熊去氧胆酸联合中药对胆囊结石家兔模型保胆取石术后胆汁酸 、胆固醇合成代谢的影响

目的 研究保胆取石术术后应用熊去氧胆酸联合中药对胆囊结石家兔模型术后胆汁酸、胆固醇合成代谢的影响.方法 选择雄性新西兰家兔60只为研究对象,建立胆囊结石模型后进行内镜下保胆取石术,根据术后处理方式不同分为3组,对照组给予普通饮食,模型组给予致石饮食,干预组给予致石饮食+熊去氧胆酸联合中药.检测3组家兔血清中胆固醇(TC)、总胆汁酸(TBA)、总胆红素(TBIL)含量以及胆固醇7-羟化酶(CYP7A1)和胆汁酸盐输出泵(BSEP)运输因子acbc11 mRNA含量.结果 干预后3周、5周时,模型组家兔血清中TC、TBIL含量高于对照组,TBA含量均低于对照组(t=3.571~24.374,P<0.05);干预组家兔血清中胆固醇TC、TBIL含量低于对照组,TBA含量均高于模型组(t=2.438~18.230,P<0.05);模型组家兔胆囊组织中CYP7A1和acbc11的mRNA含量低于对照组(t=11.369~20.096,P<0.05),干预组家兔胆囊组织中CYP7A1和acbc11的mRNA含量高于模型组(t=5.923~16.049,P<0.05).结论 熊去氧胆酸联合中药有助于修复受损胆固醇7-羟化酶和胆汁酸盐输出泵运输因子acbc11基因表达,调节胆汁酸、胆固醇、胆红素的代谢水平,预防保胆取石术后结石复发.     

肝癌切除术后口服UDCA血清胆汁酸浓度变化情况分析

目的 对原发性肝癌手术切除患者服用熊去氧胆酸(ursodeoxycholic acid,UDCA)后血清胆汁酸浓度变化进行分析,为临床治疗提供合理建议。方法 抽取2009年1月~2010年1月服用过熊去氧胆酸的原发性肝癌手术患者病历89份进行分析。结果 ①用药前血清胆汁酸浓度变化值最大值为131.10 μmol/L,最小值为-69.00 μmol/L,四分位数间距为15.30 μmol/L;用药后血清胆汁酸变化值最大为275.20 μmol/L,最小值为-49.00 μmol/L,四分位数间距为30.50 μmol/L。②与用药前血清胆汁酸浓度变化相比,用药后血清胆汁酸浓度明显升高,P<0.01。③这种升高与用药前的Child-Pugh评分显著相关,P<0.01,与熊去氧胆酸用药剂量、术中出血量、肝门阻断时间、手术者、肝硬化程度等因素不相关。结论 原发性肝癌手术患者服用熊去氧胆酸应考虑的首要因素是用药前的Child-Pugh评分。     

消石利胆胶囊与熊去氧胆酸胶囊治疗慢性胆固醇结石性胆囊炎的效果观察

目的:对消石利胆胶囊与熊去氧胆酸胶囊治疗慢性胆固醇结石性胆囊炎的效果进行观察。方法:采集2017年9月—2019年9月我院收治的慢性胆固醇结石性胆囊炎患者100例,通过随机数表法分为对照组(熊去氧胆酸胶囊)50例与研究组(消石利胆胶囊)50例,比较不同药物临床应用效果的差异性。结果:两组治疗有效率差异小且无统计学意义(P>0.05)。相较于对照组,研究组溶石有效率更高,差异大且有统计学意义(P<0.05)。两组治疗前VSA评分、PPI评分、PRI评分差异小且无统计学意义(P>0.05);相较于对照组,研究组治疗后VSA评分、PPI评分、PRI评分更低,差异大且有统计学意义(P<0.05)。两组治疗后不良反应差异小且无统计学意义(P>0.05)。结论:在慢性胆固醇结石性胆囊炎治疗中,消石利胆胶囊与熊去氧胆酸胶囊均能够达到确切治疗效果,且安全性较高,但消石利胆胶囊的溶石效果与腹痛改善效果更好,值得临床推广使用。     

