📋 Browse Articles

The large-scale development of pig farming has introduced significant stressors that negatively affect pigs' mental health, behavior, and production efficiency. The hippocampus, crucial for cognition and stress response regulation, plays a central role in these processes. However, the regulatory mechanisms underlying hippocampal function across pig breeds with different domestication statuses and their implications for behavior and breeding strategies remain unclear. We performed single-nucleus RNA sequencing (snRNA-seq) on hippocampal tissues from 22,342 cells across three pig breeds: Asian wild boar, Jinhua, and Duroc, representing different domestication statuses. We identified six major hippocampal cell types and annotated 108 breed-specific transcription factors, including GATA2, SPI1, and EBF1. Additionally, we characterized 83 co-expression modules and 50 significant ligand-receptor pairs, such as TGFβ, WNT, and SPP1, revealing complex intercellular communication networks. Oligodendrocyte expression patterns were conserved across all breeds. We identified 194 candidate genes linked to stress resilience, mental health, and feeding behavior, including MC4R, RYR2, PDE10A, and ABCG2. Alzheimer's disease-related gene enrichment was lower in Duroc pigs, consistent with reduced APOE expression. We also developed the Pig Hippocampus Single-cell Atlas (PHiSA, http://alphaindex.zju.edu.cn:8503/ ), an open-access database allowing breed-specific hippocampal analyses and validation of gene expression at the single-nucleus level. This study offers insights into hippocampal function regulation in pigs, focusing on stress resilience, behavior, and productivity. It highlights conserved and breed-specific molecular features of hippocampal cell types and their roles in adaptability and mental health. By integrating single-nucleus data, the research suggests that genetic strategies could be used to improve animal welfare, stress management, and production efficiency in pig breeding programs. Show less

Acute respiratory distress syndrome (ARDS) is a severe clinical syndrome driven by inflammation, oxidative stress, and pulmonary tissue injury, for which effective therapy drugs remain lacking. In this study, the therapeutic potential and underlying mechanisms of dipotassium glycyrrhizinate (DG) in ARDS were systematically evaluated through both In an A549 cell model, DG exhibited no cytotoxicity within the tested concentration range and significantly suppressed LPS-induced excessive reactive oxygen species (ROS) generation and pro-inflammatory cytokine expression, including Tumor necrosis factor (TNF)- In conclusion, DG alleviates ARDS-associated inflammation and oxidative stress through coordinated modulation of multiple signaling pathways, providing a theoretical and experimental foundation for its potential development as a natural therapeutic agent against ARDS. Show less

Blood-based biomarkers could improve the precision of Alzheimer's disease (AD) clinical diagnosis and expand access to targeted treatments. Therefore, we evaluated the diagnostic accuracy of plasma Elecsys p-tau217 (Roche) and compared it with Elecsys p-tau181 (Roche) and Lumipulse p-tau217 (Fujirebio). We also assessed the added value of APOE-ε4 carrier status, plasma Aβ42 and Aβ42/40 in a memory-clinic cohort and evaluated associations with longitudinal cognition. A total of 187 patients from the Cognitive Centre Ghent University (CCUG) biobank, classified as AD (n = 103) or non-AD cognitive disorders (n = 84) based on CSF biomarkers (CSF Aβ42/40 ratio, total tau and p-tau181), were included. Plasma Elecsys p-tau181, p-tau217, and APOE-ε4 were measured on the Roche cobas Elecsys plasma p-tau217 showed high discriminative performance for AD versus non-AD (AUC 0.939), comparable to Lumipulse p-tau217 (AUC 0.950; p = 0.485). Elecsys p-tau181 performed lower than Elecsys p-tau217 (AUC 0.903; p = 0.043). Using a two-cut-off strategy, the intermediate proportion was 19.9% for Elecsys p-tau217, 11.9% for Lumipulse p-tau217, and 33.2% for Elecsys p-tau181. Adding APOE-ε4 to Elecsys p-tau217 improved discriminative performance (AUC 0.970, p = 0.02) and reduced intermediates to 11.0%. Adjustment for Aβ42 on the Fujirebio platform did not significantly increase the AUC (0.950 vs. 0.957; p = 0.322) and modestly reduced intermediate classifications (11.9% to 10.0%). Higher baseline Elecsys p-tau217 was associated with lower baseline MoCA and a trend towards faster MoCA decline (p = 0.07). Age, sex, renal function, Fazekas score, and CAA were not significantly associated with Elecsys p-tau217 concentrations. Plasma Elecsys p-tau217 measured on an automated high-throughput platform shows excellent diagnostic accuracy for AD. Incorporating APOE-ε4 further improves classification, while Aβ42 adjustment had only limited additional impact. Baseline p-tau217 also reflects cognitive severity and may relate to subsequent cognitive decline in the memory-clinic setting. Show less

