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1.
Zehua Li Ji Wu Xiuli Zhang Caiwen Ou Xinglong Zhong Yanting Chen Lihe Lu Hailin Liu Yining Li Xiaoyu Liu Bo Wu Yuxi Wang Pingzhen Yang Jianyun Yan Minsheng Chen 《The Journal of pathology》2019,249(4):461-471
Vascular calcification is prevalent in patients with chronic kidney disease (CKD) and a major risk factor of cardiovascular disease. Vascular calcification is now recognised as a biological process similar to bone formation involving osteogenic differentiation of vascular smooth muscle cells (VSMCs). Cell division cycle 42 (CDC42), a Rac1 family member GTPase, is essential for cartilage development during endochondral bone formation. However, whether CDC42 affects osteogenic differentiation of VSMCs and vascular calcification remains unknown. In the present study, we observed a significant increase in the expression of CDC42 both in rat VSMCs and in calcified arteries during vascular calcification. Alizarin red staining and calcium content assay revealed that adenovirus-mediated CDC42 overexpression led to an apparent VSMC calcification in the presence of calcifying medium, accompanied with up-regulation of bone-related molecules including RUNX2 and BMP2. By contrast, inhibition of CDC42 by ML141 significantly blocked calcification of VSMCs in vitro and aortic rings ex vivo. Moreover, ML141 markedly attenuated vascular calcification in rats with CKD. Furthermore, pharmacological inhibition of AKT signal was shown to block CDC42-induced VSMC calcification. These findings demonstrate for the first time that CDC42 contributes to vascular calcification through a mechanism involving AKT signalling; this uncovered a new function of CDC42 in regulating vascular calcification. This may provide a potential therapeutic target for the treatment of vascular calcification in the context of CKD. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
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Structure-based design and biological evaluation of novel mTOR inhibitors as potential anti-cervical agents
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Peili Jiao Yiyan Li Xing Wu Yuxi Wang Beibei Mao Hongwei Jin Lihe Zhang Liangren Zhang Zhenming Liu 《中国药学》2020,29(9):603-616
The mammalian target of rapamycin (mTOR) is a critical component of the PI3K-AKT signaling pathway. It is highly activated in cervical cancer, which continues to pose an important clinical challenge with an urgent need for new and improved therapeutic approaches. Herein, we describe the structure-based drug discovery and biological evaluation of a series of mTOR kinase inhibitors as potential anti-cervical cancer agents. The results of enzymatic activity assays supported C3 as a potential mTOR inhibitor, which exhibited high inhibitory activity with an IC50 of 1.57 μM. Molecular docking and dynamics simulation were conducted to predict the binding patterns, suggesting relationships between structure and activity. The anti-proliferative assay against diverse cancer cell lines was displayed subsequently, revealing that C3 exhibited significant proliferation inhibition against cervical cancer cell HeLa (IC50 = 0.38 μM) compared with other cell lines. Moreover, C3 could effectively reduce the expression of phospho-ribosomal S6 protein (p-S6) in HeLa cells in a dose-dependent manner. Noteworthily, mTOR signaling and other cellular pathways might contribute to the significant effect of C3 against cervical cancer simultaneously. These data indicated that C3 represented a good lead molecule for further development as a therapeutic agent for cervical cancer treatment. 相似文献
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目的研究β-catenin异常表达、c-myc和Cyclin D1的高表达与胰腺癌发生、浸润、转移的关系。方法应用免疫组织化学方法检测5例正常胰腺组织和40例胰腺癌及13例相应癌旁组织中β-catenm、c-myc和Cyclin D1的表达。结果 5例正常胰腺组织及13例胰腺癌旁组织中β-catenin为正常表达,c-myc和Cyclin D1阴性表达,40例胰腺癌组织中25例有β-catenin的异常表达(25/40,62.5%),20例(20/40,50%)有c-myc的高表达,23例(23/40,57.5%)有Cyclin D1的高表达。β-catenin的异常表达率与淋巴结转移、浸润及病理分级相关(P<0.05),c-myc和Cyclin D1的高表达与分化程度,浸润,转移及病理分级无关,β-catenin的异常表达与c-myc的阳性表达不相关,而与Cyclin D1的阳性表达相关。结论β-catenin的异常表达可能主要是通过激活Cyclin D1引起细胞增殖,导致肿瘤的发生。 相似文献
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Comparative Analysis of Pharmacophore Features and Quantitative Structure–Activity Relationships for CD38 Covalent and Non‐covalent Inhibitors
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Shuang Zhang Xiwen Xue Liangren Zhang Lihe Zhang Zhenming Liu 《Chemical biology & drug design》2015,86(6):1411-1424
In the past decade, the discovery, synthesis, and evaluation for hundreds of CD38 covalent and non‐covalent inhibitors has been reported sequentially by our group and partners; however, a systematic structure‐based guidance is still lacking for rational design of CD38 inhibitor. Here, we carried out a comparative analysis of pharmacophore features and quantitative structure–activity relationships for CD38 inhibitors. The results uncover that the essential interactions between key residues and covalent/non‐covalent CD38 inhibitors include (i) hydrogen bond and hydrophobic interactions with residues Glu226 and Trp125, (ii) electrostatic or hydrogen bond interaction with the positively charged residue Arg127 region, and (iii) the hydrophobic interaction with residue Trp189. For covalent inhibitors, besides the covalent effect with residue Glu226, the electrostatic interaction with residue Arg127 is also necessary, while another hydrogen/non‐bonded interaction with residues Trp125 and Trp189 can also be detected. By means of the SYBYL multifit alignment function, the best CoMFA and CoMSIA with CD38 covalent inhibitors presented cross‐validated correlation coefficient values (q2) of 0.564 and 0.571, and non‐cross‐validated values (r2) of 0.967 and 0.971, respectively. The CD38 non‐covalent inhibitors can be classified into five groups according to their chemical scaffolds, and the residues Glu226, Trp189, and Trp125 are indispensable for those non‐covalent inhibitors binding to CD38, while the residues Ser126, Arg127, Asp155, Thr221, and Phe222 are also important. The best CoMFA and CoMSIA with the F12 analogues presented cross‐validated correlation coefficient values (q2) of 0.469 and 0.454, and non‐cross‐validated values (r2) of 0.814 and 0.819, respectively. 相似文献
7.
