<i>O</i>-Methylbulbocapnine and Dicentrine Suppress LPS-Induced Inflammatory Response by Blocking NF-κB and AP-1 Activation through Inhibiting MAPKs and Akt Signaling in RAW264.7 Macrophages

Abstract

The natural aporphine alkaloids including crebanine (CN), O-methylbulbocapnine (OMP), and dicentrine (DC), and protoberberine alkaloids, tetrahydropalmatine (THP) and N-methyl tetrahydropalmatine (NTHP), have been found in Stephania venosa. Previous reports demonstrated CN and THP exhibited anti-inflammatory properties. In this study, we investigated anti-inflammatory effect of CN analogs including OMP, DC, THP, and NTHP in RAW264.7 macrophages. The pre-treatment of macrophages with CN, OMP and DC suppressed lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and mediators including interleukin-6 (IL-6), tumor necrosis factor alpha, prostaglandin E2 and nitric oxide, in which the rank-order of inhibitory potency was DC>CN≥OMP. Whereas, high dose THP (30-40 µg/mL) reduced LPS-induced IL-6 production in RAW264.7 cells but NTHP did not effect. Moreover, CN, OMP and DC inhibited the LPS-induced expression of inducible nitric oxide synthase and cyclooxygenase-2. OMP and DC inhibited LPS-induced nuclear factor kappa B (NF-κB) activation by suppressing the phosphorylation of NF-κB at Ser536, but not the nucleus translocation and inhibitor of kappaB (IκB)-α degradation. In addition, OMP and DC also reduced the phosphorylation and nucleus translocation of activator protein-1 (AP-1). Furthermore, OMP and DC suppressed the LPS-activated myeloid differentiation factor 88 (MyD88), Akt and mitogen-activated protein kinases (MAPKs) signaling pathway, which were the upstream signaling regulators of AP-1 and NF-κB. Collectively, OMP and DC have an anti-inflammatory effect on RAW264.7 macrophages by the suppression of pro-inflammatory cytokines and mediators. The inhibitory property of OMP and DC is mediated by blockage the activation of MyD88, MAPKs, Akt, NF-κB and AP-1 signaling molecules.

Tat-ATOX1 inhibits inflammatory responses via regulation of MAPK and NF-κB pathways

“…NF-κB is the major transcription factor of the inflammatory response to LPS. LPS-induced MAPK signaling pathways have been implicated in the inflammatory response through NF-κB activation (28–30). As shown in Fig.…”

TIPE2 suppresses atherosclerosis by exerting a protective effect on macrophages via the inhibition of the Akt signaling pathway

“…The expression of NF-κB and its gene cascade may be modulated by the PI3K/Akt signaling pathway, which serves an important role in cell proliferation, apoptosis and inflammation (34). Furthermore, the expression of pro-inflammatory cytokines including IL-6 and TNF-α, are influenced by NF-κB and activator portein-1 activities (35). The present study confirmed that TIPE2 inhibits the AKT signaling pathway and NF-κB activation in macrophages.…”

A critical review: traditional uses, phytochemistry, pharmacology and toxicology of Stephania tetrandra S. Moore (Fen Fang Ji)

“…Meanwhile, this study conducted higher concentration of cepharanthine than that of Kondo's study to evaluate the antiinflammatory activity. Dicentrine (39) at the concentrations of 5.90, 7.52 or 10.0 lM was shown to suppress LPS-induced inflammation by blocking the activation of NF-jB and activator protein-1 (AP-1) through inhibition of mitogen-activated protein kinase (MAPK) and p-protein kinase B (Akt) signaling in RAW264.7 macrophages (Yodkeeree et al 2018). Although this study assessed the cytotoxicity to RAW264.7 macrophages, anti-inflammatory effects and the mechanism of action, these authors did not compare the efficacy of dicentrine with a positive control.…”

“…,Wang et al (2016a, b, c),Shen et al (2001),Choi et al (2000),Kang et al (2014),Wu and Ng (2007),Xu et al (2016a, b),Wu et al (2015),Nakamura et al (1992),Yang et al (2018a, b),Kondo et al (1993),Aota et al (2018),Yodkeeree et al (2018),Haque et al (2018) Anticancer/ antiproliferative effects…”