Gefitinib, a first-line tyrosine kinase inhibitor (TKI) target to non-small cell lung cancer (NSCLC) treatment, is known to cause hepatotoxicity, which seriously limiting its therapeutic application. This study investigated the underlying mechanisms of gefitinib-induced liver injury and the protective effects of glycyrrhizic acid (GL) in mice and AML12 cells. Sixty mice were randomly divided into six groups: control, gefitinib, glutathione (200 mg/kg), and three doses of GL (50, 100, and 200 mg/kg). Liver injury was induced in mice through daily oral administration of gefitinib (400 mg/kg) for 16 days, with hepatotoxicity was assessed through serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, and hepatic histopathology. Hepatic mRNA profiles were analyzed using RNA sequencing, with differentially expressed genes (DEGs) confirmed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot. Finally, the effect of GL on the anticancer efficacy of gefitinib was assessed in A549 and Lewis lung carcinoma (LLC) lung cancer cells, as well as in a urethane-induced lung cancer mouse model. GL treatment significantly reduced liver index and serum ALT and AST levels, while also improving hepatic histopathology. Transcriptomic analysis identified 114 DEGs linked to the p53 pathway and cell cycle regulation. Further study indicated that GL inhibited the expression of p53 and p21, thereby upregulated Cyclin D1 expression, thereby alleviating gefitinib-induced cell cycle arrest without impairing its anticancer activity in vivo and in vitro. These findings highlight the potential of GL as a safe adjunct therapy, effectively mitigating gefitinib-induced hepatotoxicity while preserving its anticancer efficacy.

Bile acids in the ileum act as a feedback regulator of their own synthesis by inducing the release of ileal fibroblast growth factor 19 (FGF19), which inhibits the cholesterol-7-alpha hydroxylase enzyme. In cholestasis, this feedback mechanism is dysregulated. FGF19 is not expressed in the healthy liver. We aimed to assess the hepatic expression of FGF19 in neonatal cholestasis (NC) and its relation to serum bile acids.

The study included 41 patients with NC. FGF19 immunohistochemical staining in liver tissue (hepatocytes, endothelial cells, bile ducts, and bile canaliculi) was evaluated as negative, weak, moderate, and strong staining. FGF19 staining in 6 liver samples from explants of children with Crigler-Najjar syndrome type-1 served as controls.

Hepatocyte, endothelial, and canalicular FGF19 expression was significantly higher in cholestasis group compared to controls (P = .039, .006, and .028 respectively). Serum bile acids had significant correlation with hepatocyte FGF19, endothelial, and bile duct FGF19 expressions (P = .002, .003, and .01, respectively) but not with canalicular FGF19 expression. Hepatocyte FGF19 expression significantly associated with cholestasis severity in terms of serum total bilirubin, direct bilirubin, and aspartate transaminase levels (P = .01, .02, and .02, respectively).

Hepatic FGF19 expression significantly upregulated in NC and correlated with cholestasis severity.

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.

To compare the predictive value of serum bile acids on native liver survival (NLS) and portal hypertension (PH) at various time points early after portoenterostomy (PE) in biliary atresia (BA).

This was a retrospective observational study. Serum bilirubin and bile acid concentrations were defined by enzymatic spectrophotometry 1, 3, and 6 months after PE. After defining optimal bilirubin and bile acids cutoffs by area under the receiver operating characteristic (AUROC) curves, cutoffs were compared with other predictors of NLS and PH in Cox regression.

Out of 56 patients, 42 (75%) achieved clearance of jaundice (COJ, bilirubin <20 µmol/L at 6 months). Both bilirubin and bile acids at 3 and 6 months were accurate predictors of NLS among all patients (AUROC 0.82-0.91, p < 0.001). In COJ patients, bile acids (AUROC 0.82, p = 0.003), but not bilirubin, at 1 month also predicted NLS. Among all patients, the strongest predictors of NLS were bilirubin >18.5 µmol/L and bile acids >150 µmol/L at 3 months, increasing the risk of transplantation/death seven- and eightfold, respectively (p < 0.001 for both). In COJ patients, the strongest predictor of NLS was bile acids >119 µmol/L at 3 months, increasing the risk of transplantation/death 12-fold (p = 0.014). Bile acids and bilirubin at 3 and 6 months predicted PH development in COJ patients with moderate accuracy (AUROC 0.72-0.78, p = 0.004-0.019). Bilirubin >8.5 µmol/L and bile acids >78 µmol/L at 6 months increased PH risk 13-fold (p < 0.001) and 4-fold (p = 0.006).

Serum bile acids offer a simple and useful additional tool to predict PE outcomes in BA, particularly after COJ.

We reported a case of recurrent liver dysfunction in an adult patient with a history of abnormal liver enzymes persisting for over ten years. The primary abnormalities included elevated levels of gamma-glutamyl transferase and alkaline phosphatase. Despite conducting a series of extensive etiological tests to identify common causes of liver disease, the diagnosis remained unclear. However, whole-exome next-generation sequencing revealed a homozygous intronic mutation in the ferrochelatase gene (c.315-48T>C), which may be associated with the patient's cholestasis.

Chronic diseases such as obesity, hypertension, and metabolic syndrome are major health concerns worldwide. Ursodeoxycholic acid (UDCA) is a bile acid that is naturally produced in the liver and has been used for the treatment of various liver disorders. In this systematic review and meta-analysis, we investigated how UDCA might affect inflammation, blood pressure, and obesity.

Five major databases were searched from inception to August 2024. The investigated outcomes included body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). A random effect was carried out to estimate pooled weighted mean difference (WMD) with 95% confidence intervals (CI). The registration code is CRD42023428064.

Of the 7912 articles in the initial search, 12 were included in the systematic review and meta-analysis. UDCA consumption significantly decreased BMI (WMD: -0.29 kg/m2, 95% CI: -0.58, -0.01, P = 0.044), and DBP (WMD: -2.16 mmHg, 95% CI: -3.66, -0.66, P = 0.005). It also increased SBP (WMD: 5.50 mmHg, 95% CI: 3.65, 7.35, P < 0.001); however, it was not associated with weight loss (WMD: -0.3 kg, 95% CI: -1.3, 0.71, P = 0.561). Our systematic review showed that UDCA consumption has no effect on IL-6 and TNF-α.

