Effect Of Ursodeoxycholic Acid Research Articles

Tauroursodeoxycholic Acid Inhibits Nuclear Factor Kappa B Signaling in Gastric Epithelial Cells and Ameliorates Gastric Mucosal Damage in Mice.

Previous studies have reported the protective effects of tauroursodeoxycholic acid (TUDCA) on gastric epithelial cells in some animal models, but the precise mechanisms are unclear. This study examined the effects of TUDCA on NF-κB signaling in gastric epithelial cells. Moreover, the protective effects of TUDCA in experimental gastritis models induced by ethanol and NSAID were evaluated and compared with ursodeoxycholic acid (UDCA). After a pretreatment with TUDCA or UDCA, human gastric epithelial MKN-45 cells were stimulated with tumor necrosis factor (TNF)-α to activate NF-κB signaling. A real-time PCR (RT-PCR) for human interleukin (IL)-1 mRNA was performed. An electrophoretic mobility shift assay (EMSA) and immunoblot analyses were carried out. In murine models, after a pretreatment with TUDCA or UDCA, ethanol and indomethacin were administered via oral gavage. Macroscopic and microscopic assessments were performed to evaluate the preventive effects of TUDCA and UDCA on murine gastritis. A pretreatment with TUDCA downregulated the IL-1α mRNA levels in MKN-45 cells stimulated with TNF-α, as assessed by RT-PCR. As determined using EMSA, a pretreatment with TUDCA reduced the TNF-α-induced NF-κB DNA binding activity. A pretreatment with TUDCA inhibited IκBα phosphorylation induced by TNF-α, as assessed by immunoblot analysis. TUDCA attenuated the ethanol-induced and NSAID-induced gastritis in murine models, as determined macroscopically and microscopically. TUDCA inhibited NF-κB signaling in gastric epithelial cells and ameliorated ethanol- and NSAID-induced gastritis in murine models. These results support the potential of TUDCA for the prevention of gastritis in humans.

Usefulness of Ursodeoxycholic Acid in Management of Gallstone Disease in Children

Objective − The aim of the study is to assess the usefulness of ursodeoxycholic acid in management of gallstone disease in children. Materials and Methods − The prospective study aimed to assess the management of gallstone disease in children. We analyzed all new cases of cholelithiasis during the period from January 2016 to March 2020. Forty-eight new cases of cholelithiasis were enrolled in the study. The diagnosis was established by ultrasound examination due to different complaints in previously healthy patients, or during regular follow-up visits in patients with a chronic disease. A Student t-test, Fisher’s test and χ2-test were used in the statistical processing, where appropriate. Results − A 6-month course of treatment with ursodeoxycholic acid was conducted in 72.9% of cases (N=35). In 27.1% (N=13) of patients this treatment was not administered. Successful dissolution of gallstones was observed in 31.4% (N=11) of treated patients (N=35), over a period of 1 to 6 months. In the group of nontreated patients (N=13), successful dissolution of gallstones was achieved in 38.5% (N=5). Cholecystectomy was performed in 10.4% (N=5) patients, and 1 patient underwent endoscopic retrograde cholangiopancreatography. No early complications, relapse or postcholecystectomy syndrome were observed in the 12-month follow-up period. Conclusion − Management of cholelithiasis in children can often be a challenge. In a selected patient group, conservative treatment may be successful. Use of ursodeoxycholic acid can lead to dissolution of gallstones in patients with preceding dehydration. The effectiveness of ursodeoxycholic acid, except in children with dehydration, was higher

The Effect of Ursodeoxycholic acid and N-acetyl cysteine on Lymphoblast Viability

