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Biomedical subjects

Shigekazu Takemura

Publications and source records attributed to Shigekazu Takemura.

At least 19 recordsLinked to original sources
PubMed2007

Nicorandil elevates tissue cGMP levels in a nitric-oxide-independent manner.

The K(+) channel opener nicorandil is a hybrid compound that contains nitrate in its structure. It has been reported that nicorandil can relax vascular tissue in vitro via a mechanism that involves activation of K(ATP) channels and stimulation of soluble guanylyl cyclase. However, it is not known whether the increase of cGMP levels occurs through an elevation of nitric oxide (NO). The aim of the present study was to determine whether NO release was a direct effect of nicorandil. We reported here that nicorandil did not generate NO using ozone chemiluminescence detection methods in human or rat liver microsomes (P450-rich fractions) with addition of NADPH. However, nicorandil elevated cGMP levels in rat liver, aorta, and human coronary smooth muscle cells in vitro. The elevation was not inhibited by the NO trapping agent carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (carboxy-PTIO). These results suggest that nicorandil elevates cGMP without NO generation.

Animals↗
PubMed2006

Calorie restriction improves cardiovascular risk factors via reduction of mitochondrial reactive oxygen species in type II diabetic rats.

Uncoupling protein 2 (UCP2) is an important regulator of intracellular reactive oxygen species (ROS) production. We determined the effects of calorie restriction (CR) on the dynamic aspects of mitochondrial ROS production, UCP2, and the nitric oxide (NO)-cGMP pathway in the cardiovascular tissues of type II diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Some rats were on restricted diets (30% reduction from free intake) from age 29 to 42 weeks. Blood glucose, hemoglobin A1c, plasma levels of free fatty acid, triacylglycerol, and plasminogen activator inhibitor-1 in OLETF rats were significantly higher than those in nondiabetic control [Long-Evans Tokushima Otsuka (LETO)] rats at 29 weeks. Mitochondrial ROS production and UCP2 expression significantly increased in the heart and aorta of OLETF rats compared with those in LETO rats. A fibrogenic growth factor, transforming growth factor (TGF)-beta1 in the coronary vessels, endothelial nitric-oxide synthase, and aortic nitrotyrosine were increased in OLETF rats at 42 weeks. In contrast, an index of the NO-cGMP pathway, phosphorylated vasodilator-stimulated phosphoprotein, and superoxide dismutase activity in the aorta were significantly diminished. The relationship between UCP2 and ROS production in the cardiovascular function of diabetic rats being fed a calorie-restricted diet is unknown. These abnormalities in OLETF rats were reversed to normal levels by CR. CR significantly improved the NO-cGMP pathway via normalizing ROS generation in OLETF rats. A decrease in UCP2 expression by CR may be a compensatory mechanism to counteract decreased intracellular oxidative stress. The data suggest that CR may prevent cardiovascular tissues from oxidative stress provoked by diabetes mellitus.

Animals↗
PubMed2006

Influence of interferon therapy on outcome after surgery for hepatitis C virus-related hepatocellular carcinoma.

Influence of interferon (IFN) therapy on postoperative outcomes in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is still inconclusive. Of 518 patients who underwent hepatic resection for HCV-related HCC, 312 patients with Japan integrated staging score 0-2 were included in this study. Of 50 patients underwent IFN therapy, 29 patients who obtained a normalized alanine aminotransferase (ALT) activity irrespective of disappearance of serum HCV RNA were classified as the response group, while 21 patients were classified as the non-response group because their ALT activities were not normalized and serum HCV RNA persisted. The non-IFN group included 262 patients who had not received IFN therapy. The tumor-free and the overall survival rates for patients in the response group were significantly higher than those in other groups. Only one patient in the response group died of HCC recurrence, and the proportion of deaths associated with liver disease (HCC recurrence or cirrhosis) was significantly lower in the response group than other two groups. IFN therapy can improve postoperative outcomes in patients with HCV-related HCC because of suppression of recurrence and preventing progress of cirrhosis, especially when IFN therapy has controlled their active hepatitis.

