Search Results (1,166)

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

Wesselsbron disease remains an underrecognized mosquito-borne flaviviral disease despite long-standing evidence of ruminant reproductive loss, neonatal disease, hepatic pathology, zoonotic infection, and mosquito-associated circulation. This narrative review critically synthesizes verified evidence on Wesselsbron virus (WSLV) at the animal–human–vector–environment interface, with the specific aim of clarifying why the virus should be considered a surveillance-sensitive One Health pathogen rather than a rare veterinary curiosity. The review integrates classical veterinary pathology, experimental infection studies, human case reports, serological and molecular evidence, mosquito surveillance, ecological suitability modelling, diagnostic-development studies, and recent evidence from molecular epidemiology, camel investigations, and digital histopathology. The review uses an evidence-weighted synthesis to distinguish experimentally and pathologically supported animal disease, confirmed but poorly quantified human infection, mosquito-associated detection, ecological suitability, diagnostic under-recognition, and unresolved reservoir or transmission questions before integrating these domains into a qualitative One Health risk-assessment framework. The evidence supports WSLV as a cause of ruminant abortion, neonatal disease, and hepatic lesions, confirms zoonotic potential, and indicates repeated detection in ecologically relevant mosquito and multi-host contexts. However, current data remain insufficient for robust estimates of animal burden, human incidence, reservoir competence, natural route frequency, or climate-driven expansion. WSLV should therefore be incorporated into targeted differential diagnosis, laboratory readiness, and One Health surveillance where ruminant abortion events, unexplained neonatal disease, compatible mosquito ecology, undiagnosed febrile illness, diagnostic ambiguity, or ecological suitability indicate plausible risk. Full article

Recently, nanosized graphene oxide (nGO) has gained significant scientific interest in biomedical strategies. However, before clinical translation, GO-based nanomaterials must be thoroughly evaluated for safety and biocompatibility. Therefore, this study investigated the in vivo effects of pristine GO and polyethylene glycol-functionalized GO (nGO-PEG) nanoparticles in male Long Evans rats, following repeated intraperitoneal administration (4 mg/kg body weight). The effects of the nanoparticles were assessed using a range of physiological and pathological markers including body weight (BW) gain, organ coefficients, diuresis, histological, hematological and biochemical parameters. Both nGO and nGO-PEG significantly suppressed BW gain and reduced diuresis in treated rats. Nanoparticle exposure resulted in significant kidney enlargement and reduced testes weight. Mild histological alterations were observed in all examined organs, with nGO showing a tendency toward slightly more pronounced changes than nGO-PEG. Serum levels of aspartate aminotransferase, alanine aminotransferase, and creatinine were significantly elevated in nGO-treated rats, whereas nGO-PEG significantly increased the urinary levels of creatinine and urea. Both nGO- and nGO-PEG-treated rats exhibited elevated serum glucose concentrations. Significant hematological changes were detected in rats treated with both nanoparticles with pronounced effects observed following nGO-PEG administration. Our results suggest possible hematological and metabolic disturbances, as well as hepatic injury and renal toxicity in rats at repeated exposure to nGO and nGO-PEG. Full article

D-box binding protein (DBP) is a high-amplitude proline- and acidic amino acid-rich basic leucine zipper (PAR bZIP) transcription factor that functions as a key circadian output regulator downstream of the core molecular clock. Although DBP is widely recognized as a clock-controlled gene, its broader role in converting circadian timing into tissue-specific physiological programs remains incompletely integrated. In this review, we synthesize current evidence supporting DBP as a context-dependent D-box-centered regulatory node. We first summarize the upstream mechanisms that establish rhythmic Dbp expression, including CLOCK–BMAL1-dependent transcription, promoter-level amplification, signaling-dependent modulation, and post-translational control of DBP stability. We then discuss how DBP, together with related PAR bZIP activators and the opposing repressor E4 promoter-binding protein 4/nuclear factor interleukin 3 regulated (E4BP4/NFIL3), regulates D-box-mediated transcriptional output. Finally, we examine tissue-selective DBP functions in hepatic metabolism, pancreatic β-cell secretory competence, neural and behavioral regulation, reproductive neuroendocrine timing, and T helper 9 (Th9)-associated antitumor immunity. Across these systems, DBP does not act as a universal circadian effector; rather, its function depends on chromatin accessibility, cofactor availability, competing transcription factors, and local signaling context. We also highlight the current limits of human translational evidence and propose that DBP-centered signatures may be useful for interpreting circadian output failure in disease. Overall, DBP provides a mechanistically informative framework for understanding how circadian time is transformed into organ-specific physiological function and pathological vulnerability. Full article

