Biofactors - Volume 32, issue 1-4

Article Type: Other

Citation: BioFactors, vol. 32, no. 1-4, pp. 1-1, 2008

Article Type: Other

Citation: BioFactors, vol. 32, no. 1-4, pp. 3-3, 2008

Authors: Crane, Frederick L.

Article Type: Research Article

Abstract: In the 50 years since the identification of coenzyme Q as an electron carrier in mitochondria, it has been identified with diverse and unexpected functions in cells. Its discovery came as a result of a search for electron carriers in mitochondria following the identification of flavin and cytochromes by Warburg, Keilin, Chance and others. As a result of investigation of membrane lipids at D.E. Green's laboratory at University of Wisconsin coenzyme Q was identified as the …electron carrier between primary flavoprotein dehydrogenases and the cytochromes. Then Peter Mitchell identified the role of transmembrane proton transfer as a basis for ATP synthesis. The general distribution of coenzyme Q in all cell membranes then led to the recognition of a role as a primary antioxidant. The protonophoric function was extended to acidification of Golgi and lysosomal vericles. A further role in proton release through the plasma membrane and its relation to cell proliferation has not been fully developed. A role in generation of H_{2} 0_{2} as a messenger for hormone and cytokine action is indicated as well as prevention of apoptosis by inhibition of ceramide release. Identification of the genes and proteins required for coenzyme Q synthesis has led to a basis for defining deficiency. For 50 years Karl Folkers has led the search for deficiency and therapeutic application. The development of large scale production, better formulation for uptake, and better methods for analysis have furthered this search. The story isn't over yet. Questions remain about effects on membrane structure, breakdown and control of cellular synthesis and uptake and the basis for therapeutic action. Show more

Citation: BioFactors, vol. 32, no. 1-4, pp. 5-11, 2008

Authors: Ohnishi, Tomoko | Ohnishi, S. Tsuyoshi | Shinzawa-Ito, Kyoko | Yoshikawa, Shinya

Article Type: Research Article

Abstract: Coenzyme Q_{10} (which is also designated as CoQ_{10} , ubiquinone-10, UQ_{10} , 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 Q_{Nf}^{˙ -} ) are observable only in the presence of the proton electrochemical potential (Δμ_{H}^{+} ); (ii) iron-sulfur cluster N2 and Q_{Nf}^{˙ -} are directly spin-coupled; and (iii) their center-to-center distance was calculated as 12Å, but Q_{Nf}^{˙ -} is only 5Å deeper than N2 perpendicularly to the membrane. After the priming reduction of Q to Q_{Nf}^{˙ -} , the proton pump operates only in the steps between the semiquinone anion (Q_{Nf}^{˙ -} ) and fully reduced quinone (QH_{2} ). 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 Q_{1} reductase reaction, Δμ_{H}^{+} would be established; (b) Δμ_{H}^{+} would enhance the SQ EPR signals; and (c) the dissipation of Δμ_{H}^{+} 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. Show more

Keywords: NADH-CoQ oxidoreductase (complex I), proteoliposome, reconstitution, membrane potential, iron-sulfur cluster N2, semiquinone, EPR

Citation: BioFactors, vol. 32, no. 1-4, pp. 13-22, 2008

Authors: Mustafa, Golam | Ishikawa, Yoshinori | Kobayashi, Kazuo | Migita, Catharina T. | Tagawa, Seiichi | Yamada, Mamoru

Article Type: Research Article

Abstract: Membrane-bound glucose dehydrogenase (mGDH) is a single integral protein in the respiratory chain in Escherichia coli which oxidizes D-glucose and feeds electrons to ubiquinol oxidase via bulk ubiquinone (UQ). mGDH contains a bound UQ, CoQ_{8} , for its intramolecular electron transfer in addition to pyrroloquinoline quinone (PQQ) as a coenzyme. Pulse radiolysis analysis revealed that the bound UQ exists very close to PQQ at a distance of 11–13 Å Studies on mGDH mutants with substitutions …for amino acid residues around PQQ showed that Asp-466 and Lys-493, which are crucial for catalytic activity, interact with bound UQ. Based on these findings, we propose that the bound UQ is involved in the catalytic reaction in addition to the intramolecular electron transfer in mGDH. Show more

Keywords: Glucose dehydrogenase, pyrroloquinoline quinone, ubiquinone, intramolecular electron transfer

Citation: BioFactors, vol. 32, no. 1-4, pp. 23-29, 2008

Authors: Fato, Romana | Bergamini, Christian | Leoni, Serena | Lenaz, Giorgio

Article Type: Research Article

Abstract: Mitochondrial reactive oxygen species (ROS) are mainly produced by the respiratory chain enzymes. The sites for ROS production in mitochondrial respiratory chain are normally ascribed to the activity of Complex I and III. The presence of specific inhibitors modulates reactive oxygen species production in Complex I: inhibitors such as rotenone induce a strong ROS increase, while inhibitors such as stigmatellin prevent it. We have investigated the effect of hydrophilic quinones on Complex I ROS production in …presence of different inhibitors. Some short chain quinones are Complex I inhibitors (CoQ_{2} , idebenone and its derivatives), while CoQ_{1} , decylubiquinone~ (DB) and duroquinone (DQ) are good electron acceptors from Complex I. Our results show that the ability of short chain quinones to induce an oxidative stress depends on the site of interaction with Complex I and on their physical-chemical characteristics. We can conclude that hydrophilic quinones may enhance oxidative stress by interaction with the electron escape sites on Complex I while more hydrophobic quinones can be reduced only at the physiological quinone reducing site without reacting with molecular oxygen. Show more

Keywords: Complex I, ROS, Complex I inhibitors, short chain quinones, submitochondrial particles

Citation: BioFactors, vol. 32, no. 1-4, pp. 31-39, 2008

Authors: Imada, Isuke | Sato, Eisuke F. | Kira, Yukimi | Inoue, Masayasu

Article Type: Research Article

Abstract: 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 Q_{2} 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. Show more

