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Biomedical subjects

Y Nojima

Publications and source records attributed to Y Nojima.

At least 55 records · Page 3Linked to original sources
PubMed1999

Glomerular overexpression and increased tyrosine phosphorylation of focal adhesion kinase p125FAK in lupus-prone MRL/MP-lpr/lpr mice.

Much progress has been made in understanding how mammalian cells receive a diverse array of external stimuli and convert them into intracellular biochemical signals. Such efforts have identified a large number of signalling molecules. However, our knowledge is limited as to their pathophysiological role in particular diseases. We demonstrate herein that an integrin-linked signalling molecule, focal adhesion kinase p125FAK (FAK), is overexpressed in glomeruli of lupus-prone MRL/MP-lpr/lpr (MRL-lpr) mouse as compared to its congeneic MRL-+/+ strain. Increased expression was specifically demonstrated in glomeruli but not in other tissues examined. The overexpression was observed in 16-week-old MRL-lpr mice with active nephritis, as well as in younger animals at 4 weeks of age. Thus, the upregulation of FAK clearly preceded the clinical onset of nephritis. FAK in MRL-lpr glomeruli is highly tyrosine phosphorylated and is associated with adapter protein Grb2. Previous in vitro studies have shown that the association of FAK/Grb2 links cell adhesion to the Ras pathway, which ultimately stimulates mitogen-activated protein (MAP) kinase, an important regulator of cell proliferation. In accordance, we observed constitutive MAP kinase activation in MRL-lpr glomeruli. Our findings suggest that signalling pathways involving FAK are activated in MRL-lpr glomeruli, and are likely to play a role in the development and progression of autoimmune-mediated murine nephritis.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Successful cerebral artery stent placement for total occlusion of the vertebrobasilar artery in a patient suffering from acute stroke. Case report.

A 64-year-old man suffering from crescendo brainstem symptoms due to acute total occlusion of the vertebrobasilar artery was successfully treated by cerebral artery stent placement. The total occlusion of a long segment of the vertebrobasilar artery was completely recanalized by implanting two flexible, balloon-expandable coronary stents. The patient's clinical outcome 30 days later was favorable. No complications occurred during or after the procedure. This therapeutic option may prove to be a useful means to revascularize an acute total occlusion of the vertebrobasilar artery.

Acute Disease↗
PubMed1999

Role of autoantibodies against tubular brush border antigens in tubulointerstitial nephritis associated with Heymann nephritis.

Previous studies have shown that a rat experimental model of membranous nephropathy (Heymann nephritis) is often associated with tubulointerstitial changes. Although antibody-dependent tubular injuries have been proposed in this model, precise mechanisms have been ill-defined. In the present report, we established a model of acute tubulointerstitial nephritis (TIN) by injecting puromycin aminonucleoside (PAN) to Wistar rats which had been immunized with tubular antigens (Tub-Ag). In this model, TIN developed 4 weeks after Tub-Ag immunization when rats had a high titer of circulating anti-Tub-Ag antibodies and began to excrete massive proteinuria. Deposits of immunoglobulins along tubular brush borders were also demonstrated. Rats receiving either Tub-Ag or PAN alone failed to develop TIN during this relatively acute phase. These results suggest that anti-Tub-Ag antibodies excreted into the urine play a role in developing TIN in this model.

Animals↗
PubMed1998

Integrin-mediated signal transduction in cells lacking focal adhesion kinase p125FAK.

We have previously shown that integrin-dependent tyrosine phosphorylation of p130Cas (Cas) could be induced in a mouse fibroblast cell line that does not express focal adhesion kinase p125FAK (FAK). By analyzing FAK-deficient (FAK-/-) cells transiently expressing Cas mutant proteins, we demonstrate here that the Src homology 3 (SH3) domain of Cas is indispensable for adhesion-mediated Cas phosphorylation in this mutant cell line. While the FAK directly binds to Cas-SH3, our findings imply that SH3-binding molecule(s) other than FAK might regulate Cas phosphorylation, at least in FAK-/- cells. In this regard, we observed that FAK-/- cells expressed cell adhesion kinase beta (CAKbeta), a protein tyrosine kinase of the FAK subfamily. CAKbeta expressed by FAK-/- cells was associated in vivo with Cas in a Cas-SH3-dependent manner. Moreover, integrin stimulation induces tyrosine phosphorylation of CAKbeta in FAK-/- cells. Thus, our results suggest that CAKbeta contributes to integrin-mediated signal transduction in place of FAK in FAK-deficient cells.

