Tapinarof (3,5-dihydroxy-4-isopropylstilbene) is a therapeutic agent used in the treatment of psoriasis (VTAMA®). In this study, we examined the redox behaviour, (photo)stability, (photo)toxicity and (bio)transformation of tapinarof in the context of a structure-activity relationship study. Selected derivatives of the structurally related tapinarof were investigated, namely resveratrol, pterostilbene, pinosylvin and its methyl ether. Tapinarof undergoes electrochemical oxidation in a neutral aqueous medium at a potential of around +0.5 V (vs. Ag|AgCl|3M KCl). The anodic reaction of this substance is a proton-dependent irreversible and adsorption-driven process. The pKa value of tapinarof corresponds to 9.19 or 9.93, based on empirical and QM calculation approach, respectively. The oxidation potentials of tapinarof and its analogues correlate well with their HOMO (highest occupied molecular orbital) energy level. The ability to scavenge the DPPH radical decreased in the order trolox ≥ resveratrol > pterostilbene > tapinarof > pinosylvin ≫ pinosylvin methyl ether. It was also confirmed that tapinarof, being a moderate electron donor, is able to scavenge the ABTS radical and inhibit lipid peroxidation. The 4'-OH group plays a pivotal role in antioxidant action of stilbenols. During the stability studies, it was shown that tapinarof is subject to spontaneous degradation under aqueous conditions, and its degradation is accelerated at elevated temperatures and after exposure to UVA (315-399 nm) radiation. In aqueous media at pH 7.4, we observed an ∼50 % degradation of tapinarof after 48 h at laboratory temperature. The main UVA photodegradation processes include dihydroxylation and hydration. In conclusion, the phototoxic effect of tapinarof on a human keratinocytes cell line (HaCaT) was evaluated. Tapinarof exhibited a clear phototoxic effect, similar to phototoxic standard chlorpromazine. The IC50 values of the cytotoxicity and phototoxic effects of tapinarof correspond to 27.6 and 3.7 μM, respectively. The main HaCaT biotransformation products of tapinarof are sulfates and glucuronides.

• MeSH
• antioxidancia farmakologie   chemie   MeSH
• buněčné linie keratinocytů HaCaT MeSH
• fototoxická dermatitida MeSH
• keratinocyty * účinky léků   metabolismus   účinky záření   MeSH
• kůže účinky léků   metabolismus   účinky záření   patologie   MeSH
• lidé MeSH
• oxidace-redukce * MeSH
• resveratrol farmakologie   analogy a deriváty   chemie   MeSH
• stilbeny * farmakologie   chemie   MeSH
• ultrafialové záření MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• Burosumab, Asfotáza, Vosoritid, Palovaroten,
• MeSH
• achondroplazie farmakoterapie   MeSH
• denosumab farmakologie   terapeutické užití   MeSH
• dítě MeSH
• humanizované monoklonální protilátky farmakologie   terapeutické užití   MeSH
• hypofosfatemická rachitida farmakoterapie   MeSH
• hypofosfatemie farmakoterapie   MeSH
• lidé MeSH
• natriuretický peptid typu C farmakologie   terapeutické užití   MeSH
• osteochondrodysplazie farmakoterapie   MeSH
• osteogenesis imperfecta farmakoterapie   MeSH
• pyrazoly farmakologie   terapeutické užití   MeSH
• stilbeny farmakologie   terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH

ETHNOPHARMACOLOGICAL RELEVANCE: Macaranga Thou. (Euphorbiaceae) is a large genus that comprises over 300 species distributed between Western Africa and the islands of the South Pacific. Plants of this genus have a long-standing history of use in traditional medicine for different purposes, including the treatment of inflammation. Fresh and dried leaves of certain Macaranga species (e.g. M. tanarius (L.) Müll.Arg.), have been used to treat cuts, bruises, boils, swellings, sores and covering of wounds in general. Several reports described Macaranga spp. being a rich source of polyphenols, such as prenylated stilbenoids and flavonoids, mostly responsible for its biological activity. Similarly, an abundant content of prenylated stilbenes was also described in M. siamensis S.J.Davies, species recently identified (2001) in Thailand. While the respective biological activity of the prenylated stilbenes from M. siamensis was poorly investigated to date, our recent study pointed out the interest as the natural source of several novel anti-inflammatory stilbenoids isolated from this species. AIM OF THE STUDY: This work investigated the potential anti-inflammatory effects of the stilbenoid macasiamenene F (MF) isolated from M. siamensis S.J.Davies (Euphorbiaceae) on the lipopolysaccharide (LPS)-induced inflammation-like response of monocytes and microglia, major cells involved in the peripheral and central inflammatory response, respectively. MATERIALS AND METHODS: LPS-induced stimulation of TLR4 signaling led to the activation of inflammatory pathways in in vitro models of THP-1 and THP-1-XBlue™-MD2-CD14 human monocytes, BV-2 mouse microglia, and an ex vivo model of brain-sorted mouse microglia. The ability of the stilbenoid MF to intervene in the IкB/NF-кB and MAPKs/AP-1 inflammatory cascade was investigated. The gene and protein expressions of the pro-inflammatory cytokines IL-1β and TNF-α were evaluated at the transcription and translation levels. The protective effect of MF against LPS-triggered microglial loss was assessed by cell counting and the LDH assay. RESULTS: MF demonstrated beneficial effects, reducing both monocyte and microglial inflammation as assessed in vitro. It efficiently inhibited the degradation of IкBα, thereby reducing the NF-кB activity and TNF-α expression in human monocytes. Furthermore, the LPS-induced expression of IL-1β and TNF-α in microglia was dampened by pre-, co-, or post-treatment with MF. In addition to its anti-inflammatory effect, MF demonstrated a cytoprotective effect against the LPS-induced death of BV-2 microglia. CONCLUSION: Our research into anti-inflammatory and protective effects of MF has shown that it is a promising candidate for further in vitro and in vivo investigations of MF interventions with respect to acute and chronic inflammation, including potentially beneficial effects on the inflammatory component of brain diseases such as stroke and Alzheimer's disease.

• MeSH
• antiflogistika izolace a purifikace   farmakologie   terapeutické užití   MeSH
• cytoprotekce účinky léků   fyziologie   MeSH
• Euphorbiaceae * MeSH
• kultivované buňky MeSH
• lidé MeSH
• lipopolysacharidy toxicita   MeSH
• mediátory zánětu antagonisté a inhibitory   metabolismus   MeSH
• mikroglie účinky léků   metabolismus   MeSH
• monocyty účinky léků   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• prenylace účinky léků   fyziologie   MeSH
• rostlinné extrakty izolace a purifikace   farmakologie   terapeutické užití   MeSH
• stilbeny izolace a purifikace   farmakologie   terapeutické užití   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zánět farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Pterostilbene (PTE), a dimethylated analogue of resveratrol, mostly contained in Vitis vinifera leaves or in other plant sources is well-known for its antioxidant activity. Due to its bioavailability, low hydrophilicity and thus ability to penetrate hydrophobic biological membranes it was found to be an antimicrobial agent. These properties of PTE offer the possibility of its use in the treatment of microbial infections. The emergence of antibiotic resistance of microorganisms is often caused by their ability to form biofilm; new substances with antibiofilm activity are therefore sought. The representatives of opportunistic pathogenic gram-positive and gram-negative bacteria as well as fungi were used for the determination of minimum inhibitory concentrations (MIC50 and MIC80), minimum biofilm inhibitory concentrations (MBIC50 and MBIC80) and minimum biofilm eradication concentrations (MBEC50 and MBEC80) of PTE and commonly used antibiotics erythromycin, polymyxin B or antimycotic amphotericin B. Total biofilm biomass was investigated by crystal violet staining, and the results were confirmed using microscopic techniques. The most significant antibiofilm action was proved for gram-positive cocci, e.g., MBEC50 of PTE for all strains of Staphylococcus epidermidis tested was 25 mg/L. By contrast, the antibiotic ERM did not exhibit antibiofilm activity in most cases. The permeabilization of cell membranes of gram-positive cocci biofilm by MBIC50 and MBEC50 of PTE was confirmed by LIVE/DEAD staining using spinning disc confocal microscopy. PTE significantly influenced the ability of gram-positive cocci to form biofilm and it effectively eradicated pre-formed biofilm in vitro; its potential for the treatment of biofilm-associated infections of Staphylococcus spp. or Enterococcus faecalis is thus apparent.

