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Curcumin (CUR) is a natural compound extracted from turmeric (Curcuma longa), which has been reported to be a promising anti-cancer drug in various cancers. However, poor water solubility and low bioavailability posed a challenge for clinical application of curcumin. In this work, four CUR prodrugs, namely PEG4000-SS-CUR, PEG1500-SS-CUR, PEG4000-SeSe-CUR and PEG1500-SeSe-CUR were synthesized. These four CUR prodrugs have high CUR loading content and can self-assemble into spherical nanoparticles (NPs) with particle size of 90–190 nm in aqueous solution. The four CUR prodrug NPs exhibit good colloidal stability in PBS buffer and promoted drug release in response to GSH. Due to the enhanced water solubility, the four CUR prodrug NPs all exhibit reduced cellular uptake amount as compared to CUR in in vitro cellular uptake study. The four CUR prodrug NPs exhibit similar cytotoxicity against 22Rv1 cells as compared to free CUR while PEG4000-SeSe-CUR NPs exhibit the highest cytotoxicity and induce the highest cell apoptosis ratio against 4T1 cells in in vitro antitumor effect study. PEG4000-SeSe-CUR NPs developed in this work were proven to be an effective nanoformulation of CUR against 4T1 cells. [ABSTRACT FROM AUTHOR]

The migration is the key step for thymic T cells to enter circulation and then lymph nodes (LNs), essential for future immune surveillance. Although promoter-based transcriptional regulation through Foxo1, Klf2, Ccr7, and Sell regulates T-cell migration, it remains largely unexplored whether and how enhancers are involved in this process. Here we found that the conditional deletion of Med1, a component of the mediator complex and a mediator between enhancers and RNA polymerase II, caused a reduction of both CD4 + and CD8 + T cells in LNs, as well as a decrease of CD8 + T cells in the spleen. Importantly, Med1 deletion hindered the migration of thymic αβT cells into the circulation and then into LNs, accompanied by the downregulation of KLF2, CCR7, and CD62L. Mechanistically, Med1 promotes Klf2 transcription by facilitating Foxo1 binding to the Klf2 enhancer. Furthermore, forced expression of Klf2 rescued Ccr7 and Sell expression, as well as αβT-cell migration into LNs. Collectively, our study unveils a crucial role for Med1 in regulating the enhancer-based Foxo1-Klf2 transcriptional program and the migration of αβT cells into LNs, providing valuable insights into the molecular mechanisms underlying T-cell migration., (© 2024 Wiley‐VCH GmbH.)

CD8 + T cell immune responses are regulated by multi-layer networks, while the post-translational regulation remains largely unknown. Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins. Here, by targeting the sheddase A Disintegrin and Metalloprotease (ADAM)17, we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8 + T cells. Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8 + T cells. T cell-specific deletion of ADAM17 led to a dramatic increase in effector CD8 + T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors. Mechanistically, ADAM17 regulated CD8 + T cells through cleavage of membrane CD122. ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8 + T cells. Intriguingly, inhibition of ADAM17 in CD8 + T cells improved the efficacy of chimeric antigen receptor (CAR) T cells in solid tumors. Our findings reveal a critical post-translational regulation in CD8 + T cells, providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity., (© 2024. The Author(s).)