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TGR5 is a bile acid-activated G protein-coupled receptor and plays an important role in the physiological and pathological processes of the biliary system. This article describes the normal expression of TGR5 in the liver and bile duct under normal physiological conditions and its functions including the regulation of bile acid secretion and metabolism and cytoprotection. This article also summarizes the changes in the expression and function of TGR5 under pathophysiological conditions and the mechanism of TGR5 in affecting the development and progression of biliary tract diseases through inflammatory response and cell proliferation and apoptosis. TGR5 may be a potential target for the treatment of biliary tract diseases in the future.
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Objective To investigate the effect of Shuganning injection (SGN) in alleviating drug-induced cholestasis and the possible mechanisms involved. Methods The liver of Sprague-Dawley rats was decellularized to prepare collagen scaffolds, and then the scaffolds were recellularized with human HepG2 cells to obtain the tissue-engineered liver (normal control group). The tissue-engineered liver was perfused with 10 μmol/L chlorpromazine (CPZ) and bile salt mixture to establish a model of drug-induced cholestasis (CPZ group), and the model was further treated with Shuganning injection (10 3 -fold dilution) as the injury protection group (SGN+CPZ group). The markers for hepatocellular injury [alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP)] and the antioxidant and oxidative stress markers [glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS)] were measured for all groups, and the normal control group, the CPZ group, and the SGN+CPZ group were compared in terms of the mRNA and protein expression levels of the enzymes associated with liver bile salt metabolism and the enzymes associated with hepatic cholestasis. HE staining was performed to observe liver pathology. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t -test was used for further comparison between two groups. Results Compared with the CPZ group, the SGN+CPZ group had significant reductions in the markers for hepatocellular injury ALT, AST, LDH, and ALP (all P < 0.000 1), significant increases in the oxidative stress markers GSH and SOD ( P < 0.000 1 and P < 0.001), and significant reductions in the markers MDA and ROS ( P < 0.000 1 and P < 0.001). Compared with the CPZ group, the SGN+CPZ group had significant reductions in the mRNA expression levels of cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CPY8B1) in hepatocytes (all P < 0.001) and significant increases in the mRNA expression levels of farnesoid X receptor (FXR), small heterodimeric partner (SHP), bile salt export pump (BSEP), and multidrug resistance-associated protein 2 (MRP2) ( P < 0.000 1, P < 0.01, P < 0.000 1, and P < 0.000 1). HE staining showed that compared with the CPZ group, the SGN+CPZ group had a significant reduction in hepatocyte injury and a significant increase in the number of cells. Conclusion Shuganning injection can alleviate drug-induced cholestatic liver injury caused by chlorpromazine, and it exerts a protective effect by activating FXR in hepatocytes and increasing the expression of SHP to regulate bile salt balance. It also inhibits CYP7A1 and CYP8B1 to reduce the synthesis of hydrophobic bile acids and upregulates the expression of BSEP and MRP2 to promote the excretion of bile salts.
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Bile acids are the end products of cholesterol metabolism and are classified as primary bile acids and secondary bile acids. They can promote nutrition absorption and regulate immune response, glucose/lipid/energy metabolism, and microbiota homeostasis by acting on bile acid nuclear receptors and membrane receptors. Cholestatic liver disease (CLD) is a type of liver disease caused by abnormalities of the hepatobiliary system due to cholestasis, with the initial manifestations of hepatocyte and/or bile duct injury, which further leads to abnormal bile acid synthesis, secretion, and excretion. In-depth studies have gradually revealed the role and mechanism of bile acids in CLD, and drugs targeting the action sites of bile acids are under research and development. This article elaborates on the role and mechanism of bile acid metabolism in CLDand summarizes the research and development of drugs for CLD treatment based on bile acid metabolism, so as to provide a reference for future research on the prevention and treatment of CLD.
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Bile acids are the end products of cholesterol metabolism and are classified as primary bile acids and secondary bile acids. They can promote nutrition absorption and regulate immune response, glucose/lipid/energy metabolism, and microbiota homeostasis by acting on bile acid nuclear receptors and membrane receptors. Cholestatic liver disease (CLD) is a type of liver disease caused by abnormalities of the hepatobiliary system due to cholestasis, with the initial manifestations of hepatocyte and/or bile duct injury, which further leads to abnormal bile acid synthesis, secretion, and excretion. In-depth studies have gradually revealed the role and mechanism of bile acids in CLD, and drugs targeting the action sites of bile acids are under research and development. This article elaborates on the role and mechanism of bile acid metabolism in CLDand summarizes the research and development of drugs for CLD treatment based on bile acid metabolism, so as to provide a reference for future research on the prevention and treatment of CLD.
