bluuebunny/crossref_metadata_2025 huggingface dataset:
Removal of soluble selenium by a selenate‐reducing bacterium Bacillus sp. SF‐1
Authors: Kashiwa Masami , Ike Michihiko , Mihara Hisaaki , Esaki Nobuyoshi , Fujita Masanori
Published: December 2008

In order to develop a biological process for removal of selenium from industrial wastewater, Bacillus sp. strain SF‐1 was isolated from selenium‐contaminated sediment. The bacterium reduces selenate to selenite and subsequently to nontoxic insoluble elemental selenium using lactate as an electron donor and selenate as an electron acceptor in an anaerobic condition. Elemental selenium transformed from soluble selenium was deposited both inside and outside of the cells. Since the selenate reduction rate of the strain SF‐1 was higher than the selenite reduction rate, selenite was transiently accumulated. In an experiment of the repeated soluble selenium reduction by strain SF‐1, 0.5 mM of selenate was sequentially treatable with a cycle of one day. Thus, our sequential system for removal of soluble selenium is very useful.
Dietary copper and dimethylhydrazine affect protein kinase C isozyme protein and mRNA expression and the formation of aberrant crypts in colon of rats
Authors: Davis Cindy D. , Johnson W. Thomas
Published: December 2008

Low dietary copper has been shown to decrease the expression of various protein kinase C (PKC) isozymes and increase the risk of colon cancer development in experimental animals. The purpose of this study was to investigate the relationship between dietary copper and carcinogen administration on PKC isozyme accumulation and aberrant crypt foci (ACF) formation in rats fed 0.9 and 7.7 μg Cu/g diet. After 24 and 31 d on the diets, the rats were injected with either dimethylhydrazine (DMH) (25 mg/kg i.p.) or saline and killed at two time points (2 wk and 8 wk after DMH). Rats fed low dietary copper had significantly lower (p<0.0001) hematocrits, hemoglobin, ceruloplasmin activity and plasma and liver copper concentrations than rats fed adequate dietary copper. Ingestion of low dietary copper significantly (p<0.005) increased the formation of DMH‐induced ACF (116.8 vs 59.6). Low dietary copper significantly (p<0.05) decreased the concentration of PKC α, δ, and ζ in the colon at 2 wk but not at 8 wk. Thus, changes in PKC isoform protein concentration may be related to increased susceptibility of copper‐deficient animals to colon cancer.
Biological effects of a nano red elemental selenium
Authors: Zhang Jin‐Song , Gao Xue‐Yun , Zhang Li‐De , Bao Yong‐Ping
Published: December 2008

A novel selenium form, nano red elemental selenium (Nano‐Se) was prepared by adding bovine serum albumin to the redox system of selenite and glutathione. Nano‐Se has a 7‐fold lower acute toxicity than sodium selenite in mice (LD50 113 and 15 mg Se/kg body weight respectively). In Se‐deficient rat, both Nano‐Se and selenite can increase tissue selenium and GPx activity. The biological activities of Nano‐Se and selenite were compared in terms of cell proliferation, enzyme induction and protection against free racial‐mediated damage in human hepatoma HepG2 cells. Nano‐Se and selenite are similarly cell growth inhibited and stimulated synthesis of glutathione peroxidase (GPx), phospholipid hydroperoxide glutathione peroxidase (PHGPx) and thioredoxin reductase (TR). When HepG2 cells were co‐treated with selenium and glutathione, Nano‐Se showed less pro‐oxidative effects than selenite, as measured by cell growth. These results demonstrate that Nano‐Se has a similar bioavailability in the rat and antioxidant effects on cells.
Absorption and excretion of orally administered inositol hexaphosphate (IP6 or phytate) in humans
Authors: Grases Felix , Simonet Bartolomé M. , Vucenik Ivana , Prieto Rafel M. , Costa‐Bauzá Antonia , March Joan G. , Shamsuddin Abulkalam M.
Published: December 2008

A study of the pharmacokinetic profile (oral absorption and renal excretion) of inositol hexaphosphate or phytate (IP6) is presented. Seven healthy volunteers were following a IP6 poor diet (IP6PD) in a first period, and on IP6 normal diet (IP6ND) in a second one. When following the IP6PD they become deficient in IP6, the basal levels found in plasma (0.07± 0.01 mg/L) being clearly lower than those found when IP6ND was consumed (0.26± 0.03 mg/L). During the restriction period the maximum concentration in plasma were obtained 4 h after the ingestion of a single dose of IP6, observing almost the same renal excretion profiles for the three different comercial sources and doses. After the IP6 restriction period, volunteers were on IP6ND, reaching normal plasma and urinary IP6 values in 16 days. Thus, the normal plasma and urinary concentrations, can be obtained either by comsumption of a IP6ND taking a long time or in a short period by IP6 supplements.
Transport of methotrexate into LNCaP human prostate cancer cells
Authors: Horne Donald W. , Reed Kathleen A.
Published: December 2008

Uptake of methotrexate into the LNCaP human prostate cancer cells was linear for the first 60∼min. The initial rate of methotrexate uptake was highest at extracellular pH 4.5 and decreased markedly until pH 7.0 to 8.0. Transport of methotrexate into LNCaP cells showed two components, one saturable ‐Km = 0.13 ± 0.06 μM and Vmax = 1.20 ± 0.16 pmol · 45 min−1 · mg−1 protein at low concentrations and the other apparently not saturable up to 10 μM. Uptake of methotrexate was inhibited by structural analogs with the Ki values being 6.53, 12.4, and 85.6 μM for 5‐formyltetrahydrofolate, 5‐methyltetrahydrofolate, and folic acid, respectively. Uptake of methotrexate into LNCaP cells was not inhibited by the energy poisons in contrast to methotrexate uptake into PC‐3 prostate cancer cells. Uptake was inhibited by increasing concentrations of sulfate and phosphate ions and by the organic anions probenecid and DIDS, suggesting that methotrexate may be transported by an anion‐exchange mechanism. These results show that methotrexate is transported into LNCaP prostate cancer cells by a carrier‐mediated process.
Antioxidant effects of α‐ and γ‐carboxyethyl‐6‐hydroxychromans
Authors: Yoshida Yasukazu , Niki Etsuo
Published: December 2008

