Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R Show more
Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R) and its post-translational modifications, especially sumoylation, is crucial in understanding the progression of AD and exploring novel therapeutic avenues. This study investigates the impact of exercise on the sumoylation of IGF1R and its role in ameliorating AD symptoms in APP/PS1 mice, with a specific focus on neuroinflammation and innovative therapeutic strategies. APP/PS1 mice were subjected to a regimen of moderate-intensity exercise. The investigation encompassed assessments of cognitive functions, alterations in hippocampal protein expressions, neuroinflammatory markers, and the effects of exercise on IGF1R and SUMO1 nuclear translocation. Additionally, the study evaluated the efficacy of KPT-330, a nuclear export inhibitor, as an alternative to exercise. Exercise notably enhanced cognitive functions in AD mice, possibly through modulations in hippocampal proteins, including Bcl-2 and BACE1. A decrease in neuroinflammatory markers such as IL-1β, IL-6, and TNF-α was observed, indicative of reduced neuroinflammation. Exercise modulated the nuclear translocation of SUMO1 and IGF1R in the hippocampus, thereby facilitating neuronal regeneration. Mutant IGF1R (MT IGF1R), lacking SUMO1 modification sites, showed reduced SUMOylation, leading to diminished expression of pro-inflammatory cytokines and apoptosis. KPT-330 impeded the formation of the IGF1R/RanBP2/SUMO1 complex, thereby limiting IGF1R nuclear translocation, inflammation, and neuronal apoptosis, while enhancing cognitive functions and neuron proliferation. Moderate-intensity exercise effectively mitigates AD symptoms in mice, primarily by diminishing neuroinflammation, through the reduction of IGF1R Sumoylation. KPT-330, as a potential alternative to physical exercise, enhances the neuroprotective role of IGF1R by inhibiting SUMOylation through targeting XPO1, presenting a promising therapeutic strategy for AD. Show less
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection te Show more
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection techniques. Herein, a unique hydrogel incorporating extracellular matrix from fish swim bladder (FSB-ECM), which has distinct advantages over mammalian derived ECM, such as low antigenicity, bioactivity, and source safety, is developed. It consists of collagen, glycoproteins, and proteoglycans, including 13 proteins common in the myocardial matrix and three specific proteins: HSPG, Col12a1, and vWF. This hydrogel enhances cardiac cell adhesion and stretching while promoting angiogenesis and M2 macrophage polarization. In addition, its storage modulus (G') increases over time, reaching about 1000 Pa after 5 min, which facilitates transcatheter delivery and in situ gelling. Furthermore, this hydrogel provides sustained support for cardiac contractions, exhibiting superior longevity. In a rat model of ischemic heart failure, the ejection fraction significantly improves with FSB-ECM treatment, accompanied by increased angiogenesis, reduced inflammation, and decreased infarct size. Finally, RNA sequencing combined with in vitro assays identifies ANGPTL4 as a key protein involved in mediating the effects of FSB-ECM treatment. Overall, this new injectable hydrogel based on FSB-ECM is suitable for transcatheter delivery and possesses remarkable reparative capabilities for treating heart failure. Show less
With the development of optical anti-counterfeiting and the increasing demand for high-level information encryption, multimodal luminescence (MML) materials attract much attention. However, the discov Show more
With the development of optical anti-counterfeiting and the increasing demand for high-level information encryption, multimodal luminescence (MML) materials attract much attention. However, the discovery of these multifunctional materials is very accidental, and the versatile host suitable for developing such materials remains unclear. Here, a grossite-type fast ionic conductor CaGa Show less
This study aims to investigate the effect of fermented onion on Liangshan black sheep's growth performance, health, meat quality, and rumen metabolite profiles. A total of 80 four-month-old female Lia Show more
This study aims to investigate the effect of fermented onion on Liangshan black sheep's growth performance, health, meat quality, and rumen metabolite profiles. A total of 80 four-month-old female Liangshan black sheep were randomly divided into four groups of five replicate pens (four sheep per pen). Sheep were fed a basal diet supplemented with 0 (control), 10, 20% or 30% fermented onion. Compared to that of the control group, dietary supplementation with 20% fermented onion improved final body weight, ADG and ADFI; enhanced GPT and GOT activities and increased IgA, IgG, IgM, C3, and C4 levels; increased the levels of IL-4, IL-10, TGF- Show less
Pesticides increase agricultural productivity, but with the widespread use of pesticides, concerns have arisen about their potential negative impacts on human health and aquatic organisms. Pydiflumeto Show more
