Effect Of Ursodeoxycholic Acid Research Articles

Rationale, completeness and quality of evidence for the use of ursodeoxycholic acid in neonatal hyperbilirubinemia

Background. Systematic reviews are considered the highest evidence of the effectiveness and safety of treatment methods used in clinical practice. The veracity of a results and conclusions of systematic reviews is directly related to their quality. The aim of the study is an assessment of the currency, completeness and methodological quality of published systematic reviews on the evaluation of the effectiveness of ursodeoxycholic acid (UDCA) for the treatment of neonatal hyperbilirubinemia. Materials and methods. A meta-epidemiological methodological study was conducted. The search for evidence sources was performed in November 2023 in the specialized databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), LILACS, CNKI, LENS.ORG, еLibrary.Ru, in registers ClinicalTrials.gov, ICTRP, ISRCTN, PROSPERO, as well as in the Google Academy and Google search engines. Additionally, the lists of references and citations of selected publications have been reviewed. Only systematic reviews and randomized clinical trials are included in the study. The search was carried out to assess the currency and completeness of systematic reviews. A systematic review is considered currency if the most recent studies are included in its analysis. A systematic review is considered complete if its analysis includes all identified studies that meet the inclusion criteria set by the review authors and are published no later than the date of the last search conducted by the review authors. The methodological quality of the systematic reviews was assessed using the AMSTAR-2 tool. Results. As a result of the search, 4 systematic reviews and 23 randomized trials were identified. All reviews evaluated the effect of UDCA in combination with phototherapy on the level of total serum bilirubin, the duration of phototherapy and the frequency of adverse events (for example, loose stools, vomiting, rash) compared with phototherapy alone and/or placebo. All systematic reviews have been published over the past two years, but have already lost their currency. There are missing studies and/or outcomes in each review. The methodological quality of the reviews was found to be extremely low. Conclusion. Given the listed shortcomings of systematic reviews, their results and conclusions should be treated with caution. In order to obtain the most accurate and reliable evidence, a new systematic review is needed.

Smooth muscle contractile responses to bile acids in mouse ileum require TGR5 but not ASBT.

Many disorders of gut-brain interaction (DGBIs) are more prevalent in women than men and feature alterations in gastrointestinal motility and bile acid homeostasis. Mechanisms by which bile acids regulate gastrointestinal motility are poorly characterized. We recently validated an adapted tissue bath technique using everted mouse ileum, which revealed differential contractile responses to ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA). Here, we aimed to determine whether these responses are dependent on host sex, the plasma membrane bile acid receptor TGR5, or the apical sodium-dependent bile acid transporter ASBT. Ileal segments from male and female mice were everted and suspended in tissue baths. Contractile responses to physiologic concentrations of UDCA and DCA were quantified with or without TGR5 or ASBT inhibitors. Phosphorylation of extracellular signal-regulated kinase (ERK) and myosin light chain (MLC), markers of TGR5 activation and smooth muscle contraction, respectively, were assessed with western blot. There were no sex differences in the dose-dependent contractile responses to bile acids. At 100 μmol/L, UDCA but not DCA increased MLC phosphorylation and increased contractility. TGR5 inhibition decreased ERK phosphorylation and led to decreases in contractility, phosphorylated MLC, and surprisingly, total MLC. ASBT inhibition did not affect contractile responses. Differential effects of UDCA and DCA on ileal smooth muscle contractility are not dependent on host sex or ASBT-mediated transport. Bile acids signal through mucosal TGR5, which regulates smooth muscle contractility by complex mechanisms. Understanding how bile acids differentially regulate gastrointestinal motility could facilitate new therapeutic options for specific DGBIs.

Ursodeoxycholic acid loaded dual-modified graphene oxide nanocomposite alleviates cholestatic liver injury through inhibiting hepatocyte apoptosis

Ursodeoxycholic acid (UDCA) is the preferred treatment for various types of cholestasis, however, its effectiveness is limited because of its insolubility in water. We used polyethylene glycol (PEG) and cationic polymer polyethylenimine (PEI) to double-modify graphite oxide (PPG) as a drug delivery system. UDCA was successfully loaded onto PPG through intermolecular interactions to form UDCA-PPG nanoparticles. UDCA-PPG nanoparticles not only improve the solubility and dispersibility of UDCA, but also have good biocompatibility and stability, which significantly improve the delivery rate of UDCA. The results indicated that UDCA-PPG significantly reduced ROS levels, promoted cell proliferation, protected mitochondrial membrane potential, reduced DNA damage and reduced apoptosis in the DCA-induced cell model. In a mouse cholestasis model established by bile duct ligation (BDL), UDCA-PPG improved liver necrosis, fibrosis, and mitochondrial damage and reduced serum ALT and AST levels, which were superior to those in the UDCA-treated group. UDCA-PPG reduced the expression of the apoptosis-related proteins, Caspase-3 and Bax, increased the expression of Bcl-2, and reduced the expression of the oxidative stress-related proteins, NQO and HO-1, as well as the autophagy-related proteins LC3, p62 and p-p62. Therefore, UDCA-PPG can enhance the therapeutic effect of UDCA in cholestasis, by significantly improving drug dispersibility and stability, extending circulation time in vivo, promoting absorption, decreasing ROS levels, enhancing autophagy flow and inhibiting apoptosis via the Bcl-2/Bax signaling pathway.