Carboxyethyl‐6‐hydroxychromans (CEHC), the major metabolites of both tocopherols (Toc) and tocotrienols (Toc‐3), have been found in human plasma. In the present study, the antioxidant properties of α‐ and γ‐CEHC were measured and compared with α‐ and γ‐ tocopherols. Following results were obtained: (1)α‐ and γ‐CEHC have the same reactivities toward radicals and exert the same antioxidant activities against lipid peroxidation in organic solution as the corresponding parent tocopherols respectively; (2) the partition coefficient decreased in the order α‐Toc (3.36) > γ‐Toc (3.14) > α‐CEHC (2.26) > pentamethyl‐6‐chromanol (1.92) > γ‐CEHC (1.83) > 0 > Trolox (‐0.97); (3) α‐ and γ‐CEHC scavenge aqueous radicals more efficiently but they inhibit the lipid peroxidation within the membranes less efficiently than the corresponding α‐ and γ‐Toc, respectively; (4) α‐CEHC inhibits the oxidation synergistically with ascorbate; and (5) α‐ andγ‐CEHC reduce Cu(II) to give Cu(I) and corresponding quinones as major product, but the prooxidant effect of CEHC in the presence of cupric ion was small. These results imply that CEHC may act as an antioxidant in vivo especially for those who take tocopherol supplement.
Detoxification of electrophilic compounds by glutathione S‐transferase catalysis: Determinants of individual response to chemical carcinogens and chemotherapeutic drugs?
Authors: Coles Brian F. , Kadlubar Fred F.
Published: December 2008

The glutathione S‐transferases (GSTs) catalyze the GSH‐dependent detoxification of reactive electrophiles such as genotoxic chemical carcinogens and cytotoxic chemotherapeutic agents. Allelic polymorphism in the GSTs has been used to investigate the hypothesis that GSTs are involved in susceptibility to human cancers. Such studies have resulted in low penetrance, high prevalence associations between cancer risk and GST polymorphisms. By examination of interindividual variation of GST expression it becomes clear that GST genotype alone is not an accurate predictor of GST expression. GST expression is tissue specific and interindividual variation of expression is at least 7‐fold in normal tissues. Thus, populations of the same genotype are actually heterogeneous as regards expression. Similarly, polymorphisms are not effective in all tissues and GST induction is not independent of genotype. Mechanistic models for chemical aspects of colorectal cancer and chemotherapy for breast cancer demonstrate some of the ways by which such interactions can be studied and the potential for future studies.
Molecular chaperones, stress proteins and redox homeostasis
Authors: Papp Eszter , Nardai Gábor , Söti Csaba , Csermely Péter
Published: December 2008

Protection against oxidative stress is highly interrelated with the function of the most ancient cellular defense system, the network of molecular chaperones, heat shock, or stress‐proteins. These ubiquitous, conserved proteins help other proteins and macromolecules to fold or re‐fold and reach their final, native conformation. Redox regulation of protein folding becomes especially important during the preparation of extracellular proteins to the outside oxidative milieu, which should take place in a gradual and step‐by‐step controlled manner in the endoplasmic reticulum or in the periplasm. Several chaperones, such as members of the Hsp33 family in yeast and the plethora of small heat shock proteins as well as one of the major chaperones, Hsp70 are able to act against cytoplasmic oxidative damage. Abrupt changes of cellular redox status lead to chaperone induction. The function of several chaperones is tightly regulated by the surrounding redox conditions. Moreover, our recent data suggest that chaperones may act as a central switchboard for the transmission of redox changes in the life of the cell.
Redox signaling and the MAP kinase pathways
Authors: Torres Martine , Forman Henry Jay
Published: December 2008

The mitogen‐activated protein (MAP) kinases are a large family of proline‐directed, serine/threonine kinases that require tyrosine and threonine phosphorylation of a TxY motif in the activation loop for activation through a phosphorylation cascade involving a MAPKKK, MAPKK and MAPK, often referred to as the MAP kinase module. Three separate such modules have been identified, based on the TxY motif of the MAP kinase and the dual‐specificity kinases that strictly phosphorylate their specific TxY sequence. They are the extracellular signal regulated kinases (ERKs), c‐jun N‐terminal kinases (JNKs) and p38 MAPKs. The ERKs are mainly associated with proliferation and differentiation while the JNKs and p38MAP kinases regulate responses to cellular stresses.

Redox homeostasis is critical for proper cellular function. While reactive oxygen species (ROS) and oxidative stress have been implicated in injury, a rapidly growing literature suggests that a transient increase in ROS levels is an important mediator of proliferation and results in activation of various signaling molecules and pathways, among which the MAP kinases. This review will summarize the role of ROS in MAP kinase activation in various systems, including in macrophages, cells of myeloid origin that play an essential role in inflammation and express a multi‐component NADPH oxidase that catalyzes the receptor‐regulated production of ROS.
Overview on coenzyme Q10 as adjunctive therapy in chronic heart failure. Rationale, design and end‐points of “Q‐symbio” ‐ A multinational trial
Authors: Mortensen Svend Aage
Published: December 2008

Energy starvation of the myocardium is probably a dominant feature of heart failure and attention has been directed towards agents which may stabilize myocardial metabolism and maintain adequate energy stores. A reduced myocardial tissue content of the essential redox‐component and natural antioxidant Coenzyme Q10 (CoQ10) has been detected in patients with heart failure and the observed level of CoQ10 deficiency was correlated to the severity of heart failure.

