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61.
Patrizia Marchese Maria Lombardi Maria Elena Mantione Domenico Baccellieri David Ferrara Roberto Chiesa Ottavio Alfieri Chiara Foglieni 《International journal of molecular sciences》2021,22(8)
Atherothrombosis exposes vascular components to blood. Currently, new antithrombotic therapies are emerging. Herein we investigated thrombogenesis of human arteries with/without atherosclerosis, and the interaction of coagulation and vascular components, we and explored the anti-thrombogenic efficacy of blockade of the P2X purinoceptor 7 (P2X7). A confocal blood flow videomicroscopy system was performed on cryosections of internal mammary artery (IMA) or carotid plaque (CPL) determining/localizing platelets and fibrin. Blood from healthy donors elicited thrombi over arterial layers. Confocal microscopy associated thrombus with tissue presence of collagen type I, laminin, fibrin(ogen) and tissue factor (TF). The addition of antibodies blocking TF (aTF) or factor XI (aFXI) to blood significantly reduced fibrin deposition, variable platelet aggregation and aTF + aFXI almost abolished thrombus formation, showing synergy between coagulation pathways. A scarce effect of aTF over sub-endothelial regions, more abundant in tissue TF and bundles of laminin and collagen type I than deep intima, may suggest tissue thrombogenicity as molecular structure-related. Consistently with TF-related vascular function and expression of P2X7, the sections from CPL but not IMA tissue cultures pre-treated with the P2X7 antagonist A740003 demonstrated poor thrombogenesis in flow experiments. These data hint to local targeting studies on P2X7 modulation for atherothrombosis prevention/therapy. 相似文献
62.
Olga A. Sukocheva Dong Gui Hu Robyn Meech Anupam Bishayee 《International journal of molecular sciences》2021,22(9)
Breast cancer MCF-7 cell-line-derived mammospheres were shown to be enriched in cells with a CD44+/CD24– surface profile, consistent with breast cancer stem cells (BCSC). These BCSC were previously reported to express key sphingolipid signaling effectors, including pro-oncogenic sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate receptor 3 (S1P3). In this study, we explored intracellular trafficking and localization of SphK1 and S1P3 in parental MCF-7 cells, and MCF-7 derived BCSC-enriched mammospheres treated with growth- or apoptosis-stimulating agents. Intracellular trafficking and localization were assessed using confocal microscopy and cell fractionation, while CD44+/CD24- marker status was confirmed by flow cytometry. Mammospheres expressed significantly higher levels of S1P3 compared to parental MCF-7 cells (p < 0.01). Growth-promoting agents (S1P and estrogen) induced SphK1 and S1P3 translocation from cytoplasm to nuclei, which may facilitate the involvement of SphK1 and S1P3 in gene regulation. In contrast, pro-apoptotic cytokine tumor necrosis factor α (TNFα)-treated MCF-7 cells demonstrated increased apoptosis and no nuclear localization of SphK1 and S1P3, suggesting that TNFα can inhibit nuclear translocation of SphK1 and S1P3. TNFα inhibited mammosphere formation and induced S1P3 internalization and degradation. No nuclear translocation of S1P3 was detected in TNFα-stimulated mammospheres. Notably, SphK1 and S1P3 expression and localization were highly heterogenous in mammospheres, suggesting the potential for a large variety of responses. The findings provide further insights into the understanding of sphingolipid signaling and intracellular trafficking in BCs. Our data indicates that the inhibition of SphK1 and S1P3 nuclear translocation represents a novel method to prevent BCSCs proliferation. 相似文献
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64.
Ann-Kathrin Eichelmann George C. Mayne Karen Chiam Steven L. Due Isabell Bastian Frederike Butz Tingting Wang Pamela J. Sykes Nicholas J. Clemons David S. Liu Michael Z. Michael Christos S. Karapetis Richard Hummel David I. Watson Damian J. Hussey 《International journal of molecular sciences》2021,22(11)
TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53. 相似文献
65.
Yurii S. Borovikov Daria D. Andreeva Stanislava V. Avrova Vladimir V. Sirenko Armen O. Simonyan Charles S. Redwood Olga E. Karpicheva 《International journal of molecular sciences》2021,22(12)
Point mutations in the genes encoding the skeletal muscle isoforms of tropomyosin can cause a range of muscle diseases. The amino acid substitution of Arg for Pro residue in the 90th position (R90P) in γ-tropomyosin (Tpm3.12) is associated with congenital fiber type disproportion and muscle weakness. The molecular mechanisms underlying muscle dysfunction in this disease remain unclear. Here, we observed that this mutation causes an abnormally high Ca2+-sensitivity of myofilaments in vitro and in muscle fibers. To determine the critical conformational changes that myosin, actin, and tropomyosin undergo during the ATPase cycle and the alterations in these changes caused by R90P replacement in Tpm3.12, we used polarized fluorimetry. It was shown that the R90P mutation inhibits the ability of tropomyosin to shift towards the outer domains of actin, which is accompanied by the almost complete depression of troponin’s ability to switch actin monomers off and to reduce the amount of the myosin heads weakly bound to F-actin at a low Ca2+. These changes in the behavior of tropomyosin and the troponin–tropomyosin complex, as well as in the balance of strongly and weakly bound myosin heads in the ATPase cycle may underlie the occurrence of both abnormally high Ca2+-sensitivity and muscle weakness. BDM, an inhibitor of myosin ATPase activity, and W7, a troponin C antagonist, restore the ability of tropomyosin for Ca2+-dependent movement and the ability of the troponin–tropomyosin complex to switch actin monomers off, demonstrating a weakening of the damaging effect of the R90P mutation on muscle contractility. 相似文献
66.
67.
FAN Yongnian TANG Baozhen QIAO Guiwen Institute of Metal Research Academia Sinica Shenyang China Associate Professor Institute of Metal Research Academia Sinica Shenyang China 《金属学报(英文版)》1993,6(7):21-24
Interfaces and surfaces of YBa_2Cu_3O_(7-x)(YBCO)-Ag have been studied by SEM-EDXand AES.No effect of Ag on 123 structure in X-ray diffraction pattern was observedfor 0.4 mol Ag doped YBCO.AES analysis indicated that Ag segregated on surfaceof YBCO and resulted in decrease of YBCO-metal lead resistance.In addition,solutionand segregation of Ag as elemental state were often appeared on interfaces and surfacesof high temperature annealed YBCO,whether elemental Ag or compound Ag_2O andAgNO_3 adopted as doping material. 相似文献
68.
69.
使用MEVVA强流金属源离子注入机对Ti6Al7Nb合金表面注入能量为80keV、剂量分别为0.5×1017,1×1017,2×1017,4×1017ions/cm2的铜离子,计算得到铜离子饱和注入量为2.15×1017ions/cm2。研究了注入的铜离子对Ti6Al7Nb合金腐蚀性能、显微硬度和磨损行为的影响,采用覆膜法研究了铜离子注入后试样对金黄色葡萄球菌的抗菌性能,并分析了注入剂量与抗菌性能的关系。结果表明,Ti6Al7Nb合金的硬度和耐磨性随着注入剂量的增加而提高,点蚀电位随着注入剂量的提高而下降。抗菌试验显示当注入量达到饱和注入量时,试样的抗菌率达到99%以上。 相似文献
70.
LD7铝合金时效工艺的研究 总被引:5,自引:3,他引:5
通过试验系统地研究了LD7铝合金的单级和两级时效工艺。结果表明,与传统的单级时效相比,两级时效在不降低室温强度,硬度的前提下,可显著提高合金的电导率及高温性能。 相似文献