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Biomedical subjects

N Ueno

Publications and source records attributed to N Ueno.

At least 37 records · Page 2Linked to original sources
PubMed2001

Coupling between cyclooxygenase, terminal prostanoid synthase, and phospholipase A2.

We have recently shown that two distinct prostaglandin (PG) E(2) synthases show preferential functional coupling with upstream cyclooxygenase (COX)-1 and COX-2 in PGE(2) biosynthesis. To investigate whether other lineage-specific PG synthases also show preferential coupling with either COX isozyme, we introduced these enzymes alone or in combination into 293 cells to reconstitute their functional interrelationship. As did the membrane-bound PGE(2) synthase, the perinuclear enzymes thromboxane synthase and PGI(2) synthase generated their respective products via COX-2 in preference to COX-1 in both the -induced immediate and interleukin-1-induced delayed responses. Hematopoietic PGD(2) synthase preferentially used COX-1 and COX-2 in the -induced immediate and interleukin-1-induced delayed PGD(2)-biosynthetic responses, respectively. This enzyme underwent stimulus-dependent translocation from the cytosol to perinuclear compartments, where COX-1 or COX-2 exists. COX selectivity of these lineage-specific PG synthases was also significantly affected by the concentrations of arachidonate, which was added exogenously to the cells or supplied endogenously by the action of cytosolic or secretory phospholipase A(2). Collectively, the efficiency of coupling between COXs and specific PG synthases may be crucially influenced by their spatial and temporal compartmentalization and by the amount of arachidonate supplied by PLA(2)s at a moment when PG production takes place.

Arachidonic Acid↗
PubMed2001

A DAF-1-binding protein BRA-1 is a negative regulator of DAF-7 TGF-beta signaling.

We have identified homologs of a human BMP receptor-associated molecule BRAM1 in Caenorhabditis elegans. One of them, BRA-1, has been found to bind DAF-1, the type I receptor in the DAF-7 transforming growth factor-beta pathway through the conserved C-terminal region. As analyzed using a BRA-1GFP (green fluorescent protein) fusion gene product, the bra-1 gene is expressed in amphid neurons such as ASK, ASI, and ASG, where daf-1 is also expressed. A loss-of-function mutation in bra-1 exhibits robust suppression of the Daf-c phenotype caused by the DAF-7 pathway mutations. We propose that BRA-1 represents a novel class of receptor-associated molecules that negatively regulate transforming growth factor-beta pathways.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Positivity of extrapulmonary Ga-67 uptake in sarcoidosis: thyroid uptake due to chronic thyroiditis and bone uptake due to fibrous dysplasia.

Ga-67 citrate scintigraphy was performed on a 29-year-old man who had been diagnosed as having pulmonary sarcoidosis by a transbronchial lung biopsy. A Ga-67 citrate scintigram showed increased uptake not only in the pulmonary hilum and mediastinum, but also in the thyroid gland and the right ilium. Chronic thyroiditis was confirmed by aspiration biopsy of the thyroid gland, and fibrous dysplasia was confirmed by CT guided biopsy of the right ilium. Extrapulmonary Ga-67 uptake in patients with sarcoidosis does not necessarily indicate the involvement of other tissues and organs.

Adult↗
PubMed2001

Thyroid-hormone-dependent and fibroblast-specific expression of BMP-4 correlates with adult epithelial development during amphibian intestinal remodeling.

We have identified one of the genes that are up-regulated by thyroid hormone (TH) in Xenopus laevis small intestine as the Xenopus homolog of bone morphogenetic protein-4 (BMP-4). To clarify possible roles of BMP-4 in intestinal remodeling during metamorphosis, we have examined its expression in X. laevis intestine by using in situ hybridization and organ culture techniques. At the beginning of metamorphic climax, BMP-4 mRNA first becomes detectable in the connective tissue, concurrently with the appearance of adult epithelial primordia. Subsequently, when the adult epithelial primordia are actively proliferating, BMP-4 mRNA becomes more abundant only in the connective tissue with a gradient toward the epithelium. Thereafter, as the adult primordia differentiate, the level of BMP-4 mRNA gradually decreases. Thus, BMP-4 expression correlates well with cell proliferation and/or initial differentiation of the adult epithelium, but not with apoptosis of the larval epithelium. Furthermore, the present culture study indicates that (1) TH-induced expression of BMP-4 mRNA is higher in the anterior part of the intestine than in the posterior part, which agrees with the better development of the adult epithelium in the more anterior part, and that (2) the expression of BMP-4 mRNA is up-regulated by TH in the presence of epithelium, but not in its absence. Therefore, BMP-4, which is indirectly induced by TH through some epithelial factor(s), probably plays important roles in adult epithelial development during amphibian intestinal remodeling.