胆固醇代谢异常与胆固醇结石形成的研究进展

胆固醇结石是一种常见病、多发病。流行病学调查显示随着老龄化、肥胖、糖尿病和高血脂发病率的升高,胆固醇结石的发病率也有逐年升高的趋势。新近研究发现胆固醇结石的发生与全身脂质代谢异常尤其是胆固醇酯代谢异常有着密切的关系。现就胆固醇结石和胆固醇代谢紊乱的关系做一综述。     

熊去氧胆酸与牛磺熊去氧胆酸治疗胆固醇性胆结石的疗效比较

目的:比较熊去氧胆酸(UDCA)和牛磺熊去氧胆酸(TUDCA)治疗胆囊胆固醇性胆结石的疗效及安全性。方法:将74例胆固醇性胆结石患者随机分为2组,分别给予UDCA(每次250mg,每日3次)和TUDCA(每次250mg,每日3次)治疗6个月,分别在治疗3个月和6个月后通过B超对患者的溶石效果进行比较并观察2组不良反应发生情况。结果:经过3个月的治疗,UDCA和TUDCA对胆结石治疗的有效率分别为37.8%和56.8%,6个月治疗的有效率分别为75.7%(28/37)和78.4%(29/37)。2组比较,3个月时TUDCA对胆结石的疗效优于UDCA(P<0.01);但经过6个月的治疗,二者的疗效无显著性差异。2组不良反应发生率比较差异无统计学意义。结论:TUDCA和UDCA均可有效溶解胆固醇性胆结石,且安全性较好,但TUDCA的溶石速度大于UDCA。     

胆固醇结石介入性溶解治疗的研究进展

胆固醇结石(Cholesterol stone,CS)主要见于胆囊结石中。目前胆囊结石虽以手术治疗为主要方法,但对于单纯胆囊结石且胆囊有浓缩和收缩功能者,非手术疗法仍有必要。溶石治疗为非手术疗法之一,本文仅就CS介入性溶解治疗的研究进展及现状综述如下:一、CS介入性溶解治疗的理论基础CS是指胆固醇含量在70%以上的胆石,也有人认为胆固醇含量在50%以上就属CS,其它要的成分还有胆红素、胆酸、自由脂肪酸、糖蛋白、钙等金属离子。几乎所有CS都含有一个与胆石主体以黑色的含硫带相分开的黑色核心,此核心由胆红素—钙—糖蛋白复合物组成。针对上述CS的结构特点,研制一种疗效高、副作用小的CS接触溶解剂,将会明显提高CS溶解治疗效果。     

熊去氧胆酸片对胆石症症状复发及其并发症作用的临床观察

胆石症是一种多发病,其病程长,症状易反复发作,且常合并感染、梗阻等并发症,给患者带来很大痛苦,对于那些非手术适应症的患者,怎样防止胆石症症状的复发和其并发症的发生,已成为当前难以解决的问题.     

薄层扫描法测定熊胆引流物中胆汁酸含量

熊胆向以贵重药材闻名,被称之为稀有药品,为开发熊胆资源,解决熊胆奇缺问题,我校解剖教研室已成功地完成了人工引流熊胆汁技术,可随时进行人工引流获取熊胆汁。为了确定胆汁的质量指标,了解其主要成分,我们进行了引流胆汁与天然熊胆的分析。文献报道,熊胆中主要含熊去氧胆酸(ursodesoxycholic acid,UDCA)、鹅去氧胆酸(cheno desoxycholic acid,CDCA)、胆酸(cholic acid,CA)、去氧胆酸(deoxycholic,acid DCA)等。     

