Search Results (2,513)

Chronic liver disease (CLD) constitutes a major global health burden, with high morbidity and mortality, limited treatment options for several etiologies, and an urgent need for novel therapeutic targets. Fibroblast growth factor 1 (FGF1) is a unique member of the FGF family capable of binding all four FGFR subtypes, thereby regulating multiple signaling pathways including PI3K/AKT, Ras/MAPK, and PLCγ, which are involved in metabolism, cell survival, proliferation, and tissue repair. Emerging evidence highlights the multifaceted and context-dependent roles of FGF1 in CLD. In drug-induced liver injury (DILI) caused by anti-tuberculosis drugs, acetaminophen, or doxorubicin, FGF1 confers protection by restoring bile acid homeostasis, reducing oxidative stress, inflammation, and apoptosis. In Metabolic dysfunction-associated steatotic liver disease (MASLD), FGF1 ameliorates hepatic steatosis, oxidative injury, and insulin resistance through downregulation of SREBP1, upregulation of PPARα, and activation of Nrf2-mediated antioxidant responses. Conversely, in primary sclerosing cholangitis (PSC), FGF1 aggravates ductular reaction, biliary senescence, and liver fibrosis via upregulation of SASP and TGF-β1, suggesting that inhibition of the FGF1/FGFR axis may be therapeutic. For alcohol-related liver disease (ALD), although direct experimental evidence is lacking, FGF1 is hypothesized to confer protection given its known activities against oxidative stress, lipid dysregulation, and cell death. Despite its promise, the mitogenic potential of FGF1 raises safety concerns; however, N-terminally modified FGF1 analogs (e.g., FGF1Δ) retain metabolic benefits with reduced proliferative activity. Collectively, FGF1 represents a versatile and disease-dependent regulator in CLD, warranting further mechanistic studies, safety evaluations, and development of targeted analogs as a novel therapeutic strategy for difficult-to-treat liver diseases. Full article

Hepassocin, also known as fibrinogen-like protein 1 (FGL-1), is a liver-derived secretory protein initially identified as a mitogenic factor involved in hepatocyte proliferation and liver regeneration. Increasing evidence has subsequently suggested that FGL-1 functions as a hepatokine linking hepatic metabolic stress to systemic metabolic regulation. Experimental and clinical studies have demonstrated that circulating FGL-1 levels are associated with obesity, insulin resistance, metabolic dysfunction-associated steatotic liver disease (MASLD), and type 2 diabetes mellitus (T2DM). Mechanistically, FGL-1 appears to contribute to metabolic dysfunction by impairing insulin signaling and promoting hepatic lipid accumulation, although its precise molecular targets remain incompletely defined. In addition to its metabolic roles, FGL-1 has been identified as a major ligand of lymphocyte activation gene-3 (LAG-3), implicating it in immune modulation and tumor progression, particularly in hepatocellular carcinoma (HCC). However, most available human data are observational, and conflicting findings from experimental models suggest that FGL-1 may function as a context-dependent mediator rather than a purely pathogenic factor. Given the expanding but sometimes conflicting evidence, a comprehensive understanding of FGL-1 biology may provide important insights into the complex interactions among hepatic stress responses, metabolic dysfunction, and immune regulation. This review therefore examines the current evidence regarding the physiological and pathological roles of FGL-1 and highlights key unresolved questions that may influence future translational research and therapeutic development. Full article

