Yimusake ameliorates corporal endothelial dysfunction by down-regulating the NLRP3 inflammasome-mediated NF-κB signaling pathway and inhibiting oxidative stress.

Abstract

Background: Yimusake, a traditional Uyghur medicine, can treat a variety of male diseases, but its effects and mechanisms on diabetes mellitus-induced erectile dysfunction (DMED) remain unclear.

Aim: This study was designed to investigate the key cytokines and mechanisms by which Yimusake ameliorates corporal endothelial dysfunction in DMED rats.

Methods: Firstly, normal rat penile corpus cavernosum endothelial cells (CCECs) were extracted and cultured in vitro, and the injury model was established after stimulation with 30 mM glucose for 24 hours. Subsequently, the cells were cultured in Yimusake drug-containing serum for 24 hours, and Sh-NLRP3 lentivirus was transfected for 8 hours. Cells were collected for the subsequent experiments. Next, the DM model was established using streptozotocin (45 mg/kg) for 2 consecutive injections, and DMED rats were screened by apomorphine and mating test at weeks 2, 4, 6, and 8, and then, we intervened for a fortnight using Yimusake (Y) and NLRP3 inhibitor (MCC950) drugs, and the penile tissues were taken for the subsequent analyses.

Outcomes: Our study demonstrates that Yimusake can downregulate the NLRP3-mediated NF-κB signalling pathway, inhibiting oxidative stress and mitigating the endothelial damage in corpus cavernosum endothelial cells.

Results: In the CCEC injury model established by 30 mM glucose, after incubation with Yimusake-containing drug serum and transfection with Sh-NLRP3 lentivirus, the expression of proteins and mRNAs related to the NF-κB signaling pathway mediated by NLRP3 was decreased, the expression of proteins related to oxidative stress was decreased, and the expression of proteins related to the endothelial function was increased. In DMED rats, after Yimusake and MCC950 interventions, the changes in pathway factors, oxidative stress levels, and endothelial function were consistent with the trends of in vitro experiments.

Clinical implications: Yimusake may ameliorate endothelial dysfunction in DMED by down-regulating the NLRP3 inflammasome-mediated NF-κB signaling pathway and inhibiting oxidative stress.

Strengths and limitations: Although we revealed that Yimusake can facilitate the restoration of the erectile tissue by improving endothelial function through inhibiting inflammation and oxidative stress, the effect was more significant with the combination of drugs, and the exact mechanism of action needs to be further explored.

Conclusion: These findings demonstrate that DM exacerbates oxidative stress and endothelial damage in the corpus cavernosum through activation of the NLRP3 inflammasome-mediated NF-κB pathway, whereas Yimusake can inhibit oxidative stress and mitigate endothelial damage by downregulating this pathway, thereby facilitating the restoration of erectile tissue in rats with DMED.