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The complex cascade of molecular and cellular events leading to bilirubin-induced neurotoxicity remains incompletely delineated. This review discusses bilirubin-induced brain damage and recent insights into its pathogenesis and prevention. Neonatal unconjugated hyperbilirubinemia and resultant clinical jaundice affect up to approximately 85% of newborns. Although this condition is generally a benign, transitional phenomenon, unconjugated bilirubin levels that can pose a direct threat of serious brain injury develop in a small proportion of neonates. Acute bilirubin encephalopathy may ensue and progress to kernicterus (chronic bilirubin encephalopathy), a permanent disabling neurologic condition that is classically characterized by the extrapyramidal movement disorders of dystonia, choreoathetosis, or both; hearing loss due to auditory neuropathy spectrum disorders; and oculomotor pareses. 1 These central nervous system (CNS) sequelae reflect the regional CNS topography of bilirubin-induced neuropathology, which . . .

Despite the decades of use of phototherapy for the management of severe neonatal jaundice, the optimum wavelength range for bilirubin photodegradation is still a matter of controversy. The standard phototherapy approach is based on the 460-nm concept, i.e., the light wavelength corresponding to the absorption maximum of bilirubin. Although used worldwide, a few studies suggested that the use of blue-green light with higher wavelengths above 490 nm might be of therapeutic value.2,3

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most prevalent chronic liver disorder among children and adolescents, mirroring the rise in pediatric obesity. The Mediterranean diet (MD) has demonstrated anti-inflammatory, antioxidant, and beneficial effects on different health outcomes across different life stages. The MD’s effect has been explored in adult MASLD, but there is limited information on the pediatric population. However, evidence on pediatric MASLD should be explored given its rising prevalence. Therefore, the aim of this review is to collect human studies assessing the effect of MD interventions on pediatric MASLD, focusing on key pathophysiological mechanisms. It also examines other interventions, including specific energy/macronutrient prescriptions, nutrition education or counseling, and physical activity components. Methods: A comprehensive search of PubMed, Scopus, and Web of Science was conducted using terms related to the Mediterranean diet, nutrition education, physical activity, pediatrics, and MASLD/NAFLD. Pre-determined inclusion and exclusion criteria were used to collect eligible studies to be included in the review. Study quality was assessed using the Academy of Nutrition and Dietetics Quality Criteria Checklist. Screening, data extraction, and appraisal were performed independently, with discrepancies resolved through discussion, and the findings were synthesized qualitatively. Results: This review synthesizes findings from eight human studies evaluating the impact of the MD, alone or integrated with structured exercise and nutrition education, on pediatric MASLD. Interventions consistently demonstrated reductions in hepatic steatosis, liver stiffness, and fibrosis markers, alongside improvements in inflammatory cytokines, oxidative stress defenses, and liver enzymes. The MD also enhanced lipid and glycemic profiles, lowering triglycerides, total cholesterol, and insulin resistance indices. Nutrition education and family-centered approaches improved adherence, while structured, enjoyable physical activity enhanced outcomes and long-term sustainability. Conclusions: Collectively, the MD, particularly when combined with exercise and tailored education, offers a safe, effective, and comprehensive lifestyle intervention for pediatric MASLD. Nonetheless, current evidence remains limited by small sample sizes, heterogeneity in protocols, and short follow-ups. Larger, multicenter randomized trials with standardized designs are needed to establish best practices and long-term efficacy.

