👤 Wan Deng

Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) is a neuronal system-specific transmembrane protein that is highly expressed in the brains of patients with Alzheimer's disease (AD), and our previous findings showed that LINGO-1 antagonism can improve cognitive function and protect hippocampal GABAergic interneurons in AD model mice. However, the specific mechanism underlying these effects is not clear. In this study, an adeno-associated virus (AAV) was used to directly interfere with hippocampal LINGO-1 in vivo, and LINGO-1 antagonists, cannabinoid type 1 receptor (CB1R) agonists, and CB1R antagonists were used to treat mouse hippocampal neurons (HT22 neurons) in vitro. We found that overexpressing hippocampal LINGO-1 in normal young mice impaired spatial learning and memory and reduced hippocampal CB1R protein levels, whereas silencing hippocampal LINGO-1 in AD model mice had the opposite effect. Additionally, antagonizing LINGO-1 increased CB1R/tyrosine kinase receptor B (TrkB) signalling and rescued CB1R- rich cholecystokinin-GABAergic (CCK-GABAergic) interneurons in HT22 neurons transduced with an APP/PS1-expressing virus. Competitive inhibition of LINGO-1 and CB1R was observed, and antagonizing LINGO-1 reversed the changes in HT22 neurons caused by the inhibition of CB1R, such as the decreases in the protein levels of doublecortin (DCX), TrkB, and phosphorylated TrkB (p-TrkB). These findings provide an important scientific basis for further exploration of the mechanism by which LINGO-1 regulates cognitive function and hippocampal GABAergic interneurons in AD model mice. Show less

Psychological empowerment is a critical factor for employee work well-being, particularly within high-stress professions such as policing. However, experiences of empowerment among individuals are not uniform. This study aims to identify distinct profiles of psychological empowerment among police officers and to examine their associations with perceived coworker support and work well-being. A person-centered approach was adopted. Data were collected from 505 Chinese police officers. Latent Profile Analysis (LPA) was employed to identify subgroups based on their psychological empowerment patterns. The analysis revealed two distinct profiles: a "Globally Disempowered" profile and a "Globally Empowered" profile. Perceived emotional support from coworkers was a significant predictor of profile membership, where higher levels of support increased the likelihood of belonging to the empowered group. Furthermore, officers in the high empowerment profile reported significantly greater work well-being compared to those in the low empowerment profile. The findings underscore the heterogeneity in psychological empowerment experiences within the policing context. They emphasize the pivotal role of fostering emotional peer support as a means to enhance officers' psychological empowerment and, consequently, their work well-being. Practical implications for organizational interventions are discussed. Show less

Exploring how different profiles of academic task values (ATVs) and academic achievement (AA) influence students' school satisfaction should enrich understanding of how school satisfaction develops in specific academic situations. This study aimed to identify profiles of ATV (attainment value [AV], utility value [UV]) and AA, as well as heterogeneous trajectories of school satisfaction, and then examine the joint predictive effects of ATV and AA on the development of school satisfaction. A total of 3548 Chinese elementary school students (M Data were collected through self-reports of ATVs and school satisfaction, while AA data were collected from final examination scores at the end of each semester. Latent profile analysis (LPA) and latent class growth analysis revealed six profiles of ATV and AA (i.e., congruent subgroups: congruent-low, congruent-high, congruent-moderate and incongruent subgroups: high ATV-low AA, lower UV-moderate AA, low ATV-moderate AA); and four heterogeneous trajectories of school satisfaction (i.e., high-decreasing, low-stable, high-stable, low-increasing). Latent transition analysis (LTA) indicated that students with congruent levels of AA and ATV were more likely to transition into the optimal school satisfaction groups (high-stable and low-increasing groups), whereas students with greater gaps between AA and ATV were more likely to transition into the adverse groups (i.e., low-stable and high-decreasing groups). These findings highlight the need for educators to tailor interventions to distinct groups to optimize students' school satisfaction. Show less

Problematic smartphone use (PSU) has become a growing concern among young populations, raising significant issues for their physical and psychological well-being. Guided by Compensatory Internet Use Theory and the Interaction of Person-Affect-Cognition-Execution (I-PACE) model, this study examined the associations between different forms of childhood trauma and PSU. Participants were 2717 college students (661 males, 22.49%; Mage = 19.81 years). Two chain mediation models were tested, and latent profile analysis (LPA) was employed to capture individual differences from a person-centred perspective. LPA revealed three distinct trauma profiles: low childhood trauma, moderate childhood abuse, and high childhood abuse. Across both variable-centred and person-centred ap-proaches, rumination and social anxiety were identified as mediators linking childhood trauma to PSU. These findings advance understanding of the pathways through which childhood trauma contributes to PSU in college students. By integrating variable- and person-centred approaches, the study highlights the importance of cognitive-emotional mechanisms and provides implications for targeted prevention and intervention strategies. Show less

Lipoprotein(a) (Lp(a)) is an established independent risk factor for atherosclerotic cardiovascular disease, particularly in the development of high-risk coronary plaques (HRPs). Elevated Lp(a) contributes to lipid accumulation, vascular inflammation, and plaque instability, primarily through oxidized phospholipids that promote monocyte adhesion and foam cell formation. Genetic studies have identified variants in the Show less