Journal Article↗
PubMed2006

Recovery of hepatic function determined by cytochrome P450-dependent drug metabolism lags after compensatory hepatic volume changes after portal vein ligation in rats.

BACKGROUND: Clinically, portal vein embolization has been proven to be useful as a preoperative treatment for major hepatic surgeries with impaired liver function. However, its effects on the metabolism and elimination of various drugs after portal vein embolization or ligation remain to be elucidated. MATERIALS AND METHODS: A portal vein branch that perfuses the central and left lobes of the liver of male Wistar rat was ligated, and changes in the weights of ligated and nonligated lobules as well as hepatic levels and activities of cytochrome P450 (CYP) isoforms, such as CYP3A2 and CYP2C11, were determined. To evaluate in vivo the effect of PVL on hepatic drug metabolism, the narcotic activity (sleep time) of midazolam, a specific substrate for CYP3A2, was measured. RESULTS: Although plasma levels of alanine aminotransferase and hepatic weight returned to basal levels at day 7 after the portal vein ligation, hepatic activities of CYP3A2 and CYP2C11 still remained low (53% and 54% of control levels, respectively), and returned to their initial levels after about day 14. The metabolism of midazolam was prolonged by approximately three times at day 7 after ligation and returned to basal levels at day 14. CONCLUSIONS: Because hepatic CYP-dependent drug metabolism by CYP isoforms recovered more slowly than the apparent recovery of hepatic volume and plasma alanine aminotransferase levels, the therapeutics of drugs metabolized by the CYP isoforms should be used carefully in patients who receive major hepatectomy with portal vein branch embolization.

Alanine Transaminase↗
PubMed2006

Clinicopathologic characteristics of hepatitis C virus-associated intrahepatic cholangiocarcinoma.

BACKGROUND: Although hepatitis C virus (HCV) infection is a possible pathogenetic factor for intrahepatic cholangiocarcinoma (ICC), clinicopathologic features of ICC patients with HCV infection remain unclear. PATIENTS AND METHODS: Of 50 patients with ICC treated, 19 were infected with HCV (HCV-positive group) and 38 underwent surgical treatment. Clinicopathologic features and postoperative outcome were compared between patients with and without HCV infection. RESULTS: In 15 patients in the HCV-positive group, ICC was detected during follow-up for chronic hepatitis C. The proportion of patients who underwent curative resection was significantly higher in the HCV-positive than in the HCV-negative group, and tumors were significantly smaller in the HCV-positive than in the HCV-negative group. In the HCV-positive group, tumors were significantly smaller in patients who were followed up for chronic hepatitis C than in patients who were not followed up. Although cumulative survival rates did not differ significantly between groups, prognoses of patients with small ICC were significantly better than those with large ICC. CONCLUSION: Follow-up for patients with chronic hepatitis C by imaging series at regular intervals is important and provides the possibility to detect a small ICC as well as a hepatocellular carcinoma. Resection should be guided by liver function and the tumor stage in patients with HCV-associated ICC.

Adult↗
PubMed2006

S-allyl cysteine attenuated CCl4-induced oxidative stress and pulmonary fibrosis in rats.

This study examined effects of S-allyl cysteine (SAC) on carbon tetrachloride (CCl4)-induced interstitial pulmonary fibrosis in Wistar rats. CCl4 (0.5 ml/kg) was intraperitoneally injected into rats twice a week for 8 weeks, and SAC (50, 100, or 200 mg/kg), N-acetyl cysteine (NAC, 200 or 600 mg/kg), or L-cysteine (CYS, 600 mg/kg) were orally administrated to rats everyday for 8 weeks. SAC significantly reduced the increases of transforming growth factor beta, lipid peroxides, AST, and ALT in plasma, induced by CCl4. Although CCl4 is mainly metabolized by hepatic cytochrome P450, CCl4 induced systemic inflammation and some organ fibrosis. SAC dose-dependently and significantly attenuated CCl4-induced systemic inflammation and fibrosis of lung. SAC also inhibited the decrease of thiol levels, the increase of inducible nitric oxide synthase expression, the infiltration of leukocytes, and the generation of reactive oxygen species in lungs. Although NAC and CYS attenuated CCl4-induced pulmonary inflammation and fibrosis, the order of preventive potency was SAC > NAC > CYS according to their applied doses. These results indicate that SAC is more effective than other cysteine compounds in reducing CCl4-induced lung injury, and might be useful in prevention of interstitial pulmonary fibrosis.

