Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune respo Show more
Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify that AXIN1 acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN1 maintains the stability of the transcription factor interferon regulatory factor 3 (IRF3) by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN1 undergoes a phase separation triggered by phosphorylated TANK-binding kinase 1 (TBK1). This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN1 RGS domain, enhances the AXIN1-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN1 expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN1 regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN1 agonist KYA1797K as an effective antiviral agent. Show less
Plant phenolics have been known for various biological activities. This study aims to extract and examine the presence of phenolics in Bao mango (Mangifera indica L. var.) peel ethanolic extract (MPE) Show more
Plant phenolics have been known for various biological activities. This study aims to extract and examine the presence of phenolics in Bao mango (Mangifera indica L. var.) peel ethanolic extract (MPE). Further, antioxidant, anti-diabetic (α-amylase, and α-glucosidase inhibitory activity), and anti- Alzheimer's disease (AD) (acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE-1) inhibitory activity) efficacy of MPE were determined. The results indicated that mangiferin (8755.89 mg/ 100 g extract) was the major phenolic compound in MPE. An antioxidant mechanism revealed that MPE had a higher radical scavenging ability (4266.70 µmol TE/g extract) compared to reducing power (FRAP) or oxygen radical absorption capacity (ORAC). Further Show less
Bladder cancer (BLCA) is a tumor that affects men more than women. The biological function and prognostic value of androgen-responsive genes (ARGs) in BLCA are currently unknown. To address this, we e Show more
Bladder cancer (BLCA) is a tumor that affects men more than women. The biological function and prognostic value of androgen-responsive genes (ARGs) in BLCA are currently unknown. To address this, we established an androgen signature to determine the prognosis of BLCA. Sequencing data for BLCA from the TCGA and GEO datasets were used for research. The tumor microenvironment (TME) was measured using Cibersort and ssGSEA. Prognosis-related genes were identified and a risk score model was constructed using univariate Cox regression, LASSO regression, and multivariate Cox regression. Drug sensitivity analysis was performed using Genomics of drug sensitivity in cancer (GDSC). Real-time quantitative PCR was performed to assess the expression of representative genes in clinical samples. ARGs (especially the CDK6, FADS1, PGM3, SCD, PTK2B, and TPD52) might regulate the progression of BLCA. The different expression patterns of ARGs may lead to different immune cell infiltration. The risk model indicates that patients with higher risk scores have a poorer prognosis, more stromal infiltration, and an enrichment of biological functions. Single-cell RNA analysis, bulk RNA data, and PCR analysis support the reliability of this risk model, and a nomogram was also established for clinical use. Drug prediction analysis showed that high-risk patients had a better response to fludarabine, AZD8186, and carmustine. ARGs played an important role in the progression, immune infiltration, and prognosis of BLCA. The ARGs model has high accuracy in predicting the prognosis of BLCA patients and provides more effective medication guidelines. Show less
To explore the mechanism by which Three-month-old male APP/PS1 transgenic mice and wild-type C57BL/6 mice were both randomized into control group, model group, donepezil (1.67 mg/kg) group, and YGS (7 Show more
To explore the mechanism by which Three-month-old male APP/PS1 transgenic mice and wild-type C57BL/6 mice were both randomized into control group, model group, donepezil (1.67 mg/kg) group, and YGS (7.5 g/kg) group and received the corresponding treatments Compared with the control mice, APP/PS1 mice showed significant impairment of learning and memory abilities, increased degeneration or necrosis of hippocampal and cortical neurons, pathological scores, Aβ-positive plaques, elevated Aβ YGS improves learning and memory changes in APP/PS1 mice by ameliorating neuronal damage and Aβ pathology in the brain and regulating brain fluid metabolism. Show less
Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide. Catheter ablation has become a crucial treatment for AF. However, there is a possibility of atrial fibrillation recurrence aft Show more
Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide. Catheter ablation has become a crucial treatment for AF. However, there is a possibility of atrial fibrillation recurrence after catheter ablation. Our study sought to elucidate the role of lncRNA‒mRNA regulatory networks in late AF recurrence after catheter ablation. We conducted RNA sequencing to profile the transcriptomes of 5 samples from the presence of recurrence after AF ablation (P-RAF) and 5 samples from the absence of recurrence after AF ablation (A-RAF). Differentially expressed genes (DEGs) and long noncoding RNAs (DE-lncRNAs) were analyzed using the DESeq2 R package. The functional correlations of the DEGs were assessed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein‒protein interaction (PPI) network was constructed using STRING and Cytoscape. We also established a lncRNA‒mRNA regulatory network between DE-lncRNAs and DEGs using BEDTools v2.1.2 software and the Pearson correlation coefficient method. To validate the high-throughput sequencing results of the hub genes, we conducted quantitative real-time polymerase chain reaction (qRT‒PCR) experiments. A total of 28,528 mRNAs and 42,333 lncRNAs were detected. A total of 96 DEGs and 203 DE-lncRNAs were identified between the two groups. GO analysis revealed that the DEGs were enriched in the biological processes (BPs) of "regulation of immune response" and "regulation of immune system process", the cellular components (CCs) of "extracellular matrix" and "cell‒cell junction", and the molecular functions (MFs) of "signaling adaptor activity" and "protein-macromolecule adaptor activity". According to the KEGG analysis, the DEGs were associated with the "PI3K-Akt signaling pathway" and "MAPK signaling pathway." Nine hub genes (MMP9, IGF2, FGFR1, HSPG2, GZMB, PEG10, GNLY, COL6A1, and KCNE3) were identified through the PPI network. lncRNA-TMEM51-AS1-201 was identified as a core regulator in the lncRNA‒mRNA regulatory network, suggesting its potential impact on the recurrence of AF after catheter ablation through the regulation of COL6A1, FGFR1, HSPG2, and IGF2. The recurrence of atrial fibrillation after catheter ablation may be associated with immune responses and fibrosis, with the extracellular matrix playing a crucial role. TMEM51-AS1-201 has been identified as a potential key target for AF recurrence after catheter ablation. Show less
