Biomedical subjects

Fumihiko Horio

Publications and source records attributed to Fumihiko Horio.

11 recordsLinked to original sources

PubMed2003

Changes in catecholamine metabolism by ascorbic acid deficiency in spontaneously hypertensive rats unable to synthesize ascorbic acid.

We have previously reported the establishment of a novel rat strain, SHR-od, with both spontaneous hypertension and a defect of ascorbic acid biosynthesis. Blood pressure in mature SHR-od fed an ascorbic acid-supplemented diet is over 190-200 mmHg, while it decreased to around 120 mmHg at 4-5 weeks after the cessation of ascorbic acid supplementation. With regard to possible mechanisms of blood pressure lowering, we focused on catecholamine synthesis in adrenal glands, since catecholamine is a major factor for blood pressure regulation and ascorbic acid is a co-factor of dopamine beta-hydroxylase (DBH) in catecholamine biosynthesis. Male SHR-od (25-week-old) and normotensive ODS rats with a defect in ascorbic acid biosynthesis (25-week-old) were fed a Funabashi-SP diet with or without ascorbic acid (300 mg/kg diet) for 28 days or 35 days. In SHR-od, systolic blood pressure (191 +/- 6 mmHg) began to decrease from day 21 in the ascorbic acid-deficient group, whereas no significant difference was found in ODS rats. In spite of significant lowering of blood pressure, no significant differences were found in catecholamine levels in serum, adrenal glands and brain on day 28. On day 35, however, urinary excretion of norepinephrine and epinephrine in the ascorbic acid-deficient SHR-od were higher at 490% (P < 0.05) and 460% (P < 0.05) of the respective control. Serum catecholamine concentrations and the adrenal catecholamine content tended to be higher in the ascorbic acid-deficient SHR-od than the control of SHR-od and reached to similar level in ODS rats. The administration of ascorbic acid (intraperitoneal injection, 60 mg ascorbic acid/kg body weight, once a day) to the ascorbic acid-deficient SHR-od restored blood pressure to the range 180-190 mmHg within two days. These findings indicate that ascorbic acid deficiency affects catecholamine metabolism in the adrenal glands of SHR-od in response to blood pressure lowering, suggesting catecholamines are not involved in the mechanism for the remarkable reduction in blood pressure in response to ascorbic acid deficiency.

Adrenal Glands↗

PubMed2003

Dietary cyanidin 3-O-beta-D-glucoside-rich purple corn color prevents obesity and ameliorates hyperglycemia in mice.

Anthocyanins, which are used as a food coloring, are widely distributed in human diets, suggesting that we ingest large amounts of anthocyanins from plant-based foods. Mice were fed control, cyanidin 3-glucoside-rich purple corn color (PCC), high fat (HF) or HF + PCC diet for 12 wk. Dietary PCC significantly suppressed the HF diet-induced increase in body weight gain, and white and brown adipose tissue weights. Feeding the HF diet markedly induced hypertrophy of the adipocytes in the epididymal white adipose tissue compared with the control group. In contrast, the induction did not occur in the HF + PCC group. The HF diet induced hyperglycemia, hyperinsulinemia and hyperleptinemia. These perturbations were completely normalized in rats fed HF + PCC. An increase in the tumor necrosis factor (TNF)-alpha mRNA level occurred in the HF group and was normalized by dietary PCC. These results suggest that dietary PCC may ameliorate HF diet-induced insulin resistance in mice. PCC suppressed the mRNA levels of enzymes involved in fatty acid and triacylglycerol synthesis and lowered the sterol regulatory element binding protein-1 mRNA level in white adipose tissue. These down-regulations may contribute to triacylglycerol accumulation in white adipose tissue. Our findings provide a biochemical and nutritional basis for the use of PCC or anthocyanins as a functional food factor that may have benefits for the prevention of obesity and diabetes.

Adipose Tissue↗

PubMed2003

Quantitative trait locus analysis of serum insulin, triglyceride, total cholesterol and phospholipid levels in the (SM/J x A/J)F2 mice.

