bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinctive features in the SelB family of elongation factors for selenoprotein synthesis. A glimpse of an evolutionary complexified translation apparatus
Authors: Fagegaltier Delphine , Carbon Philippe , Krol Alain
Published: December 2008

The last ten years have seen a dramatic increase in our understanding of the molecular mechanism allowing specific incorporation of selenocysteine into selenoproteins. Whether in prokaryotes or eukaryotes, this incorporation requires several gene products, among which the specialized elongation factor SelB and the tRNASec play a pivotal role. While the molecular actors have been discovered and their role elucidated in the eubacterial machinery, recent data from our and other laboratories pointed to a higher degree of complexity in archaea and eukaryotes. These findings also revealed that more needs to be discovered in this area.

This review will focus on phylogenetic aspects of the SelB proteins. In particular, we will discuss the concerted evolution that occurred within the SelB/tRNASec couples, and also the distinctive roles carried out by the SelB C‐terminal domains in eubacteria on the one side, and archaea and eukaryotes, on the other.
RNA binding proteins and selenocysteine
Authors: Copeland Paul R. , Driscoll Donna M.
Published: December 2008

Selenocysteine is incorporated into protein by a complex co‐translational mechanism that involves both cis and trans acting factors. Among the trans‐acting factors are RNA binding proteins that interact with the selenoprotein 3′ UTRs at a sequence known as the selenocysteine insertion sequence (SECIS). These factors are generally referred to as SBPs, and in this review we will discuss the history of the SBPs, and give a detailed description of the recently identified SBP2 which is the only SBP known to be required for Sec insertion. The mechanism by which SBP2 may be involved in this process will be discussed.
Functional Analysis of Prokaryotic SELB proteins
Authors: Thanbichler Martin , Böck August
Published: December 2008

Since the discovery of selenocysteine as the 21st amino acid considerable progress has been made in elucidating the system responsible for its insertion into proteins. Elongation factor SELB, whose amino‐terminal part shows homology to EF‐Tu, was found to be the key component mediating delivery of selenocysteyl‐tRNASec to the ribosomal A site. It exhibits a distinct tertiary structure comprising binding sites for guanosine nucleotides, the cognate tRNA, an mRNA secondary structure (SECIS element) and presumably ribosomal components. The kinetics of interaction of SELB with its ligands have been studied in detail. GDP was found to bind with about 20‐fold lower affinity than GTP and to be in rapid exchange, which obviates the need for a guanosine nucleotide exchange factor. The affinity of SELB for the SECIS element is in the range of 1 nM and further increases upon binding of selenocysteyl‐tRNASec to the protein. This supports the model that SELB forms a tight quaternary complex on the SECIS element which is loosened after insertion of the tRNA into the ribosomal A site and the concomitant hydrolysis of GTP.
Modulation of selenoprotein P expression by TGF‐β1 is mediated by Smad proteins
Authors: Mostert Volker , Dreher Ingeborg , Köhrle Josef , Wolff Sandra , Abel Josef
Published: December 2008

Selenoprotein P (SeP) is a selenium‐rich plasma protein which accounts for more than 50% this study, the effect of TGF‐β1 on the expression of SeP in the human liver cell line HepG2 was investigated. Western analysis revealed a dose‐dependent reduction of SeP content in cell supernatant. RT‐PCR analysis of SeP‐mRNA expression demonstrated a marked inhibition and a reporter gene under control of the SeP promoter was negatively regulated by TGF‐β1.

Smad proteins are the transcriptional mediators of TGF‐β signaling. A putative Smad‐binding element (SBE) is present in the SeP promoter. In electrophoretic‐mobility‐shift assays, TGF‐β1 enhanced the binding of nuclear proteins to this SBE. Overexpression of Smad3 and 4 resulted in a downregulation of SeP‐promoter activity whereas deletion of the SBE led to a loss of TGF‐β1 responsiveness. We conclude that SeP expression is modulated by the binding of Smad3/4 complexes to a functional SBE in the SeP promoter.
Effect of selenium on the immunocompetence of patients with head and neck cancer and on adoptive immunotherapy of early and established lesions
Authors: Kiremidjian‐Schumacher L. , Roy M.
Published: December 2008

Supplementation with 200 μg/day of sodium selenite during therapy for squamous cell carcinoma (SQCC) of the head and neck, e.g., surgery, radiation, or surgery and radiation, resulted in a significantly enhanced cell‐mediated immune responsiveness. The enhanced responsiveness was evident during therapy and following conclusion of therapy. In contrast, patients in the placebo arm of the study showed a decline in immune responsiveness during therapy. The results from studies on mice inoculated with SQCC cells expressing the receptor for interleukin‐2 (IL‐2) and supplemented with Se (2.00 ppm) indicated that Se significantly retards the clinical appearance of tumors; peritumoral injections of 2,000 IU of IL‐2 resulted in 50% reduction in the size of established tumors and 72% of early tumors. The combined data suggested that local immunotherapy with IL‐2 in hosts supplemented with Se may represent an effective modality of treatment for the prevention of recurrences at the site of conventionally treated primary tumors.
Se‐methylselenocysteine activates caspase‐3 in mouse mammary epithelial tumor cells in vitro
Authors: Unni Emmanual , Singh Uma , Ganther Howard E. , Sinha Raghu
Published: December 2008

