Search Results (33,363)

Interactions between alcohol and nutrition play an important role in the development and progression of alcohol-associated liver disease (ALD). Although dietary cholesterol was shown to exacerbate fatty liver and liver injury in alcohol-fed mice, findings regarding the combined effect of dietary cholesterol and heavy alcohol drinking on cholesterol homeostasis remain controversial. Ezetimibe has been widely used as a cholesterol-lowering drug in hypercholesterolemic subjects. It is not fully understood whether ezetimibe blunts the adverse effect of cholesterol on lipid and biliary bile acid metabolism in alcohol-exposed mice. In the current study, wild-type mice were subjected to NIAAA alcohol feeding model. Dietary cholesterol (0.2%, w/v) and ezetimibe (0.001%, w/v) were added to the liquid diets. Cholesterol and triglyceride contents in the liver and circulation were determined. Biliary bile acid composition, as well as hepatic and circulating inflammatory markers were analyzed. We found that ezetimibe protected mice from the synergistic effects of dietary cholesterol and alcohol on hepatic triglyceride accumulation, which was accompanied by enhanced expression of genes involved in hepatic beta oxidation. Dietary cholesterol caused great increases in liver cholesterol content and dramatic reductions in the expression of hepatic cholesterol biosynthetic genes in both control- and alcohol-fed mice. These changes were normalized by ezetimibe treatment. Ezetimibe attenuated dietary cholesterol-induced elevations in total biliary bile acids. Moreover, mice fed a diet containing both cholesterol and alcohol exhibited increased expression of monocyte chemoattractant protein 1 (Mcp1) and tumor necrosis factor alpha (Tnfα) in the distal small intestine. Collectively, our findings indicate that ezetimibe effectively mitigates the adverse effects of dietary cholesterol and alcohol consumption on hepatic lipid accumulation and liver injury. Full article

Introduction: Liver transplantation has re-emerged as a potential therapeutic option for patients with unresectable colorectal liver metastases after failure of standard treatments. This systematic review and meta-analysis evaluated survival outcomes, recurrence patterns, and prognostic factors associated with this approach. Materials and Methods: A systematic review was conducted according to PRISMA 2020 guidelines and registered in PROSPERO. Electronic databases were searched for studies published between November 2015 and November 2025, that assessed liver transplantation in the context of unresectable colorectal liver metastases. Random-effect meta-analyses were conducted to estimate the pooled overall survival, disease-free survival and recurrence rates. Heterogeneity was assessed using I² statistics. Results: Twenty-three studies involving patients with unresectable liver-only colorectal metastases were included. Pooled overall survival after liver transplantation was 96.6% at 1 year (95% CI 93.9–99.4; I² = 44.3%), 73.4% at 3 years (95% CI 62.9–83.9; I² = 95.4%), and 49.4% at 5 years (95% CI 35.4–63.3; I² = 90.5%). Ten-year overall survival was approximately 27%. The pooled recurrence rate was 63.5% (95% CI 52.5–76.8), and the type of recurrence was mainly extrahepatic, most commonly pulmonary. Disease-free survival was 64.1% (95% CI 47.5–80.7) with substantial heterogeneity (I² = 95.6%). Biological risk factors, including carcinoembryonic antigen levels, metabolic tumor volume, and composite risk scores, consistently influenced survival outcomes. Conclusions: In highly selected patients with unresectable colorectal liver metastases, liver transplantation is associated with favorable long-term survival despite frequent recurrence. Outcomes appear to be primarily driven by tumor biology rather than tumor burden, supporting the cautious use within specialized centers under structured selection protocols. Full article

