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1.  Short-term dietary phosphate restriction up-regulates ileal fibroblast growth factor 15 gene expression in mice 
Members of the fibroblast growth factor (FGF) 19 subfamily, including FGF23, FGF15/19, and FGF21, have a role as endocrine factors which influence the metabolism of inorganic phosphate (Pi) and vitamin D, bile acid, and energy. It has been reported that dietary Pi regulates circulating FGF23. In this study, the short-term effects of dietary Pi restriction on the expression of FGF19 subfamily members in mice were analyzed. An initial analysis confirmed plasma FGF23 levels positively correlated with the amount of dietary Pi. On the other hand, ileal Fgf15 gene expression, but not hepatic Fgf21 gene expression, was up-regulated by dietary Pi restriction. In addition, we observed the increase of plasma 1,25-dihydroxyvitamin D [1,25(OH)2D] levels by dietary Pi restriction, and the up-regulation of ileal Fgf15 mRNA expression by 1,25(OH)2D3 and vitamin D receptor (VDR). Importantly, dietary Pi restriction-induced Fgf15 gene expression was prevented in VDR-knockout mice. Furthermore, diurnal variations of plasma triglyceride concentrations and hepatic mRNA expression of the bile acid synthesis enzyme Cyp7a1 as one of Fgf15 negative target genes was influenced by dietary Pi restriction. These results suggest that dietary Pi restriction up-regulates ileal Fgf15 gene expression through 1,25(OH)2D3 and VDR, and may affect hepatic bile acid homeostasis.
PMCID: PMC3947966
fibroblast growth factor 15; gene regulation analysis; inorganic phosphate; 1,25-dihydroxyvitamin D; mice
2.  The astaxanthin-induced improvement in lipid metabolism during exercise is mediated by a PGC-1α increase in skeletal muscle 
Astaxanthin, a xanthophyll carotenoid, accelerates lipid utilization during aerobic exercise, although the underlying mechanism is unclear. The present study investigated the effect of astaxanthin intake on lipid metabolism associated with peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in mice. Mice were divided into 4 groups: sedentary, sedentary and astaxanthin-treated, exercised, and exercised and astaxanthin-treated. After 2 weeks of treatment, the exercise groups performed treadmill running at 25 m/min for 30 min. Immediately after running, intermuscular pH was measured in hind limb muscles, and blood was collected for measurements. Proteins were extracted from the muscle samples and PGC-1α and its downstream proteins were measured by western blotting. Levels of plasma fatty acids were significantly decreased after exercise in the astaxanthin-fed mice compared with those fed a normal diet. Intermuscular pH was significantly decreased by exercise, and this decrease was inhibited by intake of astaxanthin. Levels of PGC-1α and its downstream proteins were significantly elevated in astaxanthin-fed mice compared with mice fed a normal diet. Astaxanthin intake resulted in a PGC-1α elevation in skeletal muscle, which can lead to acceleration of lipid utilization through activation of mitochondrial aerobic metabolism.
PMCID: PMC3947967
astaxanthin; skeletal muscle; lipid metabolism; running exercise; PGC-1α
3.  The involvement of endoplasmic reticulum stress in bile acid-induced hepatocellular injury 
Secondary bile acids produced by enteric bacteria accumulate to high levels in the enterohepatic circulation and may contribute to the pathogenesis of hepatocellular injury. Relative hydrophobicity has been suggested to be an important determinant of the biological properties of these compounds, although the mechanism by which bile acids induce pathogenesis is not fully understood. On the other hand, endoplasmic reticulum stress has been shown to be involved in the induction and development of various pathogenic conditions. In this report, we demonstrated that the intensities of cytotoxicity and endoplasmic reticulum stress in HepG2 cells triggered by the bile acids tested were largely dependent on their hydrophobicity. The activation of caspase-3 and DNA fragmentation by treatment with chenodeoxycholic acid showed the contribution of apoptosis to cytotoxicity. Increases in intracellular calcium levels and the generation of reactive oxygen species stimulated by treatment with chenodeoxycholic acid contributed to endoplasmic reticulum stress. Bile acids also induced transforming growth factor-β, a potent profibrogenic factor, which is known to induce hepatocyte apoptosis and ultimately liver fibrosis. In conclusion, our study demonstrated that bile acids induced endoplasmic reticulum stress, which in turn stimulated apoptosis in HepG2 cells, in a hydrophobicity-dependent manner.
