bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural and functional organization of Complex I in the mitochondrial respiratory chain
Authors: Bianchi Cristina , Fato Romana , Genova Maria Luisa , Castelli Giovanna Parenti , Lenaz Giorgio
Published: December 2008

Metabolic flux control analysis of NADH oxidation in bovine heart submitochondrial particles revealed high flux control coefficients for both Complex I and Complex III, suggesting that the two enzymes are functionally associated as a single enzyme, with channelling of the common substrate, Coenzyme Q. This is in contrast with the more accepted view of a mobile diffusable Coenzyme Q pool between these enzymes. Dilution with phospholipids of a mitochondrial fraction enriched in Complexes I and III, with consequent increased theoretical distance between complexes, determines adherence to pool behavior for Coenzyme Q, but only at dilution higher than 1:5 (protein:phospholipids), whereas, at lower phospholipid content, the turnover of NADH cytochrome c reductase is higher than expected by the pool equation.
Regulation of coenzyme Q biosynthesis and breakdown
Authors: Dallner Gustav , Brismar Kerstin , Chojnacki Tadeusz , Swiezewska Ewa
Published: December 2008

All animal cells synthesize sufficient amounts of coenzyme Q (CoQ) and the cells also possess the capacity to metabolize the lipid. The main product of the metabolism is an intact ring with a short carboxylated side chain which glucuronidated in the liver and excreted mainly into the bile (Nakamura et al., Biofactors 9 (1999), 111–119). In other cells CoQ is phosphorylated, transferred into the blood and excreted through the urine. The biosynthesis of this lipid is regulated by nuclear receptors. PPARα is not required for the biosynthesis, or induction upon cold exposure, but it is necessary for the elevated CoQ synthesis during peroxisomal induction. RXRα is involved in the basal synthesis of CoQ and also in the increased synthesis upon cold treatment but is not required for peroxisomal induction. Dietary CoQ in human appear in the blood and it is taken up by mononuclear but not polynuclear cells. The former cells display a specific phospholipid modification, an increase of arachidonic acid content. In monocytes the CoQ administration leads to a significant decrease of the β2‐integrin CD11b and the complement receptor CD35. CD11b is one of the adhesion factors regulating the entry of these cells into the arterial wall which demonstrates that the anti‐atherogenic effect of CoQ is mediated by other mechanisms beside its antioxidant protection.
Specificity of Coenzyme Q inhibition of an aging‐related cell surface NADH oxidase (ECTO‐NOX) that generates superoxide
Authors: Morré Dorothy M. , James Morré D.
Published: December 2008

Our laboratories have described a novel class of ectoproteins at the cell surface with both NADH or hydroquinone oxidase (NOX) and protein disulfide‐thiol interchange activities (ECTO‐NOX proteins). The two activities exhibited by these proteins alternate to generate characteristic patterns of oscillations where the period length is independent of temperature. The period length for the constitutive ECTO‐NOX is 24 min. Here we describe a distinctive age‐related ECTO‐NOX (arNOX) whose activity is blocked by coenzyme Q10. arNOX occurs exclusively in aged cells and tissues. The period length of the oscillations is 26 min. Rather than reducing 1/2 O2 to H2O, electrons are transferred to O2 to form superoxide. Superoxide formation was demonstrated by superoxide dismutase‐sensitive reduction of ferricytochrome c and by reduction of a superoxide‐specific tetrazolium salt. Quinone inhibition was given by coenzymes Q8, 9 and Q10 but not by Q0, Q2, Q4, Q6 or 7. The arNOX provides a mechanism to propagate reactive oxygen species generated at the cell surface to surrounding cells and circulating lipoproteins of importance to atherogenesis. Inhibition of arNOX by dietary coenzyme Q10 provides a rational basis for dietary coenzyme 10 use to retard aging‐related arterial lesions.
Effect of UV‐C mediated oxidative stress in leukemia cell lines and its relation to ubiquinone content
Authors: Brugè F. , Tiano L. , Cacciamani T. , Principi F. , Littarru G. P.
Published: December 2008