• MeSH
• antibakteriální látky farmakologie   MeSH
• antioxidancia farmakologie   MeSH
• biofilmy účinky léků   růst a vývoj   MeSH
• Enterococcus faecalis účinky léků   MeSH
• gramnegativní bakterie účinky léků   MeSH
• grampozitivní bakterie účinky léků   MeSH
• grampozitivní koky účinky léků   MeSH
• listy rostlin chemie   MeSH
• mikrobiální testy citlivosti MeSH
• Pseudomonas aeruginosa účinky léků   MeSH
• rostlinné extrakty farmakologie   MeSH
• Staphylococcus epidermidis účinky léků   MeSH
• stilbeny farmakologie   MeSH
• Vitis chemie   MeSH
• Publikační typ
• časopisecké články MeSH

A phytochemical study of the root and bark of Brucea antidysenterica J. F. Mill. (Simaroubaceae) afforded three new compounds, including a stilbene glycoside bruceanoside A (1), and two canthinone alkaloids bruceacanthinones A (3) and B (4), along with ten known secondary metabolites, rhaponticin (2), 1,11-dimethoxycanthin-6-one (5), canthin-6-one (6), 1-methoxycanthin-6-one (7), 2-methoxycanthin-6-one (8), 2-hydroxy-1,11-dimethoxycanthin-6-one (9), β-carboline-1-propionic acid (10), cleomiscosin C (11), cleomiscosin A (12), and hydnocarpin (13). The structures of all the compounds were determined using spectrometric and spectroscopic methods including 1D and 2D NMR, and HRSEIMS. The identities of the known compounds were further confirmed by comparison of their data with those reported in the literature. The root and bark methanolic extracts, the dichloromethane and ethyl acetate soluble fractions, and the isolated compounds (3-13), were assessed for their cytotoxicity against the cancer cell lines A-549, MCF-7, and PC-3. The results suggested that compounds in the extracts might possess a synergic action in their cytotoxicity.

• MeSH
• alkaloidy chemie   farmakologie   MeSH
• antitumorózní látky fytogenní chemie   farmakologie   MeSH
• Brucea chemie   MeSH
• buňky A549 MeSH
• buňky PC-3 MeSH
• léky rostlinné čínské chemie   farmakologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• molekulární struktura MeSH
• proliferace buněk účinky léků   MeSH
• rostlinné extrakty chemie   farmakologie   MeSH
• sekundární metabolismus MeSH
• stilbeny chemie   farmakologie   MeSH
• synergismus léků MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Resveratrol (RSV) is a stilbene phytochemical common in food and red wine. RSV inhibits cytochrome P450 CYP3A4 activity and interacts with the pregnane X receptor (PXR), the central regulator of drug/xenobiotic metabolizing enzyme expression. In this work, we comprehensively examined the effects of 13 stilbenes (trans- and cis-resveratrol, trans- and cis-piceatannol, oxyresveratrol, pterostilbene, pinostilbene, a,b-dihydroresveratrol, trans- and cis-trismethoxyresveratrol, trans-3,4,5,4'-tetramethoxystilbene, trans-2,4,3',5'-tetramethoxystilbene, trans-4-methoxystilbene), on CYP3A4 and CYP2B6 mRNA induction, and on CYP3A4/5, CYP2C8/9/19, CYP2D6, CYP2A6, CYP2E1, CYP1A2 and CYP2B6 cytochrome P450 enzyme activities. Expression experiments in five different primary human hepatocyte preparations, reporter gene assays, and ligand binding assays with pregnane X (PXR) and constitutive androstane (CAR) receptors were performed. Inhibition of cytochrome P450 enzymes was examined in human microsomes. We found that only polymethoxylated stilbenes are prone to significantly induce CYP2B6 or CYP3A4 in primary human hepatocytes via pregnane X receptor (PXR) interaction. Natural resveratrol derivatives such as trans- and cis-RSV, oxyresveratrol, pinostilbene and pterostilbene significantly inhibit CYP3A4/5 enzymatic activities; however, only trans-RSV significantly inhibits CYP3A4/5 activity (both testosterone 6β-hydroxylation and midazolam 1´-hydroxylation) in micromolar concentrations by a non-competitive mechanism, suggesting a potential risk of food-drug interactions with CYP3A4/5 substrates.

