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Kyosuke Yamamoto

Publications and source records attributed to Kyosuke Yamamoto.

16 recordsLinked to original sources
PubMed2006

Influence of alcohol consumption and gene polymorphisms of ADH2 and ALDH2 on hepatocellular carcinoma in a Japanese population.

Although alcohol intake as well as hepatitis viruses has been associated with hepatocellular carcinoma (HCC), gene-alcohol interactions on HCC risk remain to be elucidated. We conducted a case-control study to examine whether polymorphisms of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) modified the HCC risk depending on the amount of alcohol intake. ADH2 and ALDH2 genotyping was performed by a duplex polymerase chain reaction with confronting two-pair primers in 209 newly diagnosed HCC cases and 2 different controls [275 hospital controls and 381 patients with chronic liver disease (CLD)]. Multiple logistic regression analyses revealed that heavy drinkers consuming >or=3 "go"s/day of sake (69 g of ethanol/day) showed an increased risk of HCC based on comparison of HCC cases with hospital controls [adjusted odds ratio (OR) = 13.5; 95% confidence interval (CI) 3.3-54.3] or CLD patients (adjusted OR = 7.0; 95% CI 2.5-19.2), whereas the overall risk was not elevated among light to moderate drinkers consuming <3 "go"s/day. Interestingly, light to moderate drinking was associated with an increased risk among those with ALDH2*1/*2 (adjusted OR = 4.5 or 2.0), but not among those with ALDH2*1/*1 (adjusted OR = 0.8 or 1.0; p interaction = 0.03 or 0.13). However, this gene-alcohol interaction was not observed for heavy drinking. Among light to moderate drinkers, people with the combination of ALDH2*1/*2 and ADH2*2/*2 revealed the highest risk of HCC. These findings indicate that the ALDH2 polymorphism may modify HCC risk among light to moderate drinkers.

Adult↗
PubMed2006

The effect of menatetrenone, a vitamin K2 analog, on disease recurrence and survival in patients with hepatocellular carcinoma after curative treatment: a pilot study.

BACKGROUND: The high recurrence rate of hepatocellular carcinoma (HCC) determines the long-term prognosis for patients with HCC. In the current study, the authors tested the effects of menatetrenone, a vitamin K2 analog, on recurrent HCC and survival after curative treatment. METHODS: Sixty-one patients who were diagnosed as free of HCC after surgical resection or percutaneous local ablation were assigned randomly assigned to either a menatetrenone group (n = 32 patients) or a control group (n = 29 patients). Patients in the menatetrenone group received a daily oral dose of 45 mg of menatetrenone. Disease recurrence and survival rates were analyzed in patients with HCC. RESULTS: The cumulative recurrence rates in the menatetrenone group were 12.5% at 12 months, 39.0% at 24 months, and 64.3% at 36 months; and the corresponding recurrence rates in the control group were 55.2%, 83.2%, and 91.6%, respectively (P = 0.0002). Similar results were obtained even for patients who had low baseline levels of serum des-gamma-carboxy-prothrombin. Univariate and multivariate Cox proportional hazard analyses showed that the administration of menatetrenone was the only factor related to the recurrence rate of HCC. The cumulative survival rates for the patients who received menatetrenone were 100% at 12 months, 96.6% at 24 months, and 87.0% at 36 months; and the corresponding survival rates for patients in the control group were 96.4%, 80.9%, and 64.0%, respectively (P = 0.051). CONCLUSIONS: The current study findings suggested that menatetrenone may have a suppressive effect on recurrence of HCC and a beneficial effect on survival, although a larger, placebo-controlled trial will be required to prove these effects.

Administration, Oral↗
PubMed2006

hOGG1 Ser326Cys polymorphism and risk of hepatocellular carcinoma among Japanese.

BACKGROUND: The Ser326Cys polymorphism in human oxoguanine glycosylase 1 (hOGG1), which is involved in the repair of 8-hydroxy-2-deoxyguanine in oxidatively damaged DNA, has been associated with susceptibility to certain cancers, but has not been examined in causation of hepatocellular carcinoma (HCC). METHODS: We conducted a case-control study to investigate whether this polymorphism was related to HCC risk with any interaction with alcohol consumption and cigarette smoking. Genotyping was performed by a polymerase chain reaction with confronting two-pair primers among 209 newly diagnosed HCC cases, 275 hospital controls, and 381 patients with chronic liver disease (CLD) without HCC. RESULTS: Overall, the hOGG1 genotype was not significantly associated with HCC; adjusted odds ratios (and 95% confidence intervals) for the Ser/Cys and Cys/Cys genotypes compared with the Ser/Ser genotype were 0.79 (0.35-1.79) and 0.48 (0.18-1.27) against hospital controls, and 1.51 (0.96-3.37) and 0.86 (0.50-1.47) against CLD patients. We could not detect any significant gene-alcohol interaction (p = 0.95 or 0.16) or gene-smoking interaction (p = 0.70 or 0.69). CONCLUSIONS: These results suggest that the hOGG1 Ser326Cys polymorphism may not play a major role as an independent factor in hepatocarcinogenesis.

