Chiral flavanones from Amygdalus lycioides Spach: structural elucidation and identification of TNFalpha inhibitors by bioactivity-guided fractionation.
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ABSTRACT:
SUBMITTER: Gaggeri R
PROVIDER: S-EPMC6268923 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Nandinadomestica (Berberidaceae) has been used in traditional medicine for the treatment of cough. This plant is distributed in Korea, Japan, China, and India This study aimed to investigate the anti-inflammatory phytochemicals obtained from the N. domestica fruits. We isolated a biflavonoid-type phytochemical, robustaflavone (R), from N. domestica fruits through bioactivity-guided fractionation based on its capacity to inhibit inflammation. The anti-inflammatory mechanism of R isolated from N. domestica has not yet been studied. In the present study, we evaluated the anti-inflammatory activities of R using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We have shown that R reduces the production of nitric oxide (NO), pro-inflammatory cytokine interleukin-1 beta (IL-1β), and IL-6. Western blot analysis showed that R suppresses the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and downregulates the expression of LPS-induced nuclear factor-kappa B (NF-κB) and the phosphorylation of extracellular-regulated kinases (pERK 1/2). Moreover, R inhibited IL-8 release in LPS-induced human colonic epithelial cells (HT-29). These results suggest that R could be a potential therapeutic candidate for inflammatory bowel disease (IBD).
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Project description:OBJECTIVE:In developed countries with westernized diets, the excessive consumption of added sugar in beverages and highly refined and processed foods is associated with increased risk for obesity, diabetes, and cardiovascular diseases. As a major constituent of added sugars, fructose has been shown to cause a variety of adverse metabolic effects, such as impaired insulin sensitivity, hypertriglyceridemia, and oxidative stress. Recent studies have shown that ketohexokinase isoform C is the key enzyme responsible in fructose metabolism that drive's fructose's adverse effects. The objective of this study was to identify botanical ingredients with potential for inhibitory activity against ketohexokinase-C and fructose-induced metabolic effects by using a series of in vitro model systems. METHODS:Extracts from 406 botanicals and 1200 purified phytochemicals were screened (initial concentration of 50 ?g/mL and 50 ?M, respectively) for their inhibitory activity using a cell free, recombinant human ketohexokinase-C assay. Dose response evaluations were conducted on botanical extracts and phytochemicals that inhibited ketohexokinase-C by > 30% and > 40%, respectively. Two different extract lots of the top botanical candidates were further evaluated in lysates of HepG2 cells overexpressing ketohexokinase-C for inhibition of fructose-induced ATP depletion. In addition, extracts were evaluated in intact Hep G2 cells for inhibition of fructose-induced elevation of triglyceride and uric acid production. RESULTS:Among the botanical extracts, phloretin (Malus domestica) extracts were the most potent (IC50: 8.9-9.2 ?g/mL) followed by extracts of Angelica archangelica (IC50: 22.6 ?g/mL-57.3 ?g/mL). Among the purified phytochemicals, methoxy-isobavachalcone (Psoralea corylifolia, IC50 = 0.2 ?M) exhibited the highest potency against ketohexokinase isoform C activity followed by osthole (Angelica archangelica, IC50 = 0.7 ?M), cratoxyarborenone E (Cratoxylum prunifolium, IC50 = 1.0 ?M), and ?-/?-mangostin (Cratoxylum prunifolium, IC50 = 1.5 ?M). Extracts of Angelica archangelica, Garcinia mangostana, Petroselinum crispum, and Scutellaria baicalensis exhibited ketohexokinase inhibitory activity and blocked fructose-induced ATP depletion and fructose-induced elevation in triglyerides and uric acid. CONCLUSIONS:Angelica archangelica, Garcinia mangostana, Petroselinum crispum, and Scutellaria baicalensis were the top four botanical candidiates identified with inhibitory activity against ketohexokinase-C. Future studies are needed to show proof of mechanism and the efficacy of these botanical extracts in humans to blunt the negative metabolic effects of fructose-containing added sugars.
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Project description:BACKGROUND:In the search for novel antidepressive drug candidates, bioguided fractionation of nonpolar constituents present in the oleoresin from ginger rhizomes (Zingiber officinale Roscoe, Zingiberaceae) was performed. This particular direction of the research was chosen due to the existing reports on the antidepressive properties of ginger total extract. The search for individual metabolites acting as MAO-A inhibitors, which correspond to the apparent effect of the total extract, is the subject of this work. METHODS:Hexane extracts from ginger rhizomes were fractionated by using column chromatography (including silica gel impregnated with silver nitrate) and semi-preparative high-performance chromatography. For the activity assessment, an in vitro monoamine oxidase A (MAO-A) inhibition luminescence assay was performed on 10 purified terpenes: 1,8-cineole, α-citronellal, geraniol, β-sesquiphellandrene, γ-terpinen, geranyl acetate, isobornyl acetate, terpinen-4-ol, (E,E)-α-farnesene, and α-zingiberene. RESULTS:Geraniol and (-)-terpinen-4-ol were found to be the strongest enzyme inhibitors with inhibition of 44.1% and 42.5%, respectively, at a concentration of 125 µg/mL. No differences in the inhibition potential were observed for the different groups of terpenes: sesquiterpenes, monoterpenes, or sesquiterpene alcohols; however, the two most active compounds contained a hydroxyl moiety. CONCLUSIONS:Terpene constituents from ginger's extract were found to exhibit moderate inhibitory properties against the MAO-A enzyme in in vitro tests.