• MeSH
• hepatocyty účinky léků   MeSH
• inhibitory cytochromu P450 metabolismus   MeSH
• interakce mezi potravou a léky * MeSH
• kultivované buňky MeSH
• lidé MeSH
• resveratrol MeSH
• steroidní receptory metabolismus   MeSH
• stilbeny metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The stilbenoids, a group of naturally occurring phenolic compounds, are found in a variety of plants, including some berries that are used as food or for medicinal purposes. They are known to be beneficial for human health as anti-inflammatory, chemopreventive, and antioxidative agents. We have investigated a group of 19 stilbenoid substances in vitro using a cellular model of THP-1 macrophage-like cells and pyocyanin-induced oxidative stress to evaluate their antioxidant or pro-oxidant properties. Then we have determined any effects that they might have on the expression of the enzymes catalase, glutathione peroxidase, and heme oxygenase-1, and their effects on the activation of Nrf2. The experimental results showed that these stilbenoids could affect the formation of reactive oxygen species in a cellular model, producing either an antioxidative or pro-oxidative effect, depending on the structure pinostilbene (2) worked as a pro-oxidant and also decreased expression of catalase in the cell culture. Piceatannol (4) had shown reactive oxygen species (ROS) scavenging activity, whereas isorhapontigenin (18) had a mild direct antioxidant effect and activated Nrf2-antioxidant response element (ARE) system and elevated expression of Nrf2 and catalase. Their effects shown on cells in vitro warrant their further study in vivo.

• MeSH
• antioxidační responzivní elementy účinky léků   MeSH
• antioxidancia chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• faktor 2 související s NF-E2 genetika   MeSH
• lidé MeSH
• peroxidace lipidů účinky léků   MeSH
• pyokyanin chemie   MeSH
• stilbeny chemie   farmakologie   MeSH
• thiobarbituráty chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Combretastatin A-4 (CA-4) is a highly cytotoxic natural product and several derivatives have been prepared which underwent clinical trial. These investigations revealed that the cis-stilbene moiety of the natural product is prone to undergo cis/trans isomerization under physiological conditions, reducing the overall activity of the drug candidates. Herein, we report the preparation of cis-restrained carbocyclic analogs of CA-4. The compounds, which differ by the size and hybridization of the carbocyclic ring have been evaluated for their cytotoxic properties and their ability to inhibit tubulin polymerization. Biological data, supported by molecular docking studies, identified cyclobutenyl and cyclobutyl derivatives of the natural product as highly promising drug candidates.