Background/Objectives: Chronic metabolic acidosis (CMA) is a mild, persistent acid–base imbalance characterized by low serum bicarbonate and urinary pH and is common in chronic illness, aging, and metabolic disorders such as type 2 diabetes (T2D). This review highlights the critical, yet often overlooked, role of CMA in T2D (CMAD) and its contribution to disease pathophysiology. Methods: We conducted a comprehensive review of the systemic impacts of CMA, from molecular mechanisms to organ-specific dysfunction. The analysis covers physiological pH dynamics in intracellular (IC) and extracellular (EC) fluids and explores their effects on cellular processes, including the cell cycle and apoptosis. Results: At the molecular level, acidosis significantly alters enzyme kinetics, macromolecule metabolism, and ion conductance. Cell-level analysis shows that pH shifts impact proliferation and programmed cell death. Systemically, the manifestations of CMA align closely with T2D features in vital organs, including the pancreas, liver, skeletal muscle, adipose tissue, and the renal, nervous, and immune systems. Our findings indicate that the pathophysiological landscape of T2D largely mirrors the biological effects of chronic acidosis. Conclusions: The alignment between the effects of CMA and the clinical features of T2D suggests that T2D pathophysiology is worth revisiting through the lens of CMAD. This perspective is further supported by therapeutic interventions showing preliminary efficacy signals in limited studies of acid-neutralization in managing T2D symptoms and progression. Full article

Liver regeneration after partial hepatectomy (PH) is critically influenced by redox balance, which may be severely disrupted under drug-induced liver injury. This study evaluated oxidative stress parameters and inflammatory markers in rats subjected to 70% PH following acetaminophen (APAP)-induced toxicity and assessed the preventive effect of the microalga Desmodesmus armatus. Reactive oxygen species (superoxide anion, hydroxyl radical, and hydrogen peroxide), antioxidant enzyme activities (superoxide dismutase and glutathione peroxidase), serum aminotransferases, bilirubin, and C-reactive protein were analyzed 0–168 h post-hepatectomy. APAP intoxication markedly increased mitochondrial ROS production, suppressed mitochondrial antioxidant enzyme activity, and prolonged elevations of ALT, AST, bilirubin, and CRP, accompanied by severe histological damage. Preventive administration of D. armatus suspension (10 mL/kg body weight at 1.5 × 10⁶ and 1.5 × 10⁷ cells/mL) attenuated oxidative stress in a dose-dependent manner. It significantly reduced ROS levels, restored mitochondrial antioxidant defenses, decreased cytolytic and cholestatic markers, and mitigated systemic inflammation. Overall, D. armatus exhibited hepatoprotective and redox-modulating properties, which may contribute to a more favorable microenvironment for liver recovery under toxic conditions. These findings highlight the potential of microalgae-based interventions as supportive strategies for reducing liver injury and improving recovery following acute liver injury. Full article

Background and goals: The outcomes of patients with primary sclerosing cholangitis (PSC) in central Missouri are unknown. The University of Missouri–Columbia services 600,000 individuals in central Missouri. Our aims were (a) to examine the outcomes of PSC patients receiving care at our academic institution, and (b) to identify the predictors of PSC-related serious adverse events. Methods: A retrospective study of patients with PSC in a non-transplant center. The primary outcome was the development of ≥1 of PSC-related serious adverse event for (1) progression to cirrhosis, or (2) development of cholangiocarcinoma. Results: From 2000 to 2018, 42 patients fulfilled the criteria for the diagnosis of PSC. A total of 55% of the patients were male, and 79% had associated inflammatory bowel disease (IBD). The median follow-up from time of diagnosis of PSC until the last follow-up or death was 5.5 years. A total of 57% of the patients developed ≥ 1 PSC-related adverse event; 36% (8/22) of those who progressed to decompensation underwent liver transplantation. The median time from diagnosis of PSC until progression to decompensation was 6.3 years; the median time from decompensation to transplantation was 10.8 years. A total of 12% of the patients developed ≥ 1 cancer (cholangiocarcinoma = 2; gallbladder cancer = 2; colon cancer = 1; and hepatocellular carcinoma = 1). The overall mortality was 9.5%. The median time from PSC diagnosis until death was 10.2 years. A Cox hazards regression analysis showed only age (HR = 1.16; p = 0.032; 95% CI, 1.01–1.13) and serum bilirubin (HR = 1.42; p = 0.036; 95% CI, 1.03–2.69) at the time of PSC diagnosis were independently associated with PSC-related serious events. Conclusions: Age and bilirubin are important predictors of PSC-related outcomes. Full article

