WA8242A1, A2 and B, novel secretory phospholipase A2 inhibitors produced by Streptomyces violaceusniger. I. Taxonomy, production and purification.
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2-Aminoadipic Acid↗
Biomedical subjects
T Otsuka
Publications and source records attributed to T Otsuka.
WA8242A1, A2 and B, novel secretary phospholipase A2 inhibitors produced by Streptomyces violaceusniger. III. Structure elucidation and total synthesis of WA8242B.
The structure of WA8242B, a potent novel inhibitor against phospholipase A2, was fully characterized by spectroscopic methods and chemical degradation. The success of total synthesis of WA8242B confirmed the structure and allowed the pharmacological study of WA8242B. The structures of WA8242A1 and A2 were also described.
Adipates↗
WA8242A1, A2 and B, novel secretory phospholipase A2 inhibitors produced by Streptomyces violaceusniger. II. Biological properties.
WA8242A1, A2 and B, novel inhibitors of secretory phospholipase A2 (PLA2), were obtained from Streptomyces violaceusniger No. 8242. WA8242B inhibited secretory group I and II PLA2s in a dose-dependent manner. The mode of inhibition of group II PLA2 by WA8242B was in competitive fashion. WA8242B inhibited group II PLA2-induced Prostaglandin I2 (PGI2) production by human umbilical vein endothelial cells. Furthermore, WA8242B was effective in mouse zymosan writhing model.
2-Aminoadipic Acid↗
[Evaluation and application of the Ewbank model].
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Asia↗
[Congenital familial tuftsin deficiency].
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Humans↗
Role of the vav proto-oncogene product (Vav) in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity.
The vav proto-oncogene product (Vav), which is specifically expressed in hematopoietic cells, contains multiple structural motifs commonly used by intracellular signaling molecules. Although a variety of stimuli including erythropoietin (Epo) have been shown to tyrosine phosphorylate Vav, little is known about the Vav signal transduction pathway. Here, we have investigated the role of Vav in the Epo signaling pathway by characterizing its interaction with other proteins, using the human Epo-responsive cell line, F-36P. Immunoprecipitation and immunoblot analyses have demonstrated that Vav was associated with the Epo receptor (EpoR) in an Epo-independent manner and was tyrosine-phosphorylated after Epo stimulation. Furthermore, two phosphotyrosine proteins (pp70 and pp100) co-immunoprecipitated with the regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) (p85) were identified as EpoR and Vav, respectively. The interaction between Vav and p85 was shown to be mediated through the SH2 domains of p85 by an in vitro binding assay and confirmed by the presence of in vitro PI3-kinase activity associated with Vav. Treatment of the cells with antisense-vav and -p85 abrogated Epo-induced cell proliferation and PI3-kinase activity. Finally, we found that JAK2 was associated with Vav in vivo and that Vav could be tyrosine-phosphorylated by activated JAK2 in vitro. These results suggest the possible role of JAK2 for tyrosine phosphorylation of Vav and involvement of Vav and PI3-kinase in Epo-induced proliferative signals.
Cell Cycle Proteins↗
Regulation by interleukin-10 and interleukin-4 of cyclooxygenase-2 expression in human neutrophils.
Neutrophils are important effector cells of acute inflammation because of their potential capacity to synthesize various proinflammatory mediators, and inhibition of their production is expected to result in anti-inflammatory effects. In this study, we investigate the effects of the anti-inflammatory cytokines, interleukin-10 (IL-10) and IL-4, on prostanoid synthesis in human neutrophils. Neutrophils isolated from healthy donors constitutively produced a small amount of prostaglandin E2 (PGE2) without any stimulations, whereas they produced a large amount of PGE2 after lipopolysaccharide (LPS) stimulation. IL-10 and IL-4 selectively inhibited their LPS-induced PGE2 production. Inhibition by both cytokines occurred at an early stage of LPS stimulation. Anti-IL-10 treatment of LPS-stimulated neutrophils resulted in enhanced PGE2 production. LPS-induced PGE2 and thromboxane B2 (TXB2) production in aspirin-treated neutrophils was significantly inhibited by IL-10, IL-4, and NS-398. Moreover, IL-10 and IL-4 inhibited LPS-induced cyclooxygenase (COX) activity in neutrophils. Western blot and immunocytochemical analysis showed that COX-2 protein was clearly induced in LPS-stimulated neutrophils and that its induction was inhibited by both IL-10 and IL-4. Moreover, both of these cytokines inhibited COX-2 mRNA expression in LPS-stimulated neutrophils. These results raise the possibility that these two cytokines may both offer potent clinical utility as anti-inflammatory agents in the future.
