Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models Show more
Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types-spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins-using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimer's disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience. Show less
Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by whi Show more
Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by which these dual agonists affect systemic metabolism remain elusive. To investigate the effects of a novel dual-receptor agonist, THDBH120, on systemic metabolism in obese individuals and the specific roles of GIPR and GLP-1R in modulating systemic and adipose tissue metabolism. To evaluate the intrinsic properties of THDBH120, we conducted a potency assay by using HEK293 cell lines overexpressing either human GIPR or GLP-1R and measured the accumulation of cAMP as a downstream second messenger following receptor activation. To evaluate the efficacy of THDBH120 on systemic metabolism, we used obese rodents and nonhuman primate species that received various doses and frequencies of THDBH120. To determine the metabolic roles of GLP-1R and GIPR in mediating the beneficial effects of THDBH120, we used GLP-1R- and GIPR-knockout mouse models treated with THDBH120, the GLP-1R agonist semaglutide, or the GIPR agonist LAGIPRA and performed transcriptomic sequencing analyses of adipose tissues. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has superior weight loss and metabolic improvement effects in rodents and mammals. The activation of GLP-1R by semaglutide or THDBH120 improved lipid metabolism, whereas the activation of GIPR by LAGIPRA or THDBH120 alleviated inflammation. THDBH120 improved lipid metabolism via GLP-1R-mediated pathways and mitigated inflammation by activating GIPR-associated pathways in the adipose tissues of obese mice. Both GLP-1R and GIPR are important in mediating the beneficial effects of dual receptors on systemic metabolism. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has potential clinical applications. Show less
Atherosclerotic cardiovascular disease remains the leading cause of global mortality, with hypercholesterolemia serving as a critical driver of atherogenesis. Although current lipid-lowering therapies Show more
Atherosclerotic cardiovascular disease remains the leading cause of global mortality, with hypercholesterolemia serving as a critical driver of atherogenesis. Although current lipid-lowering therapies substantially improve circulating lipid profiles, strategies that provide more durable, safe, and efficient control of lipid metabolism are still needed. Epigenome editing offers a promising approach for long-lasting repression of disease-modifying genes without altering the underlying DNA sequence. Here, we develop CRISPRoff platforms delivered by adeno-associated virus or lipid nanoparticle to epigenetically silence hepatic Hmgcr or Pcsk9 in vivo. In both C57BL/6J wild-type and ApoE Show less
Precise identification of vulnerable plaque (VAP) is essential for the prevention of acute cardiovascular diseases, yet current molecular probes are hampered by poor VAP lesion penetration and high ba Show more
Precise identification of vulnerable plaque (VAP) is essential for the prevention of acute cardiovascular diseases, yet current molecular probes are hampered by poor VAP lesion penetration and high background. Here, the innate tropism of circulating inflammatory monocytes for VAP, and their differentiation-driven expression of legumain (Lgmn) in response to the VAP microenvironment is exploited. A monocyte differentiation-activated fluorescent (MDAF) probe is conceived that hitchhikes monocytes to precisely migrate to VAP and is activated by Lgmn during monocyte differentiation. This activation triggers in situ self-assembly, resulting in spatiotemporally controlled aggregation-induced emission (AIE) fluorescence signals, and turning the monocyte itself into an on-site "scout" that reports plaque instability. In Apoe Show less
Glioma presents significant therapeutic challenges due to its marked heterogeneity and resistance to conventional treatments. Apolipoprotein E (APOE), a glycoprotein involved in lipid metabolism, has Show more
Glioma presents significant therapeutic challenges due to its marked heterogeneity and resistance to conventional treatments. Apolipoprotein E (APOE), a glycoprotein involved in lipid metabolism, has been reported to be dysregulated in glioma; however, its functional role in glioma progression remains poorly understood. APOE expression in glioma was analyzed using publicly available transcriptomic datasets from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA). Functional studies were performed in U251MG and U87MG glioma cells with APOE overexpression or knockout. Cell proliferation, migration, and invasion were evaluated using CCK-8, Edu, Transwell, and wound-healing assay. Mechanistic analyses included RNA sequencing, immunofluorescence, nucleocytoplasmic fractionation, Western blotting and immunoprecipitation. A nude mouse xenograft model was used to assess tumor growth in vivo. APOE expression was elevated in glioma datasets. Functional assays demonstrated that APOE promotes glioma cell proliferation, migration, and invasion. Notably, APOE was detected in the nucleus, where it exhibited transcriptional regulatory activity. Mechanistically, APOE overexpression significantly activated the PI3K/AKT signaling pathway, and this effect was effectively reversed by the PI3K inhibitor LY294002. Consistently, APOE overexpression enhanced tumor growth in vivo. These findings indicate that APOE promotes glioma progression through nuclear activity and activation of the PI3K/AKT signaling pathway, highlighting APOE-related signaling as a potential therapeutic target in glioma. Show less
Early pregnancy loss (EPL), a spontaneous death of the embryo or foetus occurring within the first trimester, is a major challenge for human reproduction with profound adverse consequences for women's Show more