Xinyang Zhou Shuhe Wang Yuejie Zhu Yufei Pan Lihe Zhang Zhenjun Yang 《Medicinal research reviews》2020,40(4):1178-1199
With the rapid development of synthetic technology and biological technology, many nucleic acid-based drugs have entered the clinical trials. However, their inherent disabilities in actively and efficiently penetrating cell membranes still severely restrict their further application. The main drawback of cationic lipids, which have been widely used as nonviral vectors of nucleic acids, is their high cytotoxicity. A series of nucleoside-based or nucleotide-based nucleolipids have been reported in recent years, due to their oligonucleotide delivery capacity and low toxicity in comparison with cationic lipids. Lipophilic prodrugs of nucleoside analogs have extremely similar structures with nucleolipid vectors and are thus helpful for improving the transmembrane ability. This review introduces the progress of nucleolipids and provides new strategies for improving the delivery efficiency of nucleic acid-based drugs, as well as lipophilic prodrugs of nucleosides or nucleotides for antiviral or anticancer therapies. 相似文献
8.
BRAF gene mutation is found in more than 60% of malignant melanomas, which are difficult to treat. In this study, a new tumor-targeting liposome was developed to deliver anti-BRAF siRNA (siBraf) for the treatment of melanomas. Nucleolin is overexpressed on the surface of cancer cells. AS1411, an aptamer showing specific binding to nucleolin, was conjugated to PEGylated cationic liposome as the targeting probe ASLP (AS1411–PEG-liposome). The ASLP/siRNA complex was formed through electrostatic interaction between ASLP and siRNA. The binding of AS1411 to the surface of PEGylated liposomes was confirmed by gel electrophoresis and capillary electrophoresis. Real-time PCR and Western blot analysis showed that ASLP/siBraf exhibited strong silencing activity of BRAF gene. The much higher accumulation of the siRNA in tumor cells comparing with normal cells indicated that ASLP displayed excellent tumor-targeting capability. Notably, ASLP/siBraf showed significant silencing activity in A375 tumor xenograft mice and inhibited the melanoma growth. These results suggested that the new nucleolin-targeted siRNA delivery system by AS1411 may have the potential for the treatment of melanoma. 相似文献
9.
目的 探讨电穿孔介导的基因治疗对下领骨牵引成骨过程中早期血管生成的影响.方法 32只新西兰大白兔随机分为4组:质粒+电穿孔组(A组),质粒组(B组),生理盐水+电穿孔组(C组),空白对照组(D组).各组动物分别于注射后1、3、7、14 d处死,取牵引区组织进行组织学检查、电镜观察、CD34免疫组织化学染色及微血管密度检测.结果 A、B组血管内皮细胞呈增殖活跃状态;C、D组多数血管内皮细胞部分呈现退变及凋亡早期改变.免疫组化染色发现,转染后第1天血管壁内皮细胞浆CD34表达较弱;第3、7、14天,牵引区肉芽组织血管内皮细胞均出现CD34阳性表达.A组CD34阳性表达较B组强,A、B组的CD34表达持续阳性且呈上升趋势;C、D组表达最弱,CD34阳性表达维持在第1天水平上平稳波动.结论 电穿孔介导的pIRES-hVEGF165-EGFP重组质粒体内转染能够促进牵引区早期微血管的生成,使局部血管增生、渗入,增加骨断端的血流量.对调节和促进骨的生长和修复过程具有重要作用. 相似文献
10.
目的 评价隆乳术治疗先天乳腺不发育、乳腺发育不良及胸大肌发育不良伴轻度鸡胸畸形临床效果.方法 对10例先天乳腺不发育、乳腺发育不良及胸大肌发育不良伴轻度鸡胸的女性行隆乳术.先在体表标出剥离范围及畸形部位,经双腋窝切口,直达皮下组织,向内分离至胸大肌外侧缘,于胸大肌后间隙,置入硅凝胶乳房假体.结果 10例于隆乳术后,随访1年,均未见发生局部感染、假体移位、心肺功能异常等并发症,前胸壁鸡胸畸形外观有明显改善.结论 应用隆乳术治疗先天性乳腺不发育、乳腺发育不良及胸大肌发育不良并伴有轻度鸡胸,操作方便、手术损伤小、效果满意.既美化乳房外观又掩饰了鸡胸畸形,具有双重手术效果,值得推广. 相似文献