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1.
Acta Pharmaceutica Sinica ; (12): 399-408, 2022.
Article in Chinese | WPRIM | ID: wpr-922931

ABSTRACT

To investigate the therapeutic effect and molecular mechanism of the main flavonoid components of Silybum marianum (S. marianum) on nonalcoholic fatty liver disease (NAFLD), we identified nine flavonoids in S. marianum through TCMSP, PubChem database and corresponding literatures. The potential therapeutic targets of NAFLD were predicted by SwissTargetPrediction, GeneCards and Venny 2.1.0 platform, while the protein-protein interaction (PPI) network of potential targets was analyzed using String platform and Cytoscape software. Then GO and KEGG pathway enrichment analysis were performed using David 6.8 database, followed by molecular docking verification using AutoDock software. In vitro, components with higher degree value in the "components-targets-pathway" network were chosen for further analysis. L02 cells were used to establish lipid accumulation model and treated with different components. Furthermore, the effects of four pure active compounds from S. marianum on lipid accumulation in hepatocytes were analyzed by oil red O staining. The results showed that the main nine flavonoids extracted from S. marianum contained 24 potential NAFLD targets. Several critical pathways closely related to NAFLD process were identified by GO and KEGG enrichment analysis, including phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) pathway, type 2 diabetes pathway, tumor necrosis factor (TNF) pathway and insulin resistance pathway. The results of molecular docking further indicated that the core components displayed strong binding abilities with key targets respectively, and silandrin showed better binding activity as compared to other components. The results obtained from L02 cells showed that the lipid accumulation was reduced by treatment with isosilybin A, isosilybin B, silydianin and silychristin, while the activity of isosilybin B was better than that of isosilybin A. Taken together, we concluded that the main flavone components of S. marianum could improve lipid accumulation through multiple signaling pathway in hepatocytes, and this could be a potential new strategy for the treatment of NAFLD.

2.
Article in English | WPRIM | ID: wpr-881081

ABSTRACT

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 receptor α (PPARα), PPARα antagonist GW6471 was co-administrated with silybin to NAFLD mice. Since silybin was proven as a PPARα partial agonist, the combined effect of silybin with PPARα agonist, fenofibrate, was then evaluated in NAFLD mice. Serum and liver samples were collected to analyze the pharmacological efficacy and expression of PPARα and 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 carboxylase α. GW6471 abolished the effect of silybin on PPARα signal 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 PPARα to diminish lipid accumulation and it is not suggested to simultaneously take silybin and classical PPARα agonists for NAFLD therapy.

3.
Article in Chinese | WPRIM | ID: wpr-879012

ABSTRACT

To evaluate the effects of Hydroxypropyl methylcellulose acetate succinate(HPMCAS MF) on absorption of silybin(SLB) from supersaturable self-nanoemulsifying drug delivery system which was pre-prepared at the early stage experiment. The cell toxicity of self-emulsifying preparation was evaluated by the MTT method, and the in vitro membrane permeability and absorption promoting effect of the self-emulsifying preparation were evaluated by establishing a Caco-2 cell monolayer model. The in vivo and in vitro supersaturation correlation was evaluated via the blood concentration of SLB. The results of MTT showed that the concentration of the preparation below 2 mg·mL~(-1)(C_(SLB) 100 μg·mL~(-1)) was not toxic to Caco-2 cells, and the addition of polymer had no significant effect on Caco-2 cells viability. As compared with the solution group, the transport results showed that the P_(app)(AP→BL) of the self-emulsifying preparation had a very significant increase; the transport rate of silybin can be reduced by polymer in 0-30 min; however, there was no difference in supersaturated transport between supersaturated SLB self-nanoemulsion drug delivery system(SLB-SSNEDDS) and SLB self-nanoemulsion drug delivery system(SLB-SNEDDS) within 2 hours. As compared with SLB suspension, pharmacokinetic parameters showed that the blood concentration of both SLB-SNEDDS and SLB-SSNEDDS groups were significantly increased, and C_(max) was 5.25 times and 9.69 times respectively of that in SLB suspension group, with a relative bioavailability of 578.45% and 1 139.44% respectively. C_(max) and relative bioavailability of SLB-SSNEDDS were 1.85 times and 197% of those of SLB-SNEDDS, respectively. Therefore, on the one hand, SSNEDDS can increase the solubility of SLB in gastrointestinal tract by maintaining stability of SLB supersaturation state; on the other hand, the osmotic transport process of SLB was regulated through the composition of its preparations, and both of them could jointly promote the transport and absorption of SLB to improve the oral bioavailability of SLB.


