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Biomedical subjects

Y Fujiwara

Publications and source records attributed to Y Fujiwara.

At least 217 records · Page 12Linked to original sources
PubMed1998

ZK1, a novel Krüppel-type zinc finger gene, is induced following exposure to ionizing radiation and enhances apoptotic cell death on hematopoietic cells.

To identify and early response factor by exposure to ionizing radiation, we cloned the cDNA of a novel Krüppel-type zinc finger (ZNF) gene, ZK1, from a cDNA library constructed from the human leukemia cell line, CMK86, using degenerate primers. This cDNA encoded a protein of 671 amino acids with an A box of Krüppel-associated box (KRAB) domain at the N-terminus, followed by 15 ZNF motifs. The expression level of the ZK1 mRNA in human leukemia cells lines, CMK86 and U937, was increased after exposure to ionizing radiation. Furthermore, murine myeloid precursor 32D cells that were stably transfected with ZK1 cDNA had higher sensitivity to ionizing radiation than the 32D parent cells. These data suggest that the ZK1 gene is one of early response genes by exposure to ionizing radiation, and may have some functions on radiation-induced apoptotic cell death on hematopoietic cells.

Amino Acid Sequence↗
PubMed1998

Propranolol attenuates haloperidol-induced Fos expression in discrete regions of rat brain: possible brain regions responsible for akathisia.

Neuroleptics induce several extra-pyramidal side effects, such as akathisia, acute dystonia and parkinsonism. Although recently developed atypical neuroleptics ameliorate some of these side effects, akathisia remains a common and severely distressing adverse reaction. Several drugs are reported to be of clinical use for the pharmacological treatment of akathisia. In particular, the beta-adrenoceptor blocker, propranolol, has been widely used for the treatment of akathisia, but it does not ameliorate other extra-pyramidal side effects. To identify the neural substrates of akathisia, we investigated the effects of propranolol on haloperidol-induced Fos expression in rat brain. Haloperidol (1 mg/kg) induced Fos-positive nuclei in several regions of the brain, including the cingulate cortex area 3, piriform cortex nucleus accumbens, caudate-putamen, ventral lateral septum and parietal cortex. Pretreatment with propranolol (5 mg/kg) reduced the number of Fos-positive nuclei in the cingulate cortex area 3, the piriform cortex and area 1 of the parietal cortex. Injection of vehicle by itself tended to increase Fos expression in the cingulate cortex area 3 and the piriform cortex. Considering the functions of these brain regions, we speculate that the most plausible neural framework for haloperidol-induced akathisia involves area I of the parietal cortex, but possible roles for the cingulate cortex area 3 and the piriform cortex cannot be ruled out.

Adrenergic beta-Antagonists↗
PubMed1998

Hair defects and pup loss in mice with targeted deletion of the first cut repeat domain of the Cux/CDP homeoprotein gene.

CDP, a ubiquitous homeoprotein homologous to Drosophila cut, is implicated as a transcriptional repressor in several developmental systems. It contains four independent DNA binding domains: three "cut repeats" plus the homeodomain. The murine Cux/CDP gene spans more than 200 kb and is composed of at least 21 exons. We designed a targeting construct to replace the first cut repeat with a neomycin resistance cassette, introducing a nonsense mutation after position 1319 of the 4.5-kb reading frame of Cux/CDP. We expected to generate a truncated product of approximately 60 kDa with this construct, but instead we obtained mice expressing a mutant form of the protein, with an internal deletion of 246 amino acids encompassing cut repeat 1, but intact in the C-terminal region. Ribonuclease protection assays and direct sequencing of mutant cDNA obtained by RT-PCR demonstrate skipping of exons 10 and 11 in the mutant. Homozygous mutant mice, designated Cux/CDPDeltaCR1, display a phenotype characterized by curly vibrissae and wavy hair. We also observed a high degree of pup loss in litters born to mutant females, most likely on a nutritional basis. The mutant protein is present at levels slightly greater than wild-type, but exhibits the same tissue distribution as wild-type protein, and has approximately normal affinity for known target sequences (though no DNA targets identified to date require the first cut repeat for binding). These results support the hypothesis that the different DNA binding domains of the ubiquitous Cux/CDP protein are responsible for regulation of different genes in diverse tissues during development.