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. It is also known to be a risk factor for Alzheimer's disease (AD). Insulin plays Show more
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. It is also known to be a risk factor for Alzheimer's disease (AD). Insulin plays a crucial role in regulating the body's metabolism and is responsible for activating the Phosphoinotide-3-Kinase (PI3K)/Protein Kinase B (Akt) signaling pathway. This pathway is activated when insulin binds to the insulin receptor on nerve cells, and it helps regulate the metabolism of glucose and lipids. Dysfunction in the insulin signaling pathway can lead to a decrease in brain insulin levels and insulin sensitivity, thereby inducing disruptions in insulin signal transduction and leading to disorders in brain energy metabolism. Moreover, these dysfunctions also contribute to the accumulation of β-amyloid (Aβ) deposition and the hyperphosphorylation of Tau protein, both of which are characteristic features of AD. Therefore, this article focuses on insulin resistance to reveal the complex mechanism between brain insulin resistance and AD occurrence in T2DM. On this basis, this article further summarizes the biological effects and mechanisms of antidiabetic drugs on the two diseases, aiming to provide new ideas for the discovery of drugs for the treatment of T2DM combined with AD. Show less
Hematopoietic stem and progenitor cells (HSPCs) possess the potential to produce all types of blood cells throughout their lives. It is well recognized that HSPCs are heterogeneous, which is of great Show more
Hematopoietic stem and progenitor cells (HSPCs) possess the potential to produce all types of blood cells throughout their lives. It is well recognized that HSPCs are heterogeneous, which is of great significance for their clinical applications and the treatment of diseases associated with HSPCs. This study presents a novel technology called Single-Cell transcriptome Analysis and Lentiviral Barcoding (SCALeBa) to investigate the molecular mechanisms underlying the heterogeneity of human HSPCs in vivo. The SCALeBa incorporates a transcribed barcoding library and algorithm to analyze the individual cell fates and their gene expression profiles simultaneously. Our findings using SCALeBa reveal that HSPCs subset with stronger stemness highly expressed MYL6B, ATP2A2, MYO19, MDN1, ING3, and so on. The high expression of COA3, RIF1, RAB14, and GOLGA4 may contribute to the pluripotent-lineage differentiation of HSPCs. Moreover, the roles of the representative genes revealed in this study regarding the stemness of HPSCs were confirmed with biological experiments. HSPCs expressing MRPL23 and RBM4 genes may contribute to differentiation bias into myeloid and lymphoid lineage, respectively. In addition, transcription factor (TF) characteristics of lymphoid and myeloid differentiation bias HSPCs subsets were identified and linked to previously identified genes. Furthermore, the stemness, pluripotency, and differentiation-bias genes identified with SCALeBa were verified in another independent HSPCs dataset. Finally, this study proposes using the SCALeBa-generated tracking trajectory to improve the accuracy of pseudo-time analysis results. In summary, our study provides valuable insights for understanding the heterogeneity of human HSPCs in vivo and introduces a novel technology, SCALeBa, which holds promise for broader applications. KEY POINTS: SCALeBa and its algorithm are developed to study the molecular mechanism underlying human HSPCs identity and function. The human HSPCs expressing MYL6B, MYO19, ATP2A2, MDN1, ING3, and PHF20 may have the capability for high stemness. The human HSPCs expressing COA3, RIF1, RAB14, and GOLGA4 may have the capability for pluripotent-lineage differentiation. The human HSPCs expressing MRPL23 and RBM4 genes may have the capability to differentiate into myeloid and lymphoid lineage respectively in vivo. The legitimacy of the identified genes with SCALeBa was validated using biological experiments and a public human HSPCs dataset. SCALeBa improves the accuracy of differentiation trajectories in monocle2-based pseudo-time analysis. Show less
COVID-19 is a highly infectious respiratory disease whose progression has been associated with multiple factors. From SARS-CoV-2 infection to death, biomarkers capable of predicting different disease Show more
COVID-19 is a highly infectious respiratory disease whose progression has been associated with multiple factors. From SARS-CoV-2 infection to death, biomarkers capable of predicting different disease processes are needed to help us further understand the molecular progression of COVID-19 disease. The aim is to find differentially expressed proteins that are associated with the progression of COVID-19 disease or can be potential biomarkers, and to provide a reference for further understanding of the molecular mechanisms of COVID-19 occurrence, progression, and treatment. Data-independent Acquisition (DIA) proteomics to obtain sample protein expression data, using R language screening differentially expressed proteins. Gene Ontology and Kyoto Encyclopedia for Genes and Genomes analysis was performed on differential proteins and protein-protein interaction (PPI) network was constructed to screen key proteins. A total of 47 differentially expressed proteins were obtained from COVID-19 incubation patients and healthy population (L/H), mainly enriched in platelet-related functions, and complement and coagulation cascade reaction pathways, such as platelet degranulation and platelet aggregation. A total of 42 differential proteins were obtained in clinical and latent phase patients (C/L), also mainly enriched in platelet-related functions and in complement and coagulation cascade reactions, platelet activation pathways. A total of 10 differential proteins were screened in recovery and clinical phase patients (R/C), mostly immune-related proteins. The differentially expressed proteins in different stages of COVID-19 are mostly closely associated with coagulation, and key differential proteins, such as FGA, FGB, FGG, ACTB, PFN1, VCL, SERPZNCL, APOC3, LTF, and DEFA1, have the potential to be used as early diagnostic markers. Show less
