipase. Results: It was found that treatment with lipoic acid or Co-Q or combined showed increase in the activity of lipoprotein lipase (P < 0.001) and reduction of atherogenic effect and obesity index (P <0.001). The effect of combined gives good results than orlistat or individual treatment. Conclusion: lipoic acid combined with Co-Q increase fat oxidation and prevent fat accumulation. The consumption of lipoic acid daily promotes fat oxidation and prevents its accumulation in visceral tissues. Further studies should be carried out to examine the mechanistic signals of these nutrients that helps in weight management. PMID:28480405

Compound Heterozygous Inheritance of Mutations in Coenzyme Q8A Results in Autosomal Recessive Cerebellar Ataxia and Coenzyme Q10 Deficiency in a Female Sib-Pair.

PubMed

Jacobsen, Jessie C; Whitford, Whitney; Swan, Brendan; Taylor, Juliet; Love, Donald R; Hill, Rosamund; Molyneux, Sarah; George, Peter M; Mackay, Richard; Robertson, Stephen P; Snell, Russell G; Lehnert, Klaus

2017-11-21

Autosomal recessive ataxias are characterised by a fundamental loss in coordination of gait with associated atrophy of the cerebellum. There is significant clinical and genetic heterogeneity amongst inherited ataxias; however, an early molecular diagnosis is essential with low-risk treatments available for some of these conditions. We describe two female siblings who presented early in life with unsteady gait and cerebellar atrophy. Whole exome sequencing revealed compound heterozygous inheritance of two pathogenic mutations (p.Leu277Pro, c.1506+1G>A) in the coenzyme Q8A gene (COQ8A), a gene central to biosynthesis of coenzyme Q (CoQ). The paternally derived p.Leu277Pro mutation is predicted to disrupt a conserved motif in the substrate-binding pocket of the protein, resulting in inhibition of CoQ 10 production. The maternal c.1506+1G>A mutation destroys a canonical splice donor site in exon 12 affecting transcript processing and subsequent protein translation. Mutations in this gene can result in primary coenzyme Q 10 deficiency type 4, which is characterized by childhood onset of cerebellar ataxia and exercise intolerance, both of which were observed in this sib-pair. Muscle biopsies revealed unequivocally low levels of CoQ 10, and the siblings were subsequently established on a therapeutic dose of CoQ 10 with distinct clinical evidence of improvement after 1 year of treatment. This case emphasises the importance of an early and accurate molecular diagnosis for suspected inherited ataxias, particularly given the availability of approved treatments for some subtypes.

Mitophagy is required for acute cardioprotection by simvastatin.

PubMed

Andres, Allen M; Hernandez, Genaro; Lee, Pamela; Huang, Chengqun; Ratliff, Eric P; Sin, Jon; Thornton, Christine A; Damasco, Marichris V; Gottlieb, Roberta A

2014-11-10

We have shown that autophagy and mitophagy are required for preconditioning. While statin's cardioprotective effects are well known, the role of autophagy/mitophagy in statin-mediated cardioprotection is not. In this study, we used HL-1 cardiomyocytes and mice subjected to ischemia/reperfusion to elucidate the mechanism of statin-mediated cardioprotection. HL-1 cardiomyocytes exposed to simvastatin for 24 h exhibited diminished protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, increased activation of unc-51-like kinase 1, and upregulation of autophagy and mitophagy. Similar findings were obtained in hearts of mice given simvastatin. Mevalonate abolished simvastatin's effects on Akt/mTOR signaling and autophagy induction in HL-1 cells, indicating that the effects are mediated through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Simvastatin-treated HL-1 cells exhibited mitochondrial translocation of Parkin and p62/SQSTM1, fission, and mitophagy. Because Parkin is required for mitophagy and is expressed in heart, we investigated the effect of simvastatin on infarct size in Parkin knockout mice. Simvastatin reduced infarct size in wild-type mice but showed no benefit in Parkin knockout mice. Inhibition of HMG-CoA reductase limits mevalonate availability for both cholesterol and coenzyme Q10 (CoQ) biosynthesis. CoQ supplementation had no effect on statin-induced Akt/mTOR dephosphorylation or macroautophagy in HL-1 cells, but it potently blocked mitophagy. Importantly, CoQ supplementation abolished statin-mediated cardioprotection in vivo. Acute simvastatin treatment suppresses mTOR signaling and triggers Parkin-dependent mitophagy, the latter which is required for cardioprotection. Coadministration of CoQ with simvastatin impairs mitophagy and cardioprotection. These results raise the concern that CoQ may interfere with anti-ischemic benefits of statins mediated through stimulation of mitophagy.

Efficacy of eyedrops containing cross-linked hyaluronic acid and coenzyme Q10 in treating patients with mild to moderate dry eye.

PubMed

Postorino, Elisa I; Rania, Laura; Aragona, Emanuela; Mannucci, Carmen; Alibrandi, Angela; Calapai, Gioacchino; Puzzolo, Domenico; Aragona, Pasquale

2018-01-01

Dry eye disease (DED) is a common condition causing substantial burden. A randomized, controlled, single-masked study was performed in 40 patients with mild to moderate DED to evaluate the efficacy and safety of a collyrium based on crosslinked hyaluronic acid (XLHA) with coenzyme Q10 (CoQ10). Enrolled subjects were divided into 2 groups: group A, treated with XLHA + CoQ10; and group B, treated with hyaluronic acid (HA). Eyedrops were administered 4 times daily for 3 months. The Ocular Surface Disease Index (OSDI) questionnaire, tear break-up time (TBUT), corneal and conjunctival staining, and meibomian gland assessment (MGD) were evaluated; furthermore, corneal aesthesiometry, in vivo corneal confocal microscopy, visual acuity, intraocular pressure (IOP), and fundus examination were performed. At the end of treatment, OSDI score significantly decreased in groups A and B (p<0.01 and p<0.05, respectively); the decrease was significantly higher in group A. Corneal staining decreased in both groups, with lower scores in group A. The MGD was significantly ameliorated in group A patients. No differences were found for corneal aesthesiometry or TBUT. Epithelial cell reflectivity was significantly reduced only in group A. For keratocytes and stromal matrix parameters, there was a significant improvement in group A. No changes were found for visual acuity, IOP, or fundus examination. The XLHA + CoQ10 treatment showed greater effectiveness in DED compared to HA alone, probably due to the longer permanency on ocular surface and the antioxidant activity of CoQ10. Therefore, XLHA + CoQ10 eyedrops could represent a new possibility in dry eye treatment.

Reduction of coenzyme q10 content: a possible effect of isoproterenol on heart failure and myocardial infarction in rat.

PubMed

Khorrami, A; Garjani, A; Ghanbarzadeh, S; Andalib, S

2014-04-01

Myocardial infarction (MI) was induced by subcutaneous injection of isoproterenol (ISO) to investigate the effect of ISO on Coenzyme Q10 (CoQ10) content of myocardium and subsequent effects on lipid peroxidation, electrocardiogram pattern and hemodynamic parameters of the rat's heart.36 male Wistar rats were divided randomly into 6 groups. To induce heart failure (HF) and MI, 10 and 100 mg/kg of ISO was administered subcutaneously for 10 and 2 consecutive days, respectively. The effects of ISO on myocardium CoQ10 content, concentration of malondialdehyde, ECG pattern and hemodynamic parameters of heart were analyzed.ISO-treated rats showed significant alteration in heart hemodynamic parameters such as reduction of left-ventricular systolic pressure, maximum and minimum rate of developed left ventricular pressure, besides increase of left ventricular end-diastolic pressure. Significant depletion of heart CoQ10 content (from 4.57 and 4.55 µg/100 mg tissue in control groups to 2.85 and 2.89 µg/100 mg tissue in ISO-induced HF and MI groups respectively) and increase in tissue levels of malondialdehyde (47.1 and 53.8 nmol/100 mg tissue in ISO-induced HF and MI groups, respectively) were also observed in ISO-treated animals compared with the normal animals (17.4 and 18.8 nmol/100 mg tissue in control groups, respectively). Additionally CoQ10 improved ISO effects on hemodynamic parameters and ECG pattern in ISO-induced HF and myocardial injury.The present findings have demonstrated that the cardiotoxic effects of ISO such as oxidative damage and hemodynamic declination might be related to depletion of CoQ10 concentration. © Georg Thieme Verlag KG Stuttgart · New York.

Coenzyme Q10 in Cardiovascular and Metabolic Diseases: Current State of the Problem.

PubMed

Zozina, Vladlena I; Covantev, Serghei; Goroshko, Olga A; Krasnykh, Liudmila M; Kukes, Vladimir G

2018-04-15

The burden of cardiovascular and metabolic diseases is increasing with every year. Although the management of these conditions has improved greatly over the years it is still far from perfect. With all of this in mind, there is a need for new methods of prophylaxis and treatment. Coenzyme Q10 (CoQ10) is an essential compound of the human body. There is growing evidence that CoQ10 is tightly linked to cardiometabolic disorders. Its supplementation can be useful in a variety of chronic and acute disorders. This review analyses the role of CoQ10 in hypertension, ischemic heart disease, myocardial infarction, heart failure, viral myocarditis, cardiomyopathies, cardiac toxicity, dyslipidemia, obesity, type 2 diabetes mellitus, metabolic syndrome, cardiac procedures and resuscitation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Wireless Sensors Grouping Proofs for Medical Care and Ambient Assisted-Living Deployment

PubMed Central

Trček, Denis

2016-01-01

Internet of Things (IoT) devices are rapidly penetrating e-health and assisted living domains, and an increasing proportion among them goes on the account of computationally-weak devices, where security and privacy provisioning alone are demanding tasks, not to mention grouping proofs. This paper, therefore, gives an extensive analysis of such proofs and states lessons learnt to avoid possible pitfalls in future designs. It sticks with prudent engineering techniques in this field and deploys in a novel way the so called non-deterministic principle to provide not only grouping proofs, but (among other) also privacy. The developed solution is analyzed by means of a tangible metric and it is shown to be lightweight, and formally for security. PMID:26729131

Wireless Sensors Grouping Proofs for Medical Care and Ambient Assisted-Living Deployment.

PubMed

Trček, Denis

2016-01-02

Internet of Things (IoT) devices are rapidly penetrating e-health and assisted living domains, and an increasing proportion among them goes on the account of computationally-weak devices, where security and privacy provisioning alone are demanding tasks, not to mention grouping proofs. This paper, therefore, gives an extensive analysis of such proofs and states lessons learnt to avoid possible pitfalls in future designs. It sticks with prudent engineering techniques in this field and deploys in a novel way the so called non-deterministic principle to provide not only grouping proofs, but (among other) also privacy. The developed solution is analyzed by means of a tangible metric and it is shown to be lightweight, and formally for security.

Cloning and Characterizing Genes Involved in Monoterpene Induced Mammary Tumor Regression.

DTIC Science & Technology

1996-10-01

causes morphologic differentiation within 4 hours as characterized by neurite outgrowths (12). Monoterpenes inhibit enzymes in the mevalonate-lipid...metabolism pathway, including a selective inhibition of isoprenylation of 21-26 kDa small G proteins (13-15) and inhibition of ubiquinone ( CoQ ) and...Letters 269(2), 305-10 18 FOOTNOTES 1 The abbreviations used are: DMBA, 7,12-dimethylbenz[a]anthracene; NMU, N-methyl-N- nitrosourea; CoQ , ubiquinone

Antioxidant status (CoQ10 and Vit. E levels) and immunohistochemical analysis of soft tissues in periodontal diseases.

PubMed

Battino, Maurizio; Bompadre, Stefano; Politi, Alessia; Fioroni, Massimiliano; Rubini, Corrado; Bullon, Pedro

2005-01-01

Reactive oxygen species and antioxidant status in periodontal diseases and periodontal-related pathologies is an item of growing interest. Immunohistochemical approach may be usefully employed in the study of soft tissues affected by periodontal disease, giving valuable information on tissue morphology and vascular proliferation that depends directly on the inflammatory state. In order to study CoQ(10) and vitamin E content in healthy gingiva and in gingivitis a new adaptation to previously published methods for their determination was adopted. During gingivitis tissue displayed a large inflammatory infiltration in the lamina propria and a VEGF positive squamous epithelium. The inflammatory infiltration consisted mainly of lymphocytes, plasma cells and neutrophils. Vitamin E dramatically decreased and CoQ(10) remained unchanged despite the increased amount of cells present in the periodontally affected tissues, indicating that continuous oxidative stress which occurred in these structure affected the antioxidant pattern of the tissue.

Inhibition of glycerophosphate-dependent H2O2 generation in brown fat mitochondria by idebenone.

PubMed

Rauchová, Hana; Vrbacký, Marek; Bergamini, Christian; Fato, Romana; Lenaz, Giorgio; Houstek, Josef; Drahota, Zdenek

2006-01-06

The established protective effect of coenzyme Q (CoQ) analogs is dependent on the location of reactive oxygen species (ROS) generation. One of these analogs--idebenone (hydroxydecyl-ubiquinone) is used as an antioxidative therapeutic drug. We tested its scavenging effect on the glycerophosphate (GP)-dependent ROS production as this enzyme was shown as a new site in the mitochondrial respiratory chain where ROS can be generated. We observed that idebenone inhibits both GP- and succinate-dependent ROS production. Idebenone and CoQ1 were found to be more efficient in the scavenging activity (IC50: 0.052 and 0.075 microM, respectively) than CoQ3 (IC50: 45.8 microM). Idebenone also inhibited ferricyanide (FeCN)-activated, GP-dependent ROS production. Our data thus extend previous findings on the scavenging effect of idebenone and show that it can also eliminate GP-dependent ROS generation.

6 CFR 27.325 - Burden of proof.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 6 Domestic Security 1 2010-01-01 2010-01-01 false Burden of proof. 27.325 Section 27.325 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY CHEMICAL FACILITY ANTI-TERRORISM STANDARDS Orders and Adjudications § 27.325 Burden of proof. The Assistant Secretary bears the initial...

6 CFR 27.325 - Burden of proof.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 6 Domestic Security 1 2011-01-01 2011-01-01 false Burden of proof. 27.325 Section 27.325 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY CHEMICAL FACILITY ANTI-TERRORISM STANDARDS Orders and Adjudications § 27.325 Burden of proof. The Assistant Secretary bears the initial...

6 CFR 27.325 - Burden of proof.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 6 Domestic Security 1 2013-01-01 2013-01-01 false Burden of proof. 27.325 Section 27.325 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY CHEMICAL FACILITY ANTI-TERRORISM STANDARDS Orders and Adjudications § 27.325 Burden of proof. The Assistant Secretary bears the initial...

6 CFR 27.325 - Burden of proof.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 6 Domestic Security 1 2014-01-01 2014-01-01 false Burden of proof. 27.325 Section 27.325 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY CHEMICAL FACILITY ANTI-TERRORISM STANDARDS Orders and Adjudications § 27.325 Burden of proof. The Assistant Secretary bears the initial...

6 CFR 27.325 - Burden of proof.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 6 Domestic Security 1 2012-01-01 2012-01-01 false Burden of proof. 27.325 Section 27.325 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY CHEMICAL FACILITY ANTI-TERRORISM STANDARDS Orders and Adjudications § 27.325 Burden of proof. The Assistant Secretary bears the initial...

Using Computer-Assisted Multiple Representations in Learning Geometry Proofs

ERIC Educational Resources Information Center

Wong, Wing-Kwong; Yin, Sheng-Kai; Yang, Hsi-Hsun; Cheng, Ying-Hao

2011-01-01

Geometry theorem proving involves skills that are difficult to learn. Instead of working with abstract and complicated representations, students might start with concrete, graphical representations. A proof tree is a graphical representation of a formal proof, with each node representing a proposition or given conditions. A computer-assisted…

Coenzyme Q10 Ameliorates Trimethyltin Chloride Neurotoxicity in Experimental Model of Injury in Dentate Gyrus of Hippocampus: A Histopathological and Behavioral Study

PubMed Central

Sakhaie, Mohammad Hassan; Soleimani, Mansoureh; Pirhajati, Vahid; Soleimani Asl, Sara; Madjd, Zahra; Mehdizadeh, Mehdi

2016-01-01

Background Coenzyme Q10 has antioxidative and free radical scavenging effects. CoQ10 supplementation is known to have neuroprotective effects in some neurodegenerative diseases, such as Parkinson’s disease and Huntington’s disease. Objectives The aim of this study was to evaluate both histopathologic and behavioral whether Coenzyme Q10 is protective against trimethyltin chloride (TMT) induced hippocampal damage. Materials and Methods This was an experimental study. Thirty-six Balb/c mice were divided into four groups, as follows: 1) control group; 2) sham group of mice that received a 100 µL intraperitoneal injection (IP) of sesame oil; 3) TMT group of mice that received a single 2.5 mg/kg/day IP injection of TMT; and 4) TMT + CoQ10 group of mice that received a 10 mg/kg IP injection of CoQ10. Body weight and Morris water maze (MWM) responses were investigated. In addition, the dentate gyrus neurons of the hippocampus were evaluated histopathologically by light and electron microscopes. Results This study revealed that the body weight scale was found to be significantly higher in the CoQ10 group (21.39 ± 2.70), compared to the TMT group (19.39 ± 2.74) (P < 0.05). In the TMT group, the animals showed body a weight loss that was significantly lower than that of the control group (22.33 ± 3.06) (P < 0.05). Our results showed that CoQ10 provided protection against MWM deficits. Furthermore, TMT impaired the ability of mice to locate the hidden platform, compared to the control group (P < 0.05). Microscopic studies showed that TMT caused histopathological changes in the dentate gyrus and increased the number of necrotic neurons (476 ± 78.51), compared to the control group (208 ± 40.84) (P < 0.001). But, CoQ10 significantly attenuated (31 9 ± 60.08) the density of necrotic neurons compared to TMT (P < 0.05). Conclusions The results of the present study indicate that Coenzyme Q10 diminished neuronal necrosis and improved learning memory. Part of its beneficial effect is due to its potential to discount oxidative stress. PMID:27781114

A Mouse Model of Familial ALS Has Increased CNS Levels of Endogenous Ubiquinol9/10 and Does Not Benefit from Exogenous Administration of Ubiquinol10

PubMed Central

Lucchetti, Jacopo; Marino, Marianna; Papa, Simonetta; Tortarolo, Massimo; Guiso, Giovanna; Pozzi, Silvia; Bonetto, Valentina; Caccia, Silvio; Beghi, Ettore; Bendotti, Caterina; Gobbi, Marco

2013-01-01

Oxidative stress and mitochondrial impairment are the main pathogenic mechanisms of Amyotrophic Lateral Sclerosis (ALS), a severe neurodegenerative disease still lacking of effective therapy. Recently, the coenzyme-Q (CoQ) complex, a key component of mitochondrial function and redox-state modulator, has raised interest for ALS treatment. However, while the oxidized form ubiquinone10 was ineffective in ALS patients and modestly effective in mouse models of ALS, no evidence was reported on the effect of the reduced form ubiquinol10, which has better bioavailability and antioxidant properties. In this study we compared the effects of ubiquinone10 and a new stabilized formulation of ubiquinol10 on the disease course of SOD1G93A transgenic mice, an experimental model of fALS. Chronic treatments (800 mg/kg/day orally) started from the onset of disease until death, to mimic the clinical trials that only include patients with definite ALS symptoms. Although the plasma levels of CoQ10 were significantly increased by both treatments (from <0.20 to 3.0–3.4 µg/mL), no effect was found on the disease progression and survival of SOD1G93A mice. The levels of CoQ10 in the brain and spinal cord of ubiquinone10- or ubiquinol10-treated mice were only slightly higher (≤10%) than the endogenous levels in vehicle-treated mice, indicating poor CNS availability after oral dosing and possibly explaining the lack of pharmacological effects. To further examine this issue, we measured the oxidized and reduced forms of CoQ9/10 in the plasma, brain and spinal cord of symptomatic SOD1G93A mice, in comparison with age-matched SOD1WT. Levels of ubiquinol9/10, but not ubiquinone9/10, were significantly higher in the CNS, but not in plasma, of SOD1G93A mice, suggesting that CoQ redox system might participate in the mechanisms trying to counteract the pathology progression. Therefore, the very low increases of CoQ10 induced by oral treatments in CNS might be not sufficient to provide significant neuroprotection in SOD1G93A mice. PMID:23936040

Loss of Bone Mineral Density Associated with Age in Male Rats Fed on Sunflower Oil Is Avoided by Virgin Olive Oil Intake or Coenzyme Q Supplementation

PubMed Central

Ochoa, Julio J.; Llamas-Elvira, José M.; López-Frías, Magdalena

2017-01-01

The role of dietary fat unsaturation and the supplementation of coenzyme Q have been evaluated in relation to bone health. Male Wistar rats were maintained for 6 or 24 months on two diets varying in the fat source, namely virgin olive oil, rich in monounsaturated fatty acids, or sunflower oil, rich in n-6 polyunsaturated fatty acids. Both dietary fats were supplemented or not with coenzyme Q10 (CoQ10). Bone mineral density (BMD) was evaluated in the femur. Serum levels of osteocalcin, osteopontin, receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), adrenocorticotropin (ACTH) and parathyroid hormone (PTH), as well as urinary F2-isoprostanes were measured. Aged animals fed on virgin olive oil showed higher BMD than those fed on sunflower oil. In addition, CoQ10 prevented the age-related decline in BMD in animals fed on sunflower oil. Urinary F2-isoprostanes analysis showed that sunflower oil led to the highest oxidative status in old animals, which was avoided by supplementation with CoQ10. In conclusion, lifelong feeding on virgin olive oil or the supplementation of sunflower oil on CoQ10 prevented, at least in part mediated by a low oxidative stress status, the age-related decrease in BMD found in sunflower oil fed animals. PMID:28661441

Does Oral Coenzyme Q10 Plus NADH Supplementation Improve Fatigue and Biochemical Parameters in Chronic Fatigue Syndrome?

PubMed Central

Cordero, Mario D.; Segundo, María José; Sáez-Francàs, Naia; Calvo, Natalia; Román-Malo, Lourdes; Aliste, Luisa; Fernández de Sevilla, Tomás; Alegre, José

2015-01-01

Abstract Chronic fatigue syndrome (CFS) is a chronic and extremely debilitating illness characterized by prolonged fatigue and multiple symptoms with unknown cause, diagnostic test, or universally effective treatment. Inflammation, oxidative stress, mitochondrial dysfunction, and CoQ10 deficiency have been well documented in CFS. We conducted an 8-week, randomized, double-blind placebo-controlled trial to evaluate the benefits of oral CoQ10 (200 mg/day) plus NADH (20 mg/day) supplementation on fatigue and biochemical parameters in 73 Spanish CFS patients. This study was registered in ClinicalTrials.gov (NCT02063126). A significant improvement of fatigue showing a reduction in fatigue impact scale total score (p<0.05) was reported in treated group versus placebo. In addition, a recovery of the biochemical parameters was also reported. NAD+/NADH (p<0.001), CoQ10 (p<0.05), ATP (p<0.05), and citrate synthase (p<0.05) were significantly higher, and lipoperoxides (p<0.05) were significantly lower in blood mononuclear cells of the treated group. These observations lead to the hypothesis that the oral CoQ10 plus NADH supplementation could confer potential therapeutic benefits on fatigue and biochemical parameters in CFS. Larger sample trials are warranted to confirm these findings. Antioxid. Redox Signal. 22, 679–685. PMID:25386668

Mitochondria-targeted molecules determine the redness of the zebra finch bill.

PubMed

Cantarero, Alejandro; Alonso-Alvarez, Carlos

2017-10-01

The evolution and production mechanisms of red carotenoid-based ornaments in animals are poorly understood. Recently, it has been suggested that enzymes transforming yellow carotenoids to red pigments (ketolases) in animal cells may be positioned in the inner mitochondrial membrane (IMM) intimately linked to the electron transport chain. These enzymes may mostly synthesize coenzyme Q 10 (coQ 10 ), a key redox-cycler antioxidant molecularly similar to yellow carotenoids. It has been hypothesized that this shared pathway favours the evolution of red traits as sexually selected individual quality indices by revealing a well-adjusted oxidative metabolism. We administered mitochondria-targeted molecules to male zebra finches ( Taeniopygia guttata ) measuring their bill redness, a trait produced by transforming yellow carotenoids. One molecule included coQ 10 (mitoquinone mesylate, MitoQ) and the other one (decyl-triphenylphosphonium; dTPP) has the same structure without the coQ 10 aromatic ring. At the highest dose, the bill colour of MitoQ and dTPP birds strongly differed: MitoQ birds' bills were redder and dTPP birds showed paler bills even compared to birds injected with saline only. These results suggest that ketolases are indeed placed at the IMM and that coQ 10 antioxidant properties may improve their efficiency. The implications for evolutionary theories of sexual signalling are discussed. © 2017 The Author(s).

Design, optimization and characterization of coenzyme Q10- and D-panthenyl triacetate-loaded liposomes

PubMed Central

Çelik, Burak; Sağıroğlu, Ali Asram; Özdemir, Samet

2017-01-01

Coenzyme Q10 (CoQ10) is a lipid-soluble molecule found naturally in many eukaryotic cells and is essential for electron transport chain and energy generation in mitochondria. D-Panthenyl triacetate (PTA) is an oil-soluble derivative of D-panthenol, which is essential for coenzyme A synthesis in the epithelium. Liposomal formulations that encapsulate both ingredients were prepared and optimized by applying response surface methodology for increased stability and skin penetration. The optimum formulation comprised 4.17 mg CoQ10, 4.22 mg PTA and 13.95 mg cholesterol per 100 mg of soy phosphatidylcholine. The encapsulation efficiency of the optimized formulation for CoQ10 and PTA was found to be 90.89%±3.61% and 87.84%±4.61%, respectively. Narrow size distribution was achieved with an average size of 161.6±3.6 nm, while a spherical and uniform shape was confirmed via scanning electron microscopy and transmission electron microscopy images. Cumulative release of 90.93% for PTA and 24.41% for CoQ10 was achieved after 24 hours of in vitro release study in sink conditions. Physical stability tests indicated that the optimized liposomes were suitable for storage at 4°C for at least 60 days. The results suggest that the optimized liposomal formulation would be a promising delivery system for both ingredients in various topical applications. PMID:28744121

Mitochondrial superoxide and coenzyme Q in insulin-deficient rats: increased electron leak

PubMed Central

Herlein, Judith A.; Fink, Brian D.; Henry, Dorlyne M.; Yorek, Mark A.; Teesch, Lynn M.

2011-01-01

Mitochondrial superoxide is important in the pathogeneses of diabetes and its complications. However, there is uncertainty regarding the intrinsic propensity of mitochondria to generate this radical. Studies to date suggest that superoxide production by mitochondria of insulin-sensitive target tissues of insulin-deficient rodents is reduced or unchanged. Moreover, little is known of the role of the Coenzyme Q (CoQ), whose semiquinone form reacts with molecular oxygen to generate superoxide. We measured reactive oxygen species (ROS) production, respiratory parameters, and CoQ content in mitochondria from gastrocnemius muscle of control and streptozotocin (STZ)-diabetic rats. CoQ content did not differ between mitochondria isolated from vehicle- or STZ-treated animals. CoQ also was unaffected by weight loss in the absence of diabetes (induced by caloric restriction). Under state 4 or state 3 conditions, both respiration and ROS release were reduced in diabetic mitochondria fueled with succinate, glutamate plus malate, or with all three substrates (continuous TCA cycle). However, H2O2 and directly measured superoxide production were substantially increased in gastrocnemius mitochondria of diabetic rats when expressed per unit oxygen consumed. On the basis of substrate and inhibitor effects, the mechanism involved multiple electron transport sites. More limited results using heart mitochondria were similar. ROS per unit respiration was greater in muscle mitochondria from diabetic compared with control rats during state 3, as well as state 4, while the reduction in ROS per unit respiration on transition to state 3 was less for diabetic mitochondria. In summary, ROS production is, in fact, increased in mitochondria from insulin-deficient muscle when considered relative to electron transport. This is evident on multiple energy substrates and in different respiratory states. CoQ is not reduced in diabetic mitochondria or with weight loss due to food restriction. The implications of these findings are discussed. PMID:21940403

Protection of rat skeletal muscle fibers by either L-carnitine or coenzyme Q10 against statins toxicity mediated by mitochondrial reactive oxygen generation

PubMed Central

La Guardia, P. G.; Alberici, L. C.; Ravagnani, F. G.; Catharino, R. R.; Vercesi, A. E.

2013-01-01

Mitochondrial redox imbalance has been implicated in mechanisms of aging, various degenerative diseases and drug-induced toxicity. Statins are safe and well-tolerated therapeutic drugs that occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Previous studies indicate that myotoxicity caused by statins may be linked to impairment of mitochondrial functions. Here, we report that 1-h incubation of permeabilized rat soleus muscle fiber biopsies with increasing concentrations of simvastatin (1–40 μM) slowed the rates of ADP-or FCCP-stimulated respiration supported by glutamate/malate in a dose-dependent manner, but caused no changes in resting respiration rates. Simvastatin (1 μM) also inhibited the ADP-stimulated mitochondrial respiration supported by succinate by 24% but not by TMPD/ascorbate. Compatible with inhibition of respiration, 1 μM simvastatin stimulated lactate release from soleus muscle samples by 26%. Co-incubation of muscle samples with 1 mM L-carnitine, 100 μM mevalonate or 10 μM coenzyme Q10 (Co-Q10) abolished simvastatin effects on both mitochondrial glutamate/malate-supported respiration and lactate release. Simvastatin (1 μM) also caused a 2-fold increase in the rate of hydrogen peroxide generation and a decrease in Co-Q10 content by 44%. Mevalonate, Co-Q10 or L-carnitine protected against stimulation of hydrogen peroxide generation but only mevalonate prevented the decrease in Co-Q10 content. Thus, independently of Co-Q10 levels, L-carnitine prevented the toxic effects of simvastatin. This suggests that mitochondrial respiratory dysfunction induced by simvastatin, is associated with increased generation of superoxide, at the levels of complexes-I and II of the respiratory chain. In all cases the damage to these complexes, presumably at the level of 4Fe-4S clusters, is prevented by L-carnitine. PMID:23720630

Beneficial effects of aged garlic extract and coenzyme Q10 on vascular elasticity and endothelial function: The FAITH randomized clinical trial

PubMed Central

Larijani, Vahid Nabavi; Ahmadi, Naser; Zeb, Irfan; Khan, Faraz; Flores, Ferdinand; Budoff, Matthew

2014-01-01

Objective Aged garlic extract (AGE) is associated with a significant decrease in atherosclerotic plaque progression and endothelial function improvement. Similarly, coenzyme Q10 (CoQ10) has significant beneficial effects on endothelial function. A stressful lifestyle is a well-known risk factor for the presence and progression of atherosclerosis. This study investigated the effect of AGE plus CoQ10 on vascular elasticity measured by pulse-wave velocity (PWV) and endothelial function measured by digital thermal monitoring (DTM) in firefighters. Methods Sixty-five Los-Angeles County firefighters who met the eligibility criteria were enrolled in this placebo-controlled, double-blinded randomized trial. The firefighters were randomized to four tablets of AGE (300 mg/tablet) plus CoQ10 (30 mg/tablet) or placebo. The participants underwent quarterly visits and 1-year follow-up. PWV and DTM were measured at baseline and at the 1-year follow-up. Results There were no significant differences in age, cardiovascular risk factors, PWV, and DTM between the AGE/CoQ10 and placebo groups at baseline (P > 0.5). At 1-y, PWV and DTM significantly improved in the AGE/CoQ10 compared with the placebo group (P < 0.05). After an adjustment for cardiovascular risk factors and statin therapy, the mean decrease in vascular stiffness (PWV) was 1.21 m/s in the AGE/CoQ10 compared with the placebo group (P = 0.005). Similarly, the mean increase in the area under the temperature curve, the DTM index of endothelial function, was 31.3 in the AGE/CoQ10 compared with the placebo group (P = 0.01). Conclusion The combination of AGE and CoQ10 was independently associated with significant beneficial effects on vascular elasticity and endothelial function in firefighters with high occupational stress, highlighting the important role of AGE and CoQ10 in atherosclerotic prevention of such individuals. PMID:22858191

Mitophagy Is Required for Acute Cardioprotection by Simvastatin

PubMed Central

Andres, Allen M.; Hernandez, Genaro; Lee, Pamela; Huang, Chengqun; Ratliff, Eric P.; Sin, Jon; Thornton, Christine A.; Damasco, Marichris V.

2014-01-01

Abstract Aims: We have shown that autophagy and mitophagy are required for preconditioning. While statin's cardioprotective effects are well known, the role of autophagy/mitophagy in statin-mediated cardioprotection is not. In this study, we used HL-1 cardiomyocytes and mice subjected to ischemia/reperfusion to elucidate the mechanism of statin-mediated cardioprotection. Results: HL-1 cardiomyocytes exposed to simvastatin for 24 h exhibited diminished protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, increased activation of unc-51-like kinase 1, and upregulation of autophagy and mitophagy. Similar findings were obtained in hearts of mice given simvastatin. Mevalonate abolished simvastatin's effects on Akt/mTOR signaling and autophagy induction in HL-1 cells, indicating that the effects are mediated through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Simvastatin-treated HL-1 cells exhibited mitochondrial translocation of Parkin and p62/SQSTM1, fission, and mitophagy. Because Parkin is required for mitophagy and is expressed in heart, we investigated the effect of simvastatin on infarct size in Parkin knockout mice. Simvastatin reduced infarct size in wild-type mice but showed no benefit in Parkin knockout mice. Inhibition of HMG-CoA reductase limits mevalonate availability for both cholesterol and coenzyme Q10 (CoQ) biosynthesis. CoQ supplementation had no effect on statin-induced Akt/mTOR dephosphorylation or macroautophagy in HL-1 cells, but it potently blocked mitophagy. Importantly, CoQ supplementation abolished statin-mediated cardioprotection in vivo. Innovation and Conclusion: Acute simvastatin treatment suppresses mTOR signaling and triggers Parkin-dependent mitophagy, the latter which is required for cardioprotection. Coadministration of CoQ with simvastatin impairs mitophagy and cardioprotection. These results raise the concern that CoQ may interfere with anti-ischemic benefits of statins mediated through stimulation of mitophagy. Antioxid. Redox Signal. 21, 1960–1973. PMID:23901824

The use of coenzyme Q0 as a template in the development of a molecularly imprinted polymer for the selective recognition of coenzyme Q10.

PubMed

Contin, Mario; Flor, Sabrina; Martinefski, Manuela; Lucangioli, Silvia; Tripodi, Valeria

2014-01-07

In this work, a novel molecularly imprinted polymer (MIP) for use as a solid phase extraction sorbent was developed for the determination of coenzyme Q10 (CoQ10) in liver extract. CoQ10 is an essential cofactor in mitochondrial oxidative phosphorylation and a powerful antioxidant agent found in low concentrations in biological samples. This fact and its high hydrophobicity make the analysis of CoQ10 technically challenging. Accordingly, a MIP was synthesised using coenzyme Q0 as the template, methacrylic acid as the functional monomer, acetonitrile as the porogen, ethylene glycol dimethacrylate as the crosslinker and benzoyl peroxide as the initiator. Various parameters affecting the polymer preparation and extraction efficiency were evaluated. Morphological characterisation of the MIP and its proper comparison with C18 as a sorbent in solid phase extraction were performed. The optimal conditions for the molecularly imprinted solid phase extraction (MISPE) consisted of 400 μL of sample mixed with 30 mg of MIP and 600 μL of water to reach the optimum solution loading. The loading was followed by a washing step consisting of 1 mL of a 1-propanol solution (1-propanol:water, 30:70,v/v) and elution with 1 mL of 1-propanol. After clean-up, the CoQ10 in the samples was analysed by high performance liquid chromatography. The extraction recoveries were higher than 73.7% with good precision (3.6-8.3%). The limits of detection and quantification were 2.4 and 7.5 μg g(-1), respectively, and a linear range between 7.5 and 150 μg g(-1) of tissue was achieved. The new MISPE procedure provided a successful clean-up for the determination of CoQ10 in a complex matrix. Copyright © 2013 Elsevier B.V. All rights reserved.

Potential Cardiovascular and Renal Protective Effects of Vitamin D and Coenzyme Q10 in l-NAME-Induced Hypertensive Rats.

PubMed

Shamardl, Hanan A; El-Ashmony, Sahar M; Kamel, Hala F; Fatani, Sameer H

2017-08-01

Hypertension is one of the primary modifiable risk factors for cardiovascular disease. Adequate vitamin D (vit D) levels have been shown to reduce vascular smooth muscle contraction and to increase arterial compliance, which may be beneficial in hypertension. Further, coenzyme Q10 (COQ10) through its action to lower oxidative stress has been reported to have beneficial effects on hypertension and heart failure. This study examined the possible cardiac and renal protective effects of vit D and COQ10 both separately and in combination with an angiotensin II receptor blocker, valsartan (vals) in l-NAME hypertensive rats. Hypertension was induced in rats by l-NAME administration. Following induction of hypertension, the rats were assigned into the following 6 subgroups: an l-NAME alone group and treated groups receiving the following drugs intraperitoneally for 6 weeks; vals, vit D, COQ10 and combination of vals with either vit D or COQ10. A group of normotensive rats were used as negative controls. At the end of the treatment period, blood pressure, serum creatinine, blood urea nitrogen, lipids and serum, cardiac and renal parameters of oxidative stress were measured. Compared to the l-NAME only group, all treatments lowered systolic, diastolic, mean arterial pressure, total cholesterol, low-density lipoprotein cholesterol, and creatinine levels as well as TNF-α and malondialdehyde. Further, the agents increased serum, cardiac and renal total antioxidant capacity. Interestingly, the combination of agents had further effects on all the parameters compared to treatment with each single agent. The study suggests that the additive protective effects of vit D and COQ10 when used alone or concurrent with vals treatment in hypertensive rats may be due to their effects as antioxidants, anticytokines and blood pressure conservers. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Balneotherapy and coenzyme Q10 in clinical and experimental medicine.

PubMed

Gvozdjakova, Anna; Kucharska, Jarmila; Sykora, L'ubomir; Singh, Ram B

2014-01-01

Balneotherapy or Spa therapy is used in neurological, cardiovascular, musculoskeletal, dermatological and gynecological diseases, in infertility as well as in metabolic disturbances. Beneficial effects of balneotherapy at the metabolic level is not fully understood. Authors have documented enhancement of antioxidants concentrations (coenzyme Q10- CoQ(10-OX) and alpha-tocopherol) of women with gynecological diseases by treatment with natural mineral water (Spa Lucky balneotherapy, Slovakia). In an experiment with rats, drinking of Spa Lucky mineral water decreased oxidative stress and enhanced concentrations of antioxidants CoQ(9-OX), CoQ(10-OX) in the myocardium, and alpha-tocopherol in uterus, ovaries and myocardium. Drinking of Spa Lucky water by rats stimulated myocardial mitochondrial respiration and energy production, and diminished skeletal muscle mitochondrial function. Simultaneous ingestion of coenzyme Q10 with drinking spa water returned mitochondrial parameters to the values of the control group. This pilot study helps explain the role of antioxidants, oxidative stress and mitochondrial energy production in beneficial effects of Spa Lucky balneotherapy.

Relationships Among Cognitive Function and Cerebral Blood Flow, Oxidative Stress, and Inflammation in Older Heart Failure Patients.

