Axin1 takes an important part in a variety of signaling pathway, such as MEKK1, GSK3β, and β-catenin, and plays a variety of physiological functions; but its effects on the brain-blood barrier (BBB) a Show more
Axin1 takes an important part in a variety of signaling pathway, such as MEKK1, GSK3β, and β-catenin, and plays a variety of physiological functions; but its effects on the brain-blood barrier (BBB) and stroke remain unclear. To explore the effects and underlying mechanisms of Axin1 on the BBB in ischemic stroke, Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO). Human brain microvascular endothelial cells (HBMEC) were subjected to oxygen/glucose deprivation/reoxygenation (OGD/R) to imitate ischemia/reperfusion (I/R) injury. We found that Axin1 was upregulated in HBMEC after OGD without reoxygenation, and downregulated in the injured hemisphere after MCAO without reperfusion. Tight junction (TJ) proteins were upregulated both in HBMEC after OGD without reoxygenation and in ischemic penumbra of the injured hemisphere in rats after MCAO without reperfusion. TJ proteins were downregulated after MCAO/R in rats. Overexpression of Axin1 upregulated the levels of TJ proteins, which alleviated BBB permeability, reduced infarction volume, and ultimately improved neurological behavioral indicators after I/R injury. Furthermore, inhibiting phosphorylation of Axin1 at Thr485 notably increased the expression of Snail and decreased the expression of TJ proteins. Our findings demonstrate that Axin1 participates in BBB protection and improvement of neurological functions during ischemic stroke by regulating TJ proteins. Axin1 may serve as a potential novel candidate to protect BBB and relieve brain injury. Show less
17α-Methyltestosterone (MT), a synthetic environmental endocrine disruptor with androgenic effects, has been shown to disrupt the reproductive system and inhibit germ cell maturation in
Acetate is associated with adipocyte differentiation and lipid deposition. To further develop this scientific point, obese mice on a high-fat diet were given an intragastric administration of acetate Show more
Acetate is associated with adipocyte differentiation and lipid deposition. To further develop this scientific point, obese mice on a high-fat diet were given an intragastric administration of acetate for 8 weeks and mouse adipose mesenchymal stem cells (mAMSCs) were treated with acetate for 24 h. The results showed that the body weight, food intake, Lee's index, adipose tissue coefficient, liver index, blood lipid levels, insulin resistance, pro-inflammatory factors levels and fatty lesions in liver and adipose tissue in obese mice treated with acetate increased markedly, while anti-inflammatory factors levels and liver function decreased significantly ( Show less
Proopiomelanocortin (POMC) is a hormone precursor, and has been reported to participate in domestication. However, its effects on feeding habit domestication in fish are poorly understood. Mandarin fi Show more
Proopiomelanocortin (POMC) is a hormone precursor, and has been reported to participate in domestication. However, its effects on feeding habit domestication in fish are poorly understood. Mandarin fish (Siniperca chuatsi) feeds solely on live prey fish since first-feeding. In the present study, the high expression of pomc in mandarin fish, both the pomc siRNA and MC4R inhibitor treatments increased the success rate of domestication from live prey fish to dead prey fish and food intake of dead prey fish, suggesting the role of pomc on the special feeding habit of live prey fish in mandarin fish. In addition, one c-fos binding site was identified in the region that from -1053 bp to -931 bp upstream of the transcription start site of pomc, and this region exhibited positive promoter activity. The mandarin fish brain cells treated with c-fos siRNA displayed suppressed pomc mRNA expression, indicating that c-fos positively regulated pomc expression. Furthermore, the mRNA expression of c-fos was higher in the mandarin fish which were more difficult to domesticate. The results of ChIP assay and inhibitor treatment confirmed that the activation of c-fos gene by histone H3K4me3 was catalyzed by Setd1b in mandarin fish. Three open peaks were found at the upstream regulatory region of setd1b by ATAC-seq, and the mRNA expression of setd1b was higher in the mandarin fish which were more difficult to domesticate. These results indicated that Setd1b could methylate histone H3K4 to activate the c-fos transcription, maintaining the high expression of pomc, which might contribute to the special feeding habit of mandarin fish. Show less
