Eight novel silybin analogues （7a-h） were synthesized and their antioxidant properties including the capability of scavenging superoxide anion free radicals and the inhibitory effect on DPPH free radicals were dete...Eight novel silybin analogues （7a-h） were synthesized and their antioxidant properties including the capability of scavenging superoxide anion free radicals and the inhibitory effect on DPPH free radicals were determined. Several synthetic compounds showed comparable antioxidative effect to that of quercetin.展开更多
Nonalcoholic fatty liver disease(NAFLD)is regarded as the most common liver disease with no approved therapeutic drug currently.Silymarin,an extract from the seeds of Silybum marianum,has been used for centuries for t...Nonalcoholic fatty liver disease(NAFLD)is regarded as the most common liver disease with no approved therapeutic drug currently.Silymarin,an extract from the seeds of Silybum marianum,has been used for centuries for the treatment of various liver diseases.Although the hepatoprotective effect of silybin against NAFLD is widely accepted,the underlying mechanism and therapeutic target remain unclear.In this study,NAFLD mice caused by methionine-choline deficient(MCD)diet were orally administrated with silybin to explore the possible mechanism and target.To clarify the contribution of peroxisome proliferator-activated receptorα(PPARα),PPARαantagonist GW6471 was co-administrated with silybin to NAFLD mice.Since silybin was proven as a PPARαpartial agonist,the combined effect of silybin with PPARαagonist,fenofibrate,was then evaluated in NAFLD mice.Serum and liver samples were collected to analyze the pharmacological efficacy and expression of PPARαand its targets.As expected,silybin significantly protected mice from MCD-induced NAFLD.Furthermore,silybin reduced lipid accumulation via activating PPARα,inducing the expression of liver cytosolic fatty acid-binding protein,carnitine palmitoyltransferase(Cpt)-1a,Cpt-2,medium chain acyl-CoA dehydrogenase and stearoyl-CoA desaturase-1,and suppressing fatty acid synthase and acetyl-CoA carboxylaseα.GW6471 abolished the effect of silybin on PPARαsignal and hepatoprotective effect against NAFLD.Moreover,as a partial agonist for PPARα,silybin impaired the powerful lipid-lowering effect of fenofibrate when used together.Taken together,silybin protected mice against NAFLD via activating PPARαto diminish lipid accumulation and it is not suggested to simultaneously take silybin and classical PPARαagonists for NAFLD therapy.展开更多
IM To establish a new experimental model system with human fetal hepatocytes to study the mechanisms of protective effect of silybin and polyporus umbellalus polysaccharides (PSP) on the ultrastructure of human fetal...IM To establish a new experimental model system with human fetal hepatocytes to study the mechanisms of protective effect of silybin and polyporus umbellalus polysaccharides (PSP) on the ultrastructure of human fetal hepatocytes.METHODS The hepatocytes were obtained from the liver of human fetus from induced labor with written consent. The primarily cultured hepatocytes were pretreated with silybin and PSP and exposed to CCl4 for 4 hours. The ultrastructural changes of hepatocytes were observed under scanning electronmicroscopy (SEM) and transmission electronmicroscope (TEM). Transaminase and SOD were also assayed at the end of culture.RESULT The levels of ALT and AST were significantly decreased and the SOD level elevated in two pretreated groups as compared with that in the control group. The cellular integrity and ultrastructure of hepatocytes were well preserved in the two drugs pretreated groups while they were seriously damaged in the control group.CONCLUSION The experimental model system with human fetal hepatocytes pretreated with CCl4 could act as an effective method for studying the protective effect of drugs on human hepatocytes, and could be used for screening the medicines for treatment of hepatitis.展开更多
Chronic liver disease results in a response resembling"wound healing",also known as fibrosis,resulting in the progressive accumulation of connective tissue.Excessive fibrogenesis that results in the disrupti...Chronic liver disease results in a response resembling"wound healing",also known as fibrosis,resulting in the progressive accumulation of connective tissue.Excessive fibrogenesis that results in the disruption of intercellular connections,interactions,and extracellular matrix composition are features of the fibrotic pro-cess mediated by various cell types and chemical mediators such as transforming growth factor-β.Redox-sensitive processes are major contributors to controlling this inflammatory and pro-fibrogenic cytokine's production and synthesis.Other essential hepatic fibrogenesis activities,such as the activation of stellate cells,the expression of metalloproteinases and their inhibitors can also be linked to ge-neration of reactive oxygen species and lipid peroxidation products,which are implicated in development and progression of fibrosis.The herb Silybum maria-num,also known as milk thistle,is widely studied for its potential to treat liver illnesses.Silymarin contains 50%to 70%silybin,which has the highest level of biological activity.In comparison,silybin seems to be relatively safer and the avai-lable evidence on its potential mechanisms of action is encouraging.The aim of this article is to analyze the increasing evidences linking biochemical oxidative events to excessive fibrogenesis and silybin's inhibitory mechanisms that aid in the reversal of fibrosis and fibrotic lesions.展开更多
