bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti‐tumor polysaccharides from mushrooms during storage
Authors: Mizuno Masashi
Published: December 2008

The changes in the contents of an anti‐tumor polysaccharide from Lentinus edodes (lentinan) and Grifola frondosa (GGF) during storage were investigated using by an ELISA inhibition assay. When the mushrooms were stored at low temperature, the contents of their anti‐tumor polysaccharides show hardly any changes, but their contents decreased markedly at higher temperature (20°C). Moreover, the effect of the extract from Lentinus edodes stored at different temperatures on tumor necrosis factor (TNF)‐α and nitric oxide (NO) productions from macrophages was investigated to confirm the influence to the stimulation of macrophages. Because lentinan stimulates macrophages to augment their antitumor activity. Their productions showed little difference between Lentinus edodes stored at low temperature and the fresh mushroom, although the cytokine production decreased significantly in Lentinus edodes stored at 20°C. These results suggest that low‐temperature storage is more effective in maintaining not only the quality of the mushrooms but also the contents of anti‐tumor polysaccharides as health‐beneficient foods.
Butyrate as a model for “Gene‐regulating chemoprevention and chemotherapy”
Authors: Sowa Yoshihiro , Sakai Toshiyuki
Published: December 2008

Recent progress in molecular genetics has facilitated understanding of the mechanisms of carcinogenesis. However, there is not yet any effective therapy or prevention for cancer based on the molecular mechanisms of carcinogenesis. So‐called “gene therapy” for cancer is expected to become a new method of treatment, but there are still several serious problems with gene therapy. As a matter of fact, it seems impossible to adopt gene therapy for prevention. We therefore tried to develop a different method of cancer prevention or therapy based on the molecular mechanisms of carcinogenesis. For instance, the tumor‐suppressor gene p53 is mutated in about 50% malignancies. It is known that p53 stimulates the promoter activities of p21/WAF1, gadd45 and bax genes, resulting in cell cycle arrest, DNA repair and apoptosis, respectively. Therefore, chemical compounds that can stimulate these genes should compensate for the function of p53. As a model of this, we found that histone deacetylase inhibitors such as butyrate or trichostatin A dramatically stimulate the p21/WAF1 gene promoter through the Sp1 sites, resulting in cell cycle arrest. Interestingly, another group has recently reported that phenylbutyrate, which is also known as a histone deacetylase inhibitor, is very effective for leukemia patients. We therefore consider methods of up‐regulating p21/WAF, gadd45 or bax genes should be useful for cancer therapy and termed this method “Gene‐regulating chemotherapy”. Theoretically, the chemicals up‐regulating such genes should be also useful for chemoprevention, and we also termed it as “Gene‐regulating chemoprevention”.

In conclusion, we propose that “Gene‐regulating chemotherapy or chemoprevention” may be a promising new method for cancer therapy or prevention and histone deacetylase inhibitor is a good candidate for this method.
Effect of dietary α‐linolenic acid on the activity and gene expression of hepatic fatty acid oxidation enzymes
Authors: Ide Takashi
Published: December 2008

The activities of hepatic fatty acid oxidation enzymes in rats fed linseed and perilla oils rich in α‐linolenic acid (α‐18:3) were compared with those in the animals fed safflower oil rich in linoleic acid (18:2) and saturated fats (coconut or palm oil). Mitochondrial and peroxisomal palmitoyl‐CoA (16:0‐CoA) oxidation rates in the liver homogenates were significantly higher in rats fed linseed and perilla oils than in those fed saturated fats and safflower oil. The fatty oxidation rates increased as dietary levels of α‐18:3 increased. Dietary α‐18:3 also increased the activity of fatty acid oxidation enzymes except for 3‐hydroxyacyl‐CoA dehydrogenase. Unexpectedly, dietary α‐18:3 caused great reduction in the activity of 3‐hydroxyacyl‐CoA dehydrogenase measured with short‐ and medium‐chain substrates but not with long‐chain substrate. Dietary α‐18:3 significantly increased the mRNA levels of hepatic fatty acid oxidation enzymes including carnitine palmitoyltransferase I and II, mitochondrial trifunctional protein, acyl‐CoA oxidase, peroxisomal bifunctional protein, mitochondrial and peroxisomal 3‐ketoacyl‐CoA thiolases, 2, 4‐dienoyl‐CoA reductase and Δ3, Δ2‐enoyl‐CoA isomerase. Fish oil rich in very long‐chain n‐3 fatty acids caused similar changes in hepatic fatty acid oxidation. Regarding the substrate specificity of β‐oxidation pathway, mitochondrial and peroxisomal β‐oxidation rate of α‐18:3‐CoA, relative to 16:0‐ and 18:2‐CoAs, was higher irrespective of the substrate/albumin ratios in the assay mixture or dietary fat sources. The substrate specificity of carnitine palmitoyltransferase I appeared to be responsible for the differential mitochondrial oxidation rates of these acyl‐CoA substrates. Dietary fats rich in α‐18:3‐CoA relative to safflower oil did not affect the hepatic activity of fatty acid synthase and glucose 6‐phosphate dehydrogenase. It was suggested that both substrate specificities and alterations in the activities of the enzymes in β‐oxidation pathway play a significant role in the regulation of the serum lipid concentrations in rats fed α‐18:3.
Platelet‐activating factor (PAF)‐like oxidized phospholipids: Relevance to atherosclerosis
Authors: Tokumura Akira , Sumida Tuneki , Toujima Masaoki , Kogure Kentaro , Fukuzawa Kenji
Published: December 2008