UV‐C radiation is able to impair cellular functions by directly damaging DNA, and by inducing an increased formation of reactive oxygen species that leads to a condition of oxidative stress. In this study we evaluated different responses to UV insult of two leukemia cell lines, HL‐60 and Raji, and the relationship with their CoQ10 content. DNA damage was monitored by means of the alkaline single cell gel electrophoresis (Comet assay); intracellular levels of ROS, mitochondrial depolarization and cell viability was measured by flow cytometry. Raji cells appeared more resistant to the UV insult; moreover, they did not show any increase in ROS content and the extent of mitochondrial depolarisation was much lower than in HL 60 cell line. Raji cells also contained significantly higher levels of CoQ10 and their ability to incorporate and to reduce exogenous CoQ10 added to the culture medium was remarkably elevated compared with HL 60.
Coenzyme Q10 reduces the toxicity of rotenone in neuronal cultures by preserving the mitochondrial membrane potential
Authors: Menke T. , Gille G. , Reber F. , Janetzky B. , Andler W. , Funk R. H. W. , Reichmann H.
Published: December 2008

Defects in mitochondrial energy metabolism due to respiratory chain disorders lead to a decrease in mitochondrial membrane potential (ΔΨm) and induce apoptosis. Since coenzyme Q10 (CoQ10) plays a dual role as an antioxidant and bioenergetic agent in the respiratory chain, it has attracted increasing attention concerning the prevention of apoptosis in mitochondrial diseases. In this study the potential of CoQ10 to antagonize the apoptosis‐inducing effects of the respiratory chain inhibitor rotenone was explored by video‐enhanced microscopy in SH‐SY5Y neuroblastoma cells. The cationic fluorescent dye JC‐1 which exhibits potential‐dependent accumulation in mitochondria was used as an indicator to monitor changes in ΔΨm. The relative changes in fluorescence intensity after incubation with rotenone for 15 minutes were calculated. Pre‐treatment with CoQ10 (10 or 100 μM) for 48h led to a significant reduction of rotenone‐induced loss of ΔΨm. These results suggest, that cytoprotection by CoQ10 may be mediated by raising cellular resistance against the initiating steps of apoptosis, namely the decrease of ΔΨm. Whether these data may provide new directions for the development of neuroprotective strategies has to be investigated in future studies.
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

The 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

Lipid‐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

Our 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

Mitochondria 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

Previous 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

Ubiquinone (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

Oxygen/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

The 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

This 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

Thyroid 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

Three 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

In 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

The 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

The 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.
In vitro protective effect of Rhodiola rosea extract against hypochlorous acid‐induced oxidative damage in human erythrocytes
Authors: De Sanctis Roberta , De Bellis Roberta , Scesa Carla , Mancini Umberto , Cucchiarini Luigi , Dachà Marina
Published: December 2008

Rhodiola rosea L. (Crassulaceae) is a plant living at high altitudes in Europe and Asia. Its roots have long been used in the traditional medical system of these geographical areas to increase the organism resistance to physical stress; today, it has become an important component of many dietary supplements. In this study we investigate the antioxidant capacity of the R. rosea aqueous extract evaluating its ability to counteract some of the main damages induced by hypochlorous acid (HOCl), a powerful oxidant generated by activated phagocytes, to human erythrocytes. Ascorbic acid was used as a reference substance because of its physiological HOCl‐scavenging ability. Our study demonstrates that R. rosea is able to significantly protect, in a dose‐dependent manner, human RBC from glutathione (GSH) depletion, glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) inactivation and hemolysis induced by the oxidant. Furthermore, we demonstrate that R. rosea aqueous extract acts from the inside of the erythrocyte suggesting a probable involving of cell components. The protection on GSH afforded by the R. rosea extract with respect to ascorbic acid, occurred also if added 2 or 5 min. later than the oxidant, suggesting a more rapid or powerful effect.
Plasma levels and redox status of coenzyme Q10 in infants and children
Authors: Menke Thomas , Niklowitz Petra , Schlüter Bernhard , Weber Michael , Buschatz Dirk , Trowitzsch Eckardt , Andler Werner
Published: December 2008