Aim To improve the dissolution rate and bioavailability of silybin. Methods Sustained-release silybin microspheres were prepared by the spherical crystallization technique with soliddispersing and release-retarding po...Aim To improve the dissolution rate and bioavailability of silybin. Methods Sustained-release silybin microspheres were prepared by the spherical crystallization technique with soliddispersing and release-retarding polymers. A differential scanning calorimeter and an X-ray diffractometer were used to investigate the dispersion state of silybin in the microspheres. The shape, surface morphology, and internal structure of the microspheres were observed using a scanning electron microscope. Characterization of the microspheres, such as average diameter, size distribution and bulk density of the microspheres was investigated. Results The particle size of the microspheres was determined mainly by the agitation speed. The dissolution rate of silybin from microspheres was enhanced by increasing the amount of the dispersing agents, and sustained by the retarding agents. The release rate of microspheres was controlled by adjusting the combination ratio of the dispersing agents to the retarding agents. The resuits of X-ray diffraction and differential scanning calorimetry analysis indicated that silybin was highly dispersed in the microspheres in amorphous state. The release profiles and content did not change after a three-month accelerated stability test at 40 ℃ and 75% relative humidity. Conclusion Sustained-release silybin microspheres with a solid dispersion structure were prepared successfully in one step by a spherical crystallization technique combined with solid dispersion technique. The preparation process is simple, reproducible and inexpensive. The method is efficient for designing sustained-release microspheres with water-insoluble drugs.展开更多
To enhance the oral absorption of the poorly water-soluble drug silybin, a self-microemulsifying drug delivery system （SMEDDS） composed of ethyl linoleate, Cremophor EL and PEG 400 for oral administration of silybin...To enhance the oral absorption of the poorly water-soluble drug silybin, a self-microemulsifying drug delivery system （SMEDDS） composed of ethyl linoleate, Cremophor EL and PEG 400 for oral administration of silybin was formulated, and its physicochemical properties and bioavailability of silybin were evaluated. The in vitro release of silybin from microemulsion and dispersion of silybin from SMEDDS were significantly faster than those from the commercial silybin hard capsule, respectively. The area under the drug concentration-time curve （AUC） and the mean maximum plasma level （Cmax） of the SMEDDS were remarkably greater than those of the hard capsule after oral administration to rats. The absorption of silybin formulated in SMEDDS exhibited a 2.3-fold increase in bioavailability as compared with the hard capsule. These results demonstrated that SMESDDS might be a useful drug delivery system for the oral delivery of the poorly water-soluble drug silybin.展开更多
To improve its solubility and dissolution,solid dispersions of silybin in PVP K30 were prepared by the conventional solvent evaporation method and characterized by equilibrium solubility and dissolution studies,differ...To improve its solubility and dissolution,solid dispersions of silybin in PVP K30 were prepared by the conventional solvent evaporation method and characterized by equilibrium solubility and dissolution studies,differential scanning calorimetry （DSC） and Fourier transform infrared spectroscopy（FTIR）.Silybin solid dispersions showed increased solubility and rates of dissolution compared with pure drug and corresponding physical mixtures of silybin and PVP K30.Thermograms of various solid dispersions did not show the melting peak of pure silybin,indicating that silybin was in amorphous form inside the polymer carrier.FTIR studies demonstrated the presence of interactions between hydroxyl groups of silybin and carbonyl groups of PVP K30 in solid dispersions.Solid dispersion techniques can be used to formulate water insoluble drugs to improve their dissolution in vitro and absorption in vivo.展开更多
Objective To investigate the bioavailability and pharmacokinetics of silybin A and silybin B in rats,respectively. Methods Following iv and ig administration of silybin to 20 Wistar rats,the plasma samples were collec...Objective To investigate the bioavailability and pharmacokinetics of silybin A and silybin B in rats,respectively. Methods Following iv and ig administration of silybin to 20 Wistar rats,the plasma samples were collected at different time points up to 12 h.Sample pretreatment was involved in one-step protein precipitation with acetonitrile. Silybin A and silybin B were simultaneously determined by LC-MS/MS.Results After ig dosing silybin 28,56,and 112 mg/kg to rats,the t1/2βvalues were 5.48,5.08,and 5.73 h for silybin A,and 4.56,4.12,and 5.53 h for silybin B; The Cmax were 674.3,1349.4,and 2042.5 ng/mL for silybin A,and 671.0,1365.4,and 2066.2 ng/mL for silybin B; The Tmax were 0.20,0.23,and 0.20 h for silybin A,and 0.20,0.23,and 0.20 h for silybin B;The AUC were 454.4, 845.9,and 1219.5 h·ng/mL for silybin A,and 432.0,817.1,and 1153.6 h·ng/mL for silybin B.The absolute bioavailabilities of silybin A and silybin B were 2.86%and 1.93%,respectively.Conclusion Silybin A and silybin B have very low bioavailability after ig administration,and there is no significant difference in the pharmacokinetic parameters between silybin A and silybin B,which indicates that the two diastereoisomers have similar pharmacokinetic behavior in rats.展开更多