The role of cholesterol metabolism in gastric cancer (GC) and its implications for tumor characteristics and immunotherapy response remain poorly understood. In this study, our aim was to investigate Show more
The role of cholesterol metabolism in gastric cancer (GC) and its implications for tumor characteristics and immunotherapy response remain poorly understood. In this study, our aim was to investigate this role, identify associated metabolic subtypes, and assess their clinical implications in GC. We conducted a comprehensive analysis of cholesterol metabolism genes (CMGs) using transcriptomic data from TCGA and GEO. Based on 23 representative CMGs, we classified GC into metabolic subtypes. We evaluated clinical features and immune cell infiltration between these subtypes. Additionally, we identified a CMG signature and assessed its clinical relevance in GC. We retrospectively enrolled thirty-five GC patients receiving chemotherapy plus a PD-1 inhibitor to assess the CMG signature using multiplex immunohistochemistry. Our analysis revealed two cholesterol metabolism subtypes in GC: Cholesterol Metabolism Type 1 (CMT1) and Cholesterol Metabolism Type 2 (CMT2). These subtypes exhibited distinct patterns: CMT1 indicated heightened cholesterol biosynthesis, while CMT2 showed abnormal cholesterol transport. CMT2 was associated with unfavorable clinical features, enriched malignant pathways, and a pro-tumor immune microenvironment. Furthermore, we developed a five-CMG prognostic signature (ABCA1, NR1H3, TSPO, NCEH1, and HMGCR) that effectively predicted the prognosis of patients with GC and their response to chemotherapy plus a PD-1 inhibitor. This signature was validated in a clinical cohort using multiplex immunohistochemistry. Our results highlight the effectiveness of cholesterol metabolism patterns as biomarkers for predicting the prognosis and immunotherapy response in GC. The expression of cholesterol metabolism genes and the assessment of cholesterol metabolism patterns have the potential to predict the outcome of immunotherapy and guide treatment strategies. Show less
Neural progenitor cells (NPCs) are essential for in vitro drug screening and cell-based therapies for brain-related disorders, necessitating well-defined and reproducible culture systems. Current stra Show more
Neural progenitor cells (NPCs) are essential for in vitro drug screening and cell-based therapies for brain-related disorders, necessitating well-defined and reproducible culture systems. Current strategies employing protein growth factors pose challenges in terms of both reproducibility and cost. In this study, we developed a novel DNA-based modulator to regulate FGFR signaling in NPCs, thereby facilitating the long-term maintenance of stemness and promoting neurogenesis. This DNA-based FGFR-agonist effectively stimulated FGFR1 phosphorylation and activated the downstream ERK signaling pathway in human embryonic stem cell (HESC)-derived NPCs. We replaced the basic fibroblast growth factor (bFGF) in the culture medium with our DNA-based FGFR-agonist to artificially modulate FGFR signaling in NPCs. Utilizing a combination of cell experiments and bioinformatics analyses, we showed that our FGFR-agonist could enhance NPC proliferation, direct migration, and promote neurosphere formation, thus mimicking the functions of bFGF. Notably, transcriptomic analysis indicated that the FGFR-agonist could specifically influence the transcriptional program associated with stemness while maintaining the neuronal differentiation program, closely resembling the effects of bFGF. Furthermore, our culture conditions allowed for the successful propagation of NPCs through over 50 passages while retaining their ability to efficiently differentiate into neurons. Collectively, our approach offers a highly effective method for expanding NPCs, thereby providing new avenues for disease-in-dish research and drug screening aimed at combating neural degeneration. Show less
Most Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA). We applied principal component analysis using Gaussian mixture models and an Ashkenazi Jewish (AJ) r Show more
Most Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA). We applied principal component analysis using Gaussian mixture models and an Ashkenazi Jewish (AJ) reference genome-wide association study (GWAS) data set to identify Ashkenazi Jews ascertained in GWAS (n = 42,682), whole genome sequencing (WGS, n = 16,815), and whole exome sequencing (WES, n = 20,504) data sets. The association of AD was tested genome wide (GW) in the GWAS and WGS data sets and exome wide (EW) in all three data sets (EW). Gene-based analyses were performed using aggregated rare variants. In addition to apolipoprotein E (APOE), GW analyses (1355 cases and 1661 controls) revealed associations with TREM2 R47H (p = 9.66 × 10 Our results highlight the efficacy of founder populations for AD genetic studies. Show less
Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, Show more
Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases. Show less
Shuai Yuan, Yuying Li, Lijuan Wang+13 more · 2023 · medRxiv : the preprint server for health sciences · Cold Spring Harbor Laboratory · added 2026-04-24
The study aimed to discover novel genetic loci for atrial fibrillation (AF), explore the shared genetic etiologies between AF and other cardiovascular and cardiometabolic traits, and uncover AF pathog Show more
The study aimed to discover novel genetic loci for atrial fibrillation (AF), explore the shared genetic etiologies between AF and other cardiovascular and cardiometabolic traits, and uncover AF pathogenesis using Mendelian randomization analysis. We conducted a genome-wide association study meta-analysis including 109,787 AF cases and 1,165,920 controls of European ancestry and identified 215 loci, among which 91 were novel. We performed Genomic Structural Equation Modeling analysis between AF and four cardiovascular comorbidities (coronary artery disease, ischemic stroke, heart failure, and vneous thromboembolism) and found 189 loci shared across these diseases as well as a universal genetic locus shared by atherosclerotic outcomes (i.e., rs1537373 near This genome-wide association study and trans-omic Mendelian randomization analysis provides insights into disease risk prediction, pathophysiology and downstream sequelae. Show less
Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European anc Show more
Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (P Show less
Currently, FRS and CRS are the two predominant dryland rearing systems in the goose industry. However, the effects of these two systems on goose growth performance and health, as well as the underlyin Show more
Currently, FRS and CRS are the two predominant dryland rearing systems in the goose industry. However, the effects of these two systems on goose growth performance and health, as well as the underlying mechanisms, have not been fully clarified. Thus, this study aimed to compare growth performance and immune status, as well as investigate the genome-wide transcriptomic profiles of spleen in geese, between CRS and FRS at 270 d of age. Phenotypically, the body weight and body size traits were higher in geese under FRS, while the weight and organ index of spleen were higher in geese under CRS ( Show less
Compared to stage I-III gastric cancer (GC), the level of cell-free DNA (cfDNA) was significantly higher in stage IV GC. The mutation patterns of different metastatic patterns between cfDNA and tumor Show more
Compared to stage I-III gastric cancer (GC), the level of cell-free DNA (cfDNA) was significantly higher in stage IV GC. The mutation patterns of different metastatic patterns between cfDNA and tumor DNA in stage IV GC have not yet been reported. We used next-generation sequencing (NGS) to analyze cfDNA and tumor DNA in 56 stage IV GC patients. Tumor DNA and cfDNA were analyzed using a 29-gene NGS panel. In tumor samples, the most commonly mutated gene was Show less
The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflamm Show more
The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, has been found to have increased expression in the joints of patients with RA compared to healthy individuals. However, the causal relationship between the expression level of IL-17 or IL-17 receptor (IL-17R) and RA remained unknown. In this study, two-sample Mendelian randomization (MR) was used to investigate the causal relationship between IL-17 and RA. Summary statistics for RA (14,361 RA cases and 43,923 healthy controls) and IL-17 (3,301 samples) were obtained from an available meta-analysis of published genome-wide association studies (GWAS). Relevant single nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. Then we used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality. MR and MVMR analyses progressed mainly using inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods, which were applied to the genetic instrumental variables (IVs) of IL-17A/IL-17 RA, IL-17C/IL-17 RC, and IL-17D/IL-17RD and RA. For assessing the robustness of the results, we also carried out a sensitivity analysis to assess heterogeneity and pleiotropy, such as MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO). Two-sample