Identification of hepatoprotective flavonolignans from silymarin

Department of Laboratory Medicine, Microbiology and Global Health, University of Washington, Seattle, WA 98104, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2010; 107(13):5995-9. DOI: 10.1073/pnas.0914009107
Source: PubMed


Silymarin, also known as milk thistle extract, inhibits hepatitis C virus (HCV) infection and also displays antioxidant, anti-inflammatory, and immunomodulatory actions that contribute to its hepatoprotective effects. In the current study, we evaluated the hepatoprotective actions of the seven major flavonolignans and one flavonoid that comprise silymarin. Activities tested included inhibition of: HCV cell culture infection, NS5B polymerase activity, TNF-alpha-induced NF-kappaB transcription, virus-induced oxidative stress, and T-cell proliferation. All compounds were well tolerated by Huh7 human hepatoma cells up to 80 muM, except for isosilybin B, which was toxic to cells above 10 muM. Select compounds had stronger hepatoprotective functions than silymarin in all assays tested except in T cell proliferation. Pure compounds inhibited JFH-1 NS5B polymerase but only at concentrations above 300 muM. Silymarin suppressed TNF-alpha activation of NF-kappaB dependent transcription, which involved partial inhibition of IkappaB and RelA/p65 serine phosphorylation, and p50 and p65 nuclear translocation, without affecting binding of p50 and p65 to DNA. All compounds blocked JFH-1 virus-induced oxidative stress, including compounds that lacked antiviral activity. The most potent compounds across multiple assays were taxifolin, isosilybin A, silybin A, silybin B, and silibinin, a mixture of silybin A and silybin B. The data suggest that silymarin- and silymarin-derived compounds may influence HCV disease course in some patients. Studies where standardized silymarin is dosed to identify specific clinical endpoints are urgently needed.