PubMed

Kure, Christina E; Rosenfeldt, Franklin L; Scholey, Andrew B; Pipingas, Andrew; Kaye, David M; Bergin, Peter J; Croft, Kevin D; Wesnes, Keith A; Myers, Stephen P; Stough, Con

2016-07-01

The mechanisms for cognitive impairment in heart failure (HF) are unclear. We investigated the relative contributions of cerebral blood flow velocity (BFV), oxidative stress, and inflammation to HF-associated cognitive impairment. Thirty-six HF patients (≥60 years) and 40 healthy controls (68 ± 7 vs 67 ± 5 years, P > .05; 69% vs 50% male, P > .05) completed the Cognitive Drug Research computerized assessment battery and Stroop tasks. Common carotid (CCA) and middle cerebral arterial BFV were obtained by transcranial Doppler. Blood samples were collected for oxidant (diacron-reactive oxygen metabolites; F2-isoprostanes), antioxidant (coenzyme Q10; CoQ10), and inflammatory markers (high-sensitivity C-reactive protein). Compared with controls, patients exhibited impaired attention (Cognitive Drug Research's Power of Attention domain, congruent Stroop) and executive function (incongruent Stroop). Multiple regression modeling showed that CCA-BFV and CoQ10 but not group predicted performance on attention and executive function. Additionally, in HF patients, CCA-BFV and CoQ10 (β = -0.34 vs β = -0.35) were significant predictors of attention, and CCA-BFV (β = -0.34) was a predictor of executive function. Power of Attention and executive function is impaired in older HF patients, and reduced CCA-BFV and CoQ10 are associated with worse cognition. Interventions addressing these mechanisms may improve cognition in older HF patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Overproduction of isoprenoids by Saccharomyces cerevisiae in a synthetic grape juice medium in the absence of plant genes.

PubMed

Camesasca, L; Minteguiaga, M; Fariña, L; Salzman, V; Aguilar, P S; Gaggero, C; Carrau, F

2018-06-06

The objective of this work is to demonstrate if the hexaprenyl pyrophosphate synthetase Coq1p might be involved in monoterpenes synthesis in Saccharomyces cerevisiae, although its currently known function in yeast is to catalyze the first step in ubiquinone biosynthesis. However, in a BY4743 laboratory strain, the presence of an empty plasmid in a chemically defined grape juice medium results in a statistically significant increase of linalool, (E)-nerolidol and (E,E)-farnesol. When COQ1 is overexpressed from a plasmid, the levels of the volatile isoprenoids are further increased. Furthermore, overexpression of COQ1 in the same genetic context but with a mutated farnesyl pyrophosphate synthetase (erg20 mutation K197E), results in statistically significant higher levels of linalool (above 750 μg/L), geraniol, α-terpineol, and the sesquiterpenes, farnesol and nerolidol (total concentration of volatile isoprenoids surpasses 1300 μg/L). We show that the levels of monoterpenes and sesquiterpenes that S. cerevisiae can produce, in the absence of plant genes, depend on the composition of the medium and the genetic context. To the best of our knowledge, this is the highest level of linalool produced by S. cerevisiae up to now. Further research will be needed for understanding how COQ1 and the medium composition might interact to increase flavor complexity of fermented beverages. Copyright © 2018. Published by Elsevier B.V.

Co-Enzyme Q10 and n-3 Polyunsaturated Fatty Acid Supplementation Reverse Intermittent Hypoxia-Induced Growth Restriction and Improved Antioxidant Profiles in Neonatal Rats

PubMed Central

Cai, Charles L.; Henry, Michael M.; Chowdhury, Sara; Valencia, Gloria B.; Aranda, Jacob V.

2017-01-01

Neonatal intermittent hypoxia (IH) increases the risk for many morbidities in extremely low birth weight/gestational age (ELBW/ELGA) neonates with compromised antioxidant systems and poor growth. We hypothesized that supplementation with coenzyme Q10 (CoQ10, ubiquinol) or n-3 polyunsaturated fatty acids (PUFAs) during neonatal IH improves antioxidant profiles and somatic growth in neonatal rats. Newborn rats were exposed to two IH paradigms at birth (P0): (1) 50% O2 with brief hypoxic episodes (12% O2); or (2) room air (RA) with brief hypoxia, until P14 during which they received daily oral CoQ10 in olive oil, n-3 PUFAs in fish oil, or olive oil only from P0 to P14. Pups were studied at P14 or placed in RA until P21 for recovery from IH (IHR). Body weight and length; organ weights; and serum antioxidants and growth factors were determined at P14 and P21. Neonatal IH resulted in sustained reductions in somatic growth, an effect that was reversed with n-3 PUFAs. Improved growth was associated with higher serum growth factors. CoQ10 decreased superoxide dismutase (SOD) and glutathione, but increased catalase, suggesting reduced oxidative stress. Further studies are needed to determine the synergistic effects of CoQ10 and n-3 PUFA co-administration for the prevention of IH-induced oxidative stress and postnatal growth deficits. PMID:29258174

Co-Enzyme Q10 and n-3 Polyunsaturated Fatty Acid Supplementation Reverse Intermittent Hypoxia-Induced Growth Restriction and Improved Antioxidant Profiles in Neonatal Rats.

PubMed

Beharry, Kay D; Cai, Charles L; Henry, Michael M; Chowdhury, Sara; Valencia, Gloria B; Aranda, Jacob V

2017-12-16

Neonatal intermittent hypoxia (IH) increases the risk for many morbidities in extremely low birth weight/gestational age (ELBW/ELGA) neonates with compromised antioxidant systems and poor growth. We hypothesized that supplementation with coenzyme Q10 (CoQ10, ubiquinol) or n -3 polyunsaturated fatty acids (PUFAs) during neonatal IH improves antioxidant profiles and somatic growth in neonatal rats. Newborn rats were exposed to two IH paradigms at birth (P0): (1) 50% O₂ with brief hypoxic episodes (12% O₂); or (2) room air (RA) with brief hypoxia, until P14 during which they received daily oral CoQ10 in olive oil, n -3 PUFAs in fish oil, or olive oil only from P0 to P14. Pups were studied at P14 or placed in RA until P21 for recovery from IH (IHR). Body weight and length; organ weights; and serum antioxidants and growth factors were determined at P14 and P21. Neonatal IH resulted in sustained reductions in somatic growth, an effect that was reversed with n -3 PUFAs. Improved growth was associated with higher serum growth factors. CoQ10 decreased superoxide dismutase (SOD) and glutathione, but increased catalase, suggesting reduced oxidative stress. Further studies are needed to determine the synergistic effects of CoQ10 and n -3 PUFA co-administration for the prevention of IH-induced oxidative stress and postnatal growth deficits.

Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth1

PubMed Central

Tarry-Adkins, Jane L; Fernandez-Twinn, Denise S; Hargreaves, Iain P; Neergheen, Viruna; Aiken, Catherine E; Martin-Gronert, Malgorzata S; McConnell, Josie M; Ozanne, Susan E

2016-01-01

Background: It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental programming are not well characterized, and potential intervention strategies are poorly defined. Objectives: We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype. Design: A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed “recuperated”). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase–polymerase chain reaction. Results: Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 μm) than in controls (5 ± 0.5 μm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 μg/mL per μg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01). Conclusions: Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia. PMID:26718412

Skeletal muscle mitochondrial bioenergetics and associations with myostatin genotypes in the Thoroughbred horse

PubMed Central

Porter, Richard K.; Katz, Lisa M.; Hill, Emmeline W.

2017-01-01

Variation in the myostatin (MSTN) gene has been reported to be associated with race distance, body composition and skeletal muscle fibre composition in the horse. The aim of the present study was to test the hypothesis that MSTN variation influences mitochondrial phenotypes in equine skeletal muscle. Mitochondrial abundance and skeletal muscle fibre types were measured in whole muscle biopsies from the gluteus medius of n = 82 untrained (21 ± 3 months) Thoroughbred horses. Skeletal muscle fibre type proportions were significantly (p < 0.01) different among the three MSTN genotypes and mitochondrial content was significantly (p < 0.01) lower in the combined presence of the C-allele of SNP g.66493737C>T (C) and the SINE insertion 227 bp polymorphism (I). Evaluation of mitochondrial complex activities indicated higher combined mitochondrial complex I+III and II+III activities in the presence of the C-allele / I allele (p ≤ 0.05). The restoration of complex I+III and complex II+III activities following addition of exogenous coenzyme Q1 (ubiquinone1) (CoQ1) in vitro in the TT/NN (homozygous T allele/homozygous no insertion) cohort indicated decreased coenzyme Q in these animals. In addition, decreased gene expression in two coenzyme Q (CoQ) biosynthesis pathway genes (COQ4, p ≤ 0.05; ADCK3, p ≤ 0.01) in the TT/NN horses was observed. This study has identified several mitochondrial phenotypes associated with MSTN genotype in untrained Thoroughbred horses and in addition, our findings suggest that nutritional supplementation with CoQ may aid to restore coenzyme Q activity in TT/NN horses. PMID:29190290

Up-regulation of antioxidant enzymes and coenzyme Q(10) in a human oral cancer cell line with acquired bleomycin resistance.

PubMed

Yen, Hsiu-Chuan; Li, Sin-Hua; Majima, Hideyuki J; Huang, Yu-Hsiang; Chen, Chiu-Ping; Liu, Chia-Chi; Tu, Ya-Chi; Chen, Chih-Wei

2011-06-01

Bleomycin (BLM) is an anti-cancer drug that can induce formation of reactive oxygen species (ROS). To investigate the association between up-regulation of antioxidant enzymes and coenzyme Q(10) (CoQ(10)) in acquired BLM resistance, one BLM-resistant clone, SBLM24 clone, was selected from a human oral cancer cell line, SCC61 clone. The BLM resistance of SBLM24 clone relative to a sub-clone of SCC61b cells was confirmed by analysis of clonogenic ability and cell cycle arrest. CoQ(10) levels and levels of Mn superoxide dismutase, glutathione peroxidase 1, catalase and thioredoxin reductase 1 were augmented in SBLM24 clone although there was also a mild increase in the expression of BLM hydrolase. Suppression of CoQ(10) levels by 4-aminobenzoate sensitized BLM-induced cytotoxicity. The results of suppression on enhanced ROS production by BLM and the cross-resistance to hydrogen peroxide in SBLM24 clone further demonstrated the development of adaptation to oxidative stress during the formation of acquired BLM resistance.

Myocardial dysfunction in mitochondrial diabetes treated with Coenzyme Q10.

PubMed

Salles, João Eduardo; Moisés, Valdir A; Almeida, Dirceu R; Chacra, Antonio R; Moisés, Regina S

2006-04-01

Maternally-inherited diabetes and deafness (MIDD) has been related to an A to G transition in the mitochondrial tRNA Leu (UUR) gene at the base pair 3243. Although some previous articles have reported that this mutation may be a cause of cardiomyopathy in diabetes, the degree of cardiac involvement and a specific treatment has not been established. Here, we reported a case of a patient with MIDD who developed congestive heart failure and the therapeutic usefulness of Coenzyme Q10 (CoQ10). In our patient, after the introduction of Coenzyme Q10 150 mg/day, there was a gradual improvement on left ventricular function evaluated by echocardiography. The fractional shortening (FS) and ejection fraction (EF) increased from 26 to 34% and from 49 to 64%, respectively. No side effects were noted. Three months after CoQ10 discontinuation, the parameters of systolic function evaluated by echocardiography decreased, suggesting that CoQ10 had a beneficial effect. Identification of diabetes and cardiomyopathy due to mitochondrial gene mutation may have therapeutic implications and Coenzyme Q10 is a possible adjunctive treatment in such patients.

A Semantic Basis for Proof Queries and Transformations

NASA Technical Reports Server (NTRS)

Aspinall, David; Denney, Ewen W.; Luth, Christoph

2013-01-01

We extend the query language PrQL, designed for inspecting machine representations of proofs, to also allow transformation of proofs. PrQL natively supports hiproofs which express proof structure using hierarchically nested labelled trees, which we claim is a natural way of taming the complexity of huge proofs. Query-driven transformations enable manipulation of this structure, in particular, to transform proofs produced by interactive theorem provers into forms that assist their understanding, or that could be consumed by other tools. In this paper we motivate and define basic transformation operations, using an abstract denotational semantics of hiproofs and queries. This extends our previous semantics for queries based on syntactic tree representations.We define update operations that add and remove sub-proofs, and manipulate the hierarchy to group and ungroup nodes. We show that

A High-Level Formalization of Floating-Point Number in PVS

NASA Technical Reports Server (NTRS)

Boldo, Sylvie; Munoz, Cesar

2006-01-01

We develop a formalization of floating-point numbers in PVS based on a well-known formalization in Coq. We first describe the definitions of all the needed notions, e.g., floating-point number, format, rounding modes, etc.; then, we present an application to polynomial evaluation for elementary function evaluation. The application already existed in Coq, but our formalization shows a clear improvement in the quality of the result due to the automation provided by PVS. We finally integrate our formalization into a PVS hardware-level formalization of the IEEE-854 standard previously developed at NASA.

Modulatory role of Co-enzyme Q10 on methionine and choline deficient diet-induced non-alcoholic steatohepatitis (NASH) in albino rats.

PubMed

Saleh, Dalia O; Ahmed, Rania F; Amin, Mohamed M

2017-03-01

The present study aimed to evaluate the hepato-protective and neuro-protective activity of Co-enzyme Q10 (CoQ10) on non-alcoholic steatohepatitis (NASH) in albino rats induced by methionine and choline-deficient (MCD) diet. Rats were fed an MCD diet for 8 weeks to induce non-alcoholic steatohepatitis. CoQ10 (10 mg/(kg·day) -1 ) was orally administered for 2 consecutive weeks. Twenty-four hours after the last dose of the drug, the behavioral test, namely the activity cage test, was performed and the activity counts were recorded. Serum alanine transaminase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, total/direct bilirubin, and albumin were valued to assess liver function. Moreover, hepatic cytokines interleukin-6 as well as its modulator nuclear factor kappa-light-chain-enhancer of activated B cells were determined. In addition, brain biomarkers, viz ammonia, nitric oxide, and brain-derived neurotrophic factor (BDNF), were measured as they are reliable indices to assess brain damage. Histopathological and immunohistochemical examination of brain proliferating cell nuclear antigen in brain and liver tissues were also evaluated. Results revealed that MCD-induced NASH showed impairment in the liver functions with an increase in the liver inflammatory markers. Moreover, NASH resulted in pronounced brain dysfunction as evidenced by hyper-locomotor activity, a decrease in the BDNF level, as well as an increase in the brain nitric oxide and ammonia contents. Oral treatment of MCD-diet-fed rats with CoQ10 for 14 days showed a marked improvement in all the assigned parameters. Finally, it can be concluded that CoQ10 has a hepatoprotective and neuroprotective role in MCD-diet-induced NASH in rats.

Effects of coenzyme Q10 supplementation on activities of selected antioxidative enzymes and lipid peroxidation in hypertensive patients treated with indapamide. A pilot study.

PubMed

Kędziora-Kornatowska, Kornelia; Czuczejko, Jolanta; Motyl, Jadwiga; Szewczyk-Golec, Karolina; Kozakiewicz, Mariusz; Pawluk, Hanna; Kędziora, Józef; Błaszczak, Robert; Banach, Maciej; Rysz, Jacek

2010-08-30

An increase in oxidative stress is strongly documented in hypertensive patients. In blood vessels, oxidative stress increases the production of superoxide anion (O(2) (•-)) that reacts with nitric oxide (NO) and impairs the ability of endothelium to relax. Many reports indicate a beneficial effect of coenzyme Q10 (CoQ) in hypertension. Coenzyme Q10 therapy may lower O(2) (•-) and thus decrease the complications associated with hypertension. The aim of our study was to evaluate the effects of CoQ supplementation on antioxidative enzyme activities and lipid peroxidation in elderly hypertensive patients. We determined the activities of superoxide dismutase (SOD-1) and glutathione peroxidase (GSH-Px) and the concentration of malondialdehyde (MDA) in erythrocytes of 27 elderly (mean age 72.5 ±6.1 year) hypertensive patients treated with indapamide at baseline and after 12 weeks of CoQ supplementation (60 mg twice a day) in comparison with 30 healthy elderly volunteers (mean age 76.8 ±8.5 year). Decrease of SOD-1 (p < 0.001) and insignificant reduction of GSH-Px activities and increase of MDA (p < 0.001) level were observed in hypertensive patients in comparison to healthy volunteers before supplementation. Coenzyme Q10 administration resulted in a significant increase only in SOD-1 activity (p < 0.001). The present study indicates that CoQ improves the most important component of the antioxidant defence system - SOD-1, which is responsible for O(2) (•-) scavenging. Coenzyme Q10 may be used as an additional therapeutic agent for prophylaxis and treatment of hypertension in elderly patients.

Postprandial antioxidant effect of the Mediterranean diet supplemented with coenzyme Q10 in elderly men and women.

PubMed

Yubero-Serrano, Elena M; Delgado-Casado, Nieves; Delgado-Lista, Javier; Perez-Martinez, Pablo; Tasset-Cuevas, Inmaculada; Santos-Gonzalez, Monica; Caballero, Javier; Garcia-Rios, Antonio; Marin, Carmen; Gutierrez-Mariscal, Francisco M; Fuentes, Francisco; Villalba, Jose M; Tunez, Isaac; Perez-Jimenez, Francisco; Lopez-Miranda, Jose

2011-12-01

Postprandial oxidative stress is characterized by an increased susceptibility of the organism towards oxidative damage after consumption of a meal rich in lipids and/or carbohydrates. We have investigated whether the quality of dietary fat alters postprandial cellular oxidative stress and whether the supplementation with coenzyme Q(10) (CoQ) lowers postprandial oxidative stress in an elderly population. In this randomized crossover study, 20 participants were assigned to receive three isocaloric diets for periods of 4 week each: (1) Mediterranean diet supplemented with CoQ (Med+CoQ diet), (2) Mediterranean diet (Med diet), and (3) saturated fatty acid-rich diet (SFA diet). After a 12-h fast, the volunteers consumed a breakfast with a fat composition similar to that consumed in each of the diets. CoQ, lipid peroxides (LPO), oxidized low-density lipoprotein (oxLDL), protein carbonyl (PC), total nitrite, nitrotyrosine plasma levels, catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities and ischemic reactive hyperaemia (IRH) were determined. Med diet produced a lower postprandial GPx activity and a lower decrease in total nitrite level compared to the SFA diet. Med and Med+CoQ diets induced a higher postprandial increase in IRH and a lower postprandial LPO, oxLDL, and nitrotyrosine plasma levels than the SFA diet. Moreover, the Med+CoQ diet produced a lower postprandial decrease in total nitrite and a greater decrease in PC levels compared to the other two diets and lower SOD, CAT, and GPx activities than the SFA diet.In conclusion, Med diet reduces postprandial oxidative stress by reducing processes of cellular oxidation and increases the action of the antioxidant system in elderly persons and the administration of CoQ further improves this redox balance.

Bioenergetic Effects of Mitochondrial-Targeted Coenzyme Q Analogs in Endothelial Cells

PubMed Central

Fink, Brian D.; Herlein, Judith A.; Yorek, Mark A.; Fenner, Amanda M.; Kerns, Robert J.

2012-01-01

Mitochondrial-targeted analogs of coenzyme Q (CoQ) are under development to reduce oxidative damage induced by a variety of disease states. However, there is a need to understand the bioenergetic effects of these agents and whether or not these effects are related to redox properties, including their known pro-oxidant effects. We examined the bioenergetic effects of two mitochondrial-targeted CoQ analogs in their quinol forms, mitoquinol (MitoQ) and plastoquinonyl-decyl-triphenylphosphonium (SkQ1), in bovine aortic endothelial cells. We used an extracellular oxygen and proton flux analyzer to assess mitochondrial action at the intact-cell level. Both agents, in dose-dependent fashion, reduced the oxygen consumption rate (OCR) directed at ATP turnover (OCRATP) (IC50 values of 189 ± 13 nM for MitoQ and 181 ± 7 for SKQ1; difference not significant) while not affecting or mildly increasing basal oxygen consumption. Both compounds increased extracellular acidification in the basal state consistent with enhanced glycolysis. Both compounds enhanced mitochondrial superoxide production assessed by using mitochondrial-targeted dihydroethidium, and both increased H2O2 production from mitochondria of cells treated before isolation of the organelles. The manganese superoxide dismutase mimetic manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin did not alter or actually enhanced the actions of the targeted CoQ analogs to reduce OCRATP. In contrast, N-acetylcysteine mitigated this effect of MitoQ and SkQ1. In summary, our data demonstrate the important bioenergetic effects of targeted CoQ analogs. Moreover, these effects are mediated, at least in part, through superoxide production but depend on conversion to H2O2. These bioenergetic and redox actions need to be considered as these compounds are developed for therapeutic purposes. PMID:22661629

Bioenergetic effects of mitochondrial-targeted coenzyme Q analogs in endothelial cells.

PubMed

Fink, Brian D; Herlein, Judith A; Yorek, Mark A; Fenner, Amanda M; Kerns, Robert J; Sivitz, William I

2012-09-01

Mitochondrial-targeted analogs of coenzyme Q (CoQ) are under development to reduce oxidative damage induced by a variety of disease states. However, there is a need to understand the bioenergetic effects of these agents and whether or not these effects are related to redox properties, including their known pro-oxidant effects. We examined the bioenergetic effects of two mitochondrial-targeted CoQ analogs in their quinol forms, mitoquinol (MitoQ) and plastoquinonyl-decyl-triphenylphosphonium (SkQ1), in bovine aortic endothelial cells. We used an extracellular oxygen and proton flux analyzer to assess mitochondrial action at the intact-cell level. Both agents, in dose-dependent fashion, reduced the oxygen consumption rate (OCR) directed at ATP turnover (OCR(ATP)) (IC₅₀ values of 189 ± 13 nM for MitoQ and 181 ± 7 for SKQ1; difference not significant) while not affecting or mildly increasing basal oxygen consumption. Both compounds increased extracellular acidification in the basal state consistent with enhanced glycolysis. Both compounds enhanced mitochondrial superoxide production assessed by using mitochondrial-targeted dihydroethidium, and both increased H₂O₂ production from mitochondria of cells treated before isolation of the organelles. The manganese superoxide dismutase mimetic manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin did not alter or actually enhanced the actions of the targeted CoQ analogs to reduce OCR(ATP). In contrast, N-acetylcysteine mitigated this effect of MitoQ and SkQ1. In summary, our data demonstrate the important bioenergetic effects of targeted CoQ analogs. Moreover, these effects are mediated, at least in part, through superoxide production but depend on conversion to H₂O₂. These bioenergetic and redox actions need to be considered as these compounds are developed for therapeutic purposes.

Oxidative stress in patients with essential hypertension: a comparison of dippers and non-dippers.

PubMed

Gönenç, Aymelek; Hacışevki, Aysun; Tavil, Yusuf; Çengel, Atiye; Torun, Meral

2013-03-01

Oxidative stress seems to play an important role in the pathophysiology of essential hypertension. We aimed to examine serum MDA, NO, 8-OHdG, ADMA, NT, CoQ10 and TAC as biomarkers of oxidative stress in dipper and non-dipper hypertensive patients. Eighteen dipper hypertensives, 20 non-dipper hypertensives and 22 healthy control subjects were included in the study. Clinical assessment and ambulatory blood pressure monitoring were performed in patients. Serum MDA, TAC and NO levels were measured by using spectrophotometric methods. CoQ10 levels were measured by HPLC method. 8-OHdG, ADMA and NT were quantitated by ELISA methods. MDA levels were significantly higher in dipper and non-dipper groups compared to controls (p<0.05 and p<0.01, respectively). TAC levels were found at low level in patients dipper and non-dipper patients compared to control group (p<0.01). Higher ADMA and NT levels but lower CoQ10 levels were found in non-dipper group compared to healthy controls (p<0.01, p<0.05, and p<0.05, respectively). ADMA levels were found higher in non-dipper group than those of dipper group (p<0.01). Increased ADMA, NT levels and decreased CoQ10 levels in non-dipper hypertensive patients might indicate more severe oxidative stres compared with dipper hypertensive patients, which plays an important role in the development of cardiovascular diseases. Increased MDA and reduced TAC levels might be considered as prospective prognostic markers of the development of cardiovascular diseases in dipper and non-dipper hypertensive patients. Copyright © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

7 CFR 1430.305 - Proof of production.

Code of Federal Regulations, 2011 CFR

2011-01-01

..., including any dumped production and dairy cow purchases, for each month of the period July 2004 through... confirm the production history and losses incurred by the dairy operation. (d) Adequate proof of dairy cow... OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS DAIRY PRODUCTS 2004 Dairy Disaster Assistance...

7 CFR 1430.305 - Proof of production.

Code of Federal Regulations, 2013 CFR

2013-01-01

..., including any dumped production and dairy cow purchases, for each month of the period July 2004 through... confirm the production history and losses incurred by the dairy operation. (d) Adequate proof of dairy cow... OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS DAIRY PRODUCTS 2004 Dairy Disaster Assistance...

7 CFR 1430.305 - Proof of production.

Code of Federal Regulations, 2014 CFR

2014-01-01

..., including any dumped production and dairy cow purchases, for each month of the period July 2004 through... confirm the production history and losses incurred by the dairy operation. (d) Adequate proof of dairy cow... OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS DAIRY PRODUCTS 2004 Dairy Disaster Assistance...

7 CFR 1430.305 - Proof of production.

Code of Federal Regulations, 2012 CFR

2012-01-01

..., including any dumped production and dairy cow purchases, for each month of the period July 2004 through... confirm the production history and losses incurred by the dairy operation. (d) Adequate proof of dairy cow... OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS DAIRY PRODUCTS 2004 Dairy Disaster Assistance...

7 CFR 786.105 - Proof of production.

Code of Federal Regulations, 2011 CFR

2011-01-01

... eligible claim period. (2) A producer must certify to the average number of cows in the dairy herd during... AGRICULTURE SPECIAL PROGRAMS DAIRY DISASTER ASSISTANCE PAYMENT PROGRAM (DDAP-III) § 786.105 Proof of... history of the dairy operation so that dairy production losses can be computed in accordance with § 786...

7 CFR 786.105 - Proof of production.

Code of Federal Regulations, 2012 CFR

2012-01-01

... eligible claim period. (2) A producer must certify to the average number of cows in the dairy herd during... AGRICULTURE SPECIAL PROGRAMS DAIRY DISASTER ASSISTANCE PAYMENT PROGRAM (DDAP-III) § 786.105 Proof of... history of the dairy operation so that dairy production losses can be computed in accordance with § 786...

7 CFR 786.105 - Proof of production.

Code of Federal Regulations, 2013 CFR

2013-01-01

... eligible claim period. (2) A producer must certify to the average number of cows in the dairy herd during... AGRICULTURE SPECIAL PROGRAMS DAIRY DISASTER ASSISTANCE PAYMENT PROGRAM (DDAP-III) § 786.105 Proof of... history of the dairy operation so that dairy production losses can be computed in accordance with § 786...

7 CFR 786.105 - Proof of production.

Code of Federal Regulations, 2014 CFR

2014-01-01

... eligible claim period. (2) A producer must certify to the average number of cows in the dairy herd during... AGRICULTURE SPECIAL PROGRAMS DAIRY DISASTER ASSISTANCE PAYMENT PROGRAM (DDAP-III) § 786.105 Proof of... history of the dairy operation so that dairy production losses can be computed in accordance with § 786...

Effect of CoQ homologues on reactive oxygen generation by mitochondria.

PubMed

Imada, Isuke; Sato, Eisuke F; Kira, Yukimi; Inoue, Masayasu

2008-01-01

Effect of CoQ compounds (Qs) on reactive oxygen (ROS) generation by mitochondrial complex I was studied using rat liver mitochondria and chemiluminescence probe L012. Kinetic analysis revealed that short chain Qs, such as Q2 and idebenone enhanced ROS generation by mitochondrial NADH oxidase system by a succinate-inhibitable mechanism. Lipid peroxidation in mitochondrial membranes induced by NADH and iron was inhibited by short chain Qs. The inhibitory activity was enhanced by co-oxidation of succinate as determined by chemiluminescence method and by electron spin resonance spectroscopy. These results suggested that the reduced form of short chain Qs inhibited mitochondrial ROS generation and lipid peroxidation.

Statin therapy and plasma coenzyme Q10 concentrations--A systematic review and meta-analysis of placebo-controlled trials.

PubMed

Banach, Maciej; Serban, Corina; Ursoniu, Sorin; Rysz, Jacek; Muntner, Paul; Toth, Peter P; Jones, Steven R; Rizzo, Manfredi; Glasser, Stephen P; Watts, Gerald F; Blumenthal, Roger S; Lip, Gregory Y H; Mikhailidis, Dimitri P; Sahebkar, Amirhossein

2015-09-01

Statin therapy may lower plasma coenzyme Q10 (CoQ10) concentrations, but the evidence as to the significance of this effect is unclear. We assessed the impact of statin therapy on plasma CoQ10 concentrations through the meta-analysis of available RCTs. The literature search included selected databases up to April 30, 2015. The meta-analysis was performed using either a fixed-effects or random-effect model according to I(2) statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). The data from 8 placebo-controlled treatment arms suggested a significant reduction in plasma CoQ10 concentrations following treatment with statins (WMD: -0.44 μmol/L, 95%CI: -0.52, -0.37, p<0.001). The pooled effect size was robust and remained significant in the leave-one-out sensitivity analysis. Subgroup analysis suggested that the impact of statins on plasma CoQ10 concentrations is significant for all 4 types of statins studied i.e. atorvastatin (WMD: -0.41 μmol/L, 95%CI: -0.53, -0.29, p<0.001), simvastatin (WMD: -0.47 μmol/L, 95% CI: -0.61, -0.33, p<0.001), rosuvastatin (WMD: -0.49 μmol/L, 95%CI: -0.67, -0.31, p<0.001) and pravastatin (WMD: -0.43 μmol/L, 95%CI: -0.69, -0.16, p=0.001). Likewise, there was no differential effect of lipophilic (WMD: -0.43 μmol/L, 95%CI: -0.53, -0.34, p<0.001) and hydrophilic statins (WMD: -0.47 μmol/L, 95%CI: -0.62, -0.32, p<0.001). With respect to treatment duration, a significant effect was observed in both subsets of trials lasting <12 weeks (WMD: -0.51 μmol/L, 95%CI: -0.64, -0.39, p<0.001) and ≥12 weeks (WMD: -0.40 μmol/L, 95%CI: -0.50, -0.30, p<0.001). The meta-analysis showed a significant reduction in plasma CoQ10 concentrations following treatment with statins. Further well-designed trials are required to confirm our findings and elucidate their clinical relevance. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of pretreatment with coenzyme Q10 on isoproterenol-induced cardiotoxicity and cardiac hypertrophy in rats.

PubMed

Ghule, Arvindkumar E; Kulkarni, Chetan P; Bodhankar, Subhash L; Pandit, Vijaya A

2009-12-01

Coenzyme Q10 (CoQ10) is a lipid-soluble, vitamin-like substance found in the hydrophobic interior of the phospholipid bilayer of most cellular membranes. It appears to be involved in the coordinated regulation between oxidative stress and antioxidant capacity of heart tissue when the heart is subjected to oxidative stress in various pathogenic conditions. The objective of the present study was to investigate the effect of pretreatment with CoQ10 (100 mg/kg) on isoproterenol (ISO)-induced cardiotoxicity and cardiac hypertrophy in rats. Albino male Wistar rats (250-300 g) were evenly divided by lottery method into 1 of the following 3 groups: the ISO group (olive oil 2 mL/kg orally for 18 days and ISO 1 mg/kg IP from days 9-18); the CoQ10 + ISO group (CoQ10 100 mg/kg orally for 18 days and ISO 1 mg/kg IP from days 9-18); and the control group (olive oil 2 mL/kg orally for 18 days and water IP from days 9-18). Twenty-four hours after the last dose of water or ISO, the rats were anesthetized and an ECG was recorded. Blood was withdrawn by retro-orbital puncture for estimation of serum creatine kinase-MB (CK-MB) isoenzyme levels, lactate dehydrogenase (LDH) levels, and aspartate aminotransferase activities. The animals were euthanized using an overdose of ether. The hearts of 6 animals from each group were used for estimation of superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, lipid peroxidation (LPO), malondialdehyde (MDA), and total protein concentration. Histopathology of the 2 remaining hearts in each group was carried out by a blinded technician. A total of 24 rats (8 in each group) were used in this study; all rats survived to study end. Compared with the control group, the ISO-treated rats had a significant change in heart to body weight ratio (P < 0.001); significant changes in the endogenous antioxidants (ie, significantly higher myocardial MDA concentration [P < 0.001]; significantly lower myocardial GSH concentration [P < 0.001] and SOD activity [P < 0.01]); and significantly higher serum activities of marker enzymes (eg, CK-MB [P < 0.001] and LDH [P < 0.001]). Compared with the ISO group, the CoQ10 + ISO group had a significant change in heart to body weight ratio (P < 0.001); significant changes in the endogenous antioxidants (ie, significantly lower MDA concentration [P < 0.05]; significantly higher myocardial GSH concentration [P < 0.001] and SOD activity [P < 0.05]); and significantly lower serum activities of marker enzymes (eg, CK-MB [P < 0.05] and LDH [P < 0.01]). Pretreatment with CoQ10 (100 mg/kg) for 18 days was associated with moderate protection against ISO-induced cardiotoxicity and cardiac hypertrophy, and with lower myocardial injury by preserving endogenous antioxidants and reducing LPO in rat heart.

Analytic proof of the existence of the Lorenz attractor in the extended Lorenz model

NASA Astrophysics Data System (ADS)

Ovsyannikov, I. I.; Turaev, D. V.

2017-01-01

We give an analytic (free of computer assistance) proof of the existence of a classical Lorenz attractor for an open set of parameter values of the Lorenz model in the form of Yudovich-Morioka-Shimizu. The proof is based on detection of a homoclinic butterfly with a zero saddle value and rigorous verification of one of the Shilnikov criteria for the birth of the Lorenz attractor; we also supply a proof for this criterion. The results are applied in order to give an analytic proof for the existence of a robust, pseudohyperbolic strange attractor (the so-called discrete Lorenz attractor) for an open set of parameter values in a 4-parameter family of 3D Henon-like diffeomorphisms.

Effect of the additives on clouding behavior and thermodynamics of coenzyme Q10-Kolliphor HS15 micelle aqueous solutions

NASA Astrophysics Data System (ADS)

Hu, Li; Zhang, Jing; Zhu, Chao; Pan, Hong-chun; Liu, Hong

2017-11-01

Herein we investigate the effect of different additives (electrolytes, amino acids, PEG, and sugars) on the cloud points (CP) of coenzyme Q10 (CoQ10) - Kolliphor HS15 (HS15) micelle aqueous solutions. The CP values were decreased with the increase of electrolytes and sugars, following: CPAl3+ < CPMg2+ < CPCa2+ < CPNa+ < CPK+ < CPNH4+; CPdisaccharide < CPmonosaccharide. The presences of Arginine and Tryptophan significantly increased the CP; while the other amino acids reduced the CP. A depression of CP for CoQ10-HS15 micelle solution with PEG was molecular weight of PEG dependent. The significant thermodynamic parameters were also evaluated and discussed.

Ubiquinol Improves Symptoms in Children with Autism

PubMed Central

Kucharská, Jarmila; Ostatníková, Daniela; Babinská, Katarína; Nakládal, Dalibor; Crane, Fred L.

2014-01-01

Background. Autism is a spectrum of neurodevelopmental disorders with manifestation within 3 years after birth. Manifestations of autism include behavior problems (hyperactivity, toys destruction, self-harm, and agression) and sleep and eating disorders. Etiology of autism is poorly understood. Oxidative stress and antioxidants can participate in pathobiochemical mechanisms of autism. Methods. Twenty-four children, aged 3–6 years, with autism according to the DSM IV criteria and using CARS were included in the study. Concentrations of CoQ10−TOTAL, γ- and α-tocopherol, β-carotene, and lipid peroxidation were determined in plasma before and after three months of supportive therapy with ubiquinol at a daily dose 2 × 50 mg. Data on behavior of the children were collected from parents at the same time. Results. Ubiquinol supportive therapy improved symptoms in children with autism, as communication with parents (in 12%), verbal communication (in 21%), playing games of children (in 42%), sleeping (in 34%), and food rejection (in 17%), with CoQ10−TOTAL plasma level above 2.5 μmol/L. Conclusions. Beneficial effect of ubiquinol in children with autism has been demonstrated for the first time. We assume that plasma concentration of CoQ10−TOTAL and lipid peroxidation could be used as relevant biomarkers of ubiquinol supportive therapy. PMID:24707344

Dynamic nuclear polarization-magnetic resonance imaging at low ESR irradiation frequency for ascorbyl free radicals.

PubMed

Ito, Shinji; Hyodo, Fuminori

2016-02-19

Highly water-soluble ubiquinone-0 (CoQ0) reacts with ascorbate monoanion (Asc) to mediate the production of ascorbyl free radicals (AFR). Using aqueous reaction mixture of CoQ0 and Asc, we obtained positively enhanced dynamic nuclear polarization (DNP)-magnetic resonance (MR) images of the AFR at low frequency (ranging from 515 to 530 MHz) of electron spin resonance (ESR) irradiation. The shape of the determined DNP spectrum was similar to ESR absorption spectra with doublet spectral peaks. The relative locational relationship of spectral peaks in the DNP spectra between the AFR (520 and 525 MHz), (14)N-labeled carbamoyl-PROXYL ((14)N-CmP) (526.5 MHz), and Oxo63 (522 MHz) was different from that in the X-band ESR spectra, but were similar to that in the 300-MHz ESR spectra. The ratio of DNP enhancement to radical concentration for the AFR was higher than those for (14)N-CmP, Oxo63, and flavin semiquinone radicals. The spectroscopic DNP properties observed for the AFR were essentially the same as those for AFR mediated by pyrroloquinoline quinone. Moreover, we made a success of in vivo DNP-MR imaging of the CoQ0-mediated AFR which was administered by the subcutaneous and oral injections as an imaging probe.

A mechanistic approach for modulation of chlorpyrifos-induced toxicity in human lymphocytes by melatonin, coenzyme Q10, and vinpocetine.

PubMed

Ghayomi, F; Navaei-Nigjeh, M; Baeeri, M; Rezvanfar, M A; Abdollahi, M

2016-08-01

Chlorpyrifos (CP) is an organophosphorus pesticide that induces oxidative stress through the production of free radicals and depletes intracellular antioxidant reserves. In this study, the efficacy of three antioxidants (melatonin, coenzyme Q10 (CoQ10), and vinpocetine) on alleviation of toxic effects of CP was evaluated. Cytotoxicity of CP, in the presence or absence of effective doses of melatonin, CoQ10, and vinpocetine, was determined in human peripheral blood lymphocytes after 72-h exposure. The levels of acetylcholinesterase (AChE) activity along with tumor necrosis factor α (TNF-α), as inflammatory index, were measured. Further, the viability and oxidative stress markers including cellular mitochondrial activity, cell death modes (apoptosis vs. necrosis), total antioxidant power (TAP), total thiol molecules (TTM), lipid peroxidation (LPO), and myeloperoxidase (MPO) activity were measured. CoQ10 and also the combination of the three antioxidants were the most notable in opposing toxicity of CP and led to increasing TAP and TTM; improvement of AChE activity; and lowering LPO, MPO, TNF-α, and apoptosis compared to CP alone. CP toxicity overwhelms the intracellular antioxidant defense mechanisms. Exogenous supplementation with antioxidants, such as the ones we have investigated, seems to be effective in the prevention of cytotoxicity of CP. © The Author(s) 2015.

