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Biomedical subjects

Y Itakura

Publications and source records attributed to Y Itakura.

At least 19 recordsLinked to original sources
PubMed2006

Global gene expression analysis in liver of obese diabetic db/db mice treated with metformin.

AIMS/HYPOTHESIS: Metformin is widely used as a hypoglycaemic reagent for type 2 diabetes. While the reduction of hepatic gluconeogenesis is thought to be a key effect, the detailed molecular mechanism of action of metformin remains to be elucidated. To gain insight into this, we performed a global gene expression profiling study. MATERIALS AND METHODS: We performed DNA microarray analysis to study global gene expression in the livers of obese diabetic db/db mice 2 h after a single administration of metformin (400 mg/kg). RESULTS: This analysis identified 14 genes that showed at least a 1.5-fold difference in expression following metformin treatment, including a reduction of glucose-6-phosphatase gene expression. The mRNA levels of glucose-6-phosphatase showed one of the best correlations with blood glucose levels among 12,000 genes. Enzymatic activity of glucose-6-phosphatase was also reduced in metformin-treated liver. Moreover, intensive analysis of the expression profile revealed that metformin effected significant alterations in gene expression across at least ten metabolic pathways, including those involved in glycolysis-gluconeogenesis, fatty acid metabolism and amino acid metabolism. CONCLUSIONS/INTERPRETATION: These results suggest that reduction of glucose-6-phosphatase activity, as well as suppression of mRNA expression levels of this gene, in liver is of prime importance for controlling blood glucose levels in vivo, at least at early time points after metformin treatment. Our results also suggest that metformin not only affects expression of specific genes, but also alters the expression level of multiple genes linked to the metabolic pathways involved in glucose and lipid metabolism in the liver.

Animals↗
PubMed2002

Brain-derived neurotrophic factor ameliorates lipid metabolism in diabetic mice.

AIM: It has been reported previously that brain-derived neurotrophic factor (BDNF) regulates blood glucose metabolism in rodent obese diabetic models such as C57BL/KsJ-leprdb/leprdb (db/db) mice. BDNF further regulates energy expenditure, possibly through the central and autonomous nervous systems. In this study, we evaluated the effect of BDNF on both lipid and glucose metabolisms to clarify its action mechanism. METHODS: To control the energy intake, we used a pellet pair-feeding apparatus to synchronize food intake precisely between BDNF-treated and vehicle-treated db/db mice. BDNF (50 mg/kg/week) was subcutaneously injected to male db/db mice twice weekly for 3 weeks, and blood glucose, serum biochemical lipid parameters and tissue weights were measured. Liver triglyceride contents were measured and liver sections were histologically analysed. RESULTS: Twice weekly BDNF treatment for 3 weeks significantly lowered blood glucose compared with pellet pair-fed, vehicle-treated db/db mice (294 +/- 109 vs. 529 +/- 91 mg/dL). Serum non-esterified free fatty acid (726 +/- 72 vs. 999 +/- 220 microEq/l), total cholesterol (125 +/- 8 vs. 151 +/- 23 mg/dL) and phospholipid levels (215 +/- 13 vs. 257 +/- 36 mg/dL) of the BDNF-treated db/db mice decreased significantly. Liver weights (1.51 +/- 0.11 vs. 2.05 +/- 0.11 g), liver triglyceride contents (17.5 +/- 1.4 vs. 26.1 +/- 2.1 mg/g) and fatty liver in histological appearance were reduced with BDNF treatment. There were no significant differences in body weights and white adipose tissue weights between the two groups. CONCLUSIONS: Taken together with the accelerating effect of BDNF on energy metabolism, these findings indicate that BDNF improves glucose and lipid metabolism in obese diabetic animals without enlarging liver or adipose tissues.

Adipose Tissue↗
PubMed2001

The effects of brain-derived neurotrophic factor on insulin signal transduction in the liver of diabetic mice.