PMCID: PMC3947968
bile acid; endoplasmic reticulum stress; apoptosis; transforming growth factor-β; hydrophobicity
4.  Scavenging rate constants of hydrophilic antioxidants against multiple reactive oxygen species 
Scavenging rate constants of eight hydrophilic antioxidants, including caffeic acid, chlorogenic acid, genistein, glutathione, N-acetylcysteine, rutin, trolox, and uric acid against multiple ROS, namely superoxide anion, hydroxyl radical, singlet oxygen, and alkoxyl radical were determined with the electron spin resonance method. Direct flash photolysis measurement of the second-order rate constant in the reaction of alkoxyl radical plus the spin trap 5,5-dimethyl-pyrroline N-oxide made it possible to evaluate scavenging rate constants in antioxidants. The magnitudes of scavenging rate constants were notably dependent on the character of each ROS and the overall rate constants were highest in hydroxyl radical scavenging and the lowest in superoxide anion. The highest scavenging rate constant against superoxide anion was obtained by chlorogenic acid (2.9 × 105 M−1 s−1) and the lowest was by N-acetylcysteine (5.0 × 102 M−1 s−1). For singlet oxygen, the highest was by glutathione (9.4 × 108 M−1 s−1) and the lowest was by uric acid (2.3 × 106 M−1 s−1). All other numbers are listed and illustrated. Redox potential measurements of the antioxidants indicated that the antioxidants are likely to react with superoxide anion and singlet oxygen through electron transfer processes.
PMCID: PMC3947969
reactive oxygen species (ROS); hydrophilic antioxidant; radical scavenging; spin trapping; redox potential
5.  Scavenging of reactive oxygen species induced by hyperthermia in biological fluid 
The scavenging activity of rat plasma against hyperthermia-induced reactive oxygen species was tested. The glutathione-dependent reduction of a nitroxyl radical, 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl, which was restricted by adding superoxide dismutase or by deoxygenating the reaction mixture, was applied to an index of superoxide (O2•−) generation. A reaction mixture containing 0.1 mM 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl and 1 mM glutathione was prepared using 100 mM phosphate buffer containing 0.05 mM diethylenetriaminepentaacetic acid. The reaction mixture was kept in a screw-top vial and incubated in a water bath at 37 or 44°C. The time course of the electron paramagnetic resonance signal of 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl in the reaction mixture was measured by an X-band EPR spectrometer (JEOL, Tokyo, Japan). When the same experiment was performed using rat plasma instead of 100 mM PB, the glutathione-dependent reduction of 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl, i.e., generation of O2•−, was not obtained. Only the first-order decay reduction of 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl, which indicates direct reduction of 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl, was obtained in rat plasma. Adding 0.5% albumin to the phosphate buffer reaction mixture could almost completely inhibit O2•− generation at 37°C. However, addition of 0.5% albumin could not inhibit O2•− generation at 44°C, i.e., hyperthermic temperature. Ascorbic acid also showed inhibition of O2•− generation by 0.01 mM at 37°C, but 0.02 mM or more could inhibit O2•− generation at 44°C. A higher concentration of ascorbic acid showed first-order reduction, i.e., direct one-electron reduction, of 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl. Hyperthermia-induced O2•− generation in rat plasma can be mostly inhibited by albumin and ascorbic acid in the plasma.
PMCID: PMC3947970
hyperthermia; reactive oxygen species; superoxide; electron paramagnetic resonance; nitroxyl redox probe
6.  Relationship between blood levels of methyl donor and folate and mild cognitive impairment in Chinese patients with type 2 diabetes: a case-control study 
Type 2 diabetes is a risk factor for Alzheimer’s disease and mild cognitive impairment. Folate insufficiency fosters a decline in the sole methyl donor, S-adenosylmethionine, and decreases methylation potential, which is associated with Alzheimer’s disease in non-diabetic patients. However, little is known in diabetic patients. We analyzed plasma levels of S-adenosylmethionine, S-adenosylhomocysteine and serum level of folate in 100 elderly type 2 diabetic patients with and without mild cognitive impairment. S-adenosylmethionine/S-adenosylhomocysteine ratio was used to reflect the methylation potential. Patients with mild cognitive impairment had significantly lower levels of S-adenosylmethionine, folate and S-adenosylmethionine/S-adenosylhomocysteineratios. Furthermore, logistic regression analysis indicated the plasma S-adenosylmethionine, S-adenosylmethionine/S-adenosylhomocysteine ratio and serum folate (OR, 0.96, 0.698, 0.72, respectively; p<0.05) were negatively associated with risk of mild cognitive impairment, even after adjusting for related covariates. In addition, folate level was positively correlated with S-adenosylmethionine and the S-adenosylmethionine/S-adenosylhomocysteine ratio (r = 0.38, 0.46, respectively; p<0.05) among patients within the middle tertile of folate levels (6.3–9.1 µg/L). These findings indicate mild cognitive impairment is associated with lower levels of S-adenosylmethionine, folate and weakened methylation potential; plasma S-adenosylmethionine and methylation potential may be predicted by serum folate within a suitable range of folate concentrations in diabetic patients.
