氯吡格雷作为抗血小板聚集药物,尤其在急性冠状动脉综合征、经皮冠状动脉介入术后治疗时发挥重要作用.然而在临床给药过程中发现,易出现氯吡格雷抵抗.参与氯吡格雷反应抵抗的因素很多,目前的关注点主要集中在CYP450酶基因多态性与氯吡格雷抵抗的研究,有关转运体和受体结合位点基因多态性的综述较少,更少见高原人群、不同民族人群间的基因多态性研究.本研究主要从药物吸收转运体的基因多态性与氯吡格雷生物利用度的关系,药物代谢酶对氯吡格雷的生物转化,氯吡格雷活性代谢产物与受体结合发挥药效的全过程进行综述,吸收转运体ABCB1基因位点突变会影响氯吡格雷的生物利用度;代谢酶基因多态性中起关键作用的是CYP2C19和CES1,应根据基因分型调整剂量;生物学活性基因P2Y12基因多态性会影响氯吡格雷的疗效.因此,掌握氯吡格雷基因多态性的影响因素,有助于氯吡格雷的个体化给药,以最大限度地减少抗血小板效应不足导致的血栓性事件或抗血小板效应过度导致的出血性事件.

Ciliary neurotrophic factor (CNTF) analogues were reported to ameliorate fatty liver in db/db or high-fat diet-fed mice. It is generally thought that CNTF exerts its actions centrally. The aim of this study was to investigate whether peripheral effects of CNTF analogues are involved in the therapeutic effect on high fat-induced hepatic steatosis. The rat model of fatty liver was induced by a high-fat diet (HFD) for 12 weeks. In the next 2 weeks, rats were fed the HFD along with subcutaneous injection of vehicle or mutant recombinant human CNTF (rhmCNTF 0.05-0.2 mg/kg per day). Steatotic HepG2 cells were induced by 50% fetal bovine serum (FBS) for 48 hours, and then treated with rhmCNTF for 24 hours. The results showed that after rhmCNTF treatment, hepatic triglyceride (TG) accumulation was attenuated both in vivo and in vitro. RhmCNTF increased protein expression of CPT-1 and PPARα, and decreased SREBP-1c, FAS and SCD-1 in steatotic HepG2 cells. But the production of nitric oxide and 8-isoPGF2α in steatotic HepG2 cells was not affected by rhmCNTF. These results suggest that rhmCNTF has a peripheral effect that alleviates fat-induced hepatic steatosis.

Ciliary neurotrophic factor (CNTF) and CNTF analogs were reported to have hepatoprotective effect and ameliorate hepatic steatosis in db/db or high-fat-diet-fed mice. Because hepatic steatosis and injury are also commonly induced by hepatotoxin, the aim of the present study is to clarify whether CNTF could alleviate hepatic steatosis and injury induced by carbon tetrachloride (CCl4). Unexpectedly, when combined with CCl4, CNTF aggravated hepatic steatosis and liver injury. The mechanism is associated with effects of CNTF that inhibited lipoprotein secretion and drastically impaired the ability of lipoproteins to act as transport vehicles for lipids from the liver to the circulation. While injected after CCl4 cessation, CNTF could improve liver function. These data suggest that CNTF could be a potential hepatoprotective agent against CCl4-induced hepatic injury after the cessation of CCl4 exposure. However, it is forbidden to combine recombinant mutant of human CNTF treatment with CCl4.

Ampelopsin is a well-known flavonoid which has variety of biological and pharmacological actions including anticancer effects and induction of apoptosis on the several cancer cell lines. The present study aimed to evaluate the role of ampelopsin sodium (Amp-Na) in the mitochondrial-mediated apoptosis of human lung adenocarcionma SPC-A-1 cells. The analysis of cell proliferation and ultrastructure were performed. Furthermore, to clarify its action mechanism by determining the mitochondrial membrane potential (Δψm), intracellular calcium (Ca2+) concentration, mitochondrial nitric oxide (NO) level and total ATPase activity. The results showed that Amp-Na markedly inhibited the SPC-A-1 cell proliferation and caused ultrastructural apoptosis feature in SPC-A-1 cells in a dose-dependent manner. Amp-Na led to a rapid and sustained Ca2+ elevation and Δψm reduction, and induced the mitochondrial NO production and decreased the total ATPase activity in SPC-A-1 cells. The results enhance the potential of Amp-Na as a therapeutic drug for treating lung cancer, and provide new information for mechanism of Amp-Na which induces mitochondrial-mediated apoptosis in tumor cells.