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Project description:Citrus junos Tanaka is a traditional medicine for treating coughs, dyspepsia, diabetes, asthma, neuralgia, and inflammatory disorders, and is distributed in Asia, especially in Korea, Japan, and China. This study aimed to use bioactivity-guided fractionation to find therapeutic phytochemicals from C. junos seeds, which can attenuate inflammatory responses. Nine coumarins (1-9) were isolated from the methanolic extract of C. junos seed shells and the inhibitory effects against inflammatory mediators were investigated using murine macrophages. Among the coumarins, compound 3, isogosferol (ISO), more potently attenuated the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW 264.7 cells. ISO also inhibited the expression of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated macrophages. Additionally, the phosphorylation of extracellular-regulated kinases (pERK)1/2 was reduced by ISO. We confirmed that ISO attenuated the release of interleukin-1 beta (IL-1?), which is a central mediator of the inflammatory response. These results demonstrate that ISO from C. junos seed shells may be a potent therapeutic candidate for the treatment of inflammatory diseases.
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Project description:BackgroundThe current perspective for the search of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor has been shifted towards a natural agent also having antioxidant property. Thus, this study was intended to isolate and identify the bioactive compounds from methanolic extract of Ficus virens bark (FVBM) and to evaluate their antioxidant, HMG-CoA reductase inhibitory and hypolipidemic activity.MethodsBioactivity guided fractionation and isolation of bioactive compound from FVBM extract has been done to isolate and characterize the potent HMG-CoA reductase (HMGR) inhibitor with antioxidant activity by using repeated extensive column chromatography followed by spectroscopic methods, including Infrared (IR), 1H & 13C nuclear magnetic resonance (NMR) and Mass spectrum analysis. The in vitro HMGR inhibition and enzyme kinetic assay was determined using HMG-CoA as substrate. In addition, antioxidant activity of the new isolated compound, was measured using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and FRAP value. In-silico molecular informatics of HMGR enzyme type inhibition and pharmacokinetics data of the new compound was further evaluated through molecular docking and ADME-T studies. Further, in-vivo hypolipidemic property of FVBM extract and newly isolated compound was also analyzed in triton-WR 1339 induced rats.ResultsThereby, we report the discovery of n-Octadecanyl-O-α-D-glucopyranosyl(6'→1″)-O-α-D-glucopyranoside (F18) as a novel HMG-CoA reductase inhibitor with strong antioxidant property. This inhibitor exhibited not only higher free radical scavenging activity but also marked HMG-CoA reductase inhibitory activity with an IC50 value of 84±2.8 ng/ml. This inhibitory activity concurred with kinetic study that showed inhibition constant (K i) of 84 ng/ml via an uncompetitive mode of inhibition. The inhibition was also corroborated by molecular docking analysis and in silico pharmacokinetics data. The in vivo study revealed that administration of FVBM extract (at higher dose, 100 mg/rat) and the inhibitor (1 mg/rat) to Triton WR-1339-induced hyperlipidemic rats significantly ameliorated the altered levels of plasma lipids and lipoproteins including hepatic HMG-CoA reductase activity; this effect was comparable to the effect of standard drug atorvastatin.ConclusionsThe in vitro, in silico and in vivo results clearly demonstrated the antioxidant potential and therapeutic efficacy of the inhibitor as an alternate drug against hyperlipidemia.
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Project description:Uraria crinita is used as a functional food ingredient. Little is known about the association between its immunomodulatory activity and its metabolites. We applied a precise strategy for screening metabolites using immunomodulatory fractions from a U. crinata root methanolic extract (UCME) in combination with bioactivity-guided fractionation and NMR-based identification. The fractions from UCME were evaluated in terms of their inhibitory activity against the production of pro-inflammatory cytokines (IL-6 and TNF-α) by lipopolysaccharide (LPS)-stimulated mouse bone marrow-derived dendritic cells (BMDC). The role of the isoflavone genistein was indicated by the 1H NMR profiling of immunomodulatory subfractions (D-4 and D-5) and supported by the result that genistein-knockout subfractions (D-4 w/o and D-5 w/o) had a lower inhibitory activity compared to genistein-containing subfractions. This study suggests that genistein contributes to the immunomodulatory activity of UCME and will help in the standardization of functional food.
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