Ursodeoxycholic acid ameliorates erectile dysfunction and corporal fibrosis in diabetic rats by inhibiting the TGF-β1/Smad2 pathway.

Corporal tissue fibrosis is critical in diabetes-associated erectile dysfunction. Transforming growth factor-β1/Small mothers against decapentaplegic-2 (TGF-β1/Smad2) contributes to the induction of fibrosis in corporal tissue. Smad7 is accepted as a general negative regulator of Smad signaling, although its role in corporal fibrosis is unknown. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid used for biliary and liver related disorders and has antifibrotic effects in the liver. This study investigated the effects of UDCA on diabetic erectile dysfunction. Forty-eight male Spraque Dawley rats were divided into six groups: nondiabetic (n = 6), nondiabetic+20 mg/kg UDCA (n = 6), nondiabetic+80 mg/kg UDCA (n = 6), diabetic (n = 10), diabetic+20 mg/kg UDCA (n = 10), diabetic+80 mg/kg UDCA (n = 10). Diabetes was induced by intraperitoneal injection of 60 mg/kg Streptozocin. UDCA (20 and 80 mg/kg/day) or saline was subsequently administered via oral gavage for 56 days. Erectile function was evaluated as measurement of maximum intracavernosal pressure (m-ICP)/mean arterial pressure (MAP) and total ICP/MAP. Corporal tissues were evaluated by Western blotting and Masson's trichrome staining. Electrical stimulation-induced m-ICP/MAP responses were higher in UDCA-treated diabetic rats compared to untreated diabetic rats, respectively (20 mg/kg; 4 V: 0.77 ± 0.11 vs 0.45 ± 0.09, p = 0.0001 and 80 mg/kg; 4 V: 0.78 ± 0.11 vs 0.45 ± 0.09, p = 0.0001) UDCA prevented the increase in phospho-Smad2 and fibronectin protein expressions in diabetic corporal tissue both at 20 mg/kg (p = 0.0002, p = 0.002 respectively) and 80 mg/kg doses (p < 0.0001 for both). Smad7 protein expressions were significantly increased in the UDCA-treated diabetic groups compared to the untreated diabetic group (20 mg/kg: p = 0.0079; 80 mg/kg: p = 0.004). Furthermore, UDCA significantly prevented diabetes-induced increase in collagen (20 mg/kg: p = 0.0172; 80 mg/kg: p = 0.0003) and smooth muscle loss (20 mg/kg: p = 0.044; 80 mg/kg: p = 0.039). In conclusion, UDCA has a potential protective effect on erectile function in diabetic rats by altering fibrotic pathways via inhibition of TGF-β1/Smad2 and activation of Smad7.

Bile Acids as Signaling Molecules: Role of Ursodeoxycholic Acid in Cholestatic Liver Disease.

Ursodeoxycholic acid (UDCA) is a natural substance physiologically produced in the liver. Initially used to dissolve gallstones, it is now successfully used in treating primary biliary cirrhosis and as adjuvant therapy for various hepatobiliary cholestatic diseases. However, the mechanisms underlying its beneficial effects still need to be clarified. Evidence suggests three mechanisms of action for UDCA that could benefit humans with cholestatic liver disease (CLD): protection of cholangiocytes against hydrophobic bile acid (BA) cytotoxicity, stimulation of hepatobiliary excretion, and protection of hepatocytes against BA-induced apoptosis. These mechanisms may act individually or together to potentiate them. At the molecular level, it has been observed that UDCA can generate modifications in the transcription and translation of proteins essential in the transport of BA, correcting the deficit in BA secretion in CLD, in addition to activating signaling pathways to translocate these transporters to the sites where they should fulfill their function. Inhibition of BA-induced hepatocyte apoptosis may play a role in CLD, characterized by BA retention in the hepatocyte. Thus, different mechanisms of action contribute to the improvement after UDCA administration in CLD. On the other hand, the effects of UDCA on tissues that possess receptors that may interact with BAs in pathological contexts, such as skeletal muscle, are still unclear. This work aims to describe the main molecular mechanisms by which UDCA acts in the human body, emphasizing the interaction in tissues other than the liver.

