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Title: Bauer ketones 23 and 24 from Echinacea paradoxa var. paradoxa inhibit lipopolysaccharide-induced nitric oxide, prostaglandin E2 and cytokines in RAW 264.7 mouse macrophages

Author
item ZHANG, XIAOZHU - Iowa State University
item RIZSHSKY, LUDMILA - Iowa State University
item HAUCK, CATHERINE - Iowa State University
item Qu, Luping
item Widrlechner, Mark
item NIKOLAU, BASIL - Iowa State University
item MURPHY, PATRICIA - Iowa State University
item BIRT, DIANE - Iowa State University

Submitted to: Phytochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/18/2011
Publication Date: 11/29/2011
Citation: Zhang, X., Rizshsky, L., Hauck, C., Qu, L., Widrlechner, M.P., Nikolau, B.J., Murphy, P.A., Birt, D.F. 2012. Bauer ketones 23 and 24 from Echinacea paradoxa var. paradoxa inhibit lipopolysaccharide-induced nitric oxide, prostaglandin E2 and cytokines in RAW 264.7 mouse macrophages. Phytochemistry. 74:146-158.

Interpretive Summary: Three species of Echinacea (E. purpurea, E. angustifolia and E. pallida) have been widely used as dietary supplements to treat the common cold, flu and other infections, but our understanding of these plants’ bioactive compounds and how they act in animal and human systems still has many gaps. We were interested in learning how different Echinacea species might counteract inflammation, so we screened these three widely-used species along with a fourth, E. paradoxa, in mouse macrophage cell cultures designed to evaluate possible anti-inflammatory activity. Of all extracts from these four species that we tested, an ethanol extract of E. paradoxa, rich in polyenes/polyacetylenes, was the most efficient at inhibiting certain inflammatory agents, including nitric oxide (NO), prostaglandin E2 (PGE2), and the cytokines, interleukin-1 beta and interleukin-6, in mouse cells when compared to a suitable control. We then tested different chemical fractions of this ethanol extract to find the most active compounds. The chemicals, Bauer ketone 23 and 24, were primarily responsible for inhibiting NO and PGE2, but not by lowering expression of the enzyme, inducible nitric oxide synthase, nor that of cyclooxygenase protein. Bauer ketone 24 was also a major inhibitor of inflammatory cytokines in mouse macrophages. Our results provide a rationale for more detailed studies on the medicinal effects of E. paradoxa, and they confirm the anti-inflammatory properties of Bauer ketones 23 and 24. These results may lead to the production of improved dietary supplements and to standardized trials to test bioactivity in human systems, ultimately leading to improved human health.

Technical Abstract: Among the nine Echinacea species, E. purpurea, E. angustifolia and E. pallida, have been widely used to treat the common cold, flu and other infections. In our study, ethanol extracts of these three Echinacea species and E. paradoxa, including its typical variety, E. paradoxa var. paradoxa, were screened in lipopolysaccharide (LPS)-stimulated macrophage cells to assess potential anti-inflammatory activity. Echinacea paradoxa var. paradoxa, rich in polyenes/polyacetylenes, was an especially efficient inhibitor of LPS-induced production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6) by 46%, 32%, 53% and 26%, respectively, when tested at 20 micrograms/ml in comparison to DMSO control. By bioactivity-guided fractionation, Bauer ketones 23 and 24 from E. paradoxa var. paradoxa were found primarily responsible for inhibitory effects on NO and PGE2 production, but not through reducing inducible nitric oxide synthase (iNOS) or cyclooxygenase protein expression. Moreover, Bauer ketone 24 was the major contributor to inhibition of inflammatory cytokine production in LPS-induced mouse macrophage cells. These results provide a rationale for exploring the medicinal effects of the Bauer ketone-rich taxon, E. paradoxa var. paradoxa, and confirm the anti-inflammatory properties of Bauer ketones 23 and 24.