👤 Yantao He

Natural killer (NK) cells are an integral component of the tumor microenvironment, and their role in immune checkpoint inhibitors (ICI) therapy has garnered increasing attention. However, comprehensive studies on NK cells across cancers, especially their impact on immunotherapy response, remain limited. We used machine learning algorithms to establish a pan-cancer natural killer cell immunotherapy predictive model (NKCIPM) by combining single-cell RNA sequencing data from 164 samples across 6 cancer types and bulk RNA-seq data from different tumor samples. Tumor immune cell infiltration analysis, drug sensitivity analysis, and cell-cell communication were also further conducted. An upregulation of NK cell proportions post-immunotherapy and the identification of 188 NK cell differentially expressed genes were observed through single-cell RNA sequencing analysis. By integrating bulk RNA-seq data and applying machine learning algorithms, 7 key hub genes were identified, ultimately leading to the construction of NKCIPM, with APOE emerging as the most influential hub gene. Further analysis using the CIBERSORT algorithm revealed that the signature genes within this model were significantly associated with immune cell infiltration and response to ICI. Additionally, therapeutic evaluation of CHEK1 and CHEK2 targets demonstrated potential significance in the communication between B cells, NK cells, and mast cells within the context of ICI therapy. In summary, the NKCIPM model offers a valuable tool for predicting immunotherapy outcomes and informing clinical decision-making, highlighting the potential of NK cell signature genes as therapeutic targets. Show less

Early life air pollution exposure may play a role in development of respiratory infections, but underlying mechanisms are still not understood. We utilized data from two independent prospective birth cohorts to investigate the influence of prenatal and postnatal ambient air pollution exposure of PM Show less

Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer's disease (AD) remains unclear. Here, we report that in the brain of AD patients and animal models, an elevation of poly(C)-binding protein 2 (PCBP2) correlates with biomolecular condensation that involves phase separation. These condensates sequester large numbers of mitochondrial and mRNA-binding proteins, leading to the outside impairment of mitochondrial morphology and function, and BACE1 mRNA decay relative to amyloid deposition. We then identify a small molecule CN-0928 that inhibits the condensates by reducing PCBP2 protein level and mitigates AD pathology and cognitive decline, in which CN-0928 binding to a target protein integrator complex subunit 1 (INTS1) allows to regulate PCBP2 expression. Our findings place PCBP2 condensates as a key player that cooperates the seemingly disparate but important pathways, and show pharmacological modulation of PCBP2 as an effective approach for treating AD. Show less

BACE1 is an indispensable enzyme for the production of β-amyloid peptides by initiating the cleavage of amyloid precursor protein at the β-secretase site. Targeting BACE1 inhibition is therefore a therapeutic strategy for treating patients with Alzheimer's disease. However, several clinical trials using brain-penetrable BACE1 inhibitors have failed due to a lack of efficacy. Previous studies, including our own, have shown that both global and neuron-specific BACE1 inhibition in mice leads to impairments in synaptic strength and spine density. In this study, we investigate the effects of BACE1 inhibition on activity-dependent synaptic vesicle exocytosis and endocytosis using a synapto-pHluorin mouse model. Our results demonstrate impaired synaptic release in BACE1-deficient mice. Furthermore, transcriptomic analysis reveals a significant downregulation of genes related to synapse structure and function. Pathway analysis suggests that BACE1 deficiency significantly downregulates neurexin-neuroligin pathway, which can modulate docking and release of synaptic vesicles at the presynaptic compartment. Our findings suggest that BACE1 inhibition may lead to deficits in synaptic vesicle exocytosis due to the downregulation of key synaptic proteins. Show less

Diabetes constitutes a risk factor for cognitive impairment, whereas insulin resistance serves as the shared pathogenesis underlying both diabetes and cognitive decline. The use of metformin for treating cognitive impairment remains controversial. The present study found that hesperetin, a flavanone derived from citrus peel, enhanced metformin's efficacy in reducing blood sugar levels, improving insulin sensitivity, and ameliorating cognitive impairment in diabetic rats. Additionally, it reduced the required dosage of metformin to one-third of its conventional dose. Transcriptome analysis and 16S rRNA sequencing revealed that the activation of insulin and cyclic-adenosine monophosphate response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathways benefited from the regulation of gut microbiota and the promotion of short-chain fatty acid (SCFA) producers such as Show less

Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD). Recent evidence reveals that lactylation modification, as a novel PTM, is implicated in the occurrence and development of AD. However, whether and how APP lactylation contributes to both the pathogenesis and cognitive function in AD remains unknown. Here, we observed a reduction in APP lactylation in AD patients and AD model mice and cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) as a crucial site for APP lactylation, influencing APP amyloidogenic processing. A lactyl-mimicking mutant (APPK612T) reduced amyloid-β peptide (Aβ) generation and slowed down cognitive deficits in vivo. Mechanistically, APPK612T appeared to facilitate APP trafficking and metabolism. However, lactylated APP entering the endosome inhibited its binding to BACE1, suppressing subsequent cleavage. Instead, it promoted protein interaction between APP and CD2-associated protein (CD2AP), thereby accelerating the endosomal-lysosomal degradation pathway of APP. In the APP23/PS45 double-transgenic mouse model of AD, APP-Kla was susceptible to L-lactate regulation, which reduced Aβ pathology and repaired spatial learning and memory deficits. Thus, these findings suggest that targeting APP lactylation may be a promising therapeutic strategy for AD in humans. Show less

Kidney tubular cell injury is largely responsible for the pathophysiological features of diabetic kidney disease (DKD). Increased leucine levels in individuals with DKD have been associated with the progression of diabetes to end-stage renal failure, yet a comprehensive understanding of leucine metabolism in kidney tubules during the progression of DKD is lacking. Human kidney biopsies and mouse models were used to assess leucine metabolism during DKD progression. Enhancement of leucine degradation was achieved through genetic ablation or pharmacological inhibition of branched-chain ketoacid dehydrogenase kinase (BCKDK). Cultured kidney tubular epithelial cells were used to analyse the underlying cellular mechanisms. The association of urinary leucine with progression of DKD was determined in individuals with diabetes. Measurements of metabolites and enzymes suggested defective leucine degradation and increased BCKDK expression in kidney tubules during DKD progression. Enhancement of leucine degradation relieved glucose-induced metabolic remodelling in tubular cells and mitigated DKD in mouse models. Accumulation of leucine stimulated metabolic remodelling via the mTOR signalling pathway; this was relieved by blocking leucine uptake or enhancing its degradation. Restricting dietary leucine significantly decreased albuminuria, kidney hypertrophy and lipid accumulation in mouse models of diabetes. Additionally, we observed that rapid decline in kidney function correlated with a higher urinary leucine-to-creatinine ratio in both female and male individuals with diabetes. In summary, we identify defective leucine degradation in renal tubules of diabetic individuals and propose leucine as a causative factor for DKD, highlighting its potential as a therapeutic target for further investigation. The transcriptomic data supporting the findings of this study are openly available at the National Center for Biotechnology Information Sequence ReadArchive (SRA) ( https://www.ncbi.nlm.nih.gov/sra , identifiers: PRJNA1180888 and PRJNA1180923). The metabolomics data associated with the manuscript are available in the ESM. Show less

While previous genome-wide association studies (GWAS) identified multiple risk loci for suicide ideation (SI) and suicide attempt (SA), there is still a limited understanding of the genetic predisposition underlying suicidal behaviors in diverse populations. This study aimed to conduct a large-scale investigation of the suicidality spectrum (SP) to generate new insights into its biology and epidemiology. Leveraging ancestrally diverse participants (SI N This study provides convergent genetic evidence for both shared and phenotype-specific components of suicidal behaviors and delineates their associated factors spanning from proximal clinical and behavioral traits to more distal social determinants. These findings refine our understanding of the etiology of suicidal behaviors and may inform targeted strategies for suicide prevention in both clinical and public health settings. Show less

Mounting evidence indicates that the short-chain fatty acid butyrate protects against obesity and associated comorbidities, partially through the induction of adipose tissue thermogenesis. However, the effects of butyrate on white adipose tissue (WAT) browning and its molecular mechanism are still elusive. The objective of this study was to investigate butyrate-induced thermogenesis in white adipose tissue and its underlying mechanism. We studied the effects of butyrate on diet-induced obesity in the humanized APOE*3-Leiden.CETP transgenic mouse model and explored factors related to white adipose browning. Specifically, mice were challenged with a high-fat diet supplemented with butyrate. Adiposity was measured to assess obesity development. Energy metabolism was detected using an indirect calorimetry system. RNA-seq analysis was conducted to analyze the transcription landscape of WAT and responsible targets. Furthermore, the revealed molecular mechanism was verified in vitro. Butyrate alleviated high-fat diet-induced obesity and promoted energy expenditure accompanied by brown adipose tissue activation and WAT browning. Mechanistically, RNA-seq analysis revealed that butyrate downregulated HDAC9 in WAT. Additionally, butyrate decreased HDAC9 while increasing thermogenesis in vitro. Inhibition of HDAC9 with TMP269 promoted thermogenic gene expression, mimicking the effects of butyrate. Butyrate protects against diet-induced obesity accompanied by decreasing the expression of HDAC9 in white adipose tissue and inducing browning. This study reveals a new mechanism whereby butyrate activates adaptive thermogenesis and provides new insights for the development of weight-loss drugs targeting adipose HDAC9. Show less

