Effect Of Ursodeoxycholic Acid Research Articles

Ursodeoxycholic acid alleviates fat embolism syndrome-induced acute lung injury by inhibiting the p38 MAPK/NF-κB signalling pathway through FXR

Acute lung injury (ALI) caused by fat embolism syndrome (FES) is a disease with high mortality. This study aimed to explore the roles of ursodeoxycholic acid (UDCA) in FES-induced ALI and its underlying mechanisms. An ALI mouse model was established by allografting mouse perinephric fat. For in vitro experiments, human pulmonary microvascular endothelial cells (HPMEC) were treated with FFAs. The effects of UDCA on the expression of farnesoid X receptor (FXR) and the inflammatory response in endothelial cells were investigated. UDCA significantly inhibited the inflammatory response and the expression of proinflammatory markers during FES-induced ALI. UDCA markedly decreased TNF-α and IL-1β expression in vitro. UDCA administration markedly upregulated FXR expression and significantly reduced the phosphorylation of p38 MAPK and NF-κB p65. Knock down FXR expression decreased the effect of UDCA in vivo. Furthermore, knock down FXR expression and overexpressing FXR increased and decreased the inflammatory response, respectively, in vitro. Moreover, administration of a p38 MAPK activator reversed the anti-inflammatory effect of FXR overexpression. UDCA ameliorated inflammation during FES-induced ALI by suppressing p38 MAPK/NF-κB signalling and activating FXR. These findings provide new evidence for the potential of UDCA for FES-induced ALI treatment.

Association between ursodeoxycholic acid use and COVID-19 in individuals with chronic liver disease: a nationwide case-control study in South Korea

BackgroundConflicting evidence exists regarding the effects of ursodeoxycholic acid (UDCA) on coronavirus disease 2019 (COVID-19). This study investigates the association between UDCA administration and COVID-19 infection and its related outcomes in individuals with chronic liver disease (CLD).MethodsA customized COVID-19 research database (n = 3,485,376) was created by integrating data from the National Health Insurance Service (NHIS) and the Korea Disease Control and Prevention Agency’s COVID-19 databases. The study focused on patients diagnosed with COVID-19 in 2021, using the NHIS data from 365 days before diagnosis. To create comparable groups with and without UDCA administration before COVID-19, we used propensity score matching. The primary endpoint was the first confirmed positive result for severe acute respiratory syndrome coronavirus-2. In addition, we identified severe COVID-19-related outcomes. Subgroup analysis were conducted based on the dose of UDCA exposure.ResultsData from 74,074 individuals with CLD was analyzed. The participants’ average age was 57.5 years, and 52.1% (19,277) of those in each group were male. Those with prior UDCA exposure had a significantly lower risk of COVID-19 infection (adjusted OR: 0.80, 95% CI [0.76–0.85]) compared to the non-UDCA group. Additionally, the UDCA group had a lower risk of severe COVID-19 outcomes (adjusted OR: 0.67, 95% CI [0.46–0.98]). Subgroup analyses indicated that there was a decrease in COVID-19 infection and its related outcomes with increasing UDCA exposure dose.ConclusionsOur large observational study highlights the potential use of readily available UDCA as an adjunctive therapy for COVID-19 in individuals with CLD.

Evaluating the protective effectiveness and risk factors of ursodeoxycholic acid on COVID-19 among outpatients.