Age Factors↗
PubMed2001

Nonmyeloablative preparative regimens for allogeneic hematopoietic transplantation.

Allogeneic hematopoietic transplantation is an effective therapy for a range of malignancies. High doses of myelosuppressive chemotherapy or radiation have been used in preparative regimens with the goal of preventing graft rejection and eradicating malignancy. Much of the benefit of transplantation, however, results from graft-versus-malignancy effects, mediated by donor immunocompetent cells. An alternative approach is to utilize less toxic, nonmyeloablative preparative regimens to achieve engraftment and allow graft-versus-malignancy effects to develop. This strategy reduces the risk of treatment-related mortality and allows transplantation for elderly or medically infirm patients not eligible for myeloablative therapy. Nonmyeloablative preparative regimens appear promising in diagnoses sensitive to graft-versus-malignancy effects and provide a platform for further development of cellular immunotherapy. Controlled clinical trials are warranted to define the role of nonmyeloablative allogeneic transplants in a range of hematologic malignancies and selected solid tumors.

Graft vs Tumor Effect↗
PubMed2001

Decitabine with allogeneic peripheral blood stem cell transplantation in the therapy of leukemia relapse following a prior transplant: results of a phase I study.

Relapse after allogeneic progenitor cell transplant is associated with a poor prognosis for patients with advanced leukemia, with few curative options available. Use of novel chemotherapeutic agents with limited toxicity is warranted. We investigated the role of decitabine, a pyrimidine analogue with significant anti-leukemic effect and limited toxicity, in this setting. Fourteen patients with advanced acute leukemia or transformed chronic myelogenous leukemia (CML) who had failed previous allogeneic transplant were treated. Decitabine at doses of 100 mg/m2 to 150 mg/m2 given every 12 h for 5 days was followed by infusion of stem cells from the original donor 2 to 5 days after the completion of chemotherapy. Dose of decitabine was escalated in cohorts of three patients based on the modified Fibonacci scheme. The primary study end-point was assessment of the toxicity of the regimen with secondary endpoints of response and survival. Eight patients responded with either a complete remission or partial hematological remission (absence of blasts in peripheral blood and bone marrow but with platelet count <100 x 10(9)/l). Toxicity was limited with no grade 3 or 4 toxicity directly attributable to the treatment. The median survival for all patients was 190 days (range 11 to 1215+ days). Decitabine at doses of 100 mg/m2 to 150 mg/m2 given every 12 h for 5 days, followed by stem cell infusion from the original donor was well tolerated, and was associated with acceptable myelosuppression. Current response data should encourage further study of this drug, either alone or in combination with other agents, for treatment of relapsed acute leukemia after an allogeneic transplant.

Adult↗
PubMed2001

BIP, a BRAM-interacting protein involved in TGF-beta signalling, regulates body length in Caenorhabditis elegans.

BACKGROUND: The TGF-beta superfamily has diverse biological activities and is involved in the early development of animals. We previously identified a novel family member, BMP receptor associated molecule (BRAM), which binds to the intracellular domain of BMP type IA receptor and is involved in the BMP signalling pathway. RESULTS: To identify novel molecules involved in TGF-beta signalling pathways, we performed yeast two-hybrid screening using BRAM as bait. From a Xenopus cDNA library, we cloned a cDNA encoding 693 amino acids and containing the motif for an oxysterol binding protein (OSBP), which we designated BRAM interacting protein (BIP). We then isolated a BIP homologue from the Caenorhabditis elegans that encodes 733 amino acids and also contains the OSBP-like motif. Immunoprecipitation and Western blotting studies revealed that C. elegans BIP could interact with the C. elegans BRAM homologues BRA-1 and BRA-2. C. elegans BIP was expressed in pharyngeal muscle, hypodermis and several neuronal cells, an expression pattern overlaps with those of BRA-1 and BRA-2. Finally, we found that inhibition of BIP expression in C. elegans by double stranded RNA interference produces a Sma phenotype. CONCLUSIONS: BIP was isolated using the yeast two-hybrid systems. BIP may function in the TGF-beta pathway and regulate body length in C. elegans.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Visualization of endogenous BMP signaling during Xenopus development.

The TGF-beta superfamily of growth factors is known to transmit signals to the nucleus mainly through the Smads, intracellular signaling components that are highly conserved from nematodes to humans. The signaling activity of the Smads is regulated by their ligand-stimulated phosphorylation through Ser/Thr kinase receptors. Here, to examine the in vivo role of BMP, we investigated the spatio-temporal activation of BMP-regulated signals during Xenopus development, using a polyclonal antibody that specifically recognizes the phosphorylated form of BMP-regulated Smads. BMP signaling was observed uniformly in embryos as early as stage 7, but was restricted to the ventral side of the embryo at the late blastula stage, supporting the proposed role of BMP4 as a ventralizing factor in Xenopus embryos. In addition, localized staining was detected in several developing organs, consistent with the predicted function of BMP family members in organogenesis.

