首页|绞股蓝总皂苷最佳治疗剂量筛选及其降脂保肝肾作用和机制研究

绞股蓝总皂苷最佳治疗剂量筛选及其降脂保肝肾作用和机制研究

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目的:探究绞股蓝总皂苷(gypenosides,GPs)不同剂量组对高血脂大鼠的降脂、肝肾保护作用及其初步机制,筛选其最佳治疗剂量.方法:高脂饮食诱导构建高血脂大鼠模型,采用不同剂量GPs对其进行分组给药治疗,通过测定大鼠血脂、肝脏脂质、肝肾功能及其氧化应激等相关指标考察其药效,检测血清中前蛋白转化枯草杆菌蛋白酶/Kexin9型(PCSK9)、羟甲基戊二酸单酰辅酶A还原酶(HMGR)、过氧化物酶体增殖物激活受体(PPAR-α和PPAR-γ)的分泌量以初步探究其作用机制.结果:GPs能显著降低血清及肝匀浆中总胆固醇(TC)、三酰甘油(TG)和低密度脂蛋白(LDL-C),提高高密度脂蛋白(HDL-C)水平,120～240 mg·kg-1 GPs与20 mg·kg-1非诺贝特表现出类似的降血脂效果,甚至对于下调肝脏脂质效果更好.120～240 mg·kg-1 GPs还降低肝匀浆中谷丙转氨酶(ALT)及谷草转氨酶(AST)的含量,明显减少肝细胞脂肪样变及气球样变,减轻肝脏病变程度;显著降低了血清中尿素氮(BUN)和肌酐(CRE)的含量,减少了高血脂大鼠肾小管变性坏死以及胞质空泡化和溶解.同时,GPs还增强了大鼠体内抗氧化酶(SOD,CAT和GSH-Px)的活性,减少了氧化应激和脂质过氧化物丙二醛(MDA)含量,并显著降低PCSK9的分泌,增加了PPAR的表达.结论:GPs具有降脂作用,药效与剂量呈正相关,剂量范围120～240 mg·kg-1疗效最佳,可能与其抑制PCSK9分泌和增强PPAR表达有关;并且GPs能有效减少高血脂造成的肝肾损伤和脂质过氧化损伤,为进一步深入开发GPs的临床应用提供可靠的理论依据.
Screening of the optimal therapeutic dose of Gynostemma pentaphyllum gypenosides and the mechanism on lowering lipids and hepatic and renal protection
Objective:To investigate the effect of lipid-lowering,hepatic and renal protection of different doses of Gynostemma pentaphyllum gypenosides(GPs)in hyperlipidemia rats and its preliminary mechanism to screen the optimal therapeutic dose.Methods:A hyperlipidemia rat model was constructed by high-fat diet,and treated by different doses of GPs.The efficacy of GPs on the rats was examined by measuring blood lipids,liver lipids,liver and kidney function and oxidative stress.The secretion levels of proprotein convertase subtilisin/kexin 9(PCSK9),3-hydroxy-3-methyl glutaryl coenzyme a reductase(HMGR),and peroxisome proliferators-activated receptors(PPAR-α and PPAR-γ)in serum were detected to preliminarily explore its mechanism of action.Results:GPs significantly reduced total cholesterol(TC),triglyceride(TG)and low-density lipoprotein cholesterol(LDL-C)in serum and liver homogenate,and increased the level of high-density lipoprotein cholesterol(HDL-C).120～240 mg·kg-1 GPs and 20 mg·kg-1 fenofibrate showed similar hypolipidemic effects,and GPs indicated a better effect on down-regulating liver lipids.120～240 mg·kg-1 GPs also reduced the content of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in liver homogenate,significantly reduced hepatocyte steatosis and ballooning,and reduced the degree of liver lesions,significantly reduced blood urea nitrogen(BUN)and creatinine(CRE),reduced renal tubular degeneration and necrosis,cytoplasmic cavitation and lysis in hyperlipidemia rats.At the same time,GPs also enhanced the activity of antioxidant enzymes(SOD,CAT and GSH-Px)in rats,reduced oxidative stress and lipid peroxidation(MDA),and significantly reduced the secretion of PCSK9 and increased the expression of PPAR receptor.Conclusion:GPs can exert a lipid-lowering effect,and the efficacy is positively dose-dependent.The dose range of 120～240 mg·kg-1 GPs has the best therapeutic effect,which may be related to its inhibition of PCSK9 secretion and enhancement of PPAR expression;and GPs can effectively reduce liver and kidney injury and lipid peroxidation damage caused by hyperlipidemia,providing a reliable theoretical basis for further development of the clinical application of Gynostemma pentaphyllum gypenosides.

gypenosidesdose screeninghyperlipidemialiver and kidney protectionantioxidantproprotein convertase subtilisin/kexin 9peroxisome proliferators-activated receptors

邓萌玥、杨长鑫、冯宝文、施和敏、夏谍、丁俞珍、晏子俊、位盼盼、何波、陈彤

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昆明医科大学药学院暨云南省天然药物药理重点实验室,昆明 650500

红云制药集团股份有限公司,成都 610200

红云制药(梁河)有限公司,梁河 679200

绞股蓝总皂苷 剂量筛选 高血脂 肝肾保护 抗氧化 蛋白转化枯草杆菌蛋白酶/Kexin9型 过氧化物酶体增殖物激活受体

国家自然科学基金地区科学基金项目第七批云南省高校工程研究中心立项建设项目云南省天然药物药理重点实验室开放基金重点项目红云制药(梁河)有限公司绞股蓝总苷胶囊最佳服用剂量的筛选横向课题

81760698[2019]-57YKLPNP-K2302202153517000228

2024

中国新药杂志
中国医药科技出版社 中国医药集团总公司 中国药学会

中国新药杂志

CSTPCD北大核心
影响因子：1.039
ISSN：1003-3734
年,卷(期)：2024.33(5)
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