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Digital literacy has become a core competency for nursing professionals, enabling them to adapt to modern healthcare environments and engage effectively with emerging technologies. It is closely linked to innovative behavior, which is essential for problem solving and advancing nursing practice. Despite its importance, limited research has examined differences in digital literacy among undergraduate nursing students and how these differences influence innovation. A cross-sectional study was conducted using a convenience sample of 450 undergraduate nursing students from four universities in Anhui Province, China. Participants completed a general information questionnaire, the Undergraduate Digital Literacy Scale, and the Innovative Behavior Scale. Latent profile analysis (LPA) was employed to classify students into distinct digital literacy profiles, while logistic regression and one-way ANOVA were used to explore factors influencing profile membership and the relationship between digital literacy and innovative behavior. Three latent profiles were identified: a "Low Digital Literacy" group (34.1%), a "Moderate Digital Literacy" group (15.9%), and a "High Digital Literacy" group (50.0%). Significant differences were observed across profiles in relation to gender, age, academic year, and frequency of artificial intelligence (AI) use in the past 6 months. Importantly, students with higher digital literacy consistently exhibited stronger innovative behavior ( Digital literacy among undergraduate nursing students is heterogeneous and shaped by demographic and experiential factors. Targeted educational interventions tailored to distinct literacy profiles are needed to bridge gaps, promote equity, and strengthen innovation. By integrating AI and advanced digital tools into nursing curricula, educators can enhance students' competencies and better prepare them to thrive in an increasingly digital and intelligent healthcare landscape. Show less

2,4-Dichlorophenol (2,4-DCP) is a persistent and toxic metabolite derived from the degradation of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and other chlorinated compounds, representing an emerging environmental concern. Despite evidence of its toxicity, its neurotoxic effects in adult organisms remain poorly understood. This study aimed to evaluate the behavioral, biochemical, and molecular responses of adult zebrafish (Danio rerio) following 14-day exposure to environmentally relevant (30 μg L Show less

This study aimed to analyze the clinical features, genetic basis, and management of late-onset carbamoyl phosphate synthetase 1 deficiency (CPS1D) through a pediatric case report and literature review, highlighting diagnostic challenges and therapeutic strategies. We present a 19-year-old female with recurrent neurological symptoms since age 8. She underwent comprehensive metabolic screening, neuroimaging, and whole-exome sequencing of theCPS1gene. Identified variants were assessed for pathogenicity using multiple orthogonalin silicoprediction tools. The patient's initial hyperammonemic crisis at age 8 was misdiagnosed as encephalitis. Workup at age 13 confirmed hyperammonemia (peak 168 µmol/L), hypocitrullinemia, and elevated glutamine. Genetic analysis identified compound heterozygousCPS1variants: a novel c.1058 T > C (p.F353S) and known pathogenic c.1145C > T (p.P382L). A self-selected low-protein diet controlled acute crises but led to severe growth failure (height 145 cm, weight 30 kg). Late-onset CPS1D's nonspecific neurological symptoms often lead to misdiagnosis. Diagnosis requires a high index of suspicion, integrating metabolic profiling with genetic confirmation. This case expands the pathogenic genotypic spectrum of CPS1D. It crucially highlights that while dietary management is life-saving, it requires expert multidisciplinary oversight to prevent devastating consequences like growth failure, especially in resource-limited settings. Routine ammonia testing in unexplained encephalopathy is paramount. Show less

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder defined by progressive cognitive impairment, neuroinflammation, oxidative stress, amyloid-β (Aβ) accumulation, synaptic dysfunction, mitochondrial impairment, and tau hyperphosphorylation. The gut-brain axis (GBA) is a crucial regulatory signaling cascade that links intestinal microbiome composition with both neural health and disease through the vagus nerve. Gut dysbiosis has increasingly been implicated in AD pathogenesis by exacerbating systemic and neuroinflammatory signaling, disrupting intestinal and blood-brain barrier (BBB) structural stability, and promoting microglial activation, thereby facilitating Aβ aggregation and neurodegeneration. Preclinical studies indicate that symbiotic interventions restore microbial balance and improve gut-brain communication, contributing to neuroprotective effects. Additionally, it has been demonstrated that symbiotics can restore synaptic plasticity and cognitive resilience by suppressing pro-inflammatory cytokines, as exemplified by interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α), and by upregulating neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF). These effects are associated with normalised glial reactivity, attenuation of oxidative stress, and improved mitochondrial bioenergetics, together contributing to enhanced synaptic function, reduced neuroinflammation, and preservation of cognitive performance. This review highlights a critical assessment of the treatment potential of symbiotic interventions in modulating the GBA in AD, emphasising mechanistic insights into neurodegenerative pathways and evaluating their capacity to mitigate symptoms and delay disease progression, as supported by current preclinical evidence. Show less

Doxorubicin (Dox) is a potent cytotoxic medication, yet its adverse properties are undeniable obstacles to its clinical use. The objective of the existing research was to inspect the potential beneficial actions of lurasidone (Lura) against the neurotoxicity and cardiotoxicity triggered by Dox in rats. Sixty rats were equally allocated to four groups: Control group; Dox group; Lur (1 mg/kg) + Dox group; Lura (3 mg/kg) + Dox group. For 18 days, Lura (1 and 3 mg/kg) was given orally, starting 7 days before giving six doses of Dox (2.5 mg/kg every other day, i.p). Lura attenuated Dox-instigated cardiac injury as assured by the decrease in cardiac troponin-I (cTn-I), kg) and creatine kinase MB (CK-MB) levels. In addition, Lura remarkably declined Dox-triggered neuronal dysfunction, as confirmed by diminished anxiety and depression-alike behaviors in the open field (OFT) and forced swimming (FST) tests, respectively. Furthermore, Lura replenished cardiac and brain antioxidant markers, mitochondrial modulator, PGC-1α, and significantly decreased inflammatory mediators, miR34a-5p, and pro-apoptotic caspase-3 levels. In the brain, Lura also mitigated the induction of glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor-1 (Iba-1). In the same context, Lura pretreatment upregulated the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/phosphoinositide 3-kinase (PI Show less

