小檗碱改善胰岛素抵抗的新进展

小檗碱又名黄连素．是从黄连等植物中提取的异喹啉类生物碱,具有广泛的药理作用。近年来,随着对小檗碱及其衍生物的深入研究发现。小檗碱具有改善胰岛素抵抗作用。现综合国内外对小檗碱的研究,对小檗碱改善胰岛素抵抗及作用机制进行综述。     

小檗碱对高脂血症伴胰岛素抵抗大鼠糖脂代谢的影响

目的:观察小檗碱对高脂血症伴胰岛素抵抗(IR)大鼠糖脂代谢的影响,探讨其调脂和改善IR的机理.方法:通过喂养高脂饲料和小剂量静注链脲佐菌素(STZ)建立高脂血症伴IR大鼠模型,测定各不同处理组血糖、脂、胰岛素水平和脂代谢关键酶活性.结果:小檗碱组大鼠总胆固醇(TC)、甘油三酯(TG)、载脂蛋白B(ApoB)、低密度脂蛋白-胆固醇(LDL-C)、游离脂肪酸(FFA)均比模型组明显降低(P＜0.05或P＜0.01),而高密度脂蛋白-胆固醇(HDL-C)、载脂蛋白A(ApoAI)、胰岛素敏感指数(ISI)显著升高;血脂蛋白脂酶(LPL)活性显著升高(P＜0.05或P＜0.01).结论:小檗碱可能通过降低血FFA而改善IR,其调脂功效可能与升高LPL活性有关.     

小檗碱对胰岛素抵抗大鼠氧化应激和内质网应激的影响

目的观察小檗碱对胰岛素抵抗大鼠氧化/抗氧化状态和内质网应激(endoplasmic reticulum stress,ERstress)的影响,并探讨其改善胰岛素抵抗的分子机制。方法采用高脂高热卡饮食饲养8wk制备胰岛素抵抗大鼠模型,成模后随机分为小檗碱组(BER组)、Alpha-硫辛酸组(ALA组)和模型组(MOD组),各组以相应的药物干预4wk。另设正常组(NOR组),予普通饲料喂养,不予药物干预。比较各组大鼠空腹血糖(FBG)、空腹胰岛素水平(Fins)和胰岛素敏感性(ISI)。血清中丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性以观察药物对大鼠氧化和抗氧化的影响。Westernblot方法测定肝脏组织中的ER应激标志物c-Jun氨基端激酶(c-junNH2-terminal kinase,JNK)和Phospho-c-Jun(Ser73)(p-c-Jun)的含量变化。RT-PCR方法测定肝脏组织ER应激标志物葡萄糖调节蛋白GRP78(glucose regulated protein78,GRP78)mRNA表达水平,以观察小檗碱对胰岛素抵抗大鼠ER应激的影响。结果与NOR组比较,MOD组大鼠血清中MDA含量明显升高,SOD、GSH-Px活性明显降低(P均<0.05)。BER组大鼠SOD、GSH-Px的活性较MOD组明显升高(P<0.01,P<0.05),MDA含量较模型组明显下降。比较各组肝组织p-c-Jun/JNK的水平,MOD组较NOR组明显升高(P<0.01),BER组及ALA组较MOD组均明显下降(P均<0.01)。比较各组肝组织中GRP78mRNA水平,MOD组较NOR组明显升高(P<0.05),BER组及ALA组较MOD组均明显下降。结论小檗碱能提高胰岛素抵抗大鼠的胰岛素敏感性,增加其抗氧化能力,改善其ER应激状态,其作用机制可能与改善ER应激有关。     

小檗碱缓解胰岛素抵抗信号通路的研究进展

糖尿病是一种代谢紊乱型疾病,恢复胰岛素敏感性和改善代谢稳态对治疗糖尿病及其并发症至关重要。小檗碱可缓解胰岛素抵抗,降低血糖。总结了小檗碱通过依赖性蛋白激酶（MAPK）信号通路、胰岛素信号通路、核因子-κB(NF-κB)信号通路以及其他信号通路改善胰岛素抵抗来说明小檗碱降血糖的作用机制。     

