Icariside II alleviates lipopolysaccharide-induced acute lung injury by inhibiting lung epithelial inflammatory and immune responses mediated by neutrophil extracellular traps.

AIMS: Acute lung injury (ALI) is a life-threatening lung disease characterized by inflammatory cell infiltration and lung epithelial injury. Icariside II (ICS II), one of the main active ingredients of Herba Epimedii, exhibits anti-inflammatory and immunomodulatory effects. However, the effect and mechanism of ICS II in ALI remain unclear. The purpose of the current study was to investigate the pharmacological effect and underlying mechanism of ICS II in ALI. MAIN METHODS: Models of neutrophil-like cells, human peripheral blood neutrophils, and lipopolysaccharide (LPS)-induced ALI mouse model were utilized. RT-qPCR and Western blotting determined the gene and protein expression levels. Protein distribution and quantification were analyzed by immunofluorescence. KEY FINDINGS: ICS II significantly reduced lung histopathological damage, edema, and inflammatory cell infiltration, and it reduced pro-inflammatory cytokines in ALI. There is an excessive activation of neutrophils leading to a significant production of NETs in ALI mice, a process mitigated by the administration of ICS II. In vivo and in vitro studies found that ICS II could decrease NET formation by targeting neutrophil C-X-C chemokine receptor type 4 (CXCR4). Further data showed that ICS II reduces the overproduction of dsDNA, a NETs-related component, thereby suppressing cGAS/STING/NF-κB signalling pathway activation and inflammatory mediators release in lung epithelial cells. SIGNIFICANCE: This study suggested that ICS II may alleviate LPS-induced ALI by modulating the inflammatory response, indicating its potential as a therapeutic agent for ALI treatment.

Preparation of 2-Methoxyestradiol Self-emulsified Drug Delivery System and the Effect on Combination Therapy with Doxorubicin Against MCF-7/ADM Cells.

Due to the poor solubility and bioavailability of 2-methoxyestradiol (2-ME), 2-ME emulsified drug delivery system (2-ME-SEDDS) was designed and characterized. After dilution with 5% glucose, 2-ME-SEDDS formed fine emulsions with mean diameter of 171 ± 14 nm and zeta potential of - 7.4 ± 0.6 mV. The cytotoxicity of 2-ME-SEDDS against MCF-7 and MCF-7/ADM cells was considerable to that of free 2-ME, and the half maximal inhibitory concentration ran up to 195 µg/mL on MCF-7/ADM cells. In order to gain a satisfactory inhibition effect on MCF-7/ADM cells, 2-ME-SEDDS combined with doxorubicin was used. It is worth noting that the combination of 2-ME-SEDDS and doxorubicin displayed a superior synergistic effect with a combined index of 0.62. And the cellular uptake of doxorubicin by MCF-7/ADM cells in the combination group was significantly higher than that of doxorubicin treatment group. The study preliminarily suggested that 2-ME-SEDDS could increase the cellular uptake of doxorubicin by MCF-7/ADM cells and the synergistic effect may be attributed to the increased cellular uptake of doxorubicin under the influence of 2-ME-SEDDS. In conclusion, SEDDS was an alternative and promising formulation for 2-ME. The combination therapy with synergistic effect by the combination of 2-ME-SEDDS and doxorubicin seems to be a promising strategy to potentiate anti-tumor efficiency against MCF-7/ADM, even other multidrug resistance tumors.