PMID: 

Int J Biol Macromol. 2020 Feb 7 ;149:1198-1206. Epub 2020 Feb 7. PMID: 32044368

Abstract Title: 

Silymarin encapsulated nanoliquid crystals for improved activity against beta amyloid induced cytotoxicity.

Abstract: 

Silymarin (SLY) a natural Aβ aggregation inhibitor, antioxidant and act as neuroprotectant. In the present study, we have prepared nano liquid crystals (NLCs) of negatively charged glycerylmonooleate (GMO) loaded with SLY for enhancing activity against Aβinduced toxicity. SLY-NLCs are characterized for physicochemical parameters such as particle size, zeta potential, and drug-loading. The average particle size, zeta potential and % DL were found≤200 nm, -22 mV, and 8.73% respectively. The amorphous form and entrapment of SLY in NLC were confirmed using DSC and FTIR analysis. The cubosomal SLY-NLCs shape was characterized by SEM and TEM. The cumulative drug release of SLY was ~76% at pH 7.4 (cerebrospinal fluid) from lyophilized SLY-NLC in 48 h. In order to understand the Aβaggregation inhibition due to SLY-NLC ThT (Thioflavin T) kinetic binding assay was also performed. The cell viability assessment of SLY-NLC was performed on SHSY5Y cell line that showed the highest viability in comparison to free SLY treated groups. ROS and apoptosis activity study SLY-NLCs reduced the Aβinduced free radical with cell death. Cellular uptake study proved enhanced intracellular internalization of FITC tagged NLCs in 24 h. SLY-NLCs can offer great prospects in the field of drug delivery for neuroprotection.

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PMID: 

Med Oncol. 2020 Feb 15 ;37(3):18. Epub 2020 Feb 15. PMID: 32062757

Abstract Title: 

Silymarin inhibited DU145 cells by activating SLIT2 protein and suppressing expression of CXCR4.

Abstract: 

Among other cancers, prostate cancer is globally the second most rampant one with the incidence of 29.4% among men. SLIT2/ROBO1 signaling is very crucial pathway causally implicated in many cancers and reported to inhibit a variety of cancer cell types. CXCR4 is a chemokine receptor implicated in cancer progression. Silymarin is a phytochemical, of which anti-carcinogenic activity was suggested in various cancers, including prostate cancer. However, there are no studies examining the effect of silymarin on SLIT2-Robo1-CXCR4 axis. Herein, our goal is to explore cytotoxic and morphological effects of silymarin on DU145 cells and to reveal its role in Slit2/Robo and CXCR1 pathway. First, 24, 48 and 72 h-long cytotoxicity tests were performed for dose analysis of silymarin, followed H-E stain for morphological evaluation with varying doses of silymarin. Afterward, western blot and immunocytochemistry analyses were carried out for SLIT2, ROBO1 and CXCR4 proteins. According to MTT analysis, IC50 concentrations for silymarin were 315, 126 and 70 µM against DU145 cells for 24, 48 and 72 h treatments. In H-E, several apoptotic hallmarks, including, condensed, kidney-shaped and eccentric nuclei, membrane blebbings and apoptotic body formations were observed. Silymarin increased the expressions of SLIT2 and ROBO1 while decreased CXCR4 when compared to control group in immunocytochemistry and Western blot. To summarize, silymarin inhibited DU145 cells dose-dependently by activating SLIT2 protein and inhibiting expression of CXCR4. This study is the first examining the interplay between Slit2-Robo1-CXCR4 proteins and silymarin in DU145 cells. We believe that our study will provide new insights for future studies.

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PMID: 

Antibiotics (Basel). 2019 Oct 31 ;8(4). Epub 2019 Oct 31. PMID: 31683548

Abstract Title: 

Silymarin, a Popular Dietary Supplement Shows Anti-Activity.

Abstract: 

Silymarin is a complex of plant-derived compounds obtained from the seed shells of the milk thistle (. It is used in medicine primarily to protect the liver. The mixture contains mainly flavonolignans, with silybin as a paramount bioactive component of the extract. This article presents the potential health benefits for silymarin as an antifungal drug against five references strains:,,, andwith MIC (minimum inhibitory concentration) values ranging from 30 to 300µg/mL. Additionally, this study revealed that the compound suppressed the growth of cells of most of the tested clinicalstrains with MIC values between 30 and 1200µg/mL. Based on the fractional inhibitory concentration index (FICI), the combination of silymarin with antifungal drugs caspofungin, fluconazole, and amphotericin B did not significantly change the MIC values for the testedstrains. Furthermore, no antagonistic reactions were observed in any combination of drugs. In addition, this substance shows anti-virulence properties including the destabilization of mature biofilm and the inhibition of the secretion of hydrolases. qRT-PCR-based experiments demonstrated that thegene involved in virulence was downregulated by silymarin. These results indicate completely new advantages of dietary supplementation with this natural plant extract.

