Age increases of brain amyloid plaques may be mediated by prior increase of soluble Aβ42. Here, we show that frontal cortex samples from brains of cognitively normal aging humans had progressively inc Show more
Age increases of brain amyloid plaques may be mediated by prior increase of soluble Aβ42. Here, we show that frontal cortex samples from brains of cognitively normal aging humans had progressively increased levels of soluble amyloid peptide Aβ40 throughout the lifespan. Aggregated amyloid fraction was subsequently obtained by formic acid, where Aβ42 showed increases only in humans over 90 years old when compared to those younger than 50. Similarly, aging wild-type mice without amyloid plaques had increases of both soluble Aβ40 and Aβ42, as previously shown in normal aging rats. Aging also alters secretase enzymes and processing of amyloid precursor protein (APP). Here, we isolate membrane domains known as lipid rafts, a site of APP cleavage. We found that lipid rafts isolated from mouse and human cerebral cortex showed age increases of β-secretase enzyme activity, while amyloidogenic secretase proteins levels BACE1 and PS1 decreased with age in mouse. Lipid rafts merit further study in aging and neurodegeneration. Show less
Oxidative deterioration of fish oil in aquafeeds poses a significant challenge to fish health and aquaculture sustainability, making it crucial to mitigate this issue through healthy and green nutriti Show more
Oxidative deterioration of fish oil in aquafeeds poses a significant challenge to fish health and aquaculture sustainability, making it crucial to mitigate this issue through healthy and green nutritional strategies. This study examined the potential of stevia chlorogenic acid (SCGA), a bioactive byproduct of stevia processing, to alleviate intestinal injury, gut microbiota dysbiosis, and lipid metabolism disorders induced by oxidized fish oil in turbot. Four diets with equal nitrogen and lipid contents were formulated: a control diet (PC) containing 5 % fresh fish oil, an oxidized fish oil diet (OFO) comprising 5 % oxidized fish oil, and two additional OFO diets supplemented with 200 mg/kg (OFO200) or 400 mg/kg (OFO400) of SCGA. Each dietary treatment was randomly assigned to three replicates, each containing 40 fish weighing approximately 16.99 ± 0.01 g, and administered over a 10-week period. Fish fed the OFO diet exhibited significantly compromised growth performance, as indicated by decreased WGR and SGR, along with reduced serum immune indices (IgM, C3, and C4) and lipid parameters (TC, HDL, LDL), and elevated serum D-LA levels (P < 0.05). Moreover, dietary OFO markedly suppressed antioxidant enzyme activities (serum SOD; intestinal SOD, GSH-Px, and CAT) and elevated MDA concentrations (P < 0.05). Additionally, OFO reduced intestinal expression of tight junction-associated genes (Claudin-4, Claudin-7, Occludin) while increasing expression levels of MLCK, Keap1, inflammatory mediators (IL-6, IL-1β, TNF-α2, NF-κB, IFN-γ), and Caspase7 (P < 0.05). Notably, the TLR signaling pathway-related genes were upregulated, accompanied by pronounced shifts in gut microbiota composition (P < 0.05). In hepatic tissue, lipogenesis-associated genes (FAS, ACC) were significantly increased, while key genes involved in lipid transport and β-oxidation (CD36, LPL, ACOX1, PPARγ) exhibited reduced expression (P < 0.05). Dietary supplementation with 200 and 400 mg/kg SCGA effectively mitigated these detrimental impacts. SCGA restored growth performance, serum immune parameters, and antioxidant enzyme activities to levels comparable to the PC group. It also normalized gene expression related to intestinal barrier function, inflammation, apoptosis, and hepatic lipid metabolism. Furthermore, SCGA supplementation modulated gut microbiota structure by increasing beneficial genera and decreasing potential pathogens. In conclusion, SCGA effectively improves growth performance, alleviates OFO-induced intestinal injury and microbial dysbiosis, and regulates lipid metabolism in turbot. These findings provide theoretical insights and technical support for the application of SCGA in aquaculture. Show less
Lung adenocarcinoma (LUAD) has become the most common pathological pattern of lung cancer in recent decades. Prediction of biological behavior of LUAD is crucial for disease management and treatment o Show more
Lung adenocarcinoma (LUAD) has become the most common pathological pattern of lung cancer in recent decades. Prediction of biological behavior of LUAD is crucial for disease management and treatment options. The objective of this study was to identify significant genes related with prognosis of LUAD, and to investigate the role and biological mechanism of caveolin-1 (CAV1) in LUAD. Bioinformatical analysis was used to identify significant genes related to the prognosis of LUAD based on GEO datasets. Then the mechanisms underlying these critical genes were explored. Enrichment analysis was implemented based on CAV1 related differentially expressed genes subsequently. The expressions of CAV1 and EGFR in LUAD tissues and adjacent tissues were detected by Western blotting, immunohistochemistry and microarray technology. Kaplan-Meier survival analysis and cox regression analysis were performed to verify the correlation between CAV1 expression level and the prognosis of LUAD. The expression of CAV1 in PC-9, H1299 and H1975 cells was inhibited by siRNA transfection. CAV1 overexpression plasmid was constructed and transfected into A549 cells. Cell proliferation was detected by cell Titer-Glo, CCK-8 and colony formation assay. Scratch test was used to compare cell migration ability. Transwell assay was used to compare cell invasion ability. Cell apoptosis and cell cycle were detected by flow cytometry. The effect of CAV1 on EGFR degradation was verified by cycloheximide inhibition assay. Western blotting was used to detect the phosphorylation of AKT and STAT3, the expression of