CoQ10 fulfills various criteria of an obvious adjunct in patients with symptomatic heart failure: it is devoid of significant side effects and it improves symptoms and quality of life. Till this date, several double‐blind placebo‐controlled trials with CoQ10 supplementation in more than 1000 patients have been positive and statistically significant with respect to various clinical parameters, e.g. improvement in NYHA Class, exercise capacity and reduced hospitalisation frequency. Also treatment with CoQ10 led to a significant improvement of relevant hemodynamic parameters. In only 3 out of 13 double‐blind studies comprising 10% of the total number of patients treated the results were neutral. Thus, based on the available controlled data CoQ10 is a promising, effective and safe approach in chronic heart failure.

This is why a double‐blind multicenter trial with focus on morbidity and mortality has been planned to start in 2003: Q‐SYMBIO. Patients in NYHA classes III to IV (N=550) receiving standard therapy are being randomized to treatment with CoQ10 100 mg t.i.d. or placebo in parallel groups. End‐points in a short‐term evaluation phase of 3 months include symptoms, functional capacity and biomarker status (BNP). The aim of a subsequent 2‐year follow‐up study is to test the hypothesis that CoQ10may reduce cardiovascular morbidity (unplanned cardiovascular hospitalisation due to worsening heart failure) and mortality as a composite endpoint. This trial should help to establish the future role of CoQ10 as part of a maintenance therapy in patients with chronic heart failure.
Relaxation of arterial smooth muscle: A new function of a water‐soluble degradation product of coenzyme Q (ubiquinone)
Authors: Bindu R. , Venkataraman B. V. , Rao Aparna V. S. , Ramasarma T.
Published: December 2008

Treatment of coenzyme Q with ozone yielded a degradation product having unmodified ring that retained its spectral characteristics and a truncated side‐chain that made it water‐soluble. This derivative, but not the intact lipid‐quinone, showed relaxation of phenylephrine‐contracted rat arterial rings. This effect offers an explanation for the known hypotensive action of exogenous coenzyme Q regardless of its side‐chain length.
Derivatised α‐tocopherol as α CoQ10 carrier in a novel water‐soluble formulation
Authors: Sikorska Marianna , Borowy‐Borowski Henryk , Zurakowski Bogdan , Roy Walker P.
Published: December 2008

We have derivatised α‐tocopherol (vitamin E) to a water‐soluble polyoxyethanyl‐α ‐ tocopheryl sebacate (PTS) and discovered that it formed a non‐covalent complex with CoQ10 at a molar ratio of 2:1 (PTS‐CoQ10). This complex was water‐soluble and remained stable for extended periods of time. After oral delivery of the formulation into rats PTS was hydrolysed to vitamin E and elevated levels of both vitamin E and CoQ10 in blood plasma were detected within 1 h. Thus, this aqueous formulation contains a combination of two potent antioxidants. The formulation's efficacy was tested against ischemic brain damage caused by a transient (8∼min) bilateral occlusion of the common carotid arteries in rats. The animals received PTS‐CoQ10 by two intraperitoneal injections given immediately after ischemia and 3 h later and the brain damage was assessed up to 12 days post‐ischemia. A significant neuroprotection was observed in the CA1 hippocampal region, for example at 12 days approximately 50% of CA1 neurons were still alive in the treated animals versus less than 5% in the non‐treated group. Our data is consistent with previously published observations indicating the therapeutic potential of antioxidants for treatments of ischemia/reperfusion injuries and the formulation described here is particularly appropriate for the application in acute conditions, such as stroke or cardiac arrest.
Serum coenzyme Q10 concentrations in healthy men supplemented with 30 mg or 100 mg coenzyme Q10 for two months in a randomised controlled study
Authors: Zita Čestmír , Overvad Kim , Mortensen Svend Aage , Sindberg Christian Dan , Moesgaard Sven , Hunter Douglas A.
Published: December 2008

Serum coenzyme Q10 (Q10) concentrations were evaluated in healthy male volunteers supplemented with 30 mg or 100 mg Q10 or placebo as a single daily dose for two months in a randomised, double‐blind, placebo‐controlled study. Median baseline serum Q10concentration in 99 men was 1.26 mg/l (10%, 90% fractiles: 0.82, 1.83). Baseline serum Q10 concentration did not depend on age, while borderline significant positive associations were found for body weight and smoking 1–10 cigarettes/d. Supplementation with 30 mg or 100 mg Q10 resulted in median increases in serum Q10 concentration of 0.55 mg/l and 1.36 mg/l, respectively, compared with a median decrease of 0.23 mg/l with placebo. The changes in the Q10 groups were significantly different from that in the placebo group, and the increase in the 100 mg Q10 group was significantly greater than that in the 30∼mg Q10 group. The change in serum Q10concentration in the Q10 groups did not depend on baseline serum 10 concentration, age, or body weight.
Cytoprotective and anticancer properties of coenzyme Q versus capsaicin
Authors: Galati Giuseppe , O'Brien Peter J.
Published: December 2008

Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and serves as an electron donor and acceptor in mitochondrial energy‐linked respiration. CoQ1was shown to prevent ROS formation and cell death in complex 1 inhibited cells. Low concentrations of capsaicin like CoQ1inhibited ROS formation but CoQ1was more effective at restoring the mitochondrial membrane potential collapse caused by complex 1 inhibitors such as rotenone. At low concentrations, capsaicin acts as a CoQ mimic by protecting against rotenone induced ROS formation and mitochondrial membrane potential collapse. Lipid peroxidation in isolated rat hepatocytes induced by cumene hydroperoxide and chloroacetaldehyde was also prevented. At higher concentrations, capsaicin and CoQ1became cytotoxic. Hep G2 cells were more susceptible than hepatocytes. The cytotoxic mechanism for both capsaicin and CoQ1was shown to involve a collapse of the mitochondrial membrane potential, however, only capsaicin caused ROS formation. The capsaicin side chain was required for capsaicin induced cytotoxicity. The anticancer properties of CoQ1and capsaicin should prove useful for inducing tumor cell apoptosis.
Pleiotropic phenotypes of fission yeast defective in ubiquinone‐10 production. A study from the abc1Sp (coq8Sp) mutant
Authors: Saiki Ryoichi , Ogiyama Yuki , Kainou Tomohiro , Nishi Tomoko , Matsuda Hideyuki , Kawamukai Makoto
Published: December 2008

We previously constructed two Schizosaccahromyces pombe ubiquinone‐10 (or Coenzyme Q10) less mutants, which are either defective for decaprenyl diphosphate synthase or p‐hydroxybenzoate polyprenyl diphosphate transferase. To further confirm the roles of ubiquinone in S. pombe, we examined the phenotype of the abc1Sp (coq8Sp) mutant, which is highly speculated to be defective in ubiquinone biosynthesis. We show here that the abc1Sp defective strain did not produce UQ‐10 and could not grow on minimal medium. The abc1Sp‐deficient strain required supplementation with antioxidants such as cysteine or glutathione to grow on minimal medium. In support of the antioxidant function of ubiquinone, the abc1Sp‐deficient strain is sensitive to H2O2 and Cu2+. In addition, expression of the stress inducible ctt1 gene was much induced in the ubiquinone less mutant than wild type. Interestingly, we also found that the abc1‐deficient strain as well as other ubiquinone less mutants produced a significant amount of H2S, which suggests that oxidation of sulfide by ubiquinone may be an important pathway for sulfur metabolism in S. pombe. Thus, analysis of the phenotypes of S. pombe ubiquinone less mutants clearly demonstrate that ubiquinone has multiple functions in the cell apart from being an integral component of the electron transfer system.
Coenzyme Q10‐containing composition (Immugen®) protects against occupational and environmental stress in workers of the gas and oil industry
Authors: Korkina Ludmila , Deeva Irina , Ibragimova Galina , Shakula Alexander , Luci Antonio , Luca Chiara De
Published: December 2008

The manual workers of the gas‐and‐oil extraction industry are exposed to hostile environmental and occupational conditions, resulting in elevated mortality and disability, due to chronic neurological and cardiovascular diseases. We evaluated the degree of oxidative stress, often associated with these pathological features, in the blood of manual and office employees of Russian Siberian extraction plants, and their psycho‐physiological conditions. Results showed increased levels of spontaneous (p < 0.05) and PMA‐activated (p < 0.01) luminol‐dependent chemiluminescence (LDCL) in the white blood cells (WBC), and decreased peroxynitrite levels (p < 0.05) in the group of manual workers, and less markedly in the clerks and technicians working on spot, vs. a control group of city clerks. Superoxide release by WBC, and plasma/WBC membrane ubiquinol levels did not display major differences in the three groups. A relevant percentage of manual/office workers of extraction platforms presented impaired cardiovascular and neurological functions. The short term administration of a nutraceutical formulation based on coenzyme10, vitamin E, selenium, methionine and phospholipids led to significant improvement of cardiovascular parameters and psycho‐emotional status, consistent with the normalization of LDCL and peroxynitrite production by WBC, with a good compliance to treatment confirmed by the increased blood levels of ubiquinol.
The effect of Cyclosporine A chronic administration on the antioxidant pattern of rat liver mitochondria: Structural and functional consequences
Authors: Battino Maurizio , Bompadre Stefano , Leone Luciana , Pugnaloni Armanda , Rubini Corrado , Ferreiro Maria Soledad , Gallardo Isabel , Bullon Pedro
Published: December 2008

Cyclosporine A (CsA) plays a pivotal role in controlling Ca2+movement in the cell modulating also the mitochondrial permeability transition pore. We investigated if chronic administration of CsA may have some effects on the lipophilic and hydrophilic antioxidant pattern of rat liver mitochondria and on their morphological structure. It seems that CsA administration does not statistically affect the redox status of the antioxidants investigated and their amounts (vitamin E, CoQ9, CoQ10, glutathione,uric acid and ascorbic acid) despite the variety of effects that this treatment produces at physiological and morphological levels. However, some kind of derangement could occur in the liver biochemical machinery since CsA treatment induces a markedly increased variability in antioxidant contents.
The effects of Coenzyme Q10 on locomotor and behavioral activity in young and aged C57BL/6 mice
Authors: Sinatra Drew S. , Sinatra Stephen T. , Heyser Charles J.
Published: December 2008

To explore the possibility that Coenzyme Q10 (CoQ10) supplementation stabilizes psychomotor behavioral function in the aging organism, the behavioral effects of CoQ10 were evaluated in young adult male C57BL/6 mice (3 months of age) and aged C57BL/6 mice (24 months of age). Mice treated with CoQ10 exhibited significantly greater locomotor activity as reflected by an increase in square crosses than non‐drug controls. The administration of CoQ10 increased all aspects of exploratory behavior in the open field. The effect was uniform across all mice and did not interact with age.

