Modification of mortality and tumorigenesis by tocopherol-mono-glucoside (TMG) administered after X irradiation in mice and rats.

The effects of TMG [2-(alpha-d-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol], a water-soluble vitamin E derivative, administered after irradiation on the mortality of X-irradiated mice and on the development of tumors in the mammary and pituitary glands in rats were investigated. When TMG (650 mg/kg) was administered intraperitoneally (i.p.) to C3H mice immediately after whole-body exposure to 7 Gy radiation, the 30-day survival was significantly higher than that of the control mice. The i.p. administration of TMG at 4 h after irradiation significantly improved survival compared to that of the controls, but administration 8 h after irradiation did not have a significant effect. Subcutaneous administration of TMG immediately after irradiation also decreased mortality significantly. When dams of lactating Wister rats were exposed to 1.5 Gy of X rays at day 21 after parturition and were then treated with diethylstilbestrol as a tumor promoter, the incidence of mammary tumors and pituitary tumors was increased compared to that in the nonirradiated control group. The administration of TMG (600 mg/kg, i.p.) after irradiation significantly reduced the incidence of mammary tumors and pituitary tumors. The number of rats that were free of both mammary and pituitary gland tumors was enhanced fourfold by TMG. These results suggest that TMG is effective in preventing radiation-induced bone marrow death in mice and in reducing mammary and pituitary tumors in rats even when it is administered after irradiation.

Homolytic cleavage of the O-glycoside bond in carbohydrates: a steady-state radiolysis study.

The formation of products resulting from the O-glycoside bond cleavage following radiolysis of aqueous solutions of methyl-alpha-D-glucopyranoside (I), 3-O-methyl-alpha-D-glucopyranose (II), maltose, lactose, gentiobiose and cellobiose were studied. Radiation-induced destruction yields were also determined for dextran, laminarin and trimethylcelulose upon irradiation of their aqueous solutions. Oxygen, quinones and compounds capable of forming quinoid structures were found to inhibit radiation-induced homolytic destruction processes taking place in glycosides, di- and polysaccharides. The data obtained in this study enabled the authors to demonstrate an important role played by the fragmentation reaction of C-2 radicals which were generated from the starting substances in the formation of final radiolysis products.

Effect of tocopherol-monoglucoside (TMG), a water-soluble glycosylated derivate of vitamin E, on hematopoietic recovery in irradiated mice.

A preparation of alpha-tocopherol monoglucoside (TMG) administered i.p. at a dose of 600 mg/kg immediately after whole body gamma irradiation was examined for its radioprotective efficacy towards bone marrow and peripheral blood nucleated cells. When mice received X-rays at a dose of 5,6 Gy, a marked decrease in bone marrow karyocytes and a reduction of peripheral leukocytes within the early post-irradiated period were observed. However these changes were attenuated in TMG-treated mice. Significant protection of blood lymphocytes was found for the TMG group of mice. The return to normal value of the reduced blood leukocyte count starting from the 8th day was more rapid in TMG-treated mice than in untreated irradiated mice. TMG administration was found to enhance hematopoietic recovery, as measured by the exceeded nucleated bone marrow cell count due to elevated amount of both lymphoid and granulocytic elements in the TMG-group, in comparison with that of both control irradiated and non-irradiated animals. These findings indicate that the radioprotective effect of TMG is apparently realized through its influence on hematopoietic system.

Effects of Helicobacter pylori water extract on expression of endothelial adhesion molecules.

The present study investigated whether Helicobacter pylori water extract induces the upregulation of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin on human umbilical vein endothelial cells, using an ELISA. The nature of the substances mediating this upregulation was also analyzed. H pylori water extract derived from type strain (NCTC 11637) significantly upregulated intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin to the same extent as interleukin-1. Treatments with extracts from clinical strains showed no significant increases in expression of these adhesion molecules. In a fractionation study, approximately 7 kDa fraction showed peak activity. This activity was tolerant to heating and trypsin digestion. These results indicate that H pylori water extract contains water-soluble, low-molecular, nonprotein substances which induce upregulation of adhesion molecules on human umbilical vein endothelial cells, suggesting that products of H pylori may elicit gastric mucosal inflammation by promoting expression of endothelial adhesion molecules.