The brain-derived neurotrophic factor (BDNF) is a potent neuroprotective factor; however, its large molecular size limits its ability to cross structural barriers such as the blood-spinal cord barrier. This study explores the therapeutic potential of exosome-mediated delivery of engineered circular BDNF (circBDNF) to promote spinal cord injury (SCI) repair through activation of the PI3K/AKT/mTOR signaling pathway. A synthetic circBDNF sequence encoding BDNF was used to construct a circBDNF overexpression plasmid, which was transfected into HEK293T cells to generate circBDNF-loaded exosomes (circBDNF-EXO). These exosomes were characterized via transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. In vitro, the protective effects of circBDNF-EXO were evaluated in an oxygen-glucose deprivation/reperfusion (OGD) injury model in HT22 cells, focusing on cell viability, reactive oxygen species (ROS) levels, apoptosis, inflammation, and signaling pathways. In vivo, a T10 SCI mouse model was employed to assess therapeutic efficacy, using behavioral, electrophysiological, histological, and molecular analyses. In vitro, circBDNF-EXO treatment significantly increased BDNF expression, enhanced cell viability, reduced ROS levels, mitigated inflammation, and inhibited apoptosis in HT22 cells following OGD injury. In vivo, administration of circBDNF-EXO resulted in improved motor function recovery, evidenced by increased Basso Mouse Scale scores, enhanced gait coordination, and better motor-evoked potentials. Histological analyses demonstrated elevated BDNF expression, decreased apoptosis, reduced oxidative stress, and enhanced axonal regeneration in the injured spinal cord. Mechanistically, circBDNF-EXO activated TrkB receptors and upregulated the PI3K/AKT/mTOR signaling pathway, as confirmed by Western blot analysis. Exosome-mediated delivery of circBDNF promotes SCI repair by activating the PI3K/AKT/mTOR pathway, suppressing apoptosis, oxidative stress, and inflammation, and enhancing axonal regeneration. This innovative approach holds substantial promise for SCI treatment and deserves further exploration in preclinical and clinical studies. Show less

Many factors, such as lifestyle, medication, and environmental exposures, are reported to cause thyroid hormone system disruption (THSD) in humans, however studies linking THSD to health effects are sparse. Adverse Outcome Pathways (AOPs) provide mechanistic links from molecular events to adverse outcomes, with effect biomarkers serving as a tool to empirically anchor key events and health effects and to assess biological relevance. This review aims to identify and evaluate effect biomarkers for thyroid hormone system-related AOPs for further validation in experimental and epidemiological studies. Using AOP-wiki, we extracted and analysed thyroid-related AOPs, focusing on the eleven AOPs with mammalian evidence. We did systematic literature search to identify potential effect biomarkers for future epidemiological studies. In an AOP network analysis of the eleven thyroid-related AOPs, we identified four AOP clusters, including hippocampal alterations, impaired learning and memory, thyroid follicular cell adenomas/carcinomas, and kidney toxicity. For the clusters on hippocampal alterations and impaired learning and memory, brain-derived neurotrophic factor emerged as a promising effect biomarker. For the cluster on thyroid follicular cell adenomas/carcinomas, no promising effect biomarkers with high specificity were identified, but interleukin-34, oxidative stress, and expression of several genes were found to be related to the adverse outcome. For kidney toxicity, a panel of effect biomarkers were identified, such as clusterin, cystatin-C, kidney injury molecule-1, N-acetyl-beta-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and osteopontin. This review operationalizes the AOP framework to support the use of mechanistically anchored effect biomarkers in human studies on THSD. By aligning key biological events with measurable endpoints, human matrices, and feasibility considerations, it provides a scientifically grounded path from mechanistic understanding to population research application. This enables more targeted biomonitoring, strengthens interpretation of epidemiological findings, and informs research and regulatory priorities for future validation efforts. Show less

Diabetic foot ulcers (DFU) are a severe complication of diabetes. Although dysregulated M2 macrophage polarization is recognized as a key driver of chronic inflammation in DFU, the molecular checkpoints that can be therapeutically targeted to restore M2 bias remain poorly defined. Here, we aimed to determine whether the RNA-binding protein TAF15 acts as a post-transcriptional stabilizer of the M2-promoting CEBPB/APOE/PTX3 axis, thereby accelerating DFU healing. First, we confirmed that APOE positively regulates PTX3, which supports M2 polarization and the proliferation and migration of HDF. CEBPB transcriptionally activated APOE and promoted M2 macrophage polarization. TAF15 stabilized CEBPB mRNA and affected HDF cell proliferation and migration by promoting M2 macrophage polarization. Additionally, TAF15 overexpression partially counteracted the disruption of M2 macrophage polarization caused by APOE silencing and facilitated DFU wound healing. Collectively, our findings establish TAF15-driven stabilization of CEBPB mRNA as a target point that sequentially activates APOE/PTX3 signaling to enforce M2 polarization and accelerate DFU closure. This study provides a preclinical rationale for the development of TAF15-targeted oligonucleotides or small-molecule strategies to reprogram wound macrophages and improve DFU outcomes in patients with diabetes. Show less

