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The fatality rate of liver failure caused by fatal amanita poisoning is high, and there are no effective antidote drugs in China. On July 30, 2020, the department of infectious diseases and liver diseases of the First People's Hospital of Yunnan Province admitted a 67-year-old female patient with liver failure caused by fatal amanita poisoning. The patient went to the emergency department for treatment due to abdominal pain, vomiting and diarrhea after eating 350-400 g of amanita mushroom for 2 days, accompanied by fatigue for 1 day. There was no abnormality in physical examination. Laboratory indexes: alanine aminotransferase (ALT) 4 798 U/L, aspartate aminotransferase (AST) 10 030 U/L, activated partial thromboplastin time (APTT) 57.5 s, prothrombin time (PT) 72.1 s, international normalized ratio (INR) 8.66, prothrombinactivity (PA) 10%. Based on the patient's medical history, clinical manifestations and laboratory data, the diagnosis was amanita peptide mushroom poisoning and acute liver failure. According to the mechanism of amanita toxin poisoning as enterohepatic circulation, endoscopic retrograde cholangiopancreatography and ultrasound-guided gallbladder puncture and drainage for drainage of bile to discharge toxins were performed to interrupt the enterohepatic circulation of toxins. However, both methods failed, so open cholecystostomy was performed. Because the patient's coagulation function was very poor, artificial hepatic plasma exchange was given to improve coagulation function before open cholecystostomy, and eventually bile was drained successfully. After a total of 19 days of comprehensive medical treatment, the patient was cured and discharged from the hospital, and no sequelae was found after 1 year of follow-up. For such patients, early identification of the disease is required, and blocking the enterohepatic circulation of toxins as soon as possible according to the characteristics and toxicological mechanism of toxins may be the key treatment for rescuing patients with liver failure poisoned by amanita toxin, and it is necessary to combine comprehensive treatments such as active fluid replacement and blood purification to further improve the survival rate.
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Bile acids (BAs) are a major component of bile salt, which plays a vital role in the metabolism of lipids in humans. Ninety-five percent of bile acids are recycled by the enterohepatic circulation (EHC), and therefore EHC is essential for bile acid homeostasis. There are four transporters that mediate the transmembrane transport of bile acids, each of which plays an important role in the enterohepatic circulation. Gene defects in bile acid transporters can lead to disorders of the enterohepatic circulation, ultimately leading to clinical phenotypes such as metabolic diseases and even death. Bile transporter expression is altered in patients with various metabolic disease states, suggesting that disruption of bile acid transporters may be a pivotal pathological mechanism for the development of metabolism diseases. Thus, many drugs targeting bile acid transporters are being developed. We provide a concise overview of the progress of bile acid transporters research, discuss the relationship between different bile acid transporters and disease development, and summarize the current progress in drug development targeting bile acid transporters.
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Gallstone is a common digestive system disease involving multiple factors, more than 80% of which are cholesterol gallstones, and its incidence rate is increasing year by year. Recent studies have shown that intestinal flora is involved in the development and progression of cholesterol gallstones. This article elaborates on the role of intestinal flora and its metabolites in the progression of cholesterol gallstones from the aspect of regulation of bile acids by intestinal flora and its metabolites, and it is pointed out that intervention strategies for intestinal flora and its metabolites may be a new target for the prevention and treatment of cholesterol gallstones in the future.