epithelial-mesenchymal transition (EMT) -related molecular markers and apoptosis-related Bax/Caspase-3/Bcl-2 pathway. The GFP plasmid loaded with shRNA was transfected into PC-9 cell line by lentivirus infection. Three groups of stable PC-9 cell lines, including shNC, shCAV1-1 and shCAV1-2 were obtained. The phenotypic experiments of proliferation, invasion, migration and apoptosis were completed. Western blotting was used to detect the phosphorylation of AKT and STAT3, as well as apoptosis-related Bax/Caspase-3/Bcl-2 pathway markers. In vivo experiments, including subcutaneous tumor formation experiment and immunohistochemical detection of CAV1, EGFR and Ki-67 were performed. Comprehensive analysis of GSE130779, GSE32863 and GSE85841 datasets identified 3 up-regulated DEGs and 86 down-regulated DEGs, which were significantly enriched in malaria pathway and proteoglycans in cancer pathway. CAV1 and CAV2 may inhibit tumor growth by degrading EGFR. Thirteen core genes including ADH1B, ALDH1A1, CAV1, CAV2, CLDN18, CXCL2 (GRO2), EDNRB, GNG11, LPL, PDK4, SCGB1A1, SDPR and SFTPC were down-regulated in LUAD tissues, which were associated with better prognosis of lung cancer significantly. Enrichment analysis of CAV1-related DEGs identified the endocytosis pathway, suggesting that CAV1 was involved in the development of LUAD by degrading EGFR through endocytosis. CAV1 was highly expressed in paracancerous tissues, and there was a negative correlation between the tissue locations of CAV1 and EGFR. Kaplan-Meier survival analysis of the cohort study showed that higher Cav-1 levels were associated with longer overall survival, and the difference was significant. Both in vitro and in vivo, CAV1 knockdown increased EGFR level, while CAV1 overexpression decreased EGFR level. This effect was mediated by Cav-1 promoting EGFR degradation. Cav-1 further inhibited the phosphorylation of downstream AKT/STAT3 pathway of EGFR. Caveolin-1 positively regulated the Bax/Caspase-3/Bcl-2 pathway, thereby participating in mediating apoptosis. Cav-1 can suppress the proliferation, migration and invasion of LUAD, while promote cell apoptosis. Our findings demonstrate that CAV1 exerts its anti-tumor effects, at least in part, by inhibiting EGFR degradation and modulating the AKT/STAT3 pathway, as well as enhancing the Bax/Caspase-3/Bcl-2 signaling pathway in LUAD cells. These results suggest that targeting CAV1 may represent a promising therapeutic strategy for the treatment of LUAD patients. Show less
Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from Show more
Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival (P = 0.025) and overall survival (P = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3-FGFR1. Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies. Show less
Hepatoid carcinoma of the ovary (HCO) is a highly uncommon and aggressive neoplasm originating from the surface epithelial cells of the ovary, characterized by hepatocyte-like differentiation. To date Show more
Hepatoid carcinoma of the ovary (HCO) is a highly uncommon and aggressive neoplasm originating from the surface epithelial cells of the ovary, characterized by hepatocyte-like differentiation. To date, most information on HCO is derived from case reports, with fewer than 50 documented cases globally. In this case report, we present a detailed account of the diagnosis, treatment, and prognosis of a patient diagnosed as having bilateral HCO, which is even rarer. Targeted next-generation sequencing revealed somatic mutations in PIK3C3 and TP53, with no BRCA1/2 alterations, and a molecular profile consistent with microsatellite stability and low tumor mutational burden. We also review the current literature to situate our findings within the broader context of existing knowledge. Given the rarity of bilateral HCO, our objective is to contribute to the existing body of knowledge by providing a comprehensive description of its clinical features, molecular characteristics, and treatment strategies. This effort may enhance understanding of this rare malignancy and offer insights to improve patient outcomes in clinical practice. Show less
Integration of human genomics and other omics across different ancestries provides novel, affordable, and systematic approach for target identification. We used Mendelian randomization approaches to u Show more
Integration of human genomics and other omics across different ancestries provides novel, affordable, and systematic approach for target identification. We used Mendelian randomization approaches to unravel causal associations between 2,940 circulating proteins and 19 CVD. We found 218 proteins that impacted risk of one or more CVDs through forward MR (106 and 182 using cis-pQTLs only and cis- + trans-pQTLs, respectively), among which 107 were previously reported as associated with CVD or CVD-related traits. There were 102 proteins replicated (FDR < 5%, 53 with cis-pQTLs only and 88 with cis- + trans-pQTLs) using the FinnGen Olink data. BTN3A2 was highlighted as a novel candidate gene for ischemic stroke, suggesting a crosstalk between immune modulation and stroke pathogenesis. Single cell integration prioritized PAM for stable angina pectoris and ventricular arrhythmia and LPL for peripheral artery disease, whose transcriptional expressions were enriched in cardiomyocytes. Forward and reverse MR found largely non-overlapping proteins (only 2 overlapped: LGALS4 and MMP12), suggesting distinct proteomic causes and consequences of CVD. Our study provides human genetics-based evidence of novel candidate genes, a foundational step towards full-scale causal human biology-based drug discovery for CVD. Show less
Vaccinia-related kinase 1 (VRK1) is involved in numerous cellular processes, including DNA repair, cell cycle and cell proliferation. However, its roles and molecular mechanism underlying the progress Show more
