Search Results (156)

Background/Objectives: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with limited epidemiological data from Central–Eastern Europe. This study characterized a Hungarian PSC cohort, comparing patients with and without inflammatory bowel disease (IBD), and longitudinally evaluated the predictive efficacy of established prognostic scores (Mayo Risk Score, Amsterdam-Oxford Model [AOM], UK-PSC short/long). Methods: Data from 135 PSC patients (median diagnosis age 31 years, 57.7% male) were collected yearly at two Hungarian centers, with a median follow-up of 8.8 years. Outcomes included liver transplantation (LT) and liver-related death. Prognostic value of baseline clinical scores was assessed for 2-, 5-, 8-, and 10-year composite outcome. Results: PSC-IBD patients (54.1%) were younger with higher baseline Mayo and AOM scores, and had increased rates of colorectal carcinoma (8.22% vs. 0.00%) and liver transplantation (26.03% vs. 9.68%) within 10 years than PSC-only patients. There were no differences in liver-related mortality or composite outcomes between the groups. All prognostic scores showed good short-term predictive ability for poor outcomes (AUROC at 2 years: 0.858–0.958), which diminished over time (AUROC at 10 years: 0.708–0.756). The AOM demonstrated the most consistent performance. Persistent alkaline phosphatase (ALP) elevation (≥2.2×ULN) 2 years post-diagnosis, despite ursodeoxycholic acid therapy, strongly predicted 10-year adverse outcomes (HR: 3.927, p < 0.001), outperforming formal scoring systems (HR: 2.688–1.522). Conclusions: While PSC-IBD patients had more CRC and liver transplantation, overall transplantation-free survival was similar to PSC-only patients. Prognostic utility of current scores declines with longer follow-up; AOM was most stable. Sustained ALP elevation is a robust long-term prognostic indicator. Full article

Background/Objectives: Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent hepatobiliary disorder unique to gestation, characterized by maternal pruritus and elevated serum bile acids. While maternal prognosis is favorable, mounting evidence links ICP to a range of neonatal complications. This narrative review aims to synthesize the current knowledge on the pathophysiological mechanisms, clinical impact and management strategies related to neonatal outcomes in ICP. Methods: A narrative review approach was employed, drawing on recent clinical guidelines, observational studies, mechanistic investigations and meta-analyses. Emphasis was placed on evidence exploring the relationship between maternal bile acid concentrations and neonatal morbidity, as well as on established and emerging therapeutic interventions. No systematic search strategy or formal quality appraisal was undertaken. Results: ICP is associated with an increased risk of adverse neonatal outcomes, including spontaneous and iatrogenic preterm birth, meconium-stained amniotic fluid, respiratory distress syndrome and stillbirth, particularly when bile acid concentrations exceed 100 μmol/L. Proposed mechanisms include placental vasoconstriction, arrhythmogenic effects and surfactant inhibition. Ursodeoxycholic acid remains the most widely used pharmacologic agent for maternal symptom relief, although evidence supporting neonatal benefit is inconclusive. Delivery by 36–37 weeks is generally recommended in cases of severe cholestasis to mitigate fetal risk. Conclusions: Severe ICP confers substantial neonatal risk, requiring individualized, bile-acid-guided management. While current therapies offer symptomatic maternal benefit, optimization of fetal outcomes requires timely diagnosis, vigilant surveillance and evidence-based delivery planning. Further research is warranted to refine therapeutic targets and standardize clinical practice. Full article

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with male predominance. This study investigated the role of microRNA-125b in PSC-related liver fibrosis, focusing on its interaction with transforming growth factor beta (TGF-β), androgen receptors (ARs), and apelin. Elevated serum and hepatic levels of miR-125b were observed in PSC patients, particularly in males and those with advanced fibrosis, and correlated with increased liver injury markers and FibroScan stiffness. miR-125b expression negatively correlated with apelin and TGF-β levels, while it positively correlated with AR expression. In vitro, miR-125b overexpression induced ARs and suppressed p53 and apelin, whereas lipopolysaccharide stimulation reduced miR-125b and enhanced pro-inflammatory genes, including TNF-α and TGF-β. Notably, ursodeoxycholic acid therapy significantly decreased serum miR-125b levels. These findings suggest that miR-125b contributes to inflammation and fibrogenesis in PSC, partly through the modulation of TGF-β, ARs, and apelin signalling. Moreover, the observed sex-based differences in miR-125b expression underscore the influence of androgens in PSC pathogenesis. 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