This systematic review and meta-analysis suggest that UDCA supplementation may improve BMI and DBP, whereas it may increase SBP and have no effect on weight or inflammation. Further long-term and well-designed RCTs are needed to further assess and confirm these results.

As the elderly population expands, the pursuit of therapeutics to reduce morbidity and extend lifespan has become increasingly crucial. As an FDA-approved drug for chronic cholestatic liver diseases, tauroursodeoxycholic acid (TUDCA), a natural bile acid, offers additional health benefits beyond liver protection. Here, we show that TUDCA extends the lifespan and healthspan of C. elegans. Importantly, oral supplementation of TUDCA improves fitness in old mice, including clinically relevant phenotypes, exercise capacity and cognitive function. Consistently, TUDCA treatment drives broad transcriptional changes correlated with anti-aging characteristics. Mechanistically, we discover that TUDCA targets the chaperone HSP90 to promote its protein refolding activity. This collaboration further alleviates aging-induced endoplasmic reticulum (ER) stress and facilitates protein homeostasis, thus offering resistance to aging. In summary, our findings uncover new molecular links between an endogenous metabolite and protein homeostasis, and propose a novel anti-aging strategy that could improve both lifespan and healthspan.

Little is known on the mechanism of liver injury mediated by bile acids following Kasai portoenterostomy (KPE) in biliary atresia (BA). We sought to quantify individual serum bile acids, 7-alpha-hydroxy-4-cholesten-3-one (C4), and fibroblast growth factor 19 (FGF19) after KPE and to evaluate their prognostic utility and transcriptomic regulation.

Serum (n=244) and liver specimens (n=105) prospectively obtained from BA patients (n=54) after KPE were included. Bile acids were analyzed using mass spectrometry, gene expression with quantitative PCR, and histopathology using a neural network model.

Following KPE, serum bile acids correlated positively with biochemical liver injury, pediatric end-stage liver disease score, liver stiffness, histological ductular reaction, and liver fibrosis. Bile acids were higher among patients who developed portal hypertension (79.6 vs. 11.9 μmol/l, p<0.0001), esophageal varices (91.6 vs. 16.2 μmol/l, p<0.0001), or required liver transplantation (LT, 115.3 vs. 22.0 μmol/l, p<0.0001) during follow up; bile acids predicted these outcomes in time-dependent regression models. Accumulation of conjugated bile acids, cholic acid, and taurine conjugates predicted LT risk while associating with histological liver injury. Serum C4 (0.04 vs. 0.00 μmol/l, p=0.04) and liver CYP7A1 were higher in native liver survivors than in LT patients (fold-change 16.9 vs. 7.0, p=0.02). Primary bile acids correlated negatively with C4 (R=-0.38, p<0.001) and CYP7A1 (R=-0.49, p=0.01). Unlike in native liver survivors (R=-0.19, p=0.66), serum FGF19 correlated with liver FGF19 (R=0.59, p=0.04) without an inverse association with serum primary bile acids in LT patients (R=0.26, p=0.08).

Accumulation and altered composition of serum bile acids predicted progressive liver disease and poorer transplant-free survival following KPE. Poor prognosis was associated with low bile acid synthesis and aberrantly increased liver FGF19.

Biliary atresia (BA), a fibro-obliterating biliary disease of infants, remains the most common indication for pediatric liver transplantation caused by rapid progression of liver injury. To identify predictive biomarkers of disease progression and to elucidate the pathophysiology of BA liver injury, we profiled serum bile acids and studied their liver metabolism after Kasai portoenterostomy. Accumulation and altered composition of circulating bile acids predicted progression of liver disease and need for liver transplantation. Patients with poor prognosis showed low bile acid synthesis and abnormal liver expression of fibroblast growth factor 19.

Liver fibrosis is a progressive scarring process primarily caused by chronic inflammation and injury, often closely associated with viral hepatitis, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), drug-induced liver injury, and autoimmune liver disease (AILD). Currently, there are very few clinical antifibrotic drugs available, and effective targeted therapy is lacking. Recently, emerging antifibrotic drugs and immunomodulators have shown promising results in animal studies, and some have entered clinical research phases. This review aims to systematically review the molecular mechanisms underlying liver fibrosis, focusing on advancements in drug treatments for hepatic fibrosis. Furthermore, since liver fibrosis is a progression or endpoint of many diseases, it is crucial to address the etiological treatment and secondary prevention for liver fibrosis. We will also review the pharmacological treatments available for common hepatitis leading to liver fibrosis.