AIM/HYPOTHESIS: We previously reported that repeated subcutaneous or intracerebroventricular injection of brain-derived neurotrophic factor (BDNF) reduces blood glucose concentrations in obese diabetic C57BL/KsJ-db/db mice. In this study, we assessed the effects of BDNF on insulin action in peripheral tissues of diabetic mice. METHODS: First, brain-derived neurotrophic factor (20 mg/kg) was subcutaneously given to male db/db mice for 14 days and then the insulin-stimulated tyrosine phosphorylation of insulin receptors and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in peripheral tissues was assessed. Second, we examined the effects of a single subcutaneous or intracerebroventricular brain-derived neurotrophic factor injection on insulin responsiveness in liver and skeletal muscle of streptozotocin (STZ)-induced diabetic mice. Third, the effects of brain-derived neurothrophic factor on insulin action were also examined in cultured cells. RESULTS: Repeated injection of BDNF to db/db mice for 14 days enhanced insulin-stimulated tyrosine phosphorylation of insulin receptors in liver and insulin-stimulated PI 3-kinase activity in liver, skeletal muscle and interscapular brown adipose tissue. We then examined the rapid effect of BDNF on insulin signalling in vivo. A single subcutaneous or intracerebroventricular injection of BDNF rapidly increased insulin-stimulated tyrosine phosphorylation of insulin receptors and PI 3-kinase activity in liver of STZ-mice. No direct effect of brain-derived neurothrophic factor was observed on insulin signalling in primary cultured hepatocytes, L6 muscle cells or 3T3-L1 adipocytes. Brain-derived neurothrophic factor did not affect either glucose uptake or gluconeogenesis in these cells. CONCLUSION/INTERPRETATION: These data indicate that brain-derived neurothrophic factor rapidly enhances insulin signal transduction in liver and shows hypoglycaemic action in diabetic mice.

3T3 Cells↗
PubMed2001

The effects of aged garlic extract on lipid peroxidation and the deformability of erythrocytes.

The effects of aged garlic extract (AGE) on lipid peroxidative damage and the deformability of erythrocytes were evaluated in rats. The deformability of erythrocytes was measured using the micropore filtration method. AGE significantly prevented the decrease of erythrocyte deformability induced by lipid peroxidation in a dose-dependent manner. The addition of AGE significantly inhibited an increase in thiobarbituric acid-reactive substances (TBARS) and hemolysis rate and prevented the loss of intraerythrocytic ATP and 2,3-diphosphoglycerate (2,3-DPG) in oxidized erythrocytes. Moreover, AGE significantly suppressed not only the hemolysis rate induced by peroxidation but also hemolysis due to nonperoxidation. These results suggest the possibility that AGE improves microcirculation and rheological blood properties and preserves the structure and function of erythrocytes not only through an antioxidant process, but also via the glycolysis pathway and membrane stabilization of erythrocytes.

2,3-Diphosphoglycerate↗
PubMed2001

Alleviation by garlic of antitumor drug-induced damage to the intestine.

Antitumour drugs such as methotrexate (MTX) and 5-fluorouracil (5-FU) induce intestinal damage. This is a serious side effect of cancer chemotherapy. The present studies examined whether or not aged garlic extract (AGE) protects against damage from these antitumor drugs. Both drugs were administered orally for 4 or 5 d to rats fed a standard laboratory diet with and without 2% AGE. The small intestinal absorption of the poorly absorbable compound, fluorescein isothiocyanate--labeled dextran (FD-4; average molecular weight, 4400) was used to evaluate the damage to the intestine using the in vitro everted intestine technique and the in situ intestinal loop technique. FD-4 absorption increased in the antitumour drug-treated rats fed the diet without garlic. Interestingly, FD-4 absorption was depressed in rats fed the diet containing AGE. These results suggest that AGE may protect the small intestine of rats from antitumour drug-induced damage.

Administration, Oral↗
PubMed2001

Immunomodulatory effects of aged garlic extract.

Using various kinds of models, we examined the effects of aged garlic extract (AGE) on immune functions. In the immunoglobulin (Ig)E-mediated allergic mouse model, AGE significantly decreased the antigen-specific ear swelling induced by picryl chloride ointment to the ear and intravenous administration of antitrinitrophenyl antibody. In the transplanted carcinoma cell model, AGE significantly inhibited the growth of Sarcoma-180 (allogenic) and LL/2 lung carcinoma (syngenic) cells transplanted into mice. Concomitantly, increases in natural killer (NK) and killer activities of spleen cells were observed in Sarcoma-180--bearing mice administered AGE. In the psychological stress model, AGE significantly prevented the decrease in spleen weight and restored the reduction of anti-SRBC hemolytic plaque-forming cells caused by the electrical stress. These studies strongly suggest that AGE could be a promising candidate as an immune modifier, which maintains the homeostasis of immune functions; further studies are warranted to determine when it is most beneficial.

Adjuvants, Immunologic↗
PubMed2001

Pharmacologic activities of aged garlic extract in comparison with other garlic preparations.

