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T Okanoue

Publications and source records attributed to T Okanoue.

At least 73 records · Page 4Linked to original sources
PubMed1997

Ursodeoxycholic acid enhances glucocorticoid-induced tyrosine aminotransferase-gene expression in cultured rat hepatocytes.

Ursodeoxycholic acid (UDCA) is an effective treatment for immune-mediated liver diseases, suggesting that UDCA is functionally similar to glucocorticoids (GCs). We investigated the effects of UDCA on the enzyme activity and the mRNA levels of tyrosine aminotransferase (TAT), a hepatocyte-specific marker of GC action, in primary cultured rat hepatocytes. Addition of UDCA resulted in a significant increase in TAT activity in the presence of dexamethasone (DEX), compared with DEX alone, and this increase was completely suppressed by sphingosine, a protein kinase C (PKC) inhibitor, or actinomycin D, a transcriptional inhibitor. UDCA could not induce TAT activity in the absence of DEX. UDCA increased the TAT mRNA levels in the presence of DEX. In conclusion, UDCA enhances the GC-induced TAT-gene expression in hepatocytes, and UDCA-activated PKC may play a role in this upregulation.

Animals↗
PubMed1997

Expression of IFN-inducible protein-10 in chronic hepatitis.

Chemokines such as IFN-inducible protein-10 (IP-10) and JE/monocyte chemotactic protein-1 (MCP-1) are induced in the murine liver in a tissue-specific manner. We examined whether IP-10 and MCP-1 are pathologically involved in chronic hepatitis. Whereas the serum levels of IP-10 and MCP-1 in patients with chronic persistent hepatitis C were elevated compared with those in normal volunteers, both chemokine levels were further significantly higher in patients with the active form (chronic active hepatitis (CAH)). The elevated IP-10 level was not a general phenomenon of inflammation, because it was not seen in patients with rheumatoid arthritis, whereas MCP-1 levels were elevated to the same extent in both patient groups. Better responsiveness to IFN therapy in CAH was related to lesser grades of necroinflammatory activity and was predicted by the lower IP-10 and higher MCP-1 levels. IP-10 levels in patients cured by IFN therapy decreased to the levels in normal volunteers, while the MCP-1 levels only slightly decreased. Serum levels of both chemokines in patients who were not cured remained unchanged after IFN therapy. In situ hybridization analysis of CAH revealed that IP-10 mRNA was expressed mainly in hepatocytes around intralobular focal and periportal piecemeal necrosis, while some MCP-1 mRNA was expressed in some sinusoidal cells. These results suggested that IP-10 plays a specific role in the intralobular accumulation of mononuclear cells and/or the death of hepatocytes in chronic hepatitis.

Chemokine CCL2↗
PubMed1997

The effects of prednisolone and interferons on serum macrophage colony stimulating factor concentrations in chronic hepatitis B.

BACKGROUNDS/AIMS: Serum concentrations of macrophage-colony stimulating factor (M-CSF) are increased in parallel with hepatic inflammation. The aim of this study was to assess the immunologic significance of elevated M-CSF in patients with chronic hepatitis B virus infection. METHODS: The subjects included 20 asymptomatic HBV carriers and 45 patients with chronic hepatitis B, including 8 undergoing prednisolone treatment, 10 experiencing an acute exacerbation, and 12 undergoing daily administration of interferons. RESULTS: Serum concentrations of M-CSF significantly decreased during prednisolone administration, but significantly increased following prednisolone withdrawal, similar to the increase during acute exacerbation. Changes in the lipopolysaccharide-stimulated production of interleukin-1-beta and tumor necrosis factor-alpha by peripheral whole blood, or of interferon-gamma by peripheral blood mononuclear cells showed a similar pattern. Serum concentrations of M-CSF did not correlate with the titers of HBV-DNA or HBV-DNA polymerase activity. However, serum M-CSF peaked preceding seroconversion to HBe antibody in three HBe antigen positive patients. Exogenous interferon-alpha, -beta, or -gamma induced significant elevation in serum M-CSF concentrations, irrespective of changes in the serum alanine aminotransferase levels. CONCLUSIONS: Increased serum M-CSF is closely associated with increased serum interferons and/ or proinflammatory cytokines produced by peripheral blood cells during hepatic inflammation in chronic hepatitis B. This may be a consequence of the altered cytokine cascade resulting from the host immune response against hepatitis B virus.

