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OBJECTIVE: The ROR1 and ROR2 receptor tyrosine kinases have both been implicated in ovarian cancer progression and have been shown to drive migration and invasion. There is an increasing importance of the role of stroma in ovarian cancer metastasis; however, neither ROR1 nor ROR2 expression in tumor or stromal cells has been analyzed in the same clinical cohort. AIM: To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicopathological characteristics. METHODS: Immunohistochemistry for ROR1 and ROR2 was used to assess receptor expression in a cohort of epithelial ovarian cancer patients (n = 178). Results were analyzed in relation to clinical and histopathological characteristics and survival. Matched patient sample case studies of normal, primary, and metastatic lesions were used to examine ROR expression in relation to ovarian cancer progression. RESULTS: ROR1 and ROR2 are abnormally expressed in malignant ovarian epithelium and stroma. Higher ROR2 tumor expression was found in early-stage, low-grade endometrioid carcinomas. ROR2 stromal expression was highest in the serous subtype. In matched patient case studies, metastatic samples had higher expression of ROR2 in the stroma, and a recurrent sample had the highest expression of ROR2 in both tumor and stroma. CONCLUSION: ROR1 and ROR2 are expressed in tumor-associated stroma in all histological subtypes of ovarian cancer and hold potential as therapeutic targets which may disrupt tumor and stroma interactions.  相似文献   

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The Azotobacter vinelandii mannuronan C-5 epimerases AlgE1-7 can be used to improve the properties of the commercially important polysaccharide alginate that is widely used in a variety of products, such as food and pharmaceuticals. Since lactic acid bacteria are generally regarded as safe, they are attractive candidates for production of the epimerases. A. vinelandii genes are GC-rich, in contrast to those of lactic acid bacteria, but we show here that significant expression levels of the epimerase AlgE6 can be obtained in Lactococcus lactis using the nisin-controlled expression system. A 1200-fold induction ratio was obtained resulting in an epimerase activity of 23900 dpm mg(-1) h(-1), using a tritiated alginate substrate. The epimerase was detected by Western blotting and nuclear magnetic resonance spectroscopy analysis of its reaction product showed that the enzyme displayed catalytic properties similar to those produced in Escherichia coli.  相似文献   

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Abstract: Using guanine nucleotides, pertussis toxin, and specific antisera against the COOH-terminals of the α-subunits of Gi1/2, Gi3, and Go, the binding and biological response of the Y2 receptor (Y2R) for peptide YY (PYY) was probed in SMS-KAN neuroblastoma cells. The specific binding of radiolabeled PYY exhibited a single apparent dissociation constant, K D = 76 p M for intact cells and K D = 906 p M for permeabilized cells. However, other data suggested existence of multiple receptor affinity states. A shift in K D and a decrease in apparent number of binding sites ( B max) was observed in permeabilized cells when incubated with guanine nucleotides. By contrast, in membrane preparations guanine nucleotides induced only a decrease in B max. In intact cells, agonist exposure inhibited the intracellular accumulation of forskolin-stimulated cyclic AMP by 80% (IC50 = 420 n M ) compared with 94% inhibition (IC50 = 380 n M ) in permeabilized cells. In permeabilized cells, preincubation with antisera against αi1/2 and αi3 blocked the functional response of PYY, with anti-αi3 being the most potent; whereas anti-αo failed to affect the cyclic AMP levels. These results suggest that permeabilized SMS-KAN cells serve as a good model system for analysis of Y2R binding kinetics and functional response and that the Y2R interacts directly with several different Gis (but not Go).  相似文献   

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Low voltage-activated, rapidly inactivating T-type Ca2+ channels are found in a variety of cells, where they regulate electrical activity and Ca2+ entry. In whole-cell patch-clamp recordings from mouse spermatogenic cells, trace element copper (Cu2+) inhibited T-type Ca2+ current (I T-Ca) with IC50 of 12.06 μM. Inhibition of I T-Ca by Cu2+ was concentration-dependent and mildly voltage-dependent. When voltage stepped to −20 mV, Cu2+ (10 μM) inhibited I T-Ca by 49.6 ± 4.1%. Inhibition of I T-Ca by Cu2+ was accompanied by a shift of −2.23 mV in the voltage dependence of steady-state inactivation. Cu2+ upshifted the current–voltage (I-V) curve. To know the change of the gating kinetics of T-type Ca2+ channels, we analyzed the effect of Cu2+ on activation, inactivation, deactivation and reactivation of T-type Ca2+ channels. Since T-type Ca2+ channels are a key component in capacitation and the acrosome reaction, our data suggest that Cu2+ can affect male reproductive function through T-type Ca2+ channels as a preconception contraceptive material.  相似文献   

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The P2X(7) gene is important for the innate immune response but known polymorphisms do not explain all subjects with loss of P2X(7) function. A splice site mutation (g-->t) was found at position +1 of the first intron of the P2X(7) gene in 7 of 336 Caucasians and 1 of 39 subjects of Indian ethnicity. All eight subjects were heterozygous for the uncommon 1513A-->C polymorphism of the P2X(7) gene. RT-PCR and sequencing showed the splice site mutation was on the 1513C allele in the Caucasians and on the 1513A allele in the Indian subject. The splice site mutation is an inherited polymorphism and gives rise to a P2X(7) null allele in 1-2% of the Caucasian population.  相似文献   