PMCID: PMC3947971
methyl donor; folate; mild cognitive impairment; type 2 diabetes
7.  Supplementation of parenteral nutrition with fish oil attenuates acute lung injury in a rat model 
Fish oil rich in n-3 polyunsaturated fatty acids has diverse immunomodulatory properties and attenuates acute lung injury when administered in enternal nutrition. However, enteral nutrition is not always feasible. Therefore, we investigated the ability of parenteral nutrition supplemented with fish oil to ameliorate acute lung injury. Rats were infused with parenteral nutrition solutions (without lipids, with soybean oil, or with soybean oil and fish oil) for three days. Lipopolysaccharide (15 mg/kg) was then administered intratracheally to induce acute lung injury, characterized by impaired lung function, polymorphonuclear leukocyte recruitment, parenchymal tissue damage, and upregulation of mRNAs for inflammatory mediators. Administration of parenteral nutrition supplemented with fish oil prior to lung insult improved gas exchange and inhibited neutrophil recruitment and upregulation of mRNAs for inflammatory mediators. Parenteral nutrition supplemented with fish oil also prolonged survival. To investigate the underlying mechanisms, leukotriene B4 and leukotriene B5 secretion was measured in neutrophils from the peritoneal cavity. The neutrophils from rats treated with fish oil-rich parenteral nutrition released significantly more leukotriene B5, an anti-inflammatory eicosanoid, than neutrophils isolated from rats given standard parenteral nutrition. Parenteral nutrition with fish oil significantly reduced lipopolysaccharide-induced lung injury in rats in part by promoting the synthesis of anti-inflammatory eicosanoids.
PMCID: PMC3947972
omega-3 fatty acids; nutritional support; acute lung injury; rat model; fish oil
8.  Sesamol suppresses cyclooxygenase-2 transcriptional activity in colon cancer cells and modifies intestinal polyp development in ApcMin/+ mice 
Excessive prostaglandin production by cyclooxygenase-2 in stromal and epithelial cells is a causative factor of colorectal carcinogenesis. Thus, compounds which inhibit cyclooxygenase-2 transcriptional activity in colon epithelial cells could be candidates for anti-carcinogenic agents. A cyclooxygenase-2 transcriptional activity in the human colon cancer cell line DLD-1 has been measured using a β-galactosidase reporter gene system. Using this system, we demonstrated that the decrease in basal cyclooxygenase-2 transcriptional activities at 100 µM sesamol, one of the lignans in sesame seeds, was 50%. Other compounds in sesame seeds such as sesamin, sesamolin, ferulic acid, and syringic acid did not exhibit significant suppression of cyclooxygenase-2 transcriptional activity at up to 100 µM. In a following experiment, 6-week-old male Min mice, Apc-deficient mice, were divided into a non-treated and 500 ppm sesamol groups. At the age of 15 weeks, it was found that treatment with sesamol decreased the number of polyps in the middle part of small intestine to 66.1% of the untreated value. Moreover, sesamol suppressed cyclooxygenase-2 and cytosolic prostaglandin E2 synthase mRNA in the polyp parts. The present findings may demonstrate the novel anti-carcinogenetic property of sesamol, and imply that agents that can suppress cyclooxygenase-2 expression may be useful cancer chemopreventive agents.
PMCID: PMC3947973
cyclooxygenase-2; reporter gene assay; sesame; sesamol; Min mice
9.  Role of Nrf2 in the alteration of cholesterol and bile acid metabolism-related gene expression by dietary cholesterol in high fat-fed mice 
Nuclear factor-E2-related factor 2 (Nrf2) is a regulator of lipid metabolism as well as various cytoprotective enzymes and may be involved in the pathogenesis of non-alcoholic fatty liver disease. Although, bile acids affect lipid metabolism, the role of Nrf2 in bile acid metabolism remains unclear. In this study, it was tested how Nrf2 modulates lipid and bile acid homeostasis in liver in response to changes of cholesterol absorption under high-fat diet using Nrf2-null mice. Eight-week-old male wild-type and Nrf2-null mice (n = 6/group) were divided into three groups fed the following diets: 1) control diet containing 4% soybean oil and 16% lard, 2) control diet plus ezetimibe, 3) control diet plus cholesterol. Blood and livers were removed after 4 weeks feeding. High cholesterol diet increased hepatic expression of liver X receptor α target genes related to fatty acid metabolism (FAS, ACC1, SREBP-1c, SCD-1c and CD36), cholesterol transport (Abcg5/abcg8) and bile acid synthesis (Cyp7a1) in wild type mice. However, these genes were not induced in Nrf2-null mice. These findings suggest that Nrf2 has a relation to liver X receptor α and controls the regulation of gene expressions related to lipid and bile acid metabolism.