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Nonalcoholic fatty liver disease is a group of diseases with unclear pathophysiological mechanism and is closely associated with metabolic syndrome. Bacterial components and metabolites produced by gut microbiota can regulate glucose and lipid metabolism, inflammatory response, and oxidative stress, and bile acids regulate immune function, energy metabolism, and material metabolism through various signaling pathways after activating their receptors. Gut microbiota and bile acids interact with each other through enterohepatic circulation, and the changes of their structure and function are involved in the development and progression of nonalcoholic fatty liver disease. This article reviews the effect of the homeostatic dysregulation of gut microbiota and bile acids and their interactions on nonalcoholic fatty liver disease.
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Objective:Based on UPLC-Q-Orbitrap HRMS and network pharmacology, the material basis, processing principle and molecular mechanism of bile processed Coptidis Rhizoma (BPRC) for reducing excess fire of liver and gallbladder were elucidated.Method:The chemical ingredients of BPRC were analyzed by UPLC-Q-Orbitrap HRMS. Chromatographic separation was achieved with 0.1% formic acid solution (A)-acetonitrile (B) as the mobile phase in gradient elution (0-20 min, 5%-80%B; 20-30 min, 80%-95%B; 30-30.1 min, 95%-5%B; 30.1-35 min, 95%-5%B). The flow rate was 0.2 mL·min-1, electrospray ionization (ESI) was applied and operated in positive and negative ion modes, the acquisition range was m/z 100-1 500. Based on the clinical manifestations and pathogenic factors of excess fire of liver and gallbladder, the potential effective ingredients, targets and functional characteristics of BPRC were predicted and analyzed by online database. Based on the characteristics of the new active ingredients after processing, the processing principle of BPRC was investigated by network pharmacology.Result:A total of 19 ingredients in BPRC were identified, six of which were newly added cholic acids after processing. It was determined that the alkaloids, including worenine, epiberberine, jatrorrhizine, coptisine, berberrubine, berberine, palmatine and cholic acids, including glycohyodeoxycholic acid, taurohyodeoxycholic acid, glycochenodeoxycholic acid, hyodeoxycholic acid and taurochenodeoxycholic acid, were identified as material basis of BPRC. A total of 66 targets of reducing excess fire of liver and gallbladder of BPRC were screened. There were 16 common targets and multiple same signaling pathways between cholic acids and alkaloids of BPRC, and many lesions of excess fire of liver and gallbladder were target organs of cholic acids. By acting on some targets, including albumin (ALB), Caspase-3 (CASP3), mitogen-activated protein kinase 14 (MAPK14), glucocorticoid receptor (NR3C1) and other targets and some signaling pathways, including interleukin (IL)-17, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), MAPK and other pathways, BPRC could reduce excess fire of liver and gallbladder.Conclusion:BPRC has the characteristics of multi-component, multi-target and multi-pathway on reducing excess fire of liver and gallbladder. Bile and Coptidis Rhizoma have synergistic effect and bile can enhance the intensity of BPRC in lesions, which confirms the processing theory that the effect of BPRC on excess fire of liver and gallbladder enhance after being processed by bile.
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Enterohepatic circulation plays an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Bile acid is the basic substance of enterohepatic circulation and plays an important role in lipid metabolism, intestinal flora regulation, and host immunity. This article summarizes the research advances in bile acid which acts as a signal molecule to activate bile acid receptors in the liver and intestine, such as farnesoid X receptor, G protein-coupled receptor 5, pregnane X receptor, and vitamin D receptor, and is thus involved in the pathogenesis of NAFLD. It is expected to develop effective drugs for the treatment of NALFD based on the above targets, but there is still a need for further exploration.
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The incidence rate of nonalcoholic fatty liver disease (NAFLD) is gradually increasing in recent years, and the treatment of NAFLD is unsatisfactory due to the failure in lifestyle adjustment and a lack of effective drugs. Farnesoid X receptor (FXR), as the main bile acid receptor, may affect NAFLD by participating in glucose and fat metabolism, and intestinal FXR (iFXR) acts on the intestinal tract alone and may thus avoid the side effects of systemic release. Therefore, it may have potential value in the treatment of NAFLD, but there are also certain controversies. This article reviews the research advances in the role of iFXR in NAFLD.
