围绕中医药对癌症的作用机制研究，本期精选发表在《中国中药杂志》的5篇双语文章，希望能为相关领域学者提供新的思路与参考，欢迎阅读。
精选文章Selected Articles
01
柴胡-白芍含药血浆通过miR-1297/PTEN信号轴对HepG2肝癌细胞的影响及机制研究
Bupleuri Radix-Paeoniae Radix Alba medicated plasma exerts effects on HepG2 hepatoma cells by regulating miR-1297/PTEN signaling axis
【摘要】研究柴胡-白芍含药血浆通过微小RNA-1297（microRNA-1297，miR-1297）/第10号染色体缺失的磷酸酶及张力蛋白同源基因（phosphatase and tensin homologue deleted on chromosome 10，PTEN）信号轴对肝癌细胞HepG2的影响及作用机制。通过实时荧光定量聚合酶链反应（real-time quantitative PCR，RT-qPCR）检测miR-1297、PTEN mRNA在肝癌细胞株中的表达，双荧光素酶报告实验验证miR-1297与PTEN的靶向关系。将HepG2肝癌细胞分为空白血浆组、含药血浆组、miR-1297 inhibitor组、miR-NC组、miR-1297 inhibitor+含药血浆组。细胞计数试剂（CCK-8）法检测细胞增殖，筛选含药血浆最佳干预浓度及时间。细胞划痕实验和Transwell实验检测细胞迁移、侵袭能力，碘化丙啶（PI）染色法检测细胞周期分布，Annexin V-FITC/PI双染法检测细胞凋亡水平。RT-qPCR检测miR-1297、PTEN、蛋白激酶B（Akt）、磷脂酰肌醇3-激酶（PI3K）基因表达。蛋白免疫印迹（Western blot，WB）检测PTEN、PI3K、磷酸化磷脂酰肌醇3-激酶（p-PI3K）、Akt、磷酸化蛋白激酶B（p-Akt）、半胱氨酸蛋白酶3（caspase-3）、半胱氨酸蛋白酶9（caspase-9）、B淋巴细胞瘤-2（Bcl-2）、Bcl-2相关X蛋白（Bax）的蛋白表达。结果显示，miR-1297在HepG2细胞中表达水平最高，选取HepG2细胞进行后续实验。双荧光素酶报告实验显示miR-1297可与PTEN mRNA3′-非翻译区（3′-untranslated region，3′UTR）结合。柴胡-白芍含药血浆可以抑制HepG2细胞增殖，最佳干预质量分数及时间为20%、72 h。与空白血浆组相比，含药血浆组、miR-1297 inhibitor组及miR-1297 inhibitor+含药血浆组均能抑制HepG2细胞增殖、侵袭及迁移，可以提高G0/G1期细胞比例，降低S期细胞比例，提高细胞凋亡率。柴胡-白芍含药血浆可以降低HepG2细胞miRNA-1297、PI3K、Akt mRNA表达，提高PTEN mRNA表达；可以下调p-PI3K、p-Akt、Bcl-2蛋白表达；上调PTEN、caspase-3、caspase-9、Bax的蛋白表达。综上，柴胡、白芍可以抑制HepG2肝癌细胞miR-1297的表达，上调PTEN表达，负调控PI3K/Akt信号通路，从而抑制HepG2细胞增殖并诱导凋亡。
【Abstract】The present study is designed to investigate the effect and mechanism of Bupleuri Radix-Paeoniae Radix Alba medicated plasma on HepG2 hepatoma cells by regulating the microRNA-1297 (miR-1297)/phosphatase and tensin homologue deleted on chromosome 10 (PTEN) signaling axis. Real-time quantitative PCR (RT-qPCR) was carried out to determine the mRNA levels of miR-1297 and PTEN in different hepatoma cell lines. The dual luciferase reporter assay was employed to verify the targeted interaction between miR-1297 and PTEN. The cell counting kit-8 (CCK-8) was used to detect cell proliferation. Optimal concentration and intervention time of the medicated plasma were determined. The cell invasion and migration were examined by Transwell experiment and wound healing assay. Cell cycle distribution was detected by PI staining. Apoptosis of cells was detected by Annexin V-FITC/PI double staining. The mRNA levels of