基于动脉粥样硬化家兔模型研究黑血藤药效及代谢组学

Study on Efficacy and Metabonomics of Mucuma macrocarpain Atherosclerosis Model of Rabbit

目的基于动脉粥样硬化(AS)家兔模型研究黑血藤在AS及肌少症预防中的药效及代谢组学,为深入研究、开发和利用黑血藤提供科学依据。方法将健康家兔分为正常组、模型组、血脂康组和黑血藤组,正常组给予基础饲料,其它组给予高脂饲料饲喂,血脂康组和黑血藤组再分别给予血脂康生药0.36g/(kg·d)和黑血藤提取物0.29g/(kg·d)灌胃处理。分析AS模型家兔血清中脂质组成、超氧化物歧化酶(SOD)含量、血液流变学参数变化及主动脉弓和比目鱼肌的组织病理形态,评价黑血藤提取物预防AS及肌少症的药效;利用超高效液相色谱-四级杆飞行时间质谱(UPLCQ-TOF-MS)研究家兔血清代谢组学,探讨黑血藤预防AS及肌少症的代谢机制。结果黑血藤具有较好的降低血脂、改善血液流变学、抑制脂质在血管内皮沉积和增强比目鱼肌横截面积等与预防AS及肌少症相关的药效,其在AS家兔模型中预防AS的药效不及血脂康但预防肌少症的药效优于血脂康。与正常组比较,从AS模型家兔血清中鉴别出37个差异代谢物,黑血藤对其中25个差异代谢物有一定程度的回调作用;在与黑血藤药效密切相关的代谢通路中,组氨酸及精氨酸-脯氨酸代谢具有重要意义,L-谷氨酰胺和L-丙氨酸在差异代谢物关系网络及差异代谢物-通路关系网络中关联作用广泛。结论黑血藤具有预防AS及肌少症的药效,开发其相关药物用于预防肥胖引起的AS及肌少症具有广泛的应用前景;其代谢机制与组氨酸及精氨酸-脯氨酸代谢相关,L-谷氨酰胺和L-丙氨酸可能为黑血藤药效的代谢标志物之一。

Objective To study the pharmacodynamics and metabolomics of Mucuma macrocarpa(M.macrocarpa)in prevention of atherosclerosis(AS)and myopathy based on AS model of rabbit.To provide scientific basis for further study and application of M.macrocarpa.Methods The healthy rabbits were randomly divided into normal group,model group,Xuezhikang group and M.macrocarpa group.Normal group were fed with basal diet and other group were fed with high-fat diet.Furthermore,Xuezhikang group and M.macrocarpagroup were orally administrated with Xuezhikang(0.36g/kg·d raw drug)and extract of M.macrocarpa(0.29g/kg·d),respectively.The efficacies of AS and myopathy were evaluated by levels of lipids and superoxide dismutase(SOD)in serum,changes of hemorheology parameters,pathology of aortic arch and soleus.In order to elucidate the metabolic mechanism,metabonomics was studied by using UPLC-Q-TOF-MS.Results The extract of M.macrocarpacould prevent atherosclerosis and sarcopenia by reducing levels of lipids,improving hemorrheology,inhibiting lipid deposition on blood vessel wall,increasing cross-sectional area of soleus muscle and so on.Compared with Xuezhikang,the efficacy of M.macrocarpawas weaker in preventing AS,yet the efficacy was stronger in preventing sarcopenia.Compared with normal group,contents of 37metabolites from the model group changed significantly(P<0.05)and M.macrocarpaextract could reverse changes in contents of 25metabolites in a certain degree.The metabolism of histidine and arginine-proline played an important role in the metabolic pathways that were closely related to the pharmacodynamics of M.macrocarpa.L-glutamine and L-alanine were associated in the differential metabolite relationship network and pathway-differential metabolite relationship network.Conclusion M.macrocarpahas the preventive effect for AS and sarcopenia.It could be exploited to prevent athero sclerosis and sarcopenia caused by obesity.Its metabolic mechanism is related with histidine metabolism as well as arginine-proline metabolism.L-Glutamine and L-Alanine might be biomarkers in pharmacological process of M.macrocarpa.