Search Results (102)

Background: Gestational diabetes mellitus (GDM) is associated with metabolic disturbance and subclinical cardiovascular changes during pregnancy and after birth. Optimal glycaemic control remains challenging for many patients despite existing management strategies. Ursodeoxycholic acid (UDCA) has shown potential metabolic effects, including enhanced insulin sensitivity and anti-inflammatory effects. Previously, we demonstrated that UDCA improves glycaemic control in women achieving higher circulating UDCA concentrations; however, its effect on maternal cardiac function remains unknown. The objective was to evaluate whether treatment with UDCA compared with placebo is associated with differences in maternal cardiac function in pregnancies complicated by GDM. Methods: In this randomized, placebo-controlled trial, 113 women with GDM were recruited, with 56 allocated to UDCA and 57 to placebo (IMIB-GU-2019-02, registration date: 17 June 2020; first participant enrolled: 3 March 2021). After measurement of maternal blood UDCA levels, 43 participants in the treatment group with levels ≥ 0.5 μmol/L were included in a per-protocol analysis. Participants had cardiac assessments at baseline, in the late third trimester (36 weeks) and postpartum. Detailed left ventricular systolic and diastolic functional indices were assessed using conventional pulse and tissue Doppler indices as well as strain imaging. Right ventricular systolic function was also assessed. Results: Baseline maternal characteristics and cardiac functional indices were comparable between the UDCA and placebo groups. In the third trimester, women treated with UDCA showed more negative left atrial strain during atrial contraction (LASct_AC) compared with placebo (p = 0.016), while no significant between-group differences were observed in conventional left ventricular systolic or diastolic parameters. In the postpartum period, UDCA treatment was associated with higher left atrial reservoir function, reflected by increased LASr_ED (p = 0.041) and LASr_AC (p = 0.036), as well as more negative left atrial conduit strain at end-diastole (LAScd_ED; p = 0.043). No consistent differences were observed in left ventricular systolic function, haemodynamic indices, or right ventricular functional parameters between the two groups. Conclusions: These findings are associated with small and time-dependent differences in reducing atrial dysfunction and improving cardiac efficiency during late pregnancy and postpartum. However, given the lack of long-term follow-up, further research is needed to determine the long-term cardiovascular relevance of UDCA in this population. Full article

Primary biliary cholangitis (PBC) is a heterogeneous autoimmune liver disease in which clinical presentation, disease progression, and response to therapy vary markedly from patient to patient. This heterogeneity reflects its complex, multifactorial, and not-completely elucidated pathogenesis. Currently, serological markers are available to non-invasively diagnose PBC, reserving liver biopsy for selected cases with atypical presentations or diagnostic uncertainty. Anyway, the accurate non-invasive prediction of liver-related and non-liver-related (i.e., extra-hepatic, including pruritus) outcomes remains an open challenge, as well as an urgent need, considering the great variability in clinical course and prognosis reported in PBC patients. Moreover, although ursodeoxycholic acid (UDCA) remains the standard first-line treatment, not all individuals respond equally, either in terms of therapeutic efficacy or timing of biochemical improvement. This further variability in treatment response underscores the inadequacy of uniform management approaches and reinforces the urgent need for personalized medicine, where treatment decisions are guided by patient-specific biological and clinical parameters. In this scenario, the identification and validation of non-invasive predictive biomarkers capable of detecting early therapeutic responsiveness are pivotal for optimizing care pathways. Finally, a growing portion of patients show an insufficient UDCA response or are UDCA intolerant, making the identification of novel strategies of care an urgent need. Concerning this, very recently, new therapeutic options beyond UDCA targeting, among the other pathways, bile acid metabolism (including the modern Peroxisome Proliferator-Activated Receptor agonists), immune regulation, and fibrogenesis, have expanded the treatment landscape. In the Era of Precision Medicine, these diagnostic, prognostic, and therapeutic innovations, by reflecting the complexity of PBC pathogenesis, underline the cruciality of a patient-tailored strategy to improve outcomes and mitigate disease progression. The present review reports recent advances, highlights ongoing challenges, and outlines future perspectives in the management of PBC. Full article

