Protective effect of forsythoside B against lipopolysaccharide-induced acute lung injury by attenuating the TLR4/NF-κB pathway.

Acute lung injury (ALI), which is mainly triggered by infection, pneumonia, vasculitis, and sepsis, has no specific and effective therapy except for primary supportive treatment or bedside care. Excessive inflammation caused by innate immune cells is the major characteristic of ALI. Forsythoside B, a phenylethanoside compound, possesses good antioxidant and anti-bacterial properties in vivo and in vitro. In this study, the therapeutic potential of forsythoside B and its mechanism of action were investigated in a lipopolysaccharide (LPS)-induced ALI mouse model. The results showed that LPS-induced edema exudation and lung pathological changes in mice were significantly suppressed by forsythoside B pre-treatment. Furthermore, it also attenuated lung inflammation caused by LPS stimulation, evidenced by decreased inflammatory cell infiltration and down-regulated expression of cytokines, chemokines, and inducible enzymes. The anti-inflammation property of forsythoside B was confirmed in vitro using LPS-stimulated RAW 264.7 macrophages. Moreover, it alleviated LPS-induced inflammation by inhibiting the activation of TLR4/NF-κB signaling pathway in vivo and in vitro. In conclusion, the results demonstrated that forsythoside B protects against LPS-induced ALI by attenuating inflammatory cell infiltration and suppressing TLR4/NF-κB-mediated lung inflammation. Therefore, it might be a potential therapeutic agent for ALI caused by sepsis.

Mutation of cysteine 46 in IKK-beta increases inflammatory responses.

Activation of IκB kinase ß (IKK-ß) and nuclear factor (NF)-κB signaling contributes to cancer pathogenesis and inflammatory disease; therefore, the IKK-ß-NF-κB signaling pathway is a potential therapeutic target. Current drug design strategies focus on blocking NF-κB signaling by binding to specific cysteine residues on IKK-ß. However, mutations in IKK-ß have been found in patients who may eventually develop drug resistance. For these patients, a new generation of IKK-ß inhibitors are required to provide novel treatment options. We demonstrate in vitro that cysteine-46 (Cys-46) is an essential residue for IKK-ß kinase activity. We then validate the role of Cys-46 in the pathogenesis of inflammation using delayed-type hypersensitivity (DTH) and an IKK-ß C46A transgenic mouse model. We show that a novel IKK-ß inhibitor, dihydromyricetin (DMY), has anti-inflammatory effects on WT DTH mice but not IKK-ß C46A transgenic mice. These findings reveal the role of Cys-46 in the promotion of inflammatory responses, and suggest that Cys-46 is a novel drug-binding site for the inhibition of IKK-ß.

Gambogenic acid inhibits proliferation of A549 cells through apoptosis inducing through up-regulation of the p38 MAPK cascade.

Gamboge is a dry resin secreted from Garcinia hanburryi, and gambogenic acid (GNA) is one of the main active compounds of gamboge. We have previously demonstrated the anticancer activity of GNA in A549 cells and pointed out its potential effects in anticancer therapies. Previous studies reported that GNA induced apoptosis in many cancer cell lines and inhibited A549 tumor growth in xenograft of nude mice in vivo. However, the anticancer mechanism of GNA has still not been well studied. In this paper, we have investigated whether GNA-induced apoptosis is critically mediated by the p38 mitogen-activated protein kinase (MAPK) pathway. Our findings revealed that GNA could induce apoptosis, inhibit proliferation, down-regulate the expression of p38 and MAPK, increase the activations of caspase-9, caspase-3, and cytochrome c release. Furthermore, using SB203580, an adenosine triphosphate-competitive inhibitor of p38 MAPK, inhibit the expression of p-p38 and the experimental results show that it may promote the occurrence of apoptosis induced by GNA. Taken together, these results suggested that up-regulation of the p38 MAPK cascade may account for the activation of GNA-induced apoptosis.