Acute spinal cord injury (SCI) results in irreversible neurological deficits. We hypothesized that local transplantation of bone marrow mesenchymal stem cells (BMSCs) combined with erythropoietin (EPO Show more
Acute spinal cord injury (SCI) results in irreversible neurological deficits. We hypothesized that local transplantation of bone marrow mesenchymal stem cells (BMSCs) combined with erythropoietin (EPO) would inhibit glial scarring and accelerate functional recovery. To quantify the therapeutic efficacy and underlying mechanisms of BMSCs+EPO versus BMSCs alone in a rat model of acute SCI. Forty SD rats (T10 Allen 60 g·cm impact) were randomized to sham, SCI, SCI+BMSCs, or SCI+BMSCs+EPO ( At 4 weeks, BBB scores in the BMSCs+EPO group reached 12.7 ± 1.5, representing a 54% increase over the BMSCs-alone group (8.3 ± 0.7, BMSCs+EPO exerts synergistic neuroprotective effects, achieving superior locomotor recovery compared with BMSCs monotherapy, and represents a promising adjuvant strategy for acute SCI. Show less
Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase of the TRIM superfamily, modulates critical cellular processes including ubiquitination, autophagy, and oxidative stress respons Show more
Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase of the TRIM superfamily, modulates critical cellular processes including ubiquitination, autophagy, and oxidative stress response. Accumulating evidence highlights its context-dependent regulatory roles in hepatocellular carcinoma (HCC)-the most prevalent primary liver malignancy with high mortality and limited therapeutic efficacy. This review systematically summarizes the core mechanisms by which TRIM21 orchestrates HCC progression: ① Autophagy regulation: TRIM21 modulates HCC autophagy via multiple axes, including CCR4-NOT complex (TNKS1BP1/CNOT4)-mediated substrate ubiquitination, ATG14-dependent autophagosome initiation, and RETREG1-driven reticulophagy, with context-dependent effects on tumor proliferation. ② Drug resistance: TRIM21 enhances oxaliplatin sensitivity by ubiquitinating and degrading G6PD (the rate-limiting enzyme of the pentose phosphate pathway), while its role in sorafenib resistance involves dual pathways-the MST1/YAP axis and the ApoE/cholesterol/PI3K-AKT cascade. ③ Metastasis suppression: TRIM21 restricts HCC invasion and metastasis by ubiquitinating key oncoproteins, preserving epithelial integrity and inhibiting mesenchymal transition. ④ Reactive oxygen species (ROS) balance: TRIM21 regulates oxidative stress in HCC via the SQSTM1/p62-Keap1-NRF2 axis, coordinating with HIF1α to modulate antioxidant responses and tumor cell survival. Additionally, we discuss the regulatory significance of TRIM21 in HCC associated with hepatitis B virus (HBV) infection (via HBx/DNA polymerase ubiquitination) and nonalcoholic steatohepatitis (NASH) (via suppressing lipogenic enzymes to reduce steatosis-driven carcinogenesis). This review provides a theoretical basis for TRIM21 as a potential diagnostic marker and therapeutic target for HCC. Show less
Vascular smooth muscle cell senescence contributes critically to vascular remodeling and atherosclerosis, with mitochondrial dysfunction and impaired mitophagy recognized as major contributors. SRC, a Show more
Vascular smooth muscle cell senescence contributes critically to vascular remodeling and atherosclerosis, with mitochondrial dysfunction and impaired mitophagy recognized as major contributors. SRC, a stress-responsive tyrosine kinase, has been linked to aging, yet its role in vascular aging remains unclear. Here, we examined the role of SRC in regulating autophagy/mitophagy using in vitro and in vivo models. An accelerated vascular aging model was established using a high-fat diet and streptozotocin injection in ApoE Show less
This study investigates the independent and interactive effects of apolipoprotein E (APOE) genotypes and white matter hyperintensities (WMH) on distinct neuropsychiatric symptom (NPS) phenotypes in pa Show more
This study investigates the independent and interactive effects of apolipoprotein E (APOE) genotypes and white matter hyperintensities (WMH) on distinct neuropsychiatric symptom (NPS) phenotypes in patients with Alzheimer's disease (AD). We enrolled 325 AD patients consecutively diagnosed at a specialized memory clinic between May 2024 and May 2025. All participants underwent comprehensive clinical assessments-including the Chinese Mini-Mental State Examination (CMMSE), Activities of Daily Living (ADL) scale, and the Neuropsychiatric Inventory (NPI)-as well as 3T brain MRI for WMH quantification and APOE genotyping. First, we compared NPS profiles and cognitive/functional scores across APOE genotype groups (ϵ2/ϵ2-ϵ2/ϵ3, ϵ3/ϵ3, ϵ3/ϵ4, ϵ4/ϵ4) using analysis of variance (ANOVA) or Kruskal-Wallis tests, as appropriate. Second, we applied mediation analysis (PROCESS macro Model 4, 5,000 bootstrap samples) to examine whether WMH burden mediates the association between APOE genotype (X) and outcomes including CMMSE total score and domain-specific NPS subscores (delusions, agitation, irritability, euphoria). Significant differences emerged across APOE genotypes in both cognition (CMMSE, p < 0.05) and functional status (ADL, p < 0.05). At the symptom level, carriers of at least one ϵ4 allele exhibited higher agitation scores than non-carriers (p < 0.05); notably, the ϵ4/ϵ4 homozygotes showed significantly greater severity in delusions, agitation, irritability, and euphoria compared with all other genotype groups (all p < 0.05). Mediation analyses revealed no statistically significant indirect effect of APOE genotype on any outcome via WMH, indicating that WMH does not mediate these associations. Instead, APOE genotype exerted robust direct effects on both cognitive performance and specific NPS domains. APOE genotype-particularly the ϵ4/ϵ4 homozygous status-is associated with more pronounced cognitive decline and a distinct, severe NPS profile in AD, especially involving delusions, agitation, Euphoria, and irritability. These associations are independent of WMH burden, suggesting that APOE exerts direct neurobiological effects on neuropsychiatric manifestations. Thus, APOE genotyping holds dual clinical value: not only as a well-established biomarker for AD risk and diagnosis but also as a potential prognostic indicator for behavioral and psychological symptoms-offering actionable insights beyond conventional neuroimaging markers. Show less
