Search Results (148)

Background: Alcohol-associated liver disease (ALD) is characterized by gut–liver axis dysfunction and metabolic dysregulation, yet the therapeutic potential of probiotics remains underexplored. This study aimed to investigate the protective effects and mechanisms of Lacticaseibacillus paracasei 36 (LP36) against ethanol-induced ALD in mice. Methods: Mice were pretreated with LP36 prior to ethanol exposure. Liver injury was assessed through serum ALT/AST levels, hepatic steatosis (TC/TG content), and ethanol detoxification capacity (ADH/ALDH activity). Intestinal barrier integrity was evaluated via Mucin2 and ZO-1 expression, and gut microbiota alterations were analyzed by 16S rRNA sequencing. Hepatic transcriptomics (RNA-seq) was performed to identify key regulatory pathways. Results: LP36 significantly attenuated ethanol-induced liver injury, evidenced by reduced ALT/AST, improved hepatic steatosis (lower TC/TG), and enhanced ADH/ALDH activity. Mechanistically, LP36 restored intestinal barrier function (upregulated Mucin2 and ZO-1), modulated gut microbiota (suppressed Parasutterella, Romboutsia, and Christensenellaceae_R-7_group; enriched Faecalibaculum and Tuzzerella), and reduced systemic inflammation. Transcriptomics revealed LP36-mediated rescue of AMPK signaling, involving regulation of Stk11, Prkag3, lipid synthesis genes (Fasn, Acaca), and metabolic modulators (Creb3l3, G6pc3, mTOR, Rps6kb2).Conclusions: LP36 ameliorates ethanol-induced ALD by enhancing intestinal barrier integrity, reshaping gut microbiota, and restoring AMPK-dependent metabolic homeostasis. These findings highlight LP36 as a promising probiotic candidate for ALD prevention. Full article

Background: Alcohol-associated liver disease (ALD) is a primary global health concern, exacerbated by oxidative stress, inflammation, and gut barrier dysfunction. Conventional phytocompounds exhibit hepatoprotective potential but are hindered by low bioavailability. This study aimed to evaluate the hepatoprotective and gut-barrier-restorative effects of green-synthesized silver nanoparticles (AgNPs) derived from Enicostemma littorale, a medicinal plant known for its antioxidant and anti-inflammatory properties. Methods: AgNPs were synthesized using aqueous leaf extract of E. littorale and characterized using UV-Vis, XRD, FTIR, DLS, and SEM. HepG2 (liver) and Caco-2 (colon) cells were exposed to 0.2 M ethanol, AgNPs (1–100 µg/mL), or both, to simulate ethanol-induced toxicity. A range of in vitro assays was performed to assess cell viability, oxidative stress (H₂DCFDA), nuclear and morphological integrity (DAPI and AO/EtBr staining), lipid accumulation (Oil Red O), and gene expression of pro- and anti-inflammatory, antioxidant, and tight-junction markers using RT-qPCR. Results: Ethanol exposure significantly increased ROS, lipid accumulation, and the expression of inflammatory genes, while decreasing antioxidant enzymes and tight-junction proteins. Green AgNPs at lower concentrations (1 and 10 µg/mL) restored cell viability, reduced ROS levels, preserved nuclear morphology, and downregulated CYP2E1 and SREBP expression. Notably, AgNPs improved the expression of Nrf2, HO-1, ZO-1, and IL-10, and reduced TNF-α and IL-6 expression in both cell lines, indicating protective effects on both liver and intestinal cells. Conclusions: Green-synthesized AgNPs from E. littorale exhibit potent hepatoprotective and gut-barrier-restoring effects through antioxidant, anti-inflammatory, and antilipidemic mechanisms. These findings support the therapeutic potential of plant-based nanoparticles in mitigating ethanol-induced gut–liver axis dysfunction. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, with metabolic-dysfunction-associated steatohepatitis (MASH) and alcohol-related liver disease (ALD) emerging as major etiologies. This review explores the epidemiological trends, pathogenesis, and clinical management of HCC arising from MASH and ALD, highlighting both the shared and distinct mechanisms. MASH-HCC is driven by metabolic dysregulation, including obesity, insulin resistance, and lipotoxicity, with genetic polymorphisms such as PNPLA3 and TM6SF2 playing critical roles in disease progression. ALD-HCC, in contrast, is propelled by the toxic byproducts of ethanol metabolism, including acetaldehyde and reactive oxygen species, which induce chronic inflammation, and fibrosis. Both conditions also involve immune dysregulation, gut dysbiosis, and increased intestinal permeability, contributing to hepatic carcinogenesis. The review emphasizes that, while there is consensus regarding the screening of HCC in cirrhosis patients, there is lack of consensus on screening strategies for non-cirrhotic MASH patients who are also at risk for HCC. This underscores the importance of the early detection of cirrhosis using advanced diagnostic tools such as transient elastography and fibrosis scores. Current therapeutic approaches, ranging from surgical resection, liver transplantation, and locoregional therapies to systemic therapies like immune checkpoint inhibitors, are discussed, with an emphasis on the need for personalized treatment strategies. Finally, the review highlights future research priorities, including the development of novel biomarkers, exploration of the gut–liver axis, and deeper investigation of the interplay between genetic predisposition and environmental factors. By synthesizing these insights, the review aims to inform multidisciplinary approaches to reduce the global burden of MASH- and ALD-related HCC and improve patient outcomes. Full article

