piplartine and Acute-Lung-Injury

Acute lung injury (ALI) is a fatal acute inflammatory illness with restricted therapeutic choices clinically. Piperlongumine (PL) is recognized as an alkaloid separated from Piper longum L, which was suggested to exhibit multiple pharmacological activities (e.g., anti-inflammatory activity). However, the effects of PL on LPS-triggered ALI and its anti-inflammatory target remain unclear. This paper intended to assess the roles of PL in LPS-triggered ALI, as well as its underlying mechanism and target.. In vivo, ALI was induced by intratracheal injection of LPS to evaluate protective effects of PL and assessed by the changes of histopathological. In vitro, the anti-inflammatory activity and mechanism of PL were investigated by ELISA, RT-qPCR, transcription factor enrichment analysis, Western blotting and Immunofluorescence assay. The binding affinity of PL to MD2 was analyzed using computer docking, surface plasmon resonance, ELISA and immunoprecipitation assay.. It was reported here that PL treatment alleviated LPS-induced pulmonary damage, inflammatory cells infiltration and inflammatory response in mice. In culture cells, PCR array showed that PL significantly inhibited LPS-induced inflammatory cytokines, chemokines, and type I IFNs genetic expression, along with the inhibition of TAK1 and TBK1 pathway. It is noteworthy that PL is capable of straightly binding to MD2 and inhibiting MD2/TLR4 complex formation and TLR4 dimerization.. As revealed from this study, PL directly binding to MD2 to block cytokines expression by inhibiting the activation of TAK1 and TBK1 pathway, which then exerted its pulmonary protective activity. Accordingly, PL may act as an underlying candidate for treating LPS-triggered ALI.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Cytokines; Inflammation; Lipopolysaccharides; Lung; Mice; NF-kappa B; Toll-Like Receptor 4

A novel series of di-carbonyl analogs of curcumin (DACs) were prepared and evaluated for their anti-inflammatory properties. Preliminary results showed that a vast majority of compounds tested in this study could effectively suppress LPS-induced production of tumor necrosis factor (TNF)-α and interleukin (IL)-6. Structure-activity relationships of the compounds were discussed. Compounds 5a27 and 5a28 showed the most potent anti-inflammatory activities and had higher structural stability and orally bioavailability than curcumin in vitro. Mechanistically, they inhibited the activation of macrophages via the blockade of mitogen-activated protein kinase (MAPK) signaling and nuclear translocation of NF-κB. In vivo, 5a27 and 5a28 markedly alleviated lipopolysaccharides (LPS)-induced acute lung injury (ALI). The wet/dry ratio of lungs was significantly normalized by the active compounds, which was consistent with the suppression of neutrophil infiltration and production of proinflammatory cytokines. Collectively, these results present a new series of curcumin analogs as promising anti-inflammatory agents for treatment of ALI.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Biological Availability; Curcumin; Drug Design; Interleukin-6; Lipopolysaccharides; Macrophage Activation; Mice; Mitogen-Activated Protein Kinases; NF-kappa B; Signal Transduction; Structure-Activity Relationship; Tumor Necrosis Factor-alpha