LY2409881

Paraquat (PQ) is one of the most extensively used herbicides, possessing high toxicity for humans and animals. The lung is the main target organ by the poisoning of PQ resulting in acute lung injury. Nonetheless, molecular mechanisms underlying PQ-induced lung injury remain unclear. Here, we ask if angiopoietin-like protein 2 (Angptl2), a pro-inflammatory protein, contributes to inflammation that accelerates acute lung injury. The results indicated that abundant Angptl2 expression was observed in lung tissues of PQ-treated mice. Histological analysis revealed that PQ-induced histological changes were alleviated by Angptl2 knockout (Angptl2^-/-). Angptl2^-/- in PQ-treated mice attenuated acute lung injury progression by reducing the number of total cells, total leukocytes, neutrophils and macrophages in bronchoalveolar lavage fluid (BALF) and reducing inflammatory response through the inactivation of nuclear factor kappa B (NF-κB) pathway. Angptl2^-/- reduced oxidative stress in PQ-treated mice, as evidenced by the enhanced superoxide dismutase (SOD) activity and reduced malondialdehyde (MDA) levels in serum or lung tissue samples, which was accompanied with increased expressions of nuclear respiratory factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1). PQ-induced fibrosis was also improved in Angptl2^-/- mice by decreasing pulmonary transforming growth factor (TGF)-β1 expressions. In vitro, we found that Angptl2 knockdown-suppressed inflammation, oxidative stress and fibrosis was restored by increasing NF-κB activation in PQ-incubated A549 cells; however, the results above were significantly reversed by inactivating NF-κB using its inhibitor, Bay 11-7085 or LY2409881. Therefore, Angptl2 could provide therapeutic effects on PQ-induced acute lung injury through inhibiting inflammation, oxidative stress and fibrosis by regulating NF-κB pathway.

To investigate the effects and its potential mechanism of IKK2 inhibitor LY2409881 on proliferation, cell cycle and apoptosis of diffuse large B-cell lymphoma (DLBCL) cell lines.

CCK8 assay was used to detect the effect of LY2409881 on proliferation of DLBCL cell lines; Flow cytometry was used to analyze cell cycle; Western blot was used to analyze apoptosis and its potential mechanism.

LY2409881 inhibited the proliferation of multiple DLBCL cell lines obviously, and caused G₁ cell arrest. Furtherly, LY2409881 inhibited the expression of c-FLIP, induced the activation of DR4 and caspase 8. Meanwhile, LY2409881 induced the expression of pro-apoptotic protein BAX and inhibited the expression of anti-apoptotic protein MCL-1 and BCL-2.

LY2409881 inhibits the proliferation of DLBCL cell lines, causes G₁ cell arrest and induces apoptosis via the endogenous and exogenous apoptotic pathways.