| Background:Diabetes macroangiopathy,which is one of the most important complications of diabetes and the foundation of diabetes and cardiac-cerebral vascular diseases,becomes the leading cause of diabetes-associated mortality and disability.It is particularly urgent and significant to explore and improve the intervention and the treatment of diabetes macroangiopathy.Diabetics are chronically in hyperglycemia,which causes the increase of diabetics' blood coagulation and viscosity and promotes platelet aggregation while induces atherosclerosis that the diabetes macroangiopathy is based on.Meanwhile,hyperglycemia induces severe oxidative stress,which will lead to tissue cell oxidative stress damage and chronic inflammation and then will induce diabetes macroangiopathy.Nuclear factor E2-related factor 2(Nrf2),which is the sensory receptor of oxidative stress,plays a vital role in regulating the antioxidant stress response of the host cells.The activated Nrf2 specifically recognizes and binds with antioxidant response element(ARE)upon oxidative stress,resulting in the upregulation of the downstream antioxidant enzymes-associated molecules,such as SOD?HO-1and ?-GCS,and cellular antioxidant abilities,and the suppression of oxidative stress responses.Thus the activation of Nrf2 pathway is beneficial to inhibit oxidative stress damage.In conclusion,effective inhibition of the diabetic's hyperglycemia with the blocking of oxidative stress is of great importance to the relief and treatment of diabetes macroangiopathy.5,6-dihydro-2,3,9,10-tetramethoxy-dibenzo [a,g] quinolizinium(palmatine,also called hindarinine),which is a quinine isoquinoline alkaloids extracted from rhizome coptidis,is a traditional Chinese herbal medicine that was firstly recorded into the Pharmacopoeia of the People's Republic of China in 1977.It has been now used in the therapy of a variety of diseases,such as gynecological inflammation,surgical infection,bacillary dysentery,enteritis,respiratory and urinary tract infections,and eye conjunctivitis.(Chinese Pharmacopoeia Commission,1977).In addition,studies have also shown that palmatine possesses the anti-diabetes and antioxidant activity.Nevertheless,whether palmatine possesses the protective efficacies against diabetes macroangiopathy has not yet been reported both domestically and internationally.To explore the protective efficacy of palmatine against diabetes-induced aorta injury and the underlying mechanisms,the db/db mouse aortic lesion model was constructed,and the critical elements in the oxidative stress signaling pathway,such as Nrf2,AREand HO-1(heme oxygenase-1)were analyzed.Objectives:To explore the protective efficacy of palmatine against diabetes-induced aorta injury and the underlying mechanisms,the db/db mouse were treated with palmatine in varying concentrations.The mouse blood glucose and lipid levels,degree of aortic intimal hyperplasia,and oxidative stress-associated factors,such as Nrf2 and HO-1,were analyzed.Methods:Thirty-two db/db mice(8 weeks old)were randomly divided into four groups,including the diabetic model group(D group),low-dose palmatine group [75 mg/(kg·d)](D+LP group),medium-dose group [150 mg/(kg·d)](D+MP group)and high-dose group[300 mg/(kg·d)](D+HP group).Eight db/m mice were used as control group(con group).Palmatine was administered by oral gavage for 16 weeks.The mice of the diabetic model group and control group were treated with the same volume of saline.HE staining was used to determine the pathological changes of the thoracic aorta tissues.Electron microscope was used to observe the ultrastructural changes of the thoracic aorta tissues.The fasting blood glucose(FBG)and lipids(total cholesterol,TC;triglyceride,TG)were analyzed by an automatic biochemical analyzer.The serum total antioxidant capacity(T-AOC),malondialdehyde(MDA),reactive oxygen species(ROS)and superoxide dismutase(SOD)were measured by commercial ELISA kit.Western blotting was applied to determine the protein expression levels of Nrf2 and HO-1 in the thoracic aorta.Results:1.The effect of palmatine on the synthesis levels of blood glucoses and lipids of db/db mice(1)Compare with the con group,the fasting blood glucose levels of D group were markedly increased(P<0.01).Compare with D group,the fasting blood glucose levels of D +LP group,D+MP group and D +HP group were gradually decreased with the increase of administration time and drug dosage..(2)Compared with the con group,the serum TG and TC of the D group were significantly increased(P<0.01;P<0.01).Compare with the D group,the serum TG and TC of the D +MP and D+HP groups were decreased significantly after the palmatine treatment in a dose-dependent manner.(3)Compare with the con group,the HbA1 c level of D group were markedly increased(P<0.01).Compare with D group,the HbA1 c levels of D +MP and D+HP groups were decreased markedly after palmatine treatment in a dose-dependent manner.2.The effect of palmatine on aortaintimal hyperplasia of the db/db mouse(1)HE staining results indicated that mice from the medium or high palmatine treated groups(D+MP group and D+HP group)shows significantly reduced aorta intimal hyperplasia and tissue lesion.(2)Electron microscope results indicated that the vacuoles of mouse aortic endothelial cells were significantly reduced in the medium-and high-dose palmatine treated groups.3.The effect of palmatine on the regulation of oxidative stress and Nrf2,HO-1 expression of db/db mouse.(1)Compare with the con group,the MDA and ROS levels of the D group were markedly increased(P<0.01;P<0.01).Compare with the D group,the MDA and ROS levels of the D +MP and D+HP groups were decreased markedly after palmatine treatment in a dose-dependent manner.Compare with the con group,the SOD and T-AOC levels of D group were markedly decreased(P<0.01;P<0.01).Compare with the D group,the SOD and T-AOC levels of the D +MP and D+HP groups were increased markedly after palmatine treatment in a dose-dependent manner.(2)Compare with the con group,the protein expression levels of Nrf2 and HO-1 of the D group were markedly decreased(P<0.01;P<0.01).Compare with the D group,the Nrf2 and HO-1 levels from the D +MP and D+HP groups were increased markedly after palmatine treatment with the increase of drug dosage.Conclusion: In this study,we found that palmatine plays a role in decreasing the concentrations of blood glucoses and lipids,alleviating aorta intimal hyperplasia and injury of aorta tissues ultrastructure of the diabetic mice.In addition,palmatine might suppress oxidative stress by activating the Nrf2/ARE/HO-1 signaling pathway. |
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