Pesticides increase agricultural productivity, but with the widespread use of pesticides, concerns have arisen about their potential negative impacts on human health and aquatic organisms. Pydiflumetofen (PYD) is a novel chiral fungicide, and the potential environmental and health hazards of PYD and its chiral isomers are not sufficiently understood. In this work, zebrafish were employed as a model organism to study the toxicity of PYD, specifically investigating the developmental and cardiovascular toxicities in zebrafish exposed to 0.2 μg/mL of PYD for 72 h. The results showed that PYD severely impeded the development of zebrafish embryos, resulting in abnormal hatching rates, enlarged yolk sacs and shortened body length. In addition, PYD resulted in morphological and functional abnormalities of the embryonic heart and blood vessels, such as pericardial edema, linearization of the heart, impeded vascular production, slowed heart rate, and reduced erythrocyte flow rate. Mechanistically, we found that PYD caused oxidative stress, lipid accumulation and apoptosis in zebrafish. Simultaneously, the expression of genes associated with cardiac (nkx2.5, gata4, tbx5, hand2, has2) and vascular (vegfc, dll4, cdh5, hey2, and notch3) development was altered. Notably, our results indicate that (+)-R-PYD exhibits higher developmental and cardiovascular toxicity than (-)-S-PYD. This paper first reveals the cardiovascular toxicity of PYD and opens new avenues for assessing the environmental and health hazards caused by chiral fungicides. Show less
Sepsis is associated with high morbidity and high mortality and has strongly motivated intense studies into its mechanisms. Antibiotics, aimed to eradicate bacteria, have some impact on the immune sys Show more
Sepsis is associated with high morbidity and high mortality and has strongly motivated intense studies into its mechanisms. Antibiotics, aimed to eradicate bacteria, have some impact on the immune system due to anti-inflammatory properties. Tigecycline, an antibiotic of the glycylcycline class, is commonly used for severe infections. This study aimed to investigate tigecycline's mechanism on the inflammatory response of sepsis to find new targets for sepsis treatment. The objective included (i) to observe the changes in inflammatory factors in LPS (lipopolysaccharide) induced septic mice after tigecycline administration, (ii) to detect the effect of tigecycline on macrophages NF-κB (nuclear factor kappa B) signalling. For LPS-induced sepsis in mice and intervention with tigecycline, mice were first injected with tigecycline (6.5 mg/kg) via tail vein followed by LPS (15 mg/kg). Luminex analysis was performed on 16 mediators. NF-κB signalling pathway antibody chip detected the expression of target sites in macrophages of the LPS group and tigecycline + LPS group. Tigecycline has inhibitory effects on LPS-induced inflammatory response in septic mice, decreasing the concentrations of IL (interleukin)-6, IL-27, TNF-α (tumour necrosis factor-α), TNF RII, IFN-γ (interferon-gamma), CCL5/RANTES (CC Motif Chemokine Ligand) while increasing IL-6Rα, IL-10, and TWEAK (TNF-related weak inducer of apoptosis). Tigecycline downregulated phosphorylation levels of key sites JNK (c-Jun N-terminal kinase)1/2/3, p-p65 (s468) and p-p105/p50 (s907) in NF-κB signalling. Tigecycline may inhibit the excessive immune response induced by LPS in sepsis, which may cause a potential protective effect on the host through immune regulation. Show less
DNA methylation plays a crucial role in species development and environmental adaptation. In mammals, there are significant dietary changes from infancy to adulthood. Notably, the red panda transition Show more
DNA methylation plays a crucial role in species development and environmental adaptation. In mammals, there are significant dietary changes from infancy to adulthood. Notably, the red panda transitions from milk consumption as juveniles to a bamboo-based diet as adults, with significant alterations in food characteristics and nutritional content. However, the regulatory role of DNA methylation in this process remains unclear. In this study, we investigate the regulatory role of DNA methylation on the expression of digestive and metabolic genes in the liver and pancreas during the red panda's dietary transition from suckling stage to adulthood. Our findings reveal significant differences in DNA methylation patterns before and after dietary transition, highlighting the specific alterations in the methylation profiles of genes involved in lipid, carbohydrate, and amino acid metabolism. We found that perilipin-4 (PLIN4) is hypomethylated and highly expressed in the liver of adult red pandas, facilitating lipid droplet formation and storage, crucial for adapting to the low-fat content in bamboo. In contrast, genes like lipoprotein lipase (LPL), crucial for lipid breakdown, exhibited hypermethylated with low-expression patterns, reflecting a reduced lipid metabolism capacity in adults. Carbohydrate metabolism-related genes like ADH4 and FAM3C are hypomethylated and highly expressed in adults, enhancing glycogen production and glucose utilization. Genes involved in protein metabolism like CTSZ and GLDC, exhibit hypomethylated with high-expression and hypermethylated with low-expression patterns in the pancreas of adults, respectively, contributing to protein metabolism balance post-weaning. This study reveals the regulatory role of DNA methylation in the dietary transition of red pandas from milk to bamboo and provides methylation evidence for the molecular regulation of adaptive expression of digestive and metabolic genes in red pandas with specialized diets. Show less