Hepatic ischemia–reperfusion injury (HIRI) is a major cause of postoperative liver dysfunction and adverse outcomes in hepatectomy, liver transplantation, and hemorrhagic shock. Among the multiple mechanisms implicated in HIRI, mitochondria are recognized as central organelles that integrate metabolic failure, oxidative stress, inflammation, and cell death. During ischemia, interruption of oxygen and nutrient supply impairs oxidative phosphorylation, depletes ATP, disrupts ionic homeostasis, and renders mitochondria highly vulnerable to subsequent injury. Upon reperfusion, reoxygenation triggers excessive reactive oxygen species production, calcium overload, mitochondrial permeability transition pore opening, and release of damage-associated molecular patterns, thereby amplifying hepatocellular injury and sterile inflammatory responses. As a key component of mitochondrial quality control, mitophagy plays a context-dependent role in HIRI. Appropriate activation of mitophagy facilitates the clearance of damaged mitochondria, limits oxidative stress, restrains inflammasome activation, and preserves hepatocellular homeostasis, whereas insufficient or dysregulated mitophagy contributes to mitochondrial accumulation and aggravates liver injury. This review summarizes mitochondrial alterations during the ischemic and reperfusion phases, outlines the major mitophagy pathways involved in HIRI and discusses recent advances in upstream regulation, disease-specific dysregulation, and mitophagy-targeted interventions. A better understanding of the dynamic and biphasic nature of mitophagy in HIRI may provide a stronger theoretical basis for precision liver-protective strategies and future translational therapies. Full article

Background/Objectives: Automated insulin delivery (AID) systems have improved the management of type 1 diabetes (T1D), but exercise and nutrition remain challenging because they rapidly alter glucose flux, substrate oxidation, hepatic glucose output, insulin requirements, and fuel availability. This narrative review aimed to synthesize current evidence on the interaction between AID systems, physical activity, and nutritional strategies from a metabolism-oriented perspective. Methods: A narrative bibliographic approach was used to integrate evidence from clinical trials, observational studies, technical studies, consensus statements, and reviews involving people with T1D across different life stages, including pediatric, adolescent, adult, and pregnancy-related contexts, when available. The review focused on AID systems, exercise physiology, nutritional strategies, meal announcement, bolus adjustment, dual-hormone systems, metabolic biomarkers, and emerging metabolomic approaches. Results: AID systems generally improve time in range and reduce hypoglycemia across several user groups, although most exercise- and nutrition-specific evidence comes from adult and pediatric/adolescent cohorts rather than pregnancy-specific exercise studies. Exercise-related glucose responses remain highly dependent on user input, exercise modality, insulin on board, meal timing, and metabolic state. Planned exercise announcement, prandial bolus reduction before postprandial activity, and individualized carbohydrate intake remain key strategies. Biomarkers such as lactate, ketone bodies, non-esterified fatty acids, and counter-regulatory hormones may help explain interindividual variability and support future personalization. Conclusions: Nutrition and exercise management in AID users should be interpreted as a dynamic metabolic interface among exogenous insulin, endogenous counter-regulation, substrate availability, and algorithmic control. Emerging approaches, including activity sensors, adaptive algorithms, dual-hormone systems, digital twins, and metabolomics-informed personalization, may improve safety and reduce user burden, but several remain exploratory and require further validation in diverse free-living conditions. Full article

Theranostics is a novel approach that integrates diagnostic and therapeutic efficacy on a single platform, holding great promise for precision medicine by enabling real-time monitoring of disease progression and therapeutic response. Despite significant advances, the successful development and delivery of theranostic systems are critically limited by multiple biological barriers present at systemic, tissue, cellular, anatomical, and immunological levels. These barriers restrict bioavailability, target accessibility, and therapeutic efficacy, while often increasing off-target accumulation and adverse effects. This review provides a comprehensive overview of the major biological barriers encountered in theranostic development, including physiological barriers such as plasma protein binding, renal clearance, and hepatic metabolism; anatomical barriers like endothelial linings, the blood–brain barrier (BBB), and the tumor microenvironment; cellular barriers involving membrane permeability, intracellular trafficking, and endo-lysosomal entrapment; and immunological barriers such as immune recognition, inflammatory responses, and complement activation. Special emphasis is placed on the BBB, highlighting its structural complexity, transport mechanisms, and strategies such as molecular Trojan-horse technology, receptor-mediated and adsorptive-mediated transcytosis, and nanocarrier-based approaches to enhance central nervous system delivery. The review further discusses targeted delivery challenges, including receptor heterogeneity and multidrug resistance, and critically evaluates current strategies to overcome these barriers through surface functionalization, stimuli-responsive systems, biomimetic carriers, and controlled-release mechanisms. Finally, recent advances, clinical challenges, and future perspectives—including personalized theranostics, artificial intelligence—assisted design, and next-generation barrier-penetrating systems—are explored. Overall, this review aims to provide a structured understanding of biological barriers in theranostics and highlight innovative approaches to improve their translational potential. Full article

