👤 Yan-ling Gao

Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC inhibitors have therapeutic effects on AD. Here, we identified sodium valproate (VPA), a pan-HDAC inhibitor, and WT161, a novel HDAC6 selective inhibitor, as potential therapeutic agents for AD. Underlying molecular mechanisms were investigated. A cellular model, N2a-APPswe, was established via lentiviral infection, and the APPswe/PSEN1dE9 transgenic mouse model was employed in the study. LC-MS/MS was applied to quantify the concentration of WT161 in the mouse brain. Western blotting, immunohistochemical staining, thioflavin-S staining and ELISA were applied to detect protein expression in cells, tissues, or serum. RNA interference was utilized to knockdown the expression of specific genes in cells. The cognitive function of mice was assessed via the nest-building test, novel object recognition test and Morris water maze test. Previous studies have focused mainly on the impact of HDAC inhibitors on histone deacetylase activity. Our study discovered that VPA and WT161 can downregulate the expression of multiple HDACs, such as HDAC1 and HDAC6, in both AD cell and mouse models. Moreover, they also affect the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). RNA interference and subsequent vitamin C induction further confirmed that the expression of APP and APP secretases is indeed regulated by HDAC1 and HDAC6, with the JNK pathway being the intermediate link in this regulatory process. Through the above pathways, VPA and WT161 effectively reduced Aβ deposition in both AD cell and mouse models and significantly improved cognitive function in AD mice. In general, we have discovered that the HDAC6-JNK-APP secretases cascade is an important pathway for VPA and WT161 to exert their therapeutic effects on AD. Investigations into the safety and efficacy of VPA and WT161 were also conducted, providing essential preclinical evidence for assessing these two epigenetic drugs for the treatment of AD. Show less

Elevated levels of the branched chain α-amino acids valine, leucine, and isoleucine are associated with heart disease and metabolic disorders. The kinase BDK, also known as branched-chain ketoacid dehydrogenase kinase (BCKDK), is a negative regulator of branched-chain α-amino acid metabolism through deactivation of BCKDC, the branched-chain α-ketoacid dehydrogenase complex. Inhibitors of BDK increase the activity of BCKDC and could be useful therapeutic leads for cardiometabolic diseases. We describe a novel bicyclic carboxy amide as an inhibitor of BDK with in vivo activity. Show less

We investigated the correlation between serum C1q/TNF-related protein 4 (CTRP4) level and flow-mediated dilation (FMD) in patients with type 2 diabetes mellitus (T2DM), and evaluated the biological effects of CTRP4 on human umbilical vein endothelial cells (HUVECs). A group of 165 patients diagnosed with T2DM were included in this study. Endothelial function was measured with the examination of brachial artery FMD. ELISA kit was used to measure the levels of CTRP4 in serum. HUVECs were stimulated with recombinant CTRP4 protein to assess its biological functions. The levels of CTRP4 showed a significant variation among three groups based on FMD tertiles (p = 0.001). What's more, FMD had a significant difference among three CTRP4 tertile groups (p < 0.05) and was negatively related to serum CTRP4 levels (r = -0.270, p < 0.001). In T2DM patients, logistic regression analysis demonstrated that CTRP4 was the primary influence factor of low FMD (p < 0.01). In receiver operating characteristic curve analysis, the area under the curve of CTRP4 for predicting low FMD was 0.66 (95%CI 0.58-0.75). When stimulated HUVECs with recombinant CTRP4 protein, we found that CTRP4 could concentration-dependently ameliorate proliferation and migration of HUVECs in wounding healing and transwell assay. This protein could also decrease the expression of IL-6 and TNF-α and promote the release of NO in HUVEC supernatants, with suppression of NF-κB and STAT3 phosphorylation. Serum CTRP4 concentrations were negatively associated with FMD. CTRP4 alleviated proliferation, migration and inflammation in HUVECs through the suppression of NF-κB and STAT3 signaling pathways. Show less

