| Objective:To study the hypolipidemic effect of total saponins of Gypenoside（GPs）in acute and chronic hyperlipidemia rats;to screen the optimal therapeutic dose of GPs for lipid lowering,liver and kidney protection in chronic hyperlipidemia rats,and to preliminarily explore its preliminary mechanism;And a preliminary evaluation of the safety of GPs.Methods:Acute and chronic hyperlipidemia rat models were respectively established by intraperitoneal injection of P407 and feeding HFD.Blood was taken to detect the content of TC,TG,HDL-C and LDL-C,exploring the role of GPs in different hyperlipidemia models.Hyperlipidemia rat model was constructed after 4 weeks of induction of HFD,using 20,40,60,80,120,180 and 240 mg·kg-1 GPs（the GPs dose group was converted according to body weight-body surface area conversion,which is approximately equivalent to the adult clinical daily dose of 180 mg of 1,2,3,4,6,9and 12 times）.It was administered in groups for 6 weeks,its efficacy was investigated by measuring blood lipids,liver lipids,liver and kidney function and oxidative stress in rats,pathological tissue sections were made,and pathological changes in rat liver and kidney tissue were observed.The expressions of PCSK9,HMGR,PPAR-αand PPAR-γin serum were detected to preliminarily explore their mechanism of action;the acute toxicity of GPs was observed by the maximum dose method,and the safety of oral administration was preliminarily evaluated.Results:Hypolipidemic effect of GPs in acute and chronic hyperlipidemic models.GPs have good hypolipidemic effect in acute and chronic hyperlipidemic models.In the acute hyperlipidemia model constructed by intraperitoneal injection of P407,compared with the normal group,the serum TC,TG,LDL-C and HDL-C in the model group were significantly increased at 4,10,24 and 48 h（P<0.01 or P<0.001）;compared with the model group,the high-dose GPs group significantly reduced the serum TC,TG,LDL-C levels at 24 h and 48 h,and increased the HDL-C level at 48 h（P<0.05 or P<0.01）,the serum TC level was significantly decreased at 48 h in the low-dose group of GPs（P<0.05）.In the chronic hyperlipidemia model induced by high-fat diet,compared with the normal group,TC,TG and LDL-C in the model group were significantly increased,and the difference was significant（P<0.001）;after 3 weeks of administration,compared with the model group,the GPs high-dose group significantly reduced the serum TC and TG levels（P<0.05 or P<0.001）,and the GPs low-dose group significantly reduced the serum TG levels（P<0.05）,but both had no significant effect on HDL-C and LDL-C.After 6 weeks of continuous administration,compared with the model group,the GPs high-dose group significantly reduced the serum TC and TG levels TC,TG and LDL-C levels（P<0.001 or P<0.01）,and HDL-C levels were increased（P<0.05）.The low-dose group of GPs reduced serum TC,TG and LDL-C levels（P<0.01 or P<0.05）.Screening of the best therapeutic dose of GPs in the chronic hyperlipidemia model and its pharmacodynamic study of lipid lowering and liver preservation.The chronic hyperlipidemia rat model was established by HFD feeding induction.The serum TC,TG and LDL-C levels increased significantly（P<0.001）,and the HDL-C level decreased（P<0.05）,indicating that the hyperlipidemia rat model has been successfully established and the lesions formed are similar to human pathology.After6 weeks of administration,GPs significantly reduced TC,TG and LDL-C in rat serum and liver homogenate,and increased HDL-C levels（P<0.05,P<0.01 or P<0.001）.Among them,120-240 mg·kg-1 GPs and fenofibrate showed similar hypolipidemic effects,and even had a better effect on down-regulating liver lipids.At the same time,120-240 mg·kg-1 GPs also reduced the contents of ALT and AST in liver homogenate（P<0.05 or P<0.01）,significantly reduced hepatocyte steatosis and ballooning,and reduced the degree of liver lesions;significantly reduced the contents of BUN and CRE in serum（P<0.001）,and reduced renal tubular degeneration and necrosis,cytoplasmic vacuolation and lysis in hyperlipidemic rats.At the same time,GPs also enhanced the activities of antioxidant enzymes SOD,CAT and GSH-Px in rats（P<0.05,P<0.01 or P<0.001）,reduced oxidative stress and lipid peroxidation（P<0.001）,and significantly reduced the secretion of PSCK9 and increased the expression of PPAR receptors（P<0.05,P<0.01 or P<0.001）.Preliminary safety evaluation of GPs.GPs were given orally to mice at a maximum dose of 30 g·kg-1.No toxic effects related to the test were found by analyzing body weight,food intake,organ status,organ index,and hematological indicators.Conclusion:GPs have good hypolipidemic effects in both P407-induced acute hyperlipidemia models and HFD-induced chronic hyperlipidemia models,and the lesions induced by HFD are similar to human pathology;at the same time,GPs in HFD-induced chronic models not only have good hypolipidemic effects,but also have the effects of organ protection,reducing organ lipotoxicity,reducing lipid oxidation and enhancing antioxidant capacity.The dose range of 120 mg·kg-1 GPs has the best therapeutic effect,and its mechanism of action may be related to inhibiting PCSK9 and agonizing PPAR receptors;and 30 g·kg-1 Gynostemma saponins did not cause death or any toxic effects after oral administration in mice,indicating that the use of Gynostemma saponins has a certain safety.Objective: To study the antioxidant activity and organ protection of different elution components of Panax notoginseng polysaccharides in D-galactose-induced oxidative damage aging model mice.Methods: Different elution components of Panax notoginseng polysaccharides were extracted and isolated from Panax notoginseng residue;a D-galactose-induced oxidative injury aging mouse model was constructed,and the contents of SOD,CAT,GSH-Px,T-AOC and MDA in mouse serum and liver were determined to investigate the antioxidant activity of different elution components of Panax notoginseng polysaccharides;the organ protective effects of different elution components of Panax notoginseng polysaccharides were analyzed by organ index and histopathology.Results: Five different Panax notoginseng polysaccharides were extracted and isolated from Panax notoginseng residue,namely CPPN,NPPN and APPN-I,APPN-II,APPNIII;an aging mouse model was successfully constructed.The SOD,CAT,GSH-PX and T-AOC in serum and liver of the model mice were significantly reduced,and the MDA content was significantly increased（P<0.01 or P<0.001）.After treatment with different elution components of Panax notoginseng polysaccharide,the oxidative indexes in mice were significantly improved.Among them,APPN-III had the best antioxidant activity,which could significantly increase the activities of SOD,CAT,T-AOC and GSH-Px in serum and liver,and reduce the content of MDA（P<0.001）.At the same time,organ index and organ HE staining results showed that different elution components of Panax notoginseng polysaccharide had no organ toxicity,and had a certain protective effect on liver,spleen and thymus damage caused by D-galactose.Conclusion: In the study of the antioxidant activity of D-galactose-induced oxidative damage in aging model mice,different elution components of Panax notoginseng polysaccharide have antioxidant activity and organ protection in vivo,400 mg·kg-1 APPN-III has the best antioxidant activity and organ protection. |
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