Keywords: Coenzyme Q, idebenone, complex I, reactive oxygen species, lipid peroxidation, oxidative stress

Citation: BioFactors, vol. 32, no. 1-4, pp. 41-48, 2008

Authors: Mukai, Kazuo | Tokunaga, Aiko | Itoh, Shingo | Kanesaki, Yu | Ouchi, Aya | Ohara, Keishi | Nagaoka, Shin-ichi | Abe, Kouichi

Article Type: Research Article

Abstract: Detailed kinetic studies have been performed for the reaction of aroxyl (ArO•) radical with vitamin E (α-, β-, γ-, δ-tocopherol, TocH), ubiquinol-10, and related antioxidants in micellar solution, using a stopped-flow spectrophotometer. The second-order reaction rates (k_{s} ) obtained increased in the order of hydroquinone < tocol<δ-TocH<ubiquinol-0<γ-TocH∼ β-TocH<ubiquinol-10<α-TocH at pH 4 ∼ 8. The antioxidants which have lower oxidation potentials (E_{p} ) showed higher reactivities. The reaction …rates obtained in micellar solution were pH dependent because of the dissociation of OH groups in the antioxidants. For instance, by comparing the k_{s} values with the mole fraction of each molecular form of ubiquinol-10, the reaction rate k_{s1} (1.21 × 10^{5} M^{-1} s^{-1} ) for undissociated form, k_{s2} (1.04 × 10^{6} M^{-1} s^{-1} ) for monoanion and k_{s3} (0 M^{-1} s^{-1} ) for dianion, and the pK_{a1} and pK_{a2} values (11.4 and 12.7) were determined. It was found that the relative ratio of k_{s} values (100:21:20:2.9) of α-, β-, γ-, δ-tocopherols in micellar dispersion has good correlation with the relative biological activities for rat fetal resorption, rat haemolysis, and chicken muscle dystrophy. The relative antioxidant activities of α-tocopherol and ubiquinol-10 have been discussed on the basis of the products of the k_{s} values and their concentrations in serum and several tissues (heart, muscle, liver, kidney, and brain). Show more

Keywords: Free radicals, Vitamin E, ubiquinol-10, antioxidant activity, reaction rate, pH dependence, stopped-flow spectrophotometer, pK_{a}

Citation: BioFactors, vol. 32, no. 1-4, pp. 49-58, 2008

Authors: Takahashi, Takayuki | Okuno, Masaaki | Okamoto, Tadashi | Kishi, Takeo

Article Type: Research Article

Abstract: 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 CoQ_{10} 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 CoQ_{10} reductases in the sensitivities to its …inhibitors and stimulators. Especially, Zn^{2+} was the most powerful inhibitor for NADPH-CoQ reductase, but CoQ_{10} reduction by the other CoQ_{10} reductases could not be inhibited by Zn^{2+} . Furthermore, the reduction of the CoQ_{9} incorporated into HeLa cells was also inhibited by Zn^{2+} 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 CoQ_{9} 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. Show more

Keywords: Antioxidant, coenzyme Q, NADPH-CoQ reductase, rat liver, ubiquinol, zinc

Citation: BioFactors, vol. 32, no. 1-4, pp. 59-70, 2008

Authors: Bruge, Francesca | Virgili, Samantha | Cacciamani, Tiziana | Principi, Federica | Tiano, Luca | Littarru, Gian Paolo

Article Type: Research Article

Abstract: Two-electron reduction of quinones catalyzed by NAD(P)H:quinone oxidoreductase (NQO1) protects cells against oxidative stress and toxic quinones. In fact, low level of NQO1 activity is often associated with increased risk of developing different types of tumours and with toxic effects linked to environmental quinones. In a previous report we analyzed the relationship between the oxidative stress induced by UV radiation and CoQ_{10} content in Burkitt's lymphoma cell lines compared to …HL-60. The basal content of CoQ_{10} in Raji cells was slightly higher compared to HL-60. Moreover, after irradiation or ubiquinone supplementation in the medium, reduced CoQ_{10} levels were higher in Raji and Daudi cells compared to HL-60. In the present work, in order to inquire if NQO1 plays a role in the CoQ reducing capacity observed in the lymphoblastoid cell lines, we analyzed the transcription and translation products of this gene in Raji and Daudi cells, compared to cell lines possessing low and high NQO1 activity. The amount of transcripts of this gene in lymphoblastoid cells was comparable to that observed in HL-60 cells (low activity), as well as the level of two alternatively spliced mRNAs; one of which is described for the first time in this work. From the genotype analysis of polymorphisms C609T and C465T we observed that HL-60, Raji and Daudi cells were all heterozygous. Furthermore, NQO1 enzyme activity and protein synthesis in the cytosol of Raji and Daudi cells were undetectable. Therefore in Burkitt's lymphoma cell lines the NQO1 gene is not efficiently translated and this effect is not related to (C609T) polymorphism. Further studies will be necessary to find the enzyme responsible for CoQ_{10} reducing activity observed in lymphoma cell lines. On the other hand, this result suggests a careful re-evaluation of data concerning loss of NQO1 activity and polymorphisms in tumour cells. Show more

Keywords: Burkitt's lymphoma, coenzyme Q oxidoreductase, polymorphism, alternative splicing

Citation: BioFactors, vol. 32, no. 1-4, pp. 71-81, 2008

Authors: Gille, Lars | Stamberg, Werner | Gregor, Wolfgang | Jäger, Walter | Reznicek, Gottfried | Netscher, Thomas | Rosenau, Thomas | Nohl, Hans