Animals↗
PubMed2006

Clinicopathological implications of immunohistochemically demonstrated mucin core protein expression in hepatocellular carcinoma.

METHODS: We examined the expression of mucin core protein 1 (MUC1) immunohistochemically in 186 surgical specimens of histopathologically nonmucinous hepatocellular carcinoma (HCC) and compared the clinicopathological features in patients with MUC1-positive HCC (MUC1-positive group) with those in patients with MUC1-negative HCC (MUC1-negative group). RESULTS: MUC1 immunoreactively was present in 85 of the 186 HCCs. Of the clinicopathological variables examined, the serum concentration of alpha-fetoprotein, tumor differentiation, bile duct invasion, lymph node metastasis, and cytokeratin 19 expression exhibited significant associations with MUC1 expression. Although cumulative and tumor-free survival rates were not different between the two groups, the percentage of patients with first recurrence of HCC in distant organs (distant metastasis) within 2 years after surgery was significantly higher in the MUC1-positive group than in the MUC1-negative group (P = 0.0104). The risk ratio of MUC1 positivity for this type of distant metastasis was 3.156 (95% confidence interval, 1.064-9.358). CONCLUSIONS: In patients with MUC1-positive HCC, careful follow-up is necessary, not only for intrahepatic recurrence but also for distant metastasis, after the resection of primary HCC.

Adult↗
PubMed2006

Immunohistochemical demonstration of c-Kit protooncogene product in gallbladder cancer.

BACKGROUND/PURPOSE: Although some gallbladder carcinomas are immunoreactive for c-Kit, the reasons for the c-Kit expression and its clinicopathologic implications are unknown. METHODS: We investigated the prevalence of c-Kit immunoreactivity, its clinicopathologic correlates (including microvessel density and postoperative outcome), and the possible mechanisms of c-Kit expression. We reviewed retrospectively, the clinicopathologic records of 47 patients who had undergone macroscopically complete gallbladder carcinoma resection. The numbers of patients at pathologic stages I to IV, according to current TNM-based staging, were 10, 5, 18, and 14, respectively. For immunohistochemical examination, we used monoclonal antibodies against c-Kit and CD 34 (progenitor cell markers), cytokeratin 7 and cytokeratin 19 (cholangiocyte markers), and OCH1E5 (a hepatocyte marker). Control tissue samples were from five gallbladder specimens each with chronic cholecystitis, polyp, and adenoma. RESULTS: Cytoplasmic immunostaining for c-Kit was detected in 21 of the 47 gallbladder carcinomas (45%), and in 1 of the 15 control specimens (diagnosis, chronic cholecystitis). Young age was significantly associated with c-Kit positivity; however, there were no significant differences in the incidence of c-Kit positivity among other variables, including tumor stage and outcome. However, microvessel density was significantly higher in c-Kit-positive gallbladder carcinoma compared with c-Kit-negative gallbladder carcinoma. None of the 47 cancer specimens or the 15 control specimens were stained for CD34 and OCH1E5, but all 47 cancer specimens were stained for cytokeratins 7 and 19. CONCLUSIONS: Gallbladder carcinomas positive for c-Kit are unlikely to arise from immature cells, but may be associated with neovascularization. Angiogenesis inhibitors, such as tyrosine kinase inhibitors, therefore, may suppress the growth of some gallbladder cancers.

Adult↗
PubMed2006

Hepatocellular carcinoma arising from nonalcoholic steatohepatitis: report of two cases.