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Inhibitory and stimulatory adenosine receptors have been identified and characterized in both membranes and intact rat C6 glioma cells. In membranes, saturation experiment performed with [3H]DPCPX, selective A1R antagonist, revealed a single binding site with a K D = 9.4 ± 1.4 nM and B max = 62.7 ± 8.6 fmol/mg protein. Binding of [3H]DPCPX in intact cell revealed a K D = 17.7 ± 1.3 nM and B max = 567.1 ± 26.5 fmol/mg protein. On the other hand, [3H]ZM241385 binding experiments revealed a single binding site population of receptors with K D = 16.5 ± 1.3 nM and B max = 358.9 ± 52.4 fmol/mg protein in intact cells, and K D = 4.7 ± 0.6 nM and B max = 74.3 ± 7.9 fmol/mg protein in plasma membranes, suggesting the presence of A2A receptor in C6 cells. A1, A2A, A2B and A3 adenosine receptors were detected by Western-blotting and immunocytochemistry, and their mRNAs quantified by real time PCR assays. Giα and Gsα proteins were also detected by Western-blotting and RT-PCR assays. Furthermore, selective A1R agonists inhibited forskolin- and GTP-stimulated adenylyl cyclase activity and CGS 21680 and NECA stimulated this enzymatic activity in C6 cells. These results suggest that C6 glioma cells endogenously express A1 and A2 receptors functionally coupled to adenylyl cyclase inhibition and stimulation, respectively, and suggest these cells as a model to study the role of adenosine receptors in tumoral cells.  相似文献   

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Somatostatin released from capsaicin-sensitive sensory nerves of the lung during endotoxin-induced murine pneumonitis inhibits inflammation and hyperresponsiveness, presumably via somatostatin receptor subtype 4 (sst4). The goal of the present study was to identify sst4 receptors in mouse and human lungs and to reveal its inflammation-induced alterations with real-time quantitative PCR, Western blot, and immunohistochemistry. In non-inflamed mouse and human lungs, mRNA expression and immunolocalization of sst4 are very similar. They are present on bronchial epithelial, vascular endothelial, and smooth-muscle cells. The sst4 receptor protein in the mouse lung significantly increases 24 hr after intranasal endotoxin administration as well as in response to 3 months of whole-body cigarette smoke exposure, owing to the infiltrating sst4-positivite mononuclear cells and neutrophils. In the chronically inflamed human lung, the large number of activated macrophages markedly elevate sst4 mRNA levels, although there is no change in acute purulent pneumonia, in which granulocytes accumulate. Despite mouse granulocytes, human neutrophils do not show sst4 immunopositivity. We provide the first evidence for the expression, localization, and inflammation-induced alterations of sst4 receptors in murine and human lungs. Inasmuch as tissue distribution of this receptor is highly similar, extrapolation of murine experimental results to human conditions might be possible. (J Histochem Cytochem 57:1127–1137, 2009)  相似文献   

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Previous measurements with CsF pipette solutions using whole-cell patch-clamp techniques in dissociated rat olfactory receptor neurons (ORNs) indicated that the sodium currents had very negative inactivation characteristics with the implication that the cell resting potential must also normally have a very negative value. This study supports the conclusions that such an effect was real and not dependent on either the nature of the pipette anions or the recording situation previously used. For all pipette solutions, sodium currents showed a threshold activation ≈−80 mV and half-maximal activation voltages ≈−55 with half-inactivation potential ≤−100 mV, without being significantly affected by the replacement of F by other pipette anions (H2PO 4 and acetate) or the addition of nucleotides and glutathione (which did cause a very slight positive shift). F, followed by H2PO 4 and to a much lesser extent by acetate, was the most favorable pipette anion for obtaining good seals and whole-cell sodium currents in these extremely small ORNs. These results implied that resting potentials, for viable responsive cells, should be more negative than about −90 mV, as supported by the observation that action potentials could only be evoked from holding potentials more negative than −90 mV. Received: 23 December 1999/Revised: 2 March 2000  相似文献   

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Abstract: With the use of the single-cell polymerase chain reaction (PCR), the GABAA receptor subunit mRNA content was analyzed in granule and Purkinje neurons from rat cerebellar slices. We used an experimental protocol to assess simultaneously the presence of two subunits in each cell while electrophysiological recordings were performed with the whole-cell patch-clamp technique. Based on a computer alignment of the nucleotide sequence corresponding to α1 and α6 GABAA receptor subunits, homologous regions were identified that allowed coamplification of both mRNAs using a single primer combination. The presence of selective restriction sites within the targeted templates allowed us to identify which receptor subunit mRNAs were coamplified by performing restriction enzyme-mediated cleavage of the amplification products. In all Purkinje neurons assayed, α1 subunit mRNA but not α6 mRNA was detected. In contrast, among individual granule neurons we found a heterogeneous distribution of the mRNA for the α1 and α6 GABAA receptor subunits. A comparison of the results of the PCR amplification and the analysis of GABA-mediated inhibitory synaptic currents does not allow us to identify kinetic characteristics of synaptic currents that clearly correlate with the presence or the absence of α6 subunit mRNA.  相似文献   

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Okuda H  Miyata S  Mori Y  Tohyama M 《FEBS letters》2007,581(24):4754-4760
The Drosophila planar cell polarity (PCP) gene prickle has been previously indicated as one of the regulators of gastrulation in the early embryonic stage. However, the functional role of prickle in the brain in particular is not known. We first indicated that mouse Prickle1 and Prickle2 are continually expressed in the brain throughout the embryonic stages and are observed to be specifically expressed in the postmitotic neurons. Furthermore, Prickle1 or Prickle2 depletion effectively decreases the neurite outgrowth levels of mouse neuroblastoma Neuro2a cells. These results indicate that mouse Prickle1 and Prickle2 possibly regulate positive neurite formation during brain development.  相似文献   

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