Article Type: Research Article

Abstract: Ubichromanol-9 (UCa_{9} ), with a side chain consisting of nine isoprene units) is a reductive cyclization product of ubiquinone-10 (UQ_{10} ). It acts as a radical scavenging antioxidant and is about half as effective as α-tocopherol. Already decades ago its one-electron oxidation product, the ubichromanoxyl radical had been identified. However, nothing was known so far about the two-electron oxidation product of this antioxidant and its bioactivity. This study proves that …ubichromanol can be oxidized to a ubiquinone-like compound with a hydroxyl-substituted side chain (UQ_{10} OH), a metabolite that is naturally present in bovine liver mitochondria. The bioactivity of this ubiquinone derivative in its reduced form as substrate for mitochondrial complex III (cytochrome bc_{1} complex) was slightly below that of native ubiquinol, but significantly higher than that of reduced α-tocopheryl quinone. Since ubiquinone-like molecules (UQ_{10} OH, UQ_{10}) were identified as oxidation products of UCa_{9} during lipid peroxidation, this ubiquinone derivative could provide a possibility to combine antioxidant properties of chromanols and bioenergetic benefits of UQ_{10} . Show more

Keywords: Ubichromanol, ubichromenol, ubiquinone metabolites, antioxidant, mitochondria, cytochrome bc_{1} complex

Citation: BioFactors, vol. 32, no. 1-4, pp. 83-90, 2008

Authors: Zhang, Mei | Wakitani, Shusoh | Hayashi, Kazuhiro | Miki, Risa | Kawamukai, Makoto

Article Type: Research Article

Abstract: We have constructed coenzyme Q deficient fission yeast strains by deletion of ten different genes, all of which are absolutely required for the CoQ_{10} biosynthesis. We found that sulfide was highly accumulated in all fission yeast CoQ_{10} deficient mutants. In fission yeast sulfide is required for the synthesis of cysteine and homocysteine which are catalyzed by cysteine synthase (Cys1a) and homocysteine synthase (Met17), respectively. To better understand the relation between …sulfide metabolism and coenzyme Q, we expressed cys1a, met17 and hmt2, which encodes sulfide-quinone oxidoreductase, in CoQ_{10} deficient mutants and other mutants, and measured the level of sulfide. Although expression of cys1a and met17 lowered sulfide production in CoQ_{10} deficient mutants, hmt2 did not lower the level of sulfide, because Hmt2 requires coenzyme Q for its function. In contrast, expression of hmt2 lowered sulfide production in cys1a and met17 mutants. These and other results indicate that coenzyme Q is important for sulfide oxidation through sulfide-quinone oxidoreductase to detoxify excess sulfide in fission yeast. Show more

Keywords: Fission yeast, sulfide, sulfide-quinone oxidoreductase

Citation: BioFactors, vol. 32, no. 1-4, pp. 91-98, 2008

Authors: Bentinger, Magnus | Tekle, Michael | Brismar, Kerstin | Chojnacki, Tadeusz | Swiezewska, Ewa | Dallner, Gustav

Article Type: Research Article

Abstract: Uptake of dietary coenzyme Q (CoQ) into organs is limited but there are some exceptions such as adrenal glands and ovaries. Under deficient conditions an optimal solution could be stimulation of the endogenous synthesis. In rodent exercise, cold exposure and a few substances elevate the CoQ levels to some extent. Investigations of the nuclear receptors PPARα, RXRα and LXRα&β did not answer the question which nuclear receptor regulates CoQ biosynthesis and at …present we cannot design a ligand for upregulation of the synthesis. Upon ultraviolet irradiation of CoQ a number of products are formed which influence the synthesis of the mevalonate pathway lipids. Among them epoxidated derivatives were identified. Upon chemical epoxidation of a series of polyisoprenoids it was found that none of the tested poly-cis polyisoprenols had any effect but some of the all-trans polyisoprenols stimulated CoQ synthesis and in some cases also inhibited cholesterol biosynthesis. Tocotrienol epoxides were proved to be very efficient, those having one epoxide in the side chain doubled or trebled the CoQ synthesis while those with two epoxides additionally also inhibited cholesterol synthesis by 50–90. The elevation of CoQ synthesis was elicited by increased mRNA levels for biosynthetic enzymes while the inhibition point in the cholesterol synthesis was localized to oxidosqualene cyclase. Show more

Keywords: Coenzyme Q synthesis, cholesterol, tocotrienols, polyisoprenoid epoxides

Citation: BioFactors, vol. 32, no. 1-4, pp. 99-111, 2008

Authors: Quinzii, C.M. | L´pez, L.C. | Naini, A. | DiMauro, S. | Hirano, M.

Article Type: Research Article

Abstract: Coenzyme Q_{10} (CoQ_{10} or ubiquinone) is a lipid-soluble component of virtually all cell membranes and has multiple metabolic functions. A major function of CoQ_{10} is to transport electrons from complexes I and II to complex III in the respiratory chain which resides in the mitochondrial inner membrane. Deficiencies of CoQ_{10} (MIM 607426) have been associated with four major clinical phenotypes: 1) encephalomyopathy characterized by …a triad of recurrent myoglobinuria, brain involvement, and ragged-red fibers; 2) infantile multisystemic disease typically with prominent nephropathy and encephalopathy; 3) cerebellar ataxia with marked cerebellar atrophy; and 4) pure myopathy. Primary CoQ_{10} deficiencies due to mutations in ubiquinone biosynthetic genes (COQ2, PDSS1, PDSS2, and ADCK3 [CABC1]) have been identified in patients with the infantile multisystemic and cerebellar ataxic phenotypes. In contrast, secondary CoQ_{10} deficiencies, due to mutations in genes not directly related to ubiquinone biosynthesis (APTX, ETFDH, and BRAF), have been identified in patients with cerebellar ataxia, pure myopathy, and cardiofaciocutaneous syndrome. In many patients with CoQ_{10} deficiencies, the causative molecular genetic defects remain unknown; therefore, it is likely that mutations in additional genes will be identified as causes of CoQ_{10} deficiencies. Show more

Citation: BioFactors, vol. 32, no. 1-4, pp. 113-118, 2008

Authors: Langsjoen, Peter H. | Langsjoen, Alena M.