Social connectedness promotes healthy aging and is associated with lower risk for psychological disorders and cognitive decline. However, little is known about the mechanisms underlying these relationships, and whether different network features are associated with unique health benefits. We used comprehensive data from 386 community-dwelling older adults with and without cognitive impairment to test the relationship between psychological and cognitive function and their personal social networks. Data were collected using a multisite sampling strategy, and included detailed social network interviews and comprehensive measures of episodic memory, executive function, and language. Longitudinal effects were evaluated using a subsample at high-risk for decline, having either at least one copy of APOE ε4 or a current diagnosis of impairment ( The online version contains supplementary material available at 10.1038/s41598-026-44571-9. Show less

Hydroxychloroquine (HCQ) has been associated with lower incidence of cardiovascular events in patients with autoimmune diseases and atherosclerosis progression in mouse models. Our study aimed at investigating the effect of HCQ on autophagy and neutrophil extracellular trap (NET) formation in aortas of ApoE-/- mice. ApoE-/- mice were treated with 10 mg/kg/day HCQ for 16 weeks. The aortas were examined histologically, while immunofluorescence staining and confocal microscopy were performed to identify the co-localization of myeloperoxidase (MPO) with DNA or microtubule-associated protein 1A/1B-light chain 3B (LC3B) as markers of NET formation and autophagy, respectively. Among 52 ApoE-/- mice (30 male, 22 female), HCQ was administered in 15 male and 12 female mice. HCQ was associated with a significant reduction of the mean (±SD) surface of the atherosclerotic plaque compared to controls (HCQ-treated vs. control, 0.04 ± 0.01 mm2 vs. 0.08 ± 0.04 mm2, p < 0.01 and 0.06 ± 0.04 mm2 vs. 0.15 ± 0.09 mm2, p = 0.012, for male and female, respectively). This reduction was associated with a significant attenuation in the mean fluorescence intensity of MPO and LC3B expression in the atherosclerotic plaque of HCQ-treated mice (p = 0.03 and p = 0.01, respectively). In line with these findings, HCQ significantly reduced the proportion of MPO+ and LC3B+ cells within the atherosclerotic lesions. HCQ administration in ApoE-/- mice may mitigate the progression of atherosclerotic plaque, by inhibiting autophagy and NET formation. Show less

Lung cancer remains a leading cause of cancer-related mortality worldwide. Depression, highly prevalent in lung cancer patients, not only impairs quality of life but also adversely affects disease progression and treatment outcomes through complex biological pathways. Previously considered merely a psychological reaction, depression is now recognized as sharing bidirectional pathophysiological interactions with lung cancer. This narrative review comprehensively reviews current evidence on the molecular mechanisms linking depression to lung cancer progression, with a focus on dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), cytokine-mediated inflammation, and the lung-brain axis involving BDNF/TrkB signaling. We also discuss the potential therapeutic implications of antidepressants, including their effects on apoptosis, autophagy, and immune modulation. Key findings suggest that depression promotes tumor progression via chronic stress pathways, while antidepressants may counter these effects through multiple mechanisms. Understanding these pathways may inform integrated treatment strategies and improve prognosis in lung cancer with comorbid depression. Show less

Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progression, and is critically important for preventing cerebrovascular events (such as stroke, transient ischemic attack (TIA), and similar events). Mechanisms influencing plaque stability are still unclear. In this study, stable plaques (n = 5) and unstable plaques (n = 5) were collected from patients and analyzed using RNA-sequencing. 594 differently expressed genes were found by RNA-seq. Pathways enriched by KEGG analysis of differentially expressed genes included inflammation related pathway, cell adhesion related pathway and TGFβ signaling pathway. Especially, we found AMIGO1 was significantly upregulated in stable plaques. Functional assays including cell adhesion, and inflammation-related factor detection revealed that AMIGO1 significantly promotes endothelial cell adhesion while downregulating inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) production, thereby mitigating inflammatory responses. Co-immunoprecipitation (Co-IP) experiments further found that AMIGO1 interacts with transforming growth factor beta receptor II (TGFRII), stabilizing TGFRII protein levels and subsequently activating the TGFβ signaling pathway. AMIGO1 overexpression with AAV9 virus tail vein injection markedly stabilized plaques in ApoE Show less

