SCOPE: This multi-omic study investigates the bidirectional interactions between gut microbiota and silymarin metabolism, highlighting the differential effects across various age groups. Silymarin, the extract from Silybum marianum (milk thistle), is commonly used for its hepatoprotective effects. METHODS AND RESULTS: An in vitro fermentation colon model was used with microbiota from 20 stool samples obtained from healthy donors divided into two age groups. A combination of three analytical advanced techniques, namely proton nuclear magnetic resonance (1H NMR), next-generation sequencing (NGS), and liquid chromatography-mass spectrometry (LC-MS) was used to determine silymarin microbial metabolites over 24 h, overall metabolome, and microbiota composition. Silymarin at a low diet-relevant dose of 50 µg mL-1 significantly altered gut microbiota metabolism, reducing short-chain fatty acid (acetate, butyrate, propionate) production, glucose utilization, and increasing alpha-diversity. Notably, the study reveals age-related differences in silymarin catabolism. Healthy elderly donors (70-80 years) exhibited a significant increase in a specific catabolite associated with Oscillibacter sp., whereas healthy young donors (12-45 years) showed a faster breakdown of silymarin components, particularly isosilybin B, which is associated with higher abundance of Faecalibacterium and Erysipelotrichaceae UCG-003. CONCLUSION: This study provides insights into microbiome functionality in metabolizing dietary flavonolignans, highlighting implications for age-specific nutritional strategies, and advancing our understanding of dietary (poly)phenol metabolism.

• Klíčová slova
• age‐related differences, gut microbiota, multi‐Omics analysis, polyphenols, silymarin metabolism,
• MeSH
• dítě MeSH
• dospělí MeSH
• feces mikrobiologie   MeSH
• fermentace MeSH
• kolon * mikrobiologie   metabolismus   účinky léků   MeSH
• kyseliny mastné těkavé metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• silymarin * farmakologie   MeSH
• střevní mikroflóra * účinky léků   fyziologie   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kyseliny mastné těkavé MeSH
• silymarin * MeSH

SCOPE: This study aims to assess in rats whether normalizing maternal diet during lactation prevents the harmful effects of western diet (WD) consumption during the whole perinatal period on the lipidomic profile in maternal milk and offspring plasma. METHODS AND RESULTS: Control dams (CON-dams), fed with standard diet (SD); WD-dams, fed with WD prior and during gestation and lactation; and reversion dams (REV-dams), fed as WD-dams but moved to SD during lactation are followed. Lipidomic analysis is performed in milk and plasma samples from pups. Milk of WD-dams presents a different triacylglycerol composition and free fatty acid (FA) profile compared to CON-dams, including an increased ratio of pro-inflammatory to anti-inflammatory long-chain polyunsaturated FA. Such alterations, which are also present in the plasma of their offspring, are widely reversed in the milk of REV-dams and the plasma of their pups. This is related with the recovery of control adiponectin expression levels in the mammary gland, and the presence of decreased expression of pro-inflammatory factors. CONCLUSION: Implementing a healthy diet during lactation prevents early alterations in the plasma lipidome of pups associated to the maternal intake of an obesogenic diet, which may be related to the normalization of milk lipid content and the inflammatory state in the mammary gland.

• Klíčová slova
• inflammation, lipidomics, milk composition, suckling, western diet,
• MeSH
• dieta MeSH
• krysa rodu Rattus MeSH
• laktace metabolismus   MeSH
• lipidomika * MeSH
• mastné kyseliny metabolismus   MeSH
• mléko * chemie   MeSH
• obezita etiologie   metabolismus   prevence a kontrola   MeSH
• těhotenství MeSH
• zdravá strava MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mastné kyseliny MeSH

