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Silymarin and Derivatives: From Biosynthesis to Health Benefits

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 95564

Special Issue Editor

1. Inserm Research Center UMR1231 "Lipids, Nutrition, Cancer", Université de Bourgogne, 7 Blvd Jeanne d’Arc, 21000 Dijon, France
2. Centre de Lutte Contre le Cancer Georges-François Leclerc Center, 21000 Dijon, France
Interests: polyhenols; flavonoids; degenerative age-related diseases; inflammation; cancers; chemosensitization; lipid metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Numerous epidemiological studies show that some nutrients may protect against vascular diseases, cancers, degenerative diseases, and associated inflammatory effects. Among these compounds, flavonolignans are a family of natural products present in plants, composed of a flavonoid moiety and a phenylpropanoid or lignan part, that could contribute to the development of new strategies to fight various modern pathologies. In this context, one of the most important compounds among flavonolignans is silymarin which is extracted from milk thistle seeds and could act as a chemopreventive compound or a therapeutic adjuvant.

This Special Issue will cover areas related to the biosynthesis of silymarin and its derivatives, its bioavailability, and its health benefits. More particularly, this Special Issue will highlight the biological properties of silymarin and its derivatives in major fields in terms of public health, including cardiovascular diseases, metabolic syndrome, cancers, degenerative age-related diseases, and inflammatory and immune pathologies.

I cordially invite authors to contribute original articles, as well as review articles, that will give the readers of Molecules an updated and new perspective about silymarin and its derivatives, helping establish new interests in the development of natural compounds for health.

Prof. Dominique Delmas
Guest Editor

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Keywords

  • Silymarin: sources and biosynthesis
  • Secondary metabolites and silymarin derivatives
  • Silymarin bioavaibility
  • Silymarin and cardiovascular diseases
  • Silymarin and metabolic syndrome
  • Silymarin and cancer
  • Silymarin and inflammation and immune diseases
  • Silymarin and degenerative age-related diseases

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Published Papers (18 papers)

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Editorial

Jump to: Research, Review

4 pages, 431 KiB  
Editorial
Silymarin and Derivatives: From Biosynthesis to Health Benefits
by Dominique Delmas
Molecules 2020, 25(10), 2415; https://doi.org/10.3390/molecules25102415 - 22 May 2020
Cited by 12 | Viewed by 2965
Abstract
The past decade has been marked by an intense scientific interest in the use of compounds or micronutrients of natural origin and their potential effects on human health, both from researchers and industry [...] Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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Research