MR Analysis showed the causal relationship between IL-17A/IL-17RA and RA. The presence of genetically high IL-17A/IL-17RA may increase the risk of RA (IL-17A(OR = 1.095; 95% C.I., 0.990-1.210, p.adj = 0.013), IL-17RA(OR = 1.113, 95%CI = 1.006-1.231, p.adj = 0.006)). However, the results indicated that IL-17C/IL-17RC, and IL-17D/IL-17RD demonstrated no causal impact on RA (IL-17C(OR = 1.007, 95%CI = 0.890-1.139, p.adj = 0.152), IL-17RC(OR = 1.006, 95%CI = 0.904-1.119, p.adj = 0.152), IL-17D(OR = 0.979, 95%CI = 0.843-1.137, p.adj = 0.130), IL-17RD(OR = 0.983, 95%CI = 0.876-1.104, p.adj = 0.129)). Furthermore, MVMR analysis shown that IL-17RA(OR = 1.049, 95% CI: 0.997-1.102, p.adj = 0.014) was associated with increased risk of RA. Sensitivity analysis showed no heterogeneity and pleiotropy, suggesting that the above results were robust and reliable. The MR analysis provides evidence that IL-17A/IL-17RA are risk factors for RA. This emphasizes the importance of intervention on IL-17A/IL-17RA in patients with RA. Developing drugs that limit IL-17A may reduce the risk of RA. Show less
Schisandra chinensis (sc) is generally demonstrated to improve antioxidant and immune functions in mammal. The present study through physiological and transcriptome analysis revealed alterations in mu Show more
Schisandra chinensis (sc) is generally demonstrated to improve antioxidant and immune functions in mammal. The present study through physiological and transcriptome analysis revealed alterations in muscle metabolisms of triploid crucian carp (Carassius auratus) cultured at different concentrations of S. chinensis diets (sc0, sc0.125%, sc0.25%, sc0.5%, sc1%, sc2%) after 8 weeks. The serum antioxidant enzyme activities analysis showed that dietary S. chinensis could reduce oxidative stress and increase organismic antioxidant capacity. Meanwhile, the detected results of muscle components presented that the amino acids and two flavor nucleotides of GMP and IMP significantly elevated while muscle crude lipid significantly reduced in S. chinensis feeding groups. In addition, springiness, chewiness, and fiber density in S. chinensis feeding groups muscle were significantly upregulated while muscle fiber diameter and area showed an opposite trend. By comparative transcriptome analysis of the muscles, functional enrichments of differentially expressed genes showed that multiple terms were related to purine metabolism, glycerolipid metabolism, regulation of actin cytoskeleton, and peroxisome. Finally, some key hub genes such as egln, gst, ggct, su1b, pi3kr4, myh9, lpl, gcdh, mylk, and col4a were identified by weighted gene co-expression network analysis. Taken together, our findings facilitate the understanding of the molecular basis underlying the muscle quality effect of dietary S. chinensis in triploid crucian carp, which provides valuable insights into the nutritional strategies of the aquaculture industry. Show less
Vogt-Koyanagi-Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole- Show more
Vogt-Koyanagi-Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole-exome sequencing study, which enrolled 25 VKH patients and 50 controls, followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations. A total of 15 de novo mutations in VKH patients were identified, with one of the most important being the membrane palmitoylated protein 2 (MPP2) p.K315N (MPP2-N315) mutation. The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions. Additionally, this mutation appears rare, being absent from the 1000 Genome Project and Genome Aggregation Database, and it is highly conserved in 10 species, including humans and mice. Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis (EAU). In vitro, we used clustered regularly interspaced short palindromic repeats (CRISPR‒Cas9) gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315. Levels of cytokines, such as IL-1β, IL-17E, and vascular endothelial growth factor A, were increased, and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells. Mechanistically, the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315, as shown by LC‒MS/MS and Co-IP, and resulted in activation of the ERK3/IL-17E pathway. Overall, our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease. Show less
This study aimed to assess the causal relationship between visceral obesity and type 2 diabetes and subsequently to screen visceral adipose tissue (VAT)-specific targets for type 2 diabetes. We examin Show more
