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Biomedical subjects

M Kasuga

Publications and source records attributed to M Kasuga.

At least 91 records · Page 5Linked to original sources
PubMed1999

CYP2C19 genotype-related efficacy of omeprazole for the treatment of infection caused by Helicobacter pylori.

OBJECTIVES: Omeprazole is used for the treatment of infection caused by Helicobacter pylori, and it is metabolized by the polymorphic cytochrome P4502C19 (CYP2C19). We have found that the anti-H pylori efficacy by the combination of omeprazole and antibiotics is related to the CYP2C19 genotype. METHODS: One hundred eight patients with cultured H pylori-positive gastritis or peptic ulcer were treated with three regimens: quadruple treatment without proton pump inhibitors (n = 25), dual treatment with omeprazole and amoxicillin (INN, amoxicilline) (n = 26), and triple treatment with omeprazole, amoxicillin, and clarithromycin (n = 57). The CYP2C19 genotype was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and the assessment of the eradication of H pylori was based on all negative examinations, including culture, histology, and 13C-urea breath test. RESULTS: The eradication rates for the extensive metabolizers were 50% and 86% for the dual and triple treatments, respectively. In contrast, all of the poor metabolizers treated with omeprazole and antibiotics (n = 15) showed an eradication of H pylori. CONCLUSION: The anti-H pylori effect of dual treatment is highly efficient for CYP2C19 poor metabolizers, which suggests that clarithromycin is not necessary as a first line of therapy for this type of patients. Genotyping can provide a choice for the optimal regimen based on individual CYP2C19 genotype.

Amoxicillin↗
PubMed1999

Decreased food intake and body weight in pancreatic polypeptide-overexpressing mice.

BACKGROUND & AIMS: Pancreatic polypeptide (PP) is a 36-amino acid hormone produced by F cells within the pancreatic islets and the exocrine pancreas. The definitive function of PP in mammalian physiology remains to be determined. This study examined the effects of chronic overexpression of PP through the development of PP transgenic mice. METHODS: PP transgenic mice were created by using mouse PP complementary DNA under the control of the cytomegalovirus immediate early enhancer-chicken beta-actin hybrid promoter (pCAGGS expression vector). RESULTS: A unique line of transgenic mice was created that overexpresses PP in the pancreatic islets with low levels of expression in other tissues including the brain. Plasma PP concentrations were more than 20 times higher than those of control littermates. However, PP overproduction led to postnatal lethality in half of the pups because of markedly decreased milk intake. The remaining PP transgenic mice gained less weight with specifically reduced food intake and fat mass compared with controls, a result that was more evident in male than in female mice. The transgenic mice exhibited a reduced rate of gastric emptying of a solid meal but had normal oxygen consumption and fasting leptin levels. Immunoneutralization with anti-PP antiserum reversed the phenotypic changes of transgenic animals. CONCLUSIONS: PP could be involved in feeding and body weight regulation partly through regulation of gastric emptying.

Animals↗
PubMed1999

Expression of heregulin alpha, erbB2, and erbB3 and their influences on proliferation of gastric epithelial cells.

BACKGROUND & AIMS: Heregulins (HRGs) regulate the proliferation and differentiation of various cell types. However, very little is known about their function in the gastrointestinal tract. The aim of this study was to investigate the role of HRGs on gastrointestinal cells. METHODS: We examined the expression of erbB receptors and HRG-alpha in human gastric cancer cell lines, rat gastrointestinal epithelial cells, and human gastric fibroblasts by Western blot analysis or reverse-transcription polymerase chain reaction. Receptor phosphorylation and heterodimerization induced by HRG-alpha were detected by Western blot analysis. We also evaluated the in vitro effects of HRG-alpha on cell proliferation and restitution. RESULTS: Cancer cell lines and rat epithelial cells expressed erbB2 and erbB3, but protein expression of erbB4 was not detected. HRG-alpha was detected only in gastric fibroblasts. HRG-alpha activated tyrosine phosphorylation of epidermal growth factor receptor (EGFR), erbB2, and erbB3 and induced not only erbB3/erbB2 but also erbB3/EGFR and erbB2/EGFR heterodimer formation in MKN-28 cancer cells. Simultaneous cultivation of MKN-28 cells with gastric fibroblasts resulted in tyrosine phosphorylation of erbB3 in MKN-28 cells. HRG-alpha also stimulated proliferation of MKN-28 cells and gastric epithelial cells. CONCLUSIONS: The data suggest that HRG-alpha may affect epithelial cell proliferation through mesenchymal-epithelial interaction in the gastric mucosa.