• MeSH
• antitumorózní látky chemická syntéza   metabolismus   farmakologie   MeSH
• kontrolní body fáze G2 buněčného cyklu účinky léků   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• modulátory tubulinu chemická syntéza   metabolismus   farmakologie   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• simulace molekulového dockingu MeSH
• stilbeny chemická syntéza   metabolismus   farmakologie   MeSH
• tubulin metabolismus   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Stilbenoids are important components of foods (e.g., peanuts, grapes, various edible berries), beverages (wine, white tea), and medicinal plants. Many publications have described the anti-inflammatory potential of stilbenoids, including the widely known trans-resveratrol and its analogues. However, comparatively little information is available regarding the activity of their prenylated derivatives. One new prenylated stilbenoid (2) was isolated from Artocarpus altilis and characterized structurally based on 1D and 2D NMR analysis and HRMS. Three other prenylated stilbenoids were prepared synthetically (9-11). Their antiphlogistic potential was determined by testing them together with known natural prenylated stilbenoids from Macaranga siamensis and Artocarpus heterophyllus in both cell-free and cell assays. The inhibition of 5-lipoxygenase (5-LOX) was also shown by simulated molecular docking for the most active stilbenoids in order to elucidate the mode of interaction between these compounds and the enzyme. Their effects on the pro-inflammatory nuclear factor-κB (NF-κB) and the activator protein 1 (AP-1) signaling pathway were also analyzed. The THP1-XBlue-MD2-CD14 cell line was used as a model for determining their anti-inflammatory potential, and lipopolysaccharide (LPS) stimulation of Toll-like receptor 4 induced a signaling cascade leading to the activation of NF-κB/AP-1. The ability of prenylated stilbenoids to attenuate the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was further evaluated using LPS-stimulated THP-1 macrophages.

• MeSH
• buněčné linie MeSH
• cyklooxygenasy metabolismus   MeSH
• inhibitory enzymů farmakologie   MeSH
• lidé MeSH
• lipoxygenasy metabolismus   MeSH
• NF-kappa B antagonisté a inhibitory   MeSH
• prenylace * MeSH
• signální transdukce účinky léků   MeSH
• stilbeny farmakologie   MeSH
• transkripční faktor AP-1 antagonisté a inhibitory   MeSH
• zánět prevence a kontrola   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The constitutive androstane receptor(CAR) activation is connected with mitogenic effects leading to liver hyperplasia and tumorigenesis in rodents. CAR activators, including phenobarbital, are considered rodent non-genotoxic carcinogens. Recently, trans-3,4,5,4´-tetramethoxystilbene(TMS), a potential anticancer drug (DMU-212), have been shown to alleviate N-nitrosodiethylamine/phenobarbital-induced liver carcinogenesis. We studied whether TMS inhibits mouse Car to protect from the PB-induced tumorigenesis. Unexpectedly, we identified TMS as a murine CAR agonist in reporter gene experiments, in mouse hepatocytes, and in C57BL/6 mice in vivo. TMS up-regulated Car target genes Cyp2b10, Cyp2c29 and Cyp2c55 mRNAs, but down-regulated expression of genes involved in gluconeogenesis and lipogenesis. TMS did not change or down-regulate genes involved in liver proliferation or apoptosis such as Mki67, Foxm1, Myc, Mcl1, Pcna, Bcl2, or Mdm2, which were up-regulated by another Car ligand TCPOBOP. TMS did not increase liver weight and had no significant effect on Ki67 and Pcna labeling indices in mouse liver in vivo. In murine hepatic AML12 cells, we confirmed a Car-independent proapoptotic effect of TMS. We conclude that TMS is a Car ligand with limited effects on hepatocyte proliferation, likely due to promoting apoptosis in mouse hepatic cells, while controlling Car target genes involved in xenobiotic and endobiotic metabolism.

• MeSH
• antikarcinogenní látky metabolismus   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• aromatické hydroxylasy genetika   metabolismus   MeSH
• buňky Hep G2 MeSH
• glukoneogeneze účinky léků   genetika   MeSH
• hepatocyty účinky léků   metabolismus   patologie   MeSH
• játra účinky léků   metabolismus   MeSH
• lidé MeSH
• lipogeneze účinky léků   genetika   MeSH
• myši inbrední C57BL MeSH
• nádory jater enzymologie   genetika   patologie   prevence a kontrola   MeSH
• proliferace buněk účinky léků   MeSH
• pyridiny farmakologie   MeSH
• receptory cytoplazmatické a nukleární agonisté   genetika   metabolismus   MeSH
• regulace genové exprese enzymů účinky léků   MeSH
• rodina 2 cytochromů P450 genetika   metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• simulace molekulového dockingu MeSH
• steroidhydroxylasy genetika   metabolismus   MeSH
• stilbeny metabolismus   farmakologie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH