Molecular Characterization of the ORF3 and S1 Genes of Porcine Epidemic Diarrhea Virus Non S-INDEL Strains in Seven Regions of China, 2015.
Molecular Characterization of the ORF3 and S1 Genes of Porcine Epidemic Diarrhea Virus Non S-INDEL Strains in Seven Regions of China, 2015.
复制标题
2015年中国7个地区猪流行性腹泻病毒非S-INDEL株ORF3和S1基因的分子特征
DOI：
10.1371/journal.pone.0160561
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Sun D
中科院分区：
文献类型：
--
作者：
Wang E;Guo D;Li C;Wei S;Wang Z;Liu Q;Zhang B;Kong F;Feng L;Sun D
我们实验室开发的新化合物NSC745885和NSC757963分别与美国国家癌症研究所的60个癌细胞株和日本癌症研究基金会的39个癌细胞株进行了对比测试。这两种化合物都表现出选择性独特的多对数不同活性模式，对癌细胞的GI50值在亚微摩尔范围内，而不是对正常的心脏细胞。NSC757963对白血病亚组有较高的选择性。这两个化合物的活性与NFKB1和CSNK2B基因的表达密切相关，表明它们可能抑制了NF-κB途径。免疫细胞化学镜检显示，治疗后细胞内有明显的NF-κB p65亚单位积聚。Western blotting显示剂量依赖性抑制了核转录因子κB p65亚单位的核表达，随后在治疗后的胞浆中积聚。对接实验表明，这两种化合物都与核因子-κB激活剂IKKβ亚基结合，阻止了其转位到细胞核。总之，这些结果证实了我们的化合物能够抑制OVCAR-3细胞的结构性活性的NF-κB途径。此外，比较分析表明，NSC757963的活性与抗结核药利福-霉素SV相似，这一点通过对NSC757963抗结核分枝杆菌活性的测试得到了证实，结果表明NSC757963具有较强的活性，适合于临床应用。分子特性和利平斯基参数预测了可接受的生物利用度特性，而没有突变、致瘤性、刺激性和生殖影响的迹象。利用人Caco-2模型进行的口服吸收实验表明，NSC745885的肠道吸收较高，为被动转运机制，无肠道外排或主动转运机制。独特的分子表征以及根据知识共享署名许可证的条款分发的文章，该许可证允许在任何媒体上不受限制地使用、分发和复制，前提是原始作者和来源必须注明。数据可用性声明：所有相关数据都在论文及其支持信息文件中。资助者在研究设计、数据收集和分析、决定发表或准备手稿方面没有任何作用。利益冲突：作者声明不存在利益冲突。活性和生物利用度的抗癌光谱证明了我们化合物的进一步开发，并为将此类化合物应用于临床实践的临床前研究提供了基础砖。
The novel compounds NSC745885 and NSC757963 developed at our laboratory were tested against a panel of 60 cancer cell lines at the National Cancer Institute, USA, and a panel of 39 cancer cell lines at the Japanese Foundation of Cancer Research. Both compounds demonstrated selective unique multi-log differential patterns of activity, with GI 50 values in the sub-micro molar range against cancer cells rather than normal cardiac cells. NSC757963 showed high selectivity towards the leukemia subpanel. Activities of both compounds strongly correlated to expression of NFKB1 and CSNK2B genes, implying that they may inhibit the NF-κB pathway. Immunocytochemical microscopy of OVCAR-3 cells showed clear cytosolic accumulation of the NF-κB p65 subunit following treatment. Western blotting showed dose dependent inhibition of the nuclear expression of the NF-κB p65 sub-unit with subsequent accumulation in the cytosol following treatment. Docking experiments showed binding of both compounds to the NF-κB activator IKKβ subunit preventing its trans-location to the nucleus. Collectively, these results confirm the ability of our compounds to inhibit the constitutively active NF-κB pathway of OVCAR-3 cells. Furthermore, COMPARE analysis indicated that the activity of NSC757963 is similar to the antituberculosis agent rifa-mycin SV, this was confirmed by testing the antimycobacterial activity of NSC757963 against Mycobacterium tuberculosis, results revealed potent activity suitable for use in clinical practice. Molecular properties and Lipinski's parameters predicted acceptable bioavail-ability properties with no indication of mutagenicity, tumorigenicity, irritability and reproductive effects. Oral absorption experiments using the human Caco-2 model showed high intestinal absorption of NSC745885 by passive transport mechanism with no intestinal efflux or active transport mechanisms. The unique molecular characterization as well as the article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. illustrated anticancer spectra of activity and bioavailability properties warrant further development of our compounds and present a foundation brick in the pre-clinical investigations to implement such compounds in clinical practice.