Search Results (3,430)

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a systemic metabolic disorder characterized by impaired metabolic flexibility involving the liver, skeletal muscle, and adipose tissue. Although weight loss has traditionally been emphasized in its management, emerging evidence suggests that exercise exerts therapeutic effects beyond body weight reduction. This narrative review aims to examine exercise as a metabolic therapy for MASLD by integrating mechanistic insights and clinical evidence. Exercise improves hepatic steatosis, insulin resistance, mitochondrial function, and inflammatory signaling through interconnected pathways, including activation of AMPK-related signaling, enhanced fatty acid oxidation, and muscle–liver crosstalk mediated by myokines. Importantly, these benefits can occur independently of weight loss, supporting a shift from weight-centered to metabolism-focused treatment strategies. Both aerobic and resistance exercise demonstrate efficacy, with combined approaches providing complementary benefits. In conclusion, exercise should be considered a central therapeutic strategy for MASLD by restoring metabolic flexibility rather than solely promoting weight reduction. Future research should focus on optimizing individualized and sustainable exercise prescriptions to enhance long-term clinical outcomes. Full article

This study compared the effects of dietary Lactobacillus plantarum (Lpl) and selenium-enriched L. plantarum (Lpl_se) on the growth, hepatic antioxidant capacity, and intestinal microbiota of juvenile largemouth bass (initial weight 12.50 ± 0.81 g). Following a 58-day trial in an indoor rearing system, data were analyzed using one-way ANOVA followed by Tukey’s HSD test. Results showed that both Lpl and Lpl_se significantly improved growth versus the control (Weight Gain Rate: 379.82% and 387.18% vs. 326.56%; p < 0.05). Both supplements significantly elevated hepatic antioxidant enzymes (SOD, CAT, GSH) and reduced malondialdehyde (MDA) levels (p < 0.05). Notably, these macroscopic parameters showed no statistical differences between the two probiotic treatments. However, 16S rRNA sequencing revealed distinct metabolic strategies. While both treatments enriched intestinal Lactobacillus, Lpl_se uniquely upregulated energy-harvesting and synthetic pathways (glycolysis and lysine biosynthesis), corroborated by increased intestinal glycogen synthase activity. In conclusion, while selenium enrichment did not further improve macroscopic growth statistically, it differentially modulated the intestinal functional profile towards enhanced carbohydrate and amino acid metabolism, presenting an alternative host nutrient assimilation strategy. Full article

Phospholipid transfer protein (PLTP) is a lipid transfer protein classically studied in the context of plasma lipoprotein metabolism, high-density lipoprotein (HDL) remodeling, and cardiovascular disease risk. PLTP facilitates phospholipid transfer between lipoproteins and regulates HDL particle size and composition through interactions with apolipoprotein A-I and apolipoprotein A-II. While its systemic roles in cholesterol handling, reverse cholesterol transport, and inflammatory signaling are well established, the cell-autonomous functions of PLTP within cardiomyocytes remain poorly defined, particularly in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Extensive experimental and clinical studies demonstrate that PLTP enhances ABCA1-dependent cholesterol efflux primarily by stabilizing ABCA1 at the plasma membrane and by promoting the generation of lipid-poor apolipoprotein A-I and pre-β HDL particles, which serve as efficient cholesterol acceptors; the magnitude of these effects depends on cellular context, PLTP expression levels, and the availability of lipid acceptors. PLTP expression is metabolically regulated and widely distributed across tissues, including macrophages and other non-hepatic cells, supporting roles beyond circulating lipoprotein remodeling. Altered PLTP activity has been linked to atherosclerosis, cardiovascular disease, and inflammatory pathways, underscoring its relevance to cardiac pathophysiology. Emerging evidence further suggests that intracellular cholesterol distribution, rather than total cholesterol content alone, critically influences mitochondrial membrane composition, bioenergetics, and stress signaling in cardiomyocytes. These observations raise the possibility that PLTP-regulated lipid flux may indirectly shape mitochondrial function by modulating cellular cholesterol homeostasis. This review synthesizes current knowledge of PLTP biology, cholesterol metabolism, and lipoprotein remodeling, and integrates these concepts with emerging frameworks in cardiomyocyte lipid metabolism and mitochondrial physiology. We highlight human iPSC-derived cardiomyocytes as a strategic and translationally relevant platform to investigate PLTP’s non-canonical, cell-intrinsic roles, identify critical knowledge gaps, and propose future directions for elucidating how PLTP may influence mitochondrial function in human cardiac cells. Full article

