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Combinative effects of akarkara root-derived metabolites on anti-inflammatory and anti-alzheimer key enzymes: integrating bioassay-guided fractionation, GC-MS analysis, and in silico studies

BACKGROUND: Anacyclus pyrethrum L. (Akarkara root), a valuable Ayurvedic remedy, is reported to exhibit various pharmacological activities. Akarkara root was subjected to bioassay-guided fractionation, to isolate its active constituents and discover their potential bioactivities, followed by computa...

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Autores principales: Ibrahim, Rana M., Abdel-Baki, Passent M., Elmasry, Ghada F., El-Rashedy, Ahmed A., Mahdy, Nariman E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10655324/
https://www.ncbi.nlm.nih.gov/pubmed/37978514
http://dx.doi.org/10.1186/s12906-023-04210-6
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author Ibrahim, Rana M.
Abdel-Baki, Passent M.
Elmasry, Ghada F.
El-Rashedy, Ahmed A.
Mahdy, Nariman E.
author_facet Ibrahim, Rana M.
Abdel-Baki, Passent M.
Elmasry, Ghada F.
El-Rashedy, Ahmed A.
Mahdy, Nariman E.
author_sort Ibrahim, Rana M.
collection PubMed
description BACKGROUND: Anacyclus pyrethrum L. (Akarkara root), a valuable Ayurvedic remedy, is reported to exhibit various pharmacological activities. Akarkara root was subjected to bioassay-guided fractionation, to isolate its active constituents and discover their potential bioactivities, followed by computational analysis. METHODS: The methanol extract and its fractions, methylene chloride, and butanol, were assessed for their antioxidant, anti-inflammatory, and anticholinergic potentials. The antioxidant activity was determined using DPPH, ABTS, FRAP, and ORAC assays. The in vitro anticholinergic effect was evaluated via acetyl- and butyryl-cholinesterase inhibition, while anti-inflammatory effect weas determined using COX-2 and 5-LOX inhibitory assays. The methylene chloride fraction was subjected to GC/MS analysis and chromatographic fractionation to isolate its major compounds. The inhibitory effect on iNOS and various inflammatory mediators in LPS-activated RAW 264.7 macrophages was investigated. In silico computational analyses (molecular docking, ADME, BBB permeability prediction, and molecular dynamics) were performed. RESULTS: Forty-one compounds were identified and quantified and the major compounds, namely, oleamide (A1), stigmasterol (A2), 2E,4E-deca-2,4-dienoic acid 2-phenylethyl amide (A3), and pellitorine (A4) were isolated from the methylene chloride fraction, the most active in all assays. All compounds showed significant in vitro antioxidant, anticholinergic and anti-inflammatory effects. They inhibited the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in activated RAW macrophages. The isolated compounds showed good fitting in the active sites of acetylcholinesterase and COX-2 with high docking scores. The ADME study revealed proper pharmacokinetics and drug likeness properties for the isolated compounds. The isolated compounds demonstrated high ability to cross the BBB and penetrate the CNS with values ranging from 1.596 to -1.651 in comparison with Donepezil (-1.464). Molecular dynamics simulation revealed stable conformations and binding patterns of the isolated compounds with the active sites of COX-2 and acetyl cholinesterase. CONCLUSIONS: Ultimately, our results specify Akarkara compounds as promising candidates for the treatment of inflammatory and neurodegenerative diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12906-023-04210-6.