Adolescent↗
PubMed1997

Role of calcitonin gene-related peptide in the vascular system on the development of the hyperdynamic circulation in conscious cirrhotic rats.

BACKGROUND/AIMS: Calcitonin gene-related peptide (CGRP), a potent vasodilator; plays an important role in modulating vascular tone, acting as a noncholinergic nonadrenergic neurotransmitter. The aim of this study was to assess the role of CGRP, present in the vascular system, in the development of the hyperdynamic circulation observed in liver cirrhosis. METHODS: Two doses of human alpha-CGRP [8-37], a specific antagonist of CGRP, were administered to cirrhotic and controls rats. Hemodynamics were evaluated using radioactive microspheres in conscious animals. To investigate the arterial depressor effect of exogenous CGRP, we constructed a dose-response curve for mean arterial pressure in cirrhotic and control rats by administering human alpha-CGRP. RESULTS: The administration of high-dose human alpha-CGRP [8-37] (300 nmol.kg body weight-1.min-1) significantly increased both the mean arterial pressure (21 +/- 2 vs. 13 +/- 1%, p < 0.01) and total vascular resistance (76 +/- 5 vs. 54 +/- 5%, p < 0.01) in cirrhotic rats, compared to control rats. The splanchnic hemodynamic effects induced by human alpha-CGRP [8-37] were a significant decrease in percent change of portal venous inflow -42 +/- 3 vs. -33 +/- 3%, p < 0.05) and a significant increase in percent change of splanchnic arterial resistance (110 +/- 9 vs. 76 +/- 5%, p < 0.01) in cirrhotic rats, compared to control rats. Low-dose human alpha-CGRP [8-37] (60 nmol.kg body weight-1. min-1) caused similar hemodynamic changes, but the degree of change was much less than for the high-dose administration. The vascular response to human alpha-CGRP was significantly reduced in cirrhotic rats as compared to controls (ANOVA, p < 0.01). Plasma concentrations of CGRP were significantly elevated in cirrhotic rats. CONCLUSIONS: CGRP in the vascular system was involved in the modulation of vasodilatation in rats with liver cirrhosis, as demonstrated by the administration of a selective CGRP antagonist and exogenous CGRP.

Animals↗
PubMed1997

Intercellular adhesion molecule-1 and CD18 are involved in neutrophil adhesion and its cytotoxicity to cultured sinusoidal endothelial cells in rats.

The expression of several adhesion molecules is increased on the hepatic sinusoidal endothelial cells (SECs) in various liver diseases. The objective of this study is to assess the roles of intercellular adhesion molecule 1 (ICAM-1) and of CD18 in the interaction between the neutrophils (polymorphonuclear leukocytes [PMNs]) and SECs and in the injury to SECs mediated by PMNs. Rat PMNs was perfused on SECs stimulated with tumor necrosis factor alpha (TNF-alpha) using an in vitro flow system. The number of adhered PMNs to SECs and that of PMNs migrated under SECs was counted and the effects of anti-ICAM-1, anti-CD18, and dexamethasone were studied. We also define the effect of these antibodies on the SEC injury mediated by PMNs stimulated with phorbol 12-myristate 13-acetate (PMA) or N-formyl-methionyl-leucyl-phenylalanine (fMLP). TNF-alpha significantly increased the adhesion of PMNs to SECs (322 +/- 26 cells/mm2) compared with controls (194 +/- 22 cells/mm2). Anti-ICAM-1 and anti-CD18 significantly inhibited the adhesion of PMNs (131 +/- 10 and 51 +/- 30 cells/mm2, respectively). These antibodies also decreased the migration rate of PMNs (6.0% and 7.9%, respectively) compared with controls (migration rate, 21.2%). The SEC injury induced by PMA- and fMLP-activated PMNs was prevented by anti-ICAM-1 and anti-CD18. The adhesion of PMNs induced by TNF-alpha was inhibited by the treatment with dexamethasone (160 +/- 20 cells/mm2) via a down-regulation of ICAM-1 expression on SECs. The interactions between ICAM-1 and CD18 appeared to be important in the adhesion and the migration of PMNs to SECs. The injury to SECs was induced by the close interaction between the activated PMNs and SECs mediated via ICAM-1 and CD18.