Se‐methylselenocysteine (MSC) inhibits mouse mammary epithelial tumor cell (TM6) growth. When synchronized TM6 cells were exposed to 50 μM MSC, either for 30 minutes or continuous, the 116 kDa poly(ADP‐ribose)polymerase (PARP) was cleaved to an 85 kDa fragment indicative of cells undergoing apoptosis. The earliest cleaved PARP appears at 24 hr time point followed by elevated levels of 85 kDa fragment at 34 hr and 48 hr time points when the cells were exposed to continuous treatment with MSC. Results also showed that MSC increased caspase‐3 activity at 24 hr time point. In addition, continuous treatment with MSC induced DNA fragmentation at 34 hr and 48 hr time points with caspase‐3 gene expression moderately increased at 16hr and 24 hr time points. Caspase‐6 and ‐8 were also involved in the MSC‐induced apoptosis but to a lesser extent. These results suggest that MSC mediates cleavage of PARP and apoptosis by activating one or more caspases in synchronized TM6 cells and the events are dependent on the duration of treatment.
The effect of a selenium supplementation on the outcome of patients with severe systemic inflammation, burn and trauma
Authors: Gärtner Roland , Albrich Werner , Angstwurm Matthias W. A.
Published: December 2008

Patients with systemic inflammatory response syndrome (SIRS) and sepsis exhibit decreased plasma selenium and glutathione peroxidase activity. This has been shown in several clinical studies. Moreover, the degree of selenium deficiency correlates with the severity of the disease and the incidence of mortality. Patients with SIRS and sepsis are exposed to severe oxidative stress. Selenoenzymes play a major role in protecting cells against peroxidation, especially lipid peroxidation and are involved in the regulation of inflammatory processes. Therefore, selenium substitution in those patients might be effective in the prevention of multiorgan failure.

The results of randomised clinical trials investigating selenium substitution in critical ill patients with inflammation are reviewed. In two independently performed randomised, prospective clinical trials, including patients with systemic inflammatory response syndrome or sepsis, the supplementation of selenium revealed a significant reduction in multiorgan failure and, especially, a lower incidence of acute renal failure and respiratory distress syndrome. One of those trials also could demonstrate a significant reduction of mortality in the most severely ill patients. Two other studies, where selenium together with other trace elements or a mixture of antioxidants were used in the treatment of patients with severe burn injuries or trauma showed a significant reduction in the secondary infection rate, including sepsis. Thus, selenium supplementation seems to improve the outcome of patients with SIRS, sepsis and severe injury, however, pivotal prospective clinical trials with sufficient statistical power are now necessary to finally prove the efficacy of a selenium supplementation in these diseases.
PHGPx and spermatogenesis
Authors: Roveri Antonella , Ursini Fulvio , Flohé Leopold , Maiorino Matilde
Published: December 2008

PHGPx of rat sperm mitochondrial capsule is cross‐linked and inactive. The enzyme is in part released in an active form by mercaptoethanol. Treatment with H2O2 of reduced and solubilised capsule proteins, in the absence of any added reductant, results in: i) H2O2 consumption which depends on the presence of both, PHGPx activity and protein thiols; ii) protein thiol oxidation with a stoichiometry of 2 equivalents of thiol per mole of hydroperoxide and, iii) PHGPx inactivation and cross‐linking. SDS‐PAGE analysis of monobromobimane‐labeled proteins, following incubation with H2O2, shows that the oxidation takes place in specific bands in the area of 20 kDa.

It is concluded that the protein thiol peroxidase activity of PHGPx is responsible for cross‐linking proteins in the mammalian sperm capsule and accounts for the selenium dependency of spermatogenesis.
The green technology of selenium phytoremediation
Authors: Bañuelos G. S.
Published: December 2008

Selenium toxicity is encountered in arid and semi‐arid regions of the world with alkaline, seleniferous soils derived from marine sediments. Once present in soils and waters at high concentrations, Se is very complicated and highly expensive to remove with conventional physical and chemical techniques. Phytoremediation is a plant‐based technology that is being considered for managing Se in central California soils. The technology involves the use of plants in conjunction with microbial activity associated with the plants to extract, accumulate, and volatilize Se. Once absorbed by plant roots, Se is translocated to the shoot where it may be harvested and removed from the site. Therefore, plant species used for phytoremediation of Se‐laden soils may by plant uptake and volatilization minimize the Se load eventually entering agricultural effluent and the harvested crop can be carefully blended with animal forage and fed to animals in Se‐deficient areas.
Dietary gangliosides positively modulate the percentages of Th1 and Th2 lymphocyte subsets in small intestine of mice at weaning
Authors: Vázquez Enrique , Gil Angel , Rueda Ricardo
Published: December 2008

We studied the influence of dietary gangliosides on the number of spontaneous cytokine‐secreting cells from two intestinal lymphocyte populations: lamina propria lymphocytes and Peyer's patches lymphocytes in Balb/c mice for 28 days after weaning. Weanling mice were separated into two groups, designated as Control and BG. The Control group was fed with a semipurified diet without gangliosides and the BG group was fed with the semipurified diet supplemented with 47 mg/kg of a mixture of bovine brain gangliosides. Intestinal lymphocytes were isolated from mice killed at 3, 7, 14 and 28 days after weaning, and the percentages of spontaneous Th1 as well as Th2 cytokine‐secreting lymphocytes were determined using the ELISPOT assay. The BG group animals showed an earlier development in the number of cytokine‐secreting cells, which appeared one week later in Control animals. In addition, mice fed with the ganglioside‐supplemented diet showed a significantly higher number of Th1 and Th2 cytokine‐secreting lymphocytes than Control mice in lamina propria and Peyer's patches lymphocytes at the end of the experimental period (28 days). Our results suggest that dietary gangliosides influence the maturation process of the intestinal immune system that take place during weaning.
Prospects for enhancement of the soluble antioxidants, ascorbate and glutathione
Authors: Foyer Christine H.
Published: December 2008

