The exposure of naked unprotected skin to solar radiation may result in numerous acute and chronic undesirable effects. Evidence suggests that silymarin, a standardized extract from Silybum marianum (L.) Gaertn. seeds, and its major component silybin suppress UVB-induced skin damage. Here, we aimed to investigate the UVA-protective effects of silymarin's less abundant flavonolignans, specifically isosilybin (ISB), silychristin (SC), silydianin (SD), and 2,3-dehydrosilybin (DHSB). Normal human dermal fibroblasts (NHDF) pre-treated for 1 h with flavonolignans were then exposed to UVA light using a solar simulator. Their effects on reactive oxygen species (ROS), carbonylated proteins and glutathione (GSH) level, caspase-3 activity, single-strand breaks' (SSBs) formation and protein level of matrix metalloproteinase-1 (MMP-1), heme oxygenase-1 (HO-1), and heat shock protein (HSP70) were evaluated. The most pronounced preventative potential was found for DHSB, a minor component of silymarin, and SC, the second most abundant flavonolignan in silymarin. They had significant effects on most of the studied parameters. Meanwhile, a photoprotective effect of SC was mostly found at double the concentration of DHSB. ISB and SD protected against GSH depletion, the generation of ROS, carbonylated proteins and SSBs, and caspase-3 activation, but had no significant effect on MMP-1, HO-1, or HSP70. In summary, DHSB and to a lesser extent other silymarin flavonolignans are potent UVA-protective compounds. However, due to the in vitro phototoxic potential of DHSB published elsewhere, further studies are needed to exclude phototoxicity for humans as well as to confirm our results on human skin ex vivo and in vivo.

• MeSH
• cytoprotekce účinky léků   MeSH
• fibroblasty účinky léků   účinky záření   MeSH
• glutathion metabolismus   MeSH
• hemoxygenasa-1 metabolismus   MeSH
• jednořetězcové zlomy DNA účinky záření   MeSH
• karbonylace proteinů účinky záření   MeSH
• kaspasa 3 metabolismus   MeSH
• kultivované buňky MeSH
• kůže účinky záření   MeSH
• lidé MeSH
• matrixová metaloproteinasa 1 metabolismus   MeSH
• přípravky chránící proti slunci farmakologie   MeSH
• proteiny tepelného šoku HSP70 metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• silymarin analogy a deriváty   farmakologie   MeSH
• ultrafialové záření škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Ostropestřec mariánský (Silybum marianum) je jednoletá nebo dvouletá bylina z čeledi hvězdnicovitých (Asteraceae). K léčbě jaterních onemocnění je používán již tisíce let. Pro tento účel se z ostropestřecových plodů vyrábí standardizovaný extrakt. Silymarin je komplex flavolignanů, hlavní složkou je silybin, silykristin a silydianin. Současný výzkum odhaluje další farmakologické účinky silymarinu včetně účinků na nervový systém. In vitro studie a experimenty na zvířatech odhalily antidepresivní, anxiolytický, neuroprotektivní a prokognitivní účinek. Klinických studií je však zatím minimum.

Milk thistle (Silybum marianum) is an annual or biennial plant of Compositae family (Asteraceae). It has been used for treatment of liver diseases for thousands of years. For this purpose, a standardized extract is made from milk thistle fruits. Silymarin is a complex of flavolignans, main active compounds are silybin, silychristin and silydianin. Current research discovers another pharmacological effects of silymarin, including effects on the nervous system. In vitro studies and animal experiments confirmed antidepressant, anxiolytic, neuroprotective, and procognitive effects. However, clinical studies ale still lacking.

• MeSH
• kazuistiky jako téma MeSH
• laboratorní zvířata MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• nervový systém účinky léků   MeSH
• ostropestřec mariánský * MeSH
• silymarin aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

Silymarin, a standardized extract of the seeds of the milk thistle (Silybum marianum) and its major component, silybin, is now used as an active component in a broad spectrum of dietary supplements, cosmetics and dermatological preparations. However, despite its use in skin products, there are no published data to exclude its phototoxic potential. The primary purpose of this study was to examine the phototoxicity of silymarin and its flavonolignans, silybin, isosilybin, silychristin, silydianin and 2,3-dehydrosilybin by validated 3T3 NRU assay. Further, we compared the validated biological system Balc/c 3T3 cell line with other cell models, particularly normal human dermal fibroblasts (NHDF), normal human epidermal keratinocytes (NHEK) and the human keratinocyte cell line (HaCaT). The results showed that silymarin and the flavonolignans silybin, isosilybin, silychristin and silydianin had no phototoxicity towards any of the cells used. In contrast, 2,3-dehydrosilybin was identified as a compound with phototoxic potential. Further study is needed to evaluate the health risks associated with 2,3-dehydrosilybin use in skin preparations.