Animals↗
PubMed1999

Urocortin reduces food intake and gastric emptying in lean and ob/ob obese mice.

BACKGROUND & AIMS: Gastric emptying plays an important role in regulating food intake. This study was designed to investigate whether intraperitoneally injected urocortin reduces gastric emptying, feeding, and body weight in lean and ob/ob obese mice. METHODS: Food intake and body weight were measured after intraperitoneal injections of one of the following: urocortin, deamidated form of urocortin (urocortin OH), corticotropin-releasing factor (CRF), CRF6-33, cholecystokinin octapeptide (CCK-8), and leptin in 16-hour food-deprived animals. Gastric emptying was assessed 2, 4, or 8 hours after intraperitoneal injection. Repeated injections of urocortin were continued for 5 days in ob/ob mice. RESULTS: Urocortin (0.003-3 nmol) dose-dependently and potently decreased food intake and body weight gain in lean mice. The ranking order of potency was urocortin > urocortin OH >/= CRF > CCK-8 > CRF6-33 > leptin. Gastric emptying was also potently reduced by urocortin with a similar ranking order of potency of urocortin > CRF > urocortin OH > CCK-8. Simultaneous administration of urocortin and CRF receptor antagonist, alpha-helical CRF9-41, blocked the effects of urocortin. Urocortin reduced food intake and body weight gain, as well as the rate of gastric emptying, in ob/ob mice, which was significantly faster than that of lean mice. Five daily injections of urocortin significantly lowered body weight and improved glycemic control in ob/ob mice. CONCLUSIONS: The urocortin-induced decrease in food intake and body weight in lean and ob/ob mice is closely related to gastric emptying and opens new possibilities for the treatment of obesity.

Animals↗
PubMed1999

Mouse pancreatic polypeptide modulates food intake, while not influencing anxiety in mice.

This study was designed to investigate the effects of synthetic mouse pancreatic polypeptide (mPP) on feeding and anxiety in mice. The intracerebroventricular (i.c.v.) injection of mPP (0.003-3 nmol) dose-dependently increased food intake. A significant increase was observed 20 min after i.c.v. injection and continued for 4 h. The intraperitoneal (i.p.) injection of mPP (0.03-30 nmol) dose-dependently decreased food intake. A significant decrease was observed 20 min after i.p. injection and continued for 4 h. In the elevated plus maze test, the i.c.v. injection of mPP (0.003-3 nmol) did not affect anxiety behavior. These results suggest that mPP modulates food intake and the Y4 receptor in the brain may contribute to the regulation of feeding, whereas appearing not to influence anxiety in mice.

Animals↗
PubMed1999

Improvement of molar ratio of branched-chain amino acids to tyrosine (BTR) associated with liver fibrosis in chronic hepatitis C patients treated with interferon-alpha.

The molar ratio of branched-chain amino acids (BCAA) to tyrosine (BTR), which has recently been possible to easily determine by an enzymatic method, can be clinically used as a substitute for that of BCAA to aromatic amino acids (AAA). We used this method to investigate the diagnostic implications of serum BTR in patients with chronic hepatitis C treated with interferon-alpha. There was a good correlation between BTR and staging (fibrosis) scores both before and after treatment. BTR increased significantly at 24 months after treatment in the responder group (P < 0.01). Moreover, a significant increase in BTR was observed in patients with improved staging (P = 0.015), but not grading (necroinflammatory), scores. BTR in chronic hepatitis C patients seems to be reflected by the extent of liver fibrosis, and, in the responder group, it can be improved, together with liver fibrosis, by interferon-alpha treatment.

Adult↗
PubMed1999

Improving plant drought, salt, and freezing tolerance by gene transfer of a single stress-inducible transcription factor.

