Search Results (189)

Sarcoidosis is a multisystemic inflammatory disease defined by non-caseating granuloma formation in involved organs. The liver is the third most implicated organ after the lungs and lymph nodes. Due to its frequently asymptomatic presentation, the true prevalence of hepatic sarcoidosis may be understated. Increased levels of alkaline phosphatase and gamma-glutamyl transferase are the most frequent biochemical abnormalities. The liver biopsy is still the gold standard and reveals non-caseating granulomas in almost all cases. The use of corticosteroids and ursodeoxycholic acid results in a significant decrease in biochemical parameters. However, the clinical course of hepatic sarcoidosis is diverse and requires individualized management strategies, especially to prevent hepatic complications. This review aims to synthesize the current evidence on epidemiology, pathogenesis, diagnostic approaches, and therapeutic strategies for this disease. Full article

Primary biliary cholangitis (PBC) is an autoimmune-mediated cholestatic liver disease characterized by the progressive destruction of intrahepatic bile ducts, which ultimately leads to hepatic fibrosis and cirrhosis. The current first-line therapy, ursodeoxycholic acid, is associated with a high rate of non-response. Moreover, second-line treatments are constrained by variable efficacy and safety concerns. Mesenchymal stem cells (MSCs), owing to their potent immunomodulatory and tissue-repairing capabilities, represent a promising new therapeutic strategy for PBC patients with poor response to conventional therapies. This review systematically outlines the pathogenesis of PBC, focusing on factors including genetics, environment, and immune dysregulation. Furthermore, it examines recent evidence on the mechanisms by which MSCs and their derivatives, such as exosomes, may intervene in PBC progression through immunomodulation, anti-fibrotic effects, and potential hepatic differentiation. This paper also reviews the current status and challenges of the clinical translation of MSCs therapy, and proposes that engineered modification and standardized preparation are the key directions to promote its application. In conclusion, this review provides a theoretical foundation and future directions for deepening the understanding of PBC pathogenesis and developing novel MSC-based therapeutic strategies. Full article

Objectives: Neonatal hyperbilirubinemia is a common disease in the neonatal period. In this meta-analysis, we aim to evaluate the efficacy of adjuvant drugs combined with phototherapy in the treatment of neonatal hyperbilirubinemia. Methods: Randomized controlled trials (RCTs) published before September 2025 were searched from PubMed, Embase, Web of Science, and the Cochrane Library. A Bayesian random-effects network meta-analysis was performed to calculate mean differences and 95% confidence intervals. Interventions were ranked using the surface under the cumulative ranking curve (SUCRA) and probability of being the best treatment (PbBT). Results: Thirty-five RCTs involving 4060 neonates were included. Compared with phototherapy alone, clofibrate, ursodeoxycholic acid, fenofibrate, and calcium phosphate significantly reduced bilirubin levels and shortened admission duration. Clofibrate showed the greatest efficacy in bilirubin reduction within 48 h (SUCRA = 0.91, PbBT = 60.9%) and in shortening hospitalization (SUCRA = 0.84, PbBT = 40.83%). Probiotics, zinc, and agar exhibited relatively modest effects, while phenobarbital showed no significant benefit. Conclusions: Adjunctive therapies were associated with greater reductions in bilirubin levels compared with phototherapy alone. Future high-quality RCTs are needed to confirm the long-term efficacy and safety of these adjuvant therapies. Full article

