[Show abstract][Hide abstract] ABSTRACT: Insulin resistance is a candidate predictive factor for virological response to peginterferon plus ribavirin (PEG/RBV) therapy in chronic hepatitis C patients. We examined whether indices of insulin resistance could serve as a predictor of sustained virological response (SVR). Fifty-one patients with genotype 1b and high viral load who received PEG/RBV therapy for 48 weeks were included. Homeostasis model assessment of insulin resistance (HOMA-IR) and whole-body insulin sensitivity index (WBISI) calculated from the 75-g oral glucose tolerance test and serum levels of soluble tumor necrosis factor receptor 2 (sTFNR2) were evaluated before therapy. Patients who achieved SVR had significantly lower HOMA-IR and sTNFR2 levels and a higher WBISI compared with non-SVR patients. The positive predictive value for SVR was 0.653 for a HOMA-IR of <2 and 0.846 for a WBISI of 6 or higher. WBISI may serve as a highly specific predictor for SVR in PEG/RBV therapy.
[Show abstract][Hide abstract] ABSTRACT: Higher arterial stiffness and greater peripheral vascular resistance reduce blood flow in lower-leg arteries and contribute to the development of ischaemic limb in diabetic patients even without peripheral artery occlusive disease. The aim of this study was to clarify whether these vascular parameters are associated with long-term hyperglycaemia in diabetic patients.
We examined 45 type 2 diabetic patients and 38 age-matched nondiabetic subjects without peripheral artery occlusive disease assessed by ankle-brachial index consecutively admitted to our hospital, and followed them over a 3-year period (3.7 +/- 0.7 years) with no vasodilative medication. Blood flow and resistive index, a measure of peripheral vascular resistance, at the popliteal artery were evaluated using gated two-dimensional cine-mode phase-contrast magnetic resonance imaging. Brachial-ankle pulse wave velocity was measured to assess arterial stiffness.
At baseline, consistent with our previous report, diabetic patients showed higher brachial-ankle pulse wave velocity (p < 0.0001) and resistive index (p < 0.0001) and lower flow volume (p = 0.0044) than those of nondiabetic subjects. Stepwise multiple regression analysis revealed that duration of diabetes, mean HbA(1c) during the study, use of renin-angiotensin system inhibitors and change per year in resistive index were identified as significant independent variables predicting change per year in blood flow (r(2) = 0.733, p < 0.0001) in diabetic patients. Mean HbA(1c) during the study was positively correlated with changes per year in brachial-ankle pulse wave velocity (p = 0.00007) and resistive index (p = 0.0014) and was negatively correlated with that in blood flow (p < 0.0001) in diabetic patients.
Long-term hyperglycaemia is a major cause of impaired peripheral circulation in lower-leg arteries in diabetic patients without peripheral artery occlusive disease.
Diabetes/Metabolism Research and Reviews 05/2009; 25(4):363-9. DOI:10.1002/dmrr.955 · 3.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate whether eradication of hepatitis C virus (HCV) by interferon (IFN) therapy influences systemic glucose metabolism.
Seventy-two patients with chronic hepatitis C were enrolled in this study. Patients received IFN therapy and were classified into two groups: sustained responders (n=48) and nonsustained responders (n=24). We analysed systemic glucose metabolism in terms of the following indices: homeostasis model assessment for insulin resistance (HOMA-IR) and beta-cell function (HOMA-beta), insulinogenic index (II), composite insulin sensitivity index (ISI composite) and the area under the curve of plasma glucose (PG-AUC) and serum insulin (SI-AUC) in oral glucose tolerance tests. In 28 sustained responders and 16 nonsustained responders, serum levels of soluble tumour necrosis factor receptor 2 (sTNFR2) were measured. Indices were determined before and 6 months after therapy.