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20 pages, 4318 KiB  
Article
Formulation of Nanomicelles to Improve the Solubility and the Oral Absorption of Silymarin
by Vieri Piazzini, Mario D’Ambrosio, Cristina Luceri, Lorenzo Cinci, Elisa Landucci, Anna Rita Bilia and Maria Camilla Bergonzi
Molecules 2019, 24(9), 1688; https://doi.org/10.3390/molecules24091688 - 30 Apr 2019
Cited by 64 | Viewed by 5491
Abstract
Two novel nanomicellar formulations were developed to improve the poor aqueous solubility and the oral absorption of silymarin. Polymeric nanomicelles made of Soluplus and mixed nanomicelles combining Soluplus with d-α-tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS) were prepared using the thin [...] Read more.
Two novel nanomicellar formulations were developed to improve the poor aqueous solubility and the oral absorption of silymarin. Polymeric nanomicelles made of Soluplus and mixed nanomicelles combining Soluplus with d-α-tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS) were prepared using the thin film method. Physicochemical parameters were investigated, in particular the average diameter, the homogeneity (expressed as polydispersity index), the zeta potential, the morphology, the encapsulation efficiency, the drug loading, the critical micellar concentration and the cloud point. The sizes of ~60 nm, the narrow size distribution (polydispersity index ≤0.1) and the encapsulation efficiency >92% indicated the high affinity between silymarin and the core of the nanomicelles. Solubility studies demonstrated that the solubility of silymarin increased by ~6-fold when loaded into nanomicelles. Furthermore, the physical and chemical parameters of SLM-loaded formulations stored at room temperature and in refrigerated conditions (4 °C) were monitored over three months. In vitro stability and release studies in media miming the physiological conditions were also performed. In addition, both formulations did not alter the antioxidant properties of silymarin as evidenced by the 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH) assay. The potential of the nanomicelles to increase the intestinal absorption of silymarin was firstly investigated by the parallel artificial membrane permeability assay. Subsequently, transport studies employing Caco-2 cell line demonstrated that mixed nanomicelles statistically enhanced the permeability of silymarin compared to polymeric nanomicelles and unformulated extract. Finally, the uptake studies indicated that both nanomicellar formulations entered into Caco-2 cells via energy-dependent mechanisms. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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12 pages, 1901 KiB  
Article
Silymarin: Friend or Foe of UV Exposed Keratinocytes?
by Eszter Fidrus, Zoltán Ujhelyi, Pálma Fehér, Csaba Hegedűs, Eszter Anna Janka, György Paragh, Gábos Vasas, Ildikó Bácskay and Éva Remenyik
Molecules 2019, 24(9), 1652; https://doi.org/10.3390/molecules24091652 - 26 Apr 2019
Cited by 9 | Viewed by 3574
Abstract
The application of natural plant extracts in UV-protection is popular and intensively studied. Silymarin (from Silibum marianum), a naturally occurring polyphenol, has recently received attention due to its antioxidant, anti-inflammatory and anti-apoptotic effects. However, its role in the UV-mediated keratinocyte cell response [...] Read more.
The application of natural plant extracts in UV-protection is popular and intensively studied. Silymarin (from Silibum marianum), a naturally occurring polyphenol, has recently received attention due to its antioxidant, anti-inflammatory and anti-apoptotic effects. However, its role in the UV-mediated keratinocyte cell response is still controversial. In this study, we investigated the effects of Silibum marianum extracts with different origins and formulations on UVA-exposed HaCaT keratinocytes in vitro. Our results show, that silymarin treatment caused an inverse dose-dependent photosensitivity relationship (at higher doses, a decrease in cell viability and ROS production) after UVA exposure. The attenuation of the UVA-induced ROS generation after silymarin treatment was also observed. Moreover, silymarin pre-treatment increased the cyclobutane pyrimidine dimer photolesions in keratinocytes after UVA exposure. These results indicated the dual role of silymarin in UVA-exposed keratinocytes. It scavenges ROS but still induces phototoxicity. Based on our results dermatological applications of silymarin and related compounds should be considered very carefully. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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16 pages, 2434 KiB  
Article
Silibinin Downregulates the NF-κB Pathway and NLRP1/NLRP3 Inflammasomes in Monocytes from Pregnant Women with Preeclampsia
by Mariana Leticia Matias, Virginia Juliani Gomes, Mariana Romao-Veiga, Vanessa Rocha Ribeiro, Priscila Rezeck Nunes, Graziela Gorete Romagnoli, Jose Carlos Peracoli and Maria Terezinha Serrao Peracoli
