狗牙花属植物生物碱类成分及生物活性的研究进展

夹竹桃科(Apocynaceae)狗牙花属(Ervatamia Stapf)植物中的化学成分以及其生物活性一直是研究热点。其在全世界有约120种,主要分布在印度、中国西南地区,东南亚、大洋洲、北美洲、南美洲部分地区以及各海岛;在我国主要有15种和5变种,主要分布在华南地区及西南地区和台湾。我国傣族将云南狗牙花茎用于治疗产后体虚、头晕目眩、恶露淋漓等症状。据《中国植物志》中记载,产于亚洲热带与亚热带地区的单瓣狗牙花,其叶有降低血压功效,常用于治眼病、疮疥、乳疮、咬伤等;根可治头痛和骨折等。生物碱是狗牙花属植物中的主要化学成分,具有新颖的化学结构。现代药理学研究发现,狗牙花属植物中生物碱类成分具有抗肿瘤和抗乙酰胆碱脂酶等生物活性,其中抗肿瘤活性最为显著。因此狗牙花属植物具有很好的开发价值。但是,科研人员对狗牙花属植物生物碱类成分的研究仅限于发现与生物活性的测定,临床功效的研究较少。笔者结合近20年来的国内外文献对该属植物中149个生物碱进行总结,为进一步研究具有显著活性的生物碱类化学成分,合理充分利用狗牙花属植物的药用资源提供有价值的参考。     

Palmatine: A review of pharmacological properties and pharmacokinetics

The aim of this review is to collect together the results of the numerous studies over the last two decades on the pharmacological properties of palmatine published in scientific databases like Scopus and PubMed, which are scattered across different publications. Palmatine, an isoquinoline alkaloid from the class of protoberberines, is a yellow compound present in the extracts from different representatives of Berberidaceae, Papaveraceae, Ranunculaceae, and Menispermaceae. It has been extensively used in traditional medicine of Asia in the treatment of jaundice, liver‐related diseases, hypertension, inflammation, and dysentery. New findings describe its possible applications in the treatment of civilization diseases like central nervous system‐related problems. This review intends to let this alkaloid come out from the shade of a more frequently described alkaloid: berberine. The toxicity, pharmacokinetics, and biological activities of this protoberberine alkaloid will be developed in this work.     

麦芽4个化学部位通过多巴胺D2受体对产后缺乳模型大鼠催乳作用研究

目的基于多巴胺D2受体(DRD2),考察小剂量麦芽4个化学部位的催乳作用,初步探讨小剂量麦芽生物碱对产后缺乳模型大鼠泌乳素(PRL)分泌的调节机制。方法采用ig甲磺酸溴隐亭方法制备缺乳大鼠模型,造模成功后,各给药组均ig给予相应的药物,应用ELISA法检测各组大鼠血清PRL、雌二醇(E_2)、孕酮(P)水平;HE染色观察各组大鼠乳腺组织病理改变;采用实时荧光定量PCR(qRT-PCR)法检测各组大鼠脑垂体中泌乳素受体及DRD2 mRNA表达。结果与对照组比较,模型组大鼠血清中PRL、P及E_2水平、脑垂体PRL mRNA表达水平显著降低;脑垂体DRD2 mRNA表达水平显著升高。与模型组比较,麦芽总生物碱组大鼠乳腺小叶体积明显增加,导管明显扩张,且导管及腺泡内含有大量乳汁。麦芽总生物碱明显增加模型大鼠血清中PRL、P、E_2水平及脑垂体PRL mRNA表达水平,降低脑垂体DRD2 mRNA表达水平。结论麦芽催乳的主要药效物质为总生物碱,其作用机制可能与促进PRL分泌,增加脑垂体PRL受体、降低DRD2 mRNA表达水平有关。     

