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Biomedical subjects

E Hashimoto

Publications and source records attributed to E Hashimoto.

At least 37 records · Page 2Linked to original sources
PubMed1999

Successful cytokine treatment of aplastic anemia following living-related orthotopic liver transplantation for non-A, non-B, non-C hepatitis.

The relationship between aplastic anemia and viral hepatitis is well recognized, and such patients usually have a high mortality. We successfully treated a case of aplastic anemia following living-related orthotopic liver transplantation (LROLT) for non-A, non-B, non-C hepatitis. A 2-yr-old boy with fulminant hepatic failure from non-A, non-B, non-C hepatitis received LROLT. Before transplantation, he had pancytopenia which was probably hepatitis associated, and viral suppression was suspected after bone marrow (BM) biopsy. After the transplantation, he developed progressive pancytopenia and a diagnosis of aplastic anemia was made via BM biopsy. With immunosuppressant agents (cyclosporine, methylprednisolone), cytokine therapy (granulocyte-colony stimulating factor (G-CSF), macrophage-colony stimulating factor (M-CSF), recombinant human erythropoietin (rhEPO)) was effectual and the patient recovered from pancytopenia. He was discharged from the hospital 57 d after the liver transplantation and remains well 1 yr after LROLT. Combined cytokine therapy with high doses of G-CSF, M-CSF and rhEPO appeared to be effective in the treatment of aplastic anemia following liver transplantation for non-A, non-B, non-C hepatitis. Since M-CSF activates macrophages, it may have contributed to the graft rejection. Careful consideration should be given to the use of high-dose M-CSF in liver transplant patients.

Anemia, Aplastic↗
PubMed1999

Inactivation of proprotein convertase, PACE4, by alpha1-antitrypsin Portland (alpha1-PDX), a blocker of proteolytic activation of bone morphogenetic protein during embryogenesis: evidence that PACE4 is able to form an SDS-stable acyl intermediate with alpha1-PDX.

PACE4 (SPC4), a member of the subtilisin-like proprotein convertase (SPC) family of proteases that cleave at paired basic amino acids, exhibits a dynamic expression pattern during embryogenesis and colocalizes with bone morphogenetic proteins (BMPs). Recently Cui et al. reported that the ectopic expression of alpha1-antitrypsin variant Portland (alpha1-PDX), an engineered serpin that contains the minimal SPC consensus motif in its reactive loop, blocks the proteolytic activation of BMP4, leading to abnormal embryogenic development [Cui, Y. et al. (1998) EMBO J. 17, 4735-4743]. TGFbeta-related factors such as BMPs are synthesized as inactive precursors and activated by limited proteolysis at multibasic amino acids. Therefore, an alpha1-PDX-inhibitable protease is thought to participate in BMP activation. However, conflicting properties, including sensitivity to alpha1-PDX, have been reported for PACE4. In this study, we examined whether alpha1-PDX is responsible for the inhibition of PACE4 by measuring the protease/inhibitor complex directly. Here we show that alpha1-PDX has the ability to form an SDS-stable acyl-intermediate (180 kDa) with PACE4 in vivo and in vitro. Further, we characterized the PACE4 secreted into the culture medium from Cos-1 cells by a specific immunological assay. An alpha1-PDX-insensitive and decanoyl-RVKR-chloromethylketone-sensitive 60-kDa protease(s) is greatly activated in conditioned medium by PACE4 overexpression, suggesting that the activation of an unknown protease(s) other than PACE4 is the cause of the variation in the properties of PACE4. PACE4 is a Ca(2+)-dependent protease with an optimal Ca(2+) requirement of 2 mM, and shows its highest activity at weakly basic pH. PACE4 activity is completely inhibited by EDTA and EGTA, but not by leupeptin. These results show that PACE4 activity can be inhibited by alpha1-PDX as well as furin (SPC1) and suggest that the inhibition of PACE4-mediated activation of factors such as BMPs by alpha1-PDX causes abnormal embryogenic development.