Cells, Cultured↗
Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor.
Hepatocyte growth factor/scatter factor (HGF/SF) is a mesenchymally derived, multifunctional paracrine regulator possessing mitogenic, motogenic, and morphogenetic activities in cultured epithelial cells containing its tyrosine kinase receptor, Met. c-met has been implicated in oncogenesis through correlation of expression with malignant phenotype in specific cell lines and tumors. Paradoxically, however, HGF/SF can also inhibit the growth of some tumor cells. To elucidate the oncogenic role of HGF/SF in vivo, transgenic mice were created such that HGF/SF was inappropriately targeted to a variety of tissues. HGF/SF transgenic mice developed a remarkably broad array of histologically distinct tumors of both mesenchymal and epithelial origin. Many neoplasms arose from tissues exhibiting abnormal development, including the mammary gland, skeletal muscle, and melanocytes, suggesting a functional link between mechanisms regulating morphogenesis and those promoting tumorigenesis. Most neoplasms, especially melanomas, demonstrated overexpression of both the HGF/SF transgene and endogenous c-met, and had enhanced Met kinase activity, strongly suggesting that autocrine signaling broadly promotes tumorigenesis. Thus, subversion of normal mesenchymal-epithelial paracrine regulation through the forced misdirection of HGF/SF expression induces aberrant morphogenesis and subsequent malignant transformation of cells of diverse origin.
Animals↗
The growth hormone receptor gene mutation of a Japanese patient with Laron syndrome.
Deletions and point mutations of the growth hormone (GH) receptor gene (GHR) have been identified in patients with Laron syndrome. We report the first detection of the GHR mutation among Japanese patients with Laron syndrome. Using the Japanese female patient's genomic DNA as a template, all exons and flanking portions of introns of GHR were amplified by polymerase chain reaction (PCR). Sequencing of the PCR products showed that the patient was homozygous for a G to A substitution at the first position of intron 4. This substitution was same as that detected in a Spanish patient and a north European patient. The base change occurred at the 5' splice consensus sequence of intron 4, resulting in the abolition of a BanI restriction site. Since this substitution was not detected by a BanI restriction analysis in 85 control individuals, it is more likely a disease-related splice mutation than a polymorphism. The mutation in our patient was predicted to destroy the original 5' splice site of intron 4 of GHR and to produce a new cryptic splice site, leading to abnormal mRNA processing and a lack of GH binding activity of GH-binding protein (GHBP).
Adult↗
Computed radiography excretory urography: can the system sensitivity value be used as an image quality indicator?
The purpose of this study is to determine whether the computed radiography system sensitivity value can be used as an image quality indicator for computed radiography excretory urography with radiation dose reduction. One hundred and twenty-four patients with gynecological malignancies were studied prospectively. Five-minute and 10-minute computed radiographic images of excretory urography were obtained in each patient with different radiation doses (ie, a standard dose image required with screen-film method and a reduced dose one). The images were subjectivity scored by three radiologists without knowledge of the exposure factors or the system sensitivity values. The quality scores of the reduced-dose images used in the five steps were compared with those of the standard dose images (the system sensitivity value was 80 to 120). The images with reduced exposures were arbitrarily divided into five steps according to the system sensitivity value (ie, 150 to 250, 260-400, 410-600, 610-1000, and 1010-1500). There was a gradual degradation of the image quality as the system sensitivity value was increased. In terms of visualization of the bones, the images taken with the system sensitivity values of 150-250 (40%-67% of the standard dose system) showed no statistically significant difference from the standard dose images. As for visualization of the renal pelvic margins, the images taken with the system sensitivity values of 260 to 400 (2%-38% of the standard dose system) showed no statistically significant difference. We conclude that system sensitivity value can be used as a practical though approximate indicator of the image quality.
