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S Kawata

Publications and source records attributed to S Kawata.

At least 55 records · Page 3Linked to original sources
PubMed1999

Reduced plasma transforming growth factor-beta1 levels in patients with chronic hepatitis C after interferon-alpha therapy: association with regression of hepatic fibrosis.

BACKGROUND/AIM: Transforming growth factor-beta1 is involved in liver fibrosis. Our aim was to examine the association of plasma transforming growth factor-beta1 levels with the degree of liver fibrosis. METHODS: We analyzed plasma transforming growth factor-beta1 levels in 43 patients with chronic hepatitis C treated with interferon-alpha using a transforming growth factor-beta1 ELISA. The content of transforming growth factor-beta1 in liver tissue obtained by needle biopsy (n=13) was also analyzed. The degree of liver fibrosis was assessed histologically and morphometrically. RESULTS: Plasma transforming growth factor-beta1 levels were significantly correlated with transforming growth factor-beta1 content in liver tissue (r=0.83, p<0.001), indicating that plasma levels correspond with tissue cytokine. Plasma transforming growth factor-beta1 levels in patients (8.1+/-1.1 ng/ml) before interferon-a therapy were significantly higher than in controls (1.9+/-0.3 ng/ml) (p<0.01). Plasma levels were significantly correlated with the degree of fibrosis (p<0.01). Plasma transforming growth factor-beta1 levels were significantly decreased in sustained responders (from 5.2+/-1.0 ng/ml to 2.9+/-0.7 ng/ml), relapsed patients (from 9.8+/-2.0 ng/ml to 3.4+/-0.6 ng/ml), and nonresponders (from 9.3+/-2.1 ng/ml to 3.9+/-0.9 ng/ml) at the end of therapy (p<0.05 for all comparisons). Significant regression of liver fibrosis after therapy was observed in both sustained responders and nonresponders (p<0.05 for both). CONCLUSIONS: These observations suggest that plasma transforming growth factor-beta1 levels appear to be associated with the degree of liver fibrosis.

Aged↗
PubMed1999

Expression of heparin-binding epidermal growth factor-like growth factor in the hepatocytes of fibrotic rat liver during hepatocarcinogenesis.

BACKGROUND: Heparin-binding epidermal growth factor-like growth factor is an hepatotrophic factor expressed in non-parenchymal liver cells but not in hepatocytes in regenerating rat liver after partial hepatectomy. Human hepatocellular carcinoma cells also produce this growth factor. In this study, the expression of the growth factor in the hepatocytes of fibrotic liver during hepatocarcinogenesis was investigated. METHODS: Hepatic fibrosis was induced in rats by oral administration of 0.05% thioacetamide. Hepatocytes were isolated by in situ perfusion methods. Growth factor gene and protein expression were investigated by northern hybridization and immunohistochemistry, respectively. Expression of glutathione s-transferase P, which is expressed when hepatocytes undergo neoplastic transformation, was also investigated. RESULTS: Some hepatocytes in fibrotic liver, but not in normal liver, stained positively by immunohistochemistry for heparin-binding epidermal growth factor-like growth factor. The growth factor and glutathione s-transferase P gene transcript were present in hepatocytes isolated from fibrotic liver, but not in those isolated from normal liver. Immunohistochemical localization of both proteins in fibrotic liver revealed similar patterns. CONCLUSIONS: In essence, hepatocytes in fibrotic rat liver produce heparin-binding epidermal growth factor-like growth factor. Expression of this growth factor may occur as hepatocytes are transformed to a neoplastic phenotype.

Animals↗
PubMed1998

Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Osaka Hepatocellular Carcinoma Prevention Study Group.