Sporadic cases of hepatocellular carcinoma (HCC) originating from nonalcoholic steatohepatitis (NASH) have recently been reported. Thus, we investigated the prevalence of NASH in patients with HCC. A review of the clinical records of 481 patients who underwent liver resection for HCC in our department between January 1991 and December 2003 revealed only two (0.4%) patients with HCC associated with NASH. Both of these patients had noninsulin-dependent diabetes mellitus, and neither had a history of alcohol consumption or blood transfusion. All serologic markers for hepatitis B and C viruses were negative. Histological examination of the noncancerous hepatic tissue revealed NASH with moderate hepatic fibrosis in one patient and cirrhosis in the other. Thus, clinical follow-up and screening for HCC should be done for patients with hepatic fibrosis caused by NASH, even though this form of hepatitis is an uncommon cause of HCC.

Aged↗
PubMed2005

Vitamin E deficiency accelerates nitrate tolerance via a decrease in cardiac P450 expression and increased oxidative stress.

Organic nitrates, such as nitroglycerin (NTG), have been used to relieve the symptoms of angina pectoris. However, their biochemical mechanisms of action, particularly in relation to the development of tolerance, are incompletely defined. It has been reported that supplemental antioxidants such as vitamin E attenuate the development of nitrate tolerance. Therefore, we examined the role of vitamin E in the regulation of nitrate tolerance. Continuous NTG infusion induced nitrate tolerance in rats after 48 h, and vitamin E concentrations decreased in a time-dependent manner in tissues and plasma. Vitamin E supplementation (0.5 g/kg diet) maintained higher concentrations of vitamin E during NTG infusion. The onset and extent of the tolerance, estimated by the decrease in blood pressure following NTG bolus injection during the infusion of NTG, were accentuated in the vitamin E-deficient group. Vitamin E supplementation inhibited nitrate tolerance 48 h after NTG infusion. Cardiac P450 expression (CYP1A2) assessed by immunoblotting, markedly decreased 48 h after NTG administration in control rats. The supplementation of vitamin E significantly attenuated the decrease in P450. Treatment of NTG enhanced vascular superoxide production (L-012 chemiluminescence, DHE fluorescence). The peak of lipid peroxidation and free radical generation in the heart was reached before tolerance developed. In contrast, vitamin E-deficient hearts had lower P450 expression and higher free radical generation than control hearts. To evaluate other vitamin E-inhibitable mechanisms of nitrate tolerance, we studied the NO-cGMP pathway. NTG markedly reduced the vasodilator-stimulated phosphoprotein (VASP) serine 239 phosphorylation (specific substrate of cGMP-activated protein kinase I; cGK-I) in tolerant hearts. Vitamin E inhibited the depletion of pVASP. In conclusion, because continuous NTG infusion causes vitamin E depletion as well as nitrate tolerance, vitamin E deficiency may further accelerate nitrate tolerance via an increase in oxidative stress, the reduced bioconversion because of decreased P450 expression, and impairment of the NO/cGMP pathway in tolerant heart tissues.

Animals↗
PubMed2005

Alcohol abuse as an etiologic factor for hepatocellular carcinoma in Japan.

The etiologic role of alcoholic liver disease for hepatocellular carcinoma is uncertain. To assess the role of alcoholic liver disease on the development of carcinoma, we examined history of alcohol abuse and viral markers in the sera and/or resected specimens in 454 patients who underwent liver resection for hepatocellular carcinoma. Sera from 20 of the 454 patients were negative for hepatitis B, C, and D viruses. Of the 20 patients, one patient had autoimmune hepatitis, one had primary biliary cirrhosis, two had non-alcoholic steatohepatitis. Of the remaining 16 patients, 8 patients were alcohol abusers and 5 of the 8 patients were heavy alcohol abusers. Hepatitis G virus was not detected in sera form the 16 patients. Although hepatitis B x gene was detected in the cancerous and/or non-cancerous tissues in all three alcohol abusers but not heavy abusers and in 5 of 6 non-alcohol abusers whose surgical specimens were available, the gene was detected in only one of the five heavy alcohol abusers. The five heavy alcohol abusers had advanced hepatic fibrosis and active hepatitis. Alcoholic liver disease with advanced hepatic fibrosis and active hepatitis is a possible cause for the development of hepatocellular carcinoma.

Journal Article↗
PubMed2005

Minoxidil, a K(ATP) channel opener, accelerates DNA synthesis following partial hepatectomy in rats.