Conflicting data have explored the association between lipoprotein(a) [Lp(a)] and atherosclerotic cardiovascular disease (ASCVD) among individuals with different glucose metabolism statuses. We aimed Show more
Conflicting data have explored the association between lipoprotein(a) [Lp(a)] and atherosclerotic cardiovascular disease (ASCVD) among individuals with different glucose metabolism statuses. We aimed to prospectively evaluate this association and to assess whether it is modified by C-reactive protein (CRP). This population-based cohort study was derived from the UK Biobank database. Lp(a) and CRP were measured between 2006 and 2010. Cox proportional hazards models and restricted cubic spline curves were employed to assess the relationship between Lp(a) levels and time to ASCVD events. A total of 307 269 participants without prevalent ASCVD were included, comprising 253 746 individuals with normal glucose regulation (NGR), 38 020 with prediabetes, and 15 503 with diabetes. The mean age was 57 years (Q1-Q3: 50-63), and 55.3% were female. Over a median follow-up of 13.2 years, 29 521 ASCVD events occurred. Higher Lp(a) levels were associated with an increased risk of ASCVD across all glucose metabolism statuses. In fully adjusted models, the hazard ratio (95% confidence interval) for ASCVD comparing participants in the top 10% of Lp(a) with those in the bottom 33% was 1.28 (1.22-1.34) among those with NGR, 1.23 (1.12-1.35) among those with prediabetes, and 1.16 (1.02-1.31) among those with diabetes. No significant interactions were observed after stratification by CRP (<2/≥2 mg/L) across glucose metabolism groups (P for interaction >0.05). Elevated Lp(a) levels were associated with a higher risk of ASCVD across different glucose metabolism statuses, particularly among individuals with NGR and prediabetes, independent of baseline CRP levels. Show less
Resveratrol (RSV), a dietary polyphenol widely present in traditional medicinal plants and foods, exhibits antioxidant and anti-inflammatory properties that are relevant to ethnopharmacological strate Show more
Resveratrol (RSV), a dietary polyphenol widely present in traditional medicinal plants and foods, exhibits antioxidant and anti-inflammatory properties that are relevant to ethnopharmacological strategies for protecting against environmental neurotoxicants. Given increasing real-world co-exposure to lead (Pb) and cadmium (Cd), elucidating RSV's capacity to preserve gut-brain axis (GBA) homeostasis has direct translational relevance for populations relying on phytochemical interventions. Sprague-Dawley rats were randomized into control, Pb-Cd model, and RSV treatment groups (10, 20, or 40 mg/kg). For 4 weeks, rats received Pb (300 mg/L) and Cd (50 mg/L) in drinking water with daily RSV. Cognitive function was assessed by Morris water maze; barrier integrity by Evans blue assay, histology, and Western blot for ZO-1/Occludin; synaptic ultrastructure by TEM; microbiota composition by 16S rRNA sequencing; and short-chain fatty acids (SCFAs) by GC-MS. Neurotransmitters (5-HT, GABA, SP, VIP) and cytokines (IL-6, IL-1β, TNF-α) were measured by ELISA. RSV improved spatial learning, reduced EB extravasation, preserved synaptic ultrastructure and proteins (BDNF, SYN, PSD-95), and restored intestinal architecture with increased ZO-1/Occludin. RSV attenuated cytokine release, normalized goblet cells, reversed dysbiosis by restoring Lactobacillaceae/Prevotellaceae, and increased acetate, propionate, and butyrate. It reinstated 5-HT and GABA while reducing SP and restoring VIP across serum, colon, and hippocampus. RSV attenuated Pb-Cd-associated neurotoxicity and was accompanied by improved intestinal and BBB-related readouts, partial normalization of gut microbiota features and SCFA levels, and preservation of synaptic and neurotransmitter-related markers, consistent with a link to gut-brain axis function. This study is among the first to test RSV in a Pb-Cd co-exposure model using a multi-dose regimen with integrated behavioral, barrier, microbial, and neurochemical endpoints. Show less
Atherosclerosis currently lacks effective therapeutic strategies specifically targeting and inhibiting foam cell formation. In this study, we engineered a macrophage nanoparticle composite drug delive Show more
Atherosclerosis currently lacks effective therapeutic strategies specifically targeting and inhibiting foam cell formation. In this study, we engineered a macrophage nanoparticle composite drug delivery system that utilizes macrophages for competitive lipid uptake, coupled with ROS-responsive statin nanoparticles aimed at inhibiting cholesterol synthesis. This integrated system embodies a "smart immunomodulatory" approach, leveraging the inherent activity and targeted capabilities of immune cells. Experimental results demonstrated that this system significantly reduced lipid accumulation within foam cells by inhibiting cholesterol uptake, promoting cholesterol efflux and inhibition of apoptosis. These effects were mediated through microenvironmental optimization and upregulation of ABCA-1 and SR-BI expression. In an APOE knockout mouse model of atherosclerosis, the system effectively lowered lipid levels, modulated inflammatory responses, and significantly reduced foam cell formation and atherosclerotic plaque development. The system enhanced Treg cell proliferation and TGF-β secretion. Moreover, the system demonstrated high biocompatibility and therapeutic efficacy, training macrophages to revert to a low-lipid and M2 phenotype. This targeted drug delivery system integrates multiple therapeutic mechanisms, including inhibition of cholesterol uptake, enhancement of cholesterol efflux, and immunomodulation, providing a promising new strategy for the treatment of atherosclerosis. Show less
p-Synephrine (p-Syn), a natural alkaloid isolated from Citrus aurantium L., promotes fat oxidation and is therefore widely used as a weight loss dietary supplement. It was recently reported to exert a Show more