Animals↗
PubMed1997

Hepatic damage influences the decay of nitroxide radicals in mice--an in vivo ESR study.

To determine the role of the liver in the elimination of free radicals from the body, the clearance rate (K) of nitroxide radicals (Tempol) at the hepatic domain was compared with that at the pelvic domain of live mice, using L-band ESR spectroscopy. The reduction of Tempol in biopsy specimens (liver tissue and femoral muscle) and blood obtained from Tempol-treated mice was also monitored using X-band ESR spectroscopy. Results indicated that the reduction of nitroxide radicals was delayed in both the liver and peripheral tissues when the liver was damaged. The decrease in both blood supply and reductants in the damaged liver might be involved in delaying the reduction in the whole body, because the liver can reduce the radicals supplied via the blood from the peripheral tissues, and the reductants such as reduced, glutathione in the peripheral tissues are supplied from the liver.

Animals↗
PubMed1996

Cytogenetic analyses of hepatocellular carcinoma by in situ hybridization with a chromosome-specific DNA probe.

BACKGROUND: Numerical chromosome analysis has been established in solid tumors by using in situ hybridization (ISH) with a chromosome-specific probe. We analyzed human hepatocellular carcinoma (HCC) by ISH for chromosome 17 and investigated the correlation of its copy number with histologic malignancy, proliferative activity, p53 mutation, and DNA ploidy. METHODS: Chromosome 17 was hybridized with a pericentromere-specific DNA probe directly on the tumor cells isolated from paraffin blocks of 25 surgically resected HCCs. Proliferative activity was measured by Ki-67 immunohistochemistry, p53 mutation was analyzed by p53 immunohistochemistry, and DNA ploidy was estimated by cytofluorometry. RESULTS: Forty-four percent of the 25 HCCs showed numerical abnormality of chromosome 17. Many disomic cases had a less malignant histology, whereas many polysomic cases had a more malignant histology. The Ki-67 positive index of polysomic cases was higher than that of disomic cases. In 22 cases (88.0%), the copy number of chromosome 17 was well matched with DNA ploidy. However, the numerical abnormality of chromosome 17 did not show a significant correlation with p53 mutation. Two of four HCCs that showed histologic heterogeneity were also heterogenous on ploidy pattern and the copy number of chromosome 17. Conversely, there was one case in which only ISH could demonstrate heterogeneity, although the other features exhibited homogeneity. CONCLUSIONS: Numerical chromosome abnormalities correlated with the increase of histologic malignancy proliferative activity, and DNA ploidy. Moreover, ISH analysis was useful in assessing the intratumoral heterogeneity in HCC, especially when current methods failed to detect it. Thus, ISH provides information on important biologic features, such as malignant potential and intratumoral heterogeneity, in HCC.

Adult↗
PubMed1996

Ischemic colitis during interferon-alpha treatment for chronic active hepatitis C.

Between 1991 and 1994, at Hoshigaoka Koseinenkin Hospital, we treated 280 patients with chronic hepatitis C with interferon (IFN), and ischemic colitis occurred in two patients (0.7%) during the treatment. Melena appeared in case 1 in the 2nd month after the initiation of IFN-alpha treatment, and in case 2 in the 6th month. In both patients, longitudinal ulcerations in the descending colon were revealed by urgent colonoscopy, and these resolved within 2 weeks after discontinuation of the IFN treatment. It appears that ischemic colitis was associated with the IFN treatment, suggesting that attention should be paid to this possible complication.

Aged↗
PubMed1996

Side effects of high-dose interferon therapy for chronic hepatitis C.