Objective: The close connection between high blood FFA and insulin resistance (IR) in obese individuals is well-known. The purpose of this study was to identify whether the blood FFA increased in obese-IR animals.Methods: Obese-IR animal models were established using high-fat diet (HFD) or HFD and streptozocin, and treated with drugs.Results: The serum FFA of obese-IR animals was not increased, even significantly lower than that of normal animals, and were not significantly decreased when insulin sensitivity and obesity-related indices were ameliorated after treatment.Conclusion: The results suggest that blood FFA are unlikely the link between obesity and insulin resistance. (C) 2015 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Aim. To investigate the role of AMPK activation and autophagy in mediating the beneficial effects of exercise and caloric restriction in obesity. Methods. Dietary-induced obesity mice were made and divided into 5 groups; one additional group of normal mice serves as control. Mice in each group received different combinations of interventions including low fat diet, caloric restriction, and exercise. Then their metabolic conditions were assessed by measuring serum glucose and insulin, serum lipids, and liver function. AMPK phosphorylation and autophagy activity were detected by western blotting. Results. Obese mice models were successfully induced by high fat diet. Caloric restriction consistently improved the metabolic conditions of the obese mice, and the effects are more prominent than the mice that received only exercise. Also, caloric restriction, exercise, and low fat diet showed a synergistic effect in the improvement of metabolic conditions. Western blotting results showed that this improvement was not related with the activation of AMPK in liver, skeletal muscle, or heart but correlates well with the autophagy activity. Conclusion. Caloric restriction has more prominent beneficial effects than exercise in dietary-induced obese mice. These effects are correlated with the autophagy activity and may be independent of AMPK activation.

Dysglycemia (hyper- and hypoglycemia) has been associated with higher mortality among patients suffering from myocardial infarction (MI). Moreover, dysglycemia may induce cell death. Cell death (necrosis, apoptosis and autophagy) is a ubiquitous process that characterizes the course of several diseases, including MI, and occurs in diverse forms varying in mechanism, pattern and consequence. Therefore, cell death is a potential pathway through which dysglycemia affects the outcome of MI and it is essential to regulate myocardial cell death in the treatment of patients with MI caused by dysglycemia. In this review, we summarized the mechanisms of MI at the cellular level and the regulatory effects of dysglycemia on myocardial cell death. The ability to modulate myocardial cell death may be a promising target of new treatments aimed at limiting MI caused by dysglycemia. However, further research is required to elucidate the mechanisms underlying cell death regulation in MI caused by dysglycemia.

细胞凋亡（apoptosis）是指由于内外环境变化或死亡信号触发以及在基因调控下所引起的细胞主动死亡的过程,这一过程对消除机体内老化和具有潜在性异常生长的细胞,以及保持机体处于稳态（homeostasis）起着重要的作用[1]。研究发现,心肌细胞凋亡参与了心肌梗死（myocardial infarction,MI）后心室重塑、心力衰竭的一系列病理生理变化,心肌细胞凋亡是MI范围

Objective: To investigate the general pharmacological actions of recombinant human interferonα 2a-NGR (rhIFNα 2a-NGR) except its main pharmacodynamic properties, and thus to provide experimental basis for clinical study and application. Methods: Mice, monkeys and rabbits were given rhIFNα 2a-NGR for injection respectively via im, and then the influences on cardiovascular, respiratory, central nervous system, and body temperature of animal were determined. Results: At therapeutic dose, rhIFNα 2a-NGR had no obvious effect on general behavior, spontaneous activity, and coordination test in mice, and no obvious effect on blood pressure, heart rate, electrocardiogram, and respiratory rate in anesthetized monkeys (P>0.05). But it slightly elevated the body temperature of a few rabbits treated with medium dose. It also caused body temperature elevation of more than 0.6°C in all rabbits in high dose group. Between 1 and 4 h after administration, the temperature had significantly difference compared with that of control group (P<0.05). Conclusion: Except for the body temperature elevation in rabbits in a dose-dependent manner, rhIFNα 2a-NGR had no effect on nervous, cardiovascular and respiratory systems of the animals.