p-Synephrine (p-Syn), a natural alkaloid isolated from Citrus aurantium L., promotes fat oxidation and is therefore widely used as a weight loss dietary supplement. It was recently reported to exert a potent antidepressant effect. However, its molecular targets remain undefined. Gastrodin (Gas), extracted from Gastrodia elata Blume, exerts antidepressant effects by targeting Melatonin Receptor 1A (MT This study aimed to evaluate whether MT Network pharmacology was applied to predict potential targets and associated signaling pathways for p-Syn and Gas. Molecular Docking simulations were employed to predict the possible binding sites of MT Using a network pharmacology approach and in vitro assays, we found that both p-Syn and Gas bind to MT1, activate the ERK/CREB signaling pathway, and up-regulate BDNF. In vivo assays showed that p-Syn alleviated Reserpine (Res)-induced depression-like symptoms in AB zebrafish larvae and C57 mice. Furthermore, p-Syn and Gas showed a remarkable synergistic effect. This study identifies a novel target for p-Syn and provides new insights into the antidepressant mechanisms of p-Syn and Gas that may contribute to the clinical application of these compounds in the development of new drugs for the treatment of depression. Show less
Immune checkpoint blockade (ICB) has improved outcomes for patients with triple-negative breast cancer (TNBC), yet resistance remains widespread and its molecular basis is not fully understood. Throug Show more
Immune checkpoint blockade (ICB) has improved outcomes for patients with triple-negative breast cancer (TNBC), yet resistance remains widespread and its molecular basis is not fully understood. Through single-cell RNA sequencing (scRNA-seq) of paired pre- and post-treatment tumor samples from patients who failed to achieve pathological complete response (non-pCR) after neoadjuvant PD-1 therapy, we identified a marked upregulation of interleukin-27 receptor subunit alpha (IL27RA) in malignant epithelial cells within residual lesions. Integration with scRNA-seq profiles from an independent cohort of three pCR patients showed that this IL27RA upregulation in malignant epithelium is largely restricted to non-pCR residual tumors, and high IL27RA expression correlated with poor survival in TNBC cohorts. Mechanistically, IL27RA suppresses MHC-I expression by activating the PI3K/AKT pathway-rather than the classical IL-27/STAT axis-thereby impairing CD8⁺ T-cell cytotoxic function. Inhibition of AKT reversed this phenotype and restored antigen-specific killing. In orthotopic tumor models, mimicking systemic loss of Il27ra significantly reduced tumor growth and prolonged survival in immunocompetent mice, with single-cell profiling indicating enhanced intratumoral T-cell and NK-cell effector activity. Collectively, our findings identify an epithelial-intrinsic IL27RA-PI3K/AKT-MHC-I axis as a central driver of immune evasion and ICB resistance in TNBC and support IL27RA as a promising therapeutic target for overcoming immunotherapy resistance. Show less
Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide. Mitochondria-associated endoplasmic reticulum membranes (MAMs) have recently emerged as critical mediators in Show more
Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide. Mitochondria-associated endoplasmic reticulum membranes (MAMs) have recently emerged as critical mediators in cardiovascular pathophysiology; however, their specific contributions to CHD pathogenesis remain largely unexplored. This study aimed to identify and validate MAM-related biomarkers in CHD through integrated analysis of transcriptomic sequencing data and Mendelian randomization, and to elucidate their underlying mechanisms. We analyzed two gene expression microarray datasets (GSE113079 and GSE42148) and one genome-wide association study (GWAS) dataset (ukb-d-I9_CHD) to identify differentially expressed genes (DEGs) associated with CHD. MAM-related DEGs were filtered using weighted gene co-expression network analysis (WGCNA). Functional enrichment analysis, Mendelian randomization, and machine learning algorithms were employed to identify biomarkers with direct causal relationships to CHD. A diagnostic model was constructed to evaluate the clinical utility of the identified biomarkers. Additionally, we validated the two hub genes in peripheral blood samples from CHD patients and normal controls, as well as in aortic tissue samples from a low-density lipoprotein receptor-deficient (LDLR-/-) atherosclerosis mouse model. We identified 4174 DEGs, from which 3326 MAM-related DEGs (DE-MRGs) were further filtered. Mendelian randomization analysis coupled with machine learning identified two biomarkers, DHX36 and GPR68, demonstrating direct causal relationships with CHD. These biomarkers exhibited excellent diagnostic performance with areas under the receiver operating characteristic (ROC) curve exceeding 0.9. A molecular interaction network was constructed to reveal the biological pathways and molecular mechanisms involving these biomarkers. Furthermore, validation using peripheral blood from CHD patients and aortic tissues from the Ldlr-/- atherosclerosis mouse model corroborated these findings. This study provides evidence supporting a mechanistic link between MAM dysfunction and CHD pathogenesis, identifying candidate biomarkers that have the potential to serve as diagnostic tools and therapeutic targets for CHD. While the validated biomarkers offer valuable insights into the molecular pathways underlying disease development, additional studies are needed to confirm their clinical relevance and therapeutic potential in larger, independent cohorts. Show less
High-dose methotrexate for pediatric cancer treatment is frequently associated with mucositis, which can lead to delayed or discontinued treatment and impact survival. While individual genetic variant Show more