Cholestatic liver injury (CLI), which occurs if bile acids are imbalanced and the liver becomes inflamed, is difficult to treat effectively OBJECTIVE: We investigated how the Chinese patent medicine Chidan Tuihuang granule (CDTH) ameliorates cholestatic liver injury with a focus on its effects on the NOD1/RIPK2 pathway and intestinal flora METHODS: We used an ANIT-induced SD rat model of CLI to evaluate the therapeutic effects of CDTH. The experimental design included control, model, UDCA (ursodeoxycholic acid) and CDTH treatment groups. UHPLC-Q-Orbitrap-HRMS was used to analyse the blood components of CDTH. The efficacy of CDTH was assessed by liver function tests, histopathological examination (HE and TUNEL staining), transmission electron microscopy, and ELISA to measure apoptosis and inflammatory markers. Mechanistic insights were obtained using transcriptomics and RT-qPCR, while alterations in the expression of key proteins were studied using western blotting, immunohistochemistry, and immunofluorescence. Furthermore, the impact of CDTH on the gut microbiota and its associated metabolite, meso-2,6-diaminopimelic acid (DAP), which is linked to NOD1 activation, was examined and confirmed through in vitro RESULTS: The experimental results demonstrated a notable elevation in serum levels of AST, ALT, ALP, TBA, TBIL, and DBIL in the rats belonging to the model group, accompanied by the infiltration of inflammatory cells, hepatocyte degeneration, and necrosis in the liver tissue. CDTH administration significantly improved liver function and cholestasis indicators. Transmission electron microscopy and TUNEL staining revealed a marked reduction in liver cell apoptosis with CDTH treatment. ELISA results showed that CDTH effectively reduced inflammatory markers. Transcriptomic analysis showed that CDTH inhibited the NOD1/RIPK2 pathway, resulting in a significant decrease in the expression of NOD1, RIPK2 and associated genes in liver tissue. Gut microbiota analysis demonstrated that CDTH regulated intestinal flora structure, reducing the abundance of DAP-producing Gram-negative bacteria such as lactobacilli. In vitro experiments confirmed that CDTH enhanced cell viability by downregulating the DAP-mediated NOD1/RIPK2 signaling pathway secreted by intestinal bacteria CONCLUSION: CDTH ameliorated liver damage in cholestatic rats by inhibiting the NOD1/RIPK2 signaling pathway through regulation of gut flora and downregulation of DAP metabolites.

The study aimed to investigate the alterations in gut microbiota among nonobese individuals with nonalcoholic fatty liver disease (NAFLD) and their response to treatment with ursodeoxycholic acid (UDCA). A total of 90 patients diagnosed with NAFLD and 36 healthy subjects were recruited to participate in this study. Among them, a subgroup of 14 nonobese nonalcoholic steatohepatitis (NASH) were treated with UDCA. Demographic and serologic data were collected for all participants, while stool samples were obtained for fecal microbiome analysis using 16S sequencing. In nonobese NAFLD patients, the alpha diversity of intestinal flora decreased (Shannon index, p < 0.05), and the composition of intestinal flora changed (beta diversity, p < 0.05). The abundance of 20 genera, including Fusobacterium, Lachnoclostridium, Klebsiella, etc., exhibited significant changes (p < 0.05). Among them, nine species including Fusobacterium, Lachnoclostridium, Klebsiella, etc. were found to be associated with abnormal liver enzymes and glucolipid metabolic disorders. Among the 14 NASH patients treated with UDCA, improvements were observed in terms of liver enzymes, CAP values, and E values (p < 0.05), however, no improve the glucolipid metabolism. While the alpha diversity of intestinal flora did not show significant changes after UDCA treatment, there was a notable alteration in the composition of intestinal flora (beta diversity, p < 0.05). Furthermore, UCDA treatment led to an improvement in the relative abundance of Alistipes, Holdemanella, Gilisia, etc. among nonobese NASH patients (p < 0.05). Nonobese NAFLD patients exhibit dysbiosis of the intestinal microbiota. UDCA can ameliorate hepatic enzyme abnormalities and reduce liver fat content in nonobese NASH patients, potentially through its ability to restore intestinal microbiota balance.

In patients with high-level radiation exposure, gastrointestinal injury is the main cause of death. Despite the severity of damage to the gastrointestinal tract, no specific therapeutic option is available. Tauroursodeoxycholic acid (TUDCA) is a conjugated form of ursodeoxycholic acid that suppresses endoplasmic reticulum (ER) stress and regulates various cell-signaling pathways. We investigated the effect of TUDCA premedication in alleviating intestinal damage and enhancing the survival of C57BL/6 mice administered a lethal dose (15Gy) of focal abdominal irradiation. TUDCA was administered to mice 1 h before radiation exposure, and reduced apoptosis of the jejunal crypts 12 h after irradiation. At later timepoint (3.5 days), irradiated mice manifested intestinal morphological changes that were detected via histological examination. TUDCA decreased the inflammatory cytokine levels and attenuated the decrease in serum citrulline levels after radiation exposure. Although radiation induced ER stress, TUDCA pretreatment decreased ER stress in the irradiated intestinal cells. The effect of TUDCA indicates the possibility of radiation therapy for cancer in tumor cells. TUDCA did not affect cell proliferation and apoptosis in the intestinal epithelium. TUDCA decreased the invasive ability of the CT26 metastatic colon cancer cell line. Reduced invasion after TUDCA treatment was associated with decreased matrix metalloproteinase (MMP)-7 and MMP-13 expression, which play important roles in invasion and metastasis. This study shows a potential role of TUDCA in protecting against radiation-induced intestinal damage and inhibiting tumor cell migration without any radiation and radiation therapy effect.

Gestational cholestasis, also known as intrahepatic cholestasis of pregnancy (ICP) or obstetric cholestasis, is a liver disease that can manifest in late pregnancy. Trophoblast cell surface antigen (TROP2) is a type I transmembrane glycoprotein identified in placental trophoblast cells that plays a critical role in trophoblast invasion of the decidua upon implantation into the placenta. Our study aims to investigate the role of TROP2 in pregnancy cholestasis.

Study groups: Group 1 (control group) (n = 10): consists of healthy normal pregnant women without any disease, Group 2 (cholestasis group) (n = 10): consists of pregnant women diagnosed with cholestasis. After routine histological follow-up, hematoxylin and eosin staining and TROP2 immunostaining were performed and scored.

In the cholestasis group, in contrast to the control group, thrombus structures were observed in the intervillous space. In the cholestasis group compared to the control group, villus mesenchymal connective tissue cells, capillary endothelium and trophoblasts around the villus showed significantly stronger anti-TROP2 staining (p < 0.05).

Cholestasis, a condition that may manifest during pregnancy, may be associated not only with observable pathological changes in placental tissues at the light microscopic level, but also with an increase in TROP2 expression. Given the critical role of TROP2 in trophoblast invasion during placental implantation, we hypothesize that TROP2 may serve as a key marker of the cholestatic processes occurring during pregnancy.