Background: Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease, characterized by cholestasis and fibrosis. Ursodeoxycholic acid (UDCA) is the first-line treatment for normalizing markers, slowing progression, and improving outcomes. Various criteria, including Paris II, POISE, and Barcelona, along with scores like GLOBE, UK-PBC, and URS, help assess response and prognosis. The aim of our study was to evaluate the patient’s profile and assess treatment response to UDCA. Methods: We conducted a retrospective study of 276 patients diagnosed with PBC, evaluated between 2011 and 2024 at Fundeni Clinical Institute in Bucharest. Of these, 117 patients were assessed for UDCA response at 12 months. Demographic, clinical, and biochemical data were collected. Treatment response was evaluated using established criteria and prognostic scores. Logistic regression analysis was used to identify significant predictors of treatment response, while ROC curves assessed predictive capabilities for liver-related outcomes (LRO) and UDCA biochemical response. Results: The cohort primarily consisted of women (95.28%) with a mean age at diagnosis of 53.89 years (95% CI, 52.43–55.34). 40.5% of patients developed liver cirrhosis during follow-up. At 12 months, the response rates to UDCA therapy were 44.44%, 41.88%, and 52.14% according to the Paris II, POISE, and Barcelona criteria, respectively. Biochemical improvement was significant, particularly the reduction of alkaline phosphatase (ALP) below 1.67× the upper limit of normal, which was observed in 62.39% of patients. ROC analysis demonstrated robust predictive capabilities, with UK-PBC (AUROC 0.899) and GLOBE (AUROC 0.867) scores accurately predicting LRO. A lower age at diagnosis, higher ALP values at diagnosis, and absence of sp100 were factors associated with non-response. Conclusions: This study is one of the first detailed analyses of PBC patients in Romania, examining population-specific characteristics and UDCA response rates. Low response rates at 12 months highlight the need for longer follow-up and the exploration of second-line therapies. Full article

Commercial feeds formulated for Larimichthys crocea are commonly used in intensive farming of Larimichthys polyactis; however, their nutritional composition is suboptimal for the latter. The study evaluated the effects of dietary chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) supplementation on mitigating nutritional mismatch-induced growth retardation and hepatopancreatic–intestinal metabolic disorders in L. polyactis. Fish were fed seven feeds: a commercial feed (control) and feeds supplemented with 300, 600, and 1200 mg/kg of CDCA or UDCA. Results showed that both bile acids (BAs) supplementation improved growth, altered thyroid hormone metabolism, with significant changes in hepatopancreatic–intestinal types of deiodination. Both BAs increased hepatopancreatic energy metabolism and cholic acid synthesis, while inducing hepatopancreatic oxidative damage. Notably, 300 mg/kg CDCA and 600 mg/kg UDCA significantly reduced hepatopancreatic vacuolation and lipid accumulation, which was associated with enhanced protease and lipase activities (p < 0.05). Dietary both BAs supplementation enhanced intestinal antioxidant capacity, but contributed to the inflammation, with 300 mg/kg UDCA improving intestinal mucosal morphology (p < 0.05). These findings suggest that supplementation with dietary 300 mg/kg CDCA, 300 and 600 mg/kg UDCA could alleviate growth restriction and liver–intestinal structural damage caused by nutritional mismatch, reduce hepatic fat accumulation, and enhance intestinal antioxidant capacity of L. polyactis. Full article

