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排序方式: 共有358条查询结果,搜索用时 15 毫秒
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Juan M. Mucci Florencia Suqueli García Pablo N. de Francesco Romina Ceci S. Di Genaro Carlos A. Fossati M. Victoria Delpino Paula A. Rozenfeld 《Gene》2013
Gaucher disease (GD) is caused by mutations in the GBA gene that confer a deficient level of activity of glucocerebrosidase (GCase). This deficiency leads to accumulation of the glycolipid glucocerebroside in the lysosomes of cells of monocyte/macrophage system. Type I GD is the mildest form and is characterized by the absence of neuronopathic affection. Bone compromise in Gaucher disease patients is the most disabling aspect of the disease. However, pathophysiological aspects of skeletal alterations are still poorly understood. 相似文献
75.
Darin J. Gustin Yihong Li Matthew L. Brown Xiaoshan Min Mike J. Schmitt Malgorzata Wanska Xiaodong Wang Richard Connors Sheere Johnstone Mario Cardozo Alan C. Cheng Shawn Jeffries Brendon Franks Shyun Li Shanling Shen Mariwil Wong Holger Wesche Guifen Xu Zhulun Wang 《Bioorganic & medicinal chemistry letters》2013,23(16):4608-4616
Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other’s loss. Thus, inhibition of both isoforms is likely required to block SphK dependent angiogenesis. A structure based approach was used to design and synthesize a series of SphK inhibitors resulting in the identification of the first potent inhibitors of both isoforms of human SphK. Additionally, to our knowledge, this series of inhibitors contains the only sufficiently potent inhibitors of murine SphK1 with suitable physico-chemical properties to pharmacologically interrogate the role of SphK1 in rodent models and to reproduce the phenotype of SphK1 (?/?) mice. 相似文献
76.
Thomas Hanke Florian Rörsch Theresa M. Thieme Nerea Ferreiros Gisbert Schneider Gerd Geisslinger Ewgenij Proschak Sabine Grösch Manfred Schubert-Zsilavecz 《Bioorganic & medicinal chemistry》2013,21(24):7874-7883
The microsomal prostaglandin E2 synthase 1 (mPGES-1) became a desirable target in recent years for the research of new anti-inflammatory drugs. Even though many potent inhibitors of human mPGES-1, tested in vitro assay systems, have been synthesized, they all failed in preclinical trials in rodent models of inflammation, due to the lack of activity on rodent enzyme. Within this work we want to present a new class of mPGES-1 inhibitors derived from a benzenesulfonamide scaffold with inhibitory potency on human and murine mPGES-1. Starting point with an IC50 of 13.8 μM on human mPGES-1 was compound 1 (4-{benzyl[(4-methoxyphenyl)methyl]sulfamoyl}benzoic acid; FR4), which was discovered by a virtual screening approach. Optimization during a structure–activity relationship (SAR) process leads to compound 28 (4-[(cyclohexylmethyl)[(4-phenylphenyl)methyl]sulfamoyl]benzoic acid) with an improved IC50 of 0.8 μM on human mPGES-1. For the most promising compounds a broad pharmacological characterization has been carried out to estimate their anti-inflammatory potential. 相似文献
77.
John A. Hickman Owen C. Blair Anita L. Stepanowski Alan C. Sartorelli 《生物化学与生物物理学报:生物膜》1984,778(3):457-462
Ionophore-induced changes in the cell-associated fluorescence of samples of approx. 50 000 individual murine L1210 leukemia cells which had been incubated with the voltage-sensitive dye 3,3′-dihexyloctacarbocyanine iodide (DiOC6(3)) were monitored by flow cytometry. The K+ ionophore valinomycin (1 μM) produced homogeneous changes in the fluorescence of the entire population, the magnitude of which was dependent upon the concentration of extracellular K+. These changes allowed the estimation of the potassium equilibrium potential of the cells, by the null-point method, to be – 11.9 mV. The Ca2+ ionophore A23187 (500 nM) produced heterogeneous changes in fluorescence, with populations of both hyperpolarised and depolarised cells. In addition, the depolarised population underwent an apparent size change, with a reduction in cell volume. This heterogeneity of response resulted in a minimal change in the median fluorescence value for the whole population, which suggests that it would not have been detectable by methods dependent upon net population-averaged changes in fluorescence. Removal of extracellular Na+ or preincubation of cells with amiloride (500 μM) effectively eliminated the depolarised population. Removal of extracellular K+ increased the hyperpolarised population. These findings provide evidence for the presence of Ca2+-induced Na+ exchange and Ca2+-induced K+ efflux mechanisms in these cells which may be expressed simultaneously in the cell population. 相似文献
78.
