Xylitol is widely used as a sweetener in foods and medications. Xylitol ingestion causes a small blood glucose rise, and it is commonly used as an alternative to high-energy supplements in diabetics. In previous studies, a xylitol metabolite, xylulose-5-phosphate, was shown to activate carbohydrate response element binding protein, and to promote lipogenic enzyme gene transcription in vitro; however, the effects of xylitol in vivo are not understood. Here we investigated the effects of dietary xylitol on lipid metabolism and visceral fat accumulation in rats fed a high-fat diet. Sprague-Dawley rats were fed a high-fat diet containing 0 g (control), 1.0 g/100 kcal (X1) or 2.0 g/100 kcal (X2) of xylitol. After the 8-week feeding period, visceral fat mass and plasma insulin and lipid concentrations were significantly lower in xylitol-fed rats than those in high-fat diet rats. Gene expression levels of ChREBP and lipogenic enzymes were higher, whereas the expression of sterol regulatory-element binding protein 1c was lower and fatty acid oxidation-related genes were significantly higher in the liver of xylitol-fed rats as compared with high-fat diet rats. In conclusion, intake of xylitol may be beneficial in preventing the development of obesity and metabolic abnormalities in rats with diet-induced obesity.
Geranylgeranoic acid, a 20-carbon polyprenoic acid (all-trans 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecatetraenoic acid) and its derivatives were previously developed as synthetic “acyclic retinoids” for cancer chemoprevention. Recently, we demonstrated the natural occurrence of geranylgeranoic acid in various medicinal herbs (Shidoji and Ogawa, 2004). In this present study, we present several lines of evidence to demonstrate that geranylgeranyl diphosphate taken in foods could be metabolized to GGA through geranylgeraniol and geranylgeranyl aldehyde via the following steps: 1) The conversion from geranylgeranyl diphosphate to geranylgeraniol was demonstrated to occur by the action of bovine intestinal alkaline phosphatase, with a Km of 46.1 μM. 2) Geranylgeraniol oxidase-mediated conversion of geranylgeraniol to geranylgeranyl aldehyde was revealed in rat liver homogenates, which activity was mainly localized in the mitochondrial fraction. The mitochondrial enzyme showed a Km of 92.9 μM. 3) The conversion of geranylgeranyl aldehyde to geranylgeranoic acid by geranylgeranyl aldehyde dehydrogenase in rat liver homogenates was absolutely dependent on exogenously added NAD+ or NADP+. The Km of the mitochondrial geranylgeranyl aldehyde dehydrogenase was 27.5 μM for geranylgeranyl aldehyde. Taken together, our data suggest that cancer preventive geranylgeranoic acid could be a physiological metabolite from commonly consumed foods.
Major physiological stress occurs during cardiac surgery with cardiopulmonary bypass. This is related to hypothermia and artificial organ perfusion. Thus, serious gastrointestinal complications, particularly upper gastrointestinal bleeding, sometimes follow cardiac surgery. We have compared the antisecretory effects of a preanesthetic H2 antagonist (roxatidine, cardiopulmonary bypass-H2 group, n = 15) and a proton pump inhibitor (rabeprazole, cardiopulmonary bypass-PPI group, n = 15) in patients undergoing cardiac surgery with cardiopulmonary bypass, and also compared in patients undergoing a off-pump coronary artery bypass graft surgery (off-pump cardiopulmonary bypass-H2 group, n = 15). Gastric pH (5.14 ± 0.61) and gastric fluid volume (13.2 ± 2.4 mL) at the end of surgery in off-pump cardiopulmonary bypass-H2 groups was significantly lower and higher than those in both cardiopulmonary bypass-H2 (6.25 ± 0.54, 51.3 ± 8.0 mL) and cardiopulmonary bypass-PPI (7.29 ± 0.13, 63.5 ± 14.8 mL) groups, respectively although those variables did not differ between groups after the induction of anesthesia. Plasma gastrin (142 ± 7 pg/mL) at the end of surgery and maximal blood lactate levels (1.50 ± 0.61 mM) in off-pump cardiopulmonary bypass-H2 group were also significantly lower than those in both cardiopulmonary bypass-H2 (455 ± 96 pg/mL, 3.97 ± 0.80 mM) and cardiopulmonary bypass-PPI (525 ± 27 pg/mL, 3.15 ± 0.44 mM) groups, respectively. In addition, there was a significant correlation between gastric fluid volume and maximal blood lactate (r = 0.596). In conclusion, cardiopulmonary bypass may cause an increase in gastric fluid volume which neither H2 antagonist nor PPI suppresses. A significant correlation between gastric fluid volume and maximal blood lactate suggests that gastric fluid volume may predict degree of gastrointestinal tract hypoperfusion.