Molecules 2019, 24(8), 1548; https://doi.org/10.3390/molecules24081548 - 19 Apr 2019
Cited by 60 | Viewed by 5269
Abstract
Preeclampsia (PE) is a human pregnancy-specific syndrome with abnormal activation of cells from the innate immune system. The present study evaluated whether silibinin (SB) treatment of monocytes from preeclamptic women could modulate NLRP1 and NLRP3 inflammasomes as well as TLR4/NF-κB pathway activation. Peripheral [...] Read more.
Preeclampsia (PE) is a human pregnancy-specific syndrome with abnormal activation of cells from the innate immune system. The present study evaluated whether silibinin (SB) treatment of monocytes from preeclamptic women could modulate NLRP1 and NLRP3 inflammasomes as well as TLR4/NF-κB pathway activation. Peripheral blood monocytes from 20 preeclamptic and 20 normotensive (NT) pregnant women, as well as the THP-1 cell line, were cultured with or without monosodium urate (MSU) or SB. NLRP1, NLRP3, Caspase-1, TLR4, MyD88, NF-κB, IL-1β, IL-18, TNF-α and IL-10 gene expression by monocytes was analysed by quantitative real-time polymerase chain reaction (qPCR), while inflammatory cytokine production and p65NF-κB activity were determined by enzyme-linked immunosorbent assays (ELISAs). TLR4/MyD88/NF-κB and NLRP1/NLRP3 inflammasomes pathways in THP-1 cells were evaluated by flow cytometry and western blot respectively. Compared with NT women, monocytes from preeclamptic women showed The Ethics Committee of the Botucatu Medical School approved the study (protocol number 2.333.216)higher endogenous activation of NLRP1/NLRP3 inflammasomes and the TLR4/NF-κB pathway as well as higher gene and protein expression of IL-1β, IL-18 and TNF-α, and lower expression of IL-10. Monocyte stimulation with MSU increased inflammation-related genes as well as NF-κB activity. In vitro, SB treatment of monocytes from preeclamptic women reduced the basal activation of these cells by decreasing NLRP1/NLRP3 inflammasomes and p65NF-κB activity. THP-1 cells exhibited a similar immunological response profile to monocytes from preeclamptic women when cultured with or without MSU or SB. These results suggest uric acid participates in the systemic inflammatory response characteristic of preeclampsia and that in vitro SB treatment can modulate the sterile inflammation established in monocytes from preeclamptic women. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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14 pages, 1743 KiB  
Article
A Water-Soluble Microencapsulated Milk Thistle Extract as Active Ingredient for Dermal Formulations
by Tiziana Esposito, Francesca Sansone, Paola Russo, Patrizia Picerno, Rita Patrizia Aquino, Franco Gasparri and Teresa Mencherini
Molecules 2019, 24(8), 1547; https://doi.org/10.3390/molecules24081547 - 19 Apr 2019
Cited by 10 | Viewed by 3609
Abstract
The choice of formulation is often of crucial importance in order to obtain a pharmaceutical product for the administration of poorly soluble drugs. Recently, a new water-soluble microparticulate powder form (MTE-mp) for the oral administration of a high functionality/low solubility silymarin rich milk [...] Read more.
The choice of formulation is often of crucial importance in order to obtain a pharmaceutical product for the administration of poorly soluble drugs. Recently, a new water-soluble microparticulate powder form (MTE-mp) for the oral administration of a high functionality/low solubility silymarin rich milk thistle extract (MTE) has been developed. Findings showed that extract-loaded microparticles by spray-drying were produced with high and reproducible yields and encapsulation efficiency. The in vitro dissolution and permeation rates of silymarin were dramatically improved with respect to the raw material, and also enhanced the silymarin anti-inflammatory abilities. Given these successful results, the new MTE-mp delivery system has been proposed as an active ingredient for dermal applications. The aim of this research was the design and development of two topical formulations, hydrogel and emulgel (O/W emulsion), containing the MTE-mp delivery system or MTE raw extract. All the formulations were compared to each other in terms of handling and incorporation amount of the active ingredient during the productive process. Moreover, the addition to the emulgel of lecithin (L) as enhancer of permeation was tested. The MTE-mp ingredient that resulted was stable and more-easily incorporated both in hydrogel and emulgel than raw MTE extract, obtaining the best permeation profile for MTE-mp from emulgel with the addition of L. The obtained results confirm that the MTE-mp system could be used as a stable, water-soluble, and easy-handling functional ingredient, giving the opportunity to develop new strategies for MTE delivery in health products. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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12 pages, 1787 KiB  
Article
Silybin Modulates Collagen Turnover in an In Vitro Model of NASH
