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Biomedical subjects

M Horimoto

Publications and source records attributed to M Horimoto.

At least 37 records · Page 2Linked to original sources
PubMed1998

Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma.

Mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) is a key molecule in intracellular signal transducing pathways that transport extracellular stimuli from cell surface to nuclei. MAPK/ERK has been revealed to be involved in the physiological proliferation of mammalian cells and also to potentiate them to transform. However, its role in the outgrowth of human hepatocellular carcinoma (HCC) has yet to be clarified. Therefore, in this study, we investigated the activation of MAPK/ERK and its associated gene expression in HCC. MAPK/ERK was activated in 15 of 26 cases of HCC we examined (58%), and its activity level was significantly higher in HCC than in the adjacent non-cancerous lesions. Besides, MAPK/ERK activation in HCC was positively correlated with protein expression of transcription factor c-Fos. Furthermore, in 25 of 26 cases of HCC which genomic DNA was available, 22 cases without genomic DNA amplification exhibited positive correlation, not only between protein expression of c-Fos and cyclin D1, but also between MAPK/ERK activation and cyclin D1 expression. Concerning the relationship between MAPK/ERK activation and the clinicohistopathological features of HCC, the tumor (HCC) versus non-tumor (non-cancerous counterpart) ratio (T/N) of MAPK/ERK activity was positively correlated with tumor size, but neither with the stage of HCC nor the degree of differentiation of HCC. In conclusion, these findings suggest that MAPK/ERK activation in human HCC may play an important role in multistep hepatocarcinogenesis, especially in the progression of HCC; at least in part, through cyclin D1 up-regulation primarily induced by MAPK/ERK via c-Fos.

Aged↗
PubMed1998

Involvement of growth factor receptor-bound protein-2 in rat hepatocyte growth.

Growth factor receptor-bound protein-2 (GRB-2) is a protein linking receptor tyrosine kinase and Sos (Son of Sevenless gene; Ras GDP/GTP exchange protein), leading to activation of the Ras-mitogen-activated protein kinase (MAPK) cascade. So far, it remains unclear how GRB-2 plays a role in signal transduction pathways evoked by hepatotrophic factors. This study was attempted to evaluate the involvement of GRB-2 in signalling in rat hepatocyte growth. Using rat cultured hepatocytes stimulated by hepatotrophic factors and regenerating livers after partial hepatectomy (PH) we examined GRB-2-mediated linkage of hepatotrophic factor receptors to signal transducing molecules such as Sos or dynamin-II by immunoprecipitation and western blot analysis. In primary cultured hepatocytes stimulated with hepatocyte growth factor (HGF) or epidermal growth factor (EGF), GRB-2 linked HGF receptor or EGF receptor, respectively, to Sos which activated the mitogen-activated protein kinase (MAPK) cascade. In contrast, in primary cultured hepatocytes stimulated with insulin, GRB-2 linked insulin receptor substrate-1 (IRS-1) to dynamin-II as well as Sos. In the early phase after PH, GRB-2 activated the Ras-MAPK cascade by linking HGF receptor, IRS-1, or EGF receptor to Sos. In the late phase after PH, a complex of IRS-1-GRB-2 associated with dynamin-II, indicating that GRB-2 may transduce signals from IRS-1 to dynamin-II. We conclude that GRB-2 may play a role in transmitting signals from hepatotrophic factors to not only MAPK but also to other signalling pathways in hepatocyte growth.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Familial evidence of vasospastic angina and possible involvement of HLA-DR2 in susceptibility to coronary spasm.

An association between genetic factors and susceptibility to coronary spasm has not been proven. Because we encountered 7 patients with familial occurrence of vasospastic angina (VSA) in 3 families, the association of a genetic factor with coronary spasm was assumed. HLA typing as one of the genetic markers was performed in the 3 families, and the affected members in each family were found to share a HLA haplotype, carrying both HLA-DR52 and DQ6. This raised the possibility that one of the susceptibility genes for coronary spasm is located in the HLA region. To assess this possibility, HLA typing was performed and compared in 110 patients with VSA but without a family history of VSA (VSA group) and 55 patients with chest pain syndrome (CPS group) as control subjects. All patients underwent a provocation test for coronary spasm, and spasm was angiographically documented in the VSA group but not in the CPS group. Of all HLA antigens, the frequency of only HLA-DR2 was significantly higher in the VSA group than in the CPS group (39.1% vs 18.2%, p<0.01). The result implied that HLA-DR2 is in linkage disequilibrium with a susceptibility gene of VSA and thus is possibly involved in susceptibility to coronary spasm in some patients with VSA.

Adult↗
PubMed1998

Head-up tilt test combined with isoproterenol infusion provokes coronary vasospastic angina.

