bluuebunny/crossref_metadata_2025_split huggingface dataset:
The clinical use of HMG CoA‐reductase inhibitors and the associated depletion of coenzyme Q10. A review of animal and human publications
Authors: Langsjoen Peter H. , Langsjoen Alena M. 
Published: December 2008

AbstractThe depletion of the essential nutrient CoQ10 by the increasingly popular cholesterol lowering drugs, HMG CoA reductase inhibitors (statins), has grown from a level of concern to one of alarm. With ever higher statin potencies and dosages, and with a steadily shrinking target LDL cholesterol, the prevalence and severity of CoQ10 deficiency is increasing noticeably. An estimated 36 million Americans are now candidates for statin drug therapy. Statin‐induced CoQ10 depletion is well documented in animal and human studies with detrimental cardiac consequences in both animal models and human trials. This drug‐induced nutrient deficiency is dose related and more notable in settings of pre‐existing CoQ10 deficiency such as in the elderly and in heart failure. Statin‐induced CoQ10 deficiency is completely preventable with supplemental CoQ10 with no adverse impact on the cholesterol lowering or anti‐inflammatory properties of the statin drugs. We are currently in the midst of a congestive heart failure epidemic in the United States, the cause or causes of which are unclear. As physicians, it is our duty to be absolutely certain that we are not inadvertently doing harm to our patients by creating a wide‐spread deficiency of a nutrient critically important for normal heart function.
Statin cardiomyopathy? A potential role for Co‐Enzyme Q10 therapy for statin‐induced changes in diastolic LV performance: Description of a clinical protocol
Authors: Silver Marc A. , Langsjoen Peter H. , Szabo Szabolcs , Patil Harish , Zelinger Allan 
Published: December 2008

AbstractLipid‐lowering statins are thought to have a favorable safety profile. Statins inhibit 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase, the rate‐limiting step of mevalonate synthesis. Mevalonate is the substrate for further synthesis of cholesterol and Co Enzyme Q10(CoQ10). CoQ10 plays an important role during oxidative phosphorylation in the myocardial cell. Since myocardial diastolic function is a highly ATP dependent, we reasoned that early changes of diastolic function may be an early marker of ventricular dysfunction.Methods: Patients who are to commence on statin therapy will be enrolled in the trial. Baseline measurements of plasma CoQ10, total cholesterol, LDL, HDL, CoQ10/LDL ratio, peak E, peak A velocities, E/A ratio, deceleration time, isovolumetric relaxation time, color M‐mode propagation velocity will be performed and patients will then begin to take Oral atorvastatin (Lipitor, Parke‐Davis) 20 mg daily for three to six months. All baseline measurement will be repeated after 3 to 6 months of statin therapy. Those patients demonstrating > 1 measurement of diastolic LV function that worsened during the 3 to 6 months of statin therapy will be supplemented with CoQ10 300 mg. daily for 3 months. A followup echocardiogram and blood CoQ10 level will be measured in patients who received CoQ10 supplementation.Results: Statistical analysis will be performed using the paired t test to compare coenzyme levels and echocardiographic indices at baseline and after treatment and after supplementation.
Primary coenzyme Q10deficiency and the brain
Authors: Naini Ali , Lewis Vernice‐Jackson , Hirano Michio , Dimauro Salvatore 
Published: December 2008

AbstractOur findings in 19 new patients with cerebellar ataxia establish the existence of an ataxic syndrome due to primary CoQ10deficiency and responsive to CoQ10therapy. As all patients presented cerebellar ataxia and cerebellar atrophy, this suggests a selective vulnerability of the cerebellum to CoQ10deficiency. We investigated the regional distribution of coenzyme Q10in the brain of adult rats and in the brain of one human subject. We also evaluated the levels of coenzyme Q9(CoQ9) and CoQ10in different brain regions and in visceral tissues of rats before and after oral administration of CoQ10. Our results show that in rats, amongst the seven brain regions studied, cerebellum contains the lowest level of CoQ. However, the relative proportion of CoQ10was the same (about 30% of total CoQ) in all regions studied. The level of CoQ10is much higher in brain than in blood or visceral tissue, such as liver, heart, or kidney. Daily oral administration of CoQ10led to substantial increases of CoQ10concentrations only in blood and liver. Of the four regions of one human brain studied, cerebellum again had the lowest CoQ10yconcentration.
Friedreich's Ataxia: Disease mechanisms, antioxidant and Coenzyme Q10therapy
Authors: Cooper J. M. , Schapira A. H. V. 
Published: December 2008