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PMID: 

Hepatol Res. 2020 Jan ;50(1):5-14. Epub 2020 Jan 5. PMID: 31661720

Abstract Title: 

Changes of gut microbiota during silybin-mediated treatment of high-fat diet-induced non-alcoholic fatty liver disease in mice.

Abstract: 

AIM: Gut microbiota are involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Silybin (Sil), a naturally occurring hepatoprotective agent, is widely used for treating NAFLD. Whether Sil affects gut microbiota during its actions in treating NAFLD is unknown. We aimed to examine the effect of Sil on intestinal flora dysbiosis induced by a high-fat diet (HFD).METHODS: After 10 weeks of feeding normal chow diet or HFD, mice were given a daily gavage for 8 weeks. Cecal contents were harvested for study of short-chain fatty acids, bile acids, and gut microbiota alteration.RESULTS: Sil showed protective effects against dietary-induced obesity and liver steatosis; accordingly, gut microbiota composition changed. At the phylum level, compared with the HFD group, mice in the Sil-treated group had significantly lower levels of Firmicutes, and the ratio of Firmicutes-to-Bacteroidetes was lower (P 

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PMID: 

J Biomed Mater Res A. 2020 Mar ;108(3):458-469. Epub 2019 Nov 11. PMID: 31657514

Abstract Title: 

Sustained release of silibinin-loaded chitosan nanoparticle induced apoptosis in glioma cells.

Abstract: 

In this study, a chitosan nanoparticle formulation was synthesized for loading silibinin as a sustained-release drug system to evaluate its effects on apoptosis in C6 glioma cells. This synthesized nanoparticle was analyzed by measurement methods including Fourier transform infrared (FTIR), field emission-scanning electron microscopy (FE-SEM), dynamic light scattering (DLS), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). The formation and amorphization of nanoparticle were confirmed by FTIR and XRD analysis, respectively. The mean diameter of silibinin-loaded chitosan nanoparticles (SCNP) was 50 ± 7 and 188.6 ± 0.17 nm by using FE-SEM and DLS, respectively. In addition, the positive zeta potential of nanoparticles was +11.5. Rhodamine-conjugated SCNP analysis showed the internalization of silibinin to C6 glioma cells. The cytotoxicity assay indicated that the nanoformulation of silibinin was toxic to C6 glioma cells. Although SCNP significantly increased the expression of the both apoptotic genes in C6 cells, Bax and caspase3, it did not have any significant effect on the level of the antiapoptotic gene, Bcl2. In contrast, SCNP did not have any toxic effect on H9C2 cells. In conclusion, the results of the current study indicated that SCNP can be considered as a sustained-release drug system for future cell-based therapeutic strategies.

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PMID: 

Biomed Pharmacother. 2020 Mar ;123:109721. Epub 2019 Dec 20. PMID: 31865143

Abstract Title: 

Silybin ameliorates hepatic lipid accumulation and modulates global metabolism in an NAFLD mouse model.

Abstract: 

Silybin shows good effects against obesity and metabolic syndrome, but the systemic modulation effect of silybin has not been fully revealed. This study aims to investigate the metabolic regulation by silybin of nonalcoholic fatty liver disease (NAFLD). C57BL/6 J mice were fed a high-fat/high-cholesterol diet for 8 weeks and treated with silybin (50 or 100 mg/kg/day) and sodium tauroursodeoxycholate (TUDCA, 50 mg/kg/day) by gavage for the last 4 weeks. Blood biochemical indexes and hepatic lipid measurement as well as Oil red O staining of the liverwere conducted to evaluate the model and the lipid-lowering effect of silybin and TUDCA. Furthermore, serum and liver samples were detected by a metabolomic platform based on gas chromatography-mass spectrometry (GC/MS). Multivariate/univariate data analysis and pathway analysis were used to investigate differential metabolites and metabolic pathways. The results showed that the mouse NAFLD model was established successfully and that silybin and TUDCA significantly lowered both serum and hepatic lipid accumulation. Metabolomic analysis of serum and liver showed that a high-fat/high-cholesterol diet caused abnormal metabolism of metabolites involved in lipid metabolism, polyol metabolism, amino acid metabolism, the urea cycle and the TCA cycle. Silybin and TUDCA treatment both reversed metabolic disorders caused by HFD feeding. In conclusion, a high-fat/high-cholesterol diet caused metabolic abnormalities in the serum and liver of mice, and silybin treatment improved hepatic lipid accumulation and modulated global metabolic pathways, which provided a possible explanation of its multiple target mechanism.