Liver diseases, ranging from chronic hepatitis and metabolic dysfunction to cirrhosis and hepatocellular carcinoma, represent a major global public health burden. As an immune-privileged organ, the liver harbors a unique and intricate immune microenvironment, which plays a dual role in pathogen clearance and chronicity. Kupffer cells (KCs), the primary resident macrophages in the liver, constitute the first line of defense in liver innate immunity and play complex and important roles in pathogen recognition, phagocytosis, and the regulation of liver inflammation and immune responses. The complement receptor of the immunoglobulin superfamily (CRIg) is a membrane receptor that is specifically expressed on KCs. It serves not only as a sentinel for the liver against pathogen invasion but also as a sophisticated regulator for maintaining immune homeostasis. As a key component of the liver’s immune system, CRIg can efficiently mediate the clearance of complement-opsonized particles, thereby playing multidimensional roles in pathogen clearance, antigen cross-presentation, and the establishment of immune tolerance, functioning as both a “pathogen catcher” and an “immune brake.” This review focuses on the CRIg molecule, detailing its mechanisms in the recognition and phagocytic clearance by KCs, and its subsequent impact on hepatic immune responses. Furthermore, we explored the potential involvement of CRIg in the pathological progression of diverse liver diseases, including persistent inflammation, fibrosis, and hepatocarcinogenesis. This synthesis provides novel insights into the immunopathology of liver diseases and establishes a theoretical foundation for developing CRIg-targeted therapeutic strategies. Full article

Type 2 diabetes mellitus (T2DM) is frequently complicated by dyslipidemia, which accelerates insulin resistance and the progression of cardiovascular and hepatic diseases. While exercise intervention is a cornerstone of T2DM management, a systems-level understanding of its underlying molecular mechanisms remains incomplete. This article summarizes current evidence to propose that exercise functions as a signaling network regulator, concurrently modulating critical lipid metabolism-related signaling pathways: cyclic adenosine monophosphate (cAMP), phosphatidylinositol 3-kinase–protein kinase B (PI3K–AKT), forkhead box O (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways. We delineate how dysregulation of these signaling pathways contributes to lipid disorders in T2DM, highlighting their tissue-specific and often bidirectional roles. Subsequently, we detail the molecular adaptations induced by various exercise modalities—from aerobic training to high-intensity intervals—that restore homeostasis of this signaling network. By integrating these findings, we present a novel framework for precision exercise—defined as the tailoring of exercise modality, intensity, and volume based on an individual’s predominant signaling pathway disturbance, assessed via circulating or tissue-specific biomarkers. This framework advocates for future exercise prescriptions to be guided by molecular profiling alongside traditional physiological indicators. This mechanistic insight not only deepens our comprehension of exercise physiology but also paves the way for more effective, personalized strategies to combat T2DM and its metabolic complications. Full article

Hepatitis C virus (HCV) infection is a global health concern, chronically affecting over 71 million people. It primarily targets the liver but also causes systemic complications through inflammation, oxidative stress, and metabolic dysregulation. HCV is a highly variable RNA virus with six major genotypes that are mainly transmitted via blood. Often asymptomatic, the infection progresses silently to chronic hepatitis C (CHC), which can lead to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have revolutionized treatment, achieving cure rates above 95%, improving liver function, reversing fibrosis, and normalizing metabolism. HCV disrupts iron metabolism by suppressing hepcidin, causing iron overload and oxidative stress. It also alters lipid metabolism, inducing steatosis, and affects glucose metabolism, contributing to insulin resistance and type 2 diabetes. DAAs improve these metabolic outcomes. HCV promotes oxidative stress via viral proteins, damaging liver cells and DNA and triggering inflammation and fibrogenesis. Even post-cure, oxidative stress and iron overload may continue to drive disease progression. Genetic and epigenetic factors influence fibrosis progression and HCC risk. Despite a sustained virologic response (SVR), patients with advanced liver damage remain at risk for HCC and metabolic diseases, highlighting the need for continued monitoring and personalized post-treatment care. Full article