Cattle body size measurements constitute the conformation traits that facilitate their production, fertility, and longevity status. Prioritizing functional variants and causal genes of conformation tr Show more
Cattle body size measurements constitute the conformation traits that facilitate their production, fertility, and longevity status. Prioritizing functional variants and causal genes of conformation traits is essential for understanding their genetic basis. In this study, we conducted single-trait and multitrait GWAS for 20 body conformation traits using imputed sequence data in 7,674 Chinese Holstein individuals and identified 27 QTL regions. Leveraging these QTL regions, we performed multitrait Bayesian fine-mapping to identify 30 independent credible sets of putative causal variants. Incorporating GWAS and cis-acting expression QTL data, Mendelian randomization was used to infer 153 putative causal gene-trait relationships. The previously reported genes, such as CCND2, TMTC2, and NRG3, were confirmed in our study. Of note, several novel candidate causal genes were also identified, such as C1R, RIMS1, SERPINB8, NETO2, TTYH3, TTC3, ANAPC4, and PSMD13. Our results provide new insights into the regulatory mechanisms of body conformation traits in cattle. Show less
Diabetic retinopathy (DR) is the main cause of blindness worldwide, and its prevalence rate is constantly rising. More in-depth exploration of its risk factors and pathogenic mechanisms is needed. Thi Show more
Diabetic retinopathy (DR) is the main cause of blindness worldwide, and its prevalence rate is constantly rising. More in-depth exploration of its risk factors and pathogenic mechanisms is needed. This study systematically identified potential therapeutic targets for DR by evaluating causal effects of 16,989 genes and 2,923 proteins on DR/subtypes via two-sample Mendelian randomization (MR), validated with colocalization/Summary-data-based Mendelian randomization (SMR). National Health and Nutrition Examination Survey (NHANES) 1999-2010 cross-sectional data (weighted logistic/Restricted cubic spline (RCS)) pinpointed key risk factors; MR explored their links to DR subtypes. Bioinformatics (bulk and single-cell transcriptomics) analyzed molecular mechanisms of shared targets (gene expression, immune infiltration, pathway enrichment). Machine learning selected key targets for models. Finally, two-step mediation MR examined how targets regulate DR via risk factors. This study identified 64 core targets with causal links to DR. Subtype analysis revealed 2,128 causal genes and subtype-specific targets (e.g. 52 for background DR, 66 for proliferative DR). SMR validated these findings. NHANES data highlighted body mass index (BMI), stroke, hypertension (HBP), and C-reactive protein (CRP) as key DR risk factors, confirmed by MR. Transcriptomics identified 29 differentially expressed genes associated with both risk factors and DR, linked to immune cell regulation. Machine learning selected core targets (LY9, WWP2, etc.) and built a nomogram for DR risk prediction. Functional enrichment showed these targets enriched in chemokine/cytokine and immune-inflammatory pathways. Two-step mediation MR further revealed LY9, ARHGAP1, and WWP2 influence DR subtypes via regulating BMI, CRP, and HBP. This study systematically elucidates the key risk factors, potential molecular mechanisms, and core regulatory targets of DR through multi-omics integration, causal inference, and bioinformatics approaches. The results indicate that inflammation, immune dysregulation, and metabolic disorders play crucial roles in the pathogenesis of DR. Key genes such as LY9, ARHGAP1, and WWP2 could serve as potential intervention targets, offering theoretical foundations and strategic support for early warning and precision treatment of DR. Show less
The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-γ production. The mechanisms underlying this functional bias remain elusive. Previous studies Show more
The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-γ production. The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4 Show less
The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunc Show more
The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunction is implicated in the pathogenesis of a wide spectrum of complex modern diseases, spanning neurodegeneration, metabolic syndromes, and chronic inflammatory conditions. This review examines the pathway's role as an integrative hub and its potential as a therapeutic target. We synthesize current mechanistic evidence from molecular, cellular, and preclinical studies to elucidate the pathway's operational logic and the consequences of its dysregulation. The analysis is structured around key disease paradigms-including Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular injury, stroke, and chronic kidney disease-to dissect its tissue-specific pathophysiological impacts. The AMPK/SIRT1/PGC-1α axis operates through a core positive feedback loop: AMPK activation elevates NAD+, thereby activating SIRT1, which in turn deacetylates and activates PGC-1α to drive mitochondrial biogenesis and function, further reinforcing SIRT1 activity. Disruption of this cascade manifests in disease-specific mechanisms: promoting Aβ production via BACE1/γ-secretase in Alzheimer's; impairing α-synuclein clearance in Parkinson's; disrupting GLUT4 translocation and insulin signaling in diabetes; exacerbating oxidative damage and mitochondrial dysfunction in cardiovascular