PMCID: PMC3947974
nuclear factor-E2-related factor 2; non-alcoholic fatty liver disease; cholesterol metabolism; bile acid metabolism; liver X receptor α
10.  Cooperative effects of soy isoflavones and carotenoids on osteoclast formation 
Osteoclasts play a major role in bone resorption. Several functional food components, such as soy isoflavones and carotenoids, are reported to inhibit osteoclast formation. However, the cooperative effect of functional foods or their constituents on bone metabolism has not been clarified. This study aimed to investigate the cooperative effect of soy isoflavones and carotenoids on osteoclast formation in vitro using cultures of RAW264 and bone marrow cells in the presence of receptor activator of nuclear factor κ-B ligand. In RAW264 cells, treatment with soy isoflavones (genistein or equol) or carotenoids (β-carotene) suppressed osteoclast formation. At 10 µM, genistein and equol inhibited RAW264 cell proliferation but did not affect cell viability. When 10 µM genistein or equol was combined with 0.1 µM β-carotene, we observed an additive suppressive effect on osteoclast differentiation. Similar results were observed with bone marrow cell cultures. We found that 10 µM of zeaxanthin or lutein suppressed osteoclast formation singly, and further enhanced the suppressive effects of daidzein or genistein when administered in combination. These results suggest that the combination of soy isoflavones and carotenoids have an enhanced suppressive effect on osteoclast formation. This knowledge might be important in planning diet for bone health.
PMCID: PMC3947975
soy isoflavones; carotenoids; osteoclast formation; bone
11.  Reactive oxygen species involved cancer cellular specific 5-aminolevulinic acid uptake in gastric epithelial cells 
Photodynamic therapy and photodynamic diagnosis using 5-aminolevulinic acid (ALA) are clinically useful for cancer treatments. Cancer cells have been reported that 5-aminolevulinic acid is incorporated via peptide transporter 1, which is one of the membrane transport proteins, and has been reported to be significantly expressed in various gastrointestinal cancer cells such as Caco-2. However, the mechanism of this protein expression has not been elucidated. Concentration of reactive oxygen species (ROS) is higher in cancer cells in comparison with that of normal cells. We have previously reported that ROS derived from mitochondria is likely related to invasions and proliferations of cancer cells. Since 5-aminolevulinic acid is the most important precursor of heme which is necessary protein for cellular proliferations, mitochondrial ROS (mitROS) may be also related to peptide transporter 1 expressions. In this study, we used a rat gastric mucosal cell line RGM1 and its cancer-like mutated cell line RGK1, and we clarified the ALA uptake mechanism and its relations between mitROS and peptide transporter 1 expression in RGK1. We also used our self-established stable clone of cell which over-expresses manganese superoxide dismutase, a mitROS scavenger. We studied differences of the photodynamic therapy effects in these cells after ALA administrations to clear the influence of mitROS.
PMCID: PMC3947976
aminolevulinic acid; reactive oxygen species; gastric epithelial cell; porphyrin; photodynamic therapy; mitROS
12.  As a host society to SFRRI 2014 in Kyoto 
PMCID: PMC3882492  PMID: 24426182
13.  Isoflavone intake inhibits the development of 7,12-dimethylbenz(a)anthracene(DMBA)-induced mammary tumors in normal and ovariectomized rats 
To determine the associations between isoflavone (49.72% genistin, 5.32% daidzin, 34.54% glycitin) and breast cancer risk, 150 rats were given 5 mg 7,12-dimethylbenz(a)anthracene and half of them were ovariectomized. Then normal rats and ovariectomized rats were divided into 5 groups: control group, isoflavone high (HI), middle (MI), or low (LI) dose group consuming 100, 500, or 1000 mg isoflavones/kg diet, estrogen group (2.5 mg stilboestrol/kg diet). After 24 weeks, tumor incidences were 73% in control group, 7% in HI, 7% in MI, 27% in LI, and 80% in estrogen group for normal rats; 60% in control group, 13% in HI, 7% in MI, 13% in LI, and 73% in estrogen group for ovariectomized rats. Isoflavone treatment decreased tumor incidence and mean tumor number per rat and increased mean latent period compared with those in control group and estrogen group group significantly (p<0.05). The mRNA and protein expression of estrogen receptor β were significantly higher in isoflavone treatment groups than those in control group group. Moreover, isoflavone treatment significantly decreased 8-hydroxydeoxyguanosine content and increased superoxide dismutase level in normal rats and decreased malondialdehyde concentrations in ovariectomized rats compared with control group. In conclusions, isoflavone intake significantly inhibited the development of premenopausal and postmenopausal mammary tumors.