Dyslipidemia is a central driver in the initiation and progression of atherosclerosis (AS). The chronic inflammation and endothelial injury triggered by dyslipidemia are key pathological events in AS development. Elucidating the molecular network underlying dyslipidemia and developing precise interventions are critical for achieving precision prevention and treatment of AS. Recent studies have demonstrated that sterol regulatory element-binding protein 1 (SREBP1) and lipoprotein(a) [Lp(a)] play pivotal roles in the regulation of lipid synthesis and transport. Additionally, gut microbiota-derived metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs), can activate inflammatory pathways and promote lipid deposition via inter-organ signaling axes, thereby accelerating the progression of AS. However, clinical studies have revealed that even when low-density lipoprotein cholesterol (LDL-C) levels are within the recommended range, a significant number of patients continue to experience cardiovascular events. This indicates the widespread presence of "residual risk". Such residual risk is primarily driven by elevated non-high-density lipoprotein cholesterol (non-HDL-C), abnormal levels of Lp(a), and imbalances in the triglyceride to HDL-C (TG/HDL-C) ratio, highlighting the limitations of traditional therapies in comprehensive lipid profile management. Emerging targeted therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, small interfering RNA (siRNA)-based treatments, and Lp(a)-lowering agents like pelacarsen, represent promising strategies for more precise lipid modulation. With the continuous advancement of related research, the precise management of AS will increasingly rely on deeper mechanistic insights and individualized therapeutic strategies. Current strategies for AS prevention and treatment focus on understanding key pathways, including lipid metabolism, inflammation, and vascular dysfunction, to develop targeted therapies. The integration of the 2023 Chinese Guidelines for Lipid Management, imaging, and AI-assisted decision-making will promote data-driven, precision medicine. Personalized drug selection, efficacy monitoring, and long-term follow-up will optimize clinical outcomes and enhance prevention strategies for high-risk patients. Show less

Patients suffering coronary artery disease (CAD) with calcific aortic valve disease (CAVD) are facing worse prognosis with more complex operation strategies. As the primary stage of CAVD, it is helpful to confirm the risk factors of aortic valve calcification (AVC) in advance for exploring the secondary prevention as well as early intervention strategies of CAVD for CAD patients. Lipoprotein(a) [Lp(a)] has been confirmed as the risk factor of both CAD and CAVD. But whether Lp(a) level still affects the occurrence and development of CAVD in CAD patients has not been demonstrated yet. We firstly investigate the predictive value of Lp(a) for new-onset AVC in patients with CAD. Patients who were admitted to the Department of Cardiology, Zhujiang Hospital, Southern Medical University from March 2021 to December 2022 and diagnosed with CAD by elective coronary angiography(CAG)were included when met the criteria. Baseline data were collected through the electronic medical record system. Patients were followed up to repeat echocardiography with an interval at least 6 months, which was up to September 2023. The primary endpoint was new-onset AVC, according to which patients were divided into new-onset AVC group (n = 43) and the opposite(n = 165). Analyses were conducted using SPSS 26.0 and GraphPad Prism 10.1.2. A total of 208 patients with CAD were included, with a median follow-up time of 16 (12, 20) months. Compared with AVC-free group, patients with new-onset AVC had higher body mass index (BMI) (p = 0.003), higher proportion of tree-vessel disease(p < 0.001), higher rates of diabetes (p = 0.001) and atrial fibrillation (p = 0.017), higher Lp(a) levels(p < 0.001), lower left ventricular systolic function (LVEF) (p < 0.001) and thicker left ventricular posterior wall (LVPW) (p < 0.001). Increased BMI, three-vessel disease, Lp(a) > 26.65 nmol/L, increased LVPW were found independent risk factors for new-onset AVC. Using a cutoff level of 26.65 nmol/L, Lp(a) predicted new-onset AVC with a sensitivity of 79.1% and a specificity of 59.4% (AUC: 0.740, 95% CI: 0.657-0.823, p < 0.001). When combined with BMI, there present a higher AUC value of 0.752(95%CI: 0.668-0.836, p < 0.001); however, the statistical significance remains limited (p = 0.732). High-level serum Lp(a) was independently associated with new-onset AVC in patients with CAD. Lp(a) demonstrates a significant predictive value for the onset of new AVC in CAD patients, with an established cut-off threshold of 26.65 nmol/L. Show less

Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by dyslipidemia and hepatic lipid deposition, has become a major public health concern. Angiopoietin-like protein 3 (ANGPTL3), a lipoprotein lipase (LPL) activity inhibitor, can inhibit triglycerides (TGs) decomposition, and fibroblast growth factor 21 (FGF21) enhances fatty acids' β-oxidation in liver. We constructed a novel fusion protein combining the anti-ANGPTL3 nanobody FD03 and FGF21 (FD03-FGF21), which exerted appropriate binding affinities to ANGPTL3 and β-Klotho respectively. Our results showed FD03-FGF21 restored bioactivity of LPL which inhibited by ANGPTL3 and activated downstream pathway of FGF21 in iLite FGF21 assay-ready cells. Next, FD03-FGF21 showed a significant therapeutic effect in MAFLD mice, including attenuation of metabolic dyslipidemia, hepatic lipid accumulation, and impaired glucose tolerance. Compared to other treatments, FD03-FGF21 achieved the most significant therapeutic effect with a 79.78 % attenuation of low-density lipoprotein cholesterol (LDL-C) and a 95.8 % reduction of hepatic lipid accumulation. Mechanistically, transcriptomic analysis revealed that differential expression genes (DEGs) were principally clustered into lipid metabolism and oxidative stress pathways after the fusion protein treatment, especially the key lipid metabolism genes of LDLR and CD36 were significantly upregulated and downregulated respectively, as confirmed by WB. Furthermore, lipidomic and metabolomic analysis indicated the fusion protein ameliorated disorders in lipid and protein metabolism mainly through the downregulation of DG and upregulation of PC. Hepatic oxidative stress and inflammation were significantly reduced after administration of the fusion protein in MAFLD mice. Collectively, FD03-FGF21 represents an effective therapeutic strategy for MAFLD therapy through ameliorating lipid metabolism and oxidative stress. Show less