Objectives: Jasminoidin (JA) and ursodeoxycholic acid (UA) have been shown to exert synergistic effects on cerebral ischemia (CI) therapy, but the underlying mechanisms remain to be elucidated. Objective: To elucidate the synergistic mechanisms involved in the combined use of JA and UA (JU) for CI therapy using a driver-induced modular screening (DiMS) strategy. Methods: Network proximity and topology-based approaches were used to identify synergistic modules and driver genes from an anti-ischemic microarray dataset (ArrayExpress, E-TABM-662). A middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in 30 Sprague Dawley rats, divided into sham, vehicle, JA (25 mg/mL), UA (7 mg/mL), and JU (JA:UA = 1:1) groups. After 90 minutes of ischemia, infarct volume and neurological deficit scores were evaluated. Western blotting was performed 24 h after administration to validate key protein changes. Results: Six, eleven, and four drug-responsive On_modules were identified for JA, UA, and JU, respectively. Three synergistic modules (Sy-modules, JU-Mod-7, 8, and 10) and 12 driver genes (e.g., NRF1, FN1, CUL3) were identified, mainly involving the PI3K-Akt and MAPK pathways and regulation of the actin cytoskeleton. JA and UA synergistically reduced infarct volume and neurological deficit score (2.5, p < 0.05) in MCAO/R rats. In vivo studies demonstrated that JU suppressed the expression of CUL3, FN1, and ITGA4, while it increased that of NRF1. Conclusions: JU acts synergistically on CI–reperfusion injury by regulating FN1, CUL3, ITGA4, and NRF1 and inducing the PI3K-Akt, MAPK, and actin cytoskeleton pathways. DiMS provides a new approach to uncover mechanisms of combination therapies. Full article

Background: Fatty liver disease and obesity are among the most prevalent health conditions in modern society and have recently garnered significant attention. Semaglutide, a well-known anti-obesity drug, has been widely used for diabetes and obesity treatment; however, nanotherapeutics utilizing semaglutide have not yet been developed. Methods: A novel statin–lipid conjugate was synthesized using rosuvastatin and ursodeoxycholic acid, a liver-protective agent. This conjugate was then formulated with semaglutide through hydrophobic interactions to create a new nanoparticle system. The physicochemical properties of the nanoparticles were analyzed, and their therapeutic efficacy was evaluated in a high-fat diet (HFD)-induced animal model. Results: The statin–lipid conjugate was successfully synthesized, forming novel nanoparticles with semaglutide in an aqueous solution. These nanoparticles exhibited distinct properties compared to conventional semaglutide formulations. In animal experiments, the treatment group demonstrated a 30.24% reduction in body weight and a 46.80% improvement in liver function markers compared to the control group. Conclusions: This study introduces a novel semaglutide-based nanoparticle (SRLC NP) system that overcomes key limitations of conventional semaglutide therapy by providing enhanced bioavailability, extended circulation time, and improved cellular uptake. These findings highlight the potential of SRLC NPs as a clinically translatable nanotherapeutic approach for more effective, sustained, and patient-friendly obesity and fatty liver disease treatment. 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: Pregnancy induces hormonal, immunologic, and vascular changes that profoundly affect dermatologic health. This systematic review aimed to assess the impact of pregnancy on dermatological disorders in terms of disease incidence, severity, maternal-fetal outcomes, and optimal management strategies. Methods: A systematic search was performed in PubMed, MEDLINE, and Web of Science databases, following PRISMA guidelines. Studies evaluating pregnant women with dermatological disorders, pregnancy-related dermatoses, and pre-existing morbidities, were included. The collaboratively extracted data included patient demographics, disease severity, treatment approaches, and pregnancy outcomes. Results: A total of 8490 pregnant cases with dermatologic changes and conditions caused by pregnancy were studied. The dermatological conditions were divided into physiological changes, pregnancy-related exacerbation of pre-existing skin conditions, and pregnancy-specific dermatoses. Intrahepatic cholestasis of pregnancy and pemphigoid gestationis were associated with increased rates of adverse fetal outcomes in patients with specific dermatoses, including increased preterm birth and fetal distress rates. The atopic eruption of pregnancy and polymorphic eruption of pregnancy were highly relevant, but their effect on fetal health was minimal. The efficacy and safety of treatment modalities, including corticosteroids, antihistamines, and ursodeoxycholic acid, were variable. Conclusions: Pregnancy drastically affects dermatological health, but the nature of the impact depends on the condition. Optimal maternal and fetal outcomes rely on early diagnosis and individualized management strategies. More randomized controlled trials are required to develop standardized diagnostic and treatment guidelines to enhance the quality of dermatologic care during pregnancy. 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