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with distinct subtypes, relapsing MS (RMS) and primary progressive MS (PPMS), which differ in clinical course and underlying immunopathology. Cytokines are pleiotropic mediators of inflammatory and regenerative processes and are considered important contributors to the pathophysiology of MS. Ocrelizumab, a CD20-targeting monoclonal antibody, is approved for the treatment of patients with RMS and PPMS, yet its effects on circulating cytokines and neurotrophic factors remain incompletely understood. In this prospective observational study, 84 patients with MS (57 RMS, 27 PPMS) were analyzed regarding demographic data, disease activity and serum cytokine profiles before and 6 months after the start of ocrelizumab therapy. Baseline analyses revealed distinct cytokine signatures between patients with RMS and PPMS, with higher levels of several proinflammatory cytokines and chemokines in patients with RMS. Following ocrelizumab treatment, divergent cytokine profiles between patients with RMS and PPMS were partially attenuated, with significant modulation of Th1-associated chemokines and an increase in brain-derived neurotrophic factor (BDNF) observed in patients with RMS. In contrast, cytokine signatures in patients with PPMS remained largely unaffected by ocrelizumab treatment. Patients with RMS with disease activity during the first 6 months of ocrelizumab treatment showed a significant increase in different chemokines compared to baseline compared with patients without disease activity or those with PPMS. Our findings support divergent immunological mechanisms in RMS and PPMS, with a stronger cytokine-driven pathology and more pronounced immunomodulatory effects of ocrelizumab on the cytokine profile in patients with RMS. Show less

Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by which these dual agonists affect systemic metabolism remain elusive. To investigate the effects of a novel dual-receptor agonist, THDBH120, on systemic metabolism in obese individuals and the specific roles of GIPR and GLP-1R in modulating systemic and adipose tissue metabolism. To evaluate the intrinsic properties of THDBH120, we conducted a potency assay by using HEK293 cell lines overexpressing either human GIPR or GLP-1R and measured the accumulation of cAMP as a downstream second messenger following receptor activation. To evaluate the efficacy of THDBH120 on systemic metabolism, we used obese rodents and nonhuman primate species that received various doses and frequencies of THDBH120. To determine the metabolic roles of GLP-1R and GIPR in mediating the beneficial effects of THDBH120, we used GLP-1R- and GIPR-knockout mouse models treated with THDBH120, the GLP-1R agonist semaglutide, or the GIPR agonist LAGIPRA and performed transcriptomic sequencing analyses of adipose tissues. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has superior weight loss and metabolic improvement effects in rodents and mammals. The activation of GLP-1R by semaglutide or THDBH120 improved lipid metabolism, whereas the activation of GIPR by LAGIPRA or THDBH120 alleviated inflammation. THDBH120 improved lipid metabolism via GLP-1R-mediated pathways and mitigated inflammation by activating GIPR-associated pathways in the adipose tissues of obese mice. Both GLP-1R and GIPR are important in mediating the beneficial effects of dual receptors on systemic metabolism. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has potential clinical applications. Show less

Conventional biomarkers such as low-density lipoprotein (LDL) and high-density lipoprotein may fail to identify patients' risk for significant coronary artery disease (CAD). This study evaluates the associations between multiple biomarkers and different CAD phenotypes, exploring a machine-learning biomarker-based patient clustering. We included 787 patients on primary prevention from the prospective ACTION registry (January 2024 to June 2025). All patients underwent coronary CTA and simultaneous biomarker testing, including LDL, high-density lipoprotein, triglyceride, apolipoprotein A-1, apolipoprotein B, lipoprotein(a) [Lp(a)], glycated hemoglobin (HbA1c), and high-sensitivity C-reactive protein. Of 382 patients (48.5%) with coronary artery calcium = 0, 42 (11%) had coronary plaque. These patients showed higher Lp(a) vs those without plaque (16.5 vs 11.5, P = .030), despite comparable SCORE2 risk (3.5% vs 3.0%, P = .284). Three biomarker-defined groups were identified after a machine learning unsupervised clustering: Cluster 1 had a favorable lipid profile with the lowest prevalence of CAD-Reporting and Data System (RADS) ≥ 3 (9.9%). Cluster 2 and 3, despite their significant intercluster differences in terms of Lp(a), LDL, and HbA1c levels, both showed a significantly higher prevalence of CAD-RADS ≥ 3 compared to cluster 1 (respectively 21.8% and 17.9%; vs cluster 1, P = .001). High-risk biomarker signatures were significantly associated to the prevalence of CAD-RADS ≥ 3, independently from the baseline SCORE2 (adjusted odds ratio 2.25; 95% confidence interval 1.32-3.82). Distinct biomarker signatures associate with distinct CAD prevalence and severity that conventional lipid markers fail to distinguish. Lp(a) appears relevant for early plaque detection in coronary artery calcium = 0 patients. A comprehensive biomarker evaluation may help identifying high-risk subgroups overlooked by a conventional assessment. Show less

Lipoprotein(a) [Lp(a)] is an independent cardiovascular risk factor, with a growing recognized role in stroke. To investigate the association between Lp(a) levels, large artery atherosclerosis (LAA) TOAST (Trial of ORG 10172 in Acute Stroke Treatment) category, and stroke-related atherosclerosis distribution (extracranial/intracranial) in a single-center retrospective cohort of patients with ischemic stroke. We included all patients with ischemic stroke admitted between March and December 2021 with Lp(a) levels and computed tomography angiography. Multivariable regression assessed the relationship between Lp(a) and LAA, extracranial carotid stenosis, or intracranial atherosclerotic stenosis (ICAS). Predicted probabilities of atherosclerosis location per Lp(a) increment were estimated from a multinomial logistic regression model. We screened 523 patients and included 397 with complete data. The median age was 78 years, and 47% were female. Median Lp(a) was significantly higher in patients with stroke-related atherosclerosis, particularly those with intracranial involvement. Statin use (adjusted β = 15.01, 95% CI: 3.32-26.70, P = .012) and low-density lipoprotein levels (adjusted β = 0.236, 95% CI: 0.09-0.38, P = .002) were independently associated with Lp(a). Lp(a) was significantly associated with LAA (per 10 mg/dL increment: adjusted odds ratio [OR]: 1.08, 95% CI: 1.03-1.14, P = .003; for Lp(a) ≥50 mg/dL vs <50 mg/dL, LAA prevalence was 27% vs 15%, P = .007; adjusted OR: 2.71, 95% CI: 1.47-5.91, P = .001). Lp(a) ≥50 mg/dL was significantly associated with ICAS (adjusted OR: 4.49, 95% CI: 2.41-8.38, P < .001), but not with extracranial carotid stenosis (P = .065). With increasing Lp(a) levels, ICAS showed the steepest increase in predicted probability. Higher Lp(a) values are associated with LAA stroke, particularly ICAS. Lp(a) levels should be included in the stroke workup. Show less