目的:观察重组人干扰素α2a-NGR(rhIFNα 2a-NGR)主要药效学以外的一般药理作用,为临床研究和安全用药提供参考.方法:小鼠、猴和家兔肌内注射rhIFNα2a-NGR后,测试其对动物心血管、呼吸、神经系统和体温的影响.结果:rhIFNα 2a-NGR对小鼠的一般行为、自发性活动和猴的血压、心率、心电图、呼吸频率和幅度无显著影响.中剂量可引起个别家兔的体温轻度升高,高剂量可使全部兔体温升高超过0.6℃,与对照组比较差别显著(P＜0.05).结论:rhIFNα 2a-NGR对动物心血管、呼吸和中枢神经系统无显著性影响,但对家兔有剂量依赖性致热作用.

The compound rh-IFNalpha-2a-NGR can inhibit tumor angiogenesis and could be used for targeted therapy. In the present study, double antibody sandwich ELISA analysis was used to determine the concentration of rh-IFNalpha-2a-NGR in serum after intramuscular administration of various dosages to mice, rats and monkeys. The results showed that the pharmacokinetic properties of rh-IFNalpha2a-NGR after i.m. administration to mice, rats and monkeys were consistent with a one-compartment open model. The main pharmacokinetic parameters in mice (9.36 microg/kg), rats (4.68 microg/kg) and monkeys (2.34 microg/kg) after i.m. rh-IFNalpha2a-NGR were as follows: T(peak) was 0.49, 1.65 and 3.60h, C(max) was 3030.20, 654.49 and 268.13 ng/L, t1/2 was 0.39, 4.52 and 2.70 h, and AUC(0-infinity)) was 4197.65, 5784.58 and 2622.06 ng/L x h, respectively. Also, mice, rats and monkeys had their own distinct metabolic characteristics. These data would provide references for further clinical pharmacokinetic study of rh-IFNalpha2a-NGR.

Metabolic syndrome (MS) is highly prevalent in developed countries and becoming a serious worldwide public health issue. In this study, we established a MS model by feeding male C57BL/6J mice with a high-fat diet (10%) for 18.5 weeks, studied the therapeutic effects of a recombinant mutant of the human ciliary neurotrophic factor (rhmCNTF) 0.1 (C-0.1) or 0.3 (C-0.3) mg x kg(-1) per day subcutaneously or pair feeding (PF, which mice were restricted to the same amount of food as eaten by C-0.3 treated mice) in MS mice. After 10 days treatment, rhmCNTF reduced obesity related indices, ameliorated glucose and lipid metabolism abnormality, and enhanced insulin sensitivity. In addition, liver function and antioxidant ability of MS mice were improved by rhmCNTF. Pair feeding revealed the same effects as C-0.3 on obesity related indices and insulin sensitivity, but aggravated hepatic steatosis and hepatic function. The results suggest that rhmCNTF could serve as an effective therapeutic agent for MS and related diseases.

The aim of the present study was to investigate the therapeutic effect and mechanism of proanthocyanidins from grape seed (GSPE) in the treatment of recurrent ulcerative colitis (UC) in rats. To induce recurrent colitis, rats were instilled with 2,4,6-trinitrobenzenesulfonic acid (TNBS) (80 mg/kg) into the colon through the cannula in the first induced phase, and then the rats were instilled a second time with TNBS (30 mg/kg) into the colon on the sixteenth day after the first induction UC. Rats were intragastrically administered GSPE (200 mg/kg) per day for 7 days after twice-induced colitis by TNBS. Sulfasalazine at 500 mg/kg was used as a positive control drug. Rats were killed 7 days after GSPE treatment. The colonic injury and inflammation were assessed by macroscopic and macroscopic damage scores, colon weight/length ratio (mg/cm), and myeloperoxidase activity. Then, superoxide dismutase, glutathione peroxidase, inducible nitric oxide synthase (iNOS) activities, and the levels of malonyldialdehyde, glutathione, and nitric oxide in serum and colonic tissues were measured. Compared with the recurrent UC group, GSPE treatment facilitated recovery of pathologic changes in the colon after induction of recurrent colitis, as demonstrated by reduced colonic weight/length ratio and macroscopic and microscopic damage scores. The myeloperoxidase and iNOS activities with malonyldialdehyde and nitric oxide levels in serum and colon tissues of colitis rats were significantly decreased in the GSPE group compared with those in the recurrent UC group. In addition, GSPE treatment was associated with notably increased superoxide dismutase, glutathione peroxidase activities, and glutathione levels of colon tissues and serum of rats. GSPE exerted a protective effect on recurrent colitis in rats by modifying the inflammatory response, inhibiting inflammatory cell infiltration and antioxidation damage, promoting damaged tissue repair to improve colonic oxidative stress, and inhibiting colonic iNOS activity to reduce the production of nitric oxide.