AIM: To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis.METHODS: Rat hepatoma FaO cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitat...AIM: To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis.METHODS: Rat hepatoma FaO cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitate for 3 h to mimic liver steatosis. Then, the steatotic cells were incubated for 24 h with different concentrations (25 to 100 μmol/L) of silybin as phytosome complex with vitamin E. The effects of silybin on lipid accumulation and metabolism, and on indices of oxidative stress were evaluated by absorption and fluorescence microscopy, quantitative real-time PCR, Western blot, spectrophotometric and fluorimetric assays.RESULTS: Lipid-loading resulted in intracellular triglyceride (TG) accumulation inside lipid droplets, whose number and size increased. TG accumulation was mediated by increased levels of peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding protein-1c (SREBP-1c). The lipid imbalance was associated with higher production of reactive oxygen species (ROS) resulting in increased lipid peroxidation, stimulation of catalase activity and activation of nuclear factor kappa-B (NF-κB). Incubation of steatotic cells with silybin 50 μmol/L significantly reduced TG accumulation likely by promoting lipid catabolism and by inhibiting lipogenic pathways, as suggested by the changes in carnitine palmitoyltransferase 1 (CPT-1), PPAR and SREBP-1c levels. The reduction in fat accumulation exerted by silybin in the steatotic cells was associated with the improvement of the oxidative imbalance caused by lipid excess as demonstrated by the reduction in ROS content, lipid peroxidation, catalase activity and NF-κB activation.CONCLUSION: We demonstrated the direct anti-steatotic and anti-oxidant effects of silybin in steatotic cells, thus elucidating at a cellular level the encouraging results demonstrated in clinical and animal studies.展开更多
Twelve 23-esterified silybin derivatives with different patterns of substituents such as aromatic and aliphatic groups （1-12） were designed and synthesized. The antioxidative properties of these compounds were evalu...Twelve 23-esterified silybin derivatives with different patterns of substituents such as aromatic and aliphatic groups （1-12） were designed and synthesized. The antioxidative properties of these compounds were evaluated. The modifed silybin analogues exhibited improved inhibitory effects against rat liver homogenate lipid peroxidation compared to silybin, with exception of the trimethoxylated ester （5） and the aliphatic one （9）. Compounds 3, 5, 7, 8 and 11 displayed their protective properties on DNA cleavage in a dose-dependent manner. 2009 Xiao Kun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.展开更多
Objective: To study the curative effect of silybin combined with pituitrin-phentolamine for pulmonary tuberculosis complicated by acute hemoptysis. Methods: A total of 78 patients with pulmonary tuberculosis complicat...Objective: To study the curative effect of silybin combined with pituitrin-phentolamine for pulmonary tuberculosis complicated by acute hemoptysis. Methods: A total of 78 patients with pulmonary tuberculosis complicated by acute hemoptysis who were treated in this hospital between December 2013 and April 2017 were divided into control group (n=39) and silybin group (n=39) by random number table. Control group received pituitrin-phentolamine hemostasis therapy, silybin group received pituitrin-phentolamine combined with silybin therapy, both were treated for 1 week. The differences in peripheral blood liver function and coagulation index levels as well as serum oxidative stress index contents were compared between the two groups of patients before treatment and after 1 week of treatment. Results:Before treatment, the differences in peripheral blood liver function and coagulation index levels as well as serum oxidative stress index contents were not statistically significant between the two groups. After 1 week of treatment, peripheral blood liver function indexes ALT, AST, ALP and STB contents of silybin group were lower than those of control group;peripheral blood coagulation indexes PT, APTT and TT levels were lower than those of control group whereas Fib level was higher than that of control group;serum oxidative stress indexes AOPPs and LHP contents were lower than those of control group whereas GSH-Px and T-AOC contents were higher than those of control group. Conclusion: pituitrin-phentolamine combined with silybin therapy can effectively protect the liver function, optimize the coagulation function and reduce the oxidative stress response in patients with pulmonary tuberculosis complicated by acute hemoptysis.展开更多
We established a RP-HPLC method for the analysis of silymarin in microemulsion. Silymarin was separated using a ODS C18 column and monitored at the wavelength 288 nm. The mobile phase consisting of methanol-water-acet...We established a RP-HPLC method for the analysis of silymarin in microemulsion. Silymarin was separated using a ODS C18 column and monitored at the wavelength 288 nm. The mobile phase consisting of methanol-water-acetic acid （42：58：0.5, v/v/v） was pumped at a flow rate of 1.0 mL/min. The linear range of calibration curve was 10-1000 μg/mL. The average recovery was 99.0%-100.7% for silybin isomers. The RSD values of inter-day and intra-day assays were lower than 1.6% for silybin isomers. The method is simple, rapid, reproducible and precise for the quantitative determination of silymarin in microemulsion.展开更多