miR-1297, PTEN, protein kinase B (Akt), and phosphatidylinositol 3-kinase (PI3K) were determined by RT-qPCR. Western blot was employed to determine the protein levels of PTEN, Akt, p-Akt, caspase-3, caspase-9, B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X protein (Bax). The results showed that HepG2 cells were the best cell line for subsequent experiments. In the dual luciferase reporter assay, it is confirmed that miR-1297 can combine with the 3′-untranslated region (3′UTR) in the mRNA of PTEN. The medicated plasma has inhibited the proliferation of HepG2 cells. Optimal intervention concentration and time are 20% and 72 h. Compared with the blank plasma, the Bupleuri Radix-Paeoniae Radix Alba medicated plasma, miR-1297 inhibitor, miR-1297 inhibitor + medicated plasma all can inhibit the proliferation, invasion, and migration of HepG2 cells, and increase the proportion of cells in the G0/G1 phase. The proportion of cells in the S phase has been decreased. The apoptosis rate can be increased. The medicated plasma can down-regulate the mRNA levels of miR-1297, PI3K, and Akt. It also can upregulate the mRNA level of PTEN. In addition, it has up-regulated the protein levels of PTEN, Bax, caspase-3, and caspase-9, and down-regulated the protein levels of p-Akt, p-PI3K, and Bcl-2. In conclusion, Bupleuri Radix-Paeoniae Radix Alba medicated plasma can inhibit the expression of miR-1297 in HepG2 hepatoma cells, and promote the expression of PTEN. Thus, it can negatively regulate PI3K/Akt signaling pathway, to inhibit the proliferation and induce the apoptosis of HepG2 cells.
02
黄芪-莪术药对通过调控缺氧诱导因子及肿瘤干细胞化抑制结肠癌进展并增强5-FU疗效的机制研究
Astragali Radix-Curcumae Rhizoma inhibits colon cancer progression and enhances 5-FU efficacy by regulating hypoxia-inducible factors and tumor stem cells
【摘要】该研究基于动物和细胞模型研究黄芪-莪术药对通过调控缺氧诱导因子及肿瘤干细胞化抑制结肠癌进展并增强5-氟尿嘧啶（5-FU）疗效的机制。建立裸鼠HCT116皮下移植瘤模型，将造模成功的24只裸鼠随机分为模型组、5-FU组、黄芪-莪术组和联合给药组，治疗后每2 d测量1次肿瘤体积，采用Western blot方法检测裸鼠HCT116皮下移植瘤组织缺氧核心区关键靶点表皮生长因子受体（epidermal growth factor receptor，EGFR）、二氢嘧啶脱氢酶(dihydropyrimidine dehydrogenase, DPYD)、胸苷酸合酶（thymidylate synthase，TYMS）以及缺氧诱导因子-1α（hypoxia-inducible factor-1α，HIF-1α）、缺氧诱导因子-2α（hypoxia-inducible factor-2α，HIF-2α）和肿瘤干细胞标志物CD133、SRY盒转录因子2（SRY-box transcription factor 2，SOX2）的蛋白表达情况。结果表明黄芪-莪术药对能减缓肿瘤生长速度，并显著提高5-FU的抑瘤率。黄芪-莪术药对明显降低肿瘤中EGFR和DPYD的蛋白表达，联合给药组中EGFR和TYMS的蛋白表达量显著降低。与模型组相比，黄芪-莪术药对可以显著抑制移植瘤组织缺氧核心区中HIF-1α、HIF-2α、SOX2、CD133的蛋白表达，与5-FU组相比，联合给药进一步抑制了HIF-1α、HIF-2α、SOX2的蛋白表达。在体外实验中，缺氧后HCT116细胞内HIF-1α、HIF-2α的蛋白表达量显著增加。与单独给予5-FU（1.38μmol·L-1）相比，单独使用黄芪-莪术（40 mg·mL-1）或5-FU联合黄芪-莪术均能更显著地抑制HIF-1α、HIF-2α、TYMS的蛋白表达。结果显示黄芪-莪术药对降低了结肠癌细胞中缺氧应答分子的表达，并减少了结肠癌的干细胞性质，从而起到了协同增强5-FU对结肠癌的治疗作用。