PMCID: PMC3882481  PMID: 24426188
isoflavones; mammary tumors; ovariectomized rats; estrogen receptor
14.  Mitochondrial reactive oxygen species accelerate gastric cancer cell invasion 
Tumor invasion is the most important factor to decide patient’s prognosis. The relation between reactive oxygen species and tumor invasion is mainly reported that nicotinamide adenine dinucleotide phosphate oxidase in the cell membrane is a reactive oxygen species producer for formulating an invadopodia. On the other hand, mitochondrion was known as one of the most important reactive oxygen species-producer in the cell via an energy transfer system. However, the relation between mitochondrial reactive oxygen species and the tumor invasion was not well clarified. In this study, we evaluated the relation between mitochondrial reactive oxygen species and tumor invasion using a normal gastric mucosal cell-line (RGM-1) and a cancerous mutant RGM-1 cell-line (RGK-1). Manganese superoxide dismutase-expressing RGK-1 cell-lines were used for a scavenging mitochondrial reactive oxygen species. The cells have been evaluated their movement ability as follows; cellular ruffling frequencies, wound healing assay to evaluate horizontal cellular migration, and invasion assay using matrigel to analyze vertical cellular migration. All cellular movement abilities were inhibited by scavenging mitochondrial reactive oxygen species with manganese superoxide dismutase. Therefore mitochondrial reactive oxygen species was one of factors enhancing the tumor invasion in gastric cancer.
PMCID: PMC3882482  PMID: 24426185
reactive oxygen species; mitochondria; tumor invasion; electron paramagnetic resonance; manganese superoxide dismutase
15.  Lipopolysaccharides accelerate hepatic steatosis in the development of nonalcoholic fatty liver disease in Zucker rats 
Nonalcoholic fatty liver disease (NAFLD) can develop into end-stage disease that includes cryptogenic cirrhosis and hepatocellular carcinoma. Bacterial endotoxin, for example lipopolysaccharide (LPS), plays an important role in the pathogenesis of NAFLD. The aim of this study was to assess the role of LPS in the development of NAFLD. Twenty-one male Zucker (fa/fa) rats were divided into three groups: rats fed for twelve weeks on a diet rich in disaccharide (D12 group), rats similarly managed but treated with LPS (LPS group), and those on the same diet for 24 weeks (D24 group). Histological examination demonstrated that this protocol induced hepatic steatosis in the LPS and D24 groups. Significant, marked accumulation of lipid droplets was observed in the LPS group, compared with the D24 group. Rats from the LPS group showed a decrease in plasma adiponectin levels, an increase in plasma leptin levels, and greater expression of FAS and SREBP-1c mRNA in the liver, compared with rats from the D24 group. These finding coincided with histological findings. We therefore suggest that LPS may accelerate the progression of hepatic steatosis.
PMCID: PMC3882483  PMID: 24426189
nonalcoholic fatty liver disease (NAFLD); lipopolysaccharides (LPS); disaccharide; hepatic steatosis; adiponectin
16.  Anti-obesity effects of traditional and standardized meju in high-fat diet-induced obese C57BL/6J mice 
The aim of the study was to evaluate the anti-obesity effects of two types of meju in diet induced obese C57BL/6J mice. Animals were randomly divided into 4 dietary group (n = 10); normal diet, high fat diet with 30% soybean, high fat diet with 30% traditional meju, high fat diet with 30% standardized meju. After 16 weeks, after animals were sacrificed. It was observed that the high fat diet with 30% traditional meju and high fat diet with 30% standardized meju significantly reduced body weight gain, epididymal fat weight, serum triglyceride along with serum insulin and leptin levels compared to the high fat diet with 30% soybean. And also, the expression levels of hepatic lipid anabolic genes were significantly decreased in the high fat diet with 30% traditional meju and high fat diet with 30% standardized meju compared to the high fat diet with 30% soybean. In conclusion, the assessment of all the obesity markers strongly advocate the anti-obesity effect of traditional as well as standardized meju in diet induce obesity conditions.