Younger animals and aged animals treated with CoQ10 may adapt rapidly to novel areas, or they are less fearful of exploration. The behavioral activation observed in CoQ10 treated mice may be the result of increased locomotor activity, psychomotor stimulation, or decreased anxiety.
Coenzyme Q10, antioxidant status and ApoE isoforms
Authors: Battino M. , Giunta S. , Galeazzi L. , Galeazzi R. , Mosca F. , Santolini C. , Principi F. , Ferretti G. , Bacchetti T. , Bencivenga R. , Piani M. , Riganello G. , Littarru G. P.
Published: December 2008

The aim of this study was to inquire the antioxidant status in plasma and lipoproteins isolated from normal subjects possessing different ApoE genotypes. For this purpose we investigated blood samples from 106 healthy blood donors: the distribution of ApoE alleles (E2/E2 = 0.9%, E2/E3 = 10.4%, E2/E4 = 2.8%, E3/E3 = 71.7%, E3/E4 = 12.3% and E4/E4 1.9% with 1, 11, 3, 76, 13, and 2 subjects respectively for each genotype) was in agreement with previous data. Almost no differences were found in the concentrations of both coenzyme Q10 (CoQ10) and vitamin E for the different genotypes. Concentration of CoQ10 in isolated lipoproteins was also similar, in the different genotypes, when referred to cholesterol; CoQ10 in LDL was higher for the E3/E3 subjects when referred to protein. Neither CoQ10 nor vitamin E correlated with paraoxonase (PON) activity or cholesteryl‐ester hydroperoxides (CHP). Furthermore, there was no correlation between the same lipophilic antioxidants and CHP levels. The only E2 homozygous subject found had high levels of PON and low levels of CHP; the two E4/E4 subjects had low PON activity together with low levels of CHP.
Peroxiredoxins in antioxidant defense and redox regulation
Authors: Flohé Leopold , Budde Heike , Hofmann Birgit
Published: December 2008

Peroxiredoxins constitute a family of peroxidases that lack prosthetic groups or catalytically active heteroatoms. Instead, their peroxidatic activity is due to a strictly conserved cysteine that is activated within a novel catalytic triad in which the cysteine thiol is coordinated to an arginine and a threonine or serine residue. Donor substrates are thiol compounds which differ between subtypes of peroxiredoxins and species. In pathogenic trypanosomatids that lack heme‐ or seleno‐peroxidases peroxiredoxins have been shown to represent the major devices to detoxify hydroperoxides and an equivalent role may be assumed for other protozoal parasites and many bacterial pathogens. In mammals equipped with more efficient peroxidases the peroxiredoxins appear to be responsible for the redox regulation of diverse metabolic processes. The substantial differences in the cosubstrate requirements of the peroxiredoxins of pathogenic microorganisms and their mammalian host may be exploited to selectively inhibit the antioxidant defense of pathogens. Thereby, the pathogen would be more readily eliminated by the innate immune response of the host's phagocytes.
Oxidative stress: The special case of diabetes
Authors: Wiernsperger N. F.
Published: December 2008

The implication of oxidative stress (OS) in diabetes is a major concern for the development of therapeutics aimed at improving the metabolic and/or vascular dysfunctions of this burdening disease. Ample evidence is available suggesting that OS is present in essentially all tissues and can even be observed in prediabetic states. This raises the question of the origin of OS and suggests that, although hyperglycemia is largely linked with free radical production, its role may mainly be the aggravation of a preexisting state. Indeed other factors are also causally linked to OS, such as hormones and lipids. The main debate is about the pertinence of antioxidant therapy since the large scale clinical trials performed recently have essentially failed to show any significant improvement in metabolic or vascular disturbances of diabetic patients. However this conclusion must be tempered by the fact that they have mainly been using vitamin E +/‐C; indeed many arguments suggest that either the choice or the application modalities of these substances may have been inadequate. Potential reasons for the actual failure of antioxidant therapy in diabetes are discussed; the indisputable involvement of OS in this disease still leaves hope for alternative therapeutic approaches.
Time‐dependent enhancement in mitochondrial glutathione status and ATP generation capacity by schisandrin B treatment decreases the susceptibility of rat hearts to ischemia‐reperfusion injury
Authors: Chiu Po Yee , Ko Kam Ming
Published: December 2008

In the present study, we examined the time‐dependent changes in the mitochondrial glutathione status and ATP generation capacity in the myocardium as well as the susceptibility of the myocardium to ischemia‐reperfusion (IR) injury in female Sprague Dawley rats treated with a single pharmacological dose (1.2 mmol/kg) of schisandrin B (Sch B). Sch B treatment produced a time‐dependent enhancement in myocardial mitochondrial glutathione status, as evidenced by increases in myocardial mitochondrial reduced glutathione (GSH) level and activities of glutathione reductase, Se‐glutathione peroxidase (GPX) and glutathione S‐transferases, with the response reaching maximum at 48 h post‐dosing and then declining gradually to the control level at 96 h post‐dosing. The enhancement of mitochondrial glutathione status was associated with an increase in myocardial ATP generation capacity, with the value peaking at 72 h post‐dosing. These beneficial effects of Sch B on the myocardium was paralleled by a time‐dependent decrease in the susceptibility to IR injury, with the maximum protection demonstrable at 48 h post‐dosing. The cardioprotection was associated with increases in myocardial GSH level and activities of glutathione antioxidant enzymes (except for GPX whose activity was suppressed) as well as tissue ATP level/ATP generation capacity. The results suggest that Sch B treatment can precondition the myocardium by enhancing the mitochondrial glutathione status and ATP generation capacity, thereby protecting against IR injury.
Iron status and oxidative stress in β‐thalassemia patients in Jakarta
Authors: Laksmitawati D. R. , Handayani S. , Udyaningsih‐Freisleben S. K. , Kurniati V. , Adhiyanto C. , Hidayat J. , Kusnandar S. , Dillon H. S. D. , Munthe B. G. , Wirawan R. , Soegianto R. R. , Ramelan W. , Freisleben H. J.
Published: December 2008