This study aimed to assess the causal relationship between visceral obesity and type 2 diabetes and subsequently to screen visceral adipose tissue (VAT)-specific targets for type 2 diabetes. We examined the causal relationship between VAT and type 2 diabetes using bidirectional Mendelian randomisation (MR) followed by multivariable MR. We conducted a transcriptome-wide association study (TWAS) leveraging prediction models and a large-scale type 2 diabetes genome-wide association study (74,124 cases and 824,006 controls) to identify candidate genes in VAT and used summary-data-based MR (SMR) and co-localisation analysis to map causal genes. We performed enrichment and single-cell RNA-seq analyses to determine the cell-specific localisation of the TWAS-identified genes. We also conducted knockdown experiments in 3T3-L1 pre-adipocytes. MR analyses showed a causal relationship between genetically increased VAT mass and type 2 diabetes (inverse-variance weighted OR 2.48 [95% CI 2.21, 2.79]). Ten VAT-specific candidate genes were associated with type 2 diabetes after Bonferroni correction, including five causal genes supported by SMR and co-localisation: PABPC4 (1p34.3); CCNE2 (8q22.1); HAUS6 (9p22.1); CWF19L1 (10q24.31); and CCDC92 (12q24.31). Combined with enrichment analyses, clarifying cell-type specificity with single-cell RNA-seq data indicated that most TWAS-identified candidate genes appear more likely to be associated with adipocytes in VAT. Knockdown experiments suggested that Pabpc4 likely contributes to regulating differentiation and energy metabolism in 3T3-L1 adipocytes. Our findings provide new insights into the genetic basis and biological processes of the association between VAT accumulation and type 2 diabetes and warrant investigation through further functional studies to validate these VAT-specific candidate genes. Show less
miRNA is a noncoding RNA found in recent years and more than one third of human genes are the target of miRNAs. miR-624, located on human chromosome 14, is associated with tumorigenesis. However, the Show more
miRNA is a noncoding RNA found in recent years and more than one third of human genes are the target of miRNAs. miR-624, located on human chromosome 14, is associated with tumorigenesis. However, the role of miR-624 in human hepatocarcinogenesis is still unclear. Herein, our results indicate that miR-624 accelerates the growth of liver cancer cells Show less
Fatty acids are involved in a wide range of immunological responses in humans. Supplementation of polyunsaturated fatty acids has been reported to help alleviate symptoms and airway inflammation in as Show more
Fatty acids are involved in a wide range of immunological responses in humans. Supplementation of polyunsaturated fatty acids has been reported to help alleviate symptoms and airway inflammation in asthma patients, whereas the effects of fatty acids on the actual risk of asthma remain controversial. This study comprehensively investigated the causal effects of serum fatty acids on asthma risk using two-sample bidirectional Mendelian Randomization (MR) analysis. Genetic variants strongly associated with 123 circulating fatty acid metabolites were extracted as instrumental variables, and a large GWAS data of asthma was used to test effects of the metabolites on this outcome. The inverse-variance weighted method was used for primary MR analysis. The weighted median, MR-Egger regression, MR-PRESSO, and leave-one-out analyses were utilized to evaluate heterogeneity and pleiotropy. Potential confounders were adjusted by performing multivariable MR analyses. Reverse MR analysis was also conducted to estimate the causal effect of asthma on candidate fatty acid metabolites. Further, we performed colocalization analysis to examine the pleiotropy of variants within the fatty acid desaturase 1 (FADS1) locus between the significant metabolite traits and the risk of asthma. Cis-eQTL-MR and colocalization analysis were also performed to determine the association between RNA expression of FADS1 and asthma. Genetically instrumented higher average number of methylene groups was causally associated with a lower risk of asthma in primary MR analysis, while inversely, the higher ratio of bis-allylic groups to double bonds and the higher ratio of bis-allylic groups to total fatty acids, were associated with higher probabilities of asthma. Consistent results were obtained in multivariable MR when adjusted for potential confounders. However, these effects were completely eliminated after SNPs correlated with the FADS1 gene were excluded. The reverse MR also found no causal association. The colocalization analysis suggested that the three candidate metabolite traits and asthma likely share causal variants within the FADS1 locus. In addition, the cis-eQTL-MR and colocalization analyses demonstrated a causal association and shared causal variants between FADS1 expression and asthma. Our study supports a negative association between several PUFA traits and the risk of asthma. However, this association is largely attributed to the influence of FADS1 polymorphisms. The results of this MR study should be carefully interpreted given the pleiotropy of SNPs associated with FADS1. Show less