Subject(s)
Administration, Oral , Biological Availability , Caco-2 Cells , Drug Delivery Systems , Emulsions , Humans , Methylcellulose/analogs & derivatives , Nanoparticles , Particle Size , Silymarin , Solubility
4.
Article in Chinese | WPRIM | ID: wpr-846103

ABSTRACT

Objective: In order to improve the bioavailability of the insoluble drug silybin, silybin supersaturated self- nanoemulsifying drug delivery systems (SLB-S-SNEDDS) containing functional oil were prepared, its characterization and in vitro evaluation were also performed. Methods: Functional oils were screened by performing potassium ferrohydride reduction and 1,1- diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging experiments. The pseudo-ternary phase diagram was drawn to investigate the emulsifying ability of emulsifier. The proportion of mixed oil phase and drug loading capacity were explored by analyzing particle size, polydispersity index (PDI), zeta potential, etc. The type and concentration of supersaturated substance in SLB-S-SNEDDS were obtained by conducting the compatibility and dissolution experiments. SLB-S-SNEDDS was characterized with appearance, particle size distribution, self-emulsification efficiency, and morphology, and its in vitro dissolution, antioxidant capacity, and cytotoxicity were also evaluated. Results: The prescriptions of SLB-S-SNEDDS were as follows: (1) wheatgerm oil/Capryol 90- Cremophor ELP-Transcutol HP; (2) seabuckthorn seed oil/Capryol 90-Cremophor ELP-Transcutol HP. One g S-SNEDDS matrix contained 0.043 g of wheatgerm oil or sea-buckthorn seed oil, 0.387 g of Capryol 90, 0.380 g of Cremophor ELP, and 0.190 g of Transcutol HP. The adding amount of silybin in S-SNEDDS prescription was 20% of the sum of the equilibrium solubility of silybin in each component, and the adding amount of Soluplus was 0.1% of the total mass described above. The two obtained SLB-S-SNEDDS were transparent homogeneous liquid with light yellow (wheat germ oil) and bright yellow (seabuckthorn seed oil) color, respectively. After being dispersed, SLB-S-SNEDDS turned into subspherical white flat emulsion droplets with the particle size of about 50 nm, and the emulsification time was 65 s. Compared with raw materials and SLB-SNEDDS, the cumulative dissolution of silybin in SLB-S-SNEDDS was maintained between 85% and 110% within 8 h, indicating that the two systems can significantly improve the dissolution of silybin. The absorbance of SLB-S-SNEDDS after reaction with potassium ferricyanide (0.452-0.782, 0.488-0.765) and the DPPH free radical clearance of SLB-S-SNEDDS (39.09%-96.02%, 30.54%-89.20%) were all higher than those of raw silybin (0.411-0.760, 22.89%-63.21%), which suggested that the two systems can enhance the antioxidant capacity of silybin. Cytotoxicity test results showed that the cell survival rate in silybin raw material group, combination of silybin and S-SNEDDS group, and blank S-SNEDDS group were greater than 90% at 5 µmol/L and 10 µmol/L drug concentration, indicating that SLB-S-SNEDDS and its auxiliary materials were safe and less toxic to human cloned colorectal adenocarcinoma cell line (Caco-2). Conclusion: The SLB-S-SNEDDS containing functional oil prepared in this paper can not only increase the cumulative dissolution of silybin, but also enhance its antioxidant capacity, which provides a useful reference for supersaturated self-nanoemulsifying drug delivery systems (S-SNEDDS) to improve the water-solubility and bioactivity of insoluble drugs.