The gut microbiota influences host immunity and metabolism, and changes in its composition and function have been implicated in several non-communicable diseases. Here, comparing germ-free (GF) and specific pathogen-free (SPF) mice using spatial transcriptomics, single-cell RNA sequencing, and targeted bile acid metabolomics across multiple organs, we systematically assessed how the gut microbiota's absence affected organ morphology, immune homeostasis, bile acid, and lipid metabolism. Through integrated analysis, we detect marked aberration in B, myeloid, and T/natural killer cells, altered mucosal zonation and nutrient uptake, and significant shifts in bile acid profiles in feces, liver, and circulation, with the alternate synthesis pathway predominant in GF mice and pronounced changes in bile acid enterohepatic circulation. Particularly, autophagy-driven lipid droplet breakdown in ileum epithelium and the liver's zinc finger and BTB domain-containing protein (ZBTB20)-Lipoprotein lipase (LPL) (ZBTB20-LPL) axis are key to plasma lipid homeostasis in GF mice. Our results unveil the complexity of microbiota-host interactions in the crosstalk between commensal gut bacteria and the host. Show less

This study aimed to evaluate the effects of butyrate, butyric glycerides (BG) and their combination with sodium selenite (SeNa) or hydroxy-selenomethionine (OH-SeMet) on the performance and egg quality of the laying hens in post-peak period as well as the potential mechanism. A total of 900 45-week-old Hy-Line brown laying hens were randomly allocated to 5 treatment groups (n = 10 replicates/diet, 18 hens/replicate). The hens were fed the basal diet supplemented with 0.3 mg/kg selenium from SeNa (Control), Control plus 240 mg/kg butyric acid from coated butyrate (CB), Control plus 240 mg/kg butyric acid from butyric glycerides, basal diet supplemented with 0.3 mg/kg selenium from OH-SeMet plus coated butyrate (CB+OH-SeMet) or butyric glycerides (BG+OH-SeMet), respectively, for 20 weeks. Serum, liver, isthmus, uterus, and jejunum were collected at the end of the trial for biochemistry, histology, redox status, and gene expression analysis. Compared with Control, diets supplemented with BG, CB+OH-SeMet and BG+OH-SeMet increased (p < 0.05) the average egg weight (0.6-2.2 %), while only BG+OH-SeMet increased (p < 0.05) the total egg weight (7.1 %) and egg-laying rate (4.6 %) and decreased (p < 0.05) the feed/egg ratio (5.0 %) throughout the whole experiment. Furthermore, BG+OH-SeMet reduced (p < 0.05) the content of IL-6 and alanine aminotransferase (15.4-32.5 %), while elevated (p < 0.05) the content of IgA, IgY, IgM and total protein (18.7-26.8 %) in the serum in comparison to the Control. Notably, dietary supplementation of BG+OH-SeMet performed more effective antioxidant capacity in decreasing (p < 0.05) malondialdehyde (16.4-27.9 %) content and increasing (p < 0.05) the activity of total antioxidant capacity and glutathione peroxidase (17.6-36.3 %) in various tissues. Further experiment revealed that dietary BG+OH-SeMet regulated the lipid metabolism by increasing (p < 0.05) the expression of Carnitine palmitoyltransferase 1A (CPT1A) and Lipoprotein lipase (LPL) in liver. In conclusion, diets supplemented with BG and OH-SeMet could improve the laying performance via the enhancement of antioxidant capacity and regulation of lipid metabolism. Show less

Intracranial aneurysms (IAs) are the major cause of subarachnoid hemorrhage. Stent-assisted coiling, especially with the Neuroform Atlas stent (NAS), has proved more effective than coiling alone for treating these aneurysms. To perform a systematic review and meta-analysis to investigate the efficacy and safety of the NAS in treating IAs. A comprehensive literature search was conducted on PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and clinicaltrials.gov from inception until June 2024. We included studies on ruptured and unruptured IAs treated with the NAS, covering experimental, observational, and case series across all age groups. The aneurysm occlusion rate was assessed by using the Raymond-Roy classification (RROC). The mRS and adverse events related to stent use were also recorded. The statistical analysis was conducted on R Version 4.3.2 by using the packages "meta" and "metasens." We reported our results as proportions with their corresponding CIs. Meta-regression, leave-one-out, and sensitivity analyses were conducted to confirm the robustness of our results. A total of 42 studies including 2434 participants with a mean age of 51 to 73 years were included. Among angiographic outcomes, the final RROC 1/RROC 2 was achieved in 95% of the patients, final RROC 1 in 82%, RROC 2 in 12%, and RROC 3 in 5% of the patients. Additionally, 93% of the patients showed mRS grade 0, 5% showed mRS grade 1, 3% showed mRS grade 2, 2% showed mRS grade 3, 0% showed mRS grade 4, 0% showed mRS grade 5, and 1% showed mRS grade 6. All adverse events had a ≤5% rate. Due to limited cause-specific data, we were unable to analyze mortality specific to the stent placement and complications. Despite the large number of studies included, comparative studies were still observed to be scarce. Although the generalizability of our findings is limited, this study demonstrates that the NAS is highly effective for treating IAs, with high occlusion rates and a low incidence of adverse events. The stent's performance, supported by comprehensive analysis, highlights its safety and efficacy in managing both ruptured and unruptured aneurysms. Show less

Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offer promising alternatives to conventional grafts, most techniques fail to replicate the multi-scale fibrous architecture of native bone extracellular matrix, limiting their biofunctionality. To address this, we developed a hybrid manufacturing strategy integrating low-temperature thermally induced phase separation with extrusion-based 3D printing of polylactic acid (PLA) scaffolds. By optimizing solvent ratios (THF: DMF = 3:1) and freezing temperatures (-196 °C-4 °C), we produced scaffolds with tunable micro-nano fibrous surfaces and macroporous structures. Key findings revealed that scaffolds processed at -196 °C (PLA-196) exhibited the highest porosity (pore size: 6.01 ± 2.06 μm), superior hydrophilicity, and enhanced compressive modulus. These scaffolds significantly promoted BMSC adhesion, proliferation, and osteogenic differentiation via activation of Show less

Microtubule associated series/threonine kinase-3 (MAST3) is a member of microtubule associated serine/threonine kinase family (MAST1-4, MAST-like), and the expression and underlying molecular mechanism of MAST3 in human tumors, including breast cancer, is not yet elucidated. We employed immunohistochemistry to assess the significant expression of MAST3 in breast cancer tissue samples. Additionally, we utilized an overexpression vector and shRNA to bi-directionally regulate MAST3 expression, aiming to observe the impact of MAST3 on the proliferation, migration, and invasion capabilities of breast cancer cells. Furthermore, we employed immunoprecipitation, immunoblotting, luciferase reporter genes and real-time quantitative PCR to investigate the interaction between MAST3 and YAP, as well as the regulatory effects on the expression of Hippo pathway-related target genes. Low MAST3 expression was observed both in breast cancer cells and tissues, which was significantly associated with advanced tumor T stage, lymph node metastasis, and poor patient prognosis. Functional experiments found that overexpression of MAST3 can gradually inhibit the proliferation and invasion of breast cancer cells, knocking-out MAST3 showed the opposite functional effect. Immunoprecipitation showed that MAST3 interacts with the key effector factor, yes-associated protein (YAP), in the Hippo pathway. The combination of MAST3-YAP promoted the phosphorylation of YAP, which led to its degradation through the ubiquitin-proteasome pathway and reduced nuclear translocation. MAST3 was identified as a novel tumor suppressor protein in breast cancer, which directly regulates the expression of YAP through the non-dependent mammalian sterile-20-like (MST)-large tumor suppressor (LATS) classical signaling pathway, providing a theoretical and experimental basis for the development of small-molecule tumor inhibitors in breast cancer. Show less

Tumor metabolic reprogramming has been recognized as a critical determinant in tumor development and cancer immunotherapy response. Aberrant choline metabolism is emerging as a defining hallmark of cancer. In this study, we found that carbohydrate-responsive element-binding protein (ChREBP)-mediated choline deprivation induced tumor-associated macrophage (TAM) reprogramming and maintained an immunosuppressive tumor microenvironment. Mechanistically, ChREBP interacted with SP1 to increase the expression of immunosuppressive chemokines CCL2 and CCL7 and choline transporter SLC44A1. As such, high CCL2 and CCL7 expression promoted recruitment of TAMs. Tumor cells with high SLC44A1 levels competed with M1-like TAMs for choline, inhibiting cGAS/STING signaling and promoting the repolarization of M1-like to M2-like macrophages. Clinically, ChREBP-SP1-choline metabolism axis expression was associated with poor clinical outcome in colorectal cancer. Thus, the study identified the interplay between tumors and TAMs via choline competition as a previously unknown immune evasion mechanism in the tumor microenvironment and proposes ChREBP as a potential immunotherapeutic target in cancer. ChREBP induces a choline-deprived tumor microenvironment and promotes chemokine secretion to facilitate immune evasion, suggesting targeting ChREBP as a therapeutic approach to improve the efficacy of immunotherapy. Show less

Pediatric primary cardiomyopathies (PCMs) are rare diseases with complex causes and nonspecific treatment. The influence of electrolytes and amino acids (AAs) on cardiomyopathies has not been extensively studied. This study aimed to explore clinical characteristics and the usage of electrolytes and AAs in children with PCMs. Children diagnosed with PCMs who had genetic test reports were included. Relevant information was collected and processed, and clinical characteristics and mutated genes were clarified. Gene databases were searched to explore related electrolytes and AAs in the treatment of PCMs. The effect of calcium was explored in children with DCM. Paired samples T tests and nonparametric Wilcoxon signed-rank tests were performed for comparison between before and after using calcium. In this study, 27 children with gene test results were enrolled to perform gene-related analysis. The median age was 2.5 years old. Mutated genes were collected, including pathogenic, likely pathogenic, uncertain significance, and other mutations. The most frequently mutated genes related to dilated cardiomyopathy (DCM) were For children with DCM, calcium supplements may be beneficial. AAs, including serine, cysteine, and arginine, could be used for supplementary treatment in children with DCM and HCM. Show less