Quantitative trait locus (QTL) analysis of serum insulin, triglyceride, total cholesterol and phospholipid levels at 10 weeks of age was performed in 321 F2 offspring from SM/J and A/J mice. Interval mapping revealed a total of 22 suggestive QTLs affecting the four traits: two insulin QTLs on Chromosomes (Chrs) 6 and 8; six triglyceride QTLs on Chrs 4, 8, 9, 11, 12 and 19; six total-cholesterol QTLs on Chrs 1, 3, 4, 14, 17 and 19; and eight phospholipid QTLs on Chrs 2, 3, 4, 6, 8, 10 and 19. Gender influenced the expression of eight of the suggestive QTLs. The total-cholesterol QTLs on Chrs 4, 14 and 17, the triglyceride QTL on Chr 9 and the phospholipid QTL on Chr 4 were specific to females. The phospholipid QTLs on Chrs 2 and 6 and the insulin QTL on Chr 8 were specific to males. In addition, common QTLs involved in the regulation of some of the traits were identified. The female-specific QTL on Chr 4 appeared to be involved in the regulation of total cholesterol and phospholipid levels. The QTL on Chr 8 affected insulin and phospholipid levels, whereas the Chr 19 QTL was common to the three lipid parameters.

Animals↗

PubMed2003

Combinations of nondiabetic parental genomes elicit impaired glucose tolerance in mouse SMXA recombinant inbred strains.

Type 2 diabetes in humans is not a single gene disorder but a multifactorial disease caused by the interaction of multiple genes and environmental factors. Recombinant inbred (RI) strains are a powerful tool for analyzing not only single genetic traits but also multifactorial genetic traits. By using the SMXA RI mice, we genetically dissected diabetes-related traits (BMI, nonfasting blood glucose concentration, and blood glucose concentration during intraperitoneal glucose tolerance tests). For minimizing the variation of glucose tolerance in each strain, all mice were fed the high-carbohydrate diet and subjected to phenotypic and genetic analyses. The parental strains, SM/J and A/J, were nondiabetic, and the differences of the mean values of diabetes-related traits were small. In contrast, an impaired glucose tolerance was observed in (SM x A)F1 mice, and marked differences in diabetes-related traits were observed in 19 SMXA RI strains. In particular, several SMXA RI strains showed markedly impaired glucose tolerance and hyperglycemia. Quantitative trait locus (QTL) analysis revealed a locus on chromosome (Chr) 10 contributing significant effect on nonfasting blood glucose concentration, as well as six diabetes-related loci on four chromosomes with suggestive evidence of linkage with diabetes-related phenotypes. The A/J-derived QTLs on Chr 2 and 18 and an SM/J-derived QTL on Chr 10 contributed to the impairment of glucose tolerance and/or the increase of blood glucose concentration. The present study indicates that QTLs derived from parental SM/J and A/J genomes, both of which are nondiabetic, interact in the RI genomes, leading to the development of hyperglycemia and diabetic phenotypes. Genetic dissection of this kind of diabetogenesis will increase our understanding of the complex gene-gene interaction and mode of inheritance in human type 2 diabetes.

Animals↗

PubMed2003

Characteristics of ascorbic acid metabolism in scurvy-prone spontaneously hypertensive rat, SHR-od.

SHR-od is a novel strain of rat that spontaneously develops hypertension and has a defect of ascorbic acid (AsA) biosynthesis. The osteogenic disorder Shionogi (ODS) rat is normotensive and also unable to synthesize AsA. To investigate whether or not genetic hypertension affects AsA metabolism, we compared the AsA metabolisms of SHR-od and ODS rats. In this study, a physiological dose of AsA equivalent to the AsA requirement in ODS rats was administered to rats intraperitoneally (i.p. group) or orally (oral group). We measured AsA concentrations in the serum, liver, kidney, adrenal glands, and spleen, and the amount of AsA excreted into the urine. At 25 wk of age (hypertensive status), the AsA concentrations of all tissues tested were significantly lower in SHR-od than in ODS rats in both the i.p. and oral groups. In the i.p. group, the amount of urinary AsA in SHR-od was also lower than that in ODS rats. At 4 wk of age (before the onset of hypertension), liver and spleen AsA concentrations in SHR-od were lower than those in ODS rats in both the i.p. and oral groups. Urinary AsA excretion from SHR-od was not different between the two groups. Our data suggest that the requirement for AsA in SHR-od is increased to maintain tissue AsA concentrations equivalent to those in ODS rats, and that a larger part of the AsA administered to rats in this study is degraded in SHR-od as compared to ODS rats.