BACKGROUND: The effect of interferon therapy on the incidence of hepatocellular carcinoma in chronic hepatitis C is poorly defined. OBJECTIVE: To compare the incidence of hepatocellular carcinoma in interferon-treated patients with chronic hepatitis C to that of historical controls and to examine whether response to therapy is related to incidence of hepatocellular carcinoma in patients with chronic hepatitis C. DESIGN: Retrospective cohort study. SETTING: One university hospital and seven university-affiliated hospitals. PATIENTS: 419 consecutive patients with chronic hepatitis C who started interferon therapy between January 1992 and December 1993 (interferon group) and 144 patients with chronic hepatitis C who had liver biopsy between January 1986 and December 1989 and did not receive interferon (controls). INTERVENTION: Patients in the interferon group received human lymphoblastoid interferon, recombinant interferon-alpha2a, or recombinant interferon-alpha2b for 6 months. MEASUREMENTS: The end point was development of hepatocellular carcinoma on abdominal ultrasonography or computed tomography. Sustained response was defined as persistent normalization of alanine aminotransferase (ALT) levels during interferon therapy and follow-up. Relapse was defined as a normal serum ALT level at the end of treatment with an increase to an abnormal level after cessation of treatment. Nonresponse included all other ALT patterns. RESULTS: Median follow-up in the interferon and control groups was 47.6 and 46.8 months, respectively. During follow-up, hepatocellular carcinoma was found in 28 interferon-treated patients and 19 controls. Cox proportional hazards regression analysis that included all patients revealed that interferon therapy (P=0.041), older age (P=0.003), greater histologic activity (P=0.029), and higher histologic stage (P=0.049) were independent factors associated with the development of hepatocellular carcinoma. The risk ratios for development of hepatocellular carcinoma in patients with sustained response, relapse, and nonresponse were 0.06 (95% CI, 0.01 to 0.46), 0.51 (CI, 0.20 to 1.27), and 0.95 (CI, 0.48 to 1.84), respectively, compared with controls. CONCLUSIONS: The incidence of hepatocellular carcinoma was lower in patients with sustained response to interferon therapy than historical controls and nonresponders. Interferon therapy may decrease the risk for hepatocellular carcinoma in patients with chronic hepatitis C.

Alanine Transaminase↗
PubMed1998

Transforming growth factor-beta1-induced degradation of activated Src tyrosine kinase in rat fibroblasts.

Transforming growth factors-beta (TGF-betas) play pivotal roles in the regulation of cell growth and differentiation, although little is known regarding the regulation of cytoplasmic components by TGF-betas. Src tyrosine kinase is required for signal transduction of various cytokine receptors, including epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and G-protein coupled receptors. Moreover, Src tyrosine kinase is important in signal cross-talk between these receptors. To determine whether Src kinase is also involved in TGF-beta signaling, we examined the effects of TGF-beta1 on Src in the rat fibroblast cell line 3Y1 and in v-Src-transformed 3Y0 (SR-3Y1). TGF-beta1 inhibited mitogen-activated protein kinase activity and inhibited growth in SR-3Y1 cells, while it did not affect the growth of 3Y1 cells. TGF-beta1 significantly decreased v-Src kinase activity and protein abundance in SR-3Y1 cells, mainly by accelerating the degradation of v-Src. In contrast, in 3Y1 cells, TGF-beta1 did not affect c-Src abundance or kinase activity. However, upon activation of c-Src in 3Y1 cells by PDGF, TGF-beta1 decreased Src abundance. Additionally, in 3Y1 cells transfected with an activated c-Src mutant which lacks the SH3 domain, its level was decreased by TGF-beta1 treatment. These findings suggest that TGF-beta1 specifically induces degradation of activated Src kinase. This may be a novel mechanism for cross-talk between growth factors and TGF-beta1.

Animals↗
PubMed1998

Plasma heparin-binding EGF-like growth factor levels in patients after partial hepatectomy as determined with an enzyme-linked immunosorbent assay.

We recently showed that heparin-binding EGF-like growth factor (HB-EGF) has hepatotrophic effects. In this study, we developed an ELISA system with high specificity and sensitivity for human plasma HB-EGF. In 14 patients who underwent partial hepatectomy, plasma HB-EGF levels were measured serially after surgery. In patients who underwent gross hepatectomy (lobectomy and segmentectomy), plasma HB-EGF levels increased, reaching maximal levels approximately 5 to 7 days after surgery. In patients who underwent minor hepatectomy (subsegmentectomy), plasma HB-EGF levels did not increase. Maximal plasma HB-EGF levels were significantly higher in patients who had a percent increased volume of the remaining liver (%ILV) above 20% than those who had a %ILV below 20% (32.4 +/- 19.6 pg/ml vs 7.4 +/- 2.7, P < 0.05). The plasma HB-EGF values did not correlate with WBC counts, C-reactive protein, or alanine aminotransferase. Plasma HB-EGF may be a marker for liver regeneration after hepatectomy in humans.

Aged↗
PubMed1998

Altered regulation of Src tyrosine kinase by transforming growth factor beta1 in a human hepatoma cell line.