Flavonoids are polyphenols that are found in numerous edible plant species. Data obtained from preclinical and clinical studies suggest that specific flavonoids are chemo-preventive and cytotoxic against various cance...Flavonoids are polyphenols that are found in numerous edible plant species. Data obtained from preclinical and clinical studies suggest that specific flavonoids are chemo-preventive and cytotoxic against various cancers via a multitude of mechanisms. However, the clinical use of flavonoids is limited due to challenges associated with their e ective use, including(1) the isolation and purification of flavonoids from their natural resources;(2) demonstration of the e ects of flavonoids in reducing the risk of certain cancer, in tandem with the cost and time needed for epidemiological studies, and(3) numerous pharmacokinetic challenges(e.g., bioavailability, drug–drug interactions, and metabolic instability). Currently, numerous approaches are being used to surmount some of these challenges, thereby increasing the likelihood of flavonoids being used as chemo-preventive drugs in the clinic. In this review, we summarize the most important challenges and e orts that are being made to surmount these challenges.展开更多
AIM: To determine the effect of Legalon-SIL (LS) on hepatitis C virus (HCV) core and NS5A expression and on heme oxygenase-1 (HMOX-1) and its transcriptional regulators in human hepatoma cells expressing full length H...AIM: To determine the effect of Legalon-SIL (LS) on hepatitis C virus (HCV) core and NS5A expression and on heme oxygenase-1 (HMOX-1) and its transcriptional regulators in human hepatoma cells expressing full length HCV genotype 1b. METHODS: CON1 cells were treated with 50 μmol/L or 200 μmol/L LS. Cells were harvested after 2, 6 and 24 h. HCV RNA and protein levels were determined by quantitative real-time polymerase chain reaction and Western blotting, respectively. RESULTS: HCV RNA (core and NS5A regions) wasdecreased after 6 h with LS 200 μmol/L (P < 0.05). Both 50 and 200 μmol/L LS decreased HCV RNA levels [core region (by 55% and 88%, respectively) and NS5A region (by 62% and 87%, respectively) after 24 h compared with vehicle (dimethyl sulphoxide) control (P < 0.01). Similarly HCV core and NS5A protein were decreased (by 85%, P < 0.01 and by 65%, P < 0.05, respectively) by LS 200 μmol/L. Bach1 and HMOX-1 RNA were also downregulated by LS treatment (P < 0.01), while Nrf2 protein was increased (P < 0.05).CONCLUSION: Our results demonstrate that treatment with LS downregulates HCV core and NS5A expression in CON1 cells which express full length HCV genotype 1b, and suggests that LS may prove to be a valuable alternative or adjunctive therapy for the treatment of HCV infection.展开更多
Flavonoids are a large class of natural poly-phenolic compounds, occurring in fruits and vegetables regularly consumed by humans. Recently, flavonoids have aroused
Increasing the degree of supersaturation of drugs and maintaining their proper stability are very important in improving the oral bioavailability of poorly soluble drugs by a supersaturated drug delivery system(SDDS)....Increasing the degree of supersaturation of drugs and maintaining their proper stability are very important in improving the oral bioavailability of poorly soluble drugs by a supersaturated drug delivery system(SDDS). In this study, we reported a complex system of Soluplus–Copovidone(Soluplus–PVPVA)loaded with the model drug silybin(SLB) that could not only maintain the stability of a supersaturated solution but also effectively promote oral absorption. The antiprecipitation effect of the polymers on SLB was observed using the solvent-shift method. In addition, the effects of the polymers on absorption were detected by cellular uptake and transport experiments. The mechanisms by which the Soluplus–PVPVA complex promotes oral absorption were explored by dynamic light scattering, transmission electron microscopy, fluorescence spectra and isothermal titration calorimetry analyses. Furthermore, a pharmacokinetic study in rats was used to demonstrate the advantages of the Soluplus–PVPVA complex. The results showed that Soluplus and PVPVA spontaneously formed complexes in aqueous solution via the adsorption of PVPVA on the hydrophilichydrophobic interface of the Soluplus micelle, and the Soluplus–PVPVA complex significantly increased the absorption of SLB. In conclusion, the Soluplus–PVPVA complex is a potential SDDS for improving the bioavailability of hydrophobic drugs.展开更多
The effects of silybin on erythrocytic sorbitol level and peripheral nerve conduction veloci-ty were studied in 14 cases of noninsulin dependent diabetes mellitus (NIDDM) . Atter oral administrationof silybin 231 mgld...The effects of silybin on erythrocytic sorbitol level and peripheral nerve conduction veloci-ty were studied in 14 cases of noninsulin dependent diabetes mellitus (NIDDM) . Atter oral administrationof silybin 231 mglday for 4 weeks, no blood glucose change was observed in patients with NIDDM, whilethe erythrocytic sorbitol level was significantly decreased from 72. 55 21. 61 to 39. 53 14. 94 nmol/g .Hb (P<0. 01) . At the same time, peripheral nerve conduction vefocity was also improved. These resultsindicate that silybin is an effective aldose reductase inhibitor which can improve the disorder of polyolpathway in NIDDM patients and prevent chronic complications of diabetes.展开更多
文摘Eight novel silybin analogues （7a-h） were synthesized and their antioxidant properties including the capability of scavenging superoxide anion free radicals and the inhibitory effect on DPPH free radicals were determined. Several synthetic compounds showed comparable antioxidative effect to that of quercetin.