Nonspecific orbital inflammation (NSOI) is an idiopathic, persistent, and proliferative inflammatory condition affecting the orbit, characterized by polymorphous lymphoid infiltration. Its pathogenesi Show more
Nonspecific orbital inflammation (NSOI) is an idiopathic, persistent, and proliferative inflammatory condition affecting the orbit, characterized by polymorphous lymphoid infiltration. Its pathogenesis and progression have been linked to imbalances in tumor metabolic pathways, with glutamine (Gln) metabolism emerging as a critical aspect in cancer. Metabolic reprogramming is known to influence clinical outcomes in various malignancies. However, comprehensive research on glutamine metabolism's significance in NSOI is lacking. This study conducted a bioinformatics analysis to identify and validate potential glutamine-related molecules (GlnMgs) associated with NSOI. The discovery of GlnMgs involved the intersection of differential expression analysis with a set of 42 candidate GlnMgs. The biological functions and pathways of the identified GlnMgs were analyzed using GSEA and GSVA. Lasso regression and SVM-RFE methods identified hub genes and assessed the diagnostic efficacy of fourteen GlnMgs in NSOI. The correlation between hub GlnMgs and clinical characteristics was also examined. The expression levels of the fourteen GlnMgs were validated using datasets GSE58331 and GSE105149. Fourteen GlnMgs related to NSOI were identified, including FTCD, CPS1, CTPS1, NAGS, DDAH2, PHGDH, GGT1, GCLM, GLUD1, ART4, AADAT, ASNSD1, SLC38A1, and GFPT2. Biological function analysis indicated their involvement in responses to extracellular stimulus, mitochondrial matrix, and lipid transport. The diagnostic performance of these GlnMgs in distinguishing NSOI showed promising results. This study successfully identified fourteen GlnMgs associated with NSOI, providing insights into potential novel biomarkers for NSOI and avenues for monitoring disease progression. Show less
Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor response to all therapeutic modalities and dismal prognosis. The presence of tertiary lymphoid structures (TLSs) in various solid cance Show more
Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor response to all therapeutic modalities and dismal prognosis. The presence of tertiary lymphoid structures (TLSs) in various solid cancers is of crucial prognostic significance, highlighting the intricate interplay between the tumor microenvironment and immune cells aggregation. However, the extent to which TLSs and immune status affect PDAC prognosis remains incompletely understood. Here, we sought to unveil the unique properties of TLSs in PDAC by leveraging both single-cell and bulk transcriptomics, culminating in a risk model that predicts clinical outcomes. We used TLS scores based on a 12-gene (CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13) and 9-gene (PTGDS, RBP5, EIF1AY, CETP, SKAP1, LAT, CCR6, CD1D, and CD79B) signature, respectively, and examined their distribution in cell clusters of single-cell data from PDAC samples. The markers involved in these clusters were selected to develop a prognostic model using The Cancer Genome Atlas Program database as the training cohort and Gene Expression Omnibus database as the validation cohort. Further, we compared the immune infiltration, drug sensitivity, and enriched and differentially expressed genes between the high- and low-risk groups in our model. Therefore, we established a risk model that has significant implications for the prognostic assessment of PADC patients with remarkable differences in immune infiltration and chemosensitivity between the low- and high-risk groups. This paradigm established by TLS-related cell marker genes provides a prognostic prediction and a panel of novel therapeutic targets for exploring potential immunotherapy. Show less
Olezarsen is a GalNAc A randomized, placebo-controlled, double-blind phase 1 study was performed in 28 healthy Japanese American participants treated with olezarsen in single-ascending doses (SAD; 30, Show more
Olezarsen is a GalNAc A randomized, placebo-controlled, double-blind phase 1 study was performed in 28 healthy Japanese American participants treated with olezarsen in single-ascending doses (SAD; 30, 60, 90 mg) or multiple doses (MD; 60 mg every 4 weeks for 4 doses). The primary, secondary, and exploratory objectives were safety and tolerability, pharmacokinetics, and effects of olezarsen on fasting serum triglycerides and apoC-III, respectively. There were 20 participants (16 active:4 placebo) in the SAD part of the study, and 8 participants (6 active:2 placebo) in the MD part of the study. For the primary endpoint, no serious adverse events or clinically relevant laboratory abnormalities were reported. The majority of olezarsen plasma exposure occurred within 24 h post-dose. In the SAD cohorts at Day 15 the percentage reduction in apoC-III/TG was - 39.4%/ - 17.8%, - 60.8%/ - 52.7%, and - 68.1%/ - 39.2% in the 30, 60 and 90 mg doses, respectively, vs 2.3%/44.5% increases in placebo. In the MD cohort, at Day 92 the percentage reduction in apoC-III/TG was - 81.6/ - 73.8% vs - 17.2/ - 40.8% reduction in placebo. Favorable changes were also present in VLDL-C, apoB and HDL-C. Single- and multiple-dose administration of olezarsen was safe, was well tolerated, and significantly reduced apoC-III and triglyceride levels in healthy Japanese Americans. Show less
Many sex-specific biomarkers have been recently revealed in Alzheimer's disease (AD); however, cerebral glial cells were rarely reported. This study analyzed 220,095 single-nuclei transcriptomes from Show more
Many sex-specific biomarkers have been recently revealed in Alzheimer's disease (AD); however, cerebral glial cells were rarely reported. This study analyzed 220,095 single-nuclei transcriptomes from the frontal cortex of thirty-three AD individuals in the GEO database. Sex-specific Differentially Expressed Genes (DEGs) were identified in glial cells, including 243 in astrocytes, 1,154 in microglia, and 572 in oligodendrocytes. Gene Ontology (GO) functional annotation analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed functional concentration in synaptic, neural, and hormone-related pathways. Protein-protein interaction network (PPI) identified MT3, CALM2, DLG2, KCND2, PAKACB, CAMK2D, and NLGN4Y in astrocytes, TREM2, FOS, APOE, APP, and NLGN4Y in microglia, and GRIN2A, ITPR2, GNAS, and NLGN4Y in oligodendrocytes as key genes. NLGN4Y was the only gene shared by the three glia and was identified as the biomarker for the gender specificity of AD. Gene-transcription factor (TF)-miRNA coregulatory network identified key regulators for NLGN4Y and its target TCMs. Ecklonia kurome Okam (Kunbu) and Herba Ephedrae (Mahuang) were identified, and the effects of the active ingredients on AD were displayed. Finally, enrichment analysis of Kunbu and Mahuang suggested that they might act as therapeutic candidates for gender specificity of AD. Show less
