Induction of histidine decarboxylase in type 2 T helper lymphocytes treated with anti-CD3 antibody.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
A Ichikawa
Publications and source records attributed to A Ichikawa.
Potentiation of retinoic acid-induced differentiation of HL-60 cells by prostaglandin EP2 receptor.
Human promyeloid HL-60 cells are differentiated by all-trans retinoic acid (RA) to granulocytes, and prostaglandin (PG) E2 potentiates the RA-induced differentiation. Here we examined which subtype of PGE receptors was involved in this potentiating activity of PGE2. Northern blot analysis demonstrated that HL-60 cells expressed three subtypes of PGE receptor, EP2, EP3, and EP4. Among various EP agonists, and EP2-selective agonist, butaprost, preferentially potentiated the RA-induced differentiation of HL-60 cells. Butaprost not only decreased the half-maximal concentration of RA but also increased the maximal level of the differentiation. Butaprost concentration-dependently stimulated the cAMP formation, and 8-Br-cAMP strongly potentiated the RA-induced differentiation. These results demonstrate that the EP2 receptor enhances the RA-induced differentiation of HL-60 cells via stimulation of adenylate cyclase.
8-Bromo Cyclic Adenosine Monophosphate↗
Inhibition of dopamine release by prostaglandin EP3 receptor via pertussis toxin-sensitive and -insensitive pathways in PC12 cells.
Prostaglandin EP3 receptor is involved in the inhibition of neurotransmitter release from presynaptic nerve terminals in various tissues. We have examined the regulation of neurotransmitter release by the EP3 receptor using a PC12 cell line that stably expresses the EP3B receptor isolated from bovine adrenal medulla. In the cells, M&B28767, an EP3 agonist, inhibited the 50 mM KCl- or 10 nM bradykinin-induced [3H]dopamine release in a concentration-dependent manner (10 pM to 0.1 microM). This inhibition was partially reversed by pretreatment with pertussis toxin, whereas under the same condition, the agonist-induced inhibition of forskolin-stimulated cyclic AMP accumulation was suppressed completely. In contrast, M&B28767 did not affect the high K(+)- or bradykinin-induced increase in intracellular Ca2+ concentration. Moreover, M&B28767 also inhibited the [3H]dopamine release induced by the Ca2+ ionophore ionomycin, and this inhibition was also partially reversed by pretreatment with pertussis toxin. These results indicate that the EP3 receptor is coupled to dual pathways, pertussis toxin-sensitive and -insensitive G-protein pathways, to regulate neurotransmitter release without changing Ca2+ influx in neuronal cells.
Adenylyl Cyclase Inhibitors↗
Protective Effects of Iganidipine on Morphological and Functional Changes of Arteries in Hypertensive Dahl Rats.
BACKGROUND: This study was performed to examine the protective effects of iganidipine, a new water-soluble calcium antagonist, on the morphological and functional changes of arteries in Dahl salt-sensitive (Dahl-S) rats. METHODS AND RESULTS: Vehicle and iganidipine were administered orally to Dahl-S rats fed a high-salt diet (HSD) for 8 weeks. Aorta, superior mesenteric arteries (SMA), and peripheral mesenteric arteries (PMA) were examined light-microscopically or electon-microscopically. Relaxant responses of isolated aorta and SMA were recorded isometrically. In rats fed HSD, blood pressure was markedly increased. Light microscopy showed intimal and medial hypertrophy, periarteritis, and narrowed arterial lumen in the PMA. Transmission and scanning electron microscopy or light microscopy showed medical thickness in the aorta and SMA and hypertrophy of endothelial cells and dilatation of the subendothelial space only in the aorta. In the SMA, both endothelium-dependent relaxation (EDR) and endothelium-independent relaxations (EIR) were reduced to a similar extent. In the aorta, the EDR was more markedly attenuated than the EIR. Iganidipine at 3 mg/kg/day showed a 24-h sustained hypotensive effect and completely prevented the morphological and functional changes in both arteries. Iganidipine at 1 mg/kg/day, which lowered blood pressure only for several hours, decreased the injuries in PMA and aortic endothelium and moderately restored the EDR in the aorta. Iganidipine at 0.3 mg/kg/day had no effects. CONCLUSIONS: In Dahl-S rats fed an HSD, iganidipine completely prevented all the changes at a sustained-hypotensive dose and prevented the injuries of PMA and aortic endothelium and the reduction of EDR in the aorta at a nonsustained hypotensive dose. Nonhemodynamic effects of iganidipine may be partly involved in its protective effects against arterial injuries.