We investigated the pharmacologic activities of four garlic preparations, raw garlic juice (RGJ), heated garlic juice (HGJ), dehydrated garlic powder (DGP) and aged garlic extract (AGE). The study used three animal models, i.e., testicular hypogonadism (hypospermatogensis and impotence) induced by warm water treatment, intoxication of acetaldehyde and growth of inoculated tumor cells. RGJ was found to be effective only in recovery of testicular function. The efficacy of HGJ was observed in three models; however, it did not improve impotence. DGP was effective in recovery of spermatogenesis and stimulated acetaldehyde detoxification. Significant beneficial effects of AGE were found in all three models. Although all four garlic preparations significantly enhanced natural killer (NK) and killer cell activities of the spleen cells of tumor-bearing mice, only AGE and HGJ inhibited the growth of inoculated tumor cells. These results suggest that different types of garlic preparations have different pharmacologic properties, and among the four garlic preparations studied, AGE could be the most useful garlic preparation.

Acetaldehyde↗
PubMed2001

Intake of garlic and its bioactive components.

The health benefits of garlic likely arise from a wide variety of components, possibly working synergistically. The complex chemistry of garlic makes it plausible that variations in processing can yield quite different preparations. Highly unstable thiosulfinates, such as allicin, disappear during processing and are quickly transformed into a variety of organosulfur components. The efficacy and safety of these preparations in preparing dietary supplements based on garlic are also contingent on the processing methods employed. Although there are many garlic supplements commercially available, they fall into one of four categories, i.e., dehydrated garlic powder, garlic oil, garlic oil macerate and aged garlic extract (AGE). Garlic and garlic supplements are consumed in many cultures for their hypolipidemic, antiplatelet and procirculatory effects. In addition to these proclaimed beneficial effects, some garlic preparations also appear to possess hepatoprotective, immune-enhancing, anticancer and chemopreventive activities. Some preparations appear to be antioxidative, whereas others may stimulate oxidation. These additional biological effects attributed to AGE may be due to compounds, such as S-allylcysteine, S-allylmercaptocysteine, N(alpha)-fructosyl arginine and others, formed during the extraction process. Although not all of the active ingredients are known, ample research suggests that several bioavailable components likely contribute to the observed beneficial effects of garlic.

Allyl Compounds↗
PubMed2001

How to distinguish garlic from the other Allium vegetables.

The establishment of international monographs for herbs is in progress. Here, we propose both a marker compound and a method for its analysis for the identification of garlic bulbs and their products. The constituents in 26 kinds of fresh edible parts of Allium vegetables and three types of garlic preparations were analyzed. Sulfur compounds are the most characteristic constituents in garlic, but manufacturing processes of garlic products dramatically affect these constituents. Thus, no sulfur compound could be specified as a universal marker of identification applicable for any type of garlic. On the other hand, garlic contains other characteristic compounds, namely, saponins. After analyzing Allium vegetables and garlic preparations, we concluded that sapogenins, especially beta-chlorogenin, may be a viable candidate for identifying and distinguishing garlic from other Allium vegetables.

Allium↗
PubMed2001

N alpha-(1-deoxy-D-fructos-1-yl)-L-arginine, an antioxidant compound identified in aged garlic extract.

Aged garlic extract (AGE) has been shown to have antioxidant activity. The organosulfur compounds, S-allyl-L-cysteine and S-allylmercapto-L-cysteine, are responsible, at least in part, for the antioxidant activity of AGE. To identify major active components, we fractionated AGE, using hydrogen peroxide scavenging activity as an antioxidative index. Strong activity in the amino acid fraction was found and the major active compound was identified as N alpha-(1-deoxy-D-fructos-1-yl)-L-arginine (Fru-Arg). Antioxidant activity of Fru-Arg was comparable to that of ascorbic acid, scavenging hydrogen peroxide completely at 50 micromol/L and 37% at 10 micromol/L. Quantitative analysis using the established HPLC system revealed that AGE contained 2.1-2.4 mmol/L of Fru-Arg, but none was detected in either raw or heated garlic juice. Furthermore, it was shown that a minimum of 4 mo aging incubation was required for Fru-Arg to be generated. These findings indicate that the aging process is critical for the production of the antioxidant compound, Fru-Arg. These results may explain some of the variation in benefits among different commercially available garlic preparations.

Antioxidants↗
PubMed2000

Intermittent administration of brain-derived neurotrophic factor ameliorates glucose metabolism in obese diabetic mice.