The association of the autonomic nervous system with coronary vasospasm has been controversial. The aim of the present study was to examine the involvement of the autonomic nervous system in coronary vasospasm by applying the head-up tilt (HUT) test to patients with coronary vasospastic angina. Fifteen consecutive patients with coronary vasospastic angina and without significant organic coronary stenoses underwent the HUT test. Prior to the test, coronary spasm was documented angiographically by using an intracoronary injection of acetylcholine or ergonovine. The HUT test was performed in the early morning and repeated in the afternoon if the test was positive in provoking angina pectoris and syncope or presyncope. If the test was negative, it was repeated under intravenous infusion of isoproterenol at a rate of 1-2 microg/min. The HUT test under isoproterenol infusion in the morning provoked vasospastic angina with syncope or presyncope in 9 of the 15 patients. In the test-positive group, heart rate was significantly reduced (104+/-17 beats/min to 84+/-25 beats/min, p<0.05), which preceded a reduction in systolic blood pressure (158+/-25 mmHg to 125+/-17 mmHg, p<0.001), angina attack and syncope. The HUT test without isoproterenol infusion in the morning and the HUT test in the afternoon with or without isoproterenol infusion failed to provoke angina. The heart rate reduction preceding reduced systemic blood pressure and anginal attack suggested that parasympathetic nerve excitation plays an important role in coronary vasospasm. The results also implied that the HUT test combined with isoproterenol infusion is useful for the provocation of coronary spasm.

Acetylcholine↗
PubMed1998

Rearrangement of the ventricular capillary network in stroke-prone spontaneously hypertensive rats (SHRSP) following a late start of treatment with the angiotensin converting enzyme blocker temocapril.

The effects of the angiotensin converting enzyme (ACE) blocker temocapril on the capillary network of the left ventricle were studied in stroke-prone spontaneously hypertensive rats (SHRSP). The ACE blocker was dissolved in the drinking water and supplied to 24 and 32 week old SHRSP ad libitum for 5 weeks. The capillaries of the wall of the left ventricle were studied using a double staining method to differentiate the arteriolar, intermediate and venular capillary portions. Capillary density increased and capillary domain areas decreased in all capillary portions compared with untreated control SHRSP in both age groups. The proportion of venular capillary portions was increased by temocapril treatment. The results indicate that the late start of ACE blockade caused the regression of the hypertrophied cardiomyocytes, which is characteristic of SHRSP, and the rearrangement of capillary portions. The plasma concentration of angiotensin II was significantly lower in temocapril-treated SHRSP compared to the control group. The implication is that intrinsic angiotensin II exerts an appreciable effect on the function, structure and capillary network in the left ventricular wall in SHRSP.

Angiotensin II↗
PubMed1998

Reproductive study. II: Prenatal and postnatal development study with candoxatril in Sprague-Dawley rats.

Candoxatril, a prodrug for candoxatrilat, a selective inhibitor of neutral endopeptidase, was administered orally to groups of 24 female rats at doses of 0, 120, 400 or 1200 mg/kg/day from gestation day 6 to lactation day 21 to assess effects on pre- and postnatal development of F1 offspring. All dams were allowed to litter and to raise their F1 offspring until lactation day 21. The F1 offspring were examined for postnatal developmental indices, reflex behaviors and memory. A functional observational battery (FOB) was also conducted. A marked increase in spontaneous activity of the dams was observed in all candoxatril-treated groups. Maternal body weight gain was decreased in the 400 and 1200 mg/kg/day groups during the treatment periods. No significant differences were found for reproductive parameters. The male and female pups in the 1200 mg/kg/day group had significantly lower body weights beginning on postnatal days 21 and 14, respectively, through to the end of the study. There were no drug-related effects on pre- and postnatal developmental indices, FOB, sensory function tests or memory test. The no observed adverse effect levels were 120 and 400 mg/kg/day for the F0 dams and F1 offspring, respectively.

Animals↗
PubMed1997

Binding cells of 125I-iodoamphetamine in rat liver.

We recently reported that transrectal or intestinal portal scintigraphy with 123I-iodoamphetamine (IMP) could be a useful method for the non-invasive and quantitative evaluation of the portosystemic shunt in portal hypertension, but what cells in the liver trap IMP has not been clarified. This study was aimed at elucidating whether IMP was extracted by parenchymal cells, sinusoidal endothelial cells, Kupffer cells or fat storing cells. Each type of liver cell was isolated from rats and cultured. The cells were incubated with 125I-IMP and the radioactivity of the lysate was determined. Nonspecific binding was assessed in the presence of an excess of unlabeled IMP, and specific binding was determined by subtracting the nonspecific from total binding. Specific binding observed in parenchymal cells, endothelial cells and Kupffer cells was 70.2 +/- 0.4, 4.2 +/- 1.4 and 2.3 +/- 0.8 pmol/well, respectively, but no specific binding was observed in fat storing cells. The binding in parenchymal cells was much higher than that in endothelial cells or Kupffer cells (p < 0.005). In addition, the binding to parenchymal cells reached equilibrium within 20 min and was not saturable over the concentration range tested (0.5-10 microM). These findings indicate that IMP is mostly extracted by parenchymal cells in the liver.