The advancement of modern lifestyles has precipitated excessive consumption of energy-dense foods, driving the escalating global burden of lipid metabolism dysregulation-related pathologies—including obesity, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disorders—which collectively pose a formidable challenge to global public health systems. The almond hull, as a by-product of almond processing, is rich in polyphenolic compounds with demonstrated antioxidant, anti-inflammatory, and lipid-lowering potential, though its precise hypo-lipidemic mechanisms remain elusive. In this study, polyphenols were extracted from almond hulls using 50% ethanol with ultrasound-assisted extraction, followed by preliminary purification via solvent partitioning. The ethyl acetate fraction was analyzed by liquid chromatography–mass spectrometry (LC-MS). Network pharmacology and molecular docking were employed to investigate the interactions between key bioactive constituents (e.g., quercetin, baicalein, and kaempferol) and targets in lipid metabolism-related pathways. Molecular dynamics (MD) simulations further evaluated the stability of the lowest-energy complexes. Results revealed that the ethyl acetate fraction exhibited potent pancreatic lipase inhibitory activity (IC50 = 204.2 µg/mL). At 0.1 mg/mL after 24 h treatment, it significantly reduced free fatty acids (FFAs)-induced intracellular triglyceride accumulation (p < 0.01) and enhanced cellular antioxidant capacity. Network pharmacology and in vitro studies suggest almond hull extract modulates PI3K-AKT signaling and improves insulin resistance, demonstrating lipid-lowering effects. These findings support its potential in functional foods and pharmaceuticals, though further in vivo validation and mechanistic investigations are required. Full article

Backgrounds: Direct-acting antiviral (DAA) therapy, which achieves a high sustained virological response (SVR) rate, has been established as a standard treatment for patients with hepatitis C virus (HCV) infection. However, the risk factors for postoperative recurrence in patients with HCV-related hepatocellular carcinoma (HCC) detected after the achievement of an SVR by DAAs are unknown. Methods: The clinical records of 95 patients with initial HCV-related HCC detected after DAA-SVR achievement, who underwent liver resection between September 2014 and December 2020, were retrospectively reviewed. Patients with major vascular invasion and/or SVR achievement induced by interferon-based therapy were excluded. In this study, the patients were divided into two groups according to their alcohol intake status: without alcohol abuse (<80 g of ethanol each day for at least 5 years, n = 85) and with (continuous) alcohol abuse (n = 10). The risk factors for recurrence after liver resection were investigated, with special reference to the alcohol intake status. Results: The 3- and 5-year disease-free survival (DFS) rates after liver resection were 68.7% and 55.3%, respectively. Univariate and multivariate analyses identified alcohol abuse [hazard ratio (HR) 3.36, p = 0.004] and tumor size (HR 2.53, p = 0.010) as independent risk factors for postoperative recurrence. The 3- and 5-year postoperative DFS rates were 72.2% and 61.5% for patients without alcohol abuse and 40.0% and 13.3% for those with alcohol abuse (p = 0.001). Conclusions: Continuous alcohol abuse is a risk factor for recurrence after surgery of HCC detected after the achievement of DAA-SVR. Full article