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors originating from the digestive system. Tertiary lymphoid structures (TLS), non-lymphoid tissues outside of the lymphoid organs, are closely connected to chronic inflammation and tumorigenesis. However, the detailed relationship between TLS and HCC prognosis remained unclear. In this study, we aimed to construct a TLS-related gene signature for predicting the prognosis of HCC patients. The Cancer Genome Atlas (TCGA) clinical data from 369 HCC tissues and 50 normal liver tissues were utilized to examine the differential expression of TLS-related genes. Based on least absolute shrinkage and selection operator (LASSO) Cox regression analysis, the prognostic model was constructed using the TCGA cohort and validated in the GSE14520 cohort and International Cancer Genome Consortium (ICGC) cohort. The Kaplan-Meier (KM) and receiver operating characteristic (ROC) curves were employed to validate the predictive ability of the prognostic model. Furthermore, Cox regression analysis was applied to identify whether the TLS score could be employed as an independent prognosis factor. A nomogram was developed to predict the survival probability of HCC patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed for TLS-related genes. Genetic mutation analysis, the CIBERSORT algorithm, and single-sample gene set enrichment analysis (ssGSEA) were used to assess the tumor mutation landscape and immune infiltration. Finally, the role of the TLS score in HCC therapy was investigated. Six genes were included in the construction of our prognostic model (CETP, DNASE1L3, PLAC8, SKAP1, C7, and VNN2), and we validated its accuracy. Survival analysis showed that patients in the high-TLS score group had a significantly better overall survival than those in the low-TLS score group. Univariate, multivariate Cox regression analysis and the establishment of a nomogram indicated that the TLS score could independently function as a potential prognostic marker. A significant association between TLS score and immunity was revealed by an analysis of gene alterations and immune cell infiltration. In addition, two subtypes of the TLS score could accurately predict the effectiveness of sorafenib, transcatheter arterial chemoembolization (TACE), and immunotherapy in HCC patients. In this research, we conducted and validated a prognostic model associated with TLS that may be helpful for predicting clinical outcomes and treatment responsiveness for HCC patients. Show less

Digitalization, as a crucial engine for promoting sustainable development, has created new prospects for enterprise green transformation. Utilizing panel data from enterprises registered in China's resource-based cities from 2010 to 2021, this study innovatively examines the role of digitalization in promoting green transformation across two key performance dimensions. The findings indicate that enterprise digitalization significantly enhances the green innovation performance, while its impact on environmental performance, although positive, is not statistically significant. Overall, enterprise digitalization greatly facilitates green transformation. Moreover, mechanism analysis reveals that enterprise digitalization promotes green transformation through the alleviation of financial mismatch and the increase of external market attention. In addition, heterogeneity analysis shows that the effectiveness of enterprise digitalization in promoting green transformation is significantly different in different opportunist risk scenarios, proving more effective in areas with low-marketization, high-competition industries, and high environmental regulation intensity. In terms of the policy level, the National Big Data Comprehensive Pilot Zone (NBDCPZ) and the Carbon Emission Trading Policy (CETP) played a positive stimulating role in the process of enterprise digitalization affecting green transformation. This paper broadens the scope of research on green transformation, offers new development philosophy for enterprises in resource-based cities, and provides new directions for the synergistic development of digitalization and greenization. Show less