Animals↗
PubMed1998

The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow.

The TEL (translocation-Ets-leukemia or ETV6) locus, which encodes an Ets family transcription factor, is frequently rearranged in human leukemias of myeloid or lymphoid origins. By gene targeting in mice, we previously showed that TEL-/- mice are embryonic lethal because of a yolk sac angiogenic defect. TEL also appears essential for the survival of selected neural and mesenchymal populations within the embryo proper. Here, we have generated mouse chimeras with TEL-/- ES cells to examine a possible requirement in adult hematopoiesis. Although not required for the intrinsic proliferation and/or differentiation of adult-type hematopoietic lineages in the yolk sac and fetal liver, TEL function is essential for the establishment of hematopoiesis of all lineages in the bone marrow. This defect is manifest within the first week of postnatal life. Our data pinpoint a critical role for TEL in the normal transition of hematopoietic activity from fetal liver to bone marrow. This might reflect an inability of TEL-/- hematopoietic stem cells or progenitors to migrate or home to the bone marrow or, more likely, the failure of these cells to respond appropriately and/or survive within the bone marrow microenvironment. These data establish TEL as the first transcription factor required specifically for hematopoiesis within the bone marrow, as opposed to other sites of hematopoietic activity during development.

Animals↗
PubMed1998

SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis.

SEK1 (MKK4/JNKK) is a mitogen-activated protein kinase activator that has been shown to participate in vitro in two stress-activated cascades terminating with the SAPK and p38 kinases. To define the role of SEK1 in vivo, we studied stress-induced signaling in SEK1(-/-) embryonic stem and fibroblast cells and evaluated the phenotype of SEK1(-/-) mouse embryos during development. Studies of SEK1(-/-) embryonic stem cells demonstrated defects in stimulated SAPK phosphorylation but not in the phosphorylation of p38 kinase. In contrast, SEK1(-/-) fibroblasts exhibited defects in both SAPK and p38 phosphorylation, demonstrating that crosstalk exists between the stress-activated cascades. Tumor necrosis factor alpha and interleukin 1 stimulation of both stress-activated cascades are severely affected in the SEK1(-/-) fibroblast cells. SEK1 deficiency leads to embryonic lethality after embryonic day 12.5 and is associated with abnormal liver development. This phenotype is similar to c-jun null mouse embryos and suggests that SEK1 is required for phosphorylation and activation of c-jun during the organo-genesis of the liver.

Animals↗
PubMed1998

Local structure study of dilute Er in III-V semiconductors by fluorescence EXAFS.

For understanding the luminescence of Er atoms in III-V semiconductors, OMVPE-grown InP doped with Er has been investigated by fluorescence EXAFS (extended X-ray absorption fine structure) in order to study the local structure around Er atoms. The local structures around the Er atoms doped in InP, with doping as dilute as 3 x 10(12) Er atoms in a 1.5 mm x 1.0 mm spot, were successfully measured by fluorescence EXAFS. The EXAFS analysis revealed that the Er atoms doped in InP above 853 K (which showed low luminescence) formed the rock-salt-structure ErP, while the Er atoms doped in InP below 823 K (which showed high luminescence) substituted on the In site of InP. The dependence of the local structure on growth temperature was observed for the samples doped with 3 x 10(12) atoms and 1.2 x 10(13) atoms of Er.

Journal Article↗
PubMed1998

Schizophrenic psychoses and the CNTF null mutation.

Genetic susceptibility plays an important role in the development of schizophrenic psychoses, and the neural maldevelopment hypothesis is suggested by neuropathological and neuroimaging findings. We investigated the association between a null mutation in the ciliary neurotrophic factor (CNTF) gene and functional psychoses including schizophrenia and schizoaffective disorder. The frequency of mutant allele was significantly increased in patients with schizoaffective disorder, but not in those with schizophrenia in comparison with controls. The CNTF null mutation resulting in CNTF deficiency may confer potential susceptibility to schizoaffective disorder.

Adult↗
PubMed1998

Failure of megakaryopoiesis and arrested erythropoiesis in mice lacking the GATA-1 transcriptional cofactor FOG.