We have previously shown that brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, interacts with the endocrine system in obese diabetic mice, and systemic peripheral administration of BDNF regulates glucose metabolism in this model. Results from the present study show that the hypoglycemic effect induced by 2 weeks' daily administration of BDNF (20 mg/kg/d) to db/db mice lasts for several weeks after treatment cessation, irrespective of food reduction. On the other hand, the antidiabetic agent, metformin had no lasting effect. This duration of the BDNF hypoglycemic action prompted us to examine the efficacy of BDNF intermittent administration on glucose metabolism. BDNF administered once or twice per week (70 mg/kg/wk) to db/db mice for 3 weeks significantly reduced blood glucose concentrations and hemoglobin A(1c), (HbA(1c)) as compared with ad libitum-fed phosphate-buffered saline (PBS)-treated and pair-fed PBS-treated groups. This suggests that BDNF not only temporarily reduced blood glucose concentrations but also ameliorated systemic glucose balance in this obese diabetic mouse model during the experimental period. Our results indicate that BDNF could be a novel hypoglycemic agent with an exceptional ability to normalize glucose metabolism even with treatment as infrequently as once per week.

Animals↗
PubMed2000

Enhanced sensitivity to alkylating agent in lymphocytes from patients with multiple endocrine neoplasia type 1.

Chromosome instability is known to be associated with certain autosomal recessive cancer-prone disorders such as Fanconi's anemia. Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disorder characterized by development of tumors in two or more endocrine organs, and chromosome instability in patients with MEN 1 has been described. The clinical features of MEN 1 are, however, distinct from other DNA instability syndromes except predisposition to tumors. Therefore, we reevaluated chromosome instability in patients with familial MEN 1. An increase in the frequency of chromosome aberrations was observed in MEN 1 patients but not in control subjects when peripheral mononuclear cells were exposed to an alkylating agent, diepoxybutane (DEB). DEB reduced survival of mononuclear cells in a dose-dependent manner in both MEN 1 patients and control subjects, but this effect was more prominent in MEN I patients. There was no apparent correlation between certain MEN1 gene mutations and sensitivity to DEB. From these results, we conclude that hypersensitivity to alkylating agents exists in patients with MEN 1. Molecular mechanisms of this phenomenon and relationship to tumorigenesis in endocrine organs should be elucidated.

Antineoplastic Agents, Alkylating↗
PubMed2000

Brain-derived neurotrophic factor regulates glucose metabolism by modulating energy balance in diabetic mice.

We previously reported that brain-derived neurotrophic factor (BDNF) regulates both food intake and blood glucose metabolism in rodent obese diabetic models such as C57BL/KsJ-lepr(db)/lepr(db) (db/db) mice. To elucidate the effect of BDNF on glucose metabolism, we designed a novel pellet pair-feeding apparatus to eliminate the effect of appetite alteration on glucose metabolism. The apparatus was used to synchronize food intake precisely between BDNF-treated and vehicle-treated db/db mice. It was shown using this pellet pair-feeding apparatus that BDNF administered daily (20 mg x kg(-1) x day(-1)) to db/db mice significantly lowered blood glucose compared with pellet pair-fed db/db mice. To evaluate the effect of BDNF on insulin action, we used streptozotocin-induced type 1 diabetic mice. In this case, BDNF did not lower blood glucose concentration but rather enhanced the hypoglycemic action of insulin. In hyperglycemic db/db mice, pancreatic insulin content was reduced and glucagon content was increased compared with normoglycemic db/m mice. BDNF administered to db/db mice significantly restored both pancreatic insulin and glucagon content. Histological observations of aldehyde-fuchsin staining and immunostaining with anti-insulin indicated that insulin-positive pancreatic beta-cells were extensively regranulated by BDNF administration. We also studied the effect of BDNF on KK mice, normoglycemic animals with impaired glucose tolerance. In these mice, BDNF administration improved insulin resistance in the oral glucose tolerance test. To elucidate how blood glucose was metabolized in BDNF-treated animals, we investigated the effect of BDNF on the energy metabolism of db/db mice. Body temperature and oxygen consumption of the pellet pair-fed vehicle-treated mice were remarkably lower than the ad libitum-fed vehicle-treated mice. Daily BDNF administration for 3 weeks completely ameliorated both of the reductions. Finally, to clarify its action mechanism, the effect of intracerebroventricular administration of BDNF on db/db mice was examined. Here, a small dose of BDNF was found to be effective in lowering blood glucose concentration. This indicates that BDNF regulates glucose metabolism by acting directly on the brain.