Article Type: Research Article

Abstract: Patients with CHF, NYHA class IV, often fail to achieve adequate plasma CoQ_{10} levels on supplemental ubiquinone at dosages up to 900 mg/day. These patients often have plasma total CoQ_{10} levels of less than 2.5 μg/ml and have limited clinical improvement. It is postulated that the intestinal edema in these critically ill patients may impair CoQ_{10} absorption. We identified seven patients with advanced CHF (mean EF 22%) with sub-therapeutic …plasma CoQ_{10} levels with mean level of 1.6 μg/ml on an average dose of 450 mg of ubiquinone daily (150–600 mg/day). All seven of these patients were changed to an average of 580 mg/day of ubiquinol (450–900 mg/day) with follow-up plasma CoQ_{10} levels, clinical status, and EF measurements by echocardiography. Mean plasma CoQ_{10} levels increased from 1.6 μg/ml (0.9–2.0 μg/ml) up to 6.5 μg/ml (2.6–9.3 μg/ml). Mean EF improved from 22% (10–35%) up to 39% (10–60%) and clinical improvement has been remarkable with NYHA class improving from a mean of IV to a mean of II (I to III). Ubiquinol has dramatically improved absorption in patients with severe heart failure and the improvement in plasma CoQ_{10} levels is correlated with both clinical improvement and improvement in measurement of left ventricular function. Show more

Keywords: Class IV congestive heart failure, end stage CHF, CoQ_{10}, coenzyme Q_{10}, ubiquinone, ubiquinol, vitamin E, cholesterol

Citation: BioFactors, vol. 32, no. 1-4, pp. 119-128, 2008

Authors: Belardinelli, Romualdo | Tiano, Luca | Littarru, Gian Paolo

Article Type: Research Article

Abstract: Reactive oxygen species seem to play an important role in vascular homeostasis. In conditions of high oxidative stress, such as chronic heart failure and multiple coronary risk factors, the rate of inactivation of nitric oxide to peroxynitrite by superoxide anions may be reduced by CoQ_{10} , which can also protect against nitrosative damage. CoQ_{10} may also influence vascular function indirectly via inhibition of oxidative damage to LDL. Patients with lower levels of …extracellular superoxide dismutase (ecSOD) demonstrate greater improvements than patients with normal ec-SOD levels, suggesting that the higher the oxidative stress the greater the improvement in the endothelium-dependent relaxation after the administration of a compound with antioxidant properties like CoQ_{10} . Future studies are needed to inquire whether these effects may translate into benefits in clinical practice. Show more

Keywords: Coenzyme Q_{10}, endothelium, FMD, ecSOD

Citation: BioFactors, vol. 32, no. 1-4, pp. 129-133, 2008

Authors: Vargiu, Romina | Littarru, Gian Paolo | Faa, Gavino | Mancinelli, Rino

Article Type: Research Article

Abstract: The inability of heart muscle to generate ventricular pressure to adequately propel blood through the cardiovascular system is a primary defect associated with congestive heart failure (CHF). Force-frequency relationship (FFR) is one of the main cardiac defects associated with congestive heart failure. Thus FFR is a convenient methodological tool for evaluating the severity of muscle contractile dysfunction and the effectiveness of therapeutic agents. Papillary muscle isolated from BIO TO-2 cardiomyopathic Syrian hamsters …(CMSHs), show a depressed FFR and represents an animal model of human idiopathic dilated cardiomyopathy. In the present study we investigated the effect of CoQ_{10} , omega-3 fatty acids, propionyl-L-carnitine (PLC) and a combination of these 3 agents (formulation HS12607) on FFR in 8 month old BIO TO-2 CMSHs. Papillary muscles isolated from the anesthetized animals were placed in an incubation bath and attached to an isometric force transducer. A digital computer with an analog/digital interface allowed control of both muscle developed force and electrical stimulus parameters. Force-frequency response was evaluated, at L_{max} , with increasing frequencies: 0.06, 0.12, 0.25, 0.5, 1, 2 and 4 Hz. HS12607-treatment produced a positive inotropic effect resulting in a significant enhancement (p < 0.05) of the peak force at the highest frequencies (1–4 Hz). In the range of frequency of 1–4 Hz also CoQ_{10} and omega-3 significantly (p < 0.05) attenuated the fractional decline in developed force. The significant improvement (p < 0.05) of the timing parameter peak rate of tension rise (+ T') and peak rate of tension fall (−T') indicating a faster rate of muscle contraction and relaxation respectively, found in CoQ_{10} , omega-3 and PLC-treated CMSHs, may be due to the positive effects of these substances on sarcoplasmic reticulum functions. These findings suggest that naturally occurring CoQ_{10} , omega-3 and PLC, particularly when administered together in a coformulation, might be a valid adjuvant to conventional therapy in dilated cardiomyopathy especially when considering that they are natural substances, devoid of side effects. Show more

Keywords: BIO TO-2 Syrian hamsters, dilated cardiomyopathy, coenzyme Q_{10}, Omega-3 fatty acids, propionyl-L-carnitine, sarcolemma

Citation: BioFactors, vol. 32, no. 1-4, pp. 135-144, 2008

Authors: Adarsh, K. | Kaur, H. | Mohan, V.

Article Type: Research Article

Abstract: It is well known that by improving mitochondrial bioenergetics, Coenzyme Q_{10} improves the systolic function in heart failure. The aim of this study was to see whether it benefits the diastolic dysfunction in hypertrophic cardiomyopathy (HCM) cases since diastolic relaxation also requires energy like the systole. 200~mg/day of CoQ_{10} was added to the conventional treatment in 46 patients with HCM diagnosed clinically and by echocardiography and by excluding …cases of long standing hypertension. A comparable group of 41 age/sex matched cases received only conventional therapy. There was a significant improvement in the parameters like NYHA class ⩾ 1, in quality of life (QOL) on 6 minutes walk test, in diastolic dysfunction by ⩾ 1 parameter and in MR ⩾ 1 grade. Post treatment echocardiogram showed significant reduction in left ventricular outflow tract (LVOT) gradient ⩾ 15 mm Hg in obstructive cases (12 out of 46) in the treatment group. The mean interventricular septal thickness (IVS) showed a 22.4% reduction (p < 0.005). The mean posterior wall thickness showed a 23.1% reduction (p < 0.005). No patient in the treatment Group had ventricular tachycardia (VT) whereas 4 cases in the control group had VT. In both groups 1 patient was lost due to sudden cardiac death (SCD). Show more

