| Objective: In experimental study,to verify the feasibility of carotid artery partial ligation and high-fat diet feeding to establish animal model of hamster atherosclerosis(As);To investigate the effects of hesperetin(HES)on regulating serum lipids and carotid atherosclerosis in hamster As animal models;To explore the effect of hesperetin on gene expression of factors related to lipid metabolism in the liver of hamster As animal models,and to explain the mechanism of hesperetin regulating lipid metabolism from molecular level;In randomized controlled clinical preliminary trial,to observe the effects orange juice rich in hesperetin diet intervention on serum lipids,blood glucose and other clinical indicators in As high-risk population;To verify the efficacy of hesperetin observed in As animal models,and to explore the clinical application value of hesperetin as diet therapy for As high-risk populations.Methods:(1)In experimental study,according to the simple randomization method,thirty eightweek-old male hamsters were randomly divided into normal control group(NC group),As model group(Model group),low-dose hesperetin group(L-HES group),mediumdose hesperetin group(M-HES group)and high-dose hesperetin group(H-HES group),six in each group;Except for the NC group hamsters,the others were treated with partial ligation of the left carotid artery;After 1 week of recovery,surgical hamsters were fed on high-fat diet,and NC group hamsters were continued feeding on standard chow diet;Meanwhile,L-HES group,M-HES group and H-HES group hamsters were given intragastric administration of hesperetin at a dose of 50 mg/kg,100 mg/kg and 150 mg/kg once a day,the NC group and Model group hamsters were given 0.5% sodium carboxymethyl cellulose for 6 weeks;The levels of serum lipids were measured at the end of experimental 3 week,5 week and 7 week,respectively;The levels of serum tumor necrosis factor ?(TNF-?),interleukin-6(IL-6)and monocyte chemotactic protein 1(MCP-1)were detected by ELISA method;At the end of experimental 7 week,the hamsters were sacrificed after anaesthesia,and the left common carotid artery was left for paraffin section;Pathological changes of carotid artery were observed with HE staining;The real-time PCR was used to detect the gene expression level of factors related to lipid metabolism in the liver;(2)In clinical preliminary trial,a randomized,controlled preliminary trial was designed;The simple random sampling method was used to randomly select 16 individuals from the pre-screened As high-risk population;The 16 subjects were randomly assigned to the intervention group and the control group,eight in each group;The control group subjects received routine health guidance and the intervention group subjects received 500 ml of orange juice rich in hesperetin daily in addition to routine health guidance for 8 weeks;Serum lipids,blood glucose and other clinical indicators were detected in the two groups of subjects at the end of trial.Results:(1)Experimental study: 1)hamster As animal models were established successfully;2)The basal serum lipid levels of experimental hamsters in each group were similar(P>0.05);At the end of experimental 3 week,the serum total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDL-C),high density lipoprotein cholesterol(HDL-C)and non high density lipoprotein cholesterol(nonHDL-C)levels increased in Model group hamsters(P<0.05),and the serum LDL-C levels in each hesperetin dose group hamsters decreased compared to the Model group hamsters(P<0.05),with no significant difference in TC,TG,HDL-C and non-HDL-C levels(P>0.05);At the end of experimental 5 week and 7 week,the serum TC,TG,LDL-C,HDL-C and non-HDL-C levels significantly increased in Model group hamsters(P<0.05),and the serum TC,TG,LDL-C and non-HDL-C levels in each hesperetin dose group hamsters decreased compared to the Model group hamsters(P<0.05),with no significant difference in HDL-C levels(P>0.05);3)The serum TNF-?,IL-6 and MCP-1 levels in the Model group hamsters were higher than those of the NC group hamsters(P<0.05);The serum TNF-?,MCP-1 levels in the L-HES and M-HES group hamsters decreased compared to the Model group hamsters(P<0.05);The serum IL-6 levels of L-HES group hamsters decreased compared to the Model group hamsters(P<0.05);4)In the Model group hamsters,the carotid artery vascular intima-media were obviously thickened,the lumen was narrowed obviously,with many pinhole cholesterol crystals forming and calcified with small focal necrosis were seen locally,while the pathological changes of carotid artery in each hesperetin dose group hamsters were improved to varying degrees;5)The m RNA expression level of hepatic low density lipoprotein receptor(LDLR),cholesterol 7?-hydroxylase(CYP7A1)and liver X receptor ?(LXR-?)decreased in the Model group hamsters(P<0.05);The LDLR,LXR-? m RNA levels in the L-HES and M-HES groups increased compared to the Model group hamsters(P<0.05),and CYP7A1 m RNA level significantly increased in each hesperetin dose group hamsters compared to the Model group hamsters(P<0.05);The m RNA expression level of hepatic 3-Hydroxy-3-Methylglutaryl-Co A Reductase(HMGCR)and sterol regulatory element binding protein-2(Srebp2)significantly increased in the Model group hamsters(P<0.05),and HMGCR and Srebp2 m RNA levels significantly decreased in each hesperetin dose group hamsters compared to the Model group hamsters(P<0.05);(2)Clinical preliminary trial: 1)The baseline levels of clinical indicators were similar between the two group subjects(P>0.05);2)After the trial,TC,TG,LDL-C,non-HDL-C in the intervention group subjects were significantly lower than those in the control group subjects(P<0.05);3)After the trial,the levels of LDL-C and non-HDL-C in the control group subjects increased compared to the baseline data(P<0.05),and there were no significant changes in other clinical indicators(P>0.05);4)After the trial,TC,TG,LDL-C,non-HDL-C,fasting blood glucose(FBG)and glycated hemoglobin(Hb A1c)in the intervention group subjects decreased compared to the baseline data(P<0.05),and there were no significant changes in HDL-C and body mass index(BMI)(P>0.05).Conclusion:(1)Hamster carotid atherosclerosis model can be established successfully by partial carotid artery ligation and feeding on high-fat diet;(2)Hesperetin has a good lipid-lowering effect on hamster carotid atherosclerosis model;(3)Hesperetin attenuates inflammatory response in hamster carotid atherosclerosis model;(4)Hesperetin can regulate lipid metabolism through affecting the gene expression of key factors associated with lipid metabolism in the liver;(5)Hesperetin has the effect of improving atherosclerotic lesions,and its mechanism may be related to its hypolipidemic and anti-inflammatory effects;(6)Orange juice rich in hesperetin diet intervention can reduce serum lipids and blood glucose levels in As high-risk population,and has better cardiovascular protection effect. |
PDF Full Text Request