Aim: To investigate invitro ursodeoxycholic acid (UDCA) and N-acetyl cysteine (NAC) effect on blast cell viability in children newly diagnosed with acute lymphoblastic leukemia (ALL).
 Patients and Methods: Samples were obtained from 52 newly diagnosed ALL patients aged 1 to 17 years. UDCA and NAC were added at clinically relevant concentrations (0-300 micrograms) onto 5x10^5 cells treated at room temperature in a dark place. Untreated and treated cells were stained with 7-amino-actinomycin D (7AAD PE) and analyzed by flow cytometry
 Results: Median (interquartile range; IQR) blast percentage and incubation time were 90% (11) and 18 (1.5) hours, respectively. The dead/live blast cells ratio (7AAD+) was lower in lymphoblasts treated with all NAC concentrations than untreated controls (P < 0.001). The use of NAC was noted to, regardless of concentration, contribute to lymphoblasts viability. On the contrary, the dead/live blast cells ratio in samples treated with UDCA at the abovementioned concentrations was relatively high, suggesting the protective role for both hepatotoxicities and against leukemia. However, the difference was not statistically significant (P >0.05). There was also no correlation between different doses of UCDA and NAC regarding blast cell viability (P > 0.232).
 Conclusion: The present study showed that in vitro NAC use had a protective effect on lymphoblast viability in newly diagnosed ALL patients before starting chemotherapy. Patient-derived ALL cells can be successfully analyzed ex vivo in a short and different period without loss of blasts.

Ursodeoxycholic Acid and SMOFlipid for Treating Parenteral Nutrition Associated Cholestasis in Infants.

Background: Parenteral nutrition-associated cholestasis (PNAC) is frequently seen in preterm infants receiving total parenteral nutrition (TPN) for a long duration. The pathogenesis of PNAC is believed to be multifactorial; however, phytosterols are hepatotoxic, resulting in cholestasis. A novel lipid emulsion consisting of a mixture of soybean oil, medium-chain triglycerides, olive oil, and fish oil (SMOFlipid) with a low level of phytosterols has been shown to improve cholestasis. Moreover, ursodeoxycholic acid (UDCA) has improved bile flow and normalized liver function tests. This study aimed to determine the effect of UDCA and SMOFlipid in preventing and treating PNAC in infants.Methods: We conducted a retrospective cohort study that included all infants who received TPN for at least five days between January 2010 and December 2018, who also received UDCA for the treatment of cholestasis, and infants who developed cholestasis but were not treated with UDCA. In addition, any infants who received SMOFlipid for parenteral nutrition during the same period were included. We recorded multiple variables, including neonatal demographic data, major medical diagnosis, liver function, medications, and maternal variables.Results: A total of 58 infants with cholestasis who received UDCA for treatment were identified. The infants were divided into two groups, Group 1 infants had gestational age (GA) of ≤32 weeks, and Group 2 had GA of >32 weeks. We found that combining SMOFlipid with UDCA resulted in a significant reduction in cholestasis duration in both groups. Infants in Group 1 who received SMOFlipid had cholestasis for a mean of 67 ± 57 days, and those who did not receive SMOFlipid had cholestasis for a mean of 145 ± 102 days (p=0.04). Infants in Group 2 who received SMOFlipid had cholestasis for a mean of 38.2 ± 28 days, and those who did not receive SMOFlipid had cholestasis for a mean of 117 ± 119 days (p=0.02).Conclusions: According to our results, the use of UDCA and SMOFlipid reduced the duration of parenteral nutrition-associated with cholestasis in very low birth weight infants.

Ursodeoxycholic Acid Decreases Incidence of Primary Biliary Cholangitis and Biliary Complications After Liver Transplantation.

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Опыт использования урсодезоксихолевой кислоты у детей с органическими заболеваниями печени

Рассмотрены механизмы действия урсодезоксихолевой кислоты на организм человека, результаты клинических исследований и наблюдений по использованию препарата урсодезоксихолевой кислоты для лечения детей с органическими заболеваниями печени.

Ursodesoxycholic acid is an FFA4 agonist and reduces hepatic steatosis via FFA4 signaling

