Dan Mei

China Pharmaceutical University, Nan-ching-hsü, Jiangxi Sheng, China

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Publications (4)8.08 Total impact

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    ABSTRACT: Plant sterols are thought to treat hypercholesterolemia via inhibiting intestinal cholesterol absorption. The aim of this study was to evaluate the contribution of impaired ATP-binding cassette transporter G5/8 (ABCG5/8) expression by diabetes to the increased β-sitosterol (BS) exposure and impact of increased BS on integrity of blood-brain barrier (BBB). Basal BS level in tissues of streptozotocin-inducted rats and ABCG5/8 protein levels in liver and intestine were investigated; pharmacokinetics of BS was studied following oral dose; and primarily cultured rat brain microvessel endothelial cells (rBMECs) were used to study BS transportation across BBB and effect of BS on BBB integrity. Diabetic rats showed greatly upgraded basal levels of BS in plasma, intestine, cerebral and hippocampus, accompanied by impairment of ABCG5/8 protein expression in liver and intestine. Pharmacokinetics studies demonstrated higher AUC0-48 and Cmax , and lower faecal recoveries of BS after oral administration, indicating enhancement of absorption or efflux impairment. In-vitro data showed increased ratio of BS/cholesterol in high levels BS-treated rBMECs was associated with increased BBB permeability of some biomarkers including BS itself. Impaired ABCG5/8 protein expression by diabetes led to increase in BS exposure, which may be harmful to BBB function.
    The Journal of pharmacy and pharmacology. 11/2013;
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    ABSTRACT: Diabetes is associated with elevated serum total cholesterol level and disrupted lipoprotein subfractions. The aim of this study was to examine alterations in the tissue cholesterol contents closely related to diabetic complications. Intraperitoneal injection of streptozotocin was used to induce type 1 diabetes in adult male Sprague-Dawley rats. On d 35 after the injection, liver, heart, intestine, kidney, pancreas, cerebral cortex and hippocampus were isolated from the rats. The content of total and free cholesterol in the tissues was determined using HPLC. The ATP-binding cassette protein A1 (ABCA1) protein and ApoE mRNA were measured using Western blot and QT-PCR analyses, respectively. In diabetic rats, the level of free cholesterol was significantly decreased in the peripheral tissues, but significantly elevated in hippocampus, as compared with those in the control rats. Diabetic rats showed a trend of decreasing the total cholesterol level in the peripheral tissues, but significant change was only found in kidney and liver. In diabetic rats, the level of the ABCA1 protein was significantly increased in the peripheral tissues and cerebral cortex; the expression of ApoE mRNA was slightly decreased in hippocampus and cerebral cortex, but the change had no statistical significance. Type 1 diabetes decreases the free cholesterol content in the peripheral tissues and increases the free cholesterol content in hippocampus. The decreased free cholesterol level in the peripheral tissues may be partly due to the increased expression of the ABCA1 protein.
    Acta Pharmacologica Sinica 06/2012; 33(7):909-17. · 2.35 Impact Factor
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    ABSTRACT: The purpose of this study was to evaluate the contributions of impaired cytochrome P450 and breast cancer resistance protein (BCRP) activity and expression to drug pharmacokinetics under diabetic conditions. Diabetes was induced in rats with the intraperitoneal administration of streptozocin. Glibenclamide (GLB), a substrate of BCRP, served as a model drug. The pharmacokinetics of orally administered GLB (10 mg/kg) were studied. The results showed that diabetes mellitus significantly increased exposure (area under the curve and peak concentration) to GLB after oral administration. Data from hepatic microsomes suggested impairment of GLB metabolism in diabetic rats. GLB metabolism in hepatic microsomes was significantly inhibited by a selective inhibitor (sulfaphenazole) of CYP2C11 and an anti-CYP2C11 antibody. Western blotting further indicated the contribution of impaired CYP2C11 expression to the impairment of GLB metabolism. Excretion data showed that ∼72% of the orally administered dose was excreted in the feces of normal rats, which indicates an important role for intestinal BCRP. Diabetes significantly decreased the recovery from feces, which was only 40% of the orally administered dose. Results from in situ, single-pass, intestinal perfusion experiments revealed that diabetes significantly increased the apparent effective permeability and decreased the efflux of GLB through the intestine; this suggests impairment of intestinal BCRP function, which may play a role in the increased exposure to orally administered GLB in diabetic rats. Insulin treatment partly or completely reversed the changes in diabetic rats. All results yielded the conclusion that impaired hepatic CYP2C11 and intestinal BCRP expression and activity induced by diabetes contributed to the increased exposure of orally administered GLB.
    Drug metabolism and disposition: the biological fate of chemicals 03/2012; 40(6):1104-12. · 3.74 Impact Factor
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    ABSTRACT: Many studies have demonstrated that Mrp2 is highly regulated in some physiopathological situations. The aim of this study was to investigate effects of diabetes mellitus on function and expression of multidrug resistance-associated protein 2 (Mrp2) in rat liver, kidney and intestine. Diabetic rats were induced by an intraperitoneal administration of streptozotocin (65 mg/kg) and randomly divided into diabetic (DM) rats and insulin-treated diabetic rats. Sulfobromophthalein (BSP), a substrate of Mrp2, was used to evaluate Mrp2 function in vivo. Data from excretion experiments demonstrated that compared with normal rats, diabetes markedly enhanced BSP excretion via bile, urine and intestinal perfusate, which contributed to the elevated plasma clearance of BSP after intravenous administration of 45 μmol/kg BSP. Western blot results showed higher levels of hepatic, renal and intestinal Mrp2 protein in DM rats, although no difference was observed in renal Mrp2. Insulin treatment partly reversed these alterations. Induction of Mrp2 by diabetes was in parallel with the increase in bile flow, levels of biliary and plasma total bile acid (TBA), and plasma conjugated bilirubin in DM rats. Diabetes may enhance Mrp2 function and expression in liver, kidney and intestine, which might be due to insulin deficiency, increased TBA and conjugated bilirubin.
    Xenobiotica 02/2012; 42(8):709-18. · 1.98 Impact Factor