Early pregnancy loss (EPL), a spontaneous death of the embryo or foetus occurring within the first trimester, is a major challenge for human reproduction with profound adverse consequences for women's health. Currently, reliable blood-based biomarkers for EPL remain limited. Therefore, there is an urgent need to discover novel biomarkers for EPL using a multi-omics-based approach to facilitate early detection and timely management. In the discovery cohort, 40 patients with EPL and 40 healthy pregnancies (HP) at 7-13 weeks of gestation were enrolled. Serum proteins and metabolites were assayed by Olink® technology and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS), respectively. Biomarkers were defined by false discovery rate (FDR) < 0.05 and fold change (FC) > 1.2. Random forest (RF) and logistic regression (LR) models incorporating selected biomarkers were employed to develop diagnostic models for EPL. In the external validation cohort, we prospectively enrolled 142 pregnancies at 7-10 gestational weeks, including 47 subjects who subsequently developed EPL and 95 pregnancies with full-term birth. Serum levels of selected biomarkers were quantified by ELISA. The combined proteomics and metabolomics screening identified 26 proteins and 21 metabolites significantly changed in the EPL group and tightly associated with EPL-related clinical phenotypes, with functional enrichment in immunoregulation and lipid oxidation processes. Moreover, integrating serum levels of angiopoietin-like 4 (ANGPTL4), programmed death-ligand 1 (PD-L1), neutrophil%, and lymphocyte% achieved an AUC of 0.944 (95% CI: 0.835-1.000) in the random forest model and 0.954 (95% CI: 0.875-1.000) in the logistic regression model to discriminate EPL from HP. Importantly, this four-biomarker model achieved an AUC of 0.857 (95% CI: 0.747-0.968) in the random survival forest model and a C-index of 0.804 (95% CI: 0.685-0.973) in the validation cohort for EPL prediction. Our integrative omics study reveals a panel of potential circulating biomarkers for EPL, which further offer mechanistic insights into EPL pathogenesis, including impaired maternal immune tolerance and dysregulated lipid metabolism pathways. Moreover, the newly identified biomarkers exhibit promising diagnostic and predictive performance for EPL, underscoring its clinical translational value for human reproduction and maternal-foetal health. This study was supported by Research Grants Council (RGC) Germany/Hong Kong Joint Research Scheme (G-CUHK415/25), 1+1+1 CUHK-CUHK(SZ)-GDST Joint Collaboration Fund (2025A0505000077), CUHK HOPE BWCH Collaborative Medical Research Fund (CF2025002), Shenzhen Medical Research Fund (C2501040), and Shenzhen Science and Technology Program (RCYX20210609104608036). Show less
Diabetic foot ulcers (DFU) are a severe complication of diabetes. Although dysregulated M2 macrophage polarization is recognized as a key driver of chronic inflammation in DFU, the molecular checkpoin Show more
Diabetic foot ulcers (DFU) are a severe complication of diabetes. Although dysregulated M2 macrophage polarization is recognized as a key driver of chronic inflammation in DFU, the molecular checkpoints that can be therapeutically targeted to restore M2 bias remain poorly defined. Here, we aimed to determine whether the RNA-binding protein TAF15 acts as a post-transcriptional stabilizer of the M2-promoting CEBPB/APOE/PTX3 axis, thereby accelerating DFU healing. First, we confirmed that APOE positively regulates PTX3, which supports M2 polarization and the proliferation and migration of HDF. CEBPB transcriptionally activated APOE and promoted M2 macrophage polarization. TAF15 stabilized CEBPB mRNA and affected HDF cell proliferation and migration by promoting M2 macrophage polarization. Additionally, TAF15 overexpression partially counteracted the disruption of M2 macrophage polarization caused by APOE silencing and facilitated DFU wound healing. Collectively, our findings establish TAF15-driven stabilization of CEBPB mRNA as a target point that sequentially activates APOE/PTX3 signaling to enforce M2 polarization and accelerate DFU closure. This study provides a preclinical rationale for the development of TAF15-targeted oligonucleotides or small-molecule strategies to reprogram wound macrophages and improve DFU outcomes in patients with diabetes. Show less
Atherosclerosis is a chronic and progressive inflammatory disease that can lead to adverse cardiovascular and cerebrovascular events. Phenotypic switching of vascular smooth muscle cells (VSMCs) plays Show more
Atherosclerosis is a chronic and progressive inflammatory disease that can lead to adverse cardiovascular and cerebrovascular events. Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a pivotal role in its development and progression, but the upstream regulatory mechanisms remain incompletely defined. Here, we identify ubiquitin-fold modifier 1 (UFM1), a ubiquitin-like protein, as a critical regulator of VSMCs plasticity and atherogenesis. In VSMCs stimulated with oxidized low-density lipoprotein (ox-LDL), UFM1 overexpression markedly attenuated phenotypic switching, restoring contractile features and suppressing synthetic activation, accompanied by reduced proliferation and migration. In contrast, UFM1 knockdown further exacerbated these phenotypic alterations. In ApoE Show less
CTNNB1-mutated hepatocellular carcinomas are characterized by a distinctive morphology and activation of the Wnt pathway. AXIN1 also plays a key role in the Wnt pathway, but the morphology of AXIN1-mu Show more
