This study integrated the the effects of dietary Lys/Met ratio in a low protein diet on the meat quality in Tibetan sheep. A total of 90 weaned Tibetan sheep, 2 months old with initial weight of 15.37 Show more
This study integrated the the effects of dietary Lys/Met ratio in a low protein diet on the meat quality in Tibetan sheep. A total of 90 weaned Tibetan sheep, 2 months old with initial weight of 15.37 ± 0.92 kg were randomly divided into 3 treatments, which were supplemented with Lys/Met ratio at 3 (LP-H), 2 (LP-M), and 1 (LP-L) in the basal diet (10 % crude protein), respectively. After slaughter (150 days of age), the growth performances and meat quality of longissimus dorsi muscle were evaluated. The LP-L group showed significantly higher final body weight compared to the LP-M group (P < 0.05). Serum albumin and total protein levels were significantly higher in the LP-L group than in the LP-H group (P < 0.05). Furthermore, meat from the LP-L group had significantly higher protein, calcium, and vitamin E content compared to the LP-M group (P < 0.05). Transcriptomic analysis revealed 3,479 differentially expressed genes enriched in pathways related to muscle growth, energy metabolism, and signaling transduction. Metabolomic analysis identified 771 differential metabolites, significantly enriched in ABC transporters, beta-alanine metabolism, and taste transduction pathways. Integrated analysis highlighted the upregulation of the ABCD4 gene and L-valine metabolite in the LP-L group, contributing to improved phenotypic traits. These findings provide molecular insights into the regulatory mechanisms underlying the effects of dietary Lys/Met ratios on Tibetan sheep meat quality and offer a basis for developing nutritional strategies to enhance premium meat production. Show less
The melanocortin system centrally regulates energy homeostasis, with key components such as melanocortin-4 receptor (MC4R) and adenylyl cyclase 3 (ADCY3) in neuronal primary cilia. Mutations in
Axin1 plays a critical role in regulating the Wnt/β-catenin signaling pathway and cancer progression, and its polymerization is indispensable for the assembly of the β-catenin destruction complex. How Show more
Axin1 plays a critical role in regulating the Wnt/β-catenin signaling pathway and cancer progression, and its polymerization is indispensable for the assembly of the β-catenin destruction complex. However, the mechanisms that control Axin1 polymerization are limited. Here, we reveal that TRIM15 interferes with the polymerization of Axin1, thereby promoting Wnt activation and colorectal cancer growth. Mechanistically, TRIM15 strongly interacts with Axin1 through its coiled-coil domain to disrupt the polymerization among Axin1 molecules. Manipulation of TRIM15 expression dramatically weakens Wnt signaling, cell proliferation, and tumor growth. Furthermore, conditional genetic ablation of Trim15 in mice inhibits tumor formation in both AOM/DSS-induced and Apc Show less
This study identified fibroblast-specific genes to develop a RiskScore model to improve prognostic accuracy and guide personalized treatment in glioblastoma (GBM). We analyzed fibroblast-specific sign Show more
This study identified fibroblast-specific genes to develop a RiskScore model to improve prognostic accuracy and guide personalized treatment in glioblastoma (GBM). We analyzed fibroblast-specific signatures in the GSE273274 cohort using "Seurat" R package for scRNA-seq data processing. Fibroblast-related gene modules were identified via WGCNA, and functional enrichment was assessed with "clusterProfiler" package. A RiskScore model was established using univariate, Lasso Cox regression analysis, and "survival" package, validated by "timeROC" for receiver operator characteristic (ROC) curve. Finally, immune infiltration and drug sensitivity was evaluated applying "ESTIMATE," "TIMER," "MCPcounter," and "pRRophetic" packages. Experimental validation included qPCR for gene expression detection, and CCK-8, wound healing, and Transwell assays for functional measurement. The scRNA-seq analysis identified nine cell types of cells, with fibroblasts elevated in the GBM group. Fibroblast signatures were linked to tumorigenesis, cytoskeleton remodeling, and regulation of neuronal development process that affected GBM invasion. A 6-gene RiskScore divided GBM patients into high- and low-risk groups in training and validation sets, with high-risk patients exhibiting poorer survival, elevated StromalScore, and negative correlations with the infiltration of neutrophils and B_cells. Moreover, high-risk