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Abstract: Several sesquiterpene lactones that have been isolated from medicinal plants are known to have many pharmacological activities. In this study, we investigated the anti-inflammatory effects of zedoarondiol, a sesquiterpene lactone isolated from the rhizoma of Curcuma heyneana, in lipopolysaccharide (LPS)-stimulated macrophage cells. Zedoarondiol dose-dependently inhibited LPS-stimulated nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) productions in RAW 264.7 macrophage and in mouse peritoneal macrophage cells. Consistent with these findings, in RAW 264.7 cells, zedoarondiol suppressed the LPS-stimulated protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and the mRNA expressions of iNOS, COX-2, TNF-α, IL-6, and IL-1β in a concentration-dependent manner. Moreover, molecular data revealed that zedoarondiol inhibited LPS-stimulated DNA binding activity and the transcription activity of nuclear factor-kappa B (NF-κB), and this effect was accompanied by decreases in the degradation and phosphorylation of inhibitory κB (IκB)-α, and in the subsequent blocking of NF-κB translocations to the nucleus. Furthermore, zedoarondiol attenuated the phosphorylations of IκB kinase (IKK), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), and c-Jun N-terminal kinase (JNK) in LPS-stimulated RAW 264.7 cells. Taken together, the findings of the present study indicate that zedoarondiol inhibits iNOS, COX-2, and pro-inflammatory cytokine expressions by suppressing the phosphorylations of IKK and MAPKs, and by subsequently inactivating the NF-κB pathway. These relations reveal, in part, the mechanism underlying the anti-inflammatory properties of zedoarondiol. [Copyright &y& Elsevier]

J. Neurochem. (2012) 122, 952-961. Abstract While free radicals and inflammation constitute major routes of neuronal injury occurring in amyotrophic lateral sclerosis (ALS), neither antioxidants nor non-steroidal anti-inflammatory drugs have shown significant efficacy in human clinical trials. We examined the possibility that concurrent blockade of free radicals and prostaglandin E2 (PGE2)-mediated inflammation might constitute a safe and effective therapeutic approach to ALS. We have developed 2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] (AAD-2004) as a derivative of aspirin. AAD-2004 completely removed free radicals at 50 nM as a potent spin-trapping molecule and inhibited microsomal PGE2 synthase-1 (mPGES-1) activity in response to both lipopolysaccharide-treated BV2 cell with IC50 of 230 nM and recombinant human mPGES-1 protein with IC50 of 249 nM in vitro. In superoxide dismutase 1G93A transgenic mouse model of ALS, AAD-2004 blocked free radical production, PGE2 formation, and microglial activation in the spinal cords. As a consequence, AAD-2004 reduced autophagosome formation, axonopathy, and motor neuron degeneration, improving motor function and increasing life span. In these assays, AAD-2004 was superior to riluzole or ibuprofen. Gastric bleeding was not induced by AAD-2004 even at a dose 400-fold higher than that required to obtain maximal therapeutic efficacy in superoxide dismutase 1G93A. Targeting both mPGES-1-mediated PGE2 and free radicals may be a promising approach to reduce neurodegeneration in ALS and possibly other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]