Keywords: Coenzyme Q_{10}, HCM, diastolic dysfunction, energy

Citation: BioFactors, vol. 32, no. 1-4, pp. 145-149, 2008

Authors: Sachdanandam, Panchanatham

Article Type: Research Article

Abstract: Tamoxifen, a non-steroidal anti-estrogen is now widely used and has led to an increase in both disease-free and overall survival of women after primary surgery. Tamoxifen therapy is found to cause hypertriglyceridemia by reducing activity of lipolytic enzymes on triglycerides, and thereby increasing the risk of cardiovascular disease. Angiogenesis promotes local tumour progression and invasion and enables tumour cell dissemination and metastasis formation. Our study has found that co-administration of Coenzyme Q_{10} …(100 mg) along with tamoxifen (10 mg, twice a day) to breast cancer patients reduced the level of angiogenesis markers and lipid levels. Show more

Keywords: Breast cancer, Tamoxifen, Coenzyme Q_{10}, angiogenesis, hypolipidemia, tumour markers

Citation: BioFactors, vol. 32, no. 1-4, pp. 151-159, 2008

Authors: Tiano, L. | Padella, L. | Carnevali, P. | Gabrielli, O. | Bruge, F. | Principi, F. | Littarru, G.P.

Article Type: Research Article

Abstract: Down syndrome (DS) is a chromosomal abnormality (trisomy 21) associated with mental retardation and Alzheimer-like dementia, characteristic change of the individual's phenotype and premature ageing. Oxidative stress is known to play a major role in this pathology since a gene dose effect leads to elevated ratio of superoxide dismutase to catalase/glutathione peroxidase compared to controls in all age categories suggesting that oxidative imbalance contributes to the clinical manifestation of DS. Hyperuricemia is another …feature of DS that has an interesting relationship with oxidative stress since uric acid represents an important free radical scavenger. However its formation is connected to the conversion of Xanthine dehydrogenase (XDH) to Xanthine oxidase (XO) which leads to concomitant production of free radicals. Here we report that plasma samples from DS patients in pediatric age, despite an increased total antioxidant capacity, largely due to elevated Uric acid content (UA), present significantly elevated markers of oxidative damage such as increased allantoin levels. Moreover DS plasma samples do not differ from healthy control ones in terms of Coenzyme Q_{10} and susceptibility to peroxidative stimuli. On the contrary, lymphocyte and platelet CoQ_{10} content was significantly lower in DS patients, a fact that might underlie oxidative imbalance at a cellular level. Show more

Citation: BioFactors, vol. 32, no. 1-4, pp. 161-167, 2008

Authors: Li, Geng | Jack, Clifford R. | Yang, Xi-Fei | Yang, Edward S.

Article Type: Research Article

Abstract: We tested the hypotheses that supplemental intake of the diet supplement Coenzyme Q_{10} (CoQ_{10} ) could delay brain atrophy in double transgenic amyloid precursor protein (APP) / presenilin 1 (PS1), single transgenic APP and PS1 as well as wild type mice by volume MR image in vivo. One hundred and twelve mice (28 APP/PS1, 28 APP, 28 PS1 and 28 wild types) were studied. Half of each genotype group (n = 14 …per group) was treated with CoQ_{10} 2400 mg/kg/day, and the other half with placebo for 60 days. Magnetic resonance (MR) images were used to obtain the volumes of the hemispheres and hippocampi. APP / PS1, APP, PS1 and wild type mice treated with CoQ_{10} exhibited significantly less atrophy in hemisphere and hippocampus than those receiving placebo. The neuro-protective effect of the CoQ_{10} on hemispheric volume, and hippocampal volume was related to genotype; greater in APP/PS1 than APP and PS1 mice and less in wild type mice. Our result indicated that CoQ_{10} may have therapeutic potential in the prevention and treatment of MCI and AD. Show more

Keywords: APP/PS1 double transgenic mice, antioxidant, Alzheimer's disease, hippocampal volume, hemispheric volume

Citation: BioFactors, vol. 32, no. 1-4, pp. 169-178, 2008

Authors: Schmelzer, Constance | Lindner, Inka | Rimbach, Gerald | Niklowitz, Petra | Menke, Thomas | Döring, Frank

Article Type: Research Article

Abstract: Clinical studies demonstrated the efficacy of Coenzyme Q_{10} (CoQ_{10} ) as an adjuvant therapeutic in cardiovascular diseases, mitochondrial myopathies and neurodegenerative diseases. More recently, expression profiling revealed that Coenzyme Q_{10} (CoQ_{10} ) influences the expression of several hundred genes. To unravel the functional connections of these genes, we performed a text mining approach using the Genomatix BiblioSphere. We identified signalling pathways of G-protein coupled receptors, JAK/STAT, …and Integrin which contain a number of CoQ_{10} sensitive genes. Further analysis suggested that IL5, thrombin, vitronectin, vitronectin receptor, and C-reactive protein are regulated by CoQ_{10} via the transcription factor NFκB1. To test this hypothesis, we studied the effect of CoQ_{10} on the NF$\kappa$B1-dependent pro-inflammatory cytokine TNF-α. As a model, we utilized the murine macrophage cell lines RAW264.7 transfected with human apolipoprotein E3 (apoE3, control) or pro-inflammatory apoE4. In the presence of 2.5 μM or 75 μM CoQ_{10} the LPS-induced TNF-α response was significantly reduced to 73.3 ± 2.8% and 74.7 ± 8.9% in apoE3 or apoE4 cells, respectively. Therefore, the in silico analysis as well as the cell culture experiments suggested that CoQ_{10} exerts anti-inflammatory properties via NFκB1-dependent gene expression. Show more

Keywords: Coenzyme Q_{10}, gene expression, in silico analysis, inflammation, TNF-α