Ursodeoxycholic acid (UDCA) is a safe bile acid effective in reducing hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). However, the mechanism of action linked to this effect is poorly defined. In the present study, we identified that UDCA acted as a free fatty acid receptor 4 (FFA4) agonist with EC50 of 10.4 ± 0.7 μM, and its activity was determined by dynamic mass redistribution, fluorometric imaging plate reader, inositol monophosphate and bioluminescence resonance energy transfer assays. Moreover, UDCA showed FFA4 selectivity over eleven other G protein-coupled receptors. Real-Time PCR and immunocytochemistry analyses showed that FFA4 was abundantly expressed in human hepatocytes HuH-7 cells. In an in vitro model of NAFLD induced by oleic acid (OA), UDCA downregulated lipid accumulation in HuH-7 cells and suppressed sterol-regulatory element binding protein-1c (SREBP-1c) mRNA expression. This suppression of SREBP-1c was restored when FFA4 expression was knocked down in siRNA assay. In a mouse model of hepatic steatosis, db/db mice were exposed to a high-fat diet (HFD), and treatment of UDCA or docosahexaenoic acid (DHA, an endogenous FFA4 agonist) effectively prevented body weight gain and hepatic fat deposition and reduced triglyceride (TG) levels in serum and liver. This study not only identified a new skeleton of FFA4 agonists, but also demonstrated that FFA4 signal was accounting for the protective effects of UDCA in the NAFLD treatment.

Effect of ursodeoxycholic acid on indirect hyperbilirubinemia (nonhaemolytic and haemolytic) in neonates treated with phototherapy

Background Hyperbilirubinemia is a global problem in neonates. Classic management for indirect neonatal hyperbilirubinemia includes phototherapy and exchange transfusion. Phototherapy shows disadvantages, and exchange transfusion is related to significant morbidity. Aim To assess the added role of ursodeoxycholic acid (UDCA) in reducing unconjugated hyperbilirubinemia in neonates undergoing phototherapy. Patients and methods Our randomized controlled trial was performed on neonates with hyperbilirubinemia who needed phototherapy and were admitted to the neonatal care unit at Tanta University Hospital from May 2017 to March 2019. A total of 120 neonates were randomly divided into four groups: group A (n=30), which included neonates with nonhemolytic indirect hyperbilirubinemia who received UDCA 10 mg/kg/day beside the usual phototherapy; group B (n=30), which included neonates with isoimmune hemolytic indirect hyperbilirubinemia who received UDCA 10 mg/kg/day, besides the usual phototherapy; group C (n=30), which included neonates with nonhemolytic indirect hyperbilirubinemia who received phototherapy only; and group D (n=30), which included neonates with isoimmune hemolytic indirect hyperbilirubinemia who received phototherapy only. The total serum bilirubin (TSB) was determined every 24 h till being less than 10 mg/dl. Results TSB was significantly decreased in group A compared with group C (P<0.05). However, TSB was comparable in groups B and D (P>0.05). Duration of phototherapy was significantly shorter in groups A and B compared with groups C and D (P<0.05). Conclusion UDCA shows a beneficial added role in the treatment of neonatal indirect hyperbilirubinemia, particularly in the nonhemolytic type.

Oral Ursodeoxycholic acid crosses the blood brain barrier in patients with retinal detachment and protects against retinal degeneration in an ex vivo model

AbstractPurposeThe neuroprotective properties of hydrophilic bile acids are recognized but whether their oral administration can benefit to patients with retinal diseases is unknown. Rhegmatogenous retinal detachment (RD) is a threatening visual condition and a human disease model for retinal degenerations. Despite surgical reattachment, vision does not fully recover, due to subretinal fluid (SFR) and photoreceptor cell death, through mechanisms that recapitulate those of retinal degenerative diseases. We have measured the ocular concentration of Ursodeoxycholic acid (UDCA) administered orally to patients with RD. We then tested the effects and mechanisms of UDCA, at concentrations found in patient’s eyes, in RD models. Finally, we analyzed the neuroprotective effects of ocular fluids from treated patients.Methods26 patients with RD were included. 21 patients received UDCA before surgery. Ocular fluids samples were collected and bile acids were measured. Rat retinal explants and WERI‐Rb‐1 human cone cell line were exposed to albumin or patient’s SRF ± UDCA. Cell death markers and transcriptome were analyzed.ResultsUDCA was detected in ocular media after oral administration and its level correlated with protein concentration in SRF and extension of RD. At 6 months after surgery, visual recovery was superior in patients who had higher UDCA ocular levels.UDCA levels measured in human ocular media, protected photoreceptors from apoptosis and necrosis in rats retinal explants exposed to albumin and UDCA protected WERI‐Rb‐1 cells from albumin‐induced death. Cell death was reduced in retinal explants exposed to SRF collected from UDCA‐treated patients as compared to SRF from controls. UDCA effects resulted from the up‐regulation of anti‐apoptotic, anti‐oxidant and anti‐inflammatory genes.ConclusionsOral UDCA reaches neuroprotective concentrations in patients with RD, showing its potential as an adjuvant to surgery but also in other retinal degenerative diseases.