Background: The incidence of early-onset colorectal cancer (EOCRC) has increased worldwide and now represents approximately 10% of colorectal cancers in high-income countries. EOCRC is frequently associated with advanced pathological features, although its clinical behavior and optimal management remain incompletely defined. Methods: We performed a retrospective single-center study including 88 consecutive patients aged ≤50 years who underwent curative-intent colorectal cancer resection between January 2019 and December 2023 at a tertiary referral center. Perioperative outcomes, pathological characteristics, and recurrence patterns were analyzed. Results: The median age was 44 years, and 67% of tumors were located in the colon. Pathological nodal involvement (pN+) was observed in 47.7% of patients, with a high prevalence of adverse features including perineural invasion (62.5%), tumor budding (17.0%), and tumor deposits (15.9%). Minimally invasive surgery was performed in 79% of patients and was associated with shorter hospital stay without increased postoperative morbidity (19.3%). During a median follow-up of 31.3 months [IQR 21.6–44.6], recurrence occurred in 40 patients (45.5%) and was predominantly distant (75.0%). Among patients with recurrence, 21 (52.5%) underwent surgical reintervention, most commonly hepatic and pulmonary resections. Rectal cancer was associated with higher rates of stoma formation and major postoperative complications compared to colon cancer. Conclusions: EOCRC is characterized by a high prevalence of adverse pathological features and a substantial rate of distant recurrence. However, a relevant proportion of recurrences remains amenable to surgical treatment in selected patients. Management in a specialized tertiary center allows achievement of high-quality surgical outcomes and supports an aggressive multidisciplinary approach. Full article

Background/Objectives: Systemic diseases such as diabetes mellitus and hepatitis C virus infection are increasingly recognized as important modifiers of oral health. However, their combined impact, as well as the role of behavioral confounders such as smoking, remains insufficiently explored. This study aimed to evaluate oral health parameters in patients with diabetes and/or hepatitis C virus infection, to investigate the prevalence of oral mucosal conditions, and to identify independent predictors of xerostomia, with particular emphasis on glycemic control and smoking. Methods: A cross-sectional study was conducted on 66 patients, including 33 systemically affected individuals and 33 healthy controls. Clinical parameters included the number of teeth, tooth mobility, bleeding on brushing, xerostomia, and oral lichen planus. Glycemic control was defined by using glycated hemoglobin thresholds (controlled < 7%, uncontrolled ≥ 7%). Statistical analyses included non-parametric tests, Spearman correlation, and multivariate logistic regression. Results: Patients with diabetes exhibited significantly fewer teeth (p = 0.001), increased tooth mobility (p = 0.001), and a higher prevalence of gingival bleeding (p = 0.042). Hepatitis C virus infection was strongly associated with oral lichen planus (p = 0.009). Xerostomia was more prevalent in hepatitis C virus infection patients, but in multivariate analysis, smoking emerged as the only independent predictor (OR = 5.73; p = 0.014). Glycemic control was not independently associated with xerostomia after adjustment. Conclusions: Diabetes primarily influences periodontal destruction, while hepatitis C virus infection is associated with mucosal pathology. Smoking plays a dominant role in xerostomia and may confound associations attributed to systemic disease. These findings highlight the importance of integrated oral-systemic assessment and behavioral risk management. Full article

