水飞蓟素抗肿瘤作用及其机制研究进展

水飞蓟素是从植物水飞蓟种子中提取得到的一类生物活性成分,含65%～80%黄酮木脂素(或称水飞蓟素混合物)、少许黄酮、20%～35%脂肪酸和一些多酚。水飞蓟素除用于治疗肝炎和肝硬化等肝脏疾病外,对前列腺癌、皮肤癌、膀胱癌、肺癌和结肠癌等具有抑制作用。近年研究发现,水飞蓟素抗肿瘤的作用机制与其调节细胞周期、诱导细胞凋亡及抑制新生血管形成等作用有关。另外,水飞蓟素具有抗炎、抗肿瘤转移及抗氧化活性,与抗肿瘤药物具有协同增效作用。     

水飞蓟素防治实验性肝病的作用及相关临床应用的研究进展

水飞蓟素是一种黄酮类化合物，具有清除活性氧、抗脂质过氧化、抗炎、抗肿瘤等多种药理作用。笔者通过查阅大量相关文献，发现水飞蓟素对各种肝病均具有较好的防治作用。随着基础研究的深入，发现水飞蓟素还可以促进肝细胞的修复与再生，与抗病毒药物及其他护肝药物联用时能更显著地降低血清转氨酶水平及改善肝纤维化，具有安全性高及耐受性好的优点。本文主要对水飞蓟素对不同肝病的防治作用、作用机制及其临床应用现状进行综述，以期为水飞蓟素在防治肝病方面的深入研究、药物开发和临床应用等方面提供参考。     

水飞蓟素抗丙型肝炎病毒作用的研究进展

慢性丙型肝炎是严重的全球性卫生问题,其进展为肝硬化、肝癌的几率较高,目前缺乏新的、有效的、不良反应小的治疗手段。水飞蓟素是广泛应用于多类肝病的常用药物,其主要作用包括具有抗氧化、抗纤维化、抗炎、免疫调节以及促肝细胞再生作用。目前研究发现水飞蓟素具有抗丙型肝炎病毒的作用,其主要作用机制为直接抑制丙型肝炎病毒的作用及间接由NF-κB介导的抗炎、调节免疫作用。临床观察发现水飞蓟素静脉制剂其可以降低HCV-RNA水平,并可辅助增强干扰素抗病毒作用,但其是否可有效抗丙型肝炎病毒仍需大样本临床试验证实。     

黄酮木脂素水飞蓟宾类似物的合成及抗氧化活性

介绍第一个黄酮木脂素类化合物——水飞蓟宾类似物的主要成分、合成及抗氧化活性。大量研究结果表明,水飞蓟素具有保肝作用,还具有抗炎、抗肿瘤等活性。     

水飞蓟宾酯化物的药理学研究进展

水飞蓟宾是水飞蓟素的活性成分,具有极强的保肝护肝作用,但是其极难溶于水,生物利用度较低,临床应用受限。近年来,国内外将水飞蓟宾酯化后形成的水飞蓟宾酯化物来提高其水溶性。水飞蓟宾经酯化后的化合物不仅与其有同样的保肝护肝、清除氧自由基、抗氧化、抑制DNA裂解、保护细胞膜、抑制丙肝病毒RNA浓度、抑制微粒体乙醇氧化系统、抗肿瘤、调节眼内压等药理作用,而且作用要强于水飞蓟宾,在肝脏保护、抗肿瘤、调节眼压方面具有广阔的应用前景。     

慢性肝病的抗氧化治疗及其病理生理学基础

氧化应激是各种肝脏疾病发生和发展的常见病理机制,抗氧化剂(如S-腺苷蛋氨酸、维生素E、多元不饱和磷脂胆碱、水飞蓟等)理论上有可能成为治疗慢性肝病的一种有效方法。目前的一些试验性研究也均获得较为肯定的结果,值得进一步研究,尤其是抗氧化剂联合抗炎和(或)抗病毒治疗等。     

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.     

水飞蓟宾保护胰岛β细胞的作用及机制

水飞蓟宾是从水飞蓟中提取的一种黄酮类天然化合物,已用于多种疾病的治疗.近年来研究显示,水飞蓟宾对胰岛β细胞具有抗氧化、抗炎、改善糖脂毒性、增加胰岛素敏感性,改善胰岛素抵抗的作用,有可能成为潜在的糖尿病防治药物.     

