Sulforaphane attenuates microglia-mediated neuronal necroptosis through down-regulation of MAPK/NF-κB signaling pathways in LPS-activated BV-2 microglia.

Sulforaphane (SFN), a natural dietary isothiocyanate in cruciferous vegetables such as broccoli and cabbage, has very strong anti-inflammatory activity. Activation of microglia leads to overexpression of a series of pro-inflammatory mediators, which play a vital role in neuronal damage. SFN may have neuroprotective effects in different neurodegenerative diseases related to inflammation. However, the mechanisms underlying SFN's protection of neurons against microglia-mediated neuronal damage are not fully understood. Here, we investigated how SFN attenuated microglia-mediated neuronal damage. Our results showed that SFN could not directly protect the viability of neurons following pro-inflammatory mediators, but increased the viability of BV-2 microglia and down-regulated the mRNA and protein levels of pro-inflammatory mediators including TNF-α, IL-1β, IL-6 and iNOS in a concentration-dependent manner in BV-2 cells. SFN also significantly blocked the phosphorylation of MAPKs (p38, JNK, and ERK1/2) and NF-κB p65, both by itself and with MAPK inhibitors (SB203580, SP 600125, and U0126) or an NF-κB inhibitor (PDTC). The expression of pro-inflammatory proteins was also blocked by SFN with or without inhibitors. Further, SFN indirectly increased the viability and maintained the morphology of neurons, and the protein expression of RIPK3 and MLKL was significantly suppressed by SFN in neuronal necroptosis through p38, JNK, and NF-κB p65 but not ERK1/2 signaling pathways. Together, our results demonstrate that SFN attenuates LPS-induced pro-inflammatory responses through down-regulation of MAPK/NF-κB signaling pathway in BV-2 microglia and thus indirectly suppresses microglia-mediated neuronal damage.

Qin S ，Yang C ，Huang W ，Du S ，Mai H ，Xiao J ，Lü T ... -  《-》

Anti-Inflammatory Effect of Sulforaphane on LPS-Activated Microglia Potentially through JNK/AP-1/NF-κB Inhibition and Nrf2/HO-1 Activation.

Subedi L ，Lee JH ，Yumnam S ，Ji E ，Kim SY ... -  《Cells》

Anti-inflammatory effect of the six compounds isolated from Nauclea officinalis Pierrc ex Pitard, and molecular mechanism of strictosamide via suppressing the NF-κB and MAPK signaling pathway in LPS-induced RAW 264.7 macrophages.

Nauclea officinalis Pierrc ex Pitard. is a Chinese medicinal herb that contains high level of alkaloids which is the most abundant and active constituent. Strictosamide isolated from Nauclea officinalis Pierrc ex Pitard. showed significant effects on inflammatory response, compared with pumiloside, 3-epi-pumiloside, vincosamide, 3α,5α-tetrahydrodeoxycordifoline lactam and naucleamide A-10-O-β-D-glucopyranoside of this plant. we investigated the biological activities of the six compounds mentioned-above, and the underlying molecular mechanism exerted by the most potent one, strictosamide. The effects of strictosamide and other five compounds on the inhibitory activity of nitric oxide (NO) were screened by Griess test. The contents of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in media were detected by using Enzyme-linked immunosorbent (ELISA) kits. The effects on the mRNA expression of nitric oxide synthase (iNOS), TNF-α and IL-1β of strictosamide were further investigated by RT-qPCR. Western blot assay was conducted to illustrate the effects of strictosamide on iNOS and phosphorylation of p65, inhibitor of NF-κB (IκB)-α, IκB-kinase (IKK)-α as well as p-extracellular signal-regulated kinase (ERK), p-c-jun N-terminal kinase (JNK) and p-p38 in the protein levels. Strictosamide potently suppressed the productions of NO, TNF-α and IL-1β in LPS-induced RAW 264.7 macrophages, and it dose-dependently alleviated the LPS-simulated protein level of iNOS as well as the mRNA expressions of iNOS, TNF-α and IL-1β. In addition, molecular data revealed that strictosamide markedly decreased the expressions of p-p65, p-IκBα and p-IKKα. Furthermore, strictosamide significantly attenuated LPS-induced the phosphorylation of p38, ERK and JNK. At present study, the results indicated that the anti-inflammatory activity of strictosamide was associated with the restraint of NO, TNF-α and IL-1β via negative regulation of both NF-κB and mitogen-activated protein kinases (MAPKs) in LPS-induced RAW 264.7 cells.

Li D ，Chen J ，Ye J ，Zhai X ，Song J ，Jiang C ，Wang J ，Zhang H ，Jia X ，Zhu F ... -  《-》

Anti-inflammatory mechanism of galangin in lipopolysaccharide-stimulated microglia: Critical role of PPAR-γ signaling pathway.

Since microglia-associated neuroinflammation plays a pivotal role in the progression of neurodegenerative diseases, controlling microglial activation has been suggested as a potential therapeutic strategy. Here, we investigated the anti-inflammatory effects of galangin (3,5,7-trihydroxyflavone) in microglia and analyzed the underlying molecular mechanisms. Galangin inhibited the expression of inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines and enhanced the expression of anti-inflammatory interleukin (IL)-10 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Galangin also suppressed microglial activation and the expression of pro-inflammatory markers in LPS-injected mouse brains. The results of mechanistic studies have shown that galangin inhibited LPS-induced phosphorylation of p38 mitogen activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3K)/Akt, and nuclear factor (NF)-κB activity. On the contrary, galangin increased the activity of transcription factors, such as nuclear factor-E2-related factor 2 (Nrf2), cAMP response element-binding protein (CREB), and peroxisome proliferator-activated receptor (PPAR)-γ, known to play an anti-inflammatory role. In addition, galangin showed antioxidant effects by suppressing the expression of NADPH oxidase subunits p47phox and gp91phox, and by enhancing hemeoxygenase-1. We then investigated whether PPAR-γ was involved in the anti-inflammatory function of galangin. Pretreatment with a PPAR-γ antagonist or siRNA significantly blocked galangin-mediated upregulation of IL-10 and attenuated the inhibition of tumor necrosis factor (TNF)-α, nitric oxide (NO), and IL-6 in LPS-stimulated microglia. Moreover, the PPAR-γ antagonist reversed the effects of galangin on NF-κB, Nrf2, and CREB. Altogether, our data suggest that PPAR-γ plays a key role in mediating the anti-inflammatory effects of galangin by modulating the NF-κB and Nrf2/CREB signaling pathways.

Choi MJ ，Lee EJ ，Park JS ，Kim SN ，Park EM ，Kim HS ... -  《-》

Aspirin-triggered lipoxin A4 attenuates LPS-induced pro-inflammatory responses by inhibiting activation of NF-κB and MAPKs in BV-2 microglial cells.

Wang YP ，Wu Y ，Li LY ，Zheng J ，Liu RG ，Zhou JP ，Yuan SY ，Shang Y ，Yao SL ... -  《Journal of Neuroinflammation》