Melanocortin-4 receptor (MC4R) functions as a crucial neuroendocrine G protein-coupled receptor (GPCR) in the central nervous system of mammals, displaying agonist-independent constitutive activity th Show more
Melanocortin-4 receptor (MC4R) functions as a crucial neuroendocrine G protein-coupled receptor (GPCR) in the central nervous system of mammals, displaying agonist-independent constitutive activity that is mainly determined by its N-terminal domain. We previously reported that zebrafish MC4R exhibited a much higher basal cAMP level in comparison to mammalian MC4Rs. However, the functional evolution of constitutive activities in chordate MC4Rs remains to be elucidated. Here we cloned and compared the constitutive activities of MC4Rs from nine vertebrate species and showed that the additive action of the N-terminus with the extracellular region or transmembrane domain exhibited a combined pharmacological effect on the MC4R constitutive activity. In addition, we demonstrated that four residues of F149, Q156, V163, and K164 of the second intracellular loop played a vital role in determining MC4R constitutive activity. This study provided novel insights into functional evolution and identified a key motif essential for constitutive modulation of MC4R signaling. Show less
Diabetes and its complications cause a heavy burden of disease worldwide. In recent years, Mendelian randomization (MR) has been widely used to discover the pathogenesis and epidemiology of diseases, Show more
Diabetes and its complications cause a heavy burden of disease worldwide. In recent years, Mendelian randomization (MR) has been widely used to discover the pathogenesis and epidemiology of diseases, as well as to discover new therapeutic targets. Therefore, based on systematic "druggable" genomics, we aim to identify new therapeutic targets for diabetes and analyze its pathophysiological mechanisms to promote its new therapeutic strategies. We used double sample MR to integrate the identified druggable genomics to evaluate the causal effect of quantitative trait loci (eQTLs) expressed by druggable genes in blood on type 1 and 2 diabetes (T1DM and T2DM). Repeat the study using different data sources on diabetes and its complications to verify the identified genes. Not only that, we also use Bayesian co-localization analysis to evaluate the posterior probabilities of different causal variations, shared causal variations, and co-localization probabilities to examine the possibility of genetic confounding. Finally, using diabetes markers with available genome-wide association studies data, we evaluated the causal relationship between established diabetes markers to explore possible mechanisms. Overall, a total of 4,477 unique druggable genes have been gathered. After filtering using methods such as Bonferroni significance (P<1.90e-05), the MR Steiger directionality test, Bayesian co-localization analysis, and validation with different datasets, Finally, 7 potential druggable genes that may affect the results of T1DM and 7 potential druggable genes that may affect the results of T2DM were identified. Reverse MR suggests that C4B may play a bidirectional role in the pathogenesis of T1DM, and none of the other 13 target genes have a reverse causal relationship. And the 7 target genes in T2DM may each affect the biomarkers of T2DM to mediate the pathogenesis of T2DM. This study provides genetic evidence supporting the potential therapeutic benefits of targeting seven druggable genes, namely MAP3K13, KCNJ11, REG4, KIF11, CCNE2, PEAK1, and NRBP1, for T2DM treatment. Similarly, targeting seven druggable genes, namely ERBB3, C4B, CD69, PTPN22, IL27, ATP2A1, and LT-β, has The potential therapeutic benefits of T1DM treatment. This will provide new ideas for the treatment of diabetes and also help to determine the priority of drug development for diabetes. Show less
Metal-organic hybrid materials with long persistent luminescence (LPL) properties have attracted a lot of attention due to their enormous potential for applications in information encryption, anticoun Show more
Metal-organic hybrid materials with long persistent luminescence (LPL) properties have attracted a lot of attention due to their enormous potential for applications in information encryption, anticounterfeiting, and other correlation fields. However, achieving multimodal luminescence in a single component remains a significant challenge. Herein, we report two two-dimensional LPL coordination polymers: {[Zn Show less
Dyslipidemia has been established as a potential risk factor for venous thromboembolism (VTE) in several observational studies. Statins and novel lipid-modifying agents are being explored for their po Show more
Dyslipidemia has been established as a potential risk factor for venous thromboembolism (VTE) in several observational studies. Statins and novel lipid-modifying agents are being explored for their potential in VTE prevention, encompassing deep vein thrombosis (DVT), and pulmonary embolism (PE). Nonetheless, conclusive evidence supporting the effectiveness remains uncertain. Without definitive proof, the current recommendation of lipid-lowering drugs (LLDs) for preventing VTE, either primarily or secondarily, is not support. An investigation into the impact of 8 classes of LLDs on VTE was conducted using a drug-target Mendelian randomization approach. The drug categories examined included 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), apolipoprotein B, proprotein convertase subtilisin/kexin type 9, Niemann-Pick C1-like 1, lipoprotein lipase (LPL), angiopoietin-like 3, apolipoprotein C3 (APOC3), and peroxisome proliferator-activated receptor alpha. Leveraging genetic variants situated proximate to or within drug-target genes linked with low-density lipoprotein and triglycerides, we acted as proxies for LLDs. The UK Biobank study was the source of data on VTE, PE, and DVT of lower extremities (LEDVT). We