Citation: BioFactors, vol. 32, no. 1-4, pp. 179-183, 2008

Authors: Teran, Enrique | Chedraui, Peter | Racines-Orbe, Marcia | Vivero, Sandra | Villena, Francisco | Duchicela, Fabian | Nacevilla, Luis | Schwager, Gino | Calle, Andres

Article Type: Research Article

Abstract: Background: Preeclampsia is a common disorder of pregnancy exhibiting abnormal plasma and placental coenzyme Q_{10} (CoQ_{10} ) levels when compared to normal pregnancies. Objective: To evaluate CoQ_{10} levels both in plasma and placenta among normal pregnant (n = 60) and preeclamptic (n = 63) primigravid women and determine the effect of high or low altitude residency. Study design: CoQ_{10} was determined using High Performance Liquid Chromatography (HPLC) technique and …group comparisons were performed. Results: Preeclamptic women living at high altitude displayed significantly lower CoQ_{10} plasma levels (0.64 ± 0.23 vs. 0.82 ± 0.46 μmol/L, p = 0.05). No differences were found in CoQ_{10} plasma levels among women living at sea level. Interestingly, plasma CoQ_{10} levels at low altitude in normal pregnancies were significantly lower than high altitude normal pregnancies. Compared to normal pregnancies, preeclamptic women displayed higher placental CoQ_{10} content, which was only significant among those living at sea level (0.120 ± 0.07 vs. 0.076 ± 0.04 ng/mg protein, p < 0.005). Normal pregnant women living at high altitude displayed higher placental CoQ_{10} content when compared to those residing at sea level (p < 0.0005). Conclusion: Women suffering from preeclampsia (high or low altitude) display high placental CoQ_{10} content, with significant low plasma CoQ_{10} levels among those residing in high altitude. More research is warranted to establish the cause-effect relationship between CoQ_{10} levels and preeclampsia. Show more

Keywords: Coenzyme Q_{10}, preeclampsia, pregnancy, placenta, altitude

Citation: BioFactors, vol. 32, no. 1-4, pp. 185-190, 2008

Authors: Haas, Dorothea | Niklowitz, Petra | Hoffmann, Georg F. | Andler, Werner | Menke, Thomas

Article Type: Research Article

Abstract: Introduction: SLOS is caused by a defect of cholesterol synthesis. HMG-CoA reductase inhibitors have been shown to improve biochemical parameters in this condition, but they have also been associated with CoQ_{10} deficiency in patients with hypercholesterolemia. The aim of this study was to analyse plasma and intracellular CoQ_{10} levels in SLOS patients and to determine the influence of HMG-CoA reductase inhibitors. Methods: Plasma concentrations of CoQ_{10} and vitamin E …were measured in 14 patients, intracellular CoQ_{10} levels were determined in platelets of 10 patients with SLOS and compared to controls. Results: Plasma CoQ_{10} and vitamin E levels were significantly lower in SLOS patients. This difference equalised after adjustment to cholesterol concentrations. Treatment with simvastatin did not influence CoQ_{10} levels and redox status. Platelet CoQ_{10} concentrations were similar between patients and controls but there were striking differences in the CoQ_{10} redox status with a decrease of oxidised CoQ_{10} . Conclusion: Decreased concentrations of plasma CoQ_{10} and vitamin E in SLOS patients are due to a diminished carrier capacity. The higher percentage of reduced CoQ_{10} in platelets points to an up-regulation of mitochondrial protection mechanisms. Further studies are needed to evaluate a possible benefit of CoQ_{10} supplementation in SLOS patients. Show more

Keywords: Smith-Lemli-Opitz syndrome, cholesterol biosynthesis, Coenzyme Q_{10}, HMG-CoA reductase inhibitors

Citation: BioFactors, vol. 32, no. 1-4, pp. 191-197, 2008

Authors: Hidaka, Takayoshi | Fujii, Kenji | Funahashi, Iwao | Fukutomi, Naoki | Hosoe, Kazunori

Article Type: Research Article

Abstract: Coenzyme Q_{10} (CoQ_{10}) is a naturally occurring component present in living cells. Its physiological function is to act as an essential cofactor for ATP production, and to perform important antioxidant activities in the body. In most countries, CoQ_{10} has been widely used as a dietary supplement for more than 20 years. Recently, the use of CoQ_{10} as a dietary supplement has grown with a corresponding increase in daily …dosage. The present review describes the safety profile of CoQ_{10} on the basis of animal and human data. The published reports concerning safety studies indicate that CoQ_{10} has low toxicity and does not induce serious adverse effects in humans. The acceptable daily intake (ADI) is 12mg/kg/day, calculated from the no-observed-adverse-effect level (NOAEL) of 1200 mg/kg/day derived from a 52-week chronic toxicity study in rats, i.e., 720 mg/day for a person weighing 60 kg. Risk assessment for CoQ_{10} based on various clinical trial data indicates that the observed safety level (OSL) for CoQ_{10} is 1200 mg/day/person. Evidence from pharmacokinetic studies suggest that exogenous CoQ_{10} does not influence the biosynthesis of endogenous CoQ_{9} /CoQ_{10} nor does it accumulate into plasma or tissues after cessation of supplementation. Overall, these data from preclinical and clinical studies indicate that CoQ_{10} is highly safe for use as a dietary supplement. Additionally, analysis of CoQ_{10} bioavailability or its pharmacokinetics provides the pertinent safety evaluation for CoQ_{10} . Show more

Keywords: Coenzyme Q_{10}, CoQ_{10}, ubiquinol, safety profile, dietary supplement, ADI, OSL, CoQ_{10} biosynthesis

Citation: BioFactors, vol. 32, no. 1-4, pp. 199-208, 2008

Authors: Nukui, Kazuki | Yamagishi, Toshihiko | Miyawaki, Hiromi | Kettawan, Aikkarach | Okamoto, Tadashi | Belardinelli, Romualdo | Tiano, Luca | Littarru, Gian Paulo | Sato, Kiyoshi