Animals↗
PubMed1998

Interleukin-12 induces tyrosine phosphorylation of an 85-kDa protein associated with the interleukin-12 receptor beta 1 subunit.

Interleukin-12 (IL12) is a heterodimeric cytokine composed of p35 and p40 subunits and having multiple immunomodulatory effects on T cells as well as on natural killer cells. Two subunits, beta 1 and beta 2, consisting of the functional IL12 receptor complex, have been recently identified as members of the hemopoietin receptor superfamily, bearing strong homology to gp130. In the present study, we attempted to further characterize the biochemical nature of the IL12 receptor complex and to delineate IL12-triggered signal transduction pathways. To this end, we established a Jurkat transfectant (JIL12R beta 1t) highly expressing the recombinant human IL12 receptor beta 1 subunit. Using this transfectant, we identified an 85-kDa protein (p85) which is associated with the beta 1 subunit and appears to be a cell surface protein, but is distinct from the beta 2 subunit (130 kDa). p85 was also detected in PHA-activated T cells. Importantly, p85 was rapidly tyrosine phosphorylated upon stimulation of both JIL12R beta 1t cells and PHA-activated T cells with IL12. These results suggest that p85 is a component of the IL12 receptor complex and may play a significant role in mediating IL12-dependent signals.

Animals↗
PubMed1998

Sulfite is released by human neutrophils in response to stimulation with lipopolysaccharide.

Exposure to sulfite, a well-known air pollutant, induces inflammatory reactions characterized by neutrophil infiltration into the airways. Using a simple and sensitive assay for sulfite concentration in biological fluids, we demonstrate herein that human neutrophils released significant amounts of sulfite (1.0 nmol/h/10(7) cells) in response to lipopolysaccharide (LPS), a major component of bacterial endotoxin. A large proportion of the sulfite release by neutrophils was dependent on inorganic sulfate contained in culture media, suggesting production via the sulfate reducing pathway in this response. We also show that glucocorticoids and FK506 completely inhibit LPS-mediated sulfite release by neutrophils. Given the well-known antimicrobial activities of sulfite, our results suggest that sulfite acts as a neutrophil mediator of host defense. A putative role of sulfite as an endogenous biological mediator is further underscored by the observation that in vivo administration of LPS is associated with a marked increase in the serum concentration of sulfite in Wistar rats. Inhibition of sulfite release by immunosuppressive agents may contribute to increased susceptibility to bacterial infection commonly associated with the administration of these drugs.

Animals↗
PubMed1998

Neuroepithelial and ependymal changes in HTX rats with congenital hydrocephalus: an ultrastructural and immunohistochemical study.

To investigate the pathogenesis of congenital hydrocephalus the brains of HTX rats aged between 16 days and 4 weeks and the brains of normal Wistar rats of the same ages were examined. In the fetal HTX rat brains, the lateral ventricles were symmetrically dilated from 20 days of gestation. The neuroepithelium bordering the ventricles showed thinning with cellular disarrangement and deformity. Similar neuroepithelial abnormalities were also found in the lateral ventricles of the HTX rat brain with no macroscopic signs of hydrocephalus at 20 days of gestation. The neuroepithelium showed flattening of the cells, widening of the intercellular spaces, formation of microvilli on the detached lateral cell surfaces, and frequent macrophage infiltration. On the other hand, the neuroepithelial cells of the third ventricle and the aqueduct were affected less severely or showed no significant abnormalities. Immunohistochemically, most of the neuroepithelium and ependyma of the lateral ventricles were positive for vimentin in both prenatal and postnatal hydrocephalic HTX rats, while a small number or none of those in normal control rats were positive. These morphological changes suggested that preferential involvement of the lateral ventricular neuroepithelium might be closely associated with the pathogenesis of congenital hydrocephalus in HTX rats.

Aging↗
PubMed1998

Levels of serum glycosaminoglycans in renal failure.

We measured the concentration of serum glycosaminoglycans (GAGs) in patients with glomerulonephritis, renal failure and on hemodialysis using the dye binding method. In glomerulonephritis, concentration of serum GAGs did not increase, and there was no correlation between serum and urinary GAGs. In patients with renal failure and hemodialysis, concentration of serum GAGs was significantly lower than in controls. Concentration of serum GAGs was correlated with concentration of serum albumin, which is an indicator of malnutrition in patients on hemodialysis. One month of hemodialysis did not affect the concentration of serum GAGs in patients with renal failure, but six months of hemodialysis increased the concentration of serum GAGs. These results suggest that matrix production is suppressed in renal failure with malnutrition.