SCOPE: CYP3A4 is the most important drug-metabolizing enzyme regulated via the vitamin D receptor (VDR) in the intestine. However, less is known about VDR in the regulation of CYP3A4 and other drug-metabolizing enzymes in the liver. METHODS AND RESULTS: This study investigates whether 1α,25-dihydroxyvitamin D3 (1α,25(OH)2 D3 ) regulates major cytochrome P450 enzymes, selected phase I and II enzymes, and transporters involved in xenobiotic and steroidal endobiotic metabolism in 2D and 3D cultures of human hepatocytes. The authors found that 1α,25(OH)2 D3 increases hepatic CYP3A4 expression and midazolam 1'-hydroxylation activity in 2D hepatocytes. The results are confirmed in 3D spheroids, where 1α,25(OH)2 D3 has comparable effect on CYP3A4 mRNA expression as 1α-hydroxyvitamin D3 , an active vitamin D metabolite. Other regulated genes such as CYP1A2, AKR1C4, SLC10A1, and SLCO4A1 display only mild changes in mRNA levels after 1α,25(OH)2 D3 treatment in 2D hepatocytes. Expression of other cytochrome P450, phase I and phase II enzyme, or transporter genes are not significantly influenced by 1α,25(OH)2 D3 . Additionally, the effect of VDR activation on CYP3A4 mRNA expression is abolished by natural dietary compound sulforaphane, a common suppressor of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). CONCLUSION: This study proposes that VDR or vitamin D supplementation is unlikely to significantly influence liver detoxification enzymes apart from CYP3A4.

• Klíčová slova
• CYP3A4, cytochrome P450, detoxification, gene regulation, hepatocyte, liver, metabolism, pregnane X receptor, vitamin D,
• MeSH
• cytochrom P-450 CYP3A * genetika   MeSH
• hepatocyty MeSH
• lidé MeSH
• messenger RNA MeSH
• receptory kalcitriolu genetika   MeSH
• stanovení celkové genové exprese MeSH
• systém (enzymů) cytochromů P-450 genetika   MeSH
• vitamin D farmakologie   MeSH
• xenobiotika * farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A * MeSH
• messenger RNA MeSH
• receptory kalcitriolu MeSH
• systém (enzymů) cytochromů P-450 MeSH
• vitamin D MeSH
• xenobiotika * MeSH

SCOPE: Flavanols are important polyphenols of the human diet with extensive demonstrations of their beneficial effects on cardiometabolic health. They contribute to preserve health acting on a large range of cellular processes. The underlying mechanisms of action of flavanols are not fully understood but involve a nutrigenomic regulation. METHODS AND RESULTS: To further capture how the intake of dietary flavanols results in the modulation of gene expression, nutrigenomics data in response to dietary flavanols obtained from animal models of cardiometabolic diseases have been collected and submitted to a bioinformatics analysis. This systematic analysis shows that dietary flavanols modulate a large range of genes mainly involved in endocrine function, fatty acid metabolism, and inflammation. Several regulators of the gene expression have been predicted and include transcription factors, miRNAs and epigenetic factors. CONCLUSION: This review highlights the complex and multilevel action of dietary flavanols contributing to their strong potential to preserve cardiometabolic health. The identification of the potential molecular mediators and of the flavanol metabolites driving the nutrigenomic response in the target organs is still a pending question which the answer will contribute to optimize the beneficial health effects of dietary bioactives.

• Klíčová slova
• animal models, cardiometabolic health, dietary intervention, flavanols, nutrigenomic,
• MeSH
• dieta * MeSH
• kardiovaskulární nemoci prevence a kontrola   MeSH
• krysa rodu Rattus MeSH
• myši MeSH
• nutrigenomika * MeSH
• polyfenoly aplikace a dávkování   MeSH
• regulace genové exprese MeSH
• výpočetní biologie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• systematický přehled MeSH
• Názvy látek
• polyfenoly MeSH

