Irbesartan ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing NLRP3 inflammasomes in vivo and in vitro.

OBJECTIVES: Diabetic nephropathy (DN) is characterized by albuminuria and renal dysfunction caused by diabetes. At present there is no specific treatment for DN. Irbesartan (IRB) is an angiotensin receptor inhibitor indicated for the treatment of hypertension and DN. However, the underlying molecular mechanisms of IRB on DN remains obscure. METHODS: RAW264.7 macrophages were incubated in RPMI-1640, cell viability was evaluated by CCK-8 assays, transcriptional level of proinflammatory cytokines and was measured by ELISA and qPCR, NLRP3 inflammasome and Nrf2/Keap1 related proteins were measured by Western blotting and immunohistochemistry. Streptozotocin (STZ)-induced diabetic male C57BL/6 mice were used to evaluate the therapeutic effect of IRB on DN. Key findings First, we found that IRB improved high glucose-induced cell inflammation by inhibiting the transcription of IL-1ß and IL-18. IRB activated the Nrf2/Keap1 pathway and decreased the release of reactive oxygen species (ROS). IRB also suppressed the expression of NLRP3 and caspase-1. IRB combined with the N-acetylcysteine (NAC) significantly inhibited the activation of NLRP3 inflammasomes. Conversely, IRB combined with the Nrf2-related inhibitor ML385 enhanced NLRP3 inflammasome activation, suggesting that IRB suppressed NLRP3 inflammasome via the Nrf2 pathway. In vivo study, HE staining and immunohistochemistry analysis further showed that IRB ameliorated high glucose-induced renal injury by elevating the expression of the Nrf2/Keap1 signaling pathway and suppressing the proinflammatory cytokine and NLRP3 inflammasome activation. CONCLUSIONS: Our results suggested that IRB ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing the NLRP3 inflammasomes in vivo and in vitro. These findings provide new therapeutic strategies of diabetic nephropathy.

Co-assembly of cisplatin and dasatinib in hyaluronan nanogel to combat triple negative breast cancer with reduced side effects.

Treatment for triple negative breast cancer (TNBC) remains a huge challenge due to the lack of targeted therapeutics and tumor heterogenicity. Cisplatin (Cis) have demonstrated favorable therapeutic response in TNBC and thus is used together with various kinase inhibitors to fight the heterogenicity of TNBC. The combination of Cis with SRC inhibitor dasatinib (DAS) has shown encouraging anti-TNBC efficacy although the additive toxicity was commonly observed. To overcome the severe side effects of this Cis involved therapy, here we co-encapsulated Cis and DAS into a self-assembled hyaluronan (HA) nanogel (designated as HA/Cis/DAS (HCD) nanogel) to afford the TNBC targeted delivery by using the 4T1 mouse model. The acquired HCD nanogel was around 181 nm in aqueous solution, demonstrating the pharmacological activities of both Cis and DAS. Taking advantages of HA's targeting capability towards CD44 that is overexpressed on many TNBC cells, the HCD could well maintain the anticancer efficacy of the Cis and DAS combination, significantly increase the maximum tolerated dose and relieve the renal toxicity in vivo. The current HCD nanogel provides a potent strategy to improve the therapeutic outcome of Cis and DAS combination and thus representing a new targeted treatment option for TNBC.