GATA transcription factors are required for the differentiation of diverse cell types in several species. Recent evidence suggests that their biologic activities may be modulated through interaction with multitype zinc finger proteins, such as Friend of GATA-1 (FOG) and U-shaped (Ush). In cell culture, FOG cooperates with the hematopoietic transcription factor GATA-1 to promote erythroid and megakaryocytic differentiation. We show here that mice lacking FOG die during mid-embryonic development with severe anemia. FOG-/- erythroid cells display a marked, but partial, blockage of maturation, reminiscent of GATA-1- erythroid precursors. In contrast to GATA-1 deficiency, however, megakaryocytes fail to develop in the absence of FOG. Although the FOG-/- erythroid phenotype supports the proposed role of FOG as a GATA-1 cofactor in vivo, the latter finding points to a pivotal, GATA-1-independent requirement for FOG in megakaryocyte development from the bipotential erythroid/megakaryocytic progenitor. We speculate that FOG and other FOG-like proteins serve as complex cofactors that act through both GATA-dependent and GATA-independent mechanisms.

Animals↗
PubMed1998

Mechanism of UV-induced apoptosis in human leukemia cells: roles of Ca2+/Mg(2+)-dependent endonuclease, caspase-3, and stress-activated protein kinases.

Ultraviolet light (UV) induced rapid apoptosis of U937 leukemia cells, concurrent with DNA fragmentation and cleavage of poly(ADP-ribose)polymerase (PARP) by activated caspase-3. The in vitro reconstitution of intact HeLa S3 nuclei and apoptotic U937 cytosolic extract (CE) revealed that (i) Ca2+/Mg(2+)-dependent, Zn(2+)-sensitive endonuclease activated in the apoptotic CE induced DNA ladder in HeLa nuclei at pH 6.8-7.4, (ii) activated caspase-3 cleaved PARP in HeLa nuclei, and (iii) when the apoptotic CE was treated with the caspase-3 inhibitor (1 microM Ac-DEVD-CHO) or the caspase-1 inhibitor (10 microM Ac-YVAD-CHO), the former, but not the latter, caused a 50% inhibition of DNA fragmentation and the complete inhibition of PARP cleavage in HeLa nuclei. Similarly, Ac-DEVD-CHO (100 microM) inhibited apoptosis and DNA ladder by 50% and PARP cleavage completely in UV-irradiated U937 cells, but Ac-YVAD-CHO (100 microM) did not. Thus, UV-induced apoptosis of U937 cells involves the Ca2+/Mg(2+)-dependent endonuclease pathway and the caspase-3-PARP cleavage-Ca2+/Mg(2+)-dependent endonuclease pathway. The former pathway produced directly 50% of apoptotic DNA ladder, and the latter involved activated caspase-3 and PARP cleavage, followed by formation of the remaining 50% DNA ladder by the activated endonuclease. In UV-irradiated B-cell lines, further, p53-dependent increase of Bax resulted in a greater caspase-3 activation compared to its absence. However, UV-induced activation of JNK1 and p38 was not affected by the caspase-1 and -3 inhibitors in U937 cells, so that caspases-1 and -3 do not function upstream of JNK1 and p38.

Apoptosis↗
PubMed1998

Unsuspected role for the T-cell leukemia protein SCL/tal-1 in vascular development.

The transcription factor SCL/tal-1 is essential for blood cell development. Though it is also expressed in vascular endothelium, SCL has been considered dispensable for vessel formation. Through transgenic rescue of hematopoietic defects of SCL-/- embryos and analysis of chimeras generated with SCL-/- ES cells tagged with a transgene expressed in vascular endothelial cells, we show that SCL is essential for angiogenic remodeling of the yolk sac capillary network into complex vitelline vessels. These findings establish a role for SCL in embryonic angiogenesis and argue for critical functions in both embryonic blood and vascular cells, the descendents of the presumptive hemangioblast.

Animals↗
PubMed1998

A thoracoabdominal hepatectomy and a transdiaphragmatic hepatectomy for patients with cirrhosis and hepatocellular carcinoma.

