Current Medical Science最新文献

Objective: To investigate the inhibitory effects of mitofusin 2 (MFN2) on hepatic stellate cell (HSC) activation and liver fibrosis progression in nonalcoholic fatty liver disease (NAFLD) through the inhibition of β-catenin nuclear translocation.

Methods: In vitro, primary mouse HSCs were treated with palmitic acid (PA), and MFN2 expression was modulated using lentiviral overexpression or knockdown. Fibrotic markers and β-catenin localization were analyzed via Western blot, cellular fractionation, and immunofluorescence. In vivo, liver fibrosis was induced in C57BL/6 J mice using a high-fat diet (HFD) combined with CCl₄ injections. MFN2 was systemically overexpressed or silenced via AAV2 vectors delivered through tail vein injection. Liver tissues were examined histologically and biochemically for fibrosis progression.

Results: PA treatment markedly downregulated MFN2 and upregulated fibrotic markers in HSCs. Overexpression of MFN2 strongly suppressed HSC activation, reduced α-SMA and N-cadherin levels, and significantly inhibited β-catenin nuclear accumulation. Conversely, MFN2 knockdown exacerbated fibrotic responses and promoted β-catenin translocation. In mice, MFN2 overexpression substantially attenuated collagen deposition and improved liver histology, while MFN2 silencing significantly aggravated fibrosis and enhanced β-catenin signaling.

Conclusion: MFN2 inhibits HSC activation and liver fibrosis by suppressing β-catenin nuclear translocation, making it a promising therapeutic target for NAFLD-related fibrosis and associated complications, such as hepatocellular carcinoma.

Objective: Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with metabolic dysregulation. This study aimed to investigate the role of homogentisic acid (HGA), a tyrosine metabolite, in AD pathogenesis and explore its potential as a noninvasive diagnostic biomarker.

Methods: Human saliva samples from AD patients and controls were analyzed. In vivo experiments were conducted using APP/PS1 (Aβ-driven) and P301S (tauopathy-focused) mouse models, which received exogenous HGA via gavage. Key techniques included behavioral tests (Morris water maze, novel object recognition, fear conditioning), Western blot, immunofluorescence, real-time PCR, and mass spectrometry to assess cognitive function, blood-brain barrier (BBB) integrity, Aβ aggregation, synaptic protein expression, and HGA metabolism. In vitro experiments were performed on HT22, SY5Y cells, and primary brain microvascular endothelial cells (BMECs) to verify HGA's direct effects.

Results: Salivary HGA levels were higher in AD patients than in controls, correlating with BBB impairment. Exogenous HGA significantly exacerbated cognitive deficits, BBB leakage, Aβ deposition, and loss of synaptic proteins (PSD93, synaptophysin) in mice, with effects more pronounced in the APP/PS1 than in the P301S model. In vitro, HGA exerted dose-dependent neurotoxicity, promoted Aβ aggregation, and downregulated tight junction proteins (claudin-5, occludin, ZO-1) in BMECs. Mechanistically, AD patients showed reduced expression of HGA-metabolizing enzymes (homogentisate 1,2-dioxygenase, maleylacetoacetate isomerase) and downstream metabolites, indicating impaired HGA catabolism. These findings confirm HGA promotes AD progression via two mutually reinforcing pathways: (1) accelerating Aβ aggregation and synaptic dysfunction; (2) disrupting BBB integrity through downregulating tight junction proteins.

Conclusion: This study identifies salivary HGA as a potential noninvasive biomarker and highlights targeting HGA metabolism or BBB protection as promising strategies for early AD intervention.

Osteoarthritis (OA) is a prevalent degenerative and inflammatory disease posing a significant financial and medical burden on patients and society. Lactic acid, the terminal metabolite of glycolysis, is recognized as a pivotal signaling molecule governing diverse physiological and pathological processes, particularly in cancer and inflammatory diseases. Emerging evidence suggests that metabolic disorders are closely associated with OA, which may provide a metabolic lens for further exploring its mechanisms. Glycolytic reprogramming is now recognized as a hallmark of OA, leading to the pronounced accumulation of lactic acid within the joint microenvironment. This review synthesizes current evidence to elucidate the role of lactic acid in OA pathogenesis. We summarize the mechanism of glycolytic reprogramming in chondrocytes and macrophages under pathological conditions. Furthermore, we demonstrate that lactic acid exacerbates cartilage degeneration while simultaneously promoting inflammation resolution. These dual roles are mediated by extracellular acidification, HCAR1, and lactylation. Given that duality, we suggest that redirecting lactate flux presents considerable potential as a therapeutic approach for the prevention and management of OA.

