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Biomedical subjects

H Nawata

Publications and source records attributed to H Nawata.

At least 109 records · Page 6Linked to original sources
PubMed2000

Platelet-derived growth factor receptor tyrosine kinase inhibitor AG1295 attenuates rat hepatic stellate cell growth.

Enhanced activity of receptor tyrosine kinases such as the platelet-derived growth factor-receptorbeta (PDGF-Rbeta) has been implicated as a contributing factor in the development of hepatic fibrosis. In this study we have used tyrosine kinase inhibitors of the tyrphostin class (AG1295) to specifically block autophosphorylation of PDGF-Rbeta and proliferation of rat hepatic stellate cells. We also examined the effect of AG1295 on the PDGF-BB-induced activation of the 44 kd and 42 kd mitogen-activated protein (MAP) kinase isoforms (p44mapk/p42mapk). Rat hepatic stellate cells were treated with AG1295 (10 micromol/L) for 24 hours and stimulated with PDGF-BB for 5 minutes. AG1295 specifically inhibited autophosphorylation of PDGF-Rbeta and caused a 20% decrease in PDGF-BB-stimulated bromodeoxyuridine incorporation by rat hepatic stellate cells. Treatment of rat hepatic stellate cells with AG1295 resulted in an inhibition of the PDGF-BB-induced activation of MAP kinase isoforms. Quantification of the immunoprecipitated tyrosine-phosphorylated phosphatidylinositol 3-kinase, phospholipase C-gamma, and p21ras guanosine triphosphatase-activating protein by Western blotting revealed that AG1295 treatment effectively inhibits tyrosine phosphorylation of these kinases in hepatic stellate cells. Our findings demonstrate that AG1295 is a selective inhibitor of the tyrosine phosphorylation of PDGF-Rbeta and its downstream signaling pathway, and this compound could offer a strategy for the treatment of fibrotic liver diseases.

Animals↗
PubMed2000

A defect in a single allele of the Mlh1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice.

Mice with mutations in both alleles of the Mgmt and the Mlh1 gene, the former encoding a DNA repair methyltransferase and the latter a protein functioning at an early step of mismatch repair, are as resistant to the killing action of alkylating agents as are wild-type mice. These mice yielded a large number of tumors when exposed to alkylating carcinogens, but this characteristic was subdued since they also showed a relatively high level of spontaneous tumorigenicity, as a consequence of the defect in mismatch repair. This complexity is now resolved by introducing the Mlh1(+/-) mutation, instead of Mlh1(-/-), in these methyltransferase-deficient mice. Mgmt(-/-) Mlh1(+/-) mice, with about half the amount of MLH1 protein as Mgmt(-/-) Mlh1(+/+) mice, were resistant to the killing action of N-methyl-N-nitrosourea (MNU), up to the level of 30 mg/kg body wt. Eight weeks after exposure to this dose of MNU, 40% of MNU-treated Mgmt(-/-) Mlh1(+/-) mice had thymic lymphomas and there were no tumors in those mice not given the treatment. It seems that the cellular content of MLH1 protein is a critical factor for determining if damaged cells enter into either one of the two pathways leading to mutation induction or to apototic cell death. Loss of Mlh1 expression was frequently observed in tumors of Mgmt(-/-) Mlh1(+/-) mice and this might be related to progression of the tumors.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Transcriptional regulation of the human FTZ-F1 gene encoding Ad4BP/SF-1.