In the sustained responders, HOMA-beta (P=0.0004) and SI-AUC (P=0.002) were significantly decreased and the ISI composite was increased (P=0.009), although there were no significant changes in HOMA-IR, II or PG-AUC. Serum sTNFR2 levels decreased significantly after therapy in sustained responders (P=0.001). In the nonsustained responders, there were no changes in any index.
Eradication of HCV by IFN therapy could improve whole-body insulin resistance and insulin hypersecretion with reduced serum TNF-alpha levels.
Liver international: official journal of the International Association for the Study of the Liver 03/2009; 29(6):871-7. DOI:10.1111/j.1478-3231.2009.01993.x · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the correlation between lifestyle improvements, in particular increased cardio-respiratory fitness and changes in the blood lipid profile.
The participants were 217 residents of Fuji and Yamato Towns, Saga City, with mildly abnormal blood pressure, serum lipids or blood glucose detected at health check-ups in 2003. Participants were randomly allocated to an Intervention (108 subjects) or Control group (109 subjects), matched for age and various conditions. The Intervention group was given exercise advice and prescription and dietary instructions. Cardio-respiratory fitness was evaluated using the work rate at double product breaking point. Changes of lipid parameters were compared before and after intervention, and examined the relationship with cardio-respiratory fitness.
Seventy nine subjects in each group could be followed up for 17 months without requiring pharmacotherapy. Body mass index, waist circumference, systolic blood pressure, homeostasis model assessment insulin resistance, and triglycerides were decreased in the Intervention group. Furthermore, apolipoprotein B levels were lower (p<0.05), and the ratio of LDL cholesterol to apolipoprotein B (LDL/ApoB) was higher (p<0.001). When all subjects were divided into 3 subgroups according to the degree of improvement in cardio-respiratory fitness, LDL/ApoB increased and apolipoprotein B decreased as the degree of improvement increased (p<0.05).
Improvement was seen in atherosclerotic risk factors through lifestyle modification. In particular, improved cardiorespiratory fitness was associated with qualitative and quantitative changes in LDLs.
Internal Medicine 01/2009; 48(1):25-32. DOI:10.2169/internalmedicine.48.1527 · 0.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To clarify the impact of visceral obesity on hepatitis C virus (HCV)-infected patients, we examined the relationship between insulin resistance development and visceral fat accumulation.
We analyzed 87 HCV-infected patients with mild fibrosis (stage 1 or 2) in comparison with 125 sex- and age-matched patients with non-alcoholic fatty liver disease (NAFLD). The degree of visceral fat area (VFA; cm(2)) at the umbilical level was measured by abdominal computed tomography and divided into two grades: no visceral obesity, VFA<100 and visceral obesity, VFA>/=100. Insulin resistance was evaluated by homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). Pancreatic beta-cell function was evaluated by homeostasis model assessment of beta-cell function (HOMA-beta). Serum soluble tumour necrosis factor (TNF)-receptors 1 and 2 and adiponectin were measured.
Insulin resistance evaluated by HOMA-IR and QUICKI was correlated with visceral fat accumulation, and was higher in HCV patients than in NAFLD patients with visceral obesity. HOMA-beta was higher in HCV patients than in NAFLD patients for each VFA grade. Serum-soluble TNF-receptors 1 and 2 were higher in HCV patients than in NAFLD patients with visceral obesity.
Hepatitis C virus infection is a risk factor for development of insulin resistance, particularly in patients with visceral obesity.