Objective: This study aimed to assess the chemopreventive effect of ursodeoxycholic acid (UDCA) against COVID-19 and to analyze infection risk factors, symptoms, and recovery in outpatients with UDCA exposure. Methods: The study enrolled outpatients prescribed UDCA from the Second Affiliated Hospital of Chongqing Medical University, China, between 01 July 2022, and 31 December 2022. Data on demographics, comorbidities, and drug combinations were collected using electronic medical records. COVID-19 infection, symptoms, severity, prognosis, vaccinations, and UDCA administration were surveyed by telephone interviews. UDCA non-users served as controls and were matched in a 1:2 ratio with UDCA users using propensity score matching with the nearest neighbor algorithm. Infection rates, symptomatology, severity, and prognosis were compared between matched and control cohorts, and risk factors and infection and recovery symptoms were analyzed in UDCA-exposed outpatients. Results: UDCA-exposed outpatients (n = 778, 74.8%) and matched UDCA users (n = 95, 74.2%) showed significantly lower SARS-CoV-2 infection rates than control patients (n = 59, 92.2%) (p < 0.05). The matched UDCA group exhibited substantially lower fever, cough, sore throat, and fatigue rates than controls (p < 0.05). Participants with UDCA exposure generally experienced mild symptoms, while those without UDCA had moderate symptoms. The matched UDCA group also had significantly shorter durations of fever and cough (p < 0.05). Risk factors such as age over 60, less than 1month of UDCA administration, diabetes mellitus, and coronary artery disease significantly increased SARS-CoV-2 infection rates (p < 0.05), while smoking led to a decrease (p < 0.05). Hypertension was associated with a prolonged COVID-19 recovery (p < 0.05), while smoking, vaccination, and fatty liver disease were associated with shorter recovery periods (p < 0.05). The main symptoms in the full UDCA cohort were fever, cough, and sore throat, with fatigue, cough, and hyposthenia being the most persistent. Conclusion: UDCA demonstrated chemopreventive effect against SARS-CoV-2 in outpatients by significantly reducing infection incidence and mitigating COVID-19 symptoms, severity, and recovery duration. Old age, short UDCA course, and comorbidities such as diabetes mellitus and CAD increased infection rates, while hypertension prolonged recovery. Smoking, vaccination, and fatty liver disease reduced infection rates and shortened recovery. UDCA had minimal impact on symptom types. Larger and longer-term clinical studies are needed further to assess UDCA's effectiveness in COVID-19 prevention or treatment.

The effect of intrahepatic cholestasis of pregnancy and ursodeoxycholic acid treatment on Doppler parameters of fetal and maternal circulation.

We aimed to evaluate feto-maternal blood flow parameters using Doppler ultrasonography (USG) in pregnant women with intrahepatic cholestasis of pregnancy (ICP) and the effect of ursodeoxycholic acid (UDCA) treatment on these parameters. This prospective cohort study was performed at Dr. Sami Ulus Women's and Children's Health Teaching and Research Hospital, in Turkey between September 2022 and February 2023. Sixty pregnant women, 30 with ICP disease and 30 healthy women were included in the study. Obstetric Doppler parameters were measured by USG at diagnosis and after 48 hours of UDCA treatment for the ICP group. The obstetric Doppler parameters did not significantly differ in the ICP group and the healthy control group. The Doppler findings were similar after UDCA treatment in the ICP group. Gestational week at delivery and birth weight were lower in the ICP group in our study. We demonstrated that pregnant women with ICP had similar obstetric Doppler parameters when compared with healthy pregnant women and that the UDCA agent used for treatment of ICP disease did not affect these parameters.

Effect of Maternal Ursodeoxycholic Acid Treatment on Fetal Atrioventricular Conduction in Patients with Intrahepatic Cholestasis of Pregnancy.

The aim of this study was, first, to investigate the difference in fetal atrioventricular conduction in patients with and without intrahepatic cholestasis of pregnancy (ICP) by measuring the fetal PR interval; second, to evaluate the altering effect of ursodeoxycholic acid (UDCA) treatment on the fetal PR interval in ICP patients. The study consisted of 42 ICP patients and 48 healthy pregnant women. Fetal echocardiography was performed to measure the mechanical PR interval. The fetal PR interval and the clinical characteristics were compared between the two groups. The effect of UDCA treatment on the fetal PR interval in ICP patients was evaluated. In ICP patients, significantly longer fetal PR intervals were observed than in the control group (123.21 ± 8.54 vs. 115.13 ± 5.95 ms, p &lt; 0.001). In the ICP group, there was a positive correlation between the fetal PR interval and maternal fasting total bile acid (TBA) levels (r = 0.514, p = 0.001). After 1 week of treatment with UDCA in patients with ICP, the PR interval was shorter than before, although the reduction was not statistically significant (120.98 ± 6.70 vs. 123.21 ± 8.54 ms, p = 0.095). In patients with severe ICP (TBA &gt;40 mmol/L, n = 10), a significant reduction in the fetal PR interval was observed after treatment with UDCA (127.5 ms [IQR, 118.0-134.75] before vs. 122 ms [IQR, 109.5-126.5] after, p = 0.037). Fetal PR interval increased in ICP patients in correlation with maternal serum TBA concentration. Treatment with UDCA may have limited positive effects on the fetal AV conduction system. The beneficial effects of UDCA on the fetal PR interval may be more pronounced in patients with higher bile acid levels.