Lipid peroxidation is involved in the pathogenesis of chronic diseases including atherosclerosis. Oxidized lipoprotein has diverse biological activities and is believed to initiate atheroma formation and maturate fatty plaque. The active components of oxidized lipoproteins still remain to be clarified, but a likely candidate is the phosphatidylcholine (PC) having an it sn‐2‐short‐chain acyl group with a methyl, hydroxyl, aldehydic or carboxylic terminal. These unique PCs, formed by oxidative fragmentation of the polyunsaturated acyl group of the parent PC in liposomes, low density lipoproteins and blood plasma, induce platelet aggregation through the activation of the receptor for platelet‐activating factor (PAF), due to their resemblance in structure with PAF. We have found that PAF‐like lipids regulate DNA synthesis and production of nitric oxide independently of the activation of the PAF receptor in vascular smooth muscle cells. Regulation of vascular cell function through two distinct signaling pathways mediated by PAF‐like lipids provides new insight into the mechanism of induction of atherosclerosis.
Anti‐stress effects of DHA
Authors: Hamazaki Tomohito , Itomura Miho , Sawazaki Shigeki , Nagao Yoko
Published: December 2008

DHA is abundant in the brain. Deficiency of DHA changes behavior in animals. The purpose of the present studies was to clarify the effect of DHA intake on hostility and plasma catecholamines. In study 1, forty‐one students took either DHA‐rich oil capsules containing 1.5–1.8 g DHA/d (17 females and 5 males) or control oil capsules containing 97% males) for 3 mon in a double blind fashion. They took a psychological test (P‐F Study) at the start and end of the study. Study 1 started at the end of summer vacation and ended in the middle of mental stress of final exams. In the control group, hostility measured by P‐F Study was significantly increased at the end of the study as compared with that measured at the start (+58%) was not significantly changed in the DHA group (‐14%) double blind two‐mon study (study 2), we measured plasma catecholamines and cortisol of students (3 females and 4 males for the DHA group and the same numbers for the control) at the start and end of the study. In study 2 the students were under a continuous stress of final exams that lasted for two mon throughout the whole study period. The plasma cortisol did not change in either group, but the norepinephrine concentration was significantly decreased in the DHA group (‐31%) group. These effects of DHA intake may be applied to people under psychological stress.
Absorption, metabolism and antioxidative effects of tea catechin in humans
Authors: Miyazawa Teruo
Published: December 2008

Green tea is consumed as a popular beverage in Japan and throughout the world. During the past decade, epidemiological studies have shown that tea catechin intake is associated with lower risk of cardiovascular disease [1,2]. In vitro biochemical studies have reported that catechins, particularly epigallocatechin‐3‐gallate (EGCg), help to prevent oxidation of plasma low‐density lipoprotein (LDL) [3–5]. LDL oxidation has been recognized to be an important step in the formation of atherosclerotic plaques and subsequent cardiovascular disease [6].

Metabolic studies have shown that EGCg supplement is incorporated into human plasma at a maximum concentration of 4400 pmol/mL [7–10]. Such concentrations would be enough to exert antioxidative activity in the blood stream. The potent antioxidant property of tea catechin may be beneficial in preventing the oxidation of LDL. It is of interest to examine the effect of green tea catechin supplementation on antioxidant capacity of plasma in humans by measuring plasma phosphatidylcholine hydroperoxide (PCOOH) as a marker of oxidized lipoproteins.
Mechanisms of cancer prevention by tea polyphenols based on inhibition of TNF‐α expression
Authors: Suganuma Masami , Sueoka Eisaburo , Sueoka Naoko , Okabe Sachiko , Fujiki Hirota
Published: December 2008

Among various biochemical and biological activities of tea polyphenols, we believe inhibition of the expression and release of tumor necrosis factor‐α (TNF‐α) is crucial, since our study with TNF‐α‐deficient mice has revealed that TNF‐α is an essential factor in tumor promotion. We found that EGCG dose‐dependently inhibited AP‐1 and NF‐κB activation in BALB/3T3 cells treated with okadaic acid, resulting in inhibition of TNF‐α gene expression. Furthermore, treatment with 0.1% gene expression as well as TNF‐α protein level in the lung of TNF‐α transgenic mice; and IL‐1β and IL‐10 gene expression in the lung was also inhibited by treatment with green tea extract, indicating that green tea inhibits both TNF‐α and the cytokines induced by TNF‐α in organs. We recently found synergistic effects of EGCG and cancer preventive agents such as tamoxifen and sulindac, on cancer preventive activity. Taken together, the results show that green tea is efficacious as a non‐toxic cancer preventive for humans.
Tea catechins and related polyphenols as anti‐cancer agents
Authors: Isemura Mamoru , Saeki Kouichi , Kimura Takashi , Hayakawa Sumio , Minami Takeshi , Sazuka Masaki
Published: December 2008

Epigallocatechin gallate (EGCg) and theaflavins, a major constituent of green tea infusion and the constituents of black tea, respectively, were found to inhibit matrix metalloproteinases (MMPs) which are intimately associated with tumor invasion and metastasis. EGCg and related polyphenols exhibited apoptosis‐inducing activity for several cancer cell lines including human stomach and colon cancer cells. Comparison of the activity of these compounds revealed the importance of the number and the steric disposition of hydroxyl groups. A pyrogallol‐type structure in a molecule is a minimum requirement for apoptosis induction of catechin compounds and that in the B ring has an important role in the activity. These data would provide useful information for designing anti‐cancer agents on the basis of anti‐inhibitory activity for MMPs and/or apoptosis‐inducing activity.
Cancer prevention by natural carotenoids
Authors: Nishino Hoyoku , Tokuda Harukuni , Murakoshi Michiaki , Satomi Yoshiko , Masuda Mitsuharu , Onozuka Mari , Yamaguchi Shino , Takayasu Junko , Tsuruta Jun , Okuda Masato , Khachik Frederick , Narisawa Tomio , Takasuka Nobuo , Yano Masamichi
Published: December 2008