【Abstract】The animal and cell models were used in this study to investigate the mechanism of Astragali Radix-Curcumae Rhizoma (HQEZ) in inhibiting colon cancer progression and enhancing the efficacy of 5-fluorouracil (5-FU) by regulating hypoxia-inducible factors and tumor stem cells. The animal model was established by subcutaneous transplantation of colon cancer HCT116 cells in nude mice, and 24 successfully modeled mice were randomized into the model, 5-FU, HQEZ, and 5-FU+HQEZ groups. The tumor volume was measured every two days. Western blot was employed to measure the protein levels of epidermal growth factor receptor (EGFR), dihydropyrimidine dehydrogenase (DPYD), and thymidylate synthase (TYMS), the key targets of the hypoxic core region, as well as the hypoxia-inducible factors HIF-1 α and HIF-2 α and the cancer stem cell surface marker CD133 and SRY-box transcription factor 2 (SOX2). The results of animal experiments showed that HQEZ slowed down tumor growth and significantly increased the tumor inhibition rate of 5-FU. Compared with the model group, HQEZ significantly down-regulated the protein levels of EGFR and DPYD, and 5-FU+HQEZ significantly down-regulated the protein levels of EGFR and TYMS in tumors. Compared with the model group, HQEZ significantly down-regulated the protein levels of HIF-1 α, HIF-2 α, SOX2, and CD133 in the hypoxic core region. Compared with the 5-FU group, 5-FU+HQEZ lowered the protein levels of HIF-1 α, HIF-2 α, and SOX2. The cell experiments showed that the protein levels of HIF-1 α and HIF-2 α in HCT116 cells elevated significantly after low oxygen treatment. Compared with 5-FU (1.38 1.38 μmol·L -1) alone, HQEZ (40 mg·mL -1) and 5-FU+HQEZ significantly down-regulated the protein levels of HIF-1 α, HIF-2 α, and TYMS. In conclusion, HQEZ can inhibit the expression of hypoxia-responsive molecules in colon cancer cells and reduce the properties of cancer stem cells, thereby enhancing the therapeutic effect of 5-FU on colon cancer.