• MeSH
• buňky 3T3 MeSH
• kultivované buňky MeSH
• lidé MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• silymarin toxicita   MeSH
• ultrafialové záření * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

• Klíčová slova
• SILYCHRISTIN, SILYDIANIN, SILYBININ,
• MeSH
• faktorová analýza statistická metody   MeSH
• farmakologie MeSH
• farmakoterapie MeSH
• léčivé přípravky analýza   MeSH
• oxymetazolin analýza   farmakologie   terapeutické užití   MeSH
• ranitidin analýza   farmakologie   terapeutické užití   MeSH
• regresní analýza metody   MeSH
• spektrofotometrie metody   přístrojové vybavení   MeSH
• Publikační typ
• přehledy MeSH

Covering: 2015 up to 2022 (Feb)Silymarin, an extract of milk thistle (Silybum marianum) fruits, has been used in various medicinal applications since ancient times. A major component of silymarin is the flavonolignan silybin and its relatives isosilybin, silychristin, silydianin, 2,3-dehydrosilybin, and some others. Except for silydianin, they occur in nature as two stereomers. This review focuses on recent developments in chemistry, biosynthesis, modern advanced analytical methods, and transformations of flavonolignans specifically reflecting their chirality. Recently described chemotypes of S. marianum, but also the newest findings regarding the pharmacokinetics, hepatoprotective, antiviral, neuroprotective, and cardioprotective activity, modulation of endocrine functions, modulation of multidrug resistance, and safety of flavonolignans are discussed. A growing number of studies show that the respective diastereomers of flavonolignans have significantly different activities in anisotropic biological systems. Moreover, it is now clear that flavonolignans do not act as antioxidants in vivo, but as specific ligands of biological targets and therefore their chirality is crucial. Many controversies often arise, mainly due to the non-standard composition of this phytopreparation, the use of various undefined mixtures, the misattribution of silymarin vs. silybin, and also the failure to consider the chemistry of the respective components of silymarin.

• MeSH
• antioxidancia farmakologie   MeSH
• ostropestřec mariánský chemie   MeSH
• silibinin MeSH
• silymarin * chemie   farmakologie   MeSH
• tradiční lékařství MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Flavonolignans occur typically in Silybum marianum (milk thistle) fruit extract, silymarin, which contains silybin, isosilybin, silychristin, silydianin, and their 2,3-dehydroderivatives, together with other minor flavonoids and a polymeric phenolic fraction. Biotransformation of individual silymarin components by human microbiota was studied ex vivo, using batch incubations inoculated by fecal slurry. Samples at selected time points were analyzed by ultrahigh-performance liquid chromatography equipped with mass spectrometry. The initial experiment using a concentration of 200 mg/L showed that flavonolignans are resistant to the metabolic action of intestinal microbiota. At the lower concentration of 10 mg/L, biotransformation of flavonolignans was much slower than that of taxifolin, which was completely degraded after 16 h. While silybin, isosilybin, and 2,3-dehydrosilybin underwent mostly demethylation, silychristin was predominantly reduced. Silydianin, 2,3-dehydrosilychristin and 2,3-dehydrosilydianin were reduced, as well, and decarbonylation and cysteine conjugation proceeded. No low-molecular-weight phenolic metabolites were detected for any of the compounds tested. Strong inter-individual differences in the biotransformation profile were observed among the four fecal-material donors. In conclusion, the flavonolignans, especially at higher (pharmacological) doses, are relatively resistant to biotransformation by gut microbiota, which, however, depends strongly on the individual structures of these isomeric compounds, but also on the stool donor.

• Publikační typ
• časopisecké články MeSH

This study examined the in vitro biotransformation of eight structurally related flavonolignans, namely silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, silydianin, 2,3-dehydrosilydianin, isosilybin A and isosilybin B. The metabolic transformations were performed using primary cultures of human hepatocytes and recombinant human cytochromes P450 (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4). The metabolites produced were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry. We found that each of the tested compounds was metabolized in vitro by one or more CYP enzymes, which catalyzed O-demethylation, hydroxylation, hydrogenation and dehydrogenation reactions. In human hepatocytes, silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, and isosilybins A and B were directly conjugated by sulfation or glucuronidation. Moreover, isosilybin A was also converted to a methyl derivative, while isosilybin B was hydroxylated and methylated. Silydianin and 2,3-dehydrosilydianin were found to undergo hydrogenation and/or glucuronidation. In addition, 2,3-dehydrosilydianin was found to be metabolically the least stable flavonolignan in human hepatocytes, and its main metabolite was a cleavage product corresponding to a loss of CO. We conclude that the hepatic biotransformation of flavonolignans primarily involves the phase II conjugation reactions, however in some cases the phase I reactions may also occur. These results are highly relevant for research focused on flavonolignan metabolism and pharmacology.