熊去氧胆酸对胆总管结石患者预防术后结石的形成和复发的影响

目的:评价熊去氧胆酸对胆总管结石患者预防术后结石的形成和复发的影响。方法:选取2015年7月—2016年11月间收治的胆总管结石患者100例资料,采用随机数字表法将其分为对照组和观察组,每组50例;对照组患者实施手术取石治疗,术后不给任何药物治疗;而观察组患者在取石手术结束后给予熊去氧胆酸连续服用1年;比较两组患者术后结石形成的复发率、胆管结石症状改善的有效率,以及再次手术率差异。结果:观察组患者术后结石形成的复发率和再次手术率分别为12.00%和16.00%低于对照组分别为48.00%和40.00%(P<0.05);临床症状(黄疸、右上腹疼痛及发热)复发率显著低于对照组(P<0.05)。结论:熊去氧胆酸对胆总管结石患者能够有效预防术后结石的形成,避免了再次手术。     

调节胆汁酸代谢及肠道菌群对非酒精性脂肪肝治疗效果研究

目的通过动物实验研究探讨调节饮食-胆汁酸-肠道菌群治疗非酒精性脂肪性肝病(NAFLD)的疗效。方法随机选择小鼠40只,分四组,每组10只,Ⅰ组采用普通饲料;Ⅱ组采用高脂饲料;Ⅲ组普通饲料,并给予头孢曲松钠。Ⅳ组高脂饲料,同时应用头孢曲松钠。喂养12周,采血化验甘油三酯(TG)、胆固醇(TC)、丙氨酸氨基转移酶(ALT)、谷氨酰氨基转移酶(AST)、胆汁酸(TBA)、脂联素、粪便胆汁酸水平,行肠道菌群培养比较,并测定肝匀浆组织血脂成分。根据Ⅳ组方式喂养小鼠32只,12周后均停用抗生素,给予普通饮食、无菌水,将其随机平均分为四组,每组8只,A组为对照组;B组给予熊去氧胆酸;C组给予枯草杆菌二联活菌;D组给予熊去氧胆酸及枯草杆菌二联活菌。ABCD四组小鼠均饲养12周后再次检测上述指标进行比较。结果Ⅱ、Ⅳ组小鼠,TG、ALT、AST、TBA、粪便胆汁酸水平均明显升高,差异有统计学意义(P 0.01)。Ⅲ组ALT、AST水平明显升高,差异有统计学意义(P 0.01)。B组ALT、AST、TBA,C组TG、ALT、AST、脂联素,D组TG、ALT、AST、TBA与A组比较,差异有统计学意义(P 0.05)。B、C、D组粪便胆汁酸水平较A组有明显变化,有统计学意义。各组与对照组比较肝匀浆血脂成分差异有统计学意义(P 0.05)。Ⅲ、Ⅳ组肠道菌群失调明显,双歧杆菌、乳酸杆菌、肠杆菌下降明显,肠球菌水平升高,差异有统计学意义(P 0.01)。C、D组肠道菌群改善明显,差异有统计学意义(P 0.01)。结论肠道菌群、胆汁酸代谢与NAFLD发生发展相关,通过调节肠道菌群及胆汁酸水平可以改善肝脏脂质代谢及肝功能,促进肝脏恢复。     

Bile acid sequestrants: Mechanisms of action on bile acid and cholesterol metabolism

Summary Interruption of the enterohepatic circulation of bile acids by cholestyramine or colestipol influences the hepatic metabolism of cholesterol in many ways. The synthesis of bile acids is increased, as reflected by a several-fold increase in the activity of the cholesterol 7 hydroxylase, the rate-determining enzyme in bile acid synthesis. The increased metabolism of cholesterol to bile acids causes an enhanced demand of cholesterol in the hepatocytes, which respond with both new synthesis of cholesterol, as reflected in a several-fold increase of the HMG-CoA reductase activity, and increased expression of LDL receptors. As a consequence, the plasma level of LDL-cholesterol is lowered. The hepatic secretion rate of VLDL particles is increased. Cholestyramine therapy does not affect the output of biliary lipids or the cholesterol saturation of bile, indicating that treatment with bile acid sequestrants should not be associated with any increased risk of gallstone formation.     