03
榅桲总多酚通过PI3K/Akt/mTOR通路影响肾癌细胞增殖和迁移
Total polyphenols of Cydonia oblonga inhibited proliferation and migration of renal cancer cells by PI3K/Akt/mTOR pathway
【摘要】通过网络药理学与生物信息学及实验验证相结合的方法来阐明榅桲总多酚（total polyphenols of Cydonia oblonga Miller，TPCOM）抗肾癌的作用机制。通过网络药理学筛选榅桲活性多酚类化合物和肾癌相关的靶点。通过对Gene Expression Omnibus（GEO）数据库中肾癌患者肿瘤组织和正常组织RNA测序数据进行差异表达基因分析，结合网络药理学预测结果和差异表达基因分析获得TPCOM作用于肾癌的核心基因，结合生存分析找出能够影响患者生存的关键靶点，进行京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）和基因本体（Gene Ontology，GO）富集分析。采用20～640μg·mL-1TPCOM处理786-O和Renca细胞进行cell counting kit-8（CCK-8）实验，40、80、160μg·mL-1 TPCOM处理肾癌细胞，检测TPCOM对肾癌细胞迁移和肾癌细胞中蛋白激酶B（protein kinase B，Akt）、雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）和磷脂酰肌醇3-激酶（phosphoinositide 3-kinase，PI3K）信号通路相关蛋白表达水平的调控作用。通过网络药理学预测获得8个榅桲多酚类活性化合物，通过生存分析获得TPCOM发挥抗肾癌作用的15个显著影响患者生存的肾癌差异表达基因。KEGG和GO分析结果显示以上15个靶点主要与PI3K/Akt信号通路、细胞迁移和增殖等生物过程有关。结果显示TPCOM能够抑制786-O和Renca细胞的增殖，IC50分别为121.4、137.9μg·mL-1。TPCOM能够抑制786-O和Renca细胞的迁移，能够抑制PI3K/Akt/mTOR信号通路。榅桲总多酚可能通过抑制PI3K/Akt/mTOR信号通路的激活从而抑制肾癌细胞的增殖和迁移来发挥抗肾癌作用。该研究为新疆天然产物榅桲的抗肿瘤作用研究提供一定的研究基础，对进一步推动新疆榅桲的开发和利用具有拓展和补充意义。
【Abstract】The mechanism of total polyphenols of Cydonia oblonga Miller (TPCOM) against kidney cancer was elucidated through a combination of network pharmacology, bioinformatics, and experimental verification. The active polyphenolic compounds from C. oblonga were screened by network pharmacological techniques and kidney cancer-related targets were collected through the database. The differential gene expression analysis was performed on RNA sequencing data from tumor tissue and normal tissue of kidney cancer patients obtained from the Gene Expression Omnibus (GEO) database. The results of network pharmacology predictions and differential gene expression analysis were used to identify the core genes targeted by TPCOM in kidney cancer. Survival analysis was conducted to identify key targets that could impact patient survival, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses. Cell proliferation and activity experiments (cell counting kit-8) were conducted using TPCOM at concentrations ranging from 20 to 640 μg·mL −1 on 786-O and Renca cells. Additionally, TPCOM at concentrations of 40, 80, and 160 μg·mL −1 was applied to kidney cancer cells to assess its effect on cell migration and its regulation of protein expression levels related to the protein kinase B (Akt), mammalian target of rapamycin (mTOR), and phosphoinositide 3-kinase (PI3K) signaling pathways. Network pharmacology predicted eight active polyphenolic compounds from C. oblonga. Survival analysis revealed 15 significantly differentially expressed genes in kidney cancer that were affected by TPCOM and had a significant impact on patient survival. KEGG and GO analysis results indicated that these 15 targets were primarily associated with the PI3K/Akt signaling pathway, cell migration, and proliferation. The results showed that TPCOM could inhibit the proliferation of 786-O and Renca cells, with IC 50 values of 121.4 and 137.9 μg·mL −1, respectively. TPCOM was also found to inhibit the migration of these cells and suppress the PI3K/Akt/mTOR signaling pathway. TPCOM may exert its anti-kidney cancer effects by inhibiting the activation of the PI3K/Akt/mTOR signaling pathway, thereby restraining the proliferation and migration of kidney cancer cells. This study provides a foundation for the research on the anti-tumor effects of natural product C. oblonga, particularly in Xinjiang, and holds significance for further promoting its development and utilization.