Background. Autoimmune sclerosing cholangitis (ASC) is a rare clinical entity characterized by overlapping features of autoimmune hepatitis and primary sclerosing cholangitis. It predominantly affects pediatric patients. Therapeutic management is often complex, requiring a multidisciplinary and individualized approach, especially in the context of associated autoimmune diseases. Case presentation. We present the case of a female patient diagnosed at the age of 10 with ASC, for which immunosuppressive therapy with prednisone, azathioprine (AZA), and ursodeoxycholic acid (UDCA) was initiated, with an initially favorable course. One year later, following a Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, the patient experienced reactivation of liver disease and subsequently developed ulcerative pancolitis (UC), for which 5-aminosalicylic acid (5-ASA) therapy was initiated. Due to repeated hepatic flares and/or colitis relapses, therapy was escalated successively to mycophenolate mofetil, tacrolimus, and eventually infliximab (IFX). Despite treatment, the liver disease progressed, culminating in liver cirrhosis. Our patient developed portal hypertension and esophageal varices, with two episodes of upper gastrointestinal bleeding requiring endoscopic band ligation. At the age of 14, the patient developed recurrent episodes of non-infectious ulcerative stomatitis. Biopsy of the lesions revealed non-specific chronic inflammation, unrelated to colitis activity (confirmed microscopic remission of UC). By exclusion, an adverse drug reaction was suspected, with AZA being the most likely cause. Following its discontinuation, the lesions resolved. Beyond the physiological and therapeutic aspects, the patient displays marked emotional fragility due to prolonged and repeated hospitalizations (18 out of 60 months), which have impacted treatment adherence. Conclusions. This case highlights the complexity of managing pediatric patients with multiple autoimmune diseases. The necessary combination of immunosuppressive therapies may lead to significant adverse effects and further complicate disease progression. Moreover, psychological components play a crucial role in treatment compliance and therapeutic success, emphasizing the need for an integrated approach that includes specialized psychological support. Full article

Introduction: Acute gallstone pancreatitis is a potentially severe disease associated with morbidity and mortality. Cholecystectomy is recommended to prevent recurrence. During pregnancy, surgical management is challenging, and in the post-partum period small gallstones may spontaneously disappear. Ursodeoxycholic acid (UDCA) is safe during the last 6 months of pregnancy and effective in dissolving small gallstones, although recurrence after discontinuation is common in the general population. The optimal strategy to prevent recurrent acute pancreatitis during and after pregnancy remains unclear. Methods: Between 2002 and 2017 we prospectively treated women with acute pancreatitis related to small gallstones (≤1 cm in diameter) during the last six months of pregnancy or within the first post-partum year who declined surgery. Patients received UDCA until stone dissolution. A patent cystic duct was confirmed by ultrasonography; after delivery, a non-contrast CT scan was performed to exclude calcified stones. Patients were followed for at least 6 years or until recurrence, with serial clinical and ultrasonographic examinations. Results: UDCA was associated with complete dissolution in 13/14 women within a mean ± SD of 7.77 + 3.1 months. One patient experienced gallstone recurrence 75 months after treatment discontinuation. Two patients developed recurrent pancreatitis (at 1 and 88 months respectively). Twelve women remained free of recurrence over a mean ± SD follow-up of 79.5 + 9.4 months. Discussion: This is an observational study in which we document that UDCA may facilitate the spontaneous dissolution of small gallstones after delivery and can be considered a bridge strategy during pregnancy when surgery is not feasible. However, this study cannot determine the additional benefit of UDCA over the spontaneous disappearance of stones observed after delivery because we had no control group. Cholecystectomy remains the standard of care post-partum. Medical therapy should be reserved for women who refuse surgery and it requires close ultrasonographic surveillance. The main strength of this study is the prospective long-term follow-up of a consecutive cohort with a rare condition. Limitations include the small sample size, missing control group and single-center design. Full article

Oxidative stress is a critical pathophysiological factor in sepsis. Ursodeoxycholic acid (UDCA), a bile acid with anti-inflammatory, antioxidant, and anti-apoptotic properties, may protect against lipopolysaccharide (LPS)-induced myocardial injury. In an experimental study, 32 male Wistar rats were randomly assigned to four groups: control, LPS, UDCA, and UDCA + LPS. UDCA was administered orally for 10 days prior to LPS-induced endotoxemia. Serum levels of high-sensitive troponin I (hsTnI), homocysteine, and oxidative stress markers were measured, and immunohistochemistry and immunofluorescence were used to assess inflammation (nuclear factor kappa B, NF-κB), apoptosis (caspase 3), and signaling pathways related to protein kinase B (Akt)/NF-κB and silent information regulator 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1). UDCA pretreatment significantly reduced myocardial pathological changes, serum hsTnI, homocysteine, and total oxidative stress compared with LPS alone. It enhanced catalase (CAT) activity and glutathione (GSH) levels while lowering thiobarbituric acid reactive substances (TBARS) and nitrite concentrations in cardiac tissue. UDCA modulated cellular signaling by decreasing Akt phosphorylation and activating the SIRT1/Nrf2/HO-1 pathway. These results indicate that UDCA protects the heart from LPS-induced damage by reducing oxidative stress, inflammation, and apoptosis. UDCA modulates cellular signaling by decreasing pro-inflammatory pathways and activating anti-inflammatory pathways associated with SIRT1/Nrf2/HO-1 signaling, emphasizing its key role in myocardial protection during sepsis. Full article

