Inhibition of Nur77 expression and translocation by compound B6 reduces ER stress and alleviates cigarette smoke-induced inflammation and injury in bronchial epithelial cells

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide with inflammation and injury in airway epithelial cells. However, few treatment options effectively reduce severity. We previously found that Nur77 is involved in lipopolysaccharide-induced inflammation and injury of lung tissue. Here, we established an in vitro model of COPD-related inflammation and injury in 16-HBE cells induced by cigarette smoke extract (CSE). In these cells, Nur77 expression and localization to the endoplasmic reticulum (ER) increased following CSE treatment, as did ER stress marker (BIP, ATF4, CHOP) expression, inflammatory cytokine expression, and apoptosis. The flavonoid derivative, named B6, which was shown to be a modulator of Nur77 in previous screen, molecular dynamics simulation revealed that B6 binds strongly to Nur77 through hydrogen bonding and hydrophobic interactions. Treating CSE-stimulated 16-HBE cells with B6 resulted in a reduction of both inflammatory cytokine expression and secretion, as well as attenuated apoptosis. Furthermore, B6 treatment resulted in a decrease in Nur77 expression and translocation to the ER, which was accompanied by a concentration-dependent reduction in the expression of ER stress markers. Meanwhile, B6 played a similar role in CSE-treated BEAS-2B cells. These combined effects suggest that B6 could inhibit inflammation and apoptosis in airway epithelial cells after cigarette smoke stimulation, and support its further development as a candidate intervention for treating COPD-related airway inflammation

Imaging-guided synergistic targeting-promoted photo-chemotherapy against cancers by methotrexate-conjugated hyaluronic acid nanoparticles

Abstract(#br)A combination of chemotherapy and photothermal therapy (PTT) against cancer, overcoming the intrinsic limitations of single-modal chemotherapy or PTT, has emerged as a promising strategy to achieve synergistic therapeutic effect. However, the lack of precise drug delivery and intelligent drug release based on photo-chemotherapy at specific tumor sites remained a challenge. Hence, the both tumor-specific targeting molecule (methotrexate) and ligand (hyaluronic acid)-introduced, glutathione-responsive amphiphiles (deoxycholic acid-hyaluronic acid-methotrexate, DA-SS-HA-MTX) were developed for synchronous delivery of indocyanine green (ICG) and doxorubicin (DOX). The as-synthesized DOX/ICG@DSHM remarkably improved the intracellular drug uptake and accumulation owing to both the CD44/folate receptors-mediated synergistic targeting and the glutathione-triggered rapid drug release. Moreover, DOX/ICG@DSHM efficiently accumulated at the tumor sites, realizing the notable tumor ablation under the guidance of dual-modal optical imaging. Taken together, this study provided a promising nanotheranostic agent for imaging-guided chemo-photothermal combination therapy

PEG–lipid–PLGA hybrid nanoparticles loaded with berberine–phospholipid complex to facilitate the oral delivery efficiency

The natural product berberine (BBR), present in various plants, arouses great interests because of its numerous pharmacological effects. However, the further development and application of BBR had been hampered by its poor oral bioavailability. In this work, we report on polymer–lipid hybrid nanoparticles (PEG–lipid–PLGA NPs) loaded with BBR phospholipid complex using a solvent evaporation method for enhancing the oral BBR efficiency. The advantage of this new drug delivery system is that the BBR–soybean phosphatidylcholine complex (BBR–SPC) could be used to enhance the liposolubility of BBR and improve the affinity with the biodegradable polymer to increase the drug-loading capacity and controlled/sustained release. The entrapment efficiency of the PEG–lipid–PLGA NPs/BBR–SPC was observed to approach approximately 89% which is more than 2.4 times compared with that of the PEG–lipid–PLGA NPs/BBR. To the best of our knowledge, this is the first report on using polymer material for effective encapsulation of BBR to improve its oral bioavailability. The prepared BBR delivery systems demonstrated a uniform spherical shape, a well-dispersed core-shell structure and a small particle size (149.6 ± 5.1 nm). The crystallographic and thermal analysis has indicated that the BBR dispersed in the PEG–lipid–PLGA NPs matrix is in an amorphous form. More importantly, the enhancement in the oral relative bioavailability of the PEG–lipid–PLGA NPs/BBR–SPC was ∼343% compared with that of BBR. These positive results demonstrated that PEG–lipid–PLGA NPs/BBR–SPC may have the potential for facilitating the oral drug delivery of BBR