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M Kasuga

Publications and source records attributed to M Kasuga.

At least 19 recordsLinked to original sources
PubMed2006

No significant difference in neutrophil activation found among three H2RAs.

BACKGROUND: Even with the most effective treatment, Helicobacter pylori eradication is difficult in some patients. Therefore, patients sometimes require acid-suppressive therapy without H. pylori eradication. It has been reported that ranitidine inhibits neutrophil activation, whereas famotidine does not. However, few studies have been published concerning the activation of neutrophils before and after treatment using clinical doses of histamine-2 receptor antagonists in patients with H. pylori infection. AIM: To examine the effects of neutrophil activation after treatment with three different histamine-2 receptor antagonists. PATIENTS: This prospective, open-label, randomised, parallel-group study was conducted. Thirty patients with H. pylori infection were enrolled. These subjects were randomly assigned to receive one of the following treatments: (a) 150 mg ranitidine, (b) 20mg famotidine, or (c) 10 mg lafutidine b.d., for 4 weeks. Before and after histamine-2 receptor antagonist treatment, histological findings, myeloperoxidase activity, and interleukin-8 in the gastric mucosa were evaluated. RESULTS: On the basis of the histological findings between before and after histamine-2 receptor antagonist treatment, no significant differences were found in any groups. Similarly, there were no significant differences in myeloperoxidase activity or interleukin-8 levels. CONCLUSION: In patients with H. pylori, when used at clinical doses, any histamine-2 receptor antagonists can be used without concerning about inhibition of neutrophil activation.

Acetamides↗
PubMed2005

Levofloxacin- versus metronidazole-based rescue therapy for H. pylori infection in Japan.

BACKGROUND: The ideal second-line treatment regimens for Helicobacter pylori infection may differ between the areas, countries and races. AIM: The aim was to confirm which was the better regimen for second-line therapy after treatment failure with a standard triple therapy in Japan, a high dosage of levofloxacin- or metronidazole-based therapy. PATIENTS: Sixty outpatients with persistent H. pylori infection after a standard triple therapy were enrolled in this prospective, open-label and randomised trial. METHODS: The subjects were randomly administered levofloxacin (300 mg b.d.)- or metronidazole (500 mg b.d.)-based therapy with lansoprazole (30 mg b.d.) and amoxicillin (1000 mg b.d.) for 7 days, and the cure rates and side effects were analysed. Antimicrobial susceptibility was also examined before second-line therapy using the E-test. RESULTS: Good compliance was obtained without severe side effects in both the groups except for two patients. The cure rates, expressed as intention-to-treat and per-protocol analyses, respectively, were 70.0 and 72.4% in the levofloxacin group, and 96.7 and 100% in the metronidazole group. Each regimen often overcame even clarithromycin-resistant strains. CONCLUSION: Metronidazole-based triple therapy is recommended as second-line therapy in Japan, and levofloxacin-based therapy can be an alternative treatment option.

Adult↗
PubMed2005

Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin.

BACKGROUND/AIMS: The gastric peptide ghrelin, an endogenous ligand for growth-hormone secretagogue receptor, has two major molecular forms: acylated ghrelin and desacyl ghrelin. Acylated ghrelin induces a positive energy balance, while desacyl ghrelin has been reported to be devoid of any endocrine activities. The authors examined the effects of desacyl ghrelin on energy balance. METHODS: The authors measured food intake, gastric emptying, c-Fos expression in the hypothalamus, and gene expression of hypothalamic neuropeptides in mice after administration of desacyl ghrelin. To explore the effects of long term overexpression of desacyl ghrelin, transgenic mice that overexpressed desacyl ghrelin were created. RESULTS: Administration of desacyl ghrelin decreased food intake and gastric emptying rate through an action on the paraventricular nucleus and the arcuate nucleus in the hypothalamus. Gene expression of anorexigenic cocaine and amphetamine regulated transcript and urocortin in the hypothalamus was increased by desacyl ghrelin. Desacyl ghrelin overexpressing mice exhibited a decrease in body weight, food intake, and fat pad mass weight accompanied by moderately decreased linear growth. Gastric emptying was also decreased in desacyl ghrelin overexpressing mice. CONCLUSIONS: These findings indicate that in contrast to acylated ghrelin, desacyl ghrelin induces a negative energy balance by decreasing food intake and delaying gastric emptying. The effect is mediated via the hypothalamus. Although derived from the same precursor, the inverse effects of these two peptides suggest that the stomach might be involved as an endocrine organ in the regulation of the energy balance.

