Airway epithelial cell (AEC) dysfunction has been proven to be involved in the pathogenesis of asthma, which may be induced by the use of dexamethasone (Dex). The altered expression of microRNAs (miRN Show more
Airway epithelial cell (AEC) dysfunction has been proven to be involved in the pathogenesis of asthma, which may be induced by the use of dexamethasone (Dex). The altered expression of microRNAs (miRNAs/miRs) has been found in asthma. However, the detailed mechanisms responsible for the effects of miR‑375 on Dex‑induced AEC dysfunction remain elusive. Thus, the present study aimed to elucidate these mechanisms. Following treatment with Dex for 0, 6, 12 and 24 h, AEC viability, migration, invasion and apoptosis were examined using Cell Counting Kit‑8 (CCK‑8), wound healing and Transwell assays, and flow cytometry, respectively. The expression levels of miR‑375, dual specificity phosphatase 6 (DUSP6) and apoptosis‑related proteins (Bcl‑2, Bax, cleaved caspase‑3) were measured using reverse transcription‑quantitative polymerase chain reaction and western blot analysis. The target genes and potential binding sites of miR‑375 and DUSP6 were predicted using TargetScan and confirmed using dual‑luciferase reporter assay. The viability, migration, invasion and apoptosis of Dex‑treated AECs were further assessed with or without miR‑375 and DUSP6. In the AECs (9HTE cells), Dex treatment suppressed cell viability and miR‑375 expression, whereas it promoted cell apoptosis and the expression of DUSP6, the target gene of miR‑375. The overexpression of miR‑375 reversed the effects of Dex treatment on miR‑375 expression, cell viability, migration and invasion, and apoptosis‑related protein expression; in turn, these effects were reversed by the overexpression of DUSP6, with the exception of miR‑375 expression. On the whole, the present study demonstrates that the overexpression of miR‑375 counteracts the effects of Dex treatment on AEC viability, migration, invasion and apoptosis by targeting DUSP6. Thus, it was suggested that the downregulated expression of miR‑375 may be a therapeutic target for AEC dysfunction. Show less
Shixin Ding, Liu Yang, Lei Huang+8 more · 2022 · Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · Elsevier · added 2026-04-24
Glucocorticoid (GC) exposure can lead to deterioration of the structure and function of hippocampal neurons and is closely involved in Alzheimer's disease (AD). Amyloid-β (Aβ) overproduction is an imp Show more
Glucocorticoid (GC) exposure can lead to deterioration of the structure and function of hippocampal neurons and is closely involved in Alzheimer's disease (AD). Amyloid-β (Aβ) overproduction is an important aspect of AD pathogenesis. Our study mainly investigated the mechanism of chronic GC exposure in accelerating Aβ production in primary cultured hippocampal neurons from APP/PS1 mice. The results indicated that chronic dexamethasone (DEX, 1 μM) significantly accelerated neuronal damage and Aβ accumulation in hippocampal neurons from APP/PS1 mice. Meanwhile, DEX exposure markedly upregulated APP, NCSTN, BACE1 and p-Tau/Tau expression in hippocampal neurons from APP/PS1 mice. Our study also indicated that chronic DEX exposure significantly increased intracellular Ca Show less
S-adenosyl-l-homocysteine (SAH), an amino acid derivative, is a key intermediate metabolite in methionine metabolism, which is normally considered as a harmful by-product and hydrolyzed quickly once f Show more
S-adenosyl-l-homocysteine (SAH), an amino acid derivative, is a key intermediate metabolite in methionine metabolism, which is normally considered as a harmful by-product and hydrolyzed quickly once formed. AHCY (adenosylhomocysteinase) converts SAH into homocysteine and adenosine. There are two other members in the AHCY family, AHCYL1 (adenosylhomocysteinase like 1) and AHCYL2 (adenosylhomocysteinase like 2). Here we define AHCYL1 function as a SAH sensor to inhibit macroautophagy/autophagy through PIK3C3. The C terminus of AHCYL1 interacts with SAH specifically and the interaction with SAH promotes the binding of the N terminus to the catalytic domain of PIK3C3, resulting in inhibition of PIK3C3. More importantly, this observation was further validated Show less
Zikuan Leng, Longyu Li, Xiang Zhou+6 more · 2022 · Medical science monitor : international medical journal of experimental and clinical research · added 2026-04-24
BACKGROUND Fundamental and clinical interest in mesenchymal stem cells (MSCs) has risen dramatically over the past 3 decades. The immunomodulatory and differentiation abilities are the main mechanisms Show more