Background/Objectives: Primary biliary cholangitis (PBC) is a chronic immune-mediated cholestatic liver disease with increasing global prevalence. However, data on this disease from Central Asia are lacking. We aimed to describe the clinical, serological, and treatment characteristics of PBC patients in Kazakhstan. Methods: This study was a multicenter, retrospective, observational study including adults diagnosed with PBC between 2014 and 2022 across seven hepatology centers in Kazakhstan. Clinical presentation, laboratory parameters, autoimmune comorbidities, liver disease severity, and ursodeoxycholic acid (UDCA) treatment response were assessed. Biochemical response at 1 year was evaluated using Paris-1 and Barcelona criteria. Results: A total of 230 patients were included; 93.9% were female and 91.3% were of Asian ethnicity, with a median age at diagnosis of 53 years. Cirrhosis was present at diagnosis in 50.2% of the patients. PBC with autoimmune hepatitis (AIH) features was identified in 56.1% of the patients and was associated with higher rates of cirrhosis, portal hypertension complications, antinuclear antibody (ANA) positivity, and higher elastography indices compared with isolated PBC. Overall, approximately 55% of the patients achieved a biochemical response to UDCA at 1 year, with similar response rates between patients with PBC and those with PBC with AIH features. Conclusions: This first comprehensive study of PBC in Kazakhstan demonstrates late disease presentation with a high burden of cirrhosis and frequent AIH features. Despite advanced disease, about half of the patients achieved biochemical remission on UDCA. These findings underscore the need for earlier diagnosis and optimized management strategies for PBC in Kazakhstan and similar settings in Central Asia. Full article

Primary biliary cholangitis (PBC) is an autoimmune-mediated disease characterized by chronic, non-suppurative, small-duct lymphocytic cholangitis. The prognosis largely depends on early disease recognition and treatment. Suboptimal response to first-line therapy (ursodeoxycholic acid) is associated with risk for disease progression. Reliable biomarkers are also required to enhance risk stratification. The traditional gold standard for assessing fibrosis is liver biopsy, but it is invasive and unsuitable for serial evaluations. Hence, trends are towards non-invasive surrogate biomarkers (blood-based and imaging biomarkers respectively) which have a much better safety profile. Blood-based biomarkers include: (i) Fibrosis-4 [Fib-4], (ii) Aspartate Aminotransferase to Platelet Ratio Index [APRI], (iii) Enhanced Liver Fibrosis score [ELF], and (iv) total bile acid to platelet ratio [TPR]. They show much potential but are not particularly sensitive tests. Ultrasound-based imaging biomarkers are increasingly being utilized for liver stiffness measurement (LSM), with vibration-controlled transient elastography (VCTE) emerging as the preferred technique. However, despite its growing popularity, VCTE is limited by technical issues. Hence, currently, none of the non-invasive tests fulfill the prerequisites to be the new gold standard as defined by the FDA. Nonetheless, there may be value to combining LSM with various serum biomarkers such as Fib-4, APRI, as aforementioned. The hope is to create nomograms for predicting liver-related events and decision tree algorithms. Newer studies are investigating microbiota in the gut-liver axis, biomolecules such as nanovesicles/nanofibers, and metabolic reprogramming as it pertains to e.g., proteomics and lipidomics. These approaches hold much promise, and if validated, could significantly change the management of PBC. Full article

