Parallel in vitro and in silico investigations into anti-inflammatory effects of non-prenylated stilbenoids

Leláková, Veronika; Šmejkal, Karel; Jakubczyk, Karolina; Veselý, Ondřej; Landa, Přemysl; Václavík, Jiří; Bobáľ, Pavel; Pizova, Hana; Temml, Veronika; Steinacher, Theresa; Schuster, Daniela; Granica, Sebastian; Hanáková, Zuzana; Hošek, Jan

doi:10.1016/j.foodchem.2019.01.128

Cited by 33 publications

(28 citation statements)

References 60 publications

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“…The level of IkB and the amount of activated (phosphorylated) mitogen-activated protein (MAP) kinase p38, ERK1/2, and JNK was determined on the THP1-Blue™ NF-κB, in a way similar to that described previously [53]. Briefly, cells cultivated in serum-free medium were pretreated with the tested compounds (8, 17, cinnamic acid, or prednisone) at concentration 2 µM.…”

Section: Signaling Pathway Analysismentioning

confidence: 99%

Investigation of Anti-Inflammatory Potential of N-Arylcinnamamide Derivatives

et al. 2019

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A series of sixteen ring-substituted N-arylcinnamanilides, previously described as highly antimicrobially effective against a wide spectrum of bacteria and fungi, together with two new derivatives from this group were prepared and characterized. Moreover, the molecular structure of (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide as a model compound was determined using single-crystal X-ray analysis. All the compounds were tested for their anti-inflammatory potential, and most tested compounds significantly attenuated the lipopolysaccharide-induced NF-κB activation and were more potent than the parental cinnamic acid. (2E)-N-[2-Chloro-5-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide, (2E)-N-(2,6-dibromophenyl)-3-phenylprop-2-enamide, and (2E)-N-(2,5-dichlorophenyl)-3-phenylprop-2-enamide demonstrated the highest inhibition effect on transcription factor NF-κB at the concentration of 2 µM and showed a similar effectiveness as the reference drug prednisone. Several compounds also decreased the level of TNF-α. Nevertheless, subsequent tests showed that the investigated compounds affect neither IκBα level nor MAPKs activity, which suggests that the N-arylcinnamanilides may have a different mode of action to prednisone. The modification of the C (2,5) or C (2,6) positions of the anilide core by rather lipophilic and bulky moieties seems to be preferable for the anti-inflammatory potential of these compounds.Molecules 2019, 24, 4531 2 of 15 drugs are directly obtained from plants or fungi or are "nature-inspired" [11]. One such molecule is cinnamic acid (CA). It is a small organic molecule, which can be found in many kinds of plants in pure form or as a part of more complicated structures. CA and its natural and synthetic derivatives possess many interesting biological effects, such as antimicrobial [12,13], anticancer [14], anti-oxidant [13], and anti-inflammatory activities [15].N-Arylcinnamides represent a group of synthetic derivatives of CA. This group of compounds possesses several potentially active moieties-styryl, amide (peptide-like [16]) bond, and aryl [17][18][19][20][21][22]. Thus, cinnamides can be considered as a privilege structure or a scaffold (a part) of more complex molecules in medicinal chemistry [23,24] The series of N-arylcinnamide derivatives presented in this work was previously tested for their anti-microbial activity (compounds 1-15 and 17) [25,26], and three new derivatives 16 and 18 were prepared and characterized. Based on the concepts of polypharmacology, multifactorial diseases, and multitarget drugs [27], as well as the above-mentioned results, a group of eighteen N-arylcinnamanilides was chosen for the screening of their ability to moderate the inflammation-like reaction in vitro. Results and Discussion ChemistryThe investigated compounds (previously published compounds 1-15 and 17 [25] and two new compounds, 16 and 18) were prepared using a one-step microwave-assisted synthesis, see Scheme 1. Briefly, the carboxyl group of CA was activated with phosphorus trichloride, and then...