AbstractMitochondria clearly play a central role in the pathogenesis of Friedreich's Ataxia. The most common genetic abnormality results in the deficiency of the protein frataxin, which is targeted to the mitochondrion. Research since this discovery has indicated that mitochondrial respiratory chain dysfunction, mitochondrial iron accumulation and oxidative damage are important components of the disease mechanism. While the role of frataxin is not known, evidence is currently pointing to a role in either mitochondrial iron handling or iron sulphur centre synthesis. These advances in our understanding of the disease mechanisms are enabling therapeutic avenues to be explored, in particular the use of established drugs such as antioxidants and enhancers of respiratory chain function. Vitamin E therapy has been shown to be beneficial in patients with ataxia with vitamin E deficiency, and CoQ10therapy was effective in some patients with ataxia associated with CoQ10deficiency. A combined therapy involving long term treatment with high doses of vitamin E and coenzyme Q10has jointly targeted two of the major features of Friedreich's Ataxia; decreased mitochondrial respiratory chain function and increased oxidative stress. This therapy clearly showed a rapid and sustained increase in the energy generated by the FRDA heart muscle, nearly returning to normal levels. The improvements in skeletal muscle energy generation parallel those of the heart but to a lower level. While this therapy appeared to slow the predicted progression of some clinical symptoms a larger placebo controlled study is required to confirm these observations. Other antioxidant strategies have involved the use of Idebenone, selenium and N acetyl cysteine but only the use of Idebenone has involved structured trials with relatively large patient numbers. Idebenone clearly had an impact upon the cardiac hypertrophy in the majority of patients, although there have not been any other significant benefits reported to date.
Hepatocyte metabolism of coenzyme Q1 (ubiquinone‐5) to its sulfate conjugate decreases its antioxidant activity
Authors: Chan Tom S. , O'Brien Peter J. 
Published: December 2008

AbstractPrevious studies on the metabolism of coenyzme Q (CoQ) have focused on products found in the urine, bile or feces. However, the metabolites found in these samples were end products from a multitude of catabolic processes which did not necessarily reflect CoQ intracellular metabolism (e.g. in the liver, the major site of CoQ synthesis or metabolism). Using isolated rat hepatocytes, we have found that the sulfation of coenzyme Q1 (CoQ1) was the initial and dominant step following its reduction to the hydroquinone. This metabolic process is important as conjugation may occur on the hydroquinone metabolites of any coenzyme10 scission product retaining the quinone ring. By using rat liver cytosol, we were able to identify the monosulfated metabolite of CoQ1. The CoQ1 sulfate conjugate was identified by mass spectrometry followed by tandem mass spectrometry. The rate of formation of the CoQ1 sulfate conjugate was markedly increased by the addition of NADH and was prevented by dicumarol, a DT‐diaphorase (NQO1) inhibitor. CoQ1 sulfate conjugate formation catalysed by cytosol was inhibited by the sulfotransferase 1A (SULT1A) inhibitor, pentachlorophenol (PCP) suggesting that sulfation was carried out by the SULT 1A isoform. CoQ1 sulfation in isolated hepatocytes and inversely CoQ1 hydroquinone formation were dependent on the concentration of inorganic sulfate in the media. Intracellular sulfation also decreased CoQ1 antioxidant and cytoprotective activity towards cumene hydroperoxide (CHP) induced cell death. Sulfotransferases may therefore play a significant role in endogenous CoQ metabolism following its degradation to short chain products.
Caenorhabditis elegans ubiquinone biosynthesis genes
Authors: Rodríguez‐Aguilera Juan C. , Asencio Claudio , Ruiz‐Ferrer Macarena , Vela Jordana , Navas Plácido 
Published: December 2008