A large number of studies have reported the action of K(ATP) channel openers in accelerating the proliferation of hepatocytes and many other cell types in vitro. Few studies, however, have examined the proliferative effect of K(ATP) channel openers in vivo. The aim of this study was to determine whether the K(ATP) channel opener minoxidil accelerates liver regeneration after partial hepatectomy (PH) in vivo. Male Wistar rats underwent a 70% partial hepatectomy (PH) after receiving a subcutaneous injection of minoxidil (0.01 mg/kg or 0.03 mg/kg). Some of the rats were intravenously treated with 5-hydroxydecanoic acid (5-HD, 10 mg/kg) just before the minoxidil injection. Seventy-two hours after PH, DNA synthesis was immunohistochemically assessed by bromodeoxyuridine (BrdU) incorporation into the nuclei. Minoxidil induced significant and dose-dependent increase in the BrdU labeling index after PH, and 5-HD reversed this minoxidil-induced change. Minoxidil did not significantly affect the changes in liver weight and liver function after PH. The hepatic levels of prealbumin decreased by about 60% after PH and minoxidil inhibited the decrease. In conclusion, the K(ATP) channel opener minoxidil enhanced DNA synthesis after PH without affecting the liver function.

Alanine Transaminase↗
PubMed2005

Prognostic effects of causative virus in hepatocellular carcinoma according to the Japan integrated staging (JIS) score.

BACKGROUND: The Japan integrated staging (JIS) score is recognized to be useful in managing hepatocellular carcinoma (HCC). We evaluated the effects of the causative virus in patients stratified by this system. METHODS: We compared clinicopathologic features, cumulative and tumor-free survival rates, and causes of death between 301 hepatitis C virus-positive patients (HCV group) and 60 hepatitis B virus-positive patients (HBV group). RESULTS: Among patients with low JIS scores (0 or 1), the proportions of patients with high aspartate and alanine aminotranferase activities, moderate-to-severe active hepatitis, and with cirrhosis were significantly higher in the HCV than in the HBV group. Among patients with high JIS scores (2 to 4), the proportion with moderate-to-severe active hepatitis was also significantly higher in the HCV group. In patients with low JIS scores, those in the HCV group had significantly lower tumor-free and cumulative survival rates than those in the HBV group. Although no patient in the HBV group died of causes other than liver disease (HCC or hepatic failure), some patients in the HCV group died of causes other than liver disease. The proportion of patients who died because of HCC recurrence tended to be higher among patients with high JIS scores than among patients with a low JIS score. CONCLUSIONS: The effects of viral status on survival outcomes are greatest in patients with JIS scores of 0 or 1.

Carcinoma, Hepatocellular↗
PubMed2005

Type IV collagen 7s domain as a predictor of poor efficacy of portal vein embolization before major hepatectomy.

PURPOSE: We investigated the correlation between serum concentrations of type IV collagen 7s domain (7s collagen) and changes in the volume of the nonembolized liver lobe after subsequent portal vein embolization (PVE). METHODS: The relationship between the pre-embolization results of laboratory tests and the increase in the left lobe volume was evaluated in 32 patients who underwent preoperative PVE via the right portal vein. RESULTS: By 2 weeks after PVE, the mean volume of the left lobe had increased significantly (P < 0.001). The percent increase in the left lobe volume correlated negatively with the pre-embolization serum concentration of 7s collagen (r = -0.472, P = 0.0063). In three of four patients with high serum concentrations (>8 ng/ml), the percent increase was less than 100% and right lobectomy was not performed. The serum 7s collagen concentration correlated with the histologic activity score (r = 0.469, P = 0.0061) and the histologic fibrosis score (r = 0.425, P = 0.0145). CONCLUSION: The serum concentration of 7s collagen may predict the efficacy of PVE. Performing PVE before right lobectomy may not be indicated in patients with high serum concentrations of 7s collagen because the increases in left lobe volume may be insufficient.

Adult↗
PubMed2005

Clinicopathologic features and outcome after liver resection for hepatocellular carcinoma in patients with concurrent versus previous chronic hepatitis B.