UDCA Inhibits Hypoxic Hepatocellular Carcinoma Cell-Induced Angiogenesis Through Suppressing HIF-1α/VEGF/IL-8 Intercellular Signaling.

Background: A hypoxic microenvironment may induce angiogenesis and promote the development of hepatocellular carcinoma (HCC). The aim of this study was to evaluate whether ursodeoxycholic acid (UDCA) may inhibit hypoxic HCC cell–induced angiogenesis and the possible mechanisms. Methods: Tube formation and matrigel plug angiogenesis assays were used to evaluate angiogenesis in vitro and in vivo, respectively. Real-time PCR, enzyme-linked immunosorbent assay, and Western blot were used to evaluate the mRNA and protein expressions of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and IL-8, respectively. Dual-luciferase reporter assay was applied to assess the reporter gene expression of hypoxia-response element (HRE). Results: UDCA antagonized hypoxic Huh 7 cell-induced tube formation of EA.hy 926 cells. In HCC cells, UDCA inhibited hypoxia-induced upregulation of VEGF and IL-8 both in mRNA and protein levels. UDCA also inhibited IL-8–induced angiogenesis in vitro and in vivo through suppressing IL-8–induced phosphorylation of ERK. The levels of HIF-1α mRNA and protein and HRE-driven luciferase activity in HCC cells were upregulated by hypoxia and were all inhibited by UDCA. The proteasome inhibitor MG132 antagonized the effect of UDCA on HIF-1α degradation. In hypoxic condition, the phosphorylation of ERK and AKT was obviously increased in HCC cells, which was suppressed by UDCA. Transfection of the HIF-1α overexpression plasmid reversed the effects of UDCA on hypoxic HCC cell–induced angiogenesis, HRE activity, and expressions of IL-8 and VEGF. Conclusions: Our results demonstrated that UDCA could inhibit hypoxic HCC cell–induced angiogenesis through suppressing HIF-1α/VEGF/IL-8–mediated intercellular signaling between HCC cells and endothelial cells.

Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery (UPGRADE): a multicentre, double-blind, randomised, placebo-controlled superiority trial

Rapid weight loss is a major risk factor for the formation of cholesterol gallstones. Consequently, patients with morbid obesity undergoing bariatric surgery frequently develop symptomatic gallstone disease. This trial assessed the efficacy of ursodeoxycholic acid versus placebo for the prevention of symptomatic gallstone disease after bariatric surgery. This multicentre, double-blind, randomised, placebo-controlled superiority trial enrolled patients with an intact gallbladder scheduled for laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy in three hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module to receive 900 mg ursodeoxycholic acid daily for 6 months or matched placebo. Randomisation was stratified by the presence of asymptomatic gallstones at baseline and type of surgery. Patients, clinicians, and study staff were masked to treatment allocation. The primary endpoint was symptomatic gallstone disease within 24 months, assessed in the modified intention-to-treat population (all randomly assigned eligible patients with any post-randomisation measurement). Prespecified subgroup analyses were done based on the stratification groups. Safety was assessed in all patients who took at least one dose of the study drug. This trial is registered with the Netherlands Trial Register, NL5954. Between Jan 11, 2017, and Oct 22, 2018, 985 patients were randomly assigned to receive either ursodeoxycholic acid (n=492) or placebo (n=493). 967 patients were included in the modified intention-to-treat population, of whom 959 had data available for primary endpoint assessment. 189 (20%) patients had asymptomatic gallstones at baseline and 78 (8%) received a sleeve gastrectomy. Symptomatic gallstone disease occurred in 31 (6·5%) of 475 patients in the ursodeoxycholic acid group and in 47 (9·7%) of 484 patients in the placebo group (relative risk 0·67, 95% CI 0·43-1·04, p=0·071). Logistic regression showed a significant interaction between ursodeoxycholic acid and the presence of asymptomatic gallstones at baseline (p=0·046), with an effect of ursodeoxycholic acid in patients without (0·47, 0·27-0·84, p=0·0081), and no effect in patients with asymptomatic gallstones at baseline (1·22, 0·61-2·47, p=0·57). The effect was stronger in patients without gallstones at baseline undergoing RYGB (0·37, 0·20-0·71, p=0·0016), whereas the subgroup of patients undergoing sleeve gastrectomy was too small to draw clear conclusions. Adverse events were rare. In the ursodeoxycholic acid group, diarrhoea occurred in four (0·9%) of 444 patients and skin rash in two (0·5%) patients. In the placebo group, diarrhoea occurred in two (0·4%) of 453 patients and skin rash in two (0·4%) patients. The total number of serious adverse events did not significantly differ between the trial groups (75 [17%] in 444 patients in the ursodeoxycholic acid group and 102 [23%] in 453 patients in the placebo group). The most common serious adverse events were abdominal pain and internal hernia. No serious adverse event was attributed to the study drug. Ursodeoxycholic acid prophylaxis did not significantly reduce the occurrence of symptomatic gallstone disease in all patients after bariatric surgery. In patients without gallstones before RYGB surgery, ursodeoxycholic acid treatment reduced the occurrence of symptomatic gallstone disease compared with placebo. Further research is needed to assess the efficacy of ursodeoxycholic acid after sleeve gastrectomy. The Netherlands Organization for Health Research and Development, Zambon Netherlands BV, Foundation for Clinical Research of the Slotervaart Hospital, the Spaarne Gasthuis Academy, and Amsterdam Gastroenterology Endocrinology Metabolism.