Ascorbic acid (vitamin C) and the tripeptide thiol, glutathione γ‐glutamyl cysteinyl glycine (glutathione) are the major low molecular weight soluble antioxidants in plant cells. The pathway of glutathione biosynthesis is similar in animals and plants while that of ascorbate biosynthesis differs considerably between the two kingdoms. The potential for obtaining substantial constitutive changes in the tissue contents of these antioxidants by manipulation of the biosynthetic enzymes has been demonstrated. Moreover, the concentrations of ascorbate and glutathione are greatly modified in response to a variety of environmental triggers, particularly those that cause increased oxidative stress. It is essential that the signals and associated signal transduction pathways that trigger enhanced antioxidant accumulation are elucidated as these offer an important alternative means of achieving greater nutritional value in edible plant organs.
Formation of novel bioactive metabolites from the reactions of pro‐inflammatory oxidants with polyphenolics
Authors: Boersma Brenda J. , Patel Rakesh P. , Botting Nigel , White C. Roger , Parks Dale , Barnes Stephen , Darley‐Usmar Victor M.
Published: December 2008

Dietary polyphenolics such as those in soy or red wine can have beneficial effects on the development of chronic human diseases. The mechanisms of action of isoflavones have been diverse and include their roles as weak estrogens, inhibitors of tyrosine kinase‐dependent signal transduction processes and as antioxidants. Recent insights into the oxidative stress model of atherosclerosis suggest an interesting synthesis of these concepts. Sites of inflammation are associated with the formation of complex mixtures of reactive oxygen, nitrogen and halogenating species capable of modifying both endogenous biomolecules and polyphenolics. Of particular significance are the halogenation reactions mediated by myeloperoxidase that can modify key amino acids such as arginine and polyphenolics such as genistein. Hypochlorite, the reaction product of myeloperoxidase can halogenate polyphenolics to form stable derivatives with modified biological activity. Thus the in situ metabolism at sites of inflammation is unique and generates novel pharmacophores with potentially distinct modes of action from the parent compounds.
Nitric oxide as a regulator of gene expression: Studies with the transcription factor proteins cJun and p50
Authors: Pineda‐Molina Estela , Lamas Santiago
Published: December 2008

Both oxidative and nitrosative stresses may result in the inactivation of the binding to DNA of redox‐sensitive transcription factors. The underlying biochemical mechanisms may involve oxidation or nitrosylation of critical thiols within the DNA binding domains of these proteins. However, S‐glutahionylation, the formation of a mixed disulfide between glutathione and the redox‐sensitive cysteine residues, has been shown to occur under NO exposure and pro‐oxidative conditions in c‐Jun, one of the AP‐1 constituents [1,2]. This modification may be functionally important as it is reversible and has been detected in other transcription factors, such as NF‐κ, by using covalent chromatography with a modified S‐nitrosoglutathione sepharose [3].
Hepatocyte proliferation factors from neonatal pig liver: Purification and characterization
Authors: Hiyoshi Mineyoshi , Ohkubo Tomoichi , Tsuji Kimiyoshi , Hagihara Masao , Nakasaki Hisao , Mukai Masaya , Makuuchi Hiroyasu , Yamamura Masaichi , Tsuda Michio
Published: December 2008

Two factors were found in the condition medium of neonatal pig liver fragments, which were capable of stimulating DNA synthesis in primary hepatocytes. They were named hepatocyte proliferation factor (HPF)‐1 and HPF‐2 and purified 1,025‐ and 2,580‐fold, respectively. Both HPF‐1 and HPF‐2 seem to be anionic at pH 8.0 judged from the elution pattern of DEAE (DE52) column chromatography. HPF‐1 was recovered as a non‐adsorbed fraction in blue Sepharose and heparin Sepharose columns, and had a molecular weight of 26–31 kDa as estimated by gel filtration in high salt condition. Purified HPF‐1 stimulated DNA synthesis of primary rat hepatocytes, but suppressed that of HepG2 cells. HPF‐2 strongly bound to blue Sepharose and heparin Sepharose columns, and had a molecular weight of 71–90 kDa as estimated by SDS‐PAGE under non‐reduced condition. Purified HPF‐2 stimulated DNA synthesis of primary rat hepatocytes dose dependently but did not suppress that of HepG2 cells.

From further biological and chemical characteristics studied in this paper, HPF‐1 and HPF‐2 may be novel stimulating proteins for hepatocyte proliferation, although the possibility that they are already known growth factors can not be excluded without complete purification and its cloning.
Membrane‐rigidifying effects of anti‐cancer dietary factors
Authors: Tsuchiya Hironori , Nagayama Motohiko , Tanaka Toshiyuki , Furusawa Miyuki , Kashimata Masanori , Takeuchi Hiroshi
Published: December 2008