SCOPE: Infant formula (IF) uses besides vegetable fats also bovine milk fat, which differs in triacylglycerol (TAG) structure. Furthermore, it differs in fatty acid (FA) composition. Whether changing fat source in IF affects postprandial energy metabolism, lipemic response, and blood lipid profile is unknown. METHODS AND RESULTS: A proof-of-principle study, with a randomized controlled double-blind cross-over design, is conducted. Twenty healthy male adults consumed drinks with either 100% vegetable fat (VEG) or 67% bovine milk fat and 33% vegetable fat (BOV), on 2 separate days. For a detailed insight in the postprandial responses, indirect calorimetry is performed continuously, and venous blood samples are taken every 30 min, until 5 h postprandially. No differences in postprandial energy metabolism, serum lipids, lipoprotein, or chylomicron concentrations are observed between drinks. After consumption of VEG-drink, C18:2n-6 in serum increased. Observed differences in chylomicron FA profile reflect differences in initial FA profile of test drinks. Serum ketone bodies concentrations increase following consumption of BOV-drink. CONCLUSIONS: The use of bovine milk fat in IF does neither affect postprandial energy metabolism nor lipemic response in healthy adults, but alters postprandial FA profiles and ketone metabolism. Whether the exact same effects occur in infants requires experimental verification.

• Klíčová slova
• bovine milk fat, chylomicrons, infant formula, lipidomics, metabolism,
• MeSH
• chylomikrony krev   MeSH
• dietní tuky * MeSH
• dvojitá slepá metoda MeSH
• energetický metabolismus * MeSH
• ketolátky krev   MeSH
• klinické křížové studie MeSH
• kojenec MeSH
• lidé MeSH
• lipidy krev   MeSH
• mastné kyseliny analýza   MeSH
• metabolismus lipidů * MeSH
• mladý dospělý MeSH
• mléko * MeSH
• náhražky mateřského mléka * MeSH
• postprandiální období fyziologie   MeSH
• zelenina MeSH
• zvířata MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• chylomikrony MeSH
• dietní tuky * MeSH
• ketolátky MeSH
• lipidy MeSH
• mastné kyseliny MeSH

SCOPE: The docosahexaenoic acid ester of hydroxy linoleic acid (13-DHAHLA) is a bioactive lipid with anti-inflammatory properties from the family of fatty acid esters of hydroxy fatty acids (FAHFA). METHODS AND RESULTS: To explore the biosynthesis of 13-DHAHLA from dietary oils, C57BL/6N mice are gavaged for 8 days with various corn oil/marine oil mixtures containing the same amount of DHA. Plasma levels of omega-3 FAHFAs are influenced by the lipid composition of the mixtures but do not reflect the changes in bioavailability of polyunsaturated fatty acids in plasma. Triacylglycerol-bound DHA and linoleic acid serve as more effective precursors for 13-DHAHLA synthesis than DHA bound in phospholipids or wax esters. Both 13(S)- and 13(R)-DHAHLA inhibit antigen and PGE2 -induced chemotaxis and degranulation of mast cells to a comparable extent and 13(S)-DHAHLA is identified as the predominant isomer in mouse adipose tissue. CONCLUSION: Here, the optimal nutritional source of DHA is identified, which supports production of anti-inflammatory FAHFAs, as triacylglycerol-based marine oil and also reveals a possible role of triacylglycerols in the synthesis of FAHFA lipokines.

• Klíčová slova
• calanus, fatty acids, krill, mast cells, stereoisomers,
• MeSH
• antiflogistika nesteroidní krev   farmakokinetika   MeSH
• biologická dostupnost MeSH
• chemotaxe účinky léků   MeSH
• kyseliny dokosahexaenové farmakokinetika   MeSH
• kyseliny linolové chemie   MeSH
• mastocyty účinky léků   MeSH
• myši inbrední C57BL MeSH
• oleje chemie   farmakokinetika   MeSH
• omega-3 mastné kyseliny farmakokinetika   farmakologie   MeSH
• stereoizomerie MeSH
• triglyceridy chemie   MeSH
• vodní organismy MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 13-hydroxylinoleic acid MeSH Prohlížeč
• antiflogistika nesteroidní MeSH
• kyseliny dokosahexaenové MeSH
• kyseliny linolové MeSH
• oleje MeSH
• omega-3 mastné kyseliny MeSH
• triglyceridy MeSH

