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Biomedicine & Pharmacotherapy =... May 2020Scoparone has been shown to ameliorate many forms of liver disease, and several underlying molecular mechanisms involved have been previously revealed. However, the...
Scoparone improves hepatic inflammation and autophagy in mice with nonalcoholic steatohepatitis by regulating the ROS/P38/Nrf2 axis and PI3K/AKT/mTOR pathway in macrophages.
BACKGROUND AND AIMS
Scoparone has been shown to ameliorate many forms of liver disease, and several underlying molecular mechanisms involved have been previously revealed. However, the potential role of scoparone in autophagy, which is dysregulated in nonalcoholic fatty liver disease-nonalcoholic steatohepatitis (NAFLD-NASH), has not been evaluated. In the current study, we investigated the effect and potential mechanisms of scoparone in hepatic autophagy in mice with NASH.
METHODS
In vivo, mice were fed a methionine-choline deficient (MCD) diet to establish a NASH model and then subjected to treatment with or without scoparone for 4 weeks. In vitro, scoparone was applied in a hepatocellular lipid overload model in AML12 cells challenged with palmitic acid (PA) and in lipopolysaccharide (LPS)-induced RAW264.7 cells.
RESULTS
Scoparone improved impaired autophagy and several key features of NASH in mice fed an MCD diet. In vitro, scoparone had an effect on the autophagy of macrophages but not hepatocytes. In RAW264.7 cells, scoparone reduced the LPS-induced accumulation of autophagosomes and autophagy substrates, the production of reactive oxygen species (ROS) and the inflammatory response. Scoparone inhibited the upregulation of p62 transcription, which is mediated by the ROS/P38/Nrf2 axis. Chloroquine (CQ), an inhibitor of autophagic flux, significantly inhibited scoparone-mediated protection against inflammation. In addition, scoparone suppressed activation of the PI3K/AKT/mTOR pathway, and MHY1485 (an mTOR activator that inhibits autophagy) inhibited the anti-inflammatory effect of scoparone.
CONCLUSIONS
In LPS-induced macrophages, scoparone regulates autophagy and further suppresses inflammation by inhibiting the ROS/P38/Nrf2 axis and PI3K/AKT/mTOR pathway and enhancing autophagic flux. Scoparone may improve hepatic autophagy and NASH partly through enhancing autophagy in macrophages but not hepatocytes. Scoparone is expected to become a novel therapeutic drug for NASH or diseases associated with dysregulated autophagy in macrophages.
Topics: Animals; Autophagy; Cholagogues and Choleretics; Coumarins; Dose-Response Relationship, Drug; Inflammation; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Non-alcoholic Fatty Liver Disease; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RAW 264.7 Cells; Reactive Oxygen Species; Signal Transduction; TOR Serine-Threonine Kinases; p38 Mitogen-Activated Protein Kinases
PubMed: 32000066
DOI: 10.1016/j.biopha.2020.109895 -
The Lancet. Gastroenterology &... Jul 2021Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes.
METHODS
In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495.
FINDINGS
The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016).
INTERPRETATION
Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment.
FUNDING
Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.