Despite significant advances in early detection and therapeutic interventions, breast cancer persists as the most frequently diagnosed malignancy and the leading cause of cancer-related deaths among women globally. Although multiple prognostic signatures have been proposed, their predictive power and clinical applicability remain limited. In this study, we utilized an integrated approach combining single-cell multi-omics analysis with machine learning to comprehensively examine the clinical relevance of mitochondrial-related gene sets in TCGA-BRCA and developed a mitochondrial gene set scoring system, termed MitoScore. Based on the median of MitoScore, BRCA patients were classified into high-risk and low-risk groups. Our multi-omics analysis revealed that BRCA patients with higher Mitoscore exhibited poorer prognoses compared to those with lower MitoScore. The predictive ability of the model was successfully validated using an external GEO dataset. Immune infiltration analysis further indicated that high-risk group contributed to an immunosuppressive tumor microenvironment, marked by a decrease in CD8 Show less

DHX36 is an ATP-dependent DNA/RNA helicase that unwinds the guanine-quadruplexes (G4s) of DNA or RNA and regulates their metabolism for key biological functions. Breast cancer is a malignant tumor and effective targeted therapy drugs are limited, even though chemotherapy is generally used. In this study, we found that overexpression of DHX36 promotes breast cancer cell growth, migration, and invasion in vitro, while knocking down or knocking out reversed in vitro and in vivo. Moreover, DHX36 was highly expressed in most clinical breast tumor tissues compared with the matched healthy tissues. Accordingly, higher DHX36 expression correlated with poor recurrence-free survival (RFS) in the patients of breast cancer. These results substantiate that DHX36 might be a diagnostic and prognostic biomarker and is a proto-oncogene that promotes the growth and metastasis of breast cancer. Thus, targeting DHX36-associated G4s in genes, particularly in proto-oncogenes, might be a novel anticancer strategy. Show less

Glioma, characterized by its cellular and molecular heterogeneity, presents formidable challenges in treatment strategy and prognostic assessment. The tumor microenvironment (TME) profoundly influences tumor behavior and treatment response, with tumor-associated neutrophils (TANs) playing a complex but understudied role. This study aimed to investigate the heterogeneity and role of TANs in glioma and to develop a prognostic model. Analysis of scRNA-seq data identified cellular subpopulations and differentially expressed neutrophil-related genes (DE-NRGs). Bulk RNA-seq was obtained from four independent datasets. Molecular subtypes of glioma samples were determined by consensus clustering. WGCNA was conducted to elucidate the association between gene modules and subtypes. We developed a risk score model. Expression of selected genes was confirmed using immunohistochemistry (IHC). In vitro experiments were also performed for functional verification, including CCK8, EdU, Transwell, and TUNEL assays. A total of 108 DE-NRGs for TANs were identified based on scRNA-seq data. Two molecular subtypes were characterized, showing significant differences in prognosis and clinical features. Immune-related analyses demonstrated varied immunological characteristics between subtypes. The risk score model was constructed with 7 genes, including AEBP1, CAVIN1, DCTD, DEPP1, DUSP6, FKBP9, and UGCG. It showed significant prognostic value and was validated across three external datasets. The mutation landscape highlighted higher IDH mutation prevalence in low-risk groups. Drug sensitivity analysis indicated TMZ resistance in high-risk groups. In vitro experiments showed that UGCG could promote glioma cell proliferation, migration, and invasion, while decreasing apoptosis. This study explored the heterogeneity of TANs and developed a prognostic model, providing insights for prognostic prediction and guiding personalized treatment strategies in glioma. Declaration of Generative AI in Scientific Writing: The authors declare nonuse of generative AI and AI-assisted technologies in the writing process. Show less