Plant productivity is greatly affected by environmental stresses such as drought, salt loading, and freezing. We reported previously that a cis-acting promoter element, the dehydration response element (DRE), plays an important role in regulating gene expression in response to these stresses. The transcription factor DREB1A specifically interacts with the DRE and induces expression of stress tolerance genes. We show here that overexpression of the cDNA encoding DREB1A in transgenic plants activated the expression of many of these stress tolerance genes under normal growing conditions and resulted in improved tolerance to drought, salt loading, and freezing. However, use of the strong constitutive 35S cauliflower mosaic virus (CaMV) promoter to drive expression of DREB1A also resulted in severe growth retardation under normal growing conditions. In contrast, expression of DREB1A from the stress inducible rd29A promoter gave rise to minimal effects on plant growth while providing an even greater tolerance to stress conditions than did expression of the gene from the CaMV promoter.

Arabidopsis↗
PubMed1999

Intracerebroventricularly administered corticotropin-releasing factor inhibits food intake and produces anxiety-like behaviour at very low doses in mice.

AIM: Previous studies have demonstrated that corticotropin-releasing factor (CRF) produces behavioural, physiological and immunological responses similar to those induced by stress. However, these findings have been validated largely in laboratory rats. METHODS: We examined the effects of intracerebroventricular (i.c.v.) administration of CRF on anxiety and food intake in mice. Using the elevated-plus maze, we measured anxiety levels after i.c.v. CRF in mice. We also measured food intake for 2 h after i.c.v. CRF. RESULTS: CRF increased the normal preference for the closed arms of the maze at a very low dose of 3 pmol, indicating an anxiogenic effect. CRF powerfully suppressed food intake at the doses of 3-300 pmol for over 2 h. CONCLUSION: Our results demonstrate that i.c.v. CRF evokes anxiogenic behaviour and suppresses feeding with the same dose-response relationships in mice. CRF may thus play a role in integrating the overall responses to stress through co-ordinated actions in the brain of this species.

Animals↗
PubMed1999

Gastric ulcer formation after the Hanshin-Awaji earthquake: a case study of Helicobacter pylori infection and stress-induced gastric ulcers.

BACKGROUND: Both Helicobacter pylori (H. pylori) infection and various stresses are known to induce peptic ulcer disease of the upper gastrointestinal tract. However, the pathogenetic relationship between the two factors has not yet been clarified. We conducted a case-control study to examine whether H. pylori infection played a role in the development of gastric ulcer (GU) induced by life-event stresses that were experienced after the Hanshin-Awaji earthquake. MATERIALS AND METHODS: Serum samples from patients in the devastated area who developed GUs during the 2 months following the Hanshin-Awaji earthquake and those from GU patients in the same area during the corresponding period of the previous year, and from gender-, age- and institute-matched ulcer-free controls were tested for the presence of the H. pylori IgG antibody. RESULTS: A significant association between H. pylori infection and the development of GU in uninjured patients was observed in all sets [matched odds ratio (OR) = 3.23, 95% confidence interval: 1.95-5.35]. Moreover, the prevalence of H. pylori infection in patients who developed GUs after the earthquake was not different from that for GU patients in the previous year. In contrast, there was no association between H. pylori infection and the development of GU in the physically injured patients after the earthquake. CONCLUSIONS: H. pylori infection may play an important role in the development of GUs that are induced by emotional life-event stresses.

Antibodies, Bacterial↗
PubMed1999

Interaction of docetaxel ("Taxotere") with human P-glycoprotein.

The interaction of docetaxel ("Taxotere") with P-glycoprotein (P-gp) was examined using porcine kidney epithelial LLC-PK1 and LLC-GA5-COL150 cells, overexpressing human P-gp selectively on the apical plasma membrane by transfection of human MDR1 cDNA into the LLC-PK1 cells. The basal-to-apical transport of [14C]docetaxel in LLC-GA5-COL150 cells significantly exceeded that in LLC-PK1 cells, but the apical-to-basal transport was decreased in LLC-GA5-COL150 cells. The intracellular accumulation after its basal or apical application to LLC-GA5-COL150 cells was 4- to 20-fold lower than that of LLC-PK1 cells. Multidrug resistance (MDR) modulators, i.e., cyclosporin A and SDZ PSC 833, inhibited the basal-to-apical transport and increased the apical-to-basal transport of [14C]docetaxel in LLC-GA5-COL150 cells, but verapamil affected only apical-to-basal transport. The intracellular accumulation after basal or apical application to LLC-GA5-COL150 cells was also increased by these three MDR modulators. These observations demonstrated that docetaxel is a substrate for human P-gp, suggesting that docetaxel-drug interactions occur via P-gp. The inhibition of [14C]docetaxel transport by the MDR modulators, as well as daunorubicin and vinblastine, was also found in LLC-PK1 cells, which endogenously express P-gp at lower levels, and concentrations showing similar levels of inhibition were lower than those in the case of LLC-GA5-COL150 cells. These observations indicate that it is necessary to consider the pharmacokinetic and pharmacodynamic interactions of docetaxel via P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt.