patients demonstrated heightened sensitivity to Cisplatin, MG-132, AZ628, Dasatinib, CGP-60474, A-770041, TGX221, and Bortezomib. Finally, qPCR showed that the VWA1 was upregulated in GBM cells, while knock-down of VWA1 inhibited the cell proliferation, migration, and invasion activity. We constructed a RiskScore model for predicting the survival outcomes based on fibroblasts-related genes. These findings highlighted the role of fibroblasts in GBM development and offered six potential therapeutic targets (VWA1, DUSP6, LOXL1, IGFBP4, CYGB, and ZIC3) for GBM treatment. Additionally, immune infiltration analysis and drug sensitivity prediction further supported the model's utility in guiding personalized treatment of GBM. Show less
Rubia cordifolia L. (RCL) is a widely used medicinal with a long history. It exhibits anti-inflammatory and antioxidant properties and prevents apoptosis. While there is growing evidence that exhauste Show more
Rubia cordifolia L. (RCL) is a widely used medicinal with a long history. It exhibits anti-inflammatory and antioxidant properties and prevents apoptosis. While there is growing evidence that exhausted exercise (EE) might cause cardiac damage, RCL has been shown to provide cardioprotective effects. The effects and mechanisms of RCL on exercise-induced myocardial injury remain unclear. In this study, we tested the RCL extract using a rat model of exhausted swimming. We evaluated the therapeutic effect of RCL on exercise-induced myocardial damage using PCR, ELISA, hematoxylin-eosin (H&E) staining, DHE staining, and other methods. UPLC-Q-TOF-MS was employed to identify the components of the RCL extract and its blood-entry components, and network pharmacology was constructed. LC-MS was utilized to investigate left ventricular metabolomics. These two approaches were combined to predict the possible metabolic pathways regulated by RCL. Finally, the targets of the metabolic pathway were verified using molecular docking and western blot analysis. The findings suggest that rubioncolin B, 4-hydroxy-2-carbexyanthraquinone, and 9-Oxo-9H-xanthene-4-carboxylic acid may be the primary active compounds of RCL. RCL promotes the degradation pathway of branched-chain amino acids (BCAA), including valine, leucine, and isoleucine, regulates the proteins BCAT2 and BCKDK, reduces pathological injuries, inflammation, oxidative stress, and collagen deposition, and mitigates the effects of exhaustion-induced myocardial injuries by influencing the key target AKR1C1 and the metabolite L-Valine. This study provides a foundation for the development of RCL as a sports supplement to alleviate EE-induced myocardial injury. Show less
Atherosclerosis (AS) is a vascular disorder characterized by lipid accumulation and chronic inflammation, with pathogenesis closely linked to genetic factors and immune regulatory mechanisms. This stu Show more
Atherosclerosis (AS) is a vascular disorder characterized by lipid accumulation and chronic inflammation, with pathogenesis closely linked to genetic factors and immune regulatory mechanisms. This study comprehensively identified ASassociated genes by integrating data from the Gene Expression Omnibus (GEO) database and expression quantitative trait locus (eQTL) analyses, complemented by Mendelian randomization (MR) analysis, followed by experimental validation of their functional roles. Results indicated significant upregulation of CLEC5A and ISG20 in patients with AS, with MR analysis revealing positive causal relationships between both genes and AS risk (CLEC5A: OR = 1.001, P = 0.047; ISG20: OR = 1.001, P = 0.030), while HOXA2 showed a negative causal association. Functional enrichment analysis highlighted CLEC5A and ISG20's involvement in immune responses, inflammatory pathways, and lipid metabolism regulation. Experimental validation in oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages and apolipoprotein E-deficient (ApoE This study represents the first to elucidate the molecular mechanism by which ISG20 promotes AS progression through macrophage lipid accumulation and inflammatory responses, positioning it as a potential novel therapeutic target for AS. Show less
To investigate the regulatory role of MACF1 and its upstream transcriptional control in focal adhesion remodeling and tumor progression in lung adenocarcinoma (LUAD). We employed in vitro loss- and ga Show more