CTNNB1-mutated hepatocellular carcinomas are characterized by a distinctive morphology and activation of the Wnt pathway. AXIN1 also plays a key role in the Wnt pathway, but the morphology of AXIN1-mutated tumors has not been examined. In addition, there are ongoing questions on the ability of AXIN1 mutations to activate the Wnt pathway in hepatocellular carcinoma. AXIN1 mutated tumors (N=18) were studied, along with control groups: CTNNB1 (N=17), APC (6), or "Other" genes in the Wnt pathway (5). Wnt pathway activation was studied by immunostains for beta-catenin and glutamine synthetase. Findings were supplemented by gene expression analysis using TCGA data. On histologic examination, the classic morphology associated with beta-catenin mutations was found in all 4 groups: 8/18 AXIN1 (44%), 10/17 CTNNB1 (59%), 4/6 APC (67%), and 1/5 Other (20%). By immunohistochemistry, Wnt pathway activation was found in 11/18 AXIN1 (61%), 15/17 CTTNB1 (88%), 6/6 APC (100%), and 5/5 (100%) of Other. In AXIN1-mutated tumors, the Wnt pathway was weakly activated. Glutamine synthetase stains also highlighted a new "progressed pattern" associated with distinct subnodules of staining. Tertiary lymphoid structures were uncommon except for cases with CTTNNB1 mutations plus additional mutations in the Wnt pathway. In summary, the classic morphology associated with CTNNB1 mutations is found in hepatocellular carcinomas with mutations in AXIN1, APC, and other Wnt genes. AXIN1 mutated tumors have Wnt activation that is detectable but at lower levels than CTNNB1 mutated tumors. As tumors progress, their level of Wnt activation can change. 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
Corneal transparency maintenance relies on the water-pumping function of the corneal endothelium. Currently, corneal transplantation remains the only available treatment for corneal endothelial dysfun Show more
Corneal transparency maintenance relies on the water-pumping function of the corneal endothelium. Currently, corneal transplantation remains the only available treatment for corneal endothelial dysfunction, therefore, the development of alternative therapies is critical due to the global shortage of donor corneas. In our previous study, we confirmed that corneal stromal cells (CSCs) secretion can promote corneal endothelial cells (CEnCs) proliferation. This effect can be enhanced by treatment with lysophosphatidic acid (LPA), a bioactive phospholipid. Nevertheless, the components involved in CSC secretion remain to be elucidated. In this study, we investigated the therapeutic potential of CSC-derived exosomes and exosomal microRNAs (miRNAs) for enhancing CEnCs proliferation and corneal endothelial healing. CSC exosomes were characterized via nanoparticle tracking (NTA), transmission electron microscopy (TEM), and immunoassays. The miRNA expression profiles of CSC exosomes were identified via RNA sequencing, revealing a total of 767 distinct miRNAs. The proliferative effects of CSC exosomes and exosomal miR-221-3p were increased by LPA. Ectopic expression of miR-221-3p further increased CEnC proliferation and suppressed the expression of the CDK inhibitor p27 Show less
Gallbladder adenosquamous carcinoma (GBASC) is an uncommon, highly aggressive neoplasm characterized by the coexistence of both glandular and squamous cells. Representing fewer than 5% of gallbladder Show more
Gallbladder adenosquamous carcinoma (GBASC) is an uncommon, highly aggressive neoplasm characterized by the coexistence of both glandular and squamous cells. Representing fewer than 5% of gallbladder malignancies, GBASC demonstrates a more aggressive behavior and has poorer prognosis, posing considerable challenges for early diagnosis and effective management. We present a case of GBASC in a 52-year-old woman who achieved long-term tumor-free survival by surgery, as well as targeted and immunotherapy after the operation. Targeted gene sequencing and bioinformatics analysis tools, including STRING, GeneMANIA, Metascape, TRRUST, Sangerbox, and cBioPortal, were used to analyze the biological functions and features of the mutated genes in GBASC. A total of 16 mutations ( Comparative analyses with other gallbladder carcinoma subtypes revealed GBASC to have distinct clinical phenotypes, molecular alterations, functional characteristics, and enriched signaling pathways. Moreover, there is an urgent need for standardized treatment protocols. Show less
Portulaca oleracea L. (purslane) is a widely cultivated herb with edible and medicinal value. Modern pharmacological studies have shown that purslane has potent anti-inflammatory effects. However, its Show more
Portulaca oleracea L. (purslane) is a widely cultivated herb with edible and medicinal value. Modern pharmacological studies have shown that purslane has potent anti-inflammatory effects. However, its potential role in ameliorating atherosclerosis remains unclear. This study aimed to investigate the efficacy of purslane extract in ameliorating atherosclerosis in apolipoprotein E(ApoE) knock-out (ApoE Show less
The neurotrophic factor (NTF) family has recently expanded its role beyond neurological conditions, but its involvement in acute inflammatory lung diseases remains largely unclear. Using well-establis Show more
The neurotrophic factor (NTF) family has recently expanded its role beyond neurological conditions, but its involvement in acute inflammatory lung diseases remains largely unclear. Using well-established acute lung injury (ALI) and sepsis models, we demonstrate that brain-derived neurotrophic factor (BDNF), a key NTF, is impaired in pulmonary epithelial cells and negatively correlates with the inflammatory response. Raising the BDNF level alleviates inflammatory lung injury, but these effects are absent in macrophage-deleted mice. Both in vivo and in vitro results show BDNF inhibits macrophage inflammation, and further proteomics analysis identifies macrophage TLR4 as a receptor that BDNF antagonizes via direct binding. The BDNF fragment (aa 104-115) is critical for BDNF-TLR4 interaction, and the corresponding synthetic BDNF-derived dodecapeptide (BDP-12) retains TLR4-antagonistic and anti-inflammatory effects both in vitro and in vivo, without pro-proliferative side effects. In conclusion, our findings reveal that epithelial-derived BDNF prevents macrophage inflammation by directly targeting TLR4 and highlights BDP-12 as a potential therapeutic agent for acute inflammatory diseases. Show less
