水飞蓟素抗肝损伤及治疗糖尿病并发症作用的研究

主要综述近3年水飞蓟素、水飞蓟宾和水飞蓟宾-磷脂复合物在药理和临床上新的应用.这些化合物具有抗氧化、抗脂质过氧化、抗纤维化、抗炎症、细胞膜稳定、免疫调节和肝再生等活性.它们最常用作肝保护剂,也应用于拮抗糖化氧化和胰岛素增敏活性以及抗糖尿病、治疗非酒精性脂肪性肝病.     

水飞蓟宾脱氢衍生物的研究进展

2,3-脱氢水飞蓟宾是水飞蓟素中的有效成分之一,有比水飞蓟宾更强的抗氧化和抗肿瘤活性,本文综述了水飞蓟宾脱氢衍生物---2,3-脱氢水飞蓟宾的研究进展。     

2，3-脱氢水飞蓟宾的合成

以水飞蓟宾为原料合成２,３－脱氢水飞蓟宾,收率达８０％,对水飞蓟宾和２,３－ 脱氢水飞蓟宾进行了抗氧化药理实验,水飞蓟宾的抗质过氧化物活性强于２,３－脱氢水飞蓟宾。     

水飞蓟宾类黄酮木质素衍生物的研究进展

水飞蓟是多国药典收载的天然药物,具有抗氧化、抗纤维化、抗炎、免疫调节以及肝细胞再生作用,临床用于治疗肝炎、脂肪肝、肝硬化、缺血性损伤、辐射损伤等。近期随着水飞蓟宾以抗肿瘤新药进入Ⅱ期临床试验,对其衍生物、构效关系以及抗氧化机制等的研究进入加速阶段。本文综述了近年来水飞蓟宾和脱氢水飞蓟宾的近百种衍生物及其活性研究结果 ,并对该类黄酮木质素类化合物今后的发展和设计研究状况做一概述。     

水飞蓟宾衍生物的研究进展

介绍近年来通过对水飞蓟宾进行结构修饰以改进其溶解性和生物活性的研究进展。水飞蓟宾具有抗脂质过氧化、清除自由基、保护肝细胞、抗肝纤维化和免疫调节等作用,但因溶解性差、生物利用度低,其临床应用受到一定限制。故以水飞蓟宾为先导化合物合成相关衍生物,并从中筛选专一性强和活性高的化合物,已成为广受关注的研究热点。     

水飞蓟宾-磷脂酰胆碱复合物与水飞蓟宾对四氯化碳所致小鼠急性肝损伤保护作用的对比

目的比较水飞蓟宾 磷脂酰胆碱复合物 (SPC)与水飞蓟宾对四氯化碳所致的小鼠肝损伤的保护作用。方法 5 0只小鼠随机分成 5组 ,通过对对照组、给药组小鼠血清中天冬氨酸氨基转移酶 (AST)、丙氨酸氨基转移酶(ALT)及肝组织学观察 ,比较SPC与水飞蓟宾对四氯化碳所致小鼠肝损伤之预防作用的效果。结果水飞蓟宾和SPC均能降低小鼠血清ALT、AST活性 ,能减轻肝脏病理学变化 ,但以SPC作用最为明显。结论SPC对四氯化碳造成的急性肝损伤有明显的保护作用 ,SPC的作用强于水飞蓟宾。     

提高水飞蓟素生物利用度的新剂型

水飞蓟素(Silymarin)是从菊科植物水飞蓟果实中提取的黄酮木脂素类有效部位,主要成分为水飞蓟宾、水飞蓟宁、水飞蓟亭等,其中活性最强的是水飞蓟宾。药理研究表明,水飞蓟素是一种优良的肝脏保护剂和肝细胞膜稳定剂,临床用作急、慢性肝炎,酒精性及中毒性肝损害,脂肪肝及早期肝硬     

