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41.
Schiedel AC Hinz S Thimm D Sherbiny F Borrmann T Maass A Müller CE 《Biochemical pharmacology》2011,(4):389-399
The adenosine A2B receptor is of considerable interest as a new drug target for the treatment of asthma, inflammatory diseases, pain, and cancer. In the present study we investigated the role of the cysteine residues in the extracellular loop 2 (ECL2) of the receptor, which is particularly cysteine-rich, by a combination of mutagenesis, molecular modeling, chemical and pharmacological experiments. Pretreatment of CHO cells recombinantly expressing the human A2B receptor with dithiothreitol led to a 74-fold increase in the EC50 value of the agonist NECA in cyclic AMP accumulation. In the C783.25S and the C17145.50S mutant high-affinity binding of the A2B antagonist radioligand [3H]PSB-603 was abolished and agonists were virtually inactive in cAMP assays. This indicates that the C3.25–C45.50 disulfide bond, which is highly conserved in GPCRs, is also important for binding and function of A2B receptors. In contrast, the C16645.45S and the C16745.46S mutant as well as the C16645.45S–C16745.46S double mutant behaved like the wild-type receptor, while in the C15445.33S mutant significant, although more subtle effects on cAMP accumulation were observed – decrease (BAY60-6583) or increase (NECA) – depending on the structure of the investigated agonist. In contrast to the X-ray structure of the closely related A2A receptor, which showed four disulfide bonds, the present data indicate that in the A2B receptor only the C3.25–C45.50 disulfide bond is essential for ligand binding and receptor activation. Thus, the cysteine residues in the ECL2 of the A2B receptor not involved in stabilization of the receptor structure may have other functions. 相似文献
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An updated model from problem solving and decision making (PS/DM) theory is presented for application to behavior therapy. The article highlights an important distinction between “static” and “dynamic” PS/DM situations. The static model presumes that the PS/ DM procedures need to be conducted only once to implement a change program. The model provides little opportunity to use outcome feedback from successive PS/DM stages for further correction of the overall plan. In the dynamic model, the stages are conceptualized as a sequence of interrelated actions guided by feedback, similar to the tracking of a moving target. The dynamic model is regarded as more characteristic of the clinical change process. Based upon this important distinction, the traditional stages of PS/DM are re-evaluated. In addition, several newly emerged issues are addressed from two different points of view—one in which the clinician is considered the problem solver helping the client with a particular problem, and one in which the client is considered the problem solver learning to deal with unforeseen difficulties. Finally, the article describes several different methods that can be used to evaluate the efficiency of the proposed PS/DM procedures. 相似文献
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BACKGROUND: Mast cells have long been recognized as the principal cell type that initiates the inflammatory response characteristic of acute allergic type 1 reactions. Our goal has been to further characterize maturation of progenitors to mast cells. METHODS: Mast cells were cultured from human cord blood derived CD133(+) progenitors. Mast cell function was tested using histamine release. During differentiation mast cells surface marker expression was monitored by flow cytometry. RESULTS: CD133(+) progenitors expressed the early haematopoietic and myeloid lineage markers CD34, CD117, CD13 and CD33. Mature mast cells expressed CD117, CD13 and CD33, and expression of the high affinity immunoglobulin E receptor FcepsilonRI increased during culture. Cytokine receptors interleukin (IL)-5R, IL-3R, granulocyte-macrophage-colony stimulating factor (GM-CSF)R and IL-18R were expressed at high levels during maturation. Chemokine receptors CXCR4 and CXCR2 were highly expressed on both newly purified CD133(+) cells and mature cells. CONCLUSION: Human mast cells can be cultured from a CD34(+)/CD117(+)/CD13(+)/CD33(+) progenitor cell population in cord blood that is tryptase and chymase negative. Developing and mature mast cells express a wide range of chemokine and cytokine receptors. We found high levels of expression of CD123, IL-5R and GM-CSF receptors, also found on eosinophils and basophils, and high levels of expression of the receptor for the inflammatory cytokine IL-18. 相似文献
47.
Chen XJ 《Current genetics》2000,38(1):1-7
The mitochondrial F1-ATPase is a multimeric enzyme, comprised of 3α, 3β, γ, δ and 603; subunits, that is primarily responsible for the synthesis
of ATP in eukaryotic cells. Recent work has shown that the F1 complex of the petite-negative yeast Kluyveromyces lactis, with specific mutations in the α, β or γ subunits, has a novel function that suppresses lethality caused by loss of mtDNA.
Previously, genes for the four largest subunits of K. lactis F1 have been identified and characterised. In this study the gene coding for the 603;-subunit of F1, KlATP603;, has been isolated and found to encode a polypeptide of 61 amino acids with only 32 residues identical to those in the protein
from Saccharomyces cerevisiae. Strains carrying a null mutation of KlATP603; are respiratory deficient while the introduction of ATP603; from S. cerevisiae restores growth on non-fermentable carbon sources. In contrast to S. cerevisiae, K. lactis disrupted in ATP603; does not have a detectable F1-related mitochondrial ATP hydrolysis activity, suggesting that the 603;-subunit plays a critical role in the formation of the
catalytic sector of F1. With a disrupted KlATP603;, the ρo-lethality suppressor function of F1 carrying the atp2-1 and atp1-6 alleles is abolished. However, inactivation of the 603; subunit does not eliminate the ρo-viable phenotype of the atp1-1, atp2-9, atp3-2 mutants. It is suggested that the absence of 603; may effect the assembly or stability of F1 in the wild-type, atp 2-1 and atp1-6 strains, whereas the defect can be suppressed by the atp1-1, atp2-9 and atp3-2 mutations in the α, β and γ subunits respectively.
