基于网络药理学分析荷丹片与他汀类药物的协同降脂作用

目的 采用网络药理学的方法,筛选荷丹片组方的活性成分和与高脂血症疾病相关的作用靶点,通过生物过程与通路富集预测其作用机制,从而获得荷丹片与他汀类药物协同作用的依据.方法 利用中药系统药理学分析平台(TCMSP,https://tcmspw.com/tcmsp.php)等数据库及文献筛选荷丹片的活性成分及靶点,利用Gee...     

(定量)构效关系预测利伐沙班有机杂质遗传毒性

目的 通过对利伐沙班原料中有机杂质进行遗传毒性预测,并以杂质遗传毒性进行分类,为实际生产中质量保障体系的建立提供依据。方法 分析利伐沙班的合成工艺,结合实际生产中有可能采用的生产工艺,推测有机杂质,按照国际认可的指导原则,采用基于专家规则和基于统计学规则的2个互补的（定量）构效关系评估[（quantitative） structure-activity relationships, （Q）SAR]预测软件,对18个有机杂质进行遗传毒性预测分析,并依据预测结果按照其致突变性和致癌性进行分类。结果 在18个有机杂质中,需要按遗传毒性杂质控制的杂质有5个,可以按非遗传毒性杂质控制的杂质有13个。结论 采用（Q）SAR评估有关物质的遗传毒性,可实现快速确定杂质毒性特征的目的。预测结果提示利伐沙班应针对具有遗传毒性警示结构的5个杂质建立有效的质量控制体系。     

The synergistic antitumor activity of 3-(2-nitrophenyl) propionic acid-paclitaxel nanoparticles (NPPA-PTX NPs) and anti-PD-L1 antibody inducing immunogenic cell death

Cancer immunotherapy is a strategy that is moving to the frontier of cancer treatment in the current decade. In this study, we show evidence that 3-(2-nitrophenyl) propionic acid-paclitaxel nanoparticles (NPPA-PTX NPs), act as immunogenic cell death (ICD) inducers, stimulating an antitumor response which results in synergistic antitumor activity by combining anti-PD-L1 antibody (aPD-L1) in vivo. To investigate the antitumor immunity induced by NPPA-PTX NPs, the expression of both ICD marker calreticulin (CRT) and high mobility group box 1 (HMGB1) were analyzed. In addition, the antitumor activity of NPPA-PTX NPs combined with aPD-L1 in vivo was also investigated. The immune response was also measured through quantitation of the infiltration of T cells and the secretion of pro-inflammatory cytokines. The results demonstrate that NPPA-PTX NPs induce ICD of MDA-MB-231 and 4T1 cells through upregulation of CRT and HMGB1, reactivating the antitumor immunity via recruitment of infiltrating CD3+, CD4+, CD8+ T cells, secreting IFN-γ, TNF-α, and the enhanced antitumor activity by combining with aPD-L1. These data suggest that the combined therapy has a synergistic antitumor activity and has the potential to be developed into a novel therapeutic regimen for cancer patients.     

Synergistic effect of the anti-PD-1 antibody with blood stable and reduction sensitive curcumin micelles on colon cancer

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a potent anticancer drug with versatile biological activities, while the clinical translation of curcumin is severely limited due to its hydrophobicity, rapid elimination, and metabolism in the blood circulation. Herein, we aim to unravel the potential of curcumin as a synergistic agent with immunotherapy in the treatment of cancers. In an effort to minimize premature release and improve the systemic bioavailability, a superior blood stable and reduction sensitive curcumin micellar formulation, of which the release can be triggered by cancer cells, is rationally designed. We have synthesized a telodendrimer (mPEG-PLA-(LA)₄) capable of forming reversible disulfide crosslinked micelles (DCMs). The curcumin loaded DCMs (Cur/DCMs) are spherical with a uniform size of 24.6 nm. The in vitro release profile demonstrates that curcumin releases significantly slower from DCMs than that from non-crosslinked micelles (NCMs), while the release can be accelerated with the increasing concentration of reducing agent glutathione (GSH). Intravenous administration of Cur/DCMs stably retains curcumin in the bloodstream and efficiently improves the systemic bioavailability. Furthermore, Cur/DCMs exhibit synergistic anticancer efficacy when combined with the anti-PD-1 antibody in an MC-38 colon cancer xenograft model. Our results potentiate the integration of blood stable curcumin nanoformulation and immunotherapy for cancer treatment.     

Synergistic anticancer effect of flavonoids from Sophora alopecuroides with Sorafenib against hepatocellular carcinoma

Sorafenib (SF), a multi-kinase inhibitor, is the first FDA-approved systemic chemotherapy drug for advanced hepatocellular carcinoma (HCC). However, its clinical application is limited by severe toxicity and side effects associated with high applied doses. Sophora alopecuroides L. is traditionally used as Chinese herbal medicine for treating gastrointestinal diseases, bacillary dysentery, viral hepatitis, and other diseases, and exerts an important role in anti-tumor. Hence, we investigated the synergistic actions of seventeen flavonoids from this herb combined with SF against HCC cell lines and their primary mechanism. In the experiment, most compounds were found to prominently enhance the inhibitory effects of SF on HCC cells than their alone treatment. Among them, three compounds leachianone A ( 1 ), sophoraflavanone G ( 3 ), and trifolirhizin ( 17 ) exhibited significantly synergistic anticancer activities against MHCC97H cells at low concentration with IC₅₀ of SF reduced by 5.8-fold, 3.6-fold, and 3.5-fold corresponding their CI values of 0.49, 0.66, and 0.46 respectively. Importantly, compounds 3 or 17 combined with SF could synergistically induce MHCC97H cells apoptosis via the endogenously mitochondrial-mediated apoptotic pathway, involving higher Bax/Bcl-2 expressions with the activation of caspase-9 and -3, and arrest the cell cycle in G1 phases. Strikingly, this synergistic effect was also closely related to the co-suppression of ERK and AKT signaling pathways. Furthermore, compound 3 significantly enhanced the suppression of SF on tumor growth in the HepG2 xenograft model, with a 79.3% inhibition ratio at high concentration, without systemic toxicity, compared to either agent alone. These results demonstrate that the combination treatment of flavonoid 3 and SF at low doses exert synergistic anticancer effects on HCC cells in vitro and in vivo.     