A study on thalassemia intermedia and major patients in Jakarta was initiated to obtain a comprehensive picture of metabolic dysregulation, iron overload, oxidative stress, and cell damage. Data are presented from a group of 14 transfusion‐dependent patients in an age range of 11‐25 years (T) and another group of 9 frequently transfused (for at least 15 years) patients aged 17‐30 years (L). A third group comprised 6 patients (aged 7 to 14 years) who had not yet obtained transfusions (N). The 21 controls (C) were voluntary students without diagnosis or clinical signs of thalassemia up to 30 years of age. The study was approved by the Ethical Clearance Board of the Medical Faculty and all blood samples from controls and patients were obtained on fully informed consent. Levels of antioxidants (vitamins A, C, E and β‐carotene) and reactive thiols are considerably decreased in transfused patients, whereas signs of iron overload and cell damage are increased (serum iron, ferritin, transferrin saturation, SGOT, SGPT, γ‐GT, bilirubin). Results can be summarized that non‐transfused thalassemia intermedia patients exert slight signs of oxidative stress, and increased hemoglobin degradation but no significant indication of tissue or cell damage. This picture differs considerably from transfusion‐dependent thalassemia major patients: highly significant decrease in antioxidants and thiols and tremendous iron overload and cell damage. The picture is even worsened in long‐term transfused patients. Iron chelation after transfusion is not sufficient in Indonesia, because it is normally (with few exceptions) applied only once together with transfusion. Hence, one major reason of the bad condition of transfusion‐dependent thalassemia patients in Indonesia appears to be frequent transfusions (on the average one per month) and insufficient chelation of one treatment per month together with transfusion.
Molecular mechanisms of cholesterol or homocysteine effect in the development of atherosclerosis: Role of vitamin E
Authors: Özer Nesrin Kartal , Negis Yesim , Aytan Nurgul
Published: December 2008

The development of atherosclerosis is a multifactorial process in which both elevated plasma cholesterol levels and proliferation of smooth muscle cells play a central role. Numerous studies have suggested the involvement of oxidative processes in the pathogenesis of atherosclerosis and especially of oxidized low density lipoprotein. Some epidemiological studies have shown an association between high dietary intake and high serum concentrations of vitamin E and lower rates of ischemic heart disease. Cell culture studies have shown that α‐tocopherol brings about inhibition of smooth muscle cell proliferation. This takes place {via} inhibition of protein kinase C activity. α‐Tocopherol also inhibits low density lipoprotein induced smooth muscle cell proliferation and protein kinase C activity. The following animal studies showed that vitamin E protects development of cholesterol induced atherosclerosis by inhibiting protein kinase C activity in smooth muscle cells in vivo.

Elevated plasma levels of homocysteine have been identified as an important and independent risk factor for cerebral, coronary and peripheral atherosclerosis. However the mechanisms by which homocysteine promotes atherosclerotic plaque formation are not clearly defined. Earlier reports have been suggested that homocysteine exert its effect via H2O2 produced during its metabolism. To evaluate the contribution of homocysteine in the pathogenesis of vascular diseases, we examined whether the homocysteine effect on vascular smooth muscle cell growth is mediated by H2O2. We show that homocysteine induces DNA synthesis and proliferation of vascular smooth muscle cells in the presence of peroxide scavenging enzyme, catalase. Our data suggest that homocysteine induces smooth muscle cell growth through the activation of an H202 independent pathway and accelerate the progression of atherosclerosis.

The results indicate a cellular mechanism for the atherogenicity of cholesterol or homocysteine and protective role of vitamin E in the development of atherosclerosis.
Isolated erythrocyte membranes of transfusion‐dependent and non‐transfused thalassemia patients in Jakarta, investigated by electron paramagnetic resonance spectroscopy
Authors: Udyaningsih‐Freisleben Seruni K. , Kurniati Vita , Prasetyo Pamulih B. , Handayani Sri , Adhiyanto Chris , Soegianto Rondang R. , Pudiantari Ratna , Munthe Bulan G. , Ramelan Wahyuning , Freisleben Hans‐Joachim
Published: December 2008

Erythrocyte membrane structural parameters were studied in transfusion‐dependent β‐thalassemia patients, in long‐term transfused patients (regularly transfused < 15 years), and in those who had not yet obtained transfusions. Controls were voluntary students up to 30 years of age without diagnosis or clinical signs of thalassemia. Membranes were isolated and investigated by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS‐PAGE) and electron paramagnetic resonance (EPR) spectroscopy. Data obtained from the thiol‐reactive spin label N‐ethyl‐maleimidoproxyl reveal immobilization of protein environment in erythrocyte membranes from thalassemic patients. SDS‐PAGE shows both degradation and aggregation of membrane proteins. Thalassemic erythrocyte membranes exert higher order parameters in the hydrophobic region as determined by 16‐doxyl‐stearic acid. Rotational correlation times of this spin label increase only in transfused patients. Polarity is higher in membranes of all patients than in controls. In the polar interface, order parameters obtained from 5‐doxyl‐stearic acid increase in non‐transfused and decrease in transfusion‐dependent patients as compared with controls. Transfused patients exert increasing membrane order in the hydrophobic region and counter‐currently decreasing order in the polar interface indicating loss of membrane integrity along with the loss of fluidity and polarity gradients and the loss the energetic barrier function of the membrane.
Thiocyanate overload and thyroid disease
Authors: Erdoǧan Murat Faik
Published: December 2008