Various natural carotenoids were proven to have anticarcinogenic activity. Epidemiological investigations have shown that cancer risk is inversely related to the consumption of green and yellow vegetables and fruits. Since β‐carotene is present in abundance in these vegetables and fruits, it has been investigated extensively as possible cancer preventive agent. However, various carotenoids which co‐exist with β‐carotene in vegetables and fruits also have anti‐carcinogenic activity. And some of them, such as α‐carotene, showed higher potency than β‐carotene to suppress experimental carcinogenesis. Thus, we have carried out more extensive studies on cancer preventive activities of natural carotenoids in foods; i.e., lutein, lycopene, zeaxanthin and β‐cryptoxanthin. Analysis of the action mechanism of these natural carotenoids is now in progress, and some interesting results have already obtained; for example, β‐cryptoxanthin was suggested to stimulate the expression of RB gene, an anti‐oncogene, and p73 gene, which is known as one of the p53‐related genes. Based on these results, multi‐carotenoids (mixture of natural carotenoids) seems to be of interest to evaluate its usefulness for practice in human cancer prevention.
Proanthocyanidins and human health: Systemic effects and local effects in the gut
Authors: Scalbert Augustin , Déprez Stéphanie , Mila Isabelle , Albrecht Anne‐Marie , Huneau Jean‐François , Rabot Sylvie
Published: December 2008

Proanthocyanidins share common properties with other polyphenols, in particular their reducing capacity and ability to chelate metal ions. However, their polymeric nature clearly makes them different. They have a high affinity for proteins and their absorption through the gut barrier is likely limited to the molecules of low polymerization degree and to the metabolites formed by the colonic microflora, as suggested by in vitro experiments. The nutritional significance of proanthocyanidins is discussed in relation to their physico‐chemical properties and bioavailability.
Chemistry and function of vegetable polyphenols with high molecular weights
Authors: Yoshida Takashi , Hatano Tsutomu , Ito Hideyuki
Published: December 2008

Structure and function of polypehnols with high molecular weights (tannins) were briefly reviewed to better understand the significance of polyphenol‐rich foods and beverages. In a survey of bioactive ellagiannins with a macrocyclic structure and/or a gluconic acid core, some new oligomeric ellagitannins (eucarpanins and elaeagnatins) have been found in species of Myrtaceae and Elaeagnaceae, and their structures were elucidated by spectroscopic and chemical methods. Cytotoxic activity against human oral tumor cell lines and antibacterial activity against Helicobacter pylori have been evaluated for the ellagitannins obtained from both plants, and related compounds. The macrocyclic dimers, oentothein B, camelliin B and woodfordin C showed a remarkable cytotoxicity against human oral squamous cell carcinoma, but not against normal cells. These active tannins induced apoptosis of tumor cells. A potent antibacterial activity against Helicobacter pylori was exhibited by monomeric ellagitannins such as tellimagrandin I and stricitinin.
Black and green tea and heart disease: A review
Authors: Vinson Joe A.
Published: December 2008

Tea is the second most consumed beverage around the world behind water. Epidemiological evidence points to both green and black tea consumption being protective with respect to heart disease. However, epidemiological evidence does not prove cause and effect and is potentially flawed by confounding variables. The recent evidence with respect to teas' beneficial effects from in vitro and in vivo studies in both animals and humans will be covered in this review. The comparative benefits of green vs. black tea will be considered. Articles published through December, l999 will be included.
Affinity of polyphenols for lipid bilayers
Authors: Nakayama Tsutomu , Hashimoto Toshihiko , Kajiya Katsuko , Kumazawa Shigenori
Published: December 2008

Interaction of tea catechins with lipid bilayers has been investigated with liposome systems. Epicatechin gallate had the highest affinity for lipid bilayers, followed by epigallocatechin gallate, epicatechin, and epigallocatechin. Epicatechin gallate and epigallocatechin gallate in the surface of lipid bilayer perturbed the membrane structure.
Antioxidant factors in plant foods and selected oilseeds
Authors: Shahidi Fereidoon
Published: December 2008

The effect of dietary factors on health promotion and disease prevention has been an issue of interest since antiquity and has become a subject of renewed research activity in recent years. Many of the components involved are antioxidative in nature and include phenolic compounds. These phenolics exist in the free, esterified, glycosylated and polymeric forms. Scrutiny of the source materials, their subsequent extraction under optimized conditions and evaluation of activity, followed by fractionation and structure elucidation of active components is generally necessary. Meals obtained from oilseeds, such as canola, mustard, flax, borage, and evening primrose, after oil extraction, contained a variety of antioxidative factors. The antioxidative effect of source materials, their extracts or fractions thereof, depended on the seed type, the content and chemical nature of their active components.
Cognitive impairment and oxidative stress in the elderly: Results of epidemiological studies
Authors: Berr Claudine
Published: December 2008

Cognitive impairment is a major component of age‐related dementing diseases and it has been suggested that it could share the same pathological pathways with neurodegenerative processes and cerebrovascular lesions. The free radical theory of ageing could be one of these pathways. Implication of free radical damage in processes related to cerebral ageing is a good argument in favour of the hypothesis that antioxidants may protect against cognitive impairment.

