The screening of novel antiviral agents from marine microorganisms is an important strategy for new drug development. Our previous study found that polyether K-41A and its analog K-41Am, derived from a marine Streptomyces strain, exhibit anti-HIV activity by suppressing the activities of HIV-1 reverse transcriptase (RT) and its integrase (IN). Among the K-41A derivatives, two disaccharide-bearing polyethers—K-41B and K-41Bm—were found to have potent anti-HIV-1IIIB activity in vitro. This study aimed to clarify whether K-41B and K-41Bm have inhibitory effects on different HIV-1 strains or whether these two derivatives have mechanisms of action different from that of their precursor, K-41A. An anti-HIV-1 assay indicated that K-41B and K-41Bm have potent anti-HIV-1BaL activity, with low 50% inhibitory concentrations (IC50s) (0.076 and 0.208 μM, respectively) and high selective indexes (SIs) (58.829 and 31.938, respectively) in the peripheral blood mononuclear cell (PBMC)-HIV-1BaL system. The time-of-addition (TOA) assay indicated that K-41B and K-41Bm may exert antiviral effects by activating multiple stages of HIV-1 replication. A cell protection assay indicated that the pretreatment of cells with K-41B or K-41Bm has almost no inhibitory effect on HIV-1 infection. A virus inactivation assay indicated that pretreatment of the virus with K-41B or K-41Bm inhibits HIV-1 infection by 60%. A cell–cell fusion assay showed that K-41B and K-41Bm blocked the cell fusion mediated by viral envelope proteins. The HIV-1 key enzyme experiment also indicated that both compounds have certain inhibitory effects on HIV-1 IN. Furthermore, molecular docking showed that K-41B and K-41Bm interact with several viral and host proteins, including HIV-1 IN, an envelope protein (gp120), a transmembrane protein (gp41), and cell surface receptors (CD4, CCR5, and CXCR4). Overall, in addition to having a similar anti-HIV-1 mechanism of inhibiting HIV-1 IN like the precursor polyether K-41A, the disaccharide-bearing polyether derivatives K-41B and K-41Bm may also inhibit viral entry. This suggests that they display anti-HIV-1 mechanisms that are different from those of their precursor polyethers.

BACKGROUND:Flavonoid glycosides are known to possess diverse bioactivities including antitumor and anti-inflammatory properties. Hesperetin is abundant in nature and can be used to synthesize bioactive flavonoids. This has the advantages of low cost, short synthetic steps, simple operation, and good yields.OBJECTIVE:In this study, we aimed to synthesize bioactive flavonoids and flavonoid glycosides from hesperetin and evaluate the antitumor and anti-inflammatory activities of these compounds.METHODS:A series of flavonoids and their derivatives were synthesized by methoxylation, oxidative dehydrogenation, benzylation, debenzylation, and deacetylation as well as using a modified peroxyacetone method and a glycoside condensation reaction. Their anti-inflammatory activities were evaluated for their inhibitory effects on nitric oxide (NO), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) production in LPS-induced RAW264.7 mouse macrophages. Their structures were characterized by HRMS, 1 H-NMR, and 13 C-NMR, and their cytotoxicity on the human triple-negative breast cancer cell (TNBC) line, SUM 149, was tested by using the MST assay.RESULTS:Most of the compounds markedly reduced NO production in LPS-stimulated murine macrophages at the tested concentrations in a dose-dependent manner. Among these, compounds 1, 7, 9, and 17 showed significant anti-inflammatory activities against NO production in LPS-induced RAW264.7 mouse macrophages. In addition, they could also reduce the release of TNF-α and IL-6 in a concentration-dependent manner. Most of the tested compounds showed remarkable anti-human TNBC activities. Compounds 1b-1m, 1, and 3 showed a certain degree of growth inhibition effect on the human TNBC cell lines and their IC50 values were all below 16.61 μM. In addition, compound 1l was the most cytotoxic with IC50 values of 1.38±0.31 μM, while the other compounds were inactive with inhibition rates <50 % at the highest concentration tested (20 μM).CONCLUSIONS:A novel series of flavonoids were synthesized from the natural flavonoid, hesperetin, including 17 new compounds. Screening tests indicated that most of these compounds reduced NO production in LPS-stimulated murine macrophages at concentrations of 15 to 60 μM, and the inhibition generally increased in a dose-dependent manner. Some compounds showed different degrees of cytotoxicity on the human TBNC cell lines, SUM 149.