Prenatal depression is a prevalent mental health disorder that adversely affects maternal well-being and offspring health. Emerging evidence suggests that vitamin C (L-ascorbic acid), a key antioxidant, may influence this process through the regulation of DNA methylation (DNAm)-a critical epigenetic mechanism governing gene expression. This review summarizes current research on the role of vitamin C in modulating DNAm and explores its potential to mitigate the intergenerational impacts of prenatal depression. We analyze findings indicating that vitamin C may alleviate depressive symptoms and improve offspring health outcomes via epigenetic pathways. Furthermore, we highlight existing research gaps and propose future directions for investigation. By elucidating the interplay between vitamin C, epigenetic regulation, and prenatal depression, this article aims to provide novel insights for developing nutritional strategies to enhance maternal mental health and promote offspring well-being.

Objective: This study aimed to investigate the protective effects of berberine (BBR) on pancreatic β-cells and explore its underlying molecular mechanisms via a proteomics-based approach.

Methods: Using db/db mice as a diabetes model, BBR was administered at doses of 100 mg/kg and 200 mg/kg for 8 weeks. The protective effects were assessed through fasting blood glucose (FBG), oral glucose tolerance test (OGTT), insulin tolerance test (ITT), pancreatic histopathological analysis, and TUNEL staining. Proteomic analysis employing the data-independent acquisition (DIA) method identified differentially expressed proteins (DEPs), whereas Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to identify potential pathways. Molecular docking, surface plasmon resonance (SPR), and immunohistochemistry (IHC) were performed to validate key target proteins.

Results: BBR significantly reduced blood glucose levels, improved insulin resistance, enhanced insulin secretion, and reversed pathological changes in pancreatic tissue, thereby alleviating β-cell damage. Proteomic analysis identified 171 DEPs, implicating the AGE/RAGE signaling pathway as a key mechanism through which BBR exerts its protective effects. The results of molecular docking, SPR and IHC confirmed that BBR markedly inhibited the activation of the AGE/RAGE pathway.

Conclusions: These findings suggest that BBR alleviates pancreatic β-cell damage, potentially through regulation of the AGE/RAGE pathway, providing insights into its therapeutic potential for diabetes management.

Objectives: This study aimed to investigate the association between laboratory biomarkers and short-term poor prognosis in patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and to develop a risk stratification model.

Methods: A retrospective analysis was conducted on clinical data from 117 EBV-HLH patients admitted to our hospital between June 2016 and December 2024. Patients were classified into poor prognosis (n = 48) and good prognosis (n = 69) groups based on 28-day outcomes. Potential predictors were screened by univariable logistic regression and receiver operating characteristic (ROC) curve analysis, and a composite laboratory-based risk scoring system was subsequently constructed.

Results: The poor prognosis group exhibited significantly higher levels of urea (UREA), direct bilirubin (DB), high-sensitivity cardiac troponin I (hscTnI), serum ferritin (Ferr), and prothrombin time (PT) than the good prognosis group did (all P < 0.05). ROC analysis determined the optimal cutoff values and corresponding odds ratios (ORs) for poor prognosis as follows: UREA (≥ 5.4 mmol/L, OR = 5.911), DB (≥ 10.0 μmol/L, OR = 2.524), hscTnI (≥ 7.4 pg/mL, OR = 2.747), Ferr (≥ 12,422 μg/L, OR = 2.366), and PT (≥ 14.1 s, OR = 3.221). A 0-5-point risk score model was constructed based on these thresholds. The incidence of poor prognosis increased progressively with the score: 23.08% (score 0-1), 27.59% (score 2), 45.00% (score 3), 66.67% (score 4), and 92.30% (score 5). Each 1-point increase in the score was associated with an OR of 1.915 for poor prognosis.

Conclusion: The composite risk scoring system incorporating UREA, DB, hscTnI, Ferr, and PT showed satisfactory predictive performance for short-term outcomes in EBV-HLH patients. A score of ≥3 identifies high-risk individuals who may benefit from intensified immunomodulatory therapy, thereby facilitating individualized and stratified clinical management.