This research investigated the potential therapeutic role of α-(phenylselanyl) acetophenone (PSAP) in the comorbidity of chronic pain and depression triggered by partial sciatic nerve ligation (PSNL). Male Swiss mice underwent PSNL surgery, and after a four-week period, they received either PSAP (1-50 mg/kg, administered intragastrically) or imipramine (IMI) (50 mg/kg) 30 min prior to behavioral assessments. Both PSAP and IMI effectively alleviated PSNL-induced hypersensitivity to pain and depressive-like symptoms, as demonstrated in forced swim and allodynia tests. Additionally, PSAP counteracted the elevated levels of lipid peroxidation and reactive oxygen species observed in the cortex and hippocampus following PSNL. These neuroprotective effects appear to be linked to PSAP's anti-inflammatory properties, as it downregulated the expression of pro-inflammatory markers such as NF-κB p65, TNF-α, and IDO mRNA in the affected brain regions. Furthermore, PSAP restored hippocampal BDNF mRNA levels, which had been diminished by nerve injury. Since inflammation is a common pathway in both chronic pain and depression, the findings indicate that PSAP holds promise as a treatment for this comorbid condition. Show less

Adverse childhood experiences (ACEs) increase susceptibility to depression and anxiety disorders in adulthood. This study investigated the potential mechanisms through which ACEs enhance vulnerability to depression and anxiety in adulthood, using a novel "two-hit" mouse model by combining maternal separation (MS) with 14 or 21 days of restraint stress (RS). Behavioral assessments (sucrose preference test, tail suspension test, open field test, elevated zero maze) confirmed depressive- and anxiety-like behaviors in the MS + RS 21d group mice. Neurobiological analyses revealed hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis (elevated serum corticosterone [CORT] and adrenocorticotropic hormone [ACTH]) and dysregulation, characterized by reduced levels of monoamine neurotransmitters (5-hydroxytryptamine [5-HT], 5-hydroxyindoleacetic acid, dopamine, norepinephrine), altered mRNA expression of key genes (e.g., increased ACTH, CRH, SERT; decreased GR, brain-derived neurotrophic factor [BDNF]), and corresponding protein-level changes (e.g., increased 5-HT1AR, CRHRs; decreased BDNF, TrkB). Our findings indicate that the two-hit mouse model, combining MS with a 21-day RS, stably induces depressive- and anxiety-like behaviors in mice. The underlying mechanism may be associated with HPA axis dysfunction, serotonergic system dysregulation, and aberrant BDNF signaling within the prefrontal cortex-amygdala-hypothalamus circuit. Show less

Classic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), have emerged as potent modulators of neuroplasticity and metaplasticity in the adult brain, offering novel therapeutic strategies for neuropsychiatric disorders. Recent findings reveal that beyond their transient psychotropic effects, these compounds activate serotonin 5-HT Show less

Lipoprotein(a) [Lp(a)] is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), but the shape and potential nonlinearity of its association remain uncertain. We assessed the linear and nonlinear associations between Lp(a) levels and ASCVD risk using observational and Mendelian randomization (MR) approaches. We analyzed 351,858 UK Biobank participants (2006-2023), stratified into Lp(a) percentiles: <70th, 70th-<80th, 80th-<90th, and ≥90th. Outcomes included ASCVD events from hospital, primary care, self-report, and death registry data. Cox models estimated the hazard ratios (HRs). MR analyses used a polygenic risk score from 10 Lp(a)-associated single-nucleotide polymorphisms, with nonlinearity tested by doubly ranked MR. Higher Lp(a) levels were associated with increased ASCVD risk. Compared with the <70th percentile, adjusted HRs (95% confidence interval) were 1.11 (1.07-1.16), 1.18 (1.14-1.22), and 1.25 (1.21-1.30) for the 70th-<80th, 80th-<90th, and ≥90th groups. Kaplan-Meier curves diverged early by group. Spline models suggested nonlinearity with an inflection near 130 nmol/L (P=0.007). MR showed a 2% higher ASCVD risk per 10 nmol/L genetically predicted Lp(a) (P<2×10 Elevated Lp(a) concentrations were causally associated with ASCVD risk, showing a predominantly graded relationship with possible nonlinearity at very high levels, supporting routine Lp(a) measurement and the development of Lp(a)-lowering therapies. Show less

Both brain-derived neurotrophic factor (BDNF) and ovarian hormones are powerful neuromodulators, yet evidence of their impact on human cognition remains mixed. As prior work has studied them in isolation, examining their interacting effects presents a key empirical opportunity for explicating their effects on cognition. We genotyped participants for the BDNF Val66Met single nucleotide polymorphism, which is associated with less efficient activity-dependent BDNF secretion and altered hippocampal function, and examined their performance on a complex learning task at two points in the menstrual cycle: early follicular (characterized by low levels of ovarian hormones) and late follicular (characterized by high estradiol). While met carriers showed advantages during the early follicular timepoint, val homozygotes outperformed them at the late follicular timepoint. Furthermore, effects in met carriers were largely driven by increased sensitivity to both absolute levels and changes in levels of estradiol. The current findings provide the first evidence of BDNF Val66Met interacting with the menstrual cycle to predict cognition, demonstrate nuanced genotype- and hormone-specific outcomes, and underscore the importance of studying effects of interacting biological systems on human cognition. Show less