Herpes simplex virus 1 (HSV-1) is a rare cause of acute hepatitis, especially in patients with chronic immunosuppression. We performed whole-genome HSV-1 sequencing with a metagenomics approach on peripheral blood samples from an Italian case of fatal acute liver failure with high circulating HSV-1 (1,129,900,000 copies/mL), followed by phylogenetic analysis. After multiple sequence alignment, a final dataset of 182 whole-genome sequences was selected. The sequenced HSV-1 strain belonged to a phylogenetic clade isolated in Florida in 2002 (OQ724868.1). A characterization of single nucleotide polymorphisms and indels was performed to determine their effects on the viral genome: only one variant, classified as an indel, was detected with a high impact effect (c.905_906insGTTTT) in the UL49A gene, which is known to encode a membrane protein regulating virion morphogenesis, replication and assembly. In addition, this study also detected variants in other genes involved in crucial steps of the HSV-1 life cycle, like alpha-regulation (US7), capsid transport (UL36) and viral polymerase function (UL30). In conclusion, the results of this variant analysis confirmed that in HSV-1 hepatitis, some viral regions may be hotspots for adaptive mutations with a substantial impact on viral replication or immune evasion. Full article

Background: Following the coronavirus disease 2019 (COVID-19) pandemic, increased reports of severe acute hepatitis of unknown etiology in children have raised concerns about virus-associated liver injury. Acute respiratory tract infections (ARTIs) are a common cause of pediatric hospitalization and may be accompanied by reactive hepatitis; however, virus-specific patterns of hepatic involvement remain incompletely defined. This study aimed to evaluate liver involvement associated with ARTIs in hospitalized children. Methods: This retrospective study included pediatric patients (<18 years) hospitalized with ARTIs between October 2021 and May 2023. Respiratory viruses were identified via multiplex real-time polymerase chain reaction assays. Liver function tests were systematically evaluated during hospitalization. Transaminase elevations were categorized according to the upper limit of normal (ULN = 40 U/L). Acute hepatic failure was defined according to the Pediatric Acute Liver Failure criteria. Results: A total of 179 patients were analyzed (median age: 38 months; 59.2% male). Elevated AST and ALT levels were observed in 24.0% and 8.4% of patients, respectively. Adenovirus was the most frequently detected virus (11.2%), followed by influenza A (7.3%) and parainfluenza virus (6.7%). Severe transaminase elevations (>5 × ULN and >500 U/L) were observed in patients with influenza infection. All cases of acute hepatic failure (n = 3) were associated with influenza infection. Other respiratory viruses were associated with mild or transient liver enzyme abnormalities. Conclusions: Severe hepatic involvement—including severe transaminase elevation and acute hepatic failure—occurred exclusively in children with influenza infection, particularly influenza B, while mild and transient liver enzyme abnormalities were common across other respiratory viral infections. These findings highlight the importance of targeted liver function monitoring in pediatric influenza patients and provide clinically relevant data on virus-specific hepatic involvement in the post-COVID-19 era. Full article

Background: The metastatic dissemination of melanoma involves adhesion of circulating tumor cells within organ-specific vascular beds; however, the relative contribution of the endothelial environment versus that of the melanoma-intrinsic molecular state remains unclear. Materials and Methods: We quantified the in vitro adhesion of primary (n = 5) and metastatic (n = 3) melanoma cell lines to human hepatic, brain, and pulmonary endothelial cells under co-culture conditions, and we profiled the expression of 86 adhesion- and extracellular-matrix-related genes in melanoma and endothelial cells. Results: Adhesion was highest for the hepatic endothelium, intermediate for the pulmonary endothelium, and lowest for the brain endothelium. This endothelial preference was conserved in both primary and metastatic melanoma cells, though metastatic cells exhibited higher absolute adhesion. The linear mixed-effect models revealed that the effects of adhesion state on melanoma gene expression were modest and varied by endothelial type, whereas melanoma origin had more widespread and larger effects (mean absolute standardized coefficients of 0.32–0.47 versus 0.60–0.87, respectively). The expression of three genes (SPP1, ITGA11, and MMP2) was associated with melanoma origin in all endothelial types. Spearman’s co-expression analysis revealed endothelial-type-specific gene networks, and within-sample permutation confirmed the non-random coordination in all three endothelial types. Conclusions: Our findings support a model in which endothelial organ specificity contributes to melanoma cell adhesion behavior and associated transcriptional patterns, highlighting the importance of the vascular interface as a biologically active mediator of early metastatic cell–endothelium interactions. Full article

