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Biomedical subjects

M Shoji

Publications and source records attributed to M Shoji.

At least 19 recordsLinked to original sources
PubMed1998

Expression of HuD protein is essential for initial phase of neuronal differentiation in rat pheochromocytoma PC12 cells.

HuD is a neuronal-specific, RNA-binding protein. Here we examined the change in the expression of HuD protein during nerve growth factor-mediated differentiation of PC12 cells. As cells differentiated and extended neurites, expression of HuD gradually increased up to 1.5-fold. When HuD expression was counteracted by antisense oligonucleotide, neurite extension was completely inhibited, yet the morphology of differentiated cells remained unchanged even after that treatment. Furthermore, this morphological change correlated well with the downregulation of cyclin-dependent kinase 2 activity. These results suggest that the HuD is critically involved in the initial phase of neuronal differentiation.

Animals↗
PubMed1998

Synthesis of pyridinium dinitrobenzyl sulfates and potassium (dinitrobenzyl beta-D-glucopyranosid)uronates.

Sulfates and glucuronides of 2,4-dinitrobenzyl alcohol 1a and 2,6-dinitrobenzyl alcohol 1b, which are major or putative metabolites of 2,4-dinitrotoluene (2,4-DNT) and 2,6-dinitrotoluene (2,6-DNT), were synthesized from 1a and 1b by reaction with pyridinium sulfonate and methyl (2,3,4-tri-O-acetyl-alpha-D-glucopyranosyl)uronate bromide 3, respectively, as their pyridinium salts (2a, 2b) and potassium salts (6a, 6b). These conjugates are important for the study of the carcinogenicity of 2,4-DNT and 2,6-DNT.

Benzyl Alcohols↗
PubMed1998

Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer.

Thrombin-catalyzed, cross-linked fibrin (XLF) formation is a characteristic histopathological finding in many human and experimental tumors and is thought to be of importance in the local host defense response. Although the pathogenesis of tumor-associated fibrin deposition is not entirely clear, several tumor procoagulants have been described as likely primary stimuli for the generation of thrombin (and XLF) in the tumor microenvironment (TME). In a previous study of a variety of human tumors we have shown that tissue factor (TF) is the major procoagulant. However, the relative contribution to fibrin deposition in the TME of tumor cell TF and host cell TF (eg, macrophage-derived) was not established. In addition, recent evidence has implicated TF in the regulation of the synthesis of the pro-angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells. In the current study we used in situ techniques to determine the cellular localization of XLF, TF, VEGF, and an alternative tumor procoagulant, so-called cancer procoagulant (CP), a cysteine protease that activates clotting factor X. In lung cancer we have found XLF localized predominantly to the surface of tumor-associated macrophages, as well as to some endothelial cells and perivascular fibroblasts in the stromal area of the tumors co-distributed with TF at the interface of the tumor and host cells. Cancer pro-coagulant was localized to tumor cells in several cases but not in conjunction with the deposition of XLF. TF and VEGF were co-localized in both lung cancer and breast cancer cells by in situ hybridization and immunohistochemical staining. Furthermore, a strong relationship was found between the synthesis of TF and VEGF levels in human breast cancer cell lines (r2 = 0.84; P < 0.0001). Taken together, these data are consistent with a highly complex interaction between tumor cells, macrophages, and endothelial cells in the TME leading to fibrin formation and tumor angiogenesis.

Blood Coagulation↗
PubMed1997

Analysis of the McLeod syndrome gene in three patients with neuroacanthocytosis.

McLeod syndrome is a rare X-linked disorder involving neurological defects and acanthocytosis. We examined the XK gene in three patients with neuroacanthocytosis, one of whom had cardiomyopathy, and his symptoms were very similar to those of McLeod syndrome. We found two new transversions (C to G at codon 204 and G to C at codon 205) in exon 3 in all those cases. However, the transversion at codon 205 was found in all 70 Japanese normal subjects and four non-Japanese (two Caucasian males, one Chinese female and one Micronesian female) and that at codon 204 was also detected in all 14 normal Japanese males and the four non-Japanese. These findings suggest that they are not the cause of McLeod syndrome, but normal polymorphisms which have not been reported. Moreover, there is a possibility that patients with neuroacanthocytosis similar to McLeod syndrome exist without the XK gene abnormalities.

Acanthocytes↗
PubMed1997

Lysosomal generation of amyloid beta protein species in transgenic mice.