Animals↗
PubMed2001

Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin.

BACKGROUND & AIMS: : Ghrelin, an endogenous ligand for growth hormone secretagogue receptor, was recently identified in the rat stomach. We examined the effects of the gastric peptide ghrelin on energy balance in association with leptin and vagal nerve activity. METHODS: : Food intake, oxygen consumption, gastric emptying, and hypothalamic neuropeptide Y (NPY) messenger RNA expression were measured after intra-third cerebroventricular or intraperitoneal injections of ghrelin in mice. The gastric vagal nerve activity was recorded after intravenous administration in rats. Gastric ghrelin gene expression was assessed by Northern blot analysis. Repeated coadministration of ghrelin and interleukin (IL)-1 beta was continued for 5 days. RESULTS: : Ghrelin exhibited gastroprokinetic activity with structural resemblance to motilin and potent orexigenic activity through action on the hypothalamic neuropeptide Y (NPY) and Y(1) receptor, which was lost after vagotomy. Ghrelin decreased gastric vagal afferent discharge in contrast to other anorexigenic peptides that increased the activity. Ghrelin gene expression in the stomach was increased by fasting and in ob/ob mice, and was decreased by administration of leptin and IL-1 beta. Peripherally administered ghrelin blocked IL-1 beta-induced anorexia and produced positive energy balance by promoting food intake and decreasing energy expenditure. CONCLUSIONS: : Ghrelin, which is negatively regulated by leptin and IL-1 beta, is secreted by the stomach and increases arcuate NPY expression, which in turn acts through Y(1) receptors to increase food intake and decrease energy expenditure. Gastric peptide ghrelin may thus function as part of the orexigenic pathway downstream from leptin and is a potential therapeutic target not only for obesity but also for anorexia and cachexia.

Amino Acid Sequence↗
PubMed2001

Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice.

This study was designed to investigate the effects of cocaine-amphetamine-regulated transcript (CART), a recently discovered hypothalamic neuropeptide, on food intake, anxiety, oxygen consumption and gastric emptying in mice. Intracerebroventricular (i. c. v.) injection of CART (1 - 100 pmol) markedly reduced food intake in a dose-related manner. A significant decrease was observed 20 min after i. c. v. injection of CART and continued for four hours. In the elevated plus maze test, i. c. v. CART injection significantly raised the normal preference for the closed arms. Furthermore, the i. c. v. injection of CART significantly reduced oxygen consumption and gastric emptying rate. These results suggest that CART modulates feeding, emotion, and autonomic functions in mice.

Animals↗
PubMed2001

Stent placement in the pancreatic duct prevents pancreatitis after endoscopic sphincter dilation for removal of bile duct stones.

BACKGROUND: Pancreatitis is the most serious complication of endoscopic sphincter dilation. The aim of this study was to determine whether temporary stent placement in the main pancreatic duct decreases the frequency of pancreatitis and level of hyperamylasemia. METHODS: Stents were placed in the pancreatic duct after endoscopic sphincter dilation in 40 consecutive patients with bile duct stones. Stents were removed endoscopically 3 days later. Changes in serum amylase and the frequency of pancreatitis for this group were compared with those in 92 patients who underwent sphincter dilation without pancreatic duct stent placement. RESULTS: Stent placement was successful in 38 of 40 patients. Although the difference in the frequency of pancreatitis was not significantly different between stent and control groups, there was a trend toward a decrease in pancreatitis in the stent group. The level of postprocedure hyperamylasemia was significantly less in the stent group (p < 0.05). There were no procedure-related complications. CONCLUSIONS: Temporary placement of a stent in the pancreatic duct after sphincter dilation for removal of bile duct stones has a beneficial effect in terms of postprocedure hyperamylasemia and appears to reduce the frequency of postprocedure pancreatitis.

Aged↗
PubMed2001

Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kappaB ligand.