Pharmacokinetics of ursodeoxycholic acid in rat

The pharmacokinetic behaviour and metabolism of ursodeoxycholic acid (UDCA) have been studied in the rat. After oral administration of both 3H-labelled (4 muCi/kg body wt) and unlabelled (20 mg) UDCA, UDCA appeared in serum almost entirely in conjugated form (taurine conjugated); UDCA was present in bile mostly as taurine conjugated; the more relevant metabolite is 3 alpha,6 alpha, 7 beta-trihydroxycholanoic acid which represents 10% of the total bile acid pool. UDCA increased bile flow and selectively decreased biliary cholesterol secretion, while phospholipid secretion was unaffected. Faecal UDCA excretion was 15-20% while the urinary extraction was 1.5% during 24 h. The data show that UDCA, when administered in high dose, is promptly secreted into bile almost entirely metabolized to tauroursodeoxycholic acid, where it (1) desaturates the cholesterol in bile, (2) exerts choleretic properties.     

Effect of ursodeoxycholic acid treatment on the altered progesterone and bile acid homeostasis in the mother-placenta-foetus trio during cholestasis of pregnancy

Aim

Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and elevated bile acid concentrations in maternal serum. This is accompanied by an enhanced risk of intra-uterine and perinatal complications. High concentrations of sulphated progesterone metabolites (PMS) have been suggested to be involved in the multifactorial aetiopathogenesis of ICP. The aim of this study was to investigate further the mechanism accounting for the beneficial effect of oral administration of ursodeoxycholic acid (UDCA), which is the standard treatment, regarding bile acid and PMS homeostasis in the mother-placenta-foetus trio.

Method

Using HPLC-MS/MS bile acids and PMS were determined in maternal and foetal serum and placenta. The expression of ABC proteins in placenta was determined by real time quantitative PCR (RT-QPCR) and immunofluorescence.

Results

In ICP, markedly increased concentrations of bile acids (tauroconjugates > glycoconjugates >> unconjugated), progesterone and PMS in placenta and maternal serum were accompanied by enhanced concentrations in foetal serum of bile acids, but not of PMS. UDCA treatment reduced bile acid accumulation in the mother-placenta-foetus trio, but had no significant effect on progesterone and PMS concentrations. ABCG2 mRNA abundance was increased in placentas from ICP patients vs. controls and remained stable following UDCA treatment, despite an apparent further increase in ABCG2.

Conclusion

UDCA administration partially reduces ICP-induced bile acid accumulation in mothers and foetuses despite the lack of effect on concentrations of progesterone and PMS in maternal serum. Up-regulation of placental ABCG2 may play an important role in protecting the foetus from high concentrations of bile acids and PMS during ICP.     

Limits and perspective of oral therapy with statins and aspirin for the prevention of symptomatic cholesterol gallstone disease

The prevalence of gallstones disease in Western countries is 10 – 15%. Gallstones can be one of two types – cholesterol or pigment – with cholesterol gallstones representing nearly the 80% of the total. Cholesterol and pigment gallstones have different predisposing factors: cholesterol gallstones are related to supersaturated bile in cholesterol, whereas black pigment gallstones are related to hyperbilirubinbilia factors (hemolysis, etc.); these are necessary, but not sufficient, factors to produce gallstones in vivo. Gall bladder mucosa factors (gall bladder secretion of mucin, local bile stasis and production of endogenous biliary β-glucuronidase) may coexist with the aforementioned factors and facilitate gallstone nucleation and growth. The gold-standard treatment for symptomatic gallstones is laparoscopic cholecystectomy. Several studies have reported a significant reduction in the onset of symptomatic gallstones disease in patients undergoing chronic therapy with statins, which can reduce bile cholesterol saturation. Aspirin, which has been shown to reduce the local production of gall bladder mucins (mucosal or parietal factors of gallstone formation) in animal experimental models, does not appear to reduce the risk of symptomatic gallstones disease when tested alone. The new horizon of oral therapy for the prevention of symptomatic gallstone disease needs to evaluate the long-term effect of statins and chronic aspirin administration in patients with dyslipidemia and/or atherosclerosis.     