Transforming growth factor betas (TGF-betas) are the potent growth inhibitors for various cell types. Certain transformed cells, however, show poor response to TGF-beta-induced growth inhibition, which contributes to their uncontrolled proliferation. Recently, we have reported that TGF-beta1 induces degradation of activated Src tyrosine kinase in rat fibroblasts. To elucidate the alteration in TGF-beta signaling pathway in tumor cells that cannot respond to the cytokine, we compared the effects of TGF-beta1 on Src kinase in two human hepatoma cell lines, TGF-beta1-insensitive Mahlavu cells and TGF-beta1-sensitive HepG2 cells. TGF-beta1 decreased Src kinase activity in HepG2 cells, but increased cellular Src levels and Src kinase activity in Mahlavu cells. Co-incubation of Mahlavu cells with TGF-beta1 and 12-O-tetradecanoyl phorbol 13-acetate (TPA) decreased Src protein levels and Src kinase activity, inducing TGF-beta1 sensitivity. TGF-beta1 induced tyrosine dephosphorylation of Ras guanosine triphosphatase-activating protein (Ras-GAP) and Ras inactivation in HepG2 cells, but induced Ras-GAP phosphorylation and Ras activation in Mahlavu cells. The Src kinase inhibitor abolished the increase of Src kinase activity in TGF-beta1-treated Mahlavu cells, and induced TGF-beta1 sensitivity. These findings suggest that regulation of Src kinase by TGF-beta1 is altered in Mahlavu cells. The altered regulation of Src may contribute to TGF-beta1 insensitivity in this cell line, at least in part through activation of Ras.

Animals↗
PubMed1998

Differential time course of induction of 1alpha,25-dihydroxyvitamin D3-24-hydroxylase mRNA expression in rats by 1alpha,25-dihydroxyvitamin D3 and its analogs.

In order to investigate the in vivo mechanisms of target gene activation by vitamin D3 analogs, we compared the effects of two vitamin D3 analogs, 22-oxa-1alpha,25-(OH)2D3 (OCT) and 2beta (3-hydroxypropoxy) -1alpha,25-(OH)2D3 (ED-71) with that of 1alpha,25-(OH)2D3 on 1alpha,25-(OH)2D3 -24-hydroxylase[24(OH)ase] mRNA expression in the kidney and intestine of normal rats. In these experiments, all three compounds induced 24(OH)ase mRNA, but the time course of induction for each respective treatment was clearly different. OCT caused the most rapid onset of increased 24(OH)ase mRNA expression and its subsequent return to pre-injection levels. In marked contrast, ED-71 was the slowest to increase expression which was prolonged over that observed with the other compounds tested. These differences probably relate to the pharmacokinetic properties of these analogs, which are mainly generated by the affinity of analogs for the vitamin D-binding protein(DBP).

Animals↗
PubMed1998

Low levels of serum acylcarnitine in chronic fatigue syndrome and chronic hepatitis type C, but not seen in other diseases.

Recently, we found a serum acylcarnitine (ACR) deficiency in Japanese patients with chronic fatigue syndrome (CFS). To clarify whether this ACR abnormality is a characteristic of CFS or not, we also studied the levels of serum carnitine in Swedish subjects. Both serum ACR and free carnitine (FCR) levels in normal healthy subjects were quite different between Japanese (n=131) and Swedish people (n=46) (p<0.001). However, it is confirmed that Swedish patients with CFS (n=57) also had serum ACR deficiency (p<0.001). When we studied the levels of serum ACR and FCR in Japanese patients with various kinds of diseases (CFS, hematological malignancies, chronic pancreatitis, hypertension, diabetes mellitus, chronic hepatitis type C, psychiatric diseases), a significant decrease in the levels of serum ACR was only found in patients with CFS and chronic hepatitis type C (p<0.001). Therefore, we concluded that ACR deficiency in serum might be a characteristic abnormality in only certain types of diseases.

Acute Disease↗
PubMed1998

[Hemochromatosis].

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Glucose Intolerance↗
PubMed1997

Role of membrane-anchored heparin-binding epidermal growth factor-like growth factor and CD9 on macrophages.

Heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) is a potent mitogen for smooth-muscle cells (SMCs) belonging to the EGF family. We have previously determined that HB-EGF is expressed in macrophages and SMCs of human atherosclerotic lesions and that its membrane-anchored precursor, proHB-EGF, also has a juxtacrine mitogenic activity which is markedly enhanced by CD9, a surface marker of lymphohaemopoietic cells. Therefore, when both proHB-EGF and CD9 are expressed on macrophages, they may strongly promote the development of atherosclerosis. In the present study we have investigated the changes in proHB-EGF and CD9 in THP-1 cells during differentiation into macrophages and by the addition of oxidized low-density lipoproteins (OxLDL) and assessed juxtacrine growth activity of THP-1 macrophages for human aortic SMCs. HB-EGF and CD9 at both the mRNA and the protein level were up-regulated after differentiation into macrophages, and further expression of HB-EGF was induced by the addition of OxLDL or lysophosphatidylcholine. Juxtacrine induction by formalin-fixed growth was suppressed to control levels by an inhibitor of HB-EGF and was partially decreased by anti-CD9 antibodies. These results suggest that co-expression of proHB-EGF and CD9 on macrophages plays an important role in the development of atherosclerosis by a juxtacrine mechanism.