槟榔中与烯丙基焦儿茶酚具有协同抗疟疾作用化合物的生物活性导向分离

目的:从槟榔中筛选出能与烯丙基焦儿茶酚具有协同抗疟疾的化合物。方法:运用生物活性导向分离的方法,把从槟榔的甲醇提取物中分离的各组分进行体外抗疟疾试验,找出活性单体。结果:筛选出能与烯丙基焦儿茶酚具有协同抗疟疾作用的两个化合物,他们与烯丙基焦儿茶酚在一定浓度下单独给药体外抗疟疾效果很差,但是联合给药具有较好的体外协同抗疟疾作用。     

消旋11-去甲胡桐素A的合成方法改进及其药理学评价

本文发展一个实用改进方法以合成具有抗人免疫缺陷病毒(HIV-1)的天然产物的类似物11-去甲胡桐素A［(±)-1］，方法改进包括以间苯三酚为起始原料与正丁酰乙酸乙酯在饱和氯化氢甲醇存在下，经过Pechmann反应生成5，7-双羟基-4-正丙基香豆素(3)，再与巴豆酸用多聚磷酸作溶剂及催化剂进行酰化，同时分子内环合得到收率为70%关键中间体苯并二氢吡喃酮(4)，并与缩醛1，1-二乙氧基-3-甲基-2-丁烯用微波辅助催化得到苯并吡喃(6)， 最后用Luche还原以CeCl₃·7H₂O作催化剂， 在低温下经NaBH₄选择性还原化合物(6)得到目标产物即消旋11-去甲胡桐素A (±)-1。上述4步反应总收率32%， 比原方法提高1倍。体外研究表明(±)-1对HIV-1(野株)及耐药株均有明显抑制逆转录酶和P24抗原的活性， (±)-1在细胞培养内分别与作用机制不同的3种治疗艾滋病药物(AZT、 T-20、 Indinavir)都有明显的协同作用。小鼠急性毒性， (±)-1的LD₅₀灌胃给药为735.65 mg·kg^-1， 腹腔给药为525.10 mg·kg^-1。小鼠灌胃给与(±)-1血浆峰浓度(C_max)与药时曲线面积AUC_0-∞分别为0.54 μg·mL^-1及1.08 (μg·mL^-1)·h。为了初步观察(±)-1的体内药效，采用血清药理学方法，小鼠腹腔注射1次(±)-1或临床有效对照药奈韦拉平，30 min和60 min后血清有相似的抑制HIV-1逆转录酶活性。实验结果提示去甲11-胡桐素A值得进一步研究。     

Genotoxic and oxidative responses in coelomocytes of Eisenia fetida and Hediste diversicolor exposed to lipid‐coated CdSe/ZnS quantum dots and CdCl2

The emerging of Quantum Dots utilization in industrial or medicinal fields involved a potentially increase of these nanoparticles in environment. In this work, the genotoxic (comet assay) and oxidative effects (SOD activity, TBARS) of functionalized‐QDs and cadmium chloride were investigated on Hediste diversicolor and Eisenia fetida coelomocytes. Results demonstrated that functionalized‐QDs (QDNs) and cadmium chloride induced DNA damages through different mechanisms that depended on the nano‐ or ionic nature of Cd. The minimal genotoxic concentrations for H. diversicolor (<0.001ng/g for QDNs and CdCl₂) were lower than for E. fetida (between 0.01 and 0.1 ng/g for QDNs, and between 0.001 and 0.01 ng/g for CdCl₂). These results showed that H. diversicolor was more sensitive than E. fetida. The two contaminants had a low impact on the oxidative stress markers. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 918–926, 2015.     

Radioprotective Effect of Achillea millefolium L Against Genotoxicity Induced by Ionizing Radiation in Human Normal Lymphocytes

The radioprotective effect of Achillea millefolium L (ACM) extract was investigated against genotoxicity induced by ionizing radiation (IR) in human lymphocytes. Peripheral blood samples were collected from human volunteers and incubated with the methanolic extract of ACM at different concentrations (10, 50, 100, and 200 μg/mL) for 2 hours. At each dose point, the whole blood was exposed in vitro to 2.5 Gy of X-ray and then the lymphocytes were cultured with mitogenic stimulation to determine the micronuclei in cytokinesis-blocked binucleated cell. Antioxidant capacity of the extract was determined using free radical-scavenging method. The treatment of lymphocytes with the extract showed a significant decrease in the incidence of micronuclei binucleated cells, as compared with similarly irradiated lymphocytes without any extract treatment. The maximum protection and decrease in frequency of micronuclei were observed at 200 μg/mL of ACM extract which completely protected genotoxicity induced by IR in human lymphocytes. Achillea millefolium extract exhibited concentration-dependent radical-scavenging activity on 1,1-diphenyl-2-picryl hydrazyl free radicals. These data suggest that the methanolic extract of ACM may play an important role in the protection of normal tissues against genetic damage induced by IR.