本文依托药学本科无机化学课程课堂教学和课后实践两个层面，在课堂教学中，从引入学科最新进展、科研常用实 验技术、科研案例三个方面进行阐述；并在课外实践中，从学生参与教师科研团队、参加大创项目、实施导师制三个 方面对近年来笔者在药学无机化学教学过程中科研反哺教学活动进行总结，希望能为个大教师提供参考。

Due to increased requirements for precision cancer treatment, cancer chemotherapy and combination therapies have gradually developed in the direction of diagnosis and treatment integration. In this study, a non-toxic nano carrier that demonstrates integrated MRI signal enhancing performance, as well as better chemotherapy and photothermal conversion performance, was prepared and characterized. Furthermore, the carrier was used to construct an integrated system of tumor diagnosis and treatment. Our in vitro studies showed that this system has a considerable inhibition effect on tumor cells during the treatment of chemotherapy when combined with PTT, and in vivo studies showed that the system could improve the MRI signal of the tumor site with application of a safe dosage. Thus, this system based on NGO/USPIO has the potential to be a multi-functional nano drug delivery system integrating diagnosis and treatment benefits and applications that are worthy of further research.

Graphene Oxide, prepared by the modified Hummer's method, was modified with a series of high polymers (polyethyleneimine, polyethylene glycol, chitosan) and Folic Acid for the delivery of platinum anticancer drugs including Cisplatin, Carboplatin, Oxaliplatin and Eptaplatin. Nanocarriers were successfully prepared and characterized by Fourier transform infrared spectroscopy, X-ray diffraction and scanning electron microscope. Measurement of drug loading efficiency showed that these nanocarriers had the ability for effective delivery of the platinum anticancer drugs. The Maximum loading ratios of Cisplatin, Carboplatin, Oxaliplatin and Eptaplatin were 25.72, 161.08, 345.21 and 67.80 μg/mg. Drug release experiments in the acid environment showed that the cumulative release rate of platinum anticancer drugs from nanocarriers was higher than that in the neutral environment. The cumulative release of all three nanocarriers in the acid environment reached above 60%. In vitro cytotoxicity assay showed that those nanocarriers had a low toxicity. The cell viability rates were above 80% for all three nanocarriers. Investigation of the anticancer activity in vitro showed that those drug delivery systems had the ability to inhibit the growth of the SKOV3 cell line. These results showed that those nanocarriers were suitable for the delivery of platinum anticancer drugs. Providing preliminary advice on the potential application of the combination of platinum anticancer drugs and the functionalized Graphene Oxide nanocarriers.

Objectives The aim of this study was to test whether CES1, UMPS, DPYS and TPYS polymorphisms influence the outcomes of gastroenteric cancer patients. Methods We consecutively enrolled 338 patients who were diagnosed with colorectal and gastric cancer from January 2016 to December 2018 at the Harbin Medical University Cancer Hospital, China. Results We found that the patients with CES1 rs7187684 CC genotype had a higher proportion of stage III-IV and relapse rate significantly compared with CT/TT genotype, and the patients with rs7187684 CC genotype had a higher level of CA199 than CT/TT genotype after adjusted for tumor stage, and medication, age, sex, smoking, and drinking. Moreover, the patients with rs7187684 CC genotype had shorter event-free survival (EFS) than CT/TT genotype, and a significant shorter EFS was also found in the patients with rs2244613 TT genotype than GG or GT genotype. Subset analysis results showed that the male, less-drinking or gastric cancer patients with rs7187684 CC genotype had shorter EFS than the patients with CT/TT genotype. Compared with the patients with CES1 rs2244613 TT genotype, the stage I-II patients with GG/GT genotype had longer progression-free survival (PFS), and the male patients with GG/GT genotype had longer EFS. Multivariate Cox regression analysis showed that stage III-IV and tumor metastasis could reduce the patients' PFS and EFS. Conclusions The identified CES1 polymorphisms might provide guide for the identification of gastroenteric cancer patients who were likely to benefit from capecitabine-based chemotherapy.

