Division of Pharmacology, Department of Pharmacology, Toxicology & Therapeutics, School of Pharmacy, Pharmacology Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Department of Applied Biological Science, Tokyo University of Agriculture and Technology, 3-5-8 Saiwaicho, Fuchu-shi, Tokyo 183-8509, Japan.
Int J Mol Sci. 2022 May 6;23(9):5187. doi: 10.3390/ijms23095187.
Diabetic neuropathy (DN) is a major complication of diabetes mellitus. We have previously reported the efficacy of triprenyl phenol-44D (SMTP-44D) for DN through its potential antioxidant and anti-inflammatory activities. However, the mechanisms underlying the antioxidant and anti-inflammatory activities of SMTP-44D remain unclear. The present study aimed to explore the mechanism of these effects of SMTP-44D in regard to its inhibition of soluble epoxide hydrolase (sEH) in immortalized mouse Schwann cells (IMS32) following high glucose treatment. IMS32 cells were incubated in a high glucose medium for 48 h and then treated with SMTP-44D for 48 h. After incubation, the ratio of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), oxidative stress markers, such as NADPH oxidase-1 and malondialdehyde, inflammatory factors, such as the ratio of nuclear to cytosolic levels of NF-κB and the levels of IL-6, MCP-1, MMP-9, the receptor for the advanced glycation end product (RAGE), and apoptosis, were evaluated. SMTP-44D treatment considerably increased the ratio of EETs to DHETs and mitigated oxidative stress, inflammation, RAGE induction, and apoptosis after high glucose treatment. In conclusion, SMTP-44D can suppress the induction of apoptosis by exerting antioxidant and anti-inflammatory effects, possibly through sEH inhibition. SMTP-44D can be a potential therapeutic agent against DN.
糖尿病神经病变（DN）是糖尿病的主要并发症。我们之前曾报道过三异戊烯基对苯二酚-44D（SMTP-44D）通过其潜在的抗氧化和抗炎活性对 DN 的疗效。然而，SMTP-44D 的抗氧化和抗炎活性的机制尚不清楚。本研究旨在探讨 SMTP-44D 在高糖处理后抑制永生化小鼠雪旺细胞（IMS32）中可溶性环氧化物水解酶（sEH）的机制。将 IMS32 细胞在高葡萄糖培养基中孵育 48 h，然后用 SMTP-44D 处理 48 h。孵育后，评估 epoxyeicosatrienoic acids（EETs）与 dihydroxyeicosatrienoic acids（DHETs）的比例、氧化应激标志物（如 NADPH 氧化酶-1 和丙二醛）、炎症因子（如核质比的 NF-κB 和 IL-6、MCP-1、MMP-9、晚期糖基化终产物受体（RAGE）的水平和细胞凋亡）。SMTP-44D 处理可显著增加 EETs 与 DHETs 的比例，并减轻高糖处理后的氧化应激、炎症、RAGE 诱导和细胞凋亡。总之，SMTP-44D 通过发挥抗氧化和抗炎作用可以抑制细胞凋亡的诱导，这可能是通过抑制 sEH 实现的。SMTP-44D 可能是治疗糖尿病神经病变的潜在治疗剂。