A novel water-soluble vitamin E derivative prevents acute lung injury by bacterial endotoxin.

1. Various chemokines, such as keratinocyte chemoattractant (KC), macrophage inflammatory protein (MIP)-1alpha and macrophage chemoattractant protein (MCP)-1, are involved in the pathogenesis of acute lung injury induced by bacterial endotoxin (lipopolysaccharide; LPS). Oxidative stress is an important regulator of the expression of these chemokines, whereas vitamin E protects against LPS-induced insults. In the present study, we determined the effects of 2-(alpha-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol (TMG), a novel water-soluble vitamin E derivative with excellent anti-oxidant activity, on acute lung injury induced by intratracheal instillation of LPS (125 micro g/kg) in mice. 2. When TMG was administered intratracheally and intravenously (0.1, 1.0 or 10 mg/kg), it dose-dependently decreased the infiltration of neutrophils into bronchoalveolar lavage fluid after LPS challenge. 3. Histological examination showed that treatment with TMG ameliorated the LPS-induced infiltration of neutrophils into the lungs. Furthermore, TMG attenuated the LPS-induced increase in pulmonary expression of KC, MIP-1alpha and MCP-1 at both the transcriptional and translational levels. 4. These results indicate that TMG is a possible treatment for acute lung injury, especially that caused by Gram-negative bacteria. The therapeutic effect of TMG may be mediated, at least in part, by suppression of the local expression of chemokines, possibly through its strong anti-oxidant activity.

In vivo postirradiation protection by a vitamin E analog, alpha-TMG.

The water-soluble vitamin E derivative alpha-TMG is an excellent radical scavenger. A dose of 600 mg/kg TMG significantly reduced radiation clastogenicity in mouse bone marrow when administered after irradiation. The present study was aimed at investigating the radioprotective effect of postirradiation treatment with alpha-TMG against a range of whole-body lethal (8.5-12 Gy) and sublethal (1-5 Gy) doses of radiation in adult Swiss albino mice. Protection against lethal irradiation was evaluated from 30-day mouse survival and against sublethal doses was assessed from micronuclei and chromosomal aberrations in the bone marrow 24 h after irradiation. An intraperitoneal injection of 600 mg/kg TMG within 10 min of lethal irradiation increased survival, giving a dose modification factor (DMF) of 1.09. TMG at doses of 400 mg/kg and 600 mg/kg significantly reduced the percentage of aberrant metaphases, the different types of aberrations, and the number of micronucleated erythrocytes. DMFs of 1.22 and 1.48 for percentage aberrant metaphases and 1.6 and 1.98 for micronuclei were obtained for 400 mg/kg and 600 mg/kg TMG, respectively. No drug toxicity was observed at these doses. The effectiveness of TMG when administered postirradiation suggests its possible utility for protection against unplanned radiation exposures.

A novel vitamin E derivative (TMG) protects against gastric mucosal damage induced by ischemia and reperfusion in rats.

The aim of the present study was to investigate the antioxidative effects of water-soluble vitamin E derivative, 2-(alpha-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol (TMG), on ischemia-reperfusion (I/R) -induced gastric mucosal injury in rats. Gastric ischemia was induced by applying a small clamp to the celiac artery and reoxygenation was produced by removal of the clamp. The area of gastric mucosal erosion, the concentration of thiobarbituric acid-reactive substances, and the myeloperoxidase activity in gastric mucosa significantly increased in I/R groups compared with those of sham-operated groups. These increases were significantly inhibited by pretreatment with TMG. The contents of both mucosal TNF-alpha and CINC-2beta in I/R groups were also increased compared with the levels of those in sham-operated groups. These increases of the inflammatory cytokines were significantly inhibited by the treatment with TMG. It is concluded that TMG inhibited lipid peroxidation and reduced development of the gastric mucosal inflammation induced by I/R in rats.

