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| 1 | 五环三萜类化合物的口服吸收与代谢研究进展显示文摘五环三萜类化合物在自然界中分布广泛、资源丰富,我国多种传统中草药如甘草、柴胡、远志、人参、三七、白头翁和积雪草等皆含有五环三萜类化合物,且大量研究表明该类化合物是上述中草药的有效成分之一。国内外研究者发现五环三萜类化合物具有多种优良的药理活性,如抗肿瘤、抗糖尿病、抗炎、抗菌和抗病毒等,但由于其口服生物利用度偏低,极大地影响了进一步的开发及在临床上的应用。药物的吸收与代谢对生物利用度和药效的影响很大。因此,就近年来国内外有关五环三萜类化合物的口服吸收特征以及体内外代谢途径研究进行综述,以期对该类化合物的进一步研究及开发利用提供参考。 | 班玉娟 陈瑞 张宇 张丽 刘婉霞 朱高峰 汤磊 | 2021 | 化学试剂2021，43，7： | 7 |
| 2 | 乌苏烷型三萜类成分及药理活性最新研究进展显示文摘乌苏烷型三萜大多是乌苏酸衍生物,该类化合物主要以游离或糖苷的形式存在于金樱根、四季青、积雪草等植物中,具有抗肿瘤、抗氧化、抗炎、抑菌等药理活性,广泛应用于医药和化妆品领域。查阅近五年来国内外有关文献,对天然产物中乌苏烷型三萜类化学成分及药理活性方面的最新研究进行综述,以期为更好地开发利用该类化学成分提供参考依据。 | 邓巧玉 江姗 陈誉丹 陈兴广 梁旭 袁经权 | 2020 | 现代中药研究与实践2020，34，6： | 5 |
| 3 | CDDO-Me对三阴性乳腺癌细胞泛素特异性蛋白酶2a活性及细胞增殖的抑制作用显示文摘目的·在三阴性乳腺癌(triple negative breast cancer,TNBC)细胞中研究筛选得到的泛素特异性蛋白酶2a(ubiquitin-specific protease 2a,USP2a)抑制剂甲基巴多索隆(bardoxolone methyl,CDDO-Me)对USP2a活性及细胞增殖的影响。方法·利用泛素特异性蛋白酶抑制剂筛选系统筛选得到USP2a抑制剂CDDO-Me,采用分子对接分析技术预测CDDO-Me与USP2a的结合情况,采用细胞热迁移实验(cellular thermal shift assay,CETSA)检测CDDO-Me与3种TNBC细胞株内USP2a蛋白的结合情况。通过Western blotting检测USP2a的底物β连环素(β-catenin)和肿瘤坏死因子受体相关因子6(tumor necrosis factor receptor-associated factor 6,TRAF6)蛋白水平以及凋亡相关蛋白胱天蛋白酶3(caspase3)和聚腺苷二磷酸核糖聚合酶1[poly(ADP-ribose)polymerase1,PARP1]的变化。利用细胞活性检测试剂盒8(cell counting kit-8,CCK8)检测CDDO-Me对TNBC细胞增殖的影响。MDA-MB-468细胞瞬时转染pLVX(pLVX组)或pLVX-USP2a(pLVX-USP2a组)质粒,经CDDO-Me处理后,采用Western blotting检测β-catenin和TRAF6的蛋白水平,流式细胞术检测细胞周期以及台盼蓝拒染法检测活细胞数。结果·CDDO-Me在体外可以抑制USP2a活性,50%抑制浓度为3.84μmol/L。分子对接分析结果显示,CDDO-Me可以和USP2a的His456残基之间形成氢键,和Phe409、Tyr514残基之间具有疏水相互作用。CETSA实验结果显示,CDDO-Me能够和3种TNBC细胞中的USP2a蛋白结合。Western blotting结果显示,CDDO-Me可以下调USP2a底物β-catenin和TRAF6的蛋白水平,而相同浓度的CDDO-Me处理USP2a过表达的MDA-MB-468细胞,发现β-catenin和TRAF6蛋白水平未出现明显降低。CDDO-Me呈剂量依赖性抑制TNBC细胞的增殖,使细胞发生caspase3活化和PARP1的剪切并且导致细胞出现S期和G2/M期阻滞。与pLVX组相比,pLVX-USP2a组活细胞数目更多,细胞也未出现周期阻滞。结论·CDDO-Me可以抑制TNBC细胞中USP2a的活性,并且抑制TNBC细胞的增殖,诱导其凋亡。 | 季艳杰 罗浩 蔡海燕 刘欣宇 金诗佳 粟深月 徐含章 雷虎 吴英理 | 2021 | 上海交通大学学报(医学版)2021，41，8： | 1 |
| 4 | Wu-5, a novel USP10 inhibitor, enhances crenolanib-induced FLT3-ITD-positive AML cell death via inhibiting FLT3 and AMPK pathways显示文摘The kinase FLT3 internal tandem duplication(FLT3-ITD)is related to poor clinical outcomes of acute myeloid leukemia(AML).FLT3 inhibitors have provided novel strategies for the treatment of FLT3-ITD-positive AML.But they are limited by rapid development of acquired resistance and refractory in monotherapy.Recent evidence shows that inducing the degradation of FLT3-mutated protein is an attractive strategy for the treatment of FLT3-ITD-positive AML,especially those with FLT3 inhibitor resistance.In this study we identified Wu-5 as a novel USP10 inhibitor inducing the degradation of FLT3-mutated protein.We showed that Wu-5 selectively inhibited the viability of FLT3 inhibitor-sensitive(MV4-11,Molm13)and-resistant(MV4-11R)FLT3-ITD-positive AML cells with IC50 of 3.794,5.056,and 8.386μM,respectively.Wu-5(1−10μM)dose-dependently