Adult↗
PubMed2004

Fenofibrate for patients with asymptomatic primary biliary cirrhosis.

AIM: Primary biliary cirrhosis (PBC) is a chronic, cholestatic disease of autoimmune etiology, the histology of which shows a destruction of the intrahepatic bile duct and portal inflammation. Ursodeoxycholic acid (UDCA) is now used as a first-line drug for asymptomatic PBC (aPBC) because it is reported that UDCA decreases mortality and prolongs the time of liver transplantation. However, only 20-30% of patients respond fully to UDCA. Recently, lipoprotein-lowering agents have been found to be effective for PBC. The aim of this study was to examine the safety and efficacy of fenofibrate, a member of the fibrate class of hypolipidemic and anti-inflammatory agent via peroxysome proliferatory-activated receptor alpha, in patients with aPBC. METHODS: Fenofibrate was administered for twelve weeks in nine patients with aPBC who failed to respond to UDCA. UDCA was used along with fenofibrate during the study. The data from aPBC patients were analyzed to assess the biochemical effect of fenofibrate during the study. RESULTS: The serum levels of alkaline phosphatase (ALP) (285+/-114.8 IU/L) and immunoglobulin M (IgM) (255.8+/-85.9 mg/dl) significantly decreased to 186.9+/-76.2 IU/L and 192.9+/-67.5 mg/dL respectively, after fenofibrate treatment in patients with aPBC (P<0.05). Moreover, the titer of antimitochondrial antibody (AMA) also decreased in 4 of 9 patients with aPBC. No adverse reactions were observed in any patients. CONCLUSION: Fenofibrate appears to be significantly effective in treating patients with aPBC who respond incompletely to UDCA alone. Although the mechanism of fenofibrate on aPBC has not yet been fully clarified, combination therapy using fenofibrate and UDCA might be related to the anti-immunological effects, such as the suppression of AMA production as well as its anti-inflammatory effect.

Adult↗
PubMed2004

Development of quantitative neuropsychological tests for diagnosis of subclinical hepatic encephalopathy in liver cirrhosis patients and establishment of diagnostic criteria-multicenter collaborative study in Japanese.

At present, there are no generally accepted diagnostic criteria or methods for subclinical hepatic encephalopathy (SHE) associated with liver cirrhosis. We therefore developed an easily conducted computer-aided quantitative neuropsychiatric function test system for use in routine medical practice. We established normal values in healthy Japanese subjects and determined differences between healthy persons and liver cirrhosis patients without clinical encephalopathy in a multi-center clinical trial. The test system consists of eight tests: number connection tests A and B, a figure position test, a digit symbol test, a block design test, and reaction time tests A, B and C. The test results were affected by age, but not by gender or facility. No learning effect was noted. The results were therefore reported by 5-year quartile ranges and differences were evaluated between 542 healthy subjects and 292 cirrhotic patients. When the cut-off value was set at the 10th/90th percentile of the results in healthy subjects, the results of each of the 8 tests were abnormal in about 25% of cirrhotic patients, and at least 1 of the 8 tests gave values greater than the 10th/90th percentile cut-off value in 58.2% of the 292 liver cirrhosis patients. SHE patients were thought to be included in these 58.2% of patients. The developed test makes it possible to quantitatively assess neuropsychiatric function, and the results obtained can be used as a basis for the diagnosis of SHE.

Journal Article↗
PubMed2004

Transforming growth factor-beta 1-induced apoptosis is blocked by beta 1-integrin-mediated mitogen-activated protein kinase activation in human hepatoma cells.

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.

Apoptosis↗
PubMed2003

Induction of multiple matrix metalloproteinase genes in human hepatocellular carcinoma by hepatocyte growth factor via a transcription factor Ets-1.

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.

Journal Article↗
PubMed2003

Mechanism of beta 1-integrin-mediated hepatoma cell growth involves p27 and S-phase kinase-associated protein 2.

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.

Carcinoma, Hepatocellular↗
PubMed2003

Endoscopic injection sclerotherapy for esophageal varices in cirrhotic patients with hepatocellular carcinoma: risk factors for survival.

GOALS: We previously showed that endoscopic injection sclerotherapy (EIS) prolonged survival in patients with esophageal varices complicated by hepatocellular carcinoma (HCC) and liver cirrhosis. Here, we evaluated risk factors that affect EIS outcomes. Among factors, the difference between prophylactic and emergency EIS was of interest, and we analyzed precisely. STUDY: Subjects were 134 patients with esophageal varices complicated by HCC and liver cirrhosis: 38 underwent emergent therapy for bleeding varices and 96 underwent prophylactic sclerotherapy. RESULTS: During 2-year observation, 22 of the 38 (57.9%) and 38 of the 96 (39.6%) died. Analysis by univariate Cox's proportional hazard model indicated that prognosis of patients receiving emergency EIS was inferior to those with prophylactic EIS. However, multivariate Cox's analysis showed that emergency EIS itself extended survivals of those with esophageal varices complicated by HCC and liver cirrhosis. Patients' hepatic function (Child-Pugh classes) and tumor sizes were also statistically significant factors for survival. Neither prophylactic nor emergency EIS prolonged survival of patients with Child C hepatic function or those with HCCs larger than 5 cm. CONCLUSIONS: The prophylactic sclerotherapy for esophageal varices prolongs long-term survival of patients with liver cirrhosis and HCC, better than emergency therapy. However, EIS itself had no beneficial effect on patients with poor disease status.