Statins are widely used to treat hyperlipidemia; however, their mechanism-inhibiting cholesterol production without promoting its utilization-causes problems, such as inducing diabetes. In our research, we develop, for the first time, a chemically engineered statin conjugate that not only inhibits cholesterol production but also enhances its consumption through its multifunctional properties. The novel rosuvastatin (RO) and ursodeoxycholic acid (UDCA) conjugate (ROUA) is designed to bind to and inhibit the core of the apical sodium-dependent bile acid transporter (ASBT), effectively blocking ASBT's function in the small intestine, maintaining the effect of rosuvastatin. Consequently, ROUA not only preserves the cholesterol-lowering function of statins but also prevents the reabsorption of bile acids, thereby increasing cholesterol consumption. Additionally, ROUA's ability to self-assemble into nanoparticles in saline-attributable to its multiple hydroxyl groups and hydrophobic nature-suggests its potential for a prolonged presence in the body. The oral administration of ROUA nanoparticles in animal models using a high-fat or high-fat/high-fructose diet shows remarkable therapeutic efficacy in fatty liver, with low systemic toxicity. This innovative self-assembling multifunctional molecule design approach, which boosts a variety of therapeutic effects while minimizing toxicity, offers a significant contribution to the advancement of drug development.

Research on intrahepatic cholestasis of pregnancy (ICP) has recently gained attention. However, no bibliometric analysis was performed in the ICP research field. Therefore, the present study aimed to use bibliometric analysis to analyze the current research hotspots and identify global research status in ICP to reference for future research directions.

We comprehensively searched the Web of Science Core Collection (WoSCC) database from its inception to December 31, 2023. Articles and reviews related to ICP were downloaded as plain text file records. We used the VOSviewer and Citespace to perform the bibliometric analysis and visualization. The main bibliometric features were tabulated and calculated.

A total of 1092 documents, including 921 original articles and 171 reviews, were identified in WoSCC. These publications were published in 395 journals by 4751 authors from 1250 institutions and 61 countries/regions. The global publication numbers exhibited a gradual upward trend. China, the United States, and the United Kingdom were top contributors to scientific research on ICP. King's College London, London Imperial Coll Sci Technol & Med, and Sichuan University were the most productive institutions. Catherine Williamson had published the most papers and received the most total citations. The most productive journal was Journal of Maternal-Fetal & Neonatal Medicine. The most cited paper was Beuers et al. in the Journal of Hepatology (2009). Citation burst terms showed that "risk factors" and "perinatal outcomes" were hotspots. "Inflammation", "risk factors", "perinatal outcomes", and "bile acid" have gained attention in more recent research.

The present study comprehensively summarizes the global research status and research trends in ICP. Our study identifies hotspots, collaborative networks, and trends that will provide new insights and guidance for further research in the field.

Sickle cell disease (SCD) is one of the most common genetic disorders in the world predominantly affecting economically disadvantaged populations. There is a notable discrepancy between the growing adult SCD population and available diagnostic and therapeutic interventions for SCD. Sickle cell hepatopathy (SCH) is an all-inclusive term to describe the acute and chronic liver manifestations of SCD. The pathophysiology of SCH follows no defined pattern or sequence that poses challenges to clinicians and researchers alike. Evidence is lacking for this underreported disease at various levels from diagnostic to therapeutic options. This paper reviews the basic pathophysiology, clinical features, biochemical and radiological findings of various SCH manifestations and outlines the management of each condition. Old and new therapy options in SCD including hydroxyurea, red blood cell exchange transfusion, ursodeoxycholic acid, voxelotor, l-glutamine and crizanlizumab have been reviewed to investigate the role of these options in treating SCH. The role of liver transplant, haematopoietic stem cell transplant and gene therapy in SCH patients have been reviewed.

Catechol-based biomaterials demonstrate biocompatibility, making them suitable for a wide range of therapeutic applications when integrated into various molecular frameworks. However, the development of orally available catechol-based biomaterials has been hindered by significant pH variations and complex interactions in the gastrointestinal (GI) tract. In this study, we introduce a novel catechol-modified bile acid (CMBA), which is synthesized by anchoring the FDA-approved drug, ursodeoxycholic acid to the neurotransmitter dopamine. This modification could form a new apical sodium-dependent bile acid transporter (ASBT) inhibitor (ASBTi) due to the bile acid moiety. The computational analysis using the TRAnsient Pockets in Proteins (TRAPP) module, coupled with MD simulations, revealed that CMBA exhibits a strong binding affinity at residues 51-55 of ASBT with a low inhibitory constant (Ki) value. Notably, in slightly alkaline biological conditions, CMBA molecules self-assemble into carrier-free nanoparticles with an average size of 240.2 ± 44.2 nm, while maintaining their ability to bind with ASBT. When administered orally, CMBA accumulates in the ileum and liver over 24 h, exhibiting significant therapeutic effects on bile acid (BA) metabolism in a high-fat diet (HFD)-fed mouse model. This study underscores the therapeutic potential of the newly developed catechol-based, pH-responsive ASBT-inhibiting nanoparticles presenting a promising avenue for advancing therapy.

Erythropoietic protoporphyria (EPP) is a rare genetic disorder stemming from ferrochelatase gene mutations, which leads to abnormal accumulation of protoporphyrin IX primarily in erythrocytes, skin, bone marrow and liver. Although porphyria-related severe liver damage is rare, its consequences can be severe with limited treatment options.

This case study highlights a successful intervention for a 35-year-old male with EPP-related liver impairment, employing a combination of red blood cell (RBC) exchange and therapeutic plasma exchange (TPE). The patient experienced significant symptom relief and a decrease in bilirubin levels following multiple PE sessions and an RBC exchange.

The findings suggest that this combined approach holds promise for managing severe hepatic impairment in EPP.

Immunosuppressed recipients of liver transplantation (LT) are more likely to develop coronavirus disease 2019 (COVID-19) and may have an increased risk of developing worse outcomes.

To assess the effect of ursodeoxycholic acid (UDCA) on preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in LT recipients.