Childhood-onset cardiomyopathies are rare and not well characterised. This study aimed to describe the clinical features of a paediatric cohort with primary cardiomyopathies, with a particular focus on aetiology and both short- and long-term outcomes. A retrospective descriptive study was conducted, including patients diagnosed with primary cardiomyopathies before the age of 18. Clinical presentation, aetiology, and outcomes were analysed for each morphological subtype of cardiomyopathy. A total of 76 patients met the inclusion criteria. Dilated cardiomyopathy was the most common subtype (48.6%), followed by hypertrophic (31.5%), left ventricular non-compaction (10.5%), restrictive (5.2%), and arrhythmogenic cardiomyopathy (3.9%). The mean age at diagnosis was 6.3 ± 5.6 years, with a slight female predominance (56.6%). The rate of genetic diagnosis was 25.6%; the most commonly identified pathogenic or likely pathogenic variants were in These findings highlight the heterogeneous aetiology of paediatric cardiomyopathies and the variability in outcomes according to morphological, genetic, and clinical subtypes. The results underscore the importance of individualised evaluation and management for affected patients. Show less

Ischemic stroke is a leading cause of mortality and disability worldwide, and there is an urgent need for safe dietary agents with neuroprotective potential. Water-soluble tomato concentrate (WSTC), a tomato-derived functional ingredient approved in Europe for cardiovascular health, was evaluated for its protective effects against cerebral ischemia-reperfusion injury. Using a middle cerebral artery occlusion/reperfusion rat model and oxygen-glucose deprivation/reoxygenation neuronal model, we demonstrated that WSTC improved cerebral perfusion, reduced infarct volume, alleviated histopathological damage, and enhanced neurological recovery. Mechanistic studies integrating transcriptomics, network pharmacology, and molecular assays revealed that WSTC inhibited oxidative stress and neuronal apoptosis while activating the ERK/CREB/BDNF signaling pathway. These findings provide the first comprehensive evidence that WSTC confers multi-target neuroprotection and highlight its translational potential as a safe, plant-based functional food ingredient for promoting brain health and reducing ischemic injury. Show less

This study, adopting a person-centered approach and using network analysis, explores latent subtypes of Junzi personality among college students and their links to Receptiveness to Opposing Views, offering empirical backing for the ancient Chinese idea of "Junzi harmonize yet remain distinct." Traditional variable-centered methods often fail to fully expose the underlying typological structure due to the possible heterogeneous combinations in Junzi personality dimensions. Thus, a person-centered latent profile analysis (LPA) was used to pinpoint typical personality trait patterns. With 1116 college students as participants, the study employed the Junzi Personality Questionnaire Based on Confucian Thought and the Receptiveness to Opposing Views Scale. LPA identified three personality types: The Moderate Type (50%), The Daring-Aggressive Type (15%), and The Virtuously-Accomplished Type (35%). Regression analysis showed significant correlations between gender, age, and personality type, with The Virtuously-Accomplished Type scoring notably higher in Receptiveness to Opposing Views. Network analysis further revealed distinct differences in the network structures of Receptiveness to Opposing Views among the three types: The Moderate Type centered on "derogation of opponents," "refraining from what should not be done," and "respectfulness and propriety"; The Daring-Aggressive Type focused on "conversancy with righteousness and cherishment of benign rule," "derogation of opponents," and "respectfulness and propriety"; while The Virtuously-Accomplished Type highlighted "negative emotions" and "wisdom, benevolence, and courage," with "taboo issues" at the periphery in all datasets. The findings uncover the heterogeneity of Junzi personality and its varied associations with Receptiveness to Opposing Views, providing insights for understanding harmonious interactions in diverse settings. Show less

Cognitive flexibility is a core executive function vital for adaptation and adjustment to new information. The brain-derived neurotrophic factor (BDNF) single nucleotide polymorphism, val66met, has been suggested to modulate cognitive flexibility but it remains unclear how confounding variables such as stress and sex influence this relationship. Environmental enrichment (EE) may protect against stress-induced effects. The aim of this study was to test whether BDNF val66met alters reversal learning, a key component of cognitive flexibility, when tested under stressful water maze conditions. We used a Sprague Dawley val66met rat model where pregnant val/met dams were moved to either low or high EE environments. Dams and offspring stayed in these environments until weaning, after which the offspring was moved to standard, moderate enrichment housing. Adult male and female val/val, val/met and met/met offspring then underwent a water maze reversal learning protocol. All groups rapidly learned the new location of the platform. Mediation analysis showed the relationship between val66met and cognitive flexibility was mediated by differential use of spatial strategies. Sequential clustering analysis demonstrated that val66met interacted with sex to predict cognitive flexibility performance with lower flexibility in met/met males and val/met females compared to other genotypes. EE was not a strong promotor of cognitive flexibility. Water maze testing increased corticosterone levels, confirming the stressful nature of the test. This study demonstrates the importance of considering stress and sex when investigating the role of BDNF val66met in cognitive flexibility. Show less

