Antioxidant and anti-inflammatory effects of SMTP-44D in a streptozotocin-induced diabetic neuropathy mouse model

IF 2.9 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Journal of diabetes and its complications Pub Date : 2025-04-29 DOI:10.1016/j.jdiacomp.2025.109061

Ryosuke Shinouchi , Keita Shibata , Taiju Nagatsuka , Keiji Hasumi , Koji Nobe

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引用次数: 0

Abstract

Background

Diabetic neuropathy (DN) is a debilitating complication of diabetes, driven by oxidative stress, inflammation, and advanced glycation end products (AGE) signaling through its receptor (RAGE). Soluble epoxide hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids (EETs) into pro-inflammatory dihydroxyeicosatrienoic acids (DHETs), exacerbating DN pathology. SMTP-44D, an sEH inhibitor, has demonstrated antioxidant and anti-inflammatory effects in vitro; however, its in vivo efficacy remains unclear.

Aim

To investigate the antioxidant and anti-inflammatory activities of SMTP-44D in relation to sEH inhibition and AGE/RAGE signaling in a streptozotocin (STZ)-induced DN mouse model.

Methodology

STZ-induced diabetic mice were treated with SMTP-44D (30 mg/kg) from days 8 to 28 post STZ injection (200 mg/kg). Oxidative stress markers, inflammatory factors, AGE in the sciatic nerve, and RAGE in serum were assessed via ELISA. DHET levels in serum were measured using LC-MS/MS, and apoptosis in the sciatic nerve was assessed via TUNEL staining and fluorescent immunohistochemistry for cleaved caspase-3.

Results

Our findings indicated that SMTP-44D inhibited sEH, reducing DHET levels and sustaining anti-inflammatory effects. It attenuated the migration of nuclear factor-kappa B, decreased AGE and RAGE levels, and suppressed oxidative stress and inflammatory markers in the sciatic nerve. Moreover, SMTP-44D inhibited apoptosis, potentially mitigating the axonal damage associated with DN.

Conclusion

Our findings suggest that SMTP-44D is a promising therapeutic agent for DN, acting through sEH inhibition and reducing AGE/RAGE levels.

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SMTP-44D在链脲佐菌素诱导的糖尿病神经病变小鼠模型中的抗氧化和抗炎作用

糖尿病神经病变（DN）是糖尿病的一种衰弱性并发症，由氧化应激、炎症和晚期糖基化终产物（AGE）信号通过其受体（RAGE）驱动。可溶性环氧化物水解酶（sEH）将抗炎环氧二碳三烯酸（EETs）代谢为促炎二羟基二碳三烯酸（DHETs），加重DN病理。SMTP-44D是一种sEH抑制剂，具有体外抗氧化和抗炎作用；然而，其体内功效尚不清楚。目的探讨SMTP-44D在链脲佐菌素（STZ）诱导的DN小鼠模型中抗氧化和抗炎活性与sEH抑制和AGE/RAGE信号通路的关系。方法STZ诱导的糖尿病小鼠在注射STZ （200 mg/kg）后第8 ~ 28天给予SMTP-44D （30 mg/kg）治疗。ELISA法检测氧化应激标志物、炎症因子、坐骨神经AGE、血清RAGE。采用LC-MS/MS检测小鼠血清DHET水平，采用TUNEL染色和裂解caspase-3荧光免疫组化检测小鼠坐骨神经凋亡情况。结果SMTP-44D抑制sEH，降低DHET水平，维持抗炎作用。它能减弱核因子κ B的迁移，降低AGE和RAGE水平，抑制坐骨神经氧化应激和炎症标志物。此外，SMTP-44D抑制细胞凋亡，可能减轻与DN相关的轴突损伤。结论SMTP-44D是一种很有前景的DN治疗药物，通过抑制sEH和降低AGE/RAGE水平发挥作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of diabetes and its complications 医学-内分泌学与代谢

CiteScore

5.90

自引率

3.30%

发文量

153

审稿时长

16 days

期刊介绍： Journal of Diabetes and Its Complications (JDC) is a journal for health care practitioners and researchers, that publishes original research about the pathogenesis, diagnosis and management of diabetes mellitus and its complications. JDC also publishes articles on physiological and molecular aspects of glucose homeostasis. The primary purpose of JDC is to act as a source of information usable by diabetes practitioners and researchers to increase their knowledge about mechanisms of diabetes and complications development, and promote better management of people with diabetes who are at risk for those complications. Manuscripts submitted to JDC can report any aspect of basic, translational or clinical research as well as epidemiology. Topics can range broadly from early prediabetes to late-stage complicated diabetes. Topics relevant to basic/translational reports include pancreatic islet dysfunction and insulin resistance, altered adipose tissue function in diabetes, altered neuronal control of glucose homeostasis and mechanisms of drug action. Topics relevant to diabetic complications include diabetic retinopathy, neuropathy and nephropathy; peripheral vascular disease and coronary heart disease; gastrointestinal disorders, renal failure and impotence; and hypertension and hyperlipidemia.