Genetic factors are thought to play an important role in antipsychotic-induced weight gain (AIWG). This study conducted a meta-analysis of current research of the pharmacogenetic associations of adult AIWG. The analysis included papers providing comparisons of weight gain across at least two allele combinations for at least one single nucleotide polymorphism (SNP). Inclusion criteria were, patients 18 years of age or older and had received a diagnosis of severe mental illness, for which antipsychotic medication was prescribed. The association with AIWG needed to be replicated across at least two papers reporting separate sample sets. Two hundred twenty-three papers were assessed for eligibility. Of the 223 papers, 148 were excluded, leaving 75 studies to be included. Six SNPs in six different genes were identified as having significant associations ( The study identified six SNPs that predispose adult individuals to AIWG, with Show less

The neurotrophic factor (NTF) family has recently expanded its role beyond neurological conditions, but its involvement in acute inflammatory lung diseases remains largely unclear. Using well-established acute lung injury (ALI) and sepsis models, we demonstrate that brain-derived neurotrophic factor (BDNF), a key NTF, is impaired in pulmonary epithelial cells and negatively correlates with the inflammatory response. Raising the BDNF level alleviates inflammatory lung injury, but these effects are absent in macrophage-deleted mice. Both in vivo and in vitro results show BDNF inhibits macrophage inflammation, and further proteomics analysis identifies macrophage TLR4 as a receptor that BDNF antagonizes via direct binding. The BDNF fragment (aa 104-115) is critical for BDNF-TLR4 interaction, and the corresponding synthetic BDNF-derived dodecapeptide (BDP-12) retains TLR4-antagonistic and anti-inflammatory effects both in vitro and in vivo, without pro-proliferative side effects. In conclusion, our findings reveal that epithelial-derived BDNF prevents macrophage inflammation by directly targeting TLR4 and highlights BDP-12 as a potential therapeutic agent for acute inflammatory diseases. Show less

Diabetic foot (DF) is a serious diabetes complication that increases ulceration, amputation and mortality risks. Effective foot self-care can prevent up to 85% of ulcer events. This study aimed to assess foot self-care behaviors among middle-aged and older DF patients, evaluate the impact of social support, and explore the mediating effects of frailty and fear of progression (FoP). We also identified patient subtypes using latent profile analysis. A cross-sectional study was conducted in a tertiary hospital from November 2024 to March 2025. A total of 361 patients with DF aged ≥45 years completed validated questionnaires, including the Social Support Rating Scale (SSRS), FRAIL Scale, FoP-Q-SF, and DFSQ-UMA. Structural equation modeling (SEM) assessed mediation effects, and latent profile analysis (LPA) identified subgroups based on frailty and FoP. A total of 383 questionnaires were distributed, with 361 valid responses collected, resulting in an effective response rate of 94.3%. The average score for foot self-care behavior was 58.52 ± 13.46, while levels of social support, frailty, and FoP were all at moderate levels. SEM indicated that Social support significantly predicted better foot self-care behavior (β = 0.225, P < 0.01). Frailty and FoP partially mediated this relationship (mediation effect: 6.68%). LPA identified three types of physical and mental profiles: Low FoP - Low Frailty Group (75.1%), Moderate FoP - Moderate Frailty Group (15.2%), and High FoP - High Frailty Group (9.7%). Importantly, patients in the High FoP-High Frailty Group demonstrated the lowest foot self-care behavior (mean = 43.70, P < 0.001), indicating the highest potential risk for ulcer occurrence and poor tissue outcomes. Social support enhances foot self-care in DF patients through reduced Frailty and FoP. Tailored interventions targeting high-risk subgroups may improve tissue outcomes and prevent ulcers. Show less

Pain is one of the leading causes of disability worldwide. Despite the various pharmacological treatments available, patients with chronic pain often remain with significant disabilities and unsatisfactory pain control. Cannabis and cannabinoids are sometimes used in the treatment of chronic pain as they have been shown to be useful in a subset of patients. Some of the adverse effects associated with cannabis use, such as cannabis use disorder (CUD) and cannabis-induced psychosis, have been associated with several genetic variants. Despite this, the paucity of the data or the contradictory results for reported variants limits our ability to use them as genetic markers to personalize cannabis treatment tailored to patients’ genetic background. The aim of this genetic association study was to investigate the link between previously reported genes and cannabinoid response in terms of pain response, CUD and risk of psychotic adverse events in patients with chronic pain. Phone or in person interviews were conducted to document participants’ characteristics, cannabis use and effects, concurrent pharmacotherapy and comorbid conditions. Screening for CUD was performed using the Cannabis Use Disorders Identification Test – Revised. Blood or saliva samples were collected for the genotyping of 18 variants in 11 genes ( One hundred participants were recruited, with blood or saliva samples collected from 77 of them. Two single-nucleotide polymorphisms (SNP) in cannabinoid receptor 1 ( These results suggest alternative allele carriers of rs1049353 and rs2023239 could be at an increased risk of psychotic adverse events related to cannabis use, although additional investigation is required to replicate and confirm these findings. The online version contains supplementary material available at 10.1186/s42238-026-00408-w. Show less

Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stromal fibrosis that promotes immune exclusion and treatment resistance, yet the upstream drivers of this pro-fibrotic cascade remain poorly defined. Here, we identify phosphoinositide 3-kinase δ (PI3Kδ) as a previously unrecognized driver of fibrosis in PDAC. Pharmacological inhibition of PI3Kδ reduces collagen deposition while enhancing the infiltration of activated CD8 Show less

Depression and anxiety during pregnancy are major public health concerns with lasting consequences for mother and child. Although the gut microbiome contributes to stress and mood regulation, its role in preconceptional stress and transgenerational outcomes remains unclear. Here, we examined behavioral, microbial, and thalamic transcriptional effects of preconceptional social isolation rearing (SIR) in female mice and tested whether maternal probiotic supplementation mitigates these alterations. SIR females displayed increased anxiety-like and social-avoidant behavior, reduced gut microbial diversity, depletion of Odoribacter, Tuzzerella, and Alloprevotella, and enrichment of Bacteroides and Lachnospiraceae. A multispecies probiotic (Lactobacillus rhamnosus HN001, L. acidophilus La-14, Bifidobacterium lactis HN019) reversed these behavioral and microbial changes. Adult offspring of SIR dams showed sex-dependent behavioral deficits and microbial alterations partly reflecting maternal patterns. Prenatal SIR was associated with reduced thalamic Bdnf expression in offspring and altered Grin2a/2b selectively in males. In contrast, prenatal probiotic exposure exerted broader transcriptional effects and restored Bdnf levels in SIR offspring. SIR-induced increases in Lachnospiraceae were transmitted to offspring, whereas reductions in Ruminococcaceae were normalized by maternal probiotic treatment. Predicted functional profiling indicated sex-dependent modulation of microbial pathways related to tryptophan and central carbon metabolism. These findings demonstrate enduring transgenerational effects of preconceptional stress on the gut-brain axis and support maternal probiotic supplementation as a potential strategy to mitigate stress-induced dysregulation. Show less

Alzheimer's disease (AD) is a widely prevalent and neurodegenerative disorder that leads to dementia and mortality worldwide. Previous investigations have reported the beneficial effects of physical exercise on brain function, linked to anti-inflammatory effects in the brain vasculature and elevated BDNF production. Empagliflozin, a conventional antidiabetic agent, has shown potential neuroprotective properties in the central nervous system, evidenced by its ability to elevate BDNF and mitigate oxidative stress and inflammation. In the present investigation, AD was induced in control, exercise, empagliflozin (10 mg/kg BW, PO), and combined intervention groups using intrahippocampal injections of an amyloid-beta (Aβ) prepared solution via stereotaxic surgery. The therapeutic effects of each treatment, exercise alone, empagliflozin alone, and exercise plus empagliflozin, were studied. After 28 days, spatial memory tests were used to assess memory and learning. Furthermore, histopathological (H&E and Congo red) and immunohistochemical (GFAP) analyses were performed, and the ADP/ATP ratio in isolated brain mitochondria was measured by HPLC. Our results showed that the combined program of physical training and empagliflozin treatment in the Aβ-induced AD model drastically improved cognitive functions and neurological parameters, including target-finding time, traveled distance, time spent in the target quadrant, and ADP/ATP ratios in brain mitochondria. Additionally, it diminished necrotic cell death and reduced Aβ plaques but did not notably affect astrocyte activity. Exercise and empagliflozin, by affecting mitochondrial energy balance and reducing amyloid deposition, play key roles in mitigating AD pathophysiology. The combined effects of the treatments used in this experimental method yielded significant improvements in cognitive functions. These findings provide a basis for further clinical studies for the exploration of the synergistic impact of the aforementioned therapeutic methods. Show less

Coronary artery disease (CAD) remains a leading cause of mortality worldwide, with substantial unmet therapeutic needs. This study aimed to identify and prioritize genetically supported therapeutic targets for CAD using Mendelian randomization (MR). We implemented a two-sample MR framework to infer the causal effects of blood druggable cis-expression quantitative trait loci (cis-eQTLs) on CAD. To consolidate MR findings, we applied Steiger filtering, Bayesian colocalization, and multiple sensitivity analyses. Mediation and phenomewide MR analyses were employed to investigate potential mechanisms and on-target effects of prioritized druggable genes. We identified 66 causal druggable genes associated with CAD in European populations (false discovery rate < 0.001). Among these, ERP29 (odds ratio [OR] = 1.311; 95% confidence interval [CI]: 1.176-1.460), MCL1 (OR = 0.877; 95% CI: 0.840-0.915), TNXB (OR = 1.183; 95% CI: 1.102-1.269), DAGLB, FES, and TRPM4 colocalized with CAD (posterior probability for colocalization > 0.8). The associations for ERP29, MCL1, and TNXB were replicated in an East Asian cohort. Protein-protein interaction network analysis highlighted MAPK3 and TNF as prioritized druggable targets at the protein level. Mediation analysis indicated that body mass index, triglycerides, blood pressure, and atrial fibrillation partially mediate the association between MAPK3 and CAD. Phenome-wide MR analysis further suggested additional beneficial effects of targeting MAPK3 and TNF on diabetes mellitus, obesity, hypertension, unstable angina, myocardial infarction, angina pectoris, coronary atherosclerosis, ischemic heart disease, and disorders of lipoid metabolism. This druggable genome-wide MR study not only corroborated the targets of FDA-approved CAD medications (e.g., FGFR1, MAPK3, NEU1) but also uncovered several novel genes, such as ERP29, MCL1, TNXB, DAGLB, FES, and TRPM4, implicating mechanisms related to blood pressure, lipid metabolism, and additional beneficial effects on endocrine/cardiometabolic traits and circulatory system disorders. Further exploration is imperative to explore their feasibility and generalizability. We identified circulating ERP29, MCL1, TNXB, DAGLB, FES, TRPM4, MAPK3, and TNF as promising, genetically supported druggable targets for CAD treatment. Notably, MAPK3 and TNF demonstrated strong protein-level interactions and close associations with cardiometabolic disorders. Show less

