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1.
Bone Cell-autonomous Contribution of Type 2 Cannabinoid Receptor to Breast Cancer-induced Osteolysis
Antonia Sophocleous Silvia Marino John G. Logan Patrick Mollat Stuart H. Ralston Aymen I. Idris 《The Journal of biological chemistry》2015,290(36):22049-22060
The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumor growth, bone remodeling, and bone pain. However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here we found that the CB2-selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micromolar concentrations. Under conditions in which these ligands are used at the nanomolar range, HU308 and JWH133 enhanced human and mouse breast cancer cell-induced osteoclastogenesis and exacerbated osteolysis, and these effects were attenuated in cultures obtained from CB2-deficient mice or in the presence of a CB2 receptor blocker. HU308 and JWH133 had no effects on osteoblast growth or differentiation in the presence of conditioned medium from breast cancer cells, but under these circumstances both agents enhanced parathyroid hormone-induced osteoblast differentiation and the ability to support osteoclast formation. Mechanistic studies in osteoclast precursors and osteoblasts showed that JWH133 and HU308 induced PI3K/AKT activity in a CB2-dependent manner, and these effects were enhanced in the presence of osteolytic and osteoblastic factors such as RANKL (receptor activator of NFκB ligand) and parathyroid hormone. When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands depending upon cell type and concentration used. We, therefore, conclude that both CB2-selective activation and antagonism have potential efficacy in cancer-associated bone disease, but further studies are warranted and ongoing. 相似文献
2.
At inflammatory sites neutrophils are stimulated to produce a variety of toxic agents, yet rarely harm the endothelium across which they migrate. We have recently found that endothelium releases adenosine which, acting via receptors on the surface of human neutrophils, inhibits generation of toxic metabolites by stimulated neutrophils but, paradoxically, promotes chemotaxis. Agents which diminish plasma membrane viscosity affect neutrophil function similarly, possibly by modulating chemoattractant receptor number or affinity. We therefore determined whether adenosine receptor agonists modulate neutrophil function by decreasing membrane viscosity and/or chaning the affinity of chemoattractant (N-fMet-Leu-Phe, FMLP) receptors. Surprisingly, 5′-(N-ethylcar☐amido)adenosine (NECA, 10 μM), the most potent agonist at neutrophil adenosine receptors, increased plasma membrane viscosity, as measured by fluorescence anisotropy of the plasma membrane specific probe 1-(4-trimethylaminophenyl)-6-diphenyl-1,3,5-hexatriene (TMA-DPH), in unstimulated neutrophils from a mean microviscosity of 1.67 ± 0.02 (S.E.) to 1.80 ± 0.02 (p < 0.001) while inosine (10 μM), a poor adenosine receptor agonist, had no effect (1.73 ± 0.04, p =n.s. vs. control, p < 0.01 vs. NECA). Adenosine receptor agonists increased plasma membrane viscosity in neutrophils with the same order of potency previously seen for inhibition of superoxide anion generation and enhancement of chemotaxis (NECA > adenosine = N6-phenylisopropyladenosine). The adenosine receptor antagonist 8-(p-sulfophenyl)theophylline reversed the effect of NECA on plasma membrane viscosity. Unlike other agents which modulate plasma membrane viscosity, NECA (10 μM) did not significantly change the number or affinity of [3H]FMLP binding sites on neutrophils. In contrast to the hypothesis of Yuli et al. these results indicate that occupancy of adenosine receptors on neutrophils increases plasma membrane viscosity without affecting chemoattractant receptor display. 相似文献
3.
Induction of vancomycin resistance in Enterococcus faecium by inhibition of transglycosylation 总被引:6,自引:0,他引:6
Vancomycin resistance has recently been recognized among clinical isolates of enterococci. Resistance is inducible, and associated with production of a novel 39 kDa membrane protein. The mechanism by which exposure to vancomycin, which does not penetrate the cell membrane, induces resistance is unknown. In the vancomycin resistant strain Enterococcus faecium 228, resistance was also inducible by moenomycin, suggesting that inhibition of the transglycosylation step in peptidoglycan synthesis may be required for induction of resistance. Cytoplasmic pools of peptidoglycan precursors were increased after exposure to vancomycin or moenomycin, representing a potential means for regulation of induction. 相似文献
4.