Acetylation↗
PubMed2004

Cell kinetic balance in gastric mucosa with intestinal metaplasia after Helicobacter pylori eradication: 2-year follow-up study.

BACKGROUND: Proliferation and apoptosis events are altered in Helicobacter pylori infection. However, whether H. pylori eradication has an effect on the disturbed kinetics in metaplastic mucosa has not been well elucidated. AIM: To investigate the effect of eradication on the gastric cell kinetics. SUBJECTS AND METHODS: Initially, biopsies were obtained from 74 H. pylori-infected subjects and repeated 12 and 24 months after eradication. Biopsies were immunohistochemically stained for apoptosis by single-stranded DNA, for proliferation by Ki-67 antibodies and for intestinal metaplasia MUC2, MUC5AC, MUC6 and CD10. RESULTS: While antral apoptosis in intestinal metaplasia was significantly lower than in non-intestinal metaplasia, proliferation was significantly higher (greater and lesser curvatures, P < 0.05, respectively). This resulted in a significantly lower apoptosis/proliferation ratio in intestinal metaplasia than in non-intestinal metaplasia (antrum greater and lesser curvatures and corpus greater curvature, P < 0.05). After successful eradication, apoptosis and proliferation decreased in both intestinal metaplasia and non-intestinal metaplasia. The pattern of reduction of apoptosis and proliferation differed in these two groups. However, in the corpus, the reduction resulted in a significant increase in the apoptosis/proliferation ratio in both. CONCLUSION: Proliferation and apoptosis are unevenly and disproportionately altered in H. pylori infection leading to an imbalance in cell kinetics. Eradication of the organism improves the balance and may possibly play a role in the prevention of malignancy transformation in the metaplastic mucosa.

Adult↗
PubMed2003

Levofloxacin based triple therapy as a second-line treatment after failure of helicobacter pylori eradication with standard triple therapy.

BACKGROUND: Successful eradication of Helicobacter pylori infection after failure of standard triple therapy is difficult. The efficacy and safety of levofloxacin based triple therapy as a first-line therapy has-been studied. AIMS: The aim was to evaluate the efficacy and tolerability of levofloxacin based therapy after a failed standard triple therapy. PATIENTS: We conducted a prospective, uncontrolled study of a consecutive series of 33 patients who failed eradication with 1 week of lansoprazole-amoxicillin-clarithromycin triple therapy. METHODS: The subjects were retreated with 1 week of LA-LVFX triple therapy (lansoprazole, 30 mg twice daily; amoxicillin, 1000 mg twice daily: levofloxacin, 200 mg twice daily). Cure of infection was defined as negative results from culture, histology and a urea breath test 4 to 8 weeks after the second-line therapy. RESULTS: The eradication rate was 69.7% (23/33) by both intention-to-treat and per-protocol analyses (95% confidence interval=61-79%). Seven (21.2%) patients experienced mild side-effects, such as soft stools and taste disturbance. No patient stopped the medication on account of adverse effects. CONCLUSIONS: Levofloxacin based triple therapy is an effective second-line treatment after a failed standard triple therapy.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2003

Antagonism of ghrelin receptor reduces food intake and body weight gain in mice.

