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71.
Concanavalin A prevents phorbol-mediated redistribution of protein kinase C and beta-adrenergic receptors in rat glioma C6 cells 总被引:1,自引:0,他引:1
Exposure of rat glioma C6 cells to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) caused an activation of protein kinase C wherein the enzyme rapidly became membrane-bound (T 1/2 of 15 min). This translocation of protein kinase C from cytosol to membrane was followed by a sequestration of cell surface beta-adrenergic receptors and a loss of isoproterenol-stimulated adenylate cyclase activity. We had reported previously that prior exposure of rat glioma cells to concanavalin A prevents the TPA-mediated sequestration of receptors and desensitization of adenylate cyclase (Kassis et al., 1985). We now show that the concanavalin A treatment also prevents the translocation and activation of protein kinase C. These results are further evidence that in the TPA-treated cells, sequestration of beta-adrenergic receptors is mediated by membrane-bound protein kinase C. 相似文献
72.
Schenck HA Lenkowski PW Choudhury-Mukherjee I Ko SH Stables JP Patel MK Brown ML 《Bioorganic & medicinal chemistry》2004,12(5):979-993
Themisone, also known as Atrolactamide, was found, in the 1950s, to be a very potent anticonvulsant. It was hypothesized that the -CF(3) substitution would maintain the anticonvulsant activity. Anticonvulsant testing of our novel compounds by the National Institute of Health's Anticonvulsant Screening Project of the Antiepileptic Drug Discovery Program identified analogue 1, 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide, to have potent anticonvulsant activity (MES ED(50) of 9.9 mg/kg, ScMET ED(50) of 34 mg/kg and TD(50) of 100 mg/kg). Therefore, a diverse range of analogues were synthesized utilizing multiple synthetic pathways to explore the structure-activity relationship. Patch clamp electrophysiology experiments demonstrate that compound 1 is an effective T-type calcium channel blocker. Altogether, these results suggest these compounds as a class of orally available anticonvulsants. 相似文献
73.
Yuran Ma Shaohua Chen Min Chen Xiang Ren Nandini Patel Wenfeng Liu 《Bioscience, biotechnology, and biochemistry》2020,84(10):2069-2076
ABSTRACT 12-O-tetradecanoylphorbol-13-acetate (TPA), is a major active constituent of the seed oil of Croton tiglium L., has pharmacological activity for the treatment of acute myeloid leukemia patients. Diethyldithiocarbamate (DTC) is a potent inhibitor of NF-κB show activity of anticancer. In this study, we determined the effect of DTC and TPA in combination on HL-60 cells cultured in vitro and in vivo. In this study, we have shown that DTC and TPA synergistically inhibited the growth of HL-60 cells and strongly induced apoptosis in the cells. Mechanistic studies showed that the combined effects of DTC and TPA were associated with a decrease in Bcl-2. The animal experiment showed that the combination of DTC and TPA more potently inhibited the growth of HL-60 tumors than either agent alone. Our results indicate that the administration of TPA and DTC in combination may be an effective strategy for inhibiting the growth of acute myeloid leukemia cells. 相似文献
74.
Expression of engrailed proteins in arthropods, annelids, and chordates 总被引:57,自引:0,他引:57
N H Patel E Martin-Blanco K G Coleman S J Poole M C Ellis T B Kornberg C S Goodman 《Cell》1989,58(5):955-968
engrailed is a homeobox gene that has an important role in Drosophila segmentation. Genes homologous to engrailed have been identified in several other organisms. Here we describe a monoclonal antibody that recognizes a conserved epitope in the homeodomain of engrailed proteins of a number of different arthropods, annelids, and chordates; we use this antibody to isolate the grasshopper engrailed gene. In Drosophila embryos, the antibody reveals engrailed protein in the posterior portion of each segment during segmentation, and in a segmentally reiterated subset of neuronal cells during neurogenesis. Other arthropods, including grasshopper and two crustaceans, have similar patterns of engrailed expression. However, these patterns of expression are not shared by the annelids or chordates we examined. Our results provide the most comprehensive view that has been obtained of how expression patterns of a regulatory gene vary during evolution. On the basis of these patterns, we suggest that engrailed is a gene whose ancestral function was in neurogenesis and whose function was co-opted during the evolution of segmentation in the arthropods, but not in the annelids and chordates. 相似文献
75.
76.
Mirko Rivara Manoj K. Patel Laura Amori Valentina Zuliani 《Bioorganic & medicinal chemistry letters》2012,22(20):6401-6404
We have synthesized and evaluated a series of 1,4-disubstituted-triazole derivatives for inhibition of the rat NaV1.6 sodium channel isoform, an isoform thought to play an important role in controlling neuronal firing. Starting from a series of 2,4(1H)-diarylimidazoles previously published, we decided to extend the SAR study by replacing the imidazole with a different heterocyclic scaffold and by varying the aryl substituents on the central aromatic ring. The 1,4-disubstituted 1,2,3-triazoles were prepared employing the copper-catalyzed azide–alkyne cycloaddition (CuAAC). Many of the new molecules were able to block the rNav1.6 currents at 10 μM by over 20%, displaying IC50 values ranging in the low micromolar, thus indicating that triazole can efficiently replace the central heterocyclic core. Moreover, the introduction of a long chain at C4 of the central triazole seems beneficial for increased rNav1.6 current block, whereas the length of N1 substituent seems less crucial for inhibition, as long as a phenyl ring is not direcly connected to the triazole. These results provide additional information on the structural features necessary for block of the voltage-gated sodium channels. These new data will be exploited in the preparation of new compounds and could result in potentially useful AEDs. 相似文献
77.