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spelling pubmed-106553242023-11-17 Combinative effects of akarkara root-derived metabolites on anti-inflammatory and anti-alzheimer key enzymes: integrating bioassay-guided fractionation, GC-MS analysis, and in silico studies Ibrahim, Rana M. Abdel-Baki, Passent M. Elmasry, Ghada F. El-Rashedy, Ahmed A. Mahdy, Nariman E. BMC Complement Med Ther Research BACKGROUND: Anacyclus pyrethrum L. (Akarkara root), a valuable Ayurvedic remedy, is reported to exhibit various pharmacological activities. Akarkara root was subjected to bioassay-guided fractionation, to isolate its active constituents and discover their potential bioactivities, followed by computational analysis. METHODS: The methanol extract and its fractions, methylene chloride, and butanol, were assessed for their antioxidant, anti-inflammatory, and anticholinergic potentials. The antioxidant activity was determined using DPPH, ABTS, FRAP, and ORAC assays. The in vitro anticholinergic effect was evaluated via acetyl- and butyryl-cholinesterase inhibition, while anti-inflammatory effect weas determined using COX-2 and 5-LOX inhibitory assays. The methylene chloride fraction was subjected to GC/MS analysis and chromatographic fractionation to isolate its major compounds. The inhibitory effect on iNOS and various inflammatory mediators in LPS-activated RAW 264.7 macrophages was investigated. In silico computational analyses (molecular docking, ADME, BBB permeability prediction, and molecular dynamics) were performed. RESULTS: Forty-one compounds were identified and quantified and the major compounds, namely, oleamide (A1), stigmasterol (A2), 2E,4E-deca-2,4-dienoic acid 2-phenylethyl amide (A3), and pellitorine (A4) were isolated from the methylene chloride fraction, the most active in all assays. All compounds showed significant in vitro antioxidant, anticholinergic and anti-inflammatory effects. They inhibited the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in activated RAW macrophages. The isolated compounds showed good fitting in the active sites of acetylcholinesterase and COX-2 with high docking scores. The ADME study revealed proper pharmacokinetics and drug likeness properties for the isolated compounds. The isolated compounds demonstrated high ability to cross the BBB and penetrate the CNS with values ranging from 1.596 to -1.651 in comparison with Donepezil (-1.464). Molecular dynamics simulation revealed stable conformations and binding patterns of the isolated compounds with the active sites of COX-2 and acetyl cholinesterase. CONCLUSIONS: Ultimately, our results specify Akarkara compounds as promising candidates for the treatment of inflammatory and neurodegenerative diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12906-023-04210-6. BioMed Central 2023-11-17 /pmc/articles/PMC10655324/ /pubmed/37978514 http://dx.doi.org/10.1186/s12906-023-04210-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Ibrahim, Rana M.
Abdel-Baki, Passent M.
Elmasry, Ghada F.
El-Rashedy, Ahmed A.
Mahdy, Nariman E.
Combinative effects of akarkara root-derived metabolites on anti-inflammatory and anti-alzheimer key enzymes: integrating bioassay-guided fractionation, GC-MS analysis, and in silico studies
title Combinative effects of akarkara root-derived metabolites on anti-inflammatory and anti-alzheimer key enzymes: integrating bioassay-guided fractionation, GC-MS analysis, and in silico studies
title_full Combinative effects of akarkara root-derived metabolites on anti-inflammatory and anti-alzheimer key enzymes: integrating bioassay-guided fractionation, GC-MS analysis, and in silico studies
title_fullStr Combinative effects of akarkara root-derived metabolites on anti-inflammatory and anti-alzheimer key enzymes: integrating bioassay-guided fractionation, GC-MS analysis, and in silico studies
title_full_unstemmed Combinative effects of akarkara root-derived metabolites on anti-inflammatory and anti-alzheimer key enzymes: integrating bioassay-guided fractionation, GC-MS analysis, and in silico studies
title_short Combinative effects of akarkara root-derived metabolites on anti-inflammatory and anti-alzheimer key enzymes: integrating bioassay-guided fractionation, GC-MS analysis, and in silico studies
title_sort combinative effects of akarkara root-derived metabolites on anti-inflammatory and anti-alzheimer key enzymes: integrating bioassay-guided fractionation, gc-ms analysis, and in silico studies
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10655324/
https://www.ncbi.nlm.nih.gov/pubmed/37978514
http://dx.doi.org/10.1186/s12906-023-04210-6
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