Background/Objectives: Obesity-associated metabolic dysfunction involves oxidative stress, gut barrier impairment, and gut–liver axis disruption. This study evaluated whether enzymatically prepared Solenocera crassicornis peptides (SCPs) provide additional benefits during diet normalization in HFD-induced obese mice and examined associations with antioxidant, microbial, and barrier markers. Methods: SCPs were characterized using UPLC-Q-TOF-MS/MS and amino acid analysis. Peptides underwent bioactivity prediction and Keap1 docking. After 7 weeks of HFD feeding, obese male C57BL/6J mice were switched to a normal diet and administered vehicle, orlistat, or SCPs for 4 weeks. Adipose tissue mass, serum lipid profiles, liver histology, hepatic antioxidant status, barrier-associated histological and biochemical markers, and gut microbiota composition were assessed. A simulated digestion–fecal fermentation model was used to assess the effects of fermentation products generated in the presence of digested SCPs on H₂O₂-induced oxidative injury and MUC2 secretion in LS174T goblet-like cells. Results: SCPs reduced epididymal and perirenal fat, improved serum lipids, improved hepatic steatosis-related morphology and enhanced hepatic antioxidant status. SCPs were also associated with improved intestinal morphology, increased mucin-associated staining, decreased serum diamine oxidase levels and reduced hepatic lipopolysaccharide accumulation. 16S rRNA sequencing showed SCP-associated microbial shifts, with correlations linking taxa to metabolic and barrier markers. Fermentation products generated in the presence of digested SCPs improved oxidative-stress and MUC2-related readouts in LS174T cells. Conclusions: During diet normalization, SCPs were associated with additional improvements in adiposity, lipid profiles, hepatic antioxidant status, intestinal barrier readouts, and gut microbiota. These findings support further investigation of SCPs as standardized marine protein hydrolysates, but active components, causal mechanisms, long-term efficacy, safety, and human relevance remain to be established. Full article

Background: Abnormalities in energy and amino acid metabolism are potentially involved in hepatocellular carcinoma (HCC) development. This study aimed to identify serum metabolites predictive of HCC following sustained virological response (SVR) with hepatitis C virus (HCV) treatment. Methods: Comparative metabolomics was conducted using time-course serum samples from patients who failed interferon-based therapy but subsequently achieved SVR with direct-acting antivirals (DAAs), minimizing inter-individual variability. Predictive biomarkers for post-SVR HCC were extracted from the results and validated by comparing 29 patients who developed post-SVR HCC with 58 age-matched patients who remained HCC-free during follow-up. Results: Metabolite concentrations changed more markedly after treatment in SVR cases than in non-SVR cases. Significant changes in methionine (Met), methionine sulfoxide (MetO), and ornithine (Orn) levels before and after treatment (Pre- and Post-Tx) were found only in the non-HCC group. Regression and survival analyses identified high levels of Pre- and Post-Tx Orn, Pre-Tx Met, and Post-Tx MetO as predictors of post-SVR HCC and enabled risk stratification. The integration of these metabolites with the fibrosis-4 (FIB-4) index and alpha-fetoprotein (AFP) facilitated risk stratification and discriminated between high- and low-risk patients. The Pre-Tx FIB-4/Met model and the Post-Tx AFP/MetO/Orn model identified low- and high-risk groups with 3-year HCC incidence rates of 6.4% and 81.8%, respectively. Conclusions: Serum Met, MetO, and Orn were identified as candidate biomarkers associated with post-SVR HCC development, which remains a concern in the fight against hepatitis C. Combining these metabolites with established clinical markers may improve post-SVR HCC risk stratification. Full article