Formant and voice source properties in two male Kunqu Opera roles: a pilot study.

PubMed

Dong, Li; Sundberg, Johan; Kong, Jiangping

2013-01-01

This investigation analyzes flow glottogram and electroglottogram (EGG) parameters as well as the relationship between formant frequencies and partials in two male Kunqu Opera roles, Colorful face (CF) and Old man (OM). Four male professional Kunqu Opera singers volunteered as participants, 2 singers for each role. Using inverse filtering of the audio signal flow glottogram parameters and formant frequencies were measured in each note of scales. Two EGG parameters, contact quotient (CoQ) and speed quotient, were measured. Formant tuning was observed only in 1 of the OM singers and appeared in a pitch range lower than the passaggio range of Western male opera singers. Both the CF and the OM role singers showed high CoQ values and low values of the normalized amplitude quotient in singing. For 3 of the 4 singers CoQ and the level difference between the first and second partials showed a positive and a negative correlation with fundamental frequency (F0), respectively. Formant tuning may be applied by a singer of the OM role, and both CF and OM role singers may use a rather pressed type of phonation, CF singers more than OM singers in the lower part of the pitch range. Most singers increased glottal adduction with rising F0.

Chromatin-remodeling SWI/SNF complex regulates coenzyme Q6 synthesis and a metabolic shift to respiration in yeast.

PubMed

Awad, Agape M; Venkataramanan, Srivats; Nag, Anish; Galivanche, Anoop Raj; Bradley, Michelle C; Neves, Lauren T; Douglass, Stephen; Clarke, Catherine F; Johnson, Tracy L

2017-09-08

Despite its relatively streamlined genome, there are many important examples of regulated RNA splicing in Saccharomyces cerevisiae Here, we report a role for the chromatin remodeler SWI/SNF in respiration, partially via the regulation of splicing. We find that a nutrient-dependent decrease in Snf2 leads to an increase in splicing of the PTC7 transcript. The spliced PTC7 transcript encodes a mitochondrial phosphatase regulator of biosynthesis of coenzyme Q 6 (ubiquinone or CoQ 6 ) and a mitochondrial redox-active lipid essential for electron and proton transport in respiration. Increased splicing of PTC7 increases CoQ 6 levels. The increase in PTC7 splicing occurs at least in part due to down-regulation of ribosomal protein gene expression, leading to the redistribution of spliceosomes from this abundant class of intron-containing RNAs to otherwise poorly spliced transcripts. In contrast, a protein encoded by the nonspliced isoform of PTC7 represses CoQ 6 biosynthesis. Taken together, these findings uncover a link between Snf2 expression and the splicing of PTC7 and establish a previously unknown role for the SWI/SNF complex in the transition of yeast cells from fermentative to respiratory modes of metabolism. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Pilot study of safety and efficacy of polyprenols in combination with coenzyme Q10 in patients with statin-induced myopathy.

PubMed

Latkovskis, Gustavs; Saripo, Vita; Sokolova, Emma; Upite, Dana; Vanaga, Ilona; Kletnieks, Ugis; Erglis, Andrejs

2016-01-01

Statin-induced myopathy (SIM) has been partially attributed to deficiency of dolichol and coenzyme Q10 (CoQ10). We aimed to test the safety and efficacy of plant polyprenols in combination with CoQ10 for alleviation of SIM. In an open-label, one-center prospective pilot study patients with SIM received conifer-tree needle polyprenols (4mg/day) and CoQ10 (100mg/day) for 8 weeks. Symptoms and safety were evaluated according to symptom severity score (0-10), creatine kinase (CK) levels, exercise test, dynamometry, complete blood count, clinical biochemistry and electrocardiography. Of the 14 patients, 11 completed the study per protocol. Two patients withdrew consent due to travels abroad, and it was discontinued for one patient with stage 3 chronic kidney disease due to asymptomatic elevations of liver enzymes at week 4. No safety parameters changed significantly in per protocol group. Non-significant increase of CK levels was observed (P=0.231). Muscle pain (n=10) and weakness (n=7) scores improved significantly (P<0.001 and P=0.018, respectively). Muscle pain completely disappeared in 2 patients, weakness resolved in 3 patients and cramps disappeared in two patients. Four patients assessed improvement strong enough to consider increase of statin dose. No changes were observed in exercise test or dynamometry. Conifer-tree polyprenols in combination with CoQ10 may be generally safe in patients with SIM, but caution should be exercised in patients with glomerular filtration rate <60mL/min and routine monitoring of the liver enzymes and CK is advocated in all patients. The observed efficacy provides the rationale for a larger, double-blind controlled study with polyprenols. Copyright © 2016 The Lithuanian University of Health Sciences. Production and hosting by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Debate-Proof Grades: Experiences and Challenges of Using a Grading Rubric in a Social Welfare Policy Course

ERIC Educational Resources Information Center

Adedoyin, Christson A.

2013-01-01

This article discusses the experiences and challenges of a graduate teaching assistant in using a grading rubric in a social welfare policy course. Using a grading rubric as a debate-proof strategy against the grade entitlement of students is expatiated. In addition, the benefits of using grading rubrics to achieve CSWE/EPAS competency…

Rigorous Numerics for ill-posed PDEs: Periodic Orbits in the Boussinesq Equation

NASA Astrophysics Data System (ADS)

Castelli, Roberto; Gameiro, Marcio; Lessard, Jean-Philippe

2018-04-01

In this paper, we develop computer-assisted techniques for the analysis of periodic orbits of ill-posed partial differential equations. As a case study, our proposed method is applied to the Boussinesq equation, which has been investigated extensively because of its role in the theory of shallow water waves. The idea is to use the symmetry of the solutions and a Newton-Kantorovich type argument (the radii polynomial approach) to obtain rigorous proofs of existence of the periodic orbits in a weighted ℓ1 Banach space of space-time Fourier coefficients with exponential decay. We present several computer-assisted proofs of the existence of periodic orbits at different parameter values.

A metabolomics-driven approach reveals metabolic responses and mechanisms in the rat heart following myocardial infarction.

PubMed

Nam, Miso; Jung, Youngae; Ryu, Do Hyun; Hwang, Geum-Sook

2017-01-15

Myocardial infarction (MI) is caused by myocardial necrosis resulting from prolonged ischemia. However, the biological mechanisms underlying MI remain unclear. We evaluated metabolic and lipidomic changes in rat heart tissue from sham and MI at 1h, 1day and 10day after coronary ligation, using global profiling based on metabolomics. A time-dependent increase or decrease in polar and lipid metabolite levels was measured. The S-adenosylmethionine (SAM) concentration and the SAM/S-adenosylhomocysteine (SAH) ratio gradually decreased in a time-dependent manner and were significantly downregulated 10days after MI. Transcriptome analysis revealed that the levels of coenzyme Q (Coq)-3 and Coq5, both of which are SAM-dependent methyltransferases, were decreased in the MI groups. These results suggested that dysregulation of SAM may be related to down regulated COQ biosynthetic pathway. In addition, short-chain (C3) and medium-chain (C4-C12) acylcarnitine levels gradually decreased, whereas long-chain acylcarnitine (C14-18) levels increased, owing to a defect in β-oxidation during ischemia. These changes are related to energy-dependent metabolic pathways, and a subsequent decrease in adenosine triphosphate concentration was observed. The comprehensive integration of various omics data provides a novel means of understanding the underlying pathophysiological mechanisms of MI. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Automatic differentiation for Fourier series and the radii polynomial approach

NASA Astrophysics Data System (ADS)

Lessard, Jean-Philippe; Mireles James, J. D.; Ransford, Julian

2016-11-01

In this work we develop a computer-assisted technique for proving existence of periodic solutions of nonlinear differential equations with non-polynomial nonlinearities. We exploit ideas from the theory of automatic differentiation in order to formulate an augmented polynomial system. We compute a numerical Fourier expansion of the periodic orbit for the augmented system, and prove the existence of a true solution nearby using an a-posteriori validation scheme (the radii polynomial approach). The problems considered here are given in terms of locally analytic vector fields (i.e. the field is analytic in a neighborhood of the periodic orbit) hence the computer-assisted proofs are formulated in a Banach space of sequences satisfying a geometric decay condition. In order to illustrate the use and utility of these ideas we implement a number of computer-assisted existence proofs for periodic orbits of the Planar Circular Restricted Three-Body Problem (PCRTBP).

CLK-1/Coq7p is a DMQ mono-oxygenase and a new member of the di-iron carboxylate protein family.

PubMed

Rea, S

2001-12-14

Strains of Caenorhabditis elegans mutant for clk-1 exhibit a 20-40% increase in mean lifespan. clk-1 encodes a mitochondrial protein thought to be either an enzyme or regulatory molecule acting within the ubiquinone biosynthesis pathway. Here CLK-1 is shown to be related to the ubiquinol oxidase, alternative oxidase, and belong to the functionally diverse di-iron-carboxylate protein family which includes bacterioferritin and methane mono-oxygenase. Construction and analysis of a homology model indicates CLK-1 is a 2-polyprenyl-3-methyl-6-methoxy-1,4-benzoquinone mono-oxygenase as originally predicted. Analysis of known CLK-1/Coq7p mutations also supports this notion. These findings raise the possibility of developing CLK-1-specific inhibitors to test for lifespan extension in higher organisms.

Rapid neonatal weight gain in rats results in a renal ubiquinone (CoQ) deficiency associated with premature death.

PubMed

Shelley, Piran; Tarry-Adkins, Jane; Martin-Gronert, Malgorzata; Poston, Lucilla; Heales, Simon; Clark, John; Ozanne, Susan; McConnell, Josie

2007-01-01

We have recently reported that maternal dietary imbalance during pregnancy and lactation can reduce the lifespan of offspring. Rats that were growth restricted in utero by maternal protein restriction and underwent rapid weight gain when suckled by control fed dams died earlier than animals whose mothers were fed a control diet throughout pregnancy and lactation. We demonstrate here that mitochondrial abnormalities and DNA damage occur in the kidney of offspring who die prematurely. We have established by direct measurement and by in vitro supplementation that mitochondrial abnormalities occur because of a functional deficit of the mitochondrial cofactor coenzyme Q9 (CoQ9). These data provide molecular insight into the association between maternal nutrition and determination of offspring lifespan, and identify, a potential dietary intervention to prevent detrimental consequences of imbalanced maternal nutrition.

Surgical Assisting

MedlinePlus

... CPR/BLS certification Acceptable health and immunization records Computer literacy Students also must be able to show proof of successful completion of basic science (college level) instruction, including: Microbiology Pathophysiology Pharmacology Anatomy ...

The Light That Doesn't Fail

NASA Technical Reports Server (NTRS)

1989-01-01

Rayovac Corporation's Luma 2 flashlight incorporates NASA's systems redundancy. The company also received assistance from NERAC. The flashlight has an extra-bright Super Krypton primary bulb and an independent backup system including a separate lithium power cell (a NASA developed technology), its own bulb and switch with corrosion proof sealed contacts. NERAC has also assisted Rayovac in developing other products.

VeriML: A Dependently-Typed, User-Extensible and Language-Centric Approach to Proof Assistants

DTIC Science & Technology

2013-01-01

the locally nameless approach [McKinna and Pollack, 1993]. The former two techniques replace all variables by numbers, whereas the locally nameless ...needs to be reasoned about together with shifting. This complicates both the statements and proofs of related lemmas. The locally nameless approach...the locally nameless approach, we separate free variables from bound variables and use deBruijn indices for bound variables (denoted as bi in Table 3.1

Proceedings of the First NASA Formal Methods Symposium

NASA Technical Reports Server (NTRS)

Denney, Ewen (Editor); Giannakopoulou, Dimitra (Editor); Pasareanu, Corina S. (Editor)

2009-01-01

Topics covered include: Model Checking - My 27-Year Quest to Overcome the State Explosion Problem; Applying Formal Methods to NASA Projects: Transition from Research to Practice; TLA+: Whence, Wherefore, and Whither; Formal Methods Applications in Air Transportation; Theorem Proving in Intel Hardware Design; Building a Formal Model of a Human-Interactive System: Insights into the Integration of Formal Methods and Human Factors Engineering; Model Checking for Autonomic Systems Specified with ASSL; A Game-Theoretic Approach to Branching Time Abstract-Check-Refine Process; Software Model Checking Without Source Code; Generalized Abstract Symbolic Summaries; A Comparative Study of Randomized Constraint Solvers for Random-Symbolic Testing; Component-Oriented Behavior Extraction for Autonomic System Design; Automated Verification of Design Patterns with LePUS3; A Module Language for Typing by Contracts; From Goal-Oriented Requirements to Event-B Specifications; Introduction of Virtualization Technology to Multi-Process Model Checking; Comparing Techniques for Certified Static Analysis; Towards a Framework for Generating Tests to Satisfy Complex Code Coverage in Java Pathfinder; jFuzz: A Concolic Whitebox Fuzzer for Java; Machine-Checkable Timed CSP; Stochastic Formal Correctness of Numerical Algorithms; Deductive Verification of Cryptographic Software; Coloured Petri Net Refinement Specification and Correctness Proof with Coq; Modeling Guidelines for Code Generation in the Railway Signaling Context; Tactical Synthesis Of Efficient Global Search Algorithms; Towards Co-Engineering Communicating Autonomous Cyber-Physical Systems; and Formal Methods for Automated Diagnosis of Autosub 6000.

Dietary and microbiome factors determine longevity in Caenorhabditis elegans

PubMed Central

Sánchez-Blanco, Adolfo; Rodríguez-Matellán, Alberto; González-Paramás, Ana; González-Manzano, Susana; Kim, Stuart K.; Mollinedo, Faustino

2016-01-01

Diet composition affects organismal health. Nutrient uptake depends on the microbiome. Caenorhabditis elegans fed a Bacillus subtilis diet live longer than those fed the standard Escherichia coli diet. Here we report that this longevity difference is primarily caused by dietary coQ, an antioxidant synthesized by E. coli but not by B. subtilis. CoQ-supplemented E. coli fed worms have a lower oxidation state yet live shorter than coQ-less B. subtilis fed worms. We showed that mutations affecting longevity for E. coli fed worms do not always lead to similar effects when worms are fed B. subtilis. We propose that coQ supplementation by the E. coli diet alters the worm cellular REDOX homeostasis, thus decreasing longevity. Our results highlight the importance of microbiome factors in longevity, argue that antioxidant supplementation can be detrimental, and suggest that the C. elegans standard E. coli diet can alter the effect of signaling pathways on longevity. PMID:27510225

A Feasibility Study of Female Active Duty Military Personnel and Exposure to Jet Fuel

DTIC Science & Technology

1996-07-01

Lancet 2:322-325, 1977. 16. Ungvary G, Cseh J, Manyai S, Molnar A, Szeberenzi S and Tatri E: Enzyme induction by o-xylene inhalation. Acta Med Acad...r.41 04 0w 0 w 0 9:L 4- - W - - -W 0) u )4 0H -H - ww (1)N (0 CID M Lf) r- O N 00 COq HO L - ( Or- rIN L -O 00’ N Nc 0 N H0 00N N CN u 117 r4iH H...W.COa a) f~~ a) 1* V 0 D0 t 00C D0 0 ) C c0 0% * Coq .c . oSq -. qqG .. J N; ; g6 .C 0 .C 6 6 cc > 0 NH Vi 66 6 LU X v ’v v* XX v ’v v X v C U) q 0) 0

MitoQ--a mitochondria-targeted antioxidant.

PubMed

Tauskela, Joseph S

2007-06-01

MitoQ is an orally active antioxidant that has the ability to target mitochondrial dysfunction. The agent is currently under development by Antipodean Pharmaceuticals Inc in phase II clinical trials for Parkinson's disease and liver damage associated with HCV infection. MitoQ has demonstrated encouraging preclinical results in numerous studies in isolated mitochondria, cells and tissues undergoing oxidative stress and apoptotic death. MitoQ aims to not only mimic the role of the endogenous mitochondrial antioxidant coenzyme Q10 (CoQ10), but also to augment substantially the antioxidant capacity of CoQ to supraphysiological levels in a mitochondrial membrane potential-dependent manner. MitoQ represents the first foray into the clinic in an attempt to deliver an antioxidant to an intracellular region that is responsible for the formation of increased levels of potentially deleterious reactive oxygen species. Results from the clinical trials with MitoQ will have important repercussions on the relevance of a mitochondrial-targeted approach.

The subtle central effect of nutraceuticals: Is it placebo or nocebo?

PubMed Central

Al-Gareeb, Ali I.

2015-01-01

Background: Herbal medicines are often perceived by the general public as a “soft” alternative to Western Medicine, but the use of these substances can be risky since they can induce nocebo effect. Aim: The aim was to evaluate the nocebo effects of Nigella sativa oil, garlic and coenzyme Q10 (CoQ10) on the integrative function of the central nervous system and psychomotor performance. Materials and Methods: This is a randomized, double-blind, controlled, and prospective study conducted in the Department of Pharmacology, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq during February 2013. A total of 160 medical students participated in this study were randomly assigned equally to one of the following groups: Group A: Received single dose of N. sativa oil (500 ml capsule); Group B: Received single dose of garlic (500 mg capsule); Group C: Received single dose of CoQ10 (120 mg capsule) and; Group D: received single dose of matching oral placebo (300 mg starch capsule). For all participants, reaction time and flicker fusion threshold were measured by the Leeds psychomotor performance test battery before and after 3 h of taking the drugs Results: Neither placebo nor nutraceuticals exerted significant effect on total reaction time. Although the recognition reaction time is insignificantly reduced by 2.77% (placebo), 5.83% (Nigella sativa), 7.21% (garlic) and 12.64% (CoQ10) from the pretreatment values, they are adversely affect the motor reaction time to reach the significant level in subjects pretreated with Garlic (P = 0.02). Conclusion: Nutraceuticals are not free from nocebo effect on psychomotor performance. PMID:26401411

The subtle central effect of nutraceuticals: Is it placebo or nocebo?

PubMed

Al-Gareeb, Ali I

2015-01-01

Herbal medicines are often perceived by the general public as a "soft" alternative to Western Medicine, but the use of these substances can be risky since they can induce nocebo effect. The aim was to evaluate the nocebo effects of Nigella sativa oil, garlic and coenzyme Q10 (CoQ10) on the integrative function of the central nervous system and psychomotor performance. This is a randomized, double-blind, controlled, and prospective study conducted in the Department of Pharmacology, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq during February 2013. A total of 160 medical students participated in this study were randomly assigned equally to one of the following groups: Group A: Received single dose of N. sativa oil (500 ml capsule); Group B: Received single dose of garlic (500 mg capsule); Group C: Received single dose of CoQ10 (120 mg capsule) and; Group D: received single dose of matching oral placebo (300 mg starch capsule). For all participants, reaction time and flicker fusion threshold were measured by the Leeds psychomotor performance test battery before and after 3 h of taking the drugs. Neither placebo nor nutraceuticals exerted significant effect on total reaction time. Although the recognition reaction time is insignificantly reduced by 2.77% (placebo), 5.83% (Nigella sativa), 7.21% (garlic) and 12.64% (CoQ10) from the pretreatment values, they are adversely affect the motor reaction time to reach the significant level in subjects pretreated with Garlic (P = 0.02). Nutraceuticals are not free from nocebo effect on psychomotor performance.

Orally delivered water soluble Coenzyme Q10 (Ubisol-Q10) blocks on-going neurodegeneration in rats exposed to paraquat: potential for therapeutic application in Parkinson's disease.

PubMed

Muthukumaran, Krithika; Leahy, Samantha; Harrison, Kate; Sikorska, Marianna; Sandhu, Jagdeep K; Cohen, Jerome; Keshan, Corrine; Lopatin, Daniel; Miller, Harvey; Borowy-Borowski, Henryk; Lanthier, Patricia; Weinstock, Shelly; Pandey, Siyaram

2014-01-31

Paraquat, still used as an herbicide in some parts of the world, is now regarded as a dangerous environmental neurotoxin and is linked to the development Parkinson's disease (PD). Paraquat interacts with cellular redox systems and causes mitochondrial dysfunction and the formation of reactive oxygen species, which in turn, plays a crucial role in the pathophysiology of PD. Various antioxidant therapies have been explored with the expectations that they deliver health benefits to the PD patients, however, no such therapies were effective. Here we have tested the neuroprotective efficacy of a novel water-soluble CoQ10 (Ubisol-Q10), in a rat model of paraquat-induced neurodegeneration in order to evaluate its potential application in the management of PD. We have developed a rat model of progressive nigrostriatal degeneration by giving rats five intraperitoneal injections of paraquat (10 mg/kg/injection), once every five days. Neuronal death occurred over a period of 8 weeks with close to 50% reduction in the number of tyrosine hydroxylase-positive cells. Ubisol-Q10, at 6 mg CoQ10/kg body weight/day, was delivered as a supplement in drinking water. The intervention begun after the completion of paraquat injections when the neurodegenerative process had already began and about 20% of TH-positive neurons were lost. Ubisol-Q10 treatment halted the progression of neurodegeneration and remaining neurons were protected. The outcomes were evaluated based on the number of surviving tyrosine hydroxylase-positive neurons in the substantia nigra region and improved motor skills in response to the Ubisol-Q10 intervention. To maintain this neuroprotection, however, continuous Ubisol- Q10 supplementation was required, if withdrawn, the neuronal death pathway resumed, suggesting that the presence of CoQ10 was essential for blocking the pathway. The CoQ10, given orally as Ubisol-Q10 in drinking solution, was effective in blocking the progression of neurodegeneration when administered therapeutically (post-toxin injection), at a much lower concentration than other previously tested oil soluble formulations and well within the acceptable daily intake of 12 mg/kg/day. Such unprecedented neuroprotection has never been reported before. These results are very encouraging and suggest that Ubisol-Q10 should be further tested and developed as a therapy for halting the progression of PD.

Effect of a hydrophilic and a hydrophobic statin on cardiac salvage after ST-elevated acute myocardial infarction - a pilot study.

PubMed

Chitose, Tadasuke; Sugiyama, Seigo; Sakamoto, Kenji; Shimomura, Hideki; Yamashita, Takuro; Hokamaki, Jun; Tsunoda, Ryusuke; Shiraishi, Shinya; Yamashita, Yasuyuki; Ogawa, Hisao

2014-11-01

Early statin therapy after acute coronary syndrome reduces atherothrombotic vascular events. This study aimed to compare the effects of hydrophilic and hydrophobic statins on myocardial salvage and left ventricular (LV) function in patients with ST-elevated myocardial infarction (STEMI). Seventy-five STEMI patients who had received emergency reperfusion therapy were enrolled and randomized into the hydrophilic statin group (rosuvastatin; 5 mg/day, n = 38) and hydrophobic statin group (atorvastatin; 10 mg/day, n = 37) for 6 months. LV ejection fraction (LVEF), and B-type natriuretic peptide (BNP) and co-enzyme Q10 (CoQ10) levels were measured at baseline and the end of treatment. The myocardial salvage index was assessed by single photon emission computed tomography with (123-)I-β-methyl-iodophenylpentadecanoic acid (ischemic area-at-risk at onset of STEMI: AAR) and (201-)thallium scintigraphy (area-at-infarction at 6 months: AAI) [myocardial salvage index = (AAR-AAI) × 100/AAR (%)]. Onset-to-balloon time and maximum creatine phosphokinase levels were comparable between the groups. After 6 months, rosuvastatin (-37.6% ± 17.2%) and atorvastatin (-32.4% ± 22.4%) equally reduced low-density lipoprotein-cholesterol (LDL-C) levels (p = 0.28). However, rosuvastatin (+3.1% ± 5.9%, p < 0.05), but not atorvastatin (+1.6% ± 5.7%, p = 0.15), improved LVEF. Rosuvastatin reduced BNP levels compared with atorvastatin (-53.3% ± 48.8% versus -13.8% ± 82.9%, p < 0.05). The myocardial salvage index was significantly higher in the rosuvastatin group than the atorvastatin group (78.6% ± 29.1% versus 52.5% ± 38.0%, p < 0.05). CoQ10/LDL-C levels at 6 months were increased in the rosuvastatin group (+23.5%, p < 0.01) and percent changes in CoQ10/LDL-C were correlated with the myocardial salvage index (r = 0.56, p < 0.01). Rosuvastatin shows better beneficial effects on myocardial salvage than atorvastatin in STEMI patients, including long-term cardiac function, associated with increasing CoQ10/LDL-C. URL http://www.umin.ac.jp/ctr/index.htm Unique Identifier: UMIN000003893. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

AfterMath: the work of proof in the age of human-machine collaboration.

PubMed

Dick, Stephanie

2011-09-01

During the 1970s and 1980s, a team of Automated Theorem Proving researchers at the Argonne National Laboratory near Chicago developed the Automated Reasoning Assistant, or AURA, to assist human users in the search for mathematical proofs. The resulting hybrid humans+AURA system developed the capacity to make novel contributions to pure mathematics by very untraditional means. This essay traces how these unconventional contributions were made and made possible through negotiations between the humans and the AURA at Argonne and the transformation in mathematical intuition they produced. At play in these negotiations were experimental practices, nonhumans, and nonmathematical modes of knowing. This story invites an earnest engagement between historians of mathematics and scholars in the history of science and science studies interested in experimental practice, material culture, and the roles of nonhumans in knowledge making.

Effectiveness of an evidence-based practice (EBP) course on the EBP competence of undergraduate nursing students: A quasi-experimental study.

PubMed

Ruzafa-Martínez, María; López-Iborra, Lidón; Armero Barranco, David; Ramos-Morcillo, Antonio Jesús

2016-03-01

International nursing institutions and experts recommend evidence-based practice (EBP) as a core component of the curriculum for nurses. However, the impact of EBP training on the competence of undergraduate nursing students remains unclear. To evaluate the effectiveness of an EBP course on the EBP competence undergraduate nursing students'. Quasi-experimental study carried out in non-randomized intervention and control groups. The study was conducted in a Spanish public university in 2010. Out of 420 second- and third-year nursing students, 75 were enrolled in the EBP course, forming the intervention group, and 73 were not enrolled in this course were recruited as controls. The educational intervention was a 15-week course designed to teach EBP competence. The EBP Competence Questionnaire (EBP-COQ) was administered before and after the intervention. Repeated-measure ANOVA was used to compare intervention and control group scores before and at two months after the 15-week intervention period. At 2months after the EBP course, mean EBP-COQ scores of the intervention group were significantly improved versus baseline in attitude (4.28 vs. 3.33), knowledge (3.92 vs. 2.82) and skills (4.01 vs. 2.75) dimensions, whereas little change was observed in control group scores over the same time period. Repeated-measures ANOVA revealed a significant effect of Time ×Group interaction on global competence and all three EBP-COQ dimensions. Undergraduate nursing students experience positive changes in EBP competence, knowledge, skills, and attitude as the result of a 15-week educational intervention on EBP. This EBP course may provide nursing school educators and policymakers with a useful model for integrating EBP teaching within the nursing curriculum. Copyright © 2015 Elsevier Ltd. All rights reserved.

Regulation of the oxidative balance with coenzyme Q10 sensitizes human glioblastoma cells to radiation and temozolomide.

PubMed

Frontiñán-Rubio, Javier; Santiago-Mora, Raquel María; Nieva-Velasco, Consuelo María; Ferrín, Gustavo; Martínez-González, Alicia; Gómez, María Victoria; Moreno, María; Ariza, Julia; Lozano, Eva; Arjona-Gutiérrez, Jacinto; Gil-Agudo, Antonio; De la Mata, Manuel; Pesic, Milica; Peinado, Juan Ramón; Villalba, José M; Pérez-Romasanta, Luis; Pérez-García, Víctor M; Alcaín, Francisco J; Durán-Prado, Mario

2018-05-18

To investigate how the modulation of the oxidative balance affects cytotoxic therapies in glioblastoma, in vitro. Human glioblastoma U251 and T98 cells and normal astrocytes C8D1A were loaded with coenzyme Q10 (CoQ). Mitochondrial superoxide ion (O 2 - ) and H 2 O 2 were measured by fluorescence microscopy. OXPHOS performance was assessed in U251 cells with an oxytherm Clark-type electrode. Radio- and chemotherapy cytotoxicity was assessed by immunostaining of γH2AX (24 h), annexin V and nuclei morphology, at short (72 h) and long (15 d) time. Hif-1α, SOD1, SOD2 and NQO1 were determined by immunolabeling. Catalase activity was measured by classic enzymatic assay. Glutathione levels and total antioxidant capacity were quantified using commercial kits. CoQ did not affect oxygen consumption but reduced the level of O 2 - and H 2 O 2 while shifted to a pro-oxidant cell status mainly due to a decrease in catalase activity and SOD2 level. Hif-1α was dampened, echoed by a decrease lactate and several key metabolites involved in glutathione synthesis. CoQ-treated cells were twofold more sensitive than control to radiation-induced DNA damage and apoptosis in short and long-term clonogenic assays, potentiating TMZ-induced cytotoxicity, without affecting non-transformed astrocytes. CoQ acts as sensitizer for cytotoxic therapies, disarming GBM cells, but not normal astrocytes, against further pro-oxidant injuries, being potentially useful in clinical practice for this fatal pathology. Copyright © 2018 Elsevier B.V. All rights reserved.

n-3 fatty acids reduce plasma 20-hydroxyeicosatetraenoic acid and blood pressure in patients with chronic kidney disease.

PubMed

Barden, Anne E; Burke, Valerie; Mas, Emilie; Beilin, Lawrence J; Puddey, Ian B; Watts, Gerald F; Irish, Ashley B; Mori, Trevor A

2015-09-01

Metabolism of arachidonic acid by cytochrome P450 ω-hydroxylase leads to the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) that regulates vascular function, sodium homeostasis and blood pressure (BP). Supplementation with n-3 fatty acids is known to alter arachidonic acid metabolism and reduce the formation of the lipid peroxidation products F2-isoprostanes, but the effect of n-3 fatty acids on 20-HETE has not been studied. We previously reported a significant effect of n-3 fatty acids but not coenzyme Q10 (CoQ) to reduce BP in a double-blind, placebo-controlled intervention, wherein patients with chronic kidney disease (CKD) were randomized to n-3 fatty acids (4 g), CoQ (200 mg), both supplements or control (4 g olive oil), daily for 8 weeks. This study examined the effect of n-3 fatty acids on plasma and urinary 20-HETE in the same study, as well as plasma and urinary F2-isoprostanes, and relate these to changes in BP. Seventy-four patients completed the 8-week intervention. n-3 fatty acids but not CoQ significantly reduced plasma 20-HETE (P = 0.001) and F2-isoprostanes (P < 0.001). In regression models adjusted for BP at baseline, postintervention plasma 20-HETE was a significant predictor of the fall in SBP (P < 0.0001) and DBP (P < 0.0001) after n-3 fatty acids. This is the first report that n-3 fatty acid supplementation reduces plasma 20-HETE in humans and that this associates with reduced BP. These results provide a plausible mechanism for the reduction in BP observed in patients with CKD following n-3 fatty acid supplementation.

Host Coenzyme Q Redox State Is an Early Biomarker of Thermal Stress in the Coral Acropora millepora

PubMed Central

Motti, Cherie A.; Miller, David J.; van Oppen, Madeleine J. H.

2015-01-01

Bleaching episodes caused by increasing seawater temperatures may induce mass coral mortality and are regarded as one of the biggest threats to coral reef ecosystems worldwide. The current consensus is that this phenomenon results from enhanced production of harmful reactive oxygen species (ROS) that disrupt the symbiosis between corals and their endosymbiotic dinoflagellates, Symbiodinium. Here, the responses of two important antioxidant defence components, the host coenzyme Q (CoQ) and symbiont plastoquinone (PQ) pools, are investigated for the first time in colonies of the scleractinian coral, Acropora millepora, during experimentally-induced bleaching under ecologically relevant conditions. Liquid chromatography-mass spectrometry (LC-MS) was used to quantify the states of these two pools, together with physiological parameters assessing the general state of the symbiosis (including photosystem II photochemical efficiency, chlorophyll concentration and Symbiodinium cell densities). The results show that the responses of the two antioxidant systems occur on different timescales: (i) the redox state of the Symbiodinium PQ pool remained stable until twelve days into the experiment, after which there was an abrupt oxidative shift; (ii) by contrast, an oxidative shift of approximately 10% had occurred in the host CoQ pool after 6 days of thermal stress, prior to significant changes in any other physiological parameter measured. Host CoQ pool oxidation is thus an early biomarker of thermal stress in corals, and this antioxidant pool is likely to play a key role in quenching thermally-induced ROS in the coral-algal symbiosis. This study adds to a growing body of work that indicates host cellular responses may precede the bleaching process and symbiont dysfunction. PMID:26426118

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koenig, Robert

We propose a generalization of the quantum entropy power inequality involving conditional entropies. For the special case of Gaussian states, we give a proof based on perturbation theory for symplectic spectra. We discuss some implications for entanglement-assisted classical communication over additive bosonic noise channels.

Impact of Chemical Analogs of 4-Hydroxybenzoic Acid on Coenzyme Q Biosynthesis: From Inhibition to Bypass of Coenzyme Q Deficiency

PubMed Central

Pierrel, Fabien

2017-01-01

Coenzyme Q is a lipid that participates to important physiological functions. Coenzyme Q is synthesized in multiple steps from the precursor 4-hydroxybenzoic acid. Mutations in enzymes that participate to coenzyme Q biosynthesis result in primary coenzyme Q deficiency, a type of mitochondrial disease. Coenzyme Q10 supplementation of patients is the classical treatment but it shows limited efficacy in some cases. The molecular understanding of the coenzyme Q biosynthetic pathway allowed the design of experiments to bypass deficient biosynthetic steps with analogs of 4-hydroxybenzoic acid. These molecules provide the defective chemical group and can reactivate endogenous coenzyme Q biosynthesis as demonstrated recently in yeast, mammalian cell cultures, and mouse models of primary coenzyme Q deficiency. This mini review presents how the chemical properties of various analogs of 4-hydroxybenzoic acid dictate the effect of the molecules on CoQ biosynthesis and how the reactivation of endogenous coenzyme Q biosynthesis may achieve better results than exogenous CoQ10 supplementation. PMID:28690551

Purification and Characterization of Put1p from Saccharomyces cerevisiae

PubMed Central

Wanduragala, Srimevan; Sanyal, Nikhilesh; Liang, Xinwen; Becker, Donald F.

2010-01-01

In Saccharomyces cerevisiae, the PUT1 and PUT2 genes are required for the conversion of proline to glutamate. The PUT1 gene encodes Put1p, a proline dehydrogenase (PRODH)1 enzyme localized in the mitochondrion. Put1p was expressed and purified from Escherichia coli and shown to have a UV-visible absorption spectrum that is typical of a bound flavin cofactor. A Km value of 36 mM proline and a kcat = 27 s−1 were determined for Put1p using an artificial electron acceptor. Put1p also exhibited high activity using ubiquinone-1 (CoQ1) as an electron acceptor with a kcat = 9.6 s−1 and a Km of 33 µM for CoQ1. In addition, knockout strains of the electron transfer flavoprotein (ETF) homolog in S. cerevisiae were able to grow on proline as the sole nitrogen source demonstrating that ETF is not required for proline utilization in yeast. PMID:20450881

Plasma coenzyme Q10 levels in type 2 diabetic patients with retinopathy

PubMed Central

Ates, Orhan; Bilen, Habip; Keles, Sadullah; Alp, H. Hakan; Keleş, Mevlüt Sait; Yıldırım, Kenan; Öndaş, Osman; Pınar, L. Can; Civelekler, Mustafa; Baykal, Orhan

2013-01-01

AIM To determine the relationship between proliferative diabetic retinopathy (PDRP) and plasma coenzyme Q10(CoQ10) concentration. METHODS Patients with type 2 diabetes and PDRP were determined to be the case group (n=50). The control group was consist of healthy individuals (n=50). Plasma CoQ10 and malondialdehyde (MDA) levels were measured in both groups. RESULTS Ubiquinone-10 (Coenzyme Q10) levels in PDRP and control subjects are 3.81±1.19µmol/L and 1.91±0.62µmol/L, respectively. Plasma MDA levels in PDRP and control subjects were 8.16±2µmol/L and 3.44±2.08µmol/L, respectively. Ratio of Ubiquinol-10/ubiquinone-10 in PDRP and control subjects were 0.26±0.16 and 1.41±0.68, respectively. CONCLUSION The ratio of ubiquinol-10/ubiquinone-10 is found lower in patients with PDRP. High levels of plasma ubiquinol-10/ubiquinone-10 ratio indicate the protective effect on diabetic retinopathy. PMID:24195048

Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.

PubMed

Floyd, Brendan J; Wilkerson, Emily M; Veling, Mike T; Minogue, Catie E; Xia, Chuanwu; Beebe, Emily T; Wrobel, Russell L; Cho, Holly; Kremer, Laura S; Alston, Charlotte L; Gromek, Katarzyna A; Dolan, Brendan K; Ulbrich, Arne; Stefely, Jonathan A; Bohl, Sarah L; Werner, Kelly M; Jochem, Adam; Westphall, Michael S; Rensvold, Jarred W; Taylor, Robert W; Prokisch, Holger; Kim, Jung-Ja P; Coon, Joshua J; Pagliarini, David J

2016-08-18

Mitochondria are essential for numerous cellular processes, yet hundreds of their proteins lack robust functional annotation. To reveal functions for these proteins (termed MXPs), we assessed condition-specific protein-protein interactions for 50 select MXPs using affinity enrichment mass spectrometry. Our data connect MXPs to diverse mitochondrial processes, including multiple aspects of respiratory chain function. Building upon these observations, we validated C17orf89 as a complex I (CI) assembly factor. Disruption of C17orf89 markedly reduced CI activity, and its depletion is found in an unresolved case of CI deficiency. We likewise discovered that LYRM5 interacts with and deflavinates the electron-transferring flavoprotein that shuttles electrons to coenzyme Q (CoQ). Finally, we identified a dynamic human CoQ biosynthetic complex involving multiple MXPs whose topology we map using purified components. Collectively, our data lend mechanistic insight into respiratory chain-related activities and prioritize hundreds of additional interactions for further exploration of mitochondrial protein function. Copyright © 2016 Elsevier Inc. All rights reserved.

Impact of Chemical Analogs of 4-Hydroxybenzoic Acid on Coenzyme Q Biosynthesis: From Inhibition to Bypass of Coenzyme Q Deficiency.

PubMed

Pierrel, Fabien

2017-01-01

Coenzyme Q is a lipid that participates to important physiological functions. Coenzyme Q is synthesized in multiple steps from the precursor 4-hydroxybenzoic acid. Mutations in enzymes that participate to coenzyme Q biosynthesis result in primary coenzyme Q deficiency, a type of mitochondrial disease. Coenzyme Q 10 supplementation of patients is the classical treatment but it shows limited efficacy in some cases. The molecular understanding of the coenzyme Q biosynthetic pathway allowed the design of experiments to bypass deficient biosynthetic steps with analogs of 4-hydroxybenzoic acid. These molecules provide the defective chemical group and can reactivate endogenous coenzyme Q biosynthesis as demonstrated recently in yeast, mammalian cell cultures, and mouse models of primary coenzyme Q deficiency. This mini review presents how the chemical properties of various analogs of 4-hydroxybenzoic acid dictate the effect of the molecules on CoQ biosynthesis and how the reactivation of endogenous coenzyme Q biosynthesis may achieve better results than exogenous CoQ 10 supplementation.