Rong-Yaun Shyu Chang-Chieh Wu Chun-Hua Wang Tzung-Chieh Tsai Lu-Kai Wang Mao-Liang Chen Shun-Yuan Jiang Fu-Ming Tsai 《Journal of biomedical science》2013,20(1):30
Background
H-rev107 is a member of the HREV107 type II tumor suppressor gene family which includes H-REV107, RIG1, and HRASLS. H-REV107 has been shown to express at high levels in differentiated tissues of post-meiotic testicular germ cells. Prostaglandin D2 (PGD2) is conjectured to induce SRY-related high-mobility group box 9 (SOX9) expression and subsequent Sertoli cell differentiation. To date, the function of H-rev107 in differentiated testicular cells has not been well defined.Results
In the study, we found that H-rev107 was co-localized with prostaglandin D2 synthase (PTGDS) and enhanced the activity of PTGDS, resulting in increase of PGD2 production in testis cells. Furthermore, when H-rev107 was expressed in human NT2/D1 testicular cancer cells, cell migration and invasion were inhibited. Also, silencing of PTGDS would reduce H-rev107-mediated increase in PGD2, cAMP, and SOX9. Silencing of PTGDS or SOX9 also alleviated H-rev107-mediated suppression of cell migration and invasion.Conclusions
These results revealed that H-rev107, through PTGDS, suppressed cell migration and invasion. Our data suggest that the PGD2-cAMP-SOX9 signal pathway might play an important role in H-rev107-mediated cancer cell invasion in testes. 相似文献79.
Ping Fu Paul Senior Ross T. Fernley Geoffrey W. Tregear G. Peter Aldred 《Journal of biochemical and biophysical methods》1999,40(3):553-112
We describe here an application of the competitive PCR technique to the analysis of copy number of recombinant rat parathyroid hormone-related protein (rPTHrP) gene in stably-transfected murine erythroleukemia (MEL) cell lines. A single-copy reference gene (endogenous mouse PTHrP gene or mPTHrP) is used as an internal control. This control gene, present in the genome of MEL cells, shares the same primer binding sites as the rPTHrP cDNA but contains an internal PvuII site, which allows resolution of the amplified products after restriction enzyme digestion by polyacrylamide gel electrophoresis (PAGE). The transgene copy number is determined by the ratio of band intensity of the rPTHrP product to that of the mPTHrP product. Using this method, we have determined the copy number of the rPTHrP transgene from isolated genomic DNA, and compared the results with those obtained from Southern blot analysis. In addition, we have demonstrated that the procedure can be applied very simply to whole MEL cells without DNA extractions and that as few as 104 cells are required for the analysis. 相似文献
80.
Involvement of impaired peritoneal immunosurveillance systems has been well established in the pathology of endometriosis. On the other hand, it has been observed that peritoneal administration of IL-12 suppress development of endometriotic lesions in a mouse endometriosis model. We investigated the effect of peritoneal administration of IL-12 on the peritoneal immunosurveillance system regarding NK cells in the mouse model. Treating the endometrial-tissue challenged mice with IL-12 for 5 consecutive days, from day -2 to day 2 (implantation of the endometrial tissues was done on day 0), cytotoxicity of splenic NK cells was enhanced immediately after the administration, on day 3, and development of the endometriotic lesions was reduced on day 21. In vivo NK cell depletion by administration of anti-IL-2Rβ mAb resulted in reduction of the cytotoxicity of splenic NK cells concomitant with a significant attenuation of suppressive effect of IL-12 on development of endometriotic lesions. Therefore, it was suggested that IL-12 suppresses development of endometriotic lesions via activation of NK cells, and that NK cells are involved in the primary defense for the development of endometriotic lesions. 相似文献