阿嗪米特对豚鼠胆囊胆固醇结石的治疗作用

目的:研究阿嗪米特(azintamide)对豚鼠胆囊胆固醇结石的治疗作用。方法:用高胆固醇饮食诱发豚鼠胆囊胆固醇结石模型,进行胆囊结石计数;测定胆囊体积和胆囊胆汁量;测定血清总胆汁酸(TBA)、总胆红素(TBIL)、胆固醇(TCHO)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-c)、低密度脂蛋白胆固醇(LDL-C)、碱性磷酸酶(ALP);测定胆汁TCHO,TBA和TBIL。观察阿嗪米特(20和80mg·kg~(-1))对胆囊胆固醇结石的治疗作用。为探讨阿嗪米特抗胆囊胆固醇结石的作用机制,对胆囊壁组织进行了黏液素(mucin)的免疫组化实验。结果:与模型组比较,阿嗪米特20和80mg·kg~(-1)组成石率明显下降;胆囊体积和胆囊胆汁量显著减少;血清TCHO及LDL-C明显降低(P＜0．05);胆汁TBA升高(P＜0．05),胆汁TCHO及TBIL降低(P＜0．05)。黏液素免疫组化实验中可观察到,模型组黏液素表达水平较高,而阿嗪米特组黏液素表达水平较低。已知利胆药熊去氧胆酸(UDCA)亦有显著效果。结论:阿嗪米特对高胆固醇饮食诱发的豚鼠胆囊胆固醇结石模型具有明显的治疗作用。     

Effect of bile acids on absorption of nitrendipine in healthy subjects

AIMS: To examine whether bile acids such as ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) can influence the absorption of nitrendipine, a highly lipophilic calcium channel blocker. METHODS: Six healthy subjects received nitrendipine (10 mg) with and without UDCA (50 mg) and CDCA (200 and 600 mg) with an interval of 1 approximately 2 weeks between study phases. RESULTS: Bile acids decreased the Cmax (ng ml(-1)) [control 10.9 +/- 5.8 (mean+/- s.d.), UDCA 5.0 +/- 4.7 (95% confidence interval for difference; 3.9, 7.8, P = 0.0006), CDCA (600 mg) 5.0 +/- 3.9 (2.6, 9.2, P = 0.0059)] and AUC (ng ml(-1) h) [(control; 60 +/- 36, UDCA 15 +/- 13 (20, 73, P = 0.0064), CDCA (600 mg) 19 +/- 19 (21, 63, P = 0.0038)] of nitrendipine, while elimination half-life remained unchanged. CONCLUSIONS: These results suggest that the amount of nitrendipine absorbed was decreased when the drug was administered with UDCA and CDCA.     