AIM:To investigate the antioxidation of proanthocyanidins from grape seeds(GSPE)on 2,4,6-trinitrobenzene sulfonic acid(TNBS)twice-induced recurrent ulcerative colitis(UC)in rats and to probe into its underlying mechanism.METHODS:Recurrent colitis model was established in Wistar male rats by rectal administration of 80 mg/kg TNBS dissolved in 50% ethanol,and then the rats were second instilled with 30 mg/kg TNBS into the colon on the 16th day after the first induction UC.Rats were intragastrically administered different doses of GSPE(100,200,and 400 mg/kg)per day for 7 days after twice-induction of colitis by TNBS.Sulfasalazine(SASP,500 mg/kg)was used as a positive control drug.Rats were killed after GSPE treatment 7 days.The colon sample was extracted,and the colon weight/length ratio(mg/cm)was assessed.The activities of,myeloperoxidase(MPO),superoxide dismutase(SOD),glutathione peroxidase(GSH-Px),inducible nitric oxide synthase(iNOS),and the contents of malonyldialdehyde(MDA)and glutathione(GSH)and NO in serum were detected by biochemistry method.RESULTS:Compared with the model group,the rat body weight was decreased,and the colonic weight/length ratio was reduced in GSPE dosage group(P<0.05 or P<0.01);the activities of MPO and iNOS and the contents of MDA,NO in serum were significantly decreased(P<0.05 or P<0.01);but the activities of MPO,iNOS and the contents of MDA,NO were decreased(P<0.05 or P<0.01);the activities of SOD,GSH-Px,the contents of GSH in serum were increased(P<0.05 or P<0.01).CONCLUSION:GSPE can alleviate the inflammatory reactions in colitis through inhibiting oxygen free reaction,exerting antioxidation effects and decreasing the production of NO.

Aim To study the characteristics of mouse metabolic syndrome(MS) model induced by high-fat diet and the effect of sibutramine on MS mice.Methods 9-week-old male C57BL/6J mice,fed with high-fat diet(10% lard,2% cholesterol,and 0.4% sodium cholate in basic diet) for 18.5 weeks were treated with saline or sibutramine 8 mg·kg-1 for 10 days.The body weight,wet weight of visceral fat and liver,liver free fatty acid(FFA) content,serum level of lipid,glucose and insulin were examined at the end of the treatment.Results The excessive fat in abdominal cavity was accumulated in MS mice accompanied with hypercholesterolemia,hyperglycemia,hyperinsulinemia,and insulin resistance.In addition,liver weight and grade of hepatic steatosis increased significantly in MS mice.These symptoms in MS mice were similar to those in human beings.After 10 days treatment,sibutramine reduced the obesity related indices,ameliorated glucose and lipid metabolism abnormality,and enhanced insulin sensitivity,but it increased liver FFA content and had no obvious effect on liver weight and hepatic steatosis in MS mice.Conclusions MS model can be induced in C57BL/6J mice by long-term feeding with high-fat diet and sibutramine has a certain therapeutic effect on MS in mice.