Adult↗
PubMed1997

Constitutive tyrosine phosphorylation of the vav proto-oncogene product in MRL/Mp-lpr/lpr mice.

MRL/Mp-lpr/lpr (lpr) mice develop autoantibodies, vasculitis, and glomerulonephritis, which are similar to human systemic lupus erythematosus, and acquire a generalized, nonmalignant, lymphoproliferative disorder. CD4- CD8- CD3+ TCR alphabeta+ (double-negative, DN) T cells accumulate in spleen and lymph nodes, and become a major T cell population in vivo. These DN T cells, however, are refractory to various stimuli, including CD3, IL-2, CD28, PMA, and PHA. Recently, the lpr gene mutation has been identified as a mutant gene for Fas, resulting in expression defects of Fas Ag. It is still unclear, however, what kinds of mechanisms cause the dysfunction of lpr DN T cells. To elucidate the pathogenic mechanisms in abnormal DN T cells, biochemical analyses were conducted for the expression and tyrosine phosphorylation of the vav proto-oncogene product (Vav) in DN T cells from lpr mice. We demonstrated that Vav, a 95-kDa cytoplasmic protein, from lpr mice was constitutively tyrosine phosphorylated several times higher than in control +/+ mice, while expression of Vav protein in lpr and +/+ mice was equal. Additionally, in contrast with +/+ T cells, tyrosine phosphorylation of Vav, which normally increases within a minute of stimulation via TCR, did not increase in lpr DN T cells following PHA or Ab activation. Taken together with the suggested roles of Vav in multiple receptor-mediated signal transductions, our findings suggest that the functional abnormalities of lpr DN T cells may be related to Vav abnormal tyrosine phosphorylation, which could lead to impaired signaling between surface receptors and G proteins in this cell population.

Animals↗
PubMed1997

Ligation of the T cell antigen receptor induces tyrosine phosphorylation of p105CasL, a member of the p130Cas-related docking protein family, and its subsequent binding to the Src homology 2 domain of c-Crk.

p105CasL (CasL) is a recently identified signaling molecule closely related to the p130Cas (Crk-associated substrate) docking protein. CasL has a single Src homology (SH) 3 domain in its N-terminal portion followed by multiple consensus motifs for binding to SH2 domains. Like original p130Cas, CasL undergoes tyrosine phosphorylation upon integrin-mediated cell adhesion. In the present report, we provide direct evidence that CasL is also involved in T cell antigen receptor (TcR)-mediated signal transduction. In binding studies in vitro using glutathione-S-transferase fusion proteins, we have identified 105- and 120-kDa phosphotyrosyl proteins (pp105 and pp120, respectively) tightly bound to the SH2 domain of the Crk adapter protein in the H9 human T cell line after stimulation through the CD3/TcR complex. pp120, but not pp105, also bound to the SH3 of another adapter protein, Ash/Grb2. Immunoblotting with specific antibodies revealed that pp120 and pp105 were identical to the c-cbl proto-oncogene product (p120cbl) and CasL, respectively. Association between Crk and tyrosine-phosphorylated CasL after TcR stimulation was also confirmed in vivo. CasL phosphorylation induced by TcR ligation reached maximal levels within 2 min and rapidly declined thereafter, whereas the integrin-dependent response occurred slowly and was more prolonged. Finally, we demonstrated that Crk/CasL association occurred in peripheral blood T lymphocytes in response to TcR engagement. Our findings suggest that CasL is involved in T cell activation signals and resides at a point where two distinct receptor-mediated signaling pathways converge. This provides one mechanism by which integrins may mediate T cell co-stimulation.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Structure and function of Cas-L, a 105-kD Crk-associated substrate-related protein that is involved in beta 1 integrin-mediated signaling in lymphocytes.