and neuronal injury; and accelerating fibrosis and sustained inflammation in renal and pulmonary diseases via NLRP3 and TGF-β/Smad3 signaling. The AMPK/SIRT1/PGC-1α pathway represents a cornerstone target at the intersection of metabolism, aging, and disease. Current therapeutic strategies-including pharmacological activators (e.g., metformin, SRT1720), natural compounds (e.g., resveratrol), lifestyle interventions (e.g., exercise, caloric restriction), and emerging technologies (e.g., gene editing, exosomal miRNAs)-offer multidimensional avenues for intervention. Future research must prioritize elucidating tissue-specific regulatory mechanisms, such as AMPK isoform diversity and PGC-1α interactome dynamics, to enable precision therapeutics and successful clinical translation for a range of complex disorders. Show less
This study evaluated the protective effects of naringin (NG) against intestinal injury in 7-day-old piglets infected with porcine epidemic diarrhea virus (PEDV). Eighteen piglets (Duroc × Landrace × L Show more
This study evaluated the protective effects of naringin (NG) against intestinal injury in 7-day-old piglets infected with porcine epidemic diarrhea virus (PEDV). Eighteen piglets (Duroc × Landrace × Large, body weight = 2.58 ± 0.05 kg) were divided into three treatment groups based on similar body weights and equal numbers of males and females: the blank control group (CON group), the PEDV infection group (PEDV group), and the NG intervention + PEDV infection group (NG + PEDV group) ( Show less
Sleep disorders show comorbidity with depression and Alzheimer's disease (AD), especially in ageing. However, the neuroimmunological role of sleep deprivation (SD) as possible inducer to these conditi Show more
Sleep disorders show comorbidity with depression and Alzheimer's disease (AD), especially in ageing. However, the neuroimmunological role of sleep deprivation (SD) as possible inducer to these conditions remains unknown. Omega-3 fatty acids (n-3 FAs) can improve depression and AD through anti-inflammation, up-regulating neurotrophins and normalizing neurotransmitters, while their therapeutic effects on sleep deprivation (SD)-induced changes in different ages requires investigation. Adult and old Fat-1 (converting n-6 to n-3 FAs) and wild-type (WT) mice were subjected to chronic SD. After behavioral evaluation, brain FAs, monoamine neurotransmitters, circadian-gene expression, TLR-4 signaling-pathway, glial polarization, cytokine profile, and AD-related markers were analyzed using GC-MS, HPLC, qPCR, ELISA and western-blotting. Furthermore, bioinformatic analysis evaluated SD-related networking with depression and AD. SD induced anxiety, anhedonia, despair, and memory impairments. The n-3:n-6 ratio, BMAL-1 gene expression, and melatonin concentration were decreased, whereas corticosterone, TLR-4, GSK3β, and NFκB concentrations increased in SD groups compared to the controls. Increased IBA-1 protein expression and proinflammatory IL-1β, TNF-α, and IL-6 concentrations were associated with decreased monoamine neuro-transmitter levels in SD groups. APP, BACE-1, RAGE and APPβ concentrations were increased, whereas LRP-1 and APPα concentrations and the APPα/APPβ ratio were decreased in SD groups than controls. These changes were more pronounced in old WT and Fat-1 animals than adults. However, compared to WT-SD, these changes were significantly ameliorated in Fat-1-SD mice, but recovery was less pronounced in old Fat-1. SD-induced neuroinflammation and impaired APP processing may contribute to behavioral impairments, which exacerbated with age. Although n-3 FAs significantly ameliorated SD-induced adverse behavioral and neuroimmunological changes, this therapeutic effect was markedly reduced in old animals. Show less
Coronary artery disease (CAD) is showing a trend toward earlier onset. Premature CAD (PCAD) is clinically defined as CAD with onset before the age of 55 in males and 65 in females. Notably, many young Show more
Coronary artery disease (CAD) is showing a trend toward earlier onset. Premature CAD (PCAD) is clinically defined as CAD with onset before the age of 55 in males and 65 in females. Notably, many young patients subsequently hospitalized with acute cardiovascular events had undergone annual physical examinations before hospitalization, yet were not identified as high-risk by current risk stratification guidelines or traditional risk assessment tools. This study aims to investigate the diagnostic capacity of novel inflammatory biomarkers (including the monocyte-to-high-density lipoprotein cholesterol ratio (MHR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), apolipoprotein B to apolipoprotein A-1 ratio (apoB/apoA-1), and low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (LDL-c/HDL-c)) for PCAD, thereby providing the evidence-based foundation for PCAD screening. A total of 1,012 young subjects (male<55 years, female<65 years) undergoing diagnostic coronary angiography (CAG) at the Third Affiliated Hospital of Zunyi Medical University (from January 2022 to February 2023) were retrospectively analyzed. We stratified 1,012 eligible participants into two groups: 521 angiographically confirmed PCAD cases and 491 controls with normal coronary arteries. Comprehensive baseline characteristics, including cardiovascular risk profiles and core laboratory-measured inflammatory markers, were recorded. The Mann-Whitney U test and binary logistic regression