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861.
We have previously shown that lmx1b, a LIM homeodomain protein, is expressed in the pronephric glomus. We now show temporal and spatial expression patterns of lmx1b and its potential binding partners in both dissected pronephric anlagen and in individual dissected components of stage 42 pronephroi. Morpholino oligonucleotide knock-down of lmx1b establishes a role for lmx1b in the development of the pronephric components. Depletion of lmx1b results in the formation of a glomus with reduced size. Pronephric tubules were also shown to be reduced in structure and/or coiling whereas more distal tubule structure was unaffected. Over-expression of lmx1b mRNA resulted in no significant phenotype. Given that lmx1b protein is known to function as a heterodimer, we have over-expressed lmx1b mRNA alone or in combination with potential interacting molecules and analysed the effects on kidney structures. Phenotypes observed by over-expression of lim1 and ldb1 are partially rescued by co-injection with lmx1b mRNA. Animal cap experiments confirm that co-injection of lmx1b with potential binding partners can up-regulate pronephric molecular markers suggesting that lmx1b lies upstream of wt1 in the gene network controlling glomus differentiation. This places lmx1b in a genetic hierarchy involved in pronephros development and suggests that it is the balance in levels of binding partners together with restricted expression domains of lmx1b and lim1 which influences differentiation into glomus or tubule derivatives in vivo. 相似文献
862.
Clarkin CE Garonna E Pitsillides AA Wheeler-Jones CP 《Experimental cell research》2008,314(17):3152-3161
In bone, angiogenesis must be initiated appropriately, but limited once remodelling or repair is complete. Our recent findings have supported a role for prostaglandins (PG), known modulators of osteoblast (OB) and endothelial cell (EC) behaviour, in facilitating VEGF-mediated paracrine communication from OBs to ‘remotely located’ ECs, but the mechanism(s) regulating OB:EC crosstalk when these cells are closely opposed are undefined. In this study we have examined: (i) the effects of exogenous PGE2 on VEGF-driven events in ECs, and (ii) the role of endogenous COX-2-derived prostanoids in mediating communication between intimately opposed OBs and ECs in direct contact. Exposure of ECs to PGE2 increased ERK1/2 phosphorylation, COX-2 induction, 6-keto-PGF1α release and EC proliferation. In contrast, PGE2 attenuated VEGF165-induced VEGFR2/Flk1 phosphorylation, ERK1/2 activation and proliferation of ECs, suggesting that exogenous PGE2 restricts the actions of VEGF. However, the COX-2-selective inhibitor, NS398, also attenuated VEGF-induced proliferation, implying a distinct role for endogenous COX-2 activity in regulating EC behaviour. To examine the effect of OB:EC proximity and the role of COX-2 products further, we used a confrontational co-culture model. These studies showed that COX-2 blockade with NS398 enhanced EC-dependent increases in OB differentiation, that this effect was reversed by exogenous PGH2 (immediate COX-2 product), and that exogenous VEGF did not influence EC-dependent OB differentiation under these conditions. Our findings indicate that locally produced prostanoids may serve distinct roles depending on OB:EC proximity and negatively modulate VEGF-mediated changes in EC behaviour when these cells are closely opposed to control angiogenesis during bone (re)modelling. 相似文献
863.
Wegner AM Nebhan CA Hu L Majumdar D Meier KM Weaver AM Webb DJ 《The Journal of biological chemistry》2008,283(23):15912-15920
Changes in the number, size, and shape of dendritic spines are associated with synaptic plasticity, which underlies cognitive functions such as learning and memory. This plasticity is attributed to reorganization of actin, but the molecular signals that regulate this process are poorly understood. In this study, we show neural Wiskott-Aldrich syndrome protein (N-WASP) regulates the formation of dendritic spines and synapses in hippocampal neurons. N-WASP localized to spines and active, functional synapses as shown by loading with FM4-64 dye. Knock down of endogenous N-WASP expression by RNA interference or inhibition of its activity by treatment with a specific inhibitor, wiskostatin, caused a significant decrease in the number of spines and excitatory synapses. Deletion of the C-terminal VCA region of N-WASP, which binds and activates the actin-related protein 2/3 (Arp2/3) complex, dramatically decreased the number of spines and synapses, suggesting activation of the Arp2/3 complex is critical for spine and synapse formation. Consistent with this, Arp3, like N-WASP, was enriched in spines and excitatory synapses and knock down of Arp3 expression impaired spine and synapse formation. A similar defect in spine and synapse formation was observed when expression of an N-WASP activator, Cdc42, was knocked down. Thus, activation of N-WASP and, subsequently, the Arp2/3 complex appears to be an important molecular signal for regulating spines and synapses. Arp2/3-mediated branching of actin could be a mechanism by which dendritic spine heads enlarge and subsequently mature. Collectively, our results point to a critical role for N-WASP and the Arp2/3 complex in spine and synapse formation. 相似文献
864.