The lack of effective pharmacotherapies for aortic aneurysms (AA) is a persistent clinical challenge. Lipid metabolism plays an essential role in AA. However, the impact of lipid-lowering drugs on AA remains controversial. The study aimed to investigate the genetic association between lipid-lowering drugs and AA. Our research used publicly available data on genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) studies. Genetic instruments, specifically eQTLs related to drug-target genes and SNPs (single nucleotide polymorphisms) located near or within the drug-target loci associated with low-density lipoprotein cholesterol (LDL-C), have been served as proxies for lipid-lowering medications. Drug-Target Mendelian Randomization (MR) study is used to determine the causal association between lipid-lowering drugs and different types of AA. The MR analysis revealed that higher expression of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) was associated with increased risk of AA (OR = 1.58, 95% CI = 1.20-2.09, P = 1.20 × 10-03) and larger lumen size (aortic maximum area: OR = 1.28, 95% CI = 1.13-1.46, P = 1.48 × 10-04; aortic minimum area: OR = 1.26, 95% CI = 1.21-1.42, P = 1.78 × 10-04). PCSK9 (proprotein convertase subtilisin/kexin type 9) and CETP (cholesteryl ester transfer protein) show a suggestive relationship with AA (PCSK9: OR = 1.34, 95% CI = 1.10-1.63, P = 3.07 × 10-03; CETP: OR = 1.38, 95% CI = 1.06-1.80, P = 1.47 × 10-02). No evidence to support genetically mediated NPC1L1 (Niemann-Pick C1-Like 1) and LDLR (low-density lipoprotein cholesterol receptor) are associated with AA. This study provides causal evidence for the genetic association between lipid-lowering drugs and AA. Higher gene expression of HMGCR, PCSK9, and CETP increases AA risk. Furthermore, HMGCR inhibitors may link with smaller aortic lumen size. Show less

Altered expression and activity of solute carrier family 4 member 4 (SLC4A4) could affect the growth, survival and metastasis of tumor cells. Currently, the role of SLC4A4 in lung adenocarcinoma (LUAD) immunotherapy and prognosis was not entirely clear. We analyzed SLC4A4 expression in LUAD tissues and cell lines using quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. The effects of SLC4A4 overexpression on angiogenesis, cell migration, invasion, and epithelial-mesenchymal transition were examined. Public databases helped construct a risk model evaluating SLC4A4's expression on LUAD prognosis and immunotherapy response. Additionally, a xenograft model, flow cytometry, and enzyme-linked immunosorbent assay further explored SLC4A4's role in tumor immune microenvironment infiltration. Upregulation of SLC4A4 promoted apoptosis in the LUAD cell line and significantly inhibited the migration and invasive ability of cancer cells (P<0.01). A total of 10 key genes (including SIGLEC6, RHOV, PIR, MOB3B, MIR3135B, LPAR6, KRT8, ITGA2, CPS1, and C6) were screened according to SLC4A4 expression, immune score and stromal score, and a prognostic model with good outcome was constructed (AUC values of which in the training cohort at 1,3, and 5 years reached 0.73, 0.73, and 0.72, respectively). Importantly, we demonstrated that high expression of SLC4A4 was able to increase the proliferation level and cytokine secretion of CD8+ T cells for the purpose of promoting the immune system response to LUAD. Our study revealed that SLC4A4 can serve as a prognostic indicator for LUAD, providing new insights into the treatment and diagnosis of LUAD. Show less