To investigate the regulatory role of MACF1 and its upstream transcriptional control in focal adhesion remodeling and tumor progression in lung adenocarcinoma (LUAD). We employed in vitro loss- and gain-of-function assays using shRNA-mediated knockdown and ectopic overexpression of MACF1 and NR2F1 in LUAD cell lines (H1299 and Calu-3). Cell proliferation, adhesion, and migration were assessed by CCK-8, EdU, crystal violet, and Transwell assays. In vivo tumor growth and metastasis were evaluated using subcutaneous and tail vein xenograft models in nude mice. RNA-seq and GSEA were performed to identify MACF1-regulated pathways, followed by nuclear-cytoplasmic fractionation, dual-luciferase reporter assays, and immunofluorescence to assess WNT/β-catenin activity. ChIP-qPCR and ChIP-seq data from ENCODE were used to validate NR2F1 binding to the MACF1 promoter. MACF1 knockdown significantly suppressed LUAD cell proliferation, DNA replication, adhesion, and migration, and reduced tumor burden and lung metastases in vivo. Mechanistically, MACF1 activated WNT/β-catenin signaling by promoting CTNNB1 nuclear translocation, which upregulated focal adhesion genes (Paxillin, FAK, ITGB1). CTNNB1 agonist TWS119 restored focal adhesion in MACF1-deficient cells. Bioinformatic prediction and ChIP validation identified NR2F1 as a transcription factor directly targeting the MACF1 promoter. NR2F1 deficiency reduced MACF1 expression and phenocopied its functional loss, while MACF1 overexpression rescued the impaired phenotype. Our study uncovers a previously unrecognized NR2F1-MACF1-WNT axis that drives focal adhesion formation and LUAD progression. Targeting this regulatory circuit may offer new avenues for anti-metastatic therapy in lung adenocarcinoma. 1. NR2F1 is identified as a direct upstream transcription factor that activates MACF1 expression in LUAD. 2. MACF1 promotes LUAD cell proliferation, adhesion, and migration by enhancing focal adhesion assembly. 3. MACF1 activates the WNT/CTNNB1 signaling cascade, facilitating CTNNB1 nuclear translocation and downstream target expression. 4. Loss of MACF1 impairs focal adhesion formation and metastatic potential both in vitro and in xenograft and tail vein models. 5. The NR2F1-MACF1-WNT axis represents a novel regulatory circuit driving LUAD metastasis and offers potential therapeutic targets. Show less
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key u Show more
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key unconventional contributor to the development of atherosclerosis. Here we present a strategy performed by orally administered nano-functionalized probiotics (PDMF@LGG) to inhibit TMAO through the gut microbiota-trimethylamine (TMA)-TMAO axis. PDMF@LGG, composed of polydopamine-coated Lacticaseibacillus rhamnosus GG and nanoparticles based on a reactive oxygen species (ROS)-responsive polymeric prodrug of fluoromethylcholine (FMC), can promote the retention of probiotics and nanoparticles in the intestine to persistently scavenge elevated ROS and release drugs. This process suppresses TMA production and absorption, lowering plasma TMAO levels. The therapeutic effects on male ApoE Show less
Cholesterol stress profoundly modulates cellular processes, but its underlying mechanisms remain incompletely understood. To investigate cholesterol-responsive networks, we performed integrated transc Show more
Cholesterol stress profoundly modulates cellular processes, but its underlying mechanisms remain incompletely understood. To investigate cholesterol-responsive networks, we performed integrated transcriptome (RNA-seq) and metabolome (LC-MS) analyses on HeLa cells treated with cholesterol for 6 and 24 h. Through transcriptomic analysis of cholesterol-stressed HeLa cells, we identified stage-specific responses characterized by early-phase stress responses and late-phase immune-metabolic coordination. This revealed 1340 upregulated and 976 downregulated genes after a 6 h cholesterol treatment, including induction and suppression of genes involved in cholesterol efflux and sterol biosynthesis, respectively, transitioning to Nuclear Factor kappa-B (NF-κB) activation and Peroxisome Proliferator-Activated Receptor (PPAR) pathway modulation by 24 h. Co-expression network analysis prioritized functional modules intersecting with differentially expressed genes. We also performed untargeted metabolomics using cells treated with cholesterol for 6 h, which demonstrated extensive remodeling of lipid species. Interestingly, integrated transcriptomic and metabolic analysis uncovered GFPT1-driven Uridine Diphosphate-N-Acetylglucosamine (UDP-GlcNAc) accumulation and increased taurine levels. Validation experiments confirmed Show less