Renal failure related death caused by diabetic kidney disease (DKD) is an inevitable outcome for most patients. This study aimed to identify the critical genes involved in the onset and progression of DKD and to explore potential therapeutic targets of DKD. We conducted a batch of protein quantitative trait loci (pQTL) Mendelian randomization analysis to obtain a group of proteins with causal relationships with DKD and then identified key proteins through colocalization analysis to determine correlations between variant proteins and disease outcomes. Subsequently, the specific mechanisms of key regulatory genes involved in disease progression were analyzed through transcriptome and single-cell analysis. Finally, we validated the mRNA expression of five key genes in the DKD mice model using reverse transcription quantitative PCR (RT-qPCR). Five characteristic genes, known as protein kinase B beta (AKT2), interleukin-2 receptor beta (IL2RB), neurexin 3(NRXN3), slit homolog 3(SLIT3), and TATA box binding protein like protein 1 (TBPL1), demonstrated causal relationships with DKD. These key genes are associated with the infiltration of immune cells, and they are related to the regulatory genes associated with immunity. In addition, we also conducted gene enrichment analysis to explore the complex network of potential signaling pathways that may regulate these key genes. Finally, we identified the effectiveness and reliability of these selected key genes through RT-qPCR in the DKD mice model. Our results indicated that the AKT2, IL2RB, NRXN3, SLIT3, and TBPL1 genes are closely related to DKD, which may be useful in the diagnosis and therapy of DKD. Show less

Dysregulation of macrophage autophagy plays a critical role in sepsis-induced acute lung injury (ALI); however, its underlying mechanism remains unclear. In this study, we aimed to identify the regulatory pathway involving the PIK3C3-MAPK14 signaling axis that drives ALI progression by controlling autophagy and macrophage polarization. Using machine learning transcriptomic analysis, MAPK14 was identified as a core gene associated with ALI, and multi-omics integration confirmed its upregulated expression in ALI tissues. MAPK14 localization to pro-inflammatory macrophages was determined using single-cell sequencing. Furthermore, we observed a significant positive correlation between MAPK14 and autophagy-related genes. Molecular docking and kinetic simulations revealed high-affinity interactions between PIK3C3 and MAPK14 (ΔG-bind = -127.722 ± 33.269 kJ/mol). In vitro experiments followed by Western Blot(WB) and RT-q polymerase chain reaction (PCR) assays demonstrated that lipopolysaccharide stimulation upregulated MAPK14 expression through downregulation of PIK3C3 expression, resulting in impaired autophagic flux (LC3-II/Ⅰ↓, TOM20↑, P62↑, HSP60↑). Flow cytometry and enzyme-linked immunosorbent assay (ELISA) confirmed a shift toward pro-inflammatory (M1) macrophage polarization. RNA pull-down assay directly captured the PIK3C3-MAPK14 complex, and functional validation showed that PIK3C3 overexpression significantly inhibited MAPK14 protein expression, whereas PIK3C3 knockdown enhanced it. In conclusion, targeting the PIK3C3-MAPK14 axis is a promising therapeutic strategy for ALI. Show less

Diabetic retinopathy (DR) is a leading cause of blindness in adults, which is characterized by neurovascular dysfunction. Retinal neurodegeneration was involved in the pathogenesis of early-stage DR. This research aims to reveal the therapeutic effects and potential molecule mechanism of Mesenchymal stem cells-derived exosomes (MSCs-EXOs) in Müller cells at the early stage of DR. More specifically, we investigated in the rat retinal Müller cell line rMC-1. We cultured rMC-1 in high glucose (HG) medium mixed with MSCs-EXOs to observe the changes in cell proliferative capacity and function. EdU assay, Immunofluorescence staining and Cell viability were used to assess cell proliferative capacity and function. Western blot and Quantitative Real-Time polymerase chain reaction (qRT-PCR) were used to assess the expression of cell proliferation-related proteins and cell cycle-related protein. Finally, dual-luciferase reporter assay, miRNA sequencing and cell transfection were used to assess the relationships between MSCs-EXOs and binding site. Here our results displayed that MSCs-EXOs promoted HG-induced cell proliferation in rMC-1. Furthermore, MSCs-EXOs protected HG-induced function of rMC-1. Mechanistically, MSCs-EXOs promoted the proliferation of rMC-1 by inhibiting the Hippo pathway to decrease the expression of Large tumor suppressor 1 (LATS1) and p-YAP and increase the expression of cell proliferation-related proteins Yes-associated protein (YAP), EGFR and cell cycle-related protein CYCLIN D1. In addition, LATS1 knockdown inhibited p-YAP expression and promoted HG-induced cell proliferation and YAP, EGFR and CYCLIN D1 expression in rMC-1. We subsequently performed bioinformatics sequencing analysis of MSCs-EXOs and confirmed that LATS1 was the target of miR-21a-5p. Our research proved that MSCs-EXOs containing miR-21a-5p increased the expression of YAP via targeting LATS1, and ultimately promoted the cell proliferation in rMC-1. Our current study clarified the molecular mechanism of MSCs-EXOs-regulated cell proliferation and function protection in rMC-1 and provided a novel strategy for the treatment of DR. Show less