Maternal psychological distress may have adverse effects on child socioemotional development. However, supportive social networks and participation in out-of-home childcare may serve as key protective factors and promote positive developmental outcomes. This study investigated whether maternal cumulative psychological distress is associated with children's (n = 528) social competence at the age of 5 years (M = 5.02, SD = 0.08) in Finland. Latent profile analyses (LPA) were conducted to identify latent classes of maternal cumulative symptoms of depression, anxiety, and parenting stress. Associations between these profiles and children's prosocial and antisocial behavior were examined. Additionally, the moderating effects of the child's age at entry into Early Childhood Education and Care (ECEC) and maternal supportive social networks were analyzed. The results showed that chronically high maternal psychological distress was subsequently associated with child's higher impulsivity, higher disruptiveness, and lower empathy. We found no evidence of early ECEC attendance or mother's social networks as moderators between maternal symptoms and child's behavior. Nevertheless, mother's supportive social networks were beneficial for all children and associated with child's higher empathy and cooperation skills. These findings underscore the need for early identification of maternal psychological distress symptoms. Moreover, social networks may serve as valuable resources for families with young children and support child development, even though they did not buffer the effects of maternal distress. Show less

Gastric cancer (GC) is a leading cause of cancer-related deaths and has high recurrence rate. Although fibronectin domain-containing protein 1 (FNDC1) is implicated in GC progression, its molecular mechanisms remain unclear. Multi-omics analyses (TCGA, GEO datasets) were used to assess FNDC1 expression and clinical correlation. In vitro (cell proliferation, invasion, EMT markers) and in vivo (xenograft) experiments, combined with molecular assays (Co-IP, WB, ChIP), explored FNDC1's function and mechanism. FNDC1 was significantly upregulated in GC, correlating with advanced clinicopathological features and poor prognosis. Knockdown of FNDC1 suppressed GC cell proliferation, invasion, and metastasis by inhibiting EMT and Wnt/β-catenin signaling. Mechanistically, FNDC1 competitively bound the WD5 domain (residues 224-254) of Gβ2, disrupting Gβγ-Dvl1 interaction. This prevented Dvl1 degradation, promoted Axin1 ubiquitination, and destabilized the β-catenin-destruction complex (GSK3 β-APC-Axin1), leading to β-catenin accumulation and Wnt pathway activation. FNDC1 drives GC malignancy by targeting the Gβ2-Dvl1 axis to activate Wnt/β-catenin signaling, suggesting FNDC1 as a novel prognostic biomarker and therapeutic target. Show less

Identifying high-performing advanced practice nursing roles and understanding the factors that contribute to their effectiveness are critical for advancing professional development, optimizing workforce deployment, and ensuring long-term sustainability in nursing. This study aimed to (1) identify distinct latent profiles of advanced practice nursing among specialist nurses in mainland China, (2) quantitatively examine the individual and contextual factors associated with high performance, as characterized by these profiles, and (3) qualitatively confirm the significant factors using explanatory semistructured interviews in the high-performance groups. A mixed-methods sequential explanatory design was used, in which quantitative data were collected first and subsequently explained through qualitative interviews. Certified specialist nurses from 16 hospitals across urban and rural areas of Shanghai were included. Latent profile analysis (LPA) was conducted using the five domains from the Advanced Practice Role Delineation tool as manifest indicators to classify nurses into distinct performance profiles. Multinomial logistic regression was used to examine potential determinants (e.g., job position) of group membership. Additionally, a backpropagation neural network (BPNN) was developed to rank the importance of contributing factors. Specialist nurses identified as high performers in the quantitative phase were purposively sampled for explanatory semistructured qualitative interviews. Three latent profiles emerged: high performance (26.1%), moderate performance (46.3%), and low performance (27.6%). Compared to APNs, staff nurses had significantly lower odds of belonging to the high-performance group ( Identifying the profiles of advanced practice nursing roles provides valuable insights for optimizing APN performance and informing targeted management and policy strategies. High-performing specialist nurses are positioned at the nexus of individual capability, interdisciplinary collaboration, and institutional support. Show less