04
芹菜素与氧化苦参碱联合用药抑制非小细胞肺癌的作用及其机制研究
Effect of apigenin in combination with oxymatrine on non-small cell lung cancer and mechanism
【摘要】研究芹菜素、氧化苦参碱、芹菜素与氧化苦参碱联合给药（以下简称“联合给药”）对非小细胞肺癌细胞系的增殖作用及其分子作用机制的影响。采用CCK-8法检测芹菜素、氧化苦参碱以及联合给药对非小细胞肺癌A549与NCI-H1975细胞活力的影响；通过平板克隆实验考察芹菜素、氧化苦参碱以及联合给药后对非小细胞肺癌细胞克隆形成能力的影响；EdU实验验证芹菜素、氧化苦参碱以及联合给药对非小细胞肺癌NCI-H1975细胞增殖率的影响；RT-qPCR与Western blot实验考察芹菜素、氧化苦参碱以及联合给药后对PLOD2 mRNA与蛋白相对表达的影响；分子对接实验探究芹菜素、氧化苦参碱与PLOD2、EGFR蛋白的直接作用能力与作用位点；利用Western blot法检测芹菜素、氧化苦参碱以及联合给药对EGFR下游信号通路相关蛋白表达水平的影响。结果发现，芹菜素、联合给药在20、40、80μmol·L-1均能显著抑制人非小细胞肺癌A549与NCI-H1975细胞的活力并呈浓度依赖性；芹菜素、联合给药作用于NCI-H1975细胞可显著抑制非小细胞肺癌细胞的克隆形成能力；芹菜素以及联合给药后可显著抑制PLOD2的mRNA与蛋白相对表达；芹菜素、氧化苦参碱与PLOD2、EGFR蛋白有较强的结合作用；芹菜素、联合给药可显著下调非小细胞肺癌细胞EGFR及其下游信号通路蛋白表达水平。联合给药能抑制非小细胞肺癌，且其作用机制可能与EGFR及其下游信号通路相关。该研究为芹菜素与氧化苦参碱联合应用治疗非小细胞肺癌提供科学依据，对联合给药抗肿瘤作用机制的深入研究具有一定的参考意义。
【Abstract】This study explored the effect of apigenin (APG), oxymatrine (OMT), and APG + OMT on the proliferation of the non-small cell lung cancer cell lines and the underlying mechanism. Cell counting kit-8 (CCK-8) assay was used to detect the vitality of A549 and NCI-H1975 cells, and colony formation assay to evaluate the colony formation ability of the cells. EdU assay was employed to examine the proliferation of NCI-H1975 cells. RT-qPCR and Western blot were performed to detect the mRNA and protein expression of PLOD2. Molecular docking was carried out to explore the direct action ability and action sites between APG/OMT and PLOD2/EGFR. Western blot was used to study the expression of related proteins in the EGFR pathway. The viability of A549 and NCI-H1975 cells was inhibited by APG and APG + OMT at 20, 40, and 80 μmol·L −1 in a dose-dependent manner. The colony formation ability of NCI-H1975 cells was significantly suppressed by APG and APG + OMT. The mRNA and protein expression of PLOD2 was significantly inhibited by APG and APG + OMT. In addition, APG and OMT had a strong binding activity with PLOD2 and EGFR. In APG and APG + OMT groups, the expression of EGFR and proteins in its downstream signaling pathways was significantly down-regulated. It is concluded that APG in combination with OMT could inhibit non-small lung cancer, and the mechanism may be related to EGFR and its downstream signaling pathways. This study lays a new theoretical basis for the clinical treatment of non-small cell lung cancer with APG in combination with OMT and provides a reference for further research on the anti-tumor mechanism of APG in combination with OMT.