Risk factors for recurrence of common bile duct stones after surgical treatment and effect of ursodeoxycholic acid intervention.

Endoscopic retrograde cholangiopancreatography (ERCP) is an accurate diagnostic method for choledocholithiasis and treatment option for stone removal. Additionally, ursodeoxycholic acid (UDCA) can dissolve cholesterol stones and prevent their development and reappearance by lowering the cholesterol concentration in bile. Despite these treatment options, there are still patients who experience stone recurrence. To analyze the risk factors for choledocholithiasis recurrence after ERCP retrograde cholangiopancreatography and the effect of UDCA intervention. The clinical data of 100 patients with choledochal stones who were hospitalized at the Yixing People's Hospital and underwent ERCP for successful stone extraction between June 2020 and December 2022 were retrospectively collected. According to the post-ERCP treatment plan, 100 patients were classified into UDCA (n = 47) and control (n = 53) groups. We aimed to assess the clinical efficacy and rate of relapse in the two patient populations. We then collected information (basic demographic data, clinical characteristics, and serum biochemical indicators) and determined the factors contributing to relapse using logistic regression analysis. Our secondary goal was to determine the effects of UDCA on liver function after ERCP. Compared to the control group, the UDCA group demonstrated a higher clinical effectiveness rate of 92.45% vs 78.72% (P < 0.05). No significant differences were observed in liver function indices, including total bilirubin, direct bilirubin, gamma-glutamyl transpeptidase, alanine aminotransferase, alkaline phosphatase, and aspartate aminotransferase, between the two groups before treatment. After treatment, all liver function indices were significantly reduced. Comparing the control vs UDCA groups, the UDCA group exhibited significantly lower levels of all indices (55.39 ± 6.53 vs 77.31 ± 8.52, 32.10 ± 4.62 vs 45.39 ± 5.69, 142.32 ± 14.21 vs 189.63 ± 16.87, 112.52 ± 14.25 vs 149.36 ± 15.36, 122.61 ± 16.00 vs 171.33 ± 22.09, 96.98 ± 10.44 vs 121.35 ± 11.57, respectively, all P < 0.05). The stone recurrence rate was lower in the UDCA group (13.21%) in contrast with the control group (44.68%). Periampullary diverticula (OR: 6.00, 95%CI: 1.69-21.30), maximum stone diameter (OR: 1.69, 95%CI: 1.01-2.85), stone quantity >3 (OR: 4.23, 95%CI: 1.17-15.26), and positive bile culture (OR: 7.61, 95%CI: 2.07-27.91) were independent factors that influenced the relapse of common bile duct stones after ERCP (P < 0.05). Furthermore, postoperative UDCA was identified as a preventive factor (OR: 0.07; 95%CI: 0.08-0.09). The intervention effect of UDCA after ERCP for common bile duct stones is adequate, providing new research directions and references for the prevention and treatment of stone recurrence.

Ursodeoxycholic acid and 18β-glycyrrhetinic acid alleviate ethinylestradiol-induced cholestasis via downregulating RORγt and CXCR3 signaling pathway in iNKT cells

Estrogen-induced intrahepatic cholestasis (IHC) is a mild but potentially serious risk and urges for new therapeutic targets and effective treatment. Our previous study demonstrated that RORγt and CXCR3 signaling pathway of invariant natural killer T (iNKT) 17 cells play pathogenic roles in 17α-ethinylestradiol (EE)-induced IHC. Ursodeoxycholic acid (UDCA) and 18β-glycyrrhetinic acid (GA) present a protective effect on IHC partially due to their immunomodulatory properties. Hence in present study, we aim to investigate the effectiveness of UDCA and 18β-GA in vitro and verify the accessibility of the above targets. Biochemical index measurement indicated that UDCA and 18β-GA presented efficacy to alleviate EE-induced cholestatic cytotoxicity. Both UDCA and 18β-GA exhibited suppression on the CXCL9/10-CXCR3 axis, and significantly restrained the expression of RORγt in vitro. In conclusion, our observations provide new therapeutic targets of UDCA and 18β-GA, and 18β-GA as an alternative treatment for EE-induced cholestasis.