BACKGROUND Fundamental and clinical interest in mesenchymal stem cells (MSCs) has risen dramatically over the past 3 decades. The immunomodulatory and differentiation abilities are the main mechanisms in vitro and in vivo. However, increasing evidence casts doubt on the stemness and immunogenicity of MSCs. MATERIAL AND METHODS We conducted a high-throughput 10x RNA sequencing and Smart-seq2 scRNA-seq analysis to reveal gene expression of Wharton jelly MSCs (WJ-MSCs) at a single-cell level. Multipotent differentiation, subpopulations, marker genes, human leucocyte antigen (HLA) gene expression, and cell cluster trajectory analysis were evaluated. RESULTS The WJ-MSCs had considerable heterogeneity between cells in terms of gene expression. They highly, partially, and hardly expressed genes related to mesodermal differentiation, endodermal differentiation, and ectodermal differentiation, respectively. Some cells seem to be bipotent or unipotent stem cells. Further, Monocle and cell cluster trajectory analysis demonstrated that 1 of the 3 divided clusters performed as stem cells, accounting for 12.6% of the population. The marker genes for a stem cell cluster were CRIM1, GLS, PLOD2, NEXN, ACTR2, FN1, MBNL1, LMOD1, COL3A1, NCL, SEC62, EPRS, COL5A2, COL8A1, and VCAN. In addition, the MSCs also highly, partially, and hardly expressed HLA-I antigen genes, HLA-II genes, and the HLA-G gene, respectively, indicating that MSCs probably have immunogenicity. A Kyoto Encyclopedia of Genes and Genomes pathway analysis of the 3 clusters demonstrated that they were mainly connected with viral infectious diseases, cancer, and endocrine and metabolic disorders. The most expressed transcription factors were zf-C2H2, HMG/HMGY, and Homeobox. CONCLUSIONS We found that only a subpopulation of WJ-MSCs are real stem cells and WJ-MSCs probably do not have immune privilege. Show less
MicroRNAs (miRNAs) play an important role in the pathogenesis of atrial fibrillation (AF). Exosomal miRNAs may develop as promising biomarkers for AF. To explore significant exosomal miRNAs in AF, pla Show more
MicroRNAs (miRNAs) play an important role in the pathogenesis of atrial fibrillation (AF). Exosomal miRNAs may develop as promising biomarkers for AF. To explore significant exosomal miRNAs in AF, plasma exosomes were extracted from 3 patients with AF and 3 patients with sinus rhythm (SR), respectively. Differential expression of exosomal miRNAs were screened by high-throughput sequencing analysis and verified by qRT-PCR from 40 patients with AF and 40 patients with SR. The target genes prediction, biological function, and signaling pathways analysis were conducted by miRanda software, gene ontology (GO), and KEGG analysis. The results showed that there were 40 differently expressed exosomal miRNAs from AF patients compared with SR patients, of which 13 miRNAs were upregulated and 27 miRNAs were downregulated. qRT-PCR validation demonstrated that miR-124-3p, miR-378d, miR-2110, and miR-3180-3p were remarkably upregulated, while miR-223-5p, miR-574-3p, miR-125a-3p, and miR-1299 were downregulated. To explore the function of miR-124-3p associated with AF, plasma exosomes derived from AF patients were co-incubated with rat myocardial fibroblasts. The expression of miR-124-3p was upregulated in myocardial fibroblasts. The viability and proliferation of myocardial fibroblasts were elevated by transfecting with miR-124-3p overexpression plasmids using CCK8 and immunofluorescence-staining methods. AXIN1 was verified to be the target of miR-124-3p by luciferase assay in vitro. Expression of AXIN1 was reduced, while β-catenin, Collagen 1, and α-SMA were increased in myocardial fibroblasts with miR-124-3p overexpression. In conclusion, these findings suggested that circulating exosomal miRNAs may serve as novel biomarkers for AF, and miR-124-3p promotes fibroblast activation and proliferation through regulating WNT/β-catenin signaling pathway via AXIN1. Show less
Diabetes is a serious disease that could greatly increase the risk of cardiovascular complications, whereas the underlying pathology of DN is still unknown. GPRC5B is a member of the RAIG subfamily of Show more
Diabetes is a serious disease that could greatly increase the risk of cardiovascular complications, whereas the underlying pathology of DN is still unknown. GPRC5B is a member of the RAIG subfamily of type 3 (family C) GPCR, and its role in DN is still unclear. To unveil the role of GPRC5B in diabetic nephropathy (DN) progression and investigate the potential signaling pathway. Podocytes were stimulated with high glucose and expression of GPRC5B was analyzed by qPCR and western blot. Then the level of GPRC5B was depleted by siRNA transfection and inflammatory cytokine level was monitored by ELISA assay. The ECM depostion and the activation of NF-κB pathway were detected by Immunoblot. We investigated the possible role of GPRC5B in the pathology of diabetic nephropathy. We found GPRC5B was highly expressed in high glocuse (HG) induced podocytes. The depletion of GPRC5B inhibited HG induced cell inflammation. In addition, the ablation of GPRC5B suppressed the HG induced ECM deposition. We further found GPRC5B could alleviate the inflammation and extracellular matrix deposition of HG-induced podocytes through NF-κB pathway. We therefore thought GPRC5B could serve as a promising target for the treatment of diabetic nephropathy. G-protein-coupled receptors. Show less