基金supported by the National Natural Science Foundation of China(Nos.81720108032,81930109,82073926,82073928)the Project for Major New Drug Innovation and Development(Nos.2018ZX09711001-002-003,2018ZX09711002-001-004)Overseas Expertise Introduction Project for Discipline Innovation(No.G20582017001).
文摘Nonalcoholic fatty liver disease(NAFLD)is regarded as the most common liver disease with no approved therapeutic drug currently.Silymarin,an extract from the seeds of Silybum marianum,has been used for centuries for the treatment of various liver diseases.Although the hepatoprotective effect of silybin against NAFLD is widely accepted,the underlying mechanism and therapeutic target remain unclear.In this study,NAFLD mice caused by methionine-choline deficient(MCD)diet were orally administrated with silybin to explore the possible mechanism and target.To clarify the contribution of peroxisome proliferator-activated receptorα(PPARα),PPARαantagonist GW6471 was co-administrated with silybin to NAFLD mice.Since silybin was proven as a PPARαpartial agonist,the combined effect of silybin with PPARαagonist,fenofibrate,was then evaluated in NAFLD mice.Serum and liver samples were collected to analyze the pharmacological efficacy and expression of PPARαand its targets.As expected,silybin significantly protected mice from MCD-induced NAFLD.Furthermore,silybin reduced lipid accumulation via activating PPARα,inducing the expression of liver cytosolic fatty acid-binding protein,carnitine palmitoyltransferase(Cpt)-1a,Cpt-2,medium chain acyl-CoA dehydrogenase and stearoyl-CoA desaturase-1,and suppressing fatty acid synthase and acetyl-CoA carboxylaseα.GW6471 abolished the effect of silybin on PPARαsignal and hepatoprotective effect against NAFLD.Moreover,as a partial agonist for PPARα,silybin impaired the powerful lipid-lowering effect of fenofibrate when used together.Taken together,silybin protected mice against NAFLD via activating PPARαto diminish lipid accumulation and it is not suggested to simultaneously take silybin and classical PPARαagonists for NAFLD therapy.
文摘IM To establish a new experimental model system with human fetal hepatocytes to study the mechanisms of protective effect of silybin and polyporus umbellalus polysaccharides (PSP) on the ultrastructure of human fetal hepatocytes.METHODS The hepatocytes were obtained from the liver of human fetus from induced labor with written consent. The primarily cultured hepatocytes were pretreated with silybin and PSP and exposed to CCl4 for 4 hours. The ultrastructural changes of hepatocytes were observed under scanning electronmicroscopy (SEM) and transmission electronmicroscope (TEM). Transaminase and SOD were also assayed at the end of culture.RESULT The levels of ALT and AST were significantly decreased and the SOD level elevated in two pretreated groups as compared with that in the control group. The cellular integrity and ultrastructure of hepatocytes were well preserved in the two drugs pretreated groups while they were seriously damaged in the control group.CONCLUSION The experimental model system with human fetal hepatocytes pretreated with CCl4 could act as an effective method for studying the protective effect of drugs on human hepatocytes, and could be used for screening the medicines for treatment of hepatitis.