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Cholestatic liver disease refers to a liver disorder caused by cholestasis, which arise from a series of etiologies such as viruses, bacteria, parasites, drugs, poisons, autoimmunity, alcohol, stones, tumors, genetics, and metabolism. This disease has the main manifestations of a change in bile flow and excessive accumulation of bile acid toxicity. In the pathogenesis of cholestatic liver disease, not only does the enterohepatic circulation of endogenous bile acids work, but also the intestinal microbiota plays an important role by regulating metabolism and causing immune responses. In addition, more attention has been paid to the close interaction between intestinal microbiota and the enterohepatic circulation of bile acids. Bile acids can alter the composition of intestinal microbiota, which in turn affects the bile acid pool. In recent years, there has been increasing research on the relationship of the enterohepatic circulation of bile acids and intestinal microbiota with cholestatic liver disease, which may provide new research directions for the pathogenesis and treatment of cholestatic liver disease.
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Hepatitis B virus (HBV) infection is closely associated with bile acid. Recent studies have shown that HBV infection is involved in the regulation of bile acid metabolism through bile acid transporters and mediation of liver injury, and bile acid changes HBV biosynthesis through FXR. This article reviews the research advances in the association between HBV infection and bile acid and the role of bile acid in the diagnosis and treatment of HBV-related liver diseases, so as to provide new ideas for the clinical diagnosis and treatment of HBV infection.
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Non-alcoholic fatty liver disease (NAFLD) has become a new health issue in the world due co its increasing incidence rate,and in particular,nonalcoholic steatohepatitis is progressive and has poor prognosis.Therefore,there is an argent need to search for the methods for the prevention of disease progression and treatment.Bile acid,as an important metabolite and signal molecule,can adjust the metabolism of lipids and carbohydrates and energy balance inside and outside the liver.Bile acid interacts with is receptors,such as the farnesoid X receptor and Takeda G-protein coupled receptor 5,bile acid transporter,and gut microbiota and is involved in the pathogenesis of NAFLD and nonalcoholic steatohepatitis at different levels.This article summarizes the research advances in the pathogenesis of bile acid-related NAFLD and related pharmacotherapy.
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Cholesterol is a component of cell membrane and plays a vital role in maintaining metabolism and normal functions in human body. Liver X receptor (LXR) is a nuclear receptor expressed in abundance in the liver. It influences the process of cholesterol metabolism through regulating the synthesis, transformation, and transportation of cholesterol and bile acid at the level of hepatocytes, and therefore, it plays an important role in maintaining cholesterol homeostasis in human body. In addition, LXR can inhibit the intestinal absorption of dietary cholesterol, reduce exogenous cholesterol level and total cholesterol level in human body, and prevent hypercholesterolemia and formation of gallstones. This article summarizes the mechanism of action of LXR in regulating cholesterol metabolism at both liver and intestinal levels.
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Bile acids play critical roles in the solubilization and absorption of lipids. The ileal apical sodium-dependent bile acid transporter( ASBT)located at the enterocyte brush border is responsible for the reuptake of bile acids and the maintenance of bile acid homeostasis. Recently,great success has been made in understanding the relationship between ASBT and intestinal inflammation,tumorigenesis,secretion,motility,sensation,gut microbiota,and gut-liver axis in addition to its expression regulation,which implicates ASBT as a contributor of some gastrointestinal diseases and a promising new therapeutic target for these diseases. In this review article,the advances in study on above-mentioned issues were summarized.
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Objective To investigate the relation of changes of fetal bile acid and morphologic ultrastructure of human placental syncytial cells in intrahepatic cholestasis of pregnancy (ICP). Methods(Total bile acid of cord venous blood was measured by cycle enzyme method between intrahepatic cholestasis of pregnancy and control groups after birth. The ultrastructure of human placental syncytial cell was analyzed by morphologic study in two groups. Results (1) The total bile acid of cord venous blood in ICP group was significantly higher than in control group[(8.6?3.2) ?mol/L vs (4.6?1.5)?mol/L ](P0.05). The average volume, surface area density and volume density of mitochondrion in ICP group [respectively (0.0200?0.0020) ?m~3,(0.600?0.010) ?m~2/?m~3,(0.0800?0.0090)?m~3/?m~3] were significantly enlarged than in control group [respectively (0.0100?0.0050)?m~3, (0.500?0.030) ?m~2/?m~3,(0.0500?0.0020) ?m~3/?m~3](P0.05). Conclusion In ICP, high levels of bile acids may impair cellular organelle, resulting in abnormality of physiological function of syncytial cells, and affecting the synthesis and transportation functions of placenta.
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28.5 ?mol/L) and liver function. Results Among 1275 women, 102 were diagnosed with ICP giving an incidence of 8.0%. The incidence was significantly higher during 33 to 36 weeks (18.80%, P