The IARC classified betel nut as Group 1 carcinogen (2004) and arecoline as Group 2B carcinogen (2020), with approximately one-third of global oral cancer cases attributed to smokeless tobacco or betel nut consumption. While current evidence establishes an association between arecoline and oral cancer, the underlying molecular mechanisms remain complex and poorly elucidated. This study employs network toxicology integrated with molecular docking techniques to systematically investigate the potential molecular pathogenesis of arecoline-induced oral cancer, aiming to provide novel insights for targeted therapeutic strategies. The SMILES structure of arecoline was retrieved from PubChem for foundational data preparation. Toxicity profiling was conducted using ProTox-3.0 and ADMETlab databases. Potential targets of arecoline were identified via STITCH and SwissTargetPrediction. Oral cancer-related targets were collated from GeneCards, OMIM, and TTD. Intersection analysis between arecoline targets and oral cancer-associated targets was performed to identify shared targets, which were further utilized to construct compound-target regulatory network and subjected to PPI, GO, and KEGG analyses. Core targets driving oral cancer were screened using the cytoHubba plugin. Then, the correlation between core targets and immune cell infiltration in oral cancer was explored, and molecular docking validated the binding affinity of arecoline to core targets. Finally, Gromacs 2022.3 software was used to simulate the molecular dynamics of the complexes obtained by molecular docking for 100 ns. Using the STITCH and SwissTargetPrediction databases, a total of 46 potential targets of arecoline were identified. Concurrently, 2,375 oral cancer-related targets were retrieved from GeneCards, OMIM, and TTD. Intersection analysis of these two target sets yielded 26 overlapping targets. PPI analysis revealed that TP53, IL6, SNAI1, and CASP3 occupied central positions in the network, exhibiting extensive interactions with other target proteins. Enrichment analysis comprehensively elucidated the molecular functions, biological processes, cellular components, and associated pathways of these overlapping targets. Further screening using Cytoscape software identified four core targets: TP53, TNF, IL6, and CASP3. Immune infiltration analysis indicated that the expression levels of TP53, TNF, IL6, and CASP3 in oral cancer tissues were positively correlated with the infiltration levels of immune cells, including CD8 + T cells, Th1 cells, NK cells, and macrophages. Molecular docking experiments demonstrated strong binding activities between arecoline and TP53, IL6, and CASP3, while TNF also exhibited moderate binding affinity. Dynamic simulation further verified the stable binding of arecoline to TP53, TNF, IL6 and CASP3. Arecoline may induce oral cancer by acting on core targets including TP53, TNF, IL6, and CASP3, which interfere with normal cellular growth regulation, inflammatory responses, and apoptotic mechanisms. Therapeutic strategies targeting TP53, TNF, IL6, and CASP3 may represent novel research directions for clinical diagnosis and treatment of oral cancer. Show less

Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis which plays an important role in thermogenesis and energy metabolism. However, the regulatory factors that inhibit BAT activity remain largely unknown. Here, cardiotrophin-like cytokine factor 1 (CLCF1) is identified as a negative regulator of thermogenesis in BAT. Adenovirus-mediated overexpression of CLCF1 in BAT greatly impairs the thermogenic capacity of BAT and reduces the metabolic rate. Consistently, BAT-specific ablation of CLCF1 enhances the BAT function and energy expenditure under both thermoneutral and cold conditions. Mechanistically, adenylate cyclase 3 (ADCY3) is identified as a downstream target of CLCF1 to mediate its role in regulating thermogenesis. Furthermore, CLCF1 is identified to negatively regulate the PERK-ATF4 signaling axis to modulate the transcriptional activity of ADCY3, which activates the PKA substrate phosphorylation. Moreover, CLCF1 deletion in BAT protects the mice against diet-induced obesity by promoting BAT activation and further attenuating impaired glucose and lipid metabolism. Therefore, our results reveal the essential role of CLCF1 in regulating BAT thermogenesis and suggest that inhibiting CLCF1 signaling might be a potential therapeutic strategy for improving obesity-related metabolic disorders. Show less

Ferritinophagy-mediated ferroptosis plays a crucial role in fighting pathogen aggression. The long non-coding RNA Mir22hg is involved in the regulation of ferroptosis and aberrantly overexpression in lipopolysaccharide (LPS)-induced sepsis mice, but whether it regulates sepsis through ferritinophagy-mediated ferroptosis is unclear. Mir22hg was screened by bioinformatics analysis. Ferroptosis was assessed by assaying malondialdehyde (MDA), reactive oxygen species (ROS), and Fe Mir22hg silencing lightened ferroptosis and ferritinophagy in LPS-induced MLE-12 cells and sepsis mouse models, as presented by the downregulated MDA, ROS, Fe Mir22hg contributed to in ferritinophagy-mediated ferroptosis in sepsis via recruiting the m6A reader YTHDC1 and strengthening Angptl4 mRNA stability, highlighting that Mir22hg may be a potential target for sepsis treatment based on ferroptosis. Show less