Antigens, CD↗
PubMed1997

The effect of cilostazol, a cyclic nucleotide phosphodiesterase III inhibitor, on heparin-binding EGF-like growth factor expression in macrophages and vascular smooth muscle cells.

Heparin-binding EGF-like growth factor (HB-EGF) is a mitogen for smooth muscle cells (SMC) and is detected in SMC and macrophages in atherosclerotic plaques, suggesting that HB-EGF may be associated with the pathogenesis of atherosclerosis. The present study indicates that cilostazol, a phosphodiesterase III inhibitor, suppresses the expression of HB-EGF in rat aortic SMC and in U-937 cells, a macrophage-like cell line, stimulated by lipopolysaccharide. Further, cilostazol diminished the induction of HB-EGF mRNA by methylglyoxsal, which is a reactive dicarbonyl metabolite produced as the result of a glycation reaction and which might be associated with macroangiopathy caused by hyperglycemia. Cilostazol suppressed the production of HB-EGF protein in the conditioned medium of SMC. These data suggest that cilostazol might act by suppressing the progression of atherogenesis by means of suppressing the expression of HB-EGF in SMC and macrophages.

Animals↗
PubMed1997

Interferon alpha induces disorder of lipid metabolism by lowering postheparin lipases and cholesteryl ester transfer protein activities in patients with chronic hepatitis C.

The effect of recombinant interferon alpha 2a (rIFN-alpha2a) on serum lipoprotein metabolism was assessed in 39 patients with chronic viral hepatitis C. rIFN-alpha2a was administered intramuscularly at a dose of 9 x 10(6) U/d for 2 weeks and then for 3 times a week over 6 months. The serum cholesterol concentration significantly decreased one week after rIFN-alpha2a administration. Approximately 67% of this decrease was attributed to the reduction of high-density lipoprotein (HDL)-cholesterol; a decrease in HDL2-cholesterol was more evident. By contrast, serum triglyceride levels, largely derived from very-low density lipoprotein (VLDL), significantly increased following rIFN-alpha2a treatment. Lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities in the postheparin plasma were reduced by 75.7% and by 79.4%, respectively, and decreases in plasma cholesteryl ester transfer protein (CETP) activity and its protein mass were also observed. However, prothrombin time was ameliorated by rIFN-alpha2a, suggesting that the decrease in LPL, HTGL, and CETP activities may not be due to a reduction in protein synthesis by the liver. Simple correlation analysis demonstrated that the changes in LPL activity before and after 2 weeks of treatment with rIFN-alpha2a showed a significant negative correlation with changes in serum triglyceride and VLDL-triglyceride and a positive correlation with changes in HDL-cholesterol and HDL2-cholesterol. These results suggest a major contribution of reduced LPL activity with regard to the lipoprotein disorders. In conclusion, rIFN-alpha2a treatment on patients with chronic hepatitis C causes marked changes in serum lipoprotein metabolism associated with decreases in LPL, HTGL, and CETP activities.

Adult↗
PubMed1997

Efficacy of combination therapy of interferon-alpha with ursodeoxycholic acid in chronic hepatitis C: a randomized controlled clinical trial.

The efficacy of interferon-alpha therapy in the treatment of chronic hepatitis C is still limited. A combination therapy of interferon-alpha with ursodeoxycholic acid (UDCA) was tested for its efficacy in the treatment of chronic hepatitis C by a randomized controlled study. Eighty consecutive Japanese patients with chronic hepatitis C were randomly divided into two groups: one group was treated with interferon-alpha (group A, n = 40) and the other with a combination of interferon-alpha and UDCA (group B, n = 40). In both groups, human interferon-alpha (6 million units per day) was intramuscularly injected daily for 2 weeks and then three times a week for 22 weeks: this 24-week period was followed by 24 weeks of observation. In group B, UDCA was also administered, daily at a dose of 600 mg orally, from the beginning of the interferon therapy and administration was continued for 48 weeks. The rates for ALT normalization and clearance of hepatitis C virus (HCV) viremia at the end of the 24-week interferon therapy were similar for groups A and B (58% vs 60% and 55% vs 48%, respectively). At the end of the 24-week follow-up, the sustained normalization rates for ALT levels for the two groups were not different (35% vs 43%), while the rate of clearance was higher in group B (40%) than in group A (23%), but the difference was not significant (P = 0.14). The sustained complete response, i.e., HCV RNA negativity at the end of the follow-up, as well as the maintenance of ALT normalization during the follow-up period, was more frequent in group B (38%) than in group A (18%) although the difference was not significant (P = 0.08). The rate of HCV reactivation after interferon was discontinued was significantly lower in group B (16%) than in group A (59%) (P < 0.01). Although this combination therapy did not lead to a sufficiently sustained complete response, it could serve as adjuvant antiviral therapy when a suitable dosage and administration period are determined.

