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51.
Expression and characterization of melanin-concentrating hormone receptors on mammalian cell lines 总被引:4,自引:0,他引:4
The neuropeptide melanin-concentrating hormone (MCH) is expressed in central and peripheral tissues where it participates in the complex network regulating energy homeostasis as well as in other physiologically important functions. Two MCH receptor subtypes, MCH-R1 and MCH-R2, have been cloned which signal through activation of Gi/o/q proteins and hence regulate different intracellular signals, such as inhibition of cAMP formation, stimulation of IP3 production, increase in intracellular free Ca2+ and/or activation of MAP kinases. Most of the data were obtained with cell systems heterologously expressing either of the MCH receptors. Fewer reports exist on studies with cell lines which endogenously express MCH receptors. Here, we describe human and other mammalian cell lines with which MCH receptor activation can be studied under "natural" conditions and we summarize the characteristics and signaling pathways of the MCH receptors in the different cell systems. 相似文献
52.
Nagai T Devergne O Mueller TF Perkins DL van Seventer JM van Seventer GA 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(10):5233-5243
Type I IFNs, IFN-alpha and IFN-beta, are early effectors of innate immune responses against microbes that can also regulate subsequent adaptive immunity by promoting antimicrobial Th1-type responses. In contrast, the ability of IFN-beta to inhibit autoimmune Th1 responses is thought to account for some of the beneficial effects of IFN-beta therapy in the treatment of relapsing remitting multiple sclerosis. To understand the basis of the paradoxical effects of IFN-beta on the expression of Th1-type immune responses, we developed an in vitro model of monocyte-derived dendritic cell (DC)-dependent, human naive Th cell differentiation, in which one can observe both positive and negative effects of IFN-beta on the generation of Th1 cells. In this model we found that the timing of IFN-beta exposure determines whether IFN-beta will have a positive or a negative effect on naive Th cell differentiation into Th1 cells. Specifically, the presence of IFN-beta during TNF-alpha-induced DC maturation strongly augments the capacity of DC to promote the generation of IFN-gamma-secreting Th1 cells. In contrast, exposure to IFN-beta during mature DC-mediated primary stimulation of naive Th cells has the opposite effect, in that it inhibits Th1 cell polarization and promotes the generation of an IL-10-secreting T cell subset. Studies with blocking mAbs and recombinant cytokines indicate that the mechanism by which IFN-beta mediates these contrasting effects on Th1 cell generation is at least in part by differentially regulating DC expression of IL-12 family cytokines (IL-12 and/or IL-23, and IL-27) and IL-18. 相似文献
53.
Hazlett KR Rusnak F Kehres DG Bearden SW La Vake CJ La Vake ME Maguire ME Perry RD Radolf JD 《The Journal of biological chemistry》2003,278(23):20687-20694
54.
55.
Styczyński J Wysocki M Debski R Kurylak A Balwierz W Rokicka-Milewska R Matysiak M Balcerska A Kowalczyk J Wachowiak J Sońta-Jakimczyk D Chybicka A 《Acta biochimica Polonica》2002,49(1):99-107
Uptake and efflux of two anthracyclines, idarubicin (IDA) and daunorubicin (DNR), was studied in childhood acute leukemia samples. A comparison of IDA and DNR transport phenomena in relation to drug cytotoxicity and expression of P-glycoprotein (PGP) was made. Intracellular content of IDA/DNR was determined by flow cytometry using the fluorescent properties of the drugs. In vitro drug cytotoxicity was measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. PGP expression was analysed by flow cytometry. The uptake and efflux rates were non-significantly higher for IDA than DNR. There were no differences between three types of leukemia with respect to drug content during accumulation and retention. After correction for the cell volume, intracellular concentration of both drugs in each moment of uptake and efflux was significantly lower in relapsed ALL and AML samples in comparison with initial ALL cells. Efflux, but not uptake, of both drugs was inversely correlated with PGP expression and IDA, but not DNR, cytotoxicity. The cytotoxicity was correlated with drug accumulation for both drugs and with drug retention for IDA. In conclusion, it seems that (1) intracellular content was related to the lipophilic properties of the drugs rather than to the type of leukemia, (2) decreased intracellular concentration of both drugs might have an impact on compromised therapy results in AML and relapsed ALL children, (3) IDA presents higher cytotoxicity, which possibly might be decreased by the presence of PGP. These results might have a practical impact on the rational design of new chemotherapy protocols. 相似文献
56.
Rudolph MJ Illig CR Subasinghe NL Wilson KJ Hoffman JB Randle T Green D Molloy CJ Soll RM Lewandowski F Zhang M Bone R Spurlino JC Deckman IC Manthey C Sharp C Maguire D Grasberger BL DesJarlais RL Zhou Z 《Bioorganic & medicinal chemistry letters》2002,12(3):491-495
A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions. Small alkyl group substitution at the 5-position provided inhibitors equipotent with but possessing improved solubility. 相似文献
57.