Liver international: official journal of the International Association for the Study of the Liver 08/2008; 29(2):213-20. DOI:10.1111/j.1478-3231.2008.01853.x · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diabetic nephropathy is a major cause of lower-limb amputation. We enrolled 250 type 2 diabetic patients without apparent occlusive peripheral arterial disease (ankle-brachial indices >0.9) and 40 age-matched nondiabetic subjects consecutively admitted to our hospital. Flow volume and resistive index (RI), an index of vascular resistance, at the popliteal artery were evaluated using gated two-dimensional cine-mode phase-contrast magnetic resonance imaging. Brachial-ankle pulse wave velocity (baPWV) was measured as an index of arterial distensibility. Flow volume was negatively correlated with both baPWV (p=0.0009) and RI (p<0.0001) among the patients. When the patients were grouped into four subgroups with or without albuminuria and renal insufficiency according to the levels of urinary albumin excretion rate (>or=20 or <20microg/min) and estimated glomerular filtration rate (eGFR) (<60 or >or=60ml/min/1.73m(2)), albuminuric patients with renal insufficiency (n=30) showed the lowest flow volume (p=0.0078) and the highest baPWV (p=0.0006) and RI (p=0.0274) among the groups. Simple linear regression analyses demonstrated that eGFR correlated positively with flow volume (p=0.0020) and negatively with baPWV (p=0.0258) and RI (p=0.0029) in patients with albuminuria (n=92), but not with normoalbuminuria (n=158). Impaired peripheral circulation in lower-leg arteries associates with nephropathy in diabetic patients even though they have normal ankle-brachial indices.
Diabetes research and clinical practice 06/2008; 80(3):416-23. DOI:10.1016/j.diabres.2008.01.023 · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bleeding and stenosis are serious complications of reflux esophagitis, although few studies have been performed in Japan regarding these complications. This study aimed to indicate the characteristics of reflux esophagitis observed during emergency endoscopic examination in Japan.
All subjects who had emergency endoscopic examination performed between 1990 and 2004 at Saga Medical School Hospital were evaluated. Patients with endoscopic reflux esophagitis were evaluated with a retrospective patient chart review.
A total of 1621 subjects underwent emergency endoscopy; 1420 of the endoscopies were because of hematemesis or melena. Endoscopic examination revealed that 19 cases with bleeding were caused by reflux esophagitis (19/1621, 1.2%). The 19 patients with bleeding and the four patients with stenosis (0.2%) had emergency endoscopy performed for complications of reflux esophagitis. The Los Angeles classification of these 23 cases showed that most were severe esophagitis (grade A, 0; B, 2; C, 8; and D, 13). The frequency of comorbidity with diabetes mellitus and collagen disease and the proportion of heavy drinkers were higher in patients who received emergency endoscopy because of reflux esophagitis than in those diagnosed with reflux esophagitis but who received emergency endoscopy because of other diseases.
Relatively small numbers of patients with reflux esophagitis undergo emergency endoscopy in Japan, and most such patients have underlying diseases, including diabetes mellitus and collagen disease. This finding is supported by a previous report that severe esophagitis is not common in Japan.
Journal of Gastroenterology 02/2008; 43(4):265-9. DOI:10.1007/s00535-007-2157-2 · 4.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine the association of baseline measures in lower-leg arteries and conventional cardiovascular risk factors with the incidence of cardiovascular disease (CVD) events in type 2 diabetic patients with normal ankle-brachial indexes (ABIs) (>0.9).
We studied 129 type 2 diabetic patients and 35 age-matched nondiabetic subjects with no apparent CVD consecutively admitted to our hospital. At baseline, total flow volume and resistive index, as an index of vascular resistance, at the popliteal artery was evaluated using gated two-dimensional cine-mode phase-contrast magnetic resonance imaging. Patients were followed 4.8 +/- 1.5 years (range 3.0-8.2) or until their first event of CVD.
On follow-up, 16 patients developed primary CVD events. Patients with CVD had lower blood flow (P < 0.01) and higher vascular resistance (P < 0.05) than patients without CVD. When the patients were grouped into tertiles according to their levels of total flow volume (129.6-85.5, 85.3-63.3, and 62.7-23.8 ml/min), Kaplan-Meier analysis showed a higher probability of developing CVD events in patients in the lowest than in patients in the highest (P = 0.0199, log-rank test) tertile. Multivariate Cox proportional hazards analysis revealed that the lowest tertile for flow volume (hazard ratio [HR] 8.60, 95% CI 1.61-45.97, P = 0.012), hypertension (3.99, 1.12-14.25, P = 0.033), and smoking status (12.01, 1.21-119.28, P = 0.034) were significant independent predictors of CVD events.