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Objective:To study the effect of emulsifier Tween-80 on radiation-induced bile acid enterohepatic circulation disturbance and the treatment strategy.Methods:Male C57BL/6 J mice were randomly divided into healthy control group, radiation-only group, radiation + Tween-80 group and radiation + Tween-80 + butyric acid group. The mice were exposed to total abdominal irradiation (TAI) using a specific steel lead chamber and γ-ray irradiator was used throughout the experiments. Mice in radiation+ Tween-80 group and radiation+ Tween-80+ butyric acid group were intragastrically administrated with Tween-80 for 7 d before irradiation, while healthy control group and radiation-only group were treated with sterile water. After irradiation, butyric acid was administrated to mice in radiation+ Tween-80+ butyric acid group until euthanasia, while healthy control group, radiation-only group and radiation+ Tween-80 group were treated with sterile water until euthanasia. Small intestine and fecal particles were collected 21 d after irradiation. The concentrations of bile acid in small intestinal and fecal samples were measured using enzyme linked immunosorbent assay (ELISA), the expression of TGR5 and JAM-A, as well as the ratio of IL-10/IL-12 in intestine were detected by quantitative real-time PCR (qRT-PCR). The expression levels of GPR43 in the colon were compared using immunohistochemistry (IHC).Results:Tween-80 pretreated mice exhibited lower concentration of bile acid in small intestine and higher level of bile acid in fecal sample after irradiation (7.92%, 7.99%, t=3.93, 2.94, P<0.05), the expression of TGR5, which mediating the biological function of bile acid, and it′s downstream JAM-A gene were down-regulated (20.93%, 9.91%, t=4.85, 5.14, P<0.05), the ratio of IL-10/IL-12 (indicator related to inhibition of inflammation) (4.59%, t=3.39, P<0.05) as well as the expression of GPR43 protein, a G-protein-coupled receptor for butyric acid, decreased in the colon of Tween-80-pretreated mice compared with the radiation-only group. ELISA assay revealed that butyric acid administration elevated bile acid level in small intestines (8.06%, t=9.25, P<0.05), but reduced that in feces (14.41%, t=4.71, P<0.05). In addition, TGR5 and JAM-A showed higher expression in the intestine of butyric acid-treated mice (19.35%, 32.71%, t=7.69, 19.23, P<0.05), as well as the ratio of IL-10/IL-12 (2.39%, 4.05%, t=3.38, 5.92, P<0.05) and the content of GPR43 protein in colon. Conclusions:Tween-80 deteriorates the disturbance of bile acid enterohepatic circulation induced by ionizing radiation in mice. Butyric acid administration erases the adverse effects of Tween-80.
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Nonalcoholic fatty liver disease (NAFLD) interacts with the intestinal immune system due to enterohepatic circulation and immune cell recruitment and recirculation. Intestinal immune imbalance promotes liver inflammation and fibrosis in the process of NAFLD, and meanwhile, NAFLD can cause disorders in the number and function of immune cells in the liver and intestinal tract. This article mainly elaborates on the impact of NAFLD on intestinal immune cells and briefly summarizes the new treatment methods for NAFLD targeting at intestinal immune cells, in order to provide a new understanding of the pathogenesis and treatment of NAFLD.
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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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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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Cholestatic liver disease (CSLD) is a group of liver diseases which can cause cholestasis and has a complex etiology. Its pathogenesis remains unclear, and there are still no effective treatment measures. In the recent decade, new achievements have been made on various aspects of CSLD, which provides more help to accurate diagnosis and treatment and reflects many pending issues which need further research. This article introduces the research advances and problems in CSLD from the following six aspects: the “ascending” pathophysiology of CSLD, mechanisms of cholestasis-induced liver fibrosis and related management measures, association of enterohepatic circulation and intestinal microbiota with CSLD, pathogenesis and diagnosis/treatment of drug-induced cholestasis, pathogenesis and management of liver failure-associated cholestasis, and research advances in treatment targets and drug research and development for CSLD.
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Jervine, a novel steroidal alkaloid from Veratrum nigrum L., exhibits both antitumor effect and potential toxicity. The aim of study was to characterize the pharmacokinetic behaviors and enterohepatic circu-lation of jervine in rats. A rapid and simple ultra-high performance liquid chromatography-tandem mass spectrometric method was developed and validated for quantification of jervine and alpinetin (internal standard) in rat plasma. After extraction from rat plasma by a simple protein-precipitation method, the analyte was separated on a C18 column (2.1 mm × 50 mm, 1.7μm) using water with 0.1％formic acid and acetonitrile as the mobile phase delivered at a flow rate of 0.4 mL/min. Jervine and alpinetin were determined in the positive mode with multiple reaction monitoring (MRM) of the ion transitions at m/z 426.3→108.8 and m/z 271.0→166.9, respectively. Molecular docking method was used to investigate the binding of jervine to p-glycoprotein and dehydroepiandrosterone sulfotransferase. The method was well validated within acceptance limits including specificity, matrix effect, recovery, precision, accuracy, and stability, and was successfully applied to the pharmacokinetic study of jervine after oral and intravenous administration to rats. Jervine presented a small volume of distribution, fast absorption, high oral bioavailability, and enterohepatic circulation. The enterohepatic circulation was first observed in veratrum alkaloids, and was further investigated by molecular docking studies, which was related to the binding of jervine to p-glycoprotein and dehydroepiandrosterone sulfotransferase. The pharmacokinetic properties and enterohepatic circulation of jervine in rats provided a significant basis for the drug-drug interaction and toxicity study in the future.