ANGPTL4 is an attractive pharmacological target for lowering plasma triglycerides and cardiovascular risk. Since most preclinical studies on ANGPTL4 were performed in male mice, little is known about sexual dimorphism in ANGPTL4 regulation and function. Here, we aimed to study potential sexual dimorphism in ANGPTL4 mRNA and protein levels and ANGPTL4 function. Additionally, we performed exploratory studies on the function of ANGPTL4 in the liver during fasting using Angptl4-transgenic and Angptl4-/- mice. Compared to female mice, male mice showed higher hepatic and adipose ANGPTL4 mRNA and protein levels, as well as a more pronounced effect of genetic ANGPTL4 modulation on plasma lipids. By contrast, very limited sexual dimorphism in ANGPTL4 levels was observed in human liver and adipose tissue. In human and mouse adipose tissue, ANGPTL8 mRNA and/or protein levels were significantly higher in females than males. Adipose LPL protein levels were higher in female than male Angptl4-/- mice, which was abolished by ANGPTL4 (over) expression. At the human genetic level, the ANGPTL4 E40K loss-of-function variant was associated with similar plasma triglyceride reductions in women and men. Finally, ANGPTL4 ablation in fasted mice was associated with changes in hepatic gene expression consistent with PPARα activation. In conclusion, the levels of ANGPTL4 and the magnitude of the effect of ANGPTL4 on plasma lipids exhibit sexual dimorphism. Nonetheless, inactivation of ANGPTL4 should confer a similar metabolic benefit in women and men. Expression levels of ANGPTL8 in human and mouse adipose tissue are highly sexually dimorphic, showing higher levels in females than males. Show less

Three-dimensional (3D) chromatin architecture frequently altered in cancer. However, its changes during the pathogenesis of hepatocellular carcinoma (HCC) remained elusive. Hi-C and RNA-seq were applied to study the 3D chromatin landscapes and gene expression of HCC and ANHT. Hi-C Pro was used to generate genome-wide raw interaction matrices, which were normalized via iterative correction (ICE). Moreover, the chromosomes were divided into different compartments according to the first principal component (E1). Furthermore, topologically associated domains (TADs) were visualized via WashU Epigenome Browser. Furthermore, differential expression analysis of ANHT and HCC was performed using the DESeq2 R package. Additionally, dysregulated genes associated with 3D genome architecture altered were confirmed using TCGA, qRT-PCR, immunohistochemistry (IHC), etc. RESULTS: First, the intrachromosomal interactions of chr1, chr2, chr5, and chr11 were significantly different, and the interchromosomal interactions of chr4-chr10, chr13-chr21, chr15-chr22, and chr16-chr19 are remarkably different between ANHT and HCC, which resulted in the up-regulation of TP53I3 and ZNF738 and the down-regulation of APOC3 and APOA5 in HCC. Second, 49 compartment regions on 18 chromosomes have significantly switched (A-B or B-A) during HCC tumorigenesis, contributing to up-regulation of RAP2A. Finally, a tumor-specific TAD boundary located on chr5: 6271000-6478000 and enhancer hijacking were identified in HCC tissues, potentially associated with the elevated expression of MED10, whose expression were associated with poor prognosis of HCC patients. This study demonstrates the crucial role of chromosomal structure variation in HCC oncogenesis and potential novel biomarkers of HCC, laying a foundation for cancer precision medicine development. Show less

Environmental contaminants (ECs) are increasingly recognized as crucial drivers of dyslipidemia and cardiovascular disease (CVD), but the comprehensive impact spectrum and interlinking mechanisms remain uncertain. We aimed to systematically evaluate the association between exposure to 80 ECs across seven divergent categories and markers of dyslipidemia and investigate their underpinning biomolecular mechanisms via an unbiased integrative approach of internal chemical exposome and multi-omics. A longitudinal study involving 76 healthy older adults was conducted in Jinan, China, and participants were followed five times from 10 September 2018 to 19 January 2019 in 1-month intervals. A broad spectrum of seven chemical categories covering the prototypes and metabolites of 102 ECs in serum or urine as well as six serum dyslipidemia markers [total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein (Apo)A1, ApoB, and ApoE4] were measured. Multi-omics, including the blood transcriptome, serum/urine metabolome, and serum lipidome, were profiled concurrently. Exposome-wide association study and the deletion/substitution/addition algorithms were applied to explore the associations between 80 EC exposures detection frequency Eight main ECs [1-naphthalene, 1-pyrene, 2-fluorene, dibutyl phosphate, tri-phenyl phosphate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, chromium, and vanadium] were significantly associated with most dyslipidemia markers. Multi-omics indicated that the associations were mediated by endogenous biomolecules and pathways, primarily pertinent to CVD, inflammation, and metabolism. Clinical measures of cytokines and electrocardiograms further cross-validated the association of these exogenous ECs with systemic inflammation and cardiac function, demonstrating their potential mechanisms in driving dyslipidemia pathogenesis. It is imperative to prioritize mitigating exposure to these ECs in the primary prevention and control of the dyslipidemia epidemic. https://doi.org/10.1289/EHP13864. Show less

