Biological and chemical warfare agents (BCWAs) are diverse in nature including synthetic low molecular weight chemical warfare agents (gaseous choking and blood agents), volatile nerve gases and blister agents, non-volatile vomit agents and lachrymators, biological toxins (polar low molecular weight toxins and proteinous toxins), and microorganisms (viruses, rickettsia, chlamydia and bacteria). In the consequence management against chemical and biological warfare terrorism, speedy decontamination of casualties, goods, items and equipments, buildings and field is required for the minimization of the terrorism damage. At present, washing casualties and contaminated materials with large volumes of water is the basic way, and hypochlorite solution is mainly used to decompose BCWAs. However, it still remains unsolved how to dispose the waste water contaminated with BCWAs, and decontaminating reagents have serious problems of high toxicity to human, despoiling nature to environment, long finishing time and non-durability. In addition, the present decontamination technologies are not effective, nonspecifically affecting the surrounding non-target materials. Therefore, it is the urgent matter to build up usable decontamination system surpassing the present system. The author introduces the joint project of research and development of the novel decontamination system against BCWAs, in the purpose of realizing non-dangerous, rapid, specific, effective and economical on-site decontamination. The project consists of establishment of the evaluation methods for decontamination, and verification of the present technologies and utilization of bacterial organophosphorus hydrolase, development of specific adsorptive elimination technologies using molecular recognition devices, and development of deactivation technologies using photocatalysis.
The present study was designed to investigate the effect of insulin on insulin resistance (IR), plasma adiponectin level and expression of adiponectin receptors 1 (AdipoR1) in obese and streptozotocin-induced type 2 diabetic rats. Male Sprague-Dowley rats were randomized to control group and 3 obese experimental groups. Type 2 diabetic mellitus was induced in the 3rd and 4th experimental groups by given 30 mg/kg of a single dose streptozotocin via intraperitoneal injection (i.p.). Fourth group was treated with i.p. 1 IU insulin/kg/day for 6 days before end of the experiment which lasts for 8 weeks while same amount of normal saline was i.p. given to other group. At the end of the study (8 weeks), plasma levels of adiponectin, triglycerides (TG), cholesterol, fasting blood glucose and insulin were measured. Obesity index (OI) and IR were calculated. AdipoR1 mRNA levels in the soleus muscle tissue were semi-quantitated. Hyperlipidemia, hyperinsulinemia and hyperglycemia were observed in both obese and diabetic rats, which were accompanied by hypoadiponectinemia and down regulation of AdipoR1 expression as compared to the control rats. Adiponectin was negatively correlated with all the biochemical parameters assessed. Insulin treatment significantly improved these metabolic abnormalities and effectively restored adiponectin and AdipoR1 to the control level. In conclusion, adiponectin and its receptor-associated cascade may be aberrantly regulated in both obesity and type 2 diabetes and targeting adiponectin and its receptors may offer a novel therapy against obesity and type 2 diabetes.
The components bringing the effects of fish oil on glucose and lipid metabolism are unclear. We used hydrogenated fish oil, which has saturated fatty acids with the same carbon chain lengths as the unsaturated fatty acids in fish oil, to clarify the functions of these unsaturated fatty acids on the improvements in lipid and glucose metabolism in mice. Mice divided into 3 groups were fed different diets: fish oil diet (FO), hydrogenated fish oil diet (HFO), and soybean oil diet (SBO) as a control. Body weight gain and white adipose tissue weight in the HFO and FO groups were significantly decreased compared with those in the SBO group. However, in the HFO group, the triglyceride (TG) levels in plasma were significantly decreased, while the lipids levels in the liver were remarkably increased compared with those in the FO group. Regarding the fatty acid composition in the liver and white adipose tissue in the HFO group, in parallel with the up-regulation of stearoyl-CoA desaturase 1 mRNA, relative amounts of C16:1 and C18:1 were significantly increased. By contrast, blood glucose levels in the oral glucose tolerance test had not deteriorated in the HFO group. Our results indicate that unsaturated fatty acids in the FO diet decrease lipid levels in the liver and maintain the balance of lipid levels in plasma, liver and white adipose tissue; in addition, in the HFO group, C16:1 and C18:1 synthesized in the liver and white adipose tissue may improve glucose tolerance and lipid metabolism.