The diploid distant hybrid (2nBY) derived from female blunt snout bream (Megalobrama amblycephal, BSB) × male Bleeker’s yellow tail (Xenocypris davidi Bleeker, YT). To investigate the hypoxia tolerance and the regulatory mechanisms of hypoxia-inducible factor-1α/2α (hif-1α/2α) in 2nBY, BSB, and YT, experiments consisting of 24 h of hypoxia treatment (DO = 2.0 ± 0.1 mg/L) followed by 6 h of reoxygenation were conducted. The loss of equilibrium critical oxygen pressure (LOEcrit), gill tissue structure, and antioxidant indices, as well as the full-length sequences and expression of hif-1α/2α in 2nBY, BSB, and YT, were compared. The results showed that the LOEcrit value of 2nBY was significantly lower than that of BSB but higher than that of YT (p < 0.05). After hypoxia treatment, the changes in gill tissue structure and antioxidant indices of 2nBY were less obvious than those of BSB, and the recovery rate was faster after reoxygenation. Sequence analysis revealed high similarity of hif-1α/2α between YT and 2nBY. After hypoxia treatment, hif-1α/2α were upregulated in the liver but showed distinct gill expression among the three groups. Their gill expression differences may contribute to varied hypoxic tolerance. Distant hybridization between BSB and YT successfully generated hybrid offspring with enhanced hypoxia tolerance relative to BSB. These results provide theoretical and technical support for the breeding of a new hypoxia-tolerant germplasm resource of bream. 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

Obesity is characterized by an excess accumulation of adipose tissue, independent of its distribution or function, and is associated with organ dysfunction and a broad range of metabolic and cardiac complications. Nutritional, environmental, behavioral, genetic, psychological, and metabolic factors contribute to obesity. It is associated with many secondary complications, including diabetes mellitus, hypertension, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, reduced quality of life, and psychological illnesses. For practical purposes, childhood obesity can be classified into polygenic, monogenic, syndromic, and endocrine causes. Management should be patient-centered and multidisciplinary, integrating lifestyle/behavioral changes with adjunctive pharmacotherapy and bariatric surgery where appropriate. In monogenic or syndromic obesity, knowing the underlying genetic etiology allows precision-guided and more effective therapy. This review aims to provide a state-of-the-art review on the management of obesity in children. Full article

Background/Objectives: Acute-on-chronic liver failure (ACLF) is a severe syndrome in chronic liver disease (CLD) patients, characterized by multi-organ failure and high mortality. Living donor liver transplantation (LDLT) is vital in donor-scarce areas. This study compares baseline characteristics, perioperative complications, and long-term survival between ACLF and non-ACLF patients, emphasizing etiology, ACLF grading, and graft factors. Methods: Data from a prospective registry of 591 adult LDLT recipients (2019–2023) were analyzed. ACLF was defined by EASL-CLIF (multi-organ failure, grades 1–3) and APASL (jaundice/coagulopathy with complications) criteria, evaluated at initial assessment and within 24 h pre-LDLT. Results: ACLF patients (n = 101, 17.1%) showed higher MELD-Na (27 vs. 20, p < 0.001), bilirubin (6.84 vs. 1.75 mg/dL, p < 0.001), creatinine (108 vs. 70.5 μmol/L, p < 0.001), metabolic/genetic etiologies (9.9% vs. 2.8%, p = 0.001), and chronic kidney disease (23.7% vs. 8.1%, p < 0.001), and lower HCC rates (11.8% vs. 29.6%, p < 0.001). GRWR was marginally lower in ACLF patients (0.59 vs. 0.66, p = 0.10). The ACLF group had elevated infection (27.7% vs. 10.4%, p < 0.001), bleeding (14.9% vs. 6.3%, p = 0.004), and biliary complications (15.8% vs. 7.8%, p = 0.010), with longer ICU (5 vs. 3 days, p < 0.001) and hospital stays (33.66 vs. 20.7 days, p = 0.036). Five-year overall survival was reduced in ACLF patients (log-rank p = 0.001), worsening with grade (EASL-CLIF grade 3: 55% vs. 81% for no ACLF, p = 0.002). Graft survival was also lower (75% vs. 85%, p = 0.02). Multivariable analysis identified chronic kidney disease as an independent mortality predictor (HR 2.09, 95% CI 1.11–3.95, p = 0.023). Conclusions: LDLT for ACLF involves higher perioperative risks and poorer long-term survival than non-ACLF patients, with outcomes deteriorating by ACLF grade. Chronic kidney disease independently predicts mortality. Timely LDLT is essential in donor-limited regions. Full article