by Beatrice Anfuso, Pablo J. Giraudi, Claudio Tiribelli and Natalia Rosso
Molecules 2019, 24(7), 1280; https://doi.org/10.3390/molecules24071280 - 02 Apr 2019
Cited by 10 | Viewed by 3145
Abstract
Silybin has been proposed as a treatment for nonalcoholic steatohepatitis (NASH). In this study, we assessed the effect of Silybin in a well-established in vitro coculture model of early-stage NASH. LX2 and Huh7 cells were exposed to free fatty acid (FFA) and Silybin [...] Read more.
Silybin has been proposed as a treatment for nonalcoholic steatohepatitis (NASH). In this study, we assessed the effect of Silybin in a well-established in vitro coculture model of early-stage NASH. LX2 and Huh7 cells were exposed to free fatty acid (FFA) and Silybin as mono- or coculture (SCC). Cell viability, LX2 activation, collagen deposition, metalloproteinase 2 and 9 (MMP2-9) activity, and ROS generation were determined at 24, 96, and 144 h. Exposure to FFA induced the activation of LX2 as shown by the increase in cell viability and upregulation of collagen biosynthesis. Interestingly, while cotreatment with Silybin did not affect collagen production in LX2, a significant reduction was observed in SCC. MMP2-9 activity was reduced in FFA-treated Huh7 and SCC and cotreatment with Silybin induced a dose-dependent increase, while no effect was observed in LX2. Silybin also showed antioxidant properties by reducing the FFA-induced production of ROS in all the cell systems. Based on these data, Silybin exerts its beneficial effects by reducing LX2 proliferation and ROS generation. Moreover, MMP2-9 modulation in hepatocytes represents the driving mechanism for the net reduction of collagen in this NASH in vitro model, highlighting the importance of hepatic cells interplay in NASH development and resolution. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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18 pages, 3499 KiB  
Article
Interactive Effects of Light and Melatonin on Biosynthesis of Silymarin and Anti-Inflammatory Potential in Callus Cultures of Silybum marianum (L.) Gaertn.
by Muzamil Shah, Muhammad Asad Ullah, Samantha Drouet, Muhammad Younas, Duangjai Tungmunnithum, Nathalie Giglioli-Guivarc’h, Christophe Hano and Bilal Haider Abbasi
Molecules 2019, 24(7), 1207; https://doi.org/10.3390/molecules24071207 - 27 Mar 2019
Cited by 30 | Viewed by 4768
Abstract
Silybum marianum (L.) Gaertn. is a well-known medicinal herb, primarily used in liver protection. Light strongly affects several physiological processes along with secondary metabolites biosynthesis in plants. Herein, S. marianum was exploited for in vitro potential under different light regimes in the presence [...] Read more.
Silybum marianum (L.) Gaertn. is a well-known medicinal herb, primarily used in liver protection. Light strongly affects several physiological processes along with secondary metabolites biosynthesis in plants. Herein, S. marianum was exploited for in vitro potential under different light regimes in the presence of melatonin. The optimal callogenic response occurred in the combination of 1.0 mg/L α-naphthalene acetic acid and 0.5 mg/L 6-benzylaminopurine under photoperiod. Continuous light associated with melatonin treatment increased total flavonoid content (TFC), total phenolic content (TPC) and antioxidant potential, followed by photoperiod and dark treatments. The increased level of melatonin has a synergistic effect on biomass accumulation under continuous light and photoperiod, while an adverse effect was observed under dark conditions. More detailed phytochemical analysis showed maximum total silymarin content (11.92 mg/g dry weight (DW)) when placed under continuous light + 1.0 mg/L melatonin. Individually, the level of silybins (A and B), silydianin, isolsilychristin and silychristin was found highest under continuous light. Anti-inflammatory activities were also studied and highest percent inhibition was recorded against 15-lipoxygenase (15-LOX) for cultures cultivated under continuous light (42.33%). The current study helps us to better understand the influence of melatonin and different light regimes on silymarin production as well as antioxidant and anti-inflammatory activities in S. marianum callus extracts. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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12 pages, 870 KiB  
Article
Skin Protective Activity of Silymarin and its Flavonolignans
by Jitka Vostálová, Eva Tinková, David Biedermann, Pavel Kosina, Jitka Ulrichová and Alena Rajnochová Svobodová
Molecules 2019, 24(6), 1022; https://doi.org/10.3390/molecules24061022 - 14 Mar 2019
Cited by 45 | Viewed by 7310
Abstract
Silybum marianum (L.) is a medicinal plant traditionally used in treatment of liver disorders. In last decades, silymarin (SM), a standardized extract from S. marianum seeds has been studied for its dermatological application, namely for UVB-protective properties. However, information on SM and its [...] Read more.