employed the inverse-variance weighted method for the core analysis in Mendelian randomization, complemented by sensitivity analysis to investigate horizontal pleiotropy and heterogeneity. Employing genetic proxies to inhibit HMGCR revealed a notable correlation with reduced LEDVT risk (odds ratio [OR]: 0.995, 95% CI: 0.992-0.998, P = .002), VTE (OR: 0.994, 95% CI: 0.988-1.000, P = .033), but a no significant association with PE (OR: 1.000, 95% CI: 0.994-1.002, P = .246). The suppression of APOB was linked with an elevated risk of experiencing LEDVT (OR: 1.002, 95% CI: 1.001-1.004, P = .006), VTE (OR: 1.005, 95% CI: 1.002-1.007, P < .001), and PE (OR: 1.002, 95% CI: 1.000-1.004, P = .031). Similarly, the activation of LPL was associated with increased risks for VTE (OR: 1.003, 95% CI: 1.001-1.005, P = .003) and PE (OR: 1.003, 95% CI: 1.002-1.005, P < .001). Additionally, the inhibition of APOC3 was linked to a higher DVT risk (OR: 1.002, 95% CI: 1.000-1.004, P = .038). Research has shown that HMGCR, out of 8 lipid-lowering drug-targets evaluated, exhibited a significant correlation with VTE and LEDVT, highlighting its potential as an effective target for the treatment or prevention of these conditions. In contrast, APOB, LPL, and APOC3 each contribute to an increased risk of VTE, PE, and LEDVT in various degrees, pharmacovigilance for VTE, PE, and LEDVT risk among users of APOB inhibitors, LPL activation, and APOC3 inhibitors may be warranted. Show less
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide. Dysregulation of various metabolism pathways may mediate the development of AD pat Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide. Dysregulation of various metabolism pathways may mediate the development of AD pathology and cognitive dysfunction. Variants of triggering receptor expressed on myeloid cells-2 (TREM2) are known to increase the risk of developing AD. TREM2 plays a role in AD development by maintaining cellular energy and biosynthesis, but the precise mechanism through which it accomplishes this is unknown. Metabolomic analysis of hippocampal tissue from APP/PS1 and APP/PS1-TREM2 knockout (KO) mice found that TREM2 KO was associated with abnormalities in several metabolism pathways, and the effect was particularly pronounced in lipid metabolism and glucose metabolism pathways. Consistently, transcriptomic analysis of these mice determined that most differentially expressed genes were involved in energy metabolism pathways. We screened seven differentially expressed genes in APP/PS1-TREM2 KO mice that may influence AD development by altering energy metabolism. Integrative analysis of the metabolomic and transcriptomic profiles showed that TREM2 may regulate lipid metabolism and sphingolipid metabolism by affecting lipoprotein lipase (LPL) expression, thereby influencing AD progression. Our results prompt further studies of the interactions among TREM2, LPL, glucolipid metabolism, and sphingolipid metabolism in AD to identify new diagnostic and treatment strategies. Show less
The aim of this study is to screen key target genes of osteoarthritis associated with aging and to preliminarily explore the associated immune infiltration cells and potential drugs. Differentially ex Show more
The aim of this study is to screen key target genes of osteoarthritis associated with aging and to preliminarily explore the associated immune infiltration cells and potential drugs. Differentially expressed senescence-related genes (DESRGs) selected from Cellular senescence-related genes (SRGs) and differentially expressed genes (DEGs) were analyzed using Gene Ontology enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and protein-protein interaction networks. Hub genes in DESRGs were selected based on degree, and diagnostic genes were further screened by gene expression and receiver operating characteristic (ROC) curve. CIBERSORTx and ssGSEA algorithms were then used to assess immune cell infiltration and to analyse the correlation between key DESRGs and immune infiltration. Finally, a miRNA-gene network of diagnostic genes was constructed and targeted drug prediction was performed. Combined with the DEGs and SRGs, we screened 19 DESRGs for further study. Five diagnostic genes were ultimately identified: CDKN1A, VEGFA, MCL1, SNAI1 and MYC. ROC analysis showed that the area under the curve (AUC). Correlation analysis showed that the five hub genes were closely associated with neutrophil, plasmacytoid dendritic cell, activated CD4 T-cell and type 2 T-helper cell infiltration in the development of Osteoarthritis (OA). Finally, we found that drugs such as lithium chloride, acetaminophen, curcumin, celecoxib and resveratrol could be targeted for the treatment of senescence-related OA. The results of this study indicate that CDKN1A, VEGFA, MCL1, SNAI1, and MYC are key biomarkers that can be used to predict and prevent early aging-related OA. Lithium chloride, acetaminophen, curcumin, celecoxib, and resveratrol can be used for personalized treatment of aging-related OA. Show less
Cyclic dipeptides (CDPs), known for their diverse biological activities, have potential therapeutic applications in mental and behavioral disorders (MBDs), particularly schizophrenia. This study explo Show more
Cyclic dipeptides (CDPs), known for their diverse biological activities, have potential therapeutic applications in mental and behavioral disorders (MBDs), particularly schizophrenia. This study explores the CDPs' therapeutic potential using bibliometric analysis, network pharmacology, molecular docking, and experimental verification, focusing on the interactions with the SIGMA1 receptor. A literature review over three decades utilizing the Web of Science Core Collection (WOSCC) was conducted to identify the emerging trends in CDPs research. A compound library was constructed from the PubChem database, and target prediction using SwissTargetPrediction revealed 800 potential protein targets. A compound-target network highlighted the key interactions with kinases, G protein-coupled receptors, and chromatin-modifying enzymes. Enrichment analysis revealed significant associations with schizophrenia and other MBDs. Schizophrenia-related targets among the potential protein targets were identified using the GEO database. Molecular docking results showed interactions of MC4R, OPRK1, SIGMA1, and CDK5R1 with various CDPs compounds, with SIGMA1 being especially noteworthy. Most CDPs exhibited lower binding energies than the control compounds NE-100 and duloxetine. Experimental validation demonstrated that CDPs such as Cyclo(Ala-Gln), Cyclo(Ala-His), and Cyclo(Val-Gly) exhibited IC Show less