Micro- and nanoplastics (MNPs) are emerging environmental contaminants of increasing relevance to human health. Growing evidence suggests that, following ingestion, inhalation, or, less convincingly, dermal exposure, MNPs may cross biological barriers, enter lymphatic and vascular compartments, and reach the liver. Owing to portal blood flow, sinusoidal architecture and Kupffer cell activity, the liver appears to be one of the principal sites of early particle sequestration. Human biomonitoring, ex vivo and postmortem studies have detected MNPs in blood and multiple organs, including the liver, although the currently available evidence remains limited and methodologically heterogeneous. Their identification relies on multistep analytical procedures that integrate sample pretreatment with FTIR, Raman spectroscopy, LD-IR, Py-GC-MS and supplementary imaging methods. However, each of these techniques presents significant limitations, particularly in the analysis of nanoplastics. Experimental studies indicate that MNPs may induce hepatic injury through oxidative stress, mitochondrial impairment, endoplasmic reticulum stress, inflammation, DNA damage, dysregulated lipid metabolism and disruption of the gut–liver axis, consequently contributing to steatosis, cholestatic anomalies and fibrosis. Consequently, MNPs should be considered potential contributors to liver pathology, although more comprehensive human data are still required. Full article

Liver fibrosis is a reversible phase of arsenic-induced chronic liver injury, with bile acid metabolic alterations closely associated with this pathological process. SIRT1 is a key metabolic regulator and promising therapeutic candidate, while its role in bile acid metabolism during arsenic-induced liver fibrosis remains poorly defined. This study established time-dependent rat models of arsenic-induced liver fibrosis with resveratrol intervention to investigate the potential association between SIRT1, bile acid metabolic disturbance, and liver fibrosis, as well as resveratrol’s hepatoprotective effects. Arsenic exposure induces progressive accumulation of hydrophobic bile acids in the liver, inflammation, hepatic stellate cell activation, and fibrosis, accompanied by suppressed expression of bile acid phase II detoxification genes (Baat, Ugt1a1, Sult2a1) and the bile acid efflux transporter gene Abcb11 (BSEP). Arsenic exposure reduces SIRT1 expression and increases C/EBPα acetylation, which may relate to impaired transcription of the aforementioned bile acid metabolic genes. Resveratrol may restore SIRT1 expression, normalize C/EBPα acetylation and bile acid homeostasis, and reduce hepatic arsenic accumulation, thereby alleviating liver fibrosis. Collectively, the SIRT1/C/EBPα axis and bile acid metabolism may be linked to the progression of arsenic-induced liver fibrosis. Resveratrol may exert protective effects via multiple mechanisms, including regulating these molecular targets and reducing hepatic arsenic accumulation. Full article

Background: Atherosclerosis is the major pathological basis of cardiovascular diseases, while current lipid-lowering therapies remain limited by suboptimal efficacy and safety. Natural flavonoids, with their multi-target pharmacological activities, are promising candidates for anti-atherosclerotic intervention. This study investigated the protective effects and mechanisms of total flavonoids from Berberis kaschgarica Rupr. (BTF) against high-fat diet (HFD)-induced atherosclerosis in ApoE^−/− mice. Methods: Bioavailable constituents of BTF were identified by UPLC-Q-TOF-MS. Network pharmacology and bioinformatics analyses were performed to predict therapeutic targets and pathways. Male ApoE^−/− mice were fed an HFD and treated with low, medium, or high doses of BTF or atorvastatin. Serum lipid profiles, oxidative stress markers, and aortic histopathology were evaluated. Hepatic proteins related to lipid metabolism were measured by Western blotting, and fecal gut microbiota were analyzed by 16S rRNA sequencing. Results: Seven flavonoid monomers, including kaempferol, apigenin, calycosin, and dihydromyricetin, were identified as absorbed constituents in serum. Bioinformatics suggested that BTF regulates targets involved in lipid metabolism, oxidative stress, and inflammation. BTF dose-dependently decreased serum TC, TG, LDL-C, MDA, and LDH, while increasing HDL-C and the activities of SOD, GSH, and CAT. BTF also reduced atherosclerotic plaque formation and preserved aortic wall structure. Mechanistically, BTF downregulated hepatic SREBP1, ACC1, FAS, APOB, and MTP expression and improved HFD-induced gut microbiota dysbiosis by enriching Akkermansia and Lactobacillus. Conclusions: BTF attenuated HFD-induced atherosclerosis by improving lipid metabolism, enhancing antioxidant capacity, and modulating gut microbiota composition, supporting its potential as a natural anti-atherosclerotic agent. Full article