Topics: Cholagogues and Choleretics; Cholestasis, Intrahepatic; Female; Humans; Pregnancy; Pregnancy Complications; Ursodeoxycholic Acid
PubMed: 33915090
DOI: 10.1016/S2468-1253(21)00074-1 -
Biochimica Et Biophysica Acta.... Apr 2018Drug-induced liver injury includes a spectrum of pathologies, some related to the mode of injury, some to the cell type primarily damaged. Among these, drug-induced bile... (Review)
Review
Drug-induced liver injury includes a spectrum of pathologies, some related to the mode of injury, some to the cell type primarily damaged. Among these, drug-induced bile duct injury is characterized by the destruction of the biliary epithelium following exposure to a drug. Most of the drugs associated with bile duct injury cause immune-mediated lesions to the epithelium of interlobular ducts. These share common histopathological features with primary biliary cholangitis, such as inflammation and necrosis at the expense of cholangiocytes and, if the insult persists, bile duct loss and biliary cirrhosis. Some drugs selectively target larger ducts. Such injury is often dose-dependent and thought to be the result of intrinsic drug toxicity. The histological changes resemble those seen in primary sclerosing cholangitis. This overview focuses on the clinical and pathological features of bile duct injury associated with drug treatment and on the immunological and biochemical effects that drugs exert on the biliary epithelium. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
Topics: Amoxicillin-Potassium Clavulanate Combination; Bile Acids and Salts; Bile Ducts; Biomarkers; Biotransformation; Carbamazepine; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cholestasis; Epithelial Cells; Humans; Liver
PubMed: 28882625
DOI: 10.1016/j.bbadis.2017.08.033 -
The Korean Journal of Gastroenterology... May 2018Gallstones are one of the most common diseases worldwide. Recently, the incidence of gallstones has increased and the pattern of gallstones has changed in Korea.... (Review)
Review
Gallstones are one of the most common diseases worldwide. Recently, the incidence of gallstones has increased and the pattern of gallstones has changed in Korea. Laparoscopic cholecystectomy is the standard treatment for symptomatic gallstones. Expectant management is considered the most appropriate choice in patients with asymptomatic gallstones. The dissolution of cholesterol gallstones by oral bile acid, such as ursodeoxycholic acid, can be considered in selected patients with gallstones. Although the advent of laparoscopic cholecystectomy has moved interest away from the pharmacologic treatment of gallstones, several promising agents related to various mechanisms are under investigation.
Topics: Cholagogues and Choleretics; Cholecystectomy, Laparoscopic; Gallstones; Humans; Terpenes; Ursodeoxycholic Acid
PubMed: 29791983
DOI: 10.4166/kjg.2018.71.5.253 -
Canadian Journal of Gastroenterology =... Aug 2008Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts, resulting in end-stage liver... (Review)
Review
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts, resulting in end-stage liver disease and reduced life expectancy. PSC primarily affects young and middle-aged men, often in association with underlying inflammatory bowel disease. The etiology of PSC includes immune-mediated components and elements of undefined nature. A cholestatic picture of liver biochemistries with elevations in serum alkaline phosphatase, nonspecific autoantibodies such as perinuclear antineutrophilic antibody, antinuclear antibodies and smooth muscle antibodies, and diffuse multifocal biliary strictures, resulting in a 'beaded' appearance on radiographic studies, are the hallmarks of the disease. No effective medical therapy is currently available, although clinical studies are in progress. Ursodeoxycholic acid at high doses (28 mg/kg/day to 30 mg/kg/day) is the most promising agent but is unproven so far. Liver transplantation is currently the only life-extending therapy for patients with end-stage disease, although recurrent disease can be observed in the transplanted liver. The multiple complications of PSC include pruritus, fatigue, vitamin deficiencies, metabolic bone disease, peristomal varices, bacterial cholangitis, dominant biliary strictures, gallbladder stones and polyps, and malignancy, particularly cholangiocarcinoma, which is the most lethal complication of PSC.
Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholagogues and Choleretics; Cholangiocarcinoma; Cholangiography; Cholangitis, Sclerosing; Humans; Liver; Liver Transplantation; Prognosis; Recurrence; Ursodeoxycholic Acid
PubMed: 18701947
DOI: 10.1155/2008/824168 -
Canadian Journal of Gastroenterology &... 2022Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic liver disease characterized by progressive cholangiocyte and bile duct destruction leading to... (Review)
Review
Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic liver disease characterized by progressive cholangiocyte and bile duct destruction leading to fibrosis and finally to liver cirrhosis. The presence of disease-specific serological antimitochondrial antibody (AMA) together with elevated alkaline phosphatase (ALP) as a biomarker of cholestasis is sufficient for diagnosis. Ursodeoxycholic acid (UDCA) is the first treatment option for PBC. Up to 40% of patients have an incomplete response to therapy, and over time disease progresses to liver cirrhosis. Several risk scores are proposed for better evaluation of patients before and during treatment to stratify patients at increased risk of disease progression. GLOBE score and UK PBC risk score are used for the evaluation of UDCA treatment and Mayo risk score for transplant-free survival. Liver transplantation (LT) is the only treatment option for end-stage liver disease. More than 10 years after LT, 40% of patients experience recurrence of the disease. A liver biopsy is required to establish rPBC (recurrent primary biliary cholangitis). The only treatment option for rPBC is UDCA, and data show biochemical and clinical improvement, plus potential beneficial effects for use after transplantation for the prevention of rPBC development. Additional studies are required to assess the full impact of rPBC on graft and recipient survival and for treatment options for rPBC.