Vaccinia-related kinase 1 (VRK1) is involved in numerous cellular processes, including DNA repair, cell cycle and cell proliferation. However, its roles and molecular mechanism underlying the progression of hepatocellular carcinoma (HCC) are yet largely unexplored. Here, we demonstrated that VRK1 expression is elevated in HCC tumor tissues, which is associated with high tumor stage and poor prognosis in HCC patients. In vitro and in vivo experiments manifested that VRK1 overexpression significantly promotes cell proliferation, colony formation, migration and tumor growth of HCC by inducing epithelial-mesenchymal transition (EMT) program. Mechanistically, immunoprecipitation combined with mass spectrometry analysis determined that VRK1 interacts with CHD1L, which mediates the phosphorylation of CHD1L at serine 122 site. RNA-seq revealed that one of the key downstream target genes of VRK1 is SNAI1, by which VRK1 promotes EMT process and HCC progression. Furthermore, VRK1 upregulates SNAI1 expression through phosphorylating CHD1L. In conclusion, these findings suggested that VRK1/CHD1L/SNAI1 axis acts as a cancer-driving pathway to promote the proliferation and EMT of HCC, indicating that targeting VRK1 may be an attractive therapeutic strategy of HCC. Show less
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by hyperphosphorylation of tau, neuroinflammation, and amyloid-beta (Aβ) plaques. Lead (Pb) exposure has been linked to an increa Show more
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by hyperphosphorylation of tau, neuroinflammation, and amyloid-beta (Aβ) plaques. Lead (Pb) exposure has been linked to an increased risk of AD and neuroinflammation. The purpose of this study is to determine if black soybean peptide (BSP1) may reduce neuroinflammation caused by Pb and associated AD-like pathology. Pb exposure was given to mouse hippocampus HT22 cells in the presence or absence of BSP1, positive control resveratrol (Rsv), or the SIRT1 inhibitor EX-527. Our findings suggest that BSP1 downregulates the expression of beta-secretase (BACE1) and amyloid precursor protein (APP), inhibits tau phosphorylation, and reduces Aβ1-42 deposition. In addition, BSP1 effectively alleviated Pb-induced neuroinflammation by reducing the phosphorylation of NF-κB and the expression of pro-inflammatory cytokines (IL-1β, TNF-α, NLRP3, and IL-18). BSP1 provides neuroprotective effect via phosphorylating LKB1 and AMPK, inhibiting mTOR signaling, and activating the AMPK/SIRT1 pathway. These results suggest that BSP1 may be therapeutically beneficial for preventing or treating AD by reducing Pb-induced neuroinflammation. Show less
Abdominal aortic aneurysm (AAA) is a severe aortic disease for which no pharmacological interventions have yet been developed. This investigation focused on identifying protein-based therapeutic targe Show more
Abdominal aortic aneurysm (AAA) is a severe aortic disease for which no pharmacological interventions have yet been developed. This investigation focused on identifying protein-based therapeutic targets and assessing how proteins mediate the interplay between modifiable risk factors and AAA development. Causal inferences between plasma proteins and AAA were drawn using 2-sample Mendelian randomization, followed by comprehensive sensitivity testing, colocalization, and replication efforts. Further analyses included database interrogation, single-cell RNA data analysis, enrichment analysis, protein-protein interaction networks, and immunohistochemistry to map the tissue-specific expression of these proteins, their expression within AAA tissues, and their biological roles. Mediation Mendelian randomization was employed to evaluate the mediating effects of AAA-related proteins on the associations between AAA and 3 risk factors: hypertension, smoking, and obesity. A total of 43 proteins were identified as having causal links to AAA. Colocalization analysis pinpointed 13 proteins with strong evidence of colocalization with AAA. Of these, the causal involvement of 10 proteins was substantiated by external validation data. Consistent evidence for PCSK9 (proprotein convertase subtilisin/kexin type 9), IL6R (interleukin-6R), ECM1 (extracellular matrix protein 1), and ANGPTL4 (angiopoietin-related protein 4) was further validated through tissue immunohistochemistry and blood data. Moreover, Mendelian randomization analysis identified 10 proteins as mediators of the influence of hypertension, smoking, and obesity on AAA development. This analysis identifies 4 proteins (PCSK9, IL6R, ECM1, and ANGPTL4) as high-priority therapeutic targets for AAA and emphasizes the intermediary role of plasma proteins in linking hypertension, smoking, obesity, and AAA. Further investigations are needed to clarify the specific roles of these proteins in AAA pathology. Show less
The pyroptosis of retinal Müller cells is intricately linked to the pathogenesis of diabetic retinopathy (DR). Ubiquitin-fold modifier 1 (UFM1)-mediated UFMylation plays an important role in insulin a Show more
The pyroptosis of retinal Müller cells is intricately linked to the pathogenesis of diabetic retinopathy (DR). Ubiquitin-fold modifier 1 (UFM1)-mediated UFMylation plays an important role in insulin and diabetes mellitus metabolism and regulates cell death such as apoptosis and pyroptosis. UFM1-specific protease 2 (UFSP2) mediates the maturation of the UFM1 precursor and thus affects UFMylation reaction. However, its role in DR remains unknown. The aim of our study was to determine the mechanism and upstream regulation of UFSP2 on the pyroptosis of rat retinal Müller cells. Pathological changes, UFSP2 expression and succinate accumulation were determined in retinal tissues of db/db diabetic mice via Hematoxylin and eosin and immunofluorescence staining and biochemical analysis. High glucose (HG) was used to construct a DR cell model using rat retinal Müller cells (rMC-1). Ufsp2 RNA interference and overexpression plasmids were constructed to determine the effects of UFSP2. Pyroptosis and