Orally delivered water soluble Coenzyme Q10 (Ubisol-Q10) blocks on-going neurodegeneration in rats exposed to paraquat: potential for therapeutic application in Parkinson’s disease

PubMed Central

2014-01-01

Background Paraquat, still used as an herbicide in some parts of the world, is now regarded as a dangerous environmental neurotoxin and is linked to the development Parkinson’s disease (PD). Paraquat interacts with cellular redox systems and causes mitochondrial dysfunction and the formation of reactive oxygen species, which in turn, plays a crucial role in the pathophysiology of PD. Various antioxidant therapies have been explored with the expectations that they deliver health benefits to the PD patients, however, no such therapies were effective. Here we have tested the neuroprotective efficacy of a novel water-soluble CoQ10 (Ubisol-Q10), in a rat model of paraquat-induced neurodegeneration in order to evaluate its potential application in the management of PD. Results We have developed a rat model of progressive nigrostriatal degeneration by giving rats five intraperitoneal injections of paraquat (10 mg/kg/injection), once every five days. Neuronal death occurred over a period of 8 weeks with close to 50% reduction in the number of tyrosine hydroxylase-positive cells. Ubisol-Q10, at 6 mg CoQ10/kg body weight/day, was delivered as a supplement in drinking water. The intervention begun after the completion of paraquat injections when the neurodegenerative process had already began and about 20% of TH-positive neurons were lost. Ubisol-Q10 treatment halted the progression of neurodegeneration and remaining neurons were protected. The outcomes were evaluated based on the number of surviving tyrosine hydroxylase-positive neurons in the substantia nigra region and improved motor skills in response to the Ubisol-Q10 intervention. To maintain this neuroprotection, however, continuous Ubisol- Q10 supplementation was required, if withdrawn, the neuronal death pathway resumed, suggesting that the presence of CoQ10 was essential for blocking the pathway. Conclusion The CoQ10, given orally as Ubisol-Q10 in drinking solution, was effective in blocking the progression of neurodegeneration when administered therapeutically (post-toxin injection), at a much lower concentration than other previously tested oil soluble formulations and well within the acceptable daily intake of 12 mg/kg/day. Such unprecedented neuroprotection has never been reported before. These results are very encouraging and suggest that Ubisol-Q10 should be further tested and developed as a therapy for halting the progression of PD. PMID:24483602

Autism and Equine-Assisted Interventions: A Systematic Mapping Review.

PubMed

McDaniel Peters, B Caitlin; Wood, Wendy

2017-10-01

This systematic mapping review mapped current knowledge of equine-assisted interventions for people with autism to help guide future practice and research. Thirty-three studies including children and adolescents with autism, 3 of which confirmed diagnoses, were reviewed. Five types of equine-assisted activities were identified across 25 studies, with reported improvements in behavior, social interaction, and communication. Four types of equine-assisted therapies were identified across 8 studies, with reported improvements in motor control and self-care. Different approaches to therapeutic riding and hippotherapy, the most studied interventions, were evident. While this literature reflected early scientific development, it offered broad proof of concept that equine-assisted interventions can benefit children and adolescents with autism. Promising outcomes support continued investigation focused on standardization, appropriateness, and efficacy.

Transcriptional Analysis of the bgIP Gene from Streptococcus mutans

DTIC Science & Technology

2006-04-21

Lactobacillus plantarum . FEMS Microbiol Lett 2000, 186(2):269-273. 5. Le Coq D, Lindner C, Kruger S, Steinmetz M, Stulke J: New beta- glucoside (bgl) genes in...longisporum [3], Lactobacillus plantarium [4], Bacillus subtilis [5,6], and Streptococcus mutans [7]. All of these organisms rely on the phosphoe

An RFID solution for enhancing inpatient medication safety with real-time verifiable grouping-proof.

PubMed

Chen, Yu-Yi; Tsai, Meng-Lin

2014-01-01

The occurrence of a medication error can threaten patient safety. The medication administration process is complex and cumbersome, and nursing staffs are prone to error when they are tired. Proper Information Technology (IT) can assist the nurse in correct medication administration. We review a recent proposal regarding a leading-edge solution to enhance inpatient medication safety by using RFID technology. The proof mechanism is the kernel concept in their design and worth studying to develop a well-designed grouping-proof scheme. Other RFID grouping-proof protocols could be similarly applied in administering physician orders. We improve on the weaknesses of previous works and develop a reading-order independent RFID grouping-proof scheme in this paper. In our scheme, tags are queried and verified under the direct control of the authorized reader without connecting to the back-end database server. Immediate verification in our design makes this application more portable and efficient and critical security issues have been analyzed by the threat model. Our scheme is suitable for the safe drug administration scenario and the drug package scenario in a hospital environment to enhance inpatient medication safety. It automatically checks for correct drug unit-dose and appropriate inpatient treatments. Copyright © 2013. Published by Elsevier Ireland Ltd.

Development of an Executive Level Stock Fund Handbook

DTIC Science & Technology

1990-09-01

graphics assistance, thorough proof-reading of countless rewrites, and prayer support. I want to thank Heike, my wife to be, for her tremendous patience...Usability........................... 46 Format Design ....................... 50 III. Methodology.................................... 52 Overall...54 Panel of Experts ....................57 Interview Instrument ................57 Handbook Format Design ............. 58 Handbook Usability

7 CFR 1430.505 - Proof of production.

Code of Federal Regulations, 2010 CFR

2010-01-01

... operation was commercially marketing milk anytime during the fourth quarter of 1998. The dairy operation... marketing milk during the fourth quarter of 1998 shall provide any available supporting documents to assist... during the fourth quarter of 1998 and the base period milk marketings indicated on Form CCC-1040...

ATAC Process Proof of Concept Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bri Rolston; Sarah Freeman

Researchers at INL with funding from the Department of Energy’s Office of Electricity Delivery and Energy Reliability (DOE-OE) evaluated a novel approach for near real-time consumption of threat intelligence. Demonstration testing in an industry environment supported the development of this new process to assist the electric sector in securing their critical networks. This report provides the reader with an understanding of the methods used during this proof of concept project. The processes and templates were further advanced with an industry partner during an onsite assessment. This report concludes with lessons learned and a roadmap for final development of these materialsmore » for use by industry.« less

Dependently Typed Programming with Domain-Specific Logics

DTIC Science & Technology

2011-02-28

van den Berg and Garner, 2010; Voevodsky, 2010). This work promises a new class of proof assistants that intrinsically support proof irrelevance, equal...InΣ (neuA⇐ neu ⊗ sem) neut : InΣ (semA⇐ neu) slam : InΣ (semA⇐ (∀6 neuC (sem ⊃ sem))) reifyenv : Vars Vars Type reifyenv Ψe Ψs = ([Ψs ] * (neuC...ϕ) = lam · reify (Ψe, , expC) (Ψs, , neuC) σ’ (ϕ [neuC ] ( neut · (. i0))) where σ’ : (reifyenv (Ψe, , expC) (Ψs, , neuC)) σ’ i0 = i0 σ’ (iS x) = iS

Postprandial antioxidant gene expression is modified by Mediterranean diet supplemented with coenzyme Q(10) in elderly men and women.

PubMed

Yubero-Serrano, Elena M; Gonzalez-Guardia, Lorena; Rangel-Zuñiga, Oriol; Delgado-Casado, Nieves; Delgado-Lista, Javier; Perez-Martinez, Pablo; Garcia-Rios, Antonio; Caballero, Javier; Marin, Carmen; Gutierrez-Mariscal, Francisco M; Tinahones, Francisco J; Villalba, Jose M; Tunez, Isaac; Perez-Jimenez, Francisco; Lopez-Miranda, Jose

2013-02-01

Postprandial oxidative stress is characterized by an increased susceptibility of the organism towards oxidative damage after consumption of a meal rich in lipids and/or carbohydrates. We have investigated whether the quality of dietary fat alters postprandial gene expression and protein levels involved in oxidative stress and whether the supplementation with coenzyme Q(10) (CoQ) improves this situation in an elderly population. Twenty participants were randomized to receive three isocaloric diets each for 4 weeks: Mediterranean diet supplemented with CoQ (Med + CoQ diet), Mediterranean diet (Med diet), saturated fatty acid-rich diet (SFA diet). After 12-h fast, volunteers consumed a breakfast with a fat composition similar to that consumed in each of the diets. Nrf2, p22(phox) and p47(phox), superoxide dismutase 1 and 2 (SOD1 and SOD2), glutathione peroxidase 1 (GPx1), thiorredoxin reductase (TrxR) gene expression and Kelch-like ECH associating protein 1 (Keap-1) and citoplasmic and nuclear Nrf2 protein levels were determined. Med and Med + CoQ diets induced lower Nrf2, p22(phox), p47(phox), SOD1, SOD2 and TrxR gene expression and higher cytoplasmic Nrf2 and Keap-1 protein levels compared to the SFA diet. Moreover, Med + CoQ diet produced lower postprandial Nrf2 gene expression and lower nuclear Nrf2 protein levels compared to the other diets and lower GPx1 gene expression than the SFA diet. Our results support the antioxidant effect of a Med diet and that exogenous CoQ supplementation has a protective effects against free radical overgeneration through the lowering of postprandial oxidative stress modifying the postprandial antioxidant protein levels and reducing the postprandial expression of antioxidant genes in peripheral blood mononuclear cells.

50 CFR 600.518 - Fee schedule for foreign fishing.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Section 600.518 Wildlife and Fisheries FISHERY CONSERVATION AND MANAGEMENT, NATIONAL OCEANIC AND... documentary proof to the Assistant Administrator that the foreign nation under which the vessel is registered... are agreed upon, NOAA will present a bill for collection as the documentary demand for payment to the...

Eastern Equine Encephalomyelitis Virus and Culiseta Melanura Activity at the Patuxent Wildlife Research Center, 1985-90

DTIC Science & Technology

1992-09-01

melanura ( Coq .), and the virus can cause for virus in 1985, 1989 and 1990. Mosquitoes for Snf severe disease or death in horses, game birds viral...prospective field evaluation of an enzyme immunoassay: detection of eastern equine Carpenter. J. W.. (G. G. Clark and D. M. Watts. 199,9

Aviation System Analysis Capability Executive Assistant Design

NASA Technical Reports Server (NTRS)

Roberts, Eileen; Villani, James A.; Osman, Mohammed; Godso, David; King, Brent; Ricciardi, Michael

1998-01-01

In this technical document, we describe the design developed for the Aviation System Analysis Capability (ASAC) Executive Assistant (EA) Proof of Concept (POC). We describe the genesis and role of the ASAC system, discuss the objectives of the ASAC system and provide an overview of components and models within the ASAC system, and describe the design process and the results of the ASAC EA POC system design. We also describe the evaluation process and results for applicable COTS software. The document has six chapters, a bibliography, three appendices and one attachment.

Proof of concept of a simple computer-assisted technique for correcting bone deformities.

PubMed

Ma, Burton; Simpson, Amber L; Ellis, Randy E

2007-01-01

We propose a computer-assisted technique for correcting bone deformities using the Ilizarov method. Our technique is an improvement over prior art in that it does not require a tracking system, navigation hardware and software, or intraoperative registration. Instead, we rely on a postoperative CT scan to obtain all of the information necessary to plan the correction and compute a correction schedule for the patient. Our laboratory experiments using plastic phantoms produced deformity corrections accurate to within 3.0 degrees of rotation and 1 mm of lengthening.

Aviation System Analysis Capability Executive Assistant Development

NASA Technical Reports Server (NTRS)

Roberts, Eileen; Villani, James A.; Anderson, Kevin; Book, Paul

1999-01-01

In this technical document, we describe the development of the Aviation System Analysis Capability (ASAC) Executive Assistant (EA) Proof of Concept (POC) and Beta version. We describe the genesis and role of the ASAC system, discuss the objectives of the ASAC system and provide an overview of components and models in the ASAC system, and describe the design process and the results of the ASAC EA POC and Beta system development. We also describe the evaluation process and results for applicable COTS software. The document has seven chapters, a bibliography, and two appendices.

MALDI-TOF mass spectrometry applied to identifying species of insect-pathogenic fungi from the Metarhizium anisopliae complex

USDA-ARS?s Scientific Manuscript database

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has proven to be a powerful tool for taxonomic resolution of microorganisms. In this proof-of-concept study, we assessed the effectiveness of this technique to track the current gene sequence-based phylogenet...

North Idaho E. coli Infections Linked to Raw Clover Sprouts > Idaho

Science.gov Websites

Stamps Nutrition Education Heating/Telephone Women, Infants and Children Nursing Home Cost Assistance WIC About WIC FAQs Contact Us Apply for WIC Vendor Health Partners Breastfeeding Staff Nutrition Education Livable Communities Idaho Physical Activity and Nutrition (IPAN) Fit and Fall Proof(tm) Nutrition Physical

A randomized, controlled proof-of-concept trial of an Internet-based, therapist-assisted self-management treatment for posttraumatic stress disorder.

PubMed

Litz, Brett T; Engel, Charles C; Bryant, Richard A; Papa, Anthony

2007-11-01

The authors report an 8-week randomized, controlled proof-of-concept trial of a new therapist-assisted, Internet-based, self-management cognitive behavior therapy versus Internet-based supportive counseling for posttraumatic stress disorder (PTSD). Service members with PTSD from the attack on the Pentagon on September 11th or the Iraq War were randomly assigned to self-management cognitive behavior therapy (N=24) or supportive counseling (N=21). The dropout rate was similar to regular cognitive behavior therapy (30%) and unrelated to treatment arm. In the intent-to-treat group, self-management cognitive behavior therapy led to sharper declines in daily log-on ratings of PTSD symptoms and global depression. In the completer group, self-management cognitive behavior therapy led to greater reductions in PTSD, depression, and anxiety scores at 6 months. One-third of those who completed self-management cognitive behavior therapy achieved high-end state functioning at 6 months. Self-management cognitive behavior therapy may be a way of delivering effective treatment to large numbers with unmet needs and barriers to care.

Pharmacological Chaperones and Coenzyme Q10 Treatment Improves Mutant β-Glucocerebrosidase Activity and Mitochondrial Function in Neuronopathic Forms of Gaucher Disease

PubMed Central

de la Mata, Mario; Cotán, David; Oropesa-Ávila, Manuel; Garrido-Maraver, Juan; Cordero, Mario D.; Villanueva Paz, Marina; Delgado Pavón, Ana; Alcocer-Gómez, Elizabet; de Lavera, Isabel; Ybot-González, Patricia; Paula Zaderenko, Ana; Ortiz Mellet, Carmen; Fernández, José M. García; Sánchez-Alcázar, José A.

2015-01-01

Gaucher disease (GD) is caused by mutations in the GBA1 gene, which encodes lysosomal β-glucocerebrosidase. Homozygosity for the L444P mutation in GBA1 is associated with high risk of neurological manifestations which are not improved by enzyme replacement therapy. Alternatively, pharmacological chaperones (PCs) capable of restoring the correct folding and trafficking of the mutant enzyme represent promising alternative therapies.Here, we report on how the L444P mutation affects mitochondrial function in primary fibroblast derived from GD patients. Mitochondrial dysfunction was associated with reduced mitochondrial membrane potential, increased reactive oxygen species (ROS), mitophagy activation and impaired autophagic flux.Both abnormalities, mitochondrial dysfunction and deficient β-glucocerebrosidase activity, were partially restored by supplementation with coenzyme Q10 (CoQ) or a L-idonojirimycin derivative, N-[N’-(4-adamantan-1-ylcarboxamidobutyl)thiocarbamoyl]-1,6-anhydro-L-idonojirimycin (NAdBT-AIJ), and more markedly by the combination of both treatments. These data suggest that targeting both mitochondria function by CoQ and protein misfolding by PCs can be promising therapies in neurological forms of GD. PMID:26045184

Non-Nutrient, Naturally Occurring Phenolic Compounds with Antioxidant Activity for the Prevention and Treatment of Periodontal Diseases

PubMed Central

Varela-López, Alfonso; Bullón, Pedro; Giampieri, Francesca; Quiles, José L.

2015-01-01

One of the main factors able to explain the pathophysiological mechanism of inflammatory conditions that occur in periodontal disease is oxidative stress. Given the emerging understanding of this relationship, host-modulatory therapies using antioxidants could be interesting to prevent or slow the breakdown of soft and hard periodontal tissues. In this context, non-nutrient phenolic compounds of various foods and plants have received considerable attention in the last decade. Here, studies focusing on the relationship between different compounds of this type with periodontal disease have been collected. Among them, thymoquinone, coenzyme Q (CoQ), mangiferin, resveratrol, verbascoside and some flavonoids have shown to prevent or ameliorate periodontal tissues damage in animal models. However evidence regarding this effect in humans is poor and only limited to topical treatments with CoQ and catechins. Along with animal experiments, in vitro studies indicate that possible mechanisms by which these compounds might exert their protective effects include antioxidative properties, oxygen and nitrogen scavenging abilities, and also inhibitory effects on cell signaling cascades related to inflammatory processes which have an effect on RNS or ROS production as well as on antioxidant defense systems. PMID:26783837

Print Still Matters in an E-Learning World, and Training Companies Need to Properly Manage It

ERIC Educational Resources Information Center

Kriesen, Gretchen L.

2011-01-01

This report demonstrates how the application of Behavioral Systems Analysis (BSA) methods assisted in assessing a small training company's Print Production Management (PPM) system. PPM is the process by which printed materials are conceptualized, estimated, released to a commercial printer, proofed, and delivered to the client. The current PPM…

49 CFR 39.93 - What wheelchairs and other assistive devices may passengers with a disability bring onto a...

Code of Federal Regulations, 2010 CFR

2010-10-01

... permit the use of other power-driven mobility devices by individuals with mobility disabilities, unless...-driven mobility device questions about the nature and extent of the individual's disability. (2) You may... proof of disability as a credible assurance that the use of the other power-driven mobility device is...

Smart Collections: Can Artificial Intelligence Tools and Techniques Assist with Discovering, Evaluating and Tagging Digital Learning Resources?

ERIC Educational Resources Information Center

Leibbrandt, Richard; Yang, Dongqiang; Pfitzner, Darius; Powers, David; Mitchell, Pru; Hayman, Sarah; Eddy, Helen

2010-01-01

This paper reports on a joint proof of concept project undertaken by researchers from the Flinders University Artificial Intelligence Laboratory in partnership with information managers from the Education Network Australia (edna) team at Education Services Australia to address the question of whether artificial intelligence techniques could be…

Just in Time and Future-Proofing? Policy, Challenges and Opportunities in the Professional Development of Part-Time Teachers

ERIC Educational Resources Information Center

Beaton, Fran

2017-01-01

Part-time teachers form a growing proportion of the global Higher Education (HE) workforce. Their backgrounds can vary from Graduate Teaching Assistants (GTAs) teaching for the first time, to practitioners bringing workplace experience into HE and sessional teachers, all with differing professional development needs. This paper builds on previous…

Can coenzyme Q10 supplementation effectively reduce human tumour necrosis factor-α and interleukin-6 levels in chronic diseases? Protocol for a systematic review and meta-analysis of randomised controlled trials.

PubMed

Farsi, Farnaz; Heshmati, Javad; Janani, Leila; Irandoost, Pardis; Mesri Alamdari, Naeimeh; Keshtkar, Abbasali; Akbari, Abolfazl; Vafa, Mohammadreza

2017-10-08

Inflammation, as a critical factor, can cause numerous chronic diseases by creating various proinflammatory cytokines. Coenzyme Q10 (CoQ10) can potentially exert an anti-inflammatory agent; in turn, this agent can reduce the systemic inflammatory response. The aims of this study are to conduct a comprehensive systematic review and a meta-analysis for the determination of the CoQ10 efficacy on the changes in serum interleukin-6 (IL-6) and the tumour necrosis factor-α (TNF-α) levels in unhealthy subjects. We will conduct an electronic search for articles published between January 1990 and January 2017 using a prespecified search strategy in MEDLINE, SCOPUS, EMBASE, CENTRAL and Web of Science.Our search will focus only on randomised controlled clinical trials in unhealthy subjects that employ either a parallel or a crossover design; this search will involve concurrent control groups. The primary outcomes of the literature are to determine the CoQ10 efficacy on the changes in the serum IL-6 and the TNF-α levels in unhealthy subjects. Secondary outcomes such as body mass index, serum adiponectin and high-sensitivity C-reactive protein levels, lipid profile and the heterogeneity assessment of the primary studies will be evaluated. The stages of screen articles, the extracts of relevant data and the assessment of study quality using the Cochrane risk of bias tool will be conducted independently by the two reviewers. Any disagreement will be resolved by discussion with a third person. If the number of eligible studies is sufficient, we will carry out a meta-analysis according to both outcomes. This study is the protocol for a systematic review and no ethics approval is needed. The findings from the full systematic review will be published in a peer-reviewed journal, and they will also be exhibited at national/international academic and clinical conferences. CRD42016052200. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

How to clean the dirtiest place in the cell: cationic antioxidants as intramitochondrial ROS scavengers.

PubMed

Skulachev, Vladimir P

2005-01-01

Membrane-penetrating triphenyl alkyl phosphonium cations have been suggested for many years in our group as having the ability to measure mitochondrial potential were recently used by Murphy as vehicles to specifically target CoQ to mitochondria. As was shown in our group, the phosphonium derivative of CoQ (MitoQ) easily penetrates a planar bilayer phospholipid membrane as a cation, generating 60 mV electric potential (Deltapsi) per a 10-fold MitoQ gradient. This means that MitoQ should be unequally distributed across the inner mitochondrial membrane, the intramitochondrial [MitoQ] = extramitochondrial [MitoQ] x 10(3) at 180 mV Deltapsi. In line with such a calculation, Murphy and his colleagues reported that antioxidant efficiency of MitoQ added to mitochondria or cells appears to be very much higher than of CoQ. It was found that H2O2-induced apoptosis (Murphy) and the H2O2-mediated bystander killing of the cultivated cells (our group) are completely arrested by pretreatement of the cells with 10(-10) - 10(-8) M MitoQ. These effects indicate that MitoQ and similar compounds may be promising in treatment of heart attack, stroke and other diseases accompanied by massive apoptosis in the injured tissue. The very fact that: (i) MitoQ is not only accumulated by mitochondria but also can be regenerated in its reduced form by mitochondrial respiratory chain, (ii) it is the mitochondrial interior that produces a large portion of reactive oxygen species (ROS) in our body, and (iii) the most sensitive ROS targets are localized in the mitochondrial matrix suggest the MitoQ-like compounds are promising tools of molecular therapy of aerobic cells. In line with this suggestion, we found that addition of MitoQ strongly improves structural and biochemical parameters of cultivated cells. As to cationic tetrapeptides, recently advertised as mitochondrially-targeted Deltapsi-independent antioxidants, their effect is most probably mediated by an opioid activity inherent in some of these substances.

Formal specification and verification of Ada software

NASA Technical Reports Server (NTRS)

Hird, Geoffrey R.

1991-01-01

The use of formal methods in software development achieves levels of quality assurance unobtainable by other means. The Larch approach to specification is described, and the specification of avionics software designed to implement the logic of a flight control system is given as an example. Penelope is described which is an Ada-verification environment. The Penelope user inputs mathematical definitions, Larch-style specifications and Ada code and performs machine-assisted proofs that the code obeys its specifications. As an example, the verification of a binary search function is considered. Emphasis is given to techniques assisting the reuse of a verification effort on modified code.

Confirming Eligibility for McKinney-Vento Services: Do's and Don'ts for Local Liaisons. Best Practices in Homeless Education

ERIC Educational Resources Information Center

National Center for Homeless Education at SERVE, 2007

2007-01-01

Under the McKinney-Vento Homeless Assistance Act, schools must identify children and youth in homeless situations and provide appropriate services. One such service is immediate enrollment in school, even when students lack paperwork normally required for enrollment, such as school records, proof of guardianship, a birth certificate, immunization…

Confirming Eligibility for McKinney-Vento Services: Do's and Don'ts for School Districts. Best Practices in Homeless Education

ERIC Educational Resources Information Center

National Center for Homeless Education at SERVE, 2007

2007-01-01

Under the McKinney-Vento Homeless Assistance Act, schools must identify children and youth in homeless situations and provide appropriate services. One such service is immediate enrollment in school, even when students lack paperwork normally required for enrollment, such as school records, proof of guardianship, a birth certificate, immunization…

Knowledge management in secondary pharmaceutical manufacturing by mining of data historians-A proof-of-concept study.

PubMed

Meneghetti, Natascia; Facco, Pierantonio; Bezzo, Fabrizio; Himawan, Chrismono; Zomer, Simeone; Barolo, Massimiliano

2016-05-30

In this proof-of-concept study, a methodology is proposed to systematically analyze large data historians of secondary pharmaceutical manufacturing systems using data mining techniques. The objective is to develop an approach enabling to automatically retrieve operation-relevant information that can assist the management in the periodic review of a manufactory system. The proposed methodology allows one to automatically perform three tasks: the identification of single batches within the entire data-sequence of the historical dataset, the identification of distinct operating phases within each batch, and the characterization of a batch with respect to an assigned multivariate set of operating characteristics. The approach is tested on a six-month dataset of a commercial-scale granulation/drying system, where several millions of data entries are recorded. The quality of results and the generality of the approach indicate that there is a strong potential for extending the method to even larger historical datasets and to different operations, thus making it an advanced PAT tool that can assist the implementation of continual improvement paradigms within a quality-by-design framework. Copyright © 2016 Elsevier B.V. All rights reserved.

Space shuttle redesigned solid rocket motor Certificate of Qualification (COQ) data report

NASA Technical Reports Server (NTRS)

Duersch, Fred, Jr.

1990-01-01

The Space Shuttle Redesigned Solid Rocket Motor (RSRM) Certification Program provides confidence that the RSRM and its components/subsystems meet or exceed Mission Oriented Requirements when manufactured per design requirements and specified/approved processes. Certification is based on documented results of tests, analyses, inspections, similarity, and demonstrations. Evidencing information is provided to certify that each RSRM component/subsystem satisfies design, mission related requirements and objectives.

Bioenergetic Approaches and Inflammation of MPTP Toxicity

DTIC Science & Technology

2011-09-01

out a large number of studies, which showed that there were indeed significant protective effects. In particular, we were able to show that CoQ ...the Nrf2/ARE pathway. We demonstrated that these compounds can induce antioxidant enzymes in normal fibroblasts, however, the ability to induce thee...2 enzymes glutathione·c transferase, NADPH quinone oxidoreductase and heme·oxygenase was blocked in fibroblasts knocked out for Nrf2/ARE. We

Effects of plant lectin from cobra lily, Arisaema curvatum Kunth on development of melon fruit fly, Bactrocera cucurbitae (Coq.).

PubMed

Singh, Kuljinder; Kaur, Manpreet; Rup, Pushpinder J; Singh, Jatinder

2008-11-01

The lectin from tubers of cobra lily, Arisaema curvatum Kunth was purified by affinity chromatography using asialofetuin-linked amino activated porous silica beads. The concentration dependent effect of lectin was studied on second instar larvae (64-72 hr) of Bactrocera cucurbitae (Coq.). The treatment not only resulted in a significant reduction in the percentage pupation and emergence of the adults from treated larvae but it also prolonged the remaining larval development period. A very low LC50 value, 39 mgl(-1) of lectin was obtained on the basis of adult emergence using probit analysis. The activity of three hydrolase enzymes (esterases, acid and alkaline phosphatases), one oxidoreductase (catalase) and one group transfer enzyme (GSTs: Glutathione S-transferases) was assayed in second instar larvae under the influence of the LC50 of lectin at increasing exposure intervals (0, 24, 48 and 72 hr). The Arisaema curvatum lectin significantly decreased the activity of all the enzymes except for esterases, where the activity increased as compared to control at all exposure intervals. The decrease in pupation and emergence as well as significant suppression in the activities of two hydrolases, one oxidoreductase and one GST enzyme in treated larvae of B. cucurbitae indicated that this lectin has anti-metabolic effect on the melon fruit fly larvae.

[Study on protective effect of Tianji soft capsule on blood lipids, internal antioxidant system and vascular endothelial system in hyperlipidemia rats].

PubMed

Ma, Hai-ying; Chen, Jin-yao; Zhang, Li-shi

2011-11-01

To study the protective effects of Tianji soft capsule (TJSC) on blood lipids, internal antioxidant system and vascular endothelial system in hyperlipidemia rats. Seventy two healthy male rats were divided into six groups. The rats in control group were administered with ordinary diet. The rats in model group were fed with high cholesterol/lipid diet to induce hyperlipidemia. The rats in TJSC and CoQ10 groups were fed with high cholesterol/lipid diet, and treated with TJSC at different doses of 83 (low-dose group, L), 250 (middle-dose group, M), 750 (high-dose group, H) mg/kg, and CoQ10 at the dose of 83 mg/kg, respectively. All animals were put to death after four weeks, effects on lipid level; antioxidant system and endothelial system were evaluated through detection of total cholesterol (TC), triglyceride (TG), very low density lipoprotein (VLDL), atherogenic index (AI), malondidehyde (MDA) and plasma endothelin (ET), HDL/TC ratio, activities of superoxide dismutase (SOD) and nitric oxide (NO). Compared with model group, serum TC, TG, VLDL, AI, MDA and ET reduced and the HDL/TC ratio increased, meanwhile activities of SOD and NO were enhanced. TJSC can regulate the lipid metabolism, enhance antioxidant system and protect the vascular endothelia system in hyperlipiemic rats.

Wearable optical-digital assistive device for low vision students.

PubMed

Afinogenov, Boris I; Coles, James B; Parthasarathy, Sailashri; Press-Williams, Jessica; Tsykunova, Ralina; Vasilenko, Anastasia; Narain, Jaya; Hanumara, Nevan C; Winter, Amos; Satgunam, PremNandhini

2016-08-01

People with low vision have limited residual vision that can be greatly enhanced through high levels of magnification. Current assistive technologies are tailored for far field or near field magnification but not both. In collaboration with L.V. Prasad Eye Institute (LVPEI), a wearable, optical-digital assistive device was developed to meet the near and far field magnification needs of students. The critical requirements, system architecture and design decisions for each module were analyzed and quantified. A proof-of-concept prototype was fabricated that can achieve magnification up to 8x and a battery life of up to 8 hours. Potential user evaluation with a Snellen chart showed identification of characters not previously discernible. Further feedback suggested that the system could be used as a general accessibility aid.

Anonymous Transactions in Computer Networks

NASA Astrophysics Data System (ADS)

Dolev, Shlomi; Kopeetsky, Marina

We present schemes for providing anonymous transactions while privacy and anonymity are preserved, providing user anonymous authentication in distributed networks such as the Internet. We first present a practical scheme for anonymous transactions while the transaction resolution is assisted by a Trusted Authority. This practical scheme is extended to a theoretical scheme where a Trusted Authority is not involved in the transaction resolution. Given an authority that generates for each player hard to produce evidence EVID (e. g., problem instance with or without a solution) to each player, the identity of a user U is defined by the ability to prove possession of said evidence. We use Zero-Knowledge proof techniques to repeatedly identify U by providing a proof that U has evidence EVID, without revealing EVID, therefore avoiding identity theft.

GP-support by means of AGnES-practice assistants and the use of telecare devices in a sparsely populated region in Northern Germany – proof of concept

PubMed Central

Berg, Neeltje van den; Fiß, Thomas; Meinke, Claudia; Heymann, Romy; Scriba, Sibylle; Hoffmann, Wolfgang

2009-01-01

Background In many rural regions in Germany, the proportion of the elderly population increases rapidly. Simultaneously, about one-third of the presently active GPs will retire until 2010. Often it is difficult to find successors for vacant GP-practices. These regions require innovative concepts to avoid the imminent shortage in primary health care. The AGnES-concept comprises the delegation of GP-home visits to qualified AGnES-practice assistants (AGnES: GP-supporting, community-based, e-health-assisted, systemic intervention). Main objectives were the assessment of the acceptance of the AGnES-concept by the participating GPs, patients, and AGnES-practice assistants, the kind of delegated tasks, and the feasibility of home telecare in a GP-practice. Methods In this paper, we report first results of the implementation of this concept in regular GP-practices, conducted November 2005 – March 2007 on the Island of Rügen, Mecklenburg-Western Pomerania, Germany. This study was meant as a proof of concept. The GP delegated routine home-visits to qualified practice employees (here: registered nurses). Eligible patients were provided with telecare-devices to monitor disease-related physiological values. All delegated tasks, modules conducted and questionnaire responses were documented. The participating patients were asked for their acceptance based on standardized questionnaires. The GPs and AGnES-practice assistants were asked for their judgement about different project components, the quality of health care provision and the competences of the AGnES-practice assistants. Results 550 home visits were conducted. 105 patients, two GPs and three AGnES-practice assistants (all registered nurses) participated in the project. 48 patients used telecare-devices to monitor health parameters. 87.4% of the patients accepted AGnES-care as comparable to common GP-care. In the course of the project, the GPs delegated an increasing number of both monitoring and interventional tasks to the AGnES-practice assistants. The GPs agreed that delegating tasks to a qualified practice assistant relieves them in their daily work. Conclusion A part of the GPs home visits can be delegated to AGnES-practice assistants to support GPs in regions with an imminent or already existing undersupply in primary care. The project triggered discussions among the institutions involved in the German healthcare system and supported a reconciliation of the respective competences of physicians and other medical professions. PMID:19545376

Fatigue Resistance of Liquid-assisted Self-repairing Aluminum Alloys Reinforced with Shape Memory Alloys

NASA Technical Reports Server (NTRS)

Wright, M. Clara; Manuel, Michele; Wallace, Terryl

2013-01-01

A self-repairing aluminum-based composite system has been developed using a liquid-assisted healing theory in conjunction with the shape memory effect of wire reinforcements. The metal-metal composite was thermodynamically designed to have a matrix with a relatively even dispersion of a low-melting eutectic phase, allowing for repair of cracks at a predetermined temperature. Additionally, shape memory alloy (SMA) wire reinforcements were used within the composite to provide crack closure. Investigators focused the research on fatigue cracks propagating through the matrix in order to show a proof-of-concept Shape Memory Alloy Self-Healing (SMASH) technology for aeronautical applications.

Data to DecisionsTerminate, Tolerate, Transfer, or Treat

DTIC Science & Technology

2016-07-25

and patching, a risk-based cyber - security decision model that enables a pre- dictive capability to respond to impending cyber -attacks is needed...States. This sensitive data includes business proprietary information on key programs of record and infrastructure, including government documents at...leverage nationally. The Institute for Defense Analyses (IDA) assisted the DoD CIO in formalizing a proof of concept for cyber initiatives and

Explicit Substitutions and All That

NASA Technical Reports Server (NTRS)

Ayala-Rincon, Mauricio; Munoz, Cesar

2000-01-01

Explicit substitution calculi are extensions of the lambda-calculus where the substitution mechanism is internalized into the theory. This feature makes them suitable for implementation and theoretical study of logic-based tools such as strongly typed programming languages and proof assistant systems. In this paper we explore new developments on two of the most successful styles of explicit substitution calculi: the lambda sigma- and lambda S(e)-calculi.

Explicit Substitutions and All That

NASA Technical Reports Server (NTRS)

Ayala-Rincon, Mauricio; Munoz, Cesar; Busnell, Dennis M. (Technical Monitor)

2000-01-01

Explicit substitution calculi are extensions of the Lambda-calculus where the substitution mechanism is internalized into the theory. This feature makes them suitable for implementation and theoretical study of logic-based tools such as strongly typed programming languages and proof assistant systems. In this paper we explore new developments on two of the most successful styles of explicit substitution calculi: the lambda(sigma)- and lambda(s(e))-calculi.

Language (Medical Terminology) Assistance to Multinational Partners in Coalition Operations

DTIC Science & Technology

2012-02-01

also without us being conscious that we are learning” [19], i.e. facilitate life-long learning as a part of other activities related to business or...research a proof of concept experiment, qualitative study, statistical evaluation Due to the varieties of the MALL studies as described above and quick...learning research agenda for active, experiential learning: Four case studies. Australasian Journal of Educational Technology, http

Bacterial Toxicity and Metabolism of Three Hydrazine Fuels.

DTIC Science & Technology

1980-09-01

4- LO 0z V) 8 LL Di: 0 0J E - N z 4 0~ 0 0 44 4’a 44~ C -0 0 0 0~ N 0 coQ NoIi ~ (ADP-SSi 6w/N- HN bw ’ap, uoipOzijInr apihssqns) 3SNOaS3 i %/ 77...irreversible bond with an amine oxidase enzyme (Reference 49). To test the significance of this binding, an experiment was conducted with the

Installation Restoration of Rocky Mountain Arsenal, Pilot Containment Operations, Final Environmental Impact Statement, Part 1.

DTIC Science & Technology

1977-02-01

0. . IIU w 00 Z -J-. z 00 D 0 0 !9 I- A, On ~ 0w NON 0~ CoQ UU 00 co qc 00NC r-.N) 0 Lf) C*12 ICD U) o C 14 N0 WU Lo LC LX...for carcinogenic, mutagenic or teratogenic activity in vitro. One report (17) stated that DIMP does not inhibit the enzyme cholinesterase, although no

An intelligent assistant for physicians.

PubMed

Gavrilis, Dimitris; Georgoulas, George; Vasiloglou, Nikolaos; Nikolakopoulos, George

2016-08-01

This paper presents a software tool developed for assisting physicians during an examination process. The tool consists of a number of modules with the aim to make the examination process not only quicker but also fault proof moving from a simple electronic medical records management system towards an intelligent assistant for the physician. The intelligent component exploits users' inputs as well as well established standards to line up possible suggestions for filling in the examination report. As the physician continues using it, the tool keeps extracting new knowledge. The architecture of the tool is presented in brief while the intelligent component which builds upon the notion of multilabel learning is presented in more detail. Our preliminary results from a real test case indicate that the performance of the intelligent module can reach quite high performance without a large amount of data.

Learning-assisted theorem proving with millions of lemmas☆

PubMed Central

Kaliszyk, Cezary; Urban, Josef

2015-01-01

Large formal mathematical libraries consist of millions of atomic inference steps that give rise to a corresponding number of proved statements (lemmas). Analogously to the informal mathematical practice, only a tiny fraction of such statements is named and re-used in later proofs by formal mathematicians. In this work, we suggest and implement criteria defining the estimated usefulness of the HOL Light lemmas for proving further theorems. We use these criteria to mine the large inference graph of the lemmas in the HOL Light and Flyspeck libraries, adding up to millions of the best lemmas to the pool of statements that can be re-used in later proofs. We show that in combination with learning-based relevance filtering, such methods significantly strengthen automated theorem proving of new conjectures over large formal mathematical libraries such as Flyspeck. PMID:26525678

N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease.