Adult patients (aged ≥ 18 years) who underwent LT between 1 January 2015 and 31 December 2022 were included and categorized into two groups according to their use of UDCA.

The prevalence and severity of COVID-19 among transplantation patients between the UDCA and non-UDCA groups were estimated and compared.

Among the 897 LT patients who met the inclusion criteria, infection rate of SARS-CoV-2 was 78.4%, and the rate of severe illness was 5.1% from January 2022 to January 2023 in China. In the multivariate analysis, only UDCA treatment (P = 0.006) was found to be a protective factor against SARS-CoV-2 infection. After propensity score matching, the SARS-CoV-2 infection rate in the UDCA group was lower than that in the non-UDCA group (74.1% vs. 84.6%, P = 0.002). This rate was further reduced to 62.1% (P = 0.002) when the oral administration dose was >15 mg/kg/day. There was no difference in the rates of severe COVID-19 illness, ICU admission, or ventilation rate or length of hospital stay with or without UDCA treatment (all P > 0.05).

The use of UDCA in LT patients significantly reduced the SARS-CoV-2 infection rate and showed a dose-dependent protective effect.

(1) Background: This study investigates the effects of Ursodeoxycholic acid (UDCA) on NF-κB signaling, farnesoid X receptor (FXR) singling, and microRNA-21 in HepG2 cells. (2) Methods: HepG2 cells were treated with lipopolysaccharide (LPS) to simulate hepatic inflammation. The investigation focused on the expression of NF-κB activation, which was analyzed using Western blot, confocal microscopy, and Electrophoretic Mobility-shift Assays (EMSA). Additionally, NF-κB and farnesoid X receptor (FXR) singling expressions of micro-RNA-21, COX-2, TNF-α, IL-6, cyp7A1, and shp were assessed by RT-PCR. (3) Results: UDCA effectively downregulated LPS-induced expressions of NF-κB/65, p65 phosphorylation, and also downregulated FXR activity by Western blot. Confocal microscopy and EMSA results confirmed UDCA's role in modulating NF-κB signaling. UDCA reduced the expressions of LPS-induced COX-2, TNF-α, and IL-6, which were related to NF-κB signaling. UDCA downregulated LPS-induced cyp7A1 gene expression and upregulated shp gene expression, demonstrating selective gene regulation via FXR. UDCA also significantly decreased micro-RNA 21 levels. (4) Conclusions: This study demonstrates UDCA's potent anti-inflammatory effects on NF-κB and FXR signaling pathways, and thus its potential to modulate hepatic inflammation and carcinogenesis through interactions with NF-κB and FXR. The decrease in micro-RNA 21 expression further underscores its therapeutic potential.

Vanishing bile duct syndrome (VBDS) is a rare, but potentially fatal adverse reaction triggered by certain medications. Few real-world studies have shown association between antibiotics and VBDS. We sought to quantify the risk and evaluate the clinical features of VBDS associated with antibiotics.

Data from 2004 to 2022 on VBDS events induced by antibiotics were retrieved from the FDA Adverse Event Reporting System (FAERS) database and disproportionality analyses were conducted. Furthermore, case reports from 2000 to 31 December 2022 on antibiotics-induced VBDS were retrieved for retrospective analysis.

We collected 132 VBDS reports from the FAERS database. Fluoroquinolones had the greatest proportion and highest positive signal values of VBDS. The RORs (95% CIs) for antibiotics were fluoroquinolones 23.68 (18.12-30.95), macrolides 19.37 (13.58-27.62), carbapenems 17.39 (7.77-38.96), beta-lactam 13.28 (9.69-18.20), trimethoprim/sulfamethoxazole 9.05 (5.57-14.7), and tetracycline 4.02 (1.50-10.77). Twenty-three cases from 22 studies showed evidence of VBDS, beta-lactam (52.2%) was the most frequently reported agent. The median age was 45 years, the typical initial symptoms included rash (30.4%), fatigue/asthenia (26.1%), dark urine (21.7%) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) (21.7%). The median time to onset of VBDS was 2 weeks. All cases had abnormal liver function test, and the median level of total bilirubin was 23.6 mg/dl (range 3.2-80 mg/dl). Cessation of culprit drugs and treatment with ursodeoxycholic acid (83.3%) were not associated with improved outcomes (57.1%).

This study identified thirteen antibacterial agents with significant reporting associations with VBDS. Fluoroquinolones may be a neglected agent of inducing VBDS.

Antibodies to gp210 and sp100 are specific and unique anti-nuclear autoantibodies (ANAs) associated with primary biliary cholangitis (PBC). Importantly the presence of anti-gp210 and anti-sp100 responses is indicative of poor clinical outcomes. However, the utility of measuring titers of these antibodies remains unclear.

Using the in-house purified gp210 (HSA108-C18) and sp100 (amino acid position 296-386), we quantitatively measured serum autoantibodies to gp210 and sp100 using chemiluminescence immunoassay (CLIA) in a very large cohort of 390 patients with PBC, including 259 cases with no prior ursodesoxycholic acid (UDCA) treatment and 131 cases with UDCA treatment. We also analyzed serial changes in anti-gp210 and anti-sp100 levels in 245 sequential samples from 88 patients.

In our cross-sectional analysis, we detected anti-gp210 immunoglobulin G (IgG) and anti-sp100 IgG autoantibodies in 129 out of 390 (33.1%) and 80 out of 390 (20.5%) PBC patients, respectively. Multivariate analysis revealed that serum IgG (st.β = 0.35, P = 0.003) and gamma-glutamyltransferase (GGT) (st.β = 0.23, P = 0.042) levels at baseline were independently associated with anti-gp210 concentrations. In serial testing, we observed significant fluctuations in anti-gp210 antibody levels. These fluctuations reflected responsiveness to UDCA therapy, particularly in anti-gp210-positive patients with initially lower concentrations in the stages of disease.

Our study reflects that quantitative changes of anti-gp210 antibody are indicative of UDCA responses. There is a great need for newer metrics in PBC and we suggest that a more detailed and longer study of these unique ANAs is warranted.