Animals↗
PubMed1999

Premature centromere division in patients with multiple endocrine neoplasia type 1.

Frequency of mitoses with premature centromere division (PCD) was examined in lymphocytes from subjects with multiple endocrine neoplasia type 1 (MEN 1). An increase in PCD after exposure to an alkylating agent was observed in subjects with MEN 1 who carry a heterozygous MEN1 gene mutation but not in normal controls or in affected subjects without the MEN1 gene mutation. These findings support the inclusion of MEN 1 as a chromosome instability syndrome and recognition of PCD as a manifestation of chromosome instability. Furthermore, these results suggest that the MEN1 gene product may function to maintain the integrity of DNA.

Adult↗
PubMed1999

Prevention of psychological stress-induced immune suppression by aged garlic extract.

We determined the effect of Aged Garlic Extract (AGE) on damage caused to immune function by a psychological stress using a communication box. After four days of a psychological stress, a decrease in spleen weight and spleen cells was observed in the psychological stress-exposed mice as compared normal mice (non-stress). AGE significantly prevented the decreases in spleen weight and cells. Additionally, AGE significantly prevented the reduction of hemolytic plaque-forming-cells in spleen cells and anti-SRBC antibody titer in serum caused by this psychological stress. Moreover, a reduction in NK activities was observed in the psychological stress-exposed mice as compared with normal mice (non-stress), whereas NK activities in the AGE administered mice were almost the same as normal mice (non-stress). These results indicate that psychological stress qualitatively and quantitatively impairs immune function, and that AGE is extremely useful for preventing psychologically-induced damage.

Animals↗
PubMed1999

Antioxidant effects of fructosyl arginine, a Maillard reaction product in aged garlic extract.

The amino-carbonyl (Maillard) reaction of amino acids with sugars is a nonenzymatic browning reaction that takes place during the processing, cooking, and storage of foods. Maillard reaction products (MRPs) have been shown to possess interesting chemical and biological properties including antimutagenic and antioxidant activity. In this study, we determined the antioxidant effects of fructosyl arginine (Fru-Arg), a MRP in aged garlic extract. Low density lipoprotein (LDL) was incubated with Cu(2+) at 37 degrees C and 5% CO(2) for 24 hours, which resulted in an increase of thiobarbituric acid reactive substances (TBARS) indicating lipid peroxidation. Coincubation of Cu(2+) with Fru-Arg and LDL resulted in a significant inhibition of TBARS formation. Pulmonary artery endothelial cells (PAEC) were exposed to 0.1 mg/mL oxidized LDL (Ox-LDL) at 37 degrees C and 5% CO(2) for 24 hours. Lactate dehydrogenase (LDH) release, as an index of cell membrane damage, and TBARS were measured. Ox-LDL caused an increase of LDH release and TBARS formation. Pretreatment of PAEC with Fru-Arg inhibited these changes. Murine macrophages were incubated with Ox-LDL, and the release of peroxides was measured using a fluorometric assay. Ox-LDL caused an increased release of peroxides. Coincubation of macrophages with Fru-Arg and Ox-LDL inhibited the release of peroxides dose-dependently. In a cell free system, Fru-Arg was shown to scavenge hydrogen peroxide. These data suggest that Fru-Arg is a potent antioxidant, and thus may be useful for the prevention of atherosclerosis and other disorders associated with oxidative stress.

Journal Article↗
PubMed1999

Protective effect of aged garlic extract on the small intestinal damage of rats induced by methotrexate administration.

The methotrexate (MTX) administration to rats causes the damage of small intestine. The small intestinal damage was evaluated by measuring the intestinal permeability of the poorly absorbable compound, fluorescein isothiocyanate (FITC)-labeled dextran (average molecular weight, 4,400) (FD-4) using the in vitro everted intestine technique and by determining the FD-4 that appeared in plasma using the in situ closed loop intestine technique. The MTX administration to rats fed with the standard laboratory diet increased the small intestinal permeability of FD-4 due to the damage of the small intestine. Interestingly, the permeability of FD-4, when MTX was administered to rats fed with the aged garlic extract containing diet, was depressed almost to the level of control rats without the MTX treatment. The present study showed that the aged garlic extract protected the small intestine from the damage induced by the action of MTX on the crypt cells.

Animals↗