Effect of Ursodeoxycholic Acid for Sars-Cov-2 Prevention in Hematological Malignancies: An Observational Real-World Study

Introduction: Disease-2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).After the adjustments and optimizations of Chinese control strategies and policies for COVID-19 on December of 2022, clinical exposure increased rapidly.There are greater concerns for patients with hematological malignancies, particularly those who have undergone hematopoietic stem cell transplantation (HSCT). One promising preventive measure that has recently gained attention is ursodeoxycholic acid (UDCA). This drug is mainly used to treat biliary tract disease and other hepatobiliary disorders, particularly primary biliary cholangitis (Hirschfield GM, et al. Gut 2018); and also has been widely used at a higher dosage to prevent sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) after HSCT in the clinical setting. Recently, Brevini et al. demonstrated that UDCA downregulated ACE2 expression by reducing farnesoid X receptor signaling, resulting in reduced SARS-Cov-2 infection (Brevini T, et al. Nature 2022), indicating that pharmacological prophylaxis using UDCA against COVID-19 in vulnerable groups was feasible, but the clinical data to support this practice is limited. Therefore, we aim to present epidemiological data for Chinese patients with hematological malignancies during this epidemic wave, and investigate the protection effects offered by UDCA against COVID-19 in these patients. Methods: This investigation was a single-center, observational real-world study, and was granted by the ethics committee of the Institute of Hematology &amp; Blood Diseases [No. QTJ2023012-EC-1]. The transplant patients were included in the “NICHE-SKIRT” project (Cao Y, et al. Am J Hematol 2023). Informed consent for the acquisition and the use of patient samples was obtained. Data for hospitalized patients at the Institute of Hematology &amp; Blood Diseases Hospital (Tianjin, China) was reviewed between December 2022 and January 2023. COVID 19 status was assessed using hospital-reported PCR and/or antigen tests for twice a week. We analyzed follow-up records up to 14th February 2023. The primary end-point was the rate of COVID -19 infection. Results: We enrolled 393 patients with a median age of 38 years old. At the cutoff date, 297 patients (75.6%) had confirmed COVID-19 infection (72.5% in the allo-HSCT cohort). Among the 273 evaluable patients, the majority (64.8%) had asymptomatic/mild disease. The severe/critical patients accounted for only 15.8%. Seven hospitalized patients had died from COVID-19 by the last follow-up date. The median period between COVID-19 diagnosis and death was 15 days (range: 2-32 days). Lower proportion of CD3+CD4+T cells associated with more severe COVID-19 clinical spectrum (Asymptomatic/mild [n = 97] moderate [n = 46], adjusted P = 0.001; Asymptomatic/mild vs. severe/critical [n = 25], adjusted P = 0.036). Among these patients, 163 received UDCA (UDCA group) while 230 did not (non-UDCA group). The COVID-19 infection rate was lower in the UDCA group (69.9% vs. 79.6%; P= 0.039). However, patients in the UDCA group had a higher ECOG score and Charlson Comorbidity Index (Table 1), suggesting that they were more likely to have underlying health conditions. To account for this potential bias, we performed PSM, which confirmed that the UDCA group had a significantly lower rate of COVID-19 infection compared to the non-UDCA group (69.0% vs. 81.0%; P = 0.049) in the validated cohort. Univariate logistic regression analysis showed that only UDCA administration was associated with COVID-19 infection (OR: 0.598; P = 0.029). To further investigate the effect of UDCA in specific populations, we carried out an exploratory analysis. Our results suggest that males, patients with a CCI ≥ 2, a history of smoking, and those with acute lymphoblastic leukemia (ALL) may benefit the most from the protective effect of UDCA against COVID-19. Conclusion: This study aimed to investigate the prevalence and clinical outcomes of SARS-CoV-2 infections in Chinese patients with hematologic disorders during the COVID-19 epidemic that began at the end of 2022. Our findings provide support for preclinical studies suggesting that UDCA may have marginal benefit in protecting against COVID-19. However, prospective studies with a higher dose of UDCA need to be performed.

Gut microbiota-mediated ursodeoxycholic acids regulate the inflammation of microglia through TGR5 signaling after MCAO

Ischemic stroke has been demonstrated to cause an imbalance of gut microbiota. However, the change in gut microbiota-mediated bile acids (BAs) metabolites remains unclear. Here, we observed a decrease in gut microbiota-mediated BAs, especially ursodeoxycholic acid (UDCA), in the serum of stroke patients as well as in the intestine, serum and brain of stroke mice. Restoration of UDCA could decrease the area of infarction and improve the neurological function and cognitive function in mice in association with inhibition of NLRP3-related pro-inflammatory cytokines through TGR5/PKA pathway. Furthermore, knocking out TGR5 and inhibiting PKA activity reduce the protective effect of UDCA. Taken together, our results suggest that microbiota-mediated UDCA plays an important role in alleviating inflammatory responses and might be a promising therapeutic target in ischemic stroke.