We have demonstrated that low blood flow estimates in lower-leg arteries may be predictive for CVD events among Japanese patients with type 2 diabetes even though they have a normal ABI.
Diabetes Care 08/2006; 29(8):1884-90. DOI:10.2337/dc06-0142 · 8.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nonalcoholic fatty liver diseases are often associated with obesity, insulin resistance, and excessive visceral fat accumulation. The aims of this study were (1) to evaluate the relationship between the severity of fatty liver and visceral fat accumulation in nonalcoholic fatty liver diseases, and (2) to investigate the relationships of fatty liver with biochemical data and insulin resistance.
One hundred twenty-nine subjects (63 women) with fatty liver diagnosed by ultrasonography were enrolled. Subjects positive for hepatitis B virus, hepatitis C virus, or autoimmune antibodies and those whose alcohol intake was over 20 g/day were excluded. The visceral fat area at the umbilical level and the liver-spleen ratio were evaluated by computed tomography.
The severity of fatty liver evaluated by ultrasonography showed a significant positive relationship with the visceral fat area and waist circumstance (fatty liver severity: mild, 92.0 +/- 30.9 cm(2); moderate, 122.1 +/- 32.6 cm(2); severe, 161.0 +/- 48.4 cm(2); P < 0.0001). The visceral fat area and liver-spleen ratio were negatively correlated (r = -0.605, P < 0.0001). The severity of fatty liver showed strong positive relationships with serum aspartate aminotransferase, alanine aminotransferase, fasting plasma glucose, fasting plasma insulin, and insulin resistance. The severity of fatty liver was positively related to the visceral fat area in 49 nonobese subjects (body mass index <25).
The severity of fatty liver was positively correlated with visceral fat accumulation and insulin resistance in both obese and nonobese subjects, suggesting that hepatic fat infiltration in nonalcoholic fatty liver disease may be influenced by visceral fat accumulation regardless of body mass index.
Journal of Gastroenterology 06/2006; 41(5):462-9. DOI:10.1007/s00535-006-1790-5 · 4.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine whether body weight and/or serum leptin were independent predictors of response to antiviral treatment in patients with chronic hepatitis C.
A retrospective evaluation was performed in 139 patients with chronic hepatitis C treated with interferon (IFN) from 1996 to 2000. Sustained response was defined as negative by hepatitis C virus (HCV) RNA analysis using PCR and normal transaminase at 24 wk after cessation of IFN therapy. Patients who remained positive for HCV RNA at the end of IFN treatment were defined as resistant to IFN therapy. Sex, age, body mass index (BMI) (> or =25 vs <25), complication of diabetes mellitus, serum leptin level (> or =8.0 microg/L vs < 8.0 microg/L), and the stage of liver fibrosis by needle biopsy (F1/F2 vs F3/F4) were examined.
Sustained response was achieved in 33 patients (23.7%), while others failed to show a response to IFN therapy. Overall, the factors associated with sustained antiviral effects were HCV-RNA load, HCV genotype, serum leptin level, and stage of liver fibrosis evaluated by univariate analysis. BMI was not associated with any therapeutic effect of IFN. Multivariate analysis indicated that HCV-RNA load was a significant risk factor, but among the patients with low viremia (HCV-RNA <100 MU/L), leptin level was an independent risk factor for IFN resistance. Namely, a high level of serum leptin attenuated the effect of IFN on both male and female patients with low viremia.
High serum leptin level is a negative predictor of response to antiviral treatment in chronic hepatitis C with low viremia.