OBJECTIVE: To evaluate the results of a thoracoabdominal hepatectomy and a transdiaphragmatic hepatectomy for hepatocellular carcinoma in patients with impaired liver function. DESIGN: Retrospective study. SETTING: A university hospital in Japan. PATIENTS: Twenty-seven patients who from 1991 to 1996 underwent a thoracoabdominal hepatectomy for hepatocellular carcinoma located mainly in the superior portion of the liver and 20 patients who underwent a transdiaphragmatic hepatectomy for hepatocellular carcinoma located near the diaphragm. MAIN OUTCOME MEASURES: Morbidity, survival, and disease-free survival after each operation. Comparisons were then made with 183 patients who had undergone an ordinary transabdominal hepatectomy during the same period. RESULTS: In the thoracoabdominal hepatectomy group, 17 patients underwent a partial resection, 4 patients underwent a subsegmentectomy, and another 6 patients underwent either a segmentectomy or a procedure that was greater in size than a segmentectomy, whereas all of the patients in the transdiaphragmatic group underwent a partial resection. The morbidities in the thoracoabdominal group included pleural effusion in 6 patients (22%); intra-abdominal infection in 5 patients (19%); and hepatic failure in 3 patients (11%), of whom 1 died (mortality rate, 4%). In the transdiaphragmatic group, only 2 patients (10%) had non-life-threatening complications. The cumulative survival rates and the disease-free survival rates of the patients at 3 years were 51% and 24% in the thoracoabdominal hepatectomy group and 62% and 30% in the transdiaphragmatic hepatectomy group; no significant differences were observed when these findings were compared with those of patients who had undergone a transabdominal hepatectomy. CONCLUSION: The outcomes of the patients undergoing thoracoabdominal hepatectomy and those undergoing a transdiaphragmatic hepatectomy were generally satisfactory in spite of the fact that these procedures were performed on patients with cirrhosis and impaired liver function.

Aged↗
PubMed1998

Treatment strategy for patients with cystic lesions mimicking a liver tumor: a recent 10-year surgical experience in Japan.

OBJECTIVE: To clarify some of the difficulties in determining the appropriate surgical indications for cystic lesions mimicking a neoplasm in the liver. DESIGN: A retrospective review of hepatic resections for cystic lesions mimicking a neoplasm in the liver between August 1, 1986, and July 31, 1996. SETTING: A university hospital with a long history of hepatic resection for cystic lesions mimicking a neoplasm in the liver. PATIENTS: Ten patients with such cystic lesions in the liver, who underwent a hepatectomy during a recent 10-year period, were included in this study. MAIN OUTCOME MEASURES: Detailed clinicopathologic data were analyzed, and comparisons were made between the preoperative and postoperative diagnoses. RESULTS: The postoperative diagnoses consisted of cysts, including cysts complicated by an infection or hemorrhage in 7 patients, localized cystic dilation of the bile duct due to hepatolithiasis in 1, cystadenoma in 1, and mucin-producing cholangiocarcinoma in 1. In only one case was postoperative diagnosis identical to the preoperative diagnosis. In one case, an intraoperative pathological examination showed the tumor to be a mucin-producing cholangiocarcinoma instead of a cystadenocarcinoma. A tumor-marker analysis of the fluid in the cystic lesions also did not contribute to a definite diagnosis. Furthermore, cytological examination of the fluid could not completely exclude malignancy. Neither mortality nor morbidity occurred in any of the patients, and their mean length of hospitalization after hepatectomy was only 13.7 days. CONCLUSIONS: The accurate diagnosis of cystic lesions mimicking a tumor remains problematic; however, the results of hepatectomy for such cases are normally satisfactory. Such cystic lesions of the liver should be indicated for hepatectomy whenever the possibility of a cancerous neoplasm cannot be completely ruled out.

Adult↗
PubMed1998

Transcription factor GATA-1 in megakaryocyte development.

The transcription factor GATA-1 is specifically expressed in hematopoietic lineages. Prior gene knockout experiments established an essential role for GATA-1 in red blood cell production, but could not provide direct evidence with respect to a requirement in megakaryopoiesis. We summarize here recent lineage-selective gene targeting in mice that establishes critical functions for GATA-1 in controlling megakaryocyte growth and maturation, and platelet production. GATA-1 megakaryocytes are delayed in their cellular maturation, exhibit marked hyperproliferation and generate fewer than normal, yet enlarged, platelets in vivo. Thus GATA-1 is a central regulator in both the erythroid and megakaryocytic lineages.