Evaluating the effect of ursodeoxycholic acid (UDCA) in comparison with dexamethasone and diclofenac in a rat model of rheumatoid arthritis.

Ursodeoxycholic acid (UDCA) is known for its major effects on the liver, but its impact on autoimmune diseases is not well understood. This study aimed to assess the effectiveness of UDCA in controlling rheumatoid arthritis (RA) in an in vivo setting. Experimental RA was induced in rats using Freund's complete adjuvant, and the effects of UDCA (50,100 mg/kg) were compared to those of dexamethasone and diclofenac by measuring changes in paw size, IL-17, pro-inflammatory cytokines, oxidative stress (GSH, MDA), and radiological changes. The administration of UDCA resulted in decreased cartilage damage, reduced paw edema, and a decrease in the release of pro-inflammatory cytokines and oxidative stress. Additionally, X-ray joint alterations were observed in the UDCA-treated group compared to the dexamethasone and diclofenac groups. These results suggest that UDCA has anti-rheumatoid arthritis properties due to its ability to minimize oxidative stress and inflammation in arthritis-affected rats.

Ursodeoxycholic acid does not affect the clinical outcome of SARS-CoV-2 infection: A retrospective study of propensity score-matched cohorts.

Ursodeoxycholic acid (UDCA) has been recently proposed as a modulator of angiotensin-converting enzyme 2 (ACE2) receptor expression, with potential effects on COVID-19. We retrospectively evaluated the clinical course and outcome of subjects taking UDCA admitted to the hospital for COVID-19 compared with matched infected subjects. Differences regarding the severity and outcome of the disease between treated and non-treated subjects were assessed. The Kaplan-Meier survival analysis and log-rank test were used to evaluate the effect of UDCA on all-cause intra-hospital mortality. Among 6444 subjects with confirmed COVID-19 admitted to the emergency department (ED) from 1 March 2020 to 31 December 2022, 109 subjects were taking UDCA. After matching 629 subjects were included in the study: 521 in the no UDCA group and 108 in the UDCA group. In our matched cohort, 144 subjects (22.9%) died, 118 (22.6%) in the no-UDCA group and 26 (24.1%) in the UDCA group. The Kaplan-Meier analysis showed no significant difference in survival between groups. In univariate regression analysis, the presence of pneumonia, National Early Warning Score (NEWS) score, and Charlson Comorbidity Index (CCI) were significant independent predictors of death. At multivariate Cox regression analysis, age, NEWS, pneumonia and CCI index were confirmed significant independent predictors of death. UDCA treatment was not a predictor of survival both in univariate and multivariate regressions. UDCA treatment does not appear to have significant effects on the outcome of COVID-19. Specially designed prospective studies are needed to evaluate efficacy in preventing infection and severe disease.

Effects of ursodeoxycholic acid and glutathione combination in spleen TNF-α and apoptotic index in rats with cholestasis

Background: Cholestasis is a disorder of the formation or flow of bile. Among its contributors, tumour necrosis factor (TNF)-α stands out as the most influential inducer of apoptosis. Meanwhile, ursodeoxycholic acid (UDCA) is a valuable agent with choleretic properties, protecting the hepatobiliary system. Glutathione (GSH) enhances endothelial response and prevents liver fibrosisObjectives: This study evaluates the effect of a combination of GSH-UDCA on splenic TNF-α expression and apoptosis index in Sprague Dawley (SD) rats with cholestasisMethods: This experiment with a post-tests-only control group design involving 28 male SD rats. They were randomly into four groups: group (K) with 20 mg UDCA, group 1 (P1) with 10 mg UDCA + 10 mg GSH, group 2 (P2) was given UDCA 20 mg + GSH 15 mg, and group 3 (P3) was given UDCA 30 mg + GSH 20 mg. Cholestasis was obtained by ligation of the common bile duct through a laparotomy. During three weeks of trial, rats were administered daily with UDCA orally and GSH intramuscularly. On day 22, rats were sacrificed and spleen samples were taken for anatomical pathology examination. Results: There were significant differences in TNF-α expression between groups K vs P3; P1 vs P3, and P2 vs P3 (p=0.002). There was a significant difference in the apoptotic index between groups K vs P1 (p&lt;0.001); K vs P2 (p=0.004), and K vs P3 (p=0.005).Conclusions: The UDCA-GSH combination demonstrated a prophylactic effect in SD rats with cholestasis and might be an effective supplemental therapy with UDCA for cholestatic diseases. The difference in TNF-α expression and apoptotic index was lower in SD rats UDCA-glutathione combination group than single dose UDCA. Between TNF-α and the apoptotic index, there is a moderate positive relation.

