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11.
The pharmacology of L-670,596, a potent and selective thromboxane/prostaglandin endoperoxide receptor antagonist 总被引:1,自引:0,他引:1
A W Ford-Hutchinson Y Girard A Lord T R Jones M Cirino J F Evans J Gillard P Hamel C Leveillé P Masson 《Canadian journal of physiology and pharmacology》1989,67(9):989-993
L-670,596 ((-)6,8-difluoro-9-rho-methylsulfonyl benzyl-1,2,3,4- tetrahydrocarbazol-1-yl-acetic acid) has been shown to be a potent receptor antagonist as evidenced by the inhibition of the binding of 125I-labeled PTA-OH to human platelets (IC50, 5.5 x 10(-9) M), inhibition of U-44069 induced aggregation of human platelet rich plasma (IC50, 1.1 x 10(-7) M), and competitive inhibition of contractions of the guinea pig tracheal chain induced by U-44069 (pA2,9.0). The compound was also active in vivo as shown by inhibition of arachidonic acid and U-44069 induced bronchoconstriction in the guinea pig (ED50 values, 0.04 and 0.03 mg/kg i.v., respectively), U44069 induced renal vasoconstriction in the pig (ED50, 0.02 mg/kg i.v.), and inhibition of ex vivo aggregation of rhesus monkey platelets to U-44069 (active 1-5 mg/kg p.o.). The selectivity of the compound was indicated by the failure to inhibit, first, ADP-induced human or primate platelet aggregation and, second, bronchoconstriction in the guinea pig in vivo and contraction of the guinea pig tracheal chain in vitro to a variety of agonists. It is concluded that L-670,596 is a potent, selective, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist. 相似文献
12.
Requirement for proliferating cell nuclear antigen expression during stages of the Chinese hamster ovary cell cycle 总被引:16,自引:0,他引:16
Y C Liu R L Marraccino P C Keng R A Bambara E M Lord W G Chou S B Zain 《Biochemistry》1989,28(7):2967-2974
Proliferating cell nuclear antigen (PCNA/cyclin) is a nuclear protein that can stimulate purified DNA polymerase delta in vitro, and its synthesis correlates with the proliferation rate of cells. We have attempted to determine whether synthesis of PCNA/cyclin in Chinese hamster ovary cells is necessary to regulate entry into S phase. We have measured cellular PCNA/cyclin concentration of the mRNA or protein throughout the cell cycle. Cells were separated by centrifugal elutriation into populations enriched for G-1, S, and G-2/M phases. Quantitative Northern hybridization analysis was performed on RNA isolated from each cell population by using a cDNA clone of PCNA/cyclin as a probe. Results demonstrated that although intact PCNA/cyclin mRNA is present during all phases of the cell cycle, an induction of about 3-fold occurs during S phase. Two-parameter staining for PCNA/cyclin and DNA, and analysis by flow cytometry, confirmed that the quantity of PCNA/cyclin protein in the cells increases severalfold in G-1 or early S phase but generally is invariant in S and G-2/M phases. This cell cycle dependence of PCNA/cyclin expression suggests that the observed synthesis is a prerequisite for initiation of DNA replication. Introduction of an antisense oligonucleotide complementary to the PCNA/cyclin mRNA to inhibit PCNA/cyclin synthesis effectively prevented entry of G-1 phase cells into S phase. A complementary sense oligonucleotide used as a control did not have an inhibitory effect. This result suggests that a threshold concentration of PCNA/cyclin is necessary for entry into S phase. 相似文献
13.