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。     

Silymarin in the prevention and treatment of liver diseases and primary liver cancer

In chronic liver diseases caused by oxidative stress (alcoholic and non-alcoholic fatty liver diseases, drug- and chemical-induced hepatic toxicity), the antioxidant medicines such as silymarin can have beneficial effect. Liver cirrhosis, non-alcoholic fatty liver and steatohepatitis are risk factors for hepatocellular carcinoma (HCC). Insulin resistance and oxidative stress are the major pathogenetic mechanisms leading the hepatic cell injury in these patients. The silymarin exerts membrane-stabilizing and antioxidant activity, it promotes hepatocyte regeneration; furthermore it reduces the inflammatory reaction, and inhibits the fibrogenesis in the liver. These results have been established by experimental and clinical trials. According to open studies the long-term administration of silymarin significantly increased survival time of patients with alcohol induced liver cirrhosis. Based on the results of studies using methods of molecular biology, silymarin can significantly reduce tumor cell proliferation, angiogenesis as well as insulin resistance. Furthermore, it exerts an anti-atherosclerotic effect, and suppresses tumor necrosis factor-alpha-induced protein production and mRNA expression due to adhesion molecules. The chemopreventive effect of silymarin on HCC has been established in several studies using in vitro and in vivo methods; it can exert a beneficial effect on the balance of cell survival and apoptosis by interfering cytokines. In addition to this, anti-inflammatory activity and inhibitory effect of silymarin on the development of metastases have also been detected. In some neoplastic diseases silymarin can be administered as adjuvant therapy as well.     

Silymarin protection against major reactive oxygen species released by environmental toxins: exogenous H2O2 exposure in erythrocytes

Silymarin is a polyphenolic plant flavonoid (a mixture of flavonoid isomers such as silibinin, isosilibinin, silidianin and silichristin) derived from Silymarin marianum that has anti-inflammatory, hepatoprotective and anticarcinogenic effects. Our earlier studies have shown that silymarin plays a protective role against the oxidative damage induced by environmental contaminants like benzo(a)pyrene in erythrocyte haemolysates. During the detoxification of these environmental contaminants, the major reactive oxygen species generated is hydrogen peroxide (H(2)O(2)). Because H(2)O(2 )can easily penetrate into the cell and cause damage to biomolecules, the protective role of silymarin was further assessed against this cytotoxic agent in vitro in erythrocyte haemolysates. The protective effect was monitored by assessing the levels of the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-s-transferase, glutathione peroxidase and malondialdehyde (LPO) in three groups: vehicle control, H(2)O(2)-exposed groups and drug co-incubation group (H(2)O(2) + silymarin). The protective effect of silymarin on the non-enzymic antioxidant glutathione and haemolysis, methaemoglobin content and protein carbonyl content were also assessed. It was observed that the activities of antioxidant enzymes and glutathione were reduced and the malondialdehyde levels were elevated after H(2)O(2 )exposure. There were also alterations in haemolysis, methaemoglobin content and protein carbonyl content, whereas after the administration of silymarin, the antioxidant enzyme activities reversed to near normal with reduced malondialdehyde content and normalized haemolysis, methaemoglobin content and protein carbonyl content. The results suggest that silymarin possesses substantial protective effect and free radical scavenging mechanism against exogenous H(2)O(2)-induced oxidative stress damages, hence, can be used as a protective drug against toxicity induced by environmental contaminants.     

Silymarin modulates the oxidant-antioxidant imbalance during diethylnitrosamine induced oxidative stress in rats

Oxidative stress is a common mechanism contributing to initiation and progression of hepatic damage in a variety of liver disorders. Hence, there is a great demand for the development of agents with potent antioxidant effect. The aim of the present investigation is to evaluate the efficacy of silymarin as a hepatoprotective and an antioxidant against diethylnitrosamine induced hepatocellular damage. Single intraperitoneal administration of diethylnitrosamine (200 mg/kg) to rats resulted in significantly elevated levels of serum aspartate transaminase (AST) and alanine transaminase (ALT), which is indicative of hepatocellular damage. Diethylnitrosamine induced oxidative stress was confirmed by elevated levels of lipid peroxidation and decreased levels of superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione reductase (GR) and glutathione-S-transferase (GST) in the liver tissue. The status of non-enzymic antioxidants like, vitamin-C, vitamin-E and reduced glutathione (GSH) were also found to be decreased in diethylnitrosamine administered rats. Further, the status of membrane bound ATPases was also altered indicating hepatocellular membrane damage. Posttreatment with the silymarin (50 mg/kg) orally for 30 days significantly reversed the diethylnitrosamine induced alterations in the liver tissue and offered almost complete protection. The results from the present study indicate that silymarin exhibits good hepatoprotective and antioxidant potential against diethylnitrosamine induced hepatocellular damage in rats.     

