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91.
Manuj Tandon Joseph M. Salamoun Evan J. Carder Elisa Farber Shuping Xu Fan Deng Hua Tang Peter Wipf Q. Jane Wang 《PloS one》2015,10(3)
Protein kinase D (PKD) has been implicated in many aspects of tumorigenesis and progression, and is an emerging molecular target for the development of anticancer therapy. Despite recent advancement in the development of potent and selective PKD small molecule inhibitors, the availability of in vivo active PKD inhibitors remains sparse. In this study, we describe the discovery of a novel PKD small molecule inhibitor, SD-208, from a targeted kinase inhibitor library screen, and the synthesis of a series of analogs to probe the structure-activity relationship (SAR) vs. PKD1. SD-208 displayed a narrow SAR profile, was an ATP-competitive pan-PKD inhibitor with low nanomolar potency and was cell active. Targeted inhibition of PKD by SD-208 resulted in potent inhibition of cell proliferation, an effect that could be reversed by overexpressed PKD1 or PKD3. SD-208 also blocked prostate cancer cell survival and invasion, and arrested cells in the G2/M phase of the cell cycle. Mechanistically, SD-208-induced G2/M arrest was accompanied by an increase in levels of p21 in DU145 and PC3 cells as well as elevated phosphorylation of Cdc2 and Cdc25C in DU145 cells. Most importantly, SD-208 given orally for 24 days significantly abrogated the growth of PC3 subcutaneous tumor xenografts in nude mice, which was accompanied by reduced proliferation and increased apoptosis and decreased expression of PKD biomarkers including survivin and Bcl-xL. Our study has identified SD-208 as a novel efficacious PKD small molecule inhibitor, demonstrating the therapeutic potential of targeted inhibition of PKD for prostate cancer treatment. 相似文献
92.
Melanoma is an aggressive skin malignancy with a high mortality rate; however, successful treatment remains a clinical challenge. Ivermectin, a broad-spectrum antiparasitic drug, has recently been characterized as a potential anticancer agent due to its observed antitumor effects. However, the molecular mechanisms of ivermectin remain poorly understood. In the current study, we tested the involvement of autophagy in the ivermectin mechanism of action in human melanoma cells. We exposed SK-MEL-28 cells to different concentrations of ivermectin (2.5, 5, and 10 μM) for 24 hours. Here, ivermectin-induced apoptosis, as evidenced by the upregulation of cleaved poly (ADP-ribose) polymerase, BAX expression, and caspase-3 activity and downregulation of BCL-2 expression. In line with the apoptosis response, ivermectin triggered autophagy. Pharmacological or genetic inhibition of autophagy further sensitized SK-MEL-28 cells to ivermectin-induced apoptosis. Mechanistically, ivermectin-induced TFE3(Ser321) dephosphorylation, activated TFE3 nuclear translocation and increased TFE3 reporter activity, which contributed to lysosomal biogenesis and the expression of autophagy-related genes, and subsequently, initiated autophagy in SK-MEL-28 cells. Moreover, N-acetyl-cysteine, an reactive oxygen species (ROS) scavenger, abrogated the effects of ivermectin on TFE3-dependent autophagy. Taken together, we demonstrated that ivermectin increases TFE3-dependent autophagy through ROS signaling pathways in human melanoma cells and that inhibiting autophagy enhances ivermectin-induced apoptosis in human melanoma cells. 相似文献
93.
94.
Eco-physiological responses of the declining population Spartina anglica to N and P fertilizer addition 总被引:2,自引:0,他引:2 下载免费PDF全文
Nitrogen and phosphorus are both important life elements. N, P and combined N-P fertilizers were added to the declining population Spartina anglica Hubbard in coastal China. Some growth parameters and eco-physiological responses of S. anglica to different fertilizer treatments (N, P and combined N-P fertilizer addition with high, medium and low levels, respectively) were measured. The fertilizer addition had a highly significant effect on the dynamics of its height-growth, number of leaves, number of roots and total biomass. Only N addition had a significant effect on leaf area and leaf thickness in all fertilizer treatments. On the dynamics of its height-growth, the effect of N addition was the most apparent, and the effect of N-P addition was not greater than those of N and P addition separately. The photosynthesis rate was enhanced and the yield was the highest with the highest N, the highest N-P and the medium P addition. The rates were higher than those of CK by 19.08 μmol·m?2·s?1, 15.47 μmol·m?2·s?1 and 11.23 μmol·m?2·s?1, respectively. The activity of SOD and POD increased with the treatments after freshwater stress for 14 days. Effects of medium N and P addition were significant for SOD activity. However, POD activity was significantly higher with the treatment of higher N and higher N-P addition. In a word, fertilizer addition improved the growth of the declining population S. anglica. The results indicated that the decline of S. anglica was correlated with the nutriment deficiency in soil, especially with the lack of N. 相似文献
95.
睫状神经营养因子对大鼠去神经骨骼肌的营养作用 总被引:6,自引:0,他引:6
目的:了解睫状神经营养因子(CNTF)对去神经引起的肌肉萎缩的治疗作用。方法:离断SD大鼠一侧坐骨神经,连续给予CNTF20d,观察肌肉湿重、蛋白含量、肌纤维横截面积、收缩性能和残肢程度。结果:①给予0.2mg/kg的CNTF,可使损务侧肌纤维横截面积增加35%,肌肉湿重增加38%,胫前肌总蛋白含量增加24%,腓长肌强直收缩强度提高40%,显著改善肢残程度;②0.2mg/kg的CNTF作用明显强于0.05mg/kg的CNTF;③此目鱼肌(慢肌)比伸趾长肌(快肌)对CNTF更敏感。结论:CNTF能显著改善成年大鼠坐骨神经离断后骨骼肌的萎缩和功能丧失,该效应的强弱与用药剂量和肌肉类型有关。 相似文献
96.