Background and Objective: Alcoholic liver disease (ALD) is a major health burden caused by chronic alcohol consumption, leading to oxidative stress, inflammation, and fibrosis. Current treatments are limited, highlighting the need for novel therapeutic agents. This study investigated the hepatoprotective effects of ‘Terpinen-4-ol (T4OL)’, a natural monoterpene from tea tree oil, against ethanol-induced liver injury, focusing on its molecular and cellular mechanisms. Materials and Methods: Network pharmacology and molecular docking were employed to predict T4OL’s interaction with ALD-associated targets. Human HepG2 cells were used to validate the in silico findings. Cells were exposed to ethanol (8%) prior to treatment with T4OL or silymarin (SIL), and cytotoxicity was assessed through MTT, crystal violet, and trypan blue assays. Moreover, ELISA and qPCR were conducted to evaluate antioxidant, inflammatory, and fibrotic markers. Results: Network pharmacology analysis suggested that T4OL exerts its hepatoprotective effects by suppressing inflammatory and fibrotic mediators (HIF-1α, TGF-β1, and TNF-α). Docking studies also exhibited a strong binding affinity of T4OL to key ALD targets, with docking scores comparable to SIL. In addition, T4OL (13–1300 µM) dose-dependently protected HepG2 cells from ethanol-induced damage, restoring viability by up to 80% at 650 µM. It significantly elevated antioxidant levels (GSH by 2.5-fold, SOD by 1.8-fold) and suppressed pro-inflammatory and fibrotic markers (IL-6, COL1A1, TIMP-1) by 40–60%. At higher concentrations (650–1300 µM), T4OL outperformed SIL in cytoprotection and anti-fibrotic effects. Conclusions: T4OL mitigates ethanol-induced liver injury by targeting oxidative stress, inflammation, and fibrosis pathways, demonstrating superior efficacy to SIL at optimal doses. Its multi-target action supports its potential as a therapeutic candidate for ALD. Full article

Chronic alcohol consumption induces oxidative stress not only in the liver but also in the gastrointestinal tract, where prolonged intestinal ethanol absorption plays a pivotal and underrecognized role. This review reframes ethanol pharmacokinetics to emphasize sustained jejunal and ileal uptake, which maintains elevated blood alcohol levels and perpetuates redox imbalance across the gut–liver axis. We integrate recent findings on ethanol-induced barrier dysfunction, CYP2E1-mediated ROS production, microbial dysbiosis, and mitochondrial disruption, proposing that the intestine is an active site of injury and a driver of systemic inflammation. Key mechanistic insights reveal that gut-derived endotoxins, compromised epithelial integrity, and microbiome–mitochondria interactions converge to exacerbate hepatic and extrahepatic damage. We further explore emerging therapeutic strategies—ranging from NAD⁺ repletion and probiotics to fecal microbiota transplantation—that target this upstream pathology. Recognizing prolonged intestinal ethanol absorption as a clinically meaningful phase offers new directions for early intervention and redox-based treatment in alcohol-associated disease. Full article

