TMPA is characterized as a high-affinity antagonist of Nur77, a mechanism that prompts the liberation and translocation of LKB1 into the cytoplasm, thereby activating AMPKα. This action has significant implications for diabetes management, as TMPA effectively reduces blood glucose levels and mitigates insulin resistance in various models of diabetes, including type II db/db, high-fat diet, and streptozotocin-induced diabetic mice. Furthermore, TMPA demonstrates potential therapeutic value in cancer and T-cell apoptosis regulation by diminishing restimulation-induced cell death (RICD) in human T cells[1][2].
体内研究
When administered intraperitoneally at a dose of 50 mg/kg daily for 19 days, TMPA significantly lowers blood glucose and enhances glucose tolerance in type II diabetic mice, showcasing its therapeutic potential for diabetes treatment[1].
体外研究
In hepatic LO2 cells, TMPA disrupts the Nur77-LKB1 interaction in both dose- and time-dependent manners, providing insight into its method of inhibiting this specific protein-protein interaction[1].
Additionally, at a concentration of 10 μM over 6 hours, TMPA fosters the interaction between LKB1 and AMPKα, while concurrently reducing the LKB1-Nur77 interaction under physiological conditions, further evidencing its role in metabolic regulation[1].
TMPA's direct binding to the ligand-binding domain (LBD) in a specific conformation underscores its targeted mechanism of action[1].
TMPA also induces the nuclear export of LKB1 to activate AMPKα in Lo2 cells, highlighting a key pathway through which it exerts its effects on glucose metabolism and insulin sensitivity[1].
At concentrations ranging from 10 to 100 μM for 4 hours, TMPA impairs RICD in human T cells, indicating its potential utility in studies focused on T-cell survival and apoptosis[2].
搜索
