Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma.

Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or ß-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2-tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM.

Simultaneous determination of allantoin and glycolic acid in snail mucus and cosmetic creams with high performance liquid chromatography and ultraviolet detection.

A new methodology for simultaneous quantitative analysis of allantoin and glycolic acid in snail mucus and cosmetic creams was developed. HPLC separation was achieved a Synergi-Hydro RP column within 7min using isocratic elution with potassium phosphate (pH 2.7; 10mM) at a flow rate of 0.7mL/min at 30°C. Sample pretreatment was performed by dilution of mucus or cosmetic cream in the elution buffer, heating at 60°C for 20min, adjusting the pH to 2.9 and purification with hexane extraction. Linearity was determined with spiked samples and the LLOQ values of 0.0125 and 0.2500mg/mL were determined for allantoin and glycolic acid, respectively. Accuracy and intra- and inter-day repeatability were studied at three levels of concentrations (0.04, 0.08 and 0.16mg/mL for allantoin and 0.1, 1.5 and 4.0mg/mL for glycolic acid) using spiked mucus and cream base samples; mean values of recovery were in the range of 96.81-102.42% in all matrices tested, whereas the respective RSDs (%Relative Standard Deviation) were less than 3.04% in all cases. Spiked mucus and cream samples were stable (RSD<4.16 and relative error<4.34%) at room temperature and at 4°C for 1 week and at -18°C for 6 months; samples were also stable after three freeze-thaw cycles. The method was applied to the analysis of different lots of snail mucus, and of three commercial creams containing snail mucus.