Silymarin as a new hepatoprotective agent in experimental cholestasis: new possibilities for an ancient medication

Silymarin is a purified extract from milk thistle (Silybum marianun (L.) Gaertn), composed of a mixture of four isomeric flavonolignans: silibinin (its main, active component), isosilibinin, silydianin and silychristin. This extract has been empirically used as a remedy for almost 2000 years, and remains being used as a medicine for many types of acute and chronic liver diseases. Despite its routinely clinical use as hepatoprotectant, the mechanisms underlying its beneficial effects remain largely unknown. This review addresses in detail a number of recent studies showing a novel feature of silymarin as a hepatoprotective drug, namely: its anticholestatic properties in experimental models of hepatocellular cholestasis with clinical correlate. For this purpose, this review will cover the following aspects: 1. The chemistry of silymarin, including chemical composition and properties. 2. The current clinical applications of silymarin as a hepatoprotective agent, including the mechanisms by which silymarin is thought to exert its hepatoprotective properties, when known. 3. The physiological events involved in bile formation, and the mechanisms of hepatocellular cholestasis, focusing on cellular targets and mechanisms of action of drugs used to reproduce experimentally cholestatic diseases of clinical interest, in particular estrogens and monohydroxylated bile salts, where anticholestatic properties of silymarin have been tested so far. 4. The recent findings describing the impact of silymarin on normal bile secretion and its novel, anticholestatic properties in experimental models of cholestasis, with particular emphasis on the cellular/molecular mechanisms involved, including modulation of bile salt synthesis, biotransformation/depuration of cholestatic compounds, changes in transporter expression/activity, and evocation of signaling pathways.     

Recent advances in herbal medicine for treatment of liver diseases

Context: Liver disease is a serious ailment and the scenario is worsened by the lack of precise therapeutic regimens. Currently available therapies for liver ailments are not apposite and systemic toxicity inhibits their long term use. Medicinal plants have been traditionally used for treating liver diseases since centuries as the toxicity factor appears to be on the lower side.

Objective: Several phytochemials have been identified which have significant hepatoprotective activity with minimal systemic adverse effects which could limit their long term use. The scenario calls for extensive investigations which can lead to development of lead molecules for hepatoprotective molecules of future. This review deals with the biological activity, mode of action and toxicity and forthcoming application of some of these leads.

Methods: These generally have strong antioxidative potential and cause induction of antioxidant enzymes like superoxide dismutase, reduced glutathione and catalase. Additional mechanisms of hepatoprotection include stimulation of heme oxygenase-1 activity, inhibition of nitric oxide production, hepatocyte apoptosis and nuclear factor-κB activation.

Results and conclusion: Out of the several leads obtained from plant sources as potential hepatoprotective agents, silymarin, andrographolide, neoandrographolide, curcumin, picroside, kutkoside, phyllanthin, hypophyllanthin, and glycyrrhizin have been established as potent hepatoprotective agents. The hepatoprotective potential of several herbal medicines has been clinically evaluated. Significant efficacy has been seen with silymarin, glycyrrhizin and Liv-52 in treatment of hepatitis, alcoholic liver disease and liver cirrhosis.     

Hepatoprotective effects of sesamol loaded solid lipid nanoparticles in carbon tetrachloride induced sub‐chronic hepatotoxicity in rats

Sesamol is a phenolic component of sesame seed oil, which has been established as an antioxidant and also possesses potential for hepatoprotection. However, its protective role in carbon tetrachloride (CCl₄) induced sub‐chronic hepatotoxicity has not been studied. Limited oral bioavailability (BA) and rapid elimination (as conjugates) in rats is reported for sesamol. Considering its significant antioxidant potential and compromised BA, we packaged sesamol into solid lipid nanoparticles (S‐SLNs) to enhance its hepatoprotective bioactivity. S‐SLNs prepared by microemulsification method were nearly spherical in shape with an average particle size of 120.30 nm and their oral administration at 8 mg/kg body weight (BW) showed significantly (p < 0.001) better hepatoprotection than free sesamol (FS) and a well established hepatoprotective antioxidant silymarin [SILY (25 mg/kg BW); p < 0.05) in CCl₄ induced sub‐chronic liver injury in rats. Evaluations were done in terms of histological changes in the liver tissue, liver injury markers (serum alanine aminotransferase, serum aspartate aminotransferase, and serum lactate dehydrogenase); oxidative stress markers (lipid peroxidation, superoxide dismutase, and reduced glutathione) and proinflammatory response marker (tumor necrosis factor‐alpha). © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 520–532, 2016.     

Effects of silymarin and its combination with succinic acid on brain bioenergetics in rats with experimental inhibition of beta-oxidation of fatty acids

In the tests on rats with a model of encephalopathy caused by 4-pentenoic acid (inhibitor of the beta-oxidation of fatty acids), the hepatoprotective agent silymarin increases the respiratory activity in brain mitochondria, improves oxidative phosphorylation coupling and energization, and inhibits lipid peroxidation. Succinic acid (a regulator of bioenergetics) improves the damaged Krebs cycle metabolic pathways and produces an antioxidant effect. The combined use of silymarin and succinic demonstrated more expressed cerebroprotective action as compared to that of each agent administered separately.     