Article Type: Research Article

Abstract: Coenzyme Q_{10} (CoQ_{10} ) is known to be highly hydrophobic and, as such, insoluble in water: this leads to serious inconvenience when trying to incorporate it in food products. Its absorption is also known to be very limited. PureSorb-Q™40 (P40) (Water-soluble type CoQ_{10} powder, CoQ_{10} content 40 w/w % was developed in order to improve its use with food products and to enhance its absorption. In the …present study the absorption of this novel formulation was compared to a conventional lipid soluble CoQ_{10} by administering both products to rats and humans. Acute, single-administration studies in rats showed that P40 has a higher absorption, compared to lipid soluble CoQ_{10} , both in prandial and fasting states. Similarly, single administration in humans revealed a higher absorption level for P40, taken in the fasting state or together with meals. In the rat study, no adverse effects were observed with P40 at doses up to 2,000 mg/kg in both sexes. In a double-blind, placebo controlled, comparative study conducted on 46 healthy volunteers and randomly divided into two groups, in the group receiving 900~mg of CoQ_{10} per day, for 4 consecutive weeks, the average level at two weeks was 8.79 ± 3.34 μg/mL, similar to the corresponding level after 4 weeks (8.33 ± 4.04 μg/mL). After 2 weeks of washout, serum CoQ_{10} level decreased to 1.30 ± 0.49 μg/mL. P40 intake did not cause any significant changes in symptoms and clinical laboratory tests as assessed by physical, hematological, blood biochemical or urinalysis. Clinical examinations also did not reveal any abnormalities. The above blood (serum) CoQ_{10} level at 2 weeks after start of intake was compared with other reported values. The same dose of CoQ_{10} (900mg/day), when administered by softgel capsules yielded a plasma CoQ_{10} concentration of 3.6 μg/mL, while P40 levels were 8.79 ± 3.34 mug/mL. These levels are remarkably high for instance when compared to the corresponding levels obtained, in patients affected by Parkinson's disease, with CoQ_{10} doses up to 2,400mg/day. A clinical study was conducted using doses of 300 mg/day and 600 mg/day, in patients affected by cardiovascular disease. Also in this case there was linearity in the response with the levels obtained by administering P40 at a dose of 100 and 900 mg/day. Show more

Keywords: Coenzyme Q_{10}, PureSorb-™Q40, P40, absorption, uptake, rat, human, blood CoQ_{10} level

Citation: BioFactors, vol. 32, no. 1-4, pp. 209-219, 2008

Authors: Morré, Dorothy M. | Morré, D. James | Rehmus, Wingfield | Kern, Dale

Article Type: Research Article

Abstract: Our work has identified an aging-related ECTO-NOX activity (arNOX), a hydroquinone oxidase which is cell surface located and generates superoxide. This activity increases with increasing age beginning >30 y. Because of its cell surface location and ability to generate superoxide, the arNOX proteins may serve to propagate an aging cascade both to adjacent cells and to oxidize circulating lipoproteins as significant factors determining atherogenic risk. The generation of superoxide by arNOX proteins is inhibited …by Coenzyme Q_{10} as one basis for an anti-aging benefit of CoQ_{10} supplementation in human subjects. In a preliminary pilot study, 25 female subjects between 45 and 55 y of age were recruited at Stanford University from the Palo Alto, CA area. Informed consent was obtained. Ten of the subjects received Coenzyme Q_{10} supplementation of 180 (3 × 60 mg) per day for 28 days. Serum, saliva and perspiration levels of arNOX were determined at 7, 14 and 28 days of CoQ_{10} supplementation and compared to the initial baseline value. Activity correlated with subject age up to a maximum between age 50 and 55 years of age for saliva and perspiration as well and then declined. With all three sources, the arNOX activity extrapolated to zero at about age 30. Response to Coenzyme Q_{10} also increased with age being least between ages 45 and 50 and greatest between ages 60 and 65. With all three biofluids, arNOX activity was reduced between 25 and 30% by a 3 × 60 mg daily dose Coenzyme Q_{10} supplementation. Inhibition was the result of Coenzyme Q_{10} presence. Show more

Citation: BioFactors, vol. 32, no. 1-4, pp. 221-230, 2008

Authors: Morré, D. James | Morré, Dorothy M.

Article Type: Research Article

Abstract: arNOX is a coenzyme Q_{10} -inhibited, aging-related ECTO-NOX protein of the cell surface also present in sera. It is capable of superoxide generation measured as superoxide dismutase-inhibited reduction of ferricytochrome c and is a potential contributor to atherogenic risk. Here, we report an arNOX activity of saliva of older individuals also inhibited by coenzyme Q_{10} . The activity first appears after age 30 to a near maximum at about age 55. Those surviving beyond …age 55 usually have reduced arNOX activities. Our studies demonstrate significant (25 to 30%) reduction of arNOX levels with coenzyme Q_{10} supplementation of 60 mg (2 × 30 mg) per day for 28 days. Activity correlated with age. Response to coenzyme Q_{10} increased with age being greatest between ages 60 and 65. Saliva arNOX levels varied in a regular pattern throughout the day so it was important that samples be collected at approximately the same time each day for comparative purposes. The coenzyme Q_{10} response was reversible and within 12 h after the last intake of coenzyme Q_{10} , the salivary arNOX levels returned to base line. The findings suggest that salivary arNOX provides a convenient and non-invasive method to monitor arNOX levels in clinical coenzyme Q_{10} intervention trials with the response levels paralleling those seen with serum and cellular arNOX. Show more

Citation: BioFactors, vol. 32, no. 1-4, pp. 231-235, 2008

Authors: Inui, M. | Ooe, M. | Fujii, K. | Matsunaka, H. | Yoshida, M. | Ichihashi, M.