Thiocyanate [SCN−] is a complex anion which is a potent inhibitor of iodide transport. It is the detoxification product of cyanide and can easily be measured in body fluids. Consumption of naturally occurring goitrogens, certain environmental toxins and cigarette smoke can significantly increase SCN− concentrations to levels potentially capable of affecting the thyroid gland. Goiter endemics were reported to develop when the critical urinary iodine/ SCN− ratio decreases below 3 μg iodine per mg SCN−. Iodine supplementation completely reverses the goitrogenic influence of SCN−. SCN− is also generated from cigarette smoking as a detoxifying product of cyanide. During the past two decades many reports dealt with the possible effects of cigarette smoking on thyroid hormone synthesis, thyroid gland size and thyroid autoimmunity including infiltrative ophtalmopathy of Graves' disease. In this mini‐review, issues regarding thiocyanate overload and thyroid disease will be summarized.
Flavonoids and thyroid disease
Authors: Van Der Heide Daan , Kastelijn Jan , Schröder‐Van Der Elst Janny P.
Published: December 2008

The most potent natural plant‐derived compounds that can affect thyroid function, thyroid hormone secretion and availability to tissues is the group of flavonoids, i.e. plant pigments. They are present in our daily food, such as vegetables, fruits, grains, nuts, wine, and tea. Epidemiological studies suggest beneficial effects on health of flavonoids, which are commonly attributed to their activity as antioxidants. Experimental studiesin vitro, however, showed inhibition of organification in thyroid cells and follicles by several flavonoids. Studiesin vivoandvitrowith synthetic and natural flavonoids showed displacement of T4from transthyretin leading to disturbances in thyroid hormone availability in tissues. Radioactive labeled flavonoids appeared to be eliminated rapidly from the body mainly through excretion in the feces. In pregnant rats synthetic flavonoids cross the placenta and accumulate in the fetal compartment, including the fetal brain. Therefore, a high intake of flavonoids is contraindicated. In conclusion: flavonoids show strong interference with many aspects of thyroid hormone synthesis and availability.
Role of iodine in antioxidant defence in thyroid and breast disease
Authors: Smyth Peter P.A.
Published: December 2008

The role played in thyroid hormonogenesis by iodide oxidation to iodine (organification) is well established. Iodine deficiency may produce conditions of oxidative stress with high TSH producing a level of H2O2, which because of lack of iodide is not being used to form thyroid hormones. The cytotoxic actions of excess iodide in thyroid cells may depend on the formation of free radicals and can be attributed to both necrotic and apoptotic mechanisms with necrosis predominating in goiter development and apoptosis during iodide induced involution. These cytotoxic effects appear to depend on the status of antioxidative enzymes and may only be evident in conditions of selenium deficiency where the activity of selenium containing antioxidative enzymes is impaired. Less compelling evidence exists of a role for iodide as an antioxidant in the breast. However the Japanese experience may indicate a protective effect against breast cancer for an iodine rich seaweed containing diet. Similarly thyroid autoimmunity may also be associated with improved prognosis. Whether this phenomenon is breast specific and its possible relationship to iodine or selenium status awaits resolution.
Selenium and thyroid function in infants, children and adolescents
Authors: Chanoine Jean‐Pierre
Published: December 2008

Selenium is an integral component of the enzymes glutathione peroxidase (GPx) and iodothyronine deiodinases. Although selenium nutrition could conceivably affect thyroid function in infants, children and adolescents, available data suggest that the effect of selenium deficiency on thyroid function is relatively modest. In patients with isolated selenium deficiency (such as patients with phenylketonuria receiving a low‐protein diet), peripheral thyroid hormone metabolism is impaired but there are no changes in thyrotropin (TSH) or clinical signs of hypothyroidism, suggesting that these patients are euthyroid. Selenium supplementation may be advisable to optimize tissue GPx activity and prevent potential oxidative stress damage. In areas where combined selenium and iodine deficiencies are present (such as endemic goiter areas in Central Africa), selenium deficiency may be responsible for the destruction of the thyroid gland in myxoedematous cretins but may also play a protective role by mitigating fetal hypothyroidism. In these areas, selenium supplementation should only be advocated at the same time or after iodine supplementation. In patients with absent or decreased production of thyroid hormones and who rely solely on deiodination of exogenous L‐thyroxine for generation of the active triiodothyronine (such as patients with congenital hypothyroidism), selenium supplementation may optimize thyroid hormone feedback at the pituitary level and decrease stimulation of the residual thyroid tissue.
Oxidative stress and Graves' ophthalmopathy: In vitro studies and therapeutic implications
Authors: Bartalena Luigi , Tanda Maria Laura , Piantanida Eliana , Lai Adriana
Published: December 2008