Hemodialysis, as one of the main alternative treatment methods for end-stage renal disease, has received much attention in recent years. Due to the particularity of hemodialysis treatment, patients ha Show more
Hemodialysis, as one of the main alternative treatment methods for end-stage renal disease, has received much attention in recent years. Due to the particularity of hemodialysis treatment, patients have a relatively high risk of infection during the treatment process. Hemodialysis nurses, who are the main executors of the treatment operations and have the most contact with patients, have a close relationship with the infection risk of patients. The level of their hospital infection prevention and control literacy is closely related to the infection risk of patients. To explore the current level of knowledge, attitudes, and practices (KAP) of hospital infection prevention and control among haemodialysis nurses in the Sichuan Province, China, and identified their potential categories. This provided evidence-based recommendations for improving infection control management in hemodialysis departments. A cross-sectional study was conducted From July 15 to August 15, 2025 using a convenience sampling method to survey 470 hemodialysis nurses from 78 hospitals in Sichuan Province. Participants were licensed nurses with over 3 months of hemodialysis experience. Data were collected using the A total of 460 valid questionnaires were collected, with an effective response rate of 97.87%. The average scores for knowledge, attitudes, and practices related to hospital infection prevention and control among haemodialysis nurses were 4.67 ± 0.43, 4.59 ± 0.43, and 4.74 ± 0.34, respectively. Three latent profile models were constructed, with the two-class model identified as the optimal solution, which were defined as the "Low KAP Group" (25.9%) and "High KAP Group" (74.1%). Logistic regression analysis revealed that sex, responsibility for infection control, hospital level, annual number of infection control training sessions, organizational support, and work engagement were significant influencing factors ( The KAP level of haemodialysis nurses in hospital infection prevention and control was relatively high. Hospital managers should tailor supportive work environments on the basis of the individual characteristics and work engagement of haemodialysis nurses to improve the KAP level of nosocomial infection prevention and control among haemodialysis nurses. Show less
Neuropathic pain (NP) is a debilitating condition with limited treatment options. The ethanolic extract of Bauhinia brachycarpa Benth (EEBb) has demonstrated antinociceptive effects in NP, but its act Show more
Neuropathic pain (NP) is a debilitating condition with limited treatment options. The ethanolic extract of Bauhinia brachycarpa Benth (EEBb) has demonstrated antinociceptive effects in NP, but its active components and underlying mechanisms of action remain largely unexplored. Bauhinia brachycarpa Benth (BBB), an ethnic medicine in China, has antinociceptive effect on neuropathic pain (NP). In this study, an effective portion from BBB was screened and its antinociceptive mechanism was investigated. After the preparation of ethanolic extract from BBB (EEBb) and different soluble portion from EEBb (peEEBb, eaEEBb, nbEEBb), the total content of flavonoids and phenolic acids were measured. A partial sciatic nerve ligation (PSNL) model in vivo was applied to evaluate the antinociceptive effect and the influence on microglia function of these samples. The possible acting target of BBB was predicted by network pharmacology. And the mechanism of nbEEBb, the most effective antinociceptive portion, were studied by PSNL model in vivo and ATP-induced activation of BV2 model in vitro. nbEEBb had the strongest ability of alleviating NP as well as the obvious effect on microglia polarization. The action of nbEEBb was positively correlated to the total content of flavonoids or phenolic acids. nbEEBb inhibited the protein and gene expressions of most key components in P2X4-BDNF-TrkB signaling pathway. nbEEBb is the most effective portion from BBB on NP, and its mechanism refers to the inhibition of P2X4-BDNF-TrkB signaling pathway, which involved in neuron-microglia interaction. Show less
Fusion genes are pivotal drivers of tumorigenesis, often generating oncogenic chimeric RNAs and fusion circular RNAs. However, the mechanisms by which these transcripts synergistically contribute to c Show more
Fusion genes are pivotal drivers of tumorigenesis, often generating oncogenic chimeric RNAs and fusion circular RNAs. However, the mechanisms by which these transcripts synergistically contribute to cancer progression remain poorly understood. Here, we identified a lung cancer-specific chimeric RNA KANSL1-ARL17A (chKANSARL) and its circular variant fusion circular RNA KANSL1-ARL17 A (F-circKA), both derived from the fusion gene KANSARL. Functional assays revealed that overexpression of either chKANSARL or F-circKA significantly enhanced lung cancer cell proliferation, migration, and invasion, while their knockdown suppressed these malignant phenotypes. In vivo experiments demonstrated that chKANSARL overexpression accelerated tumor growth in immunodeficient mice. Notably, coexpression experiments uncovered a synergistic regulatory interaction between F-circKA and chKANSARL, amplifying oncogenic effects. Mechanistically, miRNA sequencing and dual-luciferase assays revealed that F-circKA acts as a molecular sponge for miR-6860, thereby derepressing chKANSARL expression. Rescue experiments further validated this regulatory axis, wherein miR-6860 inhibition reversed the tumor-suppressive effects of F-circKA knockdown. Collectively, our study identifies and characterizes a novel F-circKA/miR-6860/chKANSARL regulatory axis, revealing how dual transcriptional outputs from the KANSARL fusion gene can synergistically drive lung cancer progression. These findings highlight a previously unrecognized layer of cooperative regulation between linear and circular fusion RNAs in oncogenesis and provide a new framework for understanding fusion gene-mediated tumorigenesis. Show less