文摘Chronic liver disease results in a response resembling"wound healing",also known as fibrosis,resulting in the progressive accumulation of connective tissue.Excessive fibrogenesis that results in the disruption of intercellular connections,interactions,and extracellular matrix composition are features of the fibrotic pro-cess mediated by various cell types and chemical mediators such as transforming growth factor-β.Redox-sensitive processes are major contributors to controlling this inflammatory and pro-fibrogenic cytokine's production and synthesis.Other essential hepatic fibrogenesis activities,such as the activation of stellate cells,the expression of metalloproteinases and their inhibitors can also be linked to ge-neration of reactive oxygen species and lipid peroxidation products,which are implicated in development and progression of fibrosis.The herb Silybum maria-num,also known as milk thistle,is widely studied for its potential to treat liver illnesses.Silymarin contains 50%to 70%silybin,which has the highest level of biological activity.In comparison,silybin seems to be relatively safer and the avai-lable evidence on its potential mechanisms of action is encouraging.The aim of this article is to analyze the increasing evidences linking biochemical oxidative events to excessive fibrogenesis and silybin's inhibitory mechanisms that aid in the reversal of fibrosis and fibrotic lesions.
文摘Aim To improve the dissolution rate and bioavailability of silybin. Methods Sustained-release silybin microspheres were prepared by the spherical crystallization technique with soliddispersing and release-retarding polymers. A differential scanning calorimeter and an X-ray diffractometer were used to investigate the dispersion state of silybin in the microspheres. The shape, surface morphology, and internal structure of the microspheres were observed using a scanning electron microscope. Characterization of the microspheres, such as average diameter, size distribution and bulk density of the microspheres was investigated. Results The particle size of the microspheres was determined mainly by the agitation speed. The dissolution rate of silybin from microspheres was enhanced by increasing the amount of the dispersing agents, and sustained by the retarding agents. The release rate of microspheres was controlled by adjusting the combination ratio of the dispersing agents to the retarding agents. The resuits of X-ray diffraction and differential scanning calorimetry analysis indicated that silybin was highly dispersed in the microspheres in amorphous state. The release profiles and content did not change after a three-month accelerated stability test at 40 ℃ and 75% relative humidity. Conclusion Sustained-release silybin microspheres with a solid dispersion structure were prepared successfully in one step by a spherical crystallization technique combined with solid dispersion technique. The preparation process is simple, reproducible and inexpensive. The method is efficient for designing sustained-release microspheres with water-insoluble drugs.
文摘To enhance the oral absorption of the poorly water-soluble drug silybin, a self-microemulsifying drug delivery system （SMEDDS） composed of ethyl linoleate, Cremophor EL and PEG 400 for oral administration of silybin was formulated, and its physicochemical properties and bioavailability of silybin were evaluated. The in vitro release of silybin from microemulsion and dispersion of silybin from SMEDDS were significantly faster than those from the commercial silybin hard capsule, respectively. The area under the drug concentration-time curve （AUC） and the mean maximum plasma level （Cmax） of the SMEDDS were remarkably greater than those of the hard capsule after oral administration to rats. The absorption of silybin formulated in SMEDDS exhibited a 2.3-fold increase in bioavailability as compared with the hard capsule. These results demonstrated that SMESDDS might be a useful drug delivery system for the oral delivery of the poorly water-soluble drug silybin.
文摘To improve its solubility and dissolution,solid dispersions of silybin in PVP K30 were prepared by the conventional solvent evaporation method and characterized by equilibrium solubility and dissolution studies,differential scanning calorimetry （DSC） and Fourier transform infrared spectroscopy（FTIR）.Silybin solid dispersions showed increased solubility and rates of dissolution compared with pure drug and corresponding physical mixtures of silybin and PVP K30.Thermograms of various solid dispersions did not show the melting peak of pure silybin,indicating that silybin was in amorphous form inside the polymer carrier.FTIR studies demonstrated the presence of interactions between hydroxyl groups of silybin and carbonyl groups of PVP K30 in solid dispersions.Solid dispersion techniques can be used to formulate water insoluble drugs to improve their dissolution in vitro and absorption in vivo.
文摘Objective To investigate the bioavailability and pharmacokinetics of silybin A and silybin B in rats,respectively. Methods Following iv and ig administration of silybin to 20 Wistar rats,the plasma samples were collected at different time points up to 12 h.Sample pretreatment was involved in one-step protein precipitation with acetonitrile. Silybin A and silybin B were simultaneously determined by LC-MS/MS.Results After ig dosing silybin 28,56,and 112 mg/kg to rats,the t1/2βvalues were 5.48,5.08,and 5.73 h for silybin A,and 4.56,4.12,and 5.53 h for silybin B; The Cmax were 674.3,1349.4,and 2042.5 ng/mL for silybin A,and 671.0,1365.4,and 2066.2 ng/mL for silybin B; The Tmax were 0.20,0.23,and 0.20 h for silybin A,and 0.20,0.23,and 0.20 h for silybin B;The AUC were 454.4, 845.9,and 1219.5 h·ng/mL for silybin A,and 432.0,817.1,and 1153.6 h·ng/mL for silybin B.The absolute bioavailabilities of silybin A and silybin B were 2.86%and 1.93%,respectively.Conclusion Silybin A and silybin B have very low bioavailability after ig administration,and there is no significant difference in the pharmacokinetic parameters between silybin A and silybin B,which indicates that the two diastereoisomers have similar pharmacokinetic behavior in rats.
