In vitro and in vivo effects of Galectin-3 inhibitor TD139 on inflammation and ERK/JNK/p38 pathway in gestational diabetes mellitus.

Abstract

This study aims to investigate the effects of the Galectin-3 (Gal-3) inhibitor TD139 on inflammation and the extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/p38 pathway in gestational diabetes mellitus (GDM). Human placental tissues were treated with TD139 and TNF-α, assessing Gal-3, ERK/JNK/p38 activation, and inflammatory cytokines. GDM was induced in mice via subcutaneous injections of streptozotocin (STZ). After confirming GDM, mice were treated with 15 mg/kg TD139 on GD 10.5 12.5, 14.5, 16.5, and 18.5. Serum inflammatory cytokines were measured on GD 20.5, and post-delivery placental tissues were analyzed. Data were analyzed using one-way or two-way repeated measures ANOVA with post hoc tests. TD139 suppressed TNF-α-induced increases in Gal-3, IL-1β, IL-6, MCP-1, and ERK/JNK/p38 activation in placental tissues. In STZ-induced GDM mice, TD139 reduced glucose levels, weight loss, and food and water intake. TD139 significantly lowered TNF-α, IL-1β, IL-6, and MCP-1 in serum and placental tissues and inhibited the ERK/JNK/p38 pathway. TD139 improved pup numbers in GDM mice compared to untreated ones. TD139 reduces inflammation and inhibits the ERK/JNK/p38 pathway in TNF-α stimulated placental tissues and STZ-induced GDM mice, suggesting its therapeutic potential for managing GDM-related placental inflammation and improving pregnancy outcomes. The study used TNF-α to mimic GDM in placental tissues and an STZ-induced GDM mouse model, which may not fully represent human GDM complexity. Future research should explore alternative models, and broader signaling pathways, and thoroughly evaluate TD139's safety in pregnancy.