海洋药物及其研发新进展

海洋来源的药物在人类与疾病的长期斗争中发挥了重要的作用,“向海洋要药”在新世纪已成为各国政府的共识、研究人员奋斗的目标。本文对截止2017年底国内外已获批上市的海洋药物进行了归纳总结,并重点介绍了欧美等发达国家和我国已上市小分子药物的药物来源、结构、最新药理作用、临床功效和用途、以及研发历程。此外,介绍了国内外进入各期临床研究阶段的67个候选海洋药物,本文以salinosporamide A和河豚毒素为代表,重点介绍了当前处于临床研究阶段的海洋药物的最新进展。     

Active elimination of the marine biotoxin okadaic acid by P-glycoprotein through an in vitro gastrointestinal barrier

The consumption of okadaic acid (OA) contaminated shellfish can induce acute toxic symptoms in humans such as diarrhea, nausea, vomiting and abdominal pain; carcinogenic and embryotoxic effects have also been described. Toxicokinetic studies with mice have shown that high cytotoxic doses of OA can pass the gastrointestinal barrier presumably by paracellular passage. However, in vitro studies using human intestinal Caco-2 cell monolayers to represent the intestinal barrier have shown that at low-dose exposure OA is transported against a concentration gradient suggesting an active efflux mechanism. Since P-glycoprotein (P-gp) transports a wide variety of substrates, we investigated its possible influence on the observed elimination of OA. We used two different cellular transwell models: (i) Caco-2 cell monolayer endogenously expressing human P-gp and simulating the intestinal barrier and (ii) MDCK-II cell monolayer stably over-expressing P-gp. Our study demonstrates clearly that OA at non-cytotoxic concentrations passes the monolayer barrier only to a low degree, and that it is actively eliminated by P-gp over the apical membrane. Therefore, our in vitro data indicate that humans appear to have efficient defense mechanisms to protect themselves against low-dose contaminated shellfish by exhibiting a low bioavailability as a result of active elimination of OA by P-gp.     

Natural products against cancer: Review on phytochemicals from marine sources in preventing cancer

Marine natural products have as of now been acknowledged as the most important source of bioactive substances and drug leads. Marine flora and fauna, such as algae, bacteria, sponges, fungi, seaweeds, corals, diatoms, ascidian etc. are important resources from oceans, accounting for more than 90% of the total oceanic biomass. They are taxonomically different with huge productive and are pharmacologically active novel chemical signatures and bid a tremendous opportunity for discovery of new anti-cancer molecules. The water bodies a rich source of potent molecules which improve existence suitability and serve as chemical shield against microbes and little or huge creatures. These molecules have exhibited a range of biological properties antioxidant, antibacterial, antitumour etc. In spite of huge resources enriched with exciting chemicals, the marine floras and faunas are largely unexplored for their anticancer properties. In recent past, numerous marine anticancer compounds have been isolated, characterized, identified and are under trials for human use. In this write up we have tried to compile about marine-derived compounds anticancer biological activities of diverse flora and fauna and their underlying mechanisms and the generous raise in these compounds examined for malignant growth treatment in the course of the most recent quite a long while.     

Jellyfish collagen scaffolds for cartilage tissue engineering

Porous scaffolds were engineered from refibrillized collagen of the jellyfish Rhopilema esculentum for potential application in cartilage regeneration. The influence of collagen concentration, salinity and temperature on fibril formation was evaluated by turbidity measurements and quantification of fibrillized collagen. The formation of collagen fibrils with a typical banding pattern was confirmed by atomic force microscopy and transmission electron microscopy analysis. Porous scaffolds from jellyfish collagen, refibrillized under optimized conditions, were fabricated by freeze-drying and subsequent chemical cross-linking. Scaffolds possessed an open porosity of 98.2%. The samples were stable under cyclic compression and displayed an elastic behavior. Cytotoxicity tests with human mesenchymal stem cells (hMSCs) did not reveal any cytotoxic effects of the material. Chondrogenic markers SOX9, collagen II and aggrecan were upregulated in direct cultures of hMSCs upon chondrogenic stimulation. The formation of typical extracellular matrix components was further confirmed by quantification of sulfated glycosaminoglycans.     