Honey lemon (H&L) is a traditional beverage known for its potential liver-protective effects, but its mechanisms against alcoholic liver disease (ALD) remain poorly understood. This study aimed to investigate the hepatoprotective properties of H&L and explore its multi-target mechanisms in alleviating ALD. Using network pharmacology and molecular docking, we identified 26 bioactive compounds in H&L and 335 potential targets associated with ALD. Pathway enrichment analysis revealed that H&L might exert its influence by regulating inflammation, oxidative stress and ethanol metabolism. Molecular docking further demonstrated strong binding interactions between key flavonoids (hesperidin, diosmin, and eriocitrin) and crucial targets, such as AKT1, SRC, STAT3, as well as ethanol-metabolizing enzymes like ADH, ALDH, and CYP2E1. In vivo experiments suggested that H&L alleviated liver injury and significantly improved selected indicators related to ethanol metabolism, oxidative stress, and inflammatory response. For several variables, including ALT/AST, ALDH, IL-6, and hepatic ethanol content, improvement trends were observed, although not all differences reached statistical significance. Overall, the results suggest that the protective effect of H&L against ALD may be associated with a multi-component, multi-target, and multi-pathway mode of action, supporting its potential for further investigation as a functional food candidate. Full article

Leucine-rich repeat kinase 2 (LRRK2) is a multidomain serine/threonine kinase and a major genetic contributor to Parkinson’s disease (PD). Although LRRK2 has been extensively studied in neurodegeneration, emerging evidence indicates that it also plays a critical role in systemic metabolism. LRRK2 regulates glucose homeostasis through modulation of insulin signaling, vesicle trafficking, mitochondrial function, and inflammatory responses. Studies using LRRK2 knockout and knock-in models, including the pathogenic G2019S mutation, have revealed abnormalities in insulin sensitivity, adipose tissue inflammation, hepatic glucose production, and skeletal muscle metabolism. Mechanistically, LRRK2 phosphorylates Rab GTPases, thereby controlling insulin receptor trafficking and GLUT4 translocation. In addition, LRRK2 influences mitochondrial dynamics and reactive oxygen species production, linking metabolic stress to inflammatory signaling. Importantly, LRRK2 also regulates innate immune pathways, including TLR4–NFκB signaling and inflammasome activation, thereby connecting peripheral metabolic dysfunction to neuroinflammation. Here, we propose an integrated metabolic–neuroinflammatory crosstalk model in which LRRK2 functions as a molecular coordinator linking peripheral metabolic dysfunction to central neurodegeneration. In this framework, systemic metabolic stress—characterized by insulin resistance, chronic inflammation, advanced glycation end product (AGE) accumulation, and blood–brain barrier disruption—drives microglial activation and neurodegenerative processes. Understanding this systemic axis may provide new therapeutic opportunities targeting both metabolic dysfunction and neurodegeneration in PD. Full article

Background: Accurate prognostic stratification remains essential for optimizing outcomes in hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT). The hemoglobin–albumin–lymphocyte–platelet (HALP) score is a composite biomarker reflecting systemic inflammation, nutritional status, and immune competence, and has demonstrated prognostic value in several malignancies. This study aimed to evaluate the predictive utility of the HALP score for survivals and recurrence in HCC patients undergoing LT. Methods: A total of 476 consecutive patients who underwent LT for HCC between 2006 and 2024 were retrospectively analyzed. Pretransplant HALP scores were calculated for all patients. Receiver operating characteristic (ROC) analysis identified an optimal cut-off value of 29 for recurrence prediction. Patients were stratified into HALP ≥ 29 and HALP < 29 groups. DFS and recurrence rates were compared. Prognostic performance was assessed using the concordance index (C-index) and area under the ROC curve (AUC). Outcomes were further compared with the Milan and Expanded Malatya criteria. Results: Of the 476 patients, 335 (70.4%) had HALP ≥ 29 and 141 (29.6%) had HALP < 29. The HALP ≥ 29 group demonstrated significantly higher 5- and 10-year DFS rates compared with the HALP < 29 group (67.1% vs. 58.5% and 49.5% vs. 33.5%, respectively; p < 0.001). Recurrence rates were significantly lower in the HALP ≥ 29 group (14.0% vs. 31.9%; p < 0.001). However, patients within the Milan and Expanded Malatya criteria showed superior long-term DFS and lower recurrence rates in the HALP ≥ 29 compared to the HALP < 29 group (p ≤ 0.037). HALP ≥ 29 was associated with lower tumor burden parameters and improved hepatic functional reserve. Despite its significance, HALP demonstrated inferior discriminative performance (C-index: 0.565) compared with the Milan (0.621) and Expanded Malatya (0.648) criteria. Patients beyond the Milan criteria (n = 233) with HALP ≥ 29 achieved a 5-year overall survival of 54.2%, compared with 37.8% with HALP < 29. Conclusions: Low HALP score is associated with poor DFS and a high post-transplant recurrence rate. Although it represents a non-invasive and cost-effective biomarker, its prognostic accuracy remains inferior to established transplant selection criteria, limiting its use as a standalone selection tool. However, individuals beyond Milan with HALP ≥ 29 achieved survival outcomes exceeding internationally accepted post-transplant benchmarks. Incorporating HALP into pre-transplant evaluation may help identify a biologically favorable subgroup among patients traditionally considered high risk based solely on tumor burden. Full article

