SM905, an artemisinin derivative, inhibited NO and pro-inflammatory cytokine production by suppressing MAPK and NF-κB pathways in RAW 264.7 macrophages

Abstract

Aim: To elucidate the anti-inflammatory potentials and underlying mechanisms of SM905, a novel artemisinin derivative, in lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells. Methods: Nitric oxide (NO) generation, cytokine production, and the protein expression levels of inducible nitric-oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were examined using a Griess assay, an enzyme-linked immunosorbent assay (ELISA) and a Western blotting assay, respectively. The mRNA expression was measured using real-time PCR. The phosphorylation of extracellular signalregulated kinase1/2 (ERK1/2), p38, c-jun N-terminal kinase (JNK), and the degradation of IκBα were assessed by Western blotting analysis. The nuclear translocation of nuclear factor-κB (NF-κB) was observed using confocal microscopy. Results: Pretreatment with SM905 (0, 0.1, 1, and 10 μmol/L) suppressed LPS-induced NO, TNF-α, IL-1β, and IL-6 production, and decreased both protein and mRNA levels of iNOS and COX-2. The mRNA expression of LPS receptor Toll-like receptor 4 (TLR4) and myeloid differentiation protein-2 (MD-2) was not changed, while LPS-induced CD14 expression was slightly reduced after SM905 treatment. SM905 markedly decreased the activation of ERK1/2, p38 and JNK suppressed the degradation of IκBα, but did not modify the expression of interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription 1 (STAT1) or interferon-inducible protein-10 (IP-10). By using confocal microscopy, we further observed that NF-κB was correspondingly inhibited in SM905-treated cells. Conclusion: SM905 inhibited NO and pro-inflammatory cytokine production in LPS-stimulated RAW 264.7 cells and these effects are at least partially mediated through suppression of the MAPK and NF-κB signaling pathways.

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

“…However, most artemisinin derivatives possess poor water solubility or low bioavailability, which limits their further applications to treat autoimmune diseases. Several series of new artemisinin derivatives have been synthesized, and the water-soluble artemisinin derivative SM934 showed higher bioavailability, better bioactivity, and lower toxicity (25)(26)(27)(28). The acute toxicity of SM934 was tested in mice, and the median lethal dose was ϳ2 gm/kg.…”

Qinghaosu (artemisinin): Chemistry and pharmacology

“…At last, SM 735, SM 905, SM 933, and SM 934 ( Figure 2) were selected and tested in the animal models for 2,4-dinitrofluorobenzene (DNFB)-induced delayed-type hypersensitivity (DTH) reaction, sheep red blood cell (SRBC)-induced antibody production, and experimental autoimmune encephalomyelitis (EAE). Up to date, a number of papers related their immuno-suppressive activity and possible mechanisms have been published mainly from this Institute [55][56][57][58][59][60][61][62][63][64] . The preclinical research of SM 934 is in progress.…”

Methyl-1-hydroxy-2-naphthoate, a novel naphthol derivative, inhibits lipopolysaccharide-induced inflammatory response in macrophages via suppression of NF-κB, JNK and p38 MAPK pathways

“…Since multiple studies have shown that LPS-induced expression of pro-inflammatory mediators such as iNOS, COX-2, IL-1b and IL-6 are regulated by NF-jB and MAPKs signaling pathways [3,37], we examined whether MHNA affected NF-jB and MAPKs signaling pathways activation. We found that MHNA inhibited the LPSinduced increases in NF-jB DNA-binding activity and NFjB transcriptional activity in a dose-dependent manner.…”

“…Macrophages, as major cells in inflammation, play an important role in the pathogenesis of inflammation by secreting various inflammatory mediators such as nitric oxide (NO), prostaglandin E 2 (PGE 2 ), tumor necrosis factor alpha (TNF-a), interleukin-1 (IL-1) and interleukin-6 (IL-6) [1][2][3]. When these mediators are overproduced, they cause an excessive inflammatory response, leading to the occurrence of inflammatory diseases [4][5][6].…”