analysis were employed to assess the associations between inflammatory biomarkers and PCAD. The areas under the receiver operating characteristic (ROC) curves (AUCs) were calculated to evaluate their diagnostic performance for PCAD. The odds ratio (OR) values for MHR, NLR, LDL-c/HDL-c, and apoB/apoA-1 were 5.592 (95% CI: 2.886-7.836), 1.671 (95% CI: 1.500-1.861), 1.663 (95% CI: 1.419-1.950), and 6.268 (95% CI: 2.765-8.213), respectively (all The apoB/apoA-1 outperformed MHR, NLR, and LDL-c/HDL-c as an inflammatory biomarker in PCAD. Its diagnostic capacity was notably enhanced in ACS subgroups. A comprehensive model combining apoB/apoA-1 with traditional risk factors demonstrated exceptional accuracy. Incorporating this biomarker into routine screening protocols could significantly strengthen preventive strategies. Show less
Bladder cancer (BLCA) is a prevalent urological malignancy. We aim to identify novel biomarkers for BLCA and elucidate the specific regulatory mechanisms of polo-like kinase 1 (PLK1). Using differenti Show more
Bladder cancer (BLCA) is a prevalent urological malignancy. We aim to identify novel biomarkers for BLCA and elucidate the specific regulatory mechanisms of polo-like kinase 1 (PLK1). Using differentially expressed genes (DEGs) screened from GSE38264 and GSE130598 datasets, we constructed protein-protein interaction networks to identify hub genes, whose expression was validated using reverse transcription-quantitative polymerase chain reaction. The malignant phenotype of BLCA cells was assessed by Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, Transwell, and wound-healing assays. Hematoxylin-eosin and immunohistochemical staining were employed to evaluate BLCA development in mouse xenograft models. The protein expression was detected by Western blot. PLK1, AURKA, AURKB, CDK1, ERBB2, ERBB3, FGFR1, FYN, ABL1, and PRKDC were hub genes with predictive value for BLCA. Among them, PLK1 was selected as a key target of BLCA. PLK1 knockdown inhibited the viability, proliferation, migration, and invasion of BLCA cells. In vivo, PLK1 knockdown inhibited tumor growth. Silencing PLK1 activated the Hippo pathway in BLCA cells and tumor tissues. The Hippo pathway inhibitor reversed the inhibitory effects of PLK1 silencing on malignant phenotype of BLCA cells. PLK1 knockdown exerts an inhibitory effect on BLCA via activating the Hippo pathway, which presents promising therapeutic strategies for BLCA. Show less
The treatment of functional tricuspid regurgitation (TR) is still controversial. Characterizing the cellular composition of the tricuspid valve and identifying the molecular alterations of each cell t Show more
The treatment of functional tricuspid regurgitation (TR) is still controversial. Characterizing the cellular composition of the tricuspid valve and identifying the molecular alterations of each cell type in valves with TR will advance our understanding of the mechanisms of TR and guide improvements in treatment. The authors aimed to investigate the changes in cellular composition and gene expression patterns of cells in regurgitant tricuspid valves and shed light on the mechanisms of functional TR. To improve our understanding of the pathogenesis of functional TR, we performed single-cell RNA sequencing of tricuspid valve from 10 patients, including 5 patients with moderate-to-severe functional TR and 5 nondiseased control subjects. Multiplexed fluorescence was used to detect the spatial distributions of valvular cell states and validated the cell-cell interaction. We assessed the transcriptional profiles of 84,102 cells and identified 6 major cell clusters, along with 25 cell subtypes, in the specimens. Valve interstitial cells (VICs) were the largest population. VICs and lymphoid cells exhibited more heterogeneity in TR patients. VICs exhibited higher transcriptional activity toward matrifibrocyte-like cells and myofibroblast-like cell differentiation, myeloid cells activated immune response, and lymphoid cells promoted fibrosis. In TR, the alternation of COMP-CD47 and FGF2-FGFR1 interaction may occur in TR specimens, which may serve as promising therapeutic targets for TR. Our single-cell atlas highlights the transcriptomic heterogeneity underlying the cell functions and interactions in human tricuspid valves and defines molecular and cellular perturbations in functional TR. We identified VIC clusters with fibrosis activation accumulated in TR valves. Show less
Fel d1, the major cat allergen responsible for over 90% of human IgE-mediated allergies, has an incompletely defined physiological role. To explore its function and assess the feasibility of producing Show more
Fel d1, the major cat allergen responsible for over 90% of human IgE-mediated allergies, has an incompletely defined physiological role. To explore its function and assess the feasibility of producing hypoallergenic cats, we knocked out the CH2 domain of Fel d1 using CRISPR/Cas9 in feline skin cells. An optimized sgRNA introduced a frameshift mutation, with knockout efficiency validated by sequencing, qRT-PCR, and Western blot. Transcriptomic alterations were profiled by RNA-seq, and functional consequences were investigated via GO, KEGG, and GSEA analyses. Key findings were confirmed by qPCR, and phenotypes were assessed using CCK-8, EdU, and flow cytometry. The approach successfully generated a three-base insertion, resulting in near-complete loss of CH2 mRNA and Fel d1 protein. RNA-seq identified 3,469 differentially expressed genes (DEGs), with significant enrichment in pathways for hypertrophic cardiomyopathy (HCM) and rheumatoid arthritis (RA). Key genes in these pathways (e.g., Show less
Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disease. Genetic linkage analyses have identified that mutations in the exostosin glycosyltransferase (EXT)1 and EXT2 genes are li Show more
Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disease. Genetic linkage analyses have identified that mutations in the exostosin glycosyltransferase (EXT)1 and EXT2 genes are linked to HME pathogenesis, with EXT1 mutation being the most frequent. The aim of this study was to generate a mice model with Ext1 gene editing to simulate human EXT1 mutation and investigate the genetic pathogenicity of Ext1 through phenotypic analyses. We designed a pair of dual sgRNAs targeting exon 1 of the mice Ext1 gene for precise deletion of a 46 bp DNA fragment, resulting in frameshift mutation of the Ext1 gene. The designed dual sgRNAs and Cas9 proteins were injected into mice zygotes cytoplasm. A total of 14 mice were obtained via embryo transfer, among which two genotypic chimera mice had a deletion of the 46 bp DNA fragment in exon 1 of the Ext1 gene. By hybridization and breeding, we successfully generated heterozygous mice with edited Ext1 gene (Ext Show less
Vascular calcification (VC), a common complication associated with diabetes mellitus (DM), substantially increases the risk of cardiovascular diseases and is associated with elevated mortality in indi Show more
Vascular calcification (VC), a common complication associated with diabetes mellitus (DM), substantially increases the risk of cardiovascular diseases and is associated with elevated mortality in individuals with DM. Endothelial-to-mesenchymal transition (EndMT) imparts phenotypic plasticity to vascular endothelial cells (VECs), granting them the potential for osteogenic differentiation, which is a crucial mechanism in regulating VC. Notably, adenosine-ADORA2A-mediated endothelial dysfunction plays a pivotal regulatory role in cardiovascular diseases. However, the specific role of endothelial ADORA2A in diabetic VC remains to be elucidated. In this study, we found that ADORA2A was upregulated in the endothelium of diabetic mice and cultured human aortic endothelial cells (HAECs) with high glucose treatment. Deletion of endothelial Adora2a or pharmacologic inhibition of ADORA2A with KW6002 attenuated EndMT, osteogenic differentiation, and calcium deposit in diabetic aortas of Ins2 Show less
Chronic kidney disease (CKD) is highly prevalent, incurable, and lacks effective treatments. Aging is closely linked to various kidney diseases. In this study, we combined CKD and aging using bioinfor Show more
Chronic kidney disease (CKD) is highly prevalent, incurable, and lacks effective treatments. Aging is closely linked to various kidney diseases. In this study, we combined CKD and aging using bioinformatics approaches to identify potential anti aging drugs and therapeutic targets for CKD. We analyzed datasets GSE37171 and GSE66494 from the GEO database, identifying 317 differentially expressed genes (DEGs). By intersecting these DEGs with aging related genes, we identified 23 aging associated differential genes (ARDEGs). A protein-protein interaction (PPI) network was constructed using the STRING database, and the top 10 hub ARDEGs were identified using Cytoscape software. Potential anti aging drugs, including Cinnamaldehyde, were identified through the ceRNA and transcription factor regulatory networks, as well as the DGldb database. Among the key regulatory genes identified in CKD patient samples were SOD2, FGF21, FOS, RELA, DDIT4, BMI1, DUSP6, LGALS3, CXCR2, and CEBPB. Cinnamaldehyde and other drugs were found to target aging associated pathways, suggesting their potential to delay CKD progression through modulating these pathways. Finally, we verified the low-expression of DDIT4 and DUSP6, the two targets of Cinnamaldehyde, in unilateral ureteral obstruction (UUO) animal model. Additionally, Cinnamaldehyde was shown to reduce the expression of fibrosis markers such as fibronectin (FN) and α-smooth muscle actin (α-SMA) in HK2 cells under TGF-β1 stimulation. This study provides a foundational understanding of aging related molecular targets in CKD and offers new directions for developing anti aging therapies to treat CKD. Show less
Neurodevelopmental disorders (NDDs) exhibit complex genotype-phenotype associations that frequently result in inconclusive variant interpretations, contributing to suboptimal diagnostic yields (~ 40%) Show more