Background/Objectives: Metabolic dysfunction-associated steatosis liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver related morbidity and mortality affecting 38% of the adult global population. As of now, there is no clear consensus on a standardized pharmacological treatment for MASLD; therefore, lifestyle interventions particularly diet and exercise remain the first-line approach for both prevention and management. Extra virgin olive oil (EVOO), the primary source of fat in the Mediterranean diet. (MD) is widely recognized as a key contributor to its well-documented health benefits. As a central component of this dietary pattern, EVOO has demonstrated promising therapeutic potential due to its high phenolic content. The primary aim of this review is to synthesize existing human studies examining the effects of olive oil primarily EVOO on key pathological features of MASLD. Methods: A systematic search of human clinical and observational studies was conducted across major databases. Key outcomes assessed include hepatic steatosis, inflammation, oxidative stress, fibrosis, liver enzymes, and anthropometric measures. Study quality was evaluated using the Academy of Nutrition and Dietetics Quality Criteria Checklist. Results: This review included 25 high-quality studies, 12 of which assessed olive oil alone and 13 evaluated the MD emphasizing extra virgin olive oil (EVOO). EVOO-rich interventions consistently improved hepatic steatosis, liver enzyme levels (ALT, AST), and inflammatory markers in MASLD patients, particularly when paired with calorie-restricted or MD patterns. Benefits were dose- and type-dependent, with EVOO showing superior effects compared to refined olive oils. Modest improvements in lipid profiles and insulin resistance were observed. Longer study durations and higher EVOO intake (>30–50 g/day) yielded greater improvements. Findings suggest EVOO may exert beneficial effects on liver health through its anti-inflammatory and antioxidant properties. Future studies on EVOO’s role in MASLD should use well-characterized oils with known polyphenol and bioactive compound levels and include clear biomarkers of oxidative stress, inflammation, and liver health outcomes on humans. Overall, EVOO represents a promising, non-pharmacological strategy for MASLD prevention and management. Conclusions: Current evidence suggests that EVOO, particularly when rich in phenolic compounds, is a promising dietary strategy for managing MASLD due to its hepato-protective effects, especially within a Mediterranean diet framework. However, findings are limited by study heterogeneity and a lack of high-quality randomized controlled trials, highlighting the need for future research to refine optimal dosing, assess long-term outcomes, and clarify underlying mechanisms.

Pharmacological treatments for non-alcoholic steatohepatitis (NASH) are still unsatisfactory. Fibrosis is the most significant predictor of mortality and many anti-fibrotic agents are under evaluation. Herein, we assessed in vitro the effects of the FXR agonist obeticholic acid (OCA) and the dual FXR/TGR5 agonist INT-767 in a well-established co-culture NASH model. Co-cultures of human hepatoma and hepatic stellate (HSCs) cells were exposed to free fatty acids (FFAs) alone or in combination with OCA or INT-767. mRNA expression of HSCs activation markers and FXR engagement were evaluated at 24, 96 and 144 hours. Collagen deposition and metalloproteinase 2 and 9 (MMP2-9) activity were compared to tropifexor and selonsertib. FFAs induced collagen deposition and MMP2-9 activity reduction. Co-treatment with OCA or INT-767 did not affect ACTA2 and COL1A1 expression, but significantly reduced FXR and induced SHP expression, as expected. OCA induced a dose-dependent reduction of collagen and induced MMP2-9 activity. Similarly, INT-767 induced collagen reduction at 96 h and a slight increase in MMP2-9. Tropifexor and Selonsertib were also effective in collagen reduction but showed no modulation of MMP2-9. All tested compounds reduced collagen deposition. OCA exerted a more potent and long-lasting effect, mainly related to modulation of collagen turn-over and MMP2-9 activity.

Despite advances in biomedicine, the incidence and the mortality of hepatocellular carcinoma (HCC) remain high. The majority of HCC cases are diagnosed in later stages leading to the less than optimal outcome of the treatments. Molecular targeted therapy with sorafenib, a dual-target inhibitor targeting the serine-threonine kinase Raf and the tyrosine kinases VEGFR/PDGFR, is at present the main treatment for advanced-stage HCC, either in a single or combinatory regimen. However, it was observed in a large number of patients that its effectiveness is hampered by drug resistance. HCC is highly heterogeneous, within the tumor and among individuals, and this influences disease progression, classification, prognosis, and naturally cellular susceptibility to drug resistance. This review aims to provide an insight on how HCC heterogeneity influences the different primary mechanisms of chemoresistance against sorafenib including reduced drug intake, enhanced drug efflux, intracellular drug metabolism, alteration of molecular targets, activation/inactivation of signaling pathways, changes in the DNA repair machinery, and negative balance between apoptosis and survival of the cancer cells. The diverse variants, mutations, and polymorphisms in molecules and their association with drug response can be a helpful tool in treatment decision making. Accordingly, the existence of heterogeneous biomarkers in the tumor must be considered to strengthen multi-target strategies in patient-tailored treatment.