Heparan sulfate (HS) is an anionic polysaccharide generated by all animal cells, but our understanding of its roles in human pluripotent stem cell (hPSC) self-renewal and differentiation is limited. W Show more
Heparan sulfate (HS) is an anionic polysaccharide generated by all animal cells, but our understanding of its roles in human pluripotent stem cell (hPSC) self-renewal and differentiation is limited. We derived HS-deficient hPSCs by disrupting the EXT1 glycosyltransferase. These EXT1 Show less
Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer's disease (AD) remains unclear. Here, we report Show more
Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer's disease (AD) remains unclear. Here, we report that in the brain of AD patients and animal models, an elevation of poly(C)-binding protein 2 (PCBP2) correlates with biomolecular condensation that involves phase separation. These condensates sequester large numbers of mitochondrial and mRNA-binding proteins, leading to the outside impairment of mitochondrial morphology and function, and BACE1 mRNA decay relative to amyloid deposition. We then identify a small molecule CN-0928 that inhibits the condensates by reducing PCBP2 protein level and mitigates AD pathology and cognitive decline, in which CN-0928 binding to a target protein integrator complex subunit 1 (INTS1) allows to regulate PCBP2 expression. Our findings place PCBP2 condensates as a key player that cooperates the seemingly disparate but important pathways, and show pharmacological modulation of PCBP2 as an effective approach for treating AD. Show less
Fatty acids serve as a crucial energy source for tumor cells during the progression of chronic lymphocytic leukemia (CLL). The present study aims to elucidate the characteristics of fatty acid metabol Show more
Fatty acids serve as a crucial energy source for tumor cells during the progression of chronic lymphocytic leukemia (CLL). The present study aims to elucidate the characteristics of fatty acid metabolism (FAM) in CLL, construct a related prognostic score, and investigate the regulatory role and mechanisms of FAM in CLL development. Bulk RNA sequencing data from CLL patients and healthy controls were analyzed to identify differentially expressed fatty acid metabolic genes. FAM-score was constructed using Cox-LASSO regression and validated. Single-cell RNA sequencing was used to analyze the expression of key FAM genes in CLL immune cell subsets and investigate cellular communication. Functional assays, including cell viability, drug sensitivity, and oxygen consumption assays, were performed to assess the impact of fatty acid oxidation (FAO) inhibition on CLL cells. Three FAM-related genes (LPL, SOCS3, CNR1) were identified with independent prognostic significance to construct the risk score. The FAM-score demonstrated superior prognostic performance compared to the Binet stage and was associated with established clinical prognostic markers. Single-cell analysis revealed distinct expression patterns of LPL, SOCS3, and CNR1 across CLL immune cell subsets. Cellular communication analysis highlighted the regulatory role of distinct B cell and Treg subsets in the CLL microenvironment. CLL patients with high FAM-score displayed distinct immune infiltration patterns, with increased FAO pathway activity. Inhibition of FAO reduced CLL cell viability, synergistically enhanced the efficacy of the PI3K inhibitor idelalisib. The present study constructed a prognostic risk score based on FAM gene expression, revealing related immune phenotypic differences and exploring the regulatory role of FAO in CLL development. Targeting fatty acid metabolism potentially modulates the CLL immune microenvironment and synergistically enhances the efficacy of PI3K inhibitors. Show less
Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to dete Show more
Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to determine its physiological and pathological functions. ANGPTL4 has been shown to be involved in many biological processes, including glucose and lipid metabolism, angiogenesis, and wound healing, with implications in diseases such as type 2 diabetes, cardiovascular (e.g., atherosclerosis) and renal diseases, and cancer. For instance, ANGPTL4 is upregulated in several cancers, including renal cell carcinoma, breast cancer, and colorectal cancer. Interestingly, ANGPTL4 has been shown to exhibit both pro-tumor-promoting tumor growth, cell survival, angiogenesis and metastasis-as well as anti-tumor activities, underscoring its complex roles in cancer biology. This review examines the comprehensive biological functions of ANGPTL4 and its contributions to disease mechanisms with a specific emphasis on cancer, as well as its potential as a therapeutic target across different types of human cancers. Show less