Vitamins, and their metabolic processes play essential regulatory roles in controlling proliferation, differentiation, and growth in carcinogenesis. However, the role of vitamin metabolism in lung adenocarcinoma (LUAD) has rarely been reported. Here, we established a novel prognostic model based on vitamin metabolism-related genes in LUAD. In this research, we aimed to identify vitamin metabolism associated with differentially expressed genes (DEGs) in LUAD utilizing The Cancer Genome Atlas (TCGA)-LUAD, GSE68465 and GSE72094 data. Unsupervised clustering classified patients into distinct subgroups. By utilizing least absolute shrinkage and selection operator (LASSO)-Cox regression analysis, vitamin metabolism-related genes could be used to construct prognostic model. Then the vitamin metabolism gene-related risk score (VRS) was calculated based on best cut-off splitting. Kaplan-Meier analysis, time-dependent receiver operating characteristic (ROC) analysis, univariate and multivariate Cox analyses, chemotherapeutic drugs sensitivity analysis, immune infiltration analysis and nomogram were conducted to verify our models' accuracy. Finally, CPS1 was identified as a relevant diagnostic marker using Random Forests algorithms, single-cell RNA sequencing data was used to confirm its expression. We investigated the relationship between vitamin metabolism patterns, overall survival (OS), and immune infiltration levels of patients with LUAD. A prognostic signature consisting of 11 genes was developed, which was able to classify patients into high and low VRS groups. Through gene enrichment analysis, cell cycle was mainly enriched. Compared to the low VRS group, the high VRS group exhibited poorer OS, as demonstrated by the Kaplan-Meier survival analysis. Furthermore, VRS was identified as an independent predictor of poor prognosis and poor OS, as indicated by both univariate and multivariate Cox regression analyses. Additionally, a nomogram was constructed to improve the accuracy of survival predictions in LUAD patients. We also found that the two groups of patients might respond differently to immune targets and anti-tumor drugs. CPS1 was identified as a relevant diagnostic marker and the expression was also as confirmed by single-cell RNA sequencing data. Overall, our findings suggest that vitamin metabolism can influence the prognosis of LUAD patients, and our prognostic signature represents a potentially helpful resource for predicting patient outcomes and informing clinical decision-making. Show less

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

Cancer is rarely the straightforward consequence of an abnormality in a single gene, but rather reflects a complex interplay of many genes, represented as gene modules. Here, we leverage the recent advances of model-agnostic interpretation approach and develop CGMega, an explainable and graph attention-based deep learning framework to perform cancer gene module dissection. CGMega outperforms current approaches in cancer gene prediction, and it provides a promising approach to integrate multi-omics information. We apply CGMega to breast cancer cell line and acute myeloid leukemia (AML) patients, and we uncover the high-order gene module formed by ErbB family and tumor factors NRG1, PPM1A and DLG2. We identify 396 candidate AML genes, and observe the enrichment of either known AML genes or candidate AML genes in a single gene module. We also identify patient-specific AML genes and associated gene modules. Together, these results indicate that CGMega can be used to dissect cancer gene modules, and provide high-order mechanistic insights into cancer development and heterogeneity. Show less

Current therapeutic options for renal cell carcinoma (RCC) are very limited, which is largely due to inadequate comprehension of molecular pathological mechanisms as well as RCC's resistance to chemotherapy. Dual-specificity phosphatase 6 (DUSP6) has been associated with numerous human diseases. However, its role in RCC is not well understood. Here, we show that diminished DUSP6 expression is linked to RCC progression and unfavorable prognosis. Mechanistically, DUSP6 serves as a tumor suppressor in RCC by intervening the TAF10 and BSCL2 via the ERK-AKT pathway. Further, DUSP6 is also transcriptionally regulated by HNF-4a. Moreover, docking experiments have indicated that DUSP6 expression is enhanced when bound by Calcium saccharate, which also inhibits RCC cell proliferation, metabolic rewiring, and sunitinib resistance. In conclusion, our study identifies Calcium saccharate as a prospective pharmacological therapeutic approach for RCC. Show less

Structural variations (SVs) have significant impacts on complex phenotypes by rearranging large amounts of DNA sequence. We present a comprehensive SV catalog based on the whole-genome sequence of 1060 pigs (Sus scrofa) representing 101 breeds, covering 9.6% of the pig genome. This catalog includes 42,487 deletions, 37,913 mobile element insertions, 3308 duplications, 1664 inversions, and 45,184 break ends. Estimates of breed ancestry and hybridization using genotyped SVs align well with those from single nucleotide polymorphisms. Geographically stratified deletions are observed, along with known duplications of the KIT gene, responsible for white coat color in European pigs. Additionally, we identify a recent SINE element insertion in MYO5A transcripts of European pigs, potentially influencing alternative splicing patterns and coat color alterations. Furthermore, a Yorkshire-specific copy number gain within ABCG2 is found, impacting chromatin interactions and gene expression across multiple tissues over a stretch of genomic region of ~200 kb. Preliminary investigations into SV's impact on gene expression and traits using the Pig Genotype-Tissue Expression (PigGTEx) data reveal SV associations with regulatory variants and gene-trait pairs. For instance, a 51-bp deletion is linked to the lead eQTL of the lipid metabolism regulating gene FADS3, whose expression in embryo may affect loin muscle area, as revealed by our transcriptome-wide association studies. This SV catalog serves as a valuable resource for studying diversity, evolutionary history, and functional shaping of the pig genome by processes like domestication, trait-based breeding, and adaptive evolution. Show less

Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17 % methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism. Show less

Inflammatory bowel disease (IBD) is a growing global health problem. IBD is commonly prevalent in Europe and America and the incidence rate in Asia is on the rise due to altered dietary structure. Diosgenin is a natural steroidal saponin derived from Dioscorea plants. Diosgenin is the main active ingredient of some Chinese medicines which are mainly used to treat coronary heart disease, angina and hyperlipidemia. Recently, growing evidence has exhibited a crucial role of diosgenin and dioscin in alleviating IBD in multiple ways. However, the precise mechanism of diosgenin against IBD needs further exploration. In this study, network pharmacological and systematic bioinformatic analyses were performed to investigate the diosgenin's targets against IBD. 71 targets such as SRC, TNF and STAT3 were identified as overlapped genes between diosgenin and IBD. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis exhibited their involvement in the tyrosine kinase signaling pathway and its membrane receptors. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance and its downstream Ras-MAPK pathway and PI3K-Akt pathway might become the mechanism of diosgenin against IBD. In addition, molecular docking analysis showed that diosgenin has the massive potential of direct binding to tyrosine kinase and its receptors such as SRC, EGFR, FGFR1 and VEGFR. The results above collectively provided evidence that diosgenin is a promising nutraceutical food against IBD. Show less

Nintedanib is a small molecule tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). The purpose of the study was to evaluate the response rate for patients with advanced non-small cell lung cancer (NSCLC) with mutations in Patients with advanced NSCLC previously treated with platinum-doublet chemotherapy with the above mutations were enrolled. Exclusion criteria included necrotic tumors with invasion of blood vessels, history of recent thromboembolic events, increased risk of bleeding or thrombosis, myocardial infarction, and weight loss >10% within past 6 months. Nintedanib was administered at a dose of 200 mg orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary endpoints included progression-free survival (PFS) and correlating outcomes with specific mutations. This study was registered with ClinicalTrials.gov, number NCT02299141. Between 2015 and 2019, 20 patients were enrolled with a median age was 66 years, 15 (75%) were females, 15 (75%) had adenocarcinoma, and 17 patients had a In this pilot study in heavily pretreated and molecularly selected patients with metastatic NSCLC, nintedanib showed modest activity. Show less

Atherosclerosis (AS) is a leading cause of cardiovascular morbidity and mortality. Atherosclerotic lesions show increased levels of proteins associated with the fibroblast growth factor receptor (FGFR) pathway. However, the functional significance and mechanisms governed by FGFR signalling in AS are not known. In the present study, we investigated fibroblast growth factor receptor 1 (FGFR1) signalling in AS development and progression. Examination of human atherosclerotic lesions and aortas of Apoe-/- mice fed a high-fat diet (HFD) showed increased levels of FGFR1 in macrophages. We deleted myeloid-expressed Fgfr1 in Apoe-/- mice and showed that Fgfr1 deficiency reduces atherosclerotic lesions and lipid accumulations in both male and female mice upon HFD feeding. These protective effects of myeloid Fgfr1 deficiency were also observed when mice with intact FGFR1 were treated with FGFR inhibitor AZD4547. To understand the mechanistic basis of this protection, we harvested macrophages from mice and show that FGFR1 is required for macrophage inflammatory responses and uptake of oxidized LDL. RNA sequencing showed that FGFR1 activity is mediated through phospholipase-C-gamma (PLCγ) and the activation of nuclear factor-κB (NF-κB) but is independent of FGFR substrate 2. Our study provides evidence of a new FGFR1-PLCγ-NF-κB axis in macrophages in inflammatory AS, supporting FGFR1 as a potentially therapeutic target for AS-related diseases. Show less