Since several anti‐cancer drugs interact with cell membrane lipids, the effects of anti‐cancer dietary factors on liposomal membranes with different lipid composition were comparatively studied by measuring fluorescence polarization. Fluidity was imparted on both hydrophobic and hydrophilic regions of lipid bilayers by decreasing cholesterol and increasing unsaturated phosphatidylcholine in membranes. At 0.625‐10 μM, (‐)‐epigallocatechin gallate, genistein, apigenin, resveratrol and a reference anti‐cancer drug, doxorubicin, rigidified the tumor cell model membranes consisting of 20 mol% cholesterol and 80 mol% phosphatidylcholine with the acyl chain 18:1/16:0 ratio of 1.0, but not daidzein. They were more effective on the membrane core than the membrane surface. Quercetin showed a biphasic effect on the hydrophobic regions of membrane lipid bilayers to rigidify above 5 μM and fluidize below 2.5 μM. In contrast, anti‐cancer dietary factors and doxorubicin were not or much less effective in rigidifying the normal cell model membranes consisting of 40 mol% cholesterol and 60 mol% phosphatidylcholine with the acyl chain 18:1/16:0 ratio of 0.5. The membrane‐rigidifying effects were greater depending on a decrease of the cholesterol/phosphatidylcholine ratio and an increase of the phosphatidylcholine unsaturation degree. Membrane‐active dietary factors and doxorubicin inhibited the growth of mouse myeloma cells at 10‐100 μM, while the growth inhibition by membrane‐inactive daidzein was relatively weak. Anti‐cancer dietary factors appear to act on more fluid membranes like tumor cells as well as doxorubicin to induce rigidification, especially in the hydrocarbon core of membrane lipids, which is determined by the composition of cholesterol and unsaturated phospholipids.
Antioxidant effects of tetrahydro‐β‐carboline derivatives identified in aged garlic extract
Authors: Ichikawa Makoto , Ryu Kenjiro , Yoshida Jiro , Ide Nagatoshi , Yoshida Susumu , Sasaoka Takashi , Sumi Shin‐Ichiro
Published: December 2008

1,2,3,4‐Tetrahydro‐β‐carboline derivatives (THβCs) are formed through Pictet‐Spengler chemical condensation between tryptophan and aldehydes during food production, storage and processing. In the present study, in order to identify the antioxidants in aged garlic extract (AGE), we fractionated it and identified four THβCs; 1‐methyl‐1,2,3,4‐tetrahydro‐β‐carboline‐3‐carboxylic acids (MTCC) and 1‐methyl‐1,2,3,4‐tetrahydro‐β‐carboline‐1,3‐dicarboxylic acid (MTCdiC) in both diastereoisomers using liquid chromatography mass spectrometry (LC‐MS). Interestingly, these compounds were not detected in raw garlic, but the contents increased during the natural aging process of garlic. In in vitro assay systems, all of these compounds have shown strong hydrogen peroxide scavenging activities. (1S, 3S)‐MTCdiC was found to be stronger than the common antioxidant, ascorbic acid. MTCC and MTCdiC inhibited AAPH‐induced lipid peroxidation. Both MTCdiCs also inhibited LPS‐induced nitrite production from murine macrophages at 10‐100 μM. Our data suggest that these compounds are potent antioxidants in AGE, and thus may be useful for prevention of disorders associated with oxidative stress.
The biomolecule ubiquinone exerts a variety of biological functions
Authors: Nohl Hans , Staniek Katrin , Kozlov Andrey V. , Gille Lars
Published: December 2008

The chemistry of ubiquinone allows reversible addition of single electrons and protons. This unique property is used in nature for aerobic energy gain, for unilateral proton accumulation, for the generation of reactive oxygen species involved in physiological signaling and a variety of pathophysiological events. Since several years ubiquinone is also considered to play a major role in the control of lipid peroxidation, since this lipophilic biomolecule was recognized to recycle α‐tocopherol radicals back to the chain‐breaking form, vitamin E. Ubiquinone is therefore a biomolecule which has increasingly focused the interest of many research groups due to its alternative pro‐ and antioxidant activity. We have intensively investigated the role of ubiquinone as prooxidant in mitochondria and will present experimental evidences on conditions required for this function, we will also show that lysosomal ubiquinone has a double function as proton translocator and radical source under certain metabolic conditions. Furthermore, we have addressed the antioxidant role of ubiquinone and found that the efficiency of this activity is widely dependent on the type of biomembrane where ubiquinone exerts its chain‐breaking activity.
Regeneration of the antioxidant ubiquinol by lipoamide dehydrogenase, thioredoxin reductase and glutathione reductase
Authors: Nordman Tomas , Xia Ling , Björkhem‐Bergman Linda , Damdimopoulos Anastassios , Nalvarte Ivan , Arnér Elias S. J. , Spyrou Giannis , Eriksson Lennart C. , Björnstedt Mikael , Olsson Jerker M.
Published: December 2008

Ubiquinol is a powerful antioxidant, which is oxidized in action and needs to be replaced or regenerated to be capable of a sustained effort. This article summarises current knowledge of extramitochondrial reduction of ubiquinone by three flavoenzymes, i.e. lipoamide dehydrogenase, glutathione reductase and thioredoxin reductase, belonging to the same pyridine nucleotide‐disulfide oxidoreductase family. These three enzymes are the most efficient extramitochondrial ubiquinone reductases so far described. The reduction of ubiquinone by lipoamide dehydrogenase and glutathione reductase is potently stimulated by zinc and the highest rate of reduction is achieved at acidic pH and the rates are equal with either NADPH or NADH as co‐factors. The most efficient ubiquinone reductases are mammalian cytosolic thioredoxin reductases, which are selenoenzymes with a number of biological functions. Reduction of ubiquinone by thioredoxin reductase is in contrast to the other two enzymes investigated, inhibited by zinc and shows a sharp physiological pH optimum at pH 7.5. Furthermore, the reaction is selenium dependent as revealed from experiments using truncated and mutant forms of the enzyme and also in a cellular context by selenium treatment of transfected thioredoxin reductase overexpressing stable cell lines. The reduction of ubiquinone by the three enzymes offers a multifunctional system for extramitochondrial regeneration of an important antioxidant.
Phylloquinone, what can we learn from plants?
Authors: Lochner K. , Döring O. , Böttger M.
Published: December 2008

The plant plasma membrane contains redox proteins able to mediate a trans‐membrane electron flow. This electron flow might be responsible for the generation of the active oxygen species observed as a reaction to pathogen attack or stress. Vitamin K1 could be identified as a possible lipid soluble electron carrier in plant plasma membrane preparations. Such a function would be analogous to coenzyme Q in animal plasma membranes.

