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Four sesquiterpenoids were isolated from an ethyl acetate-soluble fraction of A. princeps ethanolic extract: seco-tanapartholide B (5-epi-seco-tanapartholide A) (1), 4-epi-seco-tanapartholide A (2), 11,13-dehydrodesacetylmatricarin (3) and desacetylmatricarin (4). Compounds 1 − 3 dose-dependently inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-activated macrophages. These compounds also decreased mRNA and protein expression levels of inducible NO synthase and cyclooxygenase-2 as well as mRNA levels of pro-inflammatory cytokines (interleukin-1β and tumour necrosis factor-α) in LPS-stimulated RAW 264.7 macrophages. Moreover, compound 3 effectively enhanced the expression of heme oxygenase-1 (HO-1) in macrophages in the presence or absence of LPS. Additionally, the exocyclic methylene of α-methylene-γ-lactone moiety of compound 3 was found to be essential for the activation of the NF erythroid 2-related factor 2 (Nrf2)/HO-1 pathway. Here, we firstly report the isolation of compounds 3 and 4 from A. princeps and the anti-inflammatory activity of compound 3 by up-regulation of Nrf2/HO-1 pathway. [ABSTRACT FROM AUTHOR]

A germacranolide sesquiterpene lactone, 2α,5-epoxy-5,10-dihydroxy-6α-angeloyloxy-9[beta- (3methylbutyloxy)germacran-8α,12-olide (EDAG), isolated from Carpesium triste var. manshuricum, showed inhibitory activity in the production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS) mRNA and protein in LPS-activated macrophage cells. Molecular analysis reveals that these suppressive effects are correlated with the inhibition of NF-κB activation by EDAG. Immunoblotting showed that EDAG suppressed the LPS-induced degradation of I-κBα and decreased nuclear translocation of p65. Futhermore, EDAG showed reduced phosphorylation of ERK1/2 and p38 MAPK, whereas activation of JNK was not changed. These data suggest, at least in part, that EDAG utilizes the signal cascades of ERK1/2, p38 MAPK, and NF-κB for the suppression of iNOS gene expression. Key words: nitric oxide, germacranolide sesquiterpene lactone, Carpesium triste var. manshuricum, nuclear factor κB, macrophage, inflammation, inducible nitric oxide synthase. Un sesquiterpene lactone de type germacranolide, 2α,5-epoxy-5,10-dihydroxy-6 α-angeloyloxy9β-(3- methylbutyloxy)-germacran-8α,12-olide (EDAG), isole de Carpesium triste var. manshuricum, a montre une activite inhibitrice sur la production du monoxyde d'azote (NO) et l'expression de la proteine et de l'ARNm de la monoxyde d'azote synthase inductible (iNOS) dans les macrophages actives par des LPS. L'analyse moleculaire revele que ces effets suppresseurs sont correles avec l'inhibition de l'activation du NF-κB par l'EDAG. L'immunobuvardage a montre que l'EDAG a supprime la degradation induite par les LPS de la proteine I-κBα et diminue la translocation nucleeaire de la sous-unite p65. De plus, l'EDAG a diminue la phosphorylation de ERK1/2 et de la p38 MAPK, mais n'a pas modifie l'activation de la JNK. Ces resultats laissent a penser, du moins en partie, que l'EDAG utilise les cascades de signaux ERK1/2, p38 MAPK et NF-κB pour supprimer l'expression geenique de iNOS. Mots-cles: monoxyde d'azote, sesquiterpene lactone de type germacranolide, Carpesium triste var. manshuricum, facteur nucleaire κB, macrophage, inflammation, monoxyde d'azote synthase inductible. [Traduit par la Redaction], Introduction Nitric oxide (NO), a short-lived free radical, is an important inflammatory mediator that plays a critical role in patho-physiological conditions. NO is synthesized from L-arginine in various tissues and [...]

Cytoprotective effects of chemopreventive agents may be attributed to the induction of antioxidant enzymes. Among these, the induction of glutamate-cysteine ligase (GCL) protects cells from oxidative injury by increasing glutathione (GSH) content. Nuclear factor erythroid-2-related factor 2 (Nrf2) transcriptionally regulates the expression of genes encoding for GCL and other cysteine-metabolizing enzymes. Despite extensive studies on the components in garlic, little information is available on organosulfur by-products made from garlic. In this study, we investigated whether ajoene, a chemically stable garlic by-product, has the ability to activate Nrf2 and induce GCL, and, if so, what is the role of activating Nrf2 in cytoprotection against oxidative stress. Immunoblottings and reporter gene assays were performed in HepG2 cells. Ajoene treatment activated Nrf2, as indicated by increased phosphorylation and nuclear accumulation of Nrf2, decreased interaction with Kelch-like ECH-associated protein-1, and decreased Nrf2 ubiquitination. Consistently, treatment of ajoene increased antioxidant response element reporter gene activity and the mRNA and protein levels of GCL subunits. Ajoene activated protein kinase C-[delta] (PKC[delta]). Inhibition of PKC[delta] activation by rottlerin abrogated its ability to activate Nrf2 and induce GCL, suggesting that ajoene promotes the Nrf2-dependent antioxidant defense system via PKC[delta] activation. Consequently, ajoene prevented cell death, GSH depletion, and hydrogen peroxide production elicited by tertbutylhydroperoxide. The important role of Nrf2 in cytoprotection was verified by the reversal of aloene's ability to protect hepatocytes in Nrf2-knockout mice. Our results demonstrate that ajoene increases PKC[delta]-dependent Nrf2 activation, GCL induction, and the cellular GSH concentration, which may contribute to protecting cells from oxidative stress. doi: 10.3945/jn.110.121277