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Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis. Therefore, FXR is a potential drug target for several metabolic syndromes, especially those related to lipidemia disorders. In the present study, we identified small molecule SIPI-7623, a derivative of an extract from Oriental wormwood (Artemisia capillaris), and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase (CYP7A1), downregulated the expression of sterol-regulatory element-binding protein 1c (SREBP-1c) in the liver, and inhibited the expression of ileal bile acid binding-protein (IBABP) in the ileum of rats. We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride. SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro HepG2 cell models, ameliorated diet-induced atherosclerosis, and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo. Furthermore, SIPI-7623 decreased the extent of atherosclerotic lesions. Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis. In conclusion, SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.
Subject(s)
Animals , Humans , Male , Rabbits , Rats , Artemisia , Chemistry , Atherosclerosis , Drug Therapy , Genetics , Metabolism , Cholesterol , Metabolism , Cholesterol 7-alpha-Hydroxylase , Genetics , Metabolism , Drugs, Chinese Herbal , Hyperlipidemias , Drug Therapy , Genetics , Metabolism , Hypolipidemic Agents , Liver , Metabolism , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear , Genetics , Metabolism , Sterol Regulatory Element Binding Protein 1 , Genetics , Metabolism , Triglycerides , MetabolismABSTRACT
Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis. Therefore, FXR is a potential drug target for several metabolic syndromes, especially those related to lipidemia disorders. In the present study, we identified small molecule SIPI-7623, a derivative of an extract from Oriental wormwood (Artemisia capillaris), and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase (CYP7A1), downregulated the expression of sterol-regulatory element-binding protein 1c (SREBP-1c) in the liver, and inhibited the expression of ileal bile acid binding-protein (IBABP) in the ileum of rats. We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride. SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro HepG2 cell models, ameliorated diet-induced atherosclerosis, and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo. Furthermore, SIPI-7623 decreased the extent of atherosclerotic lesions. Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis. In conclusion, SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.
Subject(s)
Animals , Humans , Male , Rabbits , Rats , Artemisia , Chemistry , Atherosclerosis , Drug Therapy , Genetics , Metabolism , Cholesterol , Metabolism , Cholesterol 7-alpha-Hydroxylase , Genetics , Metabolism , Drugs, Chinese Herbal , Hyperlipidemias , Drug Therapy , Genetics , Metabolism , Hypolipidemic Agents , Liver , Metabolism , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear , Genetics , Metabolism , Sterol Regulatory Element Binding Protein 1 , Genetics , Metabolism , Triglycerides , MetabolismABSTRACT
In order to search for new adefovir analogues as anti-HBV agents with enhanced antiviral activity and hepatotrophic property,adefovir bis L-amino acid ester was used as lead compound to produce ten adefovir mono L-(thio)amino acid ester, mono bile acid ester derivatives(6a-6j). The design based on bile acid prodrug strategy,which can improve drug oral bioavaliability and liver-targeted enrichment by using enterohepatic circula-tion of bile acid.Sub-structure combination method was adopted to introduce L-(thio)amino acid ester and bile acid ester fragments on the phosphonate functionality of adefovir. The structures of target compounds were confirmed by 1H NMR, 13C NMR,ESI-MS and ESI-HRMS.HepG 2.2.15 cell were used for in vitro anti-HBV activity assessment.Compound 6c with high antiviral activity(EC500.92μmol/L,SI 512.63)was further investi-gated for its tissue distribution in mice.The results showed that content of compound 6c in liver was higher than that of adefovir dipivoxil,and in contrast its content in kidney was lower than that in positive control at all time points(0.25-12 h).Compound 6c exhibits higher antiviral activity,selective index and higher liver distribution,making it a potential anti HBV agent for further investigation.
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The development of cholestatic liver disease is closely associated with the enterohepatic circulation disorder of bile acid.This article elaborates on metabolism of bile acid,enterohepatic circulation-related mechanism of hereditary cholestasis,molecular regulation of related transporters,and association between current therapeutic regimens and enterohepatic circulation,in order to investigate the pathogenesis of cholestatic liver disease and provide a basis for the research on new drugs or therapies.
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Recently,the relationship between intestinal dysbacteriosis and chronic liver disease has received much attention. The imbalance of intestinal flora microecology,such as overgrowth of gram negative bacteria,leads to intestinal endotoxemia,and endotoxemia plays an important role in the pathogenesis of chronic liver disease. This article reviewed the advances in study on relationship between enterohepatic circulation and chronic liver disease.