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    • "It is extracted from the seeds and fruit of Silybum marianum with its active component silibinin. Silymarin is used for the treatment of various liver disorders manifested by progressive necrosis and functional deficiency[1] [2]. Furthermore, it is able to afford liver protection against damages (ischemia, radiation, iron load and viral hepatitis)[3]. "
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    ABSTRACT: Objective: To evaluate the other pharmacological actions of silymarin in Albino rats and mice such as antipyretic, anti-inflammatory, antinociceptive and antihyperlipidemic effects. Methods: Rats were injected intramuscularly with pyrogenic dose of brewer’s yeast for the antipyretic test of silymarin. Another group of rats injected with 0.1 mL of 1% carrageenan solution in saline at the subplanter area of the right hind paw for the anti-inflammatory test of silymarin. Another group of mice tested by hot plate method for determination of antinociceptive effect of silymarin. Hyperlipidemia was induced using high fat diet for 2 months to estimate the antihyperlipidemic activity of silymarin. Results: Silymarin showed a significant antipyretic effect of both doses (50 and 100 mg/ kg) compared with control untreated group. Moreover, silymarin elucidated a significant anti-inflammatory effect of both doses reflected on the decrease of the rat paw edema every hour interval for 4 h after administration in comparison with control positive group. By the same taken, both doses of silymarine revealed a significant antinociceptive action in hot plate method at 30 and 60 min post administration. Besides, it lowered significantly the serum levels of prostaglandin E2, tumor necrosis factor alpha and interleukin 1 beta after 2 h of silymarin administration in carrageenan induced rat paw edema besides the significant decrease of total cholesterol, triglycerides, low density lipoprotein and significantly elevated high density lipoprotein after 2 weeks of silymarin administration. Conclusions: These outcomes delivered a new vision into the possible pharmacological mechanisms by which silymarin advances antipyretic, anti-inflammatory, antinociceptive and antihyperlipidemic effects.
    Asian Pacific Journal of Tropical Biomedicine 05/2015; 8(5):605-609. DOI:10.1016/j.apjtb.2015.05.009
    • "The complex is composed of silybin A, silybin B, isosilybin A, isosilybin B, silychristin, silydianin taxifolin, and apigenin 7-glucoside (approximately 45 % silybin by weight) ( It has been dissolved in dimethyl sulfoxide (DMSO) (Polyak et al. 2010; Gharagozloo et al. 2013). The final concentration of DMSO was never exceeding 1 %. "
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    ABSTRACT: Limited treatment options in infectious diseases caused by resistant microorganisms created the need to search new approaches. Several herbal extracts are studied for their enormous therapeutic potential. Silymarin extract, from Silybum marianum (milk thistle), is an old and a new remedy for this goal. The purpose of this study is to evaluate the antibacterial and antiadherent effects of silymarin besides biofilm viability activity on standard bacterial strains. Minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), antiadherent/antibiofilm activity, and effects on biofilm viability of silymarin were evaluated against standard bacterial strains. MIC values were observed between 60 and >241 μg/mL (0.25->1 mmol/L). Gram-positive bacteria were inhibited at concentrations between 60 and 120 μg/mL. Gram-negative bacteria were not inhibited by the silymarin concentrations included in this study. MBC values for Gram-positive bacteria were greater than 241 μg/mL. Adherence/biofilm formations were decreased to 15 μg/mL silymarin concentration when compared with silymarin-untreated group. Silymarin reduced the biofilm viabilities to 13 and 46 % at 1 and 0.5 mmol/L concentrations, respectively. We demonstrated that silymarin shows antibacterial and antiadherent/antibiofilm activity against certain standard bacterial strains which may be beneficial when used as a dietary supplement or a drug.
    Folia Microbiologica 05/2015; 60(4). DOI:10.1007/s12223-015-0399-6 · 1.00 Impact Factor
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    • "The flavonolignan Silymarin extracted from Silybum marianum (milk thistle) has shown recently to block virus entry, RNA and protein expression, virus production and cell to cell spread of virus (Wagoner et al., 2010). Additionally, this compound demonstrated a hepatoprotective effect on treated cells (Polyak et al., 2010). Myriberine A is an alkaloid isolated from Myrioneuron faberi and demonstrated inhibition against the HCV life cycle in vitro with a good therapeutic index (CC 50 /EC 50 ) of greater than 12.0 in vitro for non-cytotoxic concentration (Huang et al., 2013). "
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    ABSTRACT: Compounds extracted from plants can provide an alternative approach to new therapies. They present characteristics such as high chemical diversity, lower cost of production and milder or inexistent side effects compared with conventional treatment. The Brazilian flora represents a vast, largely untapped, resource of potential antiviral compounds. In this study, we investigate the antiviral effects of a panel of natural compounds isolated from Brazilian plants species on hepatitis C virus (HCV) genome replication. To do this we used firefly luciferase-based HCV sub-genomic replicons of genotypes 2a (JFH-1), 1b and 3a and the compounds were assessed for their effects on both HCV replication and cellular toxicity. Initial screening of compounds was performed using the maximum non-toxic concentration and 4 compounds that exhibited a useful therapeutic index (favourable ratio of cytotoxicity to antiviral potency) were selected for extra analysis. The compounds APS (EC50 = 2.3 μM), a natural alkaloid isolated from Maytrenus ilicifolia, and the lignans 3∗43 (EC50 = 4.0 μM), 3∗20 (EC50 = 8.2 μM) and 5∗362 (EC50 = 38.9 μM) from Peperomia blanda dramatically inhibited HCV replication as judged by reductions in luciferase activity and HCV protein expression in both the subgenomic and infectious systems. We further show that these compounds are active against a daclatasvir resistance mutant subgenomic replicon. Consistent with inhibition of genome replication, production of infectious JFH-1 virus was significantly reduced by all 4 compounds. These data are the first description of Brazilian natural compounds possessing anti-HCV activity and further analyses are being performed in order to investigate the mode of action of those compounds. Copyright © 2014. Published by Elsevier B.V.
    Antiviral Research 12/2014; 115. DOI:10.1016/j.antiviral.2014.12.018 · 3.94 Impact Factor
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