Hepatocellular carcinoma (HCC) exhibits high recurrence rates and limited therapeutic options. Endothelial cell-specific molecule 1 (ESM1) and angiopoietin-like 4 (ANGPTL4) are implicated in tumor pro Show more
Hepatocellular carcinoma (HCC) exhibits high recurrence rates and limited therapeutic options. Endothelial cell-specific molecule 1 (ESM1) and angiopoietin-like 4 (ANGPTL4) are implicated in tumor progression, yet their synergistic role in HCC lipid metabolism and angiogenesis remains unexplored. We integrated multi-omics approaches, including RNA sequencing, metabolomics, and immunoprecipitation-mass spectrometry, in HCC cell lines and patient-derived xenograft models. Key experiments involved Co-IP, Western blotting, tube formation assays, and clinical tissue microarray analysis to validate the ESM1-ANGPTL4-FASN-trioleate axis. ESM1 and ANGPTL4 formed a positive feedback loop, stabilizing fatty acid synthase (FASN) to promote trioleate synthesis. Trioleate activated the NF-κB/IL-17 pathway in HCC cells and upregulated CD99 in endothelial cells, driving angiogenesis. In vivo, ESM1/ANGPTL4 knockdown suppressed tumor growth, which was rescued by trioleate supplementation. Clinical data revealed elevated ESM1/ANGPTL4 expression in bevacizumab-resistant HCC, correlating with poor prognosis. The ESM1-ANGPTL4-FASN-trioleate axis orchestrates metabolic reprogramming and endothelial activation, representing a promising therapeutic target. Future studies should explore combination therapies targeting this axis and overcoming bevacizumab resistance in HCC. Show less
Given the heterogeneous nature of Alzheimer's disease (AD) and its higher prevalence in females, it is crucial to understand sex-related differences in AD presentation and changes in the brain. This s Show more
Given the heterogeneous nature of Alzheimer's disease (AD) and its higher prevalence in females, it is crucial to understand sex-related differences in AD presentation and changes in the brain. This systematic review investigates sex differences in AD and summarizes key findings from neuroimaging studies over the past two decades to examine how genetics, hormones, and lifestyle factors influence neuroimaging biomarkers and their correlation with cognitive decline and AD progression. A comprehensive literature search was conducted across several databases for human studies from 2004 to 2024 related to AD, biological sex differences, and neuroimaging. After a 3-step review process, the final extraction included 120 peer-reviewed studies using various neuroimaging modalities, such as MRI, amyloid-beta PET, tau-PET, and fluorodeoxyglucose (FDG) PET, to investigate sex as a biological predictor variable in adults with or at risk for AD. Over 90% of the reviewed studies identified clear sex-specific patterns of imaging biomarkers related to cognitive reserve, hormonal changes, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle factors. Machine learning studies increasingly incorporate sex as a key variable, revealing sex-specific biomarkers and improving model performance in predicting disease status and progression. Considering biological sex in AD research is essential for improving diagnostic accuracy, tailoring interventions, and health outcomes. This systematic review identifies sex-specific patterns in neuroimaging biomarkers of AD, influenced by cognitive reserve, hormones, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle. Recognizing these differences is crucial for understanding, diagnosis, and treatment efficacy. Show less
Occupational stress in nursing is a critical issue that can have significant implications for both workforce stability and personal health. This study aimed to identify subgroups of occupational stres Show more
Occupational stress in nursing is a critical issue that can have significant implications for both workforce stability and personal health. This study aimed to identify subgroups of occupational stress among Chinese female clinical nurses using latent profile analysis, compare sociodemographic differences across these subgroups, and examine their associations with premenstrual syndrome (PMS). A cross-sectional study was conducted among female nurses in tertiary hospitals in Huai'an City, Jiangsu Province, China, from November to December 2023. We recruited participants via convenience sampling, and 400 valid questionnaires were collected. Data were collected using a researcher-developed general information questionnaire, the standardized Chinese Nurses Stressor Scale (35 items), and the Premenstrual Syndrome Scale. Latent profile analysis (LPA) was performed with Mplus 8.0 to identify occupational stress subtypes. Sociodemographic predictors of these subtypes were explored using chi-square tests and multivariate logistic regression in SPSS 25.0. The association between stress subtypes and PMS symptoms was assessed using ANOVA. A Three clinical female nurse occupational stress subtypes were identified: overall low-stress (38.3%, This study identified significant heterogeneity in occupational stress among clinical female nurses, categorized into three distinct subtypes differing in stress levels and demographic characteristics. These findings highlight the importance of considering individual differences when developing interventions to address occupational stress. The study advocates for the implementation of intervention strategies targeting different types of stress in nursing education and organizational reform to better support nurses in fulfilling their responsibilities. Show less
Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the ef Show more
Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the effects of Orientin on oxidized low-density lipoprotein and high glucose (ox-LDL/HG)-triggered endothelial cell injury and diabetes-accelerated atherosclerosis remain unclear. ApoE Show less