Ad4BP, also known as SF-1, is a steroidogenic tissue-specific transcription factor that is also essential for adrenal and gonadal development. Two mechanisms for the transcriptional regulation of the mammalian FTZ-F1 gene encoding Ad4BP in adrenocortical cells have been proposed in the previous studies: the crucial role of a cis-element, an E box for the steroidogenic cell-specific expression of mouse and rat FTZ-F1 genes, and a possible autoregulatory mechanism of the rFTZ-F1 gene by Ad4BP itself through binding to the Ad4 (or SF-1) site in the first intron. In the present study, the transcriptional regulation of the human FTZ-F1 gene in adrenocortical cells was investigated from several angles, including the above two mechanisms. Using a series of deletion analyses of the 5'-flanking region of the hFTZ-F1 gene and site-directed mutagenesis for transient transfection studies, an E box element, CACGTG at -87/-82 from the transcriptional start site, was also found to be essential for the transcription of the hFTZ-F1 gene in mouse or human adrenocortical cell lines as well as in non-steroidogenic CV-1 cells. Despite the presence of a corresponding Ad4 site, CCAAGGCC at +163/+156 in the first intron of the hFTZ-F1 gene, an autoregulatory mechanism through the Ad4 site was found to be unlikely in the hFTZ-F1 gene mainly due to site-directed mutagenesis. In addition, the forced expression of Ad4BP had little effect on hFTZ-F1 gene transcription in non-steroidogenic CV-1 cells. Such Ad4BP-independent regulation of the hFTZ-F1 gene was in striking contrast to the regulation of steroidogenic CYP genes, such as the human CYP11A gene, in which the proximal promoter activity is Ad4BP-dependent and the transactivation by Ad4BP is silenced by DAX-1. Even though the Ad4BP-dependent transcriptional regulation of the DAX-1 gene has been reported, DAX-1 did not affect the transcriptional activity of the hFTZ-F1 gene in our study. Taken together, these observations suggest that the E box is indeed required for the expression of the FTZ-F1 gene, at least in mammalian species, but may not determine the tissue-specific expression of the hFTZ-F1 gene, and that, unlike the steroidogenic CYP gene, the regulation of the hFTZ-F1 gene appears to be independent of both Ad4BP and DAX-1.

Adrenal Cortex↗
PubMed2000

The beneficial effect of mesalazine on esophageal ulcers in intestinal Behcet's disease.

Intestinal Behcet's disease in a 19-year-old girl was diagnosed because of the history of recurrent oral aphthous ulcers and typical endoscopic findings of esophageal and ileal ulcers. Her symptoms (e.g., dysphagia and retrosternal pain) were gradually relieved by treatment with prednisolone and total parenteral nutrition. However, about one month later, oral and esophageal ulcers appeared again. Mesalazine was added. Oral and esophageal ulcers healed promptly, and have not relapsed for about one year. Although mesalazine appears to act locally in the small intestine and colon, the therapeutic effect of mesalazine in this case may be explained by the systemic antiinflammatory effect. This case suggests that mesalazine is an effective drug and is a good candidate in the treatment of intestinal Behcet's disease, especially accompanied with esophageal involvement.

Adult↗
PubMed2000

Transforming growth factor-alpha induces the differentiation of sarcomatoid cholangiocarcinoma cells.

A sarcomatoid cholangiocarcinoma cell line, ETK-1, was established from a patient. Phenotypically, the cells corresponded to immature biliary epithelial cells. Because a small number of ETK-1 cells appeared to differentiate spontaneously along a biliary epithelial lineage in continuous culture, we examined the factors that initiate and/or promote the differentiation of the cells. Transforming growth factor-alpha (TGFalpha) induced significant changes in ETK-1 cells. After stimulation with the factor, ETK-1 cells displayed morphologic transformation at a much higher frequency, with the appearance of many large cells with intracytoplasmic vacuoles, and the production of mucinous substances. These morphologically transformed cells were phenotypically similar to well-differentiated adenocarcinoma cells. The expression pattern of integrins after TGFalpha treatment also supported the maturation of the ETK-1 cells. The antibody against the receptor of TGFalpha inhibited these changes by TGFalpha. Moreover, the proliferation rate of ETK-1 cells was suppressed by TGFalpha. Our data suggest that TGFalpha can act as a differentiation factor along a biliary epithelial lineage.

Bile Duct Neoplasms↗
PubMed2000

Effect of acid-suppressive therapy on Helicobacter pylori production of interleukin-8 in the gastric mucosa.

BACKGROUND: Recent studies have shown that acid-suppressive therapy increases the severity of Helicobacter pylori- associated gastritis in the corpus. PURPOSE: To evaluate interleukin (IL)-8 production in the gastric corpus mucosa before and during acid-suppressive therapy in H pylori-infected patients. PATIENTS AND METHODS: Ten patients with reflux esophagitis (five H pylori-positive and five H pylori-negative) were treated with omeprazole 20 mg. Serum gastrin concentrations, H pylori colonization density and mucosal IL-8 levels in the corpus were investigated at entry and two weeks after starting therapy. IL-8 levels were measured by ELISA. The organism density was determined, and scored according to area occupied by the bacterial colonies. The presence of H pylori was assessed by rapid urease testing and histological finding of gastric biopsy specimens. RESULTS: In H pylori-positive patients, concentrations of IL-8 during therapy significantly exceeded those before therapy (36.2+/-6. 8 versus 18.3+/-3.8 pg/mg protein; P<0.05) without altering H pylori density. In H pylori-negative patients, IL-8 levels were similar before and during therapy (6.1+/-2.7 versus 6.3+/-3.0 pg/mg protein). Concentrations of gastrin during therapy were significantly higher than those before therapy in all patients. CONCLUSIONS: The results suggest that acid suppression increases mucosal IL-8 levels in H pylori-infected patients with reflux esophagitis.