Oral squamous cell carcinoma (OSCC) is the most common cancer in the oral and maxillofacial region. Due to the special physiological and anatomical position of the oral cavity, the disease often has a Show more
Oral squamous cell carcinoma (OSCC) is the most common cancer in the oral and maxillofacial region. Due to the special physiological and anatomical position of the oral cavity, the disease often has a significant impact on the chewing, swallowing, language, and breathing functions of patients. In recent years, with the development of medical molecular biology, molecular targeted therapy has received increasing clinical attention and has gradually become a new method for the treatment of malignant tumors. In this research, gold nanostars with a high photothermal effect combined with the searched targeted antibody were used for OSCC therapy. We use the data set in the public database and construct a gene co-expression module by weighted gene co-expression network analysis (WGCNA). It was found that the turquoise module and the midnight blue module had the greatest connection to tumorigenesis. Cytoscape software was used to analyze the important modules, and the top 10 genes of each module were selected; the survival analysis of the top 10 genes was carried out by gene expression profiling interactive analysis (GEPIA), which indicated that these genes (SERPINH1, MMP11, ADAM12, FADS3, SLC36A2, C1QTNF7, SCRG1, and APOBEC2) have statistical significance as key genes that are related to the tumorigenesis of OSCC. Then, the anti-SERPINH1 antibody targeted to SERPINH1 was chosen as the inhibitor and combined with gold nanostars for photothermal assisted targeted therapy. Thus, the searched key genes can be regarded as biomarkers and therapeutic targets for further precise diagnosis. Show less
Feed efficiency (FE) traits are key factors that can influence the economic benefits of pig production. However, little is known about the genetic architecture of FE and FE-related traits. This study Show more
Feed efficiency (FE) traits are key factors that can influence the economic benefits of pig production. However, little is known about the genetic architecture of FE and FE-related traits. This study aimed to identify SNPs and candidate genes associated with FE and FE-related traits, namely, average daily feed intake (ADFI), average daily gain (ADG), the feed conversion ratio (FCR), and residual feed intake (RFI). The phenotypes of 5823 boars with genotyped data (50 K BeadChip) from 1365 boars from a nucleus farm were used to perform a genome-wide association study (GWAS) of two breeds, Duroc and Yorkshire. Moreover, we performed a genetic parameter estimation for four FE and FE-related traits. The heritabilities of the FE and FE-related traits ranged from 0.13 to 0.36, and there were significant genetic correlations (-0.69 to 0.52) of the FE and FE-related traits with two growth traits (age at 100 kg and backfat thickness at 100 kg). A total of 61 significant SNPs located on eight different chromosomes associated with the four FE and FE-related traits were identified. We further identified four regions associated with FE and FE-related traits that have not been previously reported, and they may be potential novel QTLs for FE. Considering their biological functions, we finally identified 35 candidate genes relevant for FE and FE-related traits, such as the widely reported Show less
Depolarized mitochondria can be degraded via mitophagy, a selective form of autophagy. The RAB GTPase RAB7A was recently shown to play a key role in this process. RAB7A regulates late endocytic traffi Show more
Depolarized mitochondria can be degraded via mitophagy, a selective form of autophagy. The RAB GTPase RAB7A was recently shown to play a key role in this process. RAB7A regulates late endocytic trafficking under normal growth conditions but is translocated to the mitochondrial surface following depolarization. However, how RAB7A activity is regulated during mitophagy is not understood. Here, using a proximity-dependent biotinylation approach (miniTurbo), we identified C5orf51 as a specific interactor of GDP-locked RAB7A. C5orf51 also interacts with the RAB7A guanine nucleotide exchange factor (GEF) complex members MON1 and CCZ1. In the absence of C5orf51, localization of RAB7A on depolarized mitochondria is compromised and the protein is degraded by the proteasome. Furthermore, depletion of C5orf51 also inhibited ATG9A recruitment to depolarized mitochondria. Together, these results indicate that C5orf51 is a positive regulator of RAB7A in its shuttling between late endosomes and mitochondria to enable mitophagy. Show less
