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
- Cell Line MeSH
- Prostaglandin-Endoperoxide Synthases metabolism MeSH
- Enzyme Inhibitors pharmacology MeSH
- Humans MeSH
- Lipoxygenases metabolism MeSH
- NF-kappa B antagonists & inhibitors MeSH
- Prenylation * MeSH
- Signal Transduction drug effects MeSH
- Stilbenes pharmacology MeSH
- Transcription Factor AP-1 antagonists & inhibitors MeSH
- Inflammation prevention & control MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Dietary exposure to aflatoxin B1 (AFB1) is harmful to the health and performance of domestic animals. The hepatic cytochrome P450s (CYPs), CYP1A1 and CYP2A6, are the primary enzymes responsible for the bioactivation of AFB1 to the highly toxic exo-AFB1-8,9-epoxide (AFBO) in chicks. However, the transcriptional regulation mechanism of these CYP genes in the liver of chicks in AFB1 metabolism remains unknown. Dual-luciferase reporter assay, bioinformatics and site-directed mutation results indicated that specificity protein 1 (SP1) and activator protein-1 (AP-1) motifs were located in the core region -1,063/-948, -606/-541 of the CYP1A1 promoter as well as -636/-595, -503/-462, -147/-1 of the CYP2A6 promoter. Furthermore, overexpression and decoy oligodeoxynucleotide technologies demonstrated that SP1 and AP-1 were pivotal transcriptional activators regulating the promoter activity of CYP1A1 and CYP2A6. Moreover, bioactivation of AFB1 to AFBO could be increased by upregulation of CYP1A1 and CYP2A6 expression, which was trans-activated owing to the upregulalion of AP-1, rather than SP1, stimulated by AFB1-induced reactive oxygen species. Additionally, nano-selenium could reduce ROS, downregulate AP-1 expression and then decrease the expression of CYP1A1 and CYP2A6, thus alleviating the toxicity of AFB1. In conclusion, AP-1 and SP1 played important roles in the transactivation of CYP1A1 and CYP2A6 expression and further bioactivated AFB1 to AFBO in chicken liver, which could provide novel targets for the remediation of aflatoxicosis in chicks.
- MeSH
- Aflatoxin B1 * metabolism MeSH
- Transcriptional Activation MeSH
- Cytochrome P-450 CYP1A1 * genetics metabolism MeSH
- Cytochrome P-450 CYP2A6 * metabolism genetics MeSH
- Liver * metabolism MeSH
- Chickens * metabolism MeSH
- Promoter Regions, Genetic * MeSH
- Transcription Factor AP-1 * metabolism genetics MeSH
- Sp1 Transcription Factor * metabolism genetics MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
Here we report the comprehensive characterization of the secondary metabolites from the leaves of Colebrookea oppositifolia Smith, a species used as medicinal plant in the traditional medicine of Nepal. Phytochemical screening of bioactives was performed using an integrated LC-MSn and high resolution MS (Mass Spectrometry) approach. Forty-three compounds were tentatively identified, mainly aglyconic and glycosilated flavonoids and phenolic acids, as well as other bioactives such as coumarins and terpenes were detected. Furthermore, the NF-κB and AP-1 inhibitory activity of C. oppositifolia extract were evaluated, as well as its cytotoxicity against THP-1 cells, in order to assess the potential use of this herb as a source of anti-inflammatory and cytotoxic compounds. The results so far obtained indicate that C. oppositifolia leaves extract could significantly reduce the viability of THP-1 cells (IC50 = 6.2 ± 1.2 µg/mL), as well as the activation of both NF-κB and AP-1 at the concentration of 2 μg/mL. Our results indicate that Nepalese C. oppositifolia is a valuable source of anti-inflammatory and cytotoxic compounds. The phytochemical composition reported here can partially justify the traditional uses of C. oppositifolia in Nepal, especially in the treatment of inflammatory diseases, although further research will be needed to assess the full potential of this species.
- MeSH
- Anti-Inflammatory Agents isolation & purification pharmacology toxicity MeSH
- Chromatography, Liquid MeSH
- Flavonoids analysis isolation & purification MeSH
- Lamiaceae metabolism MeSH
- Mass Spectrometry MeSH
- Hydroxybenzoates analysis isolation & purification MeSH
- Plants, Medicinal metabolism MeSH
- Humans MeSH
- Plant Leaves metabolism MeSH
- Metabolome MeSH
- Methanol MeSH
- NF-kappa B antagonists & inhibitors MeSH
- Plant Extracts chemistry isolation & purification pharmacology toxicity MeSH
- THP-1 Cells MeSH
- Transcription Factor AP-1 antagonists & inhibitors MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Nepal MeSH
Hypericum japonicum Thunb. ex Murray is traditionally used in Nepal to treat several diseases, among whom inflammation and acute pain. Although several secondary metabolites from the same Hypericum species have been already characterized and considered for their pharmacological use, an exhaustive phytochemical characterization of H. japonicum from Nepal is lacking, as well as the assessment of its potential pharmacological properties. Hence, the aims of this study were the characterization of a methanolic extract of H. japonicum (HJME) collected from the Northern region of Nepal by LC-MSn and UPLC-QTOF. The assessment of in vitro inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1) transcription factors and HJME's cytotoxic effect on human cell lines was performed to evaluate the potential use of this herb as a source of anti-inflammatory and cytotoxic lead compounds. Fifty-seven phytoconstituents were identified, being mainly flavonoids, phloroglucinols, phenolic acids and xanthones. Although compounds characteristic of H. japonicum were detected (quercetin, quercetin-7-O-α-l-rhamnoside, quercitrin and hyperoside), several others are here reported for the first time in this species. The results from bioassays indicated that HJME could significantly reduce the viability of human THP-1 cells (IC50 = 5.4 ± 1.1 μg mL-1), showing the promising potential of HJME as anti-tumor agent. Furthermore, HJME significantly decreased the activation of both NF-κB and AP-1 at the concentration of 2 μg mL-1. Overall, these data suggest that H. japonicum from Nepal could be used as a source of potential natural anti-inflammatory and anti-tumor lead compounds.
- MeSH
- Anti-Inflammatory Agents pharmacology MeSH
- Biological Assay MeSH
- Cell Line MeSH
- Chromatography, Liquid MeSH
- Flavonoids pharmacology MeSH
- Phloroglucinol pharmacology MeSH
- Mass Spectrometry MeSH
- Hydroxybenzoates pharmacology MeSH
- Inhibitory Concentration 50 MeSH
- Humans MeSH
- NF-kappa B p50 Subunit antagonists & inhibitors MeSH
- Antineoplastic Agents pharmacology MeSH
- Plant Extracts pharmacology MeSH
- THP-1 Cells MeSH
- Transcription Factor AP-1 antagonists & inhibitors MeSH
- Hypericum chemistry MeSH
- Cell Survival MeSH
- Xanthones pharmacology MeSH
- Inflammation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Nepal MeSH
75 s. ; 29 cm