Infants and young animals often suffer from intestinal damage caused by oxidative stress, which may adversely affect their overall health. Hydroxytyrosol, a plant polyphenol, has shown potential in decreasing intestinal oxidative stress, but its application and mechanism of action in infants and young animals are still inadequately documented. This study selected piglets as a model to investigate the alleviating effects of hydroxytyrosol on intestinal oxidative stress induced by diquat and its potential mechanism. Hydroxytyrosol improved intestinal morphology, characterized by higher villus height and villus height/crypt depth. Meanwhile, hydroxytyrosol led to higher expression of Occludin, MUC2, Nrf2, and its downstream genes, and lower expression of cytokines IL-1β, IL-6, and TNF-α. Both oxidative stress and hydroxytyrosol resulted in a higher abundance of Clostridium_sensu_stricto_1, and a lower abundance of Lactobacillus and Streptococcus, without a significant effect on short-chain fatty acids levels. Oxidative stress also led to disorders in bile acid (BA) metabolism, such as the lower levels of primary BAs, hyocholic acid, hyodeoxycholic acid, and tauroursodeoxycholic acid, which were partially restored by hydroxytyrosol. Correlation analysis revealed a positive correlation between these BA levels and the expression of Nrf2 and its downstream genes. Collectively, hydroxytyrosol may reduce oxidative stress-induced intestinal damage by regulating BA metabolism.

Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) are distinct liver diseases. Cases combining PBC and PSC, are extremely rare. Here, we present a case of a 39-year-old woman with a history of colonic Crohn's disease treated with azathioprine. Discontinuation of the medication was prompted by abnormal liver function tests, but subsequent evaluations revealed persistent liver injury. Extensive diagnostic investigations, including imaging, serological tests, and liver biopsy, were conducted leading to a diagnosis of PBC-PSC overlap syndrome based on the presence of concentric lamellar fibrosis and chronic non-suppurative destructive cholangitis. The patient responded well to ursodeoxycholic acid treatment. This case emphasizes the importance of recognizing and diagnosing rare overlap syndromes, particularly those involving PBC and PSC, to ensure appropriate management and improve patient outcomes.

Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by immune-mediated injury to small bile ducts. Although PBC is an autoimmune disease, the effectiveness of conventional immunosuppressive therapy is disappointing. Nearly 40% of PBC patients do not respond to the first-line drug UDCA. Without appropriate intervention, PBC patients eventually progress to liver cirrhosis and even death. There is an urgent need to develop new therapies. The gut-liver axis emphasizes the interconnection between the gut and the liver, and evidence is increasing that gut microbiota and bile acids play an important role in the pathogenesis of cholestatic diseases. Dysbiosis of gut microbiota, imbalance of bile acids, and immune-mediated bile duct injury constitute the triad of pathophysiology in PBC. Autoimmune cholangitis has the potential to be improved through immune system modulation. Considering the failure of conventional immunotherapies and the involvement of gut microbiota and bile acids in the pathogenesis, targeting immune factors associated with them, such as bile acid receptors, microbial-derived molecules, and related specific immune cells, may offer breakthroughs. Understanding the gut microbiota-bile acid network and related immune dysfunctions in PBC provides a new perspective on therapeutic strategies. Therefore, we summarize the latest advances in research of gut microbiota and bile acids in PBC and, for the first time, explore the possibility of related immune factors as novel immunotherapy targets. This article discusses potential therapeutic approaches focusing on regulating gut microbiota, maintaining bile acid homeostasis, their interactions, and related immune factors.

Cystic fibrosis (CF) care in Denmark has been characterized by close monitoring and pre-emptive treatment of lung disease and other CF-related complications. Continuous evaluation through data collection and commitment to clinical research has incrementally improved outcomes. This approach has been in line with best practices set forth by European Standards of Care but has also gone beyond Society standards particularly pertaining to early treatment with high-dose combination antimicrobial therapy. Despite a high prevalence of severe CF variants, lung function has been among the best in Europe. In this review, the Danish approach to management of CF prior to the introduction of new CF modulator treatment is explained and benchmarked. Downsides to the Danish approach are discussed and include increased burden of treatment, risk of antimicrobial resistance, side-effects and costs.

Hepatocyte nuclear factor 1β (HNF1β) is essential for biliary development, while its genetic defect triggers the dysplasia of interlobular bile ducts, leading to life-threatening hepatitis and cholestasis. To date, this disorder has mainly been documented in neonates. Here, we report a case of cholestasis in an adult patient caused by a de novo HNF1β mutation. A liver biopsy revealed remarkable shrinkage of the portal area accompanied by a decrease or absence of interlobular bile ducts, veins, and arteries in the portal area. Our case showed that an HNF1β defect could induce late-onset cholestasis with paucity of the portal area in adulthood.

Furan is a naturally forming compound found in heat-processed foods such as coffee, canned meats, and jarred baby food. It is concurrently found with analogues including 2-methylfuran (2-MF) and 3-methylfuran (3-MF), and toxicity studies demonstrate all are potent liver toxins. Toxicity studies found 3-MF is more toxic than either furan, or 2-MF. The present analysis assesses the transcriptional response in liver samples taken from male Fischer (F344) rats exposed to furan or 3-MF from 0 to 2.0 and 0-1.0 mg/kg bw/day, respectively, for 90 days. Transcriptional analyses found decreased liver function and fatty acid metabolism are common responses to both furan and 3-MF exposure. Furan liver injury promotes a ductular reaction through Hippo and TGFB signalling, which combined with increased immune response results in ameliorating perturbed bile acid homeostasis in treated rats. Failure to activate these pathways in 3-MF exposed rats and decreased p53 activity leads to cholestasis, and increased toxicity. Finally, BMD analysis indicate many of the most sensitive pathways affected by furan and 3-MF exposure relate to metabolism - malate dehydrogenase and glucose metabolism with BMDLs of 0.03 and 0.01 mg/kg bw/day for furan and 3-MF exposure, respectively, which agrees with BMDLs previously reported for apical and microarray data.

