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.