Lowering propionic acid levels by regulating gut microbiota with ursodeoxycholic acid appears to regress autism symptoms: an animal study

Aims: Patients with autism have altered gut microbiata, including higher frequency of bacteroidetes and clostridiales that produce of propionic acid (PPA) –a compound that is established as an autism-inducing agent. We hypothesized that lowering the PPA levels by regulating gut microbiata with ursodeoxycholic acid (UDCA) can regress the autism symptoms. The aim of this study is to examine the potential ameliorating effects of UDCA on a PPA-induced rat model of autism.&#x0D; Methods: Thirty male Wistar albino rats were divided into three groups: controls, PPA-induced (5 days of intraperitoneal 250 mg/kg/day dosage) autism model receiving oral saline, and PPA-induced autism model receiving oral UDCA (100 mg/kg/day). Oral treatments were applied for 15 days. At the end of the 15th day, all rats underwent behavioral tests and MR spectroscopy. At the end of the study, all animals were sacrificed and brain tissue / blood samples were collected for histopathological and biochemical analyses.&#x0D; Results: Sociability test, open field test and passive avoidance learning tests were impaired, similar to the autism behavioral pattern, in PPA recipients; however, results were closer to normal patterns in the PPA+UDCA group. Biochemically, MDA, TNF-alpha, IL-2, IL-17, NF-kB, lactate, NGF and NRF2 levels in brain tissues showed significant differences between controls and the PPA+Saline group, and between the PPA+Saline group and the PPA+UDCA group (p&lt; 0.05, for all). Histopathology showed that PPA injection caused increased glial activity, neural body degeneration, decreased neural count and dysmorphic changes in hippocampal and cerebellar tissues (p

Akut lösemili çocukların idame tedavisinde kemoterapiye bağlı hepatotoksisite tedavisinde ursodeoksikolik asitin rolü

Introduction: Chemotherapeutic agents used in the treatment of leukemia patients may cause toxic effects in the liver where they are metabolized. Ursodeoxycholic acid (UDCA) is used because of its hepatoprotective effect in the treatment of drug-induced liver toxicity. This study investigated the efficacy of UDCA use, despite the effect of UDCA on tumor cells being unknown, in the treatment of liver toxicity in pediatric patients on chemotherapy for leukemia. Methods: Data from pediatric leukemia patients, who were on maintenance therapy and developed liver toxicity, were retrospectively analyzed. Patients were divided into three groups and the results were compared regarding development of liver toxicity. Patients who were not given UDCA and whose chemotherapy (CT) treatment was interrupted were defined as Group 1, patients who were given UDCA and whose CT was interrupted were defined as Group 2, and patients who were given UDCA and continued CT were defined as Group 3. Results: The study cohort numbered 119 patients, of whom 64 were included in Group 1, 26 patients were in Group 2 and 29 patients were included in Group 3. The mean age of the patients was 6.29±3.03 years and 57.1% of them were male. In Group 1, alanine aminotransferase (ALT) decreased to &amp;lt;100 IU/L so UDCA was interrupted, and CT could be rechallenged in 85.9%, in Group 2 this proportion was 100%, and in 69.2% of patients in Group 3, respectively. While there was no significant difference between Group 1 versus Group 2 and Group 1 versus Group 3, a significant difference was found between Group 2 and Group 3 (p=0.005). There were no patients in any group with a bilirubin level of &amp;gt;3 mg/dL. Duration for normalization of ALT and aspartate aminotransferase levels were similar. Conclusions: The most effective treatment for chemotherapy-induced liver toxicity in pediatric patients with leukemia seems to be to interrupt CT. It was noteworthy that UDCA administration without interruption of CT treatment, the source of the liver toxicity, was effective in 69.2% of patients. Further and comprehensive studies are needed to evaluate the role of UDCA in hepatoprotection in these patients. Keywords: Ursodeoxycholic acid; leukemia; chemotherapy; hepatotoxicity

Effect of ursodeoxycholic acid on the intestinal microbiota in children with chronic liver disease