MicroRNAs can regulate various biological functions including cell proliferation, differentiation, embryo formation, and implantation. The giant panda exhibits embryonic diapause, with embryo developm Show more
MicroRNAs can regulate various biological functions including cell proliferation, differentiation, embryo formation, and implantation. The giant panda exhibits embryonic diapause, with embryo development resuming in late pregnancy. However, the changes in microRNAs during late pregnancy remain poorly understand. After mating, plasma samples were collected on day 40 of early pregnancy (EP; n = 3) and 30 days before delivery of late pregnancy (LP; n = 3). Following microRNAs screening, a total of 120 microRNAs were detected in the plasma exosomes of pregnant pandas. Nine differentially expressed microRNAs (DEmicroRNAs) were identified in LP compared to EP, including three that were upregulated and six that were downregulated. Notably, miR-25b and miR-47 were significantly downregulated in LP group. All DEmicroRNAs were predicted to target a total of 2,675 genes. Pathway enrichment analysis of these target genes revealed significant enrichment in the MAPK and Rap1 signaling pathways, which are closely related to cell proliferation, differentiation, and cell-cell and cell-matrix interactions. Analysis of protein-protein interaction networks showed that most of the hub genes (five out of eight), including Fgfr1, Fgf2, Fgf18, Erbb4, and Kras within the MAPK and Rap1 pathways are associated with the cell proliferation and differentiation. Significantly, Erbb4 was regulated by significantly differentially expressed miRNA-47. We suggest that plasma exosomal microRNAs are involved in cell proliferation and differentiation during embryonic development by regulating key hub genes within MAPK and Rap1 pathways. These findings provided new insights into the development of giant panda embryos. Show less
Blood always shows coagulation changes after spinal cord injury (SCI), and identifying these blood changes may be helpful for diagnosis and treatment of SCI. Nevertheless, studies to date on blood coa Show more
Blood always shows coagulation changes after spinal cord injury (SCI), and identifying these blood changes may be helpful for diagnosis and treatment of SCI. Nevertheless, studies to date on blood coagulation changes after SCI in humans are not comprehensive. Therefore, this study aims to identify blood coagulation diagnostic biomarkers and immune changes related to SCI and its severity levels. Human blood sequencing datasets were obtained from public databases. Differentially expressed coagulation-related genes were analyzed (DECRGs). Enrichment analysis and assessment of immune changes were conducted. Weighted gene co-expression network analysis, least absolute shrinkage and selection operator logistic regression were used to identify biomarkers. Validation for these biomarkers was performed. The correlation between biomarkers and immune cells was evaluated. Transcription factors, miRNA, lncRNA, and drugs that can regulate biomarkers were analyzed. DECRGs associated with SCI and its different grades were identified, showing enrichment in altered coagulation and immune-related signaling pathways. ADAM9, CD55, and STAT4 were identified as coagulation diagnostic biomarkers for SCI. IRF4 and PABPC4 were identified as coagulation diagnostic biomarkers for American Spinal Injury Association Impairment Scale (AIS) A grade of SCI. GP9 was designated as a diagnostic biomarker for AIS D grade of SCI. Immune changes in blood of SCI and its different grades were observed. Correlation between diagnostic biomarkers and immune cells were identified. Transcription factors, miRNA, lncRNA, and drugs that can regulate diagnostic biomarker expression were discovered. Therefore, detecting the expression of these putative diagnostic biomarkers and related immune changes may be helpful for predicting the severity of SCI. Uncovering potential regulatory mechanisms for biomarkers may be beneficial for further research. Show less
Tunable luminescence-assisted information storage and encryption holds increasing significance in today's society. A promising approach to incorporating the benefits of both organic long persistent lu Show more
Tunable luminescence-assisted information storage and encryption holds increasing significance in today's society. A promising approach to incorporating the benefits of both organic long persistent luminescent (LPL) materials and rare-earth (RE) luminescence lies in utilizing organic host materials to sensitize RE luminescence, as well as employing Förster resonance energy transfer from hydrogen-bonded organic framework (HOF) phosphorescence to RE compound luminescence. This work introduces a one-pot, in situ pyrolytic condensation method, achieved through high-temperature melting calcination, to synthesize lanthanide ion-doped HOF materials. This method circumvents the drawback of molecular triplet energy annihilation, enabling the creation of organic LPL materials with RE characteristics. The HOF material serves as the host, exhibiting blue phosphorescence and cyan LPL. By fine-tuning the doping amount, the composite material U-Tb-100 achieves green LPL with a luminescent quantum yield of 56.4 %, and an LPL duration of approximately 2-3 s, demonstrating tunable persistence. Single-crystal X-ray diffraction, spectral analysis, and theoretical calculation unveil that U-Tb-100 exhibits exceptional quantum yield and long-lived luminescence primarily due to the efficient sensitization of U monomer to RE ions and the PRET process between U and RE complexes. This ingenious strategy not only expands the repertoire of HOF materials but also facilitates the design of multifunctional LPL materials. Show less
Alzheimer's disease (AD) is the most common neurodegenerative disease. Intestinal flora and its metabolism play a significant role in ameliorating central nervous system disorders, including AD, throu Show more