水飞蓟宾的抗肿瘤、抗氧化和免疫调节分子药理学机制研究进展

 水飞蓟宾 (silibinin) 来源于菊科植物水飞蓟 (Silybum marianum), 为黄酮木脂素类化合物, 具有明显抗氧化和抗炎的特性, 临床上作为保肝药物长期应用于中国、德国和日本等国家。近年来发现水飞蓟宾有明显的抗肿瘤活性, 其主要机制为抑制肿瘤受体型酪氨酸激酶 (receptor tyrosine kinase, RTK) 的活性, 如抑制表皮生长因子受体1 (epidermal growth factor receptor 1, EGFR) 和胰岛素样生长因子1受体 (insulin-like growth factor 1 receptor, IGF-1R) 及其下游信号分子的活化。同时因为发现水飞蓟宾对羟自由基 (•OH) 的选择性清除, 以及对核因子κB (nuclear factor-κB, NF-κB) 的特异性抑制, 使其抗氧化和抗炎的分子机制更为明确。一些新的发现如水飞蓟宾通过抑制氧化应激和炎症反应而改善β-淀粉样蛋白 (amyloid β protein, Aβ) 引起的认知功能障碍等对拓展水飞蓟宾的药用前景具有重要价值。本文对水飞蓟宾的分子药理机制进行总结, 主要从水飞蓟宾抑制肿瘤RTK信号转导、抗氧化与自由基清除、调节免疫与炎症3个方面进行了阐述。     

水飞蓟宾对小鼠腹腔巨噬细胞释放纤维化因子的影响

目的：研究水飞蓟宾对小鼠腹腔巨噬细胞释放纤维化因子的影响。方法：小鼠腹腔巨噬细胞先后用卡西霉素和脂多糖刺激培养24h诱导纤维化因子。巨噬细胞培养上清中促胶原合成活性和转化生长因子p活性分别采用^3H-脯氨酸掺入法和雕肺上皮My-1-Lu细胞测定。结果：水飞蓟宾（6．25—50μg／mL）以浓度依赖方式抑制巨噬细胞产生胶原刺激活性和转化生长因子β1。结论：水飞蓟宾减少巨噬细胞释放促纤维化因子可能是其保肝抗硬化机制之一。     

水飞蓟宾对阿尔茨海默病模型大鼠学习记忆功能及对神经细胞内活性氧的影响

目的探讨水飞蓟宾对阿尔茨海默病(AD)大鼠行为的改善作用及对神经细胞内自由基的清除情况。方法大鼠60只,采用皮下注射东莨菪碱致AD模型,随机分为模型组、空白对照组、水飞蓟宾高中低剂量组及阳性对照多奈哌齐组,用Morris水迷宫法,检测大鼠的学习记忆能力。另外采用过氧化试剂诱导人神经母细胞瘤细胞(SH-SY5Y)过氧化损伤通过流式细胞仪检测水飞蓟宾对活性氧自由基的清除能力。结果模型组与空白对照组比学习记忆能力显著下降,治疗组与模型组比学习记忆能力得到显著改善,同时体外实验证实水飞蓟宾能显著降低细胞内的自由基水平。结论水飞蓟宾对AD有较好的改善作用,其机制可能与其抗自由基活性有关。     

Influence of Silybin-dihemisuccinate on fatty acid synthesis in rat liver (author's transl)]

1. The influence of silybin-dihemisuccinate, a derivative of the flavonolignane silybin from silybum marianum L. Gaertn., on fatty acid biosynthesis of rat liver was studied measuring the radioactivity incorporation of [1-14C]-acetate and 3H2O in fatty acids of the postmitochondrial supernatant of liver homogenates and in fatty acids of liver slices as well as the activities of enzymes involved in do novo synthesis of fatty acids. 2. In the postmitochondrial supernatant of liver homogenates or in liver slices, prepared 30 or 60 min after i.v. injection of 150.6 mg/kg silybin-dihemisuccinate, radioactivity incorporation of 14C-acetate or 3H2O in fatty acids was lowered by about 25%. Adding silybin-dihemisuccinate to incubation mixture in vitro in the concentration of 0.45--0.6 mmol/l silybin the radioactivity incorporation was linearly diminished with increased concentration of silybin. 3. After in vitro addition of varying concentrations of silybin to incubation mixtures in the presence of 0.1 mmol/l silybin activities of acetyl-CoA-carboxylase, fatty-acid-synthetase and ATP-citrate-lyase were diminished by about 50%, while activity of NADP-malate-dehydrogenase was lowered by 20% in the presence of 1 mmol/l silybin. 4. Our results suggest that silybin caused an unspecific and, under in vivo conditions, transitory inhibition of fatty acid synthesis in rat liver.     

