Schisandrin A suppresses lipopolysaccharide-induced inflammation and oxidative stress in RAW 264.7 macrophages by suppressing the NF-κB, MAPKs and PI3K/Akt pathways and activating Nrf2/HO-1 signaling

Abstract

Schisandrin A is a bioactive lignan occurring in the fruits of plants of the Schisandra genus that have traditionally been used in Korea for treating various inflammatory diseases. Although the anti-inflammatory and antioxidant effects of lignan analogues similar to schisandrin A have been reported, the underlying molecular mechanisms have remained elusive. In the present study, schisandrin A significantly suppressed the lipopolysaccharide (LPS)-induced production of the key pro-inflammatory mediators nitric oxide (NO) and prostaglandin E2 by suppressing the expression of inducible NO synthase and cyclooxygenase-2 at the mRNA and protein levels in RAW 264.7 macrophages. Furthermore, schisandrin A was demonstrated to reduce the LPS-induced secretion of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β; this was accompanied by a simultaneous decrease in the respective mRNA and protein levels in the macrophages. In addition, the LPS- induced translocation of nuclear factor-κB (NF-κB), as well as activation of mitogen-activated protein kinases (MAPKs) and phosphatidylinositol-3 kinase (PI3K)/Akt pathways were inhibited by schisandrin A. Furthermore, schisandrin A significantly diminished the LPS-stimulated accumulation of intracellular reactive oxygen species, and effectively enhanced the expression of NF erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). These results suggested that schisandrin A has a protective effect against LPS-induced inflammatory and oxidative responses in RAW 264.7 cells by inhibiting the NF-κB, MAPK and PI3K/Akt pathways; these effects are mediated, at least in part, by the activation of the Nrf2/HO-1 pathway. Based on these results, it is concluded that schisandrin A may have therapeutic potential for treating inflammatory and oxidative disorders caused by over-activation of macrophages.

Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine

“…Macrophages play a pivotal role in initiating both inflammation and immune response [46]. When properly stimulated (e.g., using LPS), they undergo a series of processes involving the activation and release of pro-inflammatory and pro-oxidant mediators [47,48].…”

Anti-Inflammatory Activity and ROS Regulation Effect of Sinapaldehyde in LPS-Stimulated RAW 264.7 Macrophages

“…iNOS and COX-2 are key enzymes that are involved in NO and PGE2 synthesis, respectively. Therefore, they are the major targets of anti-inflammatory agents in current research [ 46 , 47 , 48 ]. Our results showed that SNAH exerts its anti-inflammatory effects by inhibiting iNOS and COX-2 protein expression ( Figure 3 ).…”

Platycodon grandiflorus Fermented Extracts Attenuate Endotoxin-Induced Acute Liver Injury in Mice

“…The mitogen-activated protein kinases (MAPKs; p38, ERK1/2, and JNK) and PI3K/AKT signaling pathways are reported as important upstream regulators [36]. LPS has shown to increase phosphorylation of these kinases in Raw264.7 cells, and many medicinal plant extracts have been shown to mitigate these kinase signaling and NF-kB activation through antioxidant properties, such as induction of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase (HO-1) and inhibition of iNOS and cyclooxygenase-2 [37][38][39]. In this study, for the first time, we confirmed that BPG and FBPG extracts exert a beneficial effect by reducing iNOS expression, especially through p38 and ERK signaling pathways in LPS-induced Raw264.7 cells.…”