Styczyński J Wysocki M Debski R Balwierz W Rokicka-Milewska R Matysiak M Balcerska A Kowalczyk J Wachowiak J Sońta-Jakimczyk D Chybicka A 《Acta biochimica Polonica》2002,49(1):221-225
Glufosfamide (beta-D-glucosyl-ifosfamide mustard) is a new agent for cancer chemotherapy. Its pharmacology is similar to commonly used oxazaphosphorines, but it does not require activation by hepatic cytochrome P-450 and preclinically demonstrates lower nephrotoxicity and myelosuppression than ifosfamide. The aim of the study was a comparison of the drug resistance profiles of glufosfamide and other oxazaphosphorines in childhood acute leukemias. Leukemic cells, taken from children with ALL on diagnosis (n = 41), ALL on relapse (n = 12) and AML on diagnosis (n = 13) were analyzed by means of the MTT assay. The following drugs were tested: glufosfamide (GLU), 4-HOO-ifosfamide (IFO), 4-HOO-cyclophosphamide (CYC) and mafosfamide cyclohexylamine salt (MAF). In the group of initial ALL samples median cytotoxicity values for GLU, IFO, CYC and MAF were 15.5, 33.8, 15.7 and 7.8 microM, respectively. In comparison with initial ALL samples, the relative resistance for GLU and IFO in relapsed ALL samples was 1.9 (p = 0.049) and 1.3 (ns), and in initial AML samples 31 (p < 0.001) and 5 (p = 0.001), respectively. All oxazaphosphorines presented highly significant cross-resistance. Glufosfamide presented high activity against lymphoblasts both on diagnosis and on relapse. 相似文献
58.
Vyakaranam K Rana G Spielvogel BF Maguire JA Hosmane NS 《Nucleosides, nucleotides & nucleic acids》2002,21(8-9):581-598
A number of substituted (borano) nucleic acids, 3'-[diethylphosphite(cyano, carboxy, or carbamoyl) borano] deoxynucleosides (3a-4c) and 5'-[diethylphosphite(cyano or carboxy) borano] deoxynucleosides (6a-7d) were prepared by a variety of synthetic procedures. The syntheses of the pyrophosphates (2a-2c), as precursors for 3a-4c, are also described. 相似文献
59.
A near infrared spectroscopic method was developed to determine drug content in a 20% (wt/wt) ibuprofen and spray-dried hydous
lactose blend. A blending profile was obtained after blending for 0.5, 1, 3, 5, 10, and 20 minutes. Stream sampling was used
to collect about 20 blend samples at each of the blending times from a laboratory scale V-blender. The samples collected were
used to develop a near infrared calibration model. The calibration model was then used to determine the drug content of unknown
samples from 2 validation blends. The validation blends were not included in the calibration model; they were used to evaluate
the effectiveness of the calibration model. A total of 45 samples from the 2 validation blends were predicted by the near
infrared calibration model and then analyzed by a validated UV spectrophotometric method. The root mean square error of prediction
for the first validation blend was 5.69 mg/g and 3.30 mg/g for the samples from the second blend. A paired t test at the 95%
confidence level did not indicate any differences between the drug content predicted by the near infrared spectroscopy (NIRS)
method and the validated UV method for the 2 blends. The results show that the NIRS method could be developed while the blending
profile is generated and used to thoroughly characterize a new formulation during development by analyzing a large number
of samples. The new formulation could be transferred to a manufacturing plant with an NIRS method to facilitate blend uniformity
analysis. 相似文献
60.
Signalling cascades are regulated both positively and negatively by tyrosine phosphorylation. Integrin mediated platelet adhesion triggers signal transduction cascades involving translocation of proteins and tyrosine phosphorylation events, ultimately causing large signalling complexes to be assembled. In resting platelets, a small number of phosphorylated proteins are evident with molecular mass of 50-62 kDa and 120-130 kDa. In thrombin activated human platelets, however, there is a large increase in the number of tyrosine phosphorylated signalling proteins detected. These proteins include pCas (130 kDa), FAK (125 kDa), PI(3)k (85 kDa) and src (85 kDa). However, it is unlikely that this list of proteins represents all the dynamic changes that occur after platelet activation and it is understood that more proteins remain unidentified. In this study, we propose a method for the isolation of the phosphotyrosine proteome from both resting and thrombin activated human platelets. All the dynamic phosphotyrosine events that occur in the platelet after thrombin activation were isolated by immunoprecipitation, using the monoclonal antibody 4G10, allowing us to obtain higher concentrations of relatively low abundant proteins. The resulting phosphotyrosine proteomes were separated by two-dimensional gel electrophoresis. Sixty-seven proteins were reproducibly found to be unique in the thrombin activated platelet proteome when compared to resting platelets. We have positively identified ten of these proteins by Western blotting and matrix-assisted laser desorption/ionisation-time of flight mass spectrometry and these include FAK, Syk, ALK-4, P2X6 and MAPK kinase kinase. This proteomics approach to understanding the signalling events following platelet activation may elucidate potential drug targets for the treatment of coronary thrombosis. 相似文献