Esophageal and Gastric Varices↗
PubMed2003

The relationship between insulin resistance and polymorphisms of the endothelial nitric oxide synthase gene in patients with coronary artery disease.

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.

Coronary Disease↗
PubMed2002

Beta 1-integrin protects hepatoma cells from chemotherapy induced apoptosis via a mitogen-activated protein kinase dependent pathway.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Antineoplastic Agents↗
PubMed2002

Effects of fenofibrate on high-density lipoprotein particle size in patients with hyperlipidemia: a randomized, double-blind, placebo-controlled, multicenter, crossover study.

BACKGROUND: Fenofibrate lowers serum total cholesterol and triglyceride levels while it elevates serum high-density lipoprotein cholesterol (HDL-C) level. OBJECTIVE: The aim of this study was to investigate the effects of fenofibrate on the particle size of high-density lipoprotein (HDL). METHODS: Patients with hyperlipidemia (as defined by serum triglyceride level > or = 150 mg/dL in the fasting state) were enrolled in this randomized, double-blind, placebo-controlled, multicenter, crossover study. Fenofibrate 300 mg (corresponding to 200 mg of micronized fenofibrate) or placebo was administered orally once daily after dinner for 8 weeks, followed by crossover of the 2 drugs for an additional 8 weeks. RESULTS: Fifty hyperlipidemic patients (31 men, 19 women; mean [SD] age, 54.6 [12.7] years) were enrolled. Serum total cholesterol and triglyceride levels were significantly reduced with fenofibrate treatment compared with placebo (9.4% [P = 0.007] and 34.4% [P < 0.001], respectively), whereas HDL-C levels were significantly elevated (by 25.8% [P < 0.001]). Lipoprotein lipase (LPL) activity, LPL protein level, and hepatic triglyceride lipase activity increased by 10.5%, 13.4%, and 11.4%, respectively, with fenofibrate compared with placebo. HDL was classified into 3 groups by particle size: HDL3 <88 A; HDL2a > or = 88 A but <98 A; and HDL2b > or = 98 A. The amount of HDL3 increased significantly with fenofibrate compared with placebo (P < 0.001). Fenofibrate was well tolerated during the study. Abnormal clinical laboratory values were noted in 20 of 48 patients (41.7%), but these events were mild and not clinically significant. CONCLUSION: Taken together, these findings indicate that fenofibrate therapy increased the HDL subfraction with the smallest diameter (HDL3), which is largely responsible for withdrawing cholesterol from peripheral cells.

Adult↗
PubMed2002

Hepatocyte growth factor induces collagenase (matrix metalloproteinase-1) via the transcription factor Ets-1 in human hepatic stellate cell line.

BACKGROUND/AIMS: Although hepatocyte growth factor recently has been shown to decrease hepatic fibrosis in animal models, the molecular mechanisms of this effects remain to be elucidated. We investigated regulation of collagenase expression by hepatocyte growth factor in hepatic stellate cells. METHODS: A human hepatic stellate cell line, LI90, was treated with hepatocyte growth factor. Expression of collagenase, 72 kDa gelatinase, procollagen alpha 1(I), tissue inhibitor of matrix metalloproteinase-1, transforming growth factor-beta 1, or Ets-1, and carboxyterminal telopeptide of type I collagen was examined. Ets-1 binding activity was determined by gel mobility shift assay, collagenase promoter activity was evaluated by reporter gene assay. LI90 cells were also transfected with Ets-1 antisense oligonucleotides with or without hepatocyte growth factor. RESULTS: Hepatocyte growth factor increased expression of collagenase mRNA and protein, and an increase in Ets-1 mRNA preceded the increase in collagenase mRNA. Collagenase activity and protein, and a degradation product of type I collagen were increased in the medium. Nuclear extracts from treated LI90 cells also showed increased Ets-1 binding activity. Hepatocyte growth factor and cotransfection of Ets-1 enhanced promoter activity of collagenase gene. Furthermore, treatment of LI90 cells with Ets-1 antisense oligonucleotides downregulated basal and hepatocyte growth factor-induced Ets-1 and collagenase mRNA expression. CONCLUSIONS: Collectively, the results suggest that hepatocyte growth factor increases collagenase expression in hepatic stellate cells via the Ets-1 transcription factor-dependent manner.

Cell Line↗
PubMed2002

Population-based study of hepatitis C virus infection and hepatocellular carcinoma in western Japan.

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.

Journal Article↗
PubMed2002

[Fatty liver].

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Age Factors↗