5.
Chinese Journal of Hepatology ; (12): 45-50, 2019.
Article in Chinese | WPRIM | ID: wpr-810371

ABSTRACT

Objective@#To probe into the mechanism and interventional effects of silybin-phospholipid complex on amiodarone-induced steatosis in mice.@*Methods@#Eight-week-old male C57BL/6 mice were divided into three groups (5 mice in each group): a control group (WT) with normal diet, a model group with amiodarone 150mg/kg/d by oral gavage (AM), and an intervention group on amiodarone 150mg/kg/d combined with silybin-phospholipid complex(AM+SILIPHOS. All mice were fed their assigned diet for one week. Then, one week later, serum alanine aminotransferase, aspartate aminotransferase, triglyceride, total cholesterol and high-density lipoprotein were detected of each group. A liver pathological change was observed by oil red O and H&E staining. Ultrastructural pathological changes of hepatocytes were observed to evaluate the intervention effect by transmission electron microscopy. RT-q PCR was used to detect the expression of peroxisome proliferator-activated receptor alpha and its regulated lipid metabolism genes CPTI, CPTII, Acot1, Acot2, ACOX, Cyp4a10 and Cyp4a14 in liver tissues. Intra-group comparison was done by paired t-test. One-way ANOVA was used for comparison between groups and semi-quantitative data were tested using Mann-Whitney U test.@*Results@#Oil Red O and H&E staining results of liver tissue in the intervention group showed that intrahepatic steatosis was significantly reduced when compared to model group. Transmission electron microscopy showed that the model group had pyknotic nuclei, mitochondrial swelling, structural damage, and lysosomal degradation whereas the intervention group had hepatic nucleus without pyknosis, reduced mitochondrial swelling and slight structural damage than that of model group. RT-q PCR results showed that the expression of peroxisome proliferator-activated receptor alpha, CPTI, CPTII, Acot1, Acot2, ACOX, Cyp4a10 and Cyp4a14 were increased in the model group but the expression of CPTI, Cyp4a14, Acot1 and peroxisome proliferator-activated receptor alpha were decreased in the intervention group (P < 0.05).@*Conclusion@#Silybin-phospholipid complex can alleviate amiodarone-induced steatosis, and its mechanism may play a role in protecting mitochondrial function and regulating fatty acid metabolism. Thus, silybin-phospholipid complex has potential intervention effect on amiodarone-induced fatty liver.

6.
Acta Pharmaceutica Sinica B ; (6): 107-117, 2019.
Article in English | WPRIM | ID: wpr-774999

ABSTRACT

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 the adsorption of PVPVA on the hydrophilic-hydrophobic 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.

7.
Article in Chinese | WPRIM | ID: wpr-850879

ABSTRACT

Objective: To develop and optimize the silybin supersaturated self-microemulsion drug delivery system (SLB-SSMEDDS) and improve the oral bioavailability of SLB in the biological medium. Methods: The formulation of SLB-SMEDDS was selected by solubility test, emulsifying ability of emulsifier and pseudo-ternary phase diagram. The analytic hierarchy process (AHP) was used to evaluate the performance of each prescription to screen the optimal ratio. The type and dosage of precipitation inhibitors (PPIs) was optimized to maintain the supersaturation and duration of drugs in biological media in vitro; Finally, the emulsification effect, emulsion size and surface morphology of SLB-SSMEDDS was comprehensively evaluated in terms of in vitro release and in vitro supersaturation. Results: The SLB-SSMEDDS prescription was Capryol 90-Cremophor RH-Transcutol HP-HPMC-AS MF (10:67.5:22.5:2). The self-microemulsion with a drug loading of 50.19 mg/g was uniform and the emulsion droplets were spherical in shape and uniform in size. And the emulsification time was (30.67 ± 4.16) s, the average particle size was (11.67 ± 0.81) nm, and the PDI was (0.15 ± 0.04). The dissolution rate of SLB-SSMEDDS in FaSSGF and FaSSIF-V2 was significantly increased. And the in vitro dilution and supersaturation could be maintained above 10 within 120 min. Conclusion: SLB-SSMEDDS has a simple preparation process and can improve the stability of traditional SMEDDS, maintain supersaturation effectively and enhance the dissolution of SLB in vitro.