PubMed

Polyak, Erzsebet; Ostrovsky, Julian; Peng, Min; Dingley, Stephen D; Tsukikawa, Mai; Kwon, Young Joon; McCormack, Shana E; Bennett, Michael; Xiao, Rui; Seiler, Christoph; Zhang, Zhe; Falk, Marni J

2018-04-01

Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the "cellular antioxidant pathway", they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major therapeutic benefit appears to result from targeting global cellular, rather than intramitochondria-specific, oxidative stress. Clinical trials are needed to evaluate whether the two antioxidants, NAC and vitamin E, that show greatest efficacy in translational model animals significantly improve the survival, function, and feeling of human subjects with primary mitochondrial RC disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Two Novel Methods and Multi-Mode Periodic Solutions for the Fermi-Pasta-Ulam Model

NASA Astrophysics Data System (ADS)

Arioli, Gianni; Koch, Hans; Terracini, Susanna

2005-04-01

We introduce two novel methods for studying periodic solutions of the FPU β-model, both numerically and rigorously. One is a variational approach, based on the dual formulation of the problem, and the other involves computer-assisted proofs. These methods are used e.g. to construct a new type of solutions, whose energy is spread among several modes, associated with closely spaced resonances.

The Uniformed and Overseas Citizens Absentee Voting Act: Overview and Issues

DTIC Science & Technology

2009-05-29

action officers to perform voting assistance duties; establish procedures to ensure a postmark or proof of mailing date on absentee ballots; requires...CRS Report for Congress Prepared for Members and Committees of Congress The Uniformed and Overseas Citizens Absentee Voting Act...TYPE 3. DATES COVERED 00-00-2009 to 00-00-2009 4. TITLE AND SUBTITLE The Uniformed and Overseas Citizens Absentee Voting Act: Overview and

The Uniformed and Overseas Citizens Absentee Voting Act: Background and Issues

DTIC Science & Technology

2003-01-30

action officers to perform voting assistance duties; establish procedures to ensure a postmark or proof of mailing date on absentee ballots; requires...2003 The Uniformed and Overseas Citizens Absentee Voting Act: Background and Issues Kevin J. Coleman Analyst in American National Government...Government and Finance Division Summary Members of the military and U.S. citizens who live abroad are eligible to register and vote absentee in federal

Involving the pharmaceutical and biotech communities in medication development for substance abuse.

PubMed

Gorodetzky, Charles W; Grudzinskas, Charles

2005-10-01

Pharmacotherapy as adjunctive treatment is an integral part of the strategy for treating substance abuse. Although there are several approved drugs for the treatment of opioid, alcohol, and nicotine dependence, the pharmaceutical industry, for a variety of reasons, has been reluctant to enter this area to develop medications for substance abuse indications. Therefore, in 1990, a Medication Development Program was established by NIDA to carry out and assist in stimulating development of new pharmacotherapies. It is vital for NIDA to provide clear leadership and establish a collaborative working relationship with the pharmaceutical industry, providing scientific, development, and financial assistance, depending on the size, resources, and expertise of the company. An important NIDA role in this effort is setting standards, such as establishing Target Product Profiles (TPPs), predictive decision trees for selection of clinical candidates, and animal models to evaluate safety and potential effectiveness prior to human studies. NIDA can further establish standards for clinical studies, including Proof of Concept (PoC), Phase 2 (or Learning) trials to establish initial proof of safety and effectiveness, and Phase 3 (or Confirming) trials to validate Phase 2 findings. NIDA and other government agencies need to work to improve industry incentives to participate in medication development for substance abuse. Specific incentives, such as market exclusivity and patent extension, as provided in BioShield and pediatric drug legislation, should be strongly considered. NIDA can further assist industry to navigate the regulatory and, if needed, controlled substance scheduling processes, by establishing a true Federal partnership between NIDA, FDA, and DEA.

Design and Development of a Miniaturized Percutaneously Deployable Wireless Left Ventricular Assist Device: Early Prototypes and Feasibility Testing.

PubMed

Letzen, Brian; Park, Jiheum; Tuzun, Zeynep; Bonde, Pramod

The current left ventricular assist devices (LVADs) are limited by a highly invasive implantation procedure in a severely unstable group of advanced heart failure patients. Additionally, the current transcutaneous power drive line acts as a nidus for infection resulting in significant morbidity and mortality. In an effort to decrease this invasiveness and eliminate drive line complications, we have conceived a wireless miniaturized percutaneous LVAD, capable of being delivered endovascularly with a tether-free operation. The system obviates the need for a transcutaneous fluid purge line required in existing temporary devices by utilizing an incorporated magnetically coupled impeller for a complete seal. The objective of this article was to demonstrate early development and proof-of-concept feasibility testing to serve as the groundwork for future formalized device development. Five early prototypes were designed and constructed to iteratively minimize the pump size and improve fluid dynamic performance. Various magnetic coupling configurations were tested. Using SolidWorks and ANSYS software for modeling and simulation, several geometric parameters were varied. HQ curves were constructed from preliminary in vitro testing to characterize the pump performance. Bench top tests showed no-slip magnetic coupling of the impeller to the driveshaft up to the current limit of the motor. The pump power requirements were tested in vitro and were within the appropriate range for powering via a wireless energy transfer system. Our results demonstrate the proof-of-concept feasibility of a novel endovascular cardiac assist device with the potential to eventually offer patients an untethered, minimally invasive support.

Distribution of Capillary Transit Times in Isolated Lungs of Oxygen-Tolerant Rats

PubMed Central

Ramakrishna, Madhavi; Gan, Zhuohui; Clough, Anne V.; Molthen, Robert C.; Roerig, David L.; Audi, Said H.

2014-01-01

Rats pre-exposed to 85% O2 for 5–7 days tolerate the otherwise lethal effects of 100% O2. The objective was to evaluate the effect of rat exposure to 85% O2 for 7 days on lung capillary mean transit time (t̄c) and distribution of capillary transit times (hc(t)). This information is important for subsequent evaluation of the effect of this hyperoxia model on the redox metabolic functions of the pulmonary capillary endothelium. The venous concentration vs. time outflow curves of fluorescein isothiocyanate labeled dextran (FITC-dex), an intravascular indicator, and coenzyme Q1 hydroquinone (CoQ1H2), a compound which rapidly equilibrates between blood and tissue on passage through the pulmonary circulation, were measured following their bolus injection into the pulmonary artery of isolated perfused lungs from rats exposed to room air (normoxic) or 85% O2 for 7 days (hyperoxic). The moments (mean transit time and variance) of the measured FITC-dex and CoQ1H2 outflow curves were determined for each lung, and were then used in a mathematical model [Audi et al. J. Appl. Physiol. 77: 332–351, 1994] to estimate t̄c and the relative dispersion (RDc) of hc(t). Data analysis reveals that exposure to hyperoxia decreases lung t̄c by 42% and increases RDc, a measure hc(t) heterogeneity, by 40%. PMID:20552277

Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration.

PubMed

Nagase, Midori; Yamamoto, Yorihiro; Miyazaki, Yusuke; Yoshino, Hiide

2016-05-01

Compared to age-matched healthy controls (n = 55), patients with amyotrophic lateral sclerosis (ALS) (n = 26) showed increased oxidative stress as indicated by a significantly increased percentage of oxidized coenzyme Q10 (%CoQ10) in total plasma coenzyme Q10, a significantly decreased level of plasma uric acid, and a significantly decreased percentage of polyunsaturated fatty acids in total plasma free fatty acids (FFA). Therefore, the efficacy of edaravone, a radical scavenger, in these ALS patients was examined. Among 26 ALS patients, 17 received edaravone (30 mg/day, one to four times a week) for at least 3 months, and 13 continued for 6 months. Changes in revised ALS functional rating scale (ALSFRS-R) were significantly smaller in these patients than in edaravone-untreated ALS patients (n = 19). Edaravone administration significantly reduced excursions of more than one standard deviation from the mean for plasma FFA levels and the contents of palmitoleic and oleic acids, plasma markers of tissue oxidative damage, in the satisfactory progress group (ΔALSFRS-R ≥ 0) as compared to the ingravescent group (ΔALSFRS-R < -5). Edaravone treatment increased plasma uric acid, suggesting that it is an effective scavenger of peroxynitrite. However, edaravone administration did not decrease %CoQ10. Therefore, combined treatment with agents such as coenzyme Q10 may further reduce oxidative stress in ALS patients.

Serum biological antioxidant potential predicts the prognosis of hemodialysis patients.

PubMed

Ishii, Tomoko; Ohtake, Takayasu; Okamoto, Koji; Mochida, Yasuhiro; Ishioka, Kunihiro; Oka, Machiko; Maesato, Kyoko; Ikee, Ryota; Moriya, Hidekazu; Hidaka, Sumi; Doi, Kent; Noiri, Eisei; Fujita, Toshiro; Kobayashi, Shuzo

2011-01-01

It is well known that oxidative stress is enhanced in patients with end-stage renal disease. However, little is known about the relationship between serum antioxidant capacity and clinical outcome in hemodialysis (HD) patients. We examined the relationship between serum biomarkers of oxidative stress and clinical outcomes including all-cause mortality, hospitalization rate and incidence of cardiovascular events in HD patients. As biomarkers of oxidative stress, we measured serum levels of coenzyme Q10 (CoQ10) and biological antioxidant potential (BAP). 108 patients were observed for 30 months as the follow-up periods. The survival group (n = 83) showed significantly higher BAP values compared with those in death groups (n = 25; p < 0.05). When serum BAP levels were divided into two groups by their median value, the group with higher BAP values had a better survival rate than that with lower BAP values on the Kaplan-Meier survival analysis (p = 0.05). Although serum levels of CoQ10 did not show any association with clinical outcomes, lower BAP was selected as an independent risk factor for all-cause mortality as well as the absence of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers therapy by age-adjusted Cox regression analysis. This study indicated that BAP could predict the prognosis of HD patients. Copyright © 2010 S. Karger AG, Basel.

Current Experience in Testing Mitochondrial Nutrients in Disorders Featuring Oxidative Stress and Mitochondrial Dysfunction: Rational Design of Chemoprevention Trials

PubMed Central

Pagano, Giovanni; Aiello Talamanca, Annarita; Castello, Giuseppe; Cordero, Mario D.; d’Ischia, Marco; Gadaleta, Maria Nicola; Pallardó, Federico V.; Petrović, Sandra; Tiano, Luca; Zatterale, Adriana

2014-01-01

An extensive number of pathologies are associated with mitochondrial dysfunction (MDF) and oxidative stress (OS). Thus, mitochondrial cofactors termed “mitochondrial nutrients” (MN), such as α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and l-carnitine (CARN) (or its derivatives) have been tested in a number of clinical trials, and this review is focused on the use of MN-based clinical trials. The papers reporting on MN-based clinical trials were retrieved in MedLine up to July 2014, and evaluated for the following endpoints: (a) treated diseases; (b) dosages, number of enrolled patients and duration of treatment; (c) trial success for each MN or MN combinations as reported by authors. The reports satisfying the above endpoints included total numbers of trials and frequencies of randomized, controlled studies, i.e., 81 trials testing ALA, 107 reports testing CoQ10, and 74 reports testing CARN, while only 7 reports were retrieved testing double MN associations, while no report was found testing a triple MN combination. A total of 28 reports tested MN associations with “classical” antioxidants, such as antioxidant nutrients or drugs. Combinations of MN showed better outcomes than individual MN, suggesting forthcoming clinical studies. The criteria in study design and monitoring MN-based clinical trials are discussed. PMID:25380523

Existence and instability of steady states for a triangular cross-diffusion system: A computer-assisted proof

NASA Astrophysics Data System (ADS)

Breden, Maxime; Castelli, Roberto

2018-05-01

In this paper, we present and apply a computer-assisted method to study steady states of a triangular cross-diffusion system. Our approach consist in an a posteriori validation procedure, that is based on using a fixed point argument around a numerically computed solution, in the spirit of the Newton-Kantorovich theorem. It allows to prove the existence of various non homogeneous steady states for different parameter values. In some situations, we obtain as many as 13 coexisting steady states. We also apply the a posteriori validation procedure to study the linear stability of the obtained steady states, proving that many of them are in fact unstable.

The Affordable Care Act's plan for consumer assistance with insurance moves states forward but remains a work in progress.

PubMed

Grob, Rachel; Schlesinger, Mark; Davis, Sarah; Cohen, Deborah; Lapps, Joshua

2013-02-01

The Affordable Care Act provides support for state-run consumer assistance programs to help privately insured consumers who experience problems with their coverage. Its provisions signify the first national commitment to such assistance and to using cases aggregated by these state programs to inform policy. We interviewed state-level administrators and analyzed program documents to assess whether federal support for state-run consumer assistance programs achieved certain goals. We found that some federally supported programs made substantial progress in supporting and empowering patients by reorienting state agencies to become active advocates for their citizens. Yet progress across the country was inconsistent, and there was little evidence that programs addressed systemic problems experienced by consumers. On balance, the consumer assistance provisions of health care reform do not yet ensure protection for all privately insured Americans because of uneven implementation-a problem likely to be of further concern as coverage is expanded and health insurance exchanges come on line in 2014. At the same time, the demonstrated impact of consumer assistance programs in the most innovative states is arguably a useful "proof of concept" for this young federal program.

Molecular Determinants of Antiestrogen and Drug Sensitivity in Breast Carcinoma Cells

DTIC Science & Technology

1996-08-01

00 ~cd -olC CC) 00, COq -6 0 00d C5 kr0) C~U, 23l Effects of infection rate and selection pressure on gene expression from an internal promoter of a...Hybridization probes were prepared by restriction enzyme digestion of the LNCIuc plasmid, followed by the isolation of the desired fragments by...sensitivity to this drug. The bacterial neo gene encodes neomycin phosphotransferase, an enzyme that metabolically inactivates G418, with the extent of

Army Mobility Energy Research & Development Plan.

DTIC Science & Technology

1980-01-01

goal by the time specified. It does not make 3-22 uoiienjeA3 xx c IOLIOse9 o0 S sisAlojpAH oaewAzu3 0 f >A6Jau3 461H0 (n) wawdolaAao] JSO[ r, COq ulpue...requirements to syn- thetic or alternate fuels by the year 2000. STOG REFERENCE: 80-7.1:4,6,23 MAJOR TECHNOLOGICAL BARRIERS: Enzyme production...substrate pretreatment, and fermentation of enzymatic hydrolyzates to ethanol. APPROACH: a. Fungal mutation and enzyme production process optimization. b

A Contribution to Proof the Component Integrity Taking Into Account the Corrosion-Assisted Crack Growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roos, Eberhard; Otremba, Frank; Huttner, Frank

2002-07-01

The proof of the component integrity is fundamental for a safe and reliable operation of Nuclear Power Plants (NPP). The concept of the Material Testing Institute (MPA) for integrity assessment is based on fracture mechanic analysis which results in detailed regulations for nondestructive examination. This approach has to account for the main damage mechanisms as fatigue and corrosion. This paper focuses on the influence of corrosion-assisted crack growth which strongly depends on corrosion and environmental conditions (e.g. coolant purity). Up to stress intensity of approximately 60 MPam for ferritic low-alloy steels in high-purity water (acc. to specification) under constant loadmore » conditions the analysis can be based on a crack extension of max. 70 for each load cycle. Related to a test duration of 1000 hours this is equivalent to a formally calculated crack growth rate (CGR) of = 2 10{sup -8} mm/s. For austenitic stainless steels more complex dependences on material, environmental and mechanical parameters exist. Particularly, for stabilized austenitic steels the crack growth rate data base is relatively weak. Under unfavourable environmental conditions in single cases crack growth rates up to 6 mm/a have been measured. Based on experimental results an arithmetic mean value of 0.95 mm/a and a median value of 0.6 mm/a have been determined. A further improvement of data base is desirable. (authors)« less

DNA damage and antioxidants in treatment naïve children with obsessive-compulsive disorder.

PubMed

Şimşek, Şeref; Gençoğlan, Salih; Yüksel, Tuğba

2016-03-30

The current study aimed to investigate whether serum antioxidant levels and DNA damage differ between the children and adolescents with Obsessive Compulsive Disorder (OCD) and healthy controls. The study included 31 children (Male/Female, 22/9; age range 7-17 years), with treatment naïve OCD diagnosed according to Diagnostic and Statistical Manual of Mental Disorders-V (DSM-V) and 28 age- and gender-matched healthy control subjects. Children's Yale Brown Obsession Compulsion Scale (CY-BOC) was applied to the children. Glutathione peroxidase (GPx), superoxide dismutase (SOD), coenzyme Q (CoQ), and 8-Hydroxy-2-Deoxyguanosine (8-OHdG) were all measured by the enzyme-linked immunosorbent assay method. GPx, CoQ and 8-OHdG levels were found to be significantly higher in the OCD group, compared to the control group (p=0.010, p=0.034, p=0.010, respectively); however, no significant difference was found in the SOD levels between two groups (p=0.10). There were no correlations between the CY-BOC scores, depression scores, duration of the disease and biochemical parameters (p>0.05, for all). Children with OCD were found to have higher antioxidant levels and oxidative DNA damage. The findings of this study support the role of oxidative stress in the pathogenesis of OCD. In this regard, any possible effect of adding antioxidants to conventional treatment can be investigated. Copyright © 2016. Published by Elsevier Ireland Ltd.

Simple circumcision device: proof of concept for a single-visit, adjustable device to facilitate safe adult male circumcision.

PubMed

Hotaling, James M; Leddy, Laura S; Haider, Mahum A; Mossanen, Matthew; Bailey, Michael R; MacConaghy, Brian; Olson, Francis; Krieger, John N

2014-05-01

To conduct a proof-of-concept study to determine the potential utility of a novel, adjustable single-visit, disposable device to facilitate rapid adult circumcision. Prospective pilot trial of a novel surgical device. Tertiary care Veterans Administration medical center. Five adult males. Circumcisions performed by junior trainees using an adjustable, single-size surgical-assist device constructed by the University of Washington Applied Physics Laboratory. The attending surgeon and trainees completed standardized forms after each procedure to assess technical problems and ease of use. Follow-up visits were scheduled to evaluate adverse events, postoperative pain, cosmetic outcomes, and participant satisfaction at 3, 8, 30, and 90 days postoperatively. The average operative time was 16.4 minutes. All cases were performed with local anesthesia, and no case required electrocautery or conversion to standard surgery. At the postoperative day 3 visit, all subjects were happy with their results and would recommend the procedure to another patient. One participant had a minor wound separation noted at the 30-day visit that resolved during follow-up. There were no wound infections, hematomas, or other adverse events. This proof-of-study suggests that the Simple Circumcision Device may facilitate delivery of safe adult male circumcision services. Copyright © 2014 American Society for Reproductive Medicine. All rights reserved.

An Expert System For Tuning Particle-Beam Accelerators

NASA Astrophysics Data System (ADS)

Lager, Darrel L.; Brand, Hal R.; Maurer, William J.; Searfus, Robert M.; Hernandez, Jose E.

1989-03-01

We have developed a proof-of-concept prototype of an expert system for tuning particle beam accelerators. It is designed to function as an intelligent assistant for an operator. In its present form it implements the strategies and reasoning followed by the operator for steering through the beam transport section of the Advanced Test Accelerator at Lawrence Livermore Laboratory's Site 300. The system is implemented in the language LISP using the Artificial Intelligence concepts of frames, daemons, and a representation we developed called a Monitored Decision Script.

Rules for the preparation of manuscript and illustrations designed for publication by the United States Geological Survey

USGS Publications Warehouse

Hampson, Thomas

1888-01-01

In the annual report of the Director of the U. S. Geological Survey for 1885-'86, pages 40 and 41, you set forth the functions of the chief of the editorial division as follows: "To secure clear and accurate statement in the material sent to press, careful proof-reading, and uniformity in the details of book-making, as well as to assist the Director in exercising a general supervision over the publications of the Survey."

JPRS Report, Science & Technology, Japan, MITI’s Large-Scale R&D Projects Reviewed

DTIC Science & Technology

1990-02-08

pollutions, red tide, Active enzymes etc. for cleaners and detergents -- .... .... Intermediates aw materials for r rcosmetics and and medicines moisturizers...PN 00 1H carq 1 0 HZc4 IO -l~ to u .ci~’ *H 0 w 1 Q 0 r - 0 0J w H 04P 04- c0 a) 00 bD O44 0 w w 0 -p 00 021.J4 COQ )a > u0𔃺-0 T1 CL Cfp p P H -H14 OL

Animal-assisted intervention for autism spectrum disorder: a systematic literature review.

PubMed

O'Haire, Marguerite E

2013-07-01

The inclusion of animals in therapeutic activities, known as animal-assisted intervention (AAI), has been suggested as a treatment practice for autism spectrum disorder (ASD). This paper presents a systematic review of the empirical research on AAI for ASD. Fourteen studies published in peer-reviewed journals qualified for inclusion. The presentation of AAI was highly variable across the studies. Reported outcomes included improvements for multiple areas of functioning known to be impaired in ASD, namely increased social interaction and communication as well as decreased problem behaviors, autistic severity, and stress. Yet despite unanimously positive outcomes, most studies were limited by many methodological weaknesses. This review demonstrates that there is preliminary "proof of concept" of AAI for ASD and highlights the need for further, more rigorous research.

Educating Homeless Youth in Texas: The McKinney-Vento Homeless Education Assistance Improvements Act of 2001.

PubMed

Windsor, Liliane Cambraia; Thompson, Sanna J

2008-07-01

This paper discusses homeless youth in the US focusing on educational issues addressed by the implementation of the McKinney-Vento Homeless Education Assistance Improvements Act of 2001. This law requires that states ensure each homeless child has equal access to public education. Moreover, the law requires states to identify and remove barriers to homeless children's education, such as requirements for previous school records and proof of residency. Following description of homelessness, educational issues, and barriers for homeless youth, the McKinney-Vento Act is described as it is applied in Texas. Finally, the paper concludes that further development, education, and commitment from service providers in schools and other community agencies will be needed to improve outcomes for these highly vulnerable youth.

'In a twilight world'? Judging the value of life for the minimally conscious patient.

PubMed

Huxtable, Richard

2013-09-01

The recent ruling from England on the case of M is one of very few worldwide to consider whether life-sustaining treatment, in the form of clinically assisted nutrition and hydration, should continue to be provided to a patient in a minimally conscious state. Formally concerned with the English law pertaining to precedent autonomy (specifically advance decision-making) and the best interests of the incapacitated patient, the judgment issued in M's case implicitly engages with three different accounts of the value of human life, which respectively emphasise its self-determined, intrinsic and instrumental value. The judge appeared to be most persuaded by the intrinsic value of life and he concluded that treatment ought to continue. Assessing whether his approach or conclusion were ethically appropriate involves significant substantive and evidential questions regarding where the burden of proof should lie and what standard of proof should be required when decisions are to be made about the fates of patients inhabiting 'twilight worlds'.

Proof of concept: Partner-Assisted Interpersonal Psychotherapy for perinatal depression

PubMed Central

Ceccotti, Nadia; Hynan, Linda S.; Shivakumar, Geetha; Johnson, Neysa; Jarrett, Robin B.

2012-01-01

Although poor partner support is a key risk factor for depression in pregnant and postpartum women, partners are not generally involved in treatment beyond psychoeducation. The aim of this "proof of concept" study was to test safety, acceptability, and feasibility of Partner-Assisted Interpersonal Psychotherapy (PA-IPT), an intervention that includes the partner as an active participant throughout treatment. Women more than 12 weeks estimated gestational age and less than 12 weeks postpartum were invited to participate if they fulfilled DSM-IV criteria for Major Depressive Disorder and reported moderate symptom severity (HAM-D17 ≥16). The open trial included eight acute-phase sessions and a 6-week follow-up assessment. Ten couples completed the acute phase treatment and nine presented for a 6-week follow-up assessment. There were no study-related adverse events, and no women had symptomatic worsening from intake to Session Eight. All partners attended all sessions, no couples dropped out of treatment, and all reported positive treatment satisfaction at the conclusion of the study. Nine of ten women (90 %) met the criteria for clinical response (HAM-D17=9) at the conclusion of acute phase treatment, and eight of the nine (89 %) presenting at a 6-week follow-up assessment met criteria for symptomatic recovery. Incorporating partners in the treatment of major depressive disorders during the perinatal period is safe, acceptable, and feasible, but needs further testing in a larger population to evaluate efficacy. PMID:23053218

Do Medications Commonly Prescribed to Patients with Peripheral Arterial Disease Have an Effect on Nutritional Status? A Review of the Literature.

PubMed

Fenton, Renee; Brook-Barclay, Laura; Delaney, Christopher L; Spark, J Ian; Miller, Michelle D

2016-04-01

Polypharmacy is common among patients with peripheral arterial disease (PAD) with a combination of medications used for risk-factor modification and medical management of the disease itself. Interaction between commonly prescribed medications and nutritional status has not previously been well described. This review aims to critically appraise evidence exploring associations between medications commonly prescribed to patients with PAD and nutritional status and provide recommendations for practice. A comprehensive literature search was conducted to locate studies relating to nutrient interactions among lipid-lowering, antihypertensive, antiplatelet, and oral hypoglycemic drug classes. Quality of the evidence was rated on the basis of recommendations by the National Health and Medical Research Council. A total of 25 articles were identified as suitable and included in the review. No studies were specific to patients with PAD, and hence findings highlighting risk of ubiquinone (coenzyme Q10 [CoQ10]) depletion with lipid-lowering medications, zinc depletion with antihypertensive medications, and vitamin B12 depletion with oral hypoglycemic medications are extrapolated from heterogeneous groups of patients and healthy adults. The body of evidence ranged in quality from satisfactory to poor. High-quality research is required to confirm the interactions suggested by the included studies in patients with PAD specifically. It is, however, recommended that patients with PAD that are long-term consumers of the selected medications are monitored for CoQ10, zinc, and vitamin B12 to facilitate early identification of deficiencies and initiation of treatment. Treatment may involve dietary intervention and/or supplementation. Copyright © 2016 Elsevier Inc. All rights reserved.

Identification of genes showing differential expression profile associated with growth rate in skeletal muscle tissue of Landrace weanling pig.

PubMed

Komatsu, Yuuta; Sukegawa, Shin; Yamashita, Mai; Katsuda, Naoki; Tong, Bin; Ohta, Takeshi; Kose, Hiroyuki; Yamada, Takahisa

2016-06-01

Suppression subtractive hybridization was used to identify genes showing differential expression profile associated with growth rate in skeletal muscle tissue of Landrace weanling pig. Two subtracted cDNA populations were generated from musculus longissimus muscle tissues of selected pigs with extreme expected breeding values at the age of 100 kg. Three upregulated genes (EEF1A2, TSG101 and TTN) and six downregulated genes (ATP5B, ATP5C1, COQ3, HADHA, MYH1 and MYH7) in pig with genetic propensity for higher growth rate were identified by sequence analysis of 12 differentially expressed clones selected by differential screening following the generation of the subtracted cDNA population. Real-time PCR analysis confirmed difference in expression profiles of the identified genes in musculus longissimus muscle tissues between the two Landrace weanling pig groups with divergent genetic propensity for growth rate. Further, differential expression of the identified genes except for the TTN was validated by Western blot analysis. Additionally, the eight genes other than the ATP5C1 colocalized with the same chromosomal positions as QTLs that have been previously identified for growth rate traits. Finally, the changes of expression predicted from gene function suggested association of upregulation of expression of the EEF1A2, TSG101 and TTN genes and downregulation of the ATP5B, ATP5C1, COQ3, HADHA, MYH1 and MYH7 gene expression with increased growth rate. The identified genes will provide an important insight in understanding the molecular mechanism underlying growth rate in Landrace pig breed.

L-pyroglutamic acid inhibits energy production and lipid synthesis in cerebral cortex of young rats in vitro.

PubMed

Silva, A R; Silva, C G; Ruschel, C; Helegda, C; Wyse, A T; Wannmacher, C M; Wajner, M; Dutra-Filho, C S

2001-12-01

In the present study we investigated the effects of L-pyroglutamic acid (PGA), which predominantly accumulates in the inherited metabolic diseases glutathione synthetase deficiency (GSD) and gamma-glutamylcysteine synthetase deficiency (GCSD), on some in vitro parameters of energy metabolism and lipid biosynthesis. We evaluated the rates of CO2 production and lipid synthesis from [U-14C]acetate, as well as ATP levels and the activities of creatine kinase and of the respiratory chain complexes I-IV in cerebral cortex of young rats in the presence of PGA at final concentrations ranging from 0.5 to 3 mM. PGA significantly reduced brain CO2 production by 50% at the concentrations of 0.5 to 3 mM, lipid biosynthesis by 20% at concentrations of 0.5 to 3 mM and ATP levels by 52% at the concentration of 3 mM. Regarding the enzyme activities, PGA significantly decreased NADH:cytochrome c oxireductase (complex I plus CoQ plus complex III) by 40% at concentrations of 0.5-3.0 mM and cytochrome c oxidase activity by 22-30% at the concentration of 3.0 mM, without affecting the activities of succinate dehydrogenase, succinate:DCPIP oxireductase (complex II), succinate:cytochrome c oxireductase (complex II plus CoQ plus complex III) or creatine kinase. The results strongly indicate that PGA impairs brain energy production. If these effects also occur in humans, it is possible that they may contribute to the neuropathology of patients affected by these diseases.

Simple Circumcision Device: Proof-of-Concept for a Single-visit, Adjustable Device to Facilitate Safe Adult Male Circumcision

PubMed Central

Hotaling, James M; Leddy, Laura S; Haider, Mahum A; Mossanen, Matthew; Bailey, Michael R; MacConaghy, Brian; Olson, Francis; Krieger, John N

2014-01-01

Objective To conduct a proof-of-concept study to determine the potential utility of a novel, adjustable single-visit, disposable device to facilitate rapid adult circumcision. Design Prospective pilot trial of a novel surgical device Setting Tertiary care Veterans Administration medical center Patients 5 adult males Interventions Circumcisions performed by junior trainees using an adjustable, single-size surgical-assist device constructed by the University of Washington Applied Physics Laboratory. Main Outcome Measure(s) The attending surgeon and trainees completed standardized forms after each procedure to assess technical problems and ease of use. Follow-up visits were scheduled to evaluate adverse events, post-operative pain, cosmetic outcomes and participant satisfaction at 3, 8, 30 and 90 days post-operatively. Results The average operative time was 16.4 minutes. All cases were performed with local anesthesia and no case required electrocautery or conversion to standard surgery. At the post-operative day 3 visit all subjects were happy with their results and would recommend the procedure to another patient. One participant had a minor wound separation noted at the 30-day visit that resolved during follow-up. There were no wound infections, hematomas or other adverse events. Conclusions This proof-of-study suggests that the Simple Circumcision Device (SCD) may facilitate delivery of safe adult male circumcision services. PMID:24613534

Phage-protease-peptide: a novel trifecta enabling multiplex detection of viable bacterial pathogens.

PubMed

Alcaine, S D; Tilton, L; Serrano, M A C; Wang, M; Vachet, R W; Nugen, S R

2015-10-01

Bacteriophages represent rapid, readily targeted, and easily produced molecular probes for the detection of bacterial pathogens. Molecular biology techniques have allowed researchers to make significant advances in the bioengineering of bacteriophage to further improve speed and sensitivity of detection. Despite their host specificity, bacteriophages have not been meaningfully leveraged in multiplex detection of bacterial pathogens. We propose a proof-of-principal phage-based scheme to enable multiplex detection. Our scheme involves bioengineering bacteriophage to carry a gene for a specific protease, which is expressed during infection of the target cell. Upon lysis, the protease is released to cleave a reporter peptide, and the signal detected. Here we demonstrate the successful (i) modification of T7 bacteriophage to carry tobacco etch virus (TEV) protease; (ii) expression of TEV protease by Escherichia coli following infection by our modified T7, an average of 2000 units of protease per phage are produced during infection; and (iii) proof-of-principle detection of E. coli in 3 h after a primary enrichment via TEV protease activity using a fluorescent peptide and using a designed target peptide for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis (MALDI-TOF MS) analysis. This proof-of-principle can be translated to other phage-protease-peptide combinations to enable multiplex bacterial detection and readily adopted on multiple platforms, like MALDI-TOF MS or fluorescent readers, commonly found in labs.

Augmented Reality Based Navigation for Computer Assisted Hip Resurfacing: A Proof of Concept Study.

PubMed

Liu, He; Auvinet, Edouard; Giles, Joshua; Rodriguez Y Baena, Ferdinando

2018-05-23

Implantation accuracy has a great impact on the outcomes of hip resurfacing such as recovery of hip function. Computer assisted orthopedic surgery has demonstrated clear advantages for the patients, with improved placement accuracy and fewer outliers, but the intrusiveness, cost, and added complexity have limited its widespread adoption. To provide seamless computer assistance with improved immersion and a more natural surgical workflow, we propose an augmented-reality (AR) based navigation system for hip resurfacing. The operative femur is registered by processing depth information from the surgical site with a commercial depth camera. By coupling depth data with robotic assistance, obstacles that may obstruct the femur can be tracked and avoided automatically to reduce the chance of disruption to the surgical workflow. Using the registration result and the pre-operative plan, intra-operative surgical guidance is provided through a commercial AR headset so that the user can perform the operation without additional physical guides. To assess the accuracy of the navigation system, experiments of guide hole drilling were performed on femur phantoms. The position and orientation of the drilled holes were compared with the pre-operative plan, and the mean errors were found to be approximately 2 mm and 2°, results which are in line with commercial computer assisted orthopedic systems today.

Operator modeling in commerical aviation: Cognitive models, intelligent displays, and pilot's assistants

NASA Technical Reports Server (NTRS)

Govindaraj, T.; Mitchell, C. M.

1994-01-01

One of the goals of the National Aviation Safety/Automation program is to address the issue of human-centered automation in the cockpit. Human-centered automation is automation that, in the cockpit, enhances or assists the crew rather than replacing them. The Georgia Tech research program focused on this general theme, with emphasis on designing a computer-based pilot's assistant, intelligent (i.e, context-sensitive) displays, and an intelligent tutoring system for understanding and operating the autoflight system. In particular, the aids and displays were designed to enhance the crew's situational awareness of the current state of the automated flight systems and to assist the crew's situational awareness of the current state of the automated flight systems and to assist the crew in coordinating the autoflight system resources. The activities of this grant included: (1) an OFMspert to understand pilot navigation activities in a 727 class aircraft; (2) an extension of OFMspert to understand mode control in a glass cockpit, Georgia Tech Crew Activity Tracking System (GT-CATS); (3) the design of a training system to teach pilots about the vertical navigation portion of the flight management system -VNAV Tutor; and (4) a proof-of-concept display, using existing display technology, to facilitate mode awareness, particularly in situations in which controlled flight into terrain (CFIT) is a potential.

Wireless Sensor Networks for Ambient Assisted Living

PubMed Central

Aquino-Santos, Raúl; Martinez-Castro, Diego; Edwards-Block, Arthur; Murillo-Piedrahita, Andrés Felipe

2013-01-01

This paper introduces wireless sensor networks for Ambient Assisted Living as a proof of concept. Our workgroup has developed an arrhythmia detection algorithm that we evaluate in a closed space using a wireless sensor network to relay the information collected to where the information can be registered, monitored and analyzed to support medical decisions by healthcare providers. The prototype we developed is then evaluated using the TelosB platform. The proposed architecture considers very specific restrictions regarding the use of wireless sensor networks in clinical situations. The seamless integration of the system architecture enables both mobile node and network configuration, thus providing the versatile and robust characteristics necessary for real-time applications in medical situations. Likewise, this system architecture efficiently permits the different components of our proposed platform to interact efficiently within the parameters of this study. PMID:24351665

Space shuttle orbit maneuvering engine reusable thrust chamber program

NASA Technical Reports Server (NTRS)

Senneff, J. M.

1975-01-01

The feasibility of potential reusable thrust chamber concepts is studied. Propellant condidates were examined and analytically combined with potential cooling schemes. A data base of engine data which would assist in a configuration selection was produced. The data base verification was performed by the demonstration of a thrust chamber of a selected coolant scheme design. A full scale insulated columbium thrust chamber was used for propellant coolant configurations. Combustion stability of the injectors and a reduced size thrust chamber were experimentally verified as proof of concept demonstrations of the design and study results.

The Psychedelic Debriefing in Alcohol Dependence Treatment: Illustrating Key Change Phenomena through Qualitative Content Analysis of Clinical Sessions

PubMed Central

Nielson, Elizabeth M.; May, Darrick G.; Forcehimes, Alyssa A.; Bogenschutz, Michael P.

2018-01-01

Research on the clinical applications of psychedelic-assisted psychotherapy has demonstrated promising early results for treatment of alcohol dependence. Detailed description of the content and methods of psychedelic-assisted psychotherapy, as it is conducted in clinical settings, is scarce. Methods: An open-label pilot (proof-of-concept) study of psilocybin-assisted treatment of alcohol dependence (NCT01534494) was conducted to generate data for a phase 2 RCT (NCT02061293) of a similar treatment in a larger population. The present paper presents a qualitative content analysis of the 17 debriefing sessions conducted in the pilot study, which occurred the day after corresponding psilocybin medication sessions. Results: Participants articulated a series of key phenomena related to change in drinking outcomes and acute subjective effects of psilocybin. Discussion: The data illuminate change processes in patients' own words during clinical sessions, shedding light on potential therapeutic mechanisms of change and how participants express effects of psilocybin. This study is unique in analyzing actual clinical sessions, as opposed to interviews of patients conducted separately from treatment. PMID:29515449

A proof of concept study investigating the feasibility of combining iPAM robot assisted rehabilitation with functional electrical stimulation to deliver whole arm exercise in stroke survivors.

PubMed

O'Connor, Rory J; Jackson, Andrew; Makower, Sophie G; Cozens, Alastair; Levesley, Martin

2014-01-01

Rehabilitation robots can provide exercise for stroke survivors with weakness at the shoulder and elbow, but most do not facilitate hand movements. The aim was to combine robotics and functional electrical stimulation to facilitate exercise in stroke survivors with upper limb impairment. iPAM Mk II was used to assist active reaching in combination with an Odstock Pace stimulator to assist hand opening. The ABILHAND, Action Research Arm Test (ARAT) and the Stroke Impact Scale (SIS) were recorded at baseline and completion. Nine participants (eight males and one female; mean age = 58 years) were recruited; mean time since stroke was 16 months (range = 6-64). The ABILHAND at baseline was -2.73, improving to -1.45 at follow-up (p = 0.038). The ARAT changed from 4.1 to 2.6 (p = 0.180), and the SIS from 49 to 60 (p = 0.019). This study demonstrates that it is possible to combine two technologies in stroke rehabilitation.

Performance of the Satellite Test Assistant Robot in JPL's Space Simulation Facility

NASA Technical Reports Server (NTRS)

Mcaffee, Douglas; Long, Mark; Johnson, Ken; Siebes, Georg

1995-01-01

An innovative new telerobotic inspection system called STAR (the Satellite Test Assistant Robot) has been developed to assist engineers as they test new spacecraft designs in simulated space environments. STAR operates inside the ultra-cold, high-vacuum, test chambers and provides engineers seated at a remote Operator Control Station (OCS) with high resolution video and infrared (IR) images of the flight articles under test. STAR was successfully proof tested in JPL's 25-ft (7.6-m) Space Simulation Chamber where temperatures ranged from +85 C to -190 C and vacuum levels reached 5.1 x 10(exp -6) torr. STAR's IR Camera was used to thermally map the entire interior of the chamber for the first time. STAR also made several unexpected and important discoveries about the thermal processes occurring within the chamber. Using a calibrated test fixture arrayed with ten sample spacecraft materials, the IR camera was shown to produce highly accurate surface temperature data. This paper outlines STAR's design and reports on significant results from the thermal vacuum chamber test.