reactive oxygen species (ROS) levels were assessed via flow cytometry. Inflammatory cytokine (IL-1β and IL-18) levels and key molecular markers related to pyroptosis (NLRP3, ASC, Caspase-1p20, GSDMD-N) were measured by enzyme linked immunosorbent assay and Western blot, respectively. Succinate-mediated H3K3me3 enrichment in Ufsp2 promoter region was measured by chromatin immunoprecipitation. In vivo experiments revealed that the UFSP2 expression and succinate levels were increased in retinal tissues of db/db diabetic mice with thinning of retinal thickness. Moreover, in vitro experiments showed that The mRNA and protein levels of Ufsp2 exhibited a time-dependent increase under HG conditions. Upon Ufsp2 knockdown, the elevated oxidative stress, inflammatory responses, and pyroptosis stimulated by HG were significantly suppressed. The effect of Ufsp2 overexpression on pyroptosis and inflammatory responses was consistent with the HG stimulation, whereas the UFSP2-induced heightened levels of pyroptosis as well as the inflammatory state were significantly reversed when co-administered with NLRP3 inhibitor or ROS inhibitor. Further activating NLRP3 inflammasome using LPS + ATP stimulation revealed that the knockdown of Ufsp2 resulted in inhibited pyroptosis levels and inflammatory responses, while the Ufsp2 overexpression markedly increased pyroptosis and inflammatory responses. Lastly, succinate was demonstrated to influence Ufsp2 transcription, as well as the expression of H3K3me3 and its enrichment in the Ufsp2 promoter region, ultimately affecting pyroptosis and inflammatory responses. Succinate-mediated Ufsp2 transcription promotes pyroptosis in rMC-1 cells by activating NLRP3 inflammasome and oxidative stress. Show less
Fatty acids serve as a crucial energy source for tumor cells during the progression of chronic lymphocytic leukemia (CLL). The present study aims to elucidate the characteristics of fatty acid metabol Show more
Fatty acids serve as a crucial energy source for tumor cells during the progression of chronic lymphocytic leukemia (CLL). The present study aims to elucidate the characteristics of fatty acid metabolism (FAM) in CLL, construct a related prognostic score, and investigate the regulatory role and mechanisms of FAM in CLL development. Bulk RNA sequencing data from CLL patients and healthy controls were analyzed to identify differentially expressed fatty acid metabolic genes. FAM-score was constructed using Cox-LASSO regression and validated. Single-cell RNA sequencing was used to analyze the expression of key FAM genes in CLL immune cell subsets and investigate cellular communication. Functional assays, including cell viability, drug sensitivity, and oxygen consumption assays, were performed to assess the impact of fatty acid oxidation (FAO) inhibition on CLL cells. Three FAM-related genes (LPL, SOCS3, CNR1) were identified with independent prognostic significance to construct the risk score. The FAM-score demonstrated superior prognostic performance compared to the Binet stage and was associated with established clinical prognostic markers. Single-cell analysis revealed distinct expression patterns of LPL, SOCS3, and CNR1 across CLL immune cell subsets. Cellular communication analysis highlighted the regulatory role of distinct B cell and Treg subsets in the CLL microenvironment. CLL patients with high FAM-score displayed distinct immune infiltration patterns, with increased FAO pathway activity. Inhibition of FAO reduced CLL cell viability, synergistically enhanced the efficacy of the PI3K inhibitor idelalisib. The present study constructed a prognostic risk score based on FAM gene expression, revealing related immune phenotypic differences and exploring the regulatory role of FAO in CLL development. Targeting fatty acid metabolism potentially modulates the CLL immune microenvironment and synergistically enhances the efficacy of PI3K inhibitors. Show less
Lung adenocarcinoma (LUAD) is one of the leading causes of death worldwide, and thus, more biomarker and therapeutic targets need to be explored. Herein, we aimed to explore new biomarkers of LUAD by Show more
Lung adenocarcinoma (LUAD) is one of the leading causes of death worldwide, and thus, more biomarker and therapeutic targets need to be explored. Herein, we aimed to explore new biomarkers of LUAD by integrating bioinformatics analysis with cell experiments. We firstly identified 266 druggable genes that were significantly differentially expressed between LUAD tissues and adjacent normal lung tissues. Among these genes, SMR analysis with Show less
William Stewart, Bin Hu, Fengqiao Li+6 more · 2025 · Journal of controlled release : official journal of the Controlled Release Society · Elsevier · added 2026-04-24
Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabete Show more
Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabetes, cardiovascular disease, and certain cancers, all of which contribute to rising rates of preventable morbidity and mortality. Current approaches to obesity, including lifestyle modifications, and pharmacotherapy, often face limitations such as poor long-term adherence, side effects, and insufficient targeting of the complex, multifactorial pathways underlying the disease. Herein we report a dual, RNA-mediated combinatorial approach using targeting lipid nanoparticles (LNP) for the treatment of obesity. LNPs were co-encapsulated with mRNA encoding Interleukin-27 (mIL-27) to coactivate PGC-1α, PPARα, and UCP-1, thereby promoting adipocyte differentiation and enhancing adaptive thermogenesis within adipocytes, and siRNA targeting Dipeptidyl peptidase-4 (siDPP-4) to silence the primary inhibitory enzyme of GLP-1, and GIP within the incretin system, effectively restoring glucose homeostasis. Following post translational silencing of DPP-4 and upregulation of IL-27 in a diet-induced obesity (DIO) mice model, increased expression of thermogenic biomarkers PGC-1α, PPARα, and UCP-1 was observed at the molecular, protein, and tissue level, and insulin sensitivity was restored. Importantly, this gene modulation led to a 21.1 % reduction of bodyweight after treatment in the DIO model. These findings demonstrate for the first time a dual RNA-mediated combinatorial approach, leveraging liver targeting LNP delivery with synergistic effects from incretin system regulation and induction of adipocyte differentiation and thermogenesis after codelivery of siDPP-4 and mIL-27. This innovative strategy provides a promising alternate framework for addressing obesity and its associated metabolic dysfunction. Show less
