Danshensu attenuates type 2 diabetes-related osteoporosis via the PI3K/AKT/Nrf2 signaling pathway

Abstract

Danshensu (DSS), a water-soluble phenolic acid derived from Salvia miltiorrhiza, exhibits antioxidant and osteoprotective properties; however, its effects on type 2 diabetes-related osteoporosis (T2DOP) have not been fully defined. We therefore evaluated the effects of DSS on T2DOP and examined whether PI3K/AKT/Nrf2 signaling participates in its actions. Potential molecular targets and signaling pathways associated with DSS were first screened through a network pharmacology approach. In vivo, T2DOP was induced in mice by high-fat feeding followed by low-dose streptozotocin administration; in parallel, high-glucose-exposed BMSCs served as the cellular model. DSS improved trabecular bone microarchitecture and alleviated bone loss in T2DOP mice. In high-glucose-treated BMSCs, DSS reduced ROS and MDA levels, enhanced SOD and CAT activities, and preserved osteogenic capacity, with higher ALP activity, greater mineralized nodule formation, and increased expression of osteogenesis-related markers. DSS treatment was also accompanied by enhanced PI3K and AKT phosphorylation together with higher Nrf2 expression. Blocking either PI3K or Nrf2 pharmacologically weakened the DSS-induced responses. Collectively, DSS appears to counter T2DOP partly by engaging PI3K/AKT/Nrf2-related antioxidant responses and maintaining osteogenic differentiation.