Amphetamines↗
PubMed1997

Galactosyl transfer onto p-nitrophenyl beta-D-glucoside using beta-D-galactosidase from Bacillus circulans.

beta-D-Gal-(1-->4)-beta-D-Glc-OC6H4NO2-p and its isomers (beta-D-Gal-(1-->3)-beta-D-Glc-OC6H4NO2-p and beta-D-Gal-(1-->6)-beta-D-Glc-OC6H4NO2-p) were synthesized from lactose and beta-D-Glc-OC6H4NO2-p, using transglycosylation by the beta-D-galactosidase from Bacillus circulans. This reaction was efficient enough for us to do a one-pot preparation of galactosyl-glucoside from lactose. The order of the production of the transfer products was (1-->4) > > (1-->3) > (1-->6) in the initial stage of the reaction, and the same relationship was observed for the hydrolytic rate toward the three galactosyl-glucosides. The production of (1-->4)- and (1-->3)-linkages greatly decreased during the subsequent reaction and much more of the (1-->6)- than of the (1-->4)- and (1-->3)-transfer products was found in the later stage of the reaction.

Bacillus↗
PubMed1996

High expression of heparin-binding EGF-like growth factor in rat hepatocarcinogenesis.

Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a member of the EGF family and is highly expressed in hepatoma tissues but not in normal liver. However, it is unknown when HB-EGF is induced during hepatocarcinogenesis and what are the mechanisms underlying its high expression in hepatoma. To address this issue, the expression of HB-EGF was investigated during hepatocarcinogenesis in LEC (Long-Evans with a cinnamon-like coat color) rats, which spontaneously develop hepatitis and hepatoma. LEA (Long-Evans with an agouti coat color) rats were used as controls. Furthermore, the induction of HB-EGF mRNA by various agents was investigated in a rat hepatoma cell line and hepatocytes in primary culture. Expression of HB-EGF mRNA in the liver was very low at the stage of acute and chronic hepatitis and markedly increased at the stage of hepatoma in LEC rats. Non-involved tissues adjacent to hepatoma showed low expression of HB-EGF mRNA. Immunochemical studies revealed positive staining in hepatoma tissues. Induction of HB-EGF mRNA by several growth factors was observed in a hepatoma cell line but not in normal hepatocytes. Our results suggest that HB-EGF is associated with the early progression steps of hepatoma.

Animals↗
PubMed1996

Bilateral internal carotid artery disease secondary to cervical radiation. A case report.

A patient with radiation-induced bilateral carotid artery disease is presented. A fifty-six-year-old man was admitted to hospital for evaluation of recurrent transient ischemic attacks. He had received cervical radiation for pharyngeal squamous cell carcinoma five years earlier. The radiation was directed at the cervical fields bilaterally and the anterior cervical field using x-rays for a total of 120 Gy. Computed tomography of the brain obtained at admission revealed a low-density area in the right parietal lobe. Carotid arteriograms revealed a completely occluded right internal carotid artery and a severely narrowed left internal carotid artery. There was good collateral supply from the posterior communicating arteries to the internal carotid arteries, bilaterally. The patient was medically treated with anticoagulant and antiplatelet therapy and has been free of subsequent cerebral ischemic attacks.

Carcinoma, Squamous Cell↗
PubMed1995

Expression and phosphorylation of rat c-met/hepatocyte growth factor receptor during rat liver regeneration.

Hepatocyte growth factor receptor is identified as a heterodimeric tyrosine kinase encoded by the c-met gene. This study was designed to determine how the c-met/hepatocyte growth factor receptor participates in the intracellular events involved in rat liver regeneration induced by administration of carbon tetrachloride. Expression of the rat c-met mRNA increased, peaking 24 h after carbon tetrachloride administration almost in parallel with MET protein expression. Histochemical studies demonstrated that expression of the rat c-met was enhanced in cells surrounding the damaged areas, and also that the distribution of cells expressing MET was almost in accordance with that of cells expressing proliferating cells nuclear antigen. The MET protein underwent intense tyrosine phosphorylation peaking at 12 h after carbon tetrachloride administration, and prior to DNA synthesis. Phospholipase C gamma and phosphatidylinositol 3-kinase, intracellular signal transducing molecules containing Src homology 2 domain, were associated with the MET protein following tyrosine phosphorylation in vivo. These observations suggest that expression and tyrosine phosphorylation of MET protein associated with signal transducing molecules may provide a mechanism whereby hepatocyte growth factor exerts its action on hepatocyte growth during rat liver regeneration induced by carbon tetrachloride administration.

Animals↗
PubMed1995

T-cell mediated polyclonal B-cell activation in a case of B-cell lymphoma associated with polyclonal hypergammaglobulinemia.

The mechanism of abnormal immunoglobulin production in non-Hodgkin's lymphoma is still poorly understood. We report a case of B-cell type non-Hodgkin's lymphoma associated with marked elevated polyclonal hyper-gammaglobulinemia (serum IgG was 7598 mg/dl; IgM, 455 mg/dl). We conducted a mixed lymphocyte culture test using peripheral lymphocytes obtained from the patient and a healthy volunteer. After co-culture with the patient's CD3+ cells, not only the patient's CD3- cells but also control CD3- cells produced greater amounts of IgG and IgM. Elevated IL-6 was also detected from the patient's CD3+ cells. This strongly suggests that B-lymphoma cells stimulate CD3+ cells to produce IL-6 and hence activate normal CD3- cells.

B-Lymphocytes↗