Protein prenylation is one of the most important posttranslational modifications of proteins. Prenylated proteins play important roles in different developmental processes as well as stress responses in plants as the addition of hydrophobic prenyl chains (mostly farnesyl or geranyl) allow otherwise hydrophilic proteins to operate as peripheral lipid membrane proteins. This review focuses on selected aspects connecting protein prenylation with plant responses to both abiotic and biotic stresses. It summarizes how changes in protein prenylation impact plant growth, deals with several families of proteins involved in stress response and highlights prominent regulatory importance of prenylated small GTPases and chaperons. Potential possibilities of these proteins to be applicable for biotechnologies are discussed.

• MeSH
• biotechnologie MeSH
• fyziologický stres * MeSH
• prenylace proteinů * MeSH
• rostlinné proteiny metabolismus   MeSH
• rostliny metabolismus   MeSH
• substrátová specifita MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Natural phenolics are secondary plant metabolites, which can be divided into several categories with the common structural feature of phenolic hydroxyl. The biological activity of phenolics is often modified and enhanced by prenylation by prenyl and geranyl; higher terpenoid chains are rare. The type of prenyl connection and modification affects their biological activity. OBJECTIVE: This review summarizes information about prenylated phenols and some of their potential sources, and provides an overview of their anti-inflammatory potential in vitro and in vivo. METHOD: The literature search was performed using SciFinder and keywords prenyl, phenol, and inflammation. For individual compounds, an additional search was performed to find information about further activities and mechanisms of effects. RESULT: We summarized the effects of prenylated phenolics in vitro in cellular or biochemical systems on the production and release of inflammation-related cytokines; their effects on inhibition of cyclooxygenases and lipoxygenases; the effects on production of nitric oxide, antiradical and antioxidant activity; and the effect on the inhibition of the release of enzymes and mediators from neutrophils, mast cells and macrophages. The information about the antiphlogistic potential of prenylated phenolics is further supported by a review of their action in animal models. CONCLUSION: Almost 400 prenylated phenols were reviewed to overview their antiinflammatory effect. The bioactivity of several prenylated phenols was confirmed also using in vivo assays. A pool of natural prenylated phenols represents a source of inspiration for synthesis, and prenylated phenols as components of various medicinal plants used to combat inflammation could be their active principles.

• MeSH
• antiflogistika chemie   farmakologie   MeSH
• fenoly chemie   farmakologie   MeSH
• léčivé rostliny MeSH
• lidé MeSH
• molekulární struktura MeSH
• prenylace MeSH
• rostlinné extrakty chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Tento přehledový příspěvek se zabývá cytotoxickou a antiproliferativní aktivitou 57 prenylovaných fenolů izolovaných z Morus alba. Prenylovaný postranní řetězec, který může být různě modifikován, zvyšuje lipofilitu látek, čímž zlepšuje jejich prostupnost biologickými membránami a vede tak ke zvýšení biologické dostupnosti. Cílem byla snaha popsat vztah mezi strukturou prenylovaných fenolů a jejich cytotoxickým účinkem a objasnit různé mechanismy, kterými cytotoxické prenylované fenoly indukují apoptosu. Závěry ukázaly, že se cytotoxicita látek zvyšuje s rostoucím počtem prenylovaných postranních řetězců a ketalových skupin. Modifikace prenylovaného postranního řetězce, jako je například hydroxylace, cytotoxicitu naopak snižuje. Cytotoxickou aktivitu ovlivňuje také přítomnost prenylových a hydroxylových skupin ve specifických polohách.

This review deals with cytotoxic and antiproliferative activity of fifty seven prenylated phenols isolated from Morus alba. Prenyl side chain, which can be variously modified, increases lipophilicity of the substances, thereby improving their penetration through biological membranes and thus results in an increased bioavailability. The objective was to describe the relationship between structure of the prenylated phenols and their cytotoxic effect and to clarify various mechanisms by which cytotoxic prenylated phenols induce apoptosis. The conclusions showed that the cytotoxicity of the substances increases with increasing number of the prenyl side chains and ketal groups. Conversely, modification of the prenyl side chain, such as hydroxylation, reduces cytotoxicity. The cytotoxic activity is also influenced by the presence of prenyl and hydroxyl groups at specific positions.