BACKGROUND AND AIMS: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), is an appetite stimulatory signal from the stomach with structural resemblance to motilin. We examined the effects of the gastric peptide ghrelin and GHS-R antagonists on energy balance and glycaemic control in mice. MATERIALS AND METHODS: Body weight, fat mass, glucose, insulin, and gene expression of leptin, adiponectin, and resistin in white adipose tissue (WAT) were measured after repeated administrations of ghrelin under a high fat diet. Gastric ghrelin gene expression was assessed by northern blot analysis. Energy intake and gastric emptying were measured after administration of GHS-R antagonists. Repeated administration of GHS-R antagonist was continued for six days in ob/ob obese mice. RESULTS: Ghrelin induced remarkable adiposity and worsened glycaemic control under a high fat diet. Pair feeding inhibited this effect. Ghrelin elevated leptin mRNA expression and reduced resistin mRNA expression. Gastric ghrelin mRNA expression during fasting was increased by a high fat diet. GHS-R antagonists decreased energy intake in lean mice, in mice with diet induced obesity, and in ob/ob obese mice; it also reduced the rate of gastric emptying. Repeated administration of GHS-R antagonist decreased body weight gain and improved glycaemic control in ob/ob obese mice. CONCLUSIONS: Ghrelin appears to be closely related to excess weight gain, adiposity, and insulin resistance, particularly under a high fat diet and in the dynamic stage. Gastric peptide ghrelin and GHS-R may be promising therapeutic targets not only for anorexia-cachexia but also for obesity and type 2 diabetes, which are becoming increasingly prevalent worldwide.

Adiponectin↗
PubMed2003

Dedifferentiation and decreased expression of adhesion molecules, E-cadherin and ZO-1, in colorectal cancer are closely related to liver metastasis.

Carcinoma cells with high metastatic potential often show a dedifferentiated phenotype at the primary site. In this study, a total of 48 cases (24 primary tumors of colorectal cancer (Pr-CRC) with liver metastasis, 24 without) were examined for E-cadherin and ZO-1 expression by immunohistochemical staining, and for their dedifferentiated phenotype. The expression levels of E-cadherin and ZO-1 were markedly decreased in the cancer cells of tumors with liver metastasis. Moreover, dedifferentiation of cancer cells, which was evaluated by the modified Gleason score, was also related to liver metastasis. However, none of the conventional clinicopathologic parameters of invasion, except lymph node metastasis, showed any relationship with liver metastasis. These results indicate that dedifferentiation and a decreased expression of E-cadherin and ZO-1 are closely related to liver metastasis.

Cadherins↗
PubMed2002

Identification of a single nucleotide polymorphism showing no insulin-mediated suppression of the promoter activity in the human insulin receptor substrate 2 gene.

AIMS/HYPOTHESIS: To understand the transcriptional regulation and to investigate the pathological influence upon Type II (non-insulin-dependent) diabetes mellitus of insulin receptor substrate 2 ( IRS2), the 5' flanking region of the human IRS2 gene was cloned and screened in Japanese diabetic patients. METHODS: Luciferase reporter assay and electrophoretic mobility shift assay (EMSA) were combined in HepG2, Fao, RINm5F, and HeLa cells to characterise the human IRS2 promoter region. Single nucleotide polymorphisms (SNPs) were identified in Japanese Type II diabetic patients by sequencing and were genotyped. RESULTS: The proximal 2399 bp of the 5' flanking region of the human IRS2 gene was cloned. A core promoter region was extended between nucleotide positions -834 and -557 (relative to the translation initiation site). The region [(-758)AGGGGGAGGG(-749)] that appears important in the positive regulation of IRS2transcription was identified by EMSA with (32)P-labelled double-stranded oligonucleotides encompassing regions protected from DNase I digestion by nuclear extract of HepG2 cells. Two SNPs (-765 C/ T and -2062 T/ C), identified by screening Japanese Type II diabetic patients, were not associated with Type II diabetes. IRS2-driven reporter activity in the plasmid containing thymine at -765 was not suppressed by insulin when measured in Fao cells. CONCLUSION/INTERPRETATION: The 5' flanking sequence of the human IRS2 was investigated and two SNPs were identified. The SNP at -765 was suggested to be involved in the insulin-mediated regulation of the transcriptional activity of IRS2.

5' Untranslated Regions↗
PubMed2002

Mosapride, a 5HT-4 receptor agonist, improves insulin sensitivity and glycaemic control in patients with Type II diabetes mellitus.