护肝宁片联合水飞蓟宾对脂肪肝患者血脂及血管内皮素-1的影响

目的观察护肝宁片联合水飞蓟宾治疗脂肪肝的疗效,探讨其对血管内皮素-1(ET-1)的影响。方法将我院收治的脂肪肝患者随机分为2组,即水飞蓟宾组及护肝宁片联合水飞蓟宾治疗组(联合治疗组),分别给予水飞蓟宾、护肝宁片联合水飞蓟宾治疗。检测两组治疗前后TC、TG、LDL、ALT、AST、γ-GT、ET-1水平。另选20例健康成年人作为健康对照组,检测其血清ET-1水平。结果治疗后,水飞蓟宾组、联合治疗组血清TC、TG、LDL、ALT、AST、γ-GT水平明显降低(P<0.05),但联合治疗组减低更明显(P<0.05)。与健康人群相比,联合治疗组血清内皮素-1水平明显增高,治疗后,水飞蓟宾组、联合治疗组血清内皮素-1水平均明显降低(P均<0.05)。水飞蓟宾组总有效率为87.5%,联合治疗组总有效率为96.12%,两组比较差异有统计学意义(P<0.05)。结论护肝宁联合水飞蓟宾治疗脂肪肝疗效显著,脂肪肝患者ET-1明显增高,ET-1可能参与脂肪肝的病理生理过程。     

Self-assembly and characterization of Pluronic P105 micelles for liver-targeted delivery of silybin

Polymeric micelles, based on lactobionic acid (LA)-conjugated Pluronic P105 (P105), were prepared to achieve liver-targeted delivery of silybin. In the triblock copolymer structure of PEO–PPO–PEO, LA was successfully conjugated with the terminal end of PEO to produce LA-P105. The success of synthesis was confirmed using FTIR and ¹H NMR. The triblock copolymers with functional moiety were physically mixed with silybin to form micelles. Silybin-loaded LA-P105 micelles characterized by dynamic light scattering and transmission electron microscopy (TEM) were uniform spherical particles. There was a remarkable increase in the dissolubility for silybin in LA-P105 micelle solution (627?μg/mL) when compared with that for water (4.6?μg/mL). The pharmacokinetic experiments showed that the area under the curve of silybin plasma concentration–time profile in rats for LA-P105 micelles was lower than that for P105 micelles. Biodistribution studies indicated that a significantly increased amount of silybin was accumulated in liver, suggesting that LA locating on the surface of the micelles played an important role in transporting an increased amount of silybin into liver. This polymeric vehicle is, therefore, expected to be widely used as target-specific delivery vehicles for diverse water-insoluble therapeutic and diagnostic agents.     

Investigations on the actions of silybin on regenerating rat liver. Effects on Kupffer's cells

Studies were conducted on the effects of silybin upon the biological activities of Kupffer's cells in regenerating livers of rats subjected to partial hepatectomy. As far as proliferative activity is concerned, which was assessed by the colchicine stathmokinetic method on Kupffer's cells isolated from the liver by enzymatic digestion, it was appreciably increased in rats treated with silybin in respect of controls. Phagocytic and bactericidal activities were not modified. The increased mitotic activity induced on Kupffer's cells by silybin was interpreted as a further expression of the effectiveness of silybin on the cellular components of the liver.     