Introduction: Increased attention has been paid to the role of lipophilic antioxidants in childhood nutrition and diseases during recent years. The lipophilic antioxidant coenzyme Q10 (CoQ10) is known as an effective inhibitor of oxidative damage. In contrast to other lipophilic antioxidants like α‐tocopherol the plasma concentrations of CoQ10 in childhood are poorly researched. The aim of this study was to determine plasma level and redox status (oxidized form in total CoQ10 in %) of CoQ10 in clinically healthy infants, preschoolers and school‐aged children.

Methods: Plasma level and redox status of CoQ10 were measured by HPLC in 199 clinically healthy children, three groups of infants [1st‐4th month (n = 35), 5th‐8th month (n = 25), 9th‐12th month (n = 25) ], preschoolers (n = 60) and school‐aged children (n = 54). The CoQ10 plasma levels were related to plasma cholesterol concentrations. The median and the 5th and 95th percentile were calculated.

Results: Plasma levels and redox status of CoQ10 in infants were significantly higher than in preschoolers and school‐aged children. The CoQ10 redox status in the 1st‐4th month was significantly increased when compared to the remaining subgroups of infants. In elder children the CoQ10 redox status stabilized.

Conclusion: This is the first study concerning age‐related values of plasma level and redox status of CoQ10 in apparently healthy children. Decreased CoQ10 values could be involved in various pathological conditions affecting childhood. Therefore, the application of age‐adjusted reference values may provide more specific criteria to define threshold values for CoQ10 deficiency in plasma.
Plasma membrane NADH‐oxidoreductase in cells carrying mitochondrial DNA G11778A mutation and in cells devoid of mitochondrial DNA (ρ0)
Authors: Malik Safarina G. , Vaillant François , Lawen Alfons
Published: December 2008

The mammalian plasma membrane (PM) NADH‐oxidoreductase (PMOR) system is a multi‐enzyme complex located in the plasma membrane of all eukaryotic cells, harboring at least two distinct activities, the plasma membrane NADH‐ferricyanide reductase and the NADH‐oxidase. To assess the behaviour of the two activities of the PMOR system, we measured the NADH‐ferricyanide reductase and NADH‐oxidase activities in fibroblast cell lines derived from patients carrying a mitochondrial DNA (mtDNA) G11778A mutation. We also measured the two activities in other cell lines, the HL‐60 and HeLa (S3) lines, as well as in ρ0 cells (cells devoid of mtDNA) generated from those lines and the fibroblast cells. These ρ0 cells consequently lack oxidative phosphorylation and rely on anaerobic glycolysis for their ATP need. We have proposed that in ρ0 cells, at least in part, up‐regulation of the PMOR is a necessity to maintain the NAD+/NADH ratio, and a pre‐requisite for cell growth and viability. We show here that the PM NADH‐ferricyanide reductase activity was up‐regulated in HL‐AV2 (HL‐60 ρ0) cell lines, but not in the other ρ0 and mtDNA mutant lines. The plasma membrane NADH oxidase activity was found to be up‐regulated in both HL‐AV2 and HeLa ρ0 cell lines, but not significantly in the fibroblast ρ0 and G11778A lines.
Mitochondrial gene‐knockout (ρ0) cells: A versatile model for exploring the secrets of trans‐plasma membrane electron transport
Authors: Scarlett Debbie‐Jane , Herst Patries , Tan An , Prata Cecilia , Berridge Michael
Published: December 2008