Primary Biliary Cholangitis (PBC) is a chronic, immune-mediated cholestatic liver disease characterized by progressive intrahepatic bile duct destruction, leading to pruritus, fatigue, cirrhosis, and eventually hepatocellular carcinoma. Early diagnosis has improved with the development of sensitive serologic assays (e.g., antimitochondrial antibodies, antinuclear antibodies) and the introduction of newer biomarkers. Risk stratification has become standardized with the help of GLOBE and UK-PBC scores, alongside non-invasive tools such as vibration-controlled transient elastography, enabling earlier intervention. Ursodeoxycholic acid (UDCA) is the first-line therapy; however, 30–40% of patients show an incomplete response, increasing their risk of liver failure and mortality. Second-line therapies have emerged which provide viable treatment avenues for those who do not respond to UDCA or are unable to tolerate it. However, in certain situations, such as decompensated cirrhosis, carcinoma, or refractory pruritus, liver transplantation constitutes the only curative therapy. While PBC has excellent post-liver transplant (post-LT) outcomes, patients with PBC face higher waitlist mortality as they tend to have lower MELD scores. Management post-LT includes the use of UDCA, immunosuppressants, and surveillance for recurrent PBC. Our review highlights the recent advances in medical management and transplant risk stratification of patients at risk of decompensation, as well as the perioperative transplant period outcomes and long-term post-transplant management strategies in patients with PBC. Full article

Liver disease encompasses a wide range of conditions, each requiring tailored therapeutic approaches. This review describes and critically discusses treatments with robust evidence for improving liver health. Ursodeoxycholic acid (UDCA) is a drug approved by the Food and Drug Administration of the USA to treat primary biliary cholangitis (PBC). In addition, UDCA has been demonstrated to protect against metabolic dysfunction-associated steatohepatitis, fibrosis, and drug-induced liver injury (DILI). The mechanism of action of UDCA has been attributed not only to decreasing the effects of toxic bile acids but also to protecting mitochondrial integrity and function, as well as to antioxidant, anti-inflammatory, and anti-apoptotic activities. UDCA can scavenge reactive oxygen species (ROS) and activate the nuclear factor-E2-related factor-2 (Nrf2) pathway, thereby exerting antioxidant activity. The anti-inflammatory activity of UDCA is associated with its ability to inhibit the nuclear factor-κB pathway. Pirfenidone is a well-recognized antifibrotic drug for the treatment of idiopathic pulmonary fibrosis; its effects on liver fibrosis have also been demonstrated. Pirfenidone exerts anti-inflammatory effects by attenuating the nucleotide-binding oligomerization domain-like receptor 3 inflammasome signaling pathway. The antioxidant actions of pirfenidone are associated with its ability to upregulate the Nrf2 pathway. Both the anti-inflammatory and antioxidant properties of pirfenidone act together to attenuate lung and liver fibrosis, decreasing transforming growth factor-β levels, inhibiting profibrogenic hepatic stellate cell activation, and increasing extracellular matrix degradation. Methyltransferases utilize S-adenosyl-L-methionine (SAM) as a methyl donor for most transmethylation reactions in the body. SAM increases reduced glutathione (GSH) levels, exerting important antioxidant effects. Evidence indicates that SAM prevents fibrosis and attenuates hepatocellular carcinoma development, improving patient survival. N-acetylcysteine (NAC) is a precursor to L-cysteine and GSH and is used in clinical settings to treat cancer, nephropathy, heart disease, pulmonary fibrosis, polycystic ovary syndrome, and influenza. Regarding the liver, NAC is the most accepted treatment for DILI, especially after paracetamol overdose. Owing to its antioxidant and anti-inflammatory actions, NAC has been successfully used to treat chronic liver injuries, including hepatosteatosis and fibrosis. Therefore, ursodeoxycholic acid, pirfenidone, S-adenosyl-L-methionine, and N-acetylcysteine could represent therapeutic strategies for the treatment of liver pathologies. Full article