Adult↗
PubMed2000

Chronic sulfonylurea treatment and hyperglycemia aggravate disproportionately elevated plasma proinsulin levels in patients with type 2 diabetes.

It is established that disproportionately elevated plasma proinsulin levels occur in patients with Type 2 diabetes. In the present study, multivariate analysis was performed to determine what factors contributed to the disproportionately elevated plasma proinsulin levels in Japanese patients with Type 2 diabetes (n=276). Results from univariate analysis showed that both fasting proinsulin/C-peptide ratio and proinsulin/IRI ratio were approximately 2-fold higher in patients with Type 2 diabetes than those in healthy nondiabetic subjects (n=45). In patients with Type 2 diabetes, both proinsulin/C-peptide ratio and proinsulin/IRI ratio were significantly positively correlated with fasting plasma glucose level (FPG) and HbA1c. Neither proinsulin/C-peptide ratio nor proinsulin/IRI ratio was significantly correlated with BMI. Sulfonylurea-treated subjects had a significant elevation in both proinsulin/C-peptide ratio and proinsulin/IRI ratio compared with diet-treated subjects, whereas nonsulfonylurea hypoglycemic agent-treated subjects did not. Multivariate analysis confirmed that sulfonylurea treatment and FPG were significant determinants of both fasting proinsulin/C-peptide ratio (P=0.006 and P=0.030, respectively) and proinsulin/IRI ratio (P=0.003 and P=0.016, respectively) in patients with Type 2 diabetes. These results imply that disproportionate hyperproinsulinemia may reflect an excessive overwork of beta cells under chronic sulfonylurea treatment as well as hyperglycemia.

Body Mass Index↗
PubMed2000

Z-338, a newly synthetized carboxyamide derivative, stimulates gastric motility through enhancing the excitatory neurotransmission.

We studied the effects of Z-338, a newly synthesized carboxyamide derivative, on autonomic neuroeffector transmission in the guinea-pig stomach in relation to its gastrointestinal prokinetic action, by use of tension recording and microelectrode methods. Z-338 (>10(-8) M) dose-dependently enhanced the amplitude of twitch-like contractions and excitatory junction potentials (EJPs) evoked by single or repetitive electrical field stimulation (EFS) without affecting the non-adrenergic non-cholinergic (NANC) relaxation and inhibitory junction potentials (IJPs) in the circular muscle strips of the guinea-pig stomach. Similar to the action of Z 338, pirenzepine (> 10(-8) M), a muscarinic M1-antagonist, enhanced the EJP amplitude, although AF-DX116 (M2-) and 4-DAMP (M3-antagonists) reduced the EJP amplitude, dose-dependently. The EC50 of the Z-338 and pirenzepine concentration response curves on EJPs were 4.7 x 10(-8) M and 1.0 x 10(-8) M, and Hill coefficients were 0.96 and 0.94 respectively. In addition, Z-338 slightly but significantly enhanced the amplitude of slow waves with or without initial spike. These results provide the first evidence that Z-338 exerts its gastrointestinal prokinetic action mainly through enhancing excitatory neuro effector transmission with no effect on NANC inhibitory neuro-effector transmission in the guinea-pig stomach.

Animals↗
PubMed2000

Reversibility of serum NH3 level in a case of sudden onset and rapidly progressive case of type 2 citrullinemia.

A 48-year-old male presented with an acute change in mental status due to a marked elevation of plasma NH3 and was diagnosed with citrullinemia with amino acid analysis of blood. Hemodialysis and hemodiafiltration were performed, but serum chemical analysis did not show any improvement which led us to terminate dialysis following intensive care for 3 days. Surprisingly, NH3 level had decreased by 6 days after admission, coinciding with normalization of the size of the pupils. Since spontaneous remission had never been discussed, we discuss this relatively rare, but clinically significant entity with regard to its acute phase management and its potential reversibility.

Ammonia↗
PubMed2000

High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells.