8.
Article in Chinese | WPRIM | ID: wpr-811727

ABSTRACT

@#The aim of this paper was to investigate the absorption mechanism of silybin(SLB)in Caco-2 cells. Concentrations of samples in the study were determined by developing LC/MS/MS method of SLB, propranolol and atenolol in HBSS buffer to calculate apparent permeability coefficient(Papp). When Caco-2 cells were cultured to the 21st day, the TEER were above 350 Ω ·cm2. The Papp of Lucifer yellow was far less than 1 × 10-7 cm/s. As the positive control drugs, The Papp of atenolol and propranolol were similar to those reported in the literature, indicating that the Caco-2 monolayer model was successfully established in this experiment. The Papp(AP-BL) of SLB at 5, 20, and 50 μg/mL were all more than 2×10-6 cm/s, which showed that SLB was a moderately permeable drug. The efflux ratio was greater than 2 indicating the efflux transporter may be involved in the absorption process of SLB. The Papp of silybin-N-meglumine was similar to that of SLB, suggesting that salt formation did not alter the membrane permeability of SLB. In conclusion, the membrane permeability of SLB is good, and its solubility is low. SLB is a BCS class 2 drug. The release of SLB in the gastrointestinal tract is an important factor in its absorption process.

9.
Article in English | WPRIM | ID: wpr-741613

ABSTRACT

Silymarin is the standardized extract from Silybum marianum which consists mainly of flavonoids and polyphenols. It is highly regarded for its hepatoprotective ability. Silybin B is a flavonolignan and one of the active components of silymarin. The content of silybin B in various parts of S. marianum was analyzed by HPLC-UV. Results show that the extract of seeds contain the highest amount of silybin B (7.434 mg/g DW). The petioles of S. marianum showed a low content of silybin B. This study revealed that seeds of S. marianum contain high amount of silybin B and could be a good source of the compound.


Subject(s)
Flavonoids , Milk Thistle , Polyphenols , Silymarin
10.
Acta Pharmaceutica Sinica ; (12): 771-777, 2018.
Article in Chinese | WPRIM | ID: wpr-779935

ABSTRACT

Two novel Mannich base derivatives of silybin, SLB-DEA and DHSLB-PIP, were designed and synthesized. All the structures of new Mannich base derivatives of silybin were characterized by 1H NMR and HR-MS. Their protective action against CCl4-induced liver injury in mice were investigated. The changes of alanine aminotransferase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), total cholesterol (TC) and triglyceride (TG) were determined and the histopathological changes in liver tissues were examined. Pretreatment with a higher dosage of DHSLB-PIP (40 mg·kg-1) prevented CCl4-induced liver injury as indicated by the reduced levels of ALT, AST, LDH and TG. Meanwhile, liver histopathological improvement was observed in the model groups. The pharmacokinetics study in rats showed that the relative bioavailability of SLB-DEA and DHSLB-PIP were 172.5% and 259.8% compared with silybin. All the results suggest that SLB-DEA and DHSLB-PIP may protect liver against injury by CCl4 and the relative bioavailability was significantly increased, which is worth of further investigation for their druggability.

11.
Article in Chinese | WPRIM | ID: wpr-505893

ABSTRACT

Objective To evaluate the clinical efficacy of silybin combined with nucleotides in the treatment of viral hepatitis associated with nonalcoholic fatty liver disease (NAFLD).Methods 88 viral hepatitis patients with NAFLD were randomly selected into the clinical research,and they were divided into groups according to the order of treatment.Among them 44 cases of single number were the control group treated with nucleoside(acid) drugs,44 cases of double number were the observation group treated with silibinincombined silybin combined with nucleoside(acid).The therapeutic effect after the end of the course of treatment were was evaluated.Results The effective rate in the observation group was 90.91%,which that in the control group was 70.45%,the difference was statistically significant (x2 =8.87,P < 0.05).The ALT,AST,r-GGT after treatment of the observation group were (37.14 ± 3.56) U/L,(30.45 ±3.35) U/L,(51.65 ± 3.46) U/L,which were significantly reduced than before treatment(t =8.01,8.72,7.80,all P < 0.05),and the differences were significant compared with the control group (t =7.57,8.34,7.29,all P < 0.05).The TG,TC of blood lipid indexes indices after treatment of the observation group were (1.48 ±0.26) mmol/L,(5.18 ± 0.86)mmol/L,which were significantly lower than those before treatment (t =7.62,8.14,all P < 0.05),and the differences were significant compared with the control group (t =7.10,7.55,all P < 0.05).Conclusion The combination of silybin and nucleotides in the treatment of viral hepatitis with NAFLD has significant effect,can significantly improve the clinical symptoms and liver function indicators,and gradually restore the level of blood lipids,it is worthy of promoting the application.