Objective: Huaier, a traditional Chinese medicine (TCM) approved by the National Medical Products Administration (NMPA) of China for cancer therapy, demonstrates broad antitumor activity. However, its potential to overcome resistance to gefitinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in non-small cell lung cancer (NSCLC) and the underlying mechanisms remain unclear. This study aimed to determine whether Huaier aqueous extract enhances the efficacy of gefitinib against resistant NSCLC and to elucidate the molecular basis of this effect.

Methods: Cell proliferation was evaluated using the Cell Counting Kit-8 and colony formation assays. Apoptosis, reactive oxygen species (ROS), and lipid ROS were measured using flow cytometry, and mitochondrial morphology was examined using transmission electron microscopy. RNA sequencing and integrated bioinformatics analyses of GEO datasets were performed to identify ferroptosis-related genes, which were validated by qPCR and Western blotting. The in vivo efficacy was assessed using a PC-9GR xenograft model.

Results: Huaier aqueous extract significantly enhanced the sensitivity of gefitinib-resistant NSCLC cells to gefitinib in vitro, and suppressed tumor growth in vivo. Mechanistically, the combined treatment activated the ferroptosis pathway, accompanied by the upregulation of acyl-CoA synthetase long-chain family member 4 (ACSL4). Pharmacological inhibition of ferroptosis or ACSL4 partially attenuated the antitumor effect, confirming their key roles in mediating the synergistic activity of Huaier aqueous extract and gefitinib.

Conclusions: Huaier aqueous extract reversed gefitinib resistance in NSCLC cells by promoting ACSL4-dependent ferroptosis, thereby providing a promising therapeutic strategy for improving EGFR-TKI efficacy.

Yes-associated protein-1 (YAP1) is an oncogenic effector of the Hippo signaling pathway, activated in several cancer types, and has been extensively studied in cancer progression and therapy. A large number of studies have established the importance of YAP1 in promoting cell-autonomous functions, including uncontrolled growth, sustained proliferative signaling, drug resistance, and metastasis, across multiple cancer types. Therapeutic targeting of YAP1 to combat incurable neoplasms has been the focus of intense investigations. Solid tumors exhibit an organ-like morphology that comprises malignant cells, nonmalignant cells such as fibroblasts, endothelial cells, and immune cells, and non-cellular components, including the extracellular matrix and exosomal vesicles. Tumor progression is accompanied by persistent, reciprocal interactions between malignant cells and other cell types in the tumor microenvironment (TME). Ample evidence indicates the functional importance of YAP1 in nonmalignant components of the TME, which fuel cancer progression. In this review, we provide a comprehensive overview of the functional significance of YAP1 and its downstream signaling pathways across different compartments of the TME, which orchestrate cancer growth, stemness, drug resistance, and metastasis. In particular, this review focuses on understanding the mechanisms by which YAP1 drives distinct cell types in the TME, including cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and exosome-derived factors, to fuel tumor progression. Furthermore, we summarize the progress in the development of recent YAP1 inhibitors, their mechanisms of action in Hippo-YAP1-dependent cancers, and their combination benefits with existing treatment strategies.

Objective: Emerging evidence implicates neuroinflammation in the pathogenesis of major depressive disorder (MDD), yet the role of memory B cells remains unclear. In this study, we conducted a bidirectional two-sample Mendelian randomization (MR) study and Bayesian colocalization analyses to investigate the causal relationships between memory B-cell traits and MDD risk.

Methods: MDD summary data were gathered from a meta-analysis of genome-wide association studies (GWASs), whereas memory B-cell genetic variations were sourced from GWASs on immune phenotypes. MR analysis utilized the inverse variance weighted (IVW), MR-Egger, and weighted median methods. Moreover, various sensitivity analyses, including Cochran's Q test, MR Pleiotropy Residual Sum and Outlier (MR-PRESSO), MR-Egger intercept test and Leave-one-out (LOO) analysis, were performed to confirm MR result stability. Bayesian colocalization analyses were also conducted to identify genetic loci shared between memory B cells and MDD.

Results: Our results indicated that genetically predicted increased CD27 protein expression on memory B cells causally elevated MDD risk (ORs: 1.025-1.063, P_FDR < 0.05). Conversely, MDD did not causally affect memory B-cell traits. Additionally, the colocalization analysis revealed no shared genetic variants, suggesting distinct biological pathways.

Conclusions: These findings highlight CD27 as a potential novel biomarker and therapeutic target in MDD, warranting further clinical validation in the future.