OBJECTIVE:Molybdenum disulfide (MoS2) has been developed for medical uses due to its excellent medically beneficial characteristics. This research was designed to develop a multifunctional nano-drug delivery system based on the nano-structure of MoS2 for combined chemo/gene/photothermal therapy targeting multidrug-resistant cancer.METHODS:MoS2 nanosheets were prepared by a hydrothermal reaction and modified. Afterward, the nanocarrier was characterised. In vitro cytotoxicity of the drug delivery systems on human breast adenocarcinoma cell lines was assessed.KEY FINDINGS:The nanocarrier was a flake-like structure with a uniform hydrodynamic diameter and possessing good colloidal stability. The nanocarrier showed the capacity to be deployed for co-delivery of Doxorubicin (DOX) and siRNA. The release of DOX could be triggered and enhanced by pH and application of near-infrared (NIR) laser. The nanocarrier had a good photothermic response and stability. The nanocarrier had little effect on the cells and exhibited good biocompatibility. Measurement of the therapeutic efficacy showed that synergistic therapy combining chemo-, gene- and photothermal therapy deploying this drug delivery system will achieve a better anticancer effect on drug-resistant cancer cells than DOX alone.CONCLUSIONS:Our results suggest that this drug delivery system has potential application in the therapeutic strategy for drug-resistant cancer.

《基础化学》课程是医科院校医学类、药学类本科生必修的重要基础课程之一.围绕人才培养目标,坚持以学生为中心,因材施教,我们从培养目标、教学理念、教学方法、教学内容及教学手段、课程评价体系等方面深入开展教育教学改革,将思政元素贯穿人才培养全过程,通过理论与实践相结合,形成全员、全程、全方位育人格局,促进学生的全面发展.教学改革内容主要包括修订教学大纲、提高课堂教学质量、建设慕课、自学延伸、加强课程教材建设、翻转课堂、加强综合实训教学、科研反哺教学八个方面.培养医学生的自主学习能力、分析问题及解决问题能力、知识应用能力、综合实践能力、人与人交往能力;深度培养学生的严谨逻辑思维、创新思维、医德交融、医学哲学意识;建立学生专业自豪感和使命感,医者大爱情怀,以及报效祖国、服务人民的家国情怀.本文的改革探索以期为新形势下高校基础课程教育教学提供新思路和新方法.

氟尿嘧啶类药物是消化道肿瘤的一线治疗药物,但不同患者临床预后个体差异大.胸苷酸合成酶(thymidylate synthase,TS)是氟尿嘧啶类药物作用靶点,TYMS基因影响TS酶的表达进而影响药物发挥疗效.因此,明确此基因多态性位点对于氟尿嘧啶类药物精准治疗具有重要意义.本文回顾TYMS基因多态性与氟尿嘧啶类药物治疗消化道肿瘤患者的疗效和不良反应的相关性研究,指出已有论点及证据不足之处,为未来研究指明方向.

In this study, a transferrin/folic acid double-targeting graphene oxide drug delivery system loaded with doxorubicin was designed. Graphene oxide was prepared by ultrasound improved Hummers method and was modified with Pluronic F68, folic acid, and transferrin to decrease its toxicity and to allow dual-targeting. The results show that the double target drug delivery system (TFGP*DOX) has good and controllable drug delivery performance with no toxicity. Moreover, TFGP*DOX has a better inhibitory effect on SMMC-7721 cells than does a single target drug delivery system (FGP*DOX). The results of drug release analysis and cell inhibition studies showed that TFGP*DOX has a good sustained release function that can reduce the drug release rate in blood circulation over time and improve the local drug concentration in or near a targeted tumor. Therefore, the drug loading system (TFGP*DOX) has potential application value in the treatment of hepatocellular carcinoma.