Animals↗
PubMed1998

Biosynthetic processing and quaternary interactions of proprotein convertase SPC4 (PACE4).

SPC4 (PACE4), a member of the eukaryotic family of subtilisin-like proprotein convertases, is synthesized as a proenzyme (proSPC4) which undergoes proteolytic removal of N-terminal propeptide during transit through the secretory pathway. As this propeptide processing seems to be a key event in the functional expression of SPC4, we have investigated its mechanism and the intracellular site where it occurs. In transfected fibroblast cells, the 110-kDa proSPC4 undergoes slow cleavage to generate a 103-kDa mature enzyme in the endoplasmic reticulum (ER). Site-directed mutagenesis studies demonstrate that the proteolytic activation of SPC4 occurs mainly through a unimolecular autocatalytic process and propeptide cleavage is a prerequisite for its export from the ER. Sedimentation velocity and chemical cross-linking analysis demonstrate that the precursor protein in the cells exists as both a monomer and a dimer-sized complex whereas mature SPC4 exists only as a monomer. These results suggest that the cleavage of the N-terminal propeptide of SPC4 plays a regulatory role in its activation and secretion through the change in its oligomeric state.

Animals↗
PubMed1998

Cytotoxic quassinoids from Simaba cedron.

Four new quassinoids, cedronolactones A-D (1-4), together with nine known compounds, simalikalactone D (5), chaparrinone (6), chaparrin (7), glaucarubolone (8), glaucarubol (9), samaderine Z (10), guanepolide (11), ailanquassin A (12), and polyandrol (13), were isolated from the wood of Simaba cedron. The chemical structures of 1-4 were elucidated on the basis of their chemical and spectral properties. Cedronolactone A (1) was shown to exhibit a significant in vitro cytotoxicity (IC50 0.0074 microg/mL) against P-388 cells.

Alkaloids↗
PubMed1998

Down-regulation of protein kinase C-alpha detected in human colorectal cancer.

The down-regulation of protein kinase C (PKC) was examined by Western blot procedure on about 30 tissue samples derived from human colorectal cancer and the corresponding normal mucosa. PKC-alpha down-regulation was detected in 60% of the cancer tissues compared with the respective normal mucosa and was observed in a higher frequency with the tissues under more advanced cancer stages. However, the frequencies of the down-regulation of PKC-delta and PKC-zeta were lower than that of PKC-alpha. These results suggest that a decreased level of PKC-alpha may affect the cell growth and tumor promotion in colorectal tissue.

Colorectal Neoplasms↗
PubMed1998

Possible role of alteration in pH, but not in ionic strength, in the modulation of Ca(2+)-dependent and diacylglycerol-induced association of protein kinase C-alpha with plasma membrane.

In an attempt to elucidate the mechanism of the membrane binding of protein kinase C-alpha (PKC-alpha), effects of pH and ionic strength were examined on Ca(2+)-dependent and diacylglycerol-induced association of this PKC with rat liver plasma membrane. In the absence of diacylglycerol, the membrane-bound PKC-alpha increased according to the changes in pH from 6 to 8. However, these reactions were not seriously influenced by alterations in ionic strength (0-240 mM NaCl). In the presence of diacylglycerol, this pH-modulated binding of PKC-alpha to plasma membrane was more effective under lower Ca2+ concentration at pH 8. These results suggest that alkaline pH conditions seem to be important for preferable association of PKC-alpha with plasma membrane.

Amino Acid Sequence↗
PubMed1998

Differential alteration of adenylyl cyclase subtypes I, II, and V/VI in postmortem human brains of heroin addicts.