Alzheimer's disease (AD) is the most common neurodegenerative disease. Intestinal flora and its metabolism play a significant role in ameliorating central nervous system disorders, including AD, through bidirectional interactions between the gut-brain axis. A naturally occurring alkaloid compound called berberine (BBR) has neuroprotective properties and prevents Aβ-induced microglial activation. Additionally, BBR can suppress the synthesis of Aβ and decrease BACE1 expression. However, it is still unclear if BBR therapy can alleviate AD by changing the gut flora. In this study, we examined whether a partial alleviation of AD could be achieved with BBR treatment and the molecular mechanisms involved. We did this by analyzing alterations in Aβ plaques, neurons, and related neuroinflammation-related markers in the brain and the transcriptome of the mouse brain. The relationship between the intestinal flora of 5xFAD model mice and BBR treatment was investigated using high-throughput sequencing analysis of 16S rRNA from mouse feces. The findings demonstrated that treatment with BBR cleared Aβ plaques, alleviated neuroinflammation, and ameliorated spatial memory dysfunction in AD. BBR significantly alleviated intestinal inflammation, decreased intestinal permeability, and could improve intestinal microbiota composition in 5xFAD mice. Show less
Brown adipose tissue (BAT) combusts lipids and glucose to generate heat. Via this process of nonshivering thermogenesis, BAT plays a pivotal role in thermoregulation in cold environments, but its cont Show more
Brown adipose tissue (BAT) combusts lipids and glucose to generate heat. Via this process of nonshivering thermogenesis, BAT plays a pivotal role in thermoregulation in cold environments, but its contribution to immune-induced fever is less clear. Male APOE∗3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, and wild-type mice were given an intraperitoneal injection of Salmonella enterica serovar Typhimurium (S.tm). Energy expenditure and substrate utilization, plasma lipid levels, fatty acid (FA) uptake by adipose tissues, and lipid content and thermogenic markers in adipose tissues were examined. S.tm infection led to a set of characteristic symptoms, including elevated body temperature and decreased body weight. Whole-body energy expenditure was significantly decreased 72 h postinfection, but fat oxidation was increased and accompanied by a substantial reduction in plasma triglyceride (TG) levels as demonstrated in APOE∗3-Leiden.CETP mice. S.tm infection strongly increased uptake of FAs from TG-rich lipoproteins by BAT, which showed a positive correlation with body temperature in infected mice. Upon histological examination of BAT from wild-type or APOE∗3-Leiden.CETP mice, elevated levels of tyrosine hydroxylase were observed, indicative of stimulated sympathetic activity. In addition, the gene expression profile was consistent with more adrenergic stimulation, while lipid content was reduced. Furthermore, browning of white adipose tissue was observed, evidenced by a modest increase in TG-derived FA uptake, the presence of multilocular cells, and induction of uncoupling protein 1 expression. We proposed that BAT, or thermogenic adipose tissue in general, is involved in the maintenance of elevated body temperature upon invasive bacterial infection. Show less
Ovarian cancer (OC) is a malignant neoplasm that displays increased vascularization. Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that functions as a regulator of cell metabolism and angio Show more
Ovarian cancer (OC) is a malignant neoplasm that displays increased vascularization. Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that functions as a regulator of cell metabolism and angiogenesis and plays a critical role in tumorigenesis. However, the precise role of ANGPTL4 in the OC microenvironment, particularly its involvement in angiogenesis, has not been fully elucidated. The expression of ANGPTL4 was confirmed by bioinformatics and IHC in OC. The potential molecular mechanism of ANGPTL4 was measured by RNA-sequence. We used a series of molecular biological experiments to measure the ANGPTL4-JAK2-STAT3 and ANGPTL4-ESM1 axis in OC progression, including MTT, EdU, wound healing, transwell, xenograft model, oil red O staining, chick chorioallantoic membrane assay and zebrafish model. Moreover, the molecular mechanisms were confirmed by Western blot, Co-IP and molecular docking. Our study demonstrates a significant upregulation of ANGPTL4 in OC specimens and its strong association with unfavorable prognosis. RNA-seq analysis affirms that ANGPTL4 facilitates OC development by driving JAK2-STAT3 signaling pathway activation. The interaction between ANGPTL4 and ESM1 promotes ANGPTL4 binding to lipoprotein lipase (LPL), thereby resulting in reprogrammed lipid metabolism and the promotion of OC cell proliferation, migration, and invasion. In the OC microenvironment, ESM1 may interfere with the binding of ANGPTL4 to integrin and vascular-endothelial cadherin (VE-Cad), which leads to stabilization of vascular integrity and ultimately promotes angiogenesis. Our findings underscore that ANGPTL4 promotes OC development via JAK signaling and induces angiogenesis in the tumor microenvironment through its interaction with ESM1. Show less
Heart failure (HF), an end-stage clinical syndrome secondary to cardiac impairment, significantly affects patients' quality of life and long-term prognosis. Myocardial fibrosis leads to systolic and d Show more
Heart failure (HF), an end-stage clinical syndrome secondary to cardiac impairment, significantly affects patients' quality of life and long-term prognosis. Myocardial fibrosis leads to systolic and diastolic dysfunction, and promotes the progression of HF. Several studies involving the modulation of myocardial fibrosis have been conducted in an effort to improve cardiac function. Heat shock protein 27 (HSP27) is a small chaperone protein that is overexpressed in cellular stress states. HSP27 modulates epithelial-mesenchymal transition, playing a crucial role in the pathology of several fibrotic diseases. However, its association with myocardial fibrosis regulation is unknown. This study aimed to investigate the mechanisms by which HSP27 regulates myocardial fibrosis. We created cardiac-specific HSP25 (the murine ortholog of human HSP27) knockout mice and found that HSP25 knockdown inhibited endothelial-mesenchymal transition (EndMT), attenuated myocardial fibrosis, and ameliorated diastolic dysfunction in isoproterenol-induced HF mice via echocardiography, histology, and western bloting. In vitro, HSP27 knockdown attenuated transforming growth factor beta-induced EndMT, whereas HSP27 overexpression promoted EndMT. Furthermore, the SMAD3/SNAIL1 pathway was found to be crucial for HSP27-mediated EndMT regulation. As an essential molecule in EndMT regulation and myocardial fibrosis modulation, HSP27 may hold promise as a therapeutic target for patients with HF. Show less