Individuals with type 2 diabetes mellitus have an increased risk of developing Alzheimer's disease (AD). GLP-1 receptor agonists (GLP-1RAs) are used for glycemic control in diabetes and show potential Show more
Individuals with type 2 diabetes mellitus have an increased risk of developing Alzheimer's disease (AD). GLP-1 receptor agonists (GLP-1RAs) are used for glycemic control in diabetes and show potential neuroprotective properties, but their effects on AD and the underlying mechanisms are not well understood. Here we demonstrate that GLP-1RAs can alleviate AD-related phenotypes by activating 5' AMP-activated protein kinase (AMPK) signaling. We found that plasma GLP-1 levels were decreased in AD model mice and negatively correlated with amyloid-beta (Aβ) load in patients with AD. Enhancing GLP-1 signaling through GLP-1RAs increased CaMKK2-AMPK signaling, which subsequently reduced BACE1-mediated cleavage of amyloid precursor protein (APP) and Aβ generation. GLP-1RAs also increased AMPK activity in microglia, inhibiting neuroinflammation and promoting Aβ phagocytosis. Consequently, GLP-1RAs inhibited plaque formation and improved memory deficits in AD model mice. Our findings indicate that AMPK activation mediates the effects of GLP-1RAs on AD, highlighting the therapeutic potential of GLP-1RAs for the treatment of AD. Show less
Chronic stress disrupts neuroendocrine regulation, neurotransmitter balance, and neuronal redox homeostasis, thereby contributing to the development of anxiety-related neuropathology. Arecoline, the p Show more
Chronic stress disrupts neuroendocrine regulation, neurotransmitter balance, and neuronal redox homeostasis, thereby contributing to the development of anxiety-related neuropathology. Arecoline, the predominant alkaloid of Show less
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focu Show more
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focused on mild CP models (unilateral carotid artery occlusion [UCAO] model). This study explored the effect and mechanism of hUC-MSCs in a rat model of moderate-to-severe CP (bilateral carotid artery occlusion [BCAO] model). On postnatal Day 4 (P4), Wistar rat pups underwent BCAO induction. Subsequently, they received either a single intrathecal injection of hUC-MSCs on P21 or repeated injections on P21, P28, P35, and P42. Motor performance was assessed using the rotarod and front-limb suspension tests, while neuronal regeneration and inflammation were evaluated via biomarkers including neuronal nuclear antigen (NeuN), ionized calcium-binding adapter molecule-1 (Iba-1), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and brain-derived neurotrophic factor (BDNF). P18 model screening confirmed that the BCAO model resulted in more severe brain damage and motor impairment than the UCAO model. After injection of lentivirally transfected hUC-MSCs, it was found that hUC-MSCs could nest in the damaged area and survive for at least 3 days. Administration of hUC-MSCs following BCAO modeling led to notable improvements in both behavioral performance and histological outcomes. Furthermore, repeated injections offered greater therapeutic benefits compared to single injection. It indicated that the efficacy of repeated injections of hUC-MSCs in the treatment of moderate-to-severe CP was superior to that of single injection. Its mechanism was related to the improvement of damaged myelin structure, reduced immunoinflammatory responses, and increased neurotrophic support. Show less
To reveal the molecular basis of knee osteoarthritis (KOA) with Yang deficiency and blood stasis syndrome by analyzing the gene expression profiles in synovial fluid and blood of KOA patients with thi Show more
To reveal the molecular basis of knee osteoarthritis (KOA) with Yang deficiency and blood stasis syndrome by analyzing the gene expression profiles in synovial fluid and blood of KOA patients with this syndrome. A total of 80 KOA patients were recruited from October 2022 to June 2024, including 40 cases in the non- Logistic regression analysis showed that compared with KOA patients with non-Yang deficiency and blood stasis syndrome, those with Yang deficiency and blood stasis syndrome had increased BMI, LDL, fibrinogen, total cholesterol, and D-dimer, and decreased HDL, with a clear correlation between the two groups. There were 562 differential genes in the blood, among which 322 were up-regulated