Background/Objectives: This article presents the case of a 31-year-old primigravida who experienced acute liver failure in the 23rd week of pregnancy, along with a review of the literature on this rare condition during pregnancy. The purpose of this publication is to highlight the diagnostic and therapeutic challenges associated with acute liver failure in pregnant women. Methods: The patient presented with jaundice, pruritus, and dark-colored urine. Laboratory tests revealed a significant increase in aminotransferase, bilirubin, and bile acid levels, suggesting liver problems; however, due to the patient’s rapidly deteriorating condition and test results, autoimmune hepatitis was considered. Viral infections and other causes of liver damage were excluded. No clear diagnosis was established. The patient was administered ursodeoxycholic acid and due to her worsening condition, a cesarean section was performed at 23 weeks of gestation. After delivery, the patient’s condition improved, although she did experience cardiac arrest during hospitalization. The patient was discharged with a diagnosis of acute liver failure in the course of an overlap syndrome of autoimmune hepatitis and primary cholangitis or intrahepatic cholestasis of pregnancy. No abnormalities were noted during a follow-up visit 6 weeks after delivery. Despite a detailed case analysis, a final diagnosis was not established, which complicates planning for future pregnancies. Discussion: Several liver conditions can occur during pregnancy, including intrahepatic cholestasis of pregnancy, primary biliary cholangitis, and autoimmune hepatitis. Diagnosing these conditions can be challenging due to overlapping symptoms and metabolic and immunological adaptations during pregnancy that can affect the course of liver diseases. Rapid intervention is crucial to protect the health of both the mother and the fetus. Conclusions: In summary, this article aims to increase awareness of the complexities surrounding acute liver failure during pregnancy, highlighting the diagnostic challenges and importance of prompt medical intervention for the well-being of both the mother and the child. This paper aims to provide a comprehensive overview of the complexities surrounding acute liver failure during pregnancy, aiming to improve the understanding, diagnosis, and management of this condition. Full article

Objective: Intrahepatic cholestasis of pregnancy (ICP) is associated with an elevated risk of adverse perinatal outcomes, including perinatal morbidity and mortality. The objectives of this study were to evaluate the bile acid (BA) metabolism profiles in the urine of patients with ICP and to investigate the association between specific BAs and maternal and neonatal outcomes in patients with ICP. Methods: A total of 127 Chinese women with ICP and 55 healthy pregnant women were enrolled in our retrospective study. Spot urine samples and clinical data were collected from pregnant women from January 2019 to December 2022 at the First Affiliated Hospital of Chongqing Medical University, Chongqing. Based on total bile acid (TBA) levels, the ICP group was subdivided into mild (10–40 μmol/L) and severe (≥40 μmol/L) ICP groups. Patients in the ICP group were further divided into two categories according to neonatal outcomes: an ICP with adverse pregnancy outcomes group and an ICP with non-adverse pregnancy outcomes group. Metabolites from maternal urine were collected and analyzed using ultra-high-performance liquid chromatography–triple quadrupole time-of-flight mass spectroscopy (UPLC-triple TOF-MS). Results: Significant differences were observed between the mild and severe ICP groups in the onset time of symptoms, gestational weeks at time of ICP diagnosis, the duration of using ursodeoxycholic acid (UDCA) drugs during pregnancy, gestational age at delivery, premature delivery, and cesarean delivery. The expression levels of the composition of different urinary bile acids including THCA, TCA, T-ω-MCA, TCA-3-S, TCDCA-3-S, TDCA-3-S, GCDCA-3-S, DCA-3-G and GDCA-3-G were remarkably higher in the ICP with adverse pregnancy outcomes group than those in the ICP with non-adverse pregnancy outcomes group and the control group. The single-parameter model used to predict adverse pregnancy outcomes in ICP had similar areas under the curve (AUCs) of the receiver operating characteristic (ROC), ranging from 0.755 to 0.869. However, an AUC of 0.886 and 95% CI were obtained by the index of combined urinary bile acids in multiple prediction models (95% CI 0.790 to 0.983, p < 0.05). TCA-3-S in the urinary bile acids had a strong positive correlation with the aspartate aminotransferase (AST) level (r = 0.617, p < 0.05). Furthermore, TCDCA-3-S and GCDCA-3-S in the urinary bile acids had a strong positive correlation with the alanine aminotransferase (ALT) level (r = 0.607, p < 0.05; r = 0.611, p < 0.05) and AST level (r = 0.629, p < 0.05; r = 0.619, p < 0.05). Conclusions: Maternal urinary bile acid profiles were prominent for the prognosis of maternal and neonatal outcomes of ICP. Elevated levels of TCA-3-S, TCDCA-3-S, and GCDCA-3-S in urine might be important predictors for indicating adverse pregnancy outcomes in ICP. Full article