• Klíčová slova
• prenylované fenoly, Morus alba,
• MeSH
• antitumorózní látky * terapeutické užití   MeSH
• fenoly terapeutické užití   MeSH
• léčivé rostliny MeSH
• lidé MeSH
• Morus * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Morusin is a prenylated flavonoid isolated from the root bark of Morus alba. Many studies have shown the ability of flavonoids to act as anti-inflammatory agents. The aim of this study was to evaluate the effect of morusin on experimentally colitis induced by 2,4,6-trinitrobenzensulfonic acid in Wistar rats and to compare it with sulfasalazine, a drug conventionally used in the treatment of inflammatory bowel disease. Morusin was administered by gavage at doses of 12.5, 25, or 50 mg/kg/day for five days. The colonic tissue was evaluated macroscopically, histologically, and by performing immunodetection and zymographic analysis to determine the levels of antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)], interleukin (IL)-1β, and transforming growth factor (TGF)-β1 and the activities of matrix metalloproteinases (MMP) 2 and 9. The tissue damage scores were significantly reduced with increasing dose of morusin, however efficacy was not demonstrated at the highest dose. At the dose of 12.5 mg/kg, morusin exerted therapeutic effectivity similar to that of sulfasalazine (50 mg/kg). This was associated with significant reduction of TGF-β1 levels and MMP2 and MMP9 activities, and slight reduction of IL-1β. Our results suggest that morusin possesses therapeutic potential for the treatment of chronic inflammatory diseases.

• MeSH
• flavonoidy farmakologie   MeSH
• kolitida chemicky indukované   enzymologie   prevence a kontrola   MeSH
• kolon účinky léků   enzymologie   patologie   MeSH
• kyselina trinitrobenzensulfonová MeSH
• matrixová metaloproteinasa 2 metabolismus   MeSH
• potkani Wistar MeSH
• prenylace MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články 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

Chromatographic separation of root extracts of Morus alba and M. nigra led to the identification of the 2-arylbenzofurans moracin C (1), mulberrofuran Y (2), and mulberrofuran H (3), and the prenylated flavonoids kuwanon E (4), kuwanon C (5), sanggenon H (6), cudraflavone B (7), and morusinol (8), and the Diels-Alder adducts soroceal (9), and sanggenon E (10). The cytotoxicity and their antiphlogistic activity, determined as the attenuation of the secretion of TNF-α and IL-1β and the inhibition of NF-κB nuclear translocation in LPS-stimulated macrophages, were evaluated for compounds 1-10.

• MeSH
• antiflogistika farmakologie   MeSH
• benzofurany chemie   izolace a purifikace   farmakologie   MeSH
• benzopyrany chemie   izolace a purifikace   farmakologie   MeSH
• flavonoidy chemie   izolace a purifikace   farmakologie   MeSH
• kořeny rostlin chemie   MeSH
• kůra rostlin chemie   MeSH
• lidé MeSH
• lipopolysacharidy farmakologie   MeSH
• makrofágy účinky léků   MeSH
• molekulární struktura MeSH
• Morus chemie   MeSH
• myši MeSH
• NF-kappa B účinky léků   MeSH
• prenylace MeSH
• TNF-alfa farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In this study, four prenylated and geranylated flavonoids, cudraflavone B (1), pomiferin (2), osajin (3), and diplacone (4), were tested for their antioxidant and anti-inflammatory effects and to identify any potential relationships between chemical structure and antioxidant or anti-inflammatory properties. The selected flavonoids were examined in cell-free models to prove their ability to scavenge superoxide radicals, hydrogen peroxide, and hypochlorous acid. Further, the ability of the flavonoids to influence the formation of reactive oxygen species in the murine macrophage cell line J774.A1 was tested in the presence and absence of lipopolysaccharide (LPS). The ability of flavonoids to inhibit LPS-induced IκB-α degradation and COX-2 expression was used as a model for the inflammatory response. The present results indicated that the antioxidant activity was dependent on the chemical structure, where the catechol moiety is especially crucial for this effect. The most potent antioxidant activities in cell-free models were observed for diplacone (4), whereas cudraflavone B (1) and osajin (3) showed a pro-oxidant effect in J774.A1 cells. All flavonoids tested were able to inhibit IκB-α degradation, but only diplacone (4) also down-regulated COX-2 expression.