What we are going to outline in this contribution is a concept of how the electron transport system of the plant plasma membrane could interact with quinones, thus contributing to the metabolism of free radicals in plants.
Systematic review of effect of coenzyme Q10 in physical exercise, hypertension and heart failure
Authors: Rosenfeldt Franklin , Hilton Deborah , Pepe Salvatore , Krum Henry
Published: December 2008

Coenzyme Q10 in physical exercise. We identified eleven studies in which CoQ10 was tested for an effect on exercise capacity, six showed a modest improvement in exercise capacity with CoQ10 supplementation but five showed no effect.

CoQ10 in hypertension. We identified eight published trials of CoQ10 in hypertension. Altogether in the eight studies the mean decrease in systolic blood pressure was 16 mm Hg and in diastolic blood pressure, 10 mm Hg. Being devoid of significant side effects CoQ10 may have a role as an adjunct or alternative to conventional agents in the treatment of hypertension.

CoQ10 in heart failure. We performed a randomised double blind placebo‐controlled pilot trial of CoQ10 therapy in 35 patients with heart failure. Over 3 months, in the CoQ10 patients but not in the placebo patients there were significant improvements in symptom class and a trend towards improvements in exercise time.

Meta‐analysis of randomised trials of coenzyme Q10 in heart failure. In nine randomised trials of CoQ10 in heart failure published up to 2003 there were non‐significant trends towards increased ejection fraction and reduced mortality. There were insufficient numbers of patients for meaningful results. To make more definitive conclusions regarding the effect of CoQ10 in cardiac failure we recommend a prospective, randomised trial with 200–300 patients per study group. Further trials of CoQ10 in physical exercise and in hypertension are recommended.
Statins lower plasma and lymphocyte ubiquinol/ubiquinone without affecting other antioxidants and PUFA
Authors: Passi Siro , Stancato Andrea , Aleo Enrico , Dmitrieva Anna , Littarru Gian Paolo
Published: December 2008

It has been shown that treating hypercholesterolemic patients (HPC) with statins leads to a decrease, at least in plasma, not only in cholesterol, but also in important non‐sterol compounds such as ubiquinone (CoQ10), and possibly dolichols, that derive from the same biosynthetic pathway. Plasma CoQ10 decrease might result in impaired antioxidant protection, therefore leading to oxidative stress. In the present paper we investigated the levels in plasma, lymphocytes and erythrocytes, of ubiquinol and ubiquinone, other enzymatic and non‐enzymatic lipophilic and hydrophilic antioxidants, polyunsaturated fatty acids of phosfolipids and cholesterol ester fractions, as well as unsaturated lipid and protein oxidation in 42 hypercholesterolemic patients treated for 3 months. The patients were treated with different doses of 3 different statins, i.e. atorvastatin 10 mg (n = 10) and 20 mg (n = 7), simvastatin, 10 mg (n = 5) and 20 mg (n = 10), and pravastatin, 20 mg (n = 5) and 40 mg (n = 5).

Simvastatin, atorvastatin and pravastatin produced a dose dependent plasma depletion of total cholesterol (t‐CH), LDL‐C, CoQ10H2, and CoQ10, without affecting the CoQ10H2/CoQ10ratio. The other lipophilic antioxidants (d‐RRR‐α‐tocopherol‐vit E‐, α‐tocopherol, vit A, lycopene, and β‐carotene), hydrophilic antioxidants (vit C and uric acid), as well as, TBA‐RS and protein carbonyls were also unaffected. Similarly the erythrocyte concentrations of GSH and PUFA, and the activities of enzymatic antioxidants (Cu,Zn‐SOD, GPx, and CAT) were not significantly different from those of the patients before therapy. In lymphocytes the reduction concerned CoQ10H2, CoQ10, and vit E; other parameters were not investigated. The observed decline of the levels of CoQ10H2 and CoQ10 in plasma and of CoQ10H2, CoQ10 and vit E in lymphocytes following a 3 month statin therapy might lead to a reduced antioxidant capacity of LDL and lymphocytes, and probably of tissues such as liver, that have an elevated HMG‐CoA reductase enzymatic activity. However, this reduction did not appear to induce a significant oxidative stress in blood, since the levels of the other antioxidants, the pattern of PUFA as well as the oxidative damage to PUFA and proteins resulted unchanged. The concomitant administration of ubiquinone with statins, leading to its increase in plasma, lymphocytes and liver may cooperate in counteracting the adverse effects of statins, as already pointed out by various authors on the basis of human and animal studies.
Can coenzyme Q10 improve vascular function and blood pressure? Potential for effective therapeutic reduction in vascular oxidative stress
Authors: Hodgson Jonathan M. , Watts Gerald F.
Published: December 2008