Observational studies (mostly cross‐sectional) of relationships between cognitive impairment and antioxidant status are based on the evaluation of dietary intake or on the levels of carotenoids, selenium and vitamins A, C and E in plasma or red blood cells. More convincing results were obtained on vitamin C and carotenoids. Despite some limitations, the comparison between results obtained in various populations is becoming increasingly informative and these studies argue for a protective effect of antioxidants on cognitive performance.
Anti‐tumor and anti‐carcinogenic activities of triterpenoid, β‐boswellic acid
Authors: Huang Mou‐Tuan , Badmaev Vladimir , Ding Yu , Liu Yue , Xie Jian‐Guo , Ho Chi‐Tang
Published: December 2008

Boswellin (BE), a methanol extract of the gum resin exudate ofBoswellia serrata, contains naturally occurring triterpenoids, β‐boswellic acid and its structural related derivatives, has been used as a traditional medicine for the treatment of inflammatory and arthritic diseases. Topical application of BE to the backs of mice markedly inhibited 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced increases in skin inflammation, epidermal proliferation, the number of epidermal cell layers, and tumor promotion in 7,12‐dimethylbenz[a]anthracene (DMBA)‐initiated mice. Feeding 0.2% BE in the diet to CF‐1 mice for 10–24 weeks reduced the accumulation of parametrial fat pad weight under the abdomen, and inhibited azoxymethane (AOM)‐induced formation of aberrant crypt foci (ACF) by 46%. acid, 11‐keto‐β‐boswellic acid or 3‐O‐acetyl‐11‐keto‐β‐boswellic acid (Fig. 1) to human leukemia HL‐60 cell culture inhibited DNA synthesis in HL‐60 cells in a dose‐dependent manner with IC50values ranging from 0.6 to 7.1 μM. These results indicate that β‐boswellic acid and its derivatives (the major constituents of Boswellin) have anti‐carcinogenic, anti‐tumor, and anti‐hyperlipidemic activities.
The determination of metabolites of garlic preparations in breath and human plasma
Authors: Rosen Rober T. T. , Hiserodt Richard D. , Fukuda Elaine K. , Ruiz Reginald J. , Zhou Zhengyi , Lech Joseph , Rosen Sharon L. , Hartman Thomas G.
Published: December 2008

Gas Chromatography–Mass Spectrometry (GC‐ MS) was the major technique used to determine various metabolites after consumption of dehydrated granular garlic and an enteric‐coated garlic preparation, in breath, plasma, and simulated gastric fluids. A special short‐path thermal desorption device [1] was used as an introduction technique for the gas chromatograph for the determination of volatiles. These garlic preparations release allicin, which decomposes in stomach acid or with time in the intestine to release allyl sulfides, disulfides and other volatiles, some of which are postulated to be metabolized by glutathione and/or S‐adenosylmethionine to form allyl methyl sulfide, the main sulfur containing volatile metabolite.

S‐Allylcysteine, a non‐volatile bioactive component of aged garlic preparations, was determined in human plasma and urine by HPLC‐MS using the negative ion atmospheric pressure chemical ionization mode (APcI)‐ MS. The technique of selected ion monitoring was used for quantitation. A synthetic internal standard of deuterated S‐allylcysteine was added to the plasma or urine to ensure recovery and to obtain reliable quantitative data.
Antithrombotic and antineoplastic effects of phyto‐organosulfur compounds
Authors: Ariga Toyohiko , Tsuji Kentaro , Seki Taiichiro , Moritomo Tadaaki , Yamamoto Jun‐Ichiro
Published: December 2008

The antiplatelet activity of methyl allyltrisulfide (MATS), a component commonly present in steam‐distilled garlic oil, has been demonstrated by the authors. MATS inhibits arachidonic acid cascade at the reaction site with PGH synthase. However, this enzyme catalyzes two successive reactions, from arachidonic acid to PGG2, and from PGG2 to PGH2. The present study revealed that MATS inhibited the latter reaction. In addition, our recent findings that to a promyelocytic leukemia cell HL60, Allium oils shows marked anti‐neoplastic effects representing both growth suppression and differentiation activities are described. The garlic oil and onion oil showed almost equal ability in inducing the proliferation, which measured either by nitroblue‐tetrazolium reducing activity assay or by flow cytometry for detecting CD11b expression. The combination use of one of these oils with all‐trans retinoic acid or with dimethyl sulfoxide lead to the marked differentiation of the cells, and their effects were estimated to be synergistic.
Thermochemical transformation of sulfur compounds in Japanese domestic Allium, Allium victorialis L
Authors: Nishimura Hiroyuki , Takahashi Tomonari , Hanny Wijaya C. , Satoh Atsushi , Ariga Toyohiko
Published: December 2008

Sulfur compounds contributed to the health promotion in Allium species are produced via enzymic and thermal reactions. Potent antithrombotic agents which have been identified as allyl trisulfides, dithiins, and ajoene in garlic (A. sativum) and caucas (A. victorialis) are thermochemically transformed from allicin (allyl 2‐propenethiosulfinate). The leaves and stems of Japanese domestic {Allium plant, A. victorialis L. which is widely distributed in the northern part of Japan, under the name “Gyoja‐ninniku” is a nutritious vegetable. The significant flavor compounds of caucas are methyl allyl disulfide (Chinese chive odor), diallyl disulfide (garlic‐like odor), and dimethyl disulfide and methyl allyl trisulfide (pickles‐like odor) among more than 85 peaks on the gas chromatogram. 2‐Vinyl‐4H‐1,3‐dithiin and 3,4‐dihydro‐3‐vinyl‐1,2‐dithiin as platelet aggregation inhibitors were found eliminated in dichloromethane extract of caucas. The significant health promoting factors, allyl trisulfides and dithiins were relatively increased when caucas was cooked on a frying pan.
Selenocysteine incorporation directed from the 3′UTR: Characterization of eukaryotic EFsec and mechanistic implications
Authors: Berry Marla J. , Tujebajeva Rosa M. , Copeland Paul R. , Xu Xue‐Ming , Carlson Bradley A. , Martin Glover W. , Low Susan C. , Mansell John B. , Grundner‐Culemann Elisabeth , Harney John W. , Driscoll Donna M. , Hatfield Dolph L.
Published: December 2008