基于UPLC-LTQ-Orbitrap高分辨质谱的葛根芩连汤的化学成分分析

目的基于超高效液相色谱-离子阱-静电场轨道阱质谱(UPLC-LTQ-Orbitrap-MS)的分析方法鉴定葛根芩连汤中化学成分。方法采用色谱柱Dikma Endeavorsil C18(100 mm×2.1 mm,1.8μm),流动相为0.1%甲酸水(A)-乙腈(B),体积流量0.3 mL/min,梯度洗脱。质谱采用ESI源,正负离子模式分别采集一级、二级质谱数据。结果通过对照品指认、软件预测分析,结合文献报道,从葛根芩连汤中鉴定出67个化合物,包括黄酮类36个、生物碱类12个、三萜类及三萜皂苷类4个及其他15个。结论利用UPLC-LTQ-Orbitrap-MS系统阐明葛根芩连汤中化学成分,并初步归纳其各类主要化学成分的质谱裂解特点,为葛根芩根芩连汤的质量控制和作用机制研究提供了参考依据。     

吴茱萸化学成分和药理作用及质量标志物(Q-marker)的预测分析

吴茱萸是我国常用的大宗中药材,资源丰富且分布较广,具有广阔的开发利用前景。吴茱萸中化学成分类型丰富,包括生物碱、苦味素、挥发油、黄酮等类成分,传统认为生物碱和苦味素为其主要药效成分。对其化学成分、药理作用综述的基础上,根据中药质量标志物(Q-marker)理论,从生源途径、化学成分与传统功效、传统药性、新的临床用途、毒性、可测成分、入血成分及不同配伍环境几方面对吴茱萸Q-marker成分进行预测分析,为明确吴茱萸Q-marker和制定科学的质量标准提供基础。     

Differential involvement of glutathione S‐transferase mu 1 and multidrug resistance protein 1 in melanoma acquired resistance to vinca alkaloids

On account of its extreme intrinsic resistance to apoptosis and of its strong ability to become chemoresistant after a primary response to drugs, malignant melanoma (MM) is still a therapeutic challenge. We previously showed that glutathione S‐transferase mu 1 (GSTM1) acts in synergy with multidrug resistance protein 1 (MRP1) to protect GSTM1‐transfected human CAL1 melanoma cells from toxic effects of vincristine (VCR). Herein, we investigated the role of these proteins in the acquired resistance of CAL1 cells to vinca alkaloids (VAs). Resistant lines were established by continuous exposure (>1 year) of parental CAL1‐wt cells to VCR, vindesine (VDS), or vinorelbine (VRB): CAL1R‐VCR, CAL1R‐VDS, CAL1R‐VRB, respectively. All resistant lines displayed more than 10‐fold increase in resistance to their selection VA, and specifically expressed GSTM1. Suggesting a direct interaction between this protein and VAs, each VA specifically decreased the GSTM1‐mediated glutathione conjugation activity in cell lysates. Curcumin (GSTM1 inhibitor), BSO (glutathione synthesis inhibitor), and MK571 (MRP1 inhibitor) considerably reversed the acquired resistance to VCR and VDS, but not to VRB. Microarray data analysis revealed similar gene expression patterns of CAL1R‐VCR and CAL1R‐VDS, and a distinct one for CAL1R‐VRB. These data suggest a differential involvement of GSTM1 and MRP1 in acquired resistance to VAs. A coordinated expression and activity of GSTM1 and MRP1 is required to protect CAL1 cells from VCR and VDS, while the simple expression of GSTM1 is sufficient, possibly by a direct drug/protein interaction, to confer resistance against VRB.     

海南地不容生物碱抑制肿瘤细胞增殖及构效关系解析

目的研究海南地不容(Stephania hainanensis H.S.Lo et Y.Tsoong)生物碱对人肝癌细胞Hep G-2、乳腺癌细胞MCF-7、胃癌细胞SGC-7901增殖的影响,筛选出有效的抗肿瘤化合物以及其敏感细胞株;分析其生物碱的构效关系。方法采用MTT法检测不同浓度的海南地不容生物碱对人肝癌细胞Hep G-2、乳腺癌细胞MCF-7、胃癌细胞SGC-7901增殖的抑制率;通过查阅国内外相关文献,分析海南地不容生物碱抗肿瘤活性的基本构效关系。结果MTT结果显示荷包牡丹碱、氧化克班宁、去甲荷包牡丹碱和克班宁对人肝癌Hep G-2、乳腺癌MCF-7和胃癌SGC-7901细胞的增值分别具有不同程度的剂量依赖性的抑制作用,各给药组分吸光度值与空白对照组比具有显著性差异(P<0.01),与阳性对照比较无明显统计学差异(P>0.05);海南地不容生物碱结构中的1,2-亚甲二氧基、N-亚甲基等取代基以及其化学结构的平面性对其抗肿瘤活性有重要影响。结论海南地不容中具有明显抗肿瘤作用的生物碱为荷包牡丹碱、氧化克班宁、去甲荷包牡丹碱和克班宁,其敏感细胞株均为乳腺癌细胞MCF-7;通过分析海南地不容生物碱的结构和抗肿瘤活性的关系,初步明确了其抗肿瘤活性可能与其结构易于抑制DNA拓扑异构酶和诱导细胞凋亡有关。     

Tubulin inhibitors in non-small cell lung cancer: looking back and forward

Introduction: Although the advent of target therapy for lung cancer has brought about outstanding results, this benefit is confined to a subgroup of molecularly selected patients, whereas for most non-small cell lung cancer (NSCLC) patients, chemotherapy still represents the milestone of treatment. Since their introduction into clinics, microtubule targeting agents (MTA), including vinca alkaloids and taxanes, have been extensively used for NSCLC in different settings and combinations.

Areas Covered: In this review, MTA are classified according to their mechanism of action, with a focus on the most common mechanisms of resistance. Moreover, an overview of the most remarkable clinical data regarding MTA in adjuvant, neoadjuvant and advanced setting is provided. Finally, the novel mitotic kinases inhibitors are described according to their different mechanism of action and clinical activity compared to MTA.

Expert Opinion: Unfortunately, the awaited benefit deriving from the actually available chemotherapeutic regimens for advanced NSCLC has reached a plateau. In this scenario, the identification of reliable predictive biomarkers represents a major challenge. Moreover, different schedules for MTA administration are currently under investigation, such as the combination of MTA with other drugs able to bypass the resistance derived from the ‘mitotic slippage’ and the use of metronomic administration of spindle poisons with anti-angiogenic or immunomodulatory agents.     

Noscapine hydrochloride (benzyl-isoquinoline alkaloid) effectively prevents protein denaturation through reduction of IL-6, NF-kB,COX-2, Prostaglandin-E2 in rheumatic rats

Noscapine hydrochloride (benzyl-isoquinoline antitussive alkaloid) is an opium derivative and generally used as a cough suppressant. Numerous studies on noscapine hydrochloride have reported that it has potent anti-inflammatory activity. However, the mechanisms by which it exerts an anti-inflammatory function is not well understood. Protein denaturation is the primary step that leads to the organ destruction and permanent arthritic disability. The above-mentioned facts provided the ground to plan this study using different in-vitro and in-vivo approaches. RT-qPCR and ELISA assays were used to assess the inflammatory markers related to protein denaturation in complete adjuvant persuaded rheumatism in Sprague - Dawley rats. The results were collected as paw volume and body weight changes, arthritic scoring and serum antioxidant enzymes assays. These findings demonstrated that all doses of noscapine hydrochloride (10, 20 and 40 mg/kg) studied in this study, significantly (p < 0.001) decreased the protein denaturation by preventing the increase in levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nuclear factor-kB (NF-kB), cyclooxygenase-2 (COX-2) and prostaglandin E2. Noscapine hydrochloride significantly reduced the paw volume (p < 0.001), arthritic scoring and reversed the body mass as compared to arthritic control diseased rats.