World Journal of Gastroenterology 01/2006; 12(4):556-60. · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 13-year-old boy developed continuous vomiting and acute liver damage after eating fresh sea hare (Aplysia kurodai) eggs. A blood test on admission showed 661 IU/l of AST and 1186 IU/l of ALT. There was no factor, such as hepatitis virus, alcohol or drug intake that may have caused the liver damage; thus, we diagnosed acute liver damage associated with ingestion of sea hare eggs. Symptoms and laboratory data improved with rest, fluid therapy and intravenous injection of glyzirrhizin. He was discharged without any complications after 18 days. Microscopic findings of the liver revealed scattered hepatocyte necrosis with infiltration of lymphocytes and neutrophils. Some marine mollusks reportedly contain toxic substances as a self-defense system. The sea hare, known as "Amefurashi" in Japanese, is commonly found along the rocky seashore facing the sea in Japan. Its eggs appear eatable but contain a cytotoxic substance, aplysianin, which can cause hepatic disorders.
[Show abstract][Hide abstract] ABSTRACT: Growth factors and extracellular matrices cooperatively regulate cellular behavior. However, the interactions between transforming growth factor-beta 1 (TGF-beta 1) and integrins in hepatic cells are not fully understood. We investigated the effects of beta 1-integrin on TGF-beta 1-regulated growth of hepatoma cells. Human hepatoma cell lines HepG2, Huh7, and Hep3B were stably transfected with beta 1-integrin, and the parental, and mock- and beta 1-integrin-transfected hepatoma cells were treated with TGF-beta 1. Modulation of apoptosis and pathways involved in the process were investigated. TGF-beta 1 suppressed the growth of hepatoma cells, and apoptosis was observed in Hep3B and Huh7. Hepatoma cells transfected with beta 1-integrin were protected from TGF-beta 1-induced apoptosis. Mitogen-activated protein (MAP) kinase inhibitors, PD98059, SB203580, and SP600125, abolished this protective effect of beta 1-integrin, but herbimycin A and wortmannin were ineffective. Hepatoma cells overexpressing beta 1-integrin showed increased activities of MAP kinases, and TGF-beta 1 induced sustained activation of MAP kinases in these cells, but only transient activation in mock-transfected cells. These data suggest that MAP kinases activated by beta 1-integrin provide a strong anti-apoptotic signal during TGF-beta 1-induced apoptosis in human hepatoma cells. Therefore beta 1-integrin-mediated signals may contribute to the development and progression of hepatocellular carcinoma.
Cancer Science 12/2004; 95(11):878-86. · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Growth factors and extracellular matrices cooperatively regulate cellular behavior. However, the interactions between transforming growth factor-β1 (TGF-β1) and integrins in hepatic cells are not fully understood. We investigated the effects of β1-integrin on TGF-β1-regulated growth of hepatoma cells. Human hepatoma cell lines HepG2, Huh7, and Hep3B were stably transfected with β1-integrin, and the parental, and mock- and β1-integrin-transfected hepatoma cells were treated with TGF-β1. Modulation of apoptosis and pathways involved in the process were investigated. TGF-β1 suppressed the growth of hepatoma cells, and apoptosis was observed in Hep3B and Huh7. Hepatoma cells transfected with β1-integrin were protected from TGF-β1-induced apoptosis. Mitogen-activated protein (MAP) kinase inhibitors, PD98059, SB203580, and SP600125, abolished this protective effect of β1-integrin, but herbimycin A and wortmannin were ineffective. Hepatoma cells overexpressing β1-integrin showed increased activities of MAP kinases, and TGF-β1 induced sustained activation of MAP kinases in these cells, but only transient activation in mock-transfected cells. These data suggest that MAP kinases activated by β1-integrin provide a strong anti-apoptotic signal during TGF-β1-induced apoptosis in human hepatoma cells. Therefore β1-integrin-mediated signals may contribute to the development and progression of hepatocellular carcinoma.