There are no reliable molecular targets for early diagnosis and effective treatment in the clinical management of diabetic kidney disease (DKD). To identify novel gene factors underlying the progressi Show more
There are no reliable molecular targets for early diagnosis and effective treatment in the clinical management of diabetic kidney disease (DKD). To identify novel gene factors underlying the progression of DKD. The public transcriptomic datasets of the alloxan-induced DKD model and the streptozotocin-induced DKD model were retrieved to perform an integrative bioinformatic analysis of differentially expressed genes (DEGs) shared by two experimental animal models. The dominant biological processes and pathways associated with DEGs were identified through enrichment analysis. The expression changes of the key DEGs were validated in the classic db/db DKD mouse model. The downregulated and upregulated genes in DKD models were uncovered from GSE139317 and GSE131221 microarray datasets. Enrichment analysis revealed that metabolic process, extracellular exosomes, and hydrolase activity are shared biological processes and molecular activity is altered in the DEGs. Importantly, Hmgcs2, angptl4, and Slco1a1 displayed a consistent expression pattern across the two DKD models. In the classic db/db DKD mice, Hmgcs2 and angptl4 were also found to be upregulated while Slco1a1 was downregulated in comparison to the control animals. In summary, we identified the common biological processes and molecular activity being altered in two DKD experimental models, as well as the novel gene factors (Hmgcs2, Angptl4, and Slco1a1) which may be implicated in DKD. Future works are warranted to decipher the biological role of these genes in the pathogenesis of DKD. Show less
The accumulation of amyloid β (Aβ) containing senile plaques is one of the key histopathological hallmarks of Alzheimer's disease (AD). Increasing evidences demonstrated the important role of autophag Show more
The accumulation of amyloid β (Aβ) containing senile plaques is one of the key histopathological hallmarks of Alzheimer's disease (AD). Increasing evidences demonstrated the important role of autophagy in Aβ clearance. Recent studies implied that extracts from Semiaquilegia adoxoides (DC.) Makino could ameliorate the memory of D-galactose induced aging mice. However, the bioactive substance and underlying mechanism remains unknown. Thus, the present study sought to explore the effects of a novel homogenous peptidoglycan on Aβ Show less
Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical d Show more
Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical driver facilitating the malignant transformation of chronic inflammatory bowel diseases. In this study, deregulated miRNAs that could play a role in colon cancer are analyzed and investigated for specific functions Show less
Exposure to Bisphenol A (BPA) has led to an increased risk of obesity and nonalcoholic fatty liver diseases (NAFLDs). However, it is as yet unclear if the damage caused by BPA is able to be repaired s Show more
Exposure to Bisphenol A (BPA) has led to an increased risk of obesity and nonalcoholic fatty liver diseases (NAFLDs). However, it is as yet unclear if the damage caused by BPA is able to be repaired sufficiently after exposure has ceased. Therefore, this project aims to investigate the effects of BPA on the hepatic lipid metabolism function and its potential mechanisms in mice by comparing the BPA exposure model and the BPA exposure + cessation of drug treatment model. Herein, the male C57BL/6 mice were exposed in the dose of 50 μg/kg/day and 500 μg/kg/day BPA for 8 weeks, and then transferred to a standard chow diet for another 8 weeks to recover. Based on our previous RNA-seq study, we examined the expression patterns of some key genes. The results showed that the mice exposed to BPA manifested NAFLD features. Importantly, we also found that there was a significant expression reversion for Show less
Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumour-intrinsic and acquired im Show more
Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumour-intrinsic and acquired immunotherapy resistance. We developed an immunophenotype-based subtyping of human GC based on immune cells infiltration to develop a novel treatment option. A algorithm was developed to reclassify GC into immune inflamed, excluded and desert subtypes. Bioinformatics, human and mouse GC cell lines, syngeneic murine gastric tumour model, and CTLA4 blockade were used to investigate the immunotherapeutic effects by restricting receptor tyrosine kinase (RTK) signalling in immune desert (ICB-resistant) type GC. Our algorithm restratified subtypes of human GC in public databases and showed that immune desert-type and excluded-type tumours are ICB-resistant compared with immune-inflamed GC. Moreover, epithelial-mesenchymal transition (EMT) signalling was highly enriched in immune desert-type GC, and syngeneic murine tumours exhibiting mesenchymal-like, compared with epithelial-like, properties are T cell-excluded and resistant to CTLA4 blockade. Our analysis further identified a panel of RTKs as potential druggable targets in the immune desert-type GC. Dovitinib, an inhibitor of multiple RTKs, strikingly repressed EMT programming in mesenchymal-like immune desert syngeneic GC models. Dovitinib activated the tumour-intrinsic SNAI1/2-IFN-γ signalling axis and impeded the EMT programme, converting immune desert-type tumours to immune inflamed-type tumours, sensitising these mesenchymal-like 'cold' tumours to CTLA4 blockade. Our findings identified potential druggable targets relevant to patient groups, especially for refractory immune desert-type/ 'cold' GC. Dovitinib, an RTK inhibitor, sensitised desert-type immune-cold GC to CTLA4 blockade by restricting EMT and recruiting T cells. Show less
Carbamoyl phosphate synthetase 1 (CPS1) is the most abundant hepatocyte mitochondrial matrix protein. Hypoosmotic stress increases CPS1 release in isolated mouse hepatocytes without cell death. We hyp Show more
Carbamoyl phosphate synthetase 1 (CPS1) is the most abundant hepatocyte mitochondrial matrix protein. Hypoosmotic stress increases CPS1 release in isolated mouse hepatocytes without cell death. We hypothesized that increased CPS1 release during hypoosmosis is selective and associates with altered mitochondrial morphology. Both ex vivo and in vivo models were assessed. Mouse hepatocytes and livers were challenged with isotonic or hypoosmotic (35 mosM) buffer. Mice were injected intraperitoneally with water (10% body weight) with or without an antidiuretic. Mitochondrial and cytosolic fractions were isolated using differential centrifugation, then analyzed by immunoblotting to assess subcellular redistribution of four mitochondrial proteins: CPS1, ornithine transcarbamylase (OTC), pyrroline-5-carboxylate reductase 1 (PYCR1), and cytochrome c. Mitochondrial morphology alterations were examined using electron microscopy. Hypoosmotic treatment of whole livers or hepatocytes led to preferential or increased mitochondrial release, respectively, of CPS1 as compared with two mitochondrial matrix proteins (OTC/PYCR1) and with the intermembrane space protein, cytochrome c. Mitochondrial apoptosis-induced channel opening using staurosporine in hepatocytes led to preferential CPS1 and cytochrome c release. The CPS1-selective changes were accompanied by dramatic alterations in ultrastructural mitochondrial morphology. In mice, hypoosmosis/hyponatremia led to increased liver vascular congestion and increased CPS1 in bile but not blood, coupled with mitochondrial structural alterations. In contrast, isotonic increase of intravascular volume led to a decrease in mitochondrial size with limited change in bile CPS1 compared with hypoosmotic conditions and absence of the hypoosmosis-associated histological alterations. Taken together, hepatocyte CPS1 is selectively released in response to hypoosmosis/hyponatremia and provides a unique biomarker of mitochondrial injury. Show less
Apolipoprotein C3 (APOC3) is known for its important functions in metabolism-related diseases. However, the function and molecular mechanism of APOC3 in polycystic ovarian syndrome (PCOS) have not bee Show more