Hypoxic-ischemic brain damage (HIBD) represents a major cause of neonatal morbidity and mortality, resulting from perinatal oxygen deprivation and impaired cerebral blood flow. This study aims to investigate the neuroprotective effects of Arctiin, a bioactive lignan derived from Neonatal rats at postnatal day 8 were randomly assigned to four groups: Sham-operated (SHAM), Hypoxia-Ischemia (HI), Hypoxia-Ischmia with Solvent control (HI/SO), and Hypoxia-Ischemia treated with Arctiin (HI/Arc). HIBD was induced via unilateral carotid artery ligation followed by exposure to hypoxia. The HI/Arc group was administered Arctiin orally at a dosage of 60 mg/kg daily for seven consecutive days. Behavioral performance, biochemical parameters, histological integrity, and gene expression profiles were assessed to evaluate the neuroprotective efficacy of Arctiin. Arctiin administration resulted in a significant reduction in C-reactive protein (CRP), and total oxidant capacity (TOC). Simultaneously, it enhanced total antioxidant capacity (TAC) and brain-derived neurotrophic factor (BDNF) levels. Histological analysis showed diminished infarct volume in the Arctiin-treated group. Moreover, gene expression studies revealed significant restoration of Neuregulin-1 (NRG-1) in group treated by arctiin. Neurobehavioral assessments further confirmed significant improvements in sensorimotor function in the Arctiin-treated group. Our study provides evidence indicating that Arctiin mitigates hypoxic-ischemic brain damage in rat pups through a synergistic mechanism involving the suppression of inflammation and oxidative stress, coupled with the upregulation of critical neuroprotective genes and proteins, specifically NRG-1 gene expression and BDNF protein levels. Future studies should investigate the precise molecular pathways downstream of NRG-1 that mediate Arctiin's neuroprotective effects. Show less

Coronary heart disease (CHD) is driven by endothelial dysfunction and chronic vascular inflammation. hsa-miR-2110 (miR-2110) has been associated with adverse cardiovascular outcomes, but its mechanistic role in CHD remains unclear. In this study, miR-2110 expression was quantified in peripheral blood from CHD patients and healthy controls. Functional effects were assessed in EA.hy926 endothelial cells following lentiviral overexpression of miR-2110. The target gene Show less

Niemann-Pick disease, type C1 (NPC1), is a rare, fatal, neurodegenerative lysosomal disorder caused by pathological variants in Proximal Extension Assays (PEA) were used to determine relative protein expression levels from 68 serum samples from NPC1 individuals and 20 age-appropriate control serum samples. Statistical models identified NPC1 disease-specific effects after adjusting for covariates. Selected proteins were orthogonally validated by ELISA and correlated with assessments of both disease severity (Age of Neurological Onset (ANO) and Annual Severity Increment Score (ASIS)) and disease burden (NPC Neurological Severity Score (NSS). Quantifiable data was obtained on 2888 proteins, revealing 186 increased (adjusted log The statistical analysis pipeline developed in this study is flexible and scalable and supports application to high-dimensional proteomic datasets. This study identified and validated serum proteins with altered expression in individuals with NPC1, responded to miglustat therapy, and correlated with disease severity or burden. These proteins may have clinical utility as biomarkers and provide insights into cellular mechanisms contributing to NPC1 disease pathology. NCT00344331 (Registration on 2006-06-23). Show less

Heart failure (HF), with varied symptoms caused by cardiac strain or damage, has high morbidity and mortality. Protein lactylation, a post-translational modification, regulates immune and cardiovascular processes, but its role in HF's immune microenvironment remains underexplored. Differentially expressed lactylation-related genes (LacRGs) were identified by intersecting HF differentially expressed genes with LacRG data sets. Unsupervised clustering categorized patients with HF into LacRG-based subgroups. An LacRG diagnostic model was developed to assess associations with immune cell infiltration, immunotherapy potential, and single-cell RNA sequencing expression patterns. HF mouse models were constructed and verified for LacRG expression. In 200 HF versus 166 non-HF samples, 38 differentially expressed LacRGs were identified, revealing distinct immune landscapes. Two LacRG clusters exhibited unique functional enrichment and immunologic features. A 14-gene LacRG signature distinguished HF from controls with high accuracy (area under the curve: 0.999, 1.000, 0.744). Single-cell RNA sequencing (GSE145154) revealed reduced lactylation scores in fibroblast, macrophage, T-cell, and NK-cell subsets in HF, alongside characterization of altered cellular subtypes and activated signaling pathways within these populations. External data sets (GSE46224, GSE116250) identified 6 hub genes-HBB, EXT1, CENPA, NT5E, STAT4, and CAPN5, which were validated in HF mouse models. In addition, analysis of HF dataset further indicated higher LacRG scores in heart failure with preserved ejection fraction than in reduced ejection fraction. Lactylation modification is closely linked to HF's immune microenvironment. A 14-gene LacRG signature and 6 hub genes provide novel insights into HF pathophysiology and potential therapeutic avenues. Further studies are warranted to validate their regulatory roles in HF through immune microenvironmental mechanisms. Show less