Graves' ophthalmopathy (GO) is a disorder of autoimmune origin caused by a complex interplay of endogenous and environmental factors. After recognition of one or more antigens shared by thyroid and orbit, activated T lymphocytes infiltrating the orbit trigger a cascade of events leading to production of cytokines, growth factors and oxygen reactive species. Proliferation of adipocytes and fibroblasts then follows, with an increased synthesis of glycosaminoglycans (GAG), which attract water and cause edema of orbital structures and venous congestion. Proliferation of orbital fibroblasts and adipocytes, both in the retroocular tissue and in the perimysium of extraocular muscles, are among the most important events leading to the increased volume of orbital structures (fibroadipose tissue and extraocular muscles). The contribution of oxygen reactive species to the changes occurring in the orbit is underscored by in vitro studies. Superoxide radical stimulates orbital fibroblasts to proliferate and to produce GAG. Furthermore, hydrogen peroxide induces expression of HLA‐DR and heat shock protein‐72, involved in antigen recognition and T‐lymphocyte recruitment. Cigarette smoking, which is probably the most important environmental factor associated with GO occurrence and maintenance, might also act, among other mechanisms, by enhancing generation of oxygen reactive species and reducing antioxidant production. Substances such as nicotinamide, allopurinol and pentoxifylline reduce superoxide‐ or hydrogen peroxide‐induced proliferation of fibroblasts, GAG production and HLA‐DR or HSP‐72 expression by GO orbital fibroblasts, possibly through scavenging oxygen free radicals. Two small, non‐randomized and/or uncontrolled studies investigated the effects of nicotinamide, allopurinol or pentoxifylline on GO. Favorable results were reported, but data are not fully convincing and the true effectiveness of these agents needs to be verified in randomized, controlled trials enrolling a larger number of patients.It currently seems unlikely that they may find a relevant place in the limited armamentarium available for the management of severe GO.
Selenium in the treatment of autoimmune thyroiditis
Authors: Gärtner Roland , Gasnier Barbara C. H.
Published: December 2008

We recently conducted a prospective, placebo‐controlled clinical study, where we could demonstrate, that a substitution of 200 μg sodium selenite for three months in patients with autoimmune thyroiditis reduced thyroid peroxidase antibody (TPO‐Ab) concentrations significantly. Forty‐seven patients from the initially 70 patients agreed to participate in a follow‐up cross‐over study for further six months. One group (n = 13), which initially received selenium continued to take 200 μg sodium selenite (Se‐Se), one group stopped taking selenium (Se‐0) ( n = 9), another group which received placebo started to take 200 μg selenium (n = 14) (Plac‐Se) and the last group was without selenium substitution (Plac‐0) (n = 11). TPO‐Ab concentrations were measured at beginning and the end of the study. In the Se‐Se group, the TPO‐Ab concentrations further significantly p = 0.004) decreased from 625 ± 470 U/ml to 354 ± 321 U/ml, in the Se‐0 group the TPO‐Ab concentrations increased significantly p = 0.017) from 450 ± 335 to 708 ± 313 U/ml. In the placebo group, the TPO‐Ab concentrations in those patients who were followed without selenium substitution were unchanged (1351 ± 940 vs. 1724 ± 1112 U/ml, p = 0.555). In contrast, the patients who received 200 μg sodium selenite after placebo, the TPO‐Ab concentrations decreased significantly (p = 0.029) from 1182 ± 723 to 643 ± 477 U/ml.
Dietary flavonoids and iodine metabolism
Authors: Schröder‐Van der Elst Janny P. , Smit Jan W. A. , Romijn Hans A. , van der Heide Daan
Published: December 2008

Flavonoids have inhibiting effects on the proliferation of cancer cells, including thyroidal ones. In the treatment of thyroid cancer the uptake of iodide is essential. Flavonoids are known to interfere with iodide organificationin vitro, and to cause goiter. The influence of flavonoids on iodine metabolism was studied in a human thyroid cancer cell line (FTC‐133) transfected with the human sodium/iodide transporter (NIS). All flavonoids inhibited growth, and iodide uptake was decreased in most cells. NIS mRNA expression was affected during the early hours after treatment, indicating that these flavonoids can act on NIS. Pendrin mRNA expression did not change after treatment. Only myricetin increased iodide uptake. Apeginin, luteolin, kaempferol and F21388 increased the efflux of iodide, leading to a decreased retention of iodide. Instead myricetin increased the retention of iodide; this could be of use in the radioiodide treatment of thyroid cancer.
Expression of β‐catenin in external auditory canal cholesteatoma (EACC)
Authors: Naim Ramin , Riedel Frank , Bran Gregor , Hörmann Karl
Published: December 2008

External auditory canal cholesteatoma (EACC) is a chronic inflammation of the external auditory canal and is composed of hyperproliferative epithelium. The upward migration of the epithelial cells requires permanent breakdown and reformation of intercellular connection. This is established by the modulation of the adherent junctions consisting of an E‐Cadherin‐β‐catenin complex. Dissociated β‐catenin intranuclearly enables persistent activation of downstream transcription and growth factors and decreases the integrity of tissue. In our study we examined EACC and normal meatal auditory skin taken from 16 patients between 23 and 74 years of age. Immunostaining for β‐catenin was used for semiquantitative description of the specimens after assessing hematoxylin‐eosin‐stained slides. β‐catenin was expressed in all layers of AMS‐epithelium, whereas in EACC only basal layer of the matrix epithelium showed positive immunostaining for β‐catenin. In the suprabasal layer of the epithelium only faint reactivity was detectable. The immunostaining was restricted to the membrane of the cells. We assumed that either the content of membranous β‐catenin was decreased or β‐catenin was changed due to molecular modification. It is known that stimulation of endothelial cells by certain growth factors, β‐catenin is maximally phosphorylated. In regard to the increased loss of immunoreactivity for β‐catenin in the suprabasal layers of the hyperplastic EACC‐matrix, we assumed bio‐molecular modification or loss of β‐catenin decreasing the cell‐cell‐integrity. Furthermore, this might result in desquamation of keratinocytes and accumulation of dead keratin debrids. In sum, this study should be understood as a descriptive analysis of β‐catenin expression in EACC.