Pectinase-assisted processing may enhance the functional value of immature citrus peel (Qingpi, QCP), but the links between matrix degradation, metabolite remodeling, and bioactivity remain unclear. QCP aged for 1, 3, 7, and 10 years and their corresponding pectinase hydrolysates (QCPEH) were evaluated using antioxidant assays, an ethanol-injured HepG2 model, metabolite profiling, chemical-space analysis, network pharmacology, molecular docking, single-compound validation, and RT-qPCR. Pectinase hydrolysis enhanced DPPH, ABTS, and FRAP responses at all aging periods, with 10-QCPEH showing the strongest overall activity. In HepG2 cells, 10-QCPEH reduced LDH release, ALT and AST activities, ROS and MDA levels, restored SOD activity, and partially recovered ADH and ALDH activities. Changes in IL-1β, IL-6, and TNF-α were not statistically significant. Pectinase treatment decreased pectin molecular weight and remodeled both VOC and NVOC profiles, supporting increased metabolite accessibility. Tangeretin, thymol, and nobiletin each reduced ROS accumulation and LDH release. Aromaticity was positively correlated with DPPH, ABTS, and FRAP activities (ρ = 0.90-0.95, q < 0.05). Network and docking analyses highlighted targets related to redox regulation, metabolism, inflammation, and cell survival. RT-qPCR further showed increased HMOX1 and PPARA and decreased PPARG, RELA, TNF, and PTGS2 expression, whereas AKT1 was not significantly altered. These findings support pectinase hydrolysis as a strategy to improve the functional potential of aged QCP through matrix depolymerization and metabolite remodeling.

Alcoholic liver disease (ALD) is a major global health burden with limited therapeutic options. The primary aim of this study was to investigate the hepatoprotective effects of Maillard reaction products derived from Perinereis aibuhitensis (P-MRPs) in a mouse model of chronic alcohol-induced liver injury. Male ICR mice were fed a Lieber-DeCarli alcoholic liquid diet for 6 weeks with or without P-MRPs administration. P-MRPs intervention significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, alleviated hepatic histopathological injury, restored antioxidant enzyme activities (superoxide dismutase and glutathione peroxidase), and lowered malondialdehyde and interleukin (IL-6, IL-18, and IL-1β) levels. Mechanistically, P-MRPs treatment upregulated hepatic nuclear factor erythroid 2-related factor 2 (NRF2), downregulated NF-κB p65 and tumor necrosis factor (TNF)-α, and restored carnitine O-palmitoyltransferase 1A (CPT1A) expression. Liver metabolomic analysis revealed that P-MRPs administration increased N-acyl amino acids and tryptophan-derived metabolites while reversing alcohol-induced accumulation of glycerophospholipids and acylcarnitines. In vitro, P-MRPs reduced ethanol-induced ROS accumulation and attenuated ALT and AST leakage in AML12 hepatocytes. Compositional profiling identified 27 small-molecule compounds with significant changes in P-MRPs abundance, and a high proportion of small-molecule peptides. Collectively, these findings suggest that P-MRPs protect against ALD-related liver injury, potentially through coordinated regulation of antioxidant, inflammatory, and lipid metabolic pathways, and provide a hypothesis-generating framework for future mechanistic investigations.

The incidence of metabolic-associated fatty liver disease (MAFLD) continues to rise, making it a leading cause of chronic liver disease worldwide. Its pathological progression is frequently accompanied by microcirculatory dysfunction. However, effective therapeutic interventions targeting this specific process remain limited. Hydroxysafflor yellow A (HSYA) is the primary active component of Carthamus tinctorius L. It exerts diverse pharmacological effects, including anti-inflammatory, antioxidant, and microcirculation-improving activities. However, the specific mechanisms by which HSYA regulates microcirculatory dysfunction in MAFLD have yet to be elucidated. In this study, a rat model of MAFLD was established using a methionine choline-deficient (MCD) diet to investigate the protective effects of HSYA and the underlying EGFR/MAPK1 signaling mechanism. The results showed that HSYA treatment significantly reduced serum levels of ALT, AST, TC, TG, and ET-1, while increasing NO levels. HSYA administration also expanded mesenteric microvascular diameter and accelerated blood flow velocity. Furthermore, HSYA alleviated hepatic steatosis and inflammatory injury. These effects were accompanied by the downregulation of EGFR, MAPK1, and VEGF expressions in the liver, thereby inhibiting the overactivation of the EGFR/MAPK1 pathway. In summary, HSYA effectively ameliorates hepatic injury and microcirculatory dysfunction in MAFLD rats. The underlying mechanism is associated with inhibiting the overactivation of the EGFR/MAPK1 signaling pathway and downregulating VEGF expression, which collectively restores the balance of microvascular structure and function. These findings provide experimental evidence for the therapeutic potential of HSYA in treating MAFLD-related microcirculatory disorders.