Stroke is a leading cause of mortality and disability globally, with post-stroke depression and post-stroke anxiety being common and significant complications that hinder recovery and adversely affect Show more
Stroke is a leading cause of mortality and disability globally, with post-stroke depression and post-stroke anxiety being common and significant complications that hinder recovery and adversely affect quality of life. Although these conditions frequently co-occur, their heterogeneity remains poorly understood. This study integrates the Health Ecology Model (HEM) and employs Latent Profile Analysis (LPA) to identify distinct psychological profiles of depression and anxiety among patients with acute ischemic stroke (AIS), as well as to investigate their multilevel determinants. Patients with AIS from a tertiary hospital in Guangdong Province, China, from January to November 2024 were included. Within one week of stroke onset, the data of sociodemographic, clinical characteristics, swallowing function, stroke severity, activities of daily living, resilience and social support were collected according to the HEM guidelines. The Patient Health Questionnaire-9 and the Generalized Anxiety Disorder-7 were used to assess the depression and anxiety symptoms of the patients three months after stroke onset. LPA was employed to identify distinct psychological profiles, and variables with a A total of 551 patients with AIS were included in the study, 49 were lost to follow-up or withdrew, resulting in a final analytic sample of 502 participants (91.11%). Three distinct psychological profiles were identified: no depression-anxiety (67.93%), high-risk depression-anxiety (21.12%) and major depression-anxiety (10.95%). In the multivariate analysis, the results indicated that occupation (OR = 0.61, 95% CI [0.40-0.93]), National Institutes of Health Stroke Scale (NIHSS, OR = 1.60, 95% CI [1.06-2.42]), Barthel Index (BI, OR = 1.67, 95% CI [1.27-2.19]) and hypertension (OR = 2.37, 95% CI [1.29-4.35]) were independent predictors of the high-risk depression-anxiety profile, while NIHSS (OR = 2.33, 95% CI [1.42-3.85]), BI (OR = 2.65, 95% CI [1.62-4.35]) and resilience (OR = 0.92, 95% CI [0.87-0.98]) were significantly associated with the major depression-anxiety profile. This study reveals significant heterogeneity in psychological distress among AIS survivors. Key predictors of post-stroke emotional comorbidity include occupation, hypertension, stroke severity, activities of daily living and low resilience. Early identification of high-risk individuals can significantly enhance screening and intervention strategies, particularly by focusing on symptoms such as anhedonia and nervousness. Future research should focus on longitudinal designs and objective biomarkers to better understand the mechanisms behind post-stroke emotional comorbidity. Show less
The co-occurrence of plasma cell neoplasm (PCN) and lymphoplasmacytic lymphoma (LPL) is rare, and their clonal relationship remains unclear. To evaluate the clinicopathologic characteristics of concom Show more
The co-occurrence of plasma cell neoplasm (PCN) and lymphoplasmacytic lymphoma (LPL) is rare, and their clonal relationship remains unclear. To evaluate the clinicopathologic characteristics of concomitant LPL/PCN. Retrospectively analyzed clinical and laboratory data of 14 cases. Three patients initially presented with immunoglobulin (Ig) M paraprotein, 1 with IgG paraprotein, and 10 had simultaneous diagnoses of PCN and LPL. In 13 cases, flow cytometry detected both LPL and PCN in marrow biopsies. Furthermore, immunohistochemistry highlighted the 2 neoplastic populations, demonstrating an increased proportion of plasma cells and their expression of cyclin D1, CD56, and/or a non-IgM isotype restriction. All cases exhibited discordant heavy-chain isotypes between LPL and PCN. Thirteen of the 14 cases (92.9%) had concordant light-chain restrictions between the 2 neoplasms, and the remaining case (7.1%) showed discordant light-chain restrictions. Of the 12 patients with follow-up, 5 were treated with myeloma regimens, 2 with LPL regimens, 3 with combined therapy, and 2 with observation alone. Follow-up ranged from 2 to 146 months (median, 12.5 months). One patient died of PCN progression, one died of comorbidity, and 10 patients were alive with or without disease. Survival analysis showed no significant difference from the control. The discordant heavy-chain isotype restrictions between PCN and LPL suggest biclonal B-cell neoplasms, which is supported by PCN's phenotypic distinction, such as the expression of cyclin D1 and/or CD56. However, our series exhibited a tendency toward concordant light-chain restrictions between the 2 neoplasms, raising the possibility that PCN may evolve from LPL through class switching. Show less
Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease (CVD). Related mutations contributing to hypercontractility and poor relaxation in HCM are not completely u Show more
Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease (CVD). Related mutations contributing to hypercontractility and poor relaxation in HCM are not completely understood. This study aimed to explore and verify a novel variant of cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3) in an HCM family. Clinical information and cardiac parameters were collected in the pedigree. Genomic DNA was extracted from peripheral blood and second-generation sequencing technology was used to investigate the proband and his family members. Subsequent sequence analysis was performed with DNAMAN software. The cardiac expression levels of MYBPC3 mRNA and cMyBP-C protein were assessed using RT-qPCR and Western blot analysis, respectively. Typical interventricular septal thickening was detected in all four HCM patients without left ventricular outflow tract obstruction. The c.1042₁₀₄₃insCGGCA mutation in MYBPC3 was verified in the proband and family members. In silico analysis of the mutation revealed that c.1042₁₀₄₃insCGGCA led to a shift in the sequence of nucleotides, creating a premature stop codon at the new reading frame. RT-qPCR analysis of MYBPC3 mRNA revealed a marked reduction in HCM heart compared to the normal controls (P < 0.05). Consistently, Western blot analysis showed significantly reduced expression of cMyBP-C in the pedigree in comparison with the controls (P < 0.05). The novel c.1042₁₀₄₃insCGGCA MYBPC3 mutation is a genetic basis for HCM due to c-MyBP-C haploinsufficiency. Show less
Vascular calcification (VC) significantly increases the incidence and mortality of many diseases. The causal relationships of dyslipidaemia and lipid-lowering drug use with VC severity remain unclear. Show more
Vascular calcification (VC) significantly increases the incidence and mortality of many diseases. The causal relationships of dyslipidaemia and lipid-lowering drug use with VC severity remain unclear. This study explores the genetic causal associations of different circulating lipids and lipid-lowering drug targets with coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC). We obtained single-nucleotide polymorphisms (SNPs) and expression quantitative trait loci (eQTLs) associated with seven circulating lipids and 13 lipid-lowering drug targets from publicly available genome-wide association studies and eQTL databases. Causal associations were investigated by univariable, multivariable, drug-target, and summary data-based Mendelian randomization (MR) analyses. Potential mediation effects of metabolic risk factors were evaluated. MR analysis revealed that genetic proxies for low-density lipoprotein cholesterol (LDL-C), triglycerides (TC) and Lipoprotein (a) (Lp(a)) were causally associated with CAC severity, and apolipoprotein B (apoB) level was causally associated with AAC severity. A significant association was detected between hepatic Lipoprotein(A) (LPA) gene expression and CAC severity. Colocalisation analysis supported the hypothesis that the association between LPA expression and CAC quantity is driven by different causal variant sites within the ±1 Mb flanking region of LPA. Serum calcium and phosphorus had causal associations with CAC severity. Inhibitors targeting LPA might represent CAC drug candidates. Moreover, T2DM, hypercalcemia, and hyperphosphatemia are positively causally associated with CAC severity, while chronic kidney disease and estimated glomerular filtration rate are not. Show less
Cardiovascular disease (CVD) is the leading cause of mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), yet traditional risk predictors remain limited in clin Show more
Cardiovascular disease (CVD) is the leading cause of mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), yet traditional risk predictors remain limited in clinical practice. To develop machine learning (ML) models for classifying prevalent atherosclerotic cardiovascular disease (ASCVD) risk in MASLD patients, and to enhance model interpretability using SHapley Additive exPlanations (SHAP). Methods: This retrospective study included 590 MASLD patients diagnosed at the Affiliated Hospital of Qingdao University between December 2019 and December 2024. Patients were randomly divided into a training set (n=413) and a validation set (n=177), and further stratified based on ASCVD status. Least absolute shrinkage and selection operator (LASSO) regression was used for feature selection. Six ML models were developed and evaluated using sensitivity, specificity, accuracy, area under the receiver operating characteristic curve (AUC), and F1 score. SHAP analysis was performed to interpret feature contributions. ASCVD was present in 434 of 590 patients (73.6%). The Gradient Boosting (GB) model achieved the best performance, with AUCs of 0.918 (95% CI: 0.890-0.944) in the training set and 0.817 (95% CI: 0.739-0.883) in the validation set. SHAP analysis identified the top predictors as the Cholesterol-HDL-Glucose (CHG) index, Castelli Risk Index II (CRI-II), lipoprotein(a) [Lp(a)], serum creatinine (Scr), and uric acid (UA). The GB model demonstrated strong high accuracy in identifying existing ASCVD in MASLD patients and may serve as a useful tool for early risk stratification in clinical settings. Show less
SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our gen Show more
SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our genome-wide siRNA library screen. We found that defective IAV replication in SLC35B4-deficient A549 cells was independent of virus strain specificity, and the virulence of IAV in Slc35b4 knockdown mice was also decreased. By examining the individual stages of the IAV replication cycle, we discovered that the amount of internalized IAV was significantly reduced in SLC35B4-knockout A549 cells. Mechanistically, SLC35B4 facilitated IAV replication by transporting UDP-xylose, which attaches to the serine residue of heparan sulfate proteoglycans (HSPGs) in the heparan sulfate (HS) biosynthesis pathway. Knockdown of associated host factors (i.e., XYLT2, B4GALT7, EXT1, and EXT2) in the HS biosynthesis pathway also impaired IAV replication. Furthermore, we revealed that AGRN, a unique HSPG family member, was important for the endocytosis of IAV in A549 cells. Moreover, we found that the homeostasis of the AGRN protein was regulated by HS modification mediated by the initial UDP-xylose transporter SLC35B4, thereby affecting the expression level of endocytic adapter AP2B1 to influence IAV internalization. Collectively, these findings establish that SLC35B4 is an important regulator of IAV replication and uncover the underlying mechanisms by which SLC35B4 employs UDP-xylose transport activity to promote IAV internalization.IMPORTANCEThe entry process of IAV represents a favorable target for drug development. In this study, we identified SLC35B4 as an important host factor for the efficient replication of different subtypes of IAV Show less