The gut microbiota plays a central role in host energy metabolism and the development of metabolic disorders, partly through its influence on mitochondrial function. Probiotic supplementation, particularly with Lactobacillus rhamnosus GG, has been proposed as a strategy to modulate the microbiota and improve host metabolic health. Adolescent binge-like alcohol consumption is a critical public health issue known to induce neuroinflammation, oxidative stress, mitochondrial dysfunction, and intestinal dysbiosis, contributing to disorders such as alcoholic liver disease (ALD). This study aimed to evaluate the effects of L. rhamnosus GG supplementation on mitochondrial physiology in Sprague Dawley rats exposed to binge-like ethanol (BEP group) or saline (SP group) during adolescence (postnatal days 30–43). Starting on postnatal day 44, L. rhamnosus GG was administered orally for 28 days. Fecal colonization was confirmed by qPCR, and mitochondrial function was assessed in the liver, heart, and bone marrow through quantification of NADH, ATP, ADP/ATP ratio, total antioxidant capacity, and the expression of mitochondrial genes Higd2a, MnSOD1, and AMPKα1. L. rhamnosus GG supplementation induced tissue-specific mitochondrial adaptations. In the liver, it increased Higd2a expression and restored antioxidant and energy balance in ethanol-exposed rats. In the bone marrow, it reversed ethanol-induced metabolic stress and enhanced AMPKα1 expression. In contrast, in the heart, L. rhamnosus GG had minimal impact on mitochondrial energy markers but increased antioxidant capacity, indicating a more limited, redox-focused effect. These findings suggest that L. rhamnosus GG exerts context-dependent, tissue-specific benefits on mitochondrial physiology, primarily through the modulation of antioxidant defenses, activation of AMPKα1, and remodeling of respiratory complexes. This probiotic may represent a promising therapeutic strategy to mitigate mitochondrial dysfunction associated with early-life alcohol exposure. Full article

Alcoholic liver disease (ALD) is a condition resulting from liver damage linked to excessive drinking over a brief duration. It poses a significant public health challenge globally, with its prevalence and morbidity rising annually due to escalating rates of alcohol abuse, which adversely affect human health. Phaeodactylum tricornutum (PT), a diatom species of microalgae, is reported to possess active components that provide anti-inflammatory and antioxidant benefits. This study aimed to investigate the preventive and therapeutic effects of PT extract on ALD. To address our purpose, we used ethanol diet induced live disease model. Mice fed an ethanol diet showed less weight gain and higher levels of AST and ALT compared to those fed a regular diet. PT extract suppressed the inhibition of weight gain and the increase in AST/ALT levels caused by an ethanol diet. In addition, PT extract also prevented liver tissue damage caused by an ethanol diet. Thus, the effect of PT on ALD was found to be related to the inhibition of mitogen-activated protein kinase (MAP kinases) phosphorylation and TNF-α production. Full article

Alcohol-related liver disease (ALD) is a leading cause of chronic liver conditions globally. Chronic alcohol consumption induces liver damage through various mechanisms, including neutrophil extracellular trap (NET) formation. Extracellular DNA (ecDNA), released from damaged hepatocytes and NETotic neutrophils, has emerged as a potential biomarker and contributor to liver disease pathology. Enzyme DNases could be an effective therapy for the denaturation of immunogenic ecDNA. This study investigated the circulating ecDNA and NET markers in ALD and therapeutic effect of DNase I in a murine model of ALD. Female C57BL/6J mice were fed a control diet (n = 13) or Lieber–DeCarli ethanol diet for 10 days followed by a binge ethanol dose to mimic acute-on-chronic alcoholic liver injury. From day 5, mice fed ethanol were randomized into an ethanol diet group (n = 17) and ethanol + DNase group (n = 5), which received additional DNase I treatment every 12 h. Liver damage markers were analyzed. Circulating ecDNA and NETosis were measured by fluorometry and cytometry, respectively. DNase I activity was analyzed with single radial enzyme dispersion assay. The ethanol-fed mice exhibited increased mortality, neutrophil infiltration and structural damage in the liver. Total circulating ecDNA levels and NET markers did not differ between groups. DNase activity was higher in ethanol-fed mice compared to controls and additional daily administration of DNase prevented liver injury. These findings suggest that alcohol-induced liver injury modestly influences systemic NETosis and ecDNA levels. However, increased DNase activity can prevent disease progression and enhanced systemic degradation of ecDNA using DNase I. Full article