Coenzyme Q10 (CoQ) is an endogenously synthesised compound that acts as an electron carrier in the mitochondrial electron transport chain. The presence of adequate tissue concentrations of CoQ may be important in limiting oxidative and nitrosative damage in vivo. Oxidative and nitrosative stress are likely to be elevated in conditions such as diabetes and hypertension. In these conditions elevated oxidative and nitrosative stress within the arterial wall may contribute to increased blood pressure and vascular dysfunction. The major focus of this review is the potential of CoQ to improve vascular function and lower blood pressure. Although there is substantial indirect support for the putative mechanism of effect of CoQ on the vascular system, to date there is little direct support for an effect of CoQ on in vivo markers of oxidative or nitrosative stress. The limited data available from studies in animal models and from human intervention studies are generally consistent with a benefit of CoQ on vascular function and blood pressure. The observed effects of CoQ on these endpoints are potentially important therapeutically. However, before any firm clinical recommendations can be made about CoQ supplementation, further intervention studies in humans are needed to investigate the effects of CoQ on vascular function, blood pressure and cardiovascular outcomes. The particularly relevant groups of patients for these studies are those with insulin resistance, type 2 diabetes, hypertension and the metabolic syndrome.
Antioxidant response induced by serum withdrawal protects HL‐60 cells against inhibition of NAD(P)H:quinone oxidoreductase 1
Authors: Gómez‐Díaz Consuelo , Bello Rosario I. , López‐Lluch Guillermo , Forthoffer Nathalie , Navas Plácido , Villalba José M.
Published: December 2008

We have previously shown that inhibition of NAD(P)H:quinone acceptor oxidoreductase 1 with dicoumarol decreases growth and viability of HL‐60 cells in the absence of serum. Here we demonstrate that culturing HL‐60 cells in serum‐free medium in the presence of dicoumarol results in a significant potentiation of apoptosis. However, when cells were preincubated for 24 h without serum before they were treated with dicoumarol, the effect of the inhibitor on cell growth and death was much lower. We have investigated cellular changes induced in HL‐60 cells by removal of serum that could account for protection against the effects of dicoumarol. Serum removal induced significant increases of NAD(P)H:quinone acceptor oxidoreductase 1, particularly at 32 h after serum withdrawal. Total amounts of ubiquinone in cells were unchanged but, its reduction state paralleled the observed increase in quinone reductase activity. Levels of the antiapoptotic protein Bcl‐2 were also significantly increased after serum removal. Our results indicate that removal of serum evokes an antioxidant protective response that make HL‐60 cells less sensitive to cell death induced by inhibition of NAD(P)H:quinone acceptor oxidoreductase 1 with dicoumarol.
Coenzyme Q, Vitamin E and Apo‐E alleles in Alzheimer Disease
Authors: Battino M. , Bompadre S. , Leone L. , Devecchi E. , Degiuli A. , D'Agostino F. , Cambiè G. , D'Agostino M. , Faggi L. , Colturani G. , Gorini A. , Villa R. F.
Published: December 2008

Neurodegenerative Diseases represent the most commmon cause of Dementia, about 5–10% of the population aged above 65 years and about 30% above 80 years. A study about Apo‐E alleles, Coenzyme Q and Vitamins E as biological indicators was performed in plasma samples of patients aged from 30 to 85 years, affected by Neurodegenerative Diseases. The results were compared with control subjects of approximately the same ages as the reference group.

A frequency of 21.7% of ϵ4 allele in control group was estimated, against 15.8% observed in patients. The frequency of ϵ2 and ϵ3 alleles was 13.0% and 65.2% in the control group against 10.5% and 73.7% in patients. No significant differences were observed between the frequency of ϵ3/ϵ3 genotype and ϵ3/ϵ4 genotype in the control group compared to patients' group. The frequencies observed in ϵ2/ϵ3 genotype groups were 8.7% vs 15.8% and of e2/e4 genotype 17.4% vs 5.3%. The ϵ2/ϵ2 and ϵ4/ϵ4 genotypes were not identified in any groups.

Plasma CoQ10 concentrations were similar in patient and control groups and no differences were found even taking into account the distribution of male and female subjects in the two groups. Also, vitamin E did not provide evidence of any differences between groups and the analysis among sexes revealed that again vitamin E concentrations were similar in between subgroups.
Hepatoprotective action of schisandrin B against carbon tetrachloride toxicity was mediated by both enhancement of mitochondrial glutathione status and induction of heat shock proteins in mice
Authors: Tang Man Ho , Chiu Po Yee , Ko Kam Ming
Published: December 2008

In the present study, we investigated the differential role of the mitochondrial glutathione status and induction of heat shock proteins (HSPs) 25/70 in protecting against carbon tetrachloride (CCl4) hepatotoxicity in schisandrin B (Sch B)‐pretreated mice. The time‐course of Sch B‐induced changes in these hepatic parameters were examined. Dimethyl diphenyl bicarboxylate (DDB), a non‐hepatoprotective analog of Sch B, was studied for comparison. Sch B treatment (2 mmol/kg) produced maximal enhancement in hepatic mitochondrial glutathione status as well as increases in hepatic HSP 25/70 levels at 24 h post‐dosing. The stimulatory effect of Sch B then gradually subsided, but the activities of hepatic mitochondrial glutathione reductase (GR) and glutathione S‐transferases (GST) as well as the level of HSP 25 remained relatively high even at 72 h post‐dosing. CCl4challenge caused significant impairment in mitochondrial glutathione status and a decrease in HSP 70 level, but the HSP 25 level was significantly elevated. While the extent of hepatoprotection afforded by Sch B pretreatment against CCl4was found to inversely correlate with the time elapsed after the dosing, the protective effect was associated with the ability of Sch B to maintain the mitochondrial glutathione status and/or induce further production of HSP 25 in CCl4‐intoxicated condition. On the other hand, DDB treatment (2 mmol/kg), which did not increase mitochondrial GSH level and GST activity or induce further production of HSP 25 after CCl4challenge, could not protect against CCl4toxicity. The results suggest that the enhancement of mitochondrial glutathione status and induction of HSP 25/70 may contribute independently to the hepatoprotection afforded by Sch B pretreatment.
Antioxidant activity in vitro of two aromatic compounds from Caesalpinia sappan L
Authors: Safitri Ratu , Tarigan Ponis , Freisleben Hans Joachim , Rumampuk Rymond J. , Murakami Akira
Published: December 2008

