This study is the first to reveal the potential value of icaritin in the treatment of urothelial cancer, and provides new ideas and targets for the treatment of urothelial cancer by thoroughly investigating its mechanism of action.
Macrophages are myeloid cells of the innate immune system that are found in all human tissues in the body and exhibit anatomical and functional diversity. These heterogenous cells are derived from monocyte precursors in the blood that infiltrate into the tissues and differentiate in the presence of cytokines and growth factors.
Interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β) are pro-inflammatory cytokines (1). IL-1α is produced by many cell types, including epithelial cells, monocytes, and macrophages (1,2). It is typically sequestered but can be released during necroptosis or inflammasome activation (3-5). IL-1α is active in both its uncleaved (pro-IL-1α) and cleaved forms and thus acts as an alarmin, initiating signaling through IL-1R1 (6). IL-1β is not active until it is cleaved (7,8). IL-1β expression is induced by inflammatory stimuli, including TLR ligands, IL-1β itself, and tumor necrosis factor-alpha (TNF-α) (1,9,10). IL-1β is primarily synthesized by activated monocytes and macrophages. It activates innate immune cells and polarizes CD4+ T cells toward T helper (Th) 1 and Th17 cells (10).
Exosomes are small (30-150 nm) membrane-bound vesicles that are secreted by various cell types under normal and pathological conditions (1,2). They originate from intracellular multivesicular endosomes upon fusion with the plasma membrane. Exosomes have emerged as an important mechanism of intercellular communication facilitating the transfer of membrane and cytosolic proteins, lipids, and RNA.
Cluster of Differentiation 3 (CD3) is a multiunit protein complex expressed on the surface of T cells that directly associates with the T cell receptor (TCR). CD3 is composed of four polypeptides: ζ, γ, ε and δ. Engagement of the TCR complex with antigens presented in Major Histocompatibility Complexes (MHC) induces tyrosine phosphorylation in the immunoreceptor tyrosine-based activation motif (ITAM) of CD3 proteins.
Cluster of Differentiation 3 (CD3) is a multiunit protein complex expressed on the surface of T cells that directly associates with the T cell receptor (TCR). CD3 is composed of four polypeptides: ζ, γ, ε, and δ. Engagement of the TCR complex with antigens presented in major histocompatibility complexes induces tyrosine phosphorylation in the immunoreceptor tyrosine-based activation motif (ITAM) of CD3 proteins. CD3 phosphorylation is required for downstream signaling through ZAP-70 and p85 subunit of PI-3 kinase, leading to T cell activation, proliferation, and effector functions (1).
The study used BV2 microglial cells and mice as research models to systematically investigate the regulatory effect of manganese exposure on the cGAS-STING pathway, as well as the intrinsic relationship between this pathway and ROS, cell apoptosis, and ferroptosis. It deeply revealed the potential molecular mechanism of manganese-induced neurotoxicity, providing a new research perspective and solid theoretical basis for the prevention and control of manganese neurotoxicity-related diseases, target screening, and clinical intervention.
Heat shock protein (HSP) 27 is one of the small HSPs that are constitutively expressed at different levels in various cell types and tissues. Like other small HSPs, HSP27 is regulated at both the transcriptional and posttranslational levels (1). In response to stress, the HSP27 expression increases several-fold to confer cellular resistance to the adverse environmental change. HSP27 is phosphorylated at Ser15, Ser78, and Ser82 by MAPKAPK-2 as a result of the activation of the p38 MAP kinase pathway (2,3). Phosphorylation of HSP27 causes a change in its tertiary structure, which shifts from large homotypic multimers to dimers and monomers (4). It has been shown that phosphorylation and increased concentration of HSP27 modulates actin polymerization and reorganization (5,6).