Soluble amyloid beta protein (A beta)1-40 and highly amyloidogenic A beta 1-42/43 were immunocytochemically labeled in lysosomes of acinar cells and macrophages in the pancreas of transgenic mice systemically expressing a C-terminal fragment of the A beta precursor. A beta 1-42/43 and long A beta species extending their C-termini were detected in the detergent-insoluble fraction. Immunoreactivity of cathepsin D was markedly increased in lysosomes filled with A beta fibrils. These findings indicated that A beta 1-40, A beta 1-42, A beta 1-43 and longer A beta species were generated in the lysosomes of the transgenic pancreas, and suggested that the activation of cathepsin D, a candidate gamma-secretase, leads to acceleration of A beta amyloid formation.

Amyloid beta-Protein Precursor↗
PubMed1997

Human choroid plexus is an uniquely involved area of the brain in amyloidosis: a histochemical, immunohistochemical and ultrastructural study.

To better understand the characteristics of amyloid deposition in the choroid plexus, we examined autopsied brain by routine histology, immunohistochemistry, and electron microscopy in three group of patients: primary systemic amyloidosis (n = 7), cerebral amyloid angiopathy (CAA, n = 6), and controls (n = 3). Three of the CAA patients had Alzheimer's disease. Congophilic, birefringent amyloid deposits of the choroid plexus were seen in six of the seven cases of systemic light chain amyloidosis. Immunohistochemistry revealed that the deposited amyloids had reactivity for immunoglobulin light chain and amyloid P component. Accumulation of macrophages labeled with monoclonal antibodies against CD 68 and major histocompatibility complex class II antigens were observed around the massive amyloid deposits. The presence of approximately 10 nm amyloid fibrils along the epithelial basement membrane as well as in the vascular walls was ascertained by electron microscopy. In CAA, Congo red-positive amyloid deposits were consistently present in meningeal blood vessels and were often found in senile plaques of the cerebral parenchyma; congophilic amyloid deposits were absent in the choroid plexus. Choroid plexus epithelial cells exhibited immunostaining for beta amyloid precursor protein (APP) with N-terminal- and C-terminal-specific antibodies; in particular, consistent staining was obtained for the latter antibody. Immunoreactivity for amyloid beta protein (A beta) with monoclonal antibodies (6E10, 4G8) was often found in choroid plexus epithelial cells. These findings suggest that amyloid deposition of the choroid plexus depends on the major component protein in amyloidosis, and that the choroid plexus may produce APP and A beta protein although A beta amyloidosis is not evident in the choroid plexus.

Aged↗
PubMed1997

Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease.

To investigate the pathomechanism of amyloid beta protein (A beta) deposition in brains with Alzheimer's disease (AD), cerebrospinal fluid (CSF) levels of A beta species (CSF-A beta) with different carboxy termini, i.e. A betaX-40 and A betaX-42(43) as well as A beta1-40 and A beta1-42(43), were measured in patients with AD and age-matched controls without dementia (CTR) using sandwich enzyme-linked immunosorbent assays (ELISAs). The present study revealed that both CSF-A betaX-42(43) and A beta1-42(43) levels were significantly lower in the AD patients (P<0.005) than in the CTR group, whereas neither CSF-A betaX-40 nor CSF-A beta1-40 levels showed any differences between the two groups. In addition, although there was no difference between the ratios of A betaX-40 to A beta1-40 in the AD and CTR groups, the ratios of A betaX-42(43) to A beta1-42(43) were increased in the AD group compared with those in the CTR group (P<0.05). Therefore, it can be assumed that the ratios of amino terminal truncations and/or modifications of CSF-A beta42(43) with carboxy termini ending at residue 42(43) were more increased in the AD group than in the CTR group. Increased adsorption of A beta42(43) to A beta deposition in AD brains, decreased secretion of A beta42(43) to CSF and/or increased clearance of A beta42(43) from CSF might explain the diminished levels of A beta42(43) in the CSF of AD patients. In addition, CSF-A beta42(43) could reflect increased amino terminal truncations and/or modifications of A beta42(43) in AD brains.

Aged↗
PubMed1997

Cell cycle control with minimal participation of Cdk2 in a murine fibrosarcoma clone cultured in protein-free medium.

The differences in the protein expression of cyclins, cyclin-dependent kinases (cdks), and their inhibitors and cdk kinase activities were examined in serum dependent (SD) and independent (PF) clones of the murine fibrosarcoma cell line, Gc-4. The expression of cyclin A in SD was minimal in contrast to PF. Furthermore, cdk2 kinase activity in PF was remarkably lower than that in SD, yet the G1/S transition in PF appeared normal. PF was also resistant against the selective inhibitor of cdk2, butyrolactone I. These findings suggest that tumor cell proliferation and tumor progression can be promoted by the activation of a molecule(s) downstream of cdk2.

4-Butyrolactone↗
PubMed1997

Reduction of plasma glutamyl aminopeptidase activity in sporadic Alzheimer's disease.

