The Effect And Meachnism Of Novel Crystal DL1505 On Diabetic Liver Injury

With the increasing number of diabetes all over the world,the mortality of diabetic mellitus with hepatic injury are rsing year after year.However,there are no exact medicines available specially for diabetic liver disease in clinical.That makes the research on drugs used to prevention and cure significant in diabetic liver diseases.Novel crystal DL1505 is a new crystal isoflavone component.Earlier studies have demonstrated that this component has widely protecting activities such as down-regulating blood glucose,decreasing serum lipids,inhibiting oxidative stress,anti-liver injury and so on.Our library had studied the polymorphs of novel crystal DL1505 and found that this new type of crystal has the advantage of faster administration,higher concentration and longer effect maintenance compared with it's original type.In this research,we investigated the therapeutic effects of novel crystal DL1505 and its mechanisms on diabetes and diabetic liver diseases,and also explored its' pharcokinetic characteristics.Chapter 1: Effect and mechanism of novel crystal DL1505 on glycolipid metabolism and liver function in type 1 diabetic mice130 mg·kg-1 Streptozotocin was injected intraperitoneally in C57/BL6 J mice to make type 1 diabetic model.Oral administration of novel crystal DL1505(100,200,400 mg·kg-1)was performed for 3 weeks.Body weight,food and water intake,blood glucose level,blood lipids were measured.OGTT,FINS,and liver oxidative stress were examined.Result showed that,novel crystal DL1505 could alleviate excessive food and water intaking,decreasing FBG,PBG and serum lipids of T1 DM mice.Novel crystal DL1505 could also improve glucose tolerance and alleviate pancreas injury,increasing FINS thus regulating the glucose metabolism.Besides,novel crystal DL1505 could also reduce MDA,ALT and AST,increase SOD and GSH thus improving liver function.Indicating that novel crystal DL1505 could improve liver function by modifying liver oxidative stress in T1 DM mice.Chapter 2: Effect of novel crystal DL1505 on liver injury in type 2 diabetic rats and related mechanismAfter four weeks' high-fat and high-sucrose diet,SD rats were injected 45mg·kg-1 streptozotocin intraperitoneally to make the type 2 diabetic model.Diabetic rats were treated with or without novel crystal DL1505(100 mg·kg-1)by gavaging for 8 weeks.Body weight,food and water intake,FBG,blood lipids were measured;liver function,liver pathological changes and oxidative stress were examined.Immunohistochemistry of CD68,?-SMA and TGF-?1 were conducted.RT-PCR examined the mRNA expression of inflammation factors and MCP-1,western blot examined the expression NF-?B and TGF-?1/Smad signal pathways.Results showed that the disorder of glucose and lipid metabolism of T2 DM rats were regulated with the treatment of novel crystal DL1505.SOD activity was improved,MDA,8-OHdG,ALT and AST were decreased.Lesions of hepatic inflammation and fibrosis were significantly alleviated.The expressions of ?-SMA and TGF-?1 were markedly reduced in liver tissues of type 2 diabetic rats with the treatment of novel crystal DL1505.qPCR showed that the mRNA expression of IL-1?,IL-6,TNF-? and MCP-1 were remarkedly decreased,western blot indicated that the expression of NF-?B,IL-1?,IL-6,TNF-? and TGF-?1,p-Smad2/3,?-SMA,collagen-I were significantly down-regulated.In conclusion,novel crystal DL1505 could alleviate liver inflammation and fibrosis by inhabiting the activation of NF-?B and TGF-?1/Smad signal pathway.Chapter 3: Pharmacokinetic research on novel crystal DL1505 in Rhesus monkeyA new method of LC-MS was established to detect the concentration of novel crystal DL1505 in Rhesus monkey's plasma,methodology was verificated and pharmacokinetic parameters were calculated to study the administration characteristics of novel crystal DL1505.Results showed that this method could detect the target compounds easily,fastly and sensitively.Pharmacokinetic parameters are as follows: Cmax = 492.98 ± 349.2 ng·mL-1,AUC(0-t)= 3365.58 ±1191.6 ng·m L-1*h,Tmax = 2.0 ± 0 h,t1/2z =8.107 ± 9.20 h.In summary,novel crystal DL1505 could mitigate the symptom of excessive food and water intaking of diabetic animals,regulate glucose and lipid metabolism disorder,relieve oxidative stress and liver inflammation and fibrosis.The effect of novel crystal DL1505 on diabetic liver lesion are related to improving liver function,and inhabiting the activation of NF-?B and TGF-?1/Smad pathway.The research revalues that novel crystal DL1505 has the potential of being an effective therapeutic drug for diabetic liver disease in clinical application.