p59fyn, a protein tyrosine kinase belonging to the src-family, is involved in the regulatory mechanism of acute response to ethanol in the central nervous system. A previous report showed an association between src-family kinase activity and fatty acid oxidation, and it also reported that hepatic free fatty acid levels were low in Fyn−/− mice. We examined, using Fyn−/− mice whether Fyn is also involved in fatty acid metabolism and the development of pathological changes in the liver in response to chronic ethanol consumption. C57BL/6J Fyn−/− and Fyn+/+ mice were fed for 8 weeks with either a liquid diet comprising ethanol or one in which the calories from ethanol were replaced with carbohydrates. Chronic ethanol consumption for 8 weeks resulted in remarkable hepatic steatosis in Fyn+/+ mice but not in Fyn−/− mice. Chronic ethanol consumption induced a significant decrease in hepatic FFA and triglyceride levels in Fyn−/− mice. Levels of interleukin-6, which is associated with the enhancement of fatty acid oxidation, was also increased significantly in the livers of ethanol-fed Fyn−/− mice. The results suggest that Fyn is involved in the enhancement of fatty acid oxidation and the development of hepatic steatosis caused by chronic ethanol consumption.
Lansoprazole is effective in healing non-steroidal anti-inflammatory drugs induced ulcers, and antioxidant properties have been thought to play a key role in healing ulcers. We hypothesize that lansoprazole exerts a cytoprotective effect by inhibiting reactive oxygen species leakage from mitochondria and lipid peroxidation. We pretreated gastric epithelial RGM1 cells with lansoprazole and then treated them with indomethacin in vitro. We found that the lansoprazole pretreatment significantly reduced cellular injury, maintained mitochondrial transmembrane potential, and decreased lipid peroxidation. Furthermore, the signal intensity of the electron spin resonance spectrum of the indomethacin-treated mitochondria which were pretreated with lansoprazole showed considerable reduction compared to those without the lansoprazole pretreatment. These results suggest that lansoprazole reduced superoxide production in the mitochondria of indomethacin treated cells, and subsequently inhibited lipid peroxide and cellular injury in gastric epithelial cells.
Kurozu moromimatsu is the sediment of Kurozu, a jar-fermented Japanese black vinegar produced from unpolished rice. Here, we examined the protective effects of Kurozu moromimatsu in a diethylnitrosamine-induced model of hepatocellular carcinoma. Thirty-two F344 rats were divided into two groups; the control group received basal CE-2 diet, and the Kurozu moromimatsu group received CE-2 diet containing Kurozu moromimatsu. At 16 weeks after initial intraperitoneal administration of diethylnitrosamine (150 mg/kg/week), serum was collected from half the rats. These rats were sacrificed and the liver was resected for histological examination of hematoxylin-eosin-stained sections and assay of matrix metalloproteinase-2 and matrix metalloproteinase-9 levels in tumor tissues. Glutathione S-transferase placental form-positive foci were evaluated by immunostaining for glutathione S-transferase placental form. The remaining rats were maintained for evaluation of survival. There were no significant differences of serum transaminases, tumor necrosis factor-alpha, and also no marked hepatic histological differences, between the two groups. However, the size of hepatocellular carcinomas was greatly decreased and the levels of activated matrix metalloproteinase-2 and -9 were significantly reduced in the Kurozu moromimatsu group. Further, survival was significantly prolonged in the Kurozu moromimatsu group compared with the control. These results indicate that Kurozu moromimatsu inhibited the growth of hepatocellular carcinoma.
The inhibitory activity on intestinal α-glucosidase by cyanidin-3-rutinoside was examined in vitro and in vivo. The IC50 values of cyanidin-3-rutinoside against intestinal maltase, and sucrase were 2,323 ± 14.8 and 250.2 ± 8.1 μM, respectively. The kinetic analysis revealed that intestinal sucrase was inhibited by cyanidin-3-rutinoside in a mixed-type manner. The synergistic inhibition also found in combination of cyanidin-3-rutinoside with acarbose against intestinal maltase and sucrase. The oral administration of cyanidin-3-rutinoside (100 and 300 mg/kg) plus maltose or sucrose to normal rats, postprandial plasma glucose was markedly suppressed at 30–90 min after loading. Furthermore, the normal rats treated with acarbose and cyanidin-3-rutinoside (30 mg/kg) showed greater reduction of postprandial plasma glucose than the group treated with acarbose alone. These results suggest that cyanidin-3-rutinoside retards absorption of carbohydrates by inhibition of α-glucosidase which may be useful as a potential inhibitor for prevention and treatment of diabetes mellitus.