Neurodevelopmental disorders (NDDs) exhibit complex genotype-phenotype associations that frequently result in inconclusive variant interpretations, contributing to suboptimal diagnostic yields (~ 40%). Koolen-de Vries syndrome (KdVS), an autosomal dominant NDD caused by KANSL1 haploinsufficiency, exemplifies this diagnostic challenge with its multisystem manifestations and lack of systematic genotype-phenotype associations. To address this gap, we constructed a comprehensive KdVS genotype-phenotype repository by systematically integrating all molecularly confirmed cases from global literature. Comprehensive phenotypic analysis revealed that core KdVS features include developmental delay/intellectual disability, characteristic craniofacial dysmorphism, hypotonia, and multisystem abnormalities. Phenotypic association analysis identified 249 significant correlations, demonstrating that KdVS clinical manifestations are highly interconnected rather than representing isolated features, such as the association between strabismus and hydrocephalus (OR = 14.26). Application of this repository to screen a Chinese rare disease cohort identified 53 KANSL1 variants. Among these, one de novo nonsense variant (NM₀₀₁₁₉₃₄₆₆.2: c.902T > G, p.Leu301Ter) was classified as pathogenic in a Chinese boy with classic KdVS features. The remaining 52 variants were categorized as variants of uncertain significance (VUS), approximately half of which were absent from gnomAD databases. Each VUS was comprehensively annotated with detailed clinical profiles to facilitate phenotype-driven reinterpretation. In conclusion, this study establishes KdVS as a highly interconnected multisystem disorder and demonstrates that deep phenotypic association analysis enhanced genetic diagnosis. This disease-specific repository approach provides a scalable framework for improving molecular diagnostics across rare NDDs. Show less
Breast cancer (BRCA) is a prevalent malignant tumor among women, and the use of anesthetic drugs during surgical resection may influence tumor biology and patient prognosis. This study aimed to identi Show more
Breast cancer (BRCA) is a prevalent malignant tumor among women, and the use of anesthetic drugs during surgical resection may influence tumor biology and patient prognosis. This study aimed to identify prognostic biomarkers associated with dexmedetomidine and dezocine (DD) in BRCA patients. Through Mendelian Randomization analysis, we screened four DD targets that had a causal relationship with BRCA. Subsequently, utilizing TCGA-BRCA data, univariate and Lasso Cox analyses revealed two significant prognostic biomarkers (NR1H3 and ADRB1) associated with BRCA patient prognosis, leading to the successful construction and validation of a prognostic risk model. Kaplan-Meier survival curves indicated that patients with higher NR1H3 and ADRB1 expression had longer overall survival (OS). Immunoinfiltration analysis showed that high-risk group patients exhibited increased infiltration levels of CD56 bright natural killer cells, CD56 dim natural killer cells, eosinophils, and plasmacytoid dendritic cells. Conversely, activated B cells and immature B cells demonstrated greater infiltration in the low-risk group. Correlation analysis revealed significant associations between prognostic biomarkers and various immune cells, including CD56 bright natural killer cells, CD56 dim natural killer cells, and activated CD8 T cells. NR1H3 was highly positively correlated with immune checkpoints such as TIGIT, PDCD1, CD274, CTLA4, LAG3, and HAVCR2 (|cor|≥0.3, The online version contains supplementary material available at 10.1007/s12672-025-03694-7. Show less
Protein arginine methyltransferase 5 (PRMT5) complexes with methylosome protein 50 (MEP50) play crucial roles in tumor progress. However, the regulatory mechanism of governing the PRMT5-MEP50 hetero-o Show more
Protein arginine methyltransferase 5 (PRMT5) complexes with methylosome protein 50 (MEP50) play crucial roles in tumor progress. However, the regulatory mechanism of governing the PRMT5-MEP50 hetero-octameric complex remains unclear. Here, we demonstrate that C6orf223, to our knowledge an uncharacterized protein, facilitates PRMT5-MEP50 multiprotein complex assembling, thereby promoting colorectal cancer (CRC) growth and metastasis. C6orf223 forms dimers through disulfide bonds, with its N-terminal arginine-enriched region binding to the C-terminal negatively charged groove of PRMT5, thus stabilizing PRMT5-MEP50 multiprotein and enhancing PRMT5 methyltransferase activity. Consequently, PRMT5-mediated H4R3me2s substantially decreases the expression of the tumor suppressor GATA5, leading to the upregulation of multiple oncogenic target genes including WWTR1, FGFR1, and CLU. Targeting C6orf223 using siRNAs encapsulated in ferritin protein shells effectively suppresses CRC tumor growth and metastasis. Collectively, our findings characterize the role of C6orf223 in facilitating PRMT5-MEP50 hetero-octameric complex assembling and suggest that C6orf223 could serve as a potential therapeutic target for CRC. Show less
This study aimed to elucidate the psychological mechanisms underlying the relationship between alexithymia and problematic eating behaviors (EB) among older adults. Specifically, we examined whether p Show more
This study aimed to elucidate the psychological mechanisms underlying the relationship between alexithymia and problematic eating behaviors (EB) among older adults. Specifically, we examined whether physical activity (PA) mediated this association, and we further explored the heterogeneity of alexithymia using Latent Profile Analysis (LPA). A cross-sectional survey was conducted among 1,773 community-dwelling older adults in China. Participants completed validated questionnaires assessing alexithymia, PA, and EB. Mediation analysis tested the indirect effect of PA on the alexithymia-EB relationship, while LPA identified subgroups of individuals with distinct alexithymia profiles. Mediation analysis revealed that PA significantly mediated the relationship between alexithymia and maladaptive EB, accounting for 18% of the total effect. LPA supported a three-profile solution: pervasive alexithymia (21.15%), adaptive (72.81%), and affective-cognitive dissociation (6.04%). Profile membership was differentially associated with health behaviors, with the pervasive group showing the most unfavorable outcomes (high EB, low PA), and the adaptive group demonstrating the most favorable pattern. These findings highlight PA as a key behavioral pathway through which alexithymia contributes to maladaptive eating in older adults. Moreover, alexithymia is not uniform but heterogeneous, with distinct profiles that confer varied health behavior risks. Interventions to improve eating habits in elderly populations may benefit from tailoring strategies to alexithymia subtypes and systematically promoting PA as an adaptive regulatory mechanism. Show less