Cancer Science 11/2004; 95(11):878-886. DOI:10.1111/j.1349-7006.2004.tb02197.x · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Matrix metalloproteinases (MMPs) have been implicated in progression of hepatocellular carcinoma (HCC), as have hepatocyte growth factor (HGF) and its c-Met receptor. We investigated regulation of MMP gene expression by HGF in human HCC. Expression of mRNAs encoding MMPs, HGF and c-Met receptor was examined by quantitative reverse transcription-polymerase chain reaction (RT-PCR) in human HCC and in five human HCC cell lines. HCC cells were treated with HGF, and mRNA expression for MMPs and Ets-1 which activates transcription of MMPs was investigated. Ets binding activity was determined by gel mobility shift assay. MMP promoter activities were evaluated by reporter gene assay. Effects of Ets-1 antisense oligonucleotides were also examined. At the mRNA level, MMP-1, -3, -7 as well as c-Met were overexpressed in HCC compared with corresponding nonneoplastic liver tissues, although MMP-2, -9 or HGF were not. HGF dose-dependently induced Ets-1 together with an increased Ets binding activity, followed by transcription of MMP-1, -3, and -7. HGF increased MMP promoter activity, as did cotransfection with Ets-1. Ets-1 antisense oligonucleotide transfection down-regulated the MMP expression, and abolished induction by HGF. In conclusion, certain MMPs and c-Met, overexpressed in HCC cells, are induced by HGF via Ets-1. This pathway may contribute to tumor progression.
Hepatology Research 01/2004; 27(4):289-301. DOI:10.1016/S1386-6346(03)00268-7 · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although cooperative interactions between growth factors and integrins, cell surface receptors for extracellular matrices (ECM), have been reported, little is known about the interaction between hepatocyte growth factor (HGF) and integrin in hepatoma cells. We investigated the effects and mechanisms of integrin on the proliferation of hepatoma cells regulated by HGF. Human HepG2 hepatoma cells stably transfected with beta 1-integrin were treated with HGF and compared with parental and mock-transfected control cells. Cell proliferation and expression of cyclin-dependent kinase (Cdk) inhibitors and S-phase kinase-associated protein 2 (Skp2), were investigated. HGF dose-dependently suppressed the proliferation of parental and mock-transfected HepG2 cells. However, cells overexpressing beta 1-integrin exhibited increased proliferation in response to HGF. Although HGF increased p27 and decreased Skp2 expression in the parental and mock-transfected cells, the p27 and Skp2 levels in cells overexpressing beta 1-integrin were not altered by HGF. Interestingly, HepG2 cells overexpressing beta 1-integrin showed increased Skp2 expression. Furthermore, HGF did not reduce the proliferation of HepG2 cells transfected with antisense p27 or sense Skp2. Thus, HGF suppresses HepG2 cell proliferation by directly increasing p27 expression and indirectly decreasing Skp2 expression, and beta 1-integrin modulates the responsiveness of hepatoma cells to HGF via a p27-dependent manner by increasing Skp2. In conclusion, these results strongly suggest that integrin-mediated signals from the ECM can modulate growth factor-mediated signals in hepatoma cells, and may contribute to the growth of hepatocellular carcinomas.
[Show abstract][Hide abstract] ABSTRACT: Nitric oxide (NO) regulates endothelial function and is believed to prevent atherogenesis. In endothelial cells, endothelial nitric oxide synthase (eNOS) is expressed constitutively, and regulates NO synthesis. A mutation of the eNOS gene has been associated with the development of coronary artery disease (CAD). The development of CAD is also influenced by insulin resistance, and recent studies suggest that NO might affect cellular insulin activity. We investigated the association between eNOS polymorphisms and insulin resistance in patients with CAD. We screened 45 patients with a history of myocardial infarction (MI), angina pectoris (AP), or coronary spasm. Genotypes were determined by polymerase chain reaction-restriction fragment-length polymorphism analysis. We examined two polymorphisms of the eNOS gene (The T(-786)-->C variant and the missense Glu298Asp variant). Insulin resistance was measured by determining the plasma immunoreactive insulin concentration at the 120 min time point (IRI 120) of a 75 g oral glucose tolerance test. The IRI 120 of the T(-786)-->C variant group was higher than that for the control group (p<0.05). This finding demonstrates that the T(-786)-->C mutation in the eNOS gene decreases insulin sensitivity.