Plasma membrane electron transport (tPMET) pathways have been identified in all living cells, and a wide variety of tools have been used to study these processes. In our laboratory we have used the cell‐impermeable tetrazolium dye WST‐1, together with the mitochondrial gene knockout ρ0) cell model, to investigate one of these pathways. We have shown that growth of HL60ρ0 cells is dependent on oxygen, and that these cells consume oxygen at the cell surface. Similarities in inhibition profiles between non‐mitochondrial oxygen consumption and WST‐1 reduction suggest that both systems share a common tPMET pathway. In support of this, oxygen was shown to compete with the intermediate electron acceptor that mediates WST‐1 reduction, for reducing electrons. The observation that tPMET activity is higher in ρ0 cells compared to their mitochondrially‐competent counterparts was shown to be the result of competition between the mitochondrial and plasma membrane electron transport systems for intracellular reducing equivalents. Elevated rates of dye reduction appear to be mediated through increased expression of the key components of tPMET, which include the cell surface NADH oxidase, CNOX. These findings have played a critical role in shaping our current understanding of the mechanisms of this particular pathway of tPMET.
Human amyloid peptides Aβ1–40 and Aβ1–42 exhibit NADH oxidase acitivity with copper‐induced oscillations and a period length of 24 min
Authors: Markert Claudia , Morré Dorothy M. , James Morré D.
Published: December 2008

Human amyloid beta peptides Aβ1–40 and Aβ1–42 exhibit NADH oxidase activity with regular oscillations at intervals of ca 6 min. In the presence of copper, the oscillations in Aβ1–40 and Aβ1–42 become more pronounced and now assume a period length of 24 min. In the presence of copper, the oscillations are similar to those observed with NADH oxidase activities of cell surface ECTO‐NOX proteins in general including a period length of 24 min. Solutions of copper sulphate in the presence of all the reagents except for the peptides did not exhibit the oscillatory behavior. NOX proteins have been reported previously to have properties of prions and to form amyloid rods of indeterminant length similar to those formed by the 39–43 residue amyloid beta proteins (Aβ). In this report, we demonstrate a second similarity between ECTO‐NOX proteins and amyloid beta, that of an oscillating NADH oxidase activity with a period length of 24 min when assayed in the presence of copper.
Cancer prevention with food factors: Alone and in combination
Authors: Ohigashi Hajime , Murakami Akira
Published: December 2008

Cancer prevention strategies making use of combined agents with distinct molecular mechanisms, rather than individual agents, are considered promising for higher efficacy and lower toxicity. Although there is increasing understanding of the synergistic combinations of synthetic agents, our knowledge regarding such combinations of food factors remains limited. We recently found that free radical generation suppressants from food items in combination with their scavengers at low concentrations exhibited notable synergistic effects in activated leukocytes, whereas combinations of agents with similar modes of action showed additive or antagonistic effects. For example, (—)‐epigallocatechin gallate (EGCG) from green tea has been shown to increase the endotoxin‐induced production of proinflammatory mediators such as prostaglandin E2 and tumor necrosis factor‐α in RAW264.7 macrophages, whereas the soybean isoflavonoid genistein compensated for these inverse properties of EGCG, leading to marked suppression in combination. The present review briefly highlights the potential effectiveness of combinations of several agents with anti‐oxidative and anti‐inflammatory properties for cancer preventive strategies.
Antitumor activity and action mechanisms of Lactobacillus casei through the regulation of immune responses
Authors: Matsuzaki Takeshi , Takagi Akimitsu , Ikemura Haruo , Matsuguchi Tetsuya , Yokokura Teruo
Published: December 2008

Lactobacillus casei strain Shirota (LcS) has been demonstrated to have beneficial effects in numerous disease models, especially murine autoimmune disease and carcinogenesis models, via host immune modulation. It has also been reported that LcS induced recovery of the host immune responses that were decreased by treatment with carcinogens, and that augmented the natural killer activity and T cell functions of host immune cells. After LcS is ingested by the host, it is incorporated into M cells in Peyer's patches (PP) and digested to form active components. In PP, macrophages or dendritic cells that phagocytosed LcS gained ability to produce tumor necrosis factor‐α. The components of LcS digested in PP were then recognized through toll‐like receptor 2 in macrophages, resulting in the production of several cytokines which elicit varied responses in host immune cells. Also, it was observed by 2D‐PAGE analyses that the expression level and/or the phosphorylation of some proteins in PP and mesenteric lymph nodes were definitely altered after the ingestion of LcS, providing more evidence of cellular responses.
A fermented grain food mixture, AOB™, inhibits liver metastasis in the metastasis model of rat colon cancer
Authors: Minamiyama Yukiko , Takemura Shigekazu , Hirohashi Kazuhiro , Okada Shigeru
Published: December 2008