AIMS/HYPOTHESIS: We investigated the potential role of mosapride, a 5HT-4 receptor agonist, in glycaemic control in Type II (non-insulin-dependent) diabetic mellitus patients without autonomic neuropathy. METHODS: Thirty-four inpatients with Type II diabetes mellitus were randomly assigned to receive either mosapride (5 mg orally three times a day, n=17) or a placebo ( n=17) for 1 week (first study). Changes in blood glucose and insulin were determined basally as well as after intravenous glucose loading. Insulin sensitivity was evaluated during hyperinsulinaemic-normoglycaemic-clamp studies and by measuring the number of and the autophosphorylation of insulin receptors on the erythrocytes of patients ( n=9). Sixty-nine outpatients with Type II diabetes were similarly treated with mosapride or a placebo for 8 weeks (second study). Finally, tissue- specific expression of 5HT-4 receptors was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Mosapride lowered fasting blood glucose and fructosamine concentrations ( p<0.05) (first study). It significantly increased the number of (Mosapride 3323+/-518 vs 4481+/-786 [ p<0.05], Control 4227+/-761 vs 3275+/-554 per 300 microl erythrocytes) and the tyrosine autophosphorylation (Mosapride 3178+/-444 vs 4043+/-651 [ p<0.05], Control 3721+/-729 vs 3013+/-511 insulin receptor unit) of insulin receptors, as well as glucose utilisation (Mosapride 4.92+/-0.53 vs 5.88+/-0.72 [ p<0.05], Control 4.74+/-0.65 vs 4.70+/-0.31 mg/kg x min). Mosapride treatment for 8 weeks significantly reduced fasting glucose (9.91+/-0.34 vs 8.51+/-0.34 mmol/l, p<0.05), insulin (53.2+/-4.62 vs 40.8+/-5.52 pmol/l, p<0.05) and HbA(1c) (8.61+/-0.20 vs 7.67+/-0.19%, p<0.01) concentrations (second study). The RT-PCR analysis demonstrated specific expression of 5HT-4 receptors in the muscle, but not in the liver or fat tissues. CONCLUSIONS/INTERPRETATION: Mosapride could improve insulin action at muscle and glycaemic control in Type II diabetic patients.

Base Sequence↗
PubMed2002

Variation in MT expression in early-stage depressed-type and polypoid-type colorectal tumours.

Metallothionein (MT) expression is observed in various carcinomas, but its role is not fully understood. To clarify the clinicopathological significance of MT, 87 colorectal adenomas and 128 early-stage carcinomas were immunohistochemically analysed for MT expression. The degree of MT immunostaining of a specimen was graded according to the proportion of MT-positive cells; negative (<5%) and positive (focally 5-50%, diffusely >50%). MT expression significantly decreased with tumour development. For carcinomas, MT-positivity was significantly associated with depth of invasion (T1 60% versus T2 33%; P<0.01), vascular involvement (positive 35% versus negative 61%; P<0.01) and morphology (polypoid 62% versus depressed 26%; P<0.01). Regarding MT-positive distribution, the diffuse-positive rate in MT-positive polypoid lesions was 28%, while MT-positive depressed lesions were all diffusely stained (P<0.01). In conclusion, our results suggested that decreasing MT expression is an early event in colorectal carcinogenesis and may reflect local invasion. Furthermore, MT-positive distribution may reflect genetic differences between the polypoid and depressed-type.

Adult↗
PubMed2002

Orexin reverses cholecystokinin-induced reduction in feeding.

AIM: This study was designed to investigate the effect of orexin on anorexia induced by cholecystokinin (CCK),a peripheral satiety signal. METHODS: We administered orexin A (0.01-1 nmol/mouse) and CCK-8 (3 nmol/mouse) to mice. Food intake was measured at different time-points: 20 min, 1, 2 and 4 h post-intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) administrations. RESULTS: Intracerebroventricular-administered orexin significantly increased food intake in a dose-dependent manner. The inhibitory effect of i.p.-administered CCK-8 on food intake was significantly negated by the simultaneous i.c.v. injection of orexin in a dose-dependent manner. CONCLUSIONS: Orexin reversed the CCK-induced loss of appetite. Our results indicate that orexin might be a promising target for pharmacological intervention in the treatment of anorexia and cachexia induced by various diseases.