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.

The progression of cholestasis is characterized by excessive accumulation of bile acids (BAs) in the liver, which leads to oxidative stress (OS), inflammation and liver injury. There are currently limited treatments for cholestasis. Therefore, appropriate drugs for cholestasis treatment need to be developed. Dimethyl fumarate (DMF) has been widely used in the treatment of various diseases and exerts antioxidant and anti-inflammatory effects, but its effect on cholestatic liver disease remains unclarified. We fed mice 3,5-diethoxycarbonyl-1,4-dihydrocollidine or cholic acid to induce cholestatic liver injury and treated these mice with DMF to evaluate its protective ability. Alanine aminotransferase, aspartate aminotransferase, and total liver BAs were assessed as indicators of liver function. The levels of OS, liver inflammation, transporters and metabolic enzymes were also measured. DMF markedly altered the relative ALT and AST levels and enhanced the liver antioxidant capacity. DMF regulated the MST/NRF2 signaling pathway to protect against OS and reduced liver inflammation through the NLRP3/GSDMD signaling pathway. DMF also regulated the levels of BA transporters by promoting FXR protein expression. These findings provide new strategies for the treatment of cholestatic liver disorders.

Endoplasmic reticulum (ER) is the site for synthesis and folding of secreted and transmembrane proteins. Disturbance in the functioning of ER leads to the accumulation of unfolded and misfolded proteins, which finally activate the unfolded protein response (UPR) signaling. The three branches of UPR-IRE1 (Inositol requiring enzyme 1), PERK (Protein kinase RNA-activated (PKR)-like ER kinase), and ATF6 (Activating transcription factor 6)-modulate the gene expression pattern through increased expression of chaperones and restore ER homeostasis by enhancing ER protein folding capacity. The liver is a central organ which performs a variety of functions which help in maintaining the overall well-being of our body. The liver plays many roles in cellular physiology, blood homeostasis, and detoxification, and is the main site at which protein synthesis occurs. Disturbance in ER homeostasis is triggered by calcium level imbalance, change in redox status, viral infection, and so on. ER dysfunction and subsequent UPR signaling participate in various hepatic disorders like metabolic (dysfunction) associated fatty liver disease, liver cancer, viral hepatitis, and cholestasis. The exact role of ER stress and UPR signaling in various liver diseases is not fully understood and needs further investigation. Targeting UPR signaling with drugs is the subject of intensive research for therapeutic use in liver diseases. The present review summarizes the role of UPR signaling in liver disorders and describes why UPR regulators are promising therapeutic targets.

Primary sclerosing cholangitis (PSC) is a chronic and progressive immune-mediated cholangiopathy causing biliary tree inflammation and scarring, leading to liver cirrhosis and end-stage liver disease. Diagnosis of PSC is challenging due to its nonspecific symptoms and overlap with other liver diseases. Despite the rising incidence of PSC, there is no proven medical therapy that can alter the natural history of the disease. While liver transplantation (LT) is the most effective approach for managing advanced liver disease caused by PSC, post-transplantation recurrence of PSC remains a challenge. Therefore, ongoing research aims to develop better therapies for PSC, and continued efforts are necessary to improve outcomes for patients with PSC. This article provides an overview of PSC's pathogenesis, clinical presentation, and management options, including LT trends and future aspects. It also highlights the need for improved therapeutic options and ethical considerations in providing equitable access to LT for patients with PSC. Additionally, the impact of liver transplant on the quality of life and psychological outcomes of patients with PSC is discussed. Ongoing research into PSC's pathogenesis and post-transplant recurrence is crucial for improved understanding of the disease and more effective treatment options.

Paneth cells (PC) play a key role in the innate immune response of intestine epithelium, and PC defects contribute to the pathogenesis of Crohn's disease (CD). In this study, we utilized active CD tissues and advanced oxidation protein products (AOPP)-challenged C57BL/6 mouse model to investigate the effect of AOPP on PC defects in CD. We found that AOPP accumulated in active CD tissues and was negatively associated with lysozyme expression, while positively correlated with the presence of ER stress markers. Furthermore, AOPP treatment induced PC defects mainly through excessive ER stress in vivo, and AOPP also caused mitochondria-associated ER membranes formation and mitochondrial dysfunction. In addition, the effects of AOPP could be attenuated by the administration of ER stress inhibitor, TUDCA. These findings suggest a pathogenic role of AOPP contributing to PC defects and may provide the basis for developing new strategies to managing CD.

The COVID-19 pandemic has resulted in significant worldwide morbidity and mortality. In this review, we examine the intricate relationships between COVID-19 and liver diseases. While respiratory manifestations of COVID-19 are well known, its impact and consequences in patients with liver diseases remain an area of ongoing investigation. COVID-19 can induce liver injury through various mechanisms and is associated with higher mortality in individuals with preexisting chronic liver disease. Mortality increases with the severity of chronic liver disease and the level of care required. The outcomes in patients with autoimmune hepatitis remain unclear, whereas liver transplant recipients are more likely to experience symptomatic COVID-19 but have comparable outcomes to the general population. Despite suboptimal immunological response, COVID-19 vaccinations are safe and effective in liver disease, although cases of autoimmune hepatitis-like syndrome have been reported. In conclusion, COVID-19 has significant implications in liver diseases; early recognition and treatments are important for improving patient outcomes.

Evidence suggests the involvement of the microbiota, including oral, intra-tumoral and gut, in pancreatic cancer progression and response to therapy. The gut microbiota modulates the bile acid pool and is associated with maintaining host physiology. Studies have shown that the bile acid/gut microbiota axis is dysregulated in pancreatic cancer. Bile acid receptor expression and bile acid levels are dysregulated in pancreatic cancer as well. Studies have also shown that bile acids can cause pancreatic cell injury and facilitate cancer cell proliferation. The microbiota and its metabolites, including bile acids, are also altered in other conditions considered risk factors for pancreatic cancer development and can alter responses to chemotherapeutic treatments, thus affecting patient outcomes. Altogether, these findings suggest that the gut microbial and/or bile acid profiles could also serve as biomarkers for pancreatic cancer detection. This review will discuss the current knowledge on the interaction between gut microbiota interaction and bile acid metabolism in pancreatic cancer.