Background: Retinoid signaling is implicated in regulating membrane-bound polyunsaturated fatty acids (PUFAs), which serve as substrates for oxylipin biosynthesis. Dysregulated vitamin A status and altered oxylipin profiles have both been associated with the development of metabolic diseases. However, whether early-life vitamin A deficiency (VAD) causally influences oxylipin metabolism and liver health remains unclear. Methods: C57BL/6J mouse pups were exposed to either a vitamin A-deficient (VD) or vitamin A-replete (VR) AIN-93G-based diet during the fetal and suckling periods, and they weremaintained on the same diet from weaning (3 weeks of age) to 9 weeks of age. Oxylipin composition in plasma, liver and cerebral tissues was analyzed by liquid chromatography–mass spectrometry. Hepatic and cerebral expressions of genes involved in inflammation, phospholipid and PUFA catabolism, and oxylipin synthesis were analyzed using RT-qPCR. Results: Dietary deprivation induced severe VAD, which significantly altered 21 oxylipins in the liver and 34 oxylipins in the cerebrum, but did not affect the plasma oxylipin profile. In the liver, all altered oxylipins were elevated by VAD, the majority being ω-6-derived species with pro-inflammatory properties. In contrast, 27 altered oxylipins were lower in the VD cerebrum, including more ω-3-derived species. Multivariate analysis identified 11,12-EpETrE, 8,9-EpETrE, and 20-HETE as key hepatic oxylipins distinguishing VAD. VAD also altered hepatic expression of genes involved in membrane phospholipid remodeling (PNPLA8, PLA2G6, LPCAT3), and oxylipin metabolism (ALOX5, EPHX2), and it upregulated inflammatory signaling in the liver only, while fibrosis markers (TGFB1, COL1A1) remained unchanged. Conclusions: These findings demonstrate that early-life VAD is associated with tissue-specific alterations in oxylipin metabolism and hepatic inflammatory responses. Full article

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide (LIR), are widely used in humans to treat type 2 diabetes mellitus, obesity, and non-alcoholic fatty liver disease. In mammals, GLP-1 RAs have been shown to influence hepatic lipid metabolism, although the underlying mechanisms remain unclear. In fish, GLP-1 also plays an important role in regulating hepatic processes, including glycogenolysis, gluconeogenesis, and lipolysis. However, the effects of GLP-1 RAs on liver lipid metabolism in fish remain largely unexplored. Objective: This study aimed to evaluate the effects of LIR on lipid target genes using primary hepatocytes from brown trout as an in vitro model. Methodology: After 24 h, a hepatocyte monolayer culture was established, and cells were exposed for 24 and 48 h to supplemented L-15 medium (control), 0.1% dimethyl sulfoxide in supplemented L-15 medium (solvent control), and five single exposures to LIR at 1, 10, 100, 500, and 1000 nM. After 24 and 48 h, cell viability was assessed using the trypan blue exclusion assay. Gene expression was analysed by real-time qPCR, targeting genes involved in lipogenesis, lipid transport, and cholesterol efflux. Results: No concentration-dependent effects on cell viability were observed. Gene expression analysis showed that LIR exposure modulated the mRNA levels of lipid-related genes, including acetyl-CoA carboxylase (ACC), acyl-CoA long-chain synthetase 1 (Acsl1), and fatty acid synthase (FAS), with time being the main influencing factor. Overall, expression levels were higher at 48 h compared to 24 h. Additionally, dose-dependent effects were observed for ACC expression, with higher LIR concentrations showing significant differences compared to controls. Conclusions: These findings indicate that LIR modulates lipid-related gene expression in primary hepatocytes of brown trout without affecting cell viability. The results suggest that GLP-1 receptor activation may influence key pathways involved in hepatic lipid metabolism, with time-dependent effects playing a predominant role. Overall, this study supports the use of brown trout primary hepatocytes as a suitable in vitro model for investigating hepatic lipid responses to LIR and other GLP-1 receptor agonists, while providing initial insight into their potential effects in fish. Full article