In animal and culture cell experiments, the upregulation of cAMP-related signal transduction after chronic opioid administration has been hypothesized to be an adaptive change of the molecular mechanism to maintain homeostasis in intracellular signals downstream from opioid receptors. Herein, we have examined the quantitative changes of three adenylyl cyclase (AC) subtypes (I, II, and V/VI) in temporal cortex membranes from brains of heroin addicts and age-matched controls by immunoblotting. The immunoreactivity of AC-I decreased significantly (p < 0.05) in heroin addicts, compared with controls; whereas those of AC-II and AC-V/VI were not changed. The present findings indicate that differential regulation of AC subtypes occurs and that AC-I may play an important role in the signal transduction for opiate-induced tolerance and dependence mechanisms in human brain cortex.

Adenylyl Cyclases↗
PubMed1998

Reduced immunoreactivity of type I adenylyl cyclase in the postmortem brains of alcoholics.

Reduced adenylyl cyclase activity after chronic ethanol exposure has been reported. In this study, we investigated by immunoblotting whether quantitative changes of adenylyl cyclase isoforms (type I, type II, and type V/VI adenylyl cyclases) exist in membrane preparations of the temporal cortex obtained from six alcoholics and six age-matched controls. The immunoreactivity of type I adenylyl cyclase decreased significantly in the temporal cortex of alcoholics when compared with controls (p < 0.05), whereas those of type II and type V/VI adenylyl cyclases showed no changes between the groups. These findings suggest that these isoform-specific afterations in the adenylyl cyclase system may be involved in the pathophysiology of alcoholism.

Adenylyl Cyclases↗
PubMed1998

Utilization of nitrogen and macro-minerals in response to nutritional status in clinically normal adult cats.

Five male cats were used to examine utilization of nitrogen and macro-minerals (calcium, phosphorus and magnesium) in response to food restriction and subsequent repletion. For the first week, each cat was daily given 135 g of dry cat food (baseline period), followed by a restriction period for 1 week; during this period, daily food was individually restricted to 40% of the amount consumed by each cat during the baseline period. Food provision was then returned to the daily 135 g for the final week (recovery period). Fecal weight changed in association with changes in daily food intake, but urine volume changed less with the periods. Fecal and urinary excretion of nitrogen rapidly decreased during the restriction period, but the decreases were smaller than the decrease in nitrogen intake, leading to net nitrogen loss. On the other hand, the food restriction had relatively smaller effects on retention of macro-minerals, and calcium retention was not significantly affected by daily food provision, although the plasma concentration of magnesium was increased during the restriction period and tended to return during the recovery period. Nitrogen retention was increased by the removal of food restriction, but did not exceed the original level of nitrogen retention during the baseline period. These findings suggested that restriction of diet had a serious effect on nitrogen balance, and the impaired protein nutrition might not be easily recovered by subsequent nutritional repletion.

Animals↗
PubMed1997

Variants in neurotrophic factor genes and schizophrenic psychoses: no associations in a Spanish population.

Possible associations between schizophrenic psychoses, a ciliary neurotrophic factor (CNTF) null mutation and a neurotrophin in 3 (NT3) bi-allele polymorphism were investigated in a Spanish population. The sample consisted of 107 patients suffering from schizophrenic psychoses and 100 healthy volunteers. There was no statistical difference in the frequencies of the mutant CNTF allele in the index and control groups (0.125 vs. 0.121). The frequency of the rare NT3 allele (Glu) was very low and similar in both groups (0.005). Previous findings supporting the involvement of these genetic markers in the pathogenesis of schizophrenic psychoses were thus not confirmed. In light of neurodevelopmental hypotheses of schizophrenia, however, genes coding for neurotrophic factors remain interesting susceptibility loci in schizophrenia research. Subsequent studies should not focus exclusively on genetic alterations but also take into account secondary changes of the neurotrophic factor system at the mRNA and protein levels. Further, the current unsatisfying operationalized classification of the heterogeneous syndrome 'schizophrenia' remains a crucial problem that could be partially resolved by introducing more differentiated diagnoses defined on the basis of neurobiological criteria.

Ciliary Neurotrophic Factor↗
PubMed1997

Oxidative-stress associated parameters (lactoferrin, superoxide dismutases) in serum of patients with Alzheimer's disease.