AbstractUbiquinone (coenzyme Q, Q) is an essential lipid electron carrier in the mitochondria respiratory chain, and also functions as antioxidant and participates as a cofactor of mitochondrial uncoupling proteins. Caernorhabditis elegans synthesize Q9, but both dietary Q8intake and endogenous Q9 biosynthesis determine Q balance. Thus, it is of current interest to know the regulatory mechanisms of Q9 biosynthesis in this nematode. Here we review results that leaded to identification of genes involved in Q9 biosynthesis in this nematode using the RNA interference technology. C. elegans coq genes were silenced and depletion of Q content was observed, indicating that the genes related here participate in Q9 biosynthesis. Silenced populations showed an extension of adult life span, probably by the decrease of endogenous oxidative stress produced in mitochondria. We also report the heterologous complementation of C. elegans coq‐5 and coq‐7 genes in their homologue yeast coq null mutants, leading to restore its ability to growth in non‐fermentable sugars. These complemented yeast strains accumulated Q6 but also the intermediate demethoxy‐Q6. These findings support the conservative functional homology of these genes.
The protective and healing effects of a natural antioxidant formulation based on ubiquinol and Aloe vera against dextran sulfate‐induced ulcerative colitis in rats
Authors: Korkina Ludmila , Suprun Maxim , Petrova Anna , Mikhal'Chik Elena , Luci Antonio , Luca Chiara De 
Published: December 2008

AbstractOxygen/nitrogen reactive species (ROS/RNS) are currently implicated in the pathogenesis of ulcerative colitis, drawing attention on the potential prophylactic and healing properties of antioxidants, scavengers, chelators. We evaluated the possible protective/curative effects of a natural antioxidant preparation based on Aloe vera and ubiquinol, against intestinal inflammation, lesions, and pathological alterations of the intestinal electrophysiological activity and motility, in a rat model of DSS‐induced colitis. 5% dextrane sulfate (DDS) (3 days), followed by 1% DSS (4 days) was administered in drinking water. The antioxidant formulation (25 mg/kg) was delivered with a pre‐treatment protocol, or simultaneously or post‐colitis induction. Spontaneous and acetylcholine‐stimulated electrical activity were impaired in the small intestine and in distal colon, upon exposure to DSS only. Severe inflammation occurred, with increased myeloperoxidase activity, and significant alterations of the oxidant/antioxidant status in colonic tissue and peritoneal cells. Lipoperoxidation, superoxide production, glutathione peroxidase and glutathione‐S‐transferase activities, and reduced glutathione content increased, whilst superoxide dismutase and catalase activities were sharply suppressed in colon tissue. ROS/RNS formation in peritoneal cells was strongly inhibited. Inflammation, electrical/mechanical impairment in the gut, and a great majority of oxidative stress parameters were improved substantially by pre‐treatment with the antioxidant preparation, but not by simultaneous administration or post‐treatment.
The combined use of oral and topical lipophilic antioxidants increases their levels both in sebum and stratum corneum
Authors: Passi Siro , Pità Ornella De , Grandinetti Mauro , Simotti Cristina , Littarru Gian Paolo 
Published: December 2008

AbstractThe concentration of Vitamin E (vit E) and ubiquinone (CoQ10), which together with squalene (SQ), play a key role against external oxidative insult, has been shown to decrease significantly during ageing. The aim of the present study is to inquire the effect of the combined use of topical bio‐cosmetics containing natural active principles (including sebum‐like lipid fractions, sebum and epidermal lipophilic and hydrophilic antioxidants), and oral antioxidant supplements on the antioxidant content of sebum and stratum corneum. We therefore treated the face and the back of 50 female volunteers aged 21–40, daily for two months, with a base cream containing 0.05% ubiquinone, 0.1% vit E, and 1% squalene. In addition 50 mg of CoQ10 + 50 mg of d‐RRR‐α‐tocopheryl acetate + 50 μg of selenium were administered orally to half of the volunteers (Group A). Group B was represented by 25 volunteers who were treated only topically. Every 15 days during treatment the levels of CoQ10, vit E and SQ were verified in sebum, stratum corneum, and plasma.The daily topical application of the cream led to a significant increase, that peaked after 60 days, of the levels of CoQ10, d‐RRR‐α‐tocopherol and SQ in the sebum (Group B), without significantly affecting the stratum corneum or plasma concentrations of the redox couple CoQ10H2/CoQ10 and vit E. The concomitant oral admistration of antioxidants produced in Group A a significant increase of the levels of CoQ10H2/CoQ10 and vit E both in plasma and stratum corneum after 15 and 30 days treatment respectively, compared to Group B. However the sebum levels of lipophilic antioxidants and SQ did not show a significant increase. After the treatments, the levels of CoQ10H2/CoQ10, vit E and SQ went back to basal levels within 6–8 days in sebum, 12–16 days in the stratum corneum, and 3–6 days in plasma.Therefore topical application of the antioxidants was able to increase their level in sebum, while the concomitant oral administration also affected the levels of vit E and CoQ10 in the stratum corneum.
Effect of analogs with modified prenyl side chains on growth of serum deficient HL60 cells
Authors: Sun I. L. , Sun L. E. , Sun E. E. , Crane F. L. , Willis R. 
Published: December 2008