Administration, Oral↗
PubMed1997

Manumycin and gliotoxin derivative KT7595 block Ras farnesylation and cell growth but do not disturb lamin farnesylation and localization in human tumour cells.

Recently, many inhibitors of farnesyl protein transferase (FPTase) have been identified. Some of them interrupt cell growth in addition to Ras and nuclear lamin processing of Ras-transformed cells. We have tested the effect of the FPTase inhibitors manumycin, an analogue of farnesyl diphosphate, and KT7595, a gliotoxin derivative, on Ras farnesylation, DNA synthesis and the anchorage-dependent and -independent growth of human colon carcinoma (LoVo), hepatoma (Mahlavu and PLC/PRF/5) and gastric carcinoma (KATO III). Both drugs severely inhibited DNA synthesis, cellular proliferation and Ras farnesylation in LoVo and moderately reduced them in Mahlavu and PLC/PRF/5 but not in KATO III. Complete sequencing of ras genes, however, revealed that LoVo and KATO III have activated Ki-ras and activated N-ras, respectively, whereas Mahlavu and PLC/PRF/5 have no activated ras. We next checked whether the inhibition of the cellular proliferation is due to the blocking of nuclear lamin function. Neither drug disturbed lamin farnesylation and localization, as demonstrated using metabolic labelling, immunoblotting and indirect immunofluorescence. These results indicate that manumycin and KT7595 can inhibit Ras farnesylation and cell growth without disturbing the farnesylation and localization of the lamins on human tumour cell lines.

Alkyl and Aryl Transferases↗
PubMed1997

Modulation of apolipoprotein gene expression in fatty liver of obese rats: enhanced APOA-IV, but no APOB expression by a high sucrose diet.

OBJECTIVE: Hepatic lipoprotein production is important to the understanding of mechanisms involved in the development of fatty liver and hyperlipidemia. Previously, we have reported that hepatic fatty acid synthesis and apolipoproteinB transcription are increased in obese rats. Here, we describe the effects of a high sucrose diet on hepatic fatty acid synthesis and apolipoprotein gene expression in obese rats. DESIGN: Obese rats with ventromedial hypothalamic lesions were fed on a high sucrose diet (30.3% of cal) or lab chow for 11 weeks. RESULTS: Serum triglycerides and plasma immuno-reactive insulin concentrations were further increased in the obese rats fed a high sucrose diet. The experimental diet increased the activity of hepatic acetyl-CoA carboxylase, the rate limiting enzyme for hepatic fatty acid synthesis, and triglycerides content, concurrent with an increase abundance of apolipoproteinA-IC mRNA in the obese rats. Despite further accumulation of hepatic triglycerides there was no further increase in hepatic apolipoproteinB mRNA abundance in the obese rats fed the high sucrose diet. CONCLUSION: These data suggest that the synthesis of hepatic fatty acids but not of apolipoproteinB is further increased in obese rats fed the high sucrose diet, and that apolipoproteinA-IV gene expression may be modulated in response to alterations in hepatic triglycerides flux.

Acetyl-CoA Carboxylase↗
PubMed1997

Increased circulating transforming growth factor beta1 in a patient with giant hepatic hemangioma: possible contribution to an impaired immune function.

A patient, having a huge hepatic hemangioma, presented with decreases in the number of peripheral lymphocytes and in serum concentrations of gamma-globulin and immunoglobulin (Ig) G, and a negative purified protein derivatives skin test, indicating that the patient's immunity was impaired. The plasma concentration of transforming growth factor beta1 (TGF-beta1), a potent immunosuppressor, in the patient was markedly elevated (113 ng/mL, normal < 5). After the surgical removal of the tumor, the plasma TGF-beta1 concentration decreased, and the patient's immunity was restored to normal. Northern blot analysis showed an overexpression of the TGF-beta1 gene in the hemangioma tissue, while normal control liver tissue expressed undetectable levels of TGF-beta1 messenger RNA. These results suggest that the elevated levels of TGF-beta1 in the plasma were derived from the giant hemangioma tissue and may have contributed to the impaired immune function in the patient.

Cytokines↗