Celiac disease (CD) is a complex multi-organ disease with a high prevalence of extra-intestinal involvement, including neurological and psychiatric manifestations, such as cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive impairment, and depression. However, the mechanisms behind the neurological involvement in CD remain controversial. Recent evidence shows these can be related to gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and in severe cases, vitamins or nutrients deficiency. Here, we have summarized new evidence related to gut microbiota and the so-called “gut-liver-brain axis” involved in CD-related neurological manifestations. Additionally, there has yet to be an agreement on whether serological or neurophysiological findings can effectively early diagnose and properly monitor CD-associated neurological involvement; notably, most of them can revert to normal with a rigorous gluten-free diet. Moving from a molecular level to a symptom-based approach, clinical, serological, and neurophysiology data might help to disentangle the many-faceted interactions between the gut and brain in CD. Eventually, the identification of multimodal biomarkers might help diagnose, monitor, and improve the quality of life of patients with “neuroCD”.

Hyaluronic acid (HA) is a glycosaminoglycan of extracellular matrix related to cell surface which interacts with various cell types. To understand the role of HA during hepatocarcinogenesis, we assessed the effect of the inhibition of HA deposition and its association with heterogeneous hepatocellular carcinoma (HCC) cells. In this study, we used transgenic mice C57BL/6J-Tg(Alb1HBV)44Bri/J (HBV-TG) and normal C57BL/6 J (WT) for in vivo study, while HCC cells Huh7 and JHH6 as in vitro models. Both models were treated with an HA inhibitor 4-methylumbelliferone (4MU). We observed that 4MU treatments in animal model down-regulated the mRNA expressions of HA-related genes Has3 and Hyal2 only in HBV-TG but not in normal WT. As observed in vivo , in HCC cell lines, the HAS2 mRNA expression was down-regulated in Huh7 while HAS3 in JHH6, both with or without the presence of extrinsic HA. Interestingly, in both models, the expressions of various cancer stem cells (CD44, CD90, CD133, and EpCAM) were also decreased. Further, histological analysis showed that 4MU treatment with dose 25 mg/kg/day reduced fibrosis, inflammation, and steatosis in vivo , in addition to be pro-apoptotic. We concluded that the inhibition of HA reduced the expressions of HA-related genes and stem cells markers in both models, indicating a possible modulation of cells-to-cells and cells-to-matrix interaction.

The weighted gene co-expression network analysis (WGCNA) has been used to explore gene expression datasets by constructing biological networks based on the likelihood expression profile among genes. In recent years, WGCNA found application in biomarker discovery studies, including miRNA. Serum samples from 20 patients with hepatocellular carcinoma (HCC) were profiled through miRNA 3.0 gene array and miRNAs biomarker candidates were identified through WGCNA. Results were validated by qRT-PCR in 102 HCC serum samples collected at diagnosis. WGCNA identified 16 miRNA modules, nine of them were significantly associated with the clinical characteristics of the patient. The Red module had a significant negative correlation with patients Survival (− 0.59, p = 0.007) and albumin (− 0.52, p = 0.02), and a positive correlation with PCR (0.61, p = 0.004) and alpha-fetoprotein (0.51, p = 0.02). In the red module, 16 circulating miRNAs were significantly associated with patient survival. MiR-3185 and miR-4507 were identified as predictors of patient survival after the validation phase. At diagnosis, high expression of circulating miR-3185 and miR-4507 identifies patients with longer survival (HR 2.02, 95% CI 1.10–3.73, p = 0.0086, and HR of 1.75, 95% CI 1.02–3.02, p = 0.037, respectively). Thought a WGCNA we identified miR-3185 and miR-4507 as promising candidate biomarkers predicting a longer survival in HCC patients.