Background and Objectives: Hepatoblastoma (HB) is a rare pediatric liver cancer. Complete resection and chemotherapy are standard treatments, but many patients in developing countries present with unresectable tumors and show poor responses to conventional chemotherapy. Identifying somatic alterations in HB may help develop targeted molecular therapies. Materials and Methods: Exome sequencing was conducted on 34 HB patient samples to identify somatic mutations and copy number variations (CNVs) and to evaluate their relationships with clinical outcomes, including survival. Results: HB tumors showed a low mutational burden but a high rate of CNVs, averaging 181.5 CNVs compared to 3.6 somatic mutations per tumor. CNVs were enriched in pathways involved in transcription, differentiation, and development. The most common alterations were missense mutations in KMT2D (18%), CTNNB1 (12%), and MUC16 (3%). KMT2D mutations occurred more frequently than CTNNB1 mutations in this cohort. Patients with KMT2D or CTNNB1 mutations generally had better overall survival and longer disease-free intervals. Deletions of ZNF429 or FGD4 were linked to shorter survival in the cohort. Validation with an external dataset confirmed significant downregulation of FGD4 expression in HB samples, correlating with poorer survival. Conclusions: This study broadens the understanding of somatic alterations in HB patients, offering insights into the molecular mechanisms behind HB development and highlighting the potential of CNV profiling and FGD4 deletions as prognostic factors in HB. Full article

The liver is a central regulator of systemic metabolism and exhibits exceptional regenerative capacity, yet aging progressively impairs hepatic resilience through metabolic dysregulation, mitochondrial dysfunction, epigenetic instability, and chronic inflammation. Marine ecosystems constitute a vast and underexplored source of structurally diverse bioactive compounds that have evolved to modulate conserved stress response and homeostatic pathways. This review synthesizes current preclinical evidence demonstrating how marine-derived metabolites target key molecular axes implicated in liver aging, including energy sensing, redox balance, mitochondrial quality control, inflammatory signaling, and chromatin-associated regulation. Rather than focusing solely on isolated hepatoprotective effects, we frame marine bioactives within an aging biology perspective, highlighting their ability to modulate pathways associated with cellular plasticity and resilience. We further propose that this mechanistic convergence provides a theoretical framework for exploring marine compounds as potential adjunctive modulators within emerging, experimental liver rejuvenation strategies, including partial cellular reprogramming approaches that require coordinated metabolic and epigenetic control. While acknowledging that direct reversal of liver aging remains to be clinically established, integrating marine chemodiversity with contemporary aging and regenerative biology outlines a conceptual roadmap for developing liver-directed interventions targeting aging-related vulnerability as a fundamental driver of disease. Full article

Androgens regulate skeletal muscle, bone, erythropoiesis, and male reproductive function via the androgen receptor (AR), a ligand-dependent transcription factor. Pharmacologic modulation of AR has been pursued for clinical and non-medical purposes. Anabolic androgenic steroids (AAS), synthetic testosterone derivatives, act as full AR agonists, broadly activating multiple tissues. While effective in promoting muscle growth and strength, AAS cause well-known adverse effects, including hypothalamic–pituitary–gonadal (HPG) axis suppression, dyslipidemia, hepatotoxicity, cardiovascular disease, tendon injury, and neuropsychiatric disturbances. Selective androgen receptor modulators (SARMs) aim to stimulate AR in muscle and bone while minimizing androgenic effects in prostate and skin. They induce ligand-specific AR conformations, altering coactivator and corepressor recruitment, and avoiding metabolism by 5α-reductase or aromatase. Preclinical studies show favorable anabolic-to-androgenic ratios, but clinical translation is limited. Early human trials report modest lean mass gains, variable functional outcomes, and dose-dependent testosterone suppression. Emerging evidence also suggests cardiotoxicity, tendon injury, and liver toxicity, though long-term effects are unclear. Pharmacokinetically, SARMs have predictable oral absorption and moderate half-lives, enabling once-daily dosing, unlike AAS. This review compares AAS and SARMs in molecular mechanisms, pharmacokinetics, and safety. While SARMs offer partial tissue selectivity and reduced adverse effects, risks remain, and long-term safety is uncertain. Regulatory oversight is limited, and non-medical use is rising. Preclinical and clinical studies are needed to clarify whether SARMs can separate anabolic benefits from androgenic toxicity and inform safe clinical application. Full article