78.
The pathway for the aerobic catabolism of 1,3,5-trihydroxybenzene (phloroglucinol) by a new strain of Penicillium was investigated using both in vivo and in vitro cell-free systems. The fungal strain was isolated by enrichment on phloroglucinol and identified as P. simplicissimum (Oud) Thom. It grew optimally at pH 5.5 and 27°C with 119 mM (1.5%w/v) of phloroglucinol in a basal mineral salts medium. Vapours of the crystalline substrate placed in a Petri-plate lid supported the growth of the fungal colonies on the agar surface. Mycelia grown on phloroglucinol accumulated 1,2,4-trihydroxybenzene and resorcinol in the medium. Washed, resting mycelia grown on phloroglucinol, when resuspended in a buffer utilized oxygen in the presence of catechol, resorcinol, pyrogallol and phloroglucinol. A NADPH-dependent reductase in the cell-free extract reduced phloroglucinol to dihydrophloroglucinol. This electron donor could not be replaced by NADH. Resorcinol hydroxylase, phloroglucinol reductase, catechol-1,2-oxygenase, and catechol-2,3-oxygenase were detected in cell-free extracts of mycelia grown on phloroglucinol. The possible steps in the degradation of phloroglucinol are discussed. 相似文献
79.
Subtype-specific conformational differences within the V3 region of subtype B and subtype C human immunodeficiency virus type 1 Env proteins 总被引:1,自引:2,他引:1
The V3 region of the human immunodeficiency virus type 1 gp120 Env protein is a key domain in Env due to its role in interacting with the coreceptors CCR5 and CXCR4. We examined potential subtype-specific V3 region differences by comparing patterns of amino acid variability and probing for subtype-specific structures using 11 anti-V3 monoclonal antibodies (V3 MAbs). Differences between the subtypes in patterns of variability were most evident in the stem and turn regions of V3 (positions 9 to 24), with the two subtypes being very similar in the base region. The characteristics of the binding of V3 MAbs to Env proteins of the subtype B virus JR-FL and the subtype C virus BR025 suggested three patterns, as each group of MAbs recognized a specific conformation- or sequence-based epitope. Viruses pseudotyped with Env from JR-FL and BR025 were resistant to neutralization by the V3 MAbs, although the replacement of the Env V3 region of the SF162 virus with the JR-FL V3 created a pseudotyped virus that was hypersensitive to neutralization. A single mutation in V3 (H13R) made this chimeric Env selectively resistant to one group of V3 MAbs, consistent with the mAb binding properties. We hypothesize that there are intrinsic differences in V3 conformation between subtype B and subtype C that are localized to the stem and turn regions and that these differences have two important biological consequences: first, subtype B and subtype C V3 regions can have subtype-specific epitopes that will inherently limit antibody cross-reactivity, and second, V3 conformational differences may potentiate the frequent evolution of R5- into X4-tropic variants of subtype B but limit subtype C virus from using the same mechanism to evolve X4-tropic variants as efficiently. 相似文献
80.
L Jiang A Majumdar W Hu T J Jaishree W Xu D J Patel 《Structure (London, England : 1993)》1999,7(7):817-827
BACKGROUND: Aminoglycoside antibiotics can target RNA folds with micromolar affinity and inhibit biological processes ranging from protein biosynthesis to ribozyme action and viral replication. Specific features of aminoglycoside antibiotic-RNA recognition have been probed using chemical, biochemical, spectroscopic and computational approaches on both natural RNA targets and RNA aptamers identified through in vitro selection. Our previous studies on tobramycin-RNA aptamer complexes are extended to neomycin B bound to its selected RNA aptamer with 100 nM affinity. RESULTS: The neamine moiety (rings I and II) of neomycin B is sandwiched between the major groove floor of a 'zippered-up' G.U mismatch aligned segment and a looped-out purine base that flaps over the bound antibiotic. Specific intermolecular hydrogen bonds are observed between the charged amines of neomycin B and base mismatch edges and backbone phosphates. These interactions anchor 2-deoxystreptamine ring I and pyranose ring II within the RNA-binding pocket. CONCLUSIONS: The RNA aptamer complexes with tobramycin and neomycin B utilize common architectural principles to generate RNA-binding pockets for the bound aminoglycoside antibiotics. In each case, the 2-deoxystreptamine ring I and an attached pyranose ring are encapsulated within the major groove binding pocket, which is lined with mismatch pairs. The bound antibiotic within the pocket is capped over by a looped-out base and anchored in place through intermolecular hydrogen bonds involving charged amine groups of the antibiotic. 相似文献