Choline has been shown to exert atherogenic effects in Apoe Female APOE*3-Leiden.CETP mice were fed an atherogenic diet alone or supplemented with choline, butyrate or their combination for 16 weeks. Show more
Choline has been shown to exert atherogenic effects in Apoe Female APOE*3-Leiden.CETP mice were fed an atherogenic diet alone or supplemented with choline, butyrate or their combination for 16 weeks. Interestingly, choline protected against fat mass gain, increased the abundance of anti-inflammatory gut microbes, and increased the expression of gut microbial genes involved in TMA and TMAO degradation. Butyrate similarly attenuated fat mass gain and beneficially modulated the gut microbiome, as shown by increased abundance of anti-inflammatory and short chain fatty acid-producing microbes, and inhibited expression of gut microbial genes involved in lipopolysaccharide synthesis. Both choline and butyrate upregulated hepatic expression of flavin-containing monooxygenases, and their combination resulted in highest circulating TMAO levels. Nonetheless, choline, butyrate and their combination did not influence atherosclerosis development, and TMAO levels were not associated with atherosclerotic lesion size. While choline and butyrate have been reported to oppositely modulate atherosclerosis development in Apoe Show less
Macroautophagy/autophagy is a conserved cellular process associated with tumorigenesis and aggressiveness, while mechanisms regulating expression of autophagic machinery genes in cancers still remain Show more
Macroautophagy/autophagy is a conserved cellular process associated with tumorigenesis and aggressiveness, while mechanisms regulating expression of autophagic machinery genes in cancers still remain elusive. Herein, we identified E2F4 (E2F transcription factor 4) as a novel transcriptional activator of cytoprotective autophagy crucial for zinc homeostasis in cancer cells. Gain- and loss-of-function studies showed that Show less
Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid β plaques (Aβ) is a central hallmark of AD. Accumulating evidence suggest that shifting amyloid precursor p Show more
Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid β plaques (Aβ) is a central hallmark of AD. Accumulating evidence suggest that shifting amyloid precursor protein (APP) metabolism pathway to non-amyloidogenic ways and inducing autophagy play key roles in AD pathology. In published reports, there is no research on the APP metabolic process of Terminalia chebula Retz. (T. Chebula). The study aims to assess the effects of T. Chebula in AD transgenic SH-SY5Y cells to determine its underlying mechanisms on reducing Aβ level by regulating APP metabolic process. The effects of T. Chebula water extract (TWE) on APPswe transgenic SH-SY5Y cells were analyzed by cell viability. ELISA used to quantify extracellular Aβ Treatment with TWE significantly suppressed the Aβ In summary, our finding first time expounded that TWE can inhibit the generation of Aβ Show less
Histone deacetylases (HDACs) are entwined with the pathogenesis of various cancers and potentially serve as promising therapeutic targets. Herein, we intend to explore the potential role of HDAC1 inhi Show more
Histone deacetylases (HDACs) are entwined with the pathogenesis of various cancers and potentially serve as promising therapeutic targets. Herein, we intend to explore the potential role of HDAC1 inhibitor (JSL-1) in the tumorigenesis and metastasis of cholangiocarcinoma (CC) and to highlight the molecular basis of its function. As shown by bioinformatics analysis and immunohistochemical detection, high HDAC1 expression was witnessed in CC tissues relative to matched controls from patients with cholecystitis. The molecular network that HDAC1 silencing reduced the enrichment of HDAC1 and Snail on the TPX2 promoter was identified using immunoprecipitation and chromatin immunoprecipitation assays. Both short hairpin RNA (shRNA)-mediated knockdown of HDAC1 and JSL-1 treatment exhibited anti-proliferative, anti-migration and anti-invasion effects on CC cells through downregulation of TPX2. The in vivo xenograft model was developed in nude mice. Consistently, the anti-tumorigenic and anti-metastatic properties of shRNA against HDAC1 and HDAC1 inhibitor were validated in the in vivo settings. Taken together, our data supported the notion that HDAC1 inhibitor retards the initiation and development of CC via mediating the TPX2/Snail axis, highlighting the anti-tumor molecular network functioned in CC. Show less