Bone is a major storage site for TGFbeta superfamily members, including TGFbeta and bone morphogenetic proteins. It is believed that these cytokines are released from bone during bone resorption. Recent studies have shown that both RANKL and macrophage colony-stimulating factor are two essential factors produced by osteoblasts for inducing osteoclast differentiation. In the present study we examined the effects of bone morphogenetic protein-2 on osteoclast differentiation and survival supported by RANKL and/or macrophage colony-stimulating factor. Mouse bone marrow-derived macrophages differentiated into osteoclasts in the presence of RANKL and macrophage colony-stimulating factor. TGFbeta superfamily members such as bone morphogenetic protein-2, TGFbeta, and activin A markedly enhanced osteoclast differentiation induced by RANKL and macrophage colony-stimulating factor, although each cytokine alone failed to induce osteoclast differentiation in the absence of RANKL. Addition of a soluble form of bone morphogenetic protein receptor type IA to the culture markedly inhibited not only osteoclast formation induced by RANKL and bone morphogenetic protein-2, but also the basal osteoclast formation supported by RANKL alone. Either RANKL or macrophage colony-stimulating factor stimulated the survival of purified osteoclasts. Bone morphogenetic protein-2 enhanced the survival of purified osteoclasts supported by RANKL, but not by macrophage colony-stimulating factor. Both bone marrow macrophages and mature osteoclasts expressed bone morphogenetic protein-2 and bone morphogenetic protein receptor type IA mRNAs. An EMSA revealed that RANKL activated nuclear factor-kappaB in purified osteoclasts. Bone morphogenetic protein-2 alone did not activate nuclear factor-kappaB, but rather inhibited the activation of nuclear factor-kappaB induced by RANKL in purified osteoclasts. These findings suggest that bone morphogenetic protein-mediated signals cross-communicate with RANKL-mediated ones in inducing osteoclast differentiation and survival. The enhancement of RANKL-induced survival of osteoclasts by bone morphogenetic protein-2 appears unrelated to nuclear factor-kappaB activation.

Animals↗
PubMed2001

Suppression of head formation by Xmsx-1 through the inhibition of intracellular nodal signaling.

It is well established that in Xenopus, bone morphogenetic protein (BMP) ventralizes the early embryo through the activation of several target genes encoding homeobox proteins, some of which are known to be necessary and sufficient for ventralization. Here, we used an inhibitory form of Xmsx-1, one of BMP's targets, to examine its role in head formation. Interestingly, ventral overexpression of a dominant Xmsx-1 inhibitor induced an ectopic head with eyes and a cement gland in the ventral side of the embryo, suggesting that Xmsx-1 is normally required to suppress head formation in the ventral side. Supporting this observation, we also found that wild-type Xmsx-1 suppresses head formation through the inhibition of nodal signaling, which is known to induce head organizer genes such as cerberus, Xhex and Xdkk-1. We propose that negative regulation of the BMP/Xmsx-1 signal is involved not only in neural induction but also in head induction and formation. We further suggest that the inhibition of nodal signaling by Xmsx-1 may occur intracellularly, through interaction with Smads, at the level of the transcriptional complex, which activates the activin responsive element.

Animals↗
PubMed2001

Purification and characterization of an acid trehalase from Acidobacterium capsulatum.

We purified an acid trehalase (EC 3.2.1.28, alpha,alpha'-trehalose glucohydrolase) from an acidophilic bacterium, Acidobacterium capsulatum. The enzyme was homogeneous based on polyacrylamide gel electrophoresis, and was composed of a single polypeptide chain with a molecular mass of 57 kDa. Maximum trehalase activity was observed at pH 2.5. The acid trehalase exhibited an apparent K(m) of 1.0 mM for trehalose at 30 degrees C and pH 3.0. The trehalase was located in the periplasmic space. The activity of the enzyme was activated by 1.0 mM MnCl2 or CoCl2, and inhibited by 1.0 mM PbCl2, HgCl2, NiCl2, p-chloromercuribenzoate, N-ethylmaleimide, monoiodoacetate, or EDTA. The enzyme showed high specificity for trehalose. It was found that an equimolar mixture of alpha-D-glucose and beta-D-glucose was formed on hydrolysis of trehalose by the trehalase.

Journal Article↗
PubMed2001

Modest overexpression of neuropeptide Y in the brain leads to obesity after high-sucrose feeding.

Neuropeptide Y (NPY), one of the most abundant peptide transmitters in the mammalian brain, is assumed to play an important role in feeding and body weight regulation. However, there is little genetic evidence that overexpression or knockout of the NPY gene leads to altered body weight regulation. Previously, we developed NPY-overexpressing mice by using the Thy-1 promoter, which restricts NPY expression strictly within neurons in the central nervous system, but we failed to observe the obese phenotype in the heterozygote. Here we report that in the homozygous mice, overexpression of NPY leads to an obese phenotype, but only after appropriate dietary exposure. NPY-overexpressing mice exhibited significantly increased body weight gain with transiently increased food intake after 50% sucrose--loaded diet, and later they developed hyperglycemia and hyperinsulinemia without altered glucose excursion during 1 year of our observation period.

Aging↗