Previously, we hypothesized that aminopeptidase-catalyzed proteolysis may limit the rate of beta-amyloid catabolism in brain and that reduction of a certain aminopeptidase activity may lead to deposition of peptidic metabolites represented by beta-amyloid and thus to Alzheimer's disease (AD). To explore this possibility in clinical situations and to seek a possible biochemical marker for the disease, we quantitated four classes of aminopeptidase activities in cerebrospinal fluids and heparinized plasma from sporadic AD patients and agematched controls collected in two independent medical institutions. We found that only plasma glutamyl aminopeptidase activity was significantly and consistently lower in AD patients. Although the mechanism leading to such a biochemical change in plasma remains to be elucidated, the results provide support for the aminopeptidase hypothesis and indicate that the enzyme activity may potentially be used as a diagnostic/ predictive marker for AD.

Aged↗
PubMed1997

Genotype analysis of prepro-vasopressin signal peptide in vasopressin-producing and -non-producing lung tumors.

A polymorphism in the nucleic acid sequence encoding the signal peptide of the human prepro-vasopressin (AVP) has been reported in an AVP producing small cell lung carcinoma (SCLC) cell line. The difference predicts expression in tumor cells of a variant signal peptide with Pro for Leu 11. To clarify whether this difference is required for AVP secretion from SCLC cells and/or reflects increased mutagenesis in malignant tumors, the exon encoding the signal peptide of prepro-AVP in two AVP producing SCLC and 9 non-producing lung tumors was amplified using polymerase chain reaction. The variant sequence was neither found by direct sequencing nor by restriction enzyme analysis. These results suggest that similar to the hypothalamus the normal signal peptide is functional in tumor cells and that the variant signal peptide is not a prerequisite for AVP secretion from SCLC cells.

Animals↗
PubMed1997

The Wilms tumor protein is persistently associated with the nuclear matrix throughout the cell cycle.

In order to investigate the subnuclear interactions of the WT1 gene product, nuclear fractionation analyses were performed with human osteosarcoma HOS and myelogenous leukemia K562 cells. The WT1 protein was tightly associated with the nucleus and was resistant to high-salt or detergent extraction and DNase I digestion. Both the expression level and stability of WT1 and its resistance to high salt and DNase I treatments remained constant during the cell cycle. In addition, human WT1 ectopically expressed in mouse NIH3T3 cells was also resistant to these treatments. These results suggest that WT1 functions in tight association with the nuclear matrix.

3T3 Cells↗
PubMed1997

Biliary excretion and microfloral transformation of major conjugated metabolites of 2,4-dinitrotoluene and 2,6-dinitrotoluene in the male Wistar rat.

1. Major biliary conjugates of the male Wistar rat dosed orally with 2,4-dinitrotoluene (2,4-DNT) or 2,6-dinitrotoluene (2,6-DNT) were examined by hplc using potassium 2,4-dinitrobenzyl glucuronide (potassium 2,4-DNB-G), potassium 2,6-dinitrobenzyl glucuronide (potassium 2,6-DNB-G), pyridinium 2,4-dinitrobenzyl sulphate (pyridinium 2,4-DNB-S) and pyridinium 2,6-dinitrobenzyl sulphate (pyridinium 2,6-DNB-S) as authentic compounds. Other metabolites were also examined by hplc. In addition, metabolites formed by incubation of potassium 2,4-DNB-G and potassium 2,6-DNB-G with rat intestinal microflora under nitrogen were examined by hplc. 2. Conjugates detected directly from bile following administration of 2,4-DNT and 2,6-DNT were 2,4-DNB-G and 2,6-DNB-G, which accounted for 35.0 and 51.5% of the administered dose respectively. No peaks corresponding to pyridinium 2,4-DNB-S and pyridinium 2,6-DNB-S were detected in bile samples. 3. 2-Amino-4-nitrotoluene, 4-amino-2-nitrotoluene, 2,4-diaminotoluene and 4-acetylamino-2-nitrobenzoic acid (0.02-0.12% of the dose excreted in 24 h), in addition to the known metabolites 2,4-dinitrobenzyl alcohol (2,4-DNB), 2,4-dinitrobenzaldehyde and 2,4-dinitrobenzoic acid (0.09-0.14%), were detected in ether extracts of bile of rat given 2,4-DNT. 2,6-Dinitrobenzyl alcohol (2,6-DNB), 2-amino-6-nitrotoluene and 2,6-dinitrobenzaldehyde (0.02-0.03%), which are known metabolites, were detected in ether extracts of bile from rat given 2,6-DNT. 4. Potassium 2,4-DNB-G was transformed by the anaerobic incubation of rat intestinal microflora into 2,4-DNB, 4-amino-2-nitrobenzyl alcohol and 2-amino-4-nitrobenzyl alcohol. Potassium 2,6-DNB-G was transformed into 2,6-DNB and 2-amino-6-nitrobenzyl alcohol by the anaerobic incubation. Time-course studies showed that 2,4-DNB, 4-amino-2-nitrobenzyl alcohol, 2-amino-4-nitrobenzyl alcohol and 2,6-DNB, 2-amino-6-nitrobenzyl alcohol peaked at 30, 75, 120 and 10, 50 min respectively. 5. These results, together with previous findings, show that 2,4-dinitrobenzaldehyde and 2,6-dinitrobenzaldehyde, which are potent mutagens, are formed either by the hepatic metabolism of 2,4-DNB and 2,6-DNB formed by the intestinal metabolism of 2,4-DNB-G and 2,6-DNB-G excreted in bile or by the direct hepatic metabolism of 2,4-DNT and 2,6-DNT.