Adult↗
Detection of polymorphisms within the human IL10 receptor cDNA gene sequence by RT-PCR RFLP.
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Alleles↗
Effect of (-)-epigallocatechin gallate on leukemic blast cells from patients with acute myeloblastic leukemia.
Information on the anti-carcinogenic effect of EGCG, the main constituent of the polyphenols present in Japanese green tea leaves, has recently been accumulating. In this report, we evaluate the effect of EGCG on leukemic blast cells from AML patients. The results showed that EGCG inhibited the proliferation of AML cells in all cases examined. Since AML cells might proliferate by autocrine or paracrine growth mechanisms, we also examined the effect of EGCG on the production of GM-CSF from AML cells. Although EGCG did not directly inhibit the production of GM-CSF, it did inhibit the effect of TNF-alpha or TPA, both of which stimulated AML cells to produce GM-CSF. On the other hand, the modulation of receptors for growth factors might play a role in the proliferation or carcinogenesis of AML cells. We also found that EGCG inhibited the modulation of c-kit, a receptor for stem cell factor, on leukemic cells. These findings suggested that EGCG might be available as a new therapeutic tool for AML patients.
Blast Crisis↗
The treatment of enchondromas in the hand by endoscopic curettage without bone grafting.
Nine patients with enchondromas in the hand were treated by endoscopic curettage of the tumour without bone grafting. The procedure was performed on an out-patient basis using axillary block anaesthesia. New bone formation and remodelling of the lesions were observed in all patients. There were no postoperative fractures, infections, recurrences or other complications. Functional recovery was rapid. We conclude that endoscopic curettage without bone grafting is an effective treatment of enchondroma in the hand.
Adolescent↗
Primary familial polycythaemia associated with a novel point mutation in the erythropoietin receptor.
Primary familial and congenital polycythaemia (PFCP) is a rare disease characterized by congenital erythrocytosis inherited in an autosomal dominant fashion. Recently, mutations in the erythropoietin receptor (EpoR) have been identified in PFCP families. We describe a Japanese family with an autosomal dominant inheritance of PFCP. An in vitro colony assay demonstrated hypersensitivity of erythroid progenitors to erythropoietin (Epo) in affected family members. Sequence analysis of RT-PCR products amplified from the C-terminal region of EpoR transcripts in affected family members revealed that they were all heterozygous for C and T bases at position 5986, which suggested a genetic mutation (C to T) on one allele of EpoR. This mutation gave rise to a translation termination codon TAG at amino acid 435. Thus, the resulting EpoR is a truncated protein product lacking all 74 amino acids downstream of the mutation. To date, all genetic mutations affecting a family with PFCP, including this one, have been located in the cytoplasmic negative regulatory region of the EpoR. All mutations gave rise to truncated Epo receptors between Tyrosine 427 and Tyrosine 455. The phosphotyrosines in this region of EpoR have been demonstrated to be binding sites for SHP-1 phosphatase. Therefore PFCP is presumably brought about as a result of genetic mutations which cause the loss of the SHP-1 binding site in the cytoplasmic region of EpoR.
Base Sequence↗
Allelotype and replication error phenotype of small cell lung carcinoma.
Allelotype and replication error (RER) phenotype analyses were performed to clarify the pathogenetic significance of inactivation of tumor suppressor genes and genomic instability in the genesis and progression of small cell lung carcinoma (SCLC). We examined 37 cases of SCLC for loss of heterozygosity (LOH) and microsatellite instability at 49 loci on all 39 nonacrocentric chromosomal arms. LOH was frequently (>70%) detected on chromosomes 3p (29/32, 90.6%), 5q (15/21, 71.4%), 13q (25/26, 96.2%), 17p (22/25, 88.0%), and 22q (24/33, 72.7%). Frequent LOH (>70%) on these loci was observed even among seven cases of stage I tumors. The incidence of LOH on all 39 nonacrocentric chromosomal arms was not significantly different between primary tumors and metastases. These results suggest that inactivation of multiple tumor suppressor genes accumulates relatively early during progression of SCLC and it may be responsible for clinically and biologically aggressive phenotype of SCLC. RER was observed in 6/37 (16.2%) of SCLC, however, RER at multiple loci was observed only in two cases. Therefore, it was indicated that genomic instability is uncommon, but might play a role in the genesis of a small subset of SCLC.