Analysis of Variance↗
PubMed2001

Insulin regulation of gene expression through the forkhead transcription factor Foxo1 (Fkhr) requires kinases distinct from Akt.

Insulin inhibits expression of certain liver genes through the phosphoinositol (PI) 3-kinase/Akt pathway. However, whether Akt activity is both necessary and sufficient to mediate these effects remains controversial. The forkhead proteins (Foxo1, Foxo3, and Foxo4, previously known as Fkhr or Afx) are transcriptional enhancers, the activity of which is inhibited by insulin through phosphorylation-dependent translocation and nuclear exclusion. Others and we have previously shown that the forkhead protein Foxo1 is phosphorylated at three different sites: S(253), T(24), and S(316). We have also shown that T(24) fails to be phosphorylated in hepatocytes lacking insulin receptors, and we have suggested that this residue is targeted by a kinase distinct from Akt. In this study, we have further analyzed the ability of Akt to phosphorylate different Foxo1 sites in control and insulin receptor-deficient hepatocytes. Expression of a dominant negative Akt (Akt-AA) in control hepatocytes led to complete inhibition of endogenous Akt, but failed to inhibit Foxo1 T(24) phosphorylation and, consequently, insulin suppression of IGFBP-1 promoter activity. Conversely, expression of a constitutively active Akt (Akt-Myr) in insulin receptor-deficient hepatocytes led to an overall increase in the level of Foxo1 phosphorylation, but failed to induce T(24) and S(316) phosphorylation. These data indicate that the Foxo1 T(24) and S(316) kinases are distinct from Akt, and suggest that the pathways required for insulin regulation of hepatic gene expression diverge downstream of PI 3-kinase.

Animals↗
PubMed2001

Shc mediates ligand-induced internalization of epidermal growth factor receptors.

In order to clarify the physiological relevance of the interaction between Shc and adaptins, components of plasma membrane-coated pit adaptor complex AP2, we investigated the role of Shc in ligand-induced endocytosis of epidermal growth factor (EGF) receptors. In vitro peptide binding assay showed that alpha-adaptin bound to the wild-type peptide corresponding to amino acids 346-355 of Shc, RDLFDMKPFE, but not to the mutant peptide in which both phenylalanines at 349 and 354 were substituted for alanines (FA). Using adenovirus vectors carrying a herpes simplex virus epitope-tagged 52-kDa wild-type Shc and Shc FA, we examined the interaction between Shc, AP2, and EGF receptors in intact cells. Alpha-adaptin bound to wild-type Shc in an EGF-dependent manner, whereas EGF-dependent association of alpha-adaptin with Shc FA was markedly reduced. In addition, EGF increased the amount of alpha-adaptin coprecipitated with EGF receptors in cells expressing wild-type Shc but not Shc FA. These results suggest that EGF stimulates Shc-AP2 complex formation and association of Shc-AP2 complexes with EGF receptors. Internalization assay showed that (125)I-EGF internalization was reduced in cells overexpressing Shc FA. Immunofluorescence study showed that punctate staining along the plasma membrane border as well as punctate pattern characteristic of cytoplasmic vesicles near the plasma membrane was enhanced in cells expressing wild-type Shc. These results suggest, therefore, the implication of Shc in ligand-induced endocytosis of EGF receptors in intact cells.

Adaptor Protein Complex 2↗
PubMed2001

Inhibition of cell growth and spreading by stomach cancer-associated protein-tyrosine phosphatase-1 (SAP-1) through dephosphorylation of p130cas.