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PMID: 

Hum Cell. 2020 Jan 18. Epub 2020 Jan 18. PMID: 31953678

Abstract Title: 

Silibinin enhances anti-renal fibrosis effect of MK-521 via downregulation of TGF-β signaling pathway.

Abstract: 

Renal fibrosis is a common characteristic of chronic kidney disease (CKD), and it can lead to end-stage renal disease. It has been reported that silibinin or lisinopril (MK-521) can inhibit the progression of renal fibrosis. However, the effect of combination of silibinin with MK-521 on renal fibrosis remains unclear. Therefore, this study aimed to explore the combination of silibinin with MK-521 on renal fibrosis in vitro and in vivo. The cell viability of HK-2 was detected by CCK-8. The gene and protein expression in HK-2 cells were detected by qRT-PCR and Western blot, respectively. Moreover, HFD-induced renal fibrosis mouse model was established to investigate the effect of silibinin in combination with MK-521 on renal fibrosis in vivo. The expressions of collagen I,α-SMA, Smad2 and Smad3 in TGF-β-treated HK-2 cells were notably decreased by MK-521, which was further inhibited in the presence of silibinin. In addition, we found that silibinin significantly enhanced anti-fibrotic effect of MK-521 on HFD-induced renal fibrosis mice. These findings demonstratedthat silibinin could significantly increase anti-fibrotic effect of MK-521 in vitro and in vivo. Therefore, the combination of silibinin with MK-521 may serve as a potential strategy for the treatment of renal fibrosis.

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PMID: 

BMC Pharmacol Toxicol. 2020 01 23 ;21(1):8. Epub 2020 Jan 23. PMID: 31973745

Abstract Title: 

Silibinin attenuates adipose tissue inflammation and reverses obesity and its complications in diet-induced obesity model in mice.

Abstract: 

BACKGROUND: Obesity is a multifactorial chronic disease that comprises several pathological events, such as adipose hypertrophy, fatty liver and insulin resistance. Inflammation is a key contributer to development of these events, and therefore, targeting inflammation is increasingly considered for management of obesity and its complications. The aim of the current study was to investigate therapeutic outcomes of anti-inflammatory activities of the natural compound Silibinin in reversing obesity and its complication in mice.METHODS: C57BL/6 male mice were fed high-fat diet for 8 weeks until development of obesity, and then injected with 50 mg/kg silibinin intraperitoneally twice per week, or vehicle for 8 weeks. Throughout the experiment, mice were continuously checked for body weight and food intake, and glucose tolerance test was performed toward the end of the experiment. Animals were sacrificed and serum and tissues were collected for biochemical, histological, and gene expression analysis to assess silibinin effects on adipose inflammation, fat accumulation, liver adipogenesis and glucose homeostasis.RESULTS: Silibinin treatment reversed adipose tissue inflammation and adipocyte hypertrophy, and blocked progression in weight gain and obesity development with no significant effects on rates of food intake. Silibinin also reversed fatty liver disease and restored glucose homeostasis in treated animals, and reversed hyperglycemia, hyperinsulinemia and hypertriglyceridemia.CONCLUSION: In this study, we demonstrated that silibinin as an anti-inflammatory therapy is a potential alternative to manage obesity, as well as its related complications. Moreover, silibinin-based therapies could further evolve as a novel treatment to manage various inflammation-driven disorders.

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PMID: 

Arch Biochem Biophys. 2020 Jan 31:108284. Epub 2020 Jan 31. PMID: 32014401

Abstract Title: 

Silibinin-induced mitochondria fission leads to mitophagy, which attenuates silibinin-induced apoptosis in MCF-7 and MDA-MB-231 cells.