Background: Gestational diabetes mellitus (GDM) is associated with subclinical alterations in fetal cardiac morphology and function. Ursodeoxycholic acid (UDCA), widely used in pregnancy for intrahepatic cholestasis, has demonstrated cardioprotective properties in experimental fetal models, preventing conduction abnormalities and improving myocardial function. Whether UDCA modifies fetal or neonatal cardiac adaptation in GDM pregnancies has not been previously investigated. The objective was to evaluate the effect of ursodeoxycholic acid (UDCA) on fetal and neonatal cardiac function in pregnancies complicated by gestational diabetes mellitus (GDM). Methods: In this randomized, placebo-controlled study, 113 women with GDM were enrolled, of whom 56 received UDCA and 57 the placebo. After measurement of maternal blood UDCA concentrations, 43 participants in the treatment group had levels ≥0.5 µmol/L and were included in the per-protocol analysis. Echocardiographic and Doppler-derived cardiac indices were assessed at baseline, 36 weeks’ gestation, and postpartum. Comparisons were performed using univariable tests and mixed-effects multivariable models accounting for time and treatment. Results: In the treatment group, compared to the placebo group, there were no significant differences in cardiac indices at 36 weeks’ gestation or postpartum when assessed individually. However, in the mixed-effects longitudinal analysis, a significant treatment-by-time interaction was observed. Specifically, in the postpartum period, mitral A-wave velocity (MV-A) was higher in the treatment group compared to that under the placebo (9.58, 95% CI 2.29–16.87; p = 0.010), reflecting a more pronounced increase in the atrial contribution to left ventricular filling over time. Similarly, aortic peak velocity (Ao_Vmáx) was significantly higher in the treatment group compared to that under the placebo in the postpartum period (7.97, 95% CI 0.19–15.75; p = 0.045), indicating a greater augmentation in left ventricular outflow dynamics. Conclusions: In pregnancies complicated by GDM, UDCA did not lead to significant cross-sectional differences in fetal or neonatal cardiac indices at 36 weeks or postpartum. However, longitudinal modeling indicated that UDCA was associated with a greater increase in the atrial contribution to ventricular filling (MV-A) and aortic peak velocity (Ao_Vmáx) in the postpartum period compared to that under the placebo. These findings suggest that while UDCA does not broadly alter cardiac function, it may modulate specific aspects of diastolic filling and systolic outflow dynamics during late gestation and early neonatal adaptation. Full article

Gallbladder mucocele (GBM) in dogs is a condition characterized by the excessive accumulation of mucin within the gallbladder, potentially leading to bile duct obstruction and serious complications. While cholecystectomy remains the treatment of choice for symptomatic cases, medical management is often considered in dogs with subclinical GBM. This study evaluated the effects of different hepatoprotectants on disease progression in subclinical GBM. Sixty dogs diagnosed with GBM were randomly assigned to one of the three treatment groups: Group 1 (Ursodeoxycholic acid (UDCA) alone), Group 2 (S-adenosylmethionine (SAMe) and silymarin), and Group 3 (UDCA, SAMe, and silymarin). Hepatic biochemical markers (GGT, ALP, ALT, AST, bilirubin, cholesterol) and ultrasound parameters (gallbladder sludge percentage, liver echogenicity) were assessed at baseline, day 30, day 60, day 180, and day 365. Group 3 exhibited the most significant improvement, with substantial reductions in GGT, ALP, ALT, and AST levels (p < 0.05). Group 3 also demonstrated a significant decrease in gallbladder sludge percentage and improved liver echogenicity (p < 0.05). Group 1 showed mild improvement, whereas Group 2 had minimal impact on markers of cholestasis or gallbladder health. These findings suggest that a combination therapy of UDCA, SAMe, and silymarin may offer the most effective medical approach for managing subclinical GBM in dogs. Full article

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease marked by cholestasis and progressive fibrosis. While ursodeoxycholic acid (UDCA) remains the first-line therapy, approximately 30–40% of patients have an inadequate biochemical response, increasing the risk of disease progression. Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, was the first second-line agent approved by the only Food and Drug Administration (FDA) and has demonstrated moderate biochemical efficacy but limited tolerability due to dose-dependent pruritus and safety concerns in cirrhosis. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, showed substantial alkaline phosphatase (ALP) reductions when added to UDCA, although its long-term benefit remains unconfirmed in large-scale trials and its use remains off-label in the United States, unlike FDA-approved agents. Seladelpar, a selective peroxisome proliferator-activated receptor delta (PPAR-δ) agonist, and elafibranor, a dual PPAR-α/δ agonist, have both recently received FDA accelerated approval after demonstrating significant improvements in ALP, biochemical response rates, and pruritus relief in phase 3 trials. This review summarizes these second-line therapies’ mechanisms, efficacy, safety, and limitations emphasizing the need for individualized treatment decisions and ongoing research into long-term clinical outcomes. Full article

