Preparation of tritium‐labeled Silybin—a protectant for common liver diseases

Silymarin, the seed extract of milk thistle plant, Silybum marianum, has been used traditionally for the treatment of liver diseases and bile duct infection. Silybin 1 is the main bioactive components of silymarin, consisting a pair of diastereomers: Silybin A and Silybin B. In this article, we report the preparation of tritium‐labeled Silybin, which was accomplished by protection of Silybin as tritylated compound 2 and followed by oxidation of the primary alcohol to its corresponding aldehyde 3 . Subsequent reduction with NaB[³H]₄ and deprotection of the trityl group provided the tritium‐labeled Silybin 4 . Copyright © 2006 John Wiley & Sons, Ltd.     

Effect of Antihepatotoxic Agents Against Microcystin-LR Toxicity in Cultured Rat Hepatocytes

Primary cultures of adult rat hepatocytes were used to investigate the effects of two putative therapeutic agents, dithioerythritol and silymarin on microcystin-LR-induced hepatotoxicity. Cell injury was assessed by the extent of cellular [¹⁴C]adenine nucleotides and lactate dehydrogenase (LDH) release into the medium and the extent of hepatocyte detachment from monolayers. Microcystin-LR (1 µM) induced a significant release of both ¹⁴C-labeled nucleotides and LDH from hepatocytes as well as significant detachment of cells from monolayers. Although both dithioerythritol (0.63–5 mM) and silymarin (25–200 µM) reduced the amount of marker release and cell detachment from microcystin-LR-treated wells, silymarin provided significantly greater protection than dithioerythritol at one-tenth the concentration. Furthermore, silymarin and dithioerythritol treatment prevented morphological deformations and detachment of cells.     

水飞蓟素固体分散体中水飞蓟宾溶出速度的研究

[目的 ]研究载体和表面活性剂对水飞蓟素固体分散体中水飞蓟宾溶出速度的影响 .[方法 ]采用熔融法制备水飞蓟素固体分散体 ,观察固体分散体中水飞蓟宾在人工肠液中的累积溶出量变化 .[结果 ]水飞蓟素与聚乙二醇为 1∶9比例时固体分散体中水飞蓟宾的溶出速率最佳 ,其最大累积溶出率为6 4 2 7% ;表面活性剂十二烷基硫酸钠组固体分散体的累积溶出率为 6 4 48% .[结论 ]与原料药物相比 ,以聚乙二醇为载体的固体分散体提高了水飞蓟宾的溶出速率     

水飞蓟素对乳腺癌细胞系的作用及其机制研究

目的：研究水飞蓟素在体外对不同乳腺癌细胞系的作用，并进一步探讨其作用机制。方法：MTT实验测定水飞蓟素对乳腺癌细胞系MCF－7和SK－BR－3的半数抑制浓度（IC50）；软琼脂克隆形成试验检测加药后两种细胞在软琼脂内的增殖能力。在此基础上，用Her-2抑制剂AG825进行干预，对水飞蓟素的作用机制进行初步探讨。结果：水飞蓟素对两种乳腺癌细胞有不同程度的抑制作用，其中对MCF－7细胞的作用较强，IC50≤0．02％，而对SK－BR－3的作用较弱。Her-2抑制剂AG825可增加SK－BR－3细胞对药物的敏感性，抑制了水飞蓟素作用后该细胞在软琼脂中集落的形成。结论：水飞蓟素在体外对MCF－7细胞具有明显的抑制作用，而AG825可增强SK－BR－3细胞对药物的敏感性。因此，SK－BR－3细胞中Her-2的高表达可能是该细胞对水飞蓟素敏感性差的原因，而水飞蓟素也可能通过Her-2调节某个或某几个下游分子起作用。     