Journal Article↗
[Molecular biology of prostaglandin E receptors--expression of multi-function by PGE receptor subtypes and isoforms].
We reviewed the recent advance in the molecular characterization of prostaglandin E(PGE) receptor. PGE exerts versatile actions in diverse tissues and cells through specific cell surface receptors. PGE receptors(EP) consist of 4 subtypes(EP1, EP2, EP3 and EP4), which differ in the couple of signal transduction. In addition, at least three isoforms of EP3 are produced through alternative RNA splicing from a single gene and differ only in the efficiency of G protein activation and in the specificity of coupling to G proteins. These subtypes and isoforms express and function in specific tissues and cells in various organs, in where they mediate a variety of PGE2-induced physiological responses.
Animals↗
Degradation of the 74 kDa form of L-histidine decarboxylase via the ubiquitin-proteasome pathway in a rat basophilic/mast cell line (RBL-2H3).
L-Histidine decarboxylase (HDC) is a dimer consisting of two identical 53 kDa subunits. On the other hand, the size of HDC deduced from its cDNA sequence is around 74 kDa, indicating that the translated 74 kDa form of HDC is subjected to post-translational processing to generate the 53 kDa form. However, modification of the translated 74 kDa form of HDC in histamine-forming cells is unknown. Here we demonstrate that the 74 kDa form is translated in rat basophilic leukemia cells, followed by conversion to the 53 kDa form, and that the 74 kDa form is a short half-life protein because of the degradation mediated by the ubiquitin-proteasome pathway. Degradation of the 74 kDa form was stimulated in the presence of an ATP-generating system, accompanied by ubiquitination, and inhibited by specific proteasome inhibitors such as ZL3H and lactacystin. A significant amount of proteasome activity was detected in RBL-2H3 cells.
Adenosine Triphosphate↗
Expression of messenger RNA for the prostaglandin D receptor in the leptomeninges of the mouse brain.
The localization of prostaglandin D receptor in the mouse brain was examined by in situ hybridization histochemistry. The autoradiography showed significant hybridization signals of mRNA for prostaglandin D receptor in the leptomeninges covering the surface of the brain, but not in neurons or glia in the brain parenchyma. This finding was confirmed by Northern blot analysis using mRNA prepared from either the whole brain with the leptomeninges, brain parenchyma without the leptomeninges or the leptomeninges alone. A weak signal corresponding to the major 3.5-kbp transcript was detected in the whole brain. This band was significantly enriched in the leptomeninges, but was not detected in the brain parenchyma. These results suggest that prostaglandin D receptor is most highly, if not exclusively, expressed in the leptomeninges of the mouse brain.
Animals↗
Functional role of carboxyl-terminal tail of prostaglandin EP3 receptor in Gi coupling.
We recently demonstrated that the mouse EP3beta receptor and its carboxyl-terminal tail-truncated receptor showed agonist-dependent and full constitutive Gi activities, respectively (Hasegawa, H., Negishi, M. and Ichikawa, A. (1996) J. Biol. Chem. 271, 1857-1860). To assess the role of the carboxyl-terminal tail in the EP3beta receptor Gi coupling, we constructed a series of mutant receptors with progressively truncated carboxyl-termini. The truncated receptors displayed constitutive Gi activities, the degree of constitutive activity basically correlating with the inverse of the length of the carboxyl-terminal tail, but the sequence between Leu340 and Val347 was mainly contributed to the constitutive activity. Thus, the carboxyl-terminal tail plays an important role in the constraint of the EP3 receptor in its inactive conformation.