The mechanism of selenocysteine incorporation in eukaryotes has been assumed for almost a decade to be inherently different from that in prokaryotes, due to differences in the architecture of selenoprotein mRNAs in the two kingdoms. After extensive efforts in a number of laboratories spanning the same time frame, some of the essential differences between these mechanisms are finally being revealed, through identification of the factors catalyzing cotranslational selenocysteine insertion in eukaryotes. A single factor in prokaryotes recognizes both the selenoprotein mRNA, via sequences in the coding region, and the unique selenocysteyl‐tRNA, via both its secondary structure and amino acid. The correponding functions in eukaryotes are conferred by two distinct but interacting factors, one recognizing the mRNA, via structures in the 3′ untranslated region, and the second recognizing the tRNA. Now, with these factors in hand, crucial questions about the mechanistic details and efficiency of this intriguing process can begin to be addressed.
Evidence that selenium deficiency results in the cytoplasmic decay of GPx1 mRNA dependent on pre‐mRNA splicing proteins bound to the mRNA exon‐exon junction
Authors: Maquat Lynne E.
Published: December 2008

Studies of transcripts for the selenoprotein glutathione peroxidase 1 (GPx1) have provided remarkable evidence for the coupling of pre‐mRNA splicing in the nucleus and mRNA translation in the cytoplasm. Such evidence derives from the initial finding that GPx1 mRNA is a natural substrate of nonsense‐mediated decay. Here, recent work on GPx1 RNA metabolism is reviewed and future directions of study are defined.
Stability of gastrointestinal glutathione peroxidase mRNA in selenium deficiency depends on its 3′UTR
Authors: Wingler Kirstin , Müller Cordula , Brigelius‐Flohé Regina
Published: December 2008

Selenoproteins decrease upon selenium‐deprivation according to their hierarchical ranking. Whereas classical glutathione peroxidase (cGPx) responds to decreased selenium supply with a complete loss of protein and a marked reduction of mRNA levels, gastrointestinal glutathione peroxidase (GI‐GPx) remains detectable and its mRNA is stable. The impact of the 3′UTR on cGPx and GI‐GPx mRNA stability was studied in stably transfected HepG2 cells with combinations of mutually exchanged coding regions and 3′UTRs of human cGPx and GI‐GPx. Stability of chimeric mRNAs was measured by competitive RT‐PCR. We found that GI‐GPx 3′UTR is sufficient to stabilize its own mRNA but not that of cGPx.
Utilization of selenocysteine as a source of selenium for selenophosphate biosynthesis
Authors: Lacourciere Gerard M. , Stadtman Thressa C.
Published: December 2008

Selenophosphate synthetase (SPS), the selD gene product from Escherichia coli, catalyzes the biosynthesis of monoselenophosphate from selenide and ATP. Characterization of selenophosphate synthetase revealed the determined Km value for selenide is far above the optimal concentration needed for growth and approached levels which are toxic. Selenocysteine lyase enzymes, which decompose selenocysteine to elemental selenium (Se0) and alanine, were considered as candidates for the control of free selenium levels in vivo. The ability of a lyase protein to generate Se0 in the proximity of SPS maybe an attractive solution to selenium toxicity as well as the high Km value for selenide. Recently, three E. coli NifS‐like proteins, CsdB, CSD, and IscS, were characterized. All three proteins exhibit lyase activity on L‐cysteine and L‐selenocysteine and produce sulfane sulfur, S0, or Se0 respectively. Each lyase can effectively mobilize Se0 from L‐selenocysteine for selenophosphate biosynthesis.
Evolution of selenocysteine‐containing proteins: Significance of identification and functional characterization of selenoproteins
Authors: Gladyshev Vadim N. , Kryukov Gregory V.
Published: December 2008

In the genetic code, UGA serves as either a signal for termination or a codon for selenocysteine (Sec). Sec rarely occurs in protein and is different from other amino acids in that much of the biosynthetic machinery governing its incorporation into protein is unique to this amino acid. Sec‐containing proteins have diverse functions and lack a common amino acid motif or consensus sequence. Sec has previously been considered to be a relic of the primordial genetic code that was counter‐selected by the presence of oxygen in the atmosphere. In the present report, it is proposed that Sec was added to the already existing genetic code and its use has accumulated during evolution of eukaryotes culminating in vertebrates. The more recently evolved selenoproteins appear to take advantage of unique redox properties of Sec that are superior to those of Cys for specific biological functions. Further understanding of the evolution of selenoproteins as well as biological properties and biomedical applications of the trace element selenium requires identification and functional characterization of all mammalian selenoproteins.
Glutathione peroxidase‐1 gene knockout on body antioxidant defense in mice
Authors: Lei Xin Gen
Published: December 2008