and 240 were down-regulated;755 differential genes were found in the synovial fluid, with 350 up-regulated and 405 down-regulated. KEGG signaling pathway analysis of synovial fluid revealed changes in lipid metabolism-related pathways, including cholesterol metabolism, fatty acid metabolism, and PPARG signaling pathway. Analysis of the involved differential genes identified 6 genes in synovial fluid that were closely related to lipid metabolism, namely LRP1, LPL, ACOT6, TM6SF2, DGKK, and PPARG. Subsequently, PCR and immunohistochemical verification were performed using synovial fluid and cartilage samples, and the results were consistent with those of microarray sequencing. This study explores the clinical and genomic correlation between traditional Chinese medicine syndromes and knee osteoarthritis from the perspective of lipid metabolism, and proves that abnormal lipid metabolism is closely related to KOA with Show less
The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced Show more
The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced extracellular vesicles have emerged as key players in inducing angiogenesis by transferring noncoding RNAs. However, the specific role of CRC-derived hypoxic extracellular vesicles (H-EVs) in regulating premetastatic microenvironment (PMN) formation by inducing angiogenesis remains unclear. Our study demonstrates that H-EVs induce angiogenesis and liver metastasis. Through microRNA microarray analysis, we identified a reduction in miR-6084 levels within H-EVs. We found that miR-6084 inhibited angiogenesis by being transferred to endothelial cells via EVs. In endothelial cells, miR-6084 directly targeted angiopoietin like 4 (ANGPTL4) mRNA, thereby suppressing angiogenesis through the ANGPTL4-mediated JAK2/STAT3 pathway. Furthermore, we uncovered that specificity protein 1 (SP1) acted as a transcription factor regulating miR-6084 transcription, while hypoxia-inducible factor 1A (HIF1A) decreased miR-6084 expression by promoting SP1 protein dephosphorylation and facilitating ubiquitin-proteasome degradation in SW620 cells. In clinical samples, we observed low expression of miR-6084 in plasma-derived EVs from CRC patients with liver metastasis. In summary, our findings suggest that CRC-derived H-EVs promote angiogenesis and liver metastasis through the HIF1A/SP1/miR-6084/ANGPTL4 axis. Additionally, miR-6084 holds promise as a diagnostic and prognostic biomarker for CRC liver metastasis. Show less
Cadmium (Cd) contamination in plants and soil poses significant risks to livestock, particularly sheep. Cd exposure often leads to severe gastrointestinal diseases in sheep that are difficult to treat Show more
Cadmium (Cd) contamination in plants and soil poses significant risks to livestock, particularly sheep. Cd exposure often leads to severe gastrointestinal diseases in sheep that are difficult to treat. Milk-derived exosomes, particularly those from sheep milk (SM-Exo), have shown potential in treating gastrointestinal disorders, though their efficacy in Cd-induced colitis remains unclear. In this study, we investigated the therapeutic potential of SM-Exo in a Cd-induced colitis model. Hu sheep were exposed to Cd, and their fecal microbiota were collected to prepare bacterial solutions for fecal microbiota transplantation (FMT) in mice. The changes in gut microbiota and gene expression were analyzed through microbiome and transcriptomics. Our results showed that prior to treatment, harmful bacteria (e.g., Show less
Dominant follicular development and atresia are governed by the proliferation of granulosa cells (GCs), a process influenced by the delicate balance between apoptosis and autophagy. Oxidative stress, Show more
Dominant follicular development and atresia are governed by the proliferation of granulosa cells (GCs), a process influenced by the delicate balance between apoptosis and autophagy. Oxidative stress, a pivotal catalyst of GCs apoptosis, modulates gene expression through epigenetic mechanisms, including chromatin remodeling. Nevertheless, the regulatory mechanisms underpinning GCs functionality in relation to prolificacy remain inadequately elucidated. In this study, we discovered that the chromatin accessibility of nuclear receptor subfamily 1 group D member 1 (NR1D1) was markedly enhanced in dominant follicular GCs from low-prolificacy sheep, as evidenced by Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq), which correlated with elevated NR1D1 transcript levels. Remarkably, NR1D1 emerged as a novel regulator of follicular development, exhibiting heightened