Biofactors - Volume 32, issue 1-4

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