High-dose methotrexate for pediatric cancer treatment is frequently associated with mucositis, which can lead to delayed or discontinued treatment and impact survival. While individual genetic variants have been implicated, the cumulative impact of genetic variation within relevant biological pathways remains unexplored. We evaluated single nucleotide polymorphisms across 18 pathways previously identified as relevant to mucositis in 278 pediatric patients with acute lymphoblastic leukemia from six academic health centers across Canada. Pathway enrichment was assessed using the Joint Association of Genetic variants tool, and a predictive model was developed using XGBoost, a supervised machine learning algorithm based on gradient-boosted decision trees. Pathway enrichment identified significant associations in IL6 (P = 0.04) and WNT/β-catenin (P = 0.048) signaling pathways. The predictive model (area under the curve [AUC] = 0.76) highlighted single nucleotide polymorphisms associated with inflammation- and mucosa-related genes, including PRKCD, IL17B, MAST3, and CAPN9, with both risk and protective effects. Model performance dropped by 0.15 in AUC (from 0.76 to 0.61) after removing single nucleotide polymorphism features, underscoring their predictive value. This pathway-informed approach identifies genetic contributors to methotrexate-induced mucositis and supports polygenic risk prediction. Our findings provide a foundation for individualized toxicity risk profiling and suggest potential therapeutic targets to mitigate treatment-limiting mucositis in pediatric oncology. Show less
Atherosclerosis (AS) is closely associated with gut microbiota that plays an important role in regulating intestinal mucosal barrier function, chronic inflammation, and immune homeostasis. Thus, targe Show more
Atherosclerosis (AS) is closely associated with gut microbiota that plays an important role in regulating intestinal mucosal barrier function, chronic inflammation, and immune homeostasis. Thus, targeting the modulation of gut microbitoa repesents a promising strategy for the control of AS. Clostridium butyricum (C. butyricum) serving as a kind of probiotics has shown a variety of biological benefits, but it's impact on atherosclerosis remains poorly understood. Sixty male ApoE C. butyricum ameliorated dyslipidemia and attenuated atherosclerotic plaque formation in ApoE C. butyricum intervention may exert anti-AS effects by reshaping gut homeostasis via the regulation of immune cells, providing a potential strategy for clinical treatment. Show less
Dietary unsaturated fat, protein, and carbohydrate have well-established effects on HDL (high-density lipoprotein) cholesterol levels, but whether these effects are connected causally to coronary hear Show more
Dietary unsaturated fat, protein, and carbohydrate have well-established effects on HDL (high-density lipoprotein) cholesterol levels, but whether these effects are connected causally to coronary heart disease (CHD) has been called into question. Protein-based minor HDL subspecies are emerging as novel and likely causal biomarkers, direct or inverse, for risk of CHD, diabetes, and other conditions. HDL-raising drugs such as CETP (cholesteryl ester transfer protein) inhibitors raise certain HDL subspecies that have adverse effects on CHD risk. We hypothesize that dietary unsaturated fat, protein, and carbohydrate differentially affect 15 minor protein-based HDL subspecies with diverse functionality in lipid metabolism, antioxidation, immunity, hemostasis, and protease inhibition. We analyzed the apo (apolipoprotein) A1 concentrations of 15 minor HDL subspecies after 4 weeks on each diet in 141 participants in the OmniHeart trial (Optimal Macronutrient Intake Trial to Prevent Heart Disease), a randomized 3-period crossover, controlled feeding study. The diet rich in carbohydrate contained 58% carbohydrate, 27% fat, and 15% protein, and the diets rich in unsaturated fat and protein replaced 10% of carbohydrate with unsaturated fat or protein, respectively. Unsaturated fat replacing dietary carbohydrate increased concentrations of apoA1 in lipid metabolism subspecies including HDL that contains apoA2, apoE, or apoC1 that has been associated with reduced risk of CHD. Protein replacing carbohydrate increased apoE HDL, consistent with lower CHD risk, and decreased concentrations of several other HDL subspecies that were associated with higher risk of CHD including HDL that contains PLMG (plasminogen), A2M (alpha-2-macroglobulin), or apoL1. Network analysis showed connections between functional groups of HDL subspecies that are quantitatively affected by dietary macronutrients. Replacing dietary carbohydrate with unsaturated fat or protein raised levels of protein-based HDL subspecies associated with lower risk of CHD or lowered the levels of those associated with higher risk of CHD. Minor HDL subspecies with diverse functions may mediate the association of dietary patterns with risk of CHD. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00051350. 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 workfor Show more
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
Sepsis is a syndrome caused by the host's inflammatory response to an infection with an unknown mechanism. This study aimed to identify differentially expressed genes (DEGs) potentially involved in th Show more
Sepsis is a syndrome caused by the host's inflammatory response to an infection with an unknown mechanism. This study aimed to identify differentially expressed genes (DEGs) potentially involved in the development and recovery of tracheal injury from septic shock. Nine New Zealand white rabbits were randomized to control (CON), septic shock model (SS), and septic shock norepinephrine treatment (SSNE) groups (each group n = 3). The SS and SSNE groups were injected with lipopolysaccharide to induce septic shock. The SSNE group was administered Ringer lactate with norepinephrine to maintain normal blood pressure. All animals underwent cuffed endotracheal intubation for 2 h. The injured tracheal segment was harvested. RNA sequencing was performed to identify the DEGs, followed by bioinformatics analysis, and pathological staining (both HE and Masson) was performed for pathological evaluation. Bioinformatics analysis included principal component analysis (PCA), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network construction. Key findings were validated by qRT-PCR and immunohistochemistry. We obtained 124 upregulated and 28 downregulated DEGs in SS vs. CON groups, along with 60 upregulated and 178 downregulated DEGs in SSNE vs. SS groups. The pathological score showed that trachea tissue in the SS group had the highest score. The protein-protein interaction (PPI) prediction identified APOB and CD36 as the hub genes. The molecular experiments further confirmed that at mRNA and protein levels, APOB was significantly upregulated, while CD36 was significantly downregulated. Subsequent qRT-PCR and immunohistochemical analyses confirmed that APOB expression was significantly upregulated while CD36 was downregulated in the septic shock group, a trend partially reversed by norepinephrine treatment. Our study results suggest that APOB and CD36 may be involved in the pathogenesis of tracheal injury recovery in septic shock patients treated with NE. Not applicable. Show less