expression in dominant follicles. The overexpression of NR1D1 induced cell cycle arrest, autophagy activation, and mitochondrial dysfunction via the AMPK pathway, while its knockdown fostered GCs survival and functionality. Furthermore, NR1D1 inhibits the transcription of HSD17B12, thereby contributing to oxidative stress (ROS)-induced apoptosis, as demonstrated by CUT&Tag-qPCR and dual luciferase assays. The downregulation of HSD17B12 partially alleviated the effects of NR1D1 knockdown on GCs functionality. These findings indicate that NR1D1 orchestrates GCs proliferation and apoptosis through the suppression of HSD17B12 and the activation of the AMPK pathway, establishing NR1D1 as a novel transcription factor implicated in follicular development and ovarian function, with significant implications for prolificacy. Show less
Atherosclerosis serves as the core pathological basis of cardiovascular, cerebrovascular, and peripheral arterial diseases, posing a serious threat to human health. However, current mainstream treatme Show more
Atherosclerosis serves as the core pathological basis of cardiovascular, cerebrovascular, and peripheral arterial diseases, posing a serious threat to human health. However, current mainstream treatments such as statin drugs and stent implantation are associated with significant side effects or limited efficacy, highlighting the urgent need for new therapeutic strategies. Pulsed electromagnetic fields (PEMFs), due to their noninvasive nature and anti-inflammatory properties, show potential in the treatment of atherosclerosis. This study utilized ApoE-/- mice, ApoE-/-NLRP3-/- knockout mice, human umbilical vein endothelial cells (HUVECs), human aortic endothelial cells (HAECs), and human plasma samples for experiments, revealing significant endothelial cell (EC) inflammation and pyroptosis during the progression of atherosclerosis. PEMFs were found to effectively inhibit the activation of the NLRP3 inflammasome, reduce plaque formation, and delay the progression of atherosclerosis. Proteomic analysis of plasma from atherosclerosis patients further indicated elevated expression levels of proteins related to inflammation and pyroptosis, with particularly notable changes in membrane proteins. Mechanistic studies demonstrated that PEMFs improve mitochondrial dysfunction in ECs by regulating membrane tension and the mechanosensitive tension-mediated transient receptor potential vanilloid 4 (TRPV4) channels, thereby reducing pyroptosis. This discovery not only reveals a novel mechanobiological pathway but also provides a solid theoretical foundation for the development of PEMF-based therapies for atherosclerosis. Schematic diagram of the mechanism by which PEMFs treat atherosclerosis (created in BioRender). Wei, B. (2025) https://BioRender.com/undefined ). Show less
Astrocytes are key regulators of neuroinflammation in multiple sclerosis (MS). Electroacupuncture (EA), a safe and cost-effective adjuvant therapy, has shown benefits in neurodegenerative diseases, bu Show more
Astrocytes are key regulators of neuroinflammation in multiple sclerosis (MS). Electroacupuncture (EA), a safe and cost-effective adjuvant therapy, has shown benefits in neurodegenerative diseases, but its astrocyte-related mechanisms remain unclear. Here, we demonstrated that EA at ST36 alleviated blood-brain barrier (BBB) disruption and neuroinflammation during the peak period of experimental autoimmune encephalomyelitis (EAE). Additionally, EA at ST36 upregulated the expression of α-melanocyte-stimulating hormone (α-MSH) and its receptor melanocortin-4 receptor (MC4R) in spinal astrocytes. Pharmacological studies showed that MC4R agonist RO27-3225 mimicked the therapeutic effects of EA, whereas MC4R antagonist TCMCB07 weakened EA-mediated BBB protection and neuroinflammation suppression. Moreover, astrocyte-specific silencing of MC4R via adeno-associated virus (AAV) weakened EA-mediated BBB protection and neuroinflammation suppression. RNA-sequencing (RNA-seq) and western blot (WB) revealed that EA exerts neuroprotective effects by activating MC4R to inhibit MAPK and NF-κB signaling pathways. Moreover, in MC4R-overexpressing astrocytes, α-MSH and RO27-3225 reduced inflammation responses, while TCMCB07 reversed the effects by MAPK/NF-κB signaling pathways. Collectively, our findings identify astrocytic MC4R as a critical mediator of EA-driven neuroprotection by suppressing MAPK/NF-κB signaling, providing mechanistic insight and a promising therapeutic target for EAE and other neuroinflammatory disorders. Show less