Glyceric Prodrug of Ursodeoxycholic Acid (UDCA): Novozym 435-Catalyzed Synthesis of UDCA-Monoglyceride.

Bile acids (BAs) are a family of steroids synthesized from cholesterol in the liver. Among bile acids, ursodeoxycholic acid (UDCA) is the drug of choice for treating primary biliary cirrhosis and dissolving cholesterol gallstones. The clinical effectiveness of UDCA includes its choleretic activity, the capability to inhibit hydrophobic bile acid absorption by the intestine under cholestatic conditions, reducing cholangiocyte injury, stimulation of impaired biliary output, and inhibition of hepatocyte apoptosis. Despite its clinical effectiveness, UDCA is poorly soluble in the gastro-duodeno-jejunal contents, and pharmacological doses of UDCA are not readily soluble in the stomach and intestine, resulting in incomplete absorption. Indeed, the solubility of 20 mg/L greatly limits the bioavailability of UDCA. Since the bioavailability of drug products plays a critical role in the design of oral administration dosages, we investigated the enzymatic esterification of UDCA as a strategy of hydrophilization. Therefore, we decided to enzymatically synthesize a glyceric ester of UDCA bile acid to produce a more water-soluble molecule. The esterification reactions between UDCA and glycerol were performed with an immobilized lipase B from Candida antarctica (Novozym 435) in solvent-free and solvent-assisted systems. The characterization of the UDCA-monoglyceride, enzymatically synthesized, has been performed by 1H-NMR, 13C-NMR, COSY, HSQC, HMBC, IR, and MS spectroscopy.

Удосконалення терапії інфекційного мононуклеозу Епштейна — Барр вірусної етіології в дітей

Актуальність. В Україні, як і в усьому світі, відмічається тенденція до збільшення дифузних захворювань печінки. Значною мірою зростання числа хворих на захворювання печінки серед дорослих обумовлено ушкодженнями гепатобіліарної системи в дитячому віці. Мета: оцінка ефективності урсодеоксихолієвої кислоти (УДХК) у комплексній терапії уражень печінки Епштейна — Барр вірусної (ЕБВ) етіології. Матеріали та методи. Дизайн дослідження: проспективне відкрите контрольоване. Було обстежено 60 дітей з інфекційним мононуклеозом (ІМ) Епштейна — Барр вірусної етіології. Діти були віком від 1 до 18 років. Усіх хворих спостерігали й обстежували протягом гострого періоду хвороби. Хворі були розподілені на 2 групи. Діти основної групи (n = 35) отримували базисну терапію ІМ ЕБВ-етіології в поєднанні з урсодеоксихолієвою кислотою, пацієнти з групи порівняння (n = 25) отримували базисну терапію. Результати. Отримані дані свідчать про те, що удосконалена за рахунок УДХК терапія інфекційного мононуклеозу в дітей ЕБВ-етіології з ураженням печінки сприяє більш швидкому темпу регресії основних симптомів інфекції, таких як лихоманка, зниження апетиту й жовтяниця, вже на 7-й день від початку лікування і більш швидкій нормалізації показників функціонального стану печінки (аланінамінотрансфераза, білірубін, лужна фосфатаза, гамма-глутамілтрансфераза, лактатдегідрогеназа). Препарат переносився добре, відмови від лікування серед пацієнтів не було, побічних реакцій не спостерігалося. Висновки. Включення препарату УДХК у схему лікування дозволяє підвищити ефективність удосконаленої терапії порівняно з базисною терапією, сприяє більш швидкій регресії симптомів інфекції й більш швидкій нормалізації показників функціонального стану печінки.