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OBJECTIVE: To study the disposition of geniposide and genipin via intestinal absorption barrier. METHODS: The biotransformation of geniposide was studied by incubating it with intestinal flora or intestinal enzymes. The intestinal absorption of genipin at duodenum, jejunum, ileum and colon was investigated using single-pass intestinal perfusion model. RESULTS: The metabolism activity of intestinal flora for geniposide was (1098.3±519.2) μmol · h-1 · g-1. The concentration of geniposide reduced from 20.00 to 9.60 μmol · L-1 after 4 h of incubation with intestinal enzymes, while the concentration of the metabolite of geniposide, genipin, increased to 3.52 μmol · L-1. The effective permeability coefficients(Peff*) of ginipin at duodenum, jejunum, ileum, and colon were 3.77±0.38, 3.00±0.20, 2.79±0.16, and 2.11 ±0.62, respectively, and the absorption percentages at different intestinal segments of 10 cm long(10 cm% ABS) were (70.24±7.88)%, (56.94 ±4.34)%, (53.44±3.73)%, and (48.52 ±9.59)%, respectively. There were significant differences between duodenum and the other regions of intestine of rats (P < 0.05). The phase II metabolite of genipin was found in rat bile, and its UV absorption spectrum was in accordance with that of genipin hydrolyzed by β-glu-curonidase. CONCLUSION: Geniposide can be transformed to genipin in rat intestine. Genipin can be well absorbed in general intestinal tract without specific absorption site. The phase II metabolite of genipin can be excreted to small intestine through bile.
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Even though there is a strong link between breast feeding and jaundice, it is natural and it may have a partially beneficial role in the neonate. There are two types of jaundice associated with breast feeding. First, insufficient caloric intake during the first week of life may increase serum unconjugated bilirubin concentration, which is known as "breast feeding jaundice (BFJ)". This increased severity of physiologic jaundice results from the increased enterohepatic circulation (EHC) of bilirubin, but not because of a factor in breast milk. Second, prolongation of unconjugated hyperbilirubinemia into the third and later weeks of life in the healthy newborn is a regularly occurring extension of physiologic jaundice, which is known as "breast milk jaundice (BMJ)". This is caused by a factor in breast milk inhibits the glucuronyl transferase in the liver and/or increases the EHC of bilirubin. The acceptable bilirubin level in the full-term healthy breast-fed infant needs to be discussed not only to prevent unnecessary interruption of breast feeding, but also to prevent kernicterus. Optimal breast feeding practices are crucial to prevent the BFJ and to minimize the intensity of BMJ. Further research is needed to clarify the benefit of bilirubin in relation to adaptation of extrauterine life.
Subject(s)
Humans , Infant , Infant, Newborn , Aluminum Hydroxide , Bilirubin , Breast , Breast Feeding , Carbonates , Energy Intake , Enterohepatic Circulation , Hyperbilirubinemia , Jaundice , Kernicterus , Liver , Milk , Milk, Human , TransferasesABSTRACT
Objective To determine whether SC-435, a new ileal apical sodium-codependent bile acid transporter (IBAT) inhibitor, can alter the gastrointestinal motility in guinea pigs. Methods Sixty guinea pigs received regular diet or IBAT inhibitor (SC-435) diet for 2, 4, and 8 weeks, respectively. At the end of the feeding period, the gallbladder motility was assessed and then four bipolar silver electrodes were implanted on the antrum, duodenum, jejunum, and ileum. Seven days later, migrating motor complex (MMC) was recorded and the total bile acid pool size was measured according to the isotope dilution principle in the meantime. Results After feeding SC-435, the gallbla-dder motility was declined in the 4-week group and the 8-week group. The bile acid pool size decreased by 17.11% (P<0.05) in the 4-week group and 48.35% (P<0.05) in the 8-week group. The places of origin of MMC were changed where antral origins (37%) and duodenal origins (46%) decreased whereas jejunal origins (17%) increased. The MMC cycle period was prolonged in the duodenum (1.16 times in the 4-week group, P< 0.05; 1.38 times in the 8-week group, P<0.05) whereas MMC amplitude fell in the duodenum (10.58% in the 4-week group, P<0.05; 49.17% in the 8-week group, P<0.05). There were not significant differences in all parameters of MMC between the control group and the 2-week group in guinea pigs. Conclusion The IBAT inhibitor (SC-435) reduces the bile acid pool size and inhibits the MMC cycle activity. MMC is related to the enterohepatic circulation of bile acids, which is consistent with the changes of the bile acid pool size in guinea pigs.