Esophageal cancer is a formidable malignancy, presenting a significant health challenge due to its widespread prevalence and associated high mortality rates. Epithelial cell adhesion molecule (EpCAM), a pro-oncogenic glycoprotein, has been identified as an upregulated protein in esophageal adenocarcinoma (ESCA) through multi-OMICS platforms. However, its functional role in ESCA remains relatively understudied. Here, we investigated the contribution of EpCAM to ESCA pathogenesis using an EpCAM-null ESCA cell line, FLO-1, as a gain-of-function model. Introduction of a recombinant EpCAM-GFP fusion construct into FLO-1 cells resulted in enhanced cell migration, adhesion, clonogenic survival, and invasive capacity, supporting a pro-tumorigenic role for EpCAM. To define EpCAM-associated regulatory networks, RNA sequencing was performed on EpCAM-overexpressing cells, revealing 797 differentially expressed genes. Functional enrichment analyses indicated significant involvement of pathways related to cell adhesion, cell motility, transmembrane activity, and neuronal-associated processes, with enrichment in plasma membrane, focal adhesion, and neuron projection terminus compartments. Protein-protein interaction network analysis identified key hub genes, including SOX2, COL1A1, LOX, COL3A1, LUM, PXDN, BDNF, NCAM1, TLR2, and CCL5, linking EpCAM signaling to PI3K-Akt, ECM-receptor interaction, and focal adhesion pathways. Importantly, quantitative polymerase chain reaction (qPCR) validation of selected hub genes confirmed significant upregulation of the extracellular matrix components COL1A1 and PXDN in EpCAM-overexpressing FLO-1 cells, supporting the transcriptomic predictions and implicating ECM remodeling as a downstream consequence of EpCAM signaling. Collectively, these findings demonstrate that EpCAM promotes aggressive cellular phenotypes in ESCA and drives transcriptional programs associated with adhesion, invasion, and extracellular matrix regulation, highlighting potential therapeutic vulnerabilities in EpCAM-driven ESCA. Show less

The approach to physical activity in patients with epilepsy has substantially changed over the last decade. Despite multiple positive effects of physical activity on general health and well-being, patients with epilepsy have long been advised not to engage in sports activities. Recent studies have led physicians to formulate updated recommendations and to encourage patients to remain active. It has been demonstrated that sport does not increase seizure prevalence, and the rate of sport-induced injuries in people with epilepsy is comparable to that of the general population. Additionally, physical activity modulates brain plasticity through a number of mechanisms, including the effect of brain-derived neurotrophic factor (BDNF), gamma-aminobutyric acid (GABA)/glutamate balance, and maintaining long-term potentiation states in synapses. The International League Against Epilepsy (ILAE) classifies sports into three categories according to the potential risk of injury in the event of a seizure. While most activities fall into low- or moderate-risk groups, high-risk sports include aviation, climbing, diving, horse racing, motor sports, parachuting, rodeo, scuba diving, ski jumping, solitary sailing, surfing, and windsurfing. Qualification for sports participation requires individual assessments of predispositions, seizure type and frequency, reaction to specific sports disciplines, respiratory function, and adjustment of hydration and nutrition. The intensity of training should be increased gradually to avoid triggering factors, such as hyperventilation, alkalosis, and hyperthermia. Seizure occurrence differs between aerobic and anaerobic sports, which is another aspect that needs to be included. Exercise electroencephalographic (EEG) and ambulatory EEG monitoring should be taken into account in patients with exercise-induced seizures to optimize their training plan. Despite the evolving recommendations, it is difficult to formulate universal recommendations for everyone. Each patient with epilepsy should undergo an individual qualification process and be appropriately monitored. Show less

Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular diseases. Although some lipid-lowering drugs have demonstrated positive effects in patients with atherosclerotic cardiovascular diseases, their effects are limited in those with homozygous familial hypercholesterolemia. It is essential to seek new lipid-lowering targets. YAP (Yes-associated protein) may be involved in lipid metabolism in the liver; therefore, we investigated the function of hepatocyte YAP in hyperlipidemia and atherosclerosis. Hyperlipidemia models were generated in apoE knockout (apoE High-cholesterol diet-fed apoE Taken together, our findings revealed a novel role for the YAP-TEAD4-ANGPTL3 axis in lipid metabolism independent of LDLR. Inhibition of hepatocyte YAP may be an effective lipid-lowering strategy for homozygous familial hypercholesterolemia. Show less

Malignant phosphaturic mesenchymal tumors (MPMT) are rarely seen soft tissue tumors. They can result in tumor-induced osteomalacia with hypophosphatemia. These tumors show FN1::FGFR1/FGF1 gene fusions. We present a 59-year-old male patient with a swelling in his right knee. Magnetic resonance imaging examination revealed a soft tissue mass with a maximum diameter of 2 cm in his distal right thigh. Histopathologically, the tumor was composed of atypical spindle cells. Coagulative tumor cell necrosis, extensive osteoid-like matrix, calcifications, and aneurysmal bone cyst-like areas were present. Mitotic index was 16/mm Show less

Lipoprotein(a) [Lp(a)] is a causal, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). Although elevated Lp(a) affects approximately 20% of the global population, specific pharmacological options have long been unavailable, leaving a major gap in residual risk management. This review synthesizes current understanding of Lp(a) molecular architecture, genetics, and metabolism, and integrates mechanistic evidence linking Lp(a) to pro-atherogenic, pro-inflammatory, and pro-thrombotic pathways. We summarize epidemiological and genetic data associating Lp(a) with a broad spectrum of cardiovascular outcomes and discuss current clinical guidelines on screening and risk stratification. Furthermore, we provide an up-to-date overview of the emerging therapeutic landscape, including RNA-targeted therapies and novel oral small molecules. With pivotal phase 3 outcome trials nearing completion, the field is transitioning from viewing Lp(a) as an untreatable biomarker to an actionable therapeutic target, with important implications for precision cardiovascular prevention. Show less

