Extracellular vesicles (EVs) from adipose tissue-derived stem cells have been reported to attenuate lipopolysaccharide (LPS) induced inflammation and sepsis while the specific mechanism is unclear. This study explored the underlying molecular mechanisms of EVs from adipose tissue-derived stem cells in reducing inflammation. LPS- induced macrophage models and mice model were established to mimic inflammation in vitro and in vivo . EVs were extracted from adipose tissue-derived stem cells and identified. It was found that proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, substantially decreased after EVs were applied to LPS-stimulated macrophages and mice, and thus, LPS induced M1 polarization was inhibited and sepsis was strongly alleviated. In the LPS induced macrophages, the expression of Notch signaling molecules and the activation of the NF-κB pathway were substantially decreased after the administration of EVs. Then, RBP-J −/− mice and macrophages were used. It was found that the miR-148a-3p level was significantly lower in the RBP-J −/− macrophages than in the wildtype macrophages. In the LPS induced macrophages, the increasing of miR-148a-3p was milder in the RBP-J −/− macrophages than in the wild type macrophages. Then, miR-148a-3p was overexpressed in macrophages and mice, and we found that the expression of proinflammatory cytokines was increased both in vivo and in vitro . The protective effect of EVs in LPS induced sepsis was diminished by the overexpression of miR-148a-3p. In conclusion, we proved that EVs could attenuate inflammation and further protect organ function by regulating the Notch-miR148a-3p signaling axis and then decreasing macrophage polarization to M1.

Celecoxib (CXB) is a poorly aqueous solubility sulfonamide non-steroidal anti-inflammatory drug (NSAID). Hence, the formulation of CXB was selected for solubilization and bioavailability. To find out suitable formulation for microemulsion, the solubility of CXB in triacetin (oil phase), Tween 80 (surfactant), and Transcutol-P (co-surfactant) was screened respectively and optimized by using orthogonal experimental design. The Km value and concentration of oil, S, and water were confirmed by pseudo-ternary phase diagram studies and central composite design. One percent carbopol 934 was added to form CXB microemulsion-based gel. The final formulation was evaluated for its appearance, pH, viscosity, stability, drug content determination, globule size, and zeta potential. Its ex vivo drug permeation and the in vivo pharmacokinetic was investigated. Further research was performed to ensure the safety and validity by skin irritation study and in vivo anti-inflammatory activity study. Ex vivo permeation study in mice was designed to compare permeation and transdermal ability between microemulsion formulation and conventional gel. The results revealed that optimized microemulsion-based gel gained higher permeation based on smaller globule size and high drug loading of microemulsion. Transdermal ability was also greatly improved. Bioavailability was compared to market Celebrex® by the in vivo pharmacokinetic study in rabbits. The results indicated that CXB microemulsion-based gel had better bioavailability than Celebrex®.

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In this paper, a novel self-nanoemulsifying drug delivery system (SNEDDS) was used to improve the oral bioavailability in fasted state and diminish the food effect for rivaroxaban. Oil, surfactant, and co-surfactant were selected by saturated solubility study. IPM, Tween80, and 1,2-propanediol were finally selected as oil, surfactant, and co-surfactant, respectively. The pseudo-ternary-phase diagram was utilized to optimize the preliminary composition of SNEDDS formulation. The optimized rivaroxaban-SNEDDS formulation was selected by central composite design (CCD) of response surface methodology. Optimized SNEDDS formulation was evaluated for drug content, self-emulsifying time, droplet size, zeta potential, polydispersity index, Fourier transform-infrared (FTIR) spectroscopy, and transmission electron microscope (TEM). The drug dissolution profile compared to the commercial formulation Xarelto® (20 mg rivaroxaban) was determined in four different media (pH 1.2HCl, pH 4.5NaAc-HAc, pH 6.8PBS, and water). The result indicated that the SNEDDS formulation had successfully increased the drug solubility in four different media. A HPLC-MS method that indicated a high sensitivity, strong attribute, and high accuracy characteristic was built to measure the drug concentration in plasma. The fast/fed in vivo pharmacokinetics studies of SNEDDS formulation and Xarelto® were carried out in adult beagle dog, rivaroxaban with no food effect was achieved in SNEDDS formulation compared with Xarelto® in fed state. The result suggested that SNEDDS formulation in this study is useful to increase the oral bioavailability and diminish the food effect in fasted state.