Adenine derivatives invert high glucose-induced thioredoxin-interacting protein overexpression.

Overexpression of thioredoxin-interacting protein (TXNIP) is associated with reduced insulin sensitivity and β-cell apoptosis. We have previously shown that W2476 inhibited high glucose-induced TXNIP expression at both mRNA and protein levels in INS-1E cells. In this study, we describe structural modification and optimization of W2476 leading to three more active derivatives, 8d, 8g, and 9h, capable of suppressing TXNIP expression in BG73 and INS-1E cells, increasing insulin production, and reducing high glucose-induced apoptosis in INS-1E cells.

Zhong L ，Liu Q ，Ting YS ，Thien VY ，Binti Kalong NS ，Yang D ，Wang MW ... -  《-》

W2476 ameliorates β-cell dysfunction and exerts therapeutic effects in mouse models of diabetes via modulation of the thioredoxin-interacting protein signaling pathway.

Li T ，Lin GY ，Zhong L ，Zhou Y ，Wang J ，Zhu Y ，Feng Y ，Cai XQ ，Liu Q ，Nosjean O ，Boutin JA ，Renard P ，Yang DH ，Wang MW ... -  《-》

Palmitate and insulin counteract glucose-induced thioredoxin interacting protein (TXNIP) expression in insulin secreting cells via distinct mechanisms.

Panse M ，Kluth O ，Lorza-Gil E ，Kaiser G ，Mühlbauer E ，Schürmann A ，Häring HU ，Ullrich S ，Gerst F ... -  《PLoS One》

Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets.

Shaked M ，Ketzinel-Gilad M ，Ariav Y ，Cerasi E ，Kaiser N ，Leibowitz G ... -  《-》

W2476 represses TXNIP transcription via dephosphorylation of FOXO1 at Ser319.

Thioredoxin-interacting protein (TXNIP) overexpression is implicated in the pathogenesis of type 2 diabetes. Previous studies have shown that a small molecule compound (W2476) was able to improve β-cell dysfunction and exert therapeutic effects in diabetic mice via repression of TXNIP signaling pathway. The impact of W2476 on TXNIP transcription was thus investigated using the chromatin immunoprecipitation method. It was found that W2476 promotes competitive binding of forkhead box O1 transcription factor (FOXO1) to the carbohydrate response element (ChoRE) sequence associated with ChoRE-binding protein (ChREBP)/Mlx interacting protein-like(Mlx) complexes. This interaction hinders the attachment of histone acetyltransferase p300 and reduces histone H4 acetylation on the TXNIP promoter, leading to decreasing TXNIP transcription.

Zhong L ，Liu Q ，Liu Q ，Zhang S ，Cao Y ，Yang D ，Wang MW ... -  《-》