AbstractThis study was organized by Professor Karl Folkers with the objective of finding derivatives of coenzyme Q which could be more effectively absorbed and would give better biomedical effects. In this series all the compounds are 2,3 dimethoxy, 5 methyl p benzoquinone with modified side chains in the 6 position. The modifications are primarily changes in chain length, unsaturation, methyl groups and addition of terminal phenyl groups. The test system evaluates the growth of serum deficient HL60, 3T3 and HeLa cells in the presence of coenzyme Q10 or coenzyme Q analogs. Short chain coenzyme Q homologues such as coenzyme Q2 give poor growth but compounds with saturated short aliphatic side chains from C10 to C18 produce good growth. Introduction of a single double bond at the 2′ or 8′ position in the aliphatic chain retains growth stimulation at low concentration but introduces inhibition at higher concentration. Introduction of a 3′ methyl group in addition to the 2′ enyl site in the side chain decreases the growth response and maintains inhibition. Addition of a terminal phenyl group to the side chain from C5 to C10 can produce analogs which give strong stimulation or strong inhibition of growth. The action of the analogs is in addition to the natural coenzyme Q in the cell and is not based on restoration of activity after depletion of normal coenzyme Q. The effects may be based on any of the sites in the cell where coenzyme Q functions. For example, coenzyme Q2 is known to decrease mitochondrial membrane potential whereas the analog with a 10C aliphatic side chain increases potential. Both of these compounds stimulate plasma membrane electron transport. Inhibition of apoptosis by coenzyme Q may also increase net cell proliferation and the 10C analog inhibits the permeability transition pore.
Humic substances in drinking water and the epidemiology of thyroid disease
Authors: Laurberg Peter , Andersen Stig , Pedersen Inge BÜLow , Ovesen Lars , Knudsen Nils 
Published: December 2008

AbstractThyroid diseases are common in all populations but the type and frequency depends on environmental factors. In Denmark geographical differences in iodine intake are caused by different iodine contents of drinking water, which varies from < 1 to 139 μg iodine per litre. Comparative epidemiologic studies have demonstrated considerable differences in type and occurrence of thyroid disease with more goitre and hyperthyroidism in Aalborg with water iodine content around 5 μg/L, and more hypothyroidism in Copenhagen with water iodine around 20 μg/L. In Denmark, iodine in ground water is bound in humic substances, which have probably leached from marine sediments in the aquifers. Interestingly, humic substances in water from other parts of the world have goitrogenic properties, especially humic substances from coal and shale. Humic substances are heterogeneous mixtures of naturally occurring molecules, produced by decomposition of plant and animal tissues. The effect of humic substances in drinking water on the epidemiology of thyroid disease probably depends on the source of aquifer sediments.
Affinity of isoflavonoids for lipid bilayers evaluated with liposomal systems
Authors: Kato Ryuichi , Kajiya Katsuko , Tokumoto Hiromi , Kumazawa Shigenori , Nakayama Tsutomu 
Published: December 2008

AbstractThree parameters, i.e., the proportion of the amount incorporated into the liposomes, the partition coefficient in a system of n‐octanol/phosphate buffered saline, and the retention times by HPLC, were measured to determine the lipophilicity of isoflavonoids. The presence of a hydroxyl group at 5‐position of the A‐ring and a methoxyl group at 4′‐position of the B‐ring in the isoflavonoid structure increased the three parameters. The localization of isoflavonoids in lipid bilayers was investigated by a liposome system with fluorescent probes. The location of the isoflavonoid depended on its structure. The cytotoxicity of isoflavonoids was investigated by a colony‐formation assay with Chinese hamster lung fibroblast V79 cells. The structure‐activity relationship of the cytotoxic activity partly reflected those of the three parameters. This suggests that the biological activities of isoflavonoids in vitro could be attributable to their affinity for lipid components in the cases where the estrogen receptors have no role.
Comparison of recombinant cell bioassays for the detection of Ah receptor agonists
Authors: Han Dalho , Nagy Scott R. , Denison Michael S. 
Published: December 2008