Adrenal Glands↗

PubMed2002

Effects of paraquat on essential antioxidant elements in osteogenic disorder Shionogi rat.

This study reports the effect of paraquat (PQ) on concentrations of four elements (Cu, Fe, Mg, Zn) in lung, kidney, spleen, liver, and heart of male osteogenic disorder Shionogi (ODS) rats, a strain not able to synthesize vitamin C. PQ significantly increased the Cu concentrations in lung, liver, and plasma, accompanied by a fall in renal levels. Fe levels were elevated in liver and spleen but lowered in plasma. PQ produced an increase in kidney Mg and a rise in liver Mg and Zn levels. Cardiac elemental levels were not affected by PQ treatment. PQ, a known oxidant, produced changes in tissue elements involved in antioxidant mechanisms.

Animals↗

PubMed2002

Calmodulin overexpression causes Ca(2+)-dependent apoptosis of pancreatic beta cells, which can be prevented by inhibition of nitric oxide synthase.

We investigated the mechanism of beta-cell loss in transgenic mice with elevated levels of beta cell calmodulin. The transgenic mice experienced a sudden rise in blood glucose levels between 21 and 28 days of age. This change was associated with development of severe hypoinsulinemia and loss of beta cells from the islets. Ultrastructural analysis revealed that compromised granule formation and apoptotic changes in the transgenic beta cells preceded the onset of hyperglycemia. Intraperitoneal injection of tolbutamide, an antidiabetic sulfonylurea, decreased blood glucose levels but increased the number of apoptotic beta cells. Finally, injection of transgenic mice with N(omega)-nitro-L-arginine methyl ester, which inhibits nitric oxide synthase activity, prevented hyperglycemia and lessened the changes in number and size of beta cells. Because immunofluorescent staining revealed preferential distribution of neural nitric oxide synthase in pancreatic beta cells, we speculate that overexpression of calmodulin sensitizes the beta cells to Ca(2+)-dependent activation of neural nitric oxide synthase, which mediates apoptosis.

Animals↗

PubMed2002

Increase in oxidative stress in kidneys of diabetic Akita mice.

New biomarkers for oxidative damage, were used to identify whether hyperglycemia caused oxidative stress in diabetic Akita mice. At 13 weeks of age, the tissues of these mice were obtained, and the levels of N(epsilon)-(hexanonyl)lysine (HEL) and dityrosine (DT) were measured, these being related to lipid peroxide-derived protein covalent modification and protein cross-linking. The levels of HEL and DT in the kidneys of Akita mice were significantly increased compared with the control mice without any accumulation of thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal-modified protein. Immunopositive staining was clearly observed in the kidneys of the Akita mice when using the anti-HEL antibody or anti-DT antibody. These results suggest that hyperglycemia in Akita mice induced oxidative stress and increased these markers in the kidneys.

Animals↗

PubMed2002

Cyanidin 3-O-beta-D-glucoside attenuates the hepatic ischemia-reperfusion injury through a decrease in the neutrophil chemoattractant production in rats.