To determine whether lipoprotein(a) [Lp(a)] and cumulative Lp(a) (CumLp(a)) are associated with adverse outcomes in patients with acute myocardial infarction (AMI). This cohort study included 2,634 ho Show more
To determine whether lipoprotein(a) [Lp(a)] and cumulative Lp(a) (CumLp(a)) are associated with adverse outcomes in patients with acute myocardial infarction (AMI). This cohort study included 2,634 hospitalized patients diagnosed with AMI who underwent coronary angiography at Zhongda Hospital, Southeast University, from July 2013, to December 2021. The main outcome was major adverse cardiac and cerebrovascular events (MACCE), defined as cardiovascular (CV) death, non-fatal myocardial infarction, non-fatal stroke, or unplanned revascularization—occurring singly or in combination. We used Cox proportional hazards models, with subgroup and sensitivity analyses, restricted cubic spline (RCS) modeling, and threshold-effect assessment to evaluate the relationships between Lp(a), CumLp(a), and prognosis. Across a median 55.2-month follow-up, 907 participants (34.40%) experienced a MACCE, 342 (13.00%) patients had CV death, 177 (6.70%) patients had non-fatal MI, 202 (7.70%) patients had non-fatal stroke, 399 (15.10%) patients underwent unplanned revascularization, and all-cause death occurred in 547 (20.80%) patients. Multivariable Cox regression models demonstrated a significantly increased risk of MACCE, CV death, non-fatal MI, and non-fatal stroke in both the higher Lp(a) and higher CumLp(a) groups compared with the lower groups (HRs for Lp(a): 1.652, 2.157, 3.455, and 1.930; HRs for CumLp(a): 1.697, 1.675, 3.759, and 2.032), and every one-unit rise in CumLp(a), the risk of MACCE, CV death, non-fatal MI and non-fatal stroke increased by 1.3%, 1.4%, 1.9% and 1.2%, respectively. The majority of subgroup and sensitivity checks consistently supported a stable link between Lp(a)/CumLp(a) and the risks of MACCE, CV death, non-fatal MI, and stroke. Analyses using RCS and threshold models revealed that Log Higher levels of Lp(a) and CumLp(a) are linked to a greater risk of poor outcomes among patients with AMI as the index event, highlighting their potential value for risk stratification and guiding clinical decision-making. The online version contains supplementary material available at 10.1186/s12944-025-02800-6. Show less
Immune checkpoint inhibitors (ICIs) combined with antiangiogenic agents have become a standard strategy for advanced hepatocellular carcinoma (HCC). There remains an urgent need for effective biomarke Show more
Immune checkpoint inhibitors (ICIs) combined with antiangiogenic agents have become a standard strategy for advanced hepatocellular carcinoma (HCC). There remains an urgent need for effective biomarkers to guide treatment, with C-reactive protein and alpha-fetoprotein in immunotherapy (CRAFITY) scores and cytokine levels representing promising candidates. We aimed to assess the efficacy, safety, and potential biomarkers of anlotinib plus TQB2450 in patients with advanced HCC. This study was a single-arm, phase Ib trial. Twenty-five patients with advanced HCC were enrolled. Patients received an intravenous infusion of TQB2450 (1200 mg, on Day 1) and oral administration of anlotinib (initiated at 10 mg, once a day, from Day 1 to Day 14), which was repeated every 3 weeks. Blood was collected at baseline for serum cytokine analysis. After a median follow-up of 41.80 months, the median progression-free survival (mPFS) was 5.49 months, and the median overall survival (mOS) was 8.94 months. Treatment-related adverse events (TRAEs) occurred in 22 patients, with grade ⩾3 TRAEs observed in 12 patients. Patients who achieved clinical benefit (CB) had higher baseline serum brain-derived neurotrophic factor (BDNF) levels than non-CB patients (median, 227.97 vs 129.26 pg/ml, Anlotinib plus TQB2450 demonstrated promising efficacy with manageable safety in advanced HCC. Elevated serum BDNF levels might serve as a potential positive prognostic marker and, together with ECOG score, may help complement the CRAFITY score in identifying subgroups that could benefit from ICIs and antiangiogenic therapy. Show less
Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly individuals. Retinal pigment epithelium (RPE) ferroptosis is a significant pathogenetic component in AMD. T Show more
Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly individuals. Retinal pigment epithelium (RPE) ferroptosis is a significant pathogenetic component in AMD. This study aims to elucidate the role and mechanisms of fatty acid desaturase 1 (FADS1) in ferroptosis as well as AMD progression. An integrated bioinformatics analysis based on the array of data from the GEO database was conducted to identify candidates involved in ferroptosis during AMD. Subsequently, cellular and mouse models of AMD were developed using sodium iodate (NaIO FADS1 expression was upregulated in AMD patients and in vitro and in vivo models of AMD. Its pharmacological inhibition had decreased mitochondrial ROS formation, lipid peroxidation, and ferroptosis as well as increased RPE cell function in ARPE-19 cells and C57BL/6J mouse models of AMD. Mechanistically, Sp1 was identified as a key transcription factor of FADS1. Moreover, Sp1 inhibition downregulated FADS1 expression consequently attenuating FADS1-mediated ferroptosis as well as AMD phenotypes. For the first time, we demonstrated that Sp1 regulates FADS1-mediated ferroptosis in RPE cells. Our findings provide novel insights into the progression and treatment of AMD. Show less