Recent human studies have identified TNFα as a therapeutically targetable pathway in autoimmune hepatitis (AIH), but the consequences of TNFα blockade may depend on treatment timing and disease context. Whether TNFα neutralization can restore disease control once autoimmune liver inflammation is already established remains unclear. Here, we investigated late TNFα blockade in experimental autoimmune hepatitis (emAIH). Anti-TNFα treatment was initiated after disease establishment, and mice were analyzed at early and late post-treatment time points by integrating serum biochemistry, hepatic inflammatory infiltrate quantification, liver gene expression, flow cytometry, serum proteomics and regulatory immune readouts. Late TNFα blockade did not improve serum ALT or AST levels and did not reduce hepatic inflammatory infiltrate area compared with isotype-treated controls. Nevertheless, anti-TNFα treatment was associated with hepatic transcriptional remodeling, including reduced Acta2 expression and directional changes in Ccl2 and Fgf21 at the early time point. At the later time point, anti-TNFα treatment was associated with increased the frequencies of IFN-γ- and TNFα-producing splenic CD4+ T cells, whereas intrahepatic cytokine-producing T-cell frequencies remained largely unchanged. Serum proteomics identified late systemic inflammatory remodeling, including increased CCL2 abundance. In contrast, hepatic Foxp3 expression and absolute hepatic Treg numbers were not increased. Together, these findings indicate that late TNFα blockade in established emAIH remains biologically active but is uncoupled from biochemical improvement and reduced hepatic inflammatory infiltration. The data complement recent human infliximab studies by suggesting that timing and disease context may shape the consequences of TNFα-targeted therapy in AIH.

Brucellosis is a multisystem zoonosis that can mimic complicated bacterial infection in children. A 10-year-old girl presented with prolonged high-grade fever, jaundice, abdominal pain, anorexia and weight loss. The initial syndrome was managed empirically as an undifferentiated complicated bacterial illness because enteric fever and a hepatobiliary or intra-abdominal source were considered. CRP was 333.2 mg/L and total/direct bilirubin 7.24/5.21 mg/dL despite only mild aminotransferase elevation; ultrasonography showed hepatomegaly and nonspecific gallbladder-wall edema without biliary dilatation or focal lesions. CRP peaked at 407.1 mg/L and began falling during meropenem-linezolid therapy before Brucella-directed treatment, so biomarker response was not used diagnostically. Re-taking the history revealed daily consumption of unboiled dairy milk for several months. On hospital day 6, doxycycline, rifampicin and gentamicin were started simultaneously, with discontinuation of meropenem and linezolid. Brucella serology was concordant: a laboratory-reported agglutination result labelled B. melitensis was reactive at 1:80 and later EIA showed strongly positive IgM and IgG, but neither test established species identity and culture/PCR confirmation was not obtained. Fever resolved by hospital day 14. At immediate post-treatment follow-up on 8 September 2026, she remained clinically well; weight had increased from 19 to 20 kg, CRP was 1.2 mg/L, total/direct bilirubin 0.8/0.2 mg/dL, AST/ALT 34/43 IU/L and alkaline phosphatase 417 U/L (within a published pediatric reference interval), with renal function within the laboratory reference range. Hemoglobin had improved to 7.8 g/dL with persistent microcytosis, before oral iron supplementation was initiated. The diagnosis is therefore best regarded as serologically supported pediatric brucellosis rather than microbiologically confirmed disease.

Maternal protein restriction during lactation is associated with stunted growth and hyperphagia in adult offspring, yet its long-term effects on mitochondrial uncoupling-related proteins in interscapular brown adipose tissue (iBAT) remain unknown. This study investigated how postnatal protein undernutrition affects thermogenic regulators and metabolic programming in adult males. Dams received either a low-protein (LP; 4% protein) or normal-protein (NP; 20.5% protein) diet during the first two weeks of lactation. Thereafter, the NP diet was provided to LP dams until weaning and to all offspring from weaning to PND 90. Male offspring were euthanized at postnatal day 90 for somatic, biochemical, hormonal, and iBAT UCP1 and β3-AR protein analyses. Compared with NP controls, LP offspring exhibited reduced body mass, length, and visceral adiposity, despite increased food consumption (all p < 0.0001). They also showed reduced glycemia, insulin, HOMA-β, TyG index, albumin, and HDL-c (all p < 0.05), together with increased peripheral insulin sensitivity assessed by ipITT (p < 0.05). Conversely, LP offspring exhibited increased AST activity and AST/ALT ratio (both p < 0.05) and higher hepatic cholesterol content (p < 0.01). In iBAT, UCP1 protein content was reduced (p < 0.05), whereas β3-AR remained unchanged (p > 0.05). These findings indicate that maternal protein undernutrition during lactation programmed a persistent metabolic phenotype characterized by hyperphagia, reduced somatic growth and visceral adiposity, increased peripheral insulin sensitivity, and lower iBAT UCP1 protein abundance. Collectively, these results suggest long-term alterations in energy partitioning and the iBAT molecular phenotype, although functional thermogenesis was not assessed.