Cimicifugoside is a triterpenoid originating from the rhizomes of Cimicifuga simplex, and acts to inhibit the subcellular transport of nucleosides. Cimicifugoside, when used in combination with methotrexate, showed a cell-specific synergic effect on the promonocytic leukemia cell line U937, but not on the chronic myelogenetic leukemia cell line K562. Thymidine uptake was more severely inhibited by cimicifugoside in a dose-dependent fashion in U937 than in K562. The mRNA expression of one of the equilibrative Na+-independent nucleoside transporters, ENT2, was lower in U937 than in K562. This suggests that the thymidine uptake by ENT2 of U937 is more severely affected by cimicifugoside than that of K562, resulting in a decrease in DNA synthesis by methotrexate. In addition, cimicifugoside more efficiently stimulated the activity of thymidine kinase (TK) in K562 than in U937, suggesting that K562 resisted the decrease in DNA synthesis caused by the inhibition of nucleoside transporters. Cimicifugoside bifunctionally potentiated the cell-specific cytotoxicity of methotrexate by inhibiting ENT2 and activating TK.
Mouse embryonic stem cells were caused to differentiate into insulin-producing cells by 2 methods: Stem cells were cultured with or without feeder cells. In both cases, after confirmation of their differentiation into the insulin producing cells, the effects of the addition of 10 μl of 50 mM glucose, 10 μl of glycated fetal bovine serum (GFBS) and 10 μl of GFBS+20 mM iron on the differentiated stem cells were examined. The addition of GFBS or GFBS+iron to the cultures with or without the feeder cells caused them to produce a significantly higher amount of insulin than did the addition of glucose. However, this enhancement by GFBS or GFBS+iron stopped after 12 hr of addition; and the culture medium was turned yellow after 15 hr and at that time the cells died, which may be due to the cytotoxicity of GFBS or GFBS+iron.
The influence of dietary protein levels on the acute toxicity of inorganic mercury (Hg) was investigated using mice fed a 24.8% protein diet (normal protein diet, NPD) or a 7.5% protein diet (low protein diet, LPD), and relationships between tissue susceptibility and both levels of Hg and metallothionein (MT) were examined. Twenty-four hr after administration of inorganic Hg, the plasma creatinine concentrations, an index of nephrotoxicity, increased in LPD-fed mice but not in NPD-fed mice at 5 mg Hg/kg, and in both dietary groups at 7.5 mg Hg/kg compared to the respective controls. However, plasma alanine aminotransferase (ALT) activities, an index of hepatotoxicity, increased in both groups only at 7.5 mg Hg/kg. Hg concentrations in the liver was higher in LPD-fed mice than in NPD-fed mice only at 5 mg Hg/kg, although dietary protein levels did not affect concentrations in the liver at 7.5 mg Hg/kg or in the kidney at both doses. MT concentrations were similar in the two dietary groups except for the liver, in which the lowered MT level was observed in LPD-fed mice only at 7.5 mg/kg. The present results suggest that dietary protein levels can modify the acute toxicity of singly administered inorganic Hg, at least in the kidney. It is also suggested that MT induction by toxic doses of inorganic Hg is suppressed by dietary protein deficiency, especially in the liver, but this difference would not lead to the variations in the toxicity or in the Hg retention at least within 24 hr.