05
基于网络药理学及体外实验验证探讨乌药抗胃癌的作用机制
Mechanism of Linderae Radix against gastric cancer based on network pharmacology and in vitro experimental validation
【摘要】利用网络药理学、分子对接技术和体外细胞实验，研究乌药抗胃癌的主要活性成分和潜在作用机制。利用中药系统药理学分析平台（TCMSP）数据库、在线人类孟德尔遗传（OMIM）和GeneCards数据库提取乌药活性成分，并预测了乌药与胃癌有关靶点。筛选二者共同的潜在功能靶位之后，再利用STRING数据库实现与二者共同靶点的蛋白相互作用（PPI）网络构建。利用DAVID数据库进行GO和KEGG富集分析；以STRING和DAVID数据库为基础，运用Cytoscape 3.7.2软件构建“活性成分-靶点”网络和“活性成分-靶点-通路”网络；利用AutoDock Vina进行分子对接，预测有效成分与关键作用靶点的结合度，最后对关键靶点和通路进行体外实验验证。预测结果共获得乌药活性成分9个、相关靶点179个，乌药与胃癌的共同靶点107个，靶点共涉及生物过程693种，细胞组成57种，分子功能129种，参与肿瘤抗原p53、缺氧诱导因子1等信号通路161条；分子对接结果显示核心成分吉马酮与TP53有较高的结合活性。最后体外实验将筛选出的乌药活性成分吉马酮对人胃癌细胞SGC-7901进行核心靶点和通路的初步验证，结果表明吉马酮可明显抑制胃癌细胞增殖并通过调控p53、Bax、Bcl-2等关键蛋白的表达来诱导SGC-7901凋亡。综上所述，乌药通过多成分、多靶点、多通路协同作用控制胃癌的发生发展，为今后临床进一步探讨乌药治疗胃癌的机制提供理论依据。
【Abstract】The present study explored the main active ingredients and the underlying mechanism of Linderae Radix in the treatment of gastric cancer by network pharmacology, molecular docking, and in vitro cell experiments. TCMSP, OMIM and GeneCards databases were used to obtain the active ingredients of Linderae Radix to predict the related targets of both Linderae Radix and gastric cancer. After screening of the common potential action targets, the STRING database was used to construct the PPI network for protein interaction of the common targets. Enrichment analysis of GO and KEGG was performed by DAVID database. Based on STRING and DAVID platform data, Cytoscape software was used to construct an “active ingredient–target” network and an “active ingredient–target–pathway” network. Molecular docking was performed using AutoDock Vina to predict the binding of the active components to the key action targets, and finally the key targets and pathways were verified in vitro. According to the prediction results, there were 9 active components, 179 related targets of Linderae Radix, 107 common targets of Linderae Radix and gastric cancer, 693 biological processes, 57 cellular components, and 129 molecular functions involved in the targets, and 161 signaling pathways involved in tumor antigen p53, hypoxia-inducible factor 1, etc. Molecular docking found that the core component, germacrone had high binding activity with TP53. Finally, in an in vitro experiment, the screened active ingredient of Linderae Radix germacrone was used for preliminarily verifying the core targets and pathways of the human gastric cancer cell SGC-7901. The results showed that germacrone could significantly inhibit the proliferation of gastric cancer cells and induce the apoptosis of SGC-7901 by regulating the expression of p53, Bax, Bcl-2 and other key proteins. In summary, Linderae Radix can control the occurrence and development of gastric cancer through multi-components, multi-targets and multi-pathways, which will provide theoretical basis for further clinical discussion on the mechanism of Linderae Radix in treating gastric cancer.
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《中国中药杂志》是由中国科学技术协会主管，中国药学会主办，中国中医科学院中药研究所承办的综合性中医药学术期刊，创刊于1955年7月，现为半月刊，全年24期，每期240页。全面反映我国中医药与天然药物学科领域最新进展与研究动态，是中医药最高科研学术水平的交流平台之一。名誉主编肖培根院士、王永炎院士、张伯礼院士、屠呦呦研究员。现任主编为中国工程院黄璐琦院士。入选中国中医药科技期刊分级目录T1区，名列11本T1级期刊榜首；中文核心期刊；中国科技核心期刊；中国科学引文数据库（CSCD核心版）Q1区；中国学术期刊（网络版）来源期刊。在国际上，被Medline《生物医学检索系统》（美）、Scopus《文摘与引文数据库》（荷兰）、BP《生物学文摘(预评)》（美）、IPA《国际药学文摘》（美）、JST日本科学技术振兴机构数据库（日）等数据库收录。
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