Cyclic nucleotide phosphodiesterase (PDE) is an important regulator of the cellular concentrations of the second messengers cyclic AMP (cAMP) and cGMP. Insulin activates the 3B isoform of PDE in adipocytes in a phosphoinositide 3-kinase-dependent manner; however, downstream effectors that mediate signaling to PDE3B remain unknown. Insulin-induced phosphorylation and activation of endogenous or recombinant PDE3B in 3T3-L1 adipocytes have now been shown to be inhibited by a dominant-negative mutant of the serine-threonine kinase Akt, suggesting that Akt is necessary for insulin-induced phosphorylation and activation of PDE3B. Serine-273 of mouse PDE3B is located within a motif (RXRXXS) that is preferentially phosphorylated by Akt. A mutant PDE3B in which serine-273 was replaced by alanine was not phosphorylated either in response to insulin in intact cells or by purified Akt in vitro. In contrast, PDE3B mutants in which alanine was substituted for either serine-296 or serine-421, each of which lies within a sequence (RRXS) preferentially phosphorylated by cAMP-dependent protein kinase, were phosphorylated by Akt in vitro or in response to insulin in intact cells. Moreover, the serine-273 mutant of PDE3B was not activated by insulin when expressed in adipocytes. These results suggest that PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

A case of acute pancreatitis complicating Salmonella enteritis.

We report a case of acute pancreatitis complicating Salmonella enteritis. A 43-yr-old woman who was admitted to our department because of Salmonella enteritis developed clinical acute pancreatitis with laboratory and radiographic signs on the fourth hospital day. She was free from symptoms on the eighth hospital day, but her elevated serum amylase and lipase levels persisted for more than 2 m.o. In this case, clinical acute pancreatitis was a complication of bacterial enteritis caused by Salmonella enteritidis, and it was characterized by onset a few days after the onset of enteritis and by sustained elevation of serum pancreatic enzyme levels.

Acute Disease↗
PubMed1999

Hemolytic uremic syndrome associated with immunoglobulin A nephropathy: a case report and review of cases of hemolytic uremic syndrome with glomerular disease.

A 35-year-old man with immunoglobulin A (IgA) nephropathy who developed hemolytic uremic syndrome (HUS) presented with transient elevation of serum creatinine, thrombocytopenia, and hemolytic anemia with fragmented red cells with nephrotic syndrome. Hemolytic anemia and the temporarily deteriorated renal function were improved after hemodialysis and plasma exchange. Histological findings were consistent with HUS and IgA nephropathy. Including this case, we reviewed the cases of HUS accompanied by glomerular diseases reported from 1969 to 1996. Surprisingly, most cases showed nephrotic syndrome at the onset of HUS. Several possible relationships between HUS and nephrotic syndrome are discussed.

Adult↗
PubMed1999

Low phagocytic activity of resident peritoneal macrophages in diabetic mice: relevance to the formation of advanced glycation end products.