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported Show more
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations. Show less
Adipogenic differentiation of adipose-derived stem cells (ADSCs) is fundamental to both adipose tissue homeostasis and clinical applications, particularly fat grafting. However, the global and stage-s Show more
Adipogenic differentiation of adipose-derived stem cells (ADSCs) is fundamental to both adipose tissue homeostasis and clinical applications, particularly fat grafting. However, the global and stage-specific transcriptional regulatory networks underlying ADSC adipogenesis remain incompletely elucidated. In this study, we integrated bulk and single-cell RNA-seq datasets across multiple time points of ADSC adipogenesis to identify core regulators of differentiation and maturation. A total of 41 genes were consistently upregulated during early differentiation, among which eight hub genes (FABP4, FASN, FABP5, ADIPOQ, PLIN1, LPL, CIDEC, and ACSL1) formed a tightly connected protein-protein interaction (PPI) module associated with lipid metabolism, lipid droplet formation, and adipocyte maturation. Further integration of differentially expressed lncRNAs and miRNAs led to the construction of a ceRNA network involving 7 mRNAs, 9 miRNAs, and 4 lncRNAs, comprising 34 predicted lncRNA-miRNA-mRNA regulatory axes. To identify temporal transcriptional regulators, we defined five genes (TTC14, MBNL2, UBR3, ABCD2, and SORT1) as early-stage inducers of adipogenesis, and four genes (UQCR11, NDUFB4, S100A10, and PRDX3) as late-stage regulators involved in maintaining the mature phenotype. These stage-specific regulators showed distinct temporal expression patterns and were validated by qPCR. GeneMANIA network analysis further revealed that early-stage regulators were enriched in lipid transport and lipase activity regulation, while late-stage regulators were associated with mitochondrial electron transport and energy metabolism. These findings highlight the stage-dependent transcriptional landscape of ADSC adipogenesis and provide candidate regulatory targets for modulating adipocyte differentiation and stability. Show less
Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel enteric coronavirus that causes severe clinical diarrhea and intestinal pathological injury in pigs. Selective autophagy is an important Show more
Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel enteric coronavirus that causes severe clinical diarrhea and intestinal pathological injury in pigs. Selective autophagy is an important mechanism of host defense against virus invasion. However, the mechanism through which SADS-CoV-mediated selective autophagy mediates the innate immune response remains unknown. Here, we report that the host protein PABPC4 can inhibit SADS-CoV replication through targeting and degrading its N protein. Furthermore, we demonstrate that PABPC4 recruits MARCHF8 (an E3 ubiquitin ligase), which ubiquitinates the N protein and is degraded via NDP52/CALCOCO2 (a selective autophagy cargo receptor). Taken together, these findings reveal a new mechanism by which PABPC4 inhibits virus replication, and reveal a new target for antiviral drug development. Show less
Cholecystectomy alters lipid profiles and is associated with the risk of major adverse cardiac and cerebrovascular events (MACCE), yet the results are ambiguous. To assess the causal effects of cholec Show more
Cholecystectomy alters lipid profiles and is associated with the risk of major adverse cardiac and cerebrovascular events (MACCE), yet the results are ambiguous. To assess the causal effects of cholecystectomy on blood lipid levels and risks of MACCE, we performed Mendelian randomization (MR) aiming to reduce confounding. We used genetic data on gallbladder removal, lipid levels, and MACCE from public databases. MR analysis estimated causal effects using genetic variants as instruments. Enrichment analysis identified relevant metabolic pathways, while multivariable MR evaluated specific lipid subtypes. Expression Quantitative Trait Loci MR pinpointed key genes, with cellular distribution insights from single-cell sequencing. Cholecystectomy was associated with delayed onset of angina, coronary heart disease, heart failure, myocardial infarction, and stroke. The ApoB/ApoA1 ratio was a key mediator, and the LPL gene influenced lipid-related cardiovascular risk. Cholecystectomy may reduce cardiovascular risks by lowering the ApoB/ApoA1 ratio, which highlights the role of lipid regulation in mitigating cardiovascular risk post-cholecystectomy. Show less