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Section: Signaling Pathway Analysismentioning

confidence: 99%

Investigation of Anti-Inflammatory Potential of N-Arylcinnamamide Derivatives

et al. 2019

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“…Resveratrol (3,4′,5-trihydroxystilbene) is the most studied stilbenoid, and is commonly associated with the French paradox, where resveratrol is thought to lower the incidence of coronary heart disease, despite a high intake of saturated fat in the French population [2]. In mice studies, both in vitro and in vivo, resveratrol has shown strong anti-inflammatory activity by a reduction of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), an increase of interleukin 10 (IL-10), and a reduced expression of prostaglandin E synthase-1 (PGES-1), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) [3,4]. Therefore, stilbenoid could act as an anti-inflammatory agent through some of the same mechanisms as nonsteroidal antiphlogistic drugs.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of Stilbenoids by Human Faecal Microbiota

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Stilbenoids are dietary phenolics with notable biological effects on humans. Epidemiological, clinical, and nutritional studies from recent years have confirmed the significant biological effects of stilbenoids, such as oxidative stress protection and the prevention of degenerative diseases, including cancer, cardiovascular diseases, and neurodegenerative diseases. Stilbenoids are intensively metabolically transformed by colon microbiota, and their corresponding metabolites might show different or stronger biological activity than their parent molecules. The aim of the present study was to determine the metabolism of six stilbenoids (resveratrol, oxyresveratrol, piceatannol, thunalbene, batatasin III, and pinostilbene), mediated by colon microbiota. Stilbenoids were fermented in an in vitro faecal fermentation system using fresh faeces from five different donors as an inoculum. The samples of metabolized stilbenoids were collected at 0, 2, 4, 8, 24, and 48 h. Significant differences in the microbial transformation among stilbene derivatives were observed by liquid chromatography mass spectrometry (LC/MS). Four stilbenoids (resveratrol, oxyresveratrol, piceatannol and thunalbene) were metabolically transformed by double bond reduction, dihydroxylation, and demethylation, while batatasin III and pinostilbene were stable under conditions simulating the colon environment. Strong inter-individual differences in speed, intensity, and pathways of metabolism were observed among the faecal samples obtained from the donors.

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“…In order to measure the fluorescent probe 2´,7´-dichlorodihydrofluorescein diacetate (DCFH-DA) was introduced to the cell culture, where it was immediately deesterified to form 2´,7´-dichlorodihydrofluorescein, which then causes fluorescence when it was oxidized by ROS [10]. The compounds and standard of quercetin [6] (Koch Light Laboratories, Haverhill, UK) were tested at a final concentration of 2 μM, which previous cytotoxicity tests revealed as non-toxic for all of these compounds [3]. Stock solutions (20 mM) of the test compounds were prepared by dilution with DMSO, and stored frozen at −80 °C.…”

Section: Methodsmentioning

confidence: 99%

“…This stilbenoid has been the focus of thousands of studies in recent years and has been shown to possess a promising potential for interactions with many cellular components. Its antiaging, anti-inflammatory, antioxidant, and immunomodulatory properties [2,3] have inspired clinical studies and trans -resveratrol ( 1 ) is currently described as a compound that is beneficial for the treatment of inflammatory diseases, metabolic syndrome, type 2 diabetes, and cardiovascular diseases. However, its relatively low bioavailability and rapid metabolism in vivo make the efficacy of this compound uncertain and reveal the need to investigate stilbenoid derivatives with greater activities [4].…”

Section: Introductionmentioning

confidence: 99%

“…Based on our previous results concerning anti-inflammatory activity (effect of lipopolysaccharide (LPS)-stimulated activation of nuclear factor κB/activator protein 1 (NF-κB/AP-1) and also subsequent signaling pathways) [3], we have tested 19 stilbenoid derivatives in the cell model THP-1-XBlue-CD14-MD2. We observed the production of reactive oxygen species (ROS) at the basal level and after stimulation with pyocyanin [5] after short- and long-termed exposure to determine any possible antioxidative and pro-oxidative effects, and compare its effects with quercetin [6].…”

Section: Introductionmentioning

confidence: 99%

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Antioxidant Activity of Selected Stilbenoid Derivatives in a Cellular Model System

et al. 2019

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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.

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Parallel in vitro and in silico investigations into anti-inflammatory effects of non-prenylated stilbenoids

Cited by 33 publications

References 60 publications

Investigation of Anti-Inflammatory Potential of N-Arylcinnamamide Derivatives

Investigation of Anti-Inflammatory Potential of N-Arylcinnamamide Derivatives

Metabolism of Stilbenoids by Human Faecal Microbiota

Antioxidant Activity of Selected Stilbenoid Derivatives in a Cellular Model System

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