水飞蓟宾自乳化制剂对CCl4所致肝损伤的保护作用

目的 探讨水飞蓟宾自乳化制剂对CCl₄所致急性肝损伤的保护作用。方法 以CCl₄所致小鼠急性肝损伤为模型,以生理盐水为阴性对照,以联苯双酯为阳性对照,以水飞蓟宾混悬剂为参比,以血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)和肝脏中谷胱甘肽过氧化物酶(GSH-PX)活性及肝脏病理组织切片检查为指标,对比研究水飞蓟宾自乳化制剂对CCl₄所致急性肝损伤的保护作用。结果 水飞蓟宾自乳化制剂能显著的抑制CCl₄所致的血清ALT和AST活性升高,使肝脏中的GSH-PX维持在正常水平,保护肝脏并避免其发生严重病变。结论 水飞蓟宾自乳化制剂对CCl₄所致急性肝损伤有保护作用。     

Pharmacokinetics of silybin in bile following administration of silipide and silymarin in cholecystectomy patients.

The biliary excretion of silybin, the main active component of silymarin, was evaluated by using a specific HPLC method in 9 cholecystectomy patients with T-tube drainage following single oral doses of silipide (CAS 134499-06-2), a lipophilic silybin-phosphatidylcholine complex (IdB 1016), and of silymarin (120 mg, expressed as silybin equivalents). After intake of silipide, the concentration of silybin in bile reached a peak within 4 h and declined thereafter with a mean time of about 10 h. After administration of silymarin, biliary silybin concentrations were several-fold lower than those observed after intake of silipide. The bile collected after silymarin intake also contained considerable amounts of isosilybin (a silybin isomer) and very low levels of silydianin and silycristin. The amount of silybin recovered in bile in free and conjugated form within 48 h accounted for 11% of the dose after silipide and for 3% of the dose after silymarin. Plasma silybin concentrations, determined in 3 subjects, were several-fold lower than those in bile after intake of silipide and mostly undetectable after intake of silymarin. These data indicate that the bioavailability of silybin is much greater after administration of silipide than after administration of silymarin. This results in increased delivery of the compound to the liver, which represents the target organ for pharmacological action.     

Chemoenzymatic preparation of silybin beta-glucuronides and their biological evaluation.

Chemoenzymatic glucuronidation of the optically pure silybin A (1) using ovine liver glucuronyl transferase afforded three beta-glucuronides of silybin, substituted at phenolic OH groups at the positions C-20 (2), C-7 (3), and C-5 (4) formed in the yields 27, 62.5, and 2.5%, respectively. Using these standards, it was shown that the main silybin conjugate in humans is its 20-beta-D-glucuronate (2), while the C-7 regioisomer (3) was formed in lower proportion. The rate of conjugation of (natural) silybin diastereomers 10S, 11S and 10R, 11R, and therefore also their metabolism in humans is rather different. The radical scavenging activity of 2 is considerably lower than that of its aglycone (1); however, the activity of 3 is higher than in the silybin. These findings corroborate the hypothesis that, at physiological pH, the exclusive target for one-electron oxidation of the silybin molecule is the o-methoxy-phenolic structure at C-19, C-20. This is first pharmacological study using optically pure silybin.     

Phalloidine antagonists. 1. Effects of silybine derivatives on isolated perfused rat liver]

The protective effect of two silybin derivatives against phalloidin was tested in isolated rat livers, perfused with an erythrocyte free medium. Both liver swelling and potassium loss were examined for the evaluation of antagonism. Liver swelling and potassium loss were markedly decreased when silybin hemisuccinate was added to the perfusion medium before the application of phalloidin. In contrast, the protective effect of this compound was minimal after the mushroom toxin was partially absorbed by the liver. The protective efficiency of a dimer derivative (disilybin) was much greater than that of the monomer product. The binding of both derivatives in the liver cannot be very strong because the protective effect mainly could be washed out by a single change of the perfusion medium. Spectroscopical studies on isolated hepatocytes indicate that silybin inhibits the interaction of phalloidin with the cell surface.