Although various randomized controlled trials (RCTs) have evaluated the effect of raloxifene on apolipoproteins and lipoprotein(a) concentrations in postmenopausal women, the results have been inconsistent and inconclusive. Therefore, we conducted this meta-analysis of RCTs to investigate the effect of raloxifene administration on apolipoproteins and lipoprotein(a) [Lp(a)] concentrations in postmenopausal women. Two independent researchers systematically searched the scientific literature (including PubMed/Medline, Scopus, Web of Science, and EMBASE) for English-language randomized controlled trials (RCTs) published up to June 2024. We included RCTs reporting the impact of raloxifene on apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), and Lp(a) levels in postmenopausal women. The primary outcome of interest was change in Lp(a), and the secondary outcomes were changes in ApoA-I and ApoB. The present meta-analysis incorporated 12 publications with 14 RCT arms. The comprehensive outcomes derived from the random-effects model revealed a statistically significant increase in ApoA-I (WMD: 6.06 mg/dL, 95% CI: 4.38, 7.75, P < 0.001) and decrease in ApoB concentrations (WMD: -8.48 mg/dL, 95% CI: -10.60, -6.36, P < 0.001) and Lp(a) (WMD: -3.02 mg/dL, 95% CI: -4.83, -1.21, P < 0.001) following the administration of raloxifene in postmenopausal women. In the subgroup analyses, the increase in ApoA-I and the decrease in ApoB and Lp(a) levels were greater in RCTs with a mean participant age of ≥60 years and a duration of ≤12 weeks. The current meta-analysis of RCTs demonstrates that treatment with raloxifene reduces ApoB and Lp(a) levels while increasing ApoA-I levels in postmenopausal women. Since these effects on lipid components are associated with a reduced risk of cardiovascular disease (CVD), raloxifene could be a suitable therapy for postmenopausal women who are at an increased risk of CVD and have other medical indications for raloxifene administration. Show less

Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer's disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aβ and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aβ, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aβ: β-amyloid, GABA: gamma-aminobutyric acid. Show less

Β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) is a crucial protease in the production of amyloid-β (Aβ) in Alzheimer's disease (AD) patients. However, the side effects observed in clinical trials of BACE1 inhibitors, including reduction in brain volume and cognitive worsening, suggest that the exact role of BACE1 in AD pathology is not fully understood. To further investigate this, we examined cerebrospinal fluid (CSF) levels of BACE1 and its cleaved product sAPPβ that reflects BACE1 activity in the China Aging and Neurodegenerative Disorder Initiative cohort. We found significant correlations between CSF BACE1 or sAPPβ levels and CSF Aβ40, Aβ42, and Aβ42/Aβ40 ratio, but not with amyloid deposition detected by 18F-Florbetapir PET. Additionally, CSF BACE1 and sAPPβ levels were positively associated with cortical thickness in multiple brain regions, and higher levels of sAPPβ were linked to increased cortical glucose metabolism in frontal and supramarginal areas. Interestingly, individuals with higher baseline levels of CSF BACE1 exhibited slower rates of brain volume reduction and cognitive worsening over time. This suggests that increased levels and activity of BACE1 may not be the determining factor for amyloid deposition, but instead, may be associated with increased neuronal activity and potentially providing protection against neurodegeneration in AD. Show less

CLEC4G, a glycan-binding receptor, has previously been demonstrated to inhibit Aβ generation, yet its brain localization and functions in Alzheimer's disease (AD) are not clear. We explored the localization, function, and regulatory network of CLEC4G via experiments and analysis of RNA-seq databases. CLEC4G transcripts and proteins were identified in brain tissues, with the highest expression observed in neurons. Notably, AD was associated with reduced levels of CLEC4G transcripts. Bioinformatic analyses revealed interactions between CLEC4G and relevant genes such as BACE1, NPC1, PILRA, TYROBP, MGAT1, and MGAT3, all displaying a negative correlation trend. We further identified the upstream transcriptional regulators NR2F6 and XRCC4 for CLEC4G and confirmed a decrease in CLEC4G expression in APP/PS1 transgenic mice. This study highlights the role of CLEC4G in protecting against AD progression and the significance of CLEC4G for AD research and management. Show less

Elevated circulating branched-chain amino acids (BCAAs) are tightly linked to an increased risk in the development of type 2 diabetes mellitus. The rate limiting enzyme of BCAA catabolism branched-chain α-ketoacid dehydrogenase (BCKDH) is phosphorylated at E1α subunit (BCKDHA) by its kinase (BCKDK) and inactivated. Here, the liver-specific BCKDK or BCKDHA knockout mice displayed normal glucose tolerance and insulin sensitivity. However, knockout of BCKDK in the liver inhibited hepatic glucose production as well as the expression of key gluconeogenic enzymes. No abnormal gluconeogenesis was found in mice lacking hepatic BCKDHA. Consistent with the vivo results, BT2-mediated inhibition or genetic knockdown of BCKDK decreased hepatic glucose production and gluconeogenic gene expressions in primary mouse hepatocytes while BCKDK overexpression exhibited an opposite effect. Whereas, gluconeogenic gene expressions were not altered in BCKDHA-silenced hepatocytes. Mechanistically, BT2 treatment attenuated the interaction of cAMP response element binding protein (CREB) with CREB-binding protein and promoted FOXO1 protein degradation by increasing its ubiquitination. Our findings suggest that BCKDK regulates hepatic gluconeogenesis through CREB and FOXO1 signalings, independent of BCKDHA-mediated BCAA catabolism. Show less