小檗碱治疗多囊卵巢综合征合并胰岛素抵抗疗效探讨

目的研究小檗碱(BBR)治疗多囊卵巢综合征合并胰岛素抵抗的疗效。方法选择2013年7月~2014年11月到我院就诊的100例多囊卵巢综合征合并胰岛素抵抗患者,通过随机数表法的方法分为观察组和对照组,对于观察组中的患者,采取复方环丙孕酮(CPA)和BBR治疗,对于对照组中的患者,让其单独服用CPA,治疗一段时间后,对比两组患者治疗前后糖代谢以及脂代谢的变化。结果治疗一段时间后,两组患者的FIN、FPG都有一定程度的下降,而且观察组中患者的下降程度要明显高于对照组;两组患者的LDL-C、TG、TC均有不同程度的下降以及两组患者的HDL-C都有一定程度的升高,而且观察组中患者LDL-C、TG、TC的下降程度以及HDL-C的升高程度与对照组比较差异具有统计学意义(P0.05)。结论小檗碱治疗多囊卵巢综合征合并胰岛素抵抗的疗效显著,可以在临床上广泛推广应用,让更多的多囊卵巢综合征合并胰岛素抵抗患者得到治疗。     

小檗碱对高果糖饲养诱导大鼠胰岛素抵抗和肝脏TNF-α表达的影响

目的研究小檗碱对高果糖饲养诱导胰岛素抵抗大鼠的作用。方法高果糖饲料喂养SD大鼠6wk后,分为3组,模型组,小檗碱组(187.5mg.kg-1.d-1灌服)、二甲双胍组(184mg.kg-1.d-1灌服)作为对照,继续高果糖饮食。实验同时设立正常对照组,普通饮食喂养。4wk后处死大鼠;测定血糖、血清胰岛素、胰岛素抵抗指数及血脂的变化,用RT-PCR方法观察肝脏TNF-αmRNA的表达。结果模型组胰岛素、胰岛素抵抗指数、游离脂肪酸(free fatty acids,FFA)及甘油三酯(triglycerides,TG)水平均明显升高;肝脏TNF-αmRNA的表达与正常对照组比较明显升高。小檗碱降低了胰岛素抵抗大鼠的血糖、血清胰岛素、胰岛素抵抗指数、TG、FFA及TNF-αmRNA的表达。二甲双胍降低了大鼠的血糖、血清胰岛素、胰岛素抵抗指数及TG。结论小檗碱可以改善胰岛素抵抗,其机制可能包括抑制肝脏TNF-αmR-NA的表达与改善脂代谢紊乱。     

盐酸小檗碱对2型糖尿病大鼠胰岛素敏感指数影响的Meta分析

目的:系统评价盐酸小檗碱对2型糖尿病大鼠胰岛素敏感指数(ISI)的影响。方法:通过计算机检索万方医学数据库、中国期刊全文数据库、中国生物医学文献数据库以及Pub Med数据库,收集盐酸小檗碱治疗2型糖尿病大鼠的随机对照实验,采用Rev Man 5.2软件进行Meta分析。结果:共纳入6篇文献,94只大鼠。Meta分析结果显示,盐酸小檗碱可以改善2型糖尿病大鼠的ISI[WMD:-0.67,95%CI(-1.03,-0.31),P<0.000 01],各研究之间存在异质性。结论:盐酸小檗碱可以明显改善2型糖尿病大鼠的ISI。     

小檗碱对NIT-1细胞胰岛素分泌和葡萄糖激酶活性的影响

本文探讨小檗碱对NIT-1细胞胰岛素分泌的影响及其分子机制。采用不同浓度小檗碱干预NIT-1细胞后，以放射免疫法、液体闪烁计数法、酶法分析及Western blotting分别检测其胰岛素水平、葡萄糖利用、葡萄糖激酶(GK)活性、GK和葡萄糖激酶调节蛋白(GKRP)的表达。结果表明，在高浓度葡萄糖刺激下，与空白对照组相比，小檗碱组的NIT-1细胞胰岛素分泌增加、葡萄糖利用活跃，且GK酶活性增强、GK表达增加，而GKRP表达降低(P<0.05)。结果表明，小檗碱促进NIT-1细胞高浓度葡萄糖诱导的胰岛素分泌，可能与其作为GK激活剂，使NIT-1细胞葡萄糖利用增加、GK酶活性及表达增强有关。     