Metabolic dysfunction-associated (non-alcoholic) steatotic liver disease (MASLD) is a chronic inflammatory liver disorder characterized by excessive hepatic lipid accumulation. Its progressive subtype, metabolic dysfunction-associated (non-alcoholic) steatohepatitis (MASH), is featured by enhanced inflammation and liver injury. Some MASH cases are accompanied by hepatic fibrosis, which may progress to cirrhosis and hepatocellular carcinoma (HCC). MASLD is also associated with comorbidities such as cardiovascular disease and chronic kidney disease. To date, only Resmetirom has been approved by the FDA for MASH treatment, highlighting the urgency of investigating MASH pathogenesis and developing effective therapeutic agents. Establishment of experimental animal models which can mimic the clinical symptom of MASLD are fundamental to explore therapeutic targets and advance clinical drugs development. Therefore, this review focus on the pathological features of MASLD/MASH and comprehensively summarizes the current MASH-related mouse models, which can be useful for researchers to select appropriate models in order to explore the underlying mechanisms and dig novel targets for MASH treatment. Full article

N⁶-methyladenosine (m⁶A) is the most common internal modification in eukaryotic mRNA, essential for post-transcriptional regulation. MeRIP-seq is widely used for m⁶A profiling, but RNA degradation challenges accurate analysis. While the effects of sample handling on RNA are known, the impact of tissue sample storage durations on m⁶A remains unclear. We investigated how sample storage durations (0, 2, 12, 24, and 48 h at room temperature) affect RNA integrity, m⁶A peaks, and transcriptomes in mouse liver. RNA integrity declined with time, reducing m⁶A peak number and reproducibility. Prolonged storage diverged m⁶A profiles, increased unreported peaks, shifted RRACH motifs, and redistributed peaks to intergenic/intronic regions. Integrated data showed opposing changes in m⁶A and expression for some genes, suggesting storage degradation confounds epitranscriptomic interpretation. Sample storage durations are critical for m⁶A accuracy, emphasizing the need for standardized handling in MeRIP-seq studies. Full article

The Atlantic Forest is a highly diverse biome that is under constant pressure due to human action, resulting in habitat fragmentation and intensifying edge effects, affecting biodiversity. The aim was to study the edge effect and influence of biotic and abiotic parameters on Calliphoridae and Mesembrinellidae communities in Três Picos State Park. Two traps baited using beef liver were placed at each site (n = 5) across 1000 m from the edge toward the interior of the forest, with vegetal characterization at each point. Collections occurred between June 2021 and May 2023, encompassing each season twice. The dipterans were identified taxonomically using a stereoscope microscope with the aid of taxonomic keys, totaling 5476 specimens. Dipteran abundance and species composition were primarily influenced by seasonal variation, while the distance from the forest edge or vegetation structure showed no effect. Abundance peaked during warmer periods, and temperature showed a positive effect on overall dipteran abundance. No species showed a strong association with specific seasons or distance along the edge–interior gradient. These results indicate that, in a relatively continuous and well-preserved forest remnant, edge effects do not lead to significant species loss, and climatic seasonality shapes patterns of dominance and abundance. Our findings highlight the ecological stability of the studied conservation unit and support the use of Calliphoridae and Mesembrinellidae as effective bioindicators. Understanding how dipteran assemblages respond to seasonal and edge-related gradients contributes to the development of cost-effective biomonitoring tools for tropical forest conservation. Full article