基金Supported by MIUR-COFIN(Prot.20089SRS2X_002)Compagnia San Paolo Torino+1 种基金University of Genovaand Fondazione CARIGE
文摘AIM: To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis.METHODS: Rat hepatoma FaO cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitate for 3 h to mimic liver steatosis. Then, the steatotic cells were incubated for 24 h with different concentrations (25 to 100 μmol/L) of silybin as phytosome complex with vitamin E. The effects of silybin on lipid accumulation and metabolism, and on indices of oxidative stress were evaluated by absorption and fluorescence microscopy, quantitative real-time PCR, Western blot, spectrophotometric and fluorimetric assays.RESULTS: Lipid-loading resulted in intracellular triglyceride (TG) accumulation inside lipid droplets, whose number and size increased. TG accumulation was mediated by increased levels of peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding protein-1c (SREBP-1c). The lipid imbalance was associated with higher production of reactive oxygen species (ROS) resulting in increased lipid peroxidation, stimulation of catalase activity and activation of nuclear factor kappa-B (NF-κB). Incubation of steatotic cells with silybin 50 μmol/L significantly reduced TG accumulation likely by promoting lipid catabolism and by inhibiting lipogenic pathways, as suggested by the changes in carnitine palmitoyltransferase 1 (CPT-1), PPAR and SREBP-1c levels. The reduction in fat accumulation exerted by silybin in the steatotic cells was associated with the improvement of the oxidative imbalance caused by lipid excess as demonstrated by the reduction in ROS content, lipid peroxidation, catalase activity and NF-κB activation.CONCLUSION: We demonstrated the direct anti-steatotic and anti-oxidant effects of silybin in steatotic cells, thus elucidating at a cellular level the encouraging results demonstrated in clinical and animal studies.
基金supported by 985 foundation from Zhejiang University and intramural foundation from Wenzhou Medical College
文摘Twelve 23-esterified silybin derivatives with different patterns of substituents such as aromatic and aliphatic groups （1-12） were designed and synthesized. The antioxidative properties of these compounds were evaluated. The modifed silybin analogues exhibited improved inhibitory effects against rat liver homogenate lipid peroxidation compared to silybin, with exception of the trimethoxylated ester （5） and the aliphatic one （9）. Compounds 3, 5, 7, 8 and 11 displayed their protective properties on DNA cleavage in a dose-dependent manner. 2009 Xiao Kun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
文摘Objective: To study the curative effect of silybin combined with pituitrin-phentolamine for pulmonary tuberculosis complicated by acute hemoptysis. Methods: A total of 78 patients with pulmonary tuberculosis complicated by acute hemoptysis who were treated in this hospital between December 2013 and April 2017 were divided into control group (n=39) and silybin group (n=39) by random number table. Control group received pituitrin-phentolamine hemostasis therapy, silybin group received pituitrin-phentolamine combined with silybin therapy, both were treated for 1 week. The differences in peripheral blood liver function and coagulation index levels as well as serum oxidative stress index contents were compared between the two groups of patients before treatment and after 1 week of treatment. Results:Before treatment, the differences in peripheral blood liver function and coagulation index levels as well as serum oxidative stress index contents were not statistically significant between the two groups. After 1 week of treatment, peripheral blood liver function indexes ALT, AST, ALP and STB contents of silybin group were lower than those of control group;peripheral blood coagulation indexes PT, APTT and TT levels were lower than those of control group whereas Fib level was higher than that of control group;serum oxidative stress indexes AOPPs and LHP contents were lower than those of control group whereas GSH-Px and T-AOC contents were higher than those of control group. Conclusion: pituitrin-phentolamine combined with silybin therapy can effectively protect the liver function, optimize the coagulation function and reduce the oxidative stress response in patients with pulmonary tuberculosis complicated by acute hemoptysis.
文摘We established a RP-HPLC method for the analysis of silymarin in microemulsion. Silymarin was separated using a ODS C18 column and monitored at the wavelength 288 nm. The mobile phase consisting of methanol-water-acetic acid （42：58：0.5, v/v/v） was pumped at a flow rate of 1.0 mL/min. The linear range of calibration curve was 10-1000 μg/mL. The average recovery was 99.0%-100.7% for silybin isomers. The RSD values of inter-day and intra-day assays were lower than 1.6% for silybin isomers. The method is simple, rapid, reproducible and precise for the quantitative determination of silymarin in microemulsion.