CRISPR-Cpf1 assisted genome editing of Corynebacterium glutamicum

PubMed Central

Jiang, Yu; Qian, Fenghui; Yang, Junjie; Liu, Yingmiao; Dong, Feng; Xu, Chongmao; Sun, Bingbing; Chen, Biao; Xu, Xiaoshu; Li, Yan; Wang, Renxiao; Yang, Sheng

2017-01-01

Corynebacterium glutamicum is an important industrial metabolite producer that is difficult to genetically engineer. Although the Streptococcus pyogenes (Sp) CRISPR-Cas9 system has been adapted for genome editing of multiple bacteria, it cannot be introduced into C. glutamicum. Here we report a Francisella novicida (Fn) CRISPR-Cpf1-based genome-editing method for C. glutamicum. CRISPR-Cpf1, combined with single-stranded DNA (ssDNA) recombineering, precisely introduces small changes into the bacterial genome at efficiencies of 86–100%. Large gene deletions and insertions are also obtained using an all-in-one plasmid consisting of FnCpf1, CRISPR RNA, and homologous arms. The two CRISPR-Cpf1-assisted systems enable N iterative rounds of genome editing in 3N+4 or 3N+2 days. A proof-of-concept, codon saturation mutagenesis at G149 of γ-glutamyl kinase relieves L-proline inhibition using Cpf1-assisted ssDNA recombineering. Thus, CRISPR-Cpf1-based genome editing provides a highly efficient tool for genetic engineering of Corynebacterium and other bacteria that cannot utilize the Sp CRISPR-Cas9 system. PMID:28469274

Protecting the BBB Endothelium against Cigarette Smoke-Induced Oxidative Stress Using Popular Antioxidants: Are they really beneficial?

PubMed Central

Kaisar, Mohammad Abul; Prasad, Shikha; Cucullo, Luca

2015-01-01

Blood Brain Barrier (BBB) exposed to realistic concentrations (comparable to a chronic heavy smoker) of Cigarette Smoke Extract (CSE) triggers a strong endothelial inflammatory which can lead to the onset of neurological disorders. The involvement of Reactive Oxygen Species (ROS) in this inflammatory cascade is evident from the up-regulation of nuclear factor erythroid 2 related factor 2 (Nrf-2), a transcription factor involved in anti-oxidant response signaling in CSE exposed endothelial cells. We have shown that pre-treatment with α-tocopherol and/or ascorbic acid is highly protective for the BBB, thus suggesting that, prophylactic administration of antioxidants can reduce CSE and/or inflammatory-dependent BBB damage. We have assessed and ranked the protective effects of 5 popular OTC antioxidants (Coenzyme Q10, Melatonin, Glutathione, Lipoic acid and Resveratrol) against CSE-induced BBB endothelial damage using hCMEC/D3 cells. The analysis of pro-inflammatory cytokines release by ELISA revealed that, resveratrol, lipoic acid melatonin and Co-Q10 inhibited the BBB endothelial release of pro-inflammatory cytokines IL-6 & IL-8, reduced (not Co-Q10) CSE-induced up-regulation of Platelet Endothelial Cell Adhesion Molecule -1 (PECAM-1), Vascular Endothelial Cell Adhesion Molecule-1 (VCAM-1) & E-selectin and inhibited monocytes-endothelial cell adhesion. The anti-inflammatory effects correlated with the anti-oxidative protection endowed by these compounds as evidenced by upregulation of NADPH: Quinone Oxidoreductase 1 (NQO1) and reduced cellular oxidative stress. CSE-induced release of Vascular Endothelial Growth Factor (VEGF) was inhibited by all tested compounds although the effect was not strictly dose-dependent. Further in vivo studies are required to validate our results and expand our current study to include combinatorial treatments. PMID:26410779

Addition of omega-3 fatty acid and coenzyme Q10 to statin therapy in patients with combined dyslipidemia.

PubMed

Tóth, Štefan; Šajty, Matej; Pekárová, Tímea; Mughees, Adil; Štefanič, Peter; Katz, Matan; Spišáková, Katarína; Pella, Jozef; Pella, Daniel

2017-07-26

Statins represent a group of drugs that are currently indicated in the primary and secondary prevention of cardiovascular events. Their administration can be associated with side effects and the insufficient reduction of triacylglyceride (TAG) levels. This study aimed to assess the effect of the triple combination of statins with omega-3 fatty acids and coenzyme Q10 (CoQ10) on parameters associated with atherogenesis and statin side effects. In this pilot randomized double-blind trial, 105 subjects who met the criteria of combined dislipidemia and elevated TAG levels were randomly divided into three groups. In the control group, unaltered statin therapy was indicated. In the second and third groups, omega-3 PUFA 2.52 g/day (Zennix fa Pleuran) and omega-3 PUFA 2.52 g+CoQ10 200 mg/day (Pharma Nord ApS) were added, res//. At the end of the 3-month period (±1 week), all patients were evaluated. Significant reduction of hepatic enzymes activity, systolic blood preasure, inflammatory markers and TAG levels were detected in both groups in comparison to the control group. Activity of SOD and GPx increased significantly after additive therapy. Coenzyme Q10 addition significantly reduced most of the abovementioned parameters (systolic blood preasure, total cholesterol, LDL, hsCRP, IL-6, SOD) in comparison with the statin+omega-3 PUFA group. The intensity of statin adverse effects were significantly reduced in the group with the addition of CoQ10. The results of this pilot study suggest the possible beneficial effects of triple combination on the lipid and non-lipid parameters related to atherogenesis and side effects of statin treatment.

The use of coenzyme Q10 and DHEA during IUI and IVF cycles in patients with decreased ovarian reserve.

PubMed

Gat, Itai; Blanco Mejia, Sonia; Balakier, Hanna; Librach, Clifford L; Claessens, Anne; Ryan, Edward A J

2016-07-01

The objective of this study is to compare the combination of dehydroepiandrosterone (DHEA) and coenzyme Q10 (CoQ10) (D + C) with DHEA alone (D) in intrauterine insemination (IUI) and in vitro fertilization (IVF) cycles among patients with decreased ovarian reserve. We retrospectively extracted data from patients charts treated by DHEA with/without CoQ10 during IUI or IVF between February 2006 and June 2014. Prestimulation parameters included age, BMI, day 3 FSH and antral follicular count (AFC). Ovarian response parameters included total gonadotropins dosage, peak serum estradiol, number of follicles > 16 mm and fertilization rate. Clinical outcomes included clinical and ongoing pregnancy rates. Three hundred and thirty IUI cycles involved D + C compared with 467 cycles of D; 78 IVF cycles involved D + C and 175 D. In both IUI and IVF, AFC was higher with D + C compared with D (7.4 ± 5.7 versus 5.9 ± 4.7, 8.2 ± 6.3 versus 5.2 ± 5, respectively, p < 0.05). D + C resulted in a more follicles > 16 mm during IUI cycles (3.3 ± 2.3 versus 2.9 ± 2.2, respectively, p = 0.01), while lower mean total gonadotropin dosage was administered after D + C supplementation compared with D (3414 ± 1141 IUs versus 3877 ± 1143 IUs respectively, p = 0.032) in IVF cycles. Pregnancy and delivery rates were similar for both IUI and IVF. D + C significantly increases AFC and improves ovarian responsiveness during IUI and IVF without a difference in clinical outcome.

Two solanesyl diphosphate synthases with different subcellular localizations and their respective physiological roles in Oryza sativa

PubMed Central

Ohara, Kazuaki; Sasaki, Kanako; Yazaki, Kazufumi

2010-01-01

Long chain prenyl diphosphates are crucial biosynthetic precursors of ubiquinone (UQ) in many organisms, ranging from bacteria to humans, as well as precursors of plastoquinone in photosynthetic organisms. The cloning and characterization of two solanesyl diphosphate synthase genes, OsSPS1 and OsSPS2, in Oryza sativa is reported here. OsSPS1 was highly expressed in root tissue whereas OsSPS2 was found to be high in both leaves and roots. Enzymatic characterization using recombinant proteins showed that both OsSPS1 and OsSPS2 could produce solanesyl diphosphates as their final product, while OsSPS1 showed stronger activity than OsSPS2. However, an important biological difference was observed between the two genes: OsSPS1 complemented the yeast coq1 disruptant, which does not form UQ, whereas OsSPS2 only very weakly complemented the growth defect of the coq1 mutant. HPLC analyses showed that both OsSPS1 and OsSPS2 yeast transformants produced UQ9 instead of UQ6, which is the native yeast UQ. According to the complementation study, the UQ9 levels in OsSPS2 transformants were much lower than that of OsSPS1. Green fluorescent protein fusion analyses showed that OsSPS1 localized to mitochondria, while OsSPS2 localized to plastids. This suggests that OsSPS1 is involved in the supply of solanesyl diphosphate for ubiquinone-9 biosynthesis in mitochondria, whereas OsSPS2 is involved in providing solanesyl diphosphate for plastoquinone-9 formation. These findings indicate that O. sativa has a different mechanism for the supply of isoprenoid precursors in UQ biosynthesis from Arabidopsis thaliana, in which SPS1 provides a prenyl moiety for UQ9 at the endoplasmic reticulum. PMID:20421194

Characterization of CoQ₁₀ biosynthesis in fibroblasts of patients with primary and secondary CoQ₁₀ deficiency.

PubMed

Buján, Nuria; Arias, Angela; Montero, Raquel; García-Villoria, Judit; Lissens, Willy; Seneca, Sara; Espinós, Carmen; Navas, Plácido; De Meirleir, Linda; Artuch, Rafael; Briones, Paz; Ribes, Antonia

2014-01-01

Primary coenzyme Q₁₀ (CoQ₁₀) deficiencies are associated with mutations in genes encoding enzymes important for its biosynthesis and patients are responsive to CoQ₁₀ supplementation. Early treatment allows better prognosis of the disease and therefore, early diagnosis is desirable. The complex phenotype and genotype and the frequent secondary CoQ₁₀ deficiencies make it difficult to achieve a definitive diagnosis by direct quantification of CoQ₁₀. We developed a non-radioactive methodology for the quantification of CoQ₁₀ biosynthesis in fibroblasts that allows the identification of primary deficiencies. Fibroblasts were incubated 72 h with 28 μmol/L (2)H₃-mevalonate or 1.65 mmol/L (13)C₆-p-hydroxybenzoate. The newly synthesized (2)H₃- and (13)C₆- labelled CoQ₁₀ were analysed by high performance liquid chromatography-tandem mass spectrometry. The mean and the reference range for (13)C₆-CoQ₁₀ and (2)H₃-CoQ₁₀ biosynthesis were 0.97 (0.83-1.1) and 0.13 (0.09-0.17) nmol/Unit of citrate synthase, respectively. We validated the methodology through the study of one patient with COQ2 mutations and six patients with CoQ₁₀ deficiency secondary to other inborn errors of metabolism. Afterwards we investigated 16 patients' fibroblasts and nine showed decreased CoQ₁₀ biosynthesis. Therefore, the next step is to study the COQ genes in order to reach a definitive diagnosis in these nine patients. In the patients with normal rates the deficiency is probably secondary. In conclusion, we have developed a non-invasive non-radioactive method suitable for the detection of defects in CoQ₁₀ biosynthesis, which offers a good tool for the stratification of patients with these treatable mitochondrial diseases.

Two solanesyl diphosphate synthases with different subcellular localizations and their respective physiological roles in Oryza sativa.

PubMed

Ohara, Kazuaki; Sasaki, Kanako; Yazaki, Kazufumi

2010-06-01

Long chain prenyl diphosphates are crucial biosynthetic precursors of ubiquinone (UQ) in many organisms, ranging from bacteria to humans, as well as precursors of plastoquinone in photosynthetic organisms. The cloning and characterization of two solanesyl diphosphate synthase genes, OsSPS1 and OsSPS2, in Oryza sativa is reported here. OsSPS1 was highly expressed in root tissue whereas OsSPS2 was found to be high in both leaves and roots. Enzymatic characterization using recombinant proteins showed that both OsSPS1 and OsSPS2 could produce solanesyl diphosphates as their final product, while OsSPS1 showed stronger activity than OsSPS2. However, an important biological difference was observed between the two genes: OsSPS1 complemented the yeast coq1 disruptant, which does not form UQ, whereas OsSPS2 only very weakly complemented the growth defect of the coq1 mutant. HPLC analyses showed that both OsSPS1 and OsSPS2 yeast transformants produced UQ9 instead of UQ6, which is the native yeast UQ. According to the complementation study, the UQ9 levels in OsSPS2 transformants were much lower than that of OsSPS1. Green fluorescent protein fusion analyses showed that OsSPS1 localized to mitochondria, while OsSPS2 localized to plastids. This suggests that OsSPS1 is involved in the supply of solanesyl diphosphate for ubiquinone-9 biosynthesis in mitochondria, whereas OsSPS2 is involved in providing solanesyl diphosphate for plastoquinone-9 formation. These findings indicate that O. sativa has a different mechanism for the supply of isoprenoid precursors in UQ biosynthesis from Arabidopsis thaliana, in which SPS1 provides a prenyl moiety for UQ9 at the endoplasmic reticulum.

Alternative quinone substrates and inhibitors of human electron-transfer flavoprotein-ubiquinone oxidoreductase.

PubMed Central

Simkovic, Martin; Frerman, Frank E

2004-01-01

Electron-transfer flavoprotein (ETF)-ubiquinone (2,3-dimethoxy-5-methyl-1,4-benzoquinone) oxidoreductase (ETF-QO) is a membrane-bound iron-sulphur flavoprotein that participates in an electron-transport pathway between eleven mitochondrial flavoprotein dehydrogenases and the ubiquinone pool. ETF is the intermediate electron carrier between the dehydrogenases and ETF-QO. The steady-state kinetic constants of human ETF-QO were determined with ubiquinone homologues and analogues that contained saturated n-alkyl substituents at the 6 position. These experiments show that optimal substrates contain a ten-carbon-atom side chain, consistent with a preliminary crystal structure that shows that only the first two of ten isoprene units of co-enzyme Q10 (CoQ10) interact with the protein. Derivatives with saturated alkyl side chains are very good substrates, indicating that, unlike other ubiquinone oxidoreductases, there is little preference for the methyl branches or rigidity of the CoQ side chain. Few of the compounds that inhibit ubiquinone oxidoreductases inhibit ETF-QO. Compounds found to act as inhibitors of ETF-QO include 2-n-heptyl-4-hydroxyquinoline N-oxide, a naphthoquinone analogue, 2-(3-methylpentyl)-4,6-dinitrophenol and pentachlorophenol. 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone (DBMIB), which inhibits the mitochondrial bc1 complex and the chloroplast b6 f complex in redox-dependent fashion, can serve as an electron acceptor for human ETF-QO. The observation of simple Michaelis-Menten kinetic patterns and a single type of quinone-binding site, determined by fluorescence titrations of the protein with DBMIB and 6-(10-bromodecyl)ubiquinone, are consistent with one ubiquinone-binding site per ETF-QO monomer. PMID:14640977

Alternative quinone substrates and inhibitors of human electron-transfer flavoprotein-ubiquinone oxidoreductase.

PubMed

Simkovic, Martin; Frerman, Frank E

2004-03-01

Electron-transfer flavoprotein (ETF)-ubiquinone (2,3-dimethoxy-5-methyl-1,4-benzoquinone) oxidoreductase (ETF-QO) is a membrane-bound iron-sulphur flavoprotein that participates in an electron-transport pathway between eleven mitochondrial flavoprotein dehydrogenases and the ubiquinone pool. ETF is the intermediate electron carrier between the dehydrogenases and ETF-QO. The steady-state kinetic constants of human ETF-QO were determined with ubiquinone homologues and analogues that contained saturated n-alkyl substituents at the 6 position. These experiments show that optimal substrates contain a ten-carbon-atom side chain, consistent with a preliminary crystal structure that shows that only the first two of ten isoprene units of co-enzyme Q10 (CoQ10) interact with the protein. Derivatives with saturated alkyl side chains are very good substrates, indicating that, unlike other ubiquinone oxidoreductases, there is little preference for the methyl branches or rigidity of the CoQ side chain. Few of the compounds that inhibit ubiquinone oxidoreductases inhibit ETF-QO. Compounds found to act as inhibitors of ETF-QO include 2-n-heptyl-4-hydroxyquinoline N-oxide, a naphthoquinone analogue, 2-(3-methylpentyl)-4,6-dinitrophenol and pentachlorophenol. 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone (DBMIB), which inhibits the mitochondrial bc1 complex and the chloroplast b6 f complex in redox-dependent fashion, can serve as an electron acceptor for human ETF-QO. The observation of simple Michaelis-Menten kinetic patterns and a single type of quinone-binding site, determined by fluorescence titrations of the protein with DBMIB and 6-(10-bromodecyl)ubiquinone, are consistent with one ubiquinone-binding site per ETF-QO monomer.

Effect of ubiquinol supplementation on biochemical and oxidative stress indexes after intense exercise in young athletes.

PubMed

Orlando, Patrick; Silvestri, Sonia; Galeazzi, Roberta; Antonicelli, Roberto; Marcheggiani, Fabio; Cirilli, Ilenia; Bacchetti, Tiziana; Tiano, Luca

2018-12-01

Physical exercise significantly impacts the biochemistry of the organism. Ubiquinone is a key component of the mitochondrial respiratory chain and ubiquinol, its reduced and active form, is an emerging molecule in sport nutrition. The aim of this study was to evaluate the effect of ubiquinol supplementation on biochemical and oxidative stress indexes after an intense bout of exercise. 21 male young athletes (26 + 5 years of age) were randomized in two groups according to a double blind cross-over study, either supplemented with ubiquinol (200 mg/day) or placebo for 1 month. Blood was withdrawn before and after a single bout of intense exercise (40 min run at 85% maxHR). Physical performance, hematochemical parameters, ubiquinone/ubiquinol plasma content, intracellular reactive oxygen species (ROS) level, mitochondrial membrane depolarization, paraoxonase activity and oxidative DNA damage were analyzed. A single bout of intense exercise produced a significant increase in most hematochemical indexes, in particular CK and Mb while, on the contrary, normalized coenzyme Q 10 plasma content decreased significantly in all subjects. Ubiquinol supplementation prevented exercise-induced CoQ deprivation and decrease in paraoxonase activity. Moreover at a cellular level, in peripheral blood mononuclear cells, ubiquinol supplementation was associated with a significant decrease in cytosolic ROS while mitochondrial membrane potential and oxidative DNA damage remained unchanged. Data highlights a very rapid dynamic of CoQ depletion following intense exercise underlying an increased demand by the organism. Ubiquinol supplementation minimized exercise-induced depletion and enhanced plasma and cellular antioxidant levels but it was not able to improve physical performance indexes or markers of muscular damage.

New animal models reveal that coenzyme Q2 (Coq2) and placenta-specific 8 (Plac8) are candidate genes for the onset of type 2 diabetes associated with obesity in rats.

PubMed

Sasaki, Daiki; Kotoh, Jun; Watadani, Risa; Matsumoto, Kozo

2015-12-01

Obesity is a major risk factor for the onset of type 2 diabetes; however, little is known about the gene(s) involved. Therefore, we developed new animal models of obesity to search for diabetogenic genes associated with obesity. We generated double congenic rat strains with a hyperglycaemic quantitative trait locus (QTL) derived from the Otsuka Long-Evans Tokushima Fatty rat and a fa/fa (Lepr-/-) locus derived from the Zucker Fatty rat; phenotypic analysis for plasma glucose and insulin levels and RNA and protein levels were determined using reverse transcription quantitative PCR and Western blotting analyses, respectively. The double congenic strain F344-fa-nidd2 (Lepr-/- and Nidd2/of) exhibited significantly higher glucose levels and significantly lower hypoglycaemic response to insulin than the obese control strain F344-fa (Lepr-/-). These phenotypes were clearly observed in the obese strains but not in the lean strains. These results indicate that the Nidd2/of locus harbours a diabetogenic gene associated with obesity. We measured the expression of 60 genes in the Nidd2/of QTL region between the strains and found that the mRNA expression levels of five genes were significantly different between the strains under the condition of obesity. However, three of the five genes were differentially expressed in both obese and lean rats, indicating that these genes are not specific for the condition of obesity. Conversely, the other two genes, coenzyme Q2 (Coq2) and placenta-specific 8 (Plac8), were differentially expressed only in the obese rats, suggesting that these two genes are candidates for the onset of type 2 diabetes associated with obesity in rats.

Body-Machine Interface Enables People With Cervical Spinal Cord Injury to Control Devices With Available Body Movements: Proof of Concept.

PubMed

Abdollahi, Farnaz; Farshchiansadegh, Ali; Pierella, Camilla; Seáñez-González, Ismael; Thorp, Elias; Lee, Mei-Hua; Ranganathan, Rajiv; Pedersen, Jessica; Chen, David; Roth, Elliot; Casadio, Maura; Mussa-Ivaldi, Ferdinando

2017-05-01

This study tested the use of a customized body-machine interface (BoMI) for enhancing functional capabilities in persons with cervical spinal cord injury (cSCI). The interface allows people with cSCI to operate external devices by reorganizing their residual movements. This was a proof-of-concept phase 0 interventional nonrandomized clinical trial. Eight cSCI participants wore a custom-made garment with motion sensors placed on the shoulders. Signals derived from the sensors controlled a computer cursor. A standard algorithm extracted the combinations of sensor signals that best captured each participant's capacity for controlling a computer cursor. Participants practiced with the BoMI for 24 sessions over 12 weeks performing 3 tasks: reaching, typing, and game playing. Learning and performance were evaluated by the evolution of movement time, errors, smoothness, and performance metrics specific to each task. Through practice, participants were able to reduce the movement time and the distance from the target at the 1-second mark in the reaching task. They also made straighter and smoother movements while reaching to different targets. All participants became faster in the typing task and more skilled in game playing, as the pong hit rate increased significantly with practice. The results provide proof-of-concept for the customized BoMI as a means for people with absent or severely impaired hand movements to control assistive devices that otherwise would be manually operated.

Hybrid Assistive Limb Exoskeleton HAL in the Rehabilitation of Chronic Spinal Cord Injury: Proof of Concept; the Results in 21 Patients.

PubMed

Jansen, Oliver; Grasmuecke, Dennis; Meindl, Renate C; Tegenthoff, Martin; Schwenkreis, Peter; Sczesny-Kaiser, Matthias; Wessling, Martin; Schildhauer, Thomas A; Fisahn, Christian; Aach, Mirko

2018-02-01

The use of mobile exoskeletons is becoming more and more common in the field of spinal cord injury (SCI) rehabilitation. The hybrid assistive limb (HAL) exoskeleton provides a tailored support depending on the patient's voluntary drive. After a pilot study in 2014 that included 8 patients with chronic SCI, this study of 21 patients with chronic SCI serves as a proof of concept. It was conducted to provide further evidence regarding the efficacy of exoskeletal-based rehabilitation. Functional assessment included walking speed, distance, and time on a treadmill, with additional analysis of functional mobility using the following tests: 10-meter walk test (10MWT), timed up and go (TUG) test, 6-minute walk test (6MWT), and the walking index for SCI II (WISCI-II) score. After a training period of 90 days, all 21 patients significantly improved their functional and ambulatory mobility without the exoskeleton. Patients were assessed by the 6MWT, the TUG test, and the 10MWT, which also indicated an increase in the WISCI-II score along with significant improvements in HAL-associated walking speed, distance, and time. Although, exoskeletons are not yet an established treatment in the rehabilitation of spinal cord injuries, the devices will play a more important role in the future. The HAL exoskeleton training enables effective, body weight-supported treadmill training and is capable of improving ambulatory mobility. Future controlled studies are required to enable a comparison of the new advances in the field of SCI rehabilitation with traditional over-ground training. Copyright © 2017 Elsevier Inc. All rights reserved.

Proof-of-concept switchable hydrophobic/hydrophilic patterned surfaces from thermo-mechanically tailored acrylate systems

NASA Astrophysics Data System (ADS)

Laursen, Christopher M.

A novel, proof-of-concept, switchable hydrophobic/hydrophilic structured surface targeted to assist in antifouling of materials in aqueous environments was created through the development of a multi-tiered platform. The understructure consists of a thermo-mechanically tailored acrylate based polymer patterned in a pillared array, which was then overlaid with spatially tailored hydrophobic/hydrophilic surface chemistry treatments. Development focused on the synthesis of a ternary acrylate system displaying proper thermo-mechanical behavior in submerged conditions for the understructure, creation of a sufficient soft molding technique, and methods to chemically alter water-surface wetting interactions. The final acrylate based polymer constituents were chosen based on expected low-toxicity and the ability to be photopolymerized, while the final system displayed appropriate mechanical toughness, water absorption, and material stiffness over a select temperature window. This was important as alteration in wettability characteristics relied upon a stark transition in the polymeric materials stiffness within a narrow temperature range. The material qualitatively displayed a more hydrophobic state with the pillared surface structures erect, and a more hydrophilic state with the pillars bent over.

Matrix-Assisted Three-Dimensional Printing of Cellulose Nanofibers for Paper Microfluidics.

PubMed

Shin, Sungchul; Hyun, Jinho

2017-08-09

A cellulose nanofiber (CNF), one of the most attractive green bioresources, was adopted for construction of microfluidic devices using matrix-assisted three-dimensional (3D) printing. CNF hydrogels can support structures printed using CAD design in a 3D hydrogel environment with the appropriate combination of rheological properties between the CNF hydrogel and ink materials. Amazingly, the structure printed freely in the bulky CNF hydrogels was able to retain its highly resolved 3D features in an ultrathin two-dimensional (2D) paper using a simple drying process. The dimensional change in the CNF hydrogels from 3D to 2D resulted from simple dehydration of the CNFs and provided transparent, stackable paper-based 3D channel devices. As a proof of principle, the rheological properties of the CNF hydrogels, the 3D structure of the ink, the formation of channels by evacuation of the ink, and the highly localized selectivity of the devices are described.

Evanescent wave assisted nanomaterial coating.

PubMed

Mondal, Samir K; Pal, Sudipta Sarkar; Kumbhakar, Dharmadas; Tiwari, Umesh; Bhatnagar, Randhir

2013-08-01

In this work we present a novel nanomaterial coating technique using evanescent wave (EW). The gradient force in the EW is used as an optical tweezer for tweezing and self-assembling nanoparticles on the source of EW. As a proof of the concept, we have used a laser coupled etched multimode optical fiber, which generates EW for the EW assisted coating. The section-wise etched multimode optical fiber is horizontally and superficially dipped into a silver/gold nanoparticles solution while the laser is switched on. The fiber is left until the solution recedes due to evaporation leaving the fiber in air. The coating time usually takes 40-50 min at room temperature. The scanning electron microscope image shows uniform and thin coating of self-assembled nanoparticles due to EW around the etched section. A coating thickness <200 nm is achieved. The technique could be useful for making surface-plasmon-resonance-based optical fiber probes and other plasmonic circuits.

High efficiency laser-assisted H - charge exchange for microsecond duration beams

DOE PAGES

Cousineau, Sarah; Rakhman, Abdurahim; Kay, Martin; ...

2017-12-26

Laser-assisted stripping is a novel approach to H - charge exchange that overcomes long-standing limitations associated with the traditional, foil-based method of producing high-intensity, time-structured beams of protons. This paper reports on the first successful demonstration of the laser stripping technique for microsecond duration beams. The experiment represents a factor of 1000 increase in the stripped pulse duration compared with the previous proof-of-principle demonstration. The central theme of the experiment is the implementation of methods to reduce the required average laser power such that high efficiency stripping can be accomplished for microsecond duration beams using conventional laser technology. In conclusion,more » the experiment was performed on the Spallation Neutron Source 1 GeV H - beam using a 1 MW peak power UV laser and resulted in ~95% stripping efficiency.« less

High efficiency laser-assisted H - charge exchange for microsecond duration beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cousineau, Sarah; Rakhman, Abdurahim; Kay, Martin

Laser-assisted stripping is a novel approach to H - charge exchange that overcomes long-standing limitations associated with the traditional, foil-based method of producing high-intensity, time-structured beams of protons. This paper reports on the first successful demonstration of the laser stripping technique for microsecond duration beams. The experiment represents a factor of 1000 increase in the stripped pulse duration compared with the previous proof-of-principle demonstration. The central theme of the experiment is the implementation of methods to reduce the required average laser power such that high efficiency stripping can be accomplished for microsecond duration beams using conventional laser technology. In conclusion,more » the experiment was performed on the Spallation Neutron Source 1 GeV H - beam using a 1 MW peak power UV laser and resulted in ~95% stripping efficiency.« less

Characterization of microsatellite loci for the pitcher plant midge, Metriocnemus knabi Coq. (Diptera: Chironomidae).

PubMed

Rasic, Gordana; Maxwell, Sheri A; Keyghobadi, Nusha

2009-09-01

As a component of the inquiline community of the purple pitcher plant (Sarracenia purpurea), the pitcher plant midge Metriocneus knabi has been the subject of various ecological studies. However, very little is known about its characteristics beyond the larval stage, in particular the dispersal ability of adults. This study presents new molecular tools developed for testing of evolutionary and ecological questions in natural populations of this species. We describe a set of 12 microsatellite loci specific to M. knabi that are sufficiently polymorphic to provide insight into population genetic structure and dispersal patterns. © 2009 Blackwell Publishing Ltd.

Fatigue Stressors in Simulated Long-Duration Flight. Effects on Performance, Information Processing, Subjective Fatigue, and Physiological Cost

DTIC Science & Technology

1980-12-01

transferase or monoamine oxidase. These enzymes are similar to cholinesterase which destroys acetycholine, the agent secreted by the para- sympathetic nervous...the adrenergic neurons. Levels of norepinephrine are controlled in part by the intraneural metabolic activity of the enzyme monoamine oxidase. Chronic...GJ 4’ to Lu~ (n N. 0 N CIO.I V) m~ -4 4 V) -4 -- 4 ot o0m - N 0 LOlCD W m%0 w M %* " m m m v m v " -4 -4- inC-4J-4 - Coq 00.~. 0 a)) a. CD-v U X X x L

Universal Virus Adsorption on Inert Particles Utilizing the Coated Latex Adsorption Method (CLAM)

DTIC Science & Technology

1975-06-30

identification of such adsorbents as bacteria, bacteria-specific antibodies, hormones, enzymes , nucleic acids, toxins, and lipids. Any carrier particle which...hormones, anti- bodies, cellular constituents, enzymes , etc. Also particles other than latex may be employed in the method providing they are uniform in...Ha .14 4 V4 1-4 :31 10 0 U -4 w -4 4 00 0 0 4) 44-4 226 m 0 1 £0 I PO r4 -- 7ý -7 00 C)) + 0 -J .-4 o - H X 0 toII coQ -4 4J ,9rl 0 4- p 4- 0) C: 12 +0

Evaluation of the Use of Home Blood Pressure Measurement Using Mobile Phone-Assisted Technology: The iVitality Proof-of-Principle Study.

PubMed

Wijsman, Liselotte W; Richard, Edo; Cachucho, Ricardo; de Craen, Anton Jm; Jongstra, Susan; Mooijaart, Simon P

2016-06-13

Mobile phone-assisted technologies provide the opportunity to optimize the feasibility of long-term blood pressure (BP) monitoring at home, with the potential of large-scale data collection. In this proof-of-principle study, we evaluated the feasibility of home BP monitoring using mobile phone-assisted technology, by investigating (1) the association between study center and home BP measurements; (2) adherence to reminders on the mobile phone to perform home BP measurements; and (3) referrals, treatment consequences and BP reduction after a raised home BP was diagnosed. We used iVitality, a research platform that comprises a Website, a mobile phone-based app, and health sensors, to measure BP and several other health characteristics during a 6-month period. BP was measured twice at baseline at the study center. Home BP was measured on 4 days during the first week, and thereafter, at semimonthly or monthly intervals, for which participants received reminders on their mobile phone. In the monthly protocol, measurements were performed during 2 consecutive days. In the semimonthly protocol, BP was measured at 1 day. We included 151 participants (mean age [standard deviation] 57.3 [5.3] years). BP measured at the study center was systematically higher when compared with home BP measurements (mean difference systolic BP [standard error] 8.72 [1.08] and diastolic BP 5.81 [0.68] mm Hg, respectively). Correlation of study center and home measurements of BP was high (R=0.72 for systolic BP and 0.72 for diastolic BP, both P<.001). Adherence was better in participants measuring semimonthly (71.4%) compared with participants performing monthly measurements (64.3%, P=.008). During the study, 41 (27.2%) participants were referred to their general practitioner because of a high BP. Referred participants had a decrease in their BP during follow-up (mean difference final and initial [standard error] -5.29 [1.92] for systolic BP and -2.93 [1.08] for diastolic BP, both P<.05). Mobile phone-assisted technology is a reliable and promising method with good adherence to measure BP at home during a 6-month period. This provides a possibility for implementation in large-scale studies and can potentially contribute to BP reduction.

Report on the formal specification and partial verification of the VIPER microprocessor

NASA Technical Reports Server (NTRS)

Brock, Bishop; Hunt, Warren A., Jr.

1991-01-01

The formal specification and partial verification of the VIPER microprocessor is reviewed. The VIPER microprocessor was designed by RSRE, Malvern, England, for safety critical computing applications (e.g., aircraft, reactor control, medical instruments, armaments). The VIPER was carefully specified and partially verified in an attempt to provide a microprocessor with completely predictable operating characteristics. The specification of VIPER is divided into several levels of abstraction, from a gate-level description up to an instruction execution model. Although the consistency between certain levels was demonstrated with mechanically-assisted mathematical proof, the formal verification of VIPER was never completed.

Student Teachers’ Proof Schemes on Proof Tasks Involving Inequality: Deductive or Inductive?

NASA Astrophysics Data System (ADS)

Rosyidi, A. H.; Kohar, A. W.

2018-01-01

Exploring student teachers’ proof ability is crucial as it is important for improving the quality of their learning process and help their future students learn how to construct a proof. Hence, this study aims at exploring at the proof schemes of student teachers in the beginning of their studies. Data were collected from 130 proofs resulted by 65 Indonesian student teachers on two proof tasks involving algebraic inequality. To analyse, the proofs were classified into the refined proof schemes level proposed by Lee (2016) ranging from inductive, which only provides irrelevant inferences, to deductive proofs, which consider addressing formal representation. Findings present several examples of each of Lee’s level on the student teachers’ proofs spanning from irrelevant inferences, novice use of examples or logical reasoning, strategic use examples for reasoning, deductive inferences with major and minor logical coherence, and deductive proof with informal and formal representation. Besides, it was also found that more than half of the students’ proofs coded as inductive schemes, which does not meet the requirement for doing the proof for the proof tasks examined in this study. This study suggests teacher educators in teacher colleges to reform the curriculum regarding proof learning which can accommodate the improvement of student teachers’ proving ability from inductive to deductive proof as well from informal to formal proof.

Wireless intraoral tongue control of an assistive robotic arm for individuals with tetraplegia.

PubMed

Andreasen Struijk, Lotte N S; Egsgaard, Line Lindhardt; Lontis, Romulus; Gaihede, Michael; Bentsen, Bo

2017-11-06

For an individual with tetraplegia assistive robotic arms provide a potentially invaluable opportunity for rehabilitation. However, there is a lack of available control methods to allow these individuals to fully control the assistive arms. Here we show that it is possible for an individual with tetraplegia to use the tongue to fully control all 14 movements of an assistive robotic arm in a three dimensional space using a wireless intraoral control system, thus allowing for numerous activities of daily living. We developed a tongue-based robotic control method incorporating a multi-sensor inductive tongue interface. One abled-bodied individual and one individual with tetraplegia performed a proof of concept study by controlling the robot with their tongue using direct actuator control and endpoint control, respectively. After 30 min of training, the able-bodied experimental participant tongue controlled the assistive robot to pick up a roll of tape in 80% of the attempts. Further, the individual with tetraplegia succeeded in fully tongue controlling the assistive robot to reach for and touch a roll of tape in 100% of the attempts and to pick up the roll in 50% of the attempts. Furthermore, she controlled the robot to grasp a bottle of water and pour its contents into a cup; her first functional action in 19 years. To our knowledge, this is the first time that an individual with tetraplegia has been able to fully control an assistive robotic arm using a wireless intraoral tongue interface. The tongue interface used to control the robot is currently available for control of computers and of powered wheelchairs, and the robot employed in this study is also commercially available. Therefore, the presented results may translate into available solutions within reasonable time.

Health-Enabling and Ambient Assistive Technologies: Past, Present, Future.

PubMed

Haux, R; Koch, S; Lovell, N H; Marschollek, M; Nakashima, N; Wolf, K-H

2016-06-30

During the last decades, health-enabling and ambient assistive technologies became of considerable relevance for new informatics-based forms of diagnosis, prevention, and therapy. To describe the state of the art of health-enabling and ambient assistive technologies in 1992 and today, and its evolution over the last 25 years as well as to project where the field is expected to be in the next 25 years. In the context of this review, we define health-enabling and ambient assistive technologies as ambiently used sensor-based information and communication technologies, aiming at contributing to a person's health and health care as well as to her or his quality of life. Systematic review of all original articles with research focus in all volumes of the IMIA Yearbook of Medical Informatics. Surveying authors independently on key projects and visions as well as on their lessons learned in the context of health-enabling and ambient assistive technologies and summarizing their answers. Surveying authors independently on their expectations for the future and summarizing their answers. IMIA Yearbook papers containing statements on health-enabling and ambient assistive technologies appear first in 2002. These papers form a minor part of published research articles in medical informatics. However, during recent years the number of articles published has increased significantly. Key projects were identified. There was a clear progress on the use of technologies. However proof of diagnostic relevance and therapeutic efficacy remains still limited. Reforming health care processes and focussing more on patient needs are required. Health-enabling and ambient assistive technologies remain an important field for future health care and for interdisciplinary research. More and more publications assume that a person's home and their interaction therein, are becoming important components in health care provision, assessment, and management.

Health-Enabling and Ambient Assistive Technologies: Past, Present, Future

PubMed Central

2016-01-01

Summary Background During the last decades, health-enabling and ambient assistive technologies became of considerable relevance for new informatics-based forms of diagnosis, prevention, and therapy. Objectives To describe the state of the art of health-enabling and ambient assistive technologies in 1992 and today, and its evolution over the last 25 years as well as to project where the field is expected to be in the next 25 years. In the context of this review, we define health-enabling and ambient assistive technologies as ambiently used sensor-based information and communication technologies, aiming at contributing to a person’s health and health care as well as to her or his quality of life. Methods Systematic review of all original articles with research focus in all volumes of the IMIA Yearbook of Medical Informatics. Surveying authors independently on key projects and visions as well as on their lessons learned in the context of health-enabling and ambient assistive technologies and summarizing their answers. Surveying authors independently on their expectations for the future and summarizing their answers. Results IMIA Yearbook papers containing statements on health-enabling and ambient assistive technologies appear first in 2002. These papers form a minor part of published research articles in medical informatics. However, during recent years the number of articles published has increased significantly. Key projects were identified. There was a clear progress on the use of technologies. However proof of diagnostic relevance and therapeutic efficacy remains still limited. Reforming health care processes and focussing more on patient needs are required. Conclusions Health-enabling and ambient assistive technologies remain an important field for future health care and for interdisciplinary research. More and more publications assume that a person‘s home and their interaction therein, are becoming important components in health care provision, assessment, and management. PMID:27362588

Short communication: Identification of subclinical cow mastitis pathogens in milk by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

PubMed

Barreiro, J R; Ferreira, C R; Sanvido, G B; Kostrzewa, M; Maier, T; Wegemann, B; Böttcher, V; Eberlin, M N; dos Santos, M V

2010-12-01

Subclinical mastitis is a common and easily disseminated disease in dairy herds. Its routine diagnosis via bacterial culture and biochemical identification is a difficult and time-consuming process. In this work, we show that matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) allows bacterial identification with high confidence and speed (1 d for bacterial growth and analysis). With the use of MALDI-TOF MS, 33 bacterial culture isolates from milk of different dairy cows from several farms were analyzed, and the results were compared with those obtained by classical biochemical methods. This proof-of-concept case demonstrates the reliability of MALDI-TOF MS bacterial identification, and its increased selectivity as illustrated by the additional identification of coagulase-negative Staphylococcus species and mixed bacterial cultures. Matrix-assisted laser desorption-ionization mass spectrometry considerably accelerates the diagnosis of mastitis pathogens, especially in cases of subclinical mastitis. More immediate and efficient animal management strategies for mastitis and milk quality control in the dairy industry can therefore be applied. Copyright © 2010 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

The multimedia computer for office-based patient education: a systematic review.