Water soluble vitamin E (TMG) as a radioprotector.

Tocopherol monoglucoside (TMG), a water soluble derivative of vitamin E offers protection against deleterious effects of ionizing radiation, both under in vivo and in vitro conditions, to biological systems. TMG was found to be a potent antioxidant and an effective free radical scavenger. It forms a phenoxyl radical similar to trolox upon reaction with various one-electron oxidants. TMG protected DNA from radiation-induced strand breaks. It also protected thymine glycol formation induced by gamma-radiation. Gamma-radiation-induced loss of viability of EL-tumor cells and peroxidation of lipids in microsomal and mitochondrial membranes were prevented by TMG. TMG was nontoxic to mice when administered orally up to 7.0 g/kg body weight. The LD50 dose of TMG for ip administration in mice was 1.15 g/kg body wt. In rats, following oral and ip administration of TMG, the absorption (distribution) half lives were 5.8 and 3.0 min respectively and elimination half lives were 6.7 and 3.1 min respectively. Embryonic mortality resulting from exposure of pregnant mice to ionizing radiation (2 Gy) was reduced by 75% by ip administration of TMG (0.6 g/kg, body wt) prior to irradiation. TMG offered protection to mice against whole body gamma-radiation-induced lethality and weight loss. The LD50(30) of mice increased from 6 to 6.72 Gy upon post irradiation administration of a single dose of TMG (0.6 g/kg, body wt) by ip.

A novel water-soluble vitamin E derivative, 2-(alpha-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol, protects against acute lung injury and mortality in endotoxemic rats.

Satisfactory therapy for acute lung injury related to endotoxemia remains to be established. However, in vivo antioxidant treatment with N-acetylcysteine reportedly suppresses acute lung injury and proinflammatory cytokine production induced by endotoxin (lipopolysaccharide, LPS). In addition, intrinsic vitamin E is protective against LPS-induced insults. We determined the effects of a novel water-soluble vitamin E derivative, 2-(alpha-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol (TMG), on acute lung injury and mortality induced by LPS in rats. Intravenous injection of TMG (4 or 40 mg/kg) effectively decreased mortality and prevented the increased alveolar permeability and pulmonary edema that were caused by intravenous injection of LPS (20 mg/kg). Treatment with TMG decreased the enhanced lung expression of TNF-alpha caused by LPS. TMG also suppressed the sequestration of neutrophils in the lung induced by LPS. These results indicate that TMG is a possible therapeutic agent for acute lung injury and mortality, especially that caused by gram-negative bacteria. The therapeutic effects could be mediated at least partly through suppression of the increased expression of TNF-alpha and neutrophil sequestration in the lung that are caused by LPS.

Inhibitory effect of a novel water-soluble vitamin E derivative on atherosclerosis in rabbits.

A novel vitamin E derivative that is freely soluble in water, 2-(alpha-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol (TMG), was evaluated for ability to inhibit development of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits or cholesterol-loaded New Zealand White rabbits. Although TMG rapidly entered the circulation blood after oral administration, the blood TMG concentration remained low, while neither TMG nor its metabolites appeared in the low-density lipoprotein (LDL) fraction. TMG did not decrease serum total cholesterol and the various lipoprotein-associated cholesterol fractions (very LDL-, or high-density lipoprotein- (HDL) cholesterol). TMG reduced the serum concentration of thiobarbituric acid-reactive substances (TBARS; an index of lipid peroxidation) in cholesterol-loaded rabbits but not WHHL rabbits. Nonetheless, TMG inhibited aortic atherosclerosis as effectively as probucol in both models. Our results indicate that TMG opposes progression of atherosclerosis not only by preventing oxidation of LDL, but also by presently unknown mechanisms. Even an antioxidant with no uptake by LDL apparently can inhibit development of atherosclerosis despite a very low serum concentration.