The incidence of liver injury has been increasing year by year, potentially progressing to liver fibrosis, cirrhosis, and even hepatocellular carcinoma, posing a threat to human health. Gardenia, Astragalus, and Hawthorn are commonly used natural products with dual purposes as both medicine and food. While extensive research has been conducted on their individual pharmacological activities, systematic studies on the synergistic effects and efficacy evaluation of their combined use in liver protection are still lacking. This study aimed to investigate the protective effects and underlying mechanisms of the compound Gardenia and Scutellaria extract (GACE) on CCl4-induced liver injury in mice. The composition and content of GACE were analyzed by HPLC. Serum biochemical, inflammatory, and hepatic oxidative stress indicators were detected using assay kits. Liver pathological changes were examined by HE staining, while apoptosis was observed via TUNEL staining. Transcriptomic and metabolomic sequencing were employed to analyze the potential mechanisms of CCl4 in alleviating liver injury. Finally, Western blotting was performed to validate the analytical results. The results demonstrated that CCl4 significantly upregulated the levels of pro-inflammatory cytokines IL-6, IL-12 and IL-2 (p < 0.05), downregulated the level of anti-inflammatory cytokine IL-10 (p < 0.05), and caused markedly elevated serum ALT and AST levels (p < 0.01). The hepatic lobule structure was nearly obliterated in liver tissue, with disordered arrangement of hepatic cords and numerous vacuoles appearing in hepatocytes. The TUNEL staining positive cell rate increased significantly compared with the blank group (p < 0.001). Meanwhile, CCl4 also significantly inhibited SOD and GSH-Px activities in liver tissue (p < 0.05), while markedly increasing MDA levels (p < 0.05). GACE significantly alleviated liver tissue damage and reduced hepatocyte apoptosis (p < 0.05). It markedly enhanced SOD and GSH-Px activities in liver tissue while decreasing ALT, AST, MDA, IL-6, IL-12, and IL-2 levels (p < 0.05), thereby mitigating hepatic oxidative damage and inflammatory responses. Integrated transcriptomic and metabolomic analyses revealed that the PI3K-Akt and MAPK signaling pathways play crucial roles in mediating GACE’s therapeutic effects against liver injury. Further validation demonstrated that GACE can attenuate CCl4-induced liver injury by inhibiting the PI3K-Akt and MAPK pathways. Full article

Liver injury is a complex pathological condition with increasing incidence due to diverse etiologies, including drug-induced liver injury, metabolic dysfunction-associated steatotic liver disease, alcoholic liver disease, viral hepatitis, and autoimmune disorders. Its progression is characterized by persistent hepatic damage and gradual loss of liver function, which may ultimately lead to fibrosis, cirrhosis, and liver failure. However, currently available hepatoprotective drugs still present several limitations, such as insufficient target specificity, limited therapeutic efficacy, and potential adverse effects, highlighting the need for safer and more effective alternatives. Based on a comprehensive search of databases including PubMed, Web of Science, China National Knowledge Infrastructure and Google Scholar, this review summarizes the pathogenic mechanisms of major liver injury types and the therapeutic potential of natural alkaloids. As key secondary metabolites of medicinal plants, alkaloids exhibit structural diversity, potent bioactivities, and favorable safety profiles. Increasing evidence suggests that natural alkaloids exert hepatoprotective effects through multi-target and multi-pathway mechanisms, including the regulation of oxidative stress, inflammation, lipid metabolism, and cell death. These findings highlight their promising potential for the prevention and treatment of liver injury and provide a theoretical basis for the development of novel hepatoprotective agents. Full article