The gut microbiota is increasingly examined as a therapeutic target because it contributes to epithelial barrier integrity, microbial metabolite production, bile acid transformation, immune regulation, and communication between the gut and distant organs. This structured narrative review synthesizes evidence on microbiota involvement in metabolic, gastrointestinal, hepatic, cancer, and neuroimmune conditions, including MASLD/MASH, inflammatory bowel disease, irritable bowel syndrome, obesity, type 2 diabetes, hypertension, colorectal cancer, Parkinson’s disease, and autism spectrum disorder. Across these conditions, microbiome findings are biologically plausible but heterogeneous. Many associations are shaped by diet, geography, medication exposure, host genetics, disease stage, sampling methods, and analytical pipelines. Microbial alterations should therefore be interpreted as context-dependent signals and candidate modifiers rather than universal causal markers. Conventional microbiota targeted strategies include diet, physical activity, prebiotics, probiotics, synbiotics, postbiotics, and fecal microbiota transplantation. These approaches are clinically familiar, but their effects are often broad, host specific, strain dependent, and difficult to assign to one mechanism. Fecal microbiota transplantation has the clearest clinical role in recurrent Clostridioides difficile infection, while evidence for most other indications remains inconsistent. Engineered microbial therapeutics offer greater experimental precision through signal sensing, payload delivery, metabolic modulation, and genetic circuit design. However, most evidence remains preclinical or early translational. Progress requires stronger human trials, standardized methods, mechanistic validation, safety monitoring, ecological containment, transparent reporting, and proportionate regulation. Full article

Physiotherapy is an evidence-based healthcare occupation aiming to collaborate in the diagnosis, prevention and treatment of a myriad of diseases and clinical scenarios throughout all stages of human life. Its development has been accelerated over the last two decades. The scope of physiotherapy is continuously evolvig. However, the accumulated evidence in the context of rare diseases is scarce. Remarkably, the opportunity for improvement and potential benefit for complex diseases with low prevalence is also very high, both as an isolated approach or within multidisciplinary specialized units. Systemic light-chain (AL) amyloidosis is a rare, chronic, complex, heterogeneous, incurable, and challenging disease, which may involve different organs and systems, including the heart, kidney, liver, peripheral nerves, lung, muscle, skin, and others. Heart is the most frequently involved organ leading to failure and arrhythmias. Peripheral neuropathy is a relatively frequent symptom. Renal, respiratory, and hepatic failure may also occur. The aim of this narrative review is summarizing, updating, and critically underlining potential new avenues of development on the role of physiotherapy in systemic light-chain (AL) amyloidosis, compared with its application in multiple myeloma, a closely related but not so rare entity. Full article

Peroxisomes are essential metabolic organelles that support core aspects of cellular homeostasis. In the hepatocytes, peroxisomes govern key aspects of cellular homeostasis, including processing lipid substrates that are inadequately handled by mitochondria, controlling hydrogen peroxide metabolism, and regulating bile acid synthesis. Increasing evidence indicates that these organelles are not merely auxiliary metabolic compartments but active contributors to the development and progression of liver disease. Dynamic alterations in peroxisomal proteins and function are being noted. Across metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic disorders, fibrosis, and hepatocellular carcinoma, peroxisomes undergo remodeling that shows a change from adaptive reactions to maladaptive states. These changes perturb signaling pathways that regulate inflammation, stress responses, and cell fate. In addition, because peroxisomes operate within an interconnected organelle network, their dysfunction propagates to mitochondria, endoplasmic reticulum, and other cellular systems, amplifying metabolic and cellular stress. This review summarizes current understanding of how peroxisomal pathways contribute to liver disease, highlighting mechanisms involving lipid accumulation, oxidative stress, and disrupted organelle crosstalk. How peroxisome-dependent control of circulating metabolites links hepatic injury to extrahepatic organ systems is further discussed. At the end, emerging therapeutic strategies for liver disease targeting peroxisomal pathways are discussed. Together, the emerging understanding of peroxisomal remodeling, metabolic regulation, organelle crosstalk, and inter-organ communication positions peroxisomes as active and dynamic regulators of liver disease and potential targets for therapeutic intervention. Full article