不同粒径的水飞蓟素固体脂质纳米粒口服吸收比较研究

目的:考察不同粒径的固体脂质纳米粒对大鼠口服吸收水飞蓟素的影响。方法:以山榆酸甘油酯为载体材料,分别制备了150,500,1 000 nm 3种粒径的水飞蓟素固体脂质纳米粒,给大鼠灌胃后,采用RP-HPLC测定不同时间点血药浓度,数据经3p97软件进行处理。结果:口服150 nm水飞蓟素固体脂质纳米粒后的AUC分别是500,1 000 nm的2.08,2.54倍(P<0.05),这表明150 nm固体脂质纳米粒的生物利用度明显高于其他2种制剂。结论:固体脂质纳米粒粒径对水飞蓟素的口服吸收有着显著影响。     

Targeting events in melanoma carcinogenesis for the prevention of melanoma

Melanoma is one of the few tumors that have increased in incidence over the last few decades. Strategies devoted solely to protecting against ultraviolet radiation have, at best, had a modest impact on the development of melanoma. Chemoprevention is an under-explored approach that could significantly decrease the morbidity and mortality from this deadly cancer. However, the scientific and logistical challenges of performing clinical studies in chemoprevention require innovative approaches to prove the effectiveness of putative preventive agents. There are several pharmacological and nutriceutical agents that are mechanistically linked to events in melanoma carcinogenesis that are candidates for advanced human studies. We will review the data for several promising agents, including statins, curcumin, resveratrol, silymarin and green tea, and discuss some importance issues and concepts that should be considered in any melanoma chemoprevention strategy.     

Hematobiochemical effects of cadmium intoxication in male Japanese quail (Coturnix japonica) and its amelioration with silymarin and milk thistle

The present study was designed to investigate the toxico-pathological effect of cadmium (Cd) and its amelioration with silymarin (SL) and milk thistle (MT) in male Japanese quail (Coturnix japonica). A total of 144 male quail were divided into nine equal groups (A–I). Experimental feeds were offered to these groups containing different combinations of Cd chloride (Cd1: 150 and Cd2: 300?mg/kg feed), SL (250?mg/kg of feed), and MT (10?g/kg of feed). The duration of the experiment was 60 days. The physical parameters studied included feed intake and body weight. Hematobiochemical parameters included total protein, albumin, ALT, AST, creatinine, urea, hemoglobin, and hematocrit. The data were analyzed by analysis of variance (ANOVA) technique, and group means were compared by Duncan’s multiple range test. The body weight decreased significantly in Cd-treated groups while SL and MT ameliorated the toxic effects of Cd as compared to control group. The hemoglobin (Hb) concentration and hematocrit (Hct) values were decreased significantly in Cd2-treated group, while Hb and Hct decreased nonsignificantly in Cd1-treated group compared with control. Similar hematological findings were observed, when Cd was used in combinations with SL and MT. Urea, creatinine, and AST increased significantly, while ALT increased nonsignificantly in Cd-treated groups as compared to control group, while total protein, albumin, and globulin decreased significantly in Cd-treated groups as compared to control group. The SL and MT completely ameliorated these toxic effects at low dose of Cd; however, amelioration was partial at higher doses of Cd. These compounds (SL &; MT) might be used to ameliorate toxic effects of Cd in Japanese quail.     

Hepatoprotective effect of Pandanus odoratissimus seed extracts on paracetamol-induced rats

ContextPandanus odoratissimus Linn. (Pandanaceae) seed extract is known to have antioxidant activities. However, the potential hepatoprotective effect is still unclear.ObjectiveTo investigate the hepatoprotection aspect of P. odoratissimus methanol extract towards paracetamol-induced rats.Materials and methodsThirty male Sprague–Dawley rats were randomly divided into six equal groups: one group served as the healthy control and five groups with hepatotoxicity (hepatotoxic control and 4 treatment groups). The oral treatment of paracetamol-induced hepatotoxicity of 3 g/kg using three different concentrations of P. odoratissimus (300, 600 and 900 mg/kg), and silymarin (200 mg/kg) groups were administered once a day for 14 days. Enzyme activities and protein levels in serum were determined in rats at the end of the treatments. The histopathology of rat livers was observed under an electron microscope with 10× magnification.ResultsPandanus odoratissimus significantly decreased the serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT) activities in induced-paracetamol rat serum (p < 0.05). Moreover, P. odoratissimus significantly decreased total bilirubin and direct bilirubin levels (p < 0.05). It significantly blocked the decline of serum albumin and protein levels (p < 0.05). Histopathological changes amplified paracetamol-induced liver damage and the hepatoprotective effect of P. odoratissimus in the liver.Discussion and conclusionsPandanus odoratissimus improved the hepatoprotective effect in a concentration-dependent manner by reducing related hepatic enzyme and protein markers, suggesting as a useful agent in hepatotoxicity treatment, and it can be generalized to a broader study population in different hepatotoxic animal models.     

