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
Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation. Targeting both LT biosynthesis and the conversion of EETs with a dual inhibitor of FLAP and sEH may represent a novel, powerful anti-inflammatory strategy. We present a pharmacophore-based virtual screening campaign that led to 20 hit compounds of which 4 targeted FLAP and 4 were sEH inhibitors. Among them, the first dual inhibitor for sEH and FLAP was identified, N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N'-(3,4-dichlorophenyl)urea with IC50 values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay.
- MeSH
- antiflogistika chemie farmakologie MeSH
- bezbuněčný systém MeSH
- epoxid hydrolasy antagonisté a inhibitory MeSH
- inhibitory enzymů chemie farmakologie MeSH
- inhibitory proteinu aktivujícího 5-lipoxygenasu chemie farmakologie MeSH
- leukotrieny biosyntéza MeSH
- lidé MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- počítačová simulace MeSH
- preklinické hodnocení léčiv MeSH
- proteiny aktivující 5-lipoxygenasu metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antiflogistika MeSH
- epoxid hydrolasy MeSH
- inhibitory enzymů MeSH
- inhibitory proteinu aktivujícího 5-lipoxygenasu MeSH
- leukotrieny MeSH
- proteiny aktivující 5-lipoxygenasu MeSH
The Eighth Central European Conference "Chemistry towards Biology" was held in Brno, Czech Republic, on August 28-September 1, 2016 to bring together experts in biology, chemistry and design of bioactive compounds; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topics of the conference covered "Chemistry towards Biology", meaning that the event welcomed chemists working on biology-related problems, biologists using chemical methods, and students and other researchers of the respective areas that fall within the common scope of chemistry and biology. The authors of this manuscript are plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting.
- Klíčová slova
- ADME, drug delivery systems, biological chemistry, biomaterials, chemical biology, drug design, nanoparticles, natural compounds, proteins and nucleic acids, synthesis, targeting,
- MeSH
- epigeneze genetická MeSH
- farmaceutická chemie metody MeSH
- lékové transportní systémy MeSH
- proteiny chemie MeSH
- racionální návrh léčiv MeSH
- systémová biologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- kongresy MeSH
- Názvy látek
- proteiny MeSH
Natural products have always been exploited to promote health and served as a valuable source for the discovery of new drugs. In this review, the great potential of natural compounds and medicinal plants for the treatment or prevention of cardiovascular and metabolic disorders, global health problems with rising prevalence, is addressed. Special emphasis is laid on natural products for which efficacy and safety have already been proven and which are in clinical trials, as well as on plants used in traditional medicine. Potential benefits from certain dietary habits and dietary constituents, as well as common molecular targets of natural products, are also briefly discussed. A glimpse at the history of statins and biguanides, two prominent representatives of natural products (or their derivatives) in the fight against metabolic disease, is also included. The present review aims to serve as an "opening" of this special issue of Molecules, presenting key historical developments, recent advances, and future perspectives outlining the potential of natural products for prevention or therapy of cardiovascular and metabolic disease.
- Klíčová slova
- biguanides, cardiovascular disease, coffee, diabetes mellitus, dietary constituents, metabolic disorders, molecular targets, natural products, statins,
- MeSH
- biguanidy terapeutické užití MeSH
- biologické přípravky terapeutické užití MeSH
- kardiovaskulární nemoci farmakoterapie MeSH
- léčivé rostliny * MeSH
- lidé MeSH
- metabolické nemoci farmakoterapie MeSH
- objevování léků MeSH
- statiny terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- biguanidy MeSH
- biologické přípravky MeSH
- statiny MeSH
