A germacranolide sesquiterpene lactone suppressed inducible nitric oxide synthase by downregulating NF-κB activity

Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
Canadian Journal of Physiology and Pharmacology (Impact Factor: 1.77). 03/2011; 89(3):232-7. DOI: 10.1139/Y11-004
Source: PubMed


A germacranolide sesquiterpene lactone, 2α,5-epoxy-5,10-dihydroxy-6α-angeloyloxy-9β-(3-methylbutyloxy)-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. Furthermore, 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.

Download full-text


Available from: JH Kwon, May 08, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder that impacts the daily lives of many sufferers through memory loss as well as behavioral and cognitive changes. AD is the most common form of dementia. One in ten people over the age of 65, and around half of those over 85 have AD. AD can be divided into familial (early-onset) and sporadic (late-onset) cases, with the familial form (<1%) linked to mutations in three major genes (amyloid precursor protein, presenilin-1 and 2), and the sporadic form (>99% of cases) caused by a variety of genetic (e.g., apolipoprotein E), metabolic and environmental factors. The AD brain is characterized macroscopically by cortical atrophy, caused by degeneration of the cholinergic axonal arborisation and shrinkage of the dendritic tree. Microscopically, amyloid beta peptide deposits (senile plaques) and neurofibrillary tangles are present in affected areas (Gil-Bea et al., 2012). AD is also characterized by chronic neuroinflammation, driven by activation of astroglia and microglia (Rosenblum, 2014). In addition, levels of pro-inflammatory mediators or cytokines which include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors are elevated in the brains of patients with AD (Latta et al., 2014). Furthermore, nuclear translocation of NF-κB and STAT-1α, transcription factors involved in pro-inflammatory gene expression, indicates the presence of a sustained pro-inflammatory process (Lawrence, 2009). Drug Discovery Difficulties Faced in Alzheimer's Disease Drug discovery for AD has been strongly focused on β-amyloid (initially plaques, then soluble oligomers), as genetic evidence from the familial cases supported by the hypothesis that β-amyloid must be driving the disease process. Based on the " amyloid cascade hypothesis, " anti-amyloid therapies were hoped to deliver a cure for AD (Robinson et al., 2004). Unfortunately, numerous clinical trials with active and passive amyloid vaccines as well as G-secretase inhibitors have failed (reviewed in Castello et al., 2014). Currently, there are no disease-modifying drugs available for AD. Consequently, alternative therapeutic targets, such as neuroinflammation have been suggested for the prevention and treatment of AD (Shi et al., 2013; Latta et al., 2014). As the expression of many pro-inflammatory cytokines is driven by the transcription factor NF-κB (Hoffmann et al., 2006), we propose that brain-permeable inhibitors of NF-κB signaling have the potential to prevent or slow down the progression of AD.
    Full-text · Article · Jun 2015 · Frontiers in Molecular Neuroscience