Silybum marianum (L.) is a medicinal plant traditionally used in treatment of liver disorders. In last decades, silymarin (SM), a standardized extract from S. marianum seeds has been studied for its dermatological application, namely for UVB-protective properties. However, information on SM and its polyphenols effect on activity of enzymes participating in the (photo)aging process is limited. Therefore, evaluation of SM and its flavonolignans potential to inhibit collagenase, elastase, and hyaluronidase in tube tests was the goal of this study. The antioxidant and UV screening properties of SM and its flavonolignans silybin, isosilybin, silydianin, silychristin and 2,3-dehydrosilybin (DHSB) were also evaluated by a DPPH assay and spectrophotometrical measurement. DHSB showed the highest ability to scavenge DPPH radical and also revealed the highest UVA protection factor (PF-UVA) that corresponds with its absorption spectrum. SM and studied flavonolignans were found to exhibit anti-collagenase and anti-elastase activity. The most potent flavonolignan was DHSB. None of studied flavonolignans or SM showed anti-hyaluronidase activity. Our results suggest that SM and its flavonolignans may be useful agents for skin protection against the harmful effects of full-spectrum solar radiation including slowing down skin (photo)aging. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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18 pages, 2985 KiB  
Article
Modulation of Skin Inflammatory Response by Active Components of Silymarin
by Jana Juráňová, Juliette Aury-Landas, Karim Boumediene, Catherine Baugé, David Biedermann, Jitka Ulrichová and Jana Franková
Molecules 2019, 24(1), 123; https://doi.org/10.3390/molecules24010123 - 30 Dec 2018
Cited by 19 | Viewed by 5723
Abstract
In this study, we compared selected silymarin components, such as quercetin (QE), 2,3-dehydrosilybin (DHS) and silybin (SB), with the anti-inflammatory drug indomethacin (IND) in terms of their wound healing potential. In view of the fact that pathological cutaneous wound healing is associated with [...] Read more.
In this study, we compared selected silymarin components, such as quercetin (QE), 2,3-dehydrosilybin (DHS) and silybin (SB), with the anti-inflammatory drug indomethacin (IND) in terms of their wound healing potential. In view of the fact that pathological cutaneous wound healing is associated with persistent inflammation, we studied their anti-inflammatory activity against inflammation induced by bacterial lipopolysaccharide (LPS). We investigated the regulation of crucial pro-inflammatory transcription factors—nuclear factor kappa-B (NF-κB) and activator protein 1 (AP-1)—as well as the expression of downstream inflammatory targets by Western blotting, real-time PCR (RT-PCR), electrophoretic mobility shift assay (EMSA), and/or enzyme-linked immunosorbent assay (ELISA) in vitro using primary normal human dermal fibroblasts (NHDF). We demonstrated the greater ability of DHS to modulate the pro-inflammatory cytokines production via the NF-κB and AP-1 signaling pathways when compared to other tested substances. The prolonged exposure of LPS-challenged human dermal fibroblasts to DHS had both beneficial and detrimental consequences. DHS diminished interleukin-6 (IL-6) and interleukin-8 (IL-8) secretion but induced the significant upregulation of IL-8 mRNA associated with NF-κB and AP-1 activation. The observed conflicting results may compromise the main expected benefit, which is the acceleration of the healing of the wound via a diminished inflammation. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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20 pages, 3932 KiB  
Article
Dermal Delivery of Selected Polyphenols from Silybum marianum. Theoretical and Experimental Study
by Pavel Kosina, Markéta Paloncýová, Alena Rajnochová Svobodová, Bohumil Zálešák, David Biedermann, Jitka Ulrichová and Jitka Vostálová
Molecules 2019, 24(1), 61; https://doi.org/10.3390/molecules24010061 - 24 Dec 2018
Cited by 15 | Viewed by 4124
Abstract
Silymarin is a well-known standardized extract from the seeds of milk thistle (Silybum marianum L., Asteraceae) with a pleiotropic effect on human health, including skin anticancer potential. Detailed characterization of flavonolignans properties affecting interactions with human skin was of interest. The partition [...] Read more.