Ursodeoxycholic acid is a secondary bile acid (BA), present in humans at low concentrations, with well-known therapeutic properties, and was originally used to treat cholestatic liver disease. However, there are very few studies on the effect of ursodeoxycholic acid on the composition of the gut microbiota, especially in children with chronic liver diseases.Purpose. To determine differences in the taxonomic diversity of the fecal microbiota in children with chronic liver disease who receive or do not receive ursodeoxycholic acid.Material and methods. A metagenomic analysis of the intestinal microbiota of 24 children with chronic liver diseases (mean age 10.3 ± 4.7 years) was carried out with the identification of the V3–V4 region of the 16S rRNA gene. The group included 18 children with autoimmune liver diseases and 6 children with non-autoimmune liver diseases. 17 children received ursodeoxycholic acid. The comparison group consisted of 7 children who did not receive ursodeoxycholic acid.Results. This study found that fecal samples from patients treated with ursodeoxycholic acid do not differ in the taxonomic diversity of the gut microbiota from samples from patients not treated with ursodeoxycholic acid. A more detailed study to determine the existing taxonomic diversity in samples of patients treated with ursodeoxycholic acid and not treated with ursodeoxycholic acid, using the sPLS-DA method, showed that taxa such as Streptococcus anginosus, Coprococcus eutactus, Desulfovibrio desulfuricans, Angelakisella massiliensis and Gemella haemolysans dominated in patients not treated with ursodeoxycholic acid. And for patients receiving drugs with ursodeoxycholic acid, the dominance of the taxon Anaerostipes hadrus is typical. An analysis of differences in the percentage of intestinal microbiota bacterial species showed that patients receiving ursodeoxycholic acid had a higher count of Anaerostipes hadrus, while in patients not receiving ursodeoxycholic acid preparations, the count of Bacteroides dorei, Akkermansia muciniphila was significantly increased, and the counts of other bacteria were also increased.Conclusion. Studies have shown that ursodeoxycholic acid has a positive effect on the intestinal microbiota in children with chronic liver disease by increasing the number of microorganisms that produce short-chain fatty acids.

Protective effect of ursodeoxycholic acid and resveratrol against tacrolimus induced hepatotoxicity

ABSTRACT Tacrolimus (TAC) is a potent and well-tolerated immunosuppressive drug, but serious side effects including nephrotoxicity and hepatotoxicity have been reported. Ursodeoxycholic acid (UDCA) and resveratrol (RSV) exhibit hepatoprotective effects in liver diseases. We investigated the hepatoprotective effect of UDCA and RSV against TAC induced hepatotoxicity. We divided 40 male rats into five equal groups: A) control group, B) TAC group, C) TAC + UDCA group, D) TAC + RSV group, E) TAC + UDCA + RSV group. We administered 0.5 mg/kg TAC once daily, 25 mg/kg UDCA twice daily and 10 mg/kg RSV once daily. The drugs in the experimental groups were given by gavage from the first day of the study and continued for 21 days. Histopathologic and biochemical analyses were performed on day 22. In group B, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), total oxidative status (TOS) and malondialdehyde (MDA) levels were higher compared to group A, and catalase (CAT), superoxide dismutase (SOD) levels and total antioxidant status (TAS) were lower compared to group A. Severe cellular swelling, degeneration and focal necrosis were more evident in group B than in groups C–E. Histopathological improvement was observed in groups C–E, where UDCA and RSV were combined, compared to group B. We found that UDCA and RSV, together or separately, protected the liver against oxidative stress damage caused by TAC.

P288 The effects of stopping ursodeoxycholic acid in adult patients with mild cystic fibrosis-related liver disease (CFLD)

Ursodeoxycholic acid (UDCA) has been used to treat people with CFLD for years, and usually started in childhood or adolescence. This study aims to assess the effect of stopping UDCA on Liver Function Tests (LFT’s) and liver stiffness measurement (LSM) using ultrasound shear wave elastography of adult patients with CF-related liver disease (PwCFLD) under the care of the All Wales Adult CF Centre (AWACFC).

Possibilities for the use of ursodeoxycholic acid in the treatment of patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease

To investigate the effect of ursodeoxycholic acid (UDCA) on the degree of steatosis, indicators of carbohydrate, lipid metabolism, body weight in patients with type 2 diabetes mellitus (DM) in combination with non-alcoholic fatty liver disease (NAFLD). A prospective cohort comparative study included 36 patients with DM and NAFLD. Patients received UDCA at a dose of 15 mg/kg/day for 6 months, and also followed the recommendations for lifestyle changes through diet and exercise. To compare the results obtained during the study, a control group of patients was recruited that met the criteria for inclusion in the study. The statistical analysis included an assessment of the normality of the distribution of quantitative indicators, followed by the determination of the mean values and standard deviation or medians and quartiles, depending on the nature of the distribution, the reliability coefficient was determined by the Student, by Wilcoxon. Statistical processing was carried out in the Statistica 10 program. According to the results of the study, a positive trend was noted in the change in the severity of fatty hepatosis. During the study, a statistically significant decrease in the level of ALT, AST was achieved in the group receiving UDCA (Ursofalk). The results of our study showed that the inclusion of UDCA (Ursofalk) in complex hypoglycemic therapy provides an additional improvement in carbohydrate metabolism. The obtained indicators in the course of the study demonstrate the positive effect of UDCA on weight loss. The greatest result was achieved in reducing waist, which is a positive prognostic factor in reducing the development and progression of NAFLD, diabetes and cardiovascular diseases. Positive changes were observed in relation to the lipid profile. The study demonstrated the positive effect of the drug UDCA (Ursofalk) on reducing the degree of liver steatosis, on carbohydrate, lipid metabolism, body weight in patients with DM in combination with NAFLD.

