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91.
Pauwels B Korst AE Andriessen V Baay MF Pattyn GG Lambrechts HA Pooter CM Lardon F Vermorken JB 《Radiation research》2005,164(5):642-650
Gemcitabine has excellent radiosensitizing properties, as shown in both preclinical and clinical studies. Radiosensitization correlated with the early S-phase block of gemcitabine. In the present study, we investigated the role of TP53 in the radiosensitizing effect of gemcitabine. Isogenic A549 cells differing in TP53 status were treated with gemcitabine during the 24 h prior to irradiation. Cell survival was determined 7 days after irradiation by the sulforhodamine B test. In addition, cell cycle perturbation was determined by flow cytometry and TP53 expression by Western blot analysis. Gemcitabine caused a concentration-dependent radiosensitizing effect in all cell lines. Transformed A549 cells were less sensitive to the cytotoxic effect of gemcitabine. The cell cycle arrest early in the S phase was dependent on the drug dose but was comparable in the different cell lines and was not related to functional TP53. Using isogenic cell lines, we have shown that neither TP53 status nor the transfection procedure influenced the radiosensitizing effect of gemcitabine. Since both the radiosensitizing effect at equitoxic concentrations and the cell cycle effect of gemcitabine were independent of TP53 expression, it is likely that TP53 protein does not play a crucial role in the radiosensitizing mechanism of gemcitabine. 相似文献
92.
Corveleyn A Janssen H Martini A Somers R Cools J Marynen P 《Journal of cellular biochemistry》2005,94(6):1112-1125
93.
The oxidative modification of LDL may play an important role in the early events of atherogenesis. Thus the identification of antioxidative compounds may be of therapeutic and prophylactic importance regarding cardiovascular disease. Copper-chlorophyllin (Cu-CHL), a Cu2+-protoporphyrin IX complex, has been reported to inhibit lipid oxidation in biological membranes and liposomes. Hemin (Fe3+-protoporphyrin IX) has been shown to bind to LDL thereby inducing lipid peroxidation. As Cu-CHL has a similar structure as hemin, one may assume that Cu-CHL may compete with the hemin action on LDL. Therefore, in the present study Cu-CHL and the related compound magnesium-chlorophyllin (Mg-CHL) were examined in their ability to inhibit LDL oxidation initiated by hemin and other LDL oxidizing systems. LDL oxidation by hemin in presence of H2O2 was strongly inhibited by both CHLs. Both chlorophyllins were also capable of effectively inhibiting LDL oxidation initiated by transition metal ions (Cu2+), human umbilical vein endothelial cells (HUVEC) and tyrosyl radicals generated by myeloperoxidase (MPO) in presence of H2O2 and tyrosine. Cu- and Mg-CHL showed radical scavenging ability as demonstrated by the diphenylpicrylhydracylradical (DPPH)-radical assay and estimation of phenoxyl radical generated diphenyl (dityrosine) formation. As assessed by ultracentrifugation the chlorophyllins were found to bind to LDL (and HDL) in serum. The present study shows that copper chlorophyllin (Cu-CHL) and its magnesium analog could act as potent antagonists of atherogenic LDL modification induced by various oxidative stimuli. As inhibitory effects of the CHLs were found at concentrations as low as 1 μmol/l, which can be achieved in humans, the results may be physiologically/therapeutically relevant. 相似文献
94.
We investigated the effects of two NOS inhibitors (AG and l-NAME) on DMBA-induced hamster buccal-pouch carcinogenesis. Six hundred Syrian golden hamsters were split into two divisions (I and II); divisions split into three groups (experimental groups A and B, control group C); and each group into subgroups of 20 (A1-A6, B1-B6 and C1-C3). The pouches of animals in groups A1-A3 were painted first with AG of differing concentrations (10, 20, and 30 micromol/ml) and then 30 min later with DMBA (0.5%), thrice weekly for 9 weeks. Subgroups A4-A6 only received AG treatment. Groups B1 to B6 were similarly treated with l-NAME. Animals in division II were treated in the same manner for 13 weeks. Post-mortem analysis revealed that both inhibitors can suppress the development of epithelial dysplasias and squamous-cell carcinomas. An associated increase in the numbers of epithelial hyperplasias was paralleled by a decrease in iNOS protein expression. This animal model can be employed to evaluate the potential use of iNOS inhibitors as novel therapeutic tools for oral squamous-cell carcinogenesis. 相似文献
95.
De Klerck B Geboes L Hatse S Kelchtermans H Meyvis Y Vermeire K Bridger G Billiau A Schols D Matthys P 《Arthritis research & therapy》2005,7(6):R1208-R1220
CXCL12 (stromal cell-derived factor 1) is a unique biological ligand for the chemokine receptor CXCR4. We previously reported
that treatment with a specific CXCR4 antagonist, AMD3100, exerts a beneficial effect on the development of collagen-induced
arthritis (CIA) in the highly susceptible IFN-γ receptor-deficient (IFN-γR KO) mouse. We concluded that CXCL12 plays a central
role in the pathogenesis of CIA in IFN-γR KO mice by promoting delayed type hypersensitivity against the auto-antigen and
by interfering with chemotaxis of CXCR4+ cells to the inflamed joints. Here, we investigated whether AMD3100 can likewise inhibit CIA in wild-type mice and analysed
the underlying mechanism. Parenteral treatment with the drug at the time of onset of arthritis reduced disease incidence and
modestly inhibited severity in affected mice. This beneficial effect was associated with reduced serum concentrations of IL-6.
