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1.
Biochem Biophys Res Commun ; 418(1): 22-6, 2012 Feb 03.
Article in English | MEDLINE | ID: mdl-22214931

ABSTRACT

In the previous studies, we reported that carnosic acid (CA) protects cortical neurons by activating the Keap1/Nrf2 pathway, which activation is initiated by S-alkylation of the critical cysteine thiol of the Keap1 protein by the "electrophilic"quinone-type CA. Here, we found that the pro-electrophilic CA inhibited the in vitro lipopolysaccharide (LPS)-induced activation of cells of the mouse microglial cell line MG6. LPS induced the expression of IL-1ß and IL-6, typical inflammatory cytokines released from microglial cells. CA inhibited the NO production associated with a decrease in the level of inducible NO synthase. Neither CA nor LPS affected cell survival at the concentrations used here. These actions of CA seemed to be mediated by induction of phase 2 genes (gclc, gclm, nqo1 and xct). We propose that an inducer of phase 2 genes may be a critical regulator of microglial activation. Thus, CA is a unique pro-electrophilic compound that provides both a protective effect on neurons and an anti-inflammatory one on microglia through induction of phase 2 genes.


Subject(s)
Abietanes/pharmacology , G2 Phase/drug effects , Microglia/drug effects , Microglia/immunology , Plant Extracts/pharmacology , Amino Acid Transport System y+/genetics , Animals , Cell Line , G2 Phase/genetics , Glutamate-Cysteine Ligase/genetics , Interleukin-1beta/antagonists & inhibitors , Interleukin-1beta/biosynthesis , Interleukin-6/antagonists & inhibitors , Interleukin-6/biosynthesis , Lipopolysaccharides/immunology , Mice , NAD(P)H Dehydrogenase (Quinone)/genetics , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type II/antagonists & inhibitors
2.
Biochem Biophys Res Commun ; 417(1): 294-8, 2012 Jan 06.
Article in English | MEDLINE | ID: mdl-22155240

ABSTRACT

Phenylenediamine derivatives can function as a hydrogen donor and reportedly exert various biological actions including cytoprotective effects against oxidative stress, possibly by acting as an antioxidant. Previous studies showed that feeding of such compounds to mice reduced their body weight, but the precise mechanism remains unknown at present. Here, we found that these compounds inhibited the in vitro differentiation of mouse preadipocytes, 3T3-L1 cells, into adipocytes, suggesting that, at least in part, reduced generation of adipocytes might contribute to the observed weight loss in mice. Next, we performed array analysis and found that the expression of GDF-15/MIC-1, which is a TGFß superfamily cytokine, and Trib 3, an intracellular downstream effector of the cytokines, was up-regulated by these derivatives. Thus, we identified the compounds as inducers of GDF-15/MIC-1 and suggest that such induction may have led to inhibition of adipocyte differentiation, which could account for the weight-loss effect of these compounds.


Subject(s)
Adipocytes/drug effects , Adipogenesis/drug effects , Growth Differentiation Factor 15/biosynthesis , Phenylenediamines/pharmacology , 3T3-L1 Cells , Adipocytes/metabolism , Adipogenesis/genetics , Animals , Mice , Oligonucleotide Array Sequence Analysis
3.
J Neurochem ; 119(3): 569-78, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21883218

ABSTRACT

Activation of the Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and consequent induction of phase 2 antioxidant enzymes is known to afford neuroprotection. Here, we present a series of novel electrophilic compounds that protect neurons via this pathway. Natural products, such as carnosic acid (CA), are present in high amounts in the herbs rosemary and sage as ortho-dihydroquinones, and have attracted particular attention because they are converted by oxidative stress to their active form (ortho-quinone species) that stimulate the Keap1/Nrf2 transcriptional pathway. Once activated, this pathway leads to the production of a series of antioxidant phase 2 enzymes. Thus, such dihydroquinones function as redox-activated 'pro-electrophiles'. Here, we explored the concept that related para-dihydroquinones represent even more effective bioactive pro-electrophiles for the induction of phase 2 enzymes without producing toxic side effects. We synthesized several novel para-hydroquinone-type pro-electrophilic compounds (designated D1 and D2) to analyze their protective mechanism. DNA microarray, PCR, and western blot analyses showed that compound D1 induced expression of heat-shock proteins (HSPs), including HSP70, HSP27, and DnaJ, in addition to phase 2 enzymes such as hemeoxygenase-1 (HO-1), NADP(H) quinine-oxidoreductase1, and the Na(+)-independent cystine/glutamate exchanger (xCT). Treatment with D1 resulted in activation of Nrf2 and heat-shock transcription factor-1 (HSF-1) transcriptional elements, thus inducing phase 2 enzymes and HSPs, respectively. In this manner, D1 protected neuronal cells from both oxidative and endoplasmic reticulum (ER)-related stress. Additionally, D1 suppressed induction of 78 kDa glucose-regulated protein (GRP78), an ER chaperone protein, and inhibited hyperoxidation of peroxiredoxin 2 (PRX2), a molecule that is in its reduced state can protect from oxidative stress. These results suggest that D1 is a novel pro-electrophilic compound that activates both the Nrf2 and HSF-1 pathways, and may thus offer protection from oxidative and ER stress.


Subject(s)
Antioxidants/metabolism , DNA-Binding Proteins/physiology , NF-E2-Related Factor 2/physiology , Neuroprotective Agents/pharmacology , Quinones/pharmacology , Retinal Pigment Epithelium/enzymology , Signal Transduction/physiology , Transcription Factors/physiology , Antioxidants/chemical synthesis , Antioxidants/physiology , Cells, Cultured , DNA-Binding Proteins/metabolism , Endoplasmic Reticulum Chaperone BiP , Heat Shock Transcription Factors , Humans , NF-E2-Related Factor 2/metabolism , Neuroprotective Agents/chemical synthesis , Oxidative Stress/drug effects , Oxidative Stress/physiology , Quinones/chemical synthesis , Retinal Pigment Epithelium/drug effects , Signal Transduction/drug effects , Transcription Factors/metabolism
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