To determine the in vivo role of cellular glutathione peroxidase (E.C.1.11.1.9, GPX1), we challenged the GPX1 knockout [GPX1(‐/‐)], the GPX1 overexpressing [GPX1(+)], and their respective wild‐type (WT) mice of different Se and vitamin E status with acute oxidative stress. After these mice were injected with pro‐oxidants paraquat or diquat at 12 to 125 mg/kg of body weight, their survival rate and time were a function of their GPX1 activity levels. The GPX1 protection was associated with attenuation of NADPH and NADH oxidation, protein carbonyl and F2‐isoprostanes formation, and alanine transaminase release in various tissues, and was irreplaceable by high levels of dietary vitamin E or other selenoproteins. The GPX1 expression was also protective against moderate oxidative stress induced by low levels of paraquat or diquat, particularly in the Se‐deficient mice. Alteration of GPX1 expression showed no impact on the expression of other selenoproteins and antioxidant enzymes in unstressed mice. Total Se content in liver of the Se‐adequate GPX1(‐/‐) mice was reduced by 60% the WT controls. In conclusion, normal expression of GPX1 is essential and overexpression of GPX1 is beneficial to protect mice against acute oxidative stress.
Functions of GI‐GPx: Lessons from selenium‐dependent expression and intracellular localization
Authors: Brigelius‐Flohé R. , Müller C. , Menard J. , Florian S. , Schmehl K. , Wingler K.
Published: December 2008

Gastro intestinal glutathione peroxidase (GI‐GPx) is one of the four distinct mammalian selenoperoxidases. It had been reported to be restricted to the gastrointestinal tract but has more recently been identified also in human liver and some tumor cell lines. GI‐GPx ranks high in the hierarchy of selenoproteins. The GI‐GPx mRNA rather increases than decreases in selenium deficiency. GI‐GPx protein responds poorly to selenium deprivation and increases fast upon resupplementation. Putative biological roles of GI‐GPx, e.g. protection against food‐born hydroperoxides, redox‐regulation of proliferation or apoptosis, and modulation of mucosal immunity, are discussed in the light of cellular and subcellular distribution, transcriptional regulation and observations with k.o. mice.
Selenoproteins in human thyroid tissues
Authors: Zagrodzki Paweł , Nicol Fergus , Arthur John R. , Słowiaczek Marian
Published: December 2008

The aim of the present work was to clarify whether the activities of selenoenzymes can serve as markers for different tumors or goiters, as classified by histological criteria. The following parameters were determined: 1) selenium content of plasma (Se), 2) activities of the selenoenzymes: plasma glutathione peroxidase (plGSHPx), cytosolic glutathione peroxidase (cGSHPx), type I and type II iodothyronine deiodinases (ID‐I, ID‐II), thioredoxin reductase (THRR) in human thyroid tissues. The material came from follicular neoplasm, papillary carcinoma, struma nodosa, struma lymphomatosis Hashimoto, other thyroid surgery specimens, and normal tissues. There was no difference in Se nor in plGSHPx between patients and healthy volunteers. No significant differences were found for any parameter in thyroid carcinoma versus normal or goitrous thyroid tissue. In the whole group of thyroid surgery specimens the statistically significant correlations were found between ID‐I and ID‐II and between THRR and selenoperoxidases. Principal components analysis confirmed the above correlation and moreover revealed correlation between Se and plGSHPx, but did not detect any clear distinction between patients with the different diagnoses.
Induction of glutathione synthesis in human keratinocytes by Ginkgo biloba extract (EGb761)
Authors: Rimbach Gerald , Gohil Kishorchandra , Matsugo Seiichi , Moini Hadi , Virgili Claude Saliou, Fabio , Weber Packer Stefan U. , Lester
Published: December 2008

The objective of the present study was to characterize the action of Ginkgo biloba extract (EGb761) and its sub‐fractions on glutathione homeostasis in a human keratinocyte cell culture model. Cells were incubated with EGb761, its purified flavonoid (quercetin, kaempferol, rutin) or terpenoids (gingkolides A, B, C, J, bilobalide) constituents or the vehicle for up to 72 hours. Incubation of keratinocytes with the purified flavonoids or terpenoids did not affect cellular GSH levels. However, EGb761 treatment (up to 200 μg/ml) resulted in a dose‐dependent increase of cellular GSH. Western blot analysis of extracts from cells treated with EGb761 revealed increased levels of the catalytic subunit of γglutamylcysteinyl synthetase (γGCS), the rate‐limiting enzyme in GSH synthesis. The abundance of mRNA for the catalytic subunit (assayed by RT‐PCR) was also increased by the treatment with EGb761. Increased levels of cellular GSH by EGb761 were also observed in other cell lines including those from human bladder and liver as well as in murine macrophages indicating that the induction of γGCS mRNA, protein and GSH may be an ubiquitous effect of EGb761 in mammalian cells.
Cholesterol oxidation products and fibrogenesis
Authors: Leonarduzzi Gabriella , Sevanian Alex , Poli Giuseppe
Published: December 2008

Oxidatively modified low density lipoproteins (oxLDL) are known to affect various cellular processes by modulating molecolar transduction pathways and signaling nuclear transcription [1,2]. In particular, the proinflammatory and proatherosclerotic effects of oxLDL are increasingly supported by a multitude of independent but consistent experimental studies. LDL oxidation might be a sequencial process where their lipid moieties are progressively but discretely oxidized, preceding the oxidation/modification of the apolipoprotein domain, an effect that can ultimately result in the uncontrolled uptake of these particles by cells, such as macrophages, and conversion of them to foam cells which is a hallmark of early atherogenesis [3]. These lipoproteins appear to trigger a variety of events which are strongly implicated in the atherogenesis, the pathological process underlying vascular disease.
Curcumin differentially regulates TGF‐β1, its receptors and nitric oxide synthase during impaired wound healing
Authors: Mani Haresh , Sidhu Gurmel S. , Kumari Ranjana , Gaddipati Jaya P. , Seth Pankaj , Maheshwari Radha K.
Published: December 2008