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathologic Show more
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathological characteristics of AD, as confirmed by measuring mannose levels in the brains and serum of AD mice, as well as in the serum of AD patients. AD mice are given mannose by intra-cerebroventricular injection (ICV) or in drinking water to investigate the effects of mannose on cognition and AD pathological progression. Chronic mannose overload increases β-amyloid (Aβ) burdens and exacerbates cognitive impairments, which are reversed by a mannose-free diet or mannose transporter antagonists. Mechanistically, single-cell RNA sequencing and metabolomics suggested that mannose-mediated N-glycosylation of BACE1 and Nicastrin enhances their protein stability, promoting Aβ production. Additionally, reduced mannose intake decreased BACE1 and Nicastrin stability, ultimately lowering Aβ production and mitigating AD pathology. this results highlight that high-dose mannose consumption may exacerbate AD pathogenesis. Restricting dietary mannose may have therapeutic benefits. Show less
Observational studies have reported an association between visceral obesity and asthma. However, the causal direction of this relationship remains uncertain due to potential confounding and reverse ca Show more
Observational studies have reported an association between visceral obesity and asthma. However, the causal direction of this relationship remains uncertain due to potential confounding and reverse causality. Furthermore, the underlying mediating factors and potential therapeutic targets underlying this association are poorly understood. This study aimed to investigate the causal effect of visceral adipose tissue (VAT) on asthma risk, identify potential mediators, and quantify their effects using a Mendelian randomization (MR) framework. In this study, we employed MR approach to elucidate the impact of VAT on asthma and to assess the potential mediators. Subsequently, the association between seven lipid-lowering medication targets and asthma risk was investigated using the drug target MR method. Lastly, we conducted an observational study involving 12,120 participants to evaluate the relationship between visceral adiposity index (VAI) and asthma. The univariable MR analysis demonstrated that each standard deviation increase in genetically predicted VAT was associated with a 46 % higher risk of asthma (IVW: OR = 1.460, 95 % CI: 1.351-1.578, p = 1.471E-21). This association remained significant after adjusting for BMI in multivariable MR (OR = 1.137, 95 % CI: 1.023-1.262, p = 0.017). Mediation analysis revealed that HDL-C accounted for 4.3 % of this effect (OR = 1.016, 95 % CI: 1.001-1.033, p = 0.038). Drug-target MR indicated that activation of HMGCR and LDLR reduced asthma risk (OR = 0.846 and 0.866, respectively; both p < 0.01), whereas LPL activation increased risk (OR = 1.080, p = 0.015). Observational analysis of NHANES data (n = 12,120) confirmed that higher VAI was associated with increased asthma prevalence (OR = 1.290, 95 % CI: 1.101-1.479, p = 0.010). Our results reveal a significant association between increased visceral adipose tissue and elevated risk of asthma, which is partially mediated by high-density lipoprotein cholesterol. 3-hydroxy-3-methylglutaryl coenzyme A reductase, low-density lipoprotein receptor, and lipoprotein lipase exhibit potential as therapeutic targets for asthma. Show less
Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies o Show more
Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies of all-cause heart failure and examine how different classes of genetic variation impact its heritability. We identify 176 common-variant risk loci at genome-wide significance in 2,358,556 individuals and cluster these signals into five broad modules based on pleiotropic associations with anthropomorphic traits/obesity, blood pressure/renal function, atherosclerosis/lipids, immune activity and arrhythmias. In parallel, we uncover exome-wide significant associations for heart failure and rare predicted loss-of-function variants in TTN, MYBPC3, FLNC and BAG3 using exome sequencing of 376,334 individuals. We find that total burden heritability of rare coding variants is highly concentrated in a small set of Mendelian cardiomyopathy genes, while common-variant heritability is diffusely spread throughout the genome. Finally, we show that common-variant background modifies heart failure risk among carriers of rare pathogenic truncating variants in TTN. Together, these findings discern genetic links between dysregulated metabolism and heart failure and highlight a polygenic component to heart failure not captured by current clinical genetic testing. Show less