Recent studies have revealed that vascular cells can produce reactive oxygen species (ROS) through NAD(P)H oxidase, which may be involved in vascular injury. However, the pathological role of vascular NAD(P)H oxidase in diabetes or in the insulin-resistant state remains unknown. In this study, we examined the effect of high glucose level and free fatty acid (FFA) (palmitate) on ROS production in cultured aortic smooth muscle cells (SMCs) and endothelial cells (ECs) using electron spin resonance spectroscopy. Exposure of cultured SMCs or ECs to a high glucose level (400 mg/dl) for 72 h significantly increased the free radical production compared with low glucose level exposure (100 mg/dl). Treatment of the cells for 3 h with phorbol myristic acid (PMA), a protein kinase C (PKC) activator, also increased free radical production. This increase was restored to the control value by diphenylene iodonium, a NAD(P)H oxidase inhibitor, suggesting ROS production through PKC-dependent activation of NAD(P)H oxidase. The increase in free radical production by high glucose level exposure was completely restored by both diphenylene iodonium and GF109203X, a PKC-specific inhibitor. Exposure to palmitate (200 micromol/l) also increased free radical production, which was concomitant with increases in diacylglycerol level and PKC activity. Again, this increase was restored to the control value by both diphenylene iodonium and GF109203X. The present results suggest that both high glucose level and palmitate may stimulate ROS production through PKC-dependent activation of NAD(P)H oxidase in both vascular SMCs and ECs. This finding may be involved in the excessive acceleration of atherosclerosis in patients with diabetes and insulin resistance syndrome.

Animals↗
PubMed2000

Clinicopathologic study on hepatocellular carcinoma negative for hepatitis B surface antigen and antibody to hepatitis C virus.

Among 326 consecutively resected cases of hepatocellular carcinoma (HCC), we studied clinicopathologic features of 13 cases (NBNC-HCC) negative for hepatitis B surface antigen (HBsAg), antibody to HBsAg (HBsAb), antibody to hepatitis B core antigen (HBcAb), hepatitis B envelope antigen (HBeAg), antibody to HBeAg (HBeAb), and antibody to hepatitis C virus (HCVAb). Forty-four HCC cases positive only for HBsAg (B-HCC) and 232 cases positive only for HCVAb (C-HCC) were studied as controls. Clinically, NBNC-HCC cases showed good liver function reserve. None of NBNC-HCC cases had periodic medical check ups and HCC was detected in 12 cases (92.3%) incidentally. Pathologically, the mean tumor diameter was significantly larger and the histologic grade was less differentiated in NBNC-HCC cases than in B-HCC and C-HCC cases. In the background liver, liver cirrhosis was associated in 15.4% of NBNC-HCC cases, 50.0% of B-HCC and 38.2% of C-HCC cases. The degree of inflammation and fibrosis was less in NBNC-HCC cases, and two cases (15.4%) had almost normal liver histology. In NBNC-HCC cases, synchronous and metachronous multicentric occurrence was not observed. In B-HCC cases, synchronous multicentric occurrence was found in 1 case (20.0%), but no metachronous multicentric occurrence. In C-HCC cases, synchronous and metachronous multicentric occurrence was found in 13 (43.3%) and 8 (30.8%) cases, respectively. However, the cumulative recurrence-free rate was not significantly different among the three groups. Accordingly, it was suggested that better prognosis could be expected in NBNC-HCC cases compared with B- and C-HCC cases, if the cancer could be detected in the early stage.

Aged↗
PubMed2000

Inhibin-like immunoreactivity produced by the adrenal gland is circulating in vivo.

To clarify the contribution of the inhibin-like immunoreactivity (inhibin-LI) produced by adrenal glands to the total circulating levels of inhibin-LI, we measured serum inhibin-LI in normal and hypogonadal subjects under ACTH-loading or dexamethasone-loading condition. The mean basal concentration of inhibin-LI in the peripheral serum of the hypogonadal cases was 3.6 +/- 1.3 IU/ml (mean +/- SD, n = 5), which corresponded to 19.5 +/- 5.8% of that of normal controls matched for age and sex. The low levels of inhibin-LI in hypogonadal subjects (n = 7) rose significantly (3.6 +/- 1.1 vs 8.1 +/- 1.7 IU/ml, p < 0.001) after the administration of synthetic 1-24ACTH (40 units/day intramuscular injection) for 2 days, while the levels of serum inhibin-LI were not increased in two cases of Addison's disease with hypogonadism after the administration of ACTH. After the oral administration of a low dose of dexamethasone (1 mg) the serum inhibin-LI level in normal subjects (eight males and eight females) decreased significantly (male, 16.2 +/- 3.3 vs 14.5 +/- 4.1 IU/ml; female, 12.9 +/- 6.3 vs 10.8 +/- 5.6 IU/ml; p < 0.01 each) without significant change in the levels of serum gonadotropin (LH and FSH) and those of gonadal steroid (testosterone or estradiol). These results indicate that a small; but significant amount of inhibin-LI is secreted from the adrenal gland and circulating in vivo, and that the proportion of adrenal-derived inhibin-LI is much higher in patients with hypogonadism.