Stienstra R Duval C Keshtkar S van der Laak J Kersten S Müller M 《The Journal of biological chemistry》2008,283(33):22620-22627
Obesity is associated with infiltration of macrophages into adipose tissue. Adipose macrophages may contribute to an elevated inflammatory status by secreting a variety of proinflammatory mediators, including tumor necrosis factor alpha and interleukin-6 (IL-6). Recent data suggest that during diet-induced obesity the phenotype of adipose-resident macrophages changes from alternatively activated macrophages toward a more classical and pro-inflammatory phenotype. Here, we explore the effect of peroxisome proliferator-activated receptor gamma activation on obesity-induced inflammation in 129SV mice fed a high fat diet for 20 weeks. High fat feeding increased bodyweight gain, adipose tissue mass, and liver triglycerides. Rosiglitazone treatment further increased adipose mass, reduced liver triglycerides, and changed adipose tissue morphology toward smaller adipocytes. Surprisingly, rosiglitazone markedly increased the number of macrophages in adipose tissue, as shown by immunohistochemical analysis and quantification of macrophage marker genes CD68 and F4/80+. In adipose tissue, markers for classically activated macrophages including IL-18 were down-regulated, whereas markers characteristic for alternatively activated macrophages (arginase 1, IL-10) were up-regulated by rosiglitazone. Importantly, conditioned media from rosiglitazone-treated alternatively activated macrophages neutralized the inhibitory effect of macrophages on 3T3-L1 adipocyte differentiation, suggesting that alternatively activated macrophages may be involved in mediating the effects of rosiglitazone on adipose tissue morphology and mass. Our results suggest that short term rosiglitazone treatment increases infiltration of alternatively activated macrophages in adipose tissue. The alternatively activated macrophages might play a role in peroxisome proliferator-activated receptor gamma-dependent expansion and remodeling of adipose tissue. 相似文献
865.
Prudent R Moucadel V López-Ramos M Aci S Laudet B Mouawad L Barette C Einhorn J Einhorn C Denis JN Bisson G Schmidt F Roy S Lafanechere L Florent JC Cochet C 《Molecular and cellular biochemistry》2008,316(1-2):71-85
None of the already described CK2 inhibitors did fulfill the requirements for successful clinical settings. In order to find innovative CK2 inhibitors based on new scaffolds, we have performed a high-throughput screening of diverse chemical libraries. We report here the identification and characterization of several classes of new inhibitors. Whereas some share characteristics of previously known CK2 inhibitors, others are chemically unrelated and may represent new opportunities for the development of better CK2 inhibitors. By combining structure-activity relationships with a docking procedure, we were able to determine the binding mode of these inhibitors. Interestingly, beside the identification of several nanomolar ATP-competitive inhibitors, one class of chemical inhibitors displays a non-ATP competitive mode of inhibition, a feature that suggests that CK2 possess distinct druggable binding sites. For the most promising inhibitors, selectivity profiling was performed. We also provide evidence that some chemical compounds are inhibiting CK2 in living cells. Finally, the collected data allowed us to draw the rules about the chemical requirements for CK2 inhibition both in vitro and in a cellular context. 相似文献
866.
Caroline Reynaud Dominique Baas Claudine Gleyzal Dominique Le Guellec Pascal Sommer 《Matrix biology》2008,27(6):547-560
Lysyl oxidase (LOX), a copper-dependent amine oxidase known in mammals to catalyze the cross-linking of collagen and elastin in the extracellular matrix, is a member of a multigenic family. Eight genes encoding lysyl oxidase isoforms have been identified in zebrafish. Recent studies have revealed a critical role for two zebrafish lysyl oxidases-like in the formation of the notochord. We now present the role of Lox in zebrafish development. lox morpholino-mediated knockdown results in a mildly undulated notochord, truncated anterior-posterior axis, tail bending and smaller head. Analyses of morphants show a complete disorganization of muscle somites and neural defects, in accordance with the lox expression pattern. Lox inhibition also induces pigment defects and pharyngeal arch deformities consistent with neural crest dysfunction. Taken together, these data reveal a role for Lox in early morphogenesis, especially in muscle development and neurogenesis, and resume some aspects of physiopathology of copper metabolism. 相似文献
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870.
Tumor destruction using electrochemotherapy followed by CpG oligodeoxynucleotide injection induces distant tumor responses 总被引:2,自引:1,他引:1
Roux S Bernat C Al-Sakere B Ghiringhelli F Opolon P Carpentier AF Zitvogel L Mir LM Robert C 《Cancer immunology, immunotherapy : CII》2008,57(9):1291-1300
PURPOSE: Electrochemotherapy (ECT) is an effective local therapy of human cutaneous cancers but has no effect on distant untreated tumors. We addressed whether tumor-associated antigens released after ECT could induce an efficient systemic immunity when associated with an appropriate immunoadjuvant. METHODS AND RESULTS: We first studied the nature of the cellular recruitment and the expression of various toll-like receptors (TLRs) in tumors treated by ECT. We found that ECT induced a massive recruitment of CD11c and CD11b positive cells in the tumors and a strong increase of TLR9 expression. We then tested antitumor effects of the combination: ECT followed by TLR-9 ligands, CpG oligodeoxynucleotides (CpG ODN), in three murine tumor models. We found that this combination triggered both potent local synergistic antitumor effects, on the ipsi-lateral ECT-treated tumor, and more interestingly, a systemic antitumor response on the contra-lateral untreated tumor, in the three models. The systemic protection was T-cell dependent as it was not observed in nude littermates. The combination induced tumor-specific T cell effectors in the tumor-draining lymph nodes and in the spleen which secreted significantly more gamma-interferon upon activation than with ECT or CpG ODN alone. CONCLUSIONS: Our data show that ECT and CpG ODN synergize and induce a significant increase of the local effect and a systemic T-dependent antitumor response. Such combination constitutes a potential innovative vaccination strategy using in situ tumor-associated antigens that could eventually be translated into the clinic. 相似文献