SCOPE: Intake of flavonoids from the diet can be substantial, and epidemiological studies suggest that these compounds can decrease the incidence of cardiovascular diseases by involvement with increased platelet aggregation. Although parent flavonoids possess antiplatelet effects, the clinical importance is disputable due to their very low bioavailability. Most of them are metabolized by human colon bacteria to smaller phenolic compounds, which reach higher plasma concentrations than the parent flavonoids. In this study, a series of 29 known flavonoid metabolites is tested for antiplatelet potential. METHODS AND RESULTS: Four compounds appear to have a biologically relevant antiplatelet effect using whole human blood. 4-Methylcatechol (4-MC) is clearly the most efficient being about 10× times more active than clinically used acetylsalicylic acid. This ex vivo effect is also confirmed using a potentially novel in-vivo-like ex ovo hen's egg model of thrombosis, where 4-MC significantly increases the survival of the eggs. The mechanism of action is studied and it seems that it is mainly based on the influence on intracellular calcium signaling. CONCLUSION: This study shows that some flavonoid metabolites formed by human microflora have a strong antiplatelet effect. This information can help to explain the antiplatelet potential of orally given flavonoids.

• Klíčová slova
• 4-methylcatechol, aggregation, flavonoids, metabolites, platelets, pyrogallol,
• MeSH
• agregace trombocytů účinky léků   MeSH
• inhibitory agregace trombocytů farmakologie   MeSH
• inhibitory cyklooxygenasy farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• katecholy farmakologie   MeSH
• kuřecí embryo MeSH
• kyselina arachidonová farmakologie   MeSH
• lidé MeSH
• preklinické hodnocení léčiv metody   MeSH
• pyrogalol farmakologie   MeSH
• serotonin metabolismus   MeSH
• thromboxan-A-synthasa antagonisté a inhibitory   MeSH
• trombóza farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• kuřecí embryo MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 4-methylcatechol MeSH Prohlížeč
• inhibitory agregace trombocytů MeSH
• inhibitory cyklooxygenasy MeSH
• inhibitory enzymů MeSH
• katecholy MeSH
• kyselina arachidonová MeSH
• pyrogalol MeSH
• serotonin MeSH
• thromboxan-A-synthasa MeSH

SCOPE: Aberrant vascular smooth muscle cell (VSMC) proliferation is involved in atherosclerotic plaque formation and restenosis. Mediterranean spices have been reported to confer cardioprotection, but their direct influence on VSMCs has largely not been investigated. This study aims at examining rosmarinic acid (RA) and 11 related constituents for inhibition of VSMC proliferation in vitro, and at characterizing the most promising compound for their mode of action and influence on neointima formation in vivo. METHODS AND RESULTS: RA, rosmarinic acid methyl ester (RAME), and caffeic acid methyl ester inhibit VSMC proliferation in a resazurin conversion assay with IC50 s of 5.79, 3.12, and 6.78 µm, respectively. RAME significantly reduced neointima formation in vivo in a mouse femoral artery cuff model. Accordingly, RAME leads to an accumulation of VSMCs in the G0 /G1 cell-cycle phase, as indicated by blunted retinoblastoma protein phosphorylation upon mitogen stimulation and inhibition of cyclin-dependent kinase 2 in vitro. CONCLUSION: RAME represses PDGF-induced VSMC proliferation in vitro and reduces neointima formation in vivo. These results recommend RAME as an interesting compound with VSMC-inhibiting potential. Future metabolism and pharmacokinetics studies might help to further evaluate the potential relevance of RAME and other spice-derived polyphenolics for vasoprotection.