小檗碱对2型糖尿病性神经痛大鼠疼痛的影响

目的：探讨不同剂量的小檗碱（Berberine，Ber）对2型糖尿病性神经痛（DEN）大鼠疼痛及血糖的影响。方法：实验采用高脂高果糖饲料喂养1个月，再用小剂量链脲佐菌素（STZ）诱导的方法建立2型糖尿病性神经痛大鼠模型，且随机将实验动物分为正常对照组、糖尿病对照组、低剂量组、高剂量组。正常对照组不予任何处理，糖尿病对照组以磷酸盐缓冲液（PBS）1ml／kg、低剂量组以小檗碱100m异，kg、高剂量组以小檗碱187.5mg／kg体重灌胃，整个治疗持续8周（w）。用热板法测定大鼠舔后足的潜伏期即痛阔，用血糖仪测空腹血糖（FBG）。结果：（1）建模成功后，模型大鼠FBG〉113．8mmol／L，痛阈值明显降低（P〈0．05）。（2）用小檗碱治疗后，低剂量组、高剂量组的FBG均较糖尿病对照组明显降低（R=0．05）；高剂量组的痛阈值较糖尿病对照组显著升高（P〈0．01）。（3）实验还发现，在用小檗碱治疗的后期能使明显消瘦的2型糖尿病性大鼠体重回升。结论：小檗碱可明显降低糖尿病大鼠的空腹血糖，且大剂量时对DPN大鼠的神经性疼痛有一定的改善作用。     

小檗碱对大鼠口服阿托伐他汀钙药代动力学的影响

目的研究小檗碱对大鼠口服阿托伐他汀钙药代动力学的影响,为临床联合用药提供参考依据。方法大鼠随机分为5组,单次阿托伐他汀钙组(A组)、单次小剂量小檗碱+阿托伐他汀钙组(B组)、单次大剂量小檗碱+阿托伐他汀钙组(C组)、多次小剂量小檗碱+单次阿托伐他汀钙组(D组)及多次大剂量小檗碱+单次阿托伐他汀钙组(E组)。给药前后眼眶采血,采用HPLC法测定大鼠体内阿托伐他汀钙的浓度。经DAS 2.0药动学软件处理,获得各组药动学参数。结果大鼠在单次及多次灌胃不同剂量的小檗碱后,阿托伐他汀钙的体内药代动力学参数改变无统计学意义。结论正常用量下小檗碱对大鼠阿托伐他汀钙的药代动力学有一定的影响,但无统计学意义,在人体内的影响仍需进一步研究。     

水果酵素醋对胰岛素抵抗糖脂代谢紊乱大鼠的影响

目的 探讨水果酵素醋对胰岛素抵抗糖/脂代谢紊乱大鼠的作用。方法 SD大鼠随机分为5组：正常组、模型组、水果酵素醋低[玫瑰茄7.95 g（生药）/ kg + 桃金娘4.82 g（生药）/ kg]、中[玫瑰茄15.90 g（生药）/ kg + 桃金娘9.64 g（生药）/ kg]、高剂量[玫瑰茄47.72 g（生药）/ kg + 桃金娘28.92 g（生药）/ kg]组。以高脂饲料喂养联合一次性腹腔注射链脲佐菌素（STZ）复制胰岛素抵抗糖脂代谢紊乱大鼠模型,以糖耐量血糖、血糖曲线下面积（AUC）、血清胰岛素（INS）、胰岛素抵抗指数(IRI)、甘油三酯（TG）、总胆固醇（TC）、尿素氮（BUN）及肌酐（Cr）含量为评价指标,研究水果酵素醋对胰岛素抵抗糖/脂代谢紊乱大鼠的作用。结果 与模型组相比,水果酵素醋中、高剂量组0 h、0.5 h、2 h糖耐量血糖值及AUC明显降低(P<0.01),BUN含量显著下降(P<0.01)。结论 水果酵素醋具有辅助降血糖的功能,并具有一定的减轻肾功能损伤作用。     