Integrin/ligand binding evokes tyrosine phosphorylation of various proteins. We reported previously that a 105 kD protein (pp105) was tyrosine phosphorylated by the engagement of beta 1 integrins in T lymphocytes. We show here that pp105 is a novel p130Cas (Crk-associated substrate)-related protein. Deduced amino acid sequence revealed that pp105 contains conserved motifs with p130Cas, and both pp105 and p130Cas bind to focal adhesion kinase (pp125FAK) and Crk. However, pp105 has a clearly distinct structure from p130Cas, and pp105 is preferentially expressed in lymphocytes, whereas p130Cas is expressed in adherent cells. With these findings, we designate pp105 as Cas-L, lymphocyte-type Cas. Furthermore, we demonstrate that integrin/ligand binding results in the recruitment of Crk, Nck, and SHPTP2 to pp105. These findings further define the roles of pp105/Cas-L and pp125FAK in the integrin-mediated signaling pathways.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Src kinase plays an essential role in integrin-mediated tyrosine phosphorylation of Crk-associated substrate p130Cas.

A novel signaling molecule p130Cas has been shown to undergo tyrosine phosphorylation in response to integrin-mediated cell adhesion. In this study, we have attempted to identify kinases that mediate Cas phosphorylation in integrin signaling by examining various mutant cell lines that do not express either p125FAK, c-Scr, c-Fyn or c-Abl. We found that deficiency of c-Src but not of other kinases completely abrogated integrin-mediated Cas phosphorylation. Importantly, paxillin phosphorylation was not compromised in each mutant cell line examined. These results suggest that c-Src primarily mediates adhesion-dependent Cas phosphorylation. As for paxillin phosphorylation, there may exist substantial redundancy amongst multiple kinases. Finally, adhesion-induced Cas phosphorylation resulted in its association with c-Crk adapter protein via the Crk-SH2 domain. Thus, Cas plays a role in the transmission of integrin-initiated signals through tyrosine phosphorylation and subsequent binding to c-Crk.

3T3 Cells↗
PubMed1996

Chronic intestinal pseudoobstruction associated with autoantibodies against proliferating cell nuclear antigen.

Autoantibodies against proliferating cell nuclear antigen (PCNA) have been detected almost exclusively in sera from patients with systemic lupus erythematosus (SLE). Because of the extremely low prevalence of anti-PCNA, however, it has been difficult to establish its disease specificity and clinical associations. We present 2 cases in which patients with anti-PCNA developed severe gastrointestinal dysfunction that led to chronic intestinal pseudoobstruction. Neither patient had manifestations suggestive of SLE. Although sclerodermatous skin changes were minimal or absent in these patients, physical and radiographic findings indicated that systemic sclerosis was a likely cause of the gastrointestinal dysfunction. The similarity of the clinical features in these patients implies that the unusual detection of this unique autoantibody may not be a coincidence.

Autoantibodies↗
PubMed1996

Defining nursing interventions.

Nurses are giving increasing attention to independent nursing interventions. However, numerous conceptualizations of interventions have evolved and are being used. The purpose of this essay is to examine some of the existing definitions and classification systems for interventions and to provide a rationale for a common universal language for nursing interventions. Definitions and approaches used in five intervention classification systems are examined in relation to inclusion of assessment and evaluation activities, autonomy, level of conceptualization, and inclusiveness of intervention labels. Lack of a common intervention language can deter international collaboration, development of a scientific basis for practice, and reimbursement for nursing services.

Humans↗
PubMed1996

Enhanced expression of platelet-derived growth factor-beta receptor by high glucose. Involvement of platelet-derived growth factor in diabetic angiopathy.

Coronary heart disease is a major complication of diabetic subjects, and platelet-derived growth factor (PDGF) has been implicated in the development of atherosclerosis. We investigated the effects of high glucose on expression of PDGF-beta receptor. In a binding assay with 125I-labeled PDGF-BB homodimer, high concentrations of glucose increased high-affinity binding of PDGF-BB on human monocyte-derived macrophages and rabbit aortic medial smooth muscle cells. Northern blot analysis confirmed the enhanced effect of glucose on expression of PDGF-beta receptor mRNA in human monocyte-derived macrophages. The protein kinase C inhibitor, staurosporin, completely suppressed an increase in PDGF-BB binding by high glucose, and high glucose significantly activated protein kinase C. These results indicated that PDGF-beta receptor expression was enhanced by high glucose through the activation of protein kinase C. Furthermore, we observed similar effects of high glucose on both PDGF-beta receptor expression and protein kinase C activation in rat mesangial cells and human capillary endothelial cells. Our results suggest that stimulation of the PDGF system is significantly involved in the development not only of diabetic atherosclerosis but also of microangiopathy.

Alkaloids↗