The purpose of this study was to screen the genes and pathways that are involved in spermatogonia stem cell (SSC) differentiation regulation during the transition from A The GO analysis showed that RNA transport, the MAPK pathway and the p53 pathway may play vital roles in early SSC differentiation, and Show less

Adrenal and extra-adrenal paragangliomas (PGLs) are a group of neuroendocrine tumors (NETs) with strong heterogeneity, which often express somatostatin receptor subtype 2 A (SSTR2A). However, the association between SSTR2A expression and genetic status of PGLs remains unclear. The purpose of the study was to identify whether various pathogenic variants (PVs) had an impact on SSTR2A expression in PGLs. This retrospective study included 184 patients with pathologically confirmed PGLs. The immunohistochemical expression of SSTR2A were studied in 184 tumors and PVs were tested in 159 tumor samples. Clinical and genetic data were compared in SSTR2A positive and negative PGLs. SSTR2A was positive in 63.6% (117/184) of all tumors. PGLs with negative SSTR2A were more likely to be extra-adrenal (37.0% vs 18.0%; P = 0.005) and exhibited a considerably greater proportion of PVs (75.4% vs. 49.0%; P = 0.001) than those with positive SSTR2A. Compared to those without PVs, a higher proportion of PGLs with PVs in cluster 1B (P = 0.004) and cluster 2 (P = 0.004) genes, especially VHL (P = 0.009), FGFR1 (P = 0.010) and HRAS (P = 0.007), were SSTR2A negative. SSTR2A was positive in all tumors (4/4) with SDHx PVs and in 87.5% (7/8) of metastatic PGLs. SSTR2A negativity was correlated with extra-adrenal tumor location and PVs in cluster 1B and cluster 2 genes such as VHL, FGFR1 and HRAS. Immunohistochemistry of SSTR2A should be taken into consideration in the personalized management of PGLs. Show less

Fibroblast-like synoviocytes (FLSs) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLSs in relapse and remission of RA remain unknown. Identifying FLS heterogeneity and their underlying pathogenic roles may lead to discovering novel disease-modifying antirheumatic drugs. Combining single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, we sequenced six matched synovial tissue samples from three patients with relapse RA and three patients in remission. We analyzed the differences in the transcriptomes of the FLS subsets between the relapse and remitted phases. We validated several key signaling pathways using quantitative real-time PCR (qPCR) and multiplex immunohistochemistry (mIHC). We further targeted the critical signals in vitro and in vivo using the collagen-induced arthritis (CIA) model in rats. Lining and sublining FLS subsets were identified using scRNA-seq. Differential analyses indicated that the fibroblast growth factor (FGF) pathway was highly activated in the lining FLSs from patients with relapse RA for which mIHC confirmed the increased expression of FGF10. Although the type I interferon pathway was also activated in the lining FLSs, in vitro stimulation experiment suggested that it was independent of the FGF10 pathway. FGF10 knockdown by small interfering RNA in FLSs significantly reduced the expression of receptor activator of NF-κB ligand. Moreover, recombinant FGF10 protein enhanced bone erosion in the primary human-derived pannus cell culture, whereas the FGF receptor (FGFR) 1 inhibitor attenuated this process. Finally, administering an FGFR1 inhibitor displayed a therapeutic effect in a CIA rat model. The FGF pathway is a critical signaling pathway in relapse RA. Targeted tissue-specific inhibition of FGF10/FGFR1 may provide new opportunities to treat patients with relapse RA. Show less

Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness. Nowadays anti-VEGF and retinal photocoagulation are mainstream treatments for ROP, but they develop a variety of complications. Hydrogen (H In this study, mice that were seven days old and either wild-type (WT) or Nrf2-deficient (Nrf2-/-) were exposed to 75% oxygen for 5 days and then returned to normal air conditions. Different stages of hydrogen gas (H Our results indicate that 3-4% H Collectively, our results indicate that H Show less

Magnesium phosphate bone cements (MPC) have been recognized as a viable alternative for bone defect repair due to their high mechanical strength and biodegradability. However, their poor porosity and permeability limit osteogenic cell ingrowth and vascularization, which is critical for bone regeneration. In the current study, we constructed a novel hierarchically-porous magnesium phosphate bone cement by incorporating extracellular matrix (ECM)-mimicking electrospun silk fibroin (SF) nanofibers. The SF-embedded MPC (SM) exhibited a heterogeneous and hierarchical structure, which effectively facilitated the rapid infiltration of oxygen and nutrients as well as cell ingrowth. Besides, the SF fibers improved the mechanical properties of MPC and neutralized the highly alkaline environment caused by excess magnesium oxide. Bone marrow stem cells (BMSCs) adhered excellently on SM, as illustrated by formation of more pseudopodia. CCK8 assay showed that SM promoted early proliferation of BMSCs. Our study also verified that SM increased the expression of OPN, RUNX2 and BMP2, suggesting enhanced osteogenic differentiation of BMSCs. We screened for osteogenesis-related pathways, including FAK signaing, Wnt signaling and Notch signaling, and found that SM aided in the process of bone regeneration by suppressing the Notch signaling pathway, proved by the downregulation of NICD1, Hes1 and Hey2. In addition, using a bone defect model of rat calvaria, the study revealed that SM exhibited enhanced osteogenesis, bone ingrowth and vascularization compared with MPC alone. No adverse effect was found after implantation of SM Show less

Most organs are maintained lifelong by resident stem/progenitor cells. During development and regeneration, lineage-specific stem/progenitor cells can contribute to the growth or maintenance of different organs, whereas fully differentiated mature cells have less regenerative potential. However, it is unclear whether vascular endothelial cells (ECs) are also replenished by stem/progenitor cells with EC-repopulating potential residing in blood vessels. It has been reported recently that some EC populations possess higher clonal proliferative potential and vessel-forming capacity compared with mature ECs. Nevertheless, a marker to identify vascular clonal repopulating ECs (CRECs) in murine and human individuals is lacking, and, hence, the mechanism for the proliferative, self-renewal, and vessel-forming potential of CRECs is elusive. We analyzed colony-forming, self-renewal, and vessel-forming potential of ABCG2 (ATP binding cassette subfamily G member 2)-expressing ECs in human umbilical vessels. To study the contribution of In human and mouse vessels, ECs with higher These results are the first to establish that a single prospective marker identifies CRECs in mice and human individuals, which holds promise to provide new cell therapies for repair of damaged vessels in patients with endothelial dysfunction. Show less

The metabolic reprogramming of macrophages is a potential therapeutic strategy for sepsis treatment, but the mechanism underlying this reprogramming remains unclear. Since glycolysis can drive macrophage phenotype switching, the rate-limiting enzymes in glycolysis may be key to treating sepsis. Here, we found that, compared with other isoenzymes, the expression of 6-phosphofructokinase, muscle type (PFKM) was the most upregulated in monocytes from septic patients. Recombinant thrombomodulin (rTM) treatment downregulated the protein expression of PFKM in macrophages. Both rTM treatment and Pfkm knockout protected mice from sepsis and reduced the production of the proinflammatory cytokines IL-1β, IL-6, TNF-α, and IL-27, whereas PFKM overexpression increased the production of these cytokines. Mechanistically, rTM treatment inhibited glycolysis in macrophages by decreasing PFKM expression in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. HIF-1α overexpression increased methyltransferase-like 3 (METTL3) expression, elevated the m Show less