The Farnesoid-X-receptor (FXR) is a bile sensor involved in the regulation of bile acid homeostasis, fibrosis, inflammation, and metabolism. Obeticholic acid (OCA), a semisynthetic derivative of chenodeoxycholic acid (CDCA), initially named 6-ethyl-CDCA or INT-747, is the first in a class of FXR ligands that have been approved for clinical use for the treatment of patients with primary biliary cholangitis (PBC) who are unresponsive or intolerant to ursodeoxycholic acid. In this narrative review, we will examine the current status and future perspective of clinical use of OCA. Based on results from phase 2 and 3 clinical trials, OCA received a conditional market approval for its use as a second-line treatment for the management of PBC in 2016. However, concerns over drug (OCA)-induced liver injury (DILI), including hepatic decompensation in cirrhotic and non-cirrhotic PBC patients, have led to discontinuation of OCA commercialization in the EU, but not in North America and the UK, in 2024. Based on positive results from preclinical models, OCA has been investigated also for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Results from phase 2 and 3 trials, however, have shown that while OCA reduces liver fibrosis, the beneficial effects on steatosis are marginal, thus preventing its clinical approval under the current regulatory guidelines. Here, we review potential applications of OCA in PBC patients in the context of a highly competitive therapeutic landscape, generated by the approval for clinical use of safer and effective second-line therapies, including PPARs agonists such as elafibranor and seladelapar and increased off-label use of fibrates. The current status of development of second-generation FXR agonists such as cilofexor, tropifexor, and vonafexor and their potential in the treatment of liver fibrosis in MASH will be discussed and compared to recently approved therapies, resmetirom, and semaglutide, a GLP-1 agonist. Finally, since some of the novel candidates for treating MASH, have shown limited efficacy on liver fibrosis, we suggest that development of combinatorial therapies based on FXR ligands and agents acting on different molecular targets might offer the opportunity for the repositioning of drug candidates whose development has been abandoned for insufficient efficacy, minimizing/recovering costs linked to drug development. Full article

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy, typically presenting in the third trimester. It is characterized by pruritus, elevated serum bile acids, and abnormal liver function tests. While maternal symptoms resolve postpartum, ICP poses significant risks to fetal health, including spontaneous preterm labor, meconium-stained amniotic fluid, and stillbirth. This review aims to synthesize current knowledge on the pathogenesis, diagnosis, and management and highlight emerging research and possible therapy directions in ICP. A comprehensive review of recent literature was conducted, focusing on molecular mechanisms, clinical management guidelines, fetal outcomes, and novel therapeutics under investigation. Ursodeoxycholic acid (UDCA) remains the primary pharmacologic treatment of intrahepatic cholestasis of pregnancy; however, its effect on perinatal outcomes is debated. Investigational therapies—including Volixibat, FXR agonists, 4-phenylbutyrate, and NorUDCA—are under exploration. These emerging therapies hold the potential to improve both maternal symptoms and perinatal outcomes by addressing the underlying pathophysiology of ICP more effectively than current standard treatment. Additionally, emerging biomarkers and machine-learning tools hold promise for improved diagnosis and personalized care. ICP continues to pose diagnostic and therapeutic challenges. While maternal outcomes are generally favorable, optimizing fetal safety requires timely diagnosis, stratified risk assessment, and evidence-based delivery planning. Future research should prioritize identifying predictive biomarkers, refining treatment algorithms, and assessing long-term outcomes for both mothers and offspring. Special attention should also be given to the investigation of novel therapeutic targets. Full article