The effects of cholamine, a raw material for synthesis of some active lipids, are unknown in poultry. To address this, 180 52-wk-old Hyline laying hens were randomly divided into 3 groups (20 replicat Show more
The effects of cholamine, a raw material for synthesis of some active lipids, are unknown in poultry. To address this, 180 52-wk-old Hyline laying hens were randomly divided into 3 groups (20 replicates per group with three hens per replicate). The control group and the treatment groups (treatment 1 and 2) were fed basal diet and the diet supplemented with 500 or 1,000 mg of cholamine per kilogram of the diet for 35 d, respectively. The data showed that supplementary cholamine significantly lowered egg production, daily feed intake, serum high-density lipoprotein cholesterol level, liver index, and the percentages of C15:0 and C20:0 in fatty acid composition of liver, significantly elevated hepatic triglyceride content, the ratio of villus height to crypt depth (P < 0.05), and the percentage of C18:2n-6 and the ratio of n-6 to n-3 polyunsaturated fatty acids in liver fat (P < 0.10). Moreover, supplementary cholamine altered the relative abundance of some intestinal bacteria with a decrease in the alpha biodiversity (P < 0.10). Additionally, transcriptome analysis on the livers of the treatment vs. the control groups identified 1,151 up- and 914 down-regulated differentially expressed genes (DEGs), and pathway analysis revealed that the suppressed Notch signaling pathway and the enhanced Oxidative phosphorylation pathway were enriched with DEGs. Particularly, fat absorption, transport and oxidative phosphorylation-related DEGs (e.g., FABP1, APOA4, and PCK1) were significantly induced, but fatty acid synthesis, and lipid package and secretion-related DEGs (e.g., FASN, SCD, and MTTP) were not. In conclusion, supplementary cholamine may lower egg production by promoting hepatic lipid deposition and reducing abundances of beneficial intestinal bacteria and microfloral biodiversity in laying hens. Show less
MicroRNAs (miRNAs) are one type of noncoding RNAs that interfere with mRNA translation to downregulate gene expression, which results in posttranscriptional gene silencing. Over the past two decades, Show more
MicroRNAs (miRNAs) are one type of noncoding RNAs that interfere with mRNA translation to downregulate gene expression, which results in posttranscriptional gene silencing. Over the past two decades, miRNAs have been widely reported to impact the progression of malignant tumours by interfering with cancer initiation and progression; therefore, miRNAs represent potential new diagnostic and therapeutic tools. miR-650 is a newly identified miR, and increasing studies have demonstrated that miR-650 plays critical roles in cancer progression, such as mediating the Wnt signalling pathway/AXIN1 (axis inhibition protein 1) axis in hepatocellular carcinoma. Nevertheless, associations between the expression patterns and molecular mechanisms of miR-650 in cancer have not been comprehensively described. In this article, we review the existing evidence regarding the mechanisms by which miR-650 expression is altered and their relation to cancer. Moreover, the promising clinical application of miR-650 for diagnosis and treatment is highlighted. Show less
Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research disco Show more
Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4-36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics. Show less
Hepatocellular carcinoma (HCC) is a globally prevailing cancer with a low 5-year survival rate. Little is known about its intricate gene expression profile. Single-cell RNA sequencing is an indispensa Show more
Hepatocellular carcinoma (HCC) is a globally prevailing cancer with a low 5-year survival rate. Little is known about its intricate gene expression profile. Single-cell RNA sequencing is an indispensable tool to explore the genetic characteristics of HCC at a more detailed level. In this study, we profiled the gene expression of single cells from human HCC tumor and para-tumor tissues using the Smart-seq 2 sequencing method. Based on differentially expressed genes, we identified heterogeneous subclones in HCC tissues, including five HCC and two hepatocyte subclones. We then carried out hub-gene co-network and functional annotations analysis followed pseudo-time analysis with regulated transcriptional factor co-networks to determine HCC cellular trajectory. We found that MLX interacting protein like (MLXIPL) was commonly upregulated in the single cells and tissues and associated with a poor survival rate in HCC. Mechanistically, MLXIPL activation is crucial for promoting cell proliferation and inhibits cell apoptosis by accelerating cell glycolysis. Taken together, our work identifies the heterogeneity of HCC subclones, and suggests MLXIPL might be a promising therapeutic target for HCC. Show less
Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy with poor survival outcomes that is relatively resistant to chemotherapy. N6-Methyladenosine (m6A) modification, the most Show more
Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy with poor survival outcomes that is relatively resistant to chemotherapy. N6-Methyladenosine (m6A) modification, the most prevalent modification of eukaryotic messenger RNA, is involved in the progression of various tumors. However, it is unclear whether it has a physiological role in NKTCL development. To address this question, we probed its function and molecular mechanisms in NKTCL. Initially, we demonstrated that Wilms' tumor 1-associated protein (WTAP), a major RNA N6-adenosine methyltransferase, was obviously upregulated in human NKTCL cell lines (YTS and SNK-6 cells), compared with normal NK cells. Functionally, depletion of WTAP noticeably repressed proliferation and facilitated apoptosis in YTS and SNK-6 cells. Moreover, intervention of WTAP evidently prohibited NKTCL cell chemotherapy resistance to cisplatin, as reflected by a lower inhibition of cell viability and decreased expression of drug resistance-associated protein expression MRP-1 and P-gp in YTS and SNK-6 cells. With regard to the mechanism, we revealed that WTAP enhanced dual-specificity phosphatases 6 (DUSP6) expression by increasing m6A levels of DUSP6 mRNA transcript, leading to oncogenic functions in NKTCL. Interestingly, WTAP contributed to the progression and chemotherapy sensitivity of NKTCL by stabilizing DUSP6 mRNA in an m6A-dependent manner. Taken together, these findings uncovered a critical function for WTAP-guided m6A methylation and identified DUSP6 as an important target of m6A modification in the regulation of chemotherapy resistance in NKTCL oncogenesis. This study highlights WTAP as a potential therapeutic target of NKTCL treatment. Show less
Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clin Show more
Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clinical samples, we identified a carbamoyl phosphate synthetase 1 (CPS1)-deficient hepatocellular carcinoma (HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as a target for HCC prevention. A pan-cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas (TCGA) demonstrated that urea cycle (UC) was liver-specific and was down-regulated in HCC. A large-scale gene expression data analysis including 2,596 HCC cases in 7 HCC cohorts from Database of HCC Expression Atlas and 17,444 HCC cases from in-house hepatectomy cohort identified a specific CPS1-deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed the crucial role of CPS1 in HCC. Liquid chromatography-mass spectrometry assay and Seahorse analysis revealed that UC disorder (UCD) led to the deceleration of the tricarboxylic acid cycle, whereas excess ammonia caused by CPS1 deficiency activated fatty acid oxidation (FAO) through phosphorylated adenosine monophosphate-activated protein kinase. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating forkhead box protein M1. Subcutaneous xenograft tumor models and patient-derived organoids were employed to identify that blocking FAO by etomoxir may provide therapeutic benefit to HCC patients with CPS1 deficiency. In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1-deficient HCC subtype through big-data mining, and provide insights for therapeutics for this type of HCC through targeting FAO. Show less
Ferroptosis is a mode of regulated cell death that depends on iron and plays pivotal roles in regulating various biological processes in human cancers. However, the role of ferroptosis in gastric canc Show more
Ferroptosis is a mode of regulated cell death that depends on iron and plays pivotal roles in regulating various biological processes in human cancers. However, the role of ferroptosis in gastric cancer (GC) remains unclear. In our study, a total of 2721 differentially expressed genes (DEGs) were filtered based on The Cancer Genome Atlas (TCGA) ( Show less
Psoriasis is a severe skin disease with significant physical and psychological health consequences. As a typical type of immune disease, both innate and adaptive immunity disorders play key roles in t Show more