Background/Objectives: Diet plays a critical role in the development of inflammatory bowel disease (IBD). Our previous work demonstrated that oats and oat bran alleviate dextran sulfate sodium (DSS)-induced colitis in mice by modulating the gut microbiota. Methods: To further explore the underlying mechanisms, this study combined metabolomic and transcriptomic analyses to systematically compare the effects of whole oats and oat bran interventions on chronic colitis. Results: Untargeted metabolomics analysis identified three key metabolites, ursodeoxycholic acid, 3-(3-hydroxyphenyl)propionic acid, and avenanthramide C. The interactions between these metabolites and core proteins of the IL-17 signaling pathway (IL-17A, TRAF6, and ACT1) were evaluated via molecular docking. Transcriptomic and RT-qPCR analyses revealed that both oats and oat bran interventions modulated the IL-17, PI3K-Akt, and TNF signaling pathways. These treatments significantly upregulated the expression of tight junction proteins (claudin-1, claudin-5, occludin) while reducing levels of inflammatory cytokines and chemokines. Molecular docking results demonstrated stable binding between the three metabolites and target proteins primarily through hydrogen bonding and electrostatic interactions, with ursodeoxycholic acid exhibiting the highest binding affinity. Conclusions: Collectively, these findings suggest that oats and oat bran may alleviate chronic colitis by modulating the IL-17 signaling pathway and enhancing intestinal barrier function. Full article

Growth factors play a significant role in the immunopathogenesis of liver diseases, especially liver cirrhosis and hepatocellular carcinoma (HCC). The somatostatin analog octreotide has been used as treatment in advanced HCC, based on its anti-neoplastic effects in vitro. Therefore, the effect of somatostatin and octreotide was studied on several growth factors in patients with HCC. Nineteen patients with advanced HCC were treated with octreotide and compared with thirty-seven patients with viral cirrhosis (19 decompensated) treated with intravenous somatostatin for severe bleeding from portal gastropathy. Five growth factors, namely Gastrin, Insulin-like growth factor 1 (IGF 1), Hepatocyte growth factor (HGF), Stem cell factor (SCF) and Vascular endothelial growth factor (VEGF) were measured in serum before and after treatment with specific commercially available ELISAs. Seventeen healthy individuals and nineteen patients with chronic viral hepatitis C (CAH) were used as pre-treatment controls. Eighteen patients with advanced Primary Biliary Cholangitis (stage III and IV) before and after Ursodeoxycholic acid (UDCA) treatment were also studied. Pre-treatment levels of Gastrin were significantly increased in HCC, cirrhosis and PBC but not in CAH. Levels were significantly reduced by octreotide or somatostatin but also by UDCA in PBC. By contrast, IGF1 showed a mirror image being significantly reduced in HCC, cirrhosis and PBC, but not in CAH. Post-treatment levels were reduced in all groups, but not in PBC. Levels of HGF were significantly increased in HCC and cirrhosis but not in CAH and PBC. They were further increased in HCC after treatment. SCF increased only in HCC and was reduced after octreotide but not after somatostatin treatment. VEGF was reduced in cirrhosis and CAH but not in PBC. It was not significantly increased in HCC, but it was reduced by octreotide and was increased after UDCA. In this retrospective observational study, somatostatin and its analog octreotide have a significant effect on several growth factors involved in HCC pathogenesis. Full article

Drug- and alcohol-induced liver injury involves impaired bile acids or bilirubin secretion, but it is not known how senescence influences the secretion of hepatocytes exposed to drugs and alcohol. In this study, the toxic effects of ritonavir, lopinavir, and alcohol on hepatocyte transporters and the secretion of bile acids and bilirubin were investigated in hydrogen peroxide-induced senescent HepG2 and doxorubicin-induced senescent primary human hepatocytes. In HepG2, intracellular conjugated bilirubin increased upon senescence and extracellular conjugated bilirubin in culture medium was decreased by ritonavir and lopinavir treatment. In the primary hepatocytes, intracellular bile acids or medium bilirubin were not significantly changed upon senescence. However, intracellular bile acids were increased, and medium conjugated bilirubin were decreased in senescent primary hepatocytes treated with alcohol and the two drugs. Transcriptional expressions of adenosine triphosphate (ATP)-binding cassette (ABC) transporters (ABCB4, ABCC6, ABCB11, and ABCD3) were decreased whereas UDP-glucuronosyltransferase (UGT1A1) was increased by ritonavir and lopinavir in senescent HepG2. In senescent primary hepatocytes, expressions of ABCB11, ABCC1, ABCC2, ABCC3, ABCC4, and ABCC6 were apparently reduced whereas UGT1A1 and the cytochrome P450 enzyme CYP7A1 were markedly increased by alcohol combined with ritonavir and lopinavir. Selective ABCC6 knockdown in the primary hepatocytes altered expressions of two senescence markers, Lamin A/C and cyclin-dependent kinase inhibitor CKI (p21), increased expressions of CYP7A1 and hydroxy methyl glutaryl-CoA reductase (HMGCR), and increased intracellular bile acids. Further, anti-cholestasis agents, ursodeoxycholic acid and glycyrrhizin, significantly ameliorated the impaired secretions of bile acids and bilirubin as well as reducing intracellular lipid accumulation and cell death caused by ritonavir, lopinavir, and alcohol in the primary hepatocytes with ABCC6 knockdown. These results indicate that senescence moderately impairs the ABC transporters of hepatocytes and secretion of bile acids or bilirubin, which become worse in the presence of the drugs and alcohol but could be improved by anti-cholestasis agents. Full article