Bezafibrate therapy in primary biliary cholangitis refractory to ursodeoxycholic acid: a longitudinal study of paired liver biopsies at 5years of follow up.

Ursodeoxycholic acid (UDCA) is the first-line therapy for primary biliary cholangitis (PBC). However, nearly 40% of patients have an incomplete response to UDCA. The addition of bezafibrate has shown biochemical benefit in this group of patients. To evaluate the long-term effects of UDCA in combination with bezafibrate on histological outcomes in patients with UDCA-refractory PBC. Fifty-nine patients refractory to UDCA were included. Clinical parameters were monitored and paired liver biopsy (PLB) was performed after 5years of follow-up. Of the total cohort, 49 subjects were analysed and 31had PLB at 5years. Values for serum ALP, AST, ALT and GGT significantly improved with UDCA-bezafibrate. This beneficial effect was observed at 12months where 86% achieved ALP at normal levels. Analyses of PLB showed a significant decrease in liver damage as reflected by Ludwig (baseline 2.29±1.2, to 1.84±1 at year 5, P=0.0242) and Ishak (baseline 6.19±2.2 to 4.77±2.2 at year 5, P=0.0008) scores. Overall, regression of fibrosis was attained in 48% of patients. Furthermore, we observed a significant reduction in the proportion with cirrhosis from 19% at baseline to 3% at 5years (P<0.001). These beneficial effects were associated with better predictive risk scores using the GLOBE and UK-PBC prognosis models. Adding bezafibrate to UDCA in patients with UDCA-refractory PBC showed a significant decrease in fibrosis and inflammatory histological scores at 5years. These beneficial effects warrant further evaluation in long-term cohort studies and controlled trials.

Pleiotropic effects of ursodeoxycholic acid

The article summarizes the literature data on the expansion of the range of application of ursodeoxycholic acid due to its various mechanisms of action. Almost 50-year history of the study of its properties has proven choleretic, litholytic, antiapoptotic, anti-inflammatory, immunomodulatory, cytoprotective, antifibrotic and hypocholesterolemic effects. In addition to the well-known functions of bile acids, their role has been shown as signaling, endocrine molecules that regulate glucose, lipids, and energy metabolism through pathways mediated by the activation of the nuclear receptor of the farnesoid X receptor and the cell surface G protein-coupled receptor, TGR5. The variety of nosological forms in which this substance can be successfully used is substantiated.

Ursodeoxycholic acid shows antineoplastic effects in bile duct cancer cells via apoptosis induction; p53 activation; and EGFR-ERK, COX-2, and PI3K-AKT pathway inhibition.