M Bolognesi L Pugliese G Gatti F Frigerio A Coda L Antolini H P Schnebli E Menegatti G Amiconi P Ascenzi 《Journal of molecular recognition : JMR》1990,3(4):163-168
The crystal structure of the molecular complex formed by bovine alpha-chymotrypsin and the recombinant serine proteinase inhibitor eglin c from Hirudo medicinalis has been solved using monoclinic crystals of the complex, reported previously. Four circle diffractometer data at 3.0 A resolution were employed to determine the structure by molecular replacement techniques. Bovine alpha-chymotrypsin alone was used as the search model; it allowed us to correctly orient and translate the enzyme in the unit cell and to obtain sufficient electron density for positioning the eglin c molecule. After independent rigid body refinement of the two complex components, the molecular model yielded a crystallographic R factor of 0.39. Five iterative cycles of restrained crystallographic refinement and model building were conducted, gradually increasing resolution. The current R factor at 2.6 A resolution (diffractometer data) is 0.18. The model includes 56 solvent molecules. Eglin c binds to bovine alpha-chymotrypsin in a manner consistent with other known serine proteinase/inhibitor complex structures. The reactive site loop shows the expected conformation for productive binding and is in tight contact with bovine alpha-chymotrypsin between subsites P3 and P'2; Leu 451 acts as the P1 residue, located in the primary specificity S1 site of the enzyme. Hydrogen bonds equivalent to those observed in complexes of trypsin(ogen) with the pancreatic basic- and secretory-inhibitors are found around the scissile peptide bond. 相似文献
5.
Anna C. M. Pieck Huub M. W. van der Velden Antonia A. M. Rijken John M. Neis Friedrich Wanka 《Chromosoma》1985,91(2):137-144
Residual protein structures were prepared from isolated chromosomes and interphase nuclei of in vitro cultured bovine liver cells and the protein compositions were analysed. Chromosomes with minimal cytoplasmic contamination were obtained by a simple procedure using a pH 8 isolation medium containing Triton X-100 and polyamines, and residual protein-DNA complexes were prepared by extraction with 2 M NaCl. Residual protein structures were also obtained by digesting isolated chromosomes with staphylococcal nuclease. Protein compositions of both structures as obtained by SDS-polyacrylamide gel electrophoresis were essentially the same. Residual protein structures were prepared from isolated nuclei by the same procedures. The major nuclear matrix proteins, i.e., the lamins A, B, and C, were not found in the chromosomes and chromosome scaffolds. On the other hand, the residual chromosome structures contained two major polypeptides of 37 and 83 kilodalton relative molecular weights that were absent from the nuclear matrix preparations. A few polypeptides with the same or very similar electrophoretic mobilities were found in the residual structures of both the nuclei and the chromosomes. 相似文献
6.
G Pugliese E G Spokas E Marcinkiewicz P Y Wong 《The Journal of biological chemistry》1985,260(27):14621-14625
The metabolic transformation of tritium-labeled prostaglandin D2 ([3H]PGD2) was investigated in the isolated Tyrode's-perfused rabbit liver. One major product was isolated and identified in the perfusate as a new prostanoid. The structure of this metabolite was further confirmed by gas chromatography-mass spectrometry and chemical methods to be 9 alpha,11 beta,15-L-trihydroxyprosta-5-cis, 13-trans-dienoic acid, namely (9 alpha,11 beta-PGF2). This new prostanoid was found to be an inhibitor of platelet aggregation and to cause constriction of canine coronary artery strips. These results suggested that on passage through the hepatic circulation exogenous PGD2 is converted to 9 alpha,11 beta-PGF2, the latter having a biological profile which differs from that of PGD2 and PGF2 alpha. 相似文献
7.