PMCID: PMC3882484  PMID: 24426190
meju; high fat diet; lipid metabolism; C57BL/6J mice; anti-obesity
17.  α-Lipoic acid suppresses migration and invasion via downregulation of cell surface β1-integrin expression in bladder cancer cells 
Our previous study showed α-lipoic acid (LA) downregulated cell surface β1-integrin expression of v-H-ras-transformed derivative of rat fibroblast with amelioration of their malignant phenotype. Here, we evaluated the ameliorating effect of LA on the malignant characters in H-ras-transformed bladder cancer cells. H-ras mutated bladder cancer line, T24 cells were incubated with LA to evaluate the inhibitory effect on proliferation, migration, invasion and β1-integrin expression. Fluorescence staining of F-actin and western blotting analyses of the related signaling pathways were also performed. LA inhibited the proliferation of T24 cells. Cell adhesion to collagen IV and fibronectin was strikingly inhibited by LA treatment accompanied by downregulation of cell surface but not whole cell β1-integrin expression. LA clearly inhibited cell migration and invasion of T24 cells, which were mimicked by extracellular signal-regulated kinase (ERK) and Akt pathway inhibition. Actually, LA significantly downregulated the phosphorylated ERK and Akt levels. Moreover, LA downregulated phosphorylated focal adhesion kinase level with disappearance of stress fiber formation. Finally, although LA induced the internalization of cell surface β1-integrin, disruption of the raft did not affect the action of LA. Taken together, LA is a promising agent to improve malignant character of bladder cancer cells through regulation of cellular β1-integrin localization.
PMCID: PMC3882485  PMID: 24426186
bladder cancer cells; α-lipoic acid; invasion; migration; β1-integrin
18.  Different sucrose-isomaltase response of Caco-2 cells to glucose and maltose suggests dietary maltose sensing 
Using the small intestine enterocyte Caco-2 cell model, sucrase-isomaltase (SI, the mucosal α-glucosidase complex) expression and modification were examined relative to exposure to different mono- and disaccharide glycemic carbohydrates. Caco-2/TC7 cells were grown on porous supports to post-confluence for complete differentiation, and dietary carbohydrate molecules of glucose, sucrose (disaccharide of glucose and fructose), maltose (disaccharide of two glucoses α-1,4 linked), and isomaltose (disaccharide of two glucoses α-1,6 linked) were used to treat the cells. qRT-PCR results showed that all the carbohydrate molecules induced the expression of the SI gene, though maltose (and isomaltose) showed an incremental increase in mRNA levels over time that glucose did not. Western blot analysis of the SI protein revealed that only maltose treatment induced a higher molecular weight band (Mw ~245 kDa), also at higher expression level, suggesting post-translational processing of SI, and more importantly a sensing of maltose. Further work is warranted regarding this putative sensing response as a potential control point for starch digestion and glucose generation in the small intestine.
PMCID: PMC3882486  PMID: 24426192
maltose; mucosal α-glucosidases; small intestine; sensing; sucrase-isomaltase
19.  The effects of Lactobacillus pentosus strain b240 and appropriate physical training on salivary secretory IgA levels in elderly adults with low physical fitness: a randomized, double-blind, placebo-controlled trial 
The purpose of the study was to evaluate the effects of Lactobacillus pentosus strain b240 (b240) intake and appropriate physical training on salivary secretory immunoglobulin A secretion in elderly adults with low physical fitness. Elderly adults with low physical fitness (daily step count below 3,500 steps) were divided into 2 groups: a b240 intake + exercise group (b240 group) and a placebo intake + exercise group (placebo group). Each subject continued intake of b240 or placebo and moderate-intensity resistance exercise for 12 weeks. Before and 4, 8, and 12 weeks after the start of intervention, each subject underwent saliva sampling. Before and after intervention, physical fitness tests and step count were measured. Our results showed that secretory immunoglobulin A secretion in 57 subjects during the b240/placebo intake period was significantly greater in the b240 group than in the placebo group (p<0.05). There were no significant changes in physical fitness tests before and after intervention in the 2 groups. The daily amount of walking increased significantly after intervention in both groups (p<0.05). These results suggest that in elderly adults with low physical activity and fitness, intake of b240 with appropriate physical exercise elevate salivary secretory immunoglobulin A secretion.