Ankylosing spondylitis (AS) is a chronic and progressive inflammatory arthritis involving disorders of both the immune and skeletal systems. Multiple osteochondromas (MO) is a rare skeletal disorder with a variety of clinical manifestations characterized by multiple benign exostoses. Here, we investigate a Chinese family with HLA-B27-negative AS complicated with MO. Whole-exome sequencing (WES) and Sanger sequencing were used to screen and identify the pathogenic gene. In vitro functional analysis was performed, and a pathogenesis-associated interleukin (IL)-17 receptor C (IL17RC) mutation was analyzed to investigate its effect on phenotypes. WES was used to identify a known missense mutation, NM₀₀₀₁₂₇.3:c.1019 G > A(p.Arg340His), in the pathogenic gene EXT1 that is causal for MO. Moreover, a missense mutation, NM₁₅₃₄₆₁.3:c.1067 C > T(p.Thr356Met), in the IL17RC gene was identified as potentially responsible for AS or spondyloarthritis symptoms in this family. In vitro over-expression of mutant IL17RC decreased its expression and increased the expression of IL17RA, consistent with the expression of these two genes in patients. Mechanistically, mutant IL17RC enhanced the activation of the NF-κB pathway. This study increases our understanding of the pathogenesis and progression of these diseases. Our findings broaden the risk factors in non-HLA-B genes associated with the NF-κB pathway in AS. Show less

Postnatal respiration requires bulk formation of alveoli that produces extensive surface area for gas diffusion from epithelium to the circulatory system. Alveolar morphogenesis initiates at late gestation or postnatal stage during mammalian development and is mediated by coordination among multiple cell types. Here we show that fibroblast-derived Heparan Sulfate Glycosaminoglycan (HS-GAG) is essential for maintaining a niche that supports alveolar formation by modulating both biophysical and biochemical cues. Gli1-CreER mediated deletion of HS synthase gene Ext1 in lung fibroblasts results in enlarged and simplified alveolar structures. Ablation of HS results in loss of a subset of PDGFRα Show less

Chronic kidney disease (CKD) is a globally prevalent condition and still lacks effective specific medications. Metabolic dysregulation plays a crucial role in CKD. To Identify new potential targets for CKD through metabolites and their regulatory genes. A total of 233 metabolites from the genome-wide association studies (GWAS) Catalog were utilized for Mendelian randomization (MR) with CKD. External validation was conducted from UK Biobank. Cis-eQTL of genes related to very low-density lipoprotein (VLDL) were selected for MR with CKD and metabolites. The total effect of the fatty acid desaturase 1 gene (FADS1) on CKD and metabolite-mediated effects were calculated. Bulk RNA-seq were used to validate FADS1 expression in the kidney tissues of patients with CKD. The cholesteryl esters to total lipids ratio in medium VLDL (odds ratio [OR] = 0.84; P.adj = .039) and total cholesterol to total lipids ratio in small VLDL (OR = 0.84; P.adj = .003) were protective factors for CKD, whereas the triglycerides to total lipids ratio in small VLDL (OR = 1.18; P.adj = .009) and the triglycerides to total lipids ratio in very small VLDL (OR = 1.1; P.adj < .001) were risk factors. They mediated the risk of CKD by FADS1 (OR = 1.1; P.adj = .001), and mediation effects of 21.17%, 10.43%, 23.52%, and 29.96%, respectively, were obtained. The differential expression of FADS1 was observed in the kidney tissues of patients with CKD. FADS1 is a risk factor for CKD and a novel therapeutic target. Four metabolites mediate the detrimental effect of FADS1 in CKD. Show less

This study elucidated the regulatory mechanisms of age-related meat flavor precursors in naturally grazed Sunit sheep of different ages (6, 18, and 30 months) by analyzing their metabolite and mRNA profiles. The longissimus dorsi muscle was sampled from each group and subjected to metabolomics and transcriptomics analyses. A total of 395 differential metabolites (DMs) and 1482 differentially expressed genes (DEGs) were detected across the age groups. As the age increased, the expression levels of Show less

Olaparib has demonstrated therapeutic potential in treating metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene mutations, especially We performed integrative transcriptomic analyses of multiple mCRPC datasets to examine the correlation between In this study, integrative transcriptomic analyses of multiple mCRPC datasets revealed a strong positive correlation between Together, these data reveal an Show less

Bats are natural reservoirs for diverse viruses, yet they rarely develop disease, suggesting unique antiviral adaptations. In this study, we performed a comprehensive genome-wide analysis in the common vampire bat ( Show less