Epigallocatechin gallate ameliorates tetrahydrochloride-induced liver toxicity in rats via inhibition of TGFβ / p-ERK/p-Smad1/2 signaling,antioxidant, anti-inflammatory activity

Chronic liver disease is a worldwide health problem. Carbon tetra hydrochloride is an environmental toxin which is regarded as highly toxic and a potential human carcinogen. It can cause liver damage through the generation of metabolites and production of free radicals. Green tea contains catechins such as Epigallocatechin gallate which has been found to reduce the inflammation, oxidative stress, and fibrosis in experimental animal models. Hence, it represents a good source to prevent or ameliorate several chronic diseases. Silymarin is extracted from milk thistle seeds and has been found to be an effective agent to reduce the oxidative stress and free radical production and thereby exert protective effects in chronic liver conditions. The present study was planned to keep in view the above-mentioned facts. We included thirty rats in our study and divided them into five groups, each having six rats and the study continued for 8 weeks. Group I received normal saline; Group 2 received i.p. CCl4 injections; Group 3 received CCl4 i.p. injection and Epigallocatechin gallate (EGCG) oral gavage, Group 4 received CCl4 i.p. injection and silymarin by oral gavage; and Group 5 received CCl4 i.p. injection and combined EGCG + silymarin by oral gavage. The study found that in group 2, CCl4 induced significant elevation of ALT and MDA and reduced GSH thereby signifying increased oxidative stress. CCl4 also significantly increased inflammatory (TNFα, NFκB, IL1β, and TGFβ) as well as fibrotic markers (p-ERK and p-Smad1/2 protein expression). EGCG and silymarin significantly reversed the previously mentioned parameters either alone or in combination; however, the effect was more pronounced in case of EGCG. We conclude that EGCG and silymarin possess liver protective effects through their antioxidant, anti-inflammatory, and antifibrotic action.     

Hepatoprotective effect of silyamarin in individuals chronically exposed to hydrogen sulfide; modulating influence of TNF-α cytokine genetic polymorphism

Background and the purpose of the study

Silymarin, a standardized extract of the milk thistle (Silybum marianum), is believed to exert some of its hepatoprotective effects though inhibition of free radicals and inflammation. In this study the effect of some pro- and anti-inflammatory cytokines and also antioxidant genes polymorphisms on the hepatoprotective effects of silymarin in the occupationally exposed individuals to hydrogen sulfide (H₂S) in the sour natural gas refinery was investigated.

Methods

We genotyped seven polymorphisms in six genes reported by others as modifiers of oxidative stress (NQO1, mEPXH1, GSTT1 and GSTM1) and inflammation (TNF-α and TGF-β1) for an association in effect of decreasing in liver function tests (LFTs). The LFTs of 77 sour gas refinery workers were measured before and after administration of silymarin (140 mg, three times per day for 1 month).

Results

A significant reduction of blood AST, ALT and ALP was observed after 30 days of consumption (p < 0.001). The decreasing effect of silymarin on ALT in the subjects with high producer genotype (A allele carriers) was less than low producers. There were no significant associations between TGF-β1 and the studied genes of oxidative stress pathway and the effectiveness of silymarin.

Conclusion

This is the first report about the effectiveness of silymarin in the subjects exposed chronically to H₂S. Meanwhile, the modulatory effect of TNF-α on the effectiveness of silymarin might be used for individualize therapy.     

Pathophysiological basis for antioxidant therapy in chronic liver disease

Oxidative stress is a common pathogenetic mechanism contributing to initiation and progression of hepatic damage in a variety of liver disorders. Cell damage occurs when there is an excess of reactive species derived from oxygen and nitrogen, or a defect of antioxidant molecules. Experimental research on the delicately regulated molecular strategies whereby cells control the balance between oxidant and antioxidant molecules has progressed in recent years. On the basis of this evidence, antioxidants represent a logical therapeutic strategy for the treatment of chronic liver disease. Clinical studies with large numbers of patients have not yet been performed. However, results from several pilot trials support this concept and indicate that it may be worth performing multicentre studies, particularly combining antioxidants with anti-inflammatory and/or antiviral therapy. Oxidative stress plays a pathogenetic role in liver diseases such as alcoholic liver disease, chronic viral hepatitis, autoimmune liver diseases and non-alcoholic steatohepatitis. The use of antioxidants (e.g. S-adenosylmethionine [SAMe; ademetionine], tocopherol [vitamin E], polyenylphosphatidylcholine or silymarin) has already shown promising results in some of these pathologies.