We have shown that the orally administered cyanidin 3-O-beta-D-glucoside (C3G) attenuates the hepatic ischemia-reperfusion (I/R) injury, which was used as a model for oxidative stress through a decrease in neutrophil chemoattractant production in rats. The rats were subjected to hepatic I/R at 30 min after the administration of C3G (0.9 mmol/kg body weight) or vehicle. I/R treatment resulted in the elevation of oxidative stress marker [liver thiobarbituric acid-reactive substance, Nepsilon-(hexanonyl) lysine and dityrosine] levels in the liver and of the serum activities of marker enzymes for liver injury. The administration of C3G significantly suppressed these elevations, which had been caused by hepatic I/R. Liver myeloperoxidase activity, a useful marker for neutrophil infiltration into tissues, and the plasma and liver concentration of cytokine-induced neutrophil chemoattractant-1 (CINC-1), which has a potent chemotactic activity, were markedly elevated in the control group after hepatic I/R. However, these elevations were significantly suppressed in the C3G group. C3G and its metabolites in the plasma and liver were detected in the C3G group after hepatic I/R. These results suggest that the absorbed C3G and/or its metabolites can act as antioxidants in the blood and liver and scavenge the reactive oxygen species, and brought on a decrease in neutrophil infiltration into the liver through the suppression of CINC-1 production and the tissue damage caused by neutrophils after I/R is attenuated.

Animals↗

PubMed2002

Cyanidin 3-O-beta-D-glucoside suppresses nitric oxide production during a zymosan treatment in rats.

Anthocyanins are used for food color, and they are widely distributed in the human diets, suggesting that we ingest considerable amounts of anthocyanins from plant-based daily diets. We have demonstrated that a typical anthocyanin, cyanidin 3-O-beta-D-glucoside (C3G), suppressed the zymosan-induced inflammatory response in rats when it was orally administered. The elevation of the peritoneal exudate NOx, tumor necrosis factor (TNF) alpha interleukin-1beta (IL-1beta), IL-6, and the cytokine-induced neutrophil chemoattractant-1 (CINC-1) concentrations were significantly suppressed by the administration of C3G. The zymosan treatment resulted in an increase in the serum alpha2-macroglobulin and decreases in the serum albumin and transferrin levels, which are recognized as acute phase proteins. However, these levels were normalized by the administration of C3G. The inducible nitric oxide synthase (iNOS) protein level in the peritoneal exudate cells was markedly elevated in the control group treated with zymosan. However, the administration of C3G significantly reduced the level of iNOS in the peritoneal exudate cells. Taken altogether, our findings provide a biochemical basis for the use of C3G as a functional food factor and can also have important implications for the prevention of the NO-mediated inflammatory diseases.

Acute-Phase Proteins↗

PubMed2001

A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway.

Exposure of cells to a wide variety of chemoprotective compounds confers resistance to a broad set of carcinogens. For a subset of the chemoprotective compounds, protection is generated by an increase in the abundance of the protective phase II detoxification enzymes, such as glutathione S-transferase (GST). We have recently developed a cell culture system, using rat liver epithelial RL 34 cells, that potently responds to the phenolic antioxidants resulting in the induction of GST activity (Kawamoto, Y., Nakamura, Y., Naito, Y., Torii, Y., Kumagai, T., Osawa, T., Ohigashi, H., Satoh, K., Imagawa, M., and Uchida, K. (2000) J. Biol. Chem. 275, 11291-11299.) In the present study, we investigated the phase II-inducing potency of an isothiocyanate compound in vitro and in vivo and examined a possible induction mechanism. Based on an extensive screening of vegetable extracts for GST inducer activity in RL34 cells, we found Japanese horseradish, wasabi (Wasabia japonica, syn. Eutrema wasabi), as the richest source and identified 6-methylsulfinylhexyl isothiocyanate (6-HITC), an analogue of sulforaphane (4-methylsulfinylbutyl isothiocyanate) isolated from broccoli, as the major GST inducer in wasabi. 6-HITC potently induced both class alpha GSTA1 and class pi GSTP1 isozymes in RL34 cells. In animal experiments, we found that 6-MSHI was rapidly absorbed into the body and induced hepatic phase II detoxification enzymes more potently than sulforaphane. The observations that (i) 6-HITC activated the antioxidant response element (ARE), (ii) 6-HITC induced nuclear localization of the transcription factor Nrf2 that binds to ARE, and (iii) the induction of phase II enzyme genes by 6-HITC was completely abrogated in the nrf2-deficient mice, suggest that 6-HITC is a potential activator of the Nrf2/ARE-dependent detoxification pathway.

Animals↗