Ursodeoxycholic acid (UDCA) is widely used to treat cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), yet its molecular mechanisms remain unclear. This study investigated the impact of long-term UDCA therapy on circulating levels of the microRNAs miR-34a and miR-506, which are implicated in PBC pathogenesis, and explored associated changes in inflammatory markers and signaling pathways. Serum samples from patients with PBC and PSC were collected before and after UDCA treatment and analyzed for miRNA expression as well as levels of TREM-2 and sCD163. In vitro studies using human cholangiocytes and lipopolysaccharide (LPS) stimulation assessed changes in the expression of miR-34a, TREM-2, and ADAM17. The results showed that the baseline levels of miR-34a and miR-506 were significantly elevated in PBC patients compared to controls and were significantly reduced after UDCA therapy in PBC but not in PSC. UDCA also decreased serum levels of TREM-2 and sCD163. In vitro, it suppressed the LPS-induced expression of miR-34a and ADAM17 while enhancing TREM-2 expression. Single-cell RNA sequencing of liver tissue and immunofluorescence staining confirmed TREM-2 expression in cholangiocytes. These findings suggest that UDCA modulates key inflammatory pathways and miRNAs in PBC, providing mechanistic insights into its therapeutic effect Full article

Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe hepatocellular cholestasis due to biallelic variations in the ABCB11 (ATP-binding cassette B11) gene encoding the canalicular bile salt export pump (BSEP). Some missense variants identified in patients with PFIC2 do not traffic properly to the canalicular membrane. However, 4-phenybutyrate (4-PB) has been shown in vitro to partially correct the mis-trafficking of selected variants, resulting in an improvement of the medical conditions of corresponding PFIC2 patients. Herein, we report the ability of 4-PB analogous or homologous drugs and of non-4-PB related chemical correctors to rescue the canalicular expression and the activity of the folding-defective Abcb11^R1128C variant. New compounds, either identified by screening a chemical library or designed by structural homology with 4-PB (or its metabolites) and synthesized, were evaluated in vitro for their ability to (i) correct the canalicular localization of Abcb11^R1128C after transfection in hepatocellular polarized cell lines; (ii) restore the ³H-taurocholate transport of the Abcb11^R1128C protein in Madin–Darby canine kidney (MDCK) cells stably co-expressing Abcb11 and the sodium taurocholate co-transporting polypeptide (Ntcp/Slc10A1). Glycerol phenylbutyrate (GPB), phenylacetate (PA, the active metabolite of 4-PB), 3-hydroxy-2-methyl-4-phenylbutyrate (HMPB, a 4-PB metabolite analog chemically synthesized in our laboratory) and 4-oxo-1,2,3,4-tetrahydro-naphthalene-carboxylate (OTNC, from the chemical library screening) significantly increased the proportion of canalicular Abcb11^R1128C protein. GPB, PA, ursodeoxycholic acid (UDCA), alone or in combination with 4-PB, suberoylanilide hydroxamic acid (SAHA), C18, VX-445, and/or VX-661, significantly corrected both the traffic and the activity of Abcb11^R1128C. Such correctors could represent new pharmacological insights for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the transporter’s traffic. Full article

This Letter to the Editor explores synergistic mechanisms enhancing mRNA cancer vaccine efficacy through bile acid metabolism modulation in liver cancer treatment. The latest evidence indicates that bile acids significantly impair T cell function within the liver cancer microenvironment, creating an immunosuppressive milieu that hampers anti-tumor responses. Modulating bile acid composition, particularly increasing ursodeoxycholic acid (UDCA), could reshape the tumor microenvironment (TME) to favor mRNA vaccine-induced T cell activity—a promising strategy to overcome current immunotherapy limitations in liver cancer. Full article