PMCID: PMC3882487  PMID: 24426193
Lactobacillus pentosus; salivary SIgA; mucosal immunity; elderly; low physical fitness
20.  Is administrating branched-chain amino acid-enriched nutrition achieved symptom-free in malnourished cirrhotic patients? 
Administration of branched-chain amino acids (BCAA) has been reported to improve liver function, quality of life (QOL). However, in some malnourished patients, serum albumin levels do not improve in response to BCAA granules. In this study, we examined the effects of BCAA-enriched enteral nutrition in patients unresponsive to BCAA granules. Thirty-two decompensated cirrhotic patients at Osaka Medical College were enrolled in this study. Since all patients showed no improvement in serum albumin levels despite 3 months of BCAA granule administration, they were administered 50 g of a flavored BCAA-enriched enteral nutrient twice daily, i.e., during the daytime and late evening. Serum albumin levels and major cirrhotic symptoms were examined 1, 3, and 5 months after treatment initiation. Serum albumin levels improved significantly 3 months after treatment initiation (3.14 ± 0.32 g/dl vs 3.5 ± 0.31 g/dl, p<0.01), and Child–Pugh scores decreased significantly (p<0.01). In the majority (53–80%) of patients, muscles cramps, fatigue, fatigability, edema, and sleep disturbance improved within 3 months after therapy initiation. Moreover, approximately 90% of the patients became symptom-free 5 months after treatment initiation. These results indicate that switching to BCAA-enriched nutrients improves QOL of cirrhotic patients unresponsive to BCAA granules.
PMCID: PMC3882488  PMID: 24426191
BCAA-enriched nutrients; cirrhotic symptoms; QOL; LES; liver cirrhosis
21.  Effect of eating vegetables before carbohydrates on glucose excursions in patients with type 2 diabetes 
The aim of this review was to evaluate whether eating vegetables before carbohydrates could reduce the postprandial glucose, insulin, and improve long-term glycemic control in Japanese patients with type 2 diabetes. We studied the effect of eating vegetables before carbohydrates on postprandial plasma glucose, insulin, and glycemic control for 2.5 y in patients with type 2 diabetes. The postprandial glucose and insulin levels decreased significantly when the patients ate vegetables before carbohydrates compared to the reverse regimen, and the improvement of glycemic control was observed for 2.5 y. We also compared the postprandial glucose and glucose fluctuations assessed by continuous glucose monitoring system for 72-h in patients with type 2 diabetes and subjects with normal glucose tolerance when subjects ate vegetables before carbohydrates and carbohydrates before vegetables in a randomized crossover design. The glycemic excursions and incremental glucose peak were significantly lower when the subjects ate vegetables before carbohydrates compared to the reverse regimen. This evidence supports the effectiveness of eating vegetables before carbohydrates on glucose excursions in the short-term and glycemic control in the long-term in patients with type 2 diabetes.
PMCID: PMC3882489  PMID: 24426184
type 2 diabetes; diet; eating order; postprandial glucose; glucose excursion
22.  The impact of non-steroidal anti-inflammatory drugs on the small intestinal epithelium 
The small intestine has been called as a dark continent of digestive tract and it had been very difficult to diagnose or treat the disease of small intestine. However recent technological development including video capsule endoscopy or balloon-assisted endoscopy has made us to aware the various diseases of small intestine. By using capsule endoscopy, many researchers reported that more than 70% of patients treated continuously with non-steroidal anti-inflammatory drugs (NSAID) exhibit the mucosal damage of small intestine. In some cases, NSAID not only causes mucosal damage but also results in life threatening bleeding from small intestine, which had not been prevented or cured by gastro-protective drug or anti-gastric acid secretion drug administration. Therefore to investigate and identify the effective drug that protects small intestine from mucosal damage is urgently expected. In spite of extensive investigation in clinical field, only a few drugs such as misoprostol, a synthetic prostaglandin E1 analogue, has been reported as an effective one but is not satisfactory enough to fulfill the requirement of patients who suffer from NSAID-induced mucosal damage of small intestine. And now, extensive study is being performed using several gastro-mucoprotective drugs by many researchers. In this review, we introduce the current clinical situation in small intestinal injury of patients under NSAID treatment, and to summarize the molecular mechanism by which NSAID, including acetyl salicylic acid, cause small intestinal damage. In addition, we present results of clinical trials performed so far, and refer the possible preventive method or treatment in the near future.