Topics: Autoimmune Diseases; Cholagogues and Choleretics; Cholestasis; End Stage Liver Disease; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Ursodeoxycholic Acid
PubMed: 35910038
DOI: 10.1155/2022/7831165 -
Orphanet Journal of Rare Diseases Jan 2008Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology characterized by injury of the intrahepatic bile... (Review)
Review
Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology characterized by injury of the intrahepatic bile ducts that may eventually lead to liver failure. Affected individuals are usually in their fifth to seventh decades of life at time of diagnosis, and 90% are women. Annual incidence is estimated between 0.7 and 49 cases per million-population and prevalence between 6.7 and 940 cases per million-population (depending on age and sex). The majority of patients are asymptomatic at diagnosis, however, some patients present with symptoms of fatigue and/or pruritus. Patients may even present with ascites, hepatic encephalopathy and/or esophageal variceal hemorrhage. PBC is associated with other autoimmune diseases such as Sjogren's syndrome, scleroderma, Raynaud's phenomenon and CREST syndrome and is regarded as an organ specific autoimmune disease. Genetic susceptibility as a predisposing factor for PBC has been suggested. Environmental factors may have potential causative role (infection, chemicals, smoking). Diagnosis is based on a combination of clinical features, abnormal liver biochemical pattern in a cholestatic picture persisting for more than six months and presence of detectable antimitochondrial antibodies (AMA) in serum. All AMA negative patients with cholestatic liver disease should be carefully evaluated with cholangiography and liver biopsy. Ursodeoxycholic acid (UDCA) is the only currently known medication that can slow the disease progression. Patients, particularly those who start UDCA treatment at early-stage disease and who respond in terms of improvement of the liver biochemistry, have a good prognosis. Liver transplantation is usually an option for patients with liver failure and the outcome is 70% survival at 7 years. Recently, animal models have been discovered that may provide a new insight into the pathogenesis of this disease and facilitate appreciation for novel treatment in PBC.
Topics: Aged; Antibodies, Antinuclear; Autoimmune Diseases; Cholagogues and Choleretics; Female; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Middle Aged; Sex Factors; Ursodeoxycholic Acid
PubMed: 18215315
DOI: 10.1186/1750-1172-3-1 -
The Cochrane Database of Systematic... Sep 2017Abnormal biliary secretion leads to the thickening of bile and the formation of plugs within the bile ducts; the consequent obstruction and abnormal bile flow ultimately... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Abnormal biliary secretion leads to the thickening of bile and the formation of plugs within the bile ducts; the consequent obstruction and abnormal bile flow ultimately results in the development of cystic fibrosis-related liver disease. This condition peaks in adolescence with up to 20% of adolescents with cystic fibrosis developing chronic liver disease. Early changes in the liver may ultimately result in end-stage liver disease with people needing transplantation. One therapeutic option currently used is ursodeoxycholic acid. This is an update of a previous review.
OBJECTIVES
To analyse evidence that ursodeoxycholic acid improves indices of liver function, reduces the risk of developing chronic liver disease and improves outcomes in general in cystic fibrosis.
SEARCH METHODS
We searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also contacted drug companies and searched online trial registries.Date of the most recent search of the Group's trials register: 09 April 2017.