Aim To study the effect of duration of preparation on high-nutrition diet induced obesity(DIO) model and obesity related indices in rats. Methods 290 weanling male SD rats were fed with high-nutrition diet for 7, 9 and 10 weeks and administrated sibutramine 8, 4 and 4 mg·kg-1 for 18, 14 and 14 days in experiment 1, 2 and 3, respectively. The indices of experiments were body weight, Lee's index, liver and visceral fat wet weight, blood lipid and glucose level and the formation of fatty liver. Results The body weight, Lee's index, liver and visceral fat wet weight of DIO rats were significantly higher than that of normal rats when duration of model preparation was 7 wk. The hypertriglyceridemia appeared at week 9. At week 10, hyperglycemia and fatty liver appeared in addition to the significant changes of indices above. Conclusion The duration of model preparation had obvious effects on the formation of obesity related indices in DIO rats and should be determined according to the objective of the study.

AIM:To study the characteristics of diabetic obese rats induced by streptozotocin(STZ)combined with hyperalimentation animal feeds and the therapeutic effect of sibutramine on diabetes obese rats.METHODS:Rats were intravenously injected with low dose(25 mg/kg)of STZ and fed with hyperalimentation animal feeds for 4 months to establish diabetic obese rat model.The diabetic obese rats were treated with sibutramine 4 mg/kg for 17 days and the body weight and food intake daily were measured.The glucose tolerance was measured at the 15th day.At the end of the treatment,the body weight,abdominal viscera fat and right soleus muscle,the levels of blood lipid,blood sugar,insulinum demeshed in serum were measured and the insulin resistance index(FIRI)were calculated.RESULTS:The body weight,abdominal viscera fat weight and the coefficient in model rats increased significantly,but thelinea obliqua tibiae coefficient decreased significantly.The blood-fasting glocose,insulin level increased significantly,and the carbohydrate tolerance abnormality and insulin resistance occurred.The serum triglyceride(TG)level increased and the high-density lipoprotein cholesterol(HDL-C)decreased significantly.Sibutramine reduced the body weight,visceral fat mass and coefficient,ameliorated hyperinsulinemia and insulin resistant,and decreased the serum TG level and increased HDL-C level as well.But it had not obviously affected the soleus muscle coefficient,blood glucose,cholesterol and LDL-C level,and carbohydrate tolerance.CONCLUSION:The diabetic obese rat model could be induced by STZ and hyperalimentation animal feeds and sibutramine has therapeutic effect on obese diabetes rats.

AIM:To improve tumor formation rate of xenografted human lung cancer in nude mice.METHODS:Before xenograftion,human lung cancer SPC-A-1 or GLC-82 cells and their tissue homogenate were diluted with supernatant of mice sarcoma 180 ascites being rich in growth factors.The diluted SPC-A-1 or GLC-82 cell suspensions were injected subcutaneously at right back or armpit of nude mice.The effects of supernatant of mice sarcoma 180 ascites on the tumor growth rate and tumor formation rate were evaluated.RESULTS:Compared with control group,the tumor growth rate and tumor formation rate of human lung cancer SPC-A-1 or GLC-82 in nude mice were significantly improved with the addition of the supernatant of mice sarcoma 180 ascites.CONCLUSION:The supernatant of mice sarcoma 180 ascites can significantly improve the tumor growth rate and tumor formation rate of human lung cancer SPC-A-1 or GLC-82 in nude mice.

AIM:To study pharmacokinetic property of rh-IFNα2a after intravenous(i.v.) and intramuscular(i.m.) injection to mice and rats.METHODS:Double antibody sandwich ELISA analysis was used for testing drug concentration in serum,urine,bile and tissues after i.v.and i.m.administration of rh-IFNα2a in mice and rats.Pharmacokinetic parameters were calculated by DAS software.Immunohistochemistry technique was also adopted to evaluate its distribution characters.RESULTS: Pharmacokinetic model of rh-IFNα2a after i.v.and i.m.was consistent with two-compartment and one-compartment open model respectively,both submitting to first-order kinetic elimination.Rh-IFNα2a was predominantly distributed in kidney and lung tissue.The total drug accumulative excretion quantity in urine was 0.121% of the administered after rh-IFNα2a 8.19 μg/kg i.v.into mice.The total drug accumulative excretion quantity in bile was 0.247% of the administered after rh-IFNα2a 4.10 μg/kg i.v.into rats.CONCLUSION: Pharmacokinetic models after i.v.and i.m.rh-IFNα2a are two-compartment open model and one-compartment open model,respectively,both with first-order kinetic elimination.