The Value of Ursodeoxycholic Acid and Mesenchymal Stem Cells in the Treatment of Severe COVID-19.

Objective: The objective of this study was to evaluate the therapeutic efficacy of ursodeoxycholic acid (UDCA) and mesenchymal stem cells (MSCs) in patients with severe COVID-19. Methods: We included severe COVID-19 patients hospitalized at Shulan (Hangzhou) Hospital between December 2022 and June 2023. We used a logistic regression model to compare the use of UDCA and MSCs in the two distinct groups of improved and poor outcomes. It is noteworthy that the deterioration group encompassed instances of both death and abandonment of treatment. The receiver operating characteristic (ROC) curve was plotted to assess the performance of the model. The aim was to assess the therapeutic effect of UDCA and MSCs on the outcome of severe COVID-19 patients. Results: A total of 167 patients with severe COVID-19 were included in this study. The analysis revealed that out of 42 patients (25.1%), 17 patients (10.2%) had taken UDCA, and 17 patients (10.2%) had used MSCs. Following a multivariable logistic regression, the results indicated a negative association between UDCA treatment (OR = 0.38 (0.16-0.91), p = 0.029), MSCs treatment (OR = 0.21 (0.07-0.65), p = 0.007), and the risk of severe COVID-19 mortality. Additionally, age showed a positive association with the risk of mortality (OR = 1.03 (1.01-1.07), p = 0.025). Conclusions: UDCA and MSCs have shown potential in improving the prognosis of severe COVID-19 patients and could be considered as additional treatments for COVID-19 in the future.

Ursodeoxycholic Acid's Effectiveness in the Management of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis.

This meta-analysis's objective was to assess the effectiveness of ursodeoxycholic acid (UDCA) in the management of nonalcoholic fatty liver disease (NAFLD). Electronic databases like PubMed, Embase, Scopus, and Cochrane Library were thoroughly looked for randomized controlled trials determining ursodeoxycholic acid's (UDCAs) effectiveness on the serum liver function tests in NAFLD patients. After screening, seven randomized controlled trials were incorporated overall. Utilizing a fixed effects model, quantitative data synthesis was performed in R version 4.3.1. The meta-analysis showed significant reductions in alanine transaminase (ALT) (p ≤ 0.0001), aspartate transaminase (p = 0.0009), and gamma-glutamyl transferase (GGT) (p ≤ 0.0001) after UDCA therapy. However, significant reductions in bilirubin (p = 0.6989) and alkaline phosphatase (ALP) (p = 0.1172) levels were not noted. Sensitivity analysis by removing the studies with some concerns of bias was successful in demonstrating a remarkable reduction in heterogeneity for aspartate transaminase and ALP, which was also observed while performing the subgroup analyses via dosage. Ursodeoxycholic acid was beneficial in patients diagnosed with NAFLD as it significantly reduced aspartate transaminase, ALT and GGT levels. However, more randomized controlled trials are required to be conducted in the future to increase the certainty of the evident findings. This meta-analysis strengthens the evidence about the reductions in AST, ALT, and GGT levels observed with ursodeoxycholic acid therapy in NAFLD patients by pooling the data together from the latest RCTs thus proving its hepatoprotective effects which can be beneficial in preventing the associated complications. Patel VS, Mahmood SF, Bhatt KH, et al. Ursodeoxycholic Acid's Effectiveness in the Management of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Euroasian J Hepato-Gastroenterol 2024;14(1):92-98.

Synergistic effects of ursodeoxycholic acid, and quercetin on liver function and systemic inflammation in non-alcoholic fatty liver disease and atrial fibrillation patients