小檗碱对2型糖尿病大鼠骨骼肌糖脂代谢的影响及其机制

目的观察小檗碱对糖尿病大鼠骨骼肌病理结构改变和糖脂代谢紊乱的影响及其与PPARe α/γ/δ蛋白表达的关系。方法注射链脲菌素（35mg·kg^-1，i．p．）加高糖高脂饲料喂养16周建立2型糖尿病大鼠模型，随后16周每天分别拌食给予低中高剂量小檗碱（75、150、300mg·kg^-1）、非诺贝特（100mg·k^-1）和罗格列酮（4mg·k^-1），用HE染色检查骨骼肌结构病变、分光光度法测定肌糖元和甘油三脂含量及免疫组化检测PPAR α/γ/δ的表达。结果骨骼肌纤维在各组大鼠中仍正常分布，中高剂量小檗碱部分地改善糖尿病肌纤维的萎缩，增加肌糖元和降低甘油三脂含量（P〈0．01）。中高剂量小檗碱和罗格列酮都能明显降低糖尿病大鼠骨骼肌中PPARγ蛋白水平（P〈0．01），中高剂量小檗碱和非诺贝特能促进PPARα和PPARδ的表达（P〈0．01）。结论小檗碱调控骨骼肌PPARα/γ/δ蛋白的表达可能是其改善糖尿病骨骼肌纤维萎缩和糖脂代谢紊乱的机制之一。     

Protective effects of berberine against doxorubicin-induced cardiotoxicity in rats by inhibiting metabolism of doxorubicin

Abstract

1.?The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. Berberine, a botanical alkaloid, has been reported to possess cardioprotective and antitumor effects. In this study, we investigated the cardioprotective effect of berberine on doxorubicin-induced cardiotoxicity and the effect of berberine on the metabolism of doxorubicin.

2.?Adult male Sprague-Dawley rats were administered doxorubicin in the presence or absence of berberine for 2 weeks. Administration of berberine effectively prevented doxorubicin-induced body weight reduction and mortality in rats.

3.?Berberine reduced the activity of myocardial enzymes, including aspartate aminotransferase (AST), creatine kinase (CK), CK isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Echocardiographic examination further demonstrated that berberine effectively ameliorated cardiac dysfunction induced by doxorubicin.

4.?Berberine inhibited the metabolism of doxorubicin in the cytoplasm of rat heart and reduced the accumulation of doxorubicinol (a secondary alcohol metabolite of doxorubicin) in heart.

5.?These data showed that berberine alleviated the doxorubicin-induced cardiotoxicity in rats via inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts.     

I. Kinetics and metabolism of theobromine in male rats

On the basis of general pharmacological information (blood cells/plasma partition, plasma protein binding) and using HPLC as the principal analytical method, we investigated the kinetics and metabolism of theobromine (a caffeine metabolite) in male rats after a single dose and after a 2 week chronic application. Doses in both conditions varied between 1 and 100 mg/kg. In in vitro and in vivo the fraction of theobromine unbound to plasma proteins averaged 0.90 over a wide range of concentrations. No significant difference was found in the pharmacokinetic profile of the drug after acute or chronic treatment at different doses except for a reduction in the absorption rate constant as the dose increased. AUC values increased in proportion to the dose. The 2 treatment schedules were also similar as regards metabolism, at least 50% of the administered dose of theobromine being excreted unchanged, and 25% as 6-amino-5-[N-methyl-formylamino]1-methyluracil. Only at the highest doses was there a tendency for theobromine to accumulate at the expense of its major metabolite (a uracil compound).     

Effects of type 2 diabetes mellitus on the pharmacokinetics of berberine in rats

Context: Berberine is an active alkaloid isolated from Rhizoma coptidis [Coptis chinensis Franch. (Ranunculaceae)] that is widely used for the treatment of diabetes, hyperlipidemia and hypertension. However, the pharmacokinetics of berberine in normal rats and type 2 diabetes mellitus (T2DM) model rats are not clear.

Objective: This study compares the pharmacokinetics of berberine between normal and T2DM model rats.