Differentiating alcoholic hepatitis (AH) from acute decompensation of alcoholic cirrhosis (DC) is challenging, as the presentation and biochemistry are similar. We aimed to identify potential metabolomic biomarkers to differentiate between AH and DC, and to predict short-term mortality.

We included consecutive biopsy proven AH and DC patients, which were managed according to current guidelines and followed up until the end of the study. Untargeted metabolomics was assessed in all patients at baseline. Specific analyses were successively performed to identify potential biomarkers, which were further semi-quantitatively analysed against relevant clinical endpoints.

Thirty-four patients with AH and 37 with DC were included. UHPLC-MS analysis identified 83 molecules potentially differentiating between AH and DC. C16-Sphinganine-1P (S1P) was the most increased, whereas Prostaglandin E2 (PGE2) was the most decreased. The PGE2/S1P ratio < 1.03 excellently discriminates between AH and DC: AUC 0.965 (p < 0.001), Se 90%, Sp 100%, PPV 0.91, NPV 1, and diagnostic accuracy 95%. This ratio is not influenced by the presence of infection (AUC 0.967 vs. 0.962), correlates with the Lille score at 7 days (r = -0.60; P = 0.022) and tends to be lower in corticosteroid non-responders as compared with patients who responded [0.85(±0.02) vs. 0.89(±0.05), P = 0.069]. Additionally, decreased ursodeoxycholic acid levels are correlated with MELD and Maddrey scores and predict mortality with a 77.27% accuracy (NPV = 100%).

This study suggests the PGE2 (decreased)/S1P (increased) ratio as a biomarker to differentiate AH from DC. The study also finds that low levels of ursodeoxycholic acid could predict increased mortality in AH.

In this study, lithocholic acid (LCA) was prepared using commercially available plant-sourced bisnoralcohol (BA), and the overall yield of the product was 70.6% for five steps. To prevent process-related impurities, the isomerizations of catalytic hydrogenation in the C4-C5 double bond and reduction of the 3-keto group were optimized. The double bond reduction isomerization was improved (5β-H:5α-H = 97:3) using palladium-copper nanowires (Pd-Cu NWs) instead of Pd/C. The reduction of the 3-keto group was 100% converted to a 3α-OH product by 3α-hydroxysteroid dehydrogenase/carbonyl reductase catalysis. Moreover, the impurities during the optimization process were comprehensively studied. Compared with the reported synthesis methods, our developed method significantly improved the isomer ratio and overall yield, affording ICH-grade quality of LCA, and it is more cost-effective and suitable for large-scale production of LCA.

Primary biliary cholangitis (PBC), previously referred to as primary biliary cirrhosis, is an autoimmune disorder leading to the destruction of intra-hepatic bile ducts. If untreated, progressive bile duct damage and cholestasis can lead to ductopenia and result in cirrhosis. Ursodiol, the first drug approved for PBC, has changed the natural history of this disease and improved patient outcomes. Subsequently, several new prediction models incorporating a response to ursodiol were developed. These include the GLOBE score, which was shown to predict long-term outcomes in patients with PBC. In 2016, obeticholic acid (OCA) became the second drug to be approved by the FDA, predominantly based on improvement in alkaline phosphatase (ALP) levels. This trial has subsequently influenced the design of clinical trials. Several drugs are currently being evaluated as therapeutic options for PBC, with improvement in ALP being a main endpoint. In this review, we will discuss the impact of new therapies on GLOBE scores in patients with PBC.

Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. The incidence and prevalence of PBC vary widely in different regions and time periods, and although disproportionally more common among White non-Hispanic females, contemporary data show a higher prevalence in males and racial minorities than previously described. Outcomes largely depend on early recognition of the disease and prompt institution of treatment, which, in turn, are directly influenced by provider bias and socioeconomic factors. Ursodeoxycholic acid remains the initial treatment of choice for PBC, with obeticholic acid and fibrates (off-label therapy) reserved as add-on therapy for the management of inadequate responders or those with ursodeoxycholic acid intolerance. Novel and repurposed drugs are currently at different stages of clinical development not only for the treatment of PBC but also for its symptomatic management. Here, we summarize the most up-to-date data regarding the epidemiology, prognosis, and treatment of PBC, providing clinically useful information for its holistic management.

Mesenchymal stem cells (MSCs) are pluripotent stromal cells that are among the most appealing candidates for regenerative medicine and may aid in the repair and regeneration of skeletal disorders through multiple mechanisms, including angiogenesis, differentiation, and response to inflammatory conditions. Tauroursodeoxycholic acid (TUDCA) has recently been used in various cell types as one of these drugs. The mechanism of osteogenic differentiation by TUDCA in hMSCs remains unknown.

Cell proliferation was performed by the WST-1 method, and alkaline phosphatase activity and alizarin red-sulfate staining were used to confirm the osteogenic differentiation indicator. Expression of genes related to bone differentiation and specific genes related to signaling pathways was confirmed by quantitative real-time polymerase chain reaction.

We found that cell proliferation was higher as the concentration increased, and showed that the induction of osteogenic differentiation was significantly enhanced. We also show that osteogenic differentiation genes were upregulated, with the expression of the epidermal growth factor receptor (EGFR) and cAMP responsive element binding protein 1 (CREB1) being specifically high. To confirm the participation of the EGFR signaling pathway, the osteogenic differentiation index and expression of osteogenic differentiation genes were determined after using an EGFR inhibitor. As a result, EGFR expression was remarkably low, and that of CREB1, cyclin D1, and cyclin E1 was also significantly low.

Therefore, we suggest that TUDCA-induced osteogenic differentiation of human MSCs is enhanced through the EGFR/p-Akt/CREB1 pathway.