This study was conducted to investigate the clinical and genetic characteristics of a family affected by hereditary spherocytosis (HS) combined with familial chylomicronemia syndrome (FCS), identify t Show more
This study was conducted to investigate the clinical and genetic characteristics of a family affected by hereditary spherocytosis (HS) combined with familial chylomicronemia syndrome (FCS), identify the pathogenic cause, and provide a basis for the clinical diagnosis, treatment, and genetic counseling of affected children. Clinical data were collected from family members. High-throughput sequencing was performed to identify pathogenic variants in genes associated with HS and FCS in the proband. Suspected pathogenic mutations were confirmed in family members via PCR-Sanger sequencing. Bioinformatics analysis and three-dimensional protein structure prediction were also conducted. The proband presented with severe anemia, splenomegaly, and jaundice. Genetic testing revealed a heterozygous mutation, c.6005G>A (p.Trp2002*), in the spectrin beta chain ( The heterozygous mutations Show less
Atherosclerosis (AS) is the main pathological basis of atherosclerosis-related cardiovascular and cerebrovascular diseases. The phenotypic conversion and death mechanisms of vascular smooth muscle cel Show more
Atherosclerosis (AS) is the main pathological basis of atherosclerosis-related cardiovascular and cerebrovascular diseases. The phenotypic conversion and death mechanisms of vascular smooth muscle cells (VSMCs) are crucial during its development. This study reveals the molecular mechanisms of the C1qbp-DLAT axis and the U2AF2 (U2 Small Nuclear RNA Auxiliary Factor 2)-NEAT1 network in regulating cuproptosis in AS. In this study, an ApoE The study revealed elevated copper ion levels and dysregulated cuproptosis-related genes in an AS model. U2AF2 stabilized C1qbp mRNA, enhancing C1qbp protein expression, which promoted DLAT oligomerization to regulate cuproptosis. LncRNA NEAT1 facilitated this process by scaffolding U2AF2-C1qbp mRNA interaction. Targeted inhibition of U2AF2 significantly improved AS pathological characteristics, reduced lipid deposition, collagen deposition and macrophage infiltration within the plaque, increased smooth muscle cell content and lowered serum levels of total cholesterol (TC), total triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C). This study revealed the role of the U2AF2-C1qbp-copper death regulatory axis in the development of AS, providing new targets and a theoretical basis for the treatment of AS. Targeted inhibition of U2AF2 may become an effective strategy to delay progression of AS. Show less
Hailun Yao, Yao Zhang, Lizhong Lin+4 more · 2026 · Phytomedicine : international journal of phytotherapy and phytopharmacology · Elsevier · added 2026-04-24
Atherosclerosis (AS) is a chronic inflammatory disease that constitutes the primary pathological basis of cardiovascular disorders. Although the natural isoflavone C-glycoside puerarin (PU) has demons Show more
Atherosclerosis (AS) is a chronic inflammatory disease that constitutes the primary pathological basis of cardiovascular disorders. Although the natural isoflavone C-glycoside puerarin (PU) has demonstrated promising anti-atherosclerotic effects, its underlying molecular mechanisms remain incompletely elucidated. In this study, we aimed to systematically characterize the pharmacological actions and mechanistic basis of PU in AS by integrating network pharmacology analyses with experimental validation. Potential targets of PU were identified by integrating network pharmacology databases and intersecting them with AS-related genes. Protein-protein interaction analysis, functional enrichment, and machine-learning-based screening were subsequently performed to identify key regulatory targets. Molecular docking and molecular dynamics simulations were then conducted to evaluate the feasibility and stability of PU-target interactions. In addition, single-cell transcriptomic and immune infiltration analyses were used to determine the cellular localization and inflammatory relevance of the core targets. Finally, a high-fat diet (HFD)-induced ApoE This integrative analysis identified 56 potential PU-AS-related targets, among which TNF, NFKBIA, STAT3, SRC, and PTGS2 emerged as central hub genes. Notably, TNF was consistently highlighted as a key regulatory target across differential expression analysis, molecular docking, and molecular dynamics simulations. Single-cell transcriptomic and immune infiltration analyses further revealed that TNF was predominantly expressed in macrophages and related immune cell subsets. Experimental validation demonstrated that PU treatment significantly attenuated inflammatory responses, reduced aortic plaque burden, enhanced plaque stability, and suppressed macrophage infiltration in HFD-induced ApoE PU ameliorates atherogenesis by suppressing TNF-NF-κB-mediated inflammatory responses. These findings identify the TNF-NF-κB axis as a key mechanistic pathway underlying the anti-atherosclerotic effects of PU and support its potential as a natural product-based therapeutic strategy for cardiovascular disease. Show less
The clinical interpretation of Alzheimer's disease (AD) is frequently complicated by the prevalence of missense variants designated as being of uncertain significance within associated genes. Conventi Show more