Adenylyl Cyclases↗
Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma.
BACKGROUND: Mutations of the p53 gene are associated with a poor prognosis in several types of cancer. We investigated the prognostic importance of p53 mutations in patients with aggressive B-cell lymphoma. METHODS: We examined the relation between the presence or absence of a detectable p53 mutation in lymphoma cells and the response to chemotherapy and overall survival in 102 previously untreated patients with aggressive B-cell lymphoma. Mutations of the p53 gene were identified by polymerase-chain-reaction-mediated analysis of single-strand conformation polymorphisms and by direct sequencing. RESULTS: Of 102 cases of aggressive B-cell lymphoma, 22 (22 percent) involved p53 mutations. The rate of complete remission was significantly lower in patients with a tumor carrying a p53 mutation (6 of 22 patients, 27 percent) than in those with the wild-type p53 gene (61 of 80 patients, 76 percent) (P<0.001). Overall survival was significantly lower among patients with p53 mutations than among those with the wild-type p53 gene; the Kaplan-Meier estimates of survival at five years were 16 percent and 64 percent, respectively (P<0.001). Multivariate analysis incorporating prognostic factors from the international prognostic index demonstrated that p53 mutations had independent effects on the rates of complete remission and survival. When we categorized patients according to the international prognostic index, we found no effect of p53 mutations in patients in the groups at high-intermediate and high risk. However, these mutations were significantly associated (P< 0.001) with low rates of complete remission (33 percent vs. 91 percent) and survival (27 percent vs. 81 percent at five years) in the groups at low and low-intermediate risk. CONCLUSIONS: Mutations of the p53 gene are associated with a poor prognosis in patients with aggressive B-cell lymphoma.
Aged↗
Altered pain perception and inflammatory response in mice lacking prostacyclin receptor.
Prostanoids are a group of bioactive lipids working as local mediators and include D, E, F and I types of prostaglandins (PGs) and thromboxanes. Prostacyclin (PGI2) acts on platelets and blood vessels to inhibit platelet aggregation and to cause vasodilatation, and is thought to be important for vascular homeostasis. Aspirin-like drugs, including indomethacin, which inhibit prostanoid biosynthesis, suppress fever, inflammatory swelling and pain, and interfere with female reproduction, suggesting that prostanoids are involved in these processes, although it is not clear which prostanoid is the endogenous mediator of a particular process. Prostanoids act on seven-transmembrane-domain receptors which are selective for each type. Here we disrupt the gene for the prostacyclin receptor in mice by using homologous recombination. The receptor-deficient mice are viable, reproductive and normotensive. However, their susceptibility to thrombosis is increased, and their inflammatory and pain responses are reduced to the levels observed in indomethacin-treated wild-type mice. Our results establish that prostacyclin is an antithrombotic agent in vivo and provide evidence for its role as a mediator of inflammation and pain.
Animals↗
Failure of parturition in mice lacking the prostaglandin F receptor.
Mice lacking the gene encoding the receptor for prostaglandin F2alpha (FP) developed normally but were unable to deliver normal fetuses at term. Although these FP-deficient mice showed no abnormality in the estrous cycle, ovulation, fertilization, or implantation, they did not respond to exogenous oxytocin because of the lack of induction of oxytocin receptor (a proposed triggering event in parturition), and they did not show the normal decline of serum progesterone concentrations that precedes parturition. Ovariectomy at day 19 of pregnancy restored induction of the oxytocin receptor and permitted successful delivery in the FP-deficient mice. These results indicate that parturition is initiated when prostaglandin F2alpha interacts with FP in ovarian luteal cells of the pregnant mice to induce luteolysis.