Background: Alcoholic liver disease (ALD) is a significant global health concern, primarily resulting from chronic alcohol consumption, with oxidative stress as a key driver. The ethyl acetate extract of Cichorium glandulosum (CGE) exhibits antioxidant and hepatoprotective properties, but its detailed mechanism of action against ALD remains unclear. This study investigates the effects and mechanisms of CGE in alleviating alcohol-induced oxidative stress and liver injury. Methods: Ultra-Performance Liquid Chromatography coupled with Quadrupole-Orbitrap Mass Spectrometry (UPLC-Q-Orbitrap-MS) was used to identify CGE components. A C57BL/6J mouse model of ALD was established via daily oral ethanol (56%) for six weeks, with CGE treatment at low (100 mg/kg) and high doses (200 mg/kg). Silibinin (100 mg/kg) served as a positive control. Liver function markers, oxidative stress indicators, and inflammatory markers were assessed. Transcriptomic and network pharmacology analyses identified key genes and pathways, validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Results: UPLC-Q-Orbitrap-MS identified 81 CGE compounds, mainly including terpenoids, flavonoids, and phenylpropanoids. CGE significantly ameliorated liver injury by reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels and enhancing antioxidative markers such as total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) while lowering hepatic malondialdehyde (MDA) levels. Inflammation was mitigated through reduced levels of Tumor Necrosis Factor Alpha (TNF-α), Interleukin-1 Beta (IL-1β), and C-X-C Motif Chemokine Ligand 10 (CXCL-10). Transcriptomic and network pharmacology analysis revealed seven key antioxidant-related genes, including HMOX1, RSAD2, BCL6, CDKN1A, THBD, SLC2A4, and TGFβ3, validated by RT-qPCR. CGE activated the P21/Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1) signaling axis, increasing P21, Nrf2, and HO-1 protein levels while suppressing Kelch-like ECH-associated Protein 1 (Keap1) expression. Conclusions: CGE mitigates oxidative stress and liver injury by activating the P21/Nrf2/HO-1 pathway and regulating antioxidant genes. Its hepatoprotective effects and multi-target mechanisms highlight CGE’s potential as a promising therapeutic candidate for ALD treatment. Full article

About 296 million people worldwide are living with chronic hepatitis B viral (HBV) infection, and outcomes to end-stage liver diseases are potentiated by alcohol. HBV replicates in hepatocytes, but other liver non-parenchymal cells can sense the virus. In this study, we aimed to investigate the regulatory effects of macrophages on HBV marker and interferon-stimulated genes (ISGs) expressions in hepatocytes. This study was performed on HBV-replicating HepG2.2.15 cells and human monocyte-derived macrophages (MDMs). We found that exposure of HepG2.2.15 cells to an acetaldehyde-generating system (AGS) increased HBV RNA, HBV DNA, and cccDNA expressions and suppressed the activation of ISGs, APOBEC3G, ISG15, and OAS1. Supernatants collected from IFNα-activated MDMs decreased HBV marker levels and induced ISG activation in AGS-treated and untreated HepG2.215 cells. These effects were reversed by exposure of MDMs to ethanol and mimicked by treatment with exosome release inhibitor GW4869. We conclude that exosome-mediated crosstalk between IFN-activated macrophages and HBV-replicating hepatocytes plays a protective role via the up-regulation of ISGs and suppression of HBV replication. However, ethanol exposure to macrophages breaks this protection. Full article