Adolescence is a metabolically vulnerable period, during which rapid physiological maturation coincides with the dynamic remodelling of the gut microbiome. This narrative review summarises evidence from 2015 to 2025 to clarify how disturbances to the gut–liver axis driven by dysbiosis contribute to the development and progression of non-alcoholic fatty liver disease (NAFLD) in young people. Based on a systematic search of the databases PubMed, Scopus and Web of Science, we outline the basis of bidirectional communication between the gut and liver and emphasise how microbial imbalance alters the handling of lipids in the liver by enhancing de novo lipogenesis, impairing fatty acid oxidation and disrupting AMPK signalling and mitochondrial function. Consistent findings from clinical and experimental studies show that adolescents with NAFLD exhibit reduced microbial diversity, the enrichment of ethanol- and LPS-producing taxa, and altered short-chain fatty acid profiles. Each of these is associated with hepatic inflammation and metabolic reprogramming. Microbial molecules, including LPS, secondary bile acids and branched-chain amino acid metabolites, activate TLR4–NF-κB pathways, promote Kupffer cell activation and intensify oxidative stress. These mechanisms intersect with factors specific to adolescence, such as increased adiposity, hormonal shifts and diet-induced metabolic strain. Dietary patterns emerge as key modulators of these processes. Westernised diets promote dysbiosis and endotoxemia, whereas Mediterranean, fibre-rich and plant-based diets enhance SCFA production, strengthen epithelial integrity and modulate adiponectin-dependent hepatic metabolism. Micronutrient-sensitive epigenetic regulation, particularly that involving folate, choline and polyphenols, also plays a role in shaping lipid homeostasis and inflammatory tone. We also highlight emerging evidence that the activation of cytoprotective pathways, especially Nrf2, is dependent on lifestyle factors and links antioxidant-rich functional foods and physical activity to improved mitochondrial resilience and microbiome stability. We evaluate therapies targeting the microbiome, including probiotics, prebiotics, synbiotics and postbiotics, which reduce endotoxemia, restore microbial balance and complement dietary strategies. Thus, these findings emphasise the importance of age-specific, mechanistically informed interventions that integrate diet quality, microbial ecology, and the molecular pathways that govern metabolic health in adolescents with NAFLD. Full article

Microplastics are emerging environmental contaminants capable of crossing epithelial barriers and circulating systemically, potentially affecting organisms, including humans. This study investigated the hematological and biochemical effects of sub-chronic oral exposure to polystyrene microplastics (PS-MPs) in male Swiss albino mice. Animals received 1 μm PS-MPs in drinking water at 0.01 mg/day for four weeks, followed by a two-week recovery period. Blood samples were collected weekly for hematological and biochemical analysis. PS-MP exposure resulted in an increased number of certain immunocytes after the first week of treatment. The highest values compared with the control group were observed in Week 2, reaching 18.5 ± 4.61 vs. 7.2 ± 1.14; 10.9 ± 2.58 vs. 5.1 ± 1.20; and 5.8 ± 2.35 vs. 2.2 ± 0.69 × 10⁹ cells/L for white blood cells, lymphocytes, and granulocytes, respectively (p < 0.001). A significant increase in platelet count was also observed, becoming evident by Week 6 (725.8 ± 307.96 vs. 470.1 ± 121.87 × 10⁹ cells/L, p < 0.05). The elevated alanine aminotransferase and aspartate aminotransferase activities observed after PS-MP exposure were potentially associated with hepatic pathology, erythrocyte damage, and inflammatory responses. No significant recovery was observed during the period after exposure. These findings demonstrate that sub-chronic oral PS-MP exposure induces inflammatory responses and may disrupt organ function. Full article

Chronic liver diseases, including fibrosis and hepatocellular carcinoma (HCC), are primarily driven by oxidative stress, yet traditional antioxidant therapies often lack the specificity and efficacy required for clinical success. This review evaluates the emerging therapeutic potential of two atypical globins, cytoglobin (CYGB) and neuroglobin (NGB), exploring their unique hexacoordinated heme structures that enable potent reactive oxygen and nitrogen species (ROS/RNS) scavenging and redox-regulated signaling. We summarize a broad range of in vitro and in vivo evidence demonstrating that these globins deactivate hepatic stellate cells, reduce extracellular matrix accumulation, and function as tumor suppressors by modulating pathways such as Raf/MEK/ERK and NRF2. In human cohorts, CYGB expression levels inversely correlate with the progression of Metabolic Dysfunction-Associated Steatohepatitis (MASH) and HCC, highlighting its potential as a clinical biomarker. Furthermore, recombinant protein therapies involving CYGB and NGB show promise in promoting collagen degradation and inhibiting malignant transformation. We conclude that CYGB and NGB represent sophisticated catalytic redox regulators that offer a novel therapeutic paradigm for restoring redox homeostasis. While delivery and pharmacokinetic barriers remain, these globins are highly promising candidates for first-in-class biologics in hepatology. Full article