Apolipoprotein C3 (APOC3) is known for its important functions in metabolism-related diseases. However, the function and molecular mechanism of APOC3 in polycystic ovarian syndrome (PCOS) have not been reported. Quantitative polymerase chain reaction and western blot assays were used to detect the expression of APOC3 in KGN cells. Small interference APOC3 (siAPOC3) was applied to reduce APOC3 expression, and the proliferation ability of human granulosa cell line (KGN cells) was measured by cell counting kit-8 and colony formation assays. The protein levels of key genes related to apoptosis were detected by western blot assay. The transcriptional regulator of APOC3 was predicted by the UCSC and PROMO website, and verified by dual luciferase assay. siAPOC3 and pcDNA3.1-specific protein 1 (SP1) vector were co-transfected into KGN cells to detect the function of SP1 and APOC3 in KGN cells. APOC3 was overexpressed in KGN cells, and siAPOC3 transfection significantly reduced the growth ability of KGN cells and increased the apoptosis ability of KGN cells. SP1 directly bound to the promoter of APOC3 and transcriptional regulated APOC3 expression. Overexpression of SP1 increased the growth ability of KGN cells and decreased the apoptosis ability of KGN cells, which were reversed after siAPOC3 transfection. The increased levels of toll-like receptor 2 (TLR2) and p65 phosphorylation (p-P65) nuclear factor kappa B (NF-κB) caused by SP1 overexpression were inhibited by siAPOC3 transfection. APOC3, transcriptionally regulated by SP1, promoted the growth of KGN cells, and inhibited the apoptosis by regulating TLR2/NF-κB signalling pathway. Show less
Aspergillus fumigatus (A. fumigatus) is an important fungal pathogen and its conidia can be inhaled and interact with airway epithelial cells; however, the release of inflammatory factors from bronchi Show more
Aspergillus fumigatus (A. fumigatus) is an important fungal pathogen and its conidia can be inhaled and interact with airway epithelial cells; however, the release of inflammatory factors from bronchial epithelial cells upon A. fumigatus infection and its regulation remained unclear. Here it was demonstrated that the release of IL-27, MCP-1 and TNF-α from BEAS-2B cells were upregulated upon stimulation by conidia, while mitogen-activated protein kinase signaling pathway was activated. Further, the inhibition of JNK, but not p38 and ERK, could inhibit inflammatory factors release and the LC3II formation in BEAS-2B cells induced by A. fumigatus conidia. In addition, an inhibitor of autophagy, bafilomycin A1 was able to significantly down-regulate the release of inflammatory factors in BEAS-2B cells upon A. fumigatus conidia, while rapamycin could reverse the effect of JNK inhibitor on IL-27 and TNF-α release. Taken together, these data demonstrated that JNK signal might play an important role in inflammatory factor release regulated by autophagy in bronchial epithelial cells against A. fumigatus infection. Show less
This study was to investigate the relationship between the levels of Angiopoietin-Like Protein 4 (ANGPTL4) and Silent Mating-type Information Regulation 2 Homolog 1 (SIRT1) and the stability of caroti Show more
This study was to investigate the relationship between the levels of Angiopoietin-Like Protein 4 (ANGPTL4) and Silent Mating-type Information Regulation 2 Homolog 1 (SIRT1) and the stability of carotid atherosclerotic plaque. For this purpose, 108 patients with coronary heart disease in our hospital from Jan 2021 to May 2022 were selected as the coronary heart disease (CHD) group and 80 patients with the healthy examination as the control group. Patients' serum levels of ANGPTL4 and SIRT1 were collected, and their stability of carotid atherosclerotic plaque was determined by carotid ultrasound. According to their stability results, patients were divided into three subgroups: No plaque, Stable plaque, and Unstable plaque. The serum ANGPTL4 and SIRT1 levels were analyzed in different groups, and the correlation between their serum levels and the stability of carotid atherosclerotic plaque was analyzed by rank correlation. Results showed that the CHD group's serum ANGPTL4 and SIRT1 levels were lower, with statistical significance (P<0.05); A statistically significant difference in serum ANGPTL4 and SIRT1 levels were observed among patients with No plaques, Stable plaques, and Unstable plaques (P<0.05); A negative correlation was observed between serum levels of ANGPTL4 and SIRT1 and the stability of carotid atherosclerotic plaque (r=-0.438, -0.717, P<0.001); Serum ANGPTL4 and SIRT1 can be used as the evaluation method of carotid atherosclerotic plaque stability. When ANGPTL4 ≤ 30.17mg/L and SIRT1 ≤ 6.91μg/L, patients were more likely to develop unstable plaques; When ANGPTL4 ≤ 30.40mg/L and SIRT1 ≤ 6.87μg/L, patients were more likely to develop plaques (instability and/or stability). In conclusion, the serum levels of ANGPTL4 and SIRT1 in patients with CHD decreased. ANGPTL4 and SIRT1 will participate in the formation and development of carotid plaque, which can be used as a serological evaluation index to evaluate the occurrence and carotid atherosclerotic plaque's stability. Show less