• MeSH
• antiflogistika farmakologie   MeSH
• antioxidancia farmakologie   MeSH
• benzopyrany chemie   farmakologie   MeSH
• cyklooxygenasa 2 účinky léků   MeSH
• flavonoidy chemie   farmakologie   MeSH
• inhibitory cyklooxygenasy farmakologie   MeSH
• isoflavony chemie   farmakologie   MeSH
• kinasa I-kappa B antagonisté a inhibitory   MeSH
• lipopolysacharidy farmakologie   MeSH
• makrofágy účinky léků   MeSH
• myši MeSH
• oxid dusnatý biosyntéza   MeSH
• prenylace MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The review presents prenylated flavonoids as potential therapeutic agents for the treatment of topical skin infections and wounds, as they can restore the balance in the wound microenvironment. A thorough two-stage search of scientific papers published between 2000 and 2022 was conducted, with independent assessment of results by two reviewers. The main criteria were an MIC (minimum inhibitory concentration) of up to 32 μg/mL, a microdilution/macrodilution broth method according to CLSI (Clinical and Laboratory Standards Institute) or EUCAST (European Committee on Antimicrobial Susceptibility Testing), pathogens responsible for skin infections, and additional antioxidant, anti-inflammatory, and low cytotoxic effects. A total of 127 structurally diverse flavonoids showed promising antimicrobial activity against pathogens affecting wound healing, predominantly Staphylococcus aureus strains, but only artocarpin, diplacone, isobavachalcone, licochalcone A, sophoraflavanone G, and xanthohumol showed multiple activity, including antimicrobial, antioxidant, and anti-inflammatory along with low cytotoxicity important for wound healing. Although prenylated flavonoids appear to be promising in wound therapy of humans, and also animals, their activity was measured only in vitro and in vivo. Future studies are, therefore, needed to establish rational dosing according to MIC and MBC (minimum bactericidal concentration) values, test potential toxicity to human cells, measure healing kinetics, and consider formulation in smart drug release systems and/or delivery technologies to increase their bioavailability.

• MeSH
• antibakteriální látky farmakologie   MeSH
• antiinfekční látky * farmakologie   MeSH
• antioxidancia * farmakologie   MeSH
• flavonoidy farmakologie   MeSH
• hojení ran MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy 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

Antimicrobial resistance is a public health threat and the increasing number of multidrug-resistant bacteria is a major concern worldwide. Common antibiotics are becoming ineffective for skin infections and wounds, making the search for new therapeutic options increasingly urgent. The present study aimed to investigate the antibacterial potential of prenylated phenolics in wound healing. Phenolic compounds isolated from the root bark of Morus alba L. were investigated for their antistaphylococcal potential both alone and in combination with commonly used antibiotics. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) were determined by microdilution and agar method. Synergy was investigated using the checkerboard titration technique. Membrane-disrupting activity and efflux pump inhibition were evaluated to describe the potentiating effect. Prenylated phenolics inhibited bacterial growth of methicillin-resistant Staphylococcus aureus (MRSA) at lower concentrations (MIC 2-8 μg/ml) than commonly used antibiotics. The combination of active phenolics with kanamycin, oxacillin, and ciprofloxacin resulted in a decrease in the MIC of the antimicrobial agent. Kuwanon C, E, T, morusin, and albafuran C showed synergy (FICi 0.375-0.5) with oxacillin and/or kanamycin. Prenylated phenolics disrupted membrane permeability statistically significantly (from 28 ± 16.48% up to 73 ± 2.83%), and membrane disruption contributes to the complex antibacterial activity against MRSA. In addition, kuwanon C could be considered an efflux pump inhibitor. Despite the antibacterial effect on MRSA and the multiple biological activities, the prenylated phenolics at microbially significant concentrations have a minor effect on human keratinocyte (HaCaT) viability. In conclusion, prenylated phenolics in combination with commonly used antibiotics are promising candidates for the treatment of MRSA infections and wound healing, although further studies are needed.

• Publikační typ
• časopisecké články MeSH