Bt群体信号应答因子nprR基因的缺失对cry1Ac基因表达的影响 总被引:1,自引:0,他引:1
摘要:【目的】研究群体信号应答蛋白编码基因nprR在苏云金芽胞杆菌(Bacillus thuringiensis,Bt)HD-73菌株晶体蛋白形成过程中的作用。【方法】通过同源重组,构建了HD-73 nprR基因缺失突变菌株HD73(ΔnprR )。利用启动子-lacZ融合、SDS-PAGE方法,测定不同培养基中nprR基因转录活性及nprR基因缺失对cry1Ac转录及表达的影响。【结果】启动子转录活性分析表明,在LB和SSM培养基中nprR基因从对数期结束(T0)开始表达,稳定期持续表达。在LB培养基中,nprR基因的缺失使cry1Ac基因在生长过渡期和稳定期前期转录活性显著提高,同时HD73(ΔnprR )菌株Cry蛋白生成量也明显高于出发菌株HD-73,但是在芽胞形成释放后,Cry蛋白的表达没有明显的区别。【结论】在丰富培养基中苏云金芽胞杆菌nprR基因的缺失在生长过渡期和稳定期前期能够提高cry1Ac基因转录和表达,从而缩短了cry基因表达时间,并且Cry蛋白总产量与出发菌株相当。 相似文献
97.
Lei W Feng XH Deng WB Ni H Zhang ZR Jia B Yang XL Wang TS Liu JL Su RW Liang XH Qi QR Yang ZM 《The Journal of biological chemistry》2012,287(19):15174-15192
Embryo implantation into the maternal uterus is a crucial step for the successful establishment of mammalian pregnancy. Following the attachment of embryo to the uterine luminal epithelium, uterine stromal cells undergo steroid hormone-dependent decidualization, which is characterized by stromal cell proliferation and differentiation. The mechanisms underlying steroid hormone-induced stromal cell proliferation and differentiation during decidualization are still poorly understood. Ribonucleotide reductase, consisting of two subunits (RRM1 and RRM2), is a rate-limiting enzyme in deoxynucleotide production for DNA synthesis and plays an important role in cell proliferation and tumorgenicity. Based on our microarray analysis, Rrm2 expression was significantly higher at implantation sites compared with interimplantation sites in mouse uterus. However, the expression, regulation, and function of RRM2 in mouse uterus during embryo implantation and decidualization are still unknown. Here we show that although both RRM1 and RRM2 expression are markedly induced in mouse uterine stromal cells undergoing decidualization, only RRM2 is regulated by progesterone, a key regulator of decidualization. Further studies showed that the induction of progesterone on RRM2 expression in stromal cells is mediated by the AKT/c-MYC pathway. RRM2 can also be induced by replication stress and DNA damage during decidualization through the ATR/ATM-CHK1-E2F1 pathway. The weight of implantation sites and deciduoma was effectively reduced by specific inhibitors for RRM2. The expression of decidual/trophoblast prolactin-related protein (Dtprp), a reliable marker for decidualization in mice, was significantly reduced in deciduoma and steroid-induced decidual cells after HU treatment. Therefore, RRM2 may be an important effector of progesterone signaling to induce cell proliferation and decidualization in mouse uterus. 相似文献
98.
Vascular basement membrane-derived multifunctional peptide, a novel inhibitor of angiogenesis and tumor growth 总被引:8,自引:0,他引:8
Vascular basement membrane-derived multifunctional peptide(VBMDMP)gene(fusion geneof the human immunoglobulin G3 upper hinge region and two tumstatin-derived fragments)obtained bychemical synthesis was cloned into vector pUC19,and introduced into the expression vector pGEX-4T-1 toconstruct a prokaryotic expression vector pGEX-4T-1-VBMDMP.Recombinant VBMDMP produced inEscherichia coli has been shown to have significant activity of antitumor growth and antimetastasis inLewis lung carcinoma transplanted into mouse C57B1/6.In the present study,we have studied the ability ofrVBMDMP to inhibit endothelial cell tube formation and proliferation,to induce apoptosis in vitro,and tosuppress tumor growth in vivo.The experimental results showed that rVBMDMP potently inhibited prolif-eration of human endothelial(HUVEC-12)cells and human colon cancer(SW480)cells in vitro,with noinhibition of proliferation in Chinese hamster ovary(CHO-K1)cells.rVBMDMP also significantly inhibitedhuman endothelial cell tube formation and suppressed tumor growth of SW480 cells in a mouse xenograftmodel.These results suggest that rVBMDMP is a powerful therapeutic agent for suppressing angiogenesisand tumor growth. 相似文献
99.
大黄醇提液抗家兔实验性高脂血症及脂肪肝的实验研究 总被引:11,自引:0,他引:11
目的:检验大黄醇提液抗家兔实验性高脂血症及脂肪肝的影响。方法:将30只雄性健康白兔随机分为5组(n=6):对照组给予基础饲料;模型组给予高脂饲料;三个大黄组给予高脂饲料同时分别灌胃不同药量的大黄醇提液。实验过程中进行一般性指标观测,检测不同阶段五组家兔血脂水平,检测脂肪肝病变程度。结果:大黄醇提液具有降低血清甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C),升高高密度脂蛋白胆固醇(HDL-C),降低肝细胞脂肪变性的作用。并且大黄醇提液的以上作用存在一定的量效关系。结论:大黄醇提液可降低动脉粥样硬化兔模型的血脂水平、降低脂肪肝的发生发展。 相似文献
100.