AMD3100 did not affect anti-collagen type II antibodies and, in contrast with its action in IFN-γR KO mice, did not inhibit
the delayed type hypersensitivity response against collagen type II, suggesting that the beneficial effect cannot be explained
by inhibition of humoral or cellular autoimmune responses. AMD3100 inhibited the in vitro chemotactic effect of CXCL12 on splenocytes, as well as in vivo leukocyte infiltration in CXCL12-containing subcutaneous air pouches. We also demonstrate that, in addition to its effect
on cell infiltration, CXCL12 potentiates receptor activator of NF-κB ligand-induced osteoclast differentiation from splenocytes
and increases the calcium phosphate-resorbing capacity of these osteoclasts, both processes being potently counteracted by
AMD3100. Our observations indicate that CXCL12 acts as a pro-inflammatory factor in the pathogenesis of autoimmune arthritis
by attracting inflammatory cells to joints and by stimulating the differentiation and activation of osteoclasts. 相似文献
96.
Kelchtermans H De Klerck B Mitera T Van Balen M Bullens D Billiau A Leclercq G Matthys P 《Arthritis research & therapy》2005,7(2):R402-R415
Mice with a deficiency in IFN-γ or IFN-γ receptor (IFN-γR) are more susceptible to collagen-induced arthritis (CIA), an experimental
autoimmune disease that relies on the use of complete Freund's adjuvant (CFA). Here we report that the heightened susceptibility
of IFN-γR knock-out (KO) mice is associated with a functional impairment of CD4+CD25+ Treg cells. Treatment of wild-type mice with depleting anti-CD25 antibody after CFA-assisted immunisation with collagen type II
(CII) significantly accelerated the onset of arthritis and increased the severity of CIA. This is an indication of a role
of Treg cells in the effector phase of CIA. IFN-γR deficiency did not affect the number of CD4+CD25+ T cells in the central and peripheral lymphoid tissues. In addition, CD4+CD25+ T cells isolated from naive IFN-γR KO mice had a normal potential to suppress T cell proliferation in vitro. However, after immunisation with CII in CFA, the suppressive activity of CD4+CD25+ T cells became significantly more impaired in IFN-γR-deficient mice. Moreover, expression of the mRNA for Foxp3, a highly
specific marker for Treg cells, was lower. We further demonstrated that the effect of endogenous IFN-γ, which accounts for more suppressive activity
in wild-type mice, concerns both Treg cells and accessory cells. Our results demonstrate that the decrease in Treg cell activity in CIA is counter-regulated by endogenous IFN-γ. 相似文献
97.
The preparation of a series of tridentate ligands of formulae X(CH2C7H5N2)2 (X = NH, S, O, S2) is described. The ligands contain two benzimidazole moieties and one of NH, S, O, or S2 as the donor groups. Cu(I) and Cu(II) complexes of these ligands are prepared and characterized. Spectroscopic and X-ray data imply that the geometric constraints of these ligands impose a distorted coordination geometry at copper. The implications and relevance of this chemistry to copper proteins is discussed. 相似文献
98.
Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males
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Van Esch H Bauters M Ignatius J Jansen M Raynaud M Hollanders K Lugtenberg D Bienvenu T Jensen LR Gecz J Moraine C Marynen P Fryns JP Froyen G 《American journal of human genetics》2005,77(3):442-453
Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1CAM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients. 相似文献
99.
Jasmonic acid (JA) plays a crucial role in plant fertility and defense responses. It exerts an inhibitory effect on plant growth when applied exogenously. This effect seems to be somehow related to a negative regulation of cell cycle progression in the meristematic tissues. In this report, we focus on the molecular events that occur during JA-induced G2 arrest. We demonstrate that JA prevents the accumulation of B-type cyclin-dependent kinases and the expression of cyclin B1;1, which are both essential for the initiation of mitosis. This feature suggests the existence of an early G2 checkpoint that is affected by JA. 相似文献
100.
Abrahamsen H Baillie G Ngai J Vang T Nika K Ruppelt A Mustelin T Zaccolo M Houslay M Taskén K 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(8):4847-4858
Ligation of the TCR along with the coreceptor CD28 is necessary to elicit T cell activation in vivo, whereas TCR triggering alone does not allow a full T cell response. Upon T cell activation of human peripheral blood T cells, we found that the majority of cAMP was generated in T cell lipid rafts followed by activation of protein kinase A. However, upon TCR and CD28 coligation, beta-arrestin in complex with cAMP-specific phosphodiesterase 4 (PDE4) was recruited to lipid rafts which down-regulated cAMP levels. Whereas inhibition of protein kinase A increased TCR-induced immune responses, inhibition of PDE4 blunted T cell cytokine production. Conversely, overexpression of either PDE4 or beta-arrestin augmented TCR/CD28-stimulated cytokine production. We show here for the first time that the T cell immune response is potentiated by TCR/CD28-mediated recruitment of PDE4 to lipid rafts, which counteracts the local, TCR-induced production of cAMP. The specific recruitment of PDE4 thus serves to abrogate the negative feedback by cAMP which is elicited in the absence of a coreceptor stimulus. 相似文献