The combination of alcohol and a low-carbohydrate, high-protein, high-fat atherogenic diet (AD) increases the risk of lethal arrhythmias in apolipoprotein E/low-density lipoprotein receptor double-knockout (AL) mice with metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigates whether left ventricular (LV) myocardial interstitial fibrosis (MIF), formed during the progression of metabolic dysfunction-associated steatohepatitis (MASH), contributes to this increased risk. Male AL mice were fed an AD with or without ethanol for 16 weeks, while age-matched AL and wild-type mice served as controls. Liver and heart tissues were analyzed, and susceptibility to lethal arrhythmias was assessed through histopathology, fluorescence immunohistochemistry, RNA-Seq, RT-PCR, and lethal arrhythmia-evoked test. Ethanol combined with an AD significantly induced LV MIF in MASH-affected AL mice, as shown by increased fibrosis-related gene expression, Sirius-Red staining, and elevated collagen 1a1 and 3a1 mRNA levels, alongside a higher incidence of lethal arrhythmias. Cardiac myofibroblasts exhibited sympathetic activation and produced elevated levels of fibrosis-promoting factors. This study highlights the role of cardiac myofibroblasts in LV MIF, contributing to an increased incidence of lethal arrhythmias in MASH-affected AL mice fed ethanol and AD, even after the alcohol was fully metabolized on the day of consumption. Full article

Alcohol-associated liver disease (ALD) is a common non-communicable chronic liver disease characterized by a spectrum of conditions ranging from steatosis and alcohol-associated steatohepatitis (AH) to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The pathogenesis of ALD involves a complex interplay of various molecular, biochemical, genetic, epigenetic, and environmental factors. While the mechanisms are well studied, therapeutic options remain limited. Alpinetin, a natural flavonoid with antioxidant and anti-inflammatory properties, has shown potential hepatoprotective effects, though its efficacy in ALD remains unexplored. This study investigated the hepatoprotective effects of alpinetin using a Lieber–DeCarli ethanol liquid diet model of ALD in C57BL/6 mice. Mice were divided into three groups: the control group, the ethanol group, and the ethanol group treated with alpinetin. Serum activity of ALT, AST, γ-GT, and ALP was measured to assess liver function, along with antioxidative and oxidative/nitrosative stress markers in liver tissue. Pro-inflammatory cytokines and endoplasmic reticulum (ER) stress parameters in liver tissue were also evaluated. Histological assessment of disease activity was performed using the SALVE grading and staging system. Treatment with alpinetin significantly reduced serum levels of ALT, AST, γ-GT, and oxidative/nitrosative stress markers while increasing antioxidative markers. The levels of pro-inflammatory cytokines and ER stress parameters were significantly decreased. Histological analysis demonstrated reduced steatosis, hepatocyte ballooning, and inflammation. These findings suggest that alpinetin holds promise as a potential therapeutic agent for managing ALD. Full article

Non-alcoholic fatty liver disease (NAFLD) is a severe hepatic health threat with no effective treatment. Based on the results that Chenopodium quinoa Willd. flavonoids eluted with 30% ethanol (CQWF30) can effectively alleviate NAFLD, this study employed ultrahigh-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (UPLC-ESI-MS/MS) to analyze the components of CQWF30., and screened for flavonoids with potential NAFLD-mitigating effects through network pharmacology. In vitro models using HepG2 and BEL-7402 cell lines induced with free fatty acid (FFA) showed that isorhamnetin administration reduced intracellular lipid deposition and reversed elevated triglyceride (TG) and total cholesterol (T-CHO) levels. In vivo experiments in high-fat diet (HFD) mice demonstrated that isorhamnetin significantly lowered serum and liver fat content, mitigated liver damage, and modulated bile acid metabolism by upregulating FXR and BSEP and downregulating SLCO1B3. Consequently, isorhamnetin shows promise as a treatment for NAFLD due to its lipid-lowering and hepatoprotective activities. Full article