This study aimed to investigate the functions of miR-214-3p in diabetic neuropathic rodents. The diabetic neuropathy was induced by intraperitoneal injection of streptozotocin (STZ) in rats, and miR-214-3p was delivered via tail vein injection of lentivirus. Hot or cold stimulus tests demonstrated that STZ induced thermal hyperalgesia. Neurophysiological measurements revealed that motor and sensory nerve conduction velocity and nerve blood flow were decreased in diabetic neuropathic rats. However, the STZ-induced hyperalgesia, and reduced nerve conduction velocity and nerve blood flow were all significantly reversed by miR-214-3p administration. HE staining, TUNEL, ELISA, and immunoblotting demonstrated that STZ led to obvious pathological lesion, cell apoptosis, and inflammation in dorsal root ganglion (DRG), evidenced by altered levels of apoptosis-related protein molecules and inflammatory factors, and activation of Toll-like receptor 4 (TLR4)/myeloid differentiation primary response gene 88/nuclear factor kappa B signaling. The pathological alterations in diabetic neuropathic rats in DRG were significantly ameliorated by miR-214-3p application. In addition, sodium channel protein type 3 subunit alpha isoform 1 (Nav1.3) and TLR4 were identified as targets of miR-214-3p via dual-luciferase reporter assay. MiR-214-3p may play its roles by downregulating Nav1.3 and TLR4. In summary, miR-214-3p alleviated diabetes-induced nerve injury, and pathological lesion, cell apoptosis, and inflammation in DRG by regulating Nav1.3 and TLR4 in STZ-induced rats. These findings may provide novel therapeutic targets for clinical treatment of diabetic neuropathy.

中文翻译：

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MiR-214-3p 通过调节 Nav1.3 和 TLR4 在糖尿病神经病变大鼠中发挥保护作用


本研究旨在探讨 miR-214-3p 在糖尿病神经病变啮齿动物中的功能。通过腹腔注射链脲佐菌素（STZ）诱导大鼠糖尿病神经病变，并通过尾静脉注射慢病毒递送miR-214-3p。热或冷刺激试验表明 STZ 诱导热痛觉过敏。神经生理学测量显示，糖尿病神经病变大鼠的运动和感觉神经传导速度和神经血流量降低。然而，STZ 诱导的痛觉过敏以及神经传导速度和神经血流量的降低均通过 miR-214-3p 给药而显着逆转。 HE染色、TUNEL、ELISA和免疫印迹表明STZ导致背根神经节（DRG）明显的病理病变、细胞凋亡和炎症，表现为凋亡相关蛋白分子和炎症因子水平的改变以及Toll-类似受体 4 (TLR4)/骨髓分化初级反应基因 88/核因子 kappa B 信号传导。应用miR-214-3p可显着改善糖尿病神经病变大鼠DRG的病理改变。此外，通过双荧光素酶报告基因测定，钠通道蛋白 3 型亚基 α 异构体 1 (Nav1.3) 和 TLR4 被鉴定为 miR-214-3p 的靶标。 MiR-214-3p可能通过下调Nav1.3和TLR4发挥其作用。综上所述，miR-214-3p通过调节STZ诱导的大鼠的Nav1.3和TLR4来减轻糖尿病引起的神经损伤以及DRG的病理病变、细胞凋亡和炎症。这些发现可能为糖尿病神经病变的临床治疗提供新的治疗靶点。