This study investigated the expression of brain-derived neurotrophic factor (BDNF) signaling components (BDNF-TrkB-AKT1) and apoptosis-related factors (Bcl-2 and Bax) in yak brain regions at different altitudes. The cerebral cortex, cerebellum, hippocampus, thalamus, and medulla oblongata were collected from 3-year-old yaks living at low and high altitudes. The relative mRNA expression of BDNF, TrkB, AKT1, Bcl-2, and Bax was assessed by qRT-PCR. Protein abundance and cellular localization of BDNF, TrkB, AKT1, Bcl-2, and Bax were evaluated by Western blotting and immunohistochemistry, with immunoreactivity quantified by optical density analysis. Within each altitude group, BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and the corresponding protein levels (BDNF, TrkB, AKT1, and Bcl-2) were significantly higher in the cerebral cortex and hippocampus than in the cerebellum, thalamus, and medulla oblongata (P < 0.05). In contrast, Bax mRNA and Bax protein levels did not differ significantly among the five regions. Compared with low-altitude yaks, high-altitude yaks showed significantly higher BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and higher BDNF, TrkB, AKT1, and Bcl-2 protein levels in brain tissues (P < 0.05), whereas Bax protein expression did not differ between altitude groups. Immunohistochemistry revealed immunoreactivity for BDNF, TrkB, AKT1, Bcl-2, and Bax in both altitude groups, with prominent labeling in cortical pyramidal neurons and across the pyramidal cell layer in the hippocampal CA region. Immunoreactivity was also detected in large neurons of the thalamus and medulla oblongata. In the cerebellum, labeling was strongest in Purkinje cells, with weaker signals in the granule cell layer and molecular layer. BDNF-TrkB-AKT1 pathway components and Bcl-2 showed relatively higher expression in the cerebral cortex and hippocampus within each altitude group, whereas Bax expression did not vary across regions. These patterns are consistent with an association between BDNF-TrkB-AKT1 signaling and increased Bcl-2 expression without a corresponding increase in Bax, which may support neuronal adaptation in the cerebral cortex and hippocampus. Elevated expression of BDNF, TrkB, AKT1, and Bcl-2 at high altitude suggests enhanced adaptation to hypoxia in high-altitude yaks; the underlying mechanisms require further investigation. Show less

Nivolumab and nintedanib are both established agents for pre-treated NSCLC of adenocarcinoma histology. Hypothesizing that the combination of immune checkpoint inhibition (nivolumab) and anti-angiogenesis (nintedanib) increases efficacy, we intended to determine a safe and efficacious dose for the combination. Our multi-center, open-label, single arm, phase Ib/II study enrolled patients with histologically confirmed stage IIIB/IV adenocarcinoma NSCLC and one or two previous lines of systemic treatment with platinum-based chemotherapy +/- checkpoint inhibitors (CPI). A traditional 3 + 3 design was used to determine a recommended phase II dose (RP2D) for nintedanib combined with nivolumab. Primary endpoints were safety and tolerability together with 6- and 9-month rates of progression-free survival (PFS). The RP2D was determined as 200 mg nintedanib twice daily (bid) with 240 mg nivolumab biweekly (Q2W). No new safety signals were detected. PFS milestone rates at 6 and 9 months for the 52 patients who received this dose were 25% [95% CI 14.3-37.3%] and 11.5% [4.7-21.8%], respectively. Median overall survival (mOS) was 12.2 months [95% CI: 8.13-18.37]. Central biomarker analysis based on combined positive score (CPS) revealed that high PD-L1 and low PD-L1/low FGFR1 identified patients with prolonged OS at 36 months (70% and 40%, respectively), while low PD-L1/high FGFR1 was associated with shorter OS (p = 0.0195). CPI-rechallenged patients had better OS outcomes than those who were CPI-naïve (mOS 8.13 months [95% CI 2.03-15.2] vs. 14.7 months [95% CI 8.2-NR]; logrank p = 0.0493). Combination of nivolumab and nintedanib was shown to be safe and feasible. Despite missing synergistic effects on efficacy for the overall population, promising OS was observed for patients with high PD-L1 expression and for patients with previous immunotherapy. Therefore, CPI responsiveness may have been restored in some cases. Inhibition of FGFR-mediated tumor progression seems relevant in tumors with lower levels of both PD-L1 and FGFR1 expression and might be effectively inhibited by nintedanib. The combination nivolumab/nintedanib might warrant further exploration in selected patients. Show less