The gut microbiota (GM) has been implicated in neurological disorders, but the relationship with hydrocephalus, especially the underlying mechanistic pathways, is unclear. Using Mendelian randomization (MR), we aim to discover the mediating role of inflammatory factors in the relationship between GM and hydrocephalus. After removing confounders, univariable and multivariable MR analyses were performed using summary statistics to assess the causal relationships between GM, inflammatory factors (IL-17A and IL-27), and types of hydrocephalus. Meta-analyses were used to reconcile the differences in MR results between different hydrocephalus sources. Finally, mediator MR analyses were applied to determine the mediating effect of inflammatory factors. Various sensitivity analysis methods were employed to ensure the reliability and stability of the results. After correction for We reveal the connection between GM, inflammatory factors (IL-17A and IL-27), and hydrocephalus, which lays the foundation for unraveling the mechanism between GM and hydrocephalus. Show less

Interleukin-27 (IL-27), a potential mediator linking obesity to inflammatory diseases, is considered an important candidate for regulating obesity. The present study evaluated the relationship of IL-27 with obesity and insulin resistance (IR) and further investigated the changes in IL-27 levels after weight loss. The study analyzed 405 participants, of whom 62 with overweight or obesity completed one year of lifestyle intervention. The body compositions, including percent of body fat (PBF), visceral fat area (VFA), skeletal muscle mass (SMM), and visceral fat area to skeletal muscle mass ratio (VSR), were assessed using the bioelectrical impedance analysis method. Serum IL-27 levels were measured using the enzyme-linked immunosorbent assay (ELISA). IL-27 levels increased significantly with the increase in body mass index (BMI) (P < 0.001). Moreover, IL-27 levels were positively correlated with PBF, VFA, and VSR. Homeostatic model assessment for insulin resistance (HOMA-IR), the inverse of hepatic insulin sensitivity (1/HISI), adipose tissue insulin resistance (Adipo-IR), and homeostasis model assessment-adiponectin (HOMA-AD) increased significantly with each quartile of IL-27 levels (all P < 0.001). IL-27 levels significantly decreased after weight loss (P < 0.001). IL-27 was positively correlated with obesity, HOMA-IR, 1/HISI, Adipo-IR, and HOMA-AD. IL-27 levels significantly decreased after weight loss. Show less

Inflammatory cytokines have crucial roles in the pathogenesis of tuberculosis (TB), and interleukin (IL)-27 and IL-35 have a pro-inflammatory and anti-inflammatory effect on many diseases, including infectious diseases. Therefore, we evaluated the relationship between Show less

Although human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from cerebellum from 9 human cases of AD/ADRD and 8 controls, and with frontal cortex of 6 AD donors for additional comparison. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we prioritized two likely causal genes, including Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and Hi-C looping data. This first cell subtype-specific regulatory landscape in the human cerebellum identified here offer novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied. Show less

The fat tail of sheep is an adaptive trait that facilitates their adaptation to harsh natural environments. MicroRNAs (miRNAs) have been demonstrated to play crucial roles in the regulation of tail fat deposition. In this study, miRNA-Seq was employed to investigate the expression profiles of miRNAs during different developmental stages of sheep fat tails and elucidate the functions of differentially expressed miRNAs (DE miRNAs). A total of 350 DE miRNAs were identified, among which 191, 60, 26, and 21 were significantly upregulated in tail fat tissues of fetal, lamb, hogget Altay sheep, and adult Xinjiang fine wool (XFW) sheep but downregulated in other stages. Furthermore, we predicted a set of candidate target genes (4,476) for the top 20 DE miRNAs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that they involve in several adipogenesis-related pathways. Subsequent investigations indicated that four DE miRNAs, miR-433-3p, miR-485-3p, miR-409-3p, and miR-495-3p, could suppress the expression of peroxisome proliferator-activated receptor gamma ( The expression patterns of miRNAs exhibited significant fluctuations during different development periods of the fat tail, and some of them may participate in the regulation of tail fat deposition by modulating the proliferation and differentiation of preadipocytes. Show less