白藜芦醇降低高脂小鼠体内胆固醇水平的作用及胆汁酸转化分子机制的初步研究

目的：研究白藜芦醇对高脂小鼠体内胆固醇水平的降低作用及其调节胆汁酸转化的分子机制。方法：选取40只Apo E-/-小鼠给予高脂饮食制备高胆固醇小鼠模型，随机分为4组：模型组、白藜芦醇低剂量组、白藜芦醇中剂量组及白藜芦醇高剂量组，分别每天灌胃0.2 mL 生理盐水、10 g·L^-1白藜芦醇，20 g·L^-1白藜芦醇和40 g·L^-1白藜芦醇。分别在第0，5，10，20周比较4组小鼠血浆总胆固醇（total cholesterol，TC）、三酰甘油（triglyceride，TG）的水平。在第20周实验结束时，比较4组小鼠血浆低密度脂蛋白胆固醇（low density lipoprotein cholesterol，LDL-C）、高密度脂蛋白胆固醇（high density lipoprotein cholesterol，HDL-C）含量、动脉粥样硬化指数（arteriosclerosis index，AI）水平以及肝脏中TC、TG的含量。在人肝癌细胞株HepG2细胞系中加入0，6.25，12.5，25 μmol·L^-1白藜芦醇，检测加入白藜芦醇后各组细胞内胆固醇含量、细胞外胆汁酸含量差异。最后用25 μmol·L^-1白藜芦醇处理细胞，采用RT-PCR及Western blot分别检测细胞中胆固醇代谢相关基因胆固醇7-羟化酶（cholesterol 7α-hydroxylase，CYP7A1）、腺苷三磷酸结合盒转运体超家族成员（ABCG5）的mRNA及蛋白的表达水平。结果：白藜芦醇各剂量组小鼠的TC、TG、LDL-C、AI水平均显著低于模型组，而HDL-C显著高于模型组。白藜芦醇可降低HepG2细胞中总胆固醇含量，并促进细胞分泌胆汁酸含量。RT-PCR及Western blot结果显示，25 μmol·L^-1白藜芦醇处理HepG2细胞后，CYP7A1、ABCG5的mRNA及蛋白的表达水平明显增加。结论：白藜芦醇可以降低高脂小鼠体内胆固醇水平，这种作用可能是通过调节胆汁酸转化过程中相关基因CYP7A1、ABCG5的表达来实现的。     

Taurine ameliorates cholesterol metabolism by stimulating bile acid production in high‐cholesterol‐fed rats

This study was designed to investigate the effects of dietary taurine on cholesterol metabolism in high‐cholesterol‐fed rats. Male Sprague‐Dawley rats were randomly divided into two dietary groups (n = 6 in each group): a high‐cholesterol diet containing 0.5% cholesterol and 0.15% sodium cholate, and a high‐cholesterol diet with 5% (w/w) taurine. The experimental diets were given for 2 weeks. Taurine supplementation reduced the serum and hepatic cholesterol levels by 37% and 32%, respectively. Faecal excretion of bile acids was significantly increased in taurine‐treated rats, compared with untreated rats. Biliary bile acid concentrations were also increased by taurine. Taurine supplementation increased taurine‐conjugated bile acids by 61% and decreased glycine‐conjugated bile acids by 53%, resulting in a significant decrease in the glycine/taurine (G/T) ratio. Among the taurine‐conjugated bile acids, cholic acid and deoxycholic acid were significantly increased. In the liver, taurine supplementation increased the mRNA expression and enzymatic activity of hepatic cholesterol 7α‐hydroxylase (CYP7A1), the rate‐limiting enzyme for bile acid synthesis, by three‐ and two‐fold, respectively. Taurine also decreased the enzymatic activity of acyl‐CoA:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). These observations suggest that taurine supplementation increases the synthesis and excretion of taurine‐conjugated bile acids and stimulates the catabolism of cholesterol to bile acid by elevating the expression and activity of CYP7A1. This may reduce cholesterol esterification and lipoprotein assembly for very low density lipoprotein (VLDL) secretion, leading to reductions in the serum and hepatic cholesterol levels.     

顶端钠依赖性胆酸转运体及其抑制剂的研究进展

胆汁酸的肠肝循环对于胆固醇及脂类的吸收和代谢具有极其重要的作用。顶端钠依赖性胆酸转运体(apical sodium-dependent bile acid transporter ASBT)主要表达在回肠壁腔侧膜上,负责肠道中绝大部分胆酸的重吸收,在胆固醇代谢中的地位非常重要。药理学试验证明抑制ASBT活性可以有效地降低血清胆固醇和低密度脂蛋白,因此ASBT可以作为降酯药物开发的新靶点。本文阐述了ASBT的生物学功能及特性,并对以ASBT为靶点的抑制剂进行了综述。