In this study we investigated if peroxisome proliferator-activated receptor β/δ activation protects from copper-induced acute liver damage. Mice treated with copper had significant body weight loss, serum alanine aminotransferase increase, modest changes in liver histology, increase of tumor necrosis factor α and macrophage inflammatory protein 2 mRNA and 8-hydroxy-2'-deoxyguanosine. Mice treated with copper and peroxisome proliferator-activated receptor β/δ agonist GW0742 had significantly less body weight loss, less serum alanine aminotransferase increase, less tumor necrosis factor α, macrophage inflammatory protein-2 and 8-hydroxy-2'-deoxyguanosine upregulation than copper treated mice. The opposite effect was observed in mice treated with copper and peroxisome proliferator-activated receptor β/δ antagonist GSK0660. In vitro, copper induced reactive oxygen species, which was lower in cells treated with GW0742 or transfected with peroxisome proliferator-activated receptor β/δ expression vector; together, transfection and GW0742 had an additive reactive oxygen species-reducing effect. Copper also upregulated Fas ligand and Caspase 3/7 activity, effects that were significantly lower in cells also treated with GW0742. In conclusion, peroxisome proliferator-activated receptor β/δ activation reduced copper-induced reactive oxygen species, pro-inflammatory and acute phase reaction cytokines in mice liver. Peroxisome proliferator-activated receptor β/δ agonists could become useful in the management of copper-induced liver damage.
Taurine chloramine is the major chloramine generated in activated neutrophils via the reaction between the overproduced hypochlorous acid and the stored taurine. Taurine chloramine has anti-inflammatory and cytoprotective effects in inflamed tissues by inhibiting the production of inflammatory mediators. Taurine chloramine increases heme oxygenase activity and also protects against hydrogen peroxide (H2O2)-derived necrosis in macrophages. In this study, we examined further whether taurine chloramine could protect RAW 264.7 macrophages from apoptosis caused by H2O2. Macrophages treated with 0.4 mM H2O2 underwent apoptosis without showing immediate signs of necrosis, and the cells pretreated with taurine chloramine were protected from the H2O2-derived apoptosis. Taurine chloramine increased heme oxygenase-1 expression and heme oxygenase activity. The taurine chloramine-derived upregulation of heme oxygenase-1 expression was blocked by inhibition of ERK phosphorylation. Taurine chloramine decreased cellular glutathione (GSH) levels initially, but the GSH level increased above the control level by 10 h. Taurine chloramine also increased catalase expression and protected macrophages from the apoptotic effect of H2O2. Combined, these results indicate that the taurine chloramine, produced and released endogenously by the activated neutrophils, can protect the macrophages in inflamed tissues from the H2O2-derived apoptosis not only by increasing the expression of cytoprotective enzymes like heme oxygenase-1 and catalase, but also by increasing the intracellular antioxidant GSH level.
Germinated barley foodstuff contains prebiotics which are reported to have anti-cancerous effects in colorectal cancer model, but the detailed mechanism remains unclear. Recent studies revealed that the role of microbiota was strongly related to the regulation of incidence and progression of colorectal cancer. The aim of this study was to examine the anti-neoplastic mechanism by prebiotics. Azoxymethane treated F344 rats were used as the sporadic cancerous model. After azoxymethane injection, either a control or germinated barley foodstuff diet was administered to the rats for another 5 weeks, and the number of abberant crypt foci, toll like receptor 4, Kirsten rat sarcoma viral oncogene homolog, adenomatous polyposis coli tumor suppressor gene and cyclooxygenase 2 mRNA expression of colonic mucosa and cecal short chain fatty acids were examined. The germinated barley food stuff significantly attenuated the number of abberant crypt focis and the expression of toll like receptor 4 and cyclooxygenase 2 mRNA, compared to the control group. In addition, the cecal butyrate production in the germinated barley foodstuff group was significantly higher than that in the control. In conclusion, this prebiotic treatment for colorectal cancer may be useful without causing the adverse effects seen in either anti-cancer drugs or anti-inflammatory drugs.
This study aimed to examine the association of dietary vitamin intakes with plasma pro-inflammatory cytokine levels in Korean heart failure patients. Stable outpatients with heart failure were recruited and finally 91 patients were included. Dietary intakes were estimated by a developed semi-quantitative food frequency questionnaire. The simultaneous measurement of 17 cytokines was performed along with analysis of plasma C-reactive protein. Plasma C-reactive protein levels significantly correlated with dietary intakes of vitamin C (r = −0.30, p<0.005), β-carotene (r = −0.23, p<0.05), and folate (r = −0.31, p<0.005). However, these associations were no longer significant after adjusting for traditional risk factors for heart failure. On the other hand, plasma levels of monocyte chemoattractant protein-1 significantly correlated with dietary folate intake (r = −0.31, p<0.001), and plasma interleukin-8 levels significantly correlated with dietary intakes of vitamin C (r = −0.38, p<0.001), β-carotene (r = –0.42, p<0.001), and folate (r = −0.38, p<0.001) after the adjustment. Dietary folate intake was found as a primary influencing factor on plasma levels of monocyte chemoattractant protein-1 (p<0.005, R2 = 0.20) and interleukin-8 (p<0.001, R2 = 0.32) through a stepwise multiple linear regression analysis. Dietary folate intake was significantly associated with plasma levels of monocyte chemoattractant protein-1 and interleukin-8 which indicates dietary folate may have a potentially beneficial role in the prevention and treatment of heart failure.