Wound healing is a highly ordered process, requiring complex and coordinated interactions involving peptide growth factors of which transforming growth factor‐beta (TGF‐β) is one of the most important. Nitric oxide is also an important factor in healing and its production is regulated by inducible nitric oxide synthase (iNOS). We have earlier shown that curcumin (diferuloylmethane), a natural product obtained from the plant Curcuma longa, enhances cutaneous wound healing in normal and diabetic rats. In this study, we have investigated the effect of curcumin treatment by topical application in dexamethasone‐impaired cutaneous healing in a full thickness punch wound model in rats. We assessed healing in terms of histology, morphometry, and collagenization on the fourth and seventh days post‐wounding and analyzed the regulation of TGF‐β1, its receptors type I (tIrc) and type II (tIIrc) and iNOS. Curcumin significantly accelerated healing of wounds with or without dexamethasone treatment as revealed by a reduction in the wound width and gap length compared to controls. Curcumin treatment resulted in the enhanced expression of TGF‐β1 and TGF‐β tIIrc in both normal and impaired healing wounds as revealed by immunohistochemistry. Macrophages in the wound bed showed an enhanced expression of TGF‐β1 mRNA in curcumin treated wounds as evidenced by in situ hybridization. However, enhanced expression of TGF‐β tIrc by curcumin treatment observed only in dexamethasone‐impaired wounds at the 7th day post‐wounding. iNOS levels were increased following curcumin treatment in unimpaired wounds, but not so in the dexamethasone‐impaired wounds. The study indicates an enhancement in dexamethasone impaired wound repair by topical curcumin and its differential regulatory effect on TGF‐β1, it's receptors and iNOS in this cutaneous wound‐healing model.
Characteristic rat tissue accumulation of nobiletin, a chemopreventive polymethoxyflavonoid, in comparison with luteolin
Authors: Murakami Akira , Koshimizu Koichi , Ohigashi Hajime , Kuwahara Shigeru , Kuki Wataru , Takahashi Yasuo , Hosotani Keisuke , Kawahara Satsuki , Matsuoka Yumi
Published: December 2008

Nobiletin (NOB), a polymethoxyflavonoid, is an effective anti‐inflammatory and chemopreventive phytochemical found in citrus fruits. We compared the absorption and metabolism characteristics of NOB with those of luteolin (LT) in male SD rats. Each flavonoid (67.1 μmol/kg of body weight) was given separately by gastric intubation, and then concentrations were measured at 1, 4, and 24 hours after administration. In the digestive organs, NOB showed a notable tendency for localizing into the mucous membrane and muscularis from 1 to 4 hours, in contrast to LT, though both NOB and LT were completely excreted within 24 hours. Further, significant amounts of NOB were detected in the whole liver and kidney specimens, whereas LT accumulation was slight. Although serum concentrations of NOB from 1 to 4 hours were comparable to those of LT, urinary concentrations of LT were significantly higher from 4 to 24 hours. Following glucuronidase/sulfatase treatments of urinary materials, we detected 3 types of mono‐demethylated NOB, including 3′‐demethyl‐NOB, and two di‐demethylated types, as well as 3′‐demethyl‐NOB alone in serum samples using liquid chromatography‐mass spectral analysis. Our results suggest that the metabolic properties of polymethoxyflavonoids are distinct from those of other general flavonoids, because of their wide distribution and accumulation in tissue.
Impact of water‐dispersible beadlets as a vehicle for the delivery of carotenoids to cultured cells
Authors: Shahrzad Siranoush , Cadenas Enrique , Sevanian Alex , Packer Lester
Published: December 2008

Water‐dispersible beadlets of carotenoids were used as supplements for human umbilical vein endothelial cells (HUVECs), human peripheral blood mononuclear cells (PBMCs) and human monocytes. Stability, cellular association and cytotoxicity of the carotenoid beadlets were compared with carotenoids delivered with tetrahydrofuran (THF). Incubations with lycopene, β‐carotene, lutein and astaxanthin dissolved in THF resulted in a lower stability in the medium, lower cellular association, and a higher standard deviation. Beadlets provided 60, 4, 6, and 2 times greater accumulation of lycopene, β‐carotene, lutein and astaxanthin, respectively, by PBMCs than THF. The cellular association of carotenoids delivered by THF seems to be more carotenoid‐specific than when carotenoids are delivered by beadlets. After 48∼h of incubation under cell culture conditions all of the four carotenoids (1 μM) delivered by beadlets to the medium showed a reduction less than 30%. In addition, no cytotoxic effect of the carotenoid beadlets or the vehicle alone was detected in a concentration range of 0.5‐5 μM. The results show that beadlets are a non‐toxic vehicle for supplementing and stabilizing carotenoids in culture media offering a reasonable compromise in term of cell accumulation efficiency.
Amelioration of cisplatin toxicity by a fermented grain food product
Authors: Minamiyama Yukiko , Takemura Shigekazu , Toyokuni Shinya , Nishino Yoshihiro , Yamasaki Keiichi , Hai Seikan , Yamamoto Satoshi , Okada Shigeru
Published: December 2008

The most noticeable hypothesis regarding the pathogenesis of cisplatin toxicity, seen mainly in kidney and intestine, is oxidative stress, an imbalance between free‐radical generating cisplatin and radical scavenging systems. This paper describes the role of the antioxidant system in cisplatin‐induced toxicity and the protective effect by a processed grain food (Antioxidant Biofactor: AOB®), which has been shown to exhibit strong antioxidant activity.