Animals↗
Two isoforms of prostaglandin EP3 receptor exhibiting constitutive activity and agonist-dependent activity in Rho-mediated stress fiber formation.
We have cloned two isoforms of the mouse prostaglandin E receptor EP3 subtype, EP3alpha and EP3beta, with different carboxyl-terminal tails, produced through alternative splicing. To determine the functional differences between the two isoforms, we examined the role of the isoforms in regulation of the actin cytoskeleton using Mardin-Darby canine kidney cells expressing these isoforms. The EP3alpha isoform constitutively induced stress fiber formation, independent of an agonist, while the EP3beta isoform agonist-dependently induced stress fiber formation. Pertussis toxin did not prevent stress fiber formation. This signaling pathway is mediated by Rho, because C3 transferase microinjection inhibited stress fiber formation. Therefore, the physiological significance of these isoforms of the EP3 receptor may lie in their different agonist dependency in Rho-mediated stress fiber formation via a pertussis toxin-insensitive G protein.
Actins↗
Functional interaction of the carboxylic acid group of agonists and the arginine residue of the seventh transmembrane domain of prostaglandin E receptor EP3 subtype.
Prostaglandin (PG) E2 binds to PGE receptor EP3 subtype and induces Gi activity. To assess the role of the interaction of the carboxylic acid group of agonists and its putative binding site, Arg-309 in the seventh transmembrane domain of EP3alpha receptor, in receptor activation, we have mutated the positively charged Arg-309 to the polar but uncharged Gln (EP3alpha-R309Q) and Asn (EP3alpha-R309N), and to the non-polar Leu (EP3alpha-R309L). Wild-type, EP3alpha-R309Q and EP3alpha-R309N receptors showed high-affinity binding for PGE2, but the EP3alpha-R309L receptor showed very-low-affinity binding. Guanosine 5'-[gamma-thio]triphosphate increased the PGE2 binding to the wild-type receptor, decreased the binding to EP3alpha-R309Q and EP3alpha-R309N receptors, but did not affect that to the EP3alpha-R309L receptor. Furthermore we examined the Gi activities of two types of EP3 agonist, TEI-3356 with a negatively charged carboxylic acid, and TEI-4343, a methyl ester of TEI-3356 with an uncharged but polar group, towards those receptors. Both agonists inhibited the forskolin-stimulated cAMP formation in wild-type, EP3alpha-R309Q and EP3alpha-R309N receptors in the same concentration-dependent manner, but the agonists showed a very low inhibition of EP3alpha-R309L receptor. These findings demonstrate that the hydrogen-bonding interaction of EP3 agonists and residue 309 in the seventh transmembrane domain of the EP3alpha receptor is sufficient for the functional activation of the EP3alpha receptor.
Animals↗
Effect of preoperative 5-fluorouracil on apoptosis of advanced gastric cancer.
BACKGROUND: Several studies have reported on apoptosis and the effect of anticancer chemotherapy. METHODS: We studied apoptosis induced by 5-fluorouracil (5-FU) given preoperatively to 28 patients with advanced gastric cancer and compared the findings with 101 untreated patients. The expression of bcl-2 oncoprotein, cell phase fractions, and histological chemotherapeutic effects were also compared with the apoptotic changes. RESULTS: The apoptotic and S-phase fractions in 5-FU-treated patients (apoptotic fraction: 10.46 +/- 6.93%, S-phase fraction: 17.49 +/- 11.65%) were significantly greater than those in untreated controls (apoptotic fraction: 6.56 +/- 5.06%, S-phase fraction: 12.17 +/- 6.78%). A positive correlation was observed between 5-FU-induced apoptosis and accumulation of tumor cells in the S-phase fraction. There was an inverse relationship between bcl-2 oncoprotein expression and apoptosis in 5-FU-treated patients, but no significant correlation between histological effect and apoptosis. However, two patients with significant histological effects showed no bcl-2 oncoprotein expression, whereas the histological effects were mild in all the bcl-2-positive patients. CONCLUSIONS: Apoptosis may be induced by 5-FU administered preoperatively and bcl-2 oncogene expression may suppress 5-FU-induced apoptosis.