基金supported by seed-fund to AKT from Department of Pharmacology and Experimental Therapeutics at UT
文摘Flavonoids are polyphenols that are found in numerous edible plant species. Data obtained from preclinical and clinical studies suggest that specific flavonoids are chemo-preventive and cytotoxic against various cancers via a multitude of mechanisms. However, the clinical use of flavonoids is limited due to challenges associated with their e ective use, including(1) the isolation and purification of flavonoids from their natural resources;(2) demonstration of the e ects of flavonoids in reducing the risk of certain cancer, in tandem with the cost and time needed for epidemiological studies, and(3) numerous pharmacokinetic challenges(e.g., bioavailability, drug–drug interactions, and metabolic instability). Currently, numerous approaches are being used to surmount some of these challenges, thereby increasing the likelihood of flavonoids being used as chemo-preventive drugs in the clinic. In this review, we summarize the most important challenges and e orts that are being made to surmount these challenges.
基金Supported by NIH grants R01-DK38825 and contracts N01-DK92326, and U01-DK065201 (Bonkovsky HL)
文摘AIM: To determine the effect of Legalon-SIL (LS) on hepatitis C virus (HCV) core and NS5A expression and on heme oxygenase-1 (HMOX-1) and its transcriptional regulators in human hepatoma cells expressing full length HCV genotype 1b. METHODS: CON1 cells were treated with 50 μmol/L or 200 μmol/L LS. Cells were harvested after 2, 6 and 24 h. HCV RNA and protein levels were determined by quantitative real-time polymerase chain reaction and Western blotting, respectively. RESULTS: HCV RNA (core and NS5A regions) wasdecreased after 6 h with LS 200 μmol/L (P < 0.05). Both 50 and 200 μmol/L LS decreased HCV RNA levels [core region (by 55% and 88%, respectively) and NS5A region (by 62% and 87%, respectively) after 24 h compared with vehicle (dimethyl sulphoxide) control (P < 0.01). Similarly HCV core and NS5A protein were decreased (by 85%, P < 0.01 and by 65%, P < 0.05, respectively) by LS 200 μmol/L. Bach1 and HMOX-1 RNA were also downregulated by LS treatment (P < 0.01), while Nrf2 protein was increased (P < 0.05).CONCLUSION: Our results demonstrate that treatment with LS downregulates HCV core and NS5A expression in CON1 cells which express full length HCV genotype 1b, and suggests that LS may prove to be a valuable alternative or adjunctive therapy for the treatment of HCV infection.
文摘Flavonoids are a large class of natural poly-phenolic compounds, occurring in fruits and vegetables regularly consumed by humans. Recently, flavonoids have aroused
基金supported by the National Natural Science Foundation of China (grant Nos. 81573378 and 81773651)the Shanghai Science and Technology Innovation Action Plan for Basic Research, China (No. 17430741500)
文摘Increasing the degree of supersaturation of drugs and maintaining their proper stability are very important in improving the oral bioavailability of poorly soluble drugs by a supersaturated drug delivery system(SDDS). In this study, we reported a complex system of Soluplus–Copovidone(Soluplus–PVPVA)loaded with the model drug silybin(SLB) that could not only maintain the stability of a supersaturated solution but also effectively promote oral absorption. The antiprecipitation effect of the polymers on SLB was observed using the solvent-shift method. In addition, the effects of the polymers on absorption were detected by cellular uptake and transport experiments. The mechanisms by which the Soluplus–PVPVA complex promotes oral absorption were explored by dynamic light scattering, transmission electron microscopy, fluorescence spectra and isothermal titration calorimetry analyses. Furthermore, a pharmacokinetic study in rats was used to demonstrate the advantages of the Soluplus–PVPVA complex. The results showed that Soluplus and PVPVA spontaneously formed complexes in aqueous solution via the adsorption of PVPVA on the hydrophilichydrophobic interface of the Soluplus micelle, and the Soluplus–PVPVA complex significantly increased the absorption of SLB. In conclusion, the Soluplus–PVPVA complex is a potential SDDS for improving the bioavailability of hydrophobic drugs.
文摘The effects of silybin on erythrocytic sorbitol level and peripheral nerve conduction veloci-ty were studied in 14 cases of noninsulin dependent diabetes mellitus (NIDDM) . Atter oral administrationof silybin 231 mglday for 4 weeks, no blood glucose change was observed in patients with NIDDM, whilethe erythrocytic sorbitol level was significantly decreased from 72. 55 21. 61 to 39. 53 14. 94 nmol/g .Hb (P<0. 01) . At the same time, peripheral nerve conduction vefocity was also improved. These resultsindicate that silybin is an effective aldose reductase inhibitor which can improve the disorder of polyolpathway in NIDDM patients and prevent chronic complications of diabetes.