Pericytes regulate cerebral blood flow (CBF) and excess amyloid in the brain. Pericyte dysfunction may contribute to the pathology of Alzheimer's disease (AD). Acorus tatarinowii (AT), a Chinese medic Show more
Pericytes regulate cerebral blood flow (CBF) and excess amyloid in the brain. Pericyte dysfunction may contribute to the pathology of Alzheimer's disease (AD). Acorus tatarinowii (AT), a Chinese medicine commonly used to treat AD, protects the central nervous system. However, whether AT can regulate pericyte function and ameliorate cognitive dysfunction remains unclear. We employed a novel target recognition assay, quantitative measurement of CBF, hematoxylin and eosin staining, immunofluorescence staining, and Western blot to investigate the role of AT in improving cognitive function in patients with AD. Additionally, we investigated the therapeutic potential of β-Asarone, the primary active compound in AT, for treating AD by modulating pericyte function using transmission electron microscopy, silver staining, electrical impedance, and other methodologies. The results revealed that administration of AT effectively alleviated the cognitive impairments induced by D-galactose in mice, as evidenced by enhanced CBF, improved histological characteristics of damaged brain tissue cells, increased expression of platelet-derived growth factor-β (PDGF-β), decreased Aβ accumulation via enhanced lipoprotein receptor-related protein 1 (LRP1), and reduced beta-site APP-cleaving enzyme 1 (BACE1). β-Asarone treatment mitigated ROS release and BACE1 expression while elevating the cell index in Aβ1-40 injured mouse brain vascular pericytes (MBVP). These findings suggest that AT has the potential to enhance CBF and mitigate pericellular dysfunction, thereby ameliorating Aβ deposition in the brain and improving cognitive impairment in patients with AD. Show less
Lipoproteins are essential for lipid transport in all bilaterians. A single Apolipoprotein B (ApoB) molecule is the inseparable structural scaffold of each ApoB-containing lipoprotein (B-lps), which a Show more
Lipoproteins are essential for lipid transport in all bilaterians. A single Apolipoprotein B (ApoB) molecule is the inseparable structural scaffold of each ApoB-containing lipoprotein (B-lps), which are responsible for transporting lipids to peripheral tissues. The cellular mechanisms that regulate ApoB and B-lp production, secretion, transport, and degradation remain to be fully defined. In humans, elevated levels of vascular B-lps play a causative role in cardiovascular disease. Previously, we have detailed that human B-lp biology is remarkably conserved in the zebrafish using an Show less
This study aimed to investigate the role of SIRT4 in retinal protection, specifically its ability to mitigate excitotoxic damage to Müller glial cells through the regulation of mitochondrial dynamics Show more
This study aimed to investigate the role of SIRT4 in retinal protection, specifically its ability to mitigate excitotoxic damage to Müller glial cells through the regulation of mitochondrial dynamics and glutamate transporters (GLASTs). A model of retinal excitatory neurotoxicity was established in mice. Proteins related to mitochondrial dynamics, GLAST, and SIRT4 were analyzed on days 0, 1, 3, and 5 following toxic injury. The influence of SIRT4 on mitochondrial dynamics-related proteins and GLAST was examined by inducing SIRT4 overexpression through intraperitoneal injection of resveratrol or by using SIRT4 knockout (KO) mice. Additionally, the effects of upregulating and downregulating SIRT4 expression in rat Müller glial cell lines (rMC-1) were explored via lentiviral vector transfection to assess changes in mitochondrial morphology and GLAST expression. After excitotoxic injury to the mouse retina, the retinal thickness and structure were disrupted, the number of retinal ganglion cells (RGCs) decreased, and Müller glial cells were activated by day 1. The levels of OPA1, GLAST, and SIRT4 proteins peaked on the first day after injury and then gradually decreased, indicating a synchronized dynamic trend. The upregulation of SIRT4 expression promoted OPA1 and GLAST protein expression, thereby alleviating retinal excitotoxic injury. Furthermore, the upregulation of SIRT4 expression promoted mitochondrial fusion and increased GLAST expression in rMC-1 cells, reducing cellular excitotoxic damage. Conversely, downregulation of SIRT4 had the opposite effect. SIRT4 plays a significant role in mitigating excitotoxic damage in the retina, modulating Müller glial cell injury by regulating mitochondrial dynamics and glutamate transporter expression, ultimately influencing retinal health. Show less
The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascu Show more
The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascular niche to maintain stemness. However, the effect of abnormal communication between endothelial cells (ECs) and GSCs on GBM progression remains unknown. Here, we reveal that ECs-derived SEMA3G, which is aberrantly expressed in GBM patients, impairs GSCs by inducing c-Myc degradation. SEMA3G activates NRP2/PLXNA1 in a paracrine manner, subsequently inducing the inactivation of Cdc42 and dissociation of Cdc42 and WWP2 in GSCs. Once released, WWP2 interacts with c-Myc and mediates c-Myc degradation via ubiquitination. Genetic deletion of Sema3G in ECs accelerates GBM growth, whereas SEMA3G overexpression or recombinant SEMA3G protein prolongs the survival of GBM bearing mice. These findings illustrate that ECs play an intrinsic inhibitory role in GSCs stemness via the SMEA3G-c-Myc distal regulation paradigm. Targeting SEMA3G signaling may have promising therapeutic benefits for GBM patients. Show less