沙蚕消化道D2菌株胞外蛋白酶对EMT6细胞增殖的影响

目的研究沙蚕消化道产蛋白酶菌D2株胞外蛋白酶对鼠乳腺癌细胞EMT6增殖的影响。方法选用鼠乳腺癌细胞EMT6作为靶细胞，用0．0043-43μmol／L浓度的沙蚕消化道产蛋白酶菌D2株胞外蛋白酶（D2蛋白酶），通过体外细胞培养法进行细胞增殖抑制检测，测其吸光度（OD）值，计算细胞增殖抑制率，与阳性对照组（紫杉醇组）比较。结果实验组OD值低于空白对照组，且存在时间和剂量依赖关系。结论沙蚕消化道产蛋白酶菌D2株胞外蛋白酶对鼠乳腺癌细胞EMT6的增殖存在抑制作用，显示出一定的抗肿瘤活性。     

The cytotoxicity of lingshuiol: a comparative study with amphidinol 2 on membrane permeabilizing activities.

The cytotoxicity of lingshuiol, a novel polyhydroxy compound with a linear carbon-chain isolated from the cultured marine dinoflagellate Amphidinium sp., and that of amphidinol 2 (AM2) was compared with hepatocytes. Both lingshuiol and AM2 were toxic to primary rat hepatocytes with IC(50) values of 0.21 and 6.4muM, respectively. Meanwhile, lingshuiol or AM2 caused a rapid mitochondrial swelling and leakage of Ca(2+), underlying the change in permeability of mitochondria. Cyclosporin A, a specific inhibitor of mitochondrial permeability transition (MPT), could not affect these effects, indicating that CsA-sensitive MPT was not involved in the permeabilizing effects of lingshuiol or AM2. Sytox green tests further demonstrated that lingshuiol had a much stronger permeabilizing activity than AM2. Taken together, these results disclosed that lingshuiol had potent membrane permeabilizing activities, which might account for its cytotoxic effect.     

人工养殖海产品鲜样中铅的荧光分光光度测定法

目的建立人工养殖海产品中铅的荧光分光光度快速测定方法。方法采用湿式消解法对中国对虾(养殖)、南美白对虾、梭鱼、矛尾刺虾虎鱼、四角蛤蜊、光滑兰蛤、密鳞牡蛎、中国对虾(野生)样品进行处理,采用浓盐酸作溶剂,荧光分光光度法直接检测铅含量,并与双硫腙光度法的测定结果进行比较。结果该方法的线性范围为0.10～2.50μg/ml,r=0.98983,检出限为0.0089μg/ml,回收率为91.88%～104.00%,RSD为1.96%～5.30%。与双硫腙分光光度法测得结果比较,差异均无统计学意义(P>0.05)。结论该方法具有操作简便,使用药剂少,灵敏度高,结果准确可靠,常见金属离子干扰小的特点,适用于海产品中铅含量的测定。     

湖南省2005年霍乱监测分析

目的 掌握湖南省霍乱流行规律和霍乱弧菌在环境水体及食品的污染情况，为指导今后的霍乱防治工作提供依据。方法运用主动监测、被动监测、专项调查、现场流行病学调查等多种方法对湖南省的腹泻病人、环境水体、水产品、食品、霍乱疲情等进行监测。结果 2005年湖南省腹泻病人检索阳性率为0．02％，全部为O139群；外环境和食品监测阳性率为0．04％，18份阳性标本中主要为水体8份，水产品8份；全年共发生霍乱瘦情13起。其中11起与聚餐有关，共报告病例43例，带菌者29例，均为0139群；所检测其中20株O138霍乱孤菌均为产毒株；从病人、带菌者、甲鱼中分离的139霍乱菌株高度同源。结论 开展霍乱疫源监测是早期发现疲情、厦时掌握疲情动态的重要措施，今后应加强对甲鱼等海水产品的霍乱弧菌污染状况监测扣加强对农村集体聚餐的卫生指导和管理，以及加大外环境的检索力度扣加强各种水体的消毒措施，防止疫情通过水体扩散。     

苦参素胶囊联合阿德福韦酯治疗慢性乙型肝炎的临床研究

目的:观察苦参素胶囊联合阿德福韦酯治疗慢性乙型肝炎的临床疗效.方法:34例HBeAg与HBV DNA均阳性的慢性乙肝患者接受苦参素胶囊联合阿德福韦酯治疗12个月并与30例单用阿德福韦酯治疗的患者进行对比.结果:疗程结束时观察组HBV-DNA阴转率为82.3%与对照组76.7% 相比无明显差异(P＞0.05).观察组HBeAg阴转率为58.8% 明显高于对照组36.7% (P＜ 0.01).疗程结束后随访6个月观察组HBeAg与HBV DNA持续阴转率为61.8%、85.4%明显高于对照组的33.3%、73.3% (P＜ 0.01).观察组HBeAg与HBV DNA的复发率明显低于对照组(P＜ 0.05).结论: 苦参素胶囊与阿德福韦酯联合应用有协同作用,可提高疗效,减少病毒耐药降低复发率.