12.
Article in Chinese | WPRIM | ID: wpr-852871

ABSTRACT

Objective: To prepare silybin (SLB) proliposomes and evaluate its quality. Methods: SLB proliposomes were prepared by freeze-drying method, and the formulation and process were optimized by single factor investigation and orthogonal design with the encapsulation efficiency and drug loading as indexes. The optimal cryoprotetant was selected and the morphology, particle size, encapsulation efficiency, and stability of SLB proliposomes were investigated. Results: The optimized preparation process was as follows: The ratio of drug to total lipid was 1:12, the ratio of phospholipid to cholesterol was 4:1, the pH of hydration medium was 7.4 and the temperature was 45℃. Mannitol was the optimal cryprotectant to prepare SLB proliposomes, and the formation of SLB proliposomes looked plumpy and compact. The size of preliposome was around (251.40 ± 2.14) nm, the Zeta potential was around (-30.80 ± 0.89) mV, encapsulation efficiency was (88.92 ± 5.86)%, and it had good stability during storage. Conclusion: The preparation process of SLB proliposomes is simple, and it has high encapsulation efficiency and good stability, therefore, it is deserved to be further studied.

13.
Article in Chinese | WPRIM | ID: wpr-852676

ABSTRACT

Objective: To investigate the relationship between drug concentration and drug loading efficiency and to explore mechanism of drug loading by incorporating different insoluble drugs into mesoporous silica nanoparticles with dipping centrifugation method. Methods: Mesoporous silica nanoparticles were characterized by transmission electron microscopy and nitrogen adsorption-desorption analysis. Silybin, puerarin, berberine, curcumin, and ferulic acid were used as model drugs and loaded into mesoporous silica nanoparticles using two technologies: The volume of drug solution or drug amount was fixed respectively. The relationship between drug concentration and drug loading was analyzed. Paclitaxel, tanshinone IIA and tetrahydropalmatine were used to validate the law. Nanoparticles loaded silybin, puerarin, and ferulic acid with high drug loading efficiency were characterized by scan electron microscopy and DSC. Results: The average size of mesoporous silica nanoparticles was (220 ± 21) nm, with a specific surface area of 353.53 m2/g, pore size of 1.53 nm and pore volume of about 0.4 cm3/g. In the condition of a fixed mass ratio of drug to mesoporous silica nanoparticles, the drug loading efficiency was always linearly related to the drug concentration at the above preparation technology even if drug loading of different drugs were analyzed together. No obvious drug crystallines were observed in the surface of nanoparticles by scan electron microscopy. Melting peaks of silybin, puerarin and ferulic acid were all observed in DSC curves of mesoporous silica nanoparticles loaded drugs, but their heat absorption amounts per mg were all smaller than physical mixtures. Conclusion: The drug solution concentration was the key factor on drug loading efficiency of mesoporous silica nanoparticles by dipping centrifugation method and drugs existed in pores of mesoporous silica nanoparticles in crystalline and amorphous forms.

14.
Article in Chinese | WPRIM | ID: wpr-852609

ABSTRACT

Objective: To investigate the chemical constituents from the whole plant of Carpesium faberi. Methods: Compounds were isolated by various chromatographic techniques, including silica gel, ODS, sephadex LH-20, and semi-preparative HPLC, and their structures were identified by comparison of their experimental spectroscopic data with their reported data. Results: The phytochemistry investigation led to the isolation of 12 compounds, and their structures were elucidated as ent-kaurane-3β,16β,17-triol (1), 3-(hydroxy-acetyl)-1H-indole (2), 8,9,10-trihydroxythymol (3), 8-hydroxy-9,10-diisobutyryloxy-thymol (4), neryl-β-D- glucopyranoside (5), (3S)-linalyl-β-D-glucopyranoside (6), (1R,2S,4S,5R)-2,5-dihydroxy-p-menthane (7), luteolin (8), apigenin-7-O-β-D-glucopyranoside (9), medioresinol (10), pinoresinol (11), and a mixture of silybin and isosilybin (12). Conclusion: All compounds except compound 7 are not only isolated from this plant for the first time, but also from this genus for the first time.