A single nucleotide polymorphism in the brain derived neurotrophic factor (BDNF)-encoding gene leads to diminished BDNF signaling resulting from Val66Met and has been linked to obesity. Previous imaging studies regarding the impact of BDNF Val66Met on the central serotonin system, which is involved in behavior, cognition and control of satiety, have not focused on body weight or food-intake related behavior. We revisited a cohort of thirty non-depressed individuals with obesity and 15 normal-weight controls. 29 obese and 13 controls underwent [ Show less

Alzheimer's disease (AD), the leading cause of dementia, is characterized by synapse damage and loss, correlating strongly with cognitive decline. APOE4, the strongest genetic risk factor for AD, impairs synapses with the mechanisms remaining unclear. APOE, the central nervous system's primary lipid and cholesterol carrier, is critical for axonal growth, synapse formation, and spine remodeling. To investigate how APOE4 affects cholesterol and synaptic dysfunction, we studied male and female human APOE3 and APOE4 knock-in mice. Cholesterol levels were measured in brain homogenates, synaptosomes, and mitochondria using bioluminescent assays, and APOE protein expression was analyzed via immunoblotting. Proteomics of synaptosomes and mitochondrial respiratory function assessments were performed using mass spectrometry and the Seahorse XF Analyzer, respectively. We found that cholesterol levels did not differ between APOE3 and APOE4 mice in brain homogenates or synaptosomes. However, male APOE4 mice exhibited lower cholesterol levels in synaptic mitochondria than APOE3 mice, with no changes in non-synaptic mitochondria or female mice. APOE protein was present in synaptosomes and mitochondrial fractions without changes due to APOE4 expression. Synaptosomal proteomics uncovered synaptic mitochondrial membrane proteins were differentially expressed in APOE4 versus APOE3 mice. Proteomic analysis also revealed altered neurotransmitter signaling and metabolic pathways in the APOE4 mice, predominantly in males. Notably, proteins involved in synaptic vesicle endocytosis and aerobic respiration were differentially expressed. Mitochondrial respiratory function was disrupted in female APOE4 mice, which displayed increased maximal respiration and spare respiratory capacity at the synapse. These findings identify a role for APOE in regulating synaptic mitochondrial cholesterol, protein expression, and respiratory function in a sex-dependent manner, contributing to synaptic dysfunction in AD. Show less

Early diagnosis of Alzheimer's disease (AD) and related dementias remains challenging because no single biomarker sufficiently captures the complex and multifactorial nature of the underlying pathology. In recent years, multimodal artificial intelligence (AI) models capable of integrating heterogeneous data sources-such as neuroimaging, fluid biomarkers, genetics, and cognitive assessments-have emerged as a promising strategy to improve early detection and risk stratification. We performed a PRISMA-guided systematic review (PROSPERO: CRD420251049848) of studies published from 2010 to 2025. We included 27 peer-reviewed studies applying AI/ML to ≥2 biomarker modalities for diagnostic classification or prognostic prediction (e.g., MCI-to-AD conversion), with an explicit emphasis on multimodal designs that incorporated at least one minimally invasive and/or widely deployable modality (e.g., cognitive tests, blood-based biomarkers, APOE/genetics, retinal imaging, or routine clinical features). Risk of bias was assessed using QUADAS-2. Across the 27 included studies, multimodal AI models generally outperformed the best unimodal baselines, particularly when combining complementary biological information (e.g., imaging with molecular or clinical features). Diagnostic tasks more often achieved high discrimination (frequently AUCs in the ~0.85-0.95 range under internal validation), whereas prognostic prediction-especially MCI-to-AD conversion-remained more challenging (typically ~0.75-0.85 AUC in the best-performing models). However, evidence for generalizability was limited, as external validation was uncommon and QUADAS-2 frequently highlighted concerns in the Index Test domain related to overfitting risk and incomplete validation. Overall, multimodal AI provides a more comprehensive representation of AD/MCI-related pathology than unimodal approaches and can improve early diagnostic classification and, to a lesser extent, prognostic prediction. However, translation to clinical practice is still constrained by limited external validation and heterogeneous reporting, which hamper generalizability and clinical trust. Future work should prioritize prospective multi-center studies, robust external validation, and transparent reporting (including interpretability analyses) to support real-world deployment. Show less

Flavonoids are a diverse group of natural polyphenolic compounds, recognized for their ability to modulate cellular pathways and mitigate the pathological processes of many neurodegenerative diseases. This study investigates the neurotrophic potential of a polyphenolic-rich lemon peel extract (Lpe) in a Zebrafish larvae spinal cord injury (SCI) model. To evaluate its potential effects, embryos were divided into six experimental groups: a baseline control group in which larvae were neither subjected to spinal cord injury nor treated (Ctrl Group); a group with larvae subjected to spinal cord injury at 3 dpf without treatment (SCI Group); a group treated continuously with Lpe (25 µg/mL) from 0 to 5 dpf without injury (Continuous Group); a group treated continuously with Lpe and injured at 3 dpf (Continuous SCI Group); a group treated with Lpe starting at 3 dpf without injury (Curative Group); and finally, a group injured at 3 dpf and treated simultaneously with Lpe (Curative SCI Group). Lpe treatment significantly downregulated proinflammatory cytokines ( Show less