Adenocarcinoma↗
Three isoforms of the prostaglandin E receptor EP3 subtype different in agonist-independent constitutive Gi activity and agonist-dependent Gs activity.
Explore the source record for details and available documents.
Animals↗
Discrepancy between blood flow and muscarinic receptor distribution in rat brain after middle cerebral artery occlusion.
To clarify whether muscarinic acetylcholine receptor (mAChR) binding can be a viable muscarinic neuronal marker which provides therapeutic information different from perfusional information in global brain, we evaluated the discrepancy between the distribution of cerebral blood flow (CBF), mAChR and its five subtypes of messenger ribonucleic acid (mRNA) in the acute (n=9) and chronic (n=8) phases of a middle cerebral artery (MCA) occlusion model and in sham-operated controls (n=6). In the acute phase, regional CBF was markedly reduced in the MCA territory, whereas mAChR was not reduced and the mRNA was reduced only slightly. In the chronic phase, mAChR was reduced markedly in the infarcted lesion and the mRNA was also reduced. The mAChR was slightly reduced in the ipsilateral substantia nigra and pontine nucleus because of remote effects; however, regional CBF in the substantia nigra was slightly increased and did not change in the pontine nucleus. The discrepancy between CBF and mAChR was clarified, and the tendency toward a reduction in mRNA in the acute ischaemic region without a reduction in mAChR suggested the presence of cholinergic neurons which were viable but hypometabolic. It is concluded that mAChR imaging may be of value for the assessment of the viable cholinergic neuron density in vivo.
Animals↗
Intense Ga-67 uptake in adenosquamous carcinoma of the pancreas.
Gallium-67 citrate (Ga-67) scintigraphy was performed in a patient with adenosquamous carcinoma of the pancreas. Intense and homogeneous uptake was observed in the tumor. Few reports have dealt with Ga-67 findings in pancreatic cancers. Ga-67 uptake in the tumor was assumed to be due to accumulation in the component of squamous cell carcinoma. This case suggested that Ga-67 citrate scintigraphy may be useful in detecting adenosquamous carcinoma of the pancreas. To our knowledge, no report has described findings of Ga-67 citrate scintigraphy of adenosquamous carcinoma of the pancreas. Radiologists should remember adenosquamous carcinoma of the pancreas when encountering such scintigraphic findings.
Aged↗
Comparison of flow capacities of arterial and venous grafts for coronary artery bypass grafting: evaluation with exercise thallium-201 single-photon emission tomography.
Stress thallium-201 tomography was performed to compare the flow capacities of arterial and saphenous vein grafts in patients with coronary artery bypass grafting (CABG). One hundred and seven consecutive patients (95 male and 12 female; mean age 58+/-9.1 years) underwent exercise-redistribution 201Tl myocardial single-photon emission tomography 4-5 weeks after CABG. When a reversible perfusion defect was present in the area covered by a patent bypass graft, the flow capacity of the graft was defined as insufficient. Of all 285 grafts, 211 were considered as complete bypass. Reversible perfusion defects were present in 29 (27%) of 108 myocardial areas supplied by patent arterial grafts but in only 5 (5%) of 103 myocardial areas supplied by patent saphenous vein grafts (P<0.0001). In the LAD area reversible defects were observed in 22 of 82 areas covered by arterial grafts, in contrast to only 1 of 29 areas covered by venous grafts (P<0.01); in the RCA area reversible defects were observed in 7 of 17 and 4 of 41 areas respectively (P<0.01). There was no difference between the native coronary artery stenosis bypassed by patent arterial and venous grafts (88%+/-12% vs 86%+/-14% respectively, P=0.27). In conclusion, flow capacities during peak myocardial demand were more frequently insufficient in arterial bypass grafts than in saphenous vein grafts.
Coronary Artery Bypass↗