15.
Chinese Pharmacological Bulletin ; (12): 1535-1541, 2017.
Article in Chinese | WPRIM | ID: wpr-667473

ABSTRACT

Aim To examine weather fructo-oligosaccharides(FOS) and silybin(Sil) could exhibit synergetic effect on treating obesity-associated non-alcoholic fatty liver disease(NAFLD).Methods Seventy mice were randomly divided into two groups:control group (NCD,fed with normal chow diet),the other sixty mice were fed with high-fat diet (HFD) to establish NAFLD model.Seventy days after the establishment of experimental model,the latter group was then randomly subdivided into six groups:model (HFD),Sil (30mg· kg-1),FOS (2 000 mg · kg-1),Sil (30 mg ·kg-1) combined with FOS of high,medium and low dose respectively.The NCD and HFD group were given 0.5% CMC,and the other groups were fed with high-fat diet and given 10 mL · kg-1 by gavage daily,then body weight and food intake were recorded.Fasting blood glucose,insulin,homeostasis model of assessment for insulin resistence index (HOMA-IR) and oral glucose tolerance tests(OGTT) were measured after 120 days.All mice were sacrificed after 130 days,and blood and liver were collected.Levels of TC,TG,ALT,AST in serum were detected,and liver index and pathology were also examined.Results FOS (2 000 mg · kg-1) showed obvious synergism for Sil-mediated attenuation of levels of TC,TG,ALT,AST in serum,fasting blood glucose,insulin,HOMA-IR,OGTI curve,liver index and pathology,but FOS (4 000 mg · kg-1) could not bring superiority with a double dose,except for its improvement in body weight of mice with NAFLD.Conclusions In the treatment of NAFLD,FOS exhibits synergetic effect with Sil.This agent might be a potent candidate for obesity and NAFLD prevention,through modulating the composition of gut microbiota.

16.
Article in English | WPRIM | ID: wpr-159287

ABSTRACT

PURPOSE: MicroRNAs (miRNAs) have received much attention owing to their aberrant expression in various stages of cancer. In many biological processes, miRNAs negatively regulate gene expression, and may be useful in therapeutic strategies. The present study evaluated the effects of silibinin (silybin), a natural flavonoid, on miRNA expression and attempted to elucidate therapeutic targets in MCF-7 breast cancer cells. METHODS: The rates of cell proliferation and apoptosis were determined in silibinin-treated and untreated MCF-7 cells. Furthermore, the expression levels of miR-21 and miR-155 were measured in MCF-7 cells after incubation with silibinin (100 µg/mL), and the putative targets of the miRNAs within the apoptotic pathways were predicted using bioinformatic approaches. The expression levels of some of these targets were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Silibinin induced apoptosis in MCF-7 cells in a dose- and time-dependent manner. qRT-PCR analysis revealed a decrease in miR-21 and miR-155 expression levels in silibinin-treated cells relative to the levels in the untreated cells. Potential miR-21 and miR-155 targets within the apoptotic pathways, such as CASP-9, BID, APAF-1, CASP-3, CASP-8, and PDCD4, were predicted by in silico analysis. qRT-PCR analysis showed upregulation of some of these potential targets including caspase-9 (CASP-9) and BID after silibinin treatment for 48 hours. CONCLUSION: Our results suggest a correlation between the expression of miR-21 and miR-155, and MCF-7 cell proliferation. The antiproliferative activity of silibinin may partly be attributable to the downregulation of miR-21 and miR-155, and the upregulation of their apoptotic targets. Furthermore, the upregulation of CASP-9 and BID indicates that silibinin induces apoptosis through both the extrinsic and intrinsic pathways.


Subject(s)
Apoptosis , Biological Phenomena , Breast Neoplasms , Breast , Caspase 9 , Cell Proliferation , Computer Simulation , Down-Regulation , Gene Expression , Humans , MCF-7 Cells , MicroRNAs , Polymerase Chain Reaction , Reverse Transcription , Up-Regulation
17.
Article in Chinese | WPRIM | ID: wpr-500771

ABSTRACT

Objective To study the clinical efficacy and safety of Silybin-nanosuspension in the treatment of liver cancer.Methods 56 patients with liver tumor were collected from February 2014 to May 2015 in our hospital,and all patients were randomly divided into treatment group(n=24)and control group(n=32).The treatment group was treated with oral Silybin-nanosuspension 360mg(Silybin)and control group was treated with Silybin capsule 360mg(Silybin),once a day.The treatment was over once the following conditions appear,the disease progression,or intolerable toxicity,or the lesion site can be treat with surgery,or patient death.Evaluating the efficacy through comparing the data of objective response rate,disease control rate, progression-free survival and overall survival,and record the adverse reactions through measuring the values of indicators of blood toxicity ( leukocytes, neutrophils,platelets and hemoglobin ) and the liver function parameters ( Valley alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) .Results The objective response rate, disease control rate, progression-free survival and overall survival of treatment group were significantly better than control group(P<0.05),and the parameters of blood toxicity and liver function were no significant differences.Conclusion The Silybin-nanosuspension is safe and effective for the treatment of liver malignancies.