Received: 9 November 1999 / 11 February 2000 相似文献
48.
N. Haas K. Hamann J. Grabbe J. Niehus G. Kunkel G. Kolde B. M. Czarnetzki 《Allergy》1997,52(4):436-439
Haas N, Hamann K, Grabbe J, Niehus J, Kunkel G, Kolde G, Czarnetzki M. Demonstration of the high-affinity IgE receptor (Fc603;RI) on Langerhans' cells of diseased nasal mucosa.
Langerhans' cells in the skin have recently been shown to bind IgE molecules via the high-affinity IgE receptor (Fc603;RI). Using two highly specific antibodies against the antibody-binding α-chain of this receptor, 29C6 and 6F7, we demonstrate by immunohistochemistry and immunoelectron microscopy that Langerhans' cells of diseased nasal mucosa can express the Fc603;RI. Tissue sections from hyperplastic nasal conchae and nasal polyps of atopic and nonatopic patients have shown no basic differences in epithelial Fc603;RII-bearing cells. Only a few cells expressed the low-affinity IgE receptor (Fc603;RII) (Tül antibody) in some sections. These findings suggest that Langerhans' cells play an important role in the induction of transepithelial IgE-mediated allergy and in the mediation of inflammation of the nasal mucosa via their Fc603;RI. 相似文献
Langerhans' cells in the skin have recently been shown to bind IgE molecules via the high-affinity IgE receptor (Fc603;RI). Using two highly specific antibodies against the antibody-binding α-chain of this receptor, 29C6 and 6F7, we demonstrate by immunohistochemistry and immunoelectron microscopy that Langerhans' cells of diseased nasal mucosa can express the Fc603;RI. Tissue sections from hyperplastic nasal conchae and nasal polyps of atopic and nonatopic patients have shown no basic differences in epithelial Fc603;RII-bearing cells. Only a few cells expressed the low-affinity IgE receptor (Fc603;RII) (Tül antibody) in some sections. These findings suggest that Langerhans' cells play an important role in the induction of transepithelial IgE-mediated allergy and in the mediation of inflammation of the nasal mucosa via their Fc603;RI. 相似文献
49.
Purpose To evaluate the potential use of dendritic α,603;-poly(L-lysine)s (DPL) for the efficient cellular delivery of antisense oligonucleotides.
Methods A series of dendritic α,603;-polylysines of various generations were prepared. Their physical properties and the ability to form
complex with oligonucleotide were investigated by polyacrylamide gel electrophoresis, capillary zone electrophoresis (CZE),
agarose gel electrophoresis, fluorescence titration and atomic force microscopy (AFM). The efficiency to deliver oligonucleotide
to HeLa cells, stably transfected with plasmid pLuc/705, was evaluated by using antisense splicing correction assay and confocal
microscopy.
Results DPLs formed the complexes with antisense oligonucleotide with modest cytotoxicity. The charge ratio of oligonucleotide to
DPL and the size (generation) of DPLs were all critical variables for the antisense effect. Compared to low generation DPLs,
high generation DPLs were more effective in delivering oligonucleotide into cells.
Conclusions High generation DPL-oligonucleotide complexes were moderately effective for delivery antisense oligonucleotide. The complex
formation provides a promise for in vivo therapeutic application of DPLs or their derivatives in the delivery of gene or oligonucleotide. 相似文献
50.
He H Wang W Zhang H Ma L Wu H Wang P Gao J 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2006,20(4):259-271
Objective To demonstrate the alterations of Protein Kinase C603; (PKC603;) and components of its signaling complexes after treatment with
fosinopril and carvedilol and analyze potential molecular mechanisms of the two drugs for cardiac hypertrophy and heart failure.
Methods Pressure-overload cardiac hypertrophy (POH) was developed in 8-week-old male Sprague Dawley rats by abdominal aortic banding.
The rats were divided into three groups at the age of 20 weeks: POH without failure group, reversed POH with drugs group,
and POH with failure group on high diet. Western Blot analysis, co-immunoprecipitation and proteomic analysis were performed
in ventricular tissues of rat hearts.
Results Increased PKC603; was found during POH. PKC603; decreased during transition from POH to heart failure (HF). However, increased PKC603;
inclined to recover to normal levels after treatment with both drugs. There were differential proteins in PKC603; complexes during
the different stages of POH. The two significant PKC603;-binding proteins, MAD1 and Lyn A, were only present in PKC603; complex
during reversing POH with drugs.
Conclusion Chronic administration of carvedilol and fosinopril could reverse the development of POH and delay the appearance of HF, partly
by regulating PKC603; level and its signaling complex. MAD1 and Lyn A may be important proteins participating in the reversing
process. 相似文献