Oxymatrine (OMT) is the major quinolizidine alkaloid extracted from the root of Sophora flavescens Ait and has been shown to exhibit a diverse range of pharmacological properties. The aim of the present study was to investigate the role of OMT in diabetic brain injury in vivo and in vitro. Diabetic rats were induced by intraperitoneal injection of a single dose of 65 mg/kg streptozotocin (STZ) and fed a high-fat and high-cholesterol diet. Memory function was assessed using a Morris water maze test. A SH-SY5Y cell injury model was induced by incubation with glucose (30 mM/l) to simulate damage in vitro. The serum fasting blood glucose, insulin, serum S100B, malondialdehyde (MDA), and superoxide dismutase (SOD) levels were analyzed using commercial kits. Morphological changes were observed using Nissl staining and electron microscopy. Cell apoptosis was assessed using Hoechst staining and TUNEL staining. NADPH oxidase (NOX) and caspase-3 activities were determined. The effects of NOX2 and NOX4 knockdown were assessed using small interfering RNA. The expression levels of NOX1, NOX2, and NOX4 were detected using reverse transcription-quantitative PCR and western blotting, and the levels of caspase-3 were detected using western blotting. The diabetic rats exhibited significantly increased plasma glucose, insulin, reactive oxygen species (ROS), S-100B, and MDA levels and decreased SOD levels. Memory function was determined by assessing the percentage of time spent in the target quadrant, the number of times the platform was crossed, escape latency, and mean path length and was found to be significantly reduced in the diabetic rats. Hyperglycemia resulted in notable brain injury, including histological changes and apoptosis in the cortex and hippocampus. The expression levels of NOX2 and NOX4 were significantly upregulated at the protein and mRNA levels, and NOX1 expression was not altered in the diabetic rats. NOX and caspase-3 activities were increased, and caspase-3 expression was upregulated in the brain tissue of diabetic rats. OMT treatment dose-dependently reversed behavioral, biochemical, and molecular changes in the diabetic rats. In vitro, high glucose resulted in increases in reactive oxygen species (ROS), MDA levels, apoptosis, and the expressions of NOX2, NOX4, and caspase-3. siRNA-mediated knockdown of NOX2 and NOX4 decreased NOX2 and NOX4 expression levels, respectively, and reduced ROS levels and apoptosis. The results of the present study suggest that OMT alleviates diabetes-associated cognitive decline, oxidative stress, and apoptosis via NOX2 and NOX4 inhibition.

中文翻译：

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氧化苦参碱通过调节氧化应激和细胞凋亡减轻糖尿病大鼠的记忆障碍：NOX2 / NOX4的参与。

氧化苦参碱（OMT）是从苦参（Sophora flavescens Ait）的根中提取的主要喹oli嗪生物碱，已被证明具有多种药理特性。本研究的目的是研究OMT在体内和体外在糖尿病性脑损伤中的作用。腹腔注射单剂量65 mg / kg链脲佐菌素（STZ）诱导糖尿病大鼠，并喂养高脂高胆固醇饮食。使用莫里斯水迷宫测试评估记忆功能。通过与葡萄糖（30 mM / l）孵育诱导SH-SY5Y细胞损伤模型以模拟体外损伤。使用商业试剂盒分析了血清空腹血糖，胰岛素，血清S100B，丙二醛（MDA）和超氧化物歧化酶（SOD）的水平。使用Nissl染色和电子显微镜观察形态变化。使用Hoechst染色和TUNEL染色评估细胞凋亡。确定了NADPH氧化酶（NOX）和caspase-3活性。使用小的干扰RNA评估了NOX2和NOX4敲低的影响。用逆转录定量PCR和蛋白质印迹法检测NOX1，NOX2和NOX4的表达水平，并用蛋白质印迹法检测caspase-3的水平。糖尿病大鼠的血浆葡萄糖，胰岛素，活性氧（ROS），S-100B和MD​​A水平显着增加，而SOD水平降低。通过评估在目标象限中花费的时间百分比，平台越过次数，逃避潜伏期和平均路径长度来确定记忆功能，发现糖尿病大鼠的记忆功能明显降低。高血糖症导致明显的脑损伤，包括组织学变化和皮质和海马细胞凋亡。在蛋白质和mRNA水平，NOX2和NOX4的表达水平显着上调，并且在糖尿病大鼠中NOX1的表达没有改变。糖尿病大鼠脑组织中NOX和caspase-3的活性增加，而caspase-3的表达上调。OMT治疗可剂量依赖性地逆转糖尿病大鼠的行为，生化和分子变化。逃避潜伏期，平均路径长度，并发现在糖尿病大鼠中明显减少。高血糖症导致明显的脑损伤，包括组织学变化和皮质和海马细胞凋亡。在蛋白质和mRNA水平，NOX2和NOX4的表达水平显着上调，并且在糖尿病大鼠中NOX1的表达没有改变。糖尿病大鼠脑组织中NOX和caspase-3的活性增加，而caspase-3的表达上调。OMT治疗可剂量依赖性地逆转糖尿病大鼠的行为，生化和分子变化。逃避潜伏期，平均路径长度，并发现在糖尿病大鼠中明显减少。高血糖症导致明显的脑损伤，包括组织学变化和皮质和海马细胞凋亡。在蛋白质和mRNA水平，NOX2和NOX4的表达水平显着上调，并且在糖尿病大鼠中NOX1的表达没有改变。糖尿病大鼠脑组织中NOX和caspase-3的活性增加，而caspase-3的表达上调。OMT治疗可剂量依赖性地逆转糖尿病大鼠的行为，生化和分子变化。在蛋白质和mRNA水平，NOX2和NOX4的表达水平显着上调，并且在糖尿病大鼠中NOX1的表达没有改变。糖尿病大鼠脑组织中NOX和caspase-3的活性增加，而caspase-3的表达上调。OMT治疗可剂量依赖性地逆转糖尿病大鼠的行为，生化和分子变化。在蛋白质和mRNA水平，NOX2和NOX4的表达水平显着上调，并且在糖尿病大鼠中NOX1的表达没有改变。糖尿病大鼠脑组织中NOX和caspase-3的活性增加，而caspase-3的表达上调。OMT治疗可剂量依赖性地逆转糖尿病大鼠的行为，生化和分子变化。在体外，高葡萄糖导致活性氧（ROS），MDA水平，细胞凋亡以及NOX2，NOX4和caspase-3的表达增加。siRNA介导的NOX2和NOX4的敲低分别降低了NOX2和NOX4的表达水平，并降低了ROS水平和细胞凋亡。本研究的结果表明，OMT通过抑制NOX2和NOX4减轻了糖尿病相关的认知能力下降，氧化应激和细胞凋亡。