P Patrignani H Morton M Cirino A Lord L Charette J Gillard J Rokach C Patrono 《Biochimica et biophysica acta》1989,992(1):71-77
Following the intravenous administration of thromboxane (TX) B2, the stable hydration product of TXA2, to human and nonhuman primates the most abundant urinary metabolites are 2,3-dinor-TXB2 and 11-dehydro-TXB2. However, it is not known whether fractional conversion of TXB2 to its enzymatic metabolites is an accurate representation of TXA2 metabolism. Thus, we have compared the metabolic disposition of synthetic TXA2 and TXB2 via the beta-oxidation and 11-OH-dehydrogenase pathways in vivo in the monkey. TXA2 or TXB2 (20 ng/kg) was intravenously administered to four cynomolgus monkeys pretreated with aspirin in order to suppress endogenous TXA2 production. Urinary TXB2, 2,3-dinor-TXB2 and 11-dehydro-TXB2 were measured before, during and up to 24 h after thromboxane administration by means of reversed-phase high-performance liquid chromatography radioimmunoassay. Aspirin treatment suppressed urinary 2,3-dinor-TXB2 and 11-dehydro-TXB2 by approx. 75%. A similar fractional conversion of TXA2 and TXB2 into 2,3-dinor-TXB2 and 11-dehydro-TXB2 was found. These results suggest that TXA2 is hydrolyzed to TXB2 prior to enzymatic degradation and that metabolites of the latter represent reliable indices of TXA2 biosynthesis. Due to the variability in the conversion of thromboxanes into 2,3-dinor-TXB2 and 11-dehydro-TXB2, the measurement of both metabolites seems to represent a more reliable index of acute changes in TXA2 production. 相似文献
14.
The malmö polymorphism of coagulation factor IX, an immunologic polymorphism due to dimorphism of residue 148 that is in linkage disequilibrium with two other F.IX polymorphisms
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John B. Graham Dennis B. Lubahn Susan T. Lord Julie Kirshtein Inga Marie Nilsson Anders Wallmark Rolf Ljung L. D. Frazier Jerry L. Ware Shu Wah Lin Darrell W. Stafford John Bosco 《American journal of human genetics》1988,42(4):573-580
A mouse monoclonal antibody (MAB 9.9) to coagulation factor IX (F.IX) detects a polymorphism in the plasma of normal people. Its epitope has been narrowed down to <6 amino acids in the activation peptide of the X-linked F.IX protein. The activation peptide contains a dimorphism—Thr:Ala—at position 148 of the protein. Using synthetic oligonucleotides, we have demonstrated that (1) the F.IX which reacts with 9.9 has Thr at position 148 and (2) that which does not has Ala. Positive reactors (148thr) are designated Malmö A, and negative reactors (148ala) are designated Malmö B. The plasma levels of AA women are indistinguishable from those of A men, and both B men and BB women are null against MAB 9.9. The plasma level of Malmö A in AB women is approximately half that of AA women, and “lyonization” is clearly operating in the heterozygotes. The dimorphism is in strong linkage disequilibrium with two other intragenic RFLPs, TaqI and XmnI. Furthermore, intragenic crossing-over—including double crossing-over—appears to have occurred between the three sites. Seven of the eight possible haplotypes have been identified, five in men and two others in women. The immunoassay that identifies ~50% of the AB women in the pool of Malmö A females with 95% confidence identifies men unambiguously as A or B. The assay would be very useful for population-genetic studies of the Malmö epitope if the studies were limited to men. 相似文献
15.
The sensitivity of G0-state haemopoietic spleen colony-forming cells to a stimulus for proliferation
B I Lord 《Cell and tissue kinetics》1986,19(3):305-310
Haemopoietic spleen colony-forming units (CFU-s) close to the axis (axial CFU-s) of the long bones have a high probability of self-renewal. They are pluripotent cells and are largely in a G0-State. By contrast, CFU-s close to the bone surface (marginal CFU-s) have a lower probability of self-renewal and are probably more mature, though still pluripotent. Most CFU-s proliferation arises in this zone. As a consequence, marginal CFU-s tend to have shorter G0 histories than do axial CFU-s. Femoral marrow was, therefore, divided into axial and marginal populations and the sensitivity of the CFU-s to an endogenous CFU-s-specific proliferation-stimulating factor was assessed and compared by the tritiated thymidine suicide technique. It was found that axial CFU-s are considerably more resistant to stimulation than are marginal CFU-s in that larger doses for longer periods of exposure are required to increase the proliferative activity of the cells. This behaviour is consistent with the suggestion that cells with a low division probability exist in deeper levels of the quiescent G0-state. Although this hypothesis was developed from the behaviour of cells maintained in culture under sub-optimal physiological conditions, this phenomenon appears, in vivo, to be a characteristic of the stem cell population of haemopoietic tissue; their high resistance to stimulation maintaining the axial CFU-s in a quiescent state. 相似文献
16.