Adrenal Glands↗
PubMed2000

Adult onset cyclic hematopoiesis in a patient with myelodysplastic syndrome.

A 75-year-old woman presenting with myelodysplastic syndrome showed cyclic oscillations in her white blood cell and platelet counts. Each cycle lasted for 5 to 6 months, with 4 cycles occurring over the course of a 2-year period. During successive cycles, the white blood cell count fluctuated from 10.1 to 2.6; 13.8 to 1.8; 11.0 to 1.6, and 8.6 to 1.3 x 10(9)/L. The platelet count fluctuated from 242 to 38, 199 to 11, 110 to 5, and 75 to 3 x 10(9)/L. The patient underwent red blood cell transfusions because of red blood cell aplasia; the frequency of the transfusions and the erythropoietin concentration in serum were inversely correlated. The number of circulating granulocyte-macrophage colony-forming units and CD34-positive cells in peripheral blood oscillated in phase with the white blood cell and platelet counts. These patterns suggested a periodic influx of progenitor cells from hematopoietic stem cells. The ratio of neutrophils to mononuclear cells remained essentially constant throughout the clinical course. Lymphocyte subset assessments using monoclonal antibodies showed an inverse CD4/CD8 ratio (less than 1) and extreme B cell lymphopenia throughout the fourth cycle. The percentage of CD3-positive cells oscillated inversely, suggesting that the cyclic cytopenia had an immune mechanism involving T lymphocytes.

Age of Onset↗
PubMed2000

Cytotoxic T-cell lymphoma diffusely involving the entire gastrointestinal tract associated with Epstein-Barr virus and tubercle bacilli infection.

We describe a rare case of cytotoxic gastrointestinal T-cell lymphoma with protein-losing enteropathy. Initial examination revealed the coexistence of T-cell lymphoma and tuberculosis in the mesenteric lymph node and liver. Despite anti-tuberculosis and anti-cancer treatment, the patient experienced chronic diarrhea and malabsorption and died approximately 3 years after onset. Autopsy specimens revealed medium-sized lymphoma cells, with a phenotype of CD3+, CD4-, CD7+, CD8+, CD30-, CD56-, CD103 (HML-1)-, TIA-1+, and granzyme B+, proliferating primarily and consistently in the mucosa of the entire bowel tract from esophagus to rectum. Interestingly, Epstein-Barr virus (EBV)-encoded small nuclear RNAs were detected in the tumors by in situ hybridization. Southern blot analysis revealed monoclonal proliferation in the EBV-infected T cells. Although the present case can possibly be categorized as an intestinal T-cell lymphoma according to the Revised European-American Lymphoma Classification, the case showed a unique clinical course and distribution of lymphoma cells. We present here an interesting case of gastrointestinal cytotoxic T-cell lymphoma and examine the possible association with infectious agents.

Digestive System↗
PubMed2000

[Nonmyeloablative stem cell transplantation with low-dose total body irradiation (200 cGy) for a 55-year-old woman with acute lymphoblastic leukemia].

We describe a 55-year-old woman with acute lymphoblastic leukemia (ALL) in the first remission who underwent nonmyeloablative stem cell transplantation with conditioning consisting of low-dose total body irradiation and postgrafting cyclosporine and mycophenolate mofetil. Myelosuppression was mild, but on day 28 her bone marrow showed 8.8% lymphoblasts. We withdrew the cyclosporine, but the patient developed grade 2 acute GVHD and eosinophilia. The proportion of bone marrow lymphoblasts decreased transiently to 1.0% on day 40, but later increased again and the patient died on day 85. Application of this approach to patients with ALL needs to be examined on a large scale.

Cyclosporine↗