Journal of atherosclerosis and thrombosis 01/2003; 10(1):43-7. DOI:10.5551/jat.10.43 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: beta 1-integrin modulates cellular phenotype by mediating signals from the extracellular matrix (ECM). Although overexpression of integrin molecules in hepatocellular carcinoma (HCC) has been reported, the role of overexpressed beta 1-integrin in the disease process of HCC is not fully understood. The authors investigated the effects of beta 1-integrin on apoptosis in hepatoma cells.
Human hepatoma cell lines HepG2, Huh7, and HLE were stably transfected with full-length beta 1-integrin. Cells underwent apoptosis induced by chemotherapeutic reagents, including cis-platinum (II)-diammine dichloride, etoposide, and docetaxel. Cell survival and intracellular signaling pathways dependent on beta 1-integrin-mediated apoptosis effects were analyzed by treating cells with PD98059 (ERK inhibitor), SB203580 (p38MAP kinase inhibitor), wortmannin (phosphatidyl inositol-3-kinase inhibitor), and herbimycin A (tyrosine kinase inhibitor).
All three hepatoma cell lines overexpressing beta 1-integrin were protected from apoptosis induced by chemotherapeutic reagents, whereas parental or mock transfected cells were not. Treatment with PD98059 or SB203580 abolished the protective effect on apoptosis in cells overexpressing beta 1-integrin. Neither herbimycin nor wortmannin blocked the protective effects of beta 1-integrin overexpression.
These data suggest that overexpression of beta 1-integrin confers resistance to apoptosis in hepatoma cells via a MAP kinase dependent pathway. beta1-integrin mediated signaling from the ECM in HCC cells may contribute to chemotherapy resistance.
Cancer 08/2002; 95(4):896-906. DOI:10.1002/cncr.10751 · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatitis C virus (HCV) infection is a major health problem in Japan. This infection is highly prevalent in subjects with chronic liver disease and is strongly associated with hepatocellular carcinoma. Epidemiological studies conducted by the Japanese Ministry of Health and Welfare showed that the mortality rate associated with hepatocellular carcinoma (HCC) was high in several prefectures in western Japan. In 1990, Saga Prefecture on the island of Kyushu in western Japan reported the highest HCC related mortality rate. Here, we report the results of a population-based survey in Saga Prefecture, where prevalence of HCV infection and mortality rate of HCC was assessed in the general population. From 1992 to 1997, the prevalence of HCV infection was assessed in the general population of 47 districts in Saga Prefecture. Among the 161307 subjects (52590 men, 108357 women, older than 30 years) examined, 13129 (8.1%) reacted positively to HCV antibody (anti-HCV). The prevalence of HCV-Ab reactivity was highest in subjects over 60 years of age. Reactivity increased from 3.6% in subjects 30-49 years old to 11% in those >50 years old. Highly significant differences were observed among the 45 districts in seropositive rates for anti-HCV, with the range being from 0.8 to 20.0%. We evaluated the association between the prevalence of anti-HCV reactivity and age-adjusted death rate from HCC in the general population of these districts, and detected a significant association (Pearson' s correlation coefficient=0.721, P<0.0001, Y=1.86X+16.1). In conclusion, these observations indicated that the outbreak of HCV in this area was a major cause of HCC in the population.
Hepatology Research 05/2002; 23(1):18-24. DOI:10.1016/S1386-6346(01)00161-9 · 2.74 Impact Factor