Materials and methods: The T2DM model rats were fed with high fat diet for 4 weeks, induced by low-dose (30?mg/kg) streptozotocin for 72?h and validated by determining the peripheral blood glucose level. Rats were orally treated with berberine at a dose of 20?mg/kg and then berberine concentration in rat plasma was determined by employing a sensitive and rapid LC-MS/MS method.

Results: The significantly different pharmacokinetic behaviour of berberine was observed between normal and T2DM model rats. When compared with the normal group, C_max, t_1/2 and AUC_(0–t) of berberine were significantly increased in the model group (17.35?±?3.24 vs 34.41?±?4.25?μg/L; 3.95?±?1.27 vs 9.29?±?2.75?h; 151.21?±?23.96 vs 283.81?±?53.92?μg/h/L, respectively). In addition, oral clearance of berberine was significantly decreased in the model group (134.73?±?32.15 vs 62.55?±?16.34?L/h/kg).

Discussion and conclusion: In T2DM model rats, the pharmacokinetic behaviour of berberine was significantly altered, which indicated that berberine dosage should be modified in T2DM patients.     

Chronic effects of berberine on blood, liver glucolipid metabolism and liver PPARs expression in diabetic hyperlipidemic rats

Berberine is one of the main alkaloids of Rhizoma coptidis which has been used as a folk medicine to treat diabetes mellitus for more than 1400 years in China. To investigate the chronic effect of berberine on diabetic hyperlipidemic rats, fasted rats were intraperitoneally injected 35 mg/kg streptozotocin. Diabetic rats were admitted after 2 weeks and given a high-carbohydrate/high-fat diet to induce hyperlipidemia. The rats were divided into 7 groups at the end of week 16: normal and diabetic rats received no drug, 5 treatment groups were administered with either 75, 150, 300 mg/kg berberine, 100 mg/kg fenofibrate or 4 mg/kg rosiglitazone per day for 16 weeks, respectively. The blood glucose, hemoglobin A1c, lipid metabolic parameters and hepatic glycogen and triglyceride were measured, and histopathology and peroxisome proliferator-activated receptors (PPARs) alpha/delta/gamma expression of liver were determined by hematoxylin eosin and immunohistochemical staining. Berberine reduced diabetic rats' body weight, liver weight and liver to body weight ratio. Berberine restored the increased blood glucose, hemoglobin A1c, total cholesterol, triglyceride, low density lipoprotein-cholesterol, apolipoprotein B and the decreased high density lipoprotein-cholesterol, apolipoprotein AI levels in diabetic rats to near the control ones. Berberine alleviated the pathological progression of liver and reverted the increased hepatic glycogen and triglyceride to near the control levels. Berberine increased PPARalpha/delta expression and reduced PPARgamma expression in liver of diabetic rat to near the control ones. Berberine improved glucolipid metabolism both in blood and liver in diabetic rats possibly through modulating the metabolic related PPARalpha/delta/gamma protein expression in liver.     

脂糖舒对2型糖尿病大鼠胰岛素抵抗的影响

目的：观察脂糖舒(ZTS)对2型糖尿病大鼠胰岛素抵抗的改善作用。方法 分别对2型糖尿病胰岛素抗性模型两组大鼠灌服不同剂量的ZTS(每日1次)，连续9周，同时以健康大鼠(正常对照组)、二甲双胍和格列齐特作对照，进行糖耐量试验，测定血浆葡萄糖(Glu)、胰岛素(Ins)、甘油三脂(TG)、游离脂肪酸(NEFA)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL—c)和高密度脂蛋白胆固醇(HDL—c)含量并称体重和脂肪组织重量，计算胰岛素抵抗指数(IRI)。结果 脂糖舒抑制病鼠体重和脂肪组织重量增长以及降糖降脂(TG、NEFA及LDL)和降IRI作用优于格列齐特(P＜0．01)。与二甲双胍比较，脂糖舒降NEFA作用较强(P＜0．05)，降IRI作用与二甲双胍相当(P＞0．05)，且脂糖舒降IRI作用呈剂量依赖关系。结论 脂糖舒明显改善2型糖尿病的胰岛素抗性。