RESUMO
Acne vulgaris, rosacea, and hidradenitis suppurativa are enduring inflammatory skin conditions that frequently manifest with akin clinical attributes, posing a considerable challenge for their distinctive diagnosis. While these conditions do exhibit certain resemblances, they also demonstrate distinct underlying pathophysiological mechanisms and treatment modalities. Delving into both the molecular parallels and disparities among these three disorders can yield invaluable insights for refined diagnostics, effective management, and targeted therapeutic interventions. In this report, we present a comparative analysis of transcriptomic data across these three diseases, elucidating differentially expressed genes and enriched pathways specific to each ailment, as well as those shared among them. We also identified high dose dietary zinc as a potential therapeutic agent and validated its efficacy in an acne mouse model.
RESUMO
Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptosis, and protein targets for the development of anti-cancer drugs. Cellular inhibitor of apoptosis protein-1 (cIAP1) is an important member of IAPs. Peptides or small-molecular antagonists can induce the dimerization, auto-ubiquitination, and proteasomal degradation of the cellular inhibitor of apoptosis protein-1 (cIAP1). While in the absence of antagonists, several mutations of the cIAP1 protein also lead to its dimerization and auto-ubiquitination. Even though the crystal structure of cIAP1 protein has been determined, the intrinsic mechanism of its dimerization remains unexplored. Accumulating evidence indicated that intrinsic conformational change existed during the binding of antagonists with cIAP1 protein, or introduction of mutations. To reveal this intrinsic conformational change, molecular dynamics simulations at microsecond scale were applied for the wild-type and mutant-type cIAP1 proteins. Compared to the crystal structure, significant conformational change was observed during the simulations, which could explain the importance of previously identified key mutations. To validate these findings revealed by our simulations, a new mutation D303A was constructed and the following native polyacrylamide gel electrophoresis (native-PAGE) assay observed a proportion of spontaneous dimerization, in comparison with the wild-type control. Taken together, these computational and experimental results revealed the intrinsic conformational change of cIAP1, which could not only explain previously identified key mutations, but also be exploited for further design and development of anti-tumor compounds that target the cIAP1 protein.Communicated by Ramaswamy H. Sarma.