induced apoptosis of MV4-11,Molm13,and MV4-11R cells through the proteasome-mediated degradation of FLT3-ITD.We further demonstrated that Wu-5 directly interacted with and inactivated USP10,the deubiquitinase for FLT3-ITD in vitro(IC50 value=8.3μM)and in FLT3-ITD-positive AML cells.Overexpression of USP10 abrogated Wu-5-induced FLT3-ITD degradation and cell death.Also,the combined treatment of Wu-5 and crenolanib produced synergistic cell death in FLT3-ITD-positive cells via the reduction of both FLT3 and AMPKαproteins.In support of this,AMPKαinhibitor compound C synergistically enhanced the anti-leukemia effect of crenolanib,while AMPKαactivator metformin inhibited the anti-leukemia effect of crenolanib.In summary,we demonstrate that Wu-5,a novel USP10 inhibitor,can overcome FLT3 inhibitor resistance and synergistically enhance the anti-AML effect of crenolanib through targeting FLT3 and AMPKαpathway. | Miao Yu Zhi-xiao Fang Wei-wei Wang Ying Zhang Zhi-lei Bu Meng Liu Xin-hua Xiao Zi-lu Zhang Xing-ming Zhang Yang Cao Ying-ying Wang Hu Lei Han-zhang Xu Yun-zhao Wu Wei Liu Ying-li Wu | 2021 | Acta Pharmacologica Sinica2021，42，4： | 1 |
| 5 | USP7 deubiquitinates and stabilizes NOTCH1 in T-cell acute lymphoblastic leukemia显示文摘T-cell acute lymphoblastic leukemia(T-ALL)is a highly aggressive leukemia that is primarily caused by aberrant activation of the NOTCH1 signaling pathway.Recent studies have revealed that posttranslational modifications,such as ubiquitination,regulate NOTCH1 stability,activity,and localization.However,the specific deubiquitinase that affects NOTCH1 protein stability remains unestablished.Here,we report that ubiquitin-specific protease 7(USP7)can stabilize NOTCH1.USP7 deubiquitinated NOTCH1 in vivo and in vitro,whereas knockdown of USP7 increased the ubiquitination of NOTCH1.USP7 interacted with NOTCH1 protein in T-ALL cells,and the MATH and UBL domains of USP7 were responsible for this interaction.Depletion of USP7 significantly suppressed the proliferation of T-ALL cells in vitro and in vivo,accompanied by downregulation of the NOTCH1 protein level.Similarly,pharmacologic inhibition of USP7 led to apoptosis of T-ALL cells.More importantly,we found that USP7 was significantly upregulated in human T-ALL cell lines and patient samples,and a USP7 inhibitor exhibited cell cytotoxicity toward primary T-ALL cells,indicating the clinical relevance of these findings.Overall,our results demonstrate that USP7 is a novel deubiquitinase that stabilizes NOTCH1.Therefore,USP7 may be a promising therapeutic target in the currently incurable T-ALL. | Huizhuang Shan Xiangyun Li Xinhua Xiao Yuting Dai Jinyan Huang Junjun Song Meng Liu Li Yang Hu Lei Yin Tong Li Zhou Hanzhang Xu Yingli Wu | 2018 | Signal Transduction and Targeted Therapy2018，3，1： | 0 |
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