Graphene-based magnetic nanoparticles (NPs) were synthesized using a simple and effective chemical precipitation method. To determine the biocompatibility of GO-Fe₃O₄-PANI NPs with MTT assay, cytotoxicity testing from a low concentration (1 μg/mL) to a high concentration (125 μg/mL) was conducted using various cancer and normal cell lines. Cytotoxicity testing for cancer cell lines (SMMC-7721, HepG-2, RAW264.7) and normal cell lines (HL-7702) showed almost no toxicity within the 1~125 μg/mL concentration range. Carboplatin (CBP) and oxaliplatin (OXP) were then used as drug models to study the drug release of CBP and OXP loaded on GO-Fe₃O₄-PANI NPs in vitro. Results indicated that the release of CBP and OXP from GO-Fe₃O₄-PANI NPs were affected by pH, dose, and temperature. The release of CBP was more sensitive to pH, and the amounts released in neutral and acidic environments (pH 6.0 and 7.4, respectively) were higher than those released in alkaline environments (pH 8.0). Meanwhile, at different pH levels, the release of OXP was not as large. In addition, at a low temperature (27 °C), the amount released is small when the energy level does not meet that required by C═N. At a considerably higher temperature (47 °C), the energy required for C═N fracture is met, allowing the slow release of the drug over a longer period. The results of our studies suggest that GO-Fe₃O₄-PANI NPs are biocompatible with MTT assay, and as drug delivery systems, these particular NPs can lead to advances in cancer treatment.

Purpose The impact of pharmacogenetics on predicting survival in gastroenteric cancer remains unclear. Methods We tested 322 consecutive patients treated with capecitabine-based chemotherapy for CDA and MTHFR polymorphisms. Results Patients who carried the CDA 79 A>C (rs2072671) CC genotype showed significantly shorter progression-free survival (PFS) comparing with A-allele (P = 0.008). A significant better PFS was found in the patients with 451 A>G (rs532545) G-allele (P = 0.002) and 92 C>T (rs602950) T-allele (P = 0.002). In addition, a shorter PFS was also observed in patients with MTHFR 1298 A>C (rs1801131) CC genotype than the patients with AC or AA genotype after capecitabine-based chemotherapy (P = 0.002). Furthermore, the colon, female, or elder (> 65 years old) patients with MTHFR 1298 A>C CC genotype had poorer PFS than A-allele. Moreover, CDA 451 A>G was independent predictors of chemotherapy-induced toxicity in colon patients. Multivariate Cox regression analysis demonstrated that the CDA 79 A>C CC, 451 A>G AA, 92 C>T CC, and MTHFR 1298 A>C CC were predictive of shorter PFS in gastroenteric cancer patients. Conclusions The results reminded us those gastroenteric cancer patients with CDA 79 A>C CC, 451 A>G AA, 92 C>T CC, or MTHFR 1298 A>C CC genotype are not likely to benefit from the therapy of capecitabine-based chemotherapy.

目的:探讨桂圆益气补血汤(GYBD)与不同剂量龙眼肉多糖(LYP)配伍用药对环磷酰胺(CY)致免疫功能低下小鼠免疫功能的影响.方法:将70只昆明雌性小鼠随机分为7组,每组10只,即空白对照组、模型组、GYBD(相当于生药36g/kg)组、LYP(160 mg/kg)组、GYBD+低剂量LYP(80 mg/kg)组、GYBD+中剂量LYP(160 mg/kg)组、GYBD+高剂量LYP(320mg/kg)组.除空白对照组外,其他各组腹腔注射CY复制免疫抑制小鼠模型.分别灌胃给药28 d后,测定各组小鼠脾脏指数、脾淋巴细胞增殖能力、巨噬细胞吞噬能力及血清白细胞介素(IL)-2、IL-4、干扰素(IFN)-γ水平.并采用RT-PCR法检测各组小鼠脾淋巴细胞IL-4、IFN-γ、IL-2基因相对表达量.结果:与空白对照组比较,模型组小鼠脾脏指数、脾淋巴细胞增殖能力、巨噬细胞吞噬能力,血清IL-4、IFN-γ、IL-2水平及脾淋巴细胞IL-4、IFN-γ、IL-2基因相对表达量均显著降低(均P＜0.05);与模型组比较,其他各组上述指标均显著升高(P＜0.05),其中GYBD+低剂量LYP组升高最为显著,且其IFN-γ/IL-4比值与空白对照组最接近,即最大程度纠正免疫抑制小鼠Th1/Th2比值.结论:GYBD与80 mg/kg LYP配伍可明显改善CY致免疫低下小鼠的免疫功能.