Ursodeoxycholic acid induces sarcopenia associated with decreased protein synthesis and autophagic flux

BackgroundSkeletal muscle generates force and movements and maintains posture. Under pathological conditions, muscle fibers suffer an imbalance in protein synthesis/degradation. This event causes muscle mass loss and decreased strength and muscle function, a syndrome known as sarcopenia. Recently, our laboratory described secondary sarcopenia in a chronic cholestatic liver disease (CCLD) mouse model. Interestingly, the administration of ursodeoxycholic acid (UDCA), a hydrophilic bile acid, is an effective therapy for cholestatic hepatic alterations. However, the effect of UDCA on skeletal muscle mass and functionality has never been evaluated, nor the possible involved mechanisms.MethodsWe assessed the ability of UDCA to generate sarcopenia in C57BL6 mice and develop a sarcopenic-like phenotype in C2C12 myotubes and isolated muscle fibers. In mice, we measured muscle strength by a grip strength test, muscle mass by bioimpedance and mass for specific muscles, and physical function by a treadmill test. We also detected the fiber’s diameter and content of sarcomeric proteins. In C2C12 myotubes and/or isolated muscle fibers, we determined the diameter and troponin I level to validate the cellular effect. Moreover, to evaluate possible mechanisms, we detected puromycin incorporation, p70S6K, and 4EBP1 to evaluate protein synthesis and ULK1, LC3 I, and II protein levels to determine autophagic flux. The mitophagosome-like structures were detected by transmission electron microscopy.ResultsUDCA induced sarcopenia in healthy mice, evidenced by decreased strength, muscle mass, and physical function, with a decline in the fiber’s diameter and the troponin I protein levels. In the C2C12 myotubes, we observed that UDCA caused a reduction in the diameter and content of MHC, troponin I, puromycin incorporation, and phosphorylated forms of p70S6K and 4EBP1. Further, we detected increased levels of phosphorylated ULK1, the LC3II/LC3I ratio, and the number of mitophagosome-like structures. These data suggest that UDCA induces a sarcopenic-like phenotype with decreased protein synthesis and autophagic flux.ConclusionsOur results indicate that UDCA induces sarcopenia in mice and sarcopenic-like features in C2C12 myotubes and/or isolated muscle fibers concomitantly with decreased protein synthesis and alterations in autophagic flux.

The association between soluble CD163, disease severity, and ursodiol treatment in patients with primary biliary cholangitis.

The macrophage activation marker soluble (s)CD163 is associated with disease severity and prognosis in patients with primary biliary cholangitis (PBC). Ursodeoxycholic acid (UDCA) treatment attenuates fibrosis progression in PBC patients, but its effect on macrophage activation is unclear. We examined the effect of UDCA on macrophage activation, as determined by sCD163 levels. We included 2 cohorts of PBC patients; 1 cohort with prevalent PBC patients, and 1 cohort of incident PBC patients before start of UDCA treatment and with follow-up after 4 weeks and 6 months. We measured sCD163 and liver stiffness in both cohorts. Further, we measured sCD163 and TNF-α shedding in vitro in monocyte-derived macrophages after UDCA and lipopolysaccharide incubation. We included 100 patients with prevalent PBC [93% women, median age 63y (interquartile range: 51-70)] and 47 patients with incident PBC [77% women, median age 60y (49-67)]. Prevalent PBC patients had a lower median sCD163 of 3.54mg/L (2.77-4.72) than incident PBC patients with a median sCD163 of 4.33mg/L (2.83-5.99) at inclusion. Patients with an incomplete response to UDCA and patients with cirrhosis had higher sCD163 than responders to UDCA and noncirrhosis patients. After 4 weeks and 6 months of UDCA treatment median sCD163 decreased by 4.6% and 9.0%, respectively. In in vitro experiments, UDCA attenuated shedding of TNF-α, but not sCD163, from monocyte-derived macrophages. In PBC patients, sCD163 levels correlated with liver disease severity and treatment response to UDCA. Further, after 6 months of UDCA treatment, we observed a decrease in sCD163, which may be related to the treatment.