Natural antioxidants have been shown to be rich sources of microchemicals with the potential to prevent human cancers. We examined whether dietary supplement of a fermented grain food mixture (AOB), which has been shown to have a strong antioxidative effect, may protect against colon cancer metastasis. At day 5 of AOB (6.5%) supplementation in a basal diet, the rat colon cancer cells (RCN‐H4) were injected beneath the capsule of the spleen and one min later rats were splenectomized. All rats without AOB supplementation had multiple liver metastases. However, the number and the size of liver tumors were reduced by about 80% in AOB group. Combined use of cisplatin and AOB enhanced an anti‐metastatic effect. The inhibition of liver metastasis by AOB was caused by the regulation of cell cycle. This product may be used as an adjuvant in the therapy of malignant neoplasia.
Changes of the total antioxidative status of blood cells in the progression of stomach and large bowel cancers in patients subjected to primary radical treatment
Authors: Kopañski Z. , Bertrandt J. , Grabowska M. , Kosiniak‐Kamysz A. , Kołodziejski L. , Opoka W. , Schlegel‐Zawadzka M.
Published: December 2008

The analysis included 53 patients (32 men and 21 women) aged 43 to 66 years, who were subjected to radical treatment (surgical or combined) because of stomach (22 patients) or large bowel (31 patients) cancer. All the patients were included in the same model of control examinations, which considered evaluation of the erythrocytes TAS and of the Ca19–9, CEA and AFP concentrations in serum. It was confirmed that in all the patients in whom the recurrence and/or the dissemination occurred of the cancer, the average erythrocytes TAS value increased 5.5 times by comparison with the period before progression and 7 times in comparison with the patients without recurrence and/or dissemination of the cancer. Moreover it was shown that statistically significantly higher TAS values were associated with the progression of the large bowel cancer in comparison with the stomach cancer and that the blood cells TAS positively correlated with the changes of the Ca19–9, CEA and AFP concentrations in patients with progression of the cancer after radical treatment.
Antitumor activity of rice‐shochu post‐distillation slurry and vinegar produced from the post‐distillation slurry via oral administration in a mouse model
Authors: Seki Takahiro , Morimura Shigeru , Shigematsu Tohru , Maeda Hiroshi , Kida Kenji
Published: December 2008

Shochu is a Japanese spirit that is mainly produced in the Kyushu region. Rice‐shochu post‐distillation slurry (i.e. RSDS) is eluted during the conventional rice‐shochu production process. Since RSDS contains several functional components, we have produced vinegar from RSDS. This study reports the antitumor activity of RSDS and the vinegar via oral administration in a mouse model. Freeze‐dried RSDS (0.1 ∼ 1.5%) or vinegar (0.3 ∼ 1.5%) was mixed into a chemically defined diet. The tumor size and life span of tumor‐bearing mice that were fed the diet were investigated for 72 d. The RSDS‐ (> 0.3%) or vinegar‐ (> 0.5%) fed mice had significantly smaller sized tumors than the control group (p < 0.01). We also found that those mice had prolonged life spans. Oral administration of RSDS or vinegar also prolonged the life spans of mice that were implanted with Colon 38 cells. These results indicated that dietary RSDS and vinegar suppressed tumor growth. Moreover, we found that NK cytotoxic activity against K562 cells was stimulated by RSDS and vinegar.
Anti‐tumorigenic components of a sea weed, Eeteromorpha clathrata
Authors: Tang Hanjun , Inoue Mamiko , Uzawa Yuki , Kawamura Yukio
Published: December 2008