Sepsis-induced liver failure remains a serious and often under-recognized complication of abdominal sepsis. Clinical reports suggest that liver dysfunction develops in a substantial proportion of these patients, and once failure ensues, mortality rises sharply. Despite progress in antimicrobial therapy and critical care support, there is still no therapy that directly halts or reliably reverses septic liver injury. Systemic drug administration frequently underperforms in this setting. Hepatic drug accumulation becomes unpredictable, pharmacokinetics shift, and immune dysregulation further complicates therapeutic control. Nanotechnology-based delivery systems have attempted to address these shortcomings by improving drug stability and circulation time. Yet their behavior under septic conditions remains inconsistent. This inconsistency may reflect a deeper issue: most carriers are engineered under relatively stable physiological assumptions that do not hold during systemic inflammation. Biomimetic platforms, particularly those derived from erythrocyte membranes, offer a different conceptual entry point. Rather than merely evading immune recognition, erythrocyte-based systems interact naturally with hepatic clearance pathways. During sepsis, erythrocyte turnover appears to accelerate, and macrophage-mediated clearance in the liver intensifies. This shift, while pathologic, may present a therapeutic opportunity. In this review, we examine current liver-targeted delivery strategies for sepsis-induced liver failure and critically assess the underexplored role of erythrocyte ghost-based systems. We discuss how sepsis-specific pathophysiological changes reshape carrier biodistribution, identify translational constraints, and propose design considerations for inflammation-adaptive biomimetic platforms. By reconsidering hepatic clearance not solely as a pharmacokinetic barrier but as a potential delivery route, we outline a disease-aligned approach to nanomedicine design in septic organ failure. Full article

Bacterial diseases cause significant losses in the aquaculture of Amazonian fishes (Arapaima gigas, Brycon amazonicus, and Colossoma macropomum). Lactococcosis-causing bacteria (LCB) have emerged as important pathogens in global aquaculture, and although they have already been isolated from these fish species, their pathogenic role remains unconfirmed. This study evaluated the susceptibility of three Amazonian fish species to Lactococcus spp. through experimental infection and performed a detailed examination of the associated pathological damage. Lactococcus formosensis, L. garvieae, and L. petauri strains were used to intracoelomically infect juvenile Amazonian fish. Following infection, the fish were monitored for 15 days to evaluate clinical signs and mortality. Clinical signs were observed in the L. garvieae-challenged A. gigas, with one fish dying at five days post-infection. The remaining experimental animals, regardless of fish species, survived the challenge. All mortalities and surviving fish at the end of the trial underwent bacteriological and histopathological examinations. Bacteriological examination confirmed bacterial re-isolation from asymptomatic animals in the L. garvieae-challenged A. gigas (2/7) and L. formosensis-challenged C. macropomum (3/7) groups using MALDI-TOF MS and multiplex qPCR analysis. No bacterial growth or histological alterations were observed in the control groups or in the groups infected with L. petauri. Microscopic examination revealed L. garvieae-induced fibrinoid-necrotic hepatitis, lymphohistiocytic myocarditis, and myositis in diseased or asymptomatic A. gigas, while L. formosensis caused lymphohistiocytic pericarditis in surviving C. macropomum. These findings provide preliminary evidence suggestive of susceptibility of A. gigas and C. macropomum to infection by L. garvieae and L. formosensis, respectively, highlighting their potential to act as asymptomatic carriers. Furthermore, the histopathological findings were suggestive of species-associated lesion patterns of piscine lactococcosis in Amazonian fish, rather than indicative of high mortality. Full article

