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  • Recombinant human VEGF165b inhibits experimental choroidal neovascularisation. 20237252

    PURPOSE Vascular Endothelial growth Factor (VEGF-A) is the principal stimulator of angiogenesis in wet age related macular degeneration (AMD). However, VEGF-A is generated by alternate splicing into two families, the pro-angiogenic VEGF-A(xxx) family, and the anti-angiogenic VEGF-A(xxx)b family. It is the pro-angiogenic family that is responsible for the blood vessel growth seen in AMD. METHODS To determine the role of anti-angiogenic isoforms of VEGF-A as inhibitors of choroidal neovascularisation we employed a model of laser induced choroidal neovascularisation in the mouse eye, and investigated VEGF-A(165)b effects on endothelial cells and VEGFRs in vitro. RESULTS VEGF-A(165)b inhibited VEGF-A(165)-mediated endothelial cell migration with a similar dose effect as ranibizumab and bevacizumab, and 200 fold more potently than pegaptanib. VEGF-A(165)b bound both VEGFR1 and VEGFR2 with similar affinity to VEGF-A(165). After laser injury mice were injected either intraocularly or subcutaneously with recombinant human VEGF-A(165)b. Intraocular injection of rhVEGF-A(165)b gave a pronounced dose dependent inhibition of fluorescein leakage, with an IC50 of 16pg/eye, neovascularisation (IC50 0.8pg/eye) and lesion as assessed by histological staining (IC50 8pg/eye). Subcutaneous administration of 100microg twice a week also inhibited fluorescein leakage and neovascularisation and reduced lesion size. CONCLUSIONS These results show that VEGF-A(165)b is a potent anti-angiogenic agent in mouse model of age related macular degeneration, and suggest that increasing the ratio of anti-to-pro-angiogenic isoforms may be therapeutically effective in this condition.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB3045
    Nombre del producto:
    Anti-Connexin 35/36 Antibody, clone 8F6.2

  • Balance of pro- versus anti-angiogenic splice isoforms of vascular endothelial growth factor as a regulator of neuroblastoma growth. 20662003

    Neuroblastoma (NB) is the second most common extracranial tumour of childhood. Angiogenesis plays a crucial role in the growth and development of NB and vascular endothelial growth factor (VEGF), one of the most potent stimuli of angiogenesis, has been studied extensively in vitro. VEGF(165) has been shown to be the predominant angiogenic isoform expressed in NB cell lines and tumours. In this study, we investigated the anti-angiogenic isoform of VEGF-A, generated from distal splice site selection in the terminal exon of VEGF (VEGF(165)b) and shown to be down-regulated in epithelial malignancies. The expression of both the pro- (VEGF(xxx)) and the anti-angiogenic (VEGF(xxx)b) isoforms was compared in a range of NB and ganglioneuroma (GN) tumours. Whereas VEGF(xxx)b and VEGF(xxx) were both expressed in GN, specific up-regulation of the VEGF(xxx) isoforms was seen in NB at RNA and protein levels. Highly tumourigenic NB cell lines also showed up-regulation of the angiogenic isoforms relative to VEGF(xxx)b compared to less tumourigenic cell lines, and the isoforms were differentially secreted. These results indicate that VEGF(165) is up-regulated in NB and that there is a difference in the balance of isoform expression from anti-angiogenic VEGF(165)b to angiogenic VEGF(165). Treatment with recombinant human VEGF(165)b significantly reduced the growth rate of established xenografts of SK-N-BE(2)-C cells (4.24 +/- 1.01 fold increase in volume) compared with those treated with saline (9.76 +/- 3.58, p < 0.01). Microvascular density (MVD) was significantly decreased in rhVEGF(165)b-treated tumours (19.4 +/- 1.9 vessels/mm(3)) in contrast to the saline-treated tumours (45.5 +/- 8.6 vessels/mm(3)). VEGF(165)b had no significant effect on the proliferative or apoptotic activity, viability or cytotoxicity of SK-N-BE(2)-C cells after 48 h. In conclusion, VEGF(165)b is an effective inhibitor of NB growth. These findings provide the rationale for further investigation of VEGF(165)b in NB and other paediatric malignancies.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MABC595
    Nombre del producto:
    Anti-VEGF 165b Antibody, clone 56/1

  • Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor. 16193288

    Proliferative diabetic retinopathy results from excess blood vessel growth into the vitreous fluid of the eye. Retinal angiogenesis is regulated by expression of vascular endothelial growth factor (VEGF), and many studies have shown that VEGF is critically involved in proliferative diabetic retinopathy. VEGF is alternatively spliced to form the angiogenic (VEGF(xxx)) and potentially anti-angiogenic (VEGF(xxx)b) family of isoforms. The VEGF(xxx)b family is found in normal tissues, but down-regulated in renal and prostate cancer. Previous studies on endogenous expression of VEGF in the eye have not distinguished between the two families of isoforms.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MABC595
    Nombre del producto:
    Anti-VEGF 165b Antibody, clone 56/1

  • Amyloidogenic processing but not amyloid precursor protein (APP) intracellular C-terminal domain production requires a precisely oriented APP dimer assembled by transmemb ... 18201969

    The beta-amyloid peptide (Abeta) is the major constituent of the amyloid core of senile plaques found in the brain of patients with Alzheimer disease. Abeta is produced by the sequential cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. Cleavage of APP by gamma-secretase also generates the APP intracellular C-terminal domain (AICD) peptide, which might be involved in regulation of gene transcription. APP contains three Gly-XXX-Gly (GXXXG) motifs in its juxtamembrane and transmembrane (TM) regions. Such motifs are known to promote dimerization via close apposition of TM sequences. We demonstrate that pairwise replacement of glycines by leucines or isoleucines, but not alanines, in a GXXXG motif led to a drastic reduction of Abeta40 and Abeta42 secretion. beta-Cleavage of mutant APP was not inhibited, and reduction of Abeta secretion resulted from inhibition of gamma-cleavage. It was anticipated that decreased gamma-cleavage of mutant APP would result from inhibition of its dimerization. Surprisingly, mutations of the GXXXG motif actually enhanced dimerization of the APP C-terminal fragments, possibly via a different TM alpha-helical interface. Increased dimerization of the TM APP C-terminal domain did not affect AICD production.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB1563
    Nombre del producto:
    Anti-Presenilin-1 Antibody, NT, clone hPS1-NT

  • Clathrin-mediated endocytosis is inhibited during mitosis. 22493256

    A long-standing paradigm in cell biology is the shutdown of endocytosis during mitosis. There is consensus that transferrin uptake is inhibited after entry into prophase and that it resumes in telophase. A recent study proposed that endocytosis is continuous throughout the cell cycle and that the observed inhibition of transferrin uptake is due to a decrease in available transferrin receptor at the cell surface, and not to a shutdown of endocytosis. This challenge to the established view is gradually becoming accepted. Because of this controversy, we revisited the question of endocytic activity during mitosis. Using an antibody uptake assay and controlling for potential changes in surface receptor density, we demonstrate the strong inhibition of endocytosis in mitosis of CD8 chimeras containing any of the three major internalization motifs for clathrin-mediated endocytosis (YXXΦ, [DE]XXXL[LI], or FXNPXY) or a CD8 protein with the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor. The shutdown is not gradual: We describe a binary switch from endocytosis being "on" in interphase to "off" in mitosis as cells traverse the G(2)/M checkpoint. In addition, we show that the inhibition of transferrin uptake in mitosis occurs despite abundant transferrin receptor at the surface of HeLa cells. Our study finds no support for the recent idea that endocytosis continues during mitosis, and we conclude that endocytosis is temporarily shutdown during early mitosis.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo

  • WT1 protein is cleaved by caspase-3 in apoptotic leukemic cells. 28395566

    The aberrant overexpression of Wilms' tumor-1 gene (WT1) plays an important role in blast cell survival and resistance to chemotherapy in acute myeloid leukemia (AML). Here, we found in chemotherapeutic drug etoposide-induced apoptosis, WT1 protein was cleaved into smaller fragment by caspase-3 in leukemic cells. The cleavage was blocked by pan-caspase inhibitor and special caspase-3 inhibitor, suggesting that caspase-3 might cleave WT1 protein. Furthermore, recombinant active caspase-3 cleaved the Flag-WT1 and GST-WT1 proteins in vitro. However, site-directed mutagenesis analyses failed to identify caspase-3-targeted sites in WT1 protein, indicating that caspase-3 cleaved uncommon sites but not classical motifs (DXXD) and non-classical motifs (XXXD). Finally, Eto decreased c-Myc and Bcl-2 expression via reducing the binding of WT1 to the promoter and Eto-induced apoptosis was partially prevented by overexpression of WT1. Collectively, we identify a new substrate for caspase-3 and shed new light on understanding the complicated biology of WT1 in leukemia.
    Tipo de documento:
    Referencia
    Referencia del producto:
    17-371
    Nombre del producto:
    EZ-ChIP™
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