We report a valence-programmable nucleic acid construct platform targeting FGFR1 (NACFs) comprising monovalent NACF-mono, Y-shaped NACF-Bi, and dendritic NACF-multi for engineering stable and efficient agonists. The bioactivity of NACFs exhibited strong valency-dependence, with the higher-valence NACF-multi demonstrating optimal performance. The dendritic construct promoted receptor oligomerization, enhanced serum stability, and elicited potent downstream signaling, thereby stimulating fibroblast proliferation and migration while accelerating tissue regeneration Show less

Diabetic foot ulcers (DFUs) are one of the most common and serious complications of diabetes. The objective of the study is to identify key genes and cellular mechanisms driving DFU pathogenesis and healing using multi-omics integration. We used differential expression analysis and weighted co-expression network analysis (WGCNA) to identify key genes in DFU. We constructed protein-protein interaction (PPI) networks through STRING and Cytoscape. Support vector machine-recursive feature elimination (SVM-RFE) was used to screen out potential diagnostic biomarkers. Single-cell transcriptomic analysis detected differences in the cellular landscape, and intercellular communication analysis deciphered the key intercellular signaling pathway. We first found 388 differentially expressed genes that are closely related to DFU (fold change > 2 and WGCNA-derived module significantly correlated with DFU, R = 0.78). We further constructed a PPI network and identified 15 hub genes and 10 diagnostic biomarkers (including FGF7) for DFU. FGF7 is lowly expressed in DFU and enriched in stromal cells and fibroblasts in DFU, and participates in the immune microenvironment of DFU. FGF7-FGFR1 is the main pathway for intercellular communication involving fibroblasts and stromal cells in the healing process of DFU. These results provide an in-depth understanding of the multifactorial mechanisms underlying DFU progression and healing, offering a theoretical basis for optimizing clinical treatment. Show less

Cranial neural crest cells (CNCs) play a critical role in craniofacial bone morphogenesis, engaging in intricate interactions with various molecular signals to ensure proper development, yet the molecular scaffolds coordinating these processes remain incompletely defined. Here, we identify neurofibromin 2 (Nf2) as a critical regulator to direct CNC-derived skull morphogenesis. Genetic ablation of Nf2 in murine CNCs causes severe craniofacial anomalies, featuring declined proliferation and increased apoptosis in osteoprogenitors, impaired type I collagen biosynthesis and trafficking, and aberrant osteogenic mineralization. Mechanistically, we uncover that Nf2 serves as a molecular linker that individually interacts with FGF receptor 1 (FGFR1) and Akt through spatially segregated phosphor-sites, and structural modeling and mutagenesis identified Ser10 and Thr230 as essential residues, with Thr230 mutation selectively ablating Akt binding while preserving FGFR1 association. Strikingly, Akt inhibition phenocopied Nf2 deficiency, reducing collagen production and Nf2 phosphorylation, whereas phospho-mimetic Nf2 (T230D) rescued CNC-derived osteogenic defects in Nf2-mutant animals. Our findings underscore the physiological significance of Nf2 as a phosphorylation-operated scaffold licensing the FGFR1/AKT axis to regulate collagen type I biogenesis and trafficking, ensuring normal CNC-derived osteogenesis and craniofacial bone development, thus exposing the Nf2/FGFR1/AKT signaling axis as a therapeutic target and promising advancements in treatment of craniofacial anomalies. Show less

This article aims to analyze the safety and efficacy of Erdafitinib in the treatment of patients with advanced solid tumors harboring FGFR1-4 mutations. Search for relevant articles in databases such as PubMed, Embase, The Cochrane Library, Web of Science, and CNKI, covering the period from their establishment to October 25, 2024. Summarize the adverse drug reaction (AE) data, overall survival (OS), median progression-free survival (PFS), objective response rate (ORR), and other relevant data for patients with advanced solid tumors treated with Erdafitinib for FGFR1-4 mutations. Conduct a meta-analysis on the corresponding summarized data using the software Stata 18.0. Through our search, we identified a total of 10 articles involving 1019 patients. In urothelial carcinoma, the most prevalent adverse reactions are hyperphosphatemia (78.5%), diarrhea (56.5%), and stomatitis (51.1%). The most frequently reported adverse reactions in other solid tumors are hyperphosphatemia (66.5%), dry mouth (48.5%), and diarrhea (44.9%). Patients with urothelial carcinoma treated with Erdafitinib exhibit higher median progression-free survival (PFS) and objective response rate (ORR) compared to those treated with other solid tumor therapies. Current evidence indicates that Erdafitinib exhibits certain therapeutic efficacy in the treatment of advanced solid tumors harboring FGFR1-4 mutations, with the most pronounced therapeutic effect observed in urothelial carcinoma. The efficacy of Erdafitinib in treating other solid tumors requires further confirmation through larger-scale studies involving a broader range of FGFR1-4 mutant tumors. Show less