Background/Objectives: Oats and oat bran are rich in polyphenols and soluble fiber, which are metabolized by gut microbiota into bioactive compounds. Previous studies identified ursodeoxycholic acid (UDCA), 3-(3-hydroxyphenyl)propionic acid (3-HPP), and avenanthramide C (AVC) as key microbial metabolites with protective effects against colitis. Methods: This study aimed to elucidate their antioxidant and anti-inflammatory activities and underlying mechanisms using LPS-induced RAW 264.7 macrophages and AAPH-induced oxidative stress in zebrafish embryos. All three metabolites significantly reduced intracellular reactive oxygen species (ROS), nitric oxide (NO), malondialdehyde (MDA), and pro-inflammatory cytokines (IL-6, TNF-α). They also restored mitochondrial membrane potential and enhanced superoxide dismutase (SOD) activity. Results:In vivo, treatment improved zebrafish survival, normalized SOD activity to 76–89% of control levels, and decreased ROS and MDA by 2.4 to 3.8 fold, with UDCA showing the greatest efficacy. Molecular docking revealed strong binding affinities to Keap1, particularly UDCA, which interacted with residues Met577, Ala440, Val532, and Val486. qRT-PCR further demonstrated downregulation of Keap1 and upregulation of Nrf2 and SOD, indicating activation of the Keap1-Nrf2 pathway. Conclusions: Collectively, these findings show that oats and bran-derived microbial metabolites exert potent antioxidant and anti-inflammatory effects via modulation of the Keap1-Nrf2 axis. Among the metabolites, UDCA exhibited the strongest biological activity at equivalent concentrations. This study provides mechanistic insight into how microbiota-derived oat metabolites contribute to redox balance and immune regulation, supporting their potential as functional components in dietary strategies for managing oxidative stress-related inflammatory diseases. Full article

Dihydroartemisinin (DHA), a first-line treatment for uncomplicated malaria, has demonstrated antitumor activity against a variety of human cancers, emphasizing its potential for repurposing as an anticancer agent. However, its short half-life and poor bioavailability hinder its application in cancer therapy. We previously demonstrated that the molecular hybridization of DHA with bile acids (BAs) enhances its anticancer activity by improving stability and reducing toxicity. Based on this rationale, here, we designed and synthesized a library of DHA-based hybrids through conjugation with ursodeoxycholic and chenodeoxycholic bile acids. Different conjugation sites and both cleavable and non-cleavable linkages were explored to enable a comprehensive structure–activity relationship analysis. The resulting BA-DHA hybrids were evaluated in vitro for their anticancer activity against HCT116 and RKO colorectal cancer cell lines. As a result of the synergistic effect of the linker type and conjugation site, the BA-DHA hybrids synthesized via click chemistry emerged as the most active compounds in both cell lines, displaying 2- to 20-fold higher activity than the parent DHA. Mechanistic investigations further revealed that the click-derived BA-DHA hybrids possess enhanced anticancer activity and antimetastatic potential, achieving comparable or even superior efficacy to the parent compound at markedly lower concentrations. Full article