An inhibitor and stimulator of CFU-s proliferation can be obtained from haemopoietic tissue containing, respectively, relatively quiescent CFU-s (e.g. normal bone marrow) and proliferating CFU-s (e.g. regenerating bone marrow). Their effects on the proliferative behaviour of steady-state and regenerating marrow CFU-s, which produce colonies 7, 10 and 12 days post-transplantation have been investigated. The results demonstrate changing sensitivities of CFU-s to inhibitor and stimulator as they progress through a developmental age structure, 'Older' CFU-s (producing early spleen colonies) are more sensitive to stimulator, 'Younger' CFU-s (producing late spleen colonies) are more sensitive to inhibitor. 相似文献
17.
An inhibitor and stimulator of CFU-s proliferation can be obtained from haemopoietic tissue containing, respectively, relatively quiescent CFU-s (e.g. normal bone marrow) and proliferating CFU-s (e.g. regenerating bone marrow). Their effects on the proliferative behaviour of steady-state and regenerating marrow CFU-s, which produce colonies 7, 10 and 12 days post-transplantation have been investigated. The results demonstrate changing sensitivities of CFU-s to inhibitor and stimulator as they progress through a developmental age structure. ‘Older’ CFU-s (producing early spleen colonies) are more sensitive to stimulator, ‘Younger’ CFU-s (producing late spleen colonies) are more sensitive to inhibitor. 相似文献
18.
Summary An ultrastructural study of the pollen and stigma of the dimorphic flowers in the cleistogamous speciesCollomia grandiflora reveals significant differences in cytoplasmic features in the pollen and wall features in the papillae. Both pollen types contain lipid and starch reserves, but the smaller CL (cleistogamous) pollen shows a much greater abundance of starch compared to the CH (chasmogamous) pollen. In addition to the papular size and shape differences between the two stigma types, there is a more extensive cuticular stretching and wall microfibrillar loosening over the CH papillar tip. There is no apparent pellicle on the cuticle surface of either type of papilla, only scattered lipidic deposits. It is proposed that these structural differences may contribute to the cross incompatibility between the two floral morphs. 相似文献
19.
20.
Suzanne Knauf Jean Kalwas B. Frederick Helmkamp Lee W. Harwell Jackson Beecham Edith M. Lord 《Cancer immunology, immunotherapy : CII》1986,21(3):217-225
Summary Murine monoclonal antibodies (MCAs) against human ovarian tumor associated antigen NB/70K have been prepared. One of these MCAs, NB12123, was chosen for the development of a radioimmunoassay for measuring serum NB/70K levels. In this assay, the average NB/70K level in 75 normal, healthy controls was 11.9 activity units (AU) with an SD of 14.9 AU. The normal cut off value for this assay was set at 45 AU (mean +2 SD). 24 of 46 (52%) ovarian cancer patients, 7 of 18 (39%) patients with benign ovarian cysts or tumors and 3 of 85 (4%) control samples had elevated serum NB/70K levels. Comparison of NB/70K levels measured in the NB12123 assay with levels measured in an assay using a polyclonal antiNB/70K previously developed in our laboratory [13] indicated that although both assays had approximately the same percentage of positive ovarian cancer patient samples, there appeared to be no correlation between the absolute NB/70K levels measured by the two assays. The rank of ovarian cancer patient samples was also different for the two assays. Also, almost 40% of patients with benign ovarian cysts and tumors had elevated serum NB/70K levels as measured by the NB12123 assay as compared to 0% for the polyclonal assay. Reciprocal cross-blocking experiments, absorption studies, and immune precipitate analysis indicated that both the monoclonal NB12123 assay and the polyclonal antiNB/70K assay measured the same population of NB/70K molecules. However, the polyclonal antibody recognizes epitopes in addition to that recognized by NB12123. Taken together, these results suggest that the epitope recognized by NB12123 is not as specific for malignant ovarian tumors as the epitope(s) recognized by polyclonal antiNB/70K and/or that more than the one epitope detected by the MCA is responsible for the specificity for ovarian cancer of the polyclonal NB/70K assay. In spite of this, the greater sensitivity and range of the monoclonal NB12123 assay make it possible to monitor serum NB/70K levels in ovarian cancer patients. In four patients examined, the fluctuating serum NB/70K levels appeared to correlate well with clinical statusSupported in part by ACS # PDT 231 and a grant from the Elsa U. Pardee Foundation 相似文献