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[线粒体自噬的作用及熟地黄叶总苷胶囊对核苷(酸)类药物所致肾损伤的疗效]

[Role of mitochondrial autophagy and the curative effect of rehmannia glutinosa leaves total glycoside capsules on nucleos(t)ide drug-induced renal injury].

作者信息

Zhong K, Zhang M M, Zhu Z X, Liao X, Zhang B F, Cheng M L

机构信息

Department of Infection, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.

Department of Gastroenterology, Gui Yang Public Health Clinical Center, Guiyang 550004, China.

出版信息

Zhonghua Gan Zang Bing Za Zhi. 2024 Feb 20;32(2):125-132. doi: 10.3760/cma.j.cn501113-20231128-00243.

Abstract

To study the curative effect of rehmannia glutinosa leaves total glycoside capsules and the role of mitochondrial autophagy on nucleos(t)ide drug-induced renal injury. Adefovir dipivoxil (ADV) was used to construct a hepatitis B virus (HBV) transgenic mouse model for renal injury. Renal function was measured in each group at one and two weeks of modeling. Mitochondrial autophagy indicators were measured at two weeks of modeling in renal tissue. Transmission electron microscopy was used to detect mitochondrial autophagy phenomena in renal tissue. The model was established for two weeks. Mouse with renal injury were treated with rehmannia glutinosa leaves total glycoside capsules or isotonic saline for eight weeks by intragastric administration. Renal function was measured. Renal tissue morphology was observed. Mitochondrial autophagy indicators were detected in renal tissue. The protective effect of different concentrations of verbascoside (the main active ingredient of rehmannia glutinosa capsule) was observed on HK-2 cell damage induced by ADV. HK-2 cells were divided into control, ADV, and ADV plus verbascoside groups. The effects of verbascoside at different times and concentrations were observed on the HK-2 mitochondrial autophagy indicators. Fifty patients with chronic hepatitis B were collected who presented with renal injury after treatment with nucleos(t)ide analogs. The random number method was used to divide 29 cases into a control group that received conventional treatment. The treatment group of 21 cases was treated with rehmannia glutinosa leaves total glycoside capsules on the basis of the control group. Serum creatinine (Scr) and urinary protein were detected at eight weeks.The (2) test or -test was used for statistical analysis. Compared with the control group, two weeks of modeling in the ADV group induced renal function injury in HBV mice. The expression of autophagy indicators was higher in the renal tissue of the ADV group than that of the control group. Transmission electron microscopy had revealed mitochondrial autophagy in the renal tissue of the ADV group. Compared with the control group, the renal function of HBV mice treated with rehmannia glutinosa leaves total glycoside capsules improved for two months, and the expressions of autophagy indicators were down-regulated.Verbascoside promoted proliferation in ADV-damaged HK-2 cells, and the expression of autophagy indicators was down-regulated compared with the ADV alone group. In 50 patients with renal function injury, the urinary protein improvement was significantly superior in the treatment group than that in the control group, with eighteen and three cases being effective and ineffective in the treatment group and 12 and 17 cases being effective and ineffective in the control group, with a statistically significant difference ((2) = 9.975 0,  = 0.001 6). Serum creatinine was decreased in the treatment group compared with the control group, with 11 and 10 cases being effective and ineffective in the treatment group and 12 and 17 cases being effective and ineffective in the control group, with no statistically significant difference ((2) = 0.593 5,  = 0.441 1). Rehmannia glutinosa leaves total glycoside capsule can improve the nucleos(t)ide drug-induced renal function injury in chronic hepatitis B, possibly playing a role via inhibiting PINK1/Parkin-mediated mitochondrial autophagy.

摘要

研究熟地黄叶总苷胶囊对核苷(酸)类药物所致肾损伤的疗效及线粒体自噬在其中的作用。采用阿德福韦酯(ADV)构建乙型肝炎病毒(HBV)转基因小鼠肾损伤模型。建模1周和2周时检测各组小鼠肾功能。建模2周时检测肾组织线粒体自噬指标。采用透射电子显微镜观察肾组织线粒体自噬现象。造模2周后,对肾损伤小鼠灌胃给予熟地黄叶总苷胶囊或等渗盐水治疗8周,检测肾功能,观察肾组织形态,检测肾组织线粒体自噬指标。观察不同浓度毛蕊花糖苷(熟地黄胶囊主要活性成分)对ADV诱导的HK-2细胞损伤的保护作用。将HK-2细胞分为对照组、ADV组和ADV加毛蕊花糖苷组。观察不同时间和浓度的毛蕊花糖苷对HK-2细胞线粒体自噬指标的影响。收集50例核苷(酸)类似物治疗后出现肾损伤的慢性乙型肝炎患者,采用随机数字法将29例分为对照组,给予常规治疗;治疗组21例,在对照组基础上加用熟地黄叶总苷胶囊治疗。8周时检测血清肌酐(Scr)和尿蛋白。采用χ²检验或t检验进行统计分析。与对照组比较,ADV组建模2周诱导HBV小鼠肾功能损伤,ADV组肾组织自噬指标表达高于对照组,透射电子显微镜观察显示ADV组肾组织存在线粒体自噬。与对照组比较,熟地黄叶总苷胶囊治疗2个月可改善HBV小鼠肾功能,肾组织自噬指标表达下调。毛蕊花糖苷促进ADV损伤的HK-2细胞增殖,与单纯ADV组比较自噬指标表达下调。50例肾功能损伤患者中,治疗组尿蛋白改善情况明显优于对照组,治疗组有效18例、无效3例,对照组有效12例、无效17例,差异有统计学意义(χ²=9.975 0,P=0.001 6)。治疗组血清肌酐较对照组下降,治疗组有效11例、无效10例,对照组有效12例、无效17例,差异无统计学意义(χ²=0.593 5,P=0.441 1)。熟地黄叶总苷胶囊可改善慢性乙型肝炎核苷(酸)类药物所致肾功能损伤,可能通过抑制PINK1/Parkin介导的线粒体自噬发挥作用。

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