Several kinds of sesquiterpene lactones have been proven to inhibit NF-κB and to retard atherosclerosis by reducing lesion size and changing plaque composition. The anti-malarial artemisinin (Art) is a pure sesquiterpene lactone extracted from the Chinese herb Artemisia annua (qinghao, sweet wormwood). In the present study, we demonstrate that artemisinin inhibits the secretion and the mRNA levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in a dose-dependent manner in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 human monocytes. We also found that the NF-κB specific inhibitor, Bay 11-7082, inhibited the expression of these pro-inflammatory cytokines, suggesting that the NF-κB pathway may be involved in the decreased cytokine release. At all time-points (1-6 h), artemisinin impeded the phosphorylation of IKKα/ß, the phosphorylation and degradation of IκBα and the nuclear translocation of the NF-κB p65 subunit. Additionally, artemisinin inhibited the translocation of the NF-κB p65 subunit as demonstrated by confocal laser scanning microscopic analysis and by NF-κB binding assays. Our data indicate that artemisinin exerts an anti-inflammatory effect on PMA-induced THP-1 monocytes, suggesting the potential role of artemisinin in preventing the inflammatory progression of atherosclerosis.
"In human rheumatoid arthritis fibroblast-like synoviocytes, artesunate, an artemisinin derivative, has the ability to inhibit TNF-α- induced production of proinflammatory cytokines via inhibition of NF-κB and PI3 kinase/Akt signal pathway . Both in THP-1 and in RAW 264.7 macrophages, artemisinin and its derivatives inhibited pro-inflammatory cytokine production by NF-κB pathway , . Due to its anti-inflammatory properties, the role of artemisinin in LPS-activated microglia was investigated in this study. "
[Show abstract][Hide abstract] ABSTRACT: Microglial activation plays an important role in neuroinflammation, which contributes to neuronal damage, and inhibition of microglial activation may have therapeutic benefits that could alleviate the progression of neurodegeneration. Recent studies have indicated that the antimalarial agent artemisinin has the ability to inhibit NF-κB activation. In this study, the inhibitory effects of artemisinin on the production of proinflammatory mediators were investigated in lipopolysaccharide (LPS)-stimulated primary microglia. Our results show that artemisinin significantly inhibited LPS-induced production of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1) and nitric oxide (NO). Artemisinin significantly decreased both the mRNA and the protein levels of these pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) and increased the protein levels of IκB-α, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Artemisinin treatment significantly inhibited basal and LPS-induced migration of BV-2 microglia. Electrophoretic mobility shift assays revealed increased NF-κB binding activity in LPS-stimulated primary microglia, and this increase could be prevented by artemisinin. The inhibitory effects of artemisinin on LPS-stimulated microglia were blocked after IκB-α was silenced with IκB-α siRNA. Our results suggest that artemisinin is able to inhibit neuroinflammation by interfering with NF-κB signaling. The data provide direct evidence of the potential application of artemisinin for the treatment of neuroinflammatory diseases.
PLoS ONE 04/2012; 7(4):e35125. DOI:10.1371/journal.pone.0035125 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 1. Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinases (MMPs) by monocytes/macrophages has been proposed to play a significant role in atherosclerotic plaque progression and rupture. The aim of the present study was to explore whether artemisinin, a natural extract from Artemisia annua, could decrease EMMPRIN and MMP-9 expression in phorbol myristate acetate (PMA)-induced macrophages by regulating the protein kinase (PK) Cδ/c-Jun N-terminal kinase (JNK)/p38/extracellular signal-regulated kinase (ERK) pathway.
2. Human monocytic THP-1 cells were pretreated with 20–80 μg/mL artemisinin for 4 h or 1–10 μmol/L rottlerin for 1 h prior to stimulation with PMA (100 nmol/L) for another 48 h. Cells were collected to analyse the induction of EMMPRIN and MMP-9. Upstream pathway analysis using the PKCδ inhibitor rottlerin detected activation of the PKCδ/JNK/p38/ERK pathway.
3. Artemisinin (20–80 μg/mL) significantly inhibited the induction of EMMPRIN and MMP-9 at both the transcriptional and translational levels in a dose-dependent manner in PMA-induced macrophages. In addition, artemisinin (20–80 μg/mL) strongly blocked PKCδ/JNK/p38/ERK MAPK phosphorylation. The PKCδ inhibitor rottlerin (1–10 μmol/L) also significantly inhibited JNK/p38/ERK phosphorylation and decreased EMMPRIN and MMP-9 mRNA and protein expression.
4. The results of the present study suggest that artemisinin inhibits EMMPRIN and MMP-9 expression and activity by suppressing the PKCδ/ERK/p38 cascade in PMA-induced macrophages.
Clinical and Experimental Pharmacology and Physiology 10/2010; 38(1):11-8. DOI:10.1111/j.1440-1681.2010.05454.x · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite its efficacy against malaria, the relatively low yield (0.01%-0.8%) of artemisinin in Artemisia annua is a serious limitation to the commercialization of the drug. A better understanding of the biosynthetic pathway of artemisinin and its regulation by both exogenous and endogenous factors is essential to improve artemisinin yield. Increasing evidence has shown that microRNAs (miRNAs) play multiple roles in various biological processes. In this study, we used previously known miRNAs from Arabidopsis and rice against expressed sequence tag (EST) database of A. annua to search for potential miRNAs and their targets in A. annua. A total of six potential miRNAs were predicted, which belong to the miR414 and miR1310 families. Furthermore, eight potential target genes were identified in this species. Among them, seven genes encode proteins that play important roles in artemisinin biosynthesis, including HMG-CoA reductase (HMGR), amorpha-4,11-diene synthase (ADS), farnesyl pyrophosphate synthase (FPS) and cytochrome P450. In addition, a gene coding for putative AINTEGUMENTA, which is involved in signal transduction and development, was also predicted as one of the targets. This is the first in silico study to indicate that miRNAs target genes encoding enzymes involved in artemisinin biosynthesis, which may help to understand the miRNA-mediated regulation of artemisinin biosynthesis in A. annua.
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