Silymarin is a well-known standardized extract from the seeds of milk thistle (Silybum marianum L., Asteraceae) with a pleiotropic effect on human health, including skin anticancer potential. Detailed characterization of flavonolignans properties affecting interactions with human skin was of interest. The partition coefficients log Pow of main constitutive flavonolignans, taxifolin and their respective dehydro derivatives were determined by a High Performance Liquid Chromatography (HPLC) method and by mathematical (in silico) approaches in n-octanol/water and model lipid membranes. These parameters were compared with human skin intake ex vivo. The experimental log Pow values for individual diastereomers were estimated for the first time. The replacement of n-octanol with model lipid membranes in the theoretical lipophilicity estimation improved the prediction strength. During transdermal transport, all the studied compounds permeated the human skin ex vivo; none of them reached the acceptor liquid. Both experimental/theoretical tools allowed the studied polyphenols to be divided into two groups: low (taxifolin, silychristin, silydianin) vs. high (silybin, dehydrosilybin, isosilybin) lipophilicity and skin intake. In silico predictions can be usefully applied for estimating general lipophilicity trends, such as skin penetration or accumulation predictions. However, the theoretical models cannot yet provide the dermal delivery differences of compounds with very similar physico-chemical properties; e.g., between diastereomers. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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16 pages, 3972 KiB  
Article
O-Aminoalkyl-O-Trimethyl-2,3-Dehydrosilybins: Synthesis and In Vitro Effects Towards Prostate Cancer Cells
by Bao Vue, Sheng Zhang, Andre Vignau, Guanglin Chen, Xiaojie Zhang, William Diaz, Qiang Zhang, Shilong Zheng, Guangdi Wang and Qiao-Hong Chen
Molecules 2018, 23(12), 3142; https://doi.org/10.3390/molecules23123142 - 29 Nov 2018
Cited by 9 | Viewed by 4325
Abstract
As part of our ongoing silybin project, this study aims to introduce a basic nitrogen-containing group to 7-OH of 3,5,20-O-trimethyl-2,3-dehydrosilybin or 3-OH of 5,7,20-O-trimethyl-2,3-dehydrosilybin via an appropriate linker for in vitro evaluation as potential anti-prostate cancer agents. The synthetic [...] Read more.
As part of our ongoing silybin project, this study aims to introduce a basic nitrogen-containing group to 7-OH of 3,5,20-O-trimethyl-2,3-dehydrosilybin or 3-OH of 5,7,20-O-trimethyl-2,3-dehydrosilybin via an appropriate linker for in vitro evaluation as potential anti-prostate cancer agents. The synthetic approaches to 7-O-substituted-3,5,20-O-trimethyl-2,3-dehydrosilybins through a five-step procedure and to 3-O-substituted-5,7,20-O-trimethyl-2,3- dehydrosilybins via a four-step transformation have been developed. Thirty-two nitrogen-containing derivatives of silybin have been achieved through these synthetic methods for the evaluation of their antiproliferative activities towards both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145) using the WST-1 cell proliferation assay. These derivatives exhibited greater in vitro antiproliferative potency than silibinin. Among them, 11, 29, 31, 37, and 40 were identified as five optimal derivatives with IC50 values in the range of 1.40–3.06 µM, representing a 17- to 52-fold improvement in potency compared to silibinin. All these five optimal derivatives can arrest the PC-3 cell cycle in the G0/G1 phase and promote PC-3 cell apoptosis. Derivatives 11, 37, and 40 are more effective than 29 and 31 in activating PC-3 cell apoptosis. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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10 pages, 564 KiB  
Communication
Selective Synthesis of 3-O-Palmitoyl-Silybin, a New-to-Nature Flavonolignan with Increased Protective Action against Oxidative Damages in Lipophilic Media
by Samantha Drouet, Joël Doussot, Laurine Garros, David Mathiron, Solène Bassard, Alain Favre-Réguillon, Roland Molinié, Éric Lainé and Christophe Hano
Molecules 2018, 23(10), 2594; https://doi.org/10.3390/molecules23102594 - 10 Oct 2018
Cited by 18 | Viewed by 2971
Abstract
A selective acylation protocol using cerium chloride (CeCl3) as catalyst was applied to functionalize silybinin (1), a natural antioxidant flavonolignan from milk thistle fruit, in order to increase its solubility in lipophilic media while retaining its strong antioxidant activity. [...] Read more.
A selective acylation protocol using cerium chloride (CeCl3) as catalyst was applied to functionalize silybinin (1), a natural antioxidant flavonolignan from milk thistle fruit, in order to increase its solubility in lipophilic media while retaining its strong antioxidant activity. The selective esterification of 1 at the position 3-OH with a palmitate acyl chain leading to the formation of the 3-O-palmitoyl-silybin (2) was confirmed by both mass spectroscopy (MS) and nuclear magnetic resonance (NMR) analyses. The antioxidant activity of 1 was at least retained and even increased with the CUPRAC assay designed to estimate the antioxidant activity of both hydrophilic and lipophilic compounds. Finally, the 3-O-palmitoylation of 1, resulting in the formation of 2, also increased its anti-lipoperoxidant activity (i.e., inhibition of conjugated diene production) in two different lipophilic media (bulk oil and o/w emulsion) subjected to accelerated storage test. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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Review