The clinical interpretation of Alzheimer's disease (AD) is frequently complicated by the prevalence of missense variants designated as being of uncertain significance within associated genes. Conventional computational prediction tools often overlook disease-specific pathophysiological contexts and lack pertinence and interpretability. Therefore, the present study aimed to develop a novel, interpretable framework for predicting the pathogenicity of AD missense variants by integrating transcriptomic and proteomic data enrichment patterns with machine learning methods. A cross-sectional variant-level analysis was performed using publicly available databases. Missense variants in APOE, APP, PSEN1, PSEN2, SORL1, and TREM2 reported in AD patients were retrieved from Alzforum and compared with missense variants from individuals without neurological diseases, as cataloged in the gnomAD v2.1.1 non-neuro subset. Variants were annotated with tissue-specific expression, secondary structure, relative solvent accessibility, and other functional features using tools like AlphaFold. Enrichment of specific features was assessed with Fisher's exact tests with Bonferroni correction for multiple comparisons. Given that PSEN1 showed the strongest enrichment signals, six machine-learning algorithms were trained on PSEN1 variants to distinguish AD-associated variants from gnomAD variants, using a 10 × 5 nested cross-validation scheme. External validation was conducted using PSEN1 missense variants from ClinVar annotated as pathogenic/likely pathogenic or benign/likely benign. Model performance was compared with SIFT and PolyPhen-2, and interpretability was evaluated by feature ablation and SHapley Additive exPlanations analyses. AD-associated variants exhibited statistically significant enrichment within some transcriptomic or proteomic features, with PSEN1 contributing significantly to the enrichment observed across these features. Random forest and gradient boosting models achieved high performance in the internal training dataset and maintained high recall in the external validation dataset, outperforming SIFT and approaching the performance of PolyPhen-2. Relative solvent accessibility was the most discriminative individual feature, while regional and topological features provided complementary discriminative power. This integrative, multi-omics framework links disease-specific enrichment patterns with interpretable gene-level machine learning for AD missense variants. The results highlight the importance of expression level, structural context, etc. for PSEN1 variant pathogenicity and may help prioritize variants for functional studies. Further validation in additional genes and independent cohorts is warranted prior to any clinical application. Show less
Distressing dreams were previously reported to predict future all-cause dementia among predominantly white US participants aged 79-89 years, particularly in men. We investigated whether disturbing dre Show more
Distressing dreams were previously reported to predict future all-cause dementia among predominantly white US participants aged 79-89 years, particularly in men. We investigated whether disturbing dreams (nightmares and bad dreams) were associated with all-cause and Alzheimer dementia (AD) among individuals aged 60-89 years from diverse international regions. Data were from six longitudinal cohort studies across Brazil, China, France, Italy, South Korea, and Taiwan (n = 10,238, 42.5% men). Cox regressions with a random effect for study investigated associations between disturbing dreams and incident dementia, with all participants and stratified separately by sex and baseline age. Analyses examined (i) any disturbing dreams and (ii) disturbing dreams at least once a week. Fully adjusted analyses included three studies with covariates for sleep problems, medications, mental and physical health, cognition, and APOE ε4 status. Disturbing dreams were reported by 24.2% overall and all-cause dementia, and AD incidence was 10.8 and 5.3 per 1000 person-years, respectively. In fully adjusted analyses, having any disturbing dreams was associated with increased incidence of all-cause dementia among 60-69-year-olds (hazard ratio [HR] 3.93, 95% confidence interval [CI] 1.32-11.67). There were no significant effects for older individuals. In fully adjusted sex-stratified analyses, having disturbing dreams at least once a week was associated with AD only among men (HR 3.59, 95% CI 1.44-8.96). We found some evidence for disturbing dreams being associated with incident all-cause dementia among individuals aged 60-69 years and with AD among men. The mechanisms potentially underlying these associations remain to be clarified. Show less
Gary Chen, Adrienne Sexton · 2026 · Patient education and counseling · Elsevier · added 2026-04-24
This scoping review aims to map the experiences and outcomes of patients and their families undergoing genetic testing and counseling regarding dementia to inform future research directions and clinic Show more
This scoping review aims to map the experiences and outcomes of patients and their families undergoing genetic testing and counseling regarding dementia to inform future research directions and clinical practice. Rigorous scoping review methodology was followed. Ovid Medline, Embase, PsycINFO, and CINAHL were searched with keywords and MeSH terms related to "genetic testing", "genetic counseling", "dementia", "decision making", and "patient outcomes" for peer-reviewed studies with adult participants published over the last ten years. Thirty-six articles met inclusion criteria. Narrative synthesis organized findings into temporal categories including motivations for genetic testing, experiences during the testing/counseling process, and outcomes after testing. Common motivators included reducing uncertainty, reproductive planning, life planning, and the prospect of a treatment becoming available in the future. A lack of current treatments and fear that knowledge of genetic risk would be difficult to cope with were common barriers to testing. Patient-centered communication improved satisfaction. Genetic testing was generally psychologically well tolerated, and a wide range of practical responses were reported including changes to lifestyle, diet, advanced care and financial planning, and engaging in clinical trials. This review maps the experiences and outcomes of genetic testing or counseling for people with or at potentially increased genetic risk of dementia. Genetic testing and counseling for directly causal dementia genes and APOE genotype appears well tolerated but long-term outcome data is lacking. Motivations, concerns and perceived benefits of knowing genetic results vary depending on personal, familial and cultural viewpoints. Genetic counseling can help patients and families prepare, reduce decisional regret, and adapt to results. Motivations varied, and a patient-centered approach addressing both information and psychological aspects improves satisfaction. Future longitudinal research should ascertain ways to support individuals from a wide range of demographics with understanding and adjusting to genetic risk information regarding dementia. Show less