Flavonoid glycoside is commonly found in natural plants, possesses diverse bioactivities and potential medicinal values, and its synthesis methods are worthy to be studied. The synthesis of flavonoid glycosides covering the literatures from 2014 to 2018 is reviewed. The flavonoid glycoside synthesis includes two major methods of chemosynthesis and biosynthesis. Chemosynthesis includes total synthesis and semi-synthesis. The total synthesis has two classical methods of the Baker-Venkataraman (BK-VK) reaction and the Algar-Flynn-Oyamada (AFO) reaction. The semi-synthesis is usually starting from natural flavonoid, such as rutin, quercetin, kaempferol, naringenin and so on. Moreover, the chemosynthesis of flavonoid O-glucoside has three prime methods, Koening-Knorr method, phase transfer catalysis method, and glycosyl trichloroacetimidate method. As for the chemosynthesis of flavonoid C-glycoside, its glycosidic linkage is mainly completed via the O -> C rearrangement reaction. Currently, the glycosyltransferase and glycosynthase are usually employed in the enzyme-catalyzed biosynthesis of flavonoid glycosides.

Cancer cell therapy using redox response and targeted drug delivery systems can increase therapeutic effects of anti-cancer therapy. Here, we report a redox-responsive drug carrier based on nanoscale Graphene Oxide (GO) loaded with Doxorubicin (DOX). In this drug carrier demonstration, we utilized Arginine-glycine-aspartic acid (RGD) peptide, aminated polyethylene glycol (6ARM-PEG-NH2 , PEG-NH2) to functionalize the GO. To integrate the carrier with a redox responsive property, we utilized disulfide linkages (3,3'-dithiodipropionic acid (DTPA)), which can be cleaved by glutathione (GSH) combined with the PEG-NH 2 . Our results show that DOX is rapidly released in a pH = 5.50 PBS solution with GSH concentration of 10 mM. The drug-loading system (RGD-GOPEG S S DOX) combined with photo-thermotherapy possesses good inhibition activity of Hep-G2 cells at a relatively low concentration. When the concentration of RGD GO PEG S S DOX was 1.56 mu g/mL, the inhibition activity of Hep-G2 cells was 78%. Because tumor cells generally exhibit a higher concentration of GSH than normal ones, and tumor blood vessels are distorted and dilated, and the blood flow resistance tends to be large, tumor cells are more sensitive to temperature changes than normal tissues. Thus, drug delivery systems, like the one we studied, have potential applications in a therapeutic strategy for the treatment of liver cancer.

Cancer cell targeted therapy using a biocompatible targeted drug delivery system can increase the therapeutic effects of cellular cancer therapy. Here, we report a Folic Acid (FA) and polyethyleneimine (PEI) functionalized Graphene Oxide (GO) nanocarrier, FA-PEI-GO, used to deliver two new Copper complexes into the folate-receptor-positive nasopharyngeal carcinoma cell line. GO was prepared by modified Hummers method and then decorated by PEI and FA. Afterwards, the material was characterized by the X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and atomic force microscopy (AFM). Copper complexes were synthesized by a hydrothermal method and then characterized by single crystal X-ray diffraction analysis. Cytotoxicity assessment of the complexes illustrated that the IC50 values against the nasopharyngeal carcinoma cell lines, HNE-1 and CNE-2, were, respectively, 17.7 ± 1.2, 13.2 ± 1.9, 6.7 ± 0.8, 2.9 ± 0.7 μM. Flow cytometry findings suggested that both complexes were capable of decreasing cancer cell viability through causing late-stage cell apoptosis. The obtained targeted drug delivery systems had good biocompatibility and stability. Compared with Cis-Dichlorodiamineplatinum (CDDP), the non-specific antitumor drug normally used in chemotherapy, one of the obtained agents had similar therapeutic effect while the other had significantly higher activity, suggesting future possible application of this new targeted therapy against nasopharyngeal carcinoma.