Mitogen-activated protein kinase (MAPK) phosphatases [MKPs, also known as dual-specificity phosphatases (DUSPs)] regulate MAPKs -key mediators of cellular processes such as proliferation, differentiation, and survival- by dephosphorylating the threonine and tyrosine residues required for MAPK activation. MKP-3/DUSP6 is an ERK-selective phosphatase that has also been reported to regulate the transcription factor FOXO1. The full-length MKP-3 transcript has been shown to encode the MKP-3L protein, whereas alternative splicing gives rise to the shorter isoform MKP-3S. However, the available information regarding the functional differences between these variants is limited. By combining biochemical and bioinformatic approaches, we demonstrate that these isoforms differ significantly in subcellular localization and enzymatic activity. Structural analysis and molecular docking reveal that while MKP-3S retains functional binding domains and recognizes ERK2 similarly to the full-length isoform. However, the absence of critical catalytic motifs in MKP-3S leads to a structural uncoupling where the protein retains its ability to bind ERK2 but fails to induce dephosphorylation, suggesting a non-canonical role as a molecular scaffold. The results obtained demonstrate significant variations in subcellular localization, enzymatic activity, and the capacity to modulate FOXO1 transcriptional activity. This, in turn, affects the expression of genes such as p21. In conclusion, the findings indicate that MKP-3 variants exhibit distinct functional behaviours, which may result in differential regulation of a wide range of cellular processes. Show less

'Small extracellular vesicles (sEVs) are nanosized, membrane-enclosed sacs released by diverse cell types. They play a critical role in cell-cell communication through their cargo, which includes a wide range of proteins, lipids, and nucleic acids. Physiologically, sEVs circulate in various body fluids such as blood, urine, and saliva, making them accessible for diagnostic via non-invasive isolation techniques. Recent advances in high-throughput proteomics have significantly enhanced our ability to characterize the protein content of sEVs. Importantly, multiple studies on human fluids have identified specific protein markers across different cancer types, encompassing molecules involved in inflammation, cellular adhesion, immunity, and lipoprotein regulation. Interestingly, some of these proteins are consistently detected across multiple cancer types and sample sources, suggesting the existence of a shared "oncogenic signature" that may be transferred via sEVs. Among body fluids, urine and saliva are particularly promising for easy, non-invasive diagnostics. However, these sample types remain underexplored as compared to the serum, leaving substantial opportunities for future research. Taken together, these findings position sEVs as a powerful tool with significant potential for advancing precision cancer care. SIGNIFICANCE: Living cells release nanosized membrane-enclosed vesicles called small extracellular vesicles (sEVs) into the extracellular environment. sEVs contain protein cargo molecules that critically take part in cell-cell communications. Quantitative proteomics identified potential sEV associated biomarkers for early cancer diagnosis and therapy. sEV Proteins associated with cell adhesion and inflammation, lipoproteins and immunoglobulins are potential molecules that were majorly identified. Interestingly, some of these proteins such as APOA4, SAA4, ITIH4, SERPINC1 and VWF were consistently identified across multiple cancer types and sample sources, highlighting their potential as future biomarkers. Show less

Neuropathic pain (NP) frequently co-occurs with depression (DP), exhibiting complex pathogenesis and limited clinical treatment options. This study aims to investigate the efficacy of Eupalinolide B (EB) in alleviating NP co-occurring with DP and its potential molecular mechanisms. Combining network pharmacology, molecular docking, and molecular dynamics simulations to screen potential targets for EB, validated through transcriptomic data. Using a sciatic nerve branch-preserving injury (SNI) mouse model, we assessed pain and depression-like behaviors through von Frey testing, hot plate testing, tail suspension testing, forced swimming testing, and open field testing. Concurrently, Western blotting, immunofluorescence, and Nissl staining were employed to analyze relevant molecules and neuropathological alterations. Network pharmacology and bioinformatics analysis identified EGFR, PTGS2, and JUN as the key targets for EB in treating NP combined with DP. Behavioral studies showed that 20 mg/kg of EB significantly alleviated pain in SNI mice and improved depressive-like behaviors. Mechanism research indicated that EB downregulated the expression of EGFR and PTGS2, inhibited the activation of microglia and astrocytes, and reduced neuronal damage. Additionally, EB could upregulate the expression of synaptic proteins (PSD95, SYN1, and BDNF) in the hippocampus. EB alleviates neuroinflammation by reducing EGFR and PTGS2 protein expression, modulates synaptic plasticity, and improves pain-depression comorbidity. EB may represent a promising therapeutic approach for pain-related depression. Show less