In this case/control study, serum levels of oxidative stress related parameters such as Fe-binding lactoferrin (LTF), Mn- and Zn,Cu-superoxide dismutase (SOD) were determined by enzyme linked immunoassays in patients suffering from the Alzheimer's dementia as well as in non-demented controls. The Mn-SOD concentration was significantly (P<0.05, U-test) reduced in patients suffering from Alzheimer's disease if compared to non-demented controls. The other parameters investigated did not differ significantly between both groups. Our findings give evidence for the hypothesis of a disturbed free radical metabolism in Alzheimer's disease. The specificity of these results remains to be clarified. Further studies are needed to elucidate the relevance of oxidative stress in the etiopathogenesis of the Alzheimer's disease.

Aged↗
PubMed1997

Quantitative assays for hepatitis C virus in serum as predictors of the long-term response to interferon.

BACKGROUND/AIMS: Interferon therapy has a beneficial effect in patients with chronic hepatitis C who have a low viral load. The aim of this study was to compare the core protein level with HCV RNA levels and to analyze whether virus quantitation predicts the efficacy of interferon therapy. METHODS: HCV core protein level assessed by the recently developed assay was compared with HCV RNA levels measured by three different methods (Amplicor-HCV monitor, competitive RT(CRT)-PCR, and bDNA probe assay) in 352 patients with chronic hepatitis C in relation to viral serotype. RESULTS: From 91% (320/352) to 93% (299/322) of patients with viremia were detected by Amplicor-monitor and CRT-PCR, in contrast to 60% (187/312) and 74% (191/258) by bDNA and HCV core protein assay, respectively. The HCV core protein level was positively correlated with HCV RNA levels measured by the three assays (r = 0.680 to 0.731). Serum HCV RNA and core protein levels were significantly lower in patients with serotype 2 than in those with serotype 1. Viral eradication after interferon therapy was observed in 60-70% of the patients with < 1 x 10(4) copies/ml of HCV RNA by Amplicor-monitor assay, < 2 x 10(5) copies/ml by CRT-PCR, < 0.5 Meq/ml by bDNA assay, and < 20 pg/ml of core protein by HCV core protein assay. Viral eradication was uncommon (< 11%) among the patients with higher viral loads. Bivariate analysis revealed that the outcome of interferon therapy was more closely associated with both HCV core protein and RNA levels than the HCV serotype. CONCLUSIONS: Quantitation of HCV core protein and HCV RNA in useful for prediction of the interferon response.

Adolescent↗
PubMed1997

Hemosiderosis in cirrhosis: a study of 447 native livers.

BACKGROUND & AIMS: Hemosiderosis may have a detrimental effect on some chronic liver diseases. The aim of this study was to determine the prevalence and diagnostic implications of hemosiderosis in cirrhosis. METHODS: Tissue iron in 447 cirrhotic livers was studied histologically and chemically. RESULTS: Positive iron staining was found in 145 cases (32.4%), and increased chemical hepatic iron concentration was found in 91 cases (20.3%), including 38 cases (8.5%) with hepatic iron overload in the hemochromatosis range, defined by an iron index of > or = 1.9 (iron index equals hepatic iron concentration in micromoles per gram divided by age). However, homozygous hemochromatosis seemed to have caused the cirrhosis in only 5 instances. Stainable iron was found in 22%-67% of the cases with nonbiliary cirrhosis but in only 7%-20% of cases with biliary cirrhosis. Most available pretransplant biopsy specimens failed to show evidence of homozygous hemochromatosis. CONCLUSIONS: Iron overload is very common in many types of nonbiliary cirrhosis but rare in biliary cirrhosis. The hemosiderosis of affected livers seems to be acquired and to occur rapidly once cirrhosis has developed; cirrhosis alone may cause iron accumulation. In the presence of cirrhosis, hepatic iron indices of >1.9 should not be interpreted as proof of homozygous hemochromatosis.

Adult↗