Following spinal cord injury (SCI), neuroinflammation driven by lipid-laden macrophage foam cells is a key pathology, yet how these cells manage their lipid homeostasis is unclear. We delineate a neur Show more
Following spinal cord injury (SCI), neuroinflammation driven by lipid-laden macrophage foam cells is a key pathology, yet how these cells manage their lipid homeostasis is unclear. We delineate a neuroprotective axis in which macrophages deploy apolipoprotein E (APOE) to transfer intracellular lipids to neighboring cells, especially fibroblasts. Genetic ablation of The online version contains supplementary material available at 10.1186/s12974-026-03756-9. Show less
Geriatric depression affects 12.95-28.4% of adults aged ≥ 60, yet treatment rates remain critically low globally. Lifestyle factors, particularly exercise and sleep demonstrate therapeutic potential, Show more
Geriatric depression affects 12.95-28.4% of adults aged ≥ 60, yet treatment rates remain critically low globally. Lifestyle factors, particularly exercise and sleep demonstrate therapeutic potential, integrated interventions may exert synergistic effects on geriatric depression, though such interventions remain scarce. The Geriatric Exercise-Sleep Optimization (GESO) project aims to evaluate the clinical efficacy and cost-effectiveness of a combined exercise and sleep health intervention in alleviating depressive symptoms among community-dwelling older adults with depression, and exploring the potential underlying mechanisms. This is a stepped-wedge cluster-randomized trial (SW-CRT). A 12-week integrated exercise and sleep intervention will be implemented to all eligible participants during the study period. The primary aim is to evaluate the clinical efficacy in alleviating depressive symptoms. Secondary aims are to evaluate the additional health outcomes (i.e., quality of life, physical activity level, daily step count, sleep quality, and anxiety symptom), cost-effectiveness, and potential mechanisms. Costs will be aggregated and analyzed for economic evaluation. Costs will be aggregated and analyzed for economic evaluation. Salivary measured BDNF and irisin levels, and EEG-based brain function connectivity will be collected to assess potential intervention mechanisms. Mixed-effect linear regression models will be used to evaluate the effects of the integrated exercise-sleep intervention on primary and secondary outcomes. This study is expected to provide an effective and practical mode for an integrated exercise and sleep intervention among community-dwelling older adults with depression. Intended outcomes of the trial will facilitate changes in best practice to improve outcomes for this population.Trial registration Chinese Clinical Trail Registry ChiCTR2500107641, Registration date: 15 August 2025. Show less
Alport syndrome (AS) is the most common inherited glomerular disease among patients with chronic kidney disease. With exome sequencing now widely used in clinical practice, pathogenic variants in Alpo Show more
Alport syndrome (AS) is the most common inherited glomerular disease among patients with chronic kidney disease. With exome sequencing now widely used in clinical practice, pathogenic variants in Alport-related genes (COL4A3/COL4A4/COL4A5) are increasingly identified in patients with diverse phenotypes, including proteinuria‑predominant disease and kidney failure of unknown etiology. Diagnostic complexity further increases when COL4A3/COL4A4/COL4A5 variants are co‑inherited with pathogenic variants associated with other genetic kidney disorders. We reported a 31‑year‑old male presenting with kidney failure, significant proteinuria, familial hematuria and hyperlipidemia. Whole‑exome sequencing (WES) identified two pathogenic variants: a hemizygous COL4A5 variant (c.2105G > A; p.Gly702Asp) and a heterozygous APOE Kyoto variant (c.127C > T; p.Arg43Cys). Given the potential dual diagnosis of AS and lipoprotein glomerulopathy (LPG), a kidney biopsy was performed. Histologic examination revealed uneven thickness of the glomerular basement membrane consistent with the diagnosis of AS, but no LPG-related lesions were observed, indicating incomplete penetrance of APOE Kyoto variant. Cascade family screening detected APOE Kyoto variant in the patient's father and elder sister, both of whom lacked proteinuria until follow-up period. This case highlights the complementary role of kidney biopsy alongside WES in AS with complex genetic mechanisms. It also illustrates the incomplete penetrance of APOE Kyoto, common among Chinese carriers. Show less
Yiming Li, Wenxin Zou, Yan Zhang+5 more · 2026 · Phytomedicine : international journal of phytotherapy and phytopharmacology · Elsevier · added 2026-04-24
Atherosclerosis (AS) is a chronic disease characterized by lipid deposition in the vascular intima. As the pathological basis of cardiovascular diseases, AS represents a major contributor to global mo Show more