• MeSH
• biotransformace fyziologie   MeSH
• dospělí MeSH
• flavonolignany metabolismus   MeSH
• hepatocyty metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• silymarin analogy a deriváty   metabolismus   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The effect of new synthetic pyrazinecarboxamide derivatives as potential elicitors of flavonolignan and flavonoid production in Silybum marianum and Ononis arvensis cultures in vitro was investigated. Both tested elicitors increased the production of flavonolignans in S. marianum callus and suspension cultures and flavonoids in O. arvensis callus and suspension cultures. Compound I, 5-(2-hydroxybenzoyl)-pyrazine-2-carboxamide, has shown to be an effective elicitor of flavonolignans and taxifoline production in Silybum marianum culture in vitro. The maximum content of silydianin (0.11%) in S. marianum suspension culture was induced by 24 h elicitor application in concentration of 1.159 × 10⁻³ mol/L. The maximum content of silymarin complex (0.08%) in callus culture of S. marianum was induced by 168 h elicitor application of a concentration 1.159 × 10⁻⁴ mol/L, which represents contents of silydianin (0.03%), silychristin (0.01%) and isosilybin A (0.04%) compared with control. All three tested concentrations of compound II, N-(2-bromo-3-methylphenyl)-5-tert-butylpyrazin-2-carboxamide increased the flavonoid production in callus culture of O. arvensis in a statistically significant way. The best elicitation effect of all elicitor concentrations had the weakest c₃ concentration (8.36 × 10⁻⁶ mol/L) after 168 h time of duration. The maximum content of flavonoids (about 5,900%) in suspension culture of O. arvensis was induced by 48 h application of c₃ concentration (8.36 × 10⁻⁶ mol/L).

• MeSH
• amidy chemie   farmakologie   MeSH
• Fabaceae chemie   cytologie   metabolismus   MeSH
• flavonoidy biosyntéza   chemie   MeSH
• flavonolignany biosyntéza   chemie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• molekulární struktura MeSH
• ostropestřec mariánský chemie   cytologie   metabolismus   MeSH
• pyraziny chemie   farmakologie   MeSH
• rostlinné extrakty chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Natural phenolic compounds are known to be metabolized by phase II metabolic reactions. In this study, we examined the in vitro sulfation of the main constituents of silymarin, an herbal remedy produced from the fruits of the milk thistle. The study focused on major flavonolignan constituents, including silybin A, silybin B, isosilybin A, isosilybin B, silychristin, and silydianin, as well as the flavonoid taxifolin. Using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS), individual flavonolignans and taxifolin were found to be sulfated by human liver and human intestinal cytosols. Moreover, experiments with recombinant enzymes revealed that human sulfotransferases (SULTs) 1A1*1, 1A1*2, 1A2, 1A3, 1B1, 1C4, and 1E1 catalyzed the sulfation of all of the tested compounds, with the exception of silydianin, which was not sulfated by SULT1B1 and SULT1C4. The sulfation products detected were monosulfates, of which some of the major ones were identified as silybin A 20-O-sulfate, silybin B 20-O-sulfate, and isosilybin A 20-O-sulfate. Further, we also observed the sulfation of the tested compounds when they were tested in the silymarin mixture. Sulfates of flavonolignans and of taxifolin were produced by incubating silymarin with all of the above SULT enzymes, with human liver and intestinal cytosols, and also with human hepatocytes, even though the spectrum and amount of the sulfates varied among the metabolic models. Considering our results and the expression patterns of human sulfotransferases in metabolic tissues, we conclude that flavonolignans and taxifolin can potentially undergo both intestinal and hepatic sulfation, and that SULTs 1A1, 1A3, 1B1, and 1E1 could be involved in the biotransformation of the constituents of silymarin.

• Publikační typ
• časopisecké články MeSH

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.

• MeSH
• antioxidancia chemie   izolace a purifikace   MeSH
• flavonolignany chemie   izolace a purifikace   MeSH
• kůže účinky léků   patologie   účinky záření   MeSH
• lidé MeSH
• ostropestřec mariánský chemie   MeSH
• rostlinné extrakty chemie   MeSH
• semena rostlinná chemie   MeSH
• silymarin chemie   izolace a purifikace   MeSH
• ultrafialové záření škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH