Development and cytotoxicity evaluation of multiple nanoemulsions for oral co-delivery of 5-fluorouracil and short chain triglycerides for colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer in the world, but current chemotherapy options are limited due to adverse effects and low oral bioavailability of drugs. In this study, we investigated the obtainment parameters and composition of new multiple nanoemulsions (MN) based on microemulsions for oral co-delivery of 5-fluorouracil (5FU) and short-chain triglycerides (SCT, either tributyrin or tripropionin). The area of microemulsion formation was increased from 14% to 38% when monocaprylin was mixed with tricaprylin as oil phase. Addition of SCT reduced this value to 24-26%. Using sodium alginate aqueous dispersion as internal aqueous phase (to avoid phase inversion) did not further affected the area but increased microemulsion viscosity by 1.5-fold. To obtain the MN, selected microemulsions were diluted in an external aqueous phase; droplet size was 500 nm and stability improved using polyoxyethylene oleyl ether at 1-2.5% as surfactant in the external phase and a dilution ratio of 1:1 (v/v). 5FU in vitro release could be better described by the Korsmeyer-Peppas model. No pronounced changes in droplet size were observed when selected MNs were incubated in buffers mimicking gastrointestinal fluids. The 5FU cytotoxicity in monolayer cell lines presenting various mutations was influenced by its incorporation in the nanocarrier, presence of SCT and cell mutation status. The MNs selected reduced the viability of tumor spheroids (employed as 3D tumor models) by 2.2-fold compared to 5FU solution and did not affect the survival of the G. mellonella, suggesting effectiveness and safety.

Embelin potentiates venetoclax-induced apoptosis in acute myeloid leukemia cells.

Acute myeloid leukemia (AML) belongs to a group of hematological cancer whose relapse cases are often associated with chemoresistance that impairs treatment success and contributes to a poor outcome. For this reason, there is an urgent need for the development of new therapeutic strategies. Herein, we explore the combination of venetoclax, a BCL2 inhibitor, and embelin, an XIAP inhibitor, in the AML cell lines. Combinatory treatment of venetoclax and embelin potentiated cytotoxic effects of these drugs, demonstrating that both in combination present lower IC50 values than single treatment of either venetoclax or embelin alone in both cell lines analyzed. The combinatory treatment further increased the apoptosis-inducing properties of both compounds. Computer simulations suggest that embelin binds to both BIR2 and BIR3 domains of XIAP, reinforcing this inhibitory apoptosis protein as an embelin target. Although all AML cell lines presented similar basal levels of XIAP, the combinatory treatment effectively inhibited XIAP expression in OCI-AML3 cells. In conclusion, the inhibition of both apoptosis inhibitory players, BCL2 and XIAP, by venetoclax and embelin, respectively, potentiated their cytotoxic effects in AML cell lines.

Ocean acidification affects parameters of immune response and extracellular pH in tropical sea urchins Lytechinus variegatus and Echinometra luccunter.

The rising concentration of atmospheric CO2 by anthropogenic activities is changing the chemistry of the oceans, resulting in a decreased pH. Several studies have shown that the decrease in pH can affect calcification rates and reproduction of marine invertebrates, but little attention has been drawn to their immune response. Thus this study evaluated in two adult tropical sea urchin species, Lytechinus variegatus and Echinometra lucunter, the effects of ocean acidification over a period of 24h and 5days, on parameters of the immune response, the extracellular acid base balance, and the ability to recover these parameters. For this reason, the phagocytic capacity (PC), the phagocytic index (PI), the capacity of cell adhesion, cell spreading, cell spreading area of phagocytic amebocytes in vitro, and the coelomic fluid pH were analyzed in animals exposed to a pH of 8.0 (control group), 7.6 and 7.3. Experimental pH's were predicted by IPCC for the future of the two species. Furthermore, a recovery test was conducted to verify whether animals have the ability to restore these physiological parameters after being re-exposed to control conditions. Both species presented a significant decrease in PC, in the pH of coelomic fluid and in the cell spreading area. Besides that, Echinometra lucunter showed a significant decrease in cell spreading and significant differences in coelomocyte proportions. The recovery test showed that the PC of both species increased, also being below the control values. Even so, they were still significantly higher than those exposed to acidified seawater, indicating that with the re-establishment of the pH value the phagocytic capacity of cells tends to restore control conditions. These results demonstrate that the immune system and the coelomic fluid pH of these animals can be affected by ocean acidification. However, the effects of a short-term exposure can be reversible if the natural values ​​are re-established. Thus, the effects of ocean acidification could lead to consequences for pathogen resistance and survival of these sea urchin species.

The impact of rising sea temperature on innate immune parameters in the tropical subtidal sea urchin Lytechinus variegatus and the intertidal sea urchin Echinometra lucunter.

Ocean temperatures are rising throughout the world, making it necessary to evaluate the impact of these temperature changes on sea urchins, which are well-known bioindicators. This study evaluated the effect of an increase in temperature on the immune response of the subtidal Lytechinus variegatus and the intertidal Echinometra lucunter sea urchins. Both species were exposed to 20 (control), 25 and 30 °C temperatures for 24 h, 2, 7 and 14 days. Counting of coelomocytes and assays on the phagocytic response, adhesion and spreading of coelomocytes were performed. Red and colorless sphere cells were considered biomarkers for heat stress. Moreover, a significant decrease in the phagocytic indices and a decrease in both cell adhesion and cell spreading were observed at 25 and 30 °C for L. variegatus. For E. lucunter, the only alteration observed was for the cell proportions. This report shows how different species of sea urchins respond immunologically to rising temperatures.