BACKGROUND/AIMS: Various side effects have been reported in patients treated with alpha interferon, but their incidence and prognosis remain unknown. METHODS: Nine hundred and eighty-seven patients with chronic active hepatitis C received 6 to 10 MU of alpha interferon per day for 2 weeks and 3 times per week for 22 weeks. Autoantibodies, thyroid function tests, and fasting plasma glucose concentrations were evaluated prior to alpha interferon therapy. RESULTS: Of the 987 patients, 310 were required reduction in the dose of alpha interferon to 3 MU/day or cessation of alpha interferon therapy because of adverse reactions such as flu-like symptoms, leukopenia, and thrombocytopenia. Of the remaining 677, five developed diabetes mellitus, 12 had hyperthyroidism, and six acquired hypothyroidism. Of the 18 with thyroid disorders, five demonstrated antimicrosomal antibodies before therapy. Forty-four patients revealed high or low concentrations of thyroid stimulating hormone at the end of alpha interferon therapy. Three patients developed interstitial pneumonia, one acquired systemic lupus erythematosus-like syndrome, two had autoimmune hepatitis, two developed rheumatoid arthritis, and one developed autoimmune thrombocytopenic purpura. No patients had a history of an autoimmune disorder. One patient experienced sudden hearing impairment and one had retinal detachment. Melena was seen in three patients; two of these cases were compatible with ischemic colitis. Symptoms of depression were seen in 23 patients, and one patient manifested memory loss. CONCLUSION: High-dose alpha interferon therapy induces various adverse effects. Most of the side effects cannot be predicted, but are reversible.

Adult↗
PubMed1996

Precore/core mutations of hepatitis B virus in hepatocellular carcinomas developed on noncirrhotic livers.

BACKGROUND & AIMS: Hepatitis B virus genomes have been detected in hepatocellular carcinoma developed without the pretumoral step of cirrhosis; this finding is consistent with a direct effect of the virus in liver cell transformation. The aim of this study was to investigate the molecular bases for the hepatitis B virus persistence. Three hepatitis B surface antigen-positive and 2 hepatitis B surface antigen-negative patients with hepatocellular carcinoma and without cirrhosis were studied for precore/core mutations in tumorous and nontumorous tissues. METHODS: The precore/core region was amplified and analyzed both by cloning and sequencing and by direct sequencing. RESULTS: Nonsynonymous mutations were identified selectively in tumorous tissues. Clusters of mutations were identified in the viral encapsidation (epsilon) signal, in immunodominant epitopes of the core protein, and in the polymerase. Common associated point mutations were found in 3 patients infected with hepatitis B virus genotype A in the epsilon signal and in the polymerase gene. CONCLUSIONS: Precore/core mutations located in domains involved in hepatitis B virus replication and immune response to the virus were identified. The selective presence of some of these mutations in tumorous tissues is consistent with their role in the persistence of the virus in neoplastic cells and, possibly, in liver oncogenesis.

Adult↗
PubMed1996

Relationship between hepatocellular carcinoma and subtypes of hepatitis C virus: a nationwide analysis.

Although hepatitis C virus (HCV) has now been classified into several subtypes, the clinical significance of HCV subtypes is not well known. Typing of HCV is now routinely performed in Japan. In the present study, HCV subtypes in hepatocellular carcinoma (HCC) patients were analysed from nationwide data collected in Japan using a standard questionnaire. Answers to the questionnaire concerning HCV subtypes in patients with chronic hepatitis (CH), liver cirrhosis (LC) and HCC were obtained from 14 hospitals. The prevalence of the 1b-related subtype, which includes the mixed subtype of 1b and 2a or 2b, in patients with LC and HCC in each hospital was higher than in patients with CH, with few exceptions. However, the differences were not statistically significant because of the small number of patients in each hospital. In summarized data from all 14 hospitals, the 1b-related subtype was found in 1370 of 1922 patients with CH (71.2%). In 356 LC and 426 HCC patients, the prevalence of the 1b-related subtype was 79.8 and 80.5%, respectively. The prevalence of the 1b-related subtype in patients with LC and HCC was significantly higher than in patients with CH. There was no significant difference between the prevalence of the 1b-related subtype in patients with HCC and LC. These results indicate that the oncogenic activity of subtype 1b, although not yet clearly characterized, may be stronger than subtypes 2a and 2b.