Atherosclerosis (AS) is a chronic disease characterized by lipid deposition in the vascular intima. As the pathological basis of cardiovascular diseases, AS represents a major contributor to global morbidity and mortality. While Gualou Huoxue Jiedu Decoction (GHJD) has been widely used in clinical practice for the treatment of AS, the molecular mechanisms remain unclear. To investigate the anti-atherosclerotic effects and underlying mechanisms of GHJD. Apoe GHJD alleviated plaque formation, improved lipid metabolism, and suppressed inflammation in vivo. Multi-omics analysis revealed that DNA methylation of Mfap4 could be a pivotal target of GHJD efficacy. In vitro assays confirmed that GHJD suppressed Mfap4 transcription and translation, leading to downregulation of integrin receptor family expression and inhibition of VSMC phenotypic switching. GHJD exerts anti-atherosclerotic effects through epigenetic modulation of Mfap4 and downstream integrin/FAK signaling pathway, thereby inhibiting VSMC phenotypic switching. These findings provide pharmacological evidence supporting GHJD as a potential therapy for AS and, for the first time, validate MFAP4 as a pharmacological target, offering new insights into AS prevention and treatment. Show less
Huangqi Guizhi Wuwu Decoction (HGWD) is a classic formula recorded in the Jin Gui Yao Lue. It is primarily used to treat symptoms of "blood stasis", such as numbness in the limbs and poor circulation, Show more
Huangqi Guizhi Wuwu Decoction (HGWD) is a classic formula recorded in the Jin Gui Yao Lue. It is primarily used to treat symptoms of "blood stasis", such as numbness in the limbs and poor circulation, and has been widely applied clinically in the treatment of stroke. Its traditional efficacy suggests potential for promoting neurological function recovery and regulating the microenvironment. However, its mechanism in neuroprotection and functional recovery after ischemic stroke (IS) remains unclear. This study aims to elucidate the molecular mechanism by which HGWD exerts neuroprotective effects and promotes neurological recovery following IS by inducing M2 polarization of microglia through activation of the PI3K/Akt/mTOR signaling pathway. The chemical constituents of HGWD were identified using Ultra Performance Liquid Chromatography-Mass Spectrometry (UHPLC-MS). Network pharmacology was employed to predict the active components of HGWD and targets, along with potential signaling pathways. A middle cerebral artery occlusion (MCAO) in vivo model was established using Sprague-Dawley (SD) rats, whilst primary microglia were isolated to construct an oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro model. TTC staining was used to assess the volume of cerebral infarction, and neurological function was evaluated using mNSS and the rotarod test. RT-qPCR, Western blot, immunofluorescence, or flow cytometry were used to detect axonal remodeling, the PI3K/Akt/mTOR signaling pathway, and microglial polarization markers, while ELISA was used to detect inflammatory cytokines. The in vivo dosage of HGWD was 2.5 g/kg i.g. and 5 g/kg i.g., and the in vitro concentrations were 50 μg/mL and 100 μg/mL. Using LY294002 and Rapamycin as PI3K and mTOR inhibitors, we verified that HGWD promotes the recovery of neurological function after IS by activating the PI3K/Akt/mTOR signaling pathway. Network pharmacology revealed that the core components of HGWD overlap with the PI3K/Akt/mTOR signaling pathway and microglial polarization targets. HGWD significantly improved neurological function in MCAO rats, reduced cerebral infarction area, and increased neuronal survival. This formula increased the expression of GAP-43, PSD95, and BDNF, while promoting axonal remodeling and synaptic repair. HGWD inhibited the expression of M1-type markers (CD86, iNOS) and increased the expression of M2-type markers (CD206, ARG1), while ELISA showed a shift of inflammatory cytokines towards anti-inflammatory effects. In microglia, HGWD restored OGD/R-induced cell viability and promoted M2 polarization via the PI3K/Akt/mTOR signaling pathway. Both in vivo and in vitro experiments showed that HGWD significantly increased the phosphorylation levels of PI3K, Akt, and mTOR. LY294002 and rapamycin partially blocked these results, while rescue experiments using the Akt activator SC79 combined with analysis of downstream STAT3 and P65 further illustrate that this process is Akt pathway dependent. The results suggest that HGWD can exert a neuroprotective effect by activating the PI3K/Akt/mTOR signaling pathway, thereby promoting neurological function recovery. HGWD may activate the PI3K/Akt/mTOR signaling pathway, drive microglia to M2 polarization, regulate neuroinflammation, and promote neuroplasticity, thereby achieving neuroprotection and functional recovery after IS. Show less
Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating Show more
Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating heterogeneity of CAFs in renal cell carcinoma (RCC) could represent potential targets for reprogramming the TME. In this study, we conducted single-cell RNA sequence and flow cytometry analyses that identified a CAF subset overexpressing apolipoprotein E (ApoE), which was correlated with poor survival in patients with RCC. Mechanistically, NRF1 activation in CAFs induced formation of ApoEhigh CAFs and secretion of NRG1. ApoEhigh CAFs potentiated stemness properties in the surrounding RCC cells by secreting NRG1 and subsequently activating the HER2/NF-κB pathway. Interfering with NRG1 expression or inhibiting NF-κB signaling reduced ApoEhigh CAF-induced stemness of RCC cells. Furthermore, neutralizing NRG1 enhanced the efficacy of sunitinib in RCC models in vivo. Together, these findings highlight targeting the tumor-promoting functions of ApoEhigh CAFs as a promising approach for treating advanced RCC. NRF1 drives formation of ApoEhigh cancer-associated fibroblasts that secrete NRG1 to stimulate stemness of renal cell carcinoma, revealing a stromal-mediated mechanism that can be inhibited to improve treatment of advanced kidney cancer. Show less
Previous studies have reported that IGF-1 single nucleotide polymorphism is associated with milk fat traits, but they are limited to trait association analysis. We previously identified a synonymous m Show more