Ciliopathies, initially known as fibrocystic liver diseases, encompass a group of inherited disorders characterized by cystic dilatation of intrahepatic bile ducts and portal fibrosis, frequently associated with renal anomalies. These disorders are now recognized as resulting from defects in primary cilia. The hepatic manifestations, such as congenital hepatic fibrosis (CHF), Caroli syndrome, and polycystic liver disease, arise from ductal plate malformation. Recent studies have implicated variants in the TULP3 (Tubby related protein variant 3) gene in a novel monogenic ciliopathy affecting the liver, kidneys, and heart. We report an 8-year-old boy who presented with variceal bleeding and evolved to a progressive phenotype of CHF. Whole exome sequencing revealed a homozygous novel TULP3 mutation. The patient was managed by endotherapy and propranolol prophylaxis. Due to repeated episodes of variceal bleeding and progressive worsening of hepatic synthetic functions, he underwent a living donor liver transplantation at the age of 12 years. Full article

Blood metabolism in dairy cows is crucial for milk quality, functioning primarily through the “blood–milk” metabolic axis. Allium mongolicum Regel (AMR), a functional Allium herb, has been shown to regulate on ruminant lipid metabolism. This study investigated the impact of AMR ethanol extract (AME) on lactation performance, blood lipid parameters, and blood–milk metabolomes. Twelve mid-lactation Holsteins (606 ± 11 kg; milk yield 33.14 ± 2.08 kg/d) of parity 2–3 were assigned to either a basal diet (CON) or a diet supplemented with 54 g/d of AME (AEE). Results indicated that AME significantly decreased plasma triglycerides (TG), C15:0, C16:1, C18:1 n-9 c, C18:3 n-6, monounsaturated fatty acids (p < 0.05) and significantly increased C18:2 n-6 c, polyunsaturated fatty acids (p < 0.05). Lactation performance, including the average daily dry matter intake, daily yields of milk fat, protein and lactose, remained unaffected by the AME addition (p > 0.05). Metabolomic profiling revealed that AME significantly enriched the glycerophospholipid metabolism pathway in plasma, upregulating key phospholipid precursors such as L-serine and Sphinganine. Concurrently, milk metabolomics showed an upregulation of short-chain Acylcarnitines. Plasma TG correlated negatively with both plasma L-serine and milk Acylcarnitines, whereas low-density lipoprotein correlated positively with these energy-driven milk metabolites. These findings suggest that AME may contribute to remodeling the plasma lipid metabolic profile in a manner that could facilitate plasma-to-milk lipid flux. This appears to occur through enhanced hepatic lipid processing and increased mammary lipid utilization, offering preliminary insights into potential nutritional strategies for supporting lipid metabolism in dairy cows. Full article

Background: Pregnancy in women with liver cirrhosis is considered a rare clinical condition due to the decreased fertility commonly associated with chronic liver disease. Hormonal disturbances, anovulation and impaired hepatic function contribute to the lower conception rates observed in this population. However, when pregnancy occurs, it is associated with a significantly increased risk of maternal and fetal complications. Maternal risks include hepatic decompensation, variceal bleeding, ascites, coagulopathy and a higher rate of hypertensive disorders during pregnancy and related complications. Fetal complications involve prematurity, intrauterine growth restriction, and increased perinatal mortality. Methods: We present the clinical case of a woman with idiopathic liver cirrhosis who experienced four consecutive pregnancies with different clinical courses and outcomes. Results: The case highlights the complexity of managing pregnancy in patients with chronic liver disease and underscores the importance of individualized clinical assessment and multidisciplinary management. This report also reviews current management strategies and discusses key considerations for optimizing care in pregnant women with liver cirrhosis. Conclusions: Advances in multidisciplinary care and improved management strategies have contributed to better pregnancy outcomes in recent years. Careful monitoring during pregnancy, appropriate management of portal hypertension, and coordinated care between obstetricians, hepatologists, and neonatologists are essential to minimizing potential complications, ensuring favorable maternal and fetal outcomes. Full article