PubMed

Wofford, James L; Smith, Edward D; Miller, David P

2005-11-01

Use of the multimedia computer for education is widespread in schools and businesses, and yet computer-assisted patient education is rare. In order to explore the potential use of computer-assisted patient education in the office setting, we performed a systematic review of randomized controlled trials (search date April 2004 using MEDLINE and Cochrane databases). Of the 26 trials identified, outcome measures included clinical indicators (12/26, 46.1%), knowledge retention (12/26, 46.1%), health attitudes (15/26, 57.7%), level of shared decision-making (5/26, 19.2%), health services utilization (4/26, 17.6%), and costs (5/26, 19.2%), respectively. Four trials targeted patients with breast cancer, but the clinical issues were otherwise diverse. Reporting of the testing of randomization (76.9%) and appropriate analysis of main effect variables (70.6%) were more common than reporting of a reliable randomization process (35.3%), blinding of outcomes assessment (17.6%), or sample size definition (29.4%). We concluded that the potential for improving the efficiency of the office through computer-assisted patient education has been demonstrated, but better proof of the impact on clinical outcomes is warranted before this strategy is accepted in the office setting.

Future-proofing the psychiatry workforce in Australia: evaluation of an innovative enrichment programme for medical students.

PubMed

Lyons, Zaza; Hans, Davinder; Janca, Aleksandar

2015-10-01

The Claassen Institute of Psychiatry for Medical Students (the Institute) is an innovative enrichment programme aimed at attracting medical students to psychiatry. This paper reports on the effectiveness of the Institute as a strategy to increase interest in psychiatry as a career, and the career pathways of students who have attended since 2008. Students completed a baseline questionnaire on day 1 and the final day of the Institute. A follow-up survey was administered electronically to ex-Institute students to determine their career pathways and current level of interest in psychiatry. Since 2008, 117 students have attended the Institute. There was a significant increase in those 'definitely' considering a career in psychiatry from 57% at baseline to 77% at the end of the week. Eighty-nine ex-Institute students were invited to participate in the follow-up survey, and of these 21% were currently psychiatry trainees. The Institute has been successful in encouraging medical students to pursue a career in psychiatry. Enrichment programmes are emerging as an effective recruitment strategy and will assist in future-proofing the psychiatric workforce in decades to come. © The Royal Australian and New Zealand College of Psychiatrists 2015.

BaffleText: a Human Interactive Proof

NASA Astrophysics Data System (ADS)

Chew, Monica; Baird, Henry S.

2003-01-01

Internet services designed for human use are being abused by programs. We present a defense against such attacks in the form of a CAPTCHA (Completely Automatic Public Turing test to tell Computers and Humans Apart) that exploits the difference in ability between humans and machines in reading images of text. CAPTCHAs are a special case of 'human interactive proofs,' a broad class of security protocols that allow people to identify themselves over networks as members of given groups. We point out vulnerabilities of reading-based CAPTCHAs to dictionary and computer-vision attacks. We also draw on the literature on the psychophysics of human reading, which suggests fresh defenses available to CAPTCHAs. Motivated by these considerations, we propose BaffleText, a CAPTCHA which uses non-English pronounceable words to defend against dictionary attacks, and Gestalt-motivated image-masking degradations to defend against image restoration attacks. Experiments on human subjects confirm the human legibility and user acceptance of BaffleText images. We have found an image-complexity measure that correlates well with user acceptance and assists in engineering the generation of challenges to fit the ability gap. Recent computer-vision attacks, run independently by Mori and Jitendra, suggest that BaffleText is stronger than two existing CAPTCHAs.

Claims Protection in Construction Contracting.

DTIC Science & Technology

1982-01-01

cotifAca 4’O or P04F oa &ACKPI&LOO QP/W SWiO GAIY. ADo 94Y1A16 ovat rRecos vor s.4, 0, W coq~mct. AIITU AWA -MVA4 A 3~ ~ ~ ~ puvR 17ear Cvtow AiD MftR 7W A/W...sequence (from the schedule) 4. Trends in project correspondence (look for the.3 start of a "paper record"). 42 sLou *- Wih I ons90;9 1 -;111. L With 15mm...competence is a risk that must be shared by each party, as they each have their own set of managers. It is an ongoing challenge for each organization to

Evaluation of Chloropentafluorobenzene in a Battery of in vitro Short Term Assays

DTIC Science & Technology

1986-01-01

metabolic activation. The CHO/HGPRT assay measures the ability of a test agent to induce forward mutations at the enzyme hypoxanthine-guanine...phosphoribosyl transferase (HGPRT) locus of Chinese hamster ovary cells on the basis- that presumptive mutants defective in the enzyme HGPRT are unable to...10 0 4.) $4 coc H4 0 o uE p- ’-’ coQ i u ,q10 t GD 4- r ) c41 uH 0 0 41GD c t Ia) U, 40 r. 4 coV P-1- 41 E-4 0 .Z ~-H 1 0) N Cu I0 m : L0 0 z4v- +10

Preservice Teacher Beliefs about Proofs.

ERIC Educational Resources Information Center

Mingus, Tabitha T. Y.; Grassl, Richard M.

1999-01-01

Describes the study of backgrounds, beliefs, and attitudes of teachers (n=51) about proofs. Explores four issues: (1) preservice teachers' experiences/exposure to proof; (2) their beliefs about what constitutes proof; (3) the role of proof in mathematics; and (4) their beliefs about when proof should be introduced in K-12 math classes. Discusses…

Integrating Algebra and Proof in High School: Students' Work with Multiple Variables and a Single Parameter in a Proof Context

ERIC Educational Resources Information Center

Martinez, Mara V.; Castro Superfine, Alison

2012-01-01

In the United States, researchers argue that proof is largely concentrated in the domain of high school geometry, thus providing students a distorted image of what proof entails, which is at odds with the central role that proof plays in mathematics. Despite the centrality of proof, there is a lack of studies addressing how to integrate proof into…

Evaluation of the concept of pressure proof testing fuselage structures

NASA Technical Reports Server (NTRS)

Harris, Charles E.; Orringer, Oscar

1991-01-01

The FAA and NASA have recently completed independent technical evaluations of the concept of pressure proof testing the fuselage of commercial transport airplanes. The results of these evaluations are summarized. The objectives of the evaluations were to establish the potential benefit of the pressure proof test, to quantify the most desirable proof test pressure, and to quantify the required proof test interval. The focus of the evaluations was on multiple-site cracks extending from adjacent rivet holes of a typical fuselage longitudinal lap splice joint. The FAA and NASA do not support pressure proof testing the fuselage of aging commercial transport aircraft. The argument against proof testing is as follows: (1) a single proof test does not insure an indefinite life; therefore, the proof test must be repeated at regular intervals; (2) for a proof factor of 1.33, the required proof test interval must be below 300 flights to account for uncertainties in the evaluation; (3) conducting the proof test at a proof factor of 1.5 would considerably exceed the fuselage design limit load; therefore, it is not consistent with accepted safe practices; and (4) better safety can be assured by implementing enhanced nondestructive inspection requirements, and adequate reliability can be achieved by an inspection interval several times longer than the proof test interval.

The impact of OSHA regulations on nursing care cost and compliance.

PubMed

Raltz, S; Kozarek, R A; Kim-Deobald, J; Pethigal, P; Moorhouse, M A

1994-01-01

The Occupational Safety and Health Administration (OSHA) requires health care facilities to protect employees from bloodborne pathogens. One of the mandates is to provide personal protective equipment (PPE) to employees at no cost to the employee. In this article, the authors explore the cost and compliance of implementing the new OSHA regulations for nursing staff assisting with colonoscopies over a 6-month period. The data were collected on a total of 461 procedures. The cost of implementing PPE for the nursing staff was $2.98 per procedure. The PPE available for the nursing staff included goggles, splash-proof gown, face mask, shoe covers, and latex gloves. The total cost of implementing the new regulations for the nursing staff assisting with colonoscopies was $2,747.56 and was projected to cost approximately $50,000 yearly if implemented for all GI procedures in the institution. Staff compliance rates for the five pieces of PPE ranged from 6.5 to 97.8%.

Characteristics of 32 supercentenarians.

PubMed

Schoenhofen, Emily A; Wyszynski, Diego F; Andersen, Stacy; Pennington, Jaemi; Young, Robert; Terry, Dellara F; Perls, Thomas T

2006-08-01

To report phenotypic characteristics of 32 age-validated supercentenarians. Case series. U.S.-based recruitment effort. Thirty-two supercentenarians. Multiple forms of proof were used to validate age claims. Sociodemographic, activities of daily living, and medical history data were collected. Age range was 110 to 119. Fifty-nine percent had Barthel Index scores in the partially to totally dependent range, whereas 41% required minimal assistance or were independent. Few subjects had a history of clinically evident vascular-related diseases, including myocardial infarction (n=2, 6%) and stroke (n=4, 13%). Twenty-two percent (n=7) were taking medications for hypertension. Twenty-five percent (n=8) had a history of cancer (all cured). Diabetes mellitus (n=1, 3%) and Parkinson's disease (n=1, 3%) were rare. Osteoporosis (n=14, 44%) and cataract history (n=28, 88%) were common. Data collected thus far suggest that supercentenarians markedly delay and even escape clinical expression of vascular disease toward the end of their exceptionally long lives. A surprisingly substantial proportion of these individuals were still functionally independent or required minimal assistance.

A survey of noninteractive zero knowledge proof system and its applications.

PubMed

Wu, Huixin; Wang, Feng

2014-01-01

Zero knowledge proof system which has received extensive attention since it was proposed is an important branch of cryptography and computational complexity theory. Thereinto, noninteractive zero knowledge proof system contains only one message sent by the prover to the verifier. It is widely used in the construction of various types of cryptographic protocols and cryptographic algorithms because of its good privacy, authentication, and lower interactive complexity. This paper reviews and analyzes the basic principles of noninteractive zero knowledge proof system, and summarizes the research progress achieved by noninteractive zero knowledge proof system on the following aspects: the definition and related models of noninteractive zero knowledge proof system, noninteractive zero knowledge proof system of NP problems, noninteractive statistical and perfect zero knowledge, the connection between noninteractive zero knowledge proof system, interactive zero knowledge proof system, and zap, and the specific applications of noninteractive zero knowledge proof system. This paper also points out the future research directions.

Batch Proving and Proof Scripting in PVS

NASA Technical Reports Server (NTRS)

Munoz, Cesar A.

2007-01-01

The batch execution modes of PVS are powerful, but highly technical, features of the system that are mostly accessible to expert users. This paper presents a PVS tool, called ProofLite, that extends the theorem prover interface with a batch proving utility and a proof scripting notation. ProofLite enables a semi-literate proving style where specification and proof scripts reside in the same file. The goal of ProofLite is to provide batch proving and proof scripting capabilities to regular, non-expert, users of PVS.

Elastic Properties in Tension and Shear of High Strength Nonferrous Metals and Stainless Steel - Effect of Previous Deformation and Heat Treatment

NASA Technical Reports Server (NTRS)

Mebs, R W; Mcadam, D J

1947-01-01

A resume is given of an investigation of the influence of plastic deformation and of annealing temperature on the tensile and shear elastic properties of high strength nonferrous metals and stainless steels in the form of rods and tubes. The data were obtained from earlier technical reports and notes, and from unpublished work in this investigation. There are also included data obtained from published and unpublished work performed on an independent investigation. The rod materials, namely, nickel, monel, inconel, copper, 13:2 Cr-Ni steel, and 18:8 Cr-Ni steel, were tested in tension; 18:8 Cr-Ni steel tubes were tested in shear, and nickel, monel, aluminum-monel, and Inconel tubes were tested in both tension and shear. There are first described experiments on the relationship between hysteresis and creep, as obtained with repeated cyclic stressing of annealed stainless steel specimens over a constant load range. These tests, which preceded the measurements of elastic properties, assisted in devising the loading time schedule used in such measurements. From corrected stress-set curves are derived the five proof stresses used as indices of elastic or yield strength. From corrected stress-strain curves are derived the secant modulus and its variation with stress. The relationship between the forms of the stress-set and stress-strain curves and the values of the properties derived is discussed. Curves of variation of proof stress and modulus with prior extension, as obtained with single rod specimens, consist in wavelike basic curves with superposed oscillations due to differences of rest interval and extension spacing; the effects of these differences are studied. Oscillations of proof stress and modulus are generally opposite in manner. The use of a series of tubular specimens corresponding to different amounts of prior extension of cold reduction gave curves almost devoid of oscillation since the effects of variation of rest interval and extension spacing were removed. Comparison is also obtained between the variation of the several properties, as measured in tension and in shear. The rise of proof stress with extension is studied, and the work-hardening rates of the various metals evaluated. The ratio between the tensile and shear proof stresses for the various annealed and cold-worked tubular metals is likewise calculated. The influence of annealing or tempering temperature on the proof stresses and moduli for the cold-worked metals and for air-hardened 13:2 Cr-Ni steel is investigated. An improvement of elastic strength generally is obtained, without important loss of yield strength, by annealing at suitable temperature. The variation of the proof stress and modulus of elasticity with plastic deformation or annealing temperature is explained in terms of the relative dominance of three important factors: namely, (a) internal stress, (b) lattice-expansion or work-hardening, and (c) crystal reorientation. Effective values of Poisson's ratio were computed from tensile and shear moduli obtained on tubular specimens. The variation of Poisson's ratio with plastic deformation and annealing temperature is explained in terms of the degree of anisotropy produced by changes of (a) internal stress and (b) crystal orientation.

[Remember, Avert, Prevent: Franz Ludwig Berthold Kihn--A Typology of "Euthanasia"].

PubMed

Braun, B; Frewer, A; Kornhuber, J

2015-11-01

The current debate on assisted suicide provides the occasion for calling to mind the role of Berthold Kihn as a psychiatrist under National Socialism. With a historical presentation of a typology of euthanasia, the Academic Psychiatry of Erlangen together with the Medical Ethics would like to sensitize discussions on assisted suicide by drawing attention to the start and end of Kihn's scientific career. Relevant archive material, primary and secondary literature were analyzed and evaluated. As Assistant and Senior Physician at the Psychiatric and Neurological Hospital of the University of Erlangen, Kihn lectured on "the elimination of the inferiors". As Director of the Psychiatric and Neurological Hospital of Jena University, Kihn selected psychiatric patients to be murdered under the "T4 action". Kihn participated in drafting a "Euthanasia Law". Despite his involvement in the murder of mentally ill, Kihn returned to Erlangen as a "Soviet Zone refugee", where a Denazification Court considered him a "hanger-on". Kihn was reintegrated in the academic faculty of the Friedrich-Alexander-University and headed a private clinic. On 21.01.1963, the State's Attorney Nuremberg-Fuerth dropped the criminal procedure against Kihn--officially due to a lack of proof of punishable guilt. An appropriate medical historical contextualization can represent an important condition for an adequate medical ethical debate on physician-assisted suicide and the involvement of psychiatrists. FINAL COMMENT: The analysis of Kihn's patterns of thought and argumentation can help sensitize those involved in debates on physician-assisted suicide and highlights the critical role of psychiatry as a discipline in this context. © Georg Thieme Verlag KG Stuttgart · New York.

Q10 supplementation effects on cardiac enzyme CK-MB and troponin in patients undergoing coronary artery bypass graft: a randomized, double-blinded, placebo-controlled clinical trial

PubMed Central

Moludi, Jalal; Keshavarz, Seyedali; Tabaee, Ali Sadeghpour; Safiri, Saeid; Pakzad, Reza

2016-01-01

Introduction: Coronary artery bypass surgery (CABG) is associated with ischemia-reperfusion injury and tissue damage. CoQ10 as an antioxidant has an important role and may have cardio-protective effects after myocardial dysfunction and CABG. We aimed to evaluate whether CoQ10 has a myocardial cardio protective impact on cardiac biomarkers after CABG. Methods: In this double-blind study, 80 patients with coronary artery disease (CAD) who underwent CABG surgery were divided into intervention and control groups and received Q10 supplement or placebo, respectively. The surgical characteristics of the patients in the two groups were similar. The intervention group received 150 mg of Q10 supplement per day for 7 days before the surgery. The control group received placebo capsule. After operation the inter- and intra-group blood levels of CK-MB and troponin, before and after supplementation and 12 hours after the CABG, and postoperative outcomes such as intensive care unit (ICU) stay and hospital stay were compared. Results: In this study, 40 subjects were located in each group. The participation rate was 97.5% and men and women accounted for 52.5% and 47.5% respectively. The mean age of the subjects was 58.17 ± 8.55. The two groups were not significantly different in terms of basic variables. Within-group comparison showed a significant increase in the level of troponin enzymes over time (P < 0.001) and CK-MB (P < 0.001). However, between-group comparison showed no significant difference between the two groups in terms of CK-MB (P = 0.384) and troponin (P = 0.115). In the end, no interaction was observed between the intervention and time on CK-MB (P = 0.095) and troponin (P = 0.198) variables. Conclusion: Q10 supplementation 7 days before surgery was not effective in reducing CK-MB and troponin after CABG. PMID:27069560

Functional role of coenzyme Q in the energy coupling of NADH-CoQ oxidoreductase (Complex I): stabilization of the semiquinone state with the application of inside-positive membrane potential to proteoliposomes.

PubMed

Ohnishi, Tomoko; Ohnishi, S Tsuyoshi; Shinzawa-Ito, Kyoko; Yoshikawa, Shinya

2008-01-01

Coenzyme Q10 (which is also designated as CoQ10, ubiquinone-10, UQ10, CoQ, UQ or simply as Q) plays an important role in energy metabolism. For NADH-Q oxidoreductase (complex I), Ohnishi and Salerno proposed a hypothesis that the proton pump is operated by the redox-driven conformational change of a Q-binding protein, and that the bound form of semiquinone (SQ) serves as its gate [FEBS Letters 579 (2005) 45-55]. This was based on the following experimental results: (i) EPR signals of the fast-relaxing SQ anion (designated as QNf(.-)) are observable only in the presence of the proton electrochemical potential (DeltamuH+); (ii) iron-sulfur cluster N2 and QNf(.-) are directly spin-coupled; and (iii) their center-to-center distance was calculated as 12angstroms, but QNf(.-) is only 5angstroms deeper than N2 perpendicularly to the membrane. After the priming reduction of Q to QNf(.-), the proton pump operates only in the steps between the semiquinone anion (QNf(.-)) and fully reduced quinone (QH2). Thus, by cycling twice for one NADH molecule, the pump transports 4H+ per 2e(-). This hypothesis predicts the following phenomena: (a) Coupled with the piericidin A sensitive NADH-DBQ or Q1 reductase reaction, DeltamuH+ would be established; (b) DeltamuH+ would enhance the SQ EPR signals; and (c) the dissipation of DeltamuH+ with the addition of an uncoupler would increase the rate of NADH oxidation and decrease the SQ signals. We reconstituted bovine heart complex I, which was prepared at Yoshikawa's laboratory, into proteoliposomes. Using this system, we succeeded in demonstrating that all of these phenomena actually took place. We believe that these results strongly support our hypothesis.

Effect of a mixture of iprobenfos and malathion on the development of malathion resistance in the mosquito Culex pipiens pallens Coq.

PubMed

Tao, Li-Ming; Yang, Jian-Zhong; Zhuang, Pei-Jun; Tang, Zhen-Hua

2006-01-01

A malathion-resistant (RM) strain of Culex pipiens pallens Coq was obtained by successively selecting a field population with malathion in the laboratory. The synergistic effect of iprobenfos on malathion toxicity and alpha-naphthyl acetate (alpha-NA) esterase assay revealed that malathion resistance in the RM strain was associated with increased alpha-NA esterase activity and the synergism was mainly due to the inhibition by iprobenfos of this activity. There was no difference in alpha-NA esterase activity between the larvae and female adults in the susceptible (S) strain, but the activity in the adults was 13-fold higher than in the larvae of the RM strain. To understand the effect of the application of a mixture of iprobenfos and malathion on the evolution of malathion resistance, an artificial strain (Syn) was generated by mixing the RM and S strains with 0.1 frequency of the malathion-resistant individuals. The offspring of the Syn strain were divided into two sub-strains, Rm and Rm+ibp, which were successively treated with, respectively, malathion alone and malathion + iprobenfos (1:2) at LC70. In the mixture, the fungicide iprobenfos acted as a synergist of malathion. After treatment for 10 generations, the resistance level to malathion was 317.4-fold for the Rm sub-strain, whereas for the Rm+ibp sub-strain it was only 38.9-fold, compared with the Syn strain. Similar results were obtained by measurement of alpha-NA esterase activity from both larvae and female adults. The alpha-NA esterase activities in larvae and female adults at F10 generation were 2.6- and 10.9-fold from the Rm+ibp sub-strain and 5.7- and 98.5-fold from the Rm sub-strain, respectively, compared with the Syn strain. The above results suggested that iprobenfos, although it cannot completely stop or prevent the onset of malathion resistance, could dramatically delay its evolution. Copyright 2005 Society of Chemical Industry.

Repurposing atovaquone: Targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells

PubMed Central

Fiorillo, Marco; Lamb, Rebecca; Tanowitz, Herbert B.; Mutti, Luciano; Krstic-Demonacos, Marija; Cappello, Anna Rita; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.

2016-01-01

Atovaquone is an FDA-approved anti-malarial drug, which first became clinically available in the year 2000. Currently, its main usage is for the treatment of pneumocystis pneumonia (PCP) and/or toxoplasmosis in immune-compromised patients. Atovaquone is a hydroxy-1,4-naphthoquinone analogue of ubiquinone, also known as Co-enzyme Q10 (CoQ10). It is a well-tolerated drug that does not cause myelo-suppression. Mechanistically, it is thought to act as a potent and selective OXPHOS inhibitor, by targeting the CoQ10-dependence of mitochondrial complex III. Here, we show for the first time that atovaquone also has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs). More specifically, we demonstrate that atovaquone treatment of MCF7 breast cancer cells inhibits oxygen-consumption and metabolically induces aerobic glycolysis (the Warburg effect), as well as oxidative stress. Remarkably, atovaquone potently inhibits the propagation of MCF7-derived CSCs, with an IC-50 of 1 μM, as measured using the mammosphere assay. Atovaquone also maintains this selectivity and potency in mixed populations of CSCs and non-CSCs. Importantly, these results indicate that glycolysis itself is not sufficient to maintain the proliferation of CSCs, which is instead strictly dependent on mitochondrial function. In addition to targeting the proliferation of CSCs, atovaquone also induces apoptosis in both CD44+/CD24low/− CSC and ALDH+ CSC populations, during exposure to anchorage-independent conditions for 12 hours. However, it has no effect on oxygen consumption in normal human fibroblasts and, in this cellular context, behaves as an anti-inflammatory, consistent with the fact that it is well-tolerated in patients treated for infections. Future studies in xenograft models and human clinical trials may be warranted, as the IC-50 of atovaquone's action on CSCs (1 μM) is >50 times less than its average serum concentration in humans. PMID:27136895

Determining paediatric patient thickness from a single digital radiograph-a proof of principle.

PubMed

Worrall, Mark; Vinnicombe, Sarah; Sutton, David G

2018-04-05

This work presents a proof of principle for a method of estimating the thickness of an attenuator from a single radiograph using the image, the exposure factors with which it was acquired and a priori knowledge of the characteristics of the X-ray unit and detector used for the exposure. It is intended this could be developed into a clinical tool to assist with paediatric patient dose audit, for which a measurement of patient size is required. The proof of principle used measured pixel value and effective linear attenuation coefficient to estimate the thickness of a Solid Water attenuator. The kerma at the detector was estimated using a measurement of pixel value on the image and measured detector calibrations. The initial kerma was estimated using a lookup table of measured output values. The effective linear attenuation coefficient was measured for Solid Water at varying kV p . 11 test images of known and varying thicknesses of Solid Water were acquired at 60, 70 and 81 kV p . Estimates of attenuator thickness were made using the model and the results compared to the known thickness. Estimates of attenuator thickness made using the model differed from the known thickness by 3.8 mm (3.2%) on average, with a range of 0.5-10.8 mm (0.5-9%). A proof of principle is presented for a method of estimating the thickness of an attenuator using a single radiograph of the attenuator. The method has been shown to be accurate using a Solid Water attenuator, with a maximum difference between estimated and known attenuator thickness of 10.8 mm (9%). The method shows promise as a clinical tool for estimating abdominal paediatric patient thickness for paediatric patient dose audit, and is only contingent on the type of data routinely collected by Medical Physics departments. Advances in knowledge: A computational model has been created that is capable of accurately estimating the thickness of a uniform attenuator using only the radiographic image, the exposure factors with which it was acquired and a priori knowledge of the characteristics of the X-ray unit and detector used for the exposure.

A Novel Multilayered RFID Tagged Cargo Integrity Assurance Scheme

PubMed Central

Yang, Ming Hour; Luo, Jia Ning; Lu, Shao Yong

2015-01-01

To minimize cargo theft during transport, mobile radio frequency identification (RFID) grouping proof methods are generally employed to ensure the integrity of entire cargo loads. However, conventional grouping proofs cannot simultaneously generate grouping proofs for a specific group of RFID tags. The most serious problem of these methods is that nonexistent tags are included in the grouping proofs because of the considerable amount of time it takes to scan a high number of tags. Thus, applying grouping proof methods in the current logistics industry is difficult. To solve this problem, this paper proposes a method for generating multilayered offline grouping proofs. The proposed method provides tag anonymity; moreover, resolving disputes between recipients and transporters over the integrity of cargo deliveries can be expedited by generating grouping proofs and automatically authenticating the consistency between the receipt proof and pick proof. The proposed method can also protect against replay attacks, multi-session attacks, and concurrency attacks. Finally, experimental results verify that, compared with other methods for generating grouping proofs, the proposed method can efficiently generate offline grouping proofs involving several parties in a supply chain using mobile RFID. PMID:26512673

Significant issues in proof testing: A critical appraisal

NASA Technical Reports Server (NTRS)

Chell, G. G.; Mcclung, R. C.; Russell, D. A.; Chang, K. J.; Donnelly, B.

1994-01-01

Issues which impact on the interpretation and quantification of proof test benefits are reviewed. The importance of each issue in contributing to the extra quality assurance conferred by proof testing components is discussed, particularly with respect to the application of advanced fracture mechanics concepts to enhance the flaw screening capability of a proof test analysis. Items covered include the role in proof testing of elastic-plastic fracture mechanics, ductile instability analysis, deterministic versus probabilistic analysis, single versus multiple cycle proof testing, and non-destructive examination (NDE). The effects of proof testing on subsequent service life are reviewed, particularly with regard to stress redistribution and changes in fracture behavior resulting from the overload. The importance of proof test conditions are also addressed, covering aspects related to test temperature, simulation of service environments, test media and the application of real-time NDE. The role of each issue in a proof test methodology is assessed with respect to its ability to: promote proof test practice to a state-of-the-art; aid optimization of proof test design; and increase awareness and understanding of outstanding issues.

A Survey of Noninteractive Zero Knowledge Proof System and Its Applications

PubMed Central

Wu, Huixin; Wang, Feng

2014-01-01

Zero knowledge proof system which has received extensive attention since it was proposed is an important branch of cryptography and computational complexity theory. Thereinto, noninteractive zero knowledge proof system contains only one message sent by the prover to the verifier. It is widely used in the construction of various types of cryptographic protocols and cryptographic algorithms because of its good privacy, authentication, and lower interactive complexity. This paper reviews and analyzes the basic principles of noninteractive zero knowledge proof system, and summarizes the research progress achieved by noninteractive zero knowledge proof system on the following aspects: the definition and related models of noninteractive zero knowledge proof system, noninteractive zero knowledge proof system of NP problems, noninteractive statistical and perfect zero knowledge, the connection between noninteractive zero knowledge proof system, interactive zero knowledge proof system, and zap, and the specific applications of noninteractive zero knowledge proof system. This paper also points out the future research directions. PMID:24883407

An Extended Proof-Carrying Code Framework for Security Enforcement

NASA Astrophysics Data System (ADS)

Pirzadeh, Heidar; Dubé, Danny; Hamou-Lhadj, Abdelwahab

The rapid growth of the Internet has resulted in increased attention to security to protect users from being victims of security threats. In this paper, we focus on security mechanisms that are based on Proof-Carrying Code (PCC) techniques. In a PCC system, a code producer sends a code along with its safety proof to the consumer. The consumer executes the code only if the proof is valid. Although PCC has been shown to be a useful security framework, it suffers from the sheer size of typical proofs -proofs of even small programs can be considerably large. In this paper, we propose an extended PCC framework (EPCC) in which, instead of the proof, a proof generator for the program in question is transmitted. This framework enables the execution of the proof generator and the recovery of the proof on the consumer's side in a secure manner using a newly created virtual machine called the VEP (Virtual Machine for Extended PCC).

Oriented Scintillation Spectrometer Experiment (OSSE). Revision A. Volume 1

DTIC Science & Technology

1988-05-19

SYSTEM-LEVEL ENVIRONMENTAL TESTS ................... 108 3.5.1 OPERATION REPORT, PROOF MODEL STRUCTURE TESTS.. .108 3.5.1.1 PROOF MODEL MODAL SURVEY...81 3-21 ALIGNMENT ERROR BUDGET, FOV, A4 ................ 82 3-22 ALIGNMENT ERROR BUDGET, ROTATION AXIS, A4 ...... 83 3-23 OSSE PROOF MODEL MODAL SURVEY...PROOF MODEL MODAL SURVEY .................. 112 3-27-1 OSSE PROOF MODEL STATIC LOAD TEST ............. 116 3-27-2 OSSE PROOF MODEL STATIC LOAD TEST

Incorporating haptic effects into three-dimensional virtual environments to train the hemiparetic upper extremity

PubMed Central

Adamovich, Sergei; Fluet, Gerard G.; Merians, Alma S.; Mathai, Abraham; Qiu, Qinyin

2010-01-01

Current neuroscience has identified several constructs to increase the effectiveness of upper extremity rehabilitation. One is the use of progressive, skill acquisition-oriented training. Another approach emphasizes the use of bilateral activities. Building on these principles, this paper describes the design and feasibility testing of a robotic / virtual environment system designed to train the arm of persons who have had strokes. The system provides a variety of assistance modes, scalable workspaces and hand-robot interfaces allowing persons with strokes to train multiple joints in three dimensions. The simulations utilize assistance algorithms that adjust task difficulty both online and offline in relation to subject performance. Several distinctive haptic effects have been incorporated into the simulations. An adaptive master-slave relationship between the unimpaired and impaired arm encourages active movement of the subject's hemiparetic arm during a bimanual task. Adaptive anti-gravity support and damping stabilize the arm during virtual reaching and placement tasks. An adaptive virtual spring provides assistance to complete the movement if the subject is unable to complete the task in time. Finally, haptically rendered virtual objects help to shape the movement trajectory during a virtual placement task. A proof of concept study demonstrated this system to be safe, feasible and worthy of further study. PMID:19666345

Evaluation of exercise capacity after severe stroke using robotics-assisted treadmill exercise: a proof-of-concept study.

PubMed

Stoller, O; de Bruin, E D; Schindelholz, M; Schuster, C; de Bie, R A; Hunt, K J

2013-01-01

Robotics-assisted treadmill exercise (RATE) with focus on motor recovery has become popular in early post-stroke rehabilitation but low endurance for exercise is highly prevalent in these individuals. This study aimed to develop an exercise testing method using robotics-assisted treadmill exercise to evaluate aerobic capacity after severe stroke. Constant load testing (CLT) based on body weight support (BWS) control, and incremental exercise testing (IET) based on guidance force (GF) control were implemented during RATE. Analyses focussed on step change, step response kinetics, and peak performance parameters of oxygen uptake. Three subjects with severe motor impairment 16-23 days post-stroke were included. CLT yielded reasonable step change values in oxygen uptake, whereas response kinetics of oxygen uptake showed low goodness of fit. Peak performance parameters were not obtained during IET. Exercise testing in post-stroke individuals with severe motor impairments using a BWS control strategy for CLT is deemed feasible and safe. Our approach yielded reasonable results regarding cardiovascular performance parameters. IET based on GF control does not provoke peak cardiovascular performance due to uncoordinated walking patterns. GF control needs further development to optimally demand active participation during RATE. The findings warrant further research regarding the evaluation of exercise capacity after severe stroke.

Geranyl diphosphate:4-hydroxybenzoate geranyltransferase from Lithospermum erythrorhizon. Cloning and characterization of a ket enzyme in shikonin biosynthesis.

PubMed

Yazaki, Kazufumi; Kunihisa, Miyuki; Fujisaki, Takahiro; Sato, Fumihiko

2002-02-22

Two cDNAs encoding geranyl diphosphate:4-hy- droxybenzoate 3-geranyltransferase were isolated from Lithospermum erythrorhizon by nested PCR using the conserved amino acid sequences among polyprenyl- transferases for ubiquinone biosynthesis. They were functionally expressed in yeast COQ2 disruptant and showed a strict substrate specificity for geranyl diphosphate as the prenyl donor, in contrast to ubiquinone biosynthetic enzymes, suggesting that they are involved in the biosynthesis of shikonin, a naphthoquinone secondary metabolite. Regulation of their expression by various culture conditions coincided with that of geranyltransferase activity and the secondary metabolites biosynthesized via this enzyme. This is the first established plant prenyltransferase that transfers the prenyl chain to an aromatic substrate.

Determination of the In Vitro and In Vivo Activity of Compounds Tested Against Punta Toro Virus

DTIC Science & Technology

1988-12-20

2 = C CC 0 E-3 o S- EU E 0. o- coq 0 0 a)U- c 2n t 0’ E iNn~ * 00C C~J c E 0 r CE 76 .I *ý 0’E-.-..- EUE -E Z5 0 - c ~c ZN’J"- to LO U)-C E cm :- ~U...suspended in 10 mM phosphate buffer, pH 6.5. Each compound was incubated with enzyme (50:1, compound to enzyme ) at 250 C for 1 hour. Development and Detection...including adenosine, guanosine, 2,6-diaminopurne(2’-deoxy)riboside, and 6-methoxypurine. Therefore, adenosine deaminase was chosen as the likely enzyme

Gait training assisted by multi-channel functional electrical stimulation early after stroke: study protocol for a randomized controlled trial.

PubMed

van Bloemendaal, Maijke; Bus, Sicco A; de Boer, Charlotte E; Nollet, Frans; Geurts, Alexander C H; Beelen, Anita

2016-10-01

Many stroke survivors suffer from paresis of lower limb muscles, resulting in compensatory gait patterns characterised by asymmetries in spatial and temporal parameters and reduced walking capacity. Functional electrical stimulation has been used to improve walking capacity, but evidence is mostly limited to the orthotic effects of peroneal functional electrical stimulation in the chronic phase after stroke. The aim of this study is to investigate the therapeutic effects of up to 10 weeks of multi-channel functional electrical stimulation (MFES)-assisted gait training on the restoration of spatiotemporal gait symmetry and walking capacity in subacute stroke patients. In a proof-of-principle study with a randomised controlled design, 40 adult patients with walking deficits who are admitted for inpatient rehabilitation within 31 days since the onset of stroke are randomised to either MFES-assisted gait training or conventional gait training. Gait training is delivered in 30-minute sessions each workday for up to 10 weeks. The step length symmetry ratio is the primary outcome. Blinded assessors conduct outcome assessments at baseline, every 2 weeks during the intervention period, immediately post intervention and at 3-month follow-up. This study aims to provide preliminary evidence for the feasibility and effectiveness of MFES-assisted gait rehabilitation early after stroke. Results will inform the design of a larger multi-centre trial. This trial is registered at the Netherlands Trial Register (number NTR4762 , registered 28 August 2014).

Design of a smart hemodynamic monitoring simulator.

PubMed

Kilty, Brennan G; Wright, Cameron H G; Barrett, Steven F; Calkins, Jerry M; Drzewiecki, Tadeusz M

2007-01-01

We describe the design of a medical patient status simulator developed as a proof of concept for the United States Air Force. The simulator is the precursor to a system that analyzes hemodynamic information in order to act as an intelligent assistant to a Critical Care Air Transport Team (CCATT) monitoring a critically injured casualty. The simulator displays hemodynamic information, alerts to abnormal values, offers likely diagnoses, and allows the team to review recommended therapies. The focus has been to develop a user interface and modular system architecture that allows individual modules to easily be evaluated and altered as needed. While initiated by the military, this work could also be used to aid civilian first responders.

Guidance for Efficient Small Animal Imaging Quality Control.

PubMed

Osborne, Dustin R; Kuntner, Claudia; Berr, Stuart; Stout, David

2017-08-01

Routine quality control is a critical aspect of properly maintaining high-performance small animal imaging instrumentation. A robust quality control program helps produce more reliable data both for academic purposes and as proof of system performance for contract imaging work. For preclinical imaging laboratories, the combination of costs and available resources often limits their ability to produce efficient and effective quality control programs. This work presents a series of simplified quality control procedures that are accessible to a wide range of preclinical imaging laboratories. Our intent is to provide minimum guidelines for routine quality control that can assist preclinical imaging specialists in setting up an appropriate quality control program for their facility.

IntelliTable: Inclusively-Designed Furniture with Robotic Capabilities.

PubMed

Prescott, Tony J; Conran, Sebastian; Mitchinson, Ben; Cudd, Peter

2017-01-01

IntelliTable is a new proof-of-principle assistive technology system with robotic capabilities in the form of an elegant universal cantilever table able to move around by itself, or under user control. We describe the design and current capabilities of the table and the human-centered design methodology used in its development and initial evaluation. The IntelliTable study has delivered robotic platform programmed by a smartphone that can navigate around a typical home or care environment, avoiding obstacles, and positioning itself at the user's command. It can also be configured to navigate itself to pre-ordained places positions within an environment using ceiling tracking, responsive optical guidance and object-based sonar navigation.

Interactive Concept of Operations Narrative Simulators

NASA Technical Reports Server (NTRS)

Denham, Andre R.

2017-01-01

This paper reports on an exploratory design and development project. Specifically this paper discusses the design and development of Interactive Concept of Operations Narrative Simulators (ICONS) as a means of enhancing the functionality of traditional Concept of Operations documents by leveraging the affordances provided by applications commonly used within the Interactive Fiction literary genre. Recommendations for an ICONS design and development methodology, along a detailed description of a practical proof-of-concept ICONS created using this approach are discussed. The report concludes with a discussion of how ICONS can be extended to the K-12 mathematics education domain and conclude with a discussion of how ICONS can be used to assist those involved with strategic planning at Marshall Space Flight Center.