Evidence for two waves of induction of DNA enzymes in stimulated human lymphocytes 总被引:5,自引:3,他引:2 下载免费PDF全文
Guido C. F. Pedrali Noy Leda Dalpra Antonia M. Pedrini Giovanni Ciarrocchi Elena Giulotto Fiorella Nuzzo Arturo Falaschi 《Nucleic acids research》1974,1(9):1183-1199
The stimulation of human lymphocytes with phytohaemoagglutinin induces the appearance or increase of several enzymes of DNA metabolism [Pedrini etal., Biochem. Biophys. Res. Comm., 47:1221(1972)]. With long times of stimulation, two phenomena are observed; an increase in the levels of DNA polymerase, of a DNase acting on single-stranded DNA, and of an endonuclease, occurring between the third and fourth day, in parallel with a wave of DNA synthesis;a second wave of increase of the same enzymes and of DNA ligase,occurring between the fifth and eight day when the DNA replication rate, as measured by thymidine-pulses, has decreased to values close to the background. 相似文献
8.
Résumé Les Auteurs ont démontré que, en conditions histochimiques sur du matériel fixé au formol, les acides phosphotungstique et phosphomolybdique ont une double action: 1. une action oxydative à la charge des radicaux PAS-positifs (vic-glycols et éthyleniques) en milieu aqueux, et à la charge des radicaux aminiques en milieu anhydre; cette action entraine la transformation de ces radicaux en aldéhydes; 2. la formation d'une liaison chimique entre les aldéhydes et les molécules des acides phosphomolybdique et phosphotungstique. — La coloration du collagène, au contraire, n'est pas due ni aux radicaux aminiques ni vic-glycols et implique un mécanisme encore inconnu.
Observations about the specificity of staining of phosphotungstic and phosphomolybdic acid
Summary The authors demonstrated that phosphotungstic and phosphomolybdic acid applied to formol-fixed tissues explete two following actions: 1. An oxidative action on the PAS-positive radicals (double bonds, vic-glycols groups) if in water solution and on aminogroups if in anhydrous solution. This oxidation results in a production of aldehydic radicals 2. The formation of chemical bonds between the aldehydic new-formed groups and the molecules of phosphotungstic or phosphomolybdicacid.— However, the above mentioned mechanism of action is not applicable to the collagen staining for which a different explanation has to be supposed.相似文献
9.
10.
Zafar U. Khan Antonia Gutiérrez Celia P. Miralles Angel L. De Blas 《Neurochemical research》1996,21(2):147-159
Subunit-specific antibodies to all the γ subunit isoforms described in mammalian brain (γ1, γ2S, γL, and γ3) have been made. The proportion of GABAA receptors containing each γ subunit isoform in various brain regions has been determined by quantitative immunoprecipitation.
In all tested regions of the rat brain, the γ1, and γ3 subunits are present in considerable smaller proportion of GABAA receptor than the γ2 subunit. Immunocytochemistry shows that γ1 immunoreactivity concentrates in the stratum oriens and stratum radiatum of the CA1 region of the hippocampus. In the dentate
gyrus, γ1 immunoreactivity concentrates on the outer 2/3 of the molecular layer coinciding with the localization of the axospinous
synapses of the perforant pathway. In contrast, γ3 immunoreactivity concentrates on the basket cells and other GABAergic local circuit neurons of the hilus. These cells are
also rich in γ2S. In the cerebellu, γ1 immunolabeling was localized on the Bergmann glia. The γ2S and γ2L subunits are differentially expressed in various brain regions. Thus the γ2S is highly expressed in the olfactory bulb and hippocampus whereas the γ2L is very abundant in inferior colliculus and cerebellum, particularly in Purkinje cells, as immunocytochemistry, in situ hybridization
and immunoprecipitation techniques have revealed. The γ2S and γ2L coexist in some brain areas and cell types. Moreover, the γ2S and γ2L subunits can coexist in the same GABAA receptor pentamer. We have shown that this is the case in some GABAA receptors expressed in cerebellar granule cells. These GABAA receptors also have α and β subunits forming the pentamer. Immunoblots have shown that the rat γ1, γ2S, γ2L and γ3 subunits are peptides of 47, 45, 47 and 44 kDa respectively. Results also indicate that there are aging-related changes in
the expression of the γ2S and γ2L subunits in various brain regions which suggest the existence of aging-related changes in the subunit composition of the
GABAA receptors which in turn might lead to changes in receptor pharmacology. The results obtained with the various γ subunit isoforms
are discussed in terms of the high molecular and binding heterogeneity of the native GABAA receptors in brain.
Special issue dedicated to Dr. Kinya Kuriyama 相似文献