以1,3-双苯并咪唑苯和硝酸银为原料,在氨水环境下,140℃反应80 h制备1,3-双苯并咪唑银配合物,用FT-IR和X-射线单晶衍射对1,3-双苯并咪唑银配合物进行表征.通过MTT实验法、流式细胞术及与DNA的相互作用实验,检测1,3-双苯并咪唑银配合物的抗肿瘤活性.X-射线单晶衍射结果表明1,3-双苯并咪唑银配合物属于正交晶系,空间群为Pbcn,晶胞参数a=21.8309(10)?,b=13.7046(7)?,c=12.5769(6)?,V=3762.8(3)?3,Z=8,μ(MoKα)=1.817,F(000)=2032.0,Dc=1.850 g·cm3,最终残差因子R=0.0592,wR=0.1267.体外抗肿瘤活性实验MTT检测表明1,3-双苯并咪唑银配合物对肝癌细胞Hep-G2,人宫颈癌细胞Hela和乳腺癌细胞MCF-7均有抑制作用;流式细胞术结果表明1,3-双苯并咪唑银配合物可以诱导Hep-G2细胞凋亡,并在Hep-G2细胞G2期引起细胞周期阻滞;与DNA相互作用实验结果进一步说明1,3-双苯并咪唑银配合物以经典非插入方式与DNA发生相互作用,从而导致DNA损伤并具有抗癌作用.

In this study,the carboxymethylation of polysaccharides (LYP) extracted from longan (Dimocarpus longan) pulp was investigated using monochloroacetic acid (MCA) with polysaccharides-to-MCA ratio,reaction time and reaction temperature as independent variables.The degree of substitution (DS) was taken as response value to optimize the important reaction conditions by response surface methodology.Meanwhile,the antioxidant activity and immunoregulatory of carboxymethlated polysaccharides (CM-LYP) in vivo were measured.The results showed that the optimized conditions that provided the maximum DS of 1.053 were determined as follows:reaction time,3.2 h;MCA concentration,1.2 mol/L;and reaction temperature,73 ℃.The antioxidant activity.of CM-LYP was concentration dependent in a certain range of concentration.The percentage inhibition of hydroxyl and superoxide anion radicals,lipid peroxidation,red blood cell hemolysis induced by H2O2 were (42.35 ± 5.67)％,(51.91 ± 5.34)％,(67.91 ± 5.72)％,and (47.23 ± 3.5)％ by LYP,and (84.39 ± 4.47)％,(87.91 ± 7.32)％,and (79.85 ± 2.92)％,and (54.66 ± 2.83) ％ by CM-LYP,respectively,implying that the antioxidant activity of LYP was improved as compared to the native polysaccharides.The immunoregulatory activity in vivo showed that CM-LYP significantly improved spleen index in immunosuppressed,increased serum hemolysin level and lysozyme activity in serum and spleen,and maintained Th1/Th2 balance,and the effect was better than that of LYP.

Two Cu I atoms are present in the asymmetric unit of the polymeric title complex, [Cu 2 (C 20 H 12 N 4 )(C 10 H 8 N 2 )] n . One of the cations is located on an inversion centre and is linearly coordinated by the N atoms of benzimidazolyl moieties of the 1,2-bis(2-benzimidazolium)benzene ligand, whereas the second cation is located on a twofold rotation axis and is tetrahedrally coordinated by two N atoms of a chelating 2,2′-bipyridine ligand and two other N atoms of the benzimidazolyl moieties. The bridging character of the 1,2-bis(2-benzimidazolyl)benzene leads to the formation of a three-dimensional framework structure.

对龙眼肉多糖进行乙酰化修饰最佳工艺研究,采用乙酸酐法制备乙酰化龙眼肉多糖,以取代度为指标,采用响应面法对工艺条件进行优化,并研究乙酰化龙眼肉多糖的体外抗氧化活性.结果显示,龙眼肉多糖的最佳乙酰化条件为:乙酸酐-多糖物质的量比(投料比)10.2∶1、反应温度42℃、反应时间30min.该工艺条件下龙眼肉多糖乙酰化取代度达到0.443.乙酰化龙眼肉多糖能够清除羟自由基、抑制脂质过氧化以及H2O2诱导的红细胞溶血,半数抑制浓度(IC50)分别为702.41、646.04μg/mL和380.11 μg/mL,表现出比未修饰龙眼肉多糖更强的抗氧化活性.