Psoriasis is a severe skin disease with significant physical and psychological health consequences. As a typical type of immune disease, both innate and adaptive immunity disorders play key roles in the development of psoriasis. Interleukin (IL)-30 was thought as a natural antagonist of gp130-mediated signaling that affects T helper type 1 and 17 cell polarization by inhibiting IL-6 and IL-27 signaling pathways. Here, we found that, in vitro, IL-30 reduced cytokine levels of HaCaT keratinocytes and dendritic cells (DCs), weakened the maturationS of DCs, inhibited DC-mediated T cell proliferation, and blocked the activation of nuclear factor-κB. In vivo, IL-30 inhibited the development of skin disease in two animal models: Krt14-Vegfa and imiquimod (IMQ)-induced psoriasis-like skin disease. Thus, IL-30 may be useful as a therapeutic agent for controlling psoriasis. Show less
Dingxin Recipe (DXR) is a traditional Chinese medicine formula that has been reported to be effective and safe treatment for cardiovascular diseases, such as arrhythmias, coronary heart disease. Dingx Show more
Dingxin Recipe (DXR) is a traditional Chinese medicine formula that has been reported to be effective and safe treatment for cardiovascular diseases, such as arrhythmias, coronary heart disease. Dingxin Recipe IV (DXR IV) was further improved from the DXR according to the traditional use. However, the mechanism of DXR IV in atherosclerosis is unclear. This study aimed to illustrate whether DXR IV improve atherosclerosis through modulating the lipid metabolism and gut microbiota in atherosclerosis mice. 40 male ApoE DXR IV exerted the anti-atherosclerosis effect by inhibiting the excessive cholesterol deposition in aorta and regulating the level of TG, TC, LDL-C and HDL-C. The composition of gut microbiota was changed. Interestingly, the relative abundance of Muribaculaceae and Ruminococcaceae increased after DXR IV administration, whereas the abundance of Erysipelotrichaceae decreased, which have been beneficial to lipid metabolism. Nine potential metabolic biomarkers, including acetate, butyrate, propionate, alanine, succinate, valerate, xylose, choline, glutamate, were identified, which were related to fatty acid metabolism. Further, the pathway of fatty acid was detected by the RT-qPCR and western blotting. Compared with model group, the level of LXR-α and SREBP1 decreased significantly in DXR IV group while LXR-β, SREBP2 showed no statistical significance. It indicated that DXR IV modulated lipid metabolism by LXR-α/SREBP1 but not LXRβ and SREBP2. DXR IV exhibits potential anti-atherosclerosis effect, which is closely related to lipid metabolism and the gut microbiota. This study may provide novel insights into the mechanism of DXR IV on atherosclerosis and a basis for promising clinical usage. Show less
Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have bee Show more
Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies. Show less
DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age, epigenetic clocks, for many species. Using a custom methylation array, we generated DNA methylation d Show more
DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age, epigenetic clocks, for many species. Using a custom methylation array, we generated DNA methylation data from n = 238 porcine tissues including blood, bladder, frontal cortex, kidney, liver, and lung, from domestic pigs (Sus scrofa domesticus) and minipigs (Wisconsin Miniature Swine™). Samples used in this study originated from Large White X Landrace crossbred pigs, Large White X Minnesota minipig crossbred pigs, and Wisconsin Miniature Swine™. We present 4 epigenetic clocks for pigs that are distinguished by their compatibility with tissue type (pan-tissue and blood clock) and species (pig and human). Two dual-species human-pig pan-tissue clocks accurately measure chronological age and relative age, respectively. We also characterized CpGs that differ between minipigs and domestic pigs. Strikingly, several genes implicated by our epigenetic studies of minipig status overlap with genes (ADCY3, TFAP2B, SKOR1, and GPR61) implicated by genetic studies of body mass index in humans. In addition, CpGs with different levels of methylation between the two pig breeds were identified proximal to genes involved in blood LDL levels and cholesterol synthesis, of particular interest given the minipig's increased susceptibility to cardiovascular disease compared to domestic pigs. Thus, breed-specific differences of domestic and minipigs may potentially help to identify biological mechanisms underlying weight gain and aging-associated diseases. Our porcine clocks are expected to be useful for elucidating the role of epigenetics in aging and obesity, and the testing of anti-aging interventions. Show less