• Klíčová slova
• Mediterranean spices, neointima formation, rosmarinic acid, rosmarinic acid methyl ester, vascular smooth muscle cells,
• MeSH
• cévní endotel cytologie   účinky léků   patologie   MeSH
• cinnamáty aplikace a dávkování   škodlivé účinky   farmakologie   terapeutické užití   MeSH
• depsidy aplikace a dávkování   škodlivé účinky   farmakologie   terapeutické užití   MeSH
• endoteliální buňky pupečníkové žíly (lidské) cytologie   MeSH
• fosforylace účinky léků   MeSH
• kardiovaskulární látky škodlivé účinky   farmakologie   terapeutické užití   MeSH
• koření analýza   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• kyselina rozmarýnová MeSH
• lidé MeSH
• metylace MeSH
• myši inbrední C57BL MeSH
• náhodné rozdělení MeSH
• patologická angiogeneze metabolismus   patologie   prevence a kontrola   MeSH
• posttranslační úpravy proteinů účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• retinoblastomový protein metabolismus   MeSH
• rozmarýn chemie   růst a vývoj   MeSH
• strava středomořská MeSH
• svaly hladké cévní cytologie   účinky léků   metabolismus   patologie   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Středomoří MeSH
• Názvy látek
• cinnamáty MeSH
• depsidy MeSH
• kardiovaskulární látky MeSH
• retinoblastomový protein MeSH
• rosmarinic acid methyl ester MeSH Prohlížeč

There are reports of positive effects of quercetin on cardiovascular pathologies, however, mainly due to its low biovailability, the mechanism remains elusive. Here, we report that one metabolite formed by human microflora (3-(3-hydroxyphenyl)propionic acid)relaxed isolated rat aorta and decreased arterial blood pressure in rats.

• Klíčová slova
• Blood pressure, Flavonoid, Metabolite, Phenolic, Quercetin, Rat, Vascular,
• MeSH
• arteriální tlak účinky léků   MeSH
• fenoly farmakologie   MeSH
• flavonoidy farmakologie   MeSH
• hemodynamika MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• lineární modely MeSH
• potkani inbrední SHR MeSH
• potkani Wistar MeSH
• propionáty farmakologie   MeSH
• střevní mikroflóra MeSH
• tandemová hmotnostní spektrometrie MeSH
• techniky in vitro MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-hydroxyphenylpropionic acid MeSH Prohlížeč
• fenoly MeSH
• flavonoidy MeSH
• propionáty MeSH

We verified the hypothesis suggesting modulation of the effects of sodium butyrate (NaBt) by omega-3 or omega-6 PUFAs. Comparing the response of human colon epithelial cell lines of fetal (FHC) and adenocarcinoma (HT-29, HCT-116) origin, we detected significant differences in proliferation, differentiation and apoptotic response to the treatment of NaBt, arachidonic or docosahexaenoic acids and their combination. While in FHC and HT-29 cells NaBt induced G0/G1 arrest, differentiation and low level of apoptosis, in HCT-116 cells G2/M arrest, no differentiation and high degree of apoptosis were detected. Moreover, in FHC cells significant potentiation of apoptosis accompanied by increased arrest in the cell cycle, cell detachment and decrease in differentiation were detected after combined treatment with NaBt and both PUFAs. Changes in cytokinetics induced by fatty acids were accompanied by membrane lipid unpacking, reactive oxygen species (ROS) production, and decrease in mitochondrial membrane potential (MMP). Detection of caspase-3 activation and dynamic modulation of Mcl-1 protein expression imply their possible role in both cell differentiation and apoptotic response. Our results support the concept of modulation of NaBt effects by PUFAs, especially of omega-3 type, in colonic cells in vitro with diverse impact in cell lines derived from normal or neoplastic epithelium.

• MeSH
• antioxidancia farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buněčná diferenciace účinky léků   MeSH
• buněčné dělení účinky léků   MeSH
• buněčné linie MeSH
• buňky HT-29 MeSH
• butyráty farmakologie   MeSH
• epitelové buňky účinky léků   MeSH
• HCT116 buňky MeSH
• kolon účinky léků   embryologie   MeSH
• lidé MeSH
• membránové lipidy chemie   MeSH
• nádory tračníku patologie   MeSH
• nenasycené mastné kyseliny farmakologie   MeSH
• plod MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antioxidancia MeSH
• butyráty MeSH
• membránové lipidy MeSH
• nenasycené mastné kyseliny MeSH