Jump to: Editorial, Research

23 pages, 1266 KiB  
Review
Silymarin and Cancer: A Dual Strategy in Both in Chemoprevention and Chemosensitivity
by Dominique Delmas, Jianbo Xiao, Anne Vejux and Virginie Aires
Molecules 2020, 25(9), 2009; https://doi.org/10.3390/molecules25092009 - 25 Apr 2020
Cited by 53 | Viewed by 6457
Abstract
Silymarin extracted from milk thistle consisting of flavonolignan silybin has shown chemopreventive and chemosensitizing activity against various cancers. The present review summarizes the current knowledge on the potential targets of silymarin against various cancers. Silymarin may play on the system of xenobiotics, metabolizing [...] Read more.
Silymarin extracted from milk thistle consisting of flavonolignan silybin has shown chemopreventive and chemosensitizing activity against various cancers. The present review summarizes the current knowledge on the potential targets of silymarin against various cancers. Silymarin may play on the system of xenobiotics, metabolizing enzymes (phase I and phase II) to protect normal cells against various toxic molecules or to protect against deleterious effects of chemotherapeutic agents on normal cells. Furthermore, silymarin and its main bioactive compounds inhibit organic anion transporters (OAT) and ATP-binding cassettes (ABC) transporters, thus contributing to counteracting potential chemoresistance. Silymarin and its derivatives play a double role, namely, limiting the progression of cancer cells through different phases of the cycle—thus forcing them to evolve towards a process of cell death—and accumulating cancer cells in a phase of the cell cycle—thus making it possible to target a greater number of tumor cells with a specific anticancer agent. Silymarin exerts a chemopreventive effect by inducing intrinsic and extrinsic pathways and reactivating cell death pathways by modulation of the ratio of proapoptotic/antiapoptotic proteins and synergizing with agonists of death domains receptors. In summary, we highlight how silymarin may act as a chemopreventive agent and a chemosensitizer through multiple pathways. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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13 pages, 1091 KiB  
Review
Metabolism, Transport and Drug–Drug Interactions of Silymarin
by Ying Xie, Dingqi Zhang, Jin Zhang and Jialu Yuan
Molecules 2019, 24(20), 3693; https://doi.org/10.3390/molecules24203693 - 14 Oct 2019
Cited by 50 | Viewed by 7981
Abstract
Silymarin, the extract of milk thistle, and its major active flavonolignan silybin, are common products widely used in the phytotherapy of liver diseases. They also have promising effects in protecting the pancreas, kidney, myocardium, and the central nervous system. However, inconsistent results are [...] Read more.
Silymarin, the extract of milk thistle, and its major active flavonolignan silybin, are common products widely used in the phytotherapy of liver diseases. They also have promising effects in protecting the pancreas, kidney, myocardium, and the central nervous system. However, inconsistent results are noted in the different clinical studies due to the low bioavailability of silymarin. Extensive studies were conducted to explore the metabolism and transport of silymarin/silybin as well as the impact of its consumption on the pharmacokinetics of other clinical drugs. Here, we aimed to summarize and highlight the current knowledge of the metabolism and transport of silymarin. It was concluded that the major efflux transporters of silybin are multidrug resistance-associated protein (MRP2) and breast cancer resistance protein (BCRP) based on results from the transporter-overexpressing cell lines and MRP2-deficient (TR) rats. Nevertheless, compounds that inhibit the efflux transporters MRP2 and BCRP can enhance the absorption and activity of silybin. Although silymarin does inhibit certain drug-metabolizing enzymes and drug transporters, such effects are unlikely to manifest in clinical settings. Overall, silymarin is a safe and well-tolerated phytomedicine. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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29 pages, 570 KiB  
Review
Formulation Strategies for Enhancing the Bioavailability of Silymarin: The State of the Art
by Alfonso Di Costanzo and Ruggero Angelico
Molecules 2019, 24(11), 2155; https://doi.org/10.3390/molecules24112155 - 07 Jun 2019
Cited by 110 | Viewed by 10139
Abstract
Silymarin, a mixture of flavonolignan and flavonoid polyphenolic compounds extractable from milk thistle (Silybum marianum) seeds, has anti-oxidant, anti-inflammatory, anti-cancer and anti-viral activities potentially useful in the treatment of several liver disorders, such as chronic liver diseases, cirrhosis and hepatocellular carcinoma. [...] Read more.
Silymarin, a mixture of flavonolignan and flavonoid polyphenolic compounds extractable from milk thistle (Silybum marianum) seeds, has anti-oxidant, anti-inflammatory, anti-cancer and anti-viral activities potentially useful in the treatment of several liver disorders, such as chronic liver diseases, cirrhosis and hepatocellular carcinoma. Equally promising are the effects of silymarin in protecting the brain from the inflammatory and oxidative stress effects by which metabolic syndrome contributes to neurodegenerative diseases. However, although clinical trials have proved that silymarin is safe at high doses (>1500 mg/day) in humans, it suffers limiting factors such as low solubility in water (<50 μg/mL), low bioavailability and poor intestinal absorption. To improve its bioavailability and provide a prolonged silymarin release at the site of absorption, the use of nanotechnological strategies appears to be a promising method to potentiate the therapeutic action and promote sustained release of the active herbal extract. The purpose of this study is to review the different nanostructured systems available in literature as delivery strategies to improve the absorption and bioavailability of silymarin. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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17 pages, 2791 KiB  
Review
Silymarin’s Inhibition and Treatment Effects for Alzheimer’s Disease
by Hong Guo, Hui Cao, Xiaowei Cui, Wenxiu Zheng, Shanshan Wang, Jiyang Yu and Zhi Chen
Molecules 2019, 24(9), 1748; https://doi.org/10.3390/molecules24091748 - 06 May 2019
Cited by 35 | Viewed by 5232
Abstract
As a longstanding problem, Alzheimer’s disease (AD) has stymied researchers in the medical field with its increasing incidence and enormous treatment difficulty. Silymarin has always been valued by researchers for its good efficacy and safety in treating liver disease. Recent studies have shown [...] Read more.
As a longstanding problem, Alzheimer’s disease (AD) has stymied researchers in the medical field with its increasing incidence and enormous treatment difficulty. Silymarin has always been valued by researchers for its good efficacy and safety in treating liver disease. Recent studies have shown that silymarin also has good pharmacological activity in the nervous system, especially for the treatment of AD. Silymarin can control the production of Aβ by inhibiting the precursor substance of Aβ (β-amyloid precursor protein), and it can inhibit the polymerization of Aβ. Silymarin can also increase the acetylcholine content in the nervous system by inhibiting cholinesterase activity. At the same time, it also has the effect of resisting oxidative stress and the inflammatory response of the nervous system. These pharmacological activities contribute to the inhibition of the onset of AD. The good efficacy of silymarin on AD and its high safety and availability give it huge potential for the treatment of AD. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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15 pages, 437 KiB  
Review
Antiviral Activities of Silymarin and Derivatives
by Ching-Hsuan Liu, Alagie Jassey, Hsin-Ya Hsu and Liang-Tzung Lin
Molecules 2019, 24(8), 1552; https://doi.org/10.3390/molecules24081552 - 19 Apr 2019
Cited by 62 | Viewed by 6944
Abstract
Silymarin flavonolignans are well-known agents that typically possess antioxidative, anti-inflammatory, and hepatoprotective functions. Recent studies have also documented the antiviral activities of silymarin and its derivatives against several viruses, including the flaviviruses (hepatitis C virus and dengue virus), togaviruses (Chikungunya virus and Mayaro [...] Read more.
Silymarin flavonolignans are well-known agents that typically possess antioxidative, anti-inflammatory, and hepatoprotective functions. Recent studies have also documented the antiviral activities of silymarin and its derivatives against several viruses, including the flaviviruses (hepatitis C virus and dengue virus), togaviruses (Chikungunya virus and Mayaro virus), influenza virus, human immunodeficiency virus, and hepatitis B virus. This review will describe some of the latest preclinical and clinical studies detailing the antiviral profiles of silymarin and its derivatives, and discuss their relevance for antiviral drug development. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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11 pages, 1398 KiB  
Review
A New Class of Synthetic Flavonolignan-Like Dimers: Still Few Molecules, but with Attractive Properties
by Valeria Romanucci, Giovanni Di Fabio and Armando Zarrelli
Molecules 2019, 24(1), 108; https://doi.org/10.3390/molecules24010108 - 29 Dec 2018
Cited by 14 | Viewed by 4113
Abstract
In recent years, there has been increasing interest in dimeric molecules due to reports of their promising therapeutic value in the treatment of numerous diseases (such as cancer, HIV, Alzheimer’s and, malaria). Many reports in the literature have highlighted the ability of these [...] Read more.
In recent years, there has been increasing interest in dimeric molecules due to reports of their promising therapeutic value in the treatment of numerous diseases (such as cancer, HIV, Alzheimer’s and, malaria). Many reports in the literature have highlighted the ability of these molecules to interact not only with specific biologic receptors but also to induce a biological response that more than doubles the results of the corresponding monomeric counterpart. In this regard, flavonolignan dimers or simply bi-flavonolignans are an emerging class of dimeric compounds that unlike bi-flavonoids, which are very widespread in nature, consist of synthetic dimers of some flavonolignans isolated from the milk thistle Silybum marianum [L. Gaertn. (Asteraceae)]. This mini-review will discuss recent developments in the synthesis, characterization and antioxidant activity of new families of flavonolignan dimers, in light of emerging medicinal chemistry strategies. Full article
(This article belongs to the Special Issue Silymarin and Derivatives: From Biosynthesis to Health Benefits)
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