18.
Acta Pharmaceutica Sinica ; (12): 813-2016.
Article in Chinese | WPRIM | ID: wpr-779242

ABSTRACT

A new silybin nanocrystallines self-stabilizing Pickering emulsion (SN-SSPE) was developed using the high pressure homogenization method to improve the oral bioavailability of silybin. The influences of homogenization pressure from 50 to 120 MPa and drug content from 100 mg to 1000 mg on the formation of SN-SSPE were studied. The morphology, structure and size of emulsion droplet in SN-SSPE were characterized using scanning electron micrograph and confocal laser scanning microscope. SN-SSPE was evaluated, including stability, in vitro release and in vivo oral bioavailability. The particle size of silybin nanocrystallines (SN-NC) was decreased as the pressure increased until 100 MPa. When the drug content reached 300 mg or above, stable SN-SSPE was formed from sufficient SN-NC covering surfaces of oil droplets completely. The emulsion droplet of SN-SSPE with the size of 27.3±3.1 μm showed a core-shell structure consisting of oil droplet as core and SN-NC as shell. SN-SSPE showed a high stability over 40 days. In vitro release rate of SN-SSPE was faster than silybin coarse powder and similar to silybin nanocrystallines suspension (SN-NCS). After intragastric administration in rats, the peak concentration of SN-SSPE was increased by 2.5-fold and 2.3-fold compared with SN-NCS and silybin coarse powder, respectively. The AUC of SN-SSPE was increased by 1.4-fold and 3.8-fold compared with SN-NCS and silybin coarse powder, respectively. All these results showed that nanocrystallines of the poorly soluble drug could stabilize Pickering emulsions, which provides a promising application to the improvement of the oral bioavailability of poorly soluble drugs.

19.
Article in Chinese | WPRIM | ID: wpr-854349

ABSTRACT

To establish the suspension culture system of Silybum marianum cell and study the effects of different factors on silybin content. Orthogonal test was adopted to determine S. marianum cell suspension culture system and HPLC to silybin content.. The best growth cycle of cell suspension culture was defined when cultured in liquid MS medium with 6-BA 1.5 mg/L + NAA 1.0 mg/L + ZT 1.5 mg/L, light 12 h/d, pH value = 7, revolution = 110 r/min. The effects of salicylic acid, chitosan, and sodium nitroprusside on cell suspension culture were investigated. When the concentration of three impact factors were 0.05, 3, and 1 μ g/L, respectively, the growth amount of S. marianum cell reached the maximum, i. e. At the same time, the silybin content also reached the maximum. The established cell suspension culture system is suitable to use for the rapid propagation of S. marianum. Chitosan and sodium nitroprusside at proper concentration are benifit to the growth of suspensious cells and accumulation of silybin.

20.
Article in Chinese | WPRIM | ID: wpr-854213

ABSTRACT

Objective: To prepare silybin (SLB) controlled-release formulations with the utilization of solid dispersion and effervescent technology and to study their release mechanism. Methods: To determine the optimal formulation and preparation of SLB controlled release formulations was by using single factor test depending on drug release in vitro. The similarity factor method was used to explore the release mechanism of the controlled release formulations prepared. Results: The SLB controlled release formulations cores were prepared using SLB-polyethylene glycol 6000 solid dispersion (1: 2) as main drug, tartaric acid and sodium bicarbonate as effervescence, sodium carboxymethyl cellulose as blockers. The tablets were prepared using cellulose acetate as coating materials, polyethylene glycol 400 as porogen. SLB controlled release formulations released at a rate of zero-order. In the research on the release mechanism, the coating solution with/without porogen, tablet cores with/without blockers and effervescence had a significant impact on the drug release. On the contrary, the speed of the dissolution tester and the pH value of the release medium had no significant effect on the drug release. Conclusion: The preparation process of SLB controlled release formulations is simple. SLB controlled release formulations release with zero-order release in 12 h (r > 0.996 5).

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