Unlike in normal cells, ursodeoxycholic acid (UDCA) causes apoptosis rather than protection in cancer cells. Aim of this study was to demonstrate whether UDCA actually inhibits proliferation and induces apoptosis in bile duct cancer cells; the effect of UDCA on the expression of COX-2, PI3K/AKT, ERK, and EGFR; how UDCA affects cancer cell invasiveness and metastasis, since these effects are not established in bile duct cancer cells. SNU-245 cells (human extrahepatic bile duct cancer cells) were cultured. MTT assays were performed to evaluate the effect of UDCA on the cell proliferation. A cell death detection enzyme-linked immunosorbent assay and a caspase-3 activity assay were used to determine apoptosis. Western blot analysis measured expression levels of various proteins. The invasiveness of the cancer cells was evaluated by invasion assay. In cultured bile duct cancer cells, UDCA suppressed cell proliferation in bile duct cancer cells by inducing apoptosis and p53 activation, blocking deoxycholic acid (DCA)-induced activated EGFR-ERK signaling and COX-2, inhibiting DCA-induced activated PI3K-AKT signaling, and suppressing the invasiveness of bile duct cancer cells. In addition, a MEK inhibitor impaired UDCA-induced apoptosis in bile duct cancer cells. UDCA has antineoplastic and apoptotic effects in bile duct cancer cells. Thus, UDCA could be a chemopreventive agent in patients with a high risk of cancer, and/or a therapeutic option that enhances other chemotherapeutics.

Ursodeoxycholic acid suppresses the malignant progression of colorectal cancer through TGR5-YAP axis

The Hippo/YAP pathway plays an important role in the development of cancers. Previous studies have reported that bile acids can activate YAP (Yes Associated Protein) to promote tumorigenesis and tumor progression. Ursodeoxycholic acid (UDCA) is a long-established old drug used for cholestasis treatment. So far, the effect of UDCA on YAP signaling in colorectal cancer (CRC) is not well defined. This study means to explore relationship of UDCA and YAP in CRC. UDCA suppressed YAP signaling by activating the membrane G-protein-coupled bile acid receptor (TGR5). TGR5 mainly regulated cAMP/PKA signaling pathway to inhibit RhoA activity, thereby suppressing YAP signaling. Moreover, the restoration of YAP expression alleviated the inhibitory effect of UDCA on CRC cell proliferation. In AOM/DSS-induced CRC model, UDCA inhibited tumor growth in a concentration-dependent manner and decreased expression of YAP and Ki67. UDCA plays a distinguished role in regulating YAP signaling and CRC growth from the primary bile acids and partial secondary bile acids, demonstrating the importance of maintaining normal intestinal bile acid metabolism in cancer patients. It also presents a potential therapeutic intervention for CRC.

What are the effects of ursodeoxycholic acid (UDCA) for people with cystic fibrosis-related liver disease?

What are the effects of ursodeoxycholic acid (UDCA) for people with cystic fibrosis-related liver disease?

Ursodeoxycholic Acid Decreases Incidence of Primary Biliary Cholangitis and Biliary Complications After Liver Transplantation: A Meta-Analysis.

After liver transplantation (LT), the role of ursodeoxycholic acid (UDCA) is not well characterized. We examine the effect of UDCA after LT in the prophylaxis of biliary complications (BCs) in all-comers for LT and the prevention of recurrent primary biliary cholangitis (rPBC) in patients transplanted for PBC. Two authors searched PubMed/MEDLINE and Embase from January 1990 through December 2018 to identify all studies that evaluate the effectiveness of UDCA prophylaxis after LT for BCs in all LT recipients and rPBC after LT in patients transplanted for PBC. Odds ratios (ORs) were calculated for endpoints of the BC study. Pooled recurrence rates were calculated for rPBC. The study was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. A total of 15 studies were included, comprising 530 patients in the analysis for BCs and 1727 patients in the analysis for rPBC. UDCA was associated with decreased odds of BCs (OR, 0.70; 95% confidence interval [CI], 0.52-0.93; P=0.01) and biliary stones and sludge (OR, 0.49; 95% CI, 0.24-0.77; P=0.004). Prophylactic use of UDCA did not affect the odds of biliary stricture. For patients transplanted for PBC, the rate of rPBC was lower with the prophylactic use of UDCA (IR 16.7%; 95% CI, 0.114%-22.0%; I2 = 36.1%) compared with not using prophylactic UDCA (IR 23.1%; 95% CI, 16.9%-29.3%; I2 = 86.7%). UDCA after LT reduces the odds of BC and bile stones and sludge in all-comer LT recipients and reduces or delays the incidence of rPBC in patients transplanted for PBC. UDCA use after LT could be considered in all LT recipients to reduce the odds of BC and may be particularly beneficial for patients transplanted for PBC by reducing the incidence of rPBC.

Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia

Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT1*1 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT1*1 mice with UDCA or OCA at postnatal days 10–14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.