Previous studies have reported that IGF-1 single nucleotide polymorphism is associated with milk fat traits, but they are limited to trait association analysis. We previously identified a synonymous mutation c.258 A > G (rs322131043) in IGF-1, which influenced IGF-1 expression and caused differences in metabolism. This study aims to reveal a new regulatory function of IGF-1 c.258 A > G on milk fat metabolism. Livers transcriptomics was used to identify differentially expressed genes between wild type mice (WT) and IGF-1 c.258 A > G mice (Homozygous mutation, Ho). Subsequently, lipid phenotyping, followed by metabolomics of mammary glands was conducted to verify transcriptomic findings. Finally, the potential mechanisms underlying IGF-1 c.258 A > G-induced changes in milk fat metabolism were explored though integrated transcriptomics-metabolomics analysis and Western blot validation. IGF-1 c.258 A > G changed the expression of genes related to lipid metabolism in livers of 8-week-old mice, including a 10-fold lipoprotein lipase (LPL) expression (P < 0.01) and 80-90 % downregulation of acyl-CoA thioesterase 3 (Acot3), enoyl-Coenzyme A delta isomerase 3 (Eci3), fatty acid synthase (FASN), and sterol regulatory element binding protein1 (SREBP1) expression (P < 0.01). The milk fat content of Ho dams on the second day of lactation (L2D) was decreased 50 % than that of WT dams (P < 0.05), although there was no significant difference in adipose tissue of 8-week-old WT/Ho mice. The levels of triglycerides, sphingolipids and their related fatty acyl chains (10:0, 26:0, 14:2, 20:4, 11:3, 19:0) in mammary glands of L2D Ho dams were reduced 10-50 % observed by lipid metabolomics. And combined with transcriptomics and Western blot, the data suggested that a 2.5-fold upregulation of LPL expression (P < 0.05) may contribute to the milk fat metabolism changes mediated by the IGF-1 c.258 A > G. This study revealed new function of IGF-1 c.258 A > G on milk fat metabolism, thereby informing the development of targeted genetic breeding on milk fat trait. Show less
Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-II Show more
Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL cholesterol (LDL-C), and reduces apolipoprotein B (apoB) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. We conducted a coronary computed tomography angiography (CCTA) study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen vs. placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence or high risk for cardiovascular disease, and non-calcified plaque on baseline CCTA. The primary endpoint was percent change from baseline to 12 months in non-calcified plaque volume (NCPV). Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (IQR 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (IQR 197-331), and remnant cholesterol was 53 mg/dL (IQR 38-76). Median baseline NCPV was 125.3 mm Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. Show less
Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don Show more
Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang (SB-SD) exhibit diverse biological activities, such as anti-inflammatory, antioxidant, and antitumor effects, though their precise regulatory mechanisms are not fully elucidated. Here, we treated PC cells with SB-SD to assess its impact on cell viability, apoptosis, migration, and cell cycle progression, while Western blotting analyzed the expression of HSP90AA1, MAPK3, p53, CDK1, and p21. We also established a pancreatic cancer xenograft model in nude mice to evaluate the in vivo inhibitory effect of SB-SD on tumor growth. Furthermore, we employed metagenomic sequencing, untargeted metabolomics, and quantitative proteomics to comprehensively profile changes in the gut microbiota, serum metabolites, and differentially expressed proteins, with Western blotting subsequently validating BCKDK, GATM and p53 expression. The results show that SB-SD significantly inhibited PC cell proliferation, promoted apoptosis, and induced S/G2 phase cell cycle arrest, potentially via modulation of the HSP90AA1/MAPK3 signaling pathway. Measurements of tumor volume and weight, complemented by histopathological analysis, confirmed that SB-SD effectively suppressed the growth of PANC-1 xenograft tumors. Integrated multi-omics analyses suggest that the antitumor effects of SB-SD may involve the modulation of key gut microbes like Bacteroides caccae and Lactobacillus, the promotion of choline metabolism, and the regulation of BCKDK and GATM. Together, these findings not only corroborate the direct antitumor activity of SB-SD against pancreatic cancer but also offer novel mechanistic insights by constructing a microbiota-metabolite-protein interaction network. Show less
The presence of a blood-brain barrier (BBB) prevents the delivery of most drugs to the brain. This characteristic limitation poses a major challenge to effective pharmacological treatment for numerous Show more
The presence of a blood-brain barrier (BBB) prevents the delivery of most drugs to the brain. This characteristic limitation poses a major challenge to effective pharmacological treatment for numerous neurodegenerative diseases, particularly Alzheimer's disease. Delivering small interfering RNA (siRNA) via nanoparticles represents a highly promising approach for treating Alzheimer's disease. Nevertheless, developing a safe and efficient siRNA delivery system remains challenging. To enhance brain targeting and therapeutic efficacy, we developed an siRNA nanocarrier system based on PAH-AM-PEG-ApoE (PAPA) nanoparticles (PAPA/siRNA NPs), which facilitates BBB penetration. In this study, an siRNA nanocarrier delivery system modified with ApoE peptide (PAPA/siRNA NPs) developed by our research team was employed to simultaneously encapsulate BACE1-siRNA and GSK3β-siRNA. The PAPA/siRNA NPs were prepared through self-assembly and electrostatic binding. The particle size distribution profile and zeta potential of the PAPA/siRNA NPs were analysed with dynamic light scattering, while its morphology was examined with transmission electron microscopy. For in vitro assessments, flow cytometry, confocal laser scanning microscopy, PCR, and Western blotting were employed to evaluate the cellular uptake, gene silencing capacity, and endosomal escape. The biodistribution was investigated by in vivo imaging technology, and the therapeutic effect on AD was verified in AD model mice. The prepared PAPA/siRNA