AbstractIn this study, we have compared the time and dose response curves for TCDD using the pGudLuc1.1‐chemically activated luciferase expression (CALUX) cell bioassay and two new recombinant cell lines that contain a stably transfected mutated form of firefly luciferase reporter gene (pGudLuc6.1) or enhanced green fluorescent protein (EGFP) reporter gene (pGreen1.1). The time course of induction with pGudLuc1.1‐containing H1L1.1c2 cells is transient, with maximal activity observed at 4 hours after treatment with 1 nM TCDD. In contrast, expression of luciferase from the pGudLuc6.1‐containing H1L6.1c2 cells and the pGreen1.1‐containing H1G1.1c3 cells progressively increases with time, with luciferase activity increasing at a significant faster rate than that of EGFP. Dose response analysis with each cell line at optimal analysis times reveal similar relative dose response curves and EC50s for H1L6.1c2 and H1G1.1c3 cells, while the EC50for TCDD in the H1L1.1c2 cells was about 7‐fold lower. In addition, these bioassay systems respond to halogenated and/or polycyclic aromatic hydrocarbons in a dose‐specific manner. Given the above differences between cell lines and reporters, the choice of which cell line to use will certainly be dependent on the specific questions and issues being examined.
Distinct roles of BMP receptors Type IA and IB in osteo‐/chondrogenic differentiation in mesenchymal progenitors (C3H10T1/2)
Authors: Kaps Christian , Hoffmann Andrea , Zilberman Yoram , Pelled Gadi , Häupl Thomas , Sittinger Michael , Burmester Gerd , Gazit Dan , Gross Gerhard 
Published: December 2008

AbstractThe functional roles of BMP type IA and IB receptors mediating differentiation into the osteogenic and chondrogenic lineage were investigated in the mesenchymal progenitor line C3H10T1/2 in vitro. The capacity of type IA and IB BMP receptors was assessed by the forced expression of the wild‐type (wtBMPR‐IA or IB) and of the kinase‐deficient, dominant‐negative form (dnBMPR‐IA or ‐IB) in parental C3H10T1/2 progenitors as well as in C3H10T1/2 progenitors which recombinantly express BMP2 (C3H10T1/2‐BMP2) or GDF5 (C3H10T1/2‐GDF5). Consistent with the higher endogenous expression rate of BMPR‐IA in comparison with BMPR‐IB, BMPR‐IA plays the dominant role in BMP2‐mediated osteo‐/chondrogenic development. BMPR‐IB moderately influences osteogenic and hardly chondrogenic development. BMPR‐IB seems to be unable to efficiently activate downstream signaling pathways upon forced expression. However, a mutation conferring constitutive activity to the BMPR‐IB receptor indicates that this receptor possesses the capacity to activate downstream signaling cascades. These results suggest that in mesenchymal progenitors C3H10T1/2 BMPR‐IA is responsible for the initiation of the osteogenic as well as chondrogenic development and that BMPR‐IA and ‐IB receptor pathways are well separated in this mesenchymal progenitor line and may not substitute each other. In addition this indicates that type IB and IA BMP receptors may transmit different signals during the specification and differentiation of mesenchymal lineages.
The effect of estrogens and phytoestrogenic lignans on macrophage uptake of atherogenic lipoproteins
Authors: Owen Alice J. , Abbey Mavis 
Published: December 2008

AbstractThe present study examined the effect of estrogens and compounds with estrogenic activity on the uptake of atherogenic lipoproteins into macrophages, thought to be the initiating step in the development of atherosclerotic lesions. Isolated low density lipoprotein (LDL) and lipoprotein(a) (Lp(a)) were radiolabelled with 3H‐cholesterol linoleate, and incubated with J774 macrophages for 24 hours in the presence of pharmacological doses of estrogens and phytoestrogens. At a concentration of 0.1 μM, the estrogen 17β‐estradiol significantly reduced LDL uptake by macrophages by 14% (p < 0.05), but estrone did not have any effect. At 10 μM, both estrogens significantly reduced macrophage LDL uptake, but the phytoestrogenic‐lignans enterodiol and enterolactone had no effect on LDL uptake. Lp(a) uptake into cells was significantly reduced by both estrone and estradiol, and by enterolactone and enterodiol at concentrations of 10 μM (p < 0.01), with enterodiol being most effective. The results of this study suggest that the uptake of these structurally similar lipoproteins is regulated differently. Macrophage Lp(a) uptake appears more phytoestrogen sensitive than does LDL uptake.