Background. Non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) co-occur with signifi­cant clinical implications, necessitating therapeutic strategies that address the multifaceted nature of these conditions. This study evaluated the efficacy of standard treatment alone versus combined treatments with ursodeoxycholic acid (UDCA) and quercetin in patients with NAFLD and AF, focusing on improvements in liver function, lipid profile, systemic inflammation, and fibrosis markers. Aim: to evaluate and compare the efficacy of standard treatment alone versus standard treatment combined with ursodeoxycholic acid with and without quercetin in patients with non-alcoholic fatty liver disease and concurrent atrial fibrillation. Materials and methods. In a prospective, randomi­zed, controlled trial, 127 patients with diagnosed NAFLD and concurrent AF were enrolled. They were divided into three groups: group 1 — standard treatment (n = 42), group 2 — standard treatment plus UDCA (n = 44), and group 3 — standard treatment plus UDCA and quercetin (n = 41). The primary outcomes included changes in liver function tests (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase, alkaline phosphatase), lipid profile (total cholesterol, low- and high-density lipoprotein cholesterol (HDL-C), triglycerides), and non-invasive liver fibrosis scores (NFS, FIB-4). Secondary outcomes focused on systemic inflammation markers (C-reactive protein, galectin-3, soluble ST2) and fibronectin levels. Results. All treatment groups showed significant improvements in liver function tests and lipid profiles. Group 3 exhibited the most substantial reductions in ALT, AST, and improvements in HDL-C, indicating enhanced hepatoprotective and lipid-modulating effects. Systemic inflammation markers and fibronectin levels decreased significantly in groups receiving UDCA and quercetin, with the most pronounced effects observed in group 3, suggesting potent anti-inflammatory and anti-fibrotic action. Additionally, significant improvements in NFS and FIB-4 scores in group 3 highlight the anti-fibrotic potential of combining UDCA and quercetin with standard treatment. Conclusions. The addition of UDCA and quercetin to standard treatment for patients with NAFLD and AF significantly improves liver function, lipid metabolism, and reduces systemic inflammation and fibrosis, compared to standard treatment alone. These findings suggest a synergistic effect of UDCA and quercetin, offering a promising therapeutic strategy for managing the complex interplay between NAFLD and AF.

Effects of ursodeoxycholic acid on growth performance and lipid metabolism in juvenile large yellow croaker (Larimichthys crocea)

Bile acids (BAs) have been shown to exert beneficial effects on growth and metabolism in various fish species. Nevertheless, few studies have focused on the impact of ursodeoxycholic acid (UDCA). The purpose of the present study was to investigate the potential effects of dietary UDCA supplementation on growth performance and lipid metabolism in juvenile large yellow croaker (Larimichthys crocea). Four diets were formulated based on a control diet (CON), with the addition of 50 mg/kg (UL), 100 mg/kg (UM), and 500 mg/kg (UH) UDCA. A total of 400 juveniles (with an initial body weight of 15.55 ± 0.02 g) were randomly distributed into 16 tanks (1000L) with 25 juveniles per tank. Each type of experimental diet was fed to the fish in four replicates twice daily. After a 10-week feeding trial, the results demonstrated that feeding diets containing 50 and 100 mg/kg UDCA significantly improved growth performance (P < 0.05). Dietary UDCA supplementation significantly increased whole-body crude lipid content, liver, and serum total cholesterol (T-CHO) content, as well as intestinal lipase activity, while reducing liver and serum free fatty acid content (P < 0.05). To investigate the mechanisms underlying the observed growth and metabolic alterations induced by UDCA, tissue samples from the CON and the UM groups were subjected to RNA-sequencing analysis. A total of 1924, 4399, 249, and 971 differentially expressed genes (DEGs) in the liver, intestine, olfactory, and brain tissues were identified, respectively. Enrichment analysis of these DEGs suggested a high degree of pathway similarity between the liver and intestinal tissues. Specifically, the UM diet markedly upregulated genes associated with lipid synthesis and lipid transport, while concurrently downregulating those involved in fatty acid β-oxidation. Weighted gene co-expression network analysis (WGCNA) across tissues revealed a gene cluster related to cholesterol synthesis. Within this cluster, key genes such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase (hmgcr) and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (hmgcs1) were upregulated, implying that UDCA enhances of cholesterol synthesis. Furthermore, in vitro experiments in primary hepatocyte corroborated the role of UDCA in stimulating lipid synthesis, as evidenced by the augmented total triglyceride (TG) and T-CHO levels following UDCA incubation. This increase was paralleled by an upregulation in the expression of genes related to fatty acid and cholesterol synthesis as well as lipid transport. In summary, these results demonstrate that UDCA exerts a beneficial impact on growth performance, lipid transport, and lipid synthesis in juvenile large yellow croakers.

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.