Carcinoma, Hepatocellular↗
PubMed1996

Distribution of the different subtypes of hepatitis C virus in Japan and the effects of interferon: a nationwide survey.

Interferon (IFN) is now commonly used for the treatment of type C hepatitis; however, its effects differ depending upon the subtype of hepatitis C virus (HCV) being treated. It has been recently confirmed in many studies in Japan that the effectiveness of IFN treatment is poor in patients having type 1b and better in patients having type 2a HCV. However, the effects of IFN treatment on other subtypes of HCV were not clear because of the small number of patients in each hospital. In the present study, the effects of IFN treatment in patients with other HCV subtypes were analysed from nationwide data collected in Japan using a standard questionnaire. From this questionnaire, local differences in the distribution of HCV subtypes in Japan were also analysed. A standard questionnaire, consisting of questions about the number of patients with chronic type C hepatitis with different HCV subtypes and the number of patients showing different responses to IFN treatment, was sent to over 40 study groups in Japan. Answers to the questionnaire concerning HCV subtypes and the effects of IFN treatment were obtained from 26 and 22 hospitals, respectively, throughout Japan. The incidence of HCV type 1b was highest in the Kinki area (south-central Japan). The incidence of type 1b HCV decreased in parallel with distance from this area. The mortality rates of hepatic cancer in different areas were significantly correlated with the incidence of HCV type 1b. The efficacy of IFN treatment was significantly better for both types 2a and 2b HCV than for type 1b HCV; the efficacy of IFN treatment was poor in the mixed type of 1b and 2a and tended to be better in type 1a. The efficacy of IFN treatment for other types of HCV was also better. These results indicate that there are local differences in the distribution of HCV subtypes in Japan and that these differences may be closely associated with the clinical features of HCV-related liver disease. The efficacy of IFN treatment was significantly poorer in patients with the 1b-related type HCV than in patients with other types of HCV.

Carcinoma, Hepatocellular↗
PubMed1996

Synthesis of secretory protein in regenerating liver of rat after partial hepatectomy.

Albumin immunoreactivity in the liver was examined on days 2, 5 and 10 after two-thirds partial hepatectomy by light and ultrastructural immunoperoxidase methods and the ultrastructural area of the rough endoplasmic reticulum (ER) in hepatocytes was measured. Albumin immunoreactivity was seen in the rough ER and Golgi apparatus of all hepatocytes in the hepatectomized liver and ultrastructural analysis showed a significantly greater area of rough ER on day 5 than on days 2 or 10. Albumin mRNA was studied by the in situ hybridization technique using radioisotopes and their numbers were determined visually. Albumin mRNA was present as grains in all hepatocytes and the grains varied in number during regeneration of the liver, being more abundant on day 5 than on days 2 or 10. The activity of [3H]-leucine incorporated into albumin synthesis, an indicator of translational activity, was higher on days 5 and 10 than on day 2 and was highest on day 5. In conclusion, albumin synthesis varied during liver regeneration after partial hepatectomy, being reduced at the peak of cell proliferation on day 2 and being most active on day 5.

Albumins↗
PubMed1996

Haemodynamic effects of combined treatment with molsidomine and propranolol on portal hypertension in conscious and unrestrained cirrhotic rats.