SELECTION CRITERIA
Randomised controlled trials of the use of ursodeoxycholic acid for at least three months compared with placebo or no additional treatment in people with cystic fibrosis.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trial eligibility and quality. The authors used GRADE to assess the quality of the evidence.
MAIN RESULTS
Twelve trials have been identified, of which four trials involving 137 participants were included; data were only available from three of the trials (118 participants) since one cross-over trial did not report appropriate data. The dose of ursodeoxycholic acid ranged from 10 to 20 mg/kg/day for up to 12 months. The complex design used in two trials meant that data could only be analysed for subsets of participants. There was no significant difference in weight change, mean difference -0.90 kg (95% confidence interval -1.94 to 0.14) based on 30 participants from two trials. Improvement in biliary excretion was reported in only one trial and no significant change after treatment was shown. There were no data available for analysis for long-term outcomes such as death or need for liver transplantation.
AUTHORS' CONCLUSIONS
There are few trials assessing the effectiveness of ursodeoxycholic acid. The quality of the evidence identified ranged from low to very low. There is currently insufficient evidence to justify its routine use in cystic fibrosis.
Topics: Adolescent; Adult; Bile; Child; Child, Preschool; Cholagogues and Choleretics; Chronic Disease; Cystic Fibrosis; Humans; Liver; Liver Diseases; Nutritional Status; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid
PubMed: 28891588
DOI: 10.1002/14651858.CD000222.pub4 -
Expert Review of Gastroenterology &... 2016Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of... (Review)
Review
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of anti-mitochondrial antibodies and treated with ursodeoxycholic acid (UDCA). However, approximately 20-40% of patients incompletely respond to UDCA and have an increased risk of disease progression. Although there have been significant advances in the immunobiology of PBC, these have yet to be translated into newer therapeutic modalities. Current approaches to controlling the immune response include broad immunosuppression with corticosteroids as well as targeted therapies directed against T and B cells. In contrast, ameliorating cholestasis is the focus of other therapies in development, including obeticholic acid. In this article the authors will discuss ongoing clinical trials and, in particular, the rationale for choosing agents that may effectively target the aberrant immune response.
Topics: Animals; Bile Acids and Salts; Biliary Tract; Biological Products; Cholagogues and Choleretics; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Stem Cell Transplantation; Treatment Outcome
PubMed: 26577047
DOI: 10.1586/17474124.2016.1121810 -
Biochimica Et Biophysica Acta.... Apr 2018Acute kidney injury is common in patients with liver disease and associated with significant morbidity and mortality. Besides bacterial infections, fluid loss, and use... (Review)
Review
Acute kidney injury is common in patients with liver disease and associated with significant morbidity and mortality. Besides bacterial infections, fluid loss, and use of nephrotoxic drugs AKI in liver disease may be triggered by tubular toxicity of cholephiles. Cholemic nephropathy, also known as bile cast nephropathy, supposedly represents a widely underestimated but important cause of renal dysfunction in cholestasic or advanced liver diseases with jaundice. Cholemic nephropathy describes impaired renal function along with characteristic histomorphological changes consisting of intratubular cast formation and tubular epithelial cell injury directed towards distal nephron segments. The underlying pathophysiologic mechanisms are not entirely understood and clear defined diagnostic criteria are still missing. This review aims to summarize (i) the present knowledge on clinical and morphological characteristics of cholemic nephropathy, (ii) available preclinical models, (iii) potential pathomechanisms especially the potential role of bile acids, and (iv) future diagnostic and therapeutic strategies for cholemic nephropathy. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
Topics: Acute Kidney Injury; Animals; Bile Acids and Salts; Bile Ducts; Bilirubin; Cholagogues and Choleretics; Cholestasis; Disease Models, Animal; Epithelial Cells; Hepatocytes; Humans; Jaundice, Obstructive; Kidney Tubules; Liver; Renal Elimination; Ursodeoxycholic Acid
PubMed: 28851656
DOI: 10.1016/j.bbadis.2017.08.028