Animals↗
PubMed1997

Apolipoprotein E accumulates with the progression of A beta deposition in transgenic mice.

To study the role of apolipoprotein E (apoE) in vivo in deposits of amyloid beta protein (A beta), a major component of senile plaque amyloid in the brain of patients with Alzheimer disease, the transgenic mice were examined by apoE immunostaining. The mice were systemically overexpressing signal peptide and 99 amino acid residues of the carboxy-terminal fragment of human amyloid beta protein precursor (betaAPP) under control of the powerful cytomegalovirus enhancer/chicken beta-actin promotor. A beta deposits appeared at 4 months and increased with aging in the acinar cells of the transgenic pancreas. Similarly, apoE deposits appeared in the pancreatic acinar cells at 4 months old. The number and size of apoE deposits increased with aging and correlated with the progression of A beta deposits. Interstitial macrophages labeled by apoE immunostaining appeared at 8 months after birth and their number increased with aging. On serial section of the pancreata of 24-month-old mice, approximately 70% of A beta deposits were labeled with the apoE antiserum. ApoE was detected in the highly insoluble formic acid fraction of the transgenic pancreas by an immunoblot study. The Northern blot study revealed no increase in synthesis of endogenous apoE mRNA. These findings indicate that apoE is closely related to progression of A beta deposits with aging and suggest that A beta deposition in the transgenic pancreas is similar to that in the senile plaque of Alzheimer brains. Therefore, our experimental system using transgenic mice will provide a useful tool to analyze the molecular mechanism of A beta deposition in association with apoE in vivo.

Aging↗
PubMed1997

A presenilin-1 mutation in a Japanese family with Alzheimer's disease and distinctive abnormalities on cranial MRI.

Some patients with familial Alzheimer's disease (FAD) have mutations in the presenilin-1 (PS-1) gene on chromosome 14. We report a Japanese family with AD and an Ala285Val substitution in exon 8 of the PS-1 gene. FAD in this family was characterized by relatively late onset (mean age, 50 years) and absence of myoclonus, seizures, or paratonia. Levels of tau were markedly elevated in CSF whereas CSF levels of amyloid beta protein were normal. MRI of the cranium showed marked linear signal abnormalities within white matter in the parieto-occipital lobes, consistent with cortical amyloid angiopathy of the type encountered in patients with the PS-1 gene mutation.

Alzheimer Disease↗
PubMed1997

Impaired vasopressin suppression and enhanced atrial natriuretic hormone release following an acute water load in primary aldosteronism.

The release of arginine vasopressin (AVP) and atrial natriuretic hormone (ANH) and their involvement in renal water and electrolyte metabolism in primary aldosteronism in humans were studied. An oral acute water load (20 ml/kg body weight) was given to each of 12 patients before and after surgical removal of their aldosterone-producing adenoma(s). Plasma AVP and ANH were measured simultaneously, and renal water and electrolyte metabolism and tubular functions were determined. The same water load was given to seven normal subjects and the same parameters were determined. In the presence of mineralocorticoid excess before the operation, plasma AVP was relatively low compared with plasma osmolality (Posm), but was not suppressed in response to decreases in Posm after the water load. Baseline plasma ANH was high and increased further after the water load; urinary dilution and diuresis both remained normal. After the operation, baseline plasma AVP was normal and decreased in response to the decrease in Posm after the water load, with normal urinary dilution and diuresis. Baseline plasma ANH was normal, and did not increase after the water load. The ratio of urinary K and Na clearances and distal tubular reabsorption of Na increased before the operation. These results suggest that there are perturbations of AVP and ANH release in primary aldosteronism, despite the normal urinary dilution after a water load.

Adenoma↗