We investigated the systemic and splanchnic haemodynamic effects of combined treatment with molsidomine and propranolol on cirrhotic rats. Liver cirrhosis was produced by repeated intraperitoneal injections of thioacetamide. The blood flow of each organ was measured serially using the radioactive microsphere method in the awake state before and after the administration of each agent. Cirrhotic rats received molsidomine (0-.5 mg/kg), propranolol (0.1 or 0.2 mg/min), both agents or placebo. Combination treatment with molsidomine and 0.1 mg/min propranolol significantly reduced portal pressure compared with molsidomine or propranolol alone (21 +/- 4 vs 15 +/- 3 or 11 +/- 2% P < 0.05). Systemic haemodynamic changes with this combined treatment were mild. This combined treatment slightly inhibited the molsidomine-induced decrease in portal vascular resistance (27 +/- 9 vs 31 +/- 6; NS) and markedly inhibited the molsidomine-induced decrease in splanchnic arterial resistance (7 +/- 6 vs 27 +/- 5% P < 0.05). Compared with low-dose propranolol administration, the combined treatment was associated with a significant decrease in portal vascular resistance (27 +/- 9% decrease vs 2 +/- 2% increase; P < 0.001) and a significant decrease in splanchnic arterial resistance (7 +/- 6% decrease vs 5 +/- 4% increase P < 0.05). The combination of molsidomine and high-dose propranolol (0.2 mg/min) caused a marked reduction in portal venous inflow, mean arterial pressure and cardiac index. We conclude that propranolol enhances the molsidomine-induced decrease in portal pressure by splanchnic vasoconstriction in association with a slight decrease in portal vascular resistance. The combination therapy with molsidomine and low-dose propranolol combination had more beneficial and less harmful effects on systemic and splanchnic haemodynamics and thus appears to be a superior method for treating portal hypertension.

Animals↗
PubMed1996

Circulating HCV-RNA, HCV genotype, and liver histology in asymptomatic individuals reactive for anti-HCV antibody and their follow-up study.

The present study was aimed to clarify the virologic status, liver histologies, and the results of follow-up liver tests in symptom-free individuals with anti-HCV antibodies and normal liver tests. Forty-nine individuals with normal liver tests and positive second generation anti-HCV antibody assay were entered into this study. Cases with hepatitis C viremia were evaluated for HCV genotype, amount of circulating HCV-RNA, and liver histology and were followed-up for more than one year. Of the forty-nine individuals, 36 had hepatitis C viremia, indicated by polymerase chain reaction (PCR) assay. Liver histology was as follows: 3 had non-specific changes, 25 had chronic persistent hepatitis (CPH), and 8 had chronic active hepatitis (CAH). Twenty-four cases with CPH and CAH developed an elevated AST and/or ALT concentration (> 30 IU/l) between 12 and 32 months of follow-up. The amount of circulating HCV-RNA ranged from 10(2) to 10(7) copies/50 microliters serum. The distribution of HCV genotypes was nearly the same as that for symptomatic CAH. These data suggest that the histological examination and follow-up examination are very important for following symptom-free individuals with hepatitis C viremia because there are some candidates for interferon therapy among them. There are few individuals who will remain healthy among asymptomatic HCV carriers.

Adult↗
PubMed1996

Endogenous nitric oxide production is augmented as the severity advances in patients with liver cirrhosis.

1. Since endothelium-derived nitric oxide (NO) is a potent vasodilator and degraded into nitrous ions, we measured the serum nitrate ion (NO3-) and the amount of urinary excretions of NO3- as an index for endogenous NO to ascertain whether NO formation is augmented in patients with chronic liver diseases. 2. Using inpatients suffering from chronic liver diseases, serum levels and urinary excretions of NO3- were measured by using high-performance liquid chromatography with an anion exchange column. 3. Among the four patient groups of normal controls, and those with chronic liver diseases such as chronic active hepatitis, compensated cirrhosis, and decompensated cirrhosis the serum level of NO3- showed the highest level in a patient group with decompensated cirrhosis. The amount of urinary excretion of NO3- was significantly increased in both groups of patients with liver cirrhosis compared with the control group and patients with chronic active hepatitis. Patients with chronic active hepatitis did not show any difference between the normal control group. The amount of urinary excretion of NO3- correlated significantly and negatively with the level of serum albumin (P < 0.05) and counts of platelets (P < 0.01) in patients with compensated cirrhosis. 4. These findings suggest that the production of endogenous NO is augmented in patients with liver cirrhosis, particularly in a decompensated subgroup. Increases in the production of endogenous NO correspond to the progress of liver cirrhosis, but not in patients with chronic hepatitis.

Adult↗