Protective effects of silymarin on epirubicin-induced mucosal barrier injury of the gastrointestinal tract

Mucositis is a serious disorder of the gastrointestinal tract that results from cancer chemotherapy. We investigated the protective effects of silymarin on epirubicin-induced mucosal barrier injury in CD-1 mice. Immunohistochemical activity of both pro-apoptotic Bax and anti-apoptotic Bcl-2 markers, together with p53, cyt-P450 expression and DNA damage analysis on stomach, small intestine and colon were evaluated. Our results indicated stronger expression for cyt P450 in all analyzed gastrointestinal tissues of Epi group, which demonstrate intense drug detoxification. Bax immunopositivity was intense in the absorptive enterocytes and lamina connective cells of the small intestine, surface epithelial cells of the stomach and also in the colonic epithelium and lamina concomitant with a decreased Bcl-2 expression in all analyzed tissues. Epirubicin-induced gastrointestinal damage was verified by a goblet cell count and morphology analysis on histopathological sections stained for mucins. In all analyzed tissues, Bax immunopositivity has been withdrawn by highest dose of silymarin concomitant with reversal of Bcl-2 intensity at a level comparable with control. p53 expression was found in all analyzed tissues and decreased by high dose of silymarin. Also, DNA internucleosomal fragmentation was observed in the Epi groups for all analyzed tissues was almost suppressed at 100?mg/kg Sy co-treatment. Histological aspect and goblet cell count were restored at a highest dose of Sy for both small and large intestine. In conclusion, our findings suggest that silymarin may prevent cellular damage of epirubicin-induced toxicity and was effective in reducing the severity indicators of gastrointestinal mucositis in mice.     

Silymarin attenuates paraquat‐induced lung injury via Nrf2‐mediated pathway in vivo and in vitro

The present study aims to investigate the impacts and mechanisms of silymarin on paraquat (PQ)‐induced lung injury in vivo and in vitro. In in vivo experiments, a total of 32 male Sprague‐Dawley (SD) rats were randomly divided into four groups. The rats were killed on day 3. Histopathological changes in lung tissue were examined using HE and Masson's trichrome staining. Biomarkers of neutrophil activation, pulmonary oedema, pulmonary fibrosis, lung permeability and oxidative stress were detected. Several proinflammatory mediators and antioxidant related proteins were measured. In in vitro experiments, A549 cells were transfected with Nrf2 special siRNA to investigate the roles of Nrf2. The results show that silymarin administration abated PQ‐induced lung histopathologic changes, decreased inflammatory cell infiltration and lung wet weight/dry weight (W/D) ratio, suppressed myeloperoxidase (MPO) activity and nitric oxide (NO)/inducible nitric oxide synthases (iNOS) expression, downregulated hydroxyproline (HYP) levels, reduced total protein concentration and proinflammatory mediator release, and improved oxidative stress (malondialdehyde, MDA; superoxide dismutase, SOD; catalase, CAT; and glutathione peroxidase, GSH‐Px) in lung tissue and serum. Meanwhile, treatment with silymarin upregulated the levels of nuclear factor‐erythroid‐2‐related factor 2 (Nrf2), heme oxygenase‐1 (HO‐1) and NAD(P)H:quinone oxidoreductase‐1(NQO1). However, the addition of Nrf2 siRNA reduced the expression of Nrf2‐mediated antioxidant protein HO‐1 and thus reversed the protective effects of silymarin against oxidative stress and inflammatory response. These results suggest that silymarin may exert protective effects against PQ‐induced lung injury. Its mechanisms were associated with the Nrf2‐mediated pathway. Therefore, silymarin may be a potential therapeutic drug for lung injury.