SAP-1 (stomach cancer-associated protein-tyrosine phosphatase-1) is a transmembrane-type protein-tyrosine phosphatase that is abundant in the brain and certain cancer cell lines. With the use of a "substrate-trapping" approach, p130(cas), a major focal adhesion-associated phosphotyrosyl protein, has now been identified as a likely physiological substrate of SAP-1. Expression of recombinant SAP-1 induced the dephosphorylation of p130(cas) as well as that of two other components of the integrin-signaling pathway (focal adhesion kinase and p62(dok)) in intact cells. In contrast, expression of a substrate-trapping mutant of SAP-1 induced the hyperphosphorylation of these proteins, indicating a dominant negative effect of this mutant. Overexpression of SAP-1 induced disruption of the actin-based cytoskeleton as well as inhibited various cellular responses promoted by integrin-mediated cell adhesion, including cell spreading on fibronectin, growth factor-induced activation of extracellular signal-regulated kinase 2, and colony formation. Finally, the enzymatic activity of SAP-1, measured with an immunocomplex phosphatase assay, was substantially increased by cell-cell adhesion. These results suggest that SAP-1, by mediating the dephosphorylation of focal adhesion-associated substrates, negatively regulates integrin-promoted signaling processes and, thus, may contribute to contact inhibition of cell growth and motility.

Animals↗
PubMed2001

Inhibition of insulin-induced activation of Akt by a kinase-deficient mutant of the epsilon isozyme of protein kinase C.

Akt, also known as protein kinase B, is a protein-serine/threonine kinase that is activated by growth factors in a phosphoinositide (PI) 3-kinase-dependent manner. Although Akt mediates a variety of biological activities, the mechanisms by which its activity is regulated remain unclear. The potential role of the epsilon isozyme of protein kinase C (PKC) in the activation of Akt induced by insulin has now been examined. Expression of a kinase-deficient mutant of PKCepsilon (epsilonKD), but not that of wild-type PKCepsilon or of kinase-deficient mutants of PKCalpha or PKClambda, with the use of adenovirus-mediated gene transfer inhibited the phosphorylation and activation of Akt induced by insulin in Chinese hamster ovary cells or L6 myotubes. Whereas the epsilonKD mutant did not affect insulin stimulation of PI 3-kinase activity, the phosphorylation and activation of Akt induced by a constitutively active mutant of PI 3-kinase were inhibited by epsilonKD, suggesting that epsilonKD affects insulin signaling downstream of PI 3-kinase. PDK1 (3'-phosphoinositide-dependent kinase 1) is thought to participate in Akt activation. Overexpression of PDK1 with the use of an adenovirus vector induced the phosphorylation and activation of Akt; epsilonKD inhibited, whereas wild-type PKCepsilon had no effect on, these actions of PDK1. These results suggest that epsilonKD inhibits the insulin-induced phosphorylation and activation of Akt by interfering with the ability of PDK1 to phosphorylate Akt.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2001

A polymorphism in the 5' untranslated region and a Met229-->Leu variant in exon 5 of the human UCP1 gene are associated with susceptibility to type II diabetes mellitus.

AIMS/HYPOTHESIS: The cumulative effects of several thrifty factors could contribute to the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus. We screened the human UCP1 gene (UCP1) for polymorphisms associated with susceptibility to Type II diabetes. METHODS: By using PCR and single-strand conformation polymorphism analysis, UCP1 were screened for mutations in 25 Type II diabetic subjects and 25 healthy control subjects. The allele frequencies of the detected polymorphisms were determined by PCR and restriction fragment length polymorphism analysis in 320 diabetic subjects and 250 control subjects. RESULTS: An A-->C transition in the 5' untranslated region (UTR) of exon 1 (112 bp upstream of the translation initiation codon) and a Met229-->Leu variant were detected. The allele frequencies for the C variant and for the Leu229 variant were higher in the Type II diabetic group than in the control group (p = 0.017 and p = 0.038, respectively). These polymorphisms were in linkage disequilibrium (p < 0.00001). Luciferase assay showed that the former variant in the 5' UTR may affect the promoter activity of UCP1. CONCLUSION/INTERPRETATION: Both the A-->C polymorphism and the Met229-->Leu polymorphism of UCP1 are in linkage disequilibrium and could be one of the diabetes associated single nucleotide polymorphisms (SNPs).

5' Untranslated Regions↗