Investigating the Teaching and Learning of Proof: First Year Results.

ERIC Educational Resources Information Center

Martin, Tami S.; McCrone, Sharon Soucy

Although proof and reasoning are seen as fundamental components of learning mathematics, research shows that many students continue to struggle with geometric proofs. In order to relate pedagogical methods to students' understanding of geometric proof, this 3-year project focuses on 2 components of student understanding of proof, namely, students'…

Multimedia Resources Designed to Support Learning from Written Proofs: An Eye-Movement Study

ERIC Educational Resources Information Center

Roy, Somali; Inglis, Matthew; Alcock, Lara

2017-01-01

This paper presents two studies of an intervention designed to help undergraduates comprehend mathematical proofs. The intervention used multimedia resources that presented proofs with audio commentary and visual animations designed to focus attention on logical relationships. In study 1, students studied an e-Proof or a standard written proof and…

On the Analysis of Indirect Proofs: Contradiction and Contraposition

ERIC Educational Resources Information Center

Jourdan, Nicolas; Yevdokimov, Oleksiy

2016-01-01

The paper explores and clarifies the similarities and differences that exist between proof by contradiction and proof by contraposition. The paper also focuses on the concept of contradiction, and a general model for this method of proof is offered. The introduction of mathematical proof in the classroom remains a formidable challenge to students…

Proof Problems with Diagrams: An Opportunity for Experiencing Proofs and Refutations

ERIC Educational Resources Information Center

Komatsu, Kotaro; Tsujiyama, Yosuke; Sakamaki, Aruta; Koike, Norio

2014-01-01

It has become gradually accepted that proof and proving are essential at all grades of mathematical learning. Among the various aspects of proof and proving, this study addresses proofs and refutations described by Lakatos, in particular a part of increasing content by deductive guessing, to introduce an authentic process into mathematics…

Accounting for Proof Test Data in a Reliability Based Design Optimization Framework

NASA Technical Reports Server (NTRS)

Ventor, Gerharad; Scotti, Stephen J.

2012-01-01

This paper investigates the use of proof (or acceptance) test data during the reliability based design optimization of structural components. It is assumed that every component will be proof tested and that the component will only enter into service if it passes the proof test. The goal is to reduce the component weight, while maintaining high reliability, by exploiting the proof test results during the design process. The proposed procedure results in the simultaneous design of the structural component and the proof test itself and provides the designer with direct control over the probability of failing the proof test. The procedure is illustrated using two analytical example problems and the results indicate that significant weight savings are possible when exploiting the proof test results during the design process.

Tree-oriented interactive processing with an application to theorem-proving, appendix E

NASA Technical Reports Server (NTRS)

Hammerslag, David; Kamin, Samuel N.; Campbell, Roy H.

1985-01-01

The concept of unstructured structure editing and ted, an editor for unstructured trees, is described. Ted is used to manipulate hierarchies of information in an unrestricted manner. The tool was implemented and applied to the problem of organizing formal proofs. As a proof management tool, it maintains the validity of a proof and its constituent lemmas independently from the methods used to validate the proof. It includes an adaptable interface which may be used to invoke theorem provers and other aids to proof construction. Using ted, a user may construct, maintain, and verify formal proofs using a variety of theorem provers, proof checkers, and formatters.

From the necessary to the possible: the genesis of the spin-statistics theorem

NASA Astrophysics Data System (ADS)

Blum, Alexander

2014-12-01

The spin-statistics theorem, which relates the intrinsic angular momentum of a single particle to the type of quantum statistics obeyed by a system of many such particles, is one of the central theorems in quantum field theory and the physics of elementary particles. It was first formulated in 1939/40 by Wolfgang Pauli and his assistant Markus Fierz. This paper discusses the developments that led up to this first formulation, starting from early attempts in the late 1920s to explain why charged matter particles obey Fermi-Dirac statistics, while photons obey Bose-Einstein statistics. It is demonstrated how several important developments paved the way from such general philosophical musings to a general (and provable) theorem, most notably the use of quantum field theory, the discovery of new elementary particles, and the generalization of the notion of spin. It is also discussed how the attempts to prove a spin-statistics connection were driven by Pauli from formal to more physical arguments, culminating in Pauli's 1940 proof. This proof was a major success for the beleaguered theory of quantum field theory and the methods Pauli employed proved essential for the renaissance of quantum field theory and the development of renormalization techniques in the late 1940s.

Quantification of Hand Motor Symptoms in Parkinson's Disease: A Proof-of-Principle Study Using Inertial and Force Sensors.

PubMed

van den Noort, Josien C; Verhagen, Rens; van Dijk, Kees J; Veltink, Peter H; Vos, Michelle C P M; de Bie, Rob M A; Bour, Lo J; Heida, Ciska T

2017-10-01

This proof-of-principle study describes the methodology and explores and demonstrates the applicability of a system, existing of miniature inertial sensors on the hand and a separate force sensor, to objectively quantify hand motor symptoms in patients with Parkinson's disease (PD) in a clinical setting (off- and on-medication condition). Four PD patients were measured in off- and on- dopaminergic medication condition. Finger tapping, rapid hand opening/closing, hand pro/supination, tremor during rest, mental task and kinetic task, and wrist rigidity movements were measured with the system (called the PowerGlove). To demonstrate applicability, various outcome parameters of measured hand motor symptoms of the patients in off- vs. on-medication condition are presented. The methodology described and results presented show applicability of the PowerGlove in a clinical research setting, to objectively quantify hand bradykinesia, tremor and rigidity in PD patients, using a single system. The PowerGlove measured a difference in off- vs. on-medication condition in all tasks in the presented patients with most of its outcome parameters. Further study into the validity and reliability of the outcome parameters is required in a larger cohort of patients, to arrive at an optimal set of parameters that can assist in clinical evaluation and decision-making.

University Undergraduate Science Students' Validation and Comprehension of Written Proof in the Context of Infinite Series

ERIC Educational Resources Information Center

Moru, Eunice Kolitsoe; Nchejane, John; Ramollo, Motlatsi; Rammea, Lisema

2017-01-01

The reported study explored undergraduate science students' validation and comprehension of written proofs, reasons given either to accept or reject mathematical procedures employed in the proofs, and the difficulties students encountered in reading the proofs. The proofs were constructed using both the Comparison and the Integral tests in the…

A Physical Proof of the Pythagorean Theorem

ERIC Educational Resources Information Center

Treeby, David

2017-01-01

What proof of the Pythagorean theorem might appeal to a physics teacher? A proof that involved the notion of mass would surely be of interest. While various proofs of the Pythagorean theorem employ the circumcenter and incenter of a right-angled triangle, we are not aware of any proof that uses the triangle's center of mass. This note details one…

Examination of Secondary School Seventh Graders' Proof Skills and Proof Schemes

ERIC Educational Resources Information Center

Sen, Ceylan; Guler, Gursel

2015-01-01

The aim of this study is to examine current proof making skills of secondary school seventh graders using proof schemes. Data of the study were collected in two phases. Initially, Proof Schemes Test, which was developed by the researchers, was administrated to 250 seventh grade students from eight secondary schools, which were chosen randomly. The…

Proofs without Words: A Visual Application of Reasoning and Proof

ERIC Educational Resources Information Center

Bell, Carol J.

2011-01-01

Reasoning and Proof is one of the Process Standards set forth in National Council of Teachers of Mathematics' (NCTM) "Principles and Standards for School Mathematics." Thus, it is important to give students opportunities to build their reasoning skills and aid their understanding of the proof process. Teaching students how to do proofs is a…

Velocity feedback control with a flywheel proof mass actuator

NASA Astrophysics Data System (ADS)

Kras, Aleksander; Gardonio, Paolo

2017-08-01

This paper presents four new proof mass actuators to be used in velocity feedback control systems for the control of vibrations of machines and flexible structures. A classical proof mass actuator is formed by a coil-magnet linear motor, with either the magnet or the armature-coil proof mass suspended on soft springs. This arrangement produces a net force effect at frequencies above the fundamental resonance frequency of the springs-proof mass system. Thus, it can be used to implement point velocity feedback loops, although the dynamic response and static deflection of the springs-proof mass system poses some stability and control performance limitations. The four proof mass actuators presented in this study include a flywheel element, which is used to augment the inertia effect of the suspended proof mass. The paper shows that the flywheel element modifies both the dynamic response and static deflection of the springs-proof mass system in such a way as the stability and control performance of velocity feedback loops using these actuators are significantly improved.

Proof test and fatigue crack growth modeling on 2024-T3 aluminum alloy

NASA Technical Reports Server (NTRS)

Newman, J. C., Jr.; Poe, C. C., Jr.; Dawicke, D. S.

1990-01-01

Pressure proof testing of aircraft fuselage structures has been suggested as a means of screening critical crack sizes and of extending their useful life. The objective of this paper is to study the proof-test concept and to model the crack-growth process on a ductile material. Simulated proof and operational fatigue life tests have been conducted on cracked panels made of 2024-T3 aluminum alloy sheet material. A fatigue crack-closure model was modified to simulate the proof test and operational fatigue cycling. Using crack-growth rate and resistance-curve data, the model was able to predict crack growth during and after the proof load. These tests and analyses indicate that the proof test increases fatigue life; but the beneficial life, after a 1.33 or 1.5 proof, was less than a few hundred cycles.

The State of Proof in Finnish and Swedish Mathematics Textbooks--Capturing Differences in Approaches to Upper-Secondary Integral Calculus

ERIC Educational Resources Information Center

Bergwall, Andreas; Hemmi, Kirsti

2017-01-01

Students' difficulties with proof, scholars' calls for proof to be a consistent part of K-12 mathematics, and the extensive use of textbooks in mathematics classrooms motivate investigations on how proof-related items are addressed in mathematics textbooks. We contribute to textbook research by focusing on opportunities to learn proof-related…

Integrating Algebra and Proof in High School Mathematics: An Exploratory Study

ERIC Educational Resources Information Center

Martinez, Mara V.; Brizuela, Barbara M.; Superfine, Alison Castro

2011-01-01

Frequently, in the US students' work with proofs is largely concentrated to the domain of high school geometry, thus providing students with a distorted image of what proof entails, which is at odds with the central role that proof plays in mathematics. Despite the centrality of proof in mathematics, there is a lack of studies addressing how to…

On Mathematicians' Proof Skimming: A Reply to Inglis and Alcock

ERIC Educational Resources Information Center

Weber, Keith; Mejia-Ramos, Juan Pablo

2013-01-01

n a recent article, Inglis and Alcock (2012) contended that their data challenge the claim that when mathematicians validate proofs, they initially skim a proof to grasp its main idea before reading individual parts of the proof more carefully. This result is based on the fact that when mathematicians read proofs in their study, on average their…

Rethinking the Discovery Function of Proof within the Context of Proofs and Refutations

ERIC Educational Resources Information Center

Komatsu, Kotaro; Tsujiyama, Yosuke; Sakamaki, Aruta

2014-01-01

Proof and proving are important components of school mathematics and have multiple functions in mathematical practice. Among these functions of proof, this paper focuses on the discovery function that refers to invention of a new statement or conjecture by reflecting on or utilizing a constructed proof. Based on two cases in which eighth and ninth…

Kinematic and neurophysiological consequences of an assisted-force-feedback brain-machine interface training: a case study.

PubMed

Silvoni, Stefano; Cavinato, Marianna; Volpato, Chiara; Cisotto, Giulia; Genna, Clara; Agostini, Michela; Turolla, Andrea; Ramos-Murguialday, Ander; Piccione, Francesco

2013-01-01

In a proof-of-principle prototypical demonstration we describe a new type of brain-machine interface (BMI) paradigm for upper limb motor-training. The proposed technique allows a fast contingent and proportionally modulated stimulation of afferent proprioceptive and motor output neural pathways using operant learning. Continuous and immediate assisted-feedback of force proportional to rolandic rhythm oscillations during actual movements was employed and illustrated with a single case experiment. One hemiplegic patient was trained for 2 weeks coupling somatosensory brain oscillations with force-field control during a robot-mediated center-out motor-task whose execution approaches movements of everyday life. The robot facilitated actual movements adding a modulated force directed to the target, thus providing a non-delayed proprioceptive feedback. Neuro-electric, kinematic, and motor-behavioral measures were recorded in pre- and post-assessments without force assistance. Patient's healthy arm was used as control since neither a placebo control was possible nor other control conditions. We observed a generalized and significant kinematic improvement in the affected arm and a spatial accuracy improvement in both arms, together with an increase and focalization of the somatosensory rhythm changes used to provide assisted-force-feedback. The interpretation of the neurophysiological and kinematic evidences reported here is strictly related to the repetition of the motor-task and the presence of the assisted-force-feedback. Results are described as systematic observations only, without firm conclusions about the effectiveness of the methodology. In this prototypical view, the design of appropriate control conditions is discussed. This study presents a novel operant-learning-based BMI-application for motor-training coupling brain oscillations and force feedback during an actual movement.

Topics in quantum cryptography, quantum error correction, and channel simulation

NASA Astrophysics Data System (ADS)

Luo, Zhicheng

In this thesis, we mainly investigate four different topics: efficiently implementable codes for quantum key expansion [51], quantum error-correcting codes based on privacy amplification [48], private classical capacity of quantum channels [44], and classical channel simulation with quantum side information [49, 50]. For the first topic, we propose an efficiently implementable quantum key expansion protocol, capable of increasing the size of a pre-shared secret key by a constant factor. Previously, the Shor-Preskill proof [64] of the security of the Bennett-Brassard 1984 (BB84) [6] quantum key distribution protocol relied on the theoretical existence of good classical error-correcting codes with the "dual-containing" property. But the explicit and efficiently decodable construction of such codes is unknown. We show that we can lift the dual-containing constraint by employing the non-dual-containing codes with excellent performance and efficient decoding algorithms. For the second topic, we propose a construction of Calderbank-Shor-Steane (CSS) [19, 68] quantum error-correcting codes, which are originally based on pairs of mutually dual-containing classical codes, by combining a classical code with a two-universal hash function. We show, using the results of Renner and Koenig [57], that the communication rates of such codes approach the hashing bound on tensor powers of Pauli channels in the limit of large block-length. For the third topic, we prove a regularized formula for the secret key assisted capacity region of a quantum channel for transmitting private classical information. This result parallels the work of Devetak on entanglement assisted quantum communication capacity. This formula provides a new family protocol, the private father protocol, under the resource inequality framework that includes the private classical communication without the assisted secret keys as a child protocol. For the fourth topic, we study and solve the problem of classical channel simulation with quantum side information at the receiver. Our main theorem has two important corollaries: rate-distortion theory with quantum side information and common randomness distillation. Simple proofs of achievability of classical multi-terminal source coding problems can be made via a unified approach using the channel simulation theorem as building blocks. The fully quantum generalization of the problem is also conjectured with outer and inner bounds on the achievable rate pairs.

Proof test methodology for composites

NASA Technical Reports Server (NTRS)

Wu, Edward M.; Bell, David K.

1992-01-01

The special requirements for proof test of composites are identified based on the underlying failure process of composites. Two proof test methods are developed to eliminate the inevitable weak fiber sites without also causing flaw clustering which weakens the post-proof-test composite. Significant reliability enhancement by these proof test methods has been experimentally demonstrated for composite strength and composite life in tension. This basic proof test methodology is relevant to the certification and acceptance of critical composite structures. It can also be applied to the manufacturing process development to achieve zero-reject for very large composite structures.

An evaluation of the pressure proof test concept for 2024-T3 aluminium alloy sheet

NASA Technical Reports Server (NTRS)

Dawicke, D. S.; Poe, C. C., Jr.; Newman, J. C.; Harris, C. E.

1991-01-01

The concept of pressure proof testing of fuselage structures with fatigue cracks to insure structural integrity was evaluated from a fracture mechanics viewpoint. A generic analytical and experimental investigation was conducted on uniaxially loaded flat panels with crack configurations and stress levels typical of longitudinal lap splice joints in commercial transport aircraft fuselages. The results revealed that the remaining fatigue life after a proof cycle was longer than that without the proof cycle because of crack growth retardation due to increased crack closure. However, based on a crack length that is slightly less than the critical value at the maximum proof stress, the minimum assured life or proof test interval must be no more than 550 pressure cycles for a 1.33 proof factor and 1530 pressure cycles for a 1.5 proof factor to prevent in-flight failures.

An evaluation of the pressure proof test concept for thin sheet 2024-T3

NASA Technical Reports Server (NTRS)

Dawicke, D. S.; Poe, C. C., Jr.; Newman, J. C., Jr.; Harris, C. E.

1990-01-01

The concept of pressure proof testing of fuselage structures with fatigue cracks to insure structural integrity was evaluated from a fracture mechanics viewpoint. A generic analytical and experimental investigation was conducted on uniaxially loaded flat panels with crack configurations and stress levels typical of longitudinal lap-splice joints in commercial transport aircraft fuselage. The results revealed that the remaining fatigue life after a proof test was longer than that without the proof test because of crack growth retardation due to increased crack closure. However, based on a crack length that is slightly less than the critical value at the maximum proof test stress, the minimum assured life or proof test interval must be no more than 550 pressure cycles for a 1.33 proof factor and 1530 pressure cycles for a 1.5 proof factor to prevent in-flight failures.

An evaluation of the pressure proof test concept for thin sheet 2024-T3

NASA Technical Reports Server (NTRS)

Dawicke, D. S.; Poe, C. C., Jr.; Newman, James C., Jr.; Harris, Charles E.

1990-01-01

The concept of pressure proof testing of fuselage structures with fatigue cracks to insure structural integrity was evaluated from a fracture mechanics viewpoint. A generic analytical and experimental investigation was conducted on uniaxially loaded flat panels with crack configurations and stress levels typical of longitudinal lap splice joints in commercial transport aircraft fuselages. The results revealed that the remaining fatigue life after a proof test was longer than that without the proof test because of crack growth retardation due to increased crack closure. However, based on a crack length that is slightly less than the critical value at the maximum proof test stress, the minimum assured life or proof test interval must be no more than 550 pressure cycles for a 1.33 proof factor and 1530 pressure cycles for a 1.5 proof factor to prevent in-flight failures.

[Understanding mistake-proofing].

PubMed

de Saint Maurice, G; Giraud, N; Ausset, S; Auroy, Y; Lenoir, B; Amalberti, R

2011-01-01

The mistake-proofing concept often refers to physical devices that prevent actors from making a wrong action. In anaesthesiology, one immediately thinks to specific design of outlets for medical gases. More generally, the principle of mistake-proofing is to avoid an error, by placing knowledge in the world rather than knowledge in the head. As it often happens in risk management, healthcare has received information transfers from the industry. Computer is changing the concept of mistake-proofing, initially based on physical design, such as aerospace and automotive industry. The mistake-proofing concept may be applied to prevention, detection, and mitigation of errors. The forcing functions are a specific part of mistake-proofing: they prevent a wrong action or they force a virtuous one. Grout proposes a little shortcut to identify mistake-proofing devices: "If it is not possible to picture it in action, it is probably not a mistake-proofing device". Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Direct target NOTES: prospective applications for next generation robotic platforms.

PubMed

Atallah, S; Hodges, A; Larach, S W

2018-05-01

A new era in surgical robotics has centered on alternative access to anatomic targets and next generation designs include flexible, single-port systems which follow circuitous rather than straight pathways. Such systems maintain a small footprint and could be utilized for specialized operations based on direct organ target natural orifice transluminal endoscopic surgery (NOTES), of which transanal total mesorectal excision (taTME) is an important derivative. During two sessions, four direct target NOTES operations were conducted on a cadaveric model using a flexible robotic system to demonstrate proof-of-concept of the application of a next generation robotic system to specific types of NOTES operations, all of which required removal of a direct target organ through natural orifice access. These four operations were (a) robotic taTME, (b) robotic transvaginal hysterectomy in conjunction with (c) robotic transvaginal salpingo-oophorectomy, and in an ex vivo model, (d) trans-cecal appendectomy. Feasibility was demonstrated in all cases using the Flex ® Robotic System with Colorectal Drive. During taTME, the platform excursion was 17 cm along a non-linear path; operative time was 57 min for the transanal portion of the dissection. Robotic transvaginal hysterectomy was successfully completed in 78 min with transvaginal extraction of the uterus, although laparoscopic assistance was required. Robotic transvaginal unilateral salpingo-oophorectomy with transvaginal extraction of the ovary and fallopian tube was performed without laparoscopic assistance in 13.5 min. In an ex vivo model, a robotic trans-cecal appendectomy was also successfully performed for the purpose of demonstrating proof-of-concept only; this was completed in 24 min. A flexible robotic system has the potential to access anatomy along circuitous paths, making it a suitable platform for direct target NOTES. The conceptual operations posed could be considered suitable for next generation robotics once the technology is optimized, and after further preclinical validation.

Cognitive Testing in People at Increased Risk of Dementia Using a Smartphone App: The iVitality Proof-of-Principle Study

PubMed Central

Wijsman, Liselotte Willemijn; Cachucho, Ricardo; Hoevenaar-Blom, Marieke Peternella; Mooijaart, Simon Pieter; Richard, Edo

2017-01-01

Background Smartphone-assisted technologies potentially provide the opportunity for large-scale, long-term, repeated monitoring of cognitive functioning at home. Objective The aim of this proof-of-principle study was to evaluate the feasibility and validity of performing cognitive tests in people at increased risk of dementia using smartphone-based technology during a 6 months follow-up period. Methods We used the smartphone-based app iVitality to evaluate five cognitive tests based on conventional neuropsychological tests (Memory-Word, Trail Making, Stroop, Reaction Time, and Letter-N-Back) in healthy adults. Feasibility was tested by studying adherence of all participants to perform smartphone-based cognitive tests. Validity was studied by assessing the correlation between conventional neuropsychological tests and smartphone-based cognitive tests and by studying the effect of repeated testing. Results We included 151 participants (mean age in years=57.3, standard deviation=5.3). Mean adherence to assigned smartphone tests during 6 months was 60% (SD 24.7). There was moderate correlation between the firstly made smartphone-based test and the conventional test for the Stroop test and the Trail Making test with Spearman ρ=.3-.5 (P<.001). Correlation increased for both tests when comparing the conventional test with the mean score of all attempts a participant had made, with the highest correlation for Stroop panel 3 (ρ=.62, P<.001). Performance on the Stroop and the Trail Making tests improved over time suggesting a learning effect, but the scores on the Letter-N-back, the Memory-Word, and the Reaction Time tests remained stable. Conclusions Repeated smartphone-assisted cognitive testing is feasible with reasonable adherence and moderate relative validity for the Stroop and the Trail Making tests compared with conventional neuropsychological tests. Smartphone-based cognitive testing seems promising for large-scale data-collection in population studies. PMID:28546139

28 CFR 79.25 - Proof of onset of leukemia at least two years after first exposure, and proof of onset of a...

Code of Federal Regulations, 2010 CFR

2010-07-01

... years after first exposure, and proof of onset of a specified compensable disease more than five years... Specified Diseases Contracted After Exposure in an Affected Area (âDownwindersâ) § 79.25 Proof of onset of leukemia at least two years after first exposure, and proof of onset of a specified compensable disease...

28 CFR 79.25 - Proof of onset of leukemia at least two years after first exposure, and proof of onset of a...

Code of Federal Regulations, 2011 CFR

2011-07-01

... years after first exposure, and proof of onset of a specified compensable disease more than five years... Specified Diseases Contracted After Exposure in an Affected Area (âDownwindersâ) § 79.25 Proof of onset of leukemia at least two years after first exposure, and proof of onset of a specified compensable disease...

28 CFR 79.25 - Proof of onset of leukemia at least two years after first exposure, and proof of onset of a...

Code of Federal Regulations, 2012 CFR

2012-07-01

... years after first exposure, and proof of onset of a specified compensable disease more than five years... Specified Diseases Contracted After Exposure in an Affected Area (âDownwindersâ) § 79.25 Proof of onset of leukemia at least two years after first exposure, and proof of onset of a specified compensable disease...

28 CFR 79.25 - Proof of onset of leukemia at least two years after first exposure, and proof of onset of a...

Code of Federal Regulations, 2014 CFR

2014-07-01

... years after first exposure, and proof of onset of a specified compensable disease more than five years... Specified Diseases Contracted After Exposure in an Affected Area (âDownwindersâ) § 79.25 Proof of onset of leukemia at least two years after first exposure, and proof of onset of a specified compensable disease...

28 CFR 79.25 - Proof of onset of leukemia at least two years after first exposure, and proof of onset of a...

Code of Federal Regulations, 2013 CFR

2013-07-01

... years after first exposure, and proof of onset of a specified compensable disease more than five years... Specified Diseases Contracted After Exposure in an Affected Area (âDownwindersâ) § 79.25 Proof of onset of leukemia at least two years after first exposure, and proof of onset of a specified compensable disease...

Comparative Analysis on the Nature of Proof to Be Taught in Geometry: The Cases of French and Japanese Lower Secondary Schools

ERIC Educational Resources Information Center

Miyakawa, Takeshi

2017-01-01

This paper reports the results of an international comparative study on the nature of proof to be taught in geometry. Proofs in French and Japanese lower secondary schools were explored by analyzing curricular documents: mathematics textbooks and national curricula. Analyses on the three aspects of proof--statement, proof, and theory--suggested by…

The Penn State Heart Assistant: A pilot study of a web-based intervention to improve self-care of heart failure patients.

PubMed

Lloyd, Tom; Buck, Harleah; Foy, Andrew; Black, Sara; Pinter, Antony; Pogash, Rosanne; Eismann, Bobby; Balaban, Eric; Chan, John; Kunselman, Allen; Smyth, Joshua; Boehmer, John

2017-05-01

The Penn State Heart Assistant, a web-based, tablet computer-accessed, secure application was developed to conduct a proof of concept test, targeting patient self-care activities of heart failure patients including daily medication adherence, weight monitoring, and aerobic activity. Patients (n = 12) used the tablet computer-accessed program for 30 days-recording their information and viewing a short educational video. Linear random coefficient models assessed the relationship between weight and time and exercise and time. Good medication adherence (66% reporting taking 75% of prescribed medications) was reported. Group compliance over 30 days for weight and exercise was 84 percent. No persistent weight gain over 30 days, and some indication of weight loss (slope of weight vs time was negative (-0.17; p value = 0.002)), as well as increased exercise (slope of exercise vs time was positive (0.08; p value = 0.04)) was observed. This study suggests that mobile technology is feasible, acceptable, and has potential for cost-effective opportunities to manage heart failure patients safely at home.

Characteristics of 32 Supercentenarians

PubMed Central

Schoenhofen, Emily A.; Wyszynski, Diego F.; Andersen, Stacy; Pennington, JaeMi; Young, Robert; Terry, Dellara F.; Perls, Thomas T.

2010-01-01

OBJECTIVES To report phenotypic characteristics of 32 age-validated supercentenarians. DESIGN Case series. SETTING U.S.-based recruitment effort. PARTICIPANTS Thirty-two supercentenarians. MEASUREMENTS Multiple forms of proof were used to validate age claims. Sociodemographic, activities of daily living, and medical history data were collected. RESULTS Age range was 110 to 119. Fifty-nine percent had Barthel Index scores in the partially to totally dependent range, whereas 41% required minimal assistance or were independent. Few subjects had a history of clinically evident vascular-related diseases, including myocardial infarction (n = 2, 6%) and stroke (n = 4, 13%). Twenty-two percent (n = 7) were taking medications for hypertension. Twenty-five percent (n = 8) had a history of cancer (all cured). Diabetes mellitus (n = 1, 3%) and Parkinson’s disease (n = 1, 3%) were rare. Osteoporosis (n = 14, 44%) and cataract history (n = 28, 88%) were common. CONCLUSION Data collected thus far suggest that supercentenarians markedly delay and even escape clinical expression of vascular disease toward the end of their exceptionally long lives. A surprisingly substantial proportion of these individuals were still functionally independent or required minimal assistance. PMID:16913991

Geospatial Optimization of Siting Large-Scale Solar Projects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Macknick, Jordan; Quinby, Ted; Caulfield, Emmet

2014-03-01

Recent policy and economic conditions have encouraged a renewed interest in developing large-scale solar projects in the U.S. Southwest. However, siting large-scale solar projects is complex. In addition to the quality of the solar resource, solar developers must take into consideration many environmental, social, and economic factors when evaluating a potential site. This report describes a proof-of-concept, Web-based Geographical Information Systems (GIS) tool that evaluates multiple user-defined criteria in an optimization algorithm to inform discussions and decisions regarding the locations of utility-scale solar projects. Existing siting recommendations for large-scale solar projects from governmental and non-governmental organizations are not consistent withmore » each other, are often not transparent in methods, and do not take into consideration the differing priorities of stakeholders. The siting assistance GIS tool we have developed improves upon the existing siting guidelines by being user-driven, transparent, interactive, capable of incorporating multiple criteria, and flexible. This work provides the foundation for a dynamic siting assistance tool that can greatly facilitate siting decisions among multiple stakeholders.« less

An integrated experimental and computational approach to material selection for sound proof thermally insulted enclosure of a power generation system

NASA Astrophysics Data System (ADS)

Waheed, R.; Tarar, W.; Saeed, H. A.

2016-08-01

Sound proof canopies for diesel power generators are fabricated with a layer of sound absorbing material applied to all the inner walls. The physical properties of the majority of commercially available sound proofing materials reveal that a material with high sound absorption coefficient has very low thermal conductivity. Consequently a good sound absorbing material is also a good heat insulator. In this research it has been found through various experiments that ordinary sound proofing materials tend to rise the inside temperature of sound proof enclosure in certain turbo engines by capturing the heat produced by engine and not allowing it to be transferred to atmosphere. The same phenomenon is studied by creating a finite element model of the sound proof enclosure and performing a steady state and transient thermal analysis. The prospects of using aluminium foam as sound proofing material has been studied and it is found that inside temperature of sound proof enclosure can be cut down to safe working temperature of power generator engine without compromise on sound proofing.

The Wording of a Proof: Hardy's Second "Elegant" Proof--The Pythagorean School's Irrationality of Square Root of 2

ERIC Educational Resources Information Center

Padula, Janice

2006-01-01

One of the most interesting and important proofs in the history of mathematics is the Pythagorean school's proof of the "irrationality" of the square root of 2. After a brief look at G. H. Hardy (1941) thoughts regarding it, two versions of the classic Pythagorean proof are examined and discussed in this article, one written by an American…

Optimal periodic proof test based on cost-effective and reliability criteria

NASA Technical Reports Server (NTRS)

Yang, J.-N.

1976-01-01

An exploratory study for the optimization of periodic proof tests for fatigue-critical structures is presented. The optimal proof load level and the optimal number of periodic proof tests are determined by minimizing the total expected (statistical average) cost, while the constraint on the allowable level of structural reliability is satisfied. The total expected cost consists of the expected cost of proof tests, the expected cost of structures destroyed by proof tests, and the expected cost of structural failure in service. It is demonstrated by numerical examples that significant cost saving and reliability improvement for fatigue-critical structures can be achieved by the application of the optimal periodic proof test. The present study is relevant to the establishment of optimal maintenance procedures for fatigue-critical structures.

Design and Application of Strategies/Tactics in Higher Order Logics

NASA Technical Reports Server (NTRS)

Archer, Myla (Editor); diVito, Ben (Editor); Munoz, Cesar (Editor)

2003-01-01

This Proceedings includes both a paper from the implementors of PVS providing guidance for PVS strategy writers and a tutorial on PVS strategy writing distilled from the experience of three PVS users who have written extensive sets of PVS user strategies. Following these are three full papers from the higher-order logic theorem proving community that discuss PVS strategies to enhance arithmetic and other interactive reasoning in PVS; implementing first-order tactics in higher-order provers; and a proposed technique for specifying small step semantics that can be used in multiple higher order logic theorem provers, with illustrations from both Coq and PVS. The Proceedings concludes with three position papers for a panel session that discuss three settings in which development of PVS strategies is worth while.

On Mathematical Proving

NASA Astrophysics Data System (ADS)

Stefaneas, Petros; Vandoulakis, Ioannis M.

2015-12-01

This paper outlines a logical representation of certain aspects of the process of mathematical proving that are important from the point of view of Artificial Intelligence. Our starting-point is the concept of proof-event or proving, introduced by Goguen, instead of the traditional concept of mathematical proof. The reason behind this choice is that in contrast to the traditional static concept of mathematical proof, proof-events are understood as processes, which enables their use in Artificial Intelligence in such contexts, in which problem-solving procedures and strategies are studied. We represent proof-events as problem-centered spatio-temporal processes by means of the language of the calculus of events, which captures adequately certain temporal aspects of proof-events (i.e. that they have history and form sequences of proof-events evolving in time). Further, we suggest a "loose" semantics for the proof-events, by means of Kolmogorov's calculus of problems. Finally, we expose the intented interpretations for our logical model from the fields of automated theorem-proving and Web-based collective proving.

Deriving Safety Cases from Automatically Constructed Proofs

NASA Technical Reports Server (NTRS)

Basir, Nurlida; Denney, Ewen; Fischer, Bernd

2009-01-01

Formal proofs provide detailed justification for the validity of claims and are widely used in formal software development methods. However, they are often complex and difficult to understand, because the formalism in which they are constructed and encoded is usually machine-oriented, and they may also be based on assumptions that are not justified. This causes concerns about the trustworthiness of using formal proofs as arguments in safety-critical applications. Here, we present an approach to develop safety cases that correspond to formal proofs found by automated theorem provers and reveal the underlying argumentation structure and top-level assumptions. We concentrate on natural deduction style proofs, which are closer to human reasoning than resolution proofs, and show how to construct the safety cases by covering the natural deduction proof tree with corresponding safety case fragments. We also abstract away logical book-keeping steps, which reduces the size of the constructed safety cases. We show how the approach can be applied to the proofs found by the Muscadet prover.

Assurance Cases for Proofs as Evidence

NASA Technical Reports Server (NTRS)

Chaki, Sagar; Gurfinkel, Arie; Wallnau, Kurt; Weinstock, Charles

2009-01-01

Proof-carrying code (PCC) provides a 'gold standard' for establishing formal and objective confidence in program behavior. However, in order to extend the benefits of PCC - and other formal certification techniques - to realistic systems, we must establish the correspondence of a mathematical proof of a program's semantics and its actual behavior. In this paper, we argue that assurance cases are an effective means of establishing such a correspondence. To this end, we present an assurance case pattern for arguing that a proof is free from various proof hazards. We also instantiate this pattern for a proof-based mechanism to provide evidence about a generic medical device software.

Plasma-assisted oxide removal from ruthenium-coated EUV optics

NASA Astrophysics Data System (ADS)

Dolgov, A.; Lee, C. J.; Bijkerk, F.; Abrikosov, A.; Krivtsun, V. M.; Lopaev, D.; Yakushev, O.; van Kampen, M.

2018-04-01

An experimental study of oxide reduction at the surface of ruthenium layers on top of multilayer mirrors and thin Ru/Si films is presented. Oxidation and reduction processes were observed under conditions close to those relevant for extreme ultraviolet lithography. The oxidized ruthenium surface was exposed to a low-temperature hydrogen plasma, similar to the plasma induced by extreme ultraviolet radiation. The experiments show that hydrogen ions are the main reducing agent. Furthermore, the addition of hydrogen radicals increases the reduction rate beyond that expected from simple flux calculations. We show that low-temperature hydrogen plasmas can be effective for reducing oxidized top surfaces. Our proof-of-concept experiments show that an in situ, EUV-generated plasma cleaning technology is feasible.

On-chip microwave signal generation based on a silicon microring modulator.

PubMed

Shao, Haifeng; Yu, Hui; Li, Xia; Li, Yan; Jiang, Jianfei; Wei, Huan; Wang, Gencheng; Dai, Tingge; Chen, Qimei; Yang, Jianyi; Jiang, Xiaoqing

2015-07-15

A photonic-assisted microwave signal generator based on a silicon microring modulator is demonstrated. The microring cavity incorporates an embedded PN junction that enables a microwave signal to modulate the lightwave circling inside. The DC component of the modulated light is trapped in the cavity, while the high-order sideband components are able to exit the cavity and then generate microwave signals at new frequencies in a photodetector. In our proof-of-concept experiment, a 10 GHz microwave signal is converted to a 20 GHz signal in the optical domain with an electrical harmonic suppression ratio of 22 dB. An analytic model is also established to explain the operation mechanism, which agrees well with the measured data.

Detection of HIT antibody dependent platelet aggregation using novel surface imprinting approach.

PubMed

Hussain, Munawar; Northoff, Hinnak; Gehring, Frank K

2016-01-15

We present a fast, robust and straightforward spin force assisted surface imprinting approach for activated platelets and demonstrate that Heparin induced thrombocytopenia (HIT) platelet aggregation can be measured by this approach. A critical and challenging step in functional assays for HIT is platelet separation from the healthy donor's platelet-rich plasma (PRP). Our approach using surface imprinted polymer (MIP) for measurements on a quartz crystal microbalance with dissipation (QCM-D) enables monitoring of platelet aggregation directly in PRP thus eliminating the challenge of platelet separation. This is the first report of platelet imprinting. We also provide proof of principle that QCM-D technology can be applied for functional measurements of HIT antibodies. Copyright © 2015 Elsevier B.V. All rights reserved.

Minimum income protection and European integration: trends and levels of minimum benefits in comparative perspective, 1990-2005.

PubMed

Nelson, Kenneth

2008-01-01

This article draws attention to the Europeanization of social policy and the development of minimum income protection in a large number of welfare democracies. The empirical analyses are based on unique institutional and comparative data on benefit levels from the Social Assistance and Minimum Income Protection Interim Dataset. There is some evidence of convergence in benefit levels among the European countries in the new millennium, but there is no clear proof of universal ambitions to fight poverty or of the existence of a single European social model. There are still welfare front-runners and those who lag behind in this regard, not only among industrial welfare democracies in general but also in Europe.

16 CFR 23.10 - Misuse of “corrosion proof,” “noncorrosive,” “corrosion resistant,” “rust proof,” “rust resistant...

Code of Federal Regulations, 2010 CFR

2010-01-01

... INDUSTRIES § 23.10 Misuse of “corrosion proof,” “noncorrosive,” “corrosion resistant,” “rust proof,” “rust...,” “rust proof,” or any other term of similar meaning to describe an industry product unless all parts of the product will be immune from rust and other forms of corrosion during the life expectancy of the...

16 CFR 23.10 - Misuse of “corrosion proof,” “noncorrosive,” “corrosion resistant,” “rust proof,” “rust resistant...

Code of Federal Regulations, 2011 CFR

2011-01-01

... INDUSTRIES § 23.10 Misuse of “corrosion proof,” “noncorrosive,” “corrosion resistant,” “rust proof,” “rust...,” “rust proof,” or any other term of similar meaning to describe an industry product unless all parts of the product will be immune from rust and other forms of corrosion during the life expectancy of the...

16 CFR 23.10 - Misuse of “corrosion proof,” “noncorrosive,” “corrosion resistant,” “rust proof,” “rust resistant...

Code of Federal Regulations, 2013 CFR

2013-01-01

... INDUSTRIES § 23.10 Misuse of “corrosion proof,” “noncorrosive,” “corrosion resistant,” “rust proof,” “rust...,” “rust proof,” or any other term of similar meaning to describe an industry product unless all parts of the product will be immune from rust and other forms of corrosion during the life expectancy of the...