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      Flavonoids targeting of IκB phosphorylation abrogates carcinogen-induced MMP-9 and COX-2 expression in human brain endothelial cells

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          Abstract

          Brain endothelial cells play an essential role as structural and functional components of the blood–brain barrier (BBB). Increased BBB breakdown and brain injury are associated with neuroinflammation and are thought to trigger mechanisms involving matrix metalloproteinase upregulation. Emerging evidence also indicates that cyclooxygenase (COX) inhibition limits BBB disruption, but the mechanisms linking metalloproteinase to COX remain unknown. In this study, we sought to investigate the nuclear factor-kappa B (NF-κB) signaling pathway, a common pathway in both the regulation of matrix metalloproteinase-9 (MMP-9) and COX-2 expression, and the inhibitory properties of several chemopreventive flavonoids. Human brain microvascular endothelial cells were treated with a combination of phorbol 12-myristate 13-acetate (PMA), a carcinogen documented to increase MMP-9 and COX-2 through NF-κB, and several naturally occurring flavonoids. Among the molecules tested, we found that fisetin, apigenin, and luteolin specifically and dose-dependently antagonized PMA-induced COX-2 and MMP-9 gene and protein expressions as assessed by qRT-PCR, immunoblotting, and zymography respectively. We further demonstrate that flavonoids impact on IκK-mediated phosphorylation activity as demonstrated by the inhibition of PMA-induced IκB phosphorylation levels. Our results suggest that BBB disruption during neuroinflammation could be pharmacologically reduced by a specific class of flavonoids acting as NF-κB signal transduction inhibitors.

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          Most cited references 44

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          Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids.

          Prostaglandins play important and diverse roles in the CNS. The first step in prostaglandin synthesis involves enzymatic oxidation of arachidonic acid, which is catalyzed by prostaglandin H(PGH) synthase, also referred to as cyclooxygenase. We have cloned an inducible form of this enzyme from rat brain that is nearly identical to a murine, mitogen-inducible cyclooxygenase identified from fibroblasts. Our studies indicate that this gene, here termed COX-2, is expressed throughout the forebrain in discrete populations of neurons and is enriched in the cortex and hippocampus. Neuronal expression is rapidly and transiently induced by seizures or NMDA-dependent synaptic activity. No expression is detected in glia or vascular endothelial cells. Basal expression of COX-2 appears to be regulated by natural synaptic activity in the developing and adult brain. Both basal and induced expression of COX-2 are inhibited by glucocorticoids, consistent with COX-2 regulation in peripheral tissues. Our studies indicate that COX-2 expression may be important in regulating prostaglandin signaling in brain. The marked inducibility in neurons by synaptic stimuli suggests a role in activity-dependent plasticity.
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            The IkappaB kinase complex: master regulator of NF-kappaB signaling.

            The Nuclear Factor-kappa B (NF-kappaB) family of transcription factors regulates the expression of a wide range of genes critical for immune and inflammatory responses, cell survival, immune development, and cell proliferation. Dysregulated NF-kappaB activity occurs in a number of chronic inflammatory diseases and certain types of cancers making NF-kappaB signaling an attractive target for the development of anti-inflammatory and anti-cancer drugs. A pivotal regulator of all inducible NF-kappaB signaling pathways is the IkappaB kinase (IKK) complex that consists of two kinases (IKKalpha and IKKbeta) and a regulatory subunit named NF-kappaB essential modulator (NEMO). Genetic analysis of the IKK complex has identified two separate pathways named the classical and non-canonical mechanisms that are dependent on either NEMO and IKKbeta (classical) or IKKalpha alone (non-canonical). To better understand the mechanisms that regulate IKK complex activity and to address the differential functions of IKKalpha and IKKbeta we have molecularly dissected the IKKs. We describe here how these studies have identified a unique inhibitor of pro-inflammatory NF-kappaB signaling, an unforeseen role for IKKalpha in the classical NF-kappaB pathway, and a novel functional domain in IKKbeta that is not present in IKKalpha.
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              NFkappaB pathway: a good signaling paradigm and therapeutic target.

              NFkappaB was identified 20 years ago (Sen, R., & Baltimore, D. (1986) Cell, 46, 705-716) as a nuclear factor that binds the kappa light chain enhancer in B-cells (and hence, the name NFkappaB) and was shown to play roles in innate and adaptive immune responses. More recently, its role in many other cellular processes has become apparent. Perhaps, not surprisingly, deregulated activity of the NFkappaB pathway has been observed and linked to the progression of several human ailments, including cancers. Research in the last two decades has identified the major mechanisms of activation of this pathway and has documented the roles of the key players. Over 200 physiological stimuli are known to activate NFkappaB. These include bacterial and viral products, cellular receptors and ligands, mitogens and growth factors and physical and biochemical stress inducers. The major cellular targets of NFkappaB are chemokines, immune receptors, adhesion molecules, stress response genes, regulators of apoptosis, transcription factors, growth factors, enzymes and cell cycle regulators. In addition, NFkappaB is known to be important for transcription of several viral promoter/enhancers (e.g. HIV-1 and CMV). Given that, such a large number of stimuli can activate NFkappaB, which in turn activates an equally large number of target genes, understanding how specificity generated within the framework of pleiotropic signaling is a major challenge. A thorough understanding of this would be instrumental in designing pathway specific inhibitors of NFkappaB for the treatment of specific human ailments.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2011
                13 May 2011
                : 5
                : 299-309
                Affiliations
                [1 ]Centre de Recherche BioMED
                [2 ]Centre de Recherche PharmaQAM, Département de chimie, Université du Québec à Montréal, QC, Canada
                Author notes
                Correspondence: Borhane Annabi, Tel +1 514 987 3000 ext 7610, Email annabi.borhane@ 123456uqam.ca , René Roy, Tel +1 514 987 3000 ext 2546, Email roy.rene@ 123456uqam.ca , Université du Québec à Montréal, Département de Chimie, CP 8888, Succ. Centre-ville, Montréal, QC, Canada, H3C 3P8
                Article
                dddt-5-299
                10.2147/DDDT.S19931
                3100225
                21625419
                © 2011 Tahanian et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Original Research

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