PURPOSE: We compared the clinicopathologic features affecting outcome after surgery for hepatocellular carcinoma (HCC) between patients with concurrent and previous chronic hepatitis B. METHODS: Group A consisted of 58 patients with concurrent chronic hepatitis B, defined by seropositivity for the hepatitis B surface antigen (HBsAg), and group B consisted of 18 patients whose HCC was detected after disappearance of the HBsAg. We assessed the influence of various characteristics on outcome. RESULTS: The mean age and percentage of patients suffering from alcohol abuse or diabetes mellitus were significantly greater in group B than in group A, whereas histologic hepatitis activity, hepatic fibrosis, and alanine aminotransferase activity were significantly lower in group B than in group A. The tumor-free survival rates were similar between the two groups, but the risk factors of recurrence differed. In group A, relative youth, high aspartate aminotransferase activity, low platelet count, multiple tumors, large tumor size, portal invasion, cirrhosis, nonanatomic resection, and positive surgical margin were risk factors. In group B, large tumor size and poor differentiation were risk factors. CONCLUSION: Hepatitis B status, tumor factors, and the type of operation affected cancer recurrence after surgery for HCC in patients with concurrent chronic HBV, as opposed to only tumor factors in patients with previous chronic hepatitis B.

Age Distribution↗
PubMed2005

Pseudoaneurysm of the dorsal pancreatic artery with obstruction of the celiac axis after pancreatoduodenectomy: report of a case.

Pancreatoduodenectomy can be difficult in patients with obstruction of the celiac axis because of the development of collateral arteries around the head of the pancreas. Bleeding from a pseudoaneurysm is a rare and serious complication of pancreatoduodenectomy. We report a case of a pseudoaneurysm of an enlarged dorsal pancreatic artery, which formed as a result of obstruction of the celiac axis after pancreatoduodenectomy. We assumed that a weakness in the wall of this dorsal pancreatic artery caused by the dissection led to the formation of the aneurysm. Although transcatheter arterial embolization (TAE) could not treat the aneurysm or stop bleeding from the aneurysm completely, it achieved transient hemostasis, whereby the patient's condition improved, making laparotomy safe. This case demonstrates that the dissection of arteries that have developed around the head of the pancreas must be considered in patients with obstruction of the celiac axis.

Aneurysm, False↗
PubMed2004

FK778 and FK506 combination therapy to control acute rejection after rat liver allotransplantation.

BACKGROUND: In organ transplantation, several immunosuppressants are currently used to control graft rejection. Clinically, no single immunosuppressive agent can completely prevent posttransplantation immunoreaction; thus, combination therapy is usually performed. Novel agents with more powerful immunosuppressive activity and less toxicity need to be developed. METHODS: Lewis rat livers were orthotopically transplanted into Brown-Norway recipients. FK778 was administered orally from day 0 to day 6 to prevent acute rejection and from day 7 to day 13 to rescue ongoing rejection. To assess the combined effects, recipients were treated with intramuscular injection of FK506 and oral administration of FK778 from day 0 to day 6. Blood chemistry and histopathologic findings were measured to determine the patient's general condition and the graft condition. Allospecific antibodies were measured using enzyme-linked immunosorbent assays. The FK778 trough concentration was examined by using high-performance liquid chromatography. RESULTS: The acute immune response was suppressed by FK778 alone in a dose-dependent manner. The optimal FK778 dosage was determined to be 20 mg/kg per day, because adverse effects (weight loss and intestinal bleeding) occurred at 30 mg/kg per day. FK778 treatment from day 7 to day 13 rescued liver grafts from ongoing rejection. The intramuscular FK506 (0.125 mg/kg per day) injection and the oral FK778 (20 mg/kg per day) gavages suppressed acute liver graft rejection effectively and maintained better graft condition compared with monotherapy. CONCLUSIONS.: FK778 treatment effectively prevented acute rejection and rescued ongoing rejection after liver transplantation. The optimal dosage was determined to be 20 mg/kg per day. Combination therapy with FK506 was more beneficial than FK778 monotherapy.

Acute Disease↗