Animals↗
PubMed1998

Repair of wounded monolayers of cultured vascular endothelial cells after simultaneous exposure to lead and zinc.

We investigated the interaction between lead and zinc on the repair of wounded monolayers of cultured bovine aortic endothelial cells. A half area of the monolayers was wounded and then incubated in the presence of lead (5.0 and 10 microM) and/or zinc (10 microM). It was morphologically observed that the appearance of the cells in the wounded area was strongly decreased by lead alone but considerably increased by zinc alone. The repair of wounded area after simultaneous exposure to lead and zinc showed that lead inhibits not only spontaneous but also zinc-promoted repair of endothelial cell layers without a change of the leakage of lactate dehydrogenase. Interaction between lead and zinc on the DNA synthesis of growing endothelial cells was similar to that on the repair, suggesting that the repair reflected the proliferation. In growing endothelial cells, the intracellular accumulation of lead was significantly increased by zinc; that of zinc was unaffected by lead; and that of metallothionein was slightly increased by zinc and lead but the effect of zinc was suppressed in the presence of lead. Although zinc significantly decreased the intracellular accumulation of radioactive calcium, lead increased it in the presence or absence of zinc. It was therefore concluded that lead inhibits not only spontaneous but also zinc-promoted repair of the damaged endothelial cell layers through an inhibition of the proliferation mediated by the calcium-mediated signalling pathways and/or a disturbance of intracellular calcium homeostasis.

Animals↗
PubMed1998

Promotion of cultured vascular smooth muscle cell proliferation by low levels of cadmium.

Cadmium is a toxic heavy metal which has been shown to be a possible risk factor of atherosclerosis in epidemiological and experimental studies. Since intimal hyperplasia in vascular tissue is an important component of atherosclerosis, we examined the effect of cadmium on the proliferation of vascular smooth muscle cells cultured in a serum-free medium. It was found that cadmium at 100 nM or less can increase the incorporation of [3H]thymidine into the acid-insoluble fraction of growing bovine and rabbit aortic smooth muscle cells but not of growing bovine aortic endothelial cells. Although vascular smooth muscle cells are sensitive to cadmium cytotoxicity, no increase in the leakage of lactate dehydrogenase from the cells was caused by the metal at 200 nM or less in bovine aortic smooth muscle cells. Intracellular accumulation of radioactive calcium in bovine aortic smooth muscle cells was significantly increased by cadmium. It was therefore suggested that low levels of cadmium may promote the proliferation of vascular smooth muscle cells through intracellular calcium-dependent signalling pathway. The present study supports the hypothesis that cadmium can be a risk factor of atherosclerosis through dysfunction of vascular smooth muscle cells as well as vascular endothelial cells under certain conditions.

Animals↗
PubMed1998

Expression of gamma-glutamylcysteine synthetase (gamma-GCS) and multidrug resistance-associated protein (MRP), but not human canalicular multispecific organic anion transporter (cMOAT), genes correlates with exposure of human lung cancers to platinum drugs.

We examined the steady-state levels of mRNA for gamma-glutamylcysteine synthetase (gamma-GCS), multidrug resistance-associated protein (MRP) and human canalicular multispecific organic anion transporter (cMOAT) in human lung cancer specimens to elucidate their roles in relation to platinum drug resistance in vivo. Seventy-six autopsy samples (38 primary tumours and their corresponding normal lung tissues) obtained from 38 patients were analysed using the quantitative reverse transcription polymerase chain reaction (RT-PCR) method. Both subunits (heavy and light subunits) of gamma-GCS expression levels of normal lung and tumour tissues exposed to platinum drugs during life were significantly higher than those of non-exposed tissues, whereas only the MRP expression levels of tumours were elevated in association with ante-mortem platinum drug exposure. The gamma-GCS and MRP expression levels correlated significantly. The cMOAT expression levels did not correlate with ante-mortem platinum drug exposure. Next, we monitored gamma-GCS heavy subunit expression levels in peripheral mononuclear cells of eight previously untreated lung cancer patients after platinum drug administration, which revealed that these drugs induced gamma-GCS expression in vivo. These results suggest that gamma-GCS expression is induced by platinum drugs in vivo and/or the physiological stress response to xenobiotics.

ATP-Binding Cassette Transporters↗