| Diabetes mellitus (DM) is a progressive and complex metabolic disorder in the endocrine system, resulting from defects in insulin secretion, action or both. In ancient china, DM is categorized as Xiaoke Zheng mainly characterized by abnormally high blood glucose levels (hyperglycemia), polydipsia, polyuria, polyphagia and emaciation. The treatment of DM by chemical drugs has made many side effects, poor effect on improving clinical symptoms of diabetes, and difficult to against the development of diabetes complications. Additionally, traditional Chinese medicine has a long history and potential to treat diabetes and its complications. Therefore, researches focus on discovering new natural components from traditional Chinese medicines that able to be used in the management of diabetes and its complications.Rhizoma Coptidis (RC), the root of Coptis chinensis Franch, has commonly been prescribed for treatment of DM in Chinese traditional herbal medicine for thousand of years. RC is known to harbor a diversity of alkaloids, including berberine, coptisine, palmatine, epiberberine, and jatrorrhizine. RC alkaloids have a common quinolizidine ring system, which were reported to exhibit similar pharmacological effects. Previous researches have demonstrated that BBR had a good antihyperglycemic effect, but little attention was paid to other RC alkaloids and the structure-activity relationship. The objectives of the present work are to evaluate the antihyperglycemic effect, scavenging free radicals, improving clinical symptoms of diabetes, ameliorating insulin resistance and regulating lipid metabolism disorders in HepG2cells and diabetic KK-Ay mice, and preliminary explore the relationship between hypoglycemic effect of protoberberine alkaloids and structure. The following is the main contents and results of this project:(1) The physicochemical properties of RC alkaloids:Referring to the relevant literature to summarize the physicochemical properties of RC alkaloids. The oil-water partition coefficient was evaluated by UV method. The results show that many plants contain the five alkaloids, the best solubility in water of RC alkaloids is palmatine and coptisine is the worst. The logP values of five alkaloids are ranged from0to-1.5, which indicates that the bioavailability of RC alkaloid is not high.(2) Effects of RC alkaloids on glucose consumption in HepG2cells:The content of glucose was evaluated by the method of glucose oxidase-peroxidase. The glucose consumption in HepG2cells mediated by BBR and COP were significantly higher, and the mediation was in dose-dependent manner. At the dose of5μg/mL, BBR and COP promoted the glucose consumption rate by33.9%and20.4%, respectively, compared with blank control.(3) Antioxidative activity of RC alkaloids in vitro:The ROS model was established by culturing cell with high glucose medium and the ability to clean up active oxygen by DCF-DA method. At the dose of0.1mmol/L, there were significant difference among five group, the inhibitory rate is epiberberine (50.1%), followed by jatrorrhizine (34.7%), coptisine (32.2%), palmatine (28.4%) and berberine (16.69%).(4) Effects of RC alkaloids on KK-Ay diabetic mice:Berberine and coptisine mainly suppressed the elevated fasting blood glucose level and ameliorated the glucose tolerance. Body weight gain, food consumption, water intake and urinary output of KK-Ay mice were significantly decreased in the epiberberine-treated group. The concentrations of serum total cholesterol and triglyceride were decreased, high-density lipoprotein cholesterol levels increased after berberine and jatrorrhizine administrated. Berberine improved insulin resistance. Five kinds of alkaloids could increase SOD activity in the liver, reducing the content of MDA enzyme, delaying hepatomegaly diabetic mice.(5) The structure-activity relationship of hypoglycemic effect of RC alkaloids:The methylene-dioxy groups at the C-2, C-3, C-9and C-10positions were the key functional groups in RC alkaloids. The presence of the methylene-dioxy group at the C-2and C-3positions and the two methoxy groups at the C-9and C-10positions plays an important role for antihyperglycemic effect, which may related to the oxidation of the methylene-dioxy groups at the C-2and C-3positions. |
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