We have previously hypothesized that mental fatigue is caused by neuronal brain damage through the activation of N-methyl-D-aspartate receptors by quinolinic acid (QUIN). QUIN is a metabolite of tryp-tophan in the kynurenine pathway; this pathway is stimulated by several cytokines, including tumor necrosis factor (TNF)-α. Recently, we proved this mental-fatigue hypothesis by studying stress-loaded and lipopolysaccharide-treated mice. In the present study, we measured blood QUIN levels after exercise in mice to investigate whether QUIN also participates in causing the sensation of fatigue after exercise. In a weight-loaded swimming test, steel wires weighing about 5% of body weight were attached to the tails of mice that were then forced to swim until exhaustion. The serum QUIN levels of swimming mice were significantly higher than those of non-swimming mice. The serum TNF-α levels were also increased in swimming mice compared with non-swimming mice, although this effect was not significant. In a treadmill-running test, mice were forced to run for 150 min on a 10-degree uphill incline. The serum levels of both QUIN and TNF-α were significantly higher in treadmill-running mice than in non-running mice. Wheel-running counts, which reflect mental activity, were also measured in a running wheel-equipped home cage. Wheel-running counts of treadmill-running mice were significantly reduced compared with those of non-running mice. These results suggest that blood QUIN levels are increased after exercise and that this effect occurs through enhanced tryptophan metabolism in the kynurenine pathway due to TNF-α production. It is implied that QUIN participates in the sensation of fatigue after exercise.
The mutagenicities and endocrine-disrupting activities of two isomers of mononitrated 1-hydroxypyrene [1-hydroxy-x-nitropyrenes (1-OH-x-NPs); x=2 and 5], which are not only photoreaction products of 1-nitropyrene (1-NP) but also constituent of ambient airborne particles, were evaluated for the first time using the Ames plate incorporation assay and the yeast two-hybrid assay, respectively. The mutagenicity of 1-OH-5-NP was weakly positive in the absence of rat liver S9, but was enhanced up to 3-fold with the metabolic activation by S9. On the contrary, 1-OH-2-NP did not exhibit significant mutagenicity in the presence or absence of S9. 1-OH-5-NP showed weak estrogenic activity, but 1-OH-2-NP did not show any estrogenic activity. The concentration of 1-OH-5-NP that gave 10% of activity of 1.0×10-6 M 17β-estradiol (E2) was 5.4×10-7 M. 1-OH-5-NP exhibited stronger antiestrogenic and antiandrogenic activities than 1-OH-2-NP. 1-OH-5-NP at a concentration of 1.0×10-6 M inhibited 71 and 90% of β-galactosidase activity induced by 1.0×10-9 M of E2 and 1.0×10-8 M of 5α-dihydrotestosterone (DHT), respectively. On the other hand, 1.0×10-6 M of 1-OH-2-NP inhibited 16 and 43% of β-galactosidase activity induced by 1.0×10-9 M of E2 and 1.0×10-8 M of DHT, respectively. These findings point out the need for determining the environmental sources and distribution of 1-OH-2-NP and 1-OH-5-NP as well as the other hydroxynitropyrene isomers.
Increased activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) has been implicated in the development of the metabolic syndromes by amplification of local glucocorticoid actions through regeneration of active glucocorticoid receptor. The present study was examined whether inhibition of 11β-HSD-1 by carbenoxolone (CBX), a non-selective 11β-HSD inhibitor, improved carbohydrate metabolism in insulin resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats or not. Rats received subcutaneous CBX, twice a day [50 mg/kg bodyweight (b.w.)] or vehicle for 2 weeks, and then were evaluated fasting blood glucose levels, glucose tolerance, serum fasting insulin levels, and blood lipid levels in the both groups. The fasting blood glucose and insulin were lower in CBX-treated OLETF rats at 2 weeks than those of compared to day 0 and vehicle-treated OLETF rats at 2 weeks. Blood glucose fluctuations of the CBX-treated OLETF rats were more normal than those of vehicle-treated ones during intraperitoneal glucose tolerance tests. Blood concentrations of cholesterol and free fatty acids in the CBX-treated OLETF rats were lesser than those of vehicle-treated ones. The area under time-concentration curve (AUC120 min) of blood glucose during the glucose tolerance test and of CBX-treated OLETF rats was significantly lower than that of the vehicle-treated ones, and insulinogenic index (ISI30 min) was significantly different between CBX-and vehicle-treated groups. These results suggested that inhibition of 11β-HSD-1 by CBX might be improved carbohydrate metabolism and lipid profile in the insulin-resistant OLETF rats.
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