Anti‐tumorigenic action of compounds in some seaweed was evaluated by using selective cytotoxicity against a transformed mouse 3T3 cell (SV‐T2) and its normal counter part. The extracts of seaweeds (Wakame, Konbu, Mirin, Aosa, and Sujiaonori) were added to the cells in 96 well microplate. The viability of the cell was measured at 24 hr after sample addition. Of the five weeds, the ethanol extracts from Sujiaonori exhibited the selective cytotoxicity. The ethanol extracts from Sujiaonori was applied to gel permeation chromatography on Sephadex G‐50. The anti‐cancer activity was detected in two fractions with high molecular weight near void volume and with small molecular weight. The high molecular weight fractions had absorbance at 280 nm, suggesting that they contained proteineous substances. The small molecular weight fractions were estimated to be around 500 Dalton.
Cytoplasmic fraction of Lactococcus lactis ssp. lactis induces apoptosis in SNU‐1 stomach adenocarcinoma cells
Authors: Kim Seo Young , Lee Ki Won , Kim Ji Yeon , Lee Hyong Joo
Published: December 2008

Lactic acid bacteria are known to have antitumor activity, but the underlying mechanisms remain unclear. Recently we showed that a cytoplasmic fraction ‐ but not peptidoglycan ‐ of Lactococcus lactis ssp. lactis (L.lac CF) had strong antiproliferative activity on SNU‐1 human stomach adenocarcinoma cells. The present study investigated whether the antiproliferative activity of L.lac CF on SNU‐1 is linked to the induction of apoptosis. Treatment of L.lac CF inhibited the proliferation of SNU‐1 cells in a dose‐ and time‐dependent manner. Furthermore, treatment of the cells with 50 μ/ml and 100 μ/ml L.lac CF resulted in DNA fragmentation and chromatin condensation, respectively. The results indicate that the inhibitory effect of L.lac CF on SNU‐1 cell growth is mainly attributable to the induction of apoptosis.
Effects of tea catechins on lipid metabolism and body fat accumulation
Authors: Tokimitsu Ichiro
Published: December 2008

Long‐term feeding of tea catechins suppressed body fat accumulation in high‐fat diet‐induced obesity in mice, and that their effects might be attributed, at least in part, to the activation of hepatic lipid metabolism. Consecutive intake of tea catechins (588 mg/day) reduced body fat, especially abdominal fat in humans. These results demonstrate that intake of tea catechins is beneficial for body fat accumulation.
Effects of combination of Caiapo® with other plant‐derived substance on anti‐diabetic efficacy in KK‐Ay mice
Authors: Sakuramata Yasuhide , Oe Hiromi , Kusano Syuichi , Aki Osami
Published: December 2008

B. Ludvik et al., have recently shown the effect of Caiapo® (Ipomoea batatas L.) on reducing fasting blood glucose and insulin resistance in type‐2 diabetic patients. It, however, was required 2–4 weeks after the single administration of Caiapo®. The present study aimed to determine if the combination therapy of Caiapo® with a mulberry leaf powder, which inhibits α‐glucosidase, or with a loquat leaf extract, which shows an insulin‐like effect, could make it possible to enhance the antidiabetic activities of Caiapo®, and to shorten the time necessary for the inhibition of increasing blood glucose levels.

A mixture of the pulverized tuber of Caiapo® (357 mg/kg) and the mulberry leaf powder (143 mg/kg), or a mixture of the pulverized skin of Caiapo® (194 mg/kg) and the powdered loquat leaf extract (6 mg/kg) was orally administered to 6 weeks‐old male KK‐Ay mice for 28 days and the glucose loading test was conducted every 7 days.

In the glucose loading test after one week feeding, a reduction in blood glucose concentration after 60 minutes of the administration of glucose was observed in both mixture groups against the control group (p < 0.05) in the case of Caiapo® only, similar delayed effects were seen in 2–3 weeks after feeding.