Immune checkpoint inhibitors, particularly PD-1/PD-L1 blockades, have been approved for unresectable hepatocellular carcinoma (HCC). However, high resistance rates still limit their efficacy, highligh Show more
Immune checkpoint inhibitors, particularly PD-1/PD-L1 blockades, have been approved for unresectable hepatocellular carcinoma (HCC). However, high resistance rates still limit their efficacy, highlighting the urgent need to understand the underlying mechanisms and develop strategies for overcoming the resistance. In this study, tankyrasel binding protein 1 (TNKS1BP1) was found to interact with tripartite motif containing 21 (TRIM21) and mediated the ubiquitination of CCR4-NOT transcription complex subunit 4 (CNOT4) at the K239 residue via K48 and K6 linkage, which was essential for its tumorigenesis function. Autophagy and lipid reprogramming were identified as two possible mechanisms underlying the pro-tumor effect of TNKS1BP1. Upregulated TNKS1BP1 inhibited autophagy while induced lipid accumulation by inhibiting the JAK2/STAT3 pathway upon the degradation of CNOT4 in HCC. Importantly, knocking down TNKS1BP1 synergized with anti-PD-L1 treatment by upregulating PD-L1 expression on tumor cells via the JAK2/STAT3 pathway, and remodeling the tumor microenvironment by increasing infiltration of tumor-infiltrating lymphocytes as well as augmenting the effect of cytotoxic T lymphocytes. In conclusion, this study identified TNKS1BP1 as a predictive biomarker for patient prognosis and a promising therapeutic target to overcome anti-PD-L1 resistance in HCC. Show less
Tumor cell metastasis is the key cause of death in patients with nasopharyngeal carcinoma (NPC). MiR-2110 was cloned and identified in Epstein-Barr virus (EBV)-positive NPC, but its role is unclear in Show more
Tumor cell metastasis is the key cause of death in patients with nasopharyngeal carcinoma (NPC). MiR-2110 was cloned and identified in Epstein-Barr virus (EBV)-positive NPC, but its role is unclear in NPC. In this study, we investigated the effect of miR-2110 on NPC metastasis and its related molecular basis. In addition, we also explored whether miR-2110 can be regulated by cinobufotalin (CB) and participate in the inhibition of CB on NPC metastasis. Bioinformatics, RT-PCR, and in situ hybridization were used to observe the expression of miR-2110 in NPC tissues and cells. Scratch, Boyden, and tail vein metastasis model of nude mouse were used to detect the effect of miR-2110 on NPC metastasis. Western blot, Co-IP, luciferase activity, colocalization of micro confocal and ubiquitination assays were used to identify the molecular mechanism of miR-2110 affecting NPC metastasis. Finally, miR-2110 induced by CB participates in CB-stimulated inhibition of NPC metastasis was explored. The data showed that increased miR-2110 significantly suppresses NPC cell migration, invasion, and metastasis. Suppressing miR-2110 markedly restored NPC cell migration and invasion. Mechanistically, miR-2110 directly targeted FGFR1 and reduced its protein expression. Decreased FGFR1 attenuated its recruitment of NEDD4, which downregulated NEDD4-induced phosphatase and tensin homolog (PTEN) ubiquitination and degradation and further increased PTEN protein stability, thereby inactivating PI3K/AKT-stimulated epithelial-mesenchymal transition signaling and ultimately suppressing NPC metastasis. Interestingly, CB, a potential new inhibitory drug for NPC metastasis, significantly induced miR-2110 expression by suppressing PI3K/AKT/c-Jun-mediated transcription inhibition. Suppression of miR-2110 significantly restored cell migration and invasion in CB-treated NPC cells. Finally, a clinical sample assay indicated that reduced miR-2110 was negatively correlated with NPC lymph node metastasis and positively related to NPC patient survival prognosis. In summary, miR-2110 is a metastatic suppressor involving in CB-induced suppression of NPC metastasis. Show less
Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the β-oxidation of fatty acids. Yet, the functions of AN Show more
Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the β-oxidation of fatty acids. Yet, the functions of ANGPTL4 and ACACA in dyslipidemia of obstructive sleep apnea (OSA) remain unclear. This study included 125 male OSA subjects from the Shanghai Sleep Health Study (SSHS) who were matched for age, body mass index (BMI), and lipid profile. Serum ANGPTL4 levels were measured Serum ANGPTL4 levels significantly decreased with increasing OSA severity (non-OSA: 59.6 ± 17.4 ng/mL, mild OSA: 50.0 ± 17.5 ng/mL, moderate OSA: 46.3 ± 15.5 ng/mL, severe OSA: 19.9 ± 14.3 ng/mL, respectively, Serum ANGTPL4 levels were significantly decreased in OSA patients, particularly among individuals with severe OSA. Although functional ANGTPL4 T266M variants were not associated with lipid levels in OSA, ANGTPL4 T266M could enhance binding affinity for the ACACA protein, potentially regulating lipid metabolism. Show less
The lion-head goose is the only large goose species in China, and it is one of the largest goose species in the world. Lion-head geese have a strong tolerance for massive energy intake and show a prio Show more
The lion-head goose is the only large goose species in China, and it is one of the largest goose species in the world. Lion-head geese have a strong tolerance for massive energy intake and show a priority of fat accumulation in liver tissue through special feeding. Therefore, the aim of this study was to investigate the impact of high feed intake compared to normal feeding conditions on the transcriptome changes associated with fatty liver development in lion-head geese. In this study, 20 healthy adult lion-head geese were randomly assigned to a control group (CONTROL, n = 10) and high-intake-fed group (CASE, n = 10). After 38 d of treatment, all geese were sacrificed, and liver samples were collected. Three geese were randomly selected from the CONTROL and CASE groups, respectively, to perform whole-transcriptome analysis to analyze the key regulatory genes. We identified 716 differentially expressed mRNAs, 145 differentially expressed circRNAs, and 39 differentially expressed lncRNAs, including upregulated and downregulated genes. GO enrichment analysis showed that these genes were significantly enriched in molecular function. The node degree analysis and centrality metrics of the mRNA-lncRNA-circRNA triple regulatory network indicate the presence of crucial functional nodes in the network. We identified differentially expressed genes, including Show less