Background: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by progressive bile duct damage and cholestasis. While ursodeoxycholic acid (UDCA) is the first-line therapy, approximately 40% of patients have incomplete responses, necessitating alternative treatments. This systematic review and meta-analysis evaluate the efficacy and safety of novel oral anti-cholestatic agents for PBC. Methods: A systematic literature search was conducted in electronic databases up to September 2024. Randomized controlled trials, cohort studies, and case-control studies evaluating novel oral anti-cholestatic agents in adult PBC patients were included. The primary outcome was a change in alkaline phosphatase (ALP) levels. Safety was assessed by the incidence of serious adverse events. Random-effect meta-analyses were performed. Results: Ten studies involving 878 patients were analyzed. Novel agents included seladelpar, fenofibrate, saroglitazar, bezafibrate, elafibranor, and budesonide. The meta-analysis showed significant reductions in ALP levels with novel agents compared to the controls (SMD −2.80; 95% CI −3.56, −2.03; p < 0.00001), with high heterogeneity (I² = 93%). Saroglitazar achieved the largest effect size. There was no significant difference in serious adverse events between novel agents and controls (OR 1.21; 95% CI 0.81, 1.83; p = 0.35). Conclusions: Novel oral anti-cholestatic agents show promise in improving biochemical markers in PBC patients with suboptimal UDCA responses, with a safety profile comparable to controls. However, study heterogeneity and limited long-term data restrict direct comparisons. Larger standardized trials with extended follow-up are needed to confirm long-term efficacy and safety. Full article

Ursodeoxycholic acid (UDCA), a critical secondary bile acid in human physiology, demonstrates significant industrial potential through synthetic routes from bisnoralcohol (BA). Current synthetic routes rely on hydroxyl oxidation and Horner–Wadsworth–Emmons reactions as critical initial steps, facing unresolved challenges in reaction scale-up dynamics and impurity evolution. In this work, we systematically investigated the scale-up effects and innovatively addressed the impurity control problem. In the OH-C(22) selective oxidation of BA, the impurity C(22) carboxylic acid was synthesized, the emulsification was eliminated by process optimization, and the yield was increased from 89.0% to 95.2%. In the Horner–Wadsworth–Emmons reaction, the C(20)-methyl racemate and the C(22)-Z-ene isomer were synthesized, followed by the validation of the remaining byproducts. Based on impurity profile analysis, we innovatively modified the reaction feeding protocol, increased the yield from 79.1% to 90.8%, and significantly improved reaction selectivity. This optimized process demonstrates superior scalability and provides valuable insights for the industrial production of plant-derived UDCA. Full article

Background/Objectives: Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, exhibits anti-inflammatory effects and attenuates the process of colon carcinogenesis. Certain healthy diets increase colonic UDCA concentrations, but its anticancer mechanistic actions remain largely unknown. We hypothesize that UDCA preferentially inhibits cancerous colon cell proliferation with a minimal effect on noncancerous colon cells. Methods: With human noncancerous NCM460 colon cell and cancerous HCT116 colon cell culture models, we performed biochemical, western blotting, PCR array, cell cycle, apoptosis, and immunofluorescent assays to determine the effects of UDCA treatment on colon cell proliferation and the underlying molecular mechanisms. Results: The inhibitory potential of UDCA against cell proliferation (via cell cycle arrest and apoptosis) was 90% greater in cancerous HCT116 cells than noncancerous NCM460 cells when treated with UDCA (0 to 0.4 mM) for 48 h. In UDCA-treated HCT116 cells, we identified 18 genes with ≥80% change (compared to untreated cells) in mRNA levels out of 93 apoptotic genes which were involved in caspase, death receptor, and NFκB pathways. At the molecular level, 0.4 mM UDCA reduced the protein level of the proto-oncogenic c-Myc gene but increased the putative tumor suppressor p21 gene (≥100%) via the ERK1/2/c-Myc/p21 pathway, which regulates cell cycle and apoptosis. These data are consistent with lower c-Myc but higher p21 expression in normal colon tissues compared to cancerous colon tissues. Conclusions: Collectively, UDCA inhibits cancerous HCT116 colon cells to a higher degree than in noncancerous NCM460 colon cells through cell cycle and apoptosis involving ERK1/2/c-Myc/p21 signaling. Full article