Male Fischer 344 rats were used. They were pre‐fed either a basal diet (control, 15 g/day) or the diet supplemented with AOB® to provide 6.5% or 20% of total diet throughout the experiment. Cisplatin (5 mg/kg, i.v.) was administered at the start of the experiment, and the animals were sacrificed 5 days later. Blood urea nitrogen (BUN) and plasma creatinine, NO2‐} and NO3−(NOx) were determined from the plasma. The levels of 4‐hydroxy‐2‐nonenal (a lipid peroxidation product), 8‐hydroxy‐deoxyguanosine (8‐OHdG, an oxidatively modified DNA adduct) and nitrotyrosine were histologically analyzed. The cisplatin administration resulted in a loss of body weight and elevations of BUN, serum creatinine and NOx levels, whereas AOB supplement reversed these effects. The severe morphological damages induced in the kidney and intestine by the cisplatin administration were markedly improved in the AOB group. The levels of lipid peroxidation, 8‐OHdG, and nitrotyrosine all paralleled the morphological damage. The AOB effect was dose dependent. In conclusion, the present study suggests that certain food additives like AOB may be of benefit against the side effects of cisplatin.
Glutathione transport in the endo/sarcoplasmic reticulum
Authors: Csala Miklós , Fulceri Rosella , Mandl József , Benedetti Angelo , Bánhegyi Gábor
Published: December 2008

Glutathione transport through the endo/sarcoplasmic reticulum (ER/SR) membrane might play a role in the maintenance of the thiol redox potential difference between the lumen and the cytosol.The transport of glutathione (both GSH and glutathione disulfide, GSSG) is entirely different in the ER and SR membranes.

The transport measurements based on either rapid filtration or light scattering techniques revealed that the SR membrane transports glutathione much faster than the hepatic ER membrane or microsomal membranes prepared from heart or brain. The fastest transport has been measured in the membrane of muscle terminal cisternae, which is enriched in ryanodine receptor type 1 (RyR1). All the studied membranes have been found to be equally impermeable to various hydrophilic substances of similar size to glutathione, thus the glutathione transport in muscle microsomes and terminal cysternae as well as the correlation between the rate of glutathione transport and the abundance of RyR1 are specific. In both muscle microsomes and terminal cysternae, glutathione influx can be either inhibited or activated by antagonists and agonists of the ryanodine receptor, respectively, while these agents do not influence the transport of other small permeant molecules. These findings strongly suggest that the ryanodine receptor channel activity is directly associated with glutathione transport activity in the skeletal muscle sarcoplasmic reticulum membrane.
Multidrug resistance‐associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate
Authors: Homolya László , Váradi András , Sarkadi Balázs
Published: December 2008

Many endogenous or xenobiotic lipophilic substances are eliminated from the cells by the sequence of oxidation, conjugation to an anionic group (glutathione, glucuronate or sulfate) and transport across the plasma membrane into the extracellular space. The latter step is mediated by integral membrane glycoproteins belonging to the superfamily of ATP‐Binding Cassette (ABC) transporters. A subfamily, referred as ABCC, includes the famous/infamous cystic fibrosis transmembrane regulator (CFTR), the sulfonylurea receptors (SUR 1 and 2), and the multidrug resistance‐associated proteins (MRPs). The name of the MRPs refers to their potential role in clinical multidrug resistance, a phenomenon that hinders the effective chemotherapy of tumors. The MRPs that have been functionally characterized so far share the property of ATP‐dependent export pumps for conjugates with glutathione (GSH), glucuronate or sulfate. MRP1 and MRP2 are also mediating the cotransport of unconjugated amphiphilic compounds together with free GSH. MRP3 preferentially transports glucuronides but not glutathione S‐conjugates or free GSH. MRP1 and MRP2 also contribute to the control of the intracellular glutathione disulfide (GSSG) level. Although these proteins are low affinity GSSG transporters, they can play essential role in response to oxidative stress when the activity of GSSG reductase becomes rate limiting. The human MRP4, MRP5 and MRP6 have only partially been characterized. However, it has been revealed that MRP4 can function as an efflux pump for cyclic nucleotides and nucleoside analogues, used as anti‐HIV drugs. MRP5 also transports GSH conjugates, nucleoside analogues, and possibly heavy metal complexes. Transport of glutathione S‐conjugates mediated by MRP6, the mutation of which causes pseudoxantoma elasticum, has recently been shown. In summary, numerous members of the multidrug resistance‐associated protein family serve as export pumps that prevent the accumulation of anionic conjugates and GSSG in the cytoplasm, and play, therefore, an essential role in detoxification and defense against oxidative stress.
Reduction of the endoplasmic reticulum accompanies the oxidative damage of diabetes mellitus
Authors: Nardai Gábor , Korcsmáros Tamás , Papp Eszter , Csermely Péter
Published: December 2008

The endoplasmic reticulum (ER), similary to other subcompartments of the eukaryotic cell possesses a relatively oxidizing environment. The special milieu of ER lumen is important for many ER‐specific processes (redox protein folding, glycoprotein synthesis, quality control of secreted proteins, antigen presentation, etc.). Despite of the vital importance of redox regulation in the ER, we have a surprisingly fragmented knowledge about the mechanisms responsible for the ER redox balance. Moreover, new observations on disulfide bridge synthesis and on glutathione functions urge us to revise our recent theories based on many indirect and in vitro results. We have also very little information about the effects of different pathological conditions on the thiol metabolism and redox folding in the ER. Examining the role of molecular chaperones in the cellular pathology of diabetes mellitus we found that the ER redox environment shifted to a more reducing state, which was followed by changes of the thiol metabolism and structural‐functional changes of the protein machinery involved in the redox folding process in diabetes. The possible consequences of these unexpected changes are also discussed.