Two antioxidant compounds were isolated from C. sappan L by multiple steps of column chromatography and thin layer chromatography in succession with superoxide scavenging assay as activity monitor. Structures of the two compounds were determined by spectroscopic methods as 1′,4′‐dihydro‐spiro[benzofuran‐3(2H),3′‐[3H‐2]benzopyran]‐1′,6′,6′,7′‐tetrol (compound 1) and 3‐[[4,5‐dihydroxy‐2(hydroxymethyl) phenyl]‐methyl]‐2,3‐dihydro‐3,6‐benzofurandiol (compound 2). Characterization of antioxidant properties of these two compounds was done by determining the inhibitory effect on xanthine oxidase activity as well as scavenging effect on superoxide anion and hydroxyl radicals. Our results indicated that compounds 1 and 2 inhibited xanthine oxidase activity and scavenged superoxide anion and hydroxyl radicals. Compounds 1 and 2 possessed similar radical scavenging activities as ascorbic acid, and they were more effective than other well‐known antioxidants such as α‐tocopherol, β‐carotene, and BHT. As inhibitors of free radical formation, compounds 1 and 2 were more effective than all the other antioxidants tested. In conclusion, compounds 1 and 2 can be regarded as primary antioxidants with radical‐scavenging and chain‐breaking activities as well as secondary antioxidants with inhibitory effect on radical generation.
Caroverine, a multifunctional drug with antioxidant functions
Authors: Nohl Hans , Bieberschulte Werner , Dietrich Barbara , Udilova Natalia , Kozlov Andrey V.
Published: December 2008

Here we show that lipid peroxidation of liposomal membranes was suppressed in the presence of Caroverine, a spasmolytic drug used in some countries. In order to understand the mechanism of this antioxidant action of Caroverine we studied the interaction of Caroverine with superoxide radicals, hydroxyl radicals and peroxynitrite. The results of the study show that the reaction of Caroverine with O radicals is of marginal significance. However, it is efficient in removing peroxynitrite and a particular high reaction constant was found for reaction with hydroxyl radicals. The strong antioxidant activity of Caroverine is therefore based both on the partial prevention of the formation and the highly active scavenging of hydroxyl radicals.
The accumulation of α‐Tocopherol and Retinol in the milk of water buffalo is correlated with the plasma levels of triiodothyronine
Authors: Spagnuolo M. S. , Cigliano L. , Sarubbi F. , Polimeno F. , Ferrara L. , Bertoni G. , Abrescia P.
Published: December 2008

Milk is the most important source of Retinol and α‐Tocopherol for calves. These antioxidants save the food quality and prevent lipid oxidation in the mammary gland and the calf growing tissues. In Bubalus bubalis, seasonal changes for the plasma levels of both antioxidants were not found. The levels of Retinol and α‐Tocopherol in the milk were 2 and 1.7 times higher in winter than in summer, respectively. These levels were correlated with the plasma level of triiodothyronine, and markedly increased in cows injected with triiodothyronine in summer. The cytosol from alveolar epithelial cells of mammary glands was incubated with α‐Tocopherol and 3H‐Retinol and, after gel filtration chromatography, both antioxidants were found associated with proteins migrating as a single peak of 33 kD. The amount of α‐Tocopherol and Retinol binding proteins was 1.5 and 2.3 times higher in winter than in summer respectively. The Retinol binding proteins migrated as two bands (33 and 16 kD) by electrophoresis in denaturing and reducing conditions. Our data suggest that triiodothyronine enhances the transport of both liposoluble antioxidants through the blood‐mammary barrier, and demonstrate that proteins of the mammary epithelial cells are involved in such a transport.
Resveratrol protects against 4‐HNE induced oxidative stress and apoptosis in Swiss 3T3 fibroblasts
Authors: Kutuk Ozgur , Adli Mazhar , Poli Giuseppe , Basaga Huveyda
Published: December 2008

Here we report on the marked protective effect of resveratrol on 4‐hydroxynonenal (4‐HNE) induced oxidative stress and apoptotic death in Swiss 3T3 fibroblasts. 4‐HNE, one of the major aldehydic products of the peroxidation of membrane w‐6 polyunsaturated fatty acids, has been suggested to contribute to oxidant stress mediated cell injury. Indeed, in vitro treatment of 3T3 fibroblasts with 4‐HNE induced a condition of oxidative stress as monitored by the oxidation of dichlorofluorescein diacetate; this reaction was prevented when cells were pretreated with resveratrol. Further, 4‐HNE‐treated fibroblasts eventually underwent apoptotic death as determined by differential staining and internucleosomal DNA fragmentation. Resveratrol pretreatment also prevented 4‐HNE induced DNA fragmentation and apoptosis. These observations are consistent with a potential role of lipid peroxidation‐derived products in programmed cell death and demonstrate that resveratrol can counteract this effect by quenching cell oxidative stress.
Prevention of diabetic nephropathy by treatment with astaxanthin in diabetic db/db mice
Authors: Naito Yuji , Uchiyama Kazuhiko , Aoi Wataru , Hasegawa Goji , Nakamura Naoto , Yoshida Norimasa , Maoka Takashi , Takahashi Jiro , Yoshikawa Toshikazu
Published: December 2008

Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. Astaxanthin, which is found as a common pigment in algae, fish, and birds, is a carotenoid with significant potential for antioxidative activity. In this study, we examined whether chronic administration of astaxanthin could prevent the progression of diabetic nephropathy induced by oxidative stress in mice. We used female db/db mice, a rodent model of type 2 diabetes, and their non‐diabetic db/m littermates. The mice were divided into three groups as follows: non‐diabetic db/m, diabetic db/db, and diabetic db/db treated with astaxanthin. Blood glucose level, body weight, urinary albumin, and urinary 8‐hydroxydeoxyguanosine (8‐OHdG) were measured during the experiments. Histological and 8‐OHdG immunohistochemical studies were performed for 12 weeks from the beginning of treatment. After 12 weeks of treatment, the astaxanthin‐treated group showed a lower level of blood glucose compared with the non‐treated db/db group; however, both groups had a significantly high level compared with the db/m mice. The relative mesangial area calculated by the mesangial area/total glomerular area ratio was significantly ameliorated in the astaxanthin‐treated group compared with the non‐treated db/db group. The increases in urinary albumin and 8‐OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with astaxanthin. The 8‐OHdG immunoreactive cells in glomeruli of non‐treated db/db mice were more numerous than in the astaxanthin‐treated db/db mice. In this study, treatment with astaxanthin ameliorated the progression and acceleration of diabetic nephropathy in the rodent model of type 2 diabetes. The results suggested that the antioxidative activity of astaxanthin reduced the oxidative stress on the kidneys and prevented renal cell damage. In conclusion, administration of astaxanthin might be a novel approach for the prevention of diabetes nephropathy.
Selenium deficiency impairs corticosterone and leptin responses to adrenocorticotropin in the rat
Authors: Chanoine Jean‐Pierre , Wong Alfred C.K. , Lavoie Jean‐Claude
Published: December 2008

Selenium deficiency causes oxidative stress and impairs steroidogenesis in vitro. Leptin is closely related to the hypothalamo‐pituitary‐adrenal (HPA) axis. Leptin inhibits the HPA axis at the central level while corticosteroids have been shown to stimulate leptin secretion in most studies. We hypothesized that oxidative stress impairs adrenal steroidogenesis and decreases leptin production in vivo. The goal of this study was to investigate in rats the effects of selenium deficiency and oxidative stress on adrenal function and on leptin concentrations.

Weanling rats were fed a selenium‐deficient (Se‐) or selenium‐sufficient (Se+) diet for 4–10 weeks. Selenium deficiency caused a marked decrease in liver (≥ 99%) and adrenal (≥ 81%) glutathione peroxidase (GPx) activities. Selenium deficiency did not affect basal and short‐term adrenocorticotropin (ACTH) stimulated corticosterone or leptin concentrations. In contrast, after long‐term ACTH stimulation, selenium deficiency caused a doubling in adrenal isoprostane content and blunted the increase in corticosterone and leptin concentrations observed in Se+ animals. Plasma leptin concentrations were 50% lower in Se‐ compared to Se+ animals following long‐term ACTH. Our results suggest that oxidative stress causes a decrease in circulating corticosterone in response to ACTH, and, as a consequence, a decrease in plasma leptin concentrations.
Study of factors affecting binding of zinc with albumin at physiological zinc concentrations
Authors: Agte V.V. , Nagmote R.V.
Published: December 2008

Albumin has very high affinity for many organic and inorganic compounds that may influence albumin bound Zn (ABZn). To get insight of these molecular interactions, the effect of riboflavin, nicotinic acid, thiamine, folic acid, pyruvic acid and glucose on ABZn were studied. The ABZn was separated from the unbound zinc using equilibrium dialysis and estimated using atomic absorption spectrometer. At therapeutic zinc concentrations, folic acid and thiamine significantly enhanced the ABZn (p< 0.010), while nicotinic acid inhibited zinc binding to albumin. Folic acid was found to enhance the ABZn also at lower zinc concentrations representing physiological levels of plasma zinc (138–150 micromoles) (p< 0.05).
Plasma membrane oxidoreductase activity in cultured cells in relation to mitochondrial function and oxidative stress
Authors: Deleonardi Giulia , Biondi Annalisa , D'Aurelio Marilena , Pich Milena Merlo , Stankov Karmen , Falasca Anna , Formiggini Gabriella , Bovina Carla , Romeo Giovanni , Lenaz Giorgio
Published: December 2008

Dichlorophenol indophenol (DCIP) reduction by intracellualr pyridine nucleotides was investigated in two different lines of cultured cells characterized by enhanced production of reacive oxygen species (ROS) with respect to suitable controls. The first line denominated XTC‐UC1 was derived from a metastasis of an oxyphilic thyroid tumor characterized by mitochondrial hyperplasia and compared with a line (B‐CPAP) derived from a papillary thyroid carcinoma with normal mitochondrial mass. The second line (170 MN) was a cybrid line derived from ρ0 cells from an osteosarcoma line (143B) fused with platelets from a patient with a nucleotide 9957 mutation in mitochondrial DNA (encoding for cytochrome c oxidase subunit III) in comparison with the parent 143B line. The experimental lines had no major decreases of electron transfer activities with respect to the controls; both of them, however, exhibited an increased peroxide production.

The XTC‐UC1 cell line exhibited enhanced activity with respect to control of dicoumarol‐sensitive DCIP reduction, identified with membrane bound DT‐diaphorase, whereas dicoumarol insensitive DCIP reduction was not significantly changed. On the other hand the mtDNA mutated cybrids exhibited a strong increase of both dicoumarol sensitive and insensitive DCIP reduction.

The results suggest that enhanced oxidative stress and not deficient respiratory activity per se is the stimulus triggering over‐expression of plasma membrane oxidative enzymes.