Abstract: 

We reported previously that higher doses (150-250 μM) of silibinin enhanced fission and inhibited fusion of mitochondria, accompanying apoptosis of double-positive breast cancer cell line MCF-7 cells and triple-negative breast cancer cell line MDA-MB-231 cells. We report here three important questions yet unclarified in the previous study;1) Whether enhanced fission of mitochondria by the treatment of silibinin leads to mitophagy, 2) Whether mitophagy positively contributes to apoptosis and 3) Whether estrogen receptor-positive (ER) MCF-7 cells and estrogen receptor-negative (ER) MDA-MB-231 cells are affected in a different way by silibinin treatment, since silibinin often works through ERs signaling pathway. Mitophagy driven by Pink1/Parkin signaling, plays an important role in eliminating damaged mitochondria. Indeed, increased expression of Pink1 and the recruitment of Parkin andLC3-II to mitochondria by the treatment with silibinin account for silibinin induction of mitophagy. In this study, the effects of mitochondrial division inhibitor 1 (mdivi-1) and small interfering RNA targeting dynamin-related protein 1 (DRP1) were examined to reveal the effect of mitochondrial fission on mitophagy. As expected, mdivi-1 or siRNA targeting DRP1 reversed silibinin-induced mitochondrial fission due to down-regulation in the expression of DRP1. Inhibition of mitochondrial fission by mdivi-1 prevented induction of mitophagy as well as autophagy in both MCF-7 and MDA-MB-231 cells, indicating that silibinin-induced mitochondrial fission leads to mitophagy. Inhibition of mitochondrial fission efficiently prevented silibinin-induced apoptosis in MCF-7 and MDA-MB-231 cells in our previous work, and the second point of the present study, inhibition of mitophagy by Pink1 or Parkin knockdown increased silibinin-induced apoptosis of these cells, respectively, suggesting that the mitophagy induced by silibinin treatment serves as a cytoprotective effect, resulting in reduction of apoptosis of cancer cells in both cells. In the third point, we studied whether estrogen receptors (ERs) played a role in silibinin-induced mitophagy and apoptosis in MCF-7 and MDA-MB-231 cells. ERα and ERβ are not involved in silibinin-induced mitophagic process in MCF-7 and MDA-MB-231 cells. These findings demonstrated that silibinin induced mitochondria fission leads to mitophagy, which attenuates silibinin-induced apoptosis not through ERs-Pink1 or -Parkin pathway in MCF-7 and MDA-MB-231.

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PMID: 

Environ Mol Mutagen. 2020 Feb 20. Epub 2020 Feb 20. PMID: 32078183

Abstract Title: 

Inhibition of urinary bladder cancer cell proliferation by silibinin.

Abstract: 

Silibinin, a natural compound extracted from milk thistle, has demonstrated antitumor properties in urinary bladder cancer cells; however the role of TP53 gene in these effects is unclear. In order to better understand the molecular and antiproliferative mechanisms of this compound, urinary bladder cancer cells with different TP53 gene status, RT4 (low grade tumor, wild TP53 gene), 5,637 (high grade tumor, grade 2, mutated TP53 gene) and T24 (high grade tumor, grade 3, mutated TP53 gene), were treated with several concentrations of silibinin (1; 5; 10; 50; 100 and 150 μM). Cytotoxicity, pro-oxidant effect, morphological changes, cell migration, cell cycle progression, global methylation profile and relative expression of HOXB3, c-MYC, PLK1, SMAD4, SRC, HAT, HDAC and RASSF1A genes were evaluated. The silibinin presented cytotoxic and pro-oxidant effects in thethree cell lines. In mutated TP53 cells, significant interference in cell migration and cell cycle arrest at the G2/M phase was observed. Additionally, silibinin induced global DNA hypomethylation in the highest grade tumor cells. For wild-type TP53 cells, a sub-G1 apoptotic population was present.Furthermore, there was modulation of gene expression responsible for cell growth (SMAD and c-MYC), migration (SRC), cell cycle kinetics (PLK1), angiogenesis (HOXB3) and of genes associated with epigenetic events such as DNA acetylation (HAT) and deacetylation (HDAC). In conclusion, the silibinin inhibited the urinary bladder tumor cell proliferation independently of TP53 status; however cell cycle effects, gene expression changes and alteration of cell migration are dependent on TP53 status. This article is protected by copyright. All rights reserved.

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