This study aims to elucidate the pharmacological basis and antidepressant mechanisms of a combined extract from Eucommia ulmoides Oliv. And Gastrodia elata Bl. (Eucommia-Gastrodia extract), employing an integrated strategy that combines UHPLC-QTOF-MS analysis, network pharmacology, molecular docking, and in vivo validation. This research integrated computational approaches network pharmacology, molecular docking and in vivo experimental investigations. Initially, the active constituents of the EGE were identified through ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Potential targets related to depression were predicted using the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and SwissADME. Protein-protein interaction (PPI) networks were constructed via the STRING database, followed by the development of a comprehensive "drug-active ingredient-target-disease" network. Functional annotation through Gene Ontology (GO) and pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted on the intersecting targets using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Molecular docking studies were erformed employing AutoDock software to validate the interactions. Finally, the antidepressant-like behavioral effects were evaluated in treated and non-treated corticosterone-induced mouse models using sucrose preference tests, forced swimming tests, open field tests, and tail suspension tests. The morphological impacts and molecular basis of disease on the hippocampal neurons were assessed using Hematoxylin and Eosin staining (HE) staining, Nissl staining, immunohistochemistry, and Western blot analysis to substantiate the identified through network pharmacology. Network pharmacology analysis revealed a complex interplay between identified active ingredients of Eucommia-Gastrodia extract and depression targets. From an initial pool of 131 active components, 34 identified as interacting with 233 shared depression related molecular targets. These targets were involved in 390 biological processes (BP), 60 cellular compounds (CC), 134 molecular functions (MF), and 148 KEGG-enriched signaling pathways. Molecular docking studies highlighted 20 principal compounds that bind to key targets such as AKT1, SRC, HIF-1, CREB, BDNF, and EPO. The Eucommia-Gastrodia extract alleviated depression like behaviors in a cortisol-induced mouse model, as indicated by increased sucrose preference and mobility time, etc. Additionally, the extract restored the levels of neurotransmitters 5-hydroxytryptamine (5-HT) and dopamine (DA), alleviated hippocampal neuronal damage, and increased the positive expression of EPO and BDNF in the hippocampus. Furthermore, treatment with the extract significantly upregulated the protein expression of HIF-1, EPO, EPOR, CREB, p-CREB, BDNF and p-TrkB, which were otherwise downregulated in cortisol-induced depressive mice. The results indicate that the Eucommia-Gastrodia extract containing bioactive compounds such as oxysophocarpine, aucubin, pinoresinol, leonurine, syringaresinol, formononetin, icaritin, casticin, and 6-gingerol mitigates cortisol-induced neurodegeneration and depressive-like behaviors. This effect is mediated through modulation of the of HIF-1α-EPO/cAMP-CREB-BDNF signaling pathways. Show less

To date, the burden of alcohol-related seizures is increasing, with an unexplored etiological complex, and the psychopharmacological interplay remains significantly scarce. In this study, we developed an experimental approach to investigate the contrasting impact of alcohol on pentylenetetrazol-induced seizures and the effects of diosgenin, a phytosteroid agent with neuroprotective effects. After 7 days of binge alcoholism with ethanol (2 g/kg, oral gavage) in male mice, they were subjected to maximum and sub-convulsive pentylenetetrazol-induced seizures concomitantly with diosgenin (25 and 50 mg/kg, p.o.) or diazepam (3 mg/kg, p.o) treatments from days 8-14. The interaction between ethanol and pentylenetetrazol-induced seizures was investigated, along with behavioral comorbidities, hypothalamic-adrenal-pituitary-axis (HPA-axis), neurochemical and neurotrophic dysfunctions, oxidative stress, and neuroinflammation in the hippocampus, prefrontal cortex, and striatum. Ethanol-exacerbated pentylenetetrazol-induced seizure and frequency, characterized by rearing with myoclonic jerks, and clonic-tonic convulsions. It increased anxiety, depressive behavior and impaired spatial working memory, influenced by heightened alcohol preference and corticosterone levels, which were normalized by diosgenin. Concomitant ethanol administration exacerbated reductions in GABAergic-dependent glutamic acid decarboxylase and increased glutamate levels associated with pentylenetetrazol-induced seizures, alongside depletions of serotonin and brain-derived neurotrophic factor in the hippocampus, prefrontal cortex, and striatum. Among others, diosgenin, compared to ethanol-pentylenetetrazol exacerbation, reduced levels of myeloperoxidase, TNF-α, and IL-6, nitrite and malondialdehyde in the hippocampus, prefrontal cortex, and striatum while increasing IL-10 cytokine and antioxidant system (superoxide-dismutase, glutathione, and glutathione-transferase). These findings suggest that alcoholism exacerbates seizures across brain regions, involving neurochemical imbalance, HPA-axis dysfunction, oxidative stress, and neuroinflammation, which are reversible by diosgenin. Show less

Brusatol (BRU), a major bioactive quassinoid isolated from Brucea javanica, has shown potential in the treatment of inflammatory diseases. As mitochondrial dysfunction has been implicated in chronic inflammatory disorders, modulation of mitochondrial homeostasis may offer a potential approach for the treatment of rheumatoid arthritis (RA) and atherosclerosis (AS). To develop a novel BRU derivative through rational modification at the C11‑hydroxyl group and to compare the therapeutic effects of BRU and its derivative BRUD in experimental models of RA and AS, with particular focus on mitochondrial regulation and Drp1-associated signaling. This study combined in vivo and in vitro experiments to evaluate the pharmacological effects of BRU and BRUD and investigate the underlying mechanisms. The chemical constituents of BRU and BRUD were confirmed by HPLC and NMR spectroscopy ( In vivo studies demonstrated that both compounds ameliorated joint damage in CIA rats and reduced atherosclerotic lesion burden in ApoE These findings suggest that BRUD exhibits improved activity compared with BRU in RA and AS models, with protective effects associated with modulation of mitochondrial dysfunction, supporting its further evaluation as a lead compound. Show less