Article Type: Research Article

Abstract: Photodamaged skin exhibits wrinkles, pigmented spots, dryness and tumors. Solar UV radiation induces cyclobutane pyrimidine dimers (CPD) and further produces base oxidation by reactive oxygen species (ROS). ROS are thought to be a major factor to initiate the up-regulation of matrix metalloproteinases (MMPs) in keratinocytes and fibroblasts via activation of receptor proteins on the cell membrane of keratinocytes and fibroblasts, and to degrade fiber components in dermis, leading to wrinkle formation. Coenzyme Q_{10} …(CoQ_{10} ) was reported to reduce ROS production and DNA damage triggered by UVA irradiation in human keratinocytes in vitro. Further, CoQ10 was shown to reduce UVA-induced MMPs in cultured human dermal fibroblasts. We speculated that UVB radiation-induced cytokine production in keratinocytes may be inhibited by CoQ_{10} , resulting in the reduction of MMPs in fibroblasts leading to wrinkle reduction. Our in vitro studies showed that UVB-induced IL-6 production of normal human keratinocyte (NHKC) decreased in the presence of CoQ_{10} . Furthermore, MMP-1 production of fibroblasts cultured with the medium containing CoQ_{10} collected from UVB-irradiated NHKC significantly decreased during 24 h culture. In the clinical trial study, we found that the use of 1% CoQ_{10} cream for five months reduced wrinkle score grade observed by a dermatologist. Taken together, our results indicate that CoQ_{10} may inhibit the production of IL-6 which stimulate fibroblasts in dermis by paracrine manner to up-regulate MMPs production, and contribute to protecting dermal fiber components from degradation, leading to rejuvenation of wrinkled skin. Show more

Keywords: UVB, matrix metalloproteinase (MMP), keratinocyte, cytokine, wrinkle

Citation: BioFactors, vol. 32, no. 1-4, pp. 237-243, 2008

Authors: Prahl, S. | Kueper, T. | Biernoth, T. | Wöhrmann, Y. | Münster, A. | Fürstenau, M. | Schmidt, M. | Schulze, C. | Wittern, K.-P. | Wenck, H. | Muhr, G.-M. | Blatt, T.

Article Type: Research Article

Abstract: The functional loss of mitochondria represents an inherent part in modern theories trying to explain the cutaneous aging process. The present study shows significant age-dependent differences in mitochondrial function of keratinocytes isolated from skin biopsies of young and old donors. Our data let us postulate that energy metabolism shifts to a predominantly non-mitochondrial pathway and is therefore functionally anaerobic with advancing age. CoQ_{10} positively influences the age-affected cellular metabolism and …enables to combat signs of aging starting at the cellular level. As a consequence topical application of CoQ10 is beneficial for human skin as it rapidly improves mitochondrial function in skin in vivo. Show more

Keywords: CoQ_{10}, topical application, skin aging, keratinocytes, glucose, lactate, mitochondria

Citation: BioFactors, vol. 32, no. 1-4, pp. 245-255, 2008

Authors: Bompadre, Stefano | Tulipani, Sara | Romandini, Stefania | Giorgetti, Raffaele | Battino, Maurizio

Article Type: Research Article

Abstract: A novel isocratic modified column-switching HPLC method for automated quantitative analysis of Vitamin E and Coenzyme Q, in the reduced and oxidized form, is described. Many column-switching HPLC methods are found in the literature, also for determining antioxidant substances, but we developed a different system of column-switching. An empty column, 5 cm long, was connected to the switching valve, before the sample loop and the extraction column. The sample loop was connected directly after the empty …column. The inserted column, containing about 1.4 ml of the extraction eluent simulated a gradient elution, enhancing sensitivity and resolution. When switching the columns, the empty column is placed right before the extraction column and acts as a static mixer for the extraction phase and the incoming analytical phase. Samples were cleaned from interfering compounds by transfer onto a extraction-column, using a C-8 silica. Separation was performed onto an analytical column C18 3 μm, 150 mm × 4.6 mm at a flow rate of 1.0 ml/min with 20 mmol/l lithium perchlorate/perchloric acid, pH3.0 in Ethanol as analytical eluent. Detection was performed with a ESA Coulochem 5100 A model. The method was found to be suitable for automated analysis of Coenzyme Q, reduced and oxidized form, and Vitamin E in serum. Show more

Keywords: Solid-phase extraction, column-switching, HPLC-EC

Citation: BioFactors, vol. 32, no. 1-4, pp. 257-262, 2008

Authors: Ramirez-Tortosa, M. Carmen | Granados, Sergio | Ramirez-Tortosa, Cesar L. | Ochoa, Julio J. | Camacho, Pedro | García-Valdés, Luz | Battino, Maurizio | Quiles, Jose L.

Article Type: Research Article

Abstract: The effects of the administration of water soluble coenzyme Q_{10} (25 mg/kg per day) over 30 days, after 50 days feeding on a high-fat diet (3% lard + 1.3% cholesterol), were investigated in the plasma and liver mitochondria of rabbits. Results showed that this atherogenic diet enhanced lipid levels both in plasma and liver mitochondria, reduced plasma and mitochondrial concentrations of retinol and coenzyme Q_{10} , led to higher DNA damage in peripheral …blood lymphocytes and reactive oxygen species concentration in liver mitochondria. The treatment of animals with coenzyme Q_{10} reduced (to the healthy group levels) lipid concentration in liver mitochondria with no effect on plasma lipids, increased mitochondrial levels of α-tocopherol, restored mitochondrial coenzyme Q_{10} and improved α-tocopherol levels in plasma. Moreover, coenzyme Q_{10} supplementation reduced mitochondrial reactive oxygen species levels and decreased DNA damage in peripheral blood lymphocytes. The findings suggest that antioxidant therapy with coenzyme Q_{10} may be used in the treatment of liver pathologies associated to the intake of high-fat, atherogenic, diets. Show more

Keywords: Comet assay, dichlorofluorescein, DNA strand breaks, high fat diet, retinol, tocopherol, ubiquinone, vitamin A, vitamin E

Citation: BioFactors, vol. 32, no. 1-4, pp. 263-273, 2008

Article Type: Other

Citation: BioFactors, vol. 32, no. 1-4, pp. 275-275, 2008