Micro- and nanoplastics (MNPs) have emerged as pervasive contaminants in aquatic ecosystems, raising concerns regarding their biological impacts on aquatic organisms. The liver plays a central role in metabolism, detoxification, and immune regulation, making it particularly vulnerable to MNP-induced toxicity. Importantly, MNPs also function as vectors and modulators of co-occurring environmental contaminants, including heavy metals, pesticides, antibiotics, PFASs, algal toxins, and polycyclic aromatic hydrocarbons (PAHs), thereby influencing contaminant bioavailability and hepatic toxicity. This narrative review synthesizes current evidence on hepatic alterations induced by micro- and nanoplastic exposure in zebrafish (Danio rerio), with emphasis on histopathological changes and underlying mechanisms. Relevant peer-reviewed studies were identified through systematic searches of Web of Science, Scopus, PubMed, and ScienceDirect, covering the period 2013–2026, and screened according to predefined inclusion criteria focusing on hepatic endpoints in zebrafish exposed to micro- and nanoplastics. Across the available literature, MNPs consistently accumulate in hepatic tissue and induce structural alterations, including hepatocellular vacuolization, steatosis, inflammatory infiltration, and necrosis. Mechanistically, these pathological changes are closely linked to oxidative stress, impairment of antioxidant defense systems, reprogramming of lipid and glucose metabolism, and activation of inflammatory and regulated cell death signaling pathways. In addition, interactions with co-occurring environmental contaminants—such as heavy metals, pesticides, antibiotics, and algal toxins—frequently exacerbate hepatic injury through synergistic toxicological mechanisms. Disruption of the gut–liver axis and intestinal microbiota has also emerged as an important contributor to systemic metabolic and inflammatory responses. Overall, zebrafish studies demonstrate that the liver represents a critical target organ for MNP toxicity. Future research should prioritize environmentally realistic exposure scenarios, standardized particle characterization, and integrated multi-omics approaches to improve ecological and human health risk assessment. Full article

Although schistosome eggs are widely recognized as the principal drivers of hepatic granulomatous inflammation and fibrosis, the independent effects of adult worms may be masked by strong egg antigen-mediated responses. This study aimed to investigate whether adult Schistosoma japonicum worms alter the miRNA expression profile of hepatic stellate cells and to explore the potential relevance of these changes to liver fibrosis and hepatocellular carcinoma-related processes. A non-contact Transwell co-culture system was established using paired Schistosoma japonicum worms or male worms and hepatic stellate cells. Male worms were additionally included to further assess worm-derived effects independent of egg production–related influences. Untreated hepatic stellate cells served as controls. Total RNA was extracted for miRNA sequencing, and differentially expressed miRNAs were identified. Target gene prediction, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and validation using The Cancer Genome Atlas database were subsequently performed. Both paired worms and male worms significantly altered the miRNA expression profile of hepatic stellate cells. Several differentially expressed miRNAs were identified, among which hsa-miR-103a-3p showed relatively stable changes. Pathway enrichment analysis suggested that the potential target genes of hsa-miR-103a-3p were mainly enriched in AMP-activated protein kinase, mechanistic target of rapamycin, tumor necrosis factor, insulin signaling, and cellular senescence pathways. Further analysis using The Cancer Genome Atlas database showed that hsa-miR-103a-3p had diagnostic value in hepatocellular carcinoma and was associated with alpha-fetoprotein level, albumin level, Ishak fibrosis score, pathological stage, histological type, and tumor status. These findings suggest that adult S. japonicum worms may alter the miRNA expression profile of hepatic stellate cells, and that hsa-miR-103a-3p may be associated with fibrogenic responses and may have potential relevance to hepatocellular carcinoma-related processes. However, this inference is based on correlative TCGA data and does not imply a causal role in schistosomiasis-associated hepatocarcinogenesis. Full article