NPs exhibited a regular spherical appearance with a uniform particle size distribution profile. In in vitro cell experiments, the PAPA/siRNA NPs demonstrated excellent cellular uptake ability and efficient endosomal escape. Meanwhile, the dual-loaded siRNA nanocarrier delivery system effectively inhibited the expression of GSK3β and BACE1 genes. In vivo experimental results showed that the siRNA could successfully cross the BBB and deliver to the brain. It not only significantly prolonged the half-life of siRNA but also greatly reduced the generation of pathological β-amyloid and phosphorylated microtubule-associated protein tau, showing excellent therapeutic effects in the treatment of AD. In this study, we successfully constructed a brain-targeted siRNA nanocarrier delivery system for double-gene knockdown. This system can efficiently overcome the obstacle of the BBB, markedly alleviating cognitive and memory deficits in AD mice. It paves the way for novel strategies in the clinical treatment of AD and is expected to bring new breakthroughs and changes to the conquest of this disease. Show less
Guoan Zhang, Baoguo Song, Xiaoyan Huang+1 more · 2026 · Inflammation research : official journal of the European Histamine Research Society ... [et al.] · Springer · added 2026-04-24
In our previous study, we identified Niemann-Pick C1 like intracellular cholesterol transporter 1 (NPC1L1) as a key contributor in lipid oxidative stress during atherosclerosis (AS) progression. Howev Show more
In our previous study, we identified Niemann-Pick C1 like intracellular cholesterol transporter 1 (NPC1L1) as a key contributor in lipid oxidative stress during atherosclerosis (AS) progression. However, the regulation mode of its expression and the specific approaches by which it functions in lipid oxidative stress are still unclear. HUVECs and macrophages were treated with oxidized low-density lipoprotein (ox-LDL) to induce endothelial cell injury. First, the effects of the RNA binding proteins IGF2BP1 and poly (A) binding protein cytoplasmic 1 (PABPC1) on the stability of NPC1L1 mRNA was evaluated. The interaction between NPC1L1 and cytochrome P450 family 11 subfamily A member 1 (CYP11A1) was analyzed using Co-IP, and the co-localization of the two was detected using immunofluorescence. Combined with qPCR, Western blotting, CCK8, ferroptosis-related index and mitophagy-related index determination were performed to evaluate the expression of CYP11A1 in ox-LDL-treated HUVECs and its role of ferroptosis and mitophagy. Subsequently, pcDNA-NPC1L1 or CYP11A1 siRNA were individually or altogether transfected into ox-LDL-treated HUVECs to verify the involvement of CYP11A1 in NPC1L1-mediated ferroptosis and mitochondrial oxidative stress. Finally, ApoE-/- mice were fed with high-fat diet to establish an AS model in vivo and sh-NPC1L1 and/or Ad-CYP11A1 were injected via tail vein to verify the therapeutic effect of NPC1L1 knockdown on AS and reversal effect of CYP11A1. Either knockdown of IGF2BP1 or PABPC1 reduced NPC1L1 mRNA stability. Mechanistically, NPC1L1 interacted with CYP11A1 and promoted CYP11A1 protein expression. CYP11A1 was upregulated in ox-LDL-treated HUVECs and overexpression of CYP11A1 induced ferroptosis by activating excessive mitophagy, and knockdown of CYP11A1 reversed the promotion of NPC1L1 on mitophagy and ferroptosis in ox-LDL treated HUVECs. In vivo, injection of the sh-NPC1L1 lentiviral vector inhibited AS progression, while injection of the LV-CYP11A1 lentiviral vector attenuated the protective effect of sh-NPC1L1 on AS. PABPC1 and IGF2BP1 synergistically stabilized NPC1L1 mRNA, and NPC1L1 interacted with CYP11A1 to induce endothelial mitophagy and ferroptosis during AS. Show less
Nursing interns often face maladjustment during the early stages of clinical practice, which not only directly affects their physical and mental health as well as work efficiency but also significantl Show more
Nursing interns often face maladjustment during the early stages of clinical practice, which not only directly affects their physical and mental health as well as work efficiency but also significantly inhibits their proactive feedback-seeking behavior (FSB). As an active self-regulation strategy, FSB can enhance interns' work initiative and promote role transition. However, existing research has yet to thoroughly investigate the potential heterogeneity and categorical characteristics of FSB within this population, and the role of psychological resources such as career adaptability in shaping these patterns requires further investigation. To investigate the status of FSB in early-stage nursing interns, identify latent subgroups via latent profile analysis (LPA), and analyze associated factors, thereby providing evidence for targeted clinical educational interventions. Multicenter cross-sectional research. This study employed a multistage stratified cluster sampling to survey 1,308 early-stage nursing interns from nine universities in Hubei, China, between June and September 2024. Data were collected using a demographic questionnaire, Feedback-Seeking Behavior Scale, and Career Adapt-Abilities Scale. LPA was employed to delineate FSB profiles and multivariate logistic regression analysis to examine the associated predictors. A total of 1,370 questionnaires were distributed, with 1,308 valid responses, yielding an effective response rate of 95.47%. The mean score on the feedback-seeking behavior scale was 5.06 ± 1.08. LPA identified three distinct feedback-seeking profiles: low (20.87%), moderate (38.3%), and high (40.83%). Education level, student cadre experience, internship hospital type, and career adaptability were significant predictors of profile membership ( FSB among early-stage nursing interns exhibited heterogeneity. Nursing educators and managers should implement tiered interventions: for the low and moderate feedback-seeking groups, career guidance and feedback awareness cultivation should be strengthened; for the high feedback-seeking group, peer modeling should be encouraged. This strategy can enhance proactive FSB, supports role transition and professional identity, and promotes long-term nursing workforce stability. Show less