Formation of advanced glycation end products (AGEs) is accelerated in diabetic subjects along with hyperglycemia. Although several lines of evidence indicate that AGEs stimulate macrophages to secrete several cytokines and growth factors, little is known about the effect of AGEs on the primary function of macrophages, such as phagocytosis. On the other hand, impairment of the phagocytic function of monocytes/macrophages is suggested to contribute to the low resistance to infection in diabetic subjects. In the present study, we examined the effect of AGEs on the phagocytic function of macrophages. Using flow cytometric analysis of mouse resident peritoneal macrophages, we showed that AGEs suppress phagocytosis of fluorescent microspheres by cultured macrophages. In addition, experiments using streptozotocin-induced diabetic mice demonstrated a significant decrease in the phagocytic activity of resident peritoneal macrophages 12 weeks after induction of diabetes compared with age-matched control mice. The phagocytic activity of peritoneal macrophages correlated inversely with AGE content in the adjacent peritoneal tissue. Furthermore, reduced phagocytic activity of macrophages was associated with a reduction in intracellular ATP content. Because phagocytosis is an important component of the defense system, suppression of such activity by AGEs may explain, at least in part, the increased susceptibility of diabetic patients to infection.

Adenosine Triphosphate↗
PubMed1999

[Molecular biology and clinical diabetology].

Recent advancement of molecular biology highlighted three areas of basic research which may be important for clinical diabetology. One is the understanding of mechanisms of differentiation in pancreatic beta-cells and adipocytes. The second is the development of methods of tissue-specific knock-out mouse. This approach revealed that muscle may not be important for insulin-dependent glucose disposal in vivo. The third is the advancement of genetics which enabled to clone a major susceptibililly gene for type 2 diabetes mellitus (NIDDM1). These progress may bring new therapies for clinical diabetology.

Animals↗
PubMed1999

HLA-DQB1 locus and the development of atrophic gastritis with Helicobacter pylori infection.

Helicobacter pylori is known to be involved in digestive diseases such as peptic ulcer, atrophic gastritis, and gastric cancer. It is supposed that the incidence of these digestive diseases associated with H. pylori is influenced by the strain diversity of H. pylori, factors involving the host or environment, and the duration of infection. In this study, we directed our attention to HLA, a host factor, and investigated the relation between HLA-DQB1 genotype of H. pylori-infected patients and the development of atrophic gastritis. HLA-DQB1 genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method on 122 H. pylori-infected patients with atrophic gastritis and 28 uninfected Japanese controls. Infected patients with developed atrophic gastritis were classified as the open type and those with undeveloped atrophic gastritis as the closed type. To estimate the grade of atrophic gastritis reliably, histological and serological evaluations were also undertaken. The allele frequency of DQB1*0401 was significantly higher in the open-type group compared to either the closed-type or the uninfected group. These results suggest that immunogenic factors play an important role in the development of atrophic gastritis in H. pylori-infected patients, and that DQB1*0401 is a useful marker for determining susceptibility to this disease.

Adolescent↗
PubMed1999

Sufficient effect of 1-week omeprazole and amoxicillin dual treatment for Helicobacter pylori eradication in cytochrome P450 2C19 poor metabolizers.

Omeprazole is widely used for the treatment of Helicobacter pylori infection. It is metabolized by cytochrome P450 2C19 enzyme (CYP2C19) in the liver. Because this enzyme exhibits a genetic polymorphism, patients with low metabolic activity (poor metabolizers) may be exposed to higher concentrations of this drug than are patients who are extensive metabolizers. Eighty-six patients with cultured H. pylori-positive gastritis or peptic ulcers who completed the treatment and assessment of anti-H. pylori therapy were analyzed for CYP2C19 genotyping using a polymerase chain reaction-restriction fragment length polymorphism method [the wild-type or two mutant genes (ml in exon 5 and m2 in exon 4), or both]. Patients were classified into three groups according to the H. pylori eradication regimen: group I (n = 21; omeprazole 40mg/ day and amoxicillin 2000mg/day for 1 week); group II (n = 21; group I regimen plus sucralfate 4000mg/day, for 1 week); group III (n = 44; group I regimen plus clarithromycin 800mg/day, for 1 week). The combination of two mutant alleles (ml/ml, ml/m2, m2/m2-poor metabolizers) was observed in 13 of 86 patients (15%), and all poor metabolizer patients achieved H. pylori eradication regardless of their treatment regimens. In addition, the eradication rates of the poor metabolizers were significantly higher than those of other genotypes who carry homozygous or heterozygous normal allele (extensive metabolizers) in group I or groups I and II combined. CYP2C19 genotyping can provide a new strategy to choose an optimal regimen, and this genotyping is especially useful for Japanese, as the frequency of poor metabolizers is five times greater than that found among Caucasians.

Amoxicillin↗