Keratoconus (KC) is a progressive disorder of corneal thinning characterized by responses in the extracellular matrix and cellular interactions. This study used bioinformatics methods to identify key Show more
Keratoconus (KC) is a progressive disorder of corneal thinning characterized by responses in the extracellular matrix and cellular interactions. This study used bioinformatics methods to identify key genes involved in KC development and in anoikis and endoplasmic reticulum (ER) stress. KC and control datasets from the GEO database were analyzed to identify differentially expressed genes (DEGs). These were cross-referenced with anoikis and ER stress-related genes from Genecards. Functional enrichment, immune infiltration analysis, and machine learning techniques (LASSO, Random Forest) were used to identify candidate molecular signatures, which were then validated in an animal model. We identified 46 DEGs associated with anoikis and 41 DEGs related to ER stress. Functional analysis linked them to apoptosis and IL-17 signaling. Five key molecular signatures were identified: CDKN1A, MCL1, PTGS2, PTHLH, and ANGPTL4. The expression of ANGPTL4, CDKN1A, and MCL1 was consistent in the animal model. These genes are associated with inflammatory and oxidative stress responses. Twelve potential therapeutic drugs were predicted. This study identifies five candidate molecular signatures for KC related to anoikis and ER stress, offering insights into KC pathogenesis and potential targeted therapies. Show less
Nailton José Neto, Guy Hajj-Boutros, Wayne Lok+32 more · 2026 · The journals of gerontology. Series A, Biological sciences and medical sciences · Oxford University Press · added 2026-04-24
Intrinsic Capacity (IC) is defined as the composite of physical and mental abilities an individual possesses, encompassing five domains: cognition, psychological health, sensory function, vitality, an Show more
Intrinsic Capacity (IC) is defined as the composite of physical and mental abilities an individual possesses, encompassing five domains: cognition, psychological health, sensory function, vitality, and locomotion. This construct is central to the World Health Organization's framework for assessing functional ability in older adults. Growing evidence highlights the critical role of the musculoskeletal system in maintaining these domains, while conditions such as sarcopenia, osteoporosis, and their coexistence as osteosarcopenia (OS) are increasingly associated with IC decline. This narrative review compiles current evidence on the modulatory role of muscles and bones in IC and the impacts of sarcopenia, osteoporosis, and OS. Most findings suggest that musculoskeletal tissues influence IC not only through biomechanical functions but also as secretory organs, releasing myokines and osteokines with endocrine, paracrine, and autocrine effects. Among the most studied are brain-derived neurotrophic factor, irisin, osteocalcin, and interleukin-6. Dysregulation of these pathways, along with biomechanical dysfunction and systemic inflammation, links sarcopenia, osteoporosis, and OS to IC impairment. Further research is needed to clarify the specific mechanisms involved, particularly in the sensory and vitality domains, to inform targeted interventions that promote healthy aging. Show less
The polyphenols in grains are highly active, but some polyphenols in highland barley are in a bound form and have extremely low bioavailability. Fermentation by lactic acid bacteria (LAB) is capable o Show more
The polyphenols in grains are highly active, but some polyphenols in highland barley are in a bound form and have extremely low bioavailability. Fermentation by lactic acid bacteria (LAB) is capable of altering the functionality of foods. This research investigated the effects of fermentation with different LAB, such as Lactobacillus acidophilus (LAC), Lactobacillus casei (LCA), Lactobacillus rhamnosus (LRH), Lactobacillus plantarum (LPL), and Lactobacillus bulgaricus (LBU), on the hypoglycemic activity and mechanism of polyphenols in highland barley. The hypoglycemic activity of the fermentation products was measured by in vitro antioxidant, enzyme activity, and glucose consumption experiments. Untargeted metabolomic analysis used UHPLC-Q Exactive HF-X/MS to reveal distinct metabolic profiles among the fermented groups. Molecular docking and western blot experiments were conducted to elucidate the mechanism underlying the hypoglycemic effect of fermentation products. Polyphenolic antioxidant activity in highland barley and its inhibitory activities against α-glucosidase and α-amylase were increased after LAC fermentation. Furthermore, the fermented extracts improved glucose consumption in HepG2 cells. The content determination and metabolomic analysis showed that fermented highland barley polyphenols were increased, and 113 differential phenolic metabolites were identified and annotated, among which 44 exhibited a significant upregulation compared with raw highland barley polyphenols. At the molecular level, the polyphenol extract upregulated PI3K and phosphorylated Akt expression in HepG2 cells. Overall, the results indicate that fermentation by LAC biotransformed highland barley polyphenols into smaller molecules with improved hypoglycemic activities, thereby enhancing their bioavailability. Show less