PMCID: PMC3882490  PMID: 24426183
small intestine; NSAID; capsule endoscopy; balloon endoscopy; reactive oxygen species
23.  Selective accumulation of hematoporphyrin derivative in glioma through proton-coupled folate transporter SLC46A1 
The mechanism of tumor-specific porphyrin accumulation is not clear. We investigated the expression of proton-coupled folate transporter SLC46A1 in glioma and aimed to clarify the relationship between tumor fluorescence and SLC46A1 expression.We confirmed the expression of SLC46A1 in surgical specimens from 24 glioma patients by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). We also investigated SLC46A1 expression in glioma cell lines by RT-PCR. The cellular uptake of hematoporphyrin derivative in vitro was measured with a microplate reader and fluorescence microscope. In these experiments, we used three human malignant glioma cell lines: U87, U251 and T98G. Immunohistochemistry showed SLC46A1 positivity in the malignant tumor lesion of each specimen. Strong positive SLC46A1 expression was observed in 33% of grade IV, 22% of grade III and 17% of grade II gliomas. All four randomly obtained malignant glioma frozen sections expressed SLC46A1 mRNA by RT-PCR. In vitro, U87 showed the least SLC46A1 expression, U251 was intermediate, and T98G showed the most expression. The amount of hematoporphyrin derivative (HpD) cellular uptake correlated with SLC46A1 expression. These results suggest that the accumulation of HpD in glioma cells is related to SLC46A1 function and SLC46A1 is involved in the mechanism of glioma fluorescence.
PMCID: PMC3882491  PMID: 24426187
glioma; proton-coupled folate transporter; SLC46A1; hematoporphyrin derivative; photodynamic diagnosis
24.  Evaluation of biochemical effects of Casuarina equisetifolia extract on gentamicin-induced nephrotoxicity and oxidative stress in rats. Phytochemical analysis 
Nephrotoxicity is defined as renal dysfunction that arises as result of exposure to external agents such as drugs and environmental chemicals. The present work was undertaken to carry out the phytochemical study and nephroprotective activity of methanolic extract of Casuarina equisetifolia leaves in gentamicin-induced nephrotoxicity in Wistar rats. Flavonoids and phenolic acids were identified and quantified using high performance liquid chromatography. Subcutaneous injection of rats with gentamicin (80 mg/kg body weight/day) for six consecutive days induced marked acute renal toxicity, manifested by a significant increase in serum urea, creatinine and uric acid levels, along with a significant depletion of serum potassium level, compared to normal controls. Also oxidative stress was noticed in renal tissue as evidenced by a significant decrease in glutathione level, superoxide dismutase, glutathione-S-transferase activities, also a significant increase in malondialdehyde and nitric oxide levels when compared to control group. Administration of plant extract at a dose of 300 mg/kg once daily for 4 weeks restored normal renal functions and attenuated oxidative stress. In conclusion, Casuarina equisetifolia leaves extract ameliorates gentamicin-induced nephrotoxicity and oxidative damage by scavenging oxygen free radicals, decreasing lipid peroxidation and improving intracellular antioxidant defense, thus extract may be used as nephroprotective agent.
PMCID: PMC3818266  PMID: 24249970
Casuarina equisetifolia; nephroprotective; gentamicin; oxidative stress; nephrotoxicity
25.  2,2'-Azobis(isobutyronitrile)-derived alkylperoxyl radical scavenging activity assay of hydrophilic antioxidants by employing EPR spin trap method 
As interest in the study of antioxidant intake from foods and other agricultural products increases, methods for performing radical scavenging activity assays based on the electron paramagnetic resonance spectroscopic method, in which there is no interference from the sample color and turbidity, are required. In this study, we have developed a rapid and simple electron paramagnetic resonance based assay to evaluate the alkylperoxyl radical scavenging activity of several antioxidants. The alkylperoxyl radical species was generated by the photolysis of azo-radical initiator 2,2'-azobis(isobutyronitrile), in which the radical generation rate and period were controlled by the illumination light. The relative alkylperoxyl radical scavenging activity was obtained by a simple formula of competing reaction of antioxidant and spin trap toward the oxygen radical. The scavenging activities toward alkylperoxyl radical and alkoxy radical species were evaluated in six antioxidants. Although quercetin showed the highest activity toward both radicals, the order of the relative activities in the other antioxidants was different mutually between the alkylperoxyl radical and the alkoxyl radical. This alkylperoxyl radical scavenging activity assay based on electron paramagnetic resonance spectroscopy is useful for evaluation of colored and turbid food samples.
PMCID: PMC3818267  PMID: 24249966
alkylperoxyl radical; radical scavenging activity; EPR spin trapping; AIBN

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