Twenty types of GABAergic interneurons form intricate networks to fine-tune neural circuits in the brain. Parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons, which are the two largest populations of neocortical interneurons, innervate the soma and/or proximal dendrites, and distal dendrites of pyramidal neurons, respectively. Using PV- and SST-specific knockout mouse models, we show that PV+ interneurons require FGFR2, which responds to FGF7, to drive PV+ inhibitory presynaptic maturation on perisomatic regions of Layer V pyramidal neurons. In contrast, SST+ interneurons rely on both FGFR1 and FGFR2, which respond to FGF10 or FGF22, to promote SST+ inhibitory presynaptic maturation on distal dendrites of pyramidal neurons in cortical Layer I. Mechanistically, FGF-FGFR signaling sustains VGAT protein levels in interneurons through PP2A and Akt pathways. Together, these findings demonstrate that distinct FGF ligand-receptor combinations regulate inhibitory presynaptic differentiation by PV+ and SST+ interneurons, contributing to the formation of compartment-specific synaptic patterns. Show less

Membrane protein degradation is a cutting-edge field in targeted protein degradation (TPD). Herein, we developed glypican-3 (GPC3)-mediated lysosome-targeting chimeras (GLTACs) as a novel strategy for the targeted degradation of tumor-specific membrane proteins. GLTACs utilize tumor-specific expression and endocytosis properties of GPC3 to degrade membrane proteins. By conjugating a GPC3-targeting peptide with the ligand of protein of interest (POI), GLTACs induce the formation of a ternary complex that is internalized into lysosomes, leading to the degradation of the POI. The effectiveness and specificity of GLTACs were validated by designing PD-L1, c-Met, and FGFR1 degraders. In particular, GLTAC Show less

The current study aims to investigate whether exosomal miRNAs are involved in lipid reduction by selenium (Se) in the liver of grass carp, through miRNA sequencing, transfection of miRNA mimic (miR-22m) or inhibitor (miR-22i), isolation of hepatocyte-derived exosomes and treatment, and detection of lipid metabolism-related genes and proteins. The miRNAs sequencing and bioinformatics revealed that miR-22 was most abundantly expressed in the differentially expressed miRNAs after selenium treatment, and was enriched in lipid metabolism-related pathways. Moreover, Se significantly up-regulated the miR-22 levels and reduced the lipid content in liver or hepatocytes of grass carp. Furthermore, the miR-22m significantly increased levels of miR-22 and reduced lipid content in grass carp hepatocytes, which were consistent with the Se-treatment. However, the miR-22i reversed these trends. Besides, the miR-22 suppressed the FGFR1-PI3K-AKT-mTOR signaling pathway and its downstream genes related to lipid synthesis. More importantly, the Se-treated hepatocyte-exosomes which were enriched in the miR-22 significantly reduced the triglycerides content in the oleic acid-treated hepatocytes. In summary, Se alleviated high fat-induced lipid accumulation in grass carp liver by up-regulating the expression of miR-22 which negatively regulates FGFR1 and its downstream regulatory genes. Moreover, exosomes participate in the lipid reduction by Se, which may be through carrying miR-22. Show less

Diabetic retinopathy (DR) is the leading manifestation of diabetic microangiopathy. However, effective biomarkers and therapies are lacking. Circular RNAs (circRNAs) have been implicated in various diseases including DR. However, the role of circRNAs in DR remains elusive. In the present study, circNXN was upregulated in high glucose (HG)-treated human retinal microvascular endothelial cells (hRMECs). circNXN knockdown inhibited the proliferation, migration, and angiogenesis of hRMECs and promoted apoptosis. In addition, circNXN acted as a sponge for miR-338-3p to facilitate the FGFR1 (fibroblast growth factor receptor 1) expression. Furthermore, rescue assays revealed that the reduced promoting effect on hRMECs induced by the knockdown of circNXN could be reversed by a miR-338-3p inhibitor in HG-treated hRMECs. Additionally, in a DR rat model, circNXN downregulation ameliorated retinal vasculature changes. Our findings reveal a new therapeutic strategy for DR that may provide a new approach to clinical DR therapy. Show less

Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function. Show less