Alleles↗
Gliostatin/platelet-derived endothelial cell growth factor as a clinical marker of rheumatoid arthritis and its regulation in fibroblast-like synoviocytes.
The objective was to assess the congruity of gliostatin/platelet-derived endothelial cell growth factor (GLS PD-ECGF) with other clinical markers of rheumatoid arthritis (RA) and to define its molecular mechanism of action in the complicated cytokine network during RA pathogenesis. Immunoassay systems were used to quantify GLS or cytokine levels in laboratory and clinical samples. Expression levels of GLS were determined by reverse transcription-polymerase chain reaction methods. The GLS levels in synovial fluid were correlated with interleukin-1 (IL-1) and IL-8. The serial data of serum GLS levels reflected well changes in the disease activity during the clinical course of four representative patients with RA. In cultured fibroblast-like synoviocytes, tumour necrosis factor-alpha (TNF-alpha), IL-1, IL-6 and IL-8 induced GLS expression. In conclusion, our results suggest that the serum GLS level, mostly derived from cytokine-stimulated synoviocytes, was a useful clinical marker of RA.
Arthritis, Rheumatoid↗
Effect of exercise training and detraining on gas exchange kinetics in patients with chronic obstructive pulmonary disease.
Symptom-limited incremental exercise tests are used to estimate the training effect on patients with chronic obstructive pulmonary disease (COPD). However, there is a need for objective parameters for measurement on submaximal exercise testing. The purpose of this study was to assess the usefulness of measurement of oxygen uptake (VO2) kinetics during a constant work rate exercise test of patients with COPD after exercise training. Eleven patients with COPD performed exercise tests before and after cycle ergometer training on 3 days per week for 8 weeks; they then went without training for 5 months and performed the same tests. They performed an incremental exercise test to symptom-limited maximum and a constant work rate exercise test for 6 min on a cycle ergometer. The time constant of VO2 during the onset of constant work rate exercise was significantly decreased (from 63.5 +/- 7.8 s to 53.2 +/- 8.0 s) after exercise training (P = 0.021), but was significantly increased (to 73.4 +/- 14.9 s) after 5 months without training (P = 0.001). The oxygen pulse at steady state during constant work rate exercise testing was significantly increased after exercise training but decreased 5 months later. The change in blood lactate from rest to steady state during constant work rate exercise was significantly decreased after exercise training, but increased 5 months later. Measurement of the time constant of VO2 and oxygen pulse during constant work rate exercise are useful for the objective evaluation of the training effect of patients with COPD.
Aged↗
[Immunodeficiency and carcinogenesis in patients with chronic active Epstein-Barr virus infection].
Three adult patients with chronic active Epstein-Barr virus infection (CAEBV) had high anti-EBV-VCA antibody, positive anti-EA, low anti-EBNA and were associated with systemic lymphadenopathies and immunosuppression. The case 1 and 2 had elevated serum immunoglobulin levels, and recurrent infections, and case 3 showed pancytopenia. These 3 cases developed both EBV and latent membrane protein (LMP) positive malignant histiocytosis, EBV positive but LMP negative plasmacytoma, and EBV negative acute myelogeneous leukemia, respectively. It was suggested that CAEBV belonged to high risk groups for the development of malignant neoplasms. Since HLA of the case 1 and his father was identical, we conducted a in vitro cytotoxicity test using EBV transformed autologous B lymphocytes, K562 cells, and Raji cells to clarify the association of immunosuppression and HLA. The case 1 showed a low level of specific cytotoxicity to autologous EBV transformed B cells, while his parents were negative for the specific cytotoxicity. The patient and his parents developed inducible cytotoxicity to all targets after in vitro incubation of peripheral mononuclear cells with recombinant interleukin 2 (rIL-2) for 7 days. The patient and his mother showed lower enhancement of cytotoxicity, while HLA identical father could induce good cytotoxic activity to all targets as well as normal controls, indicating that a low IL-2 induced cytotoxic activity observed in CAEBV was independent of HLA associated immunoregulation at least in the case 1. Further studies are required to clarify the exact mechanisms responsible for the development of CAEBV.
Adult↗