Genome-wide association studies (GWASs) have identified hundreds of loci for body mass index (BMI), but functional variants in these loci are less known. The purpose of this study was to identify RNA Show more
Genome-wide association studies (GWASs) have identified hundreds of loci for body mass index (BMI), but functional variants in these loci are less known. The purpose of this study was to identify RNA modification-related SNPs (RNAm-SNPs) for BMI in GWAS loci. BMI-associated RNAm-SNPs were identified in a GWAS of approximately 700,000 individuals. Gene expression and circulating protein levels affected by the RNAm-SNPs were identified by QTL analyses. Mendelian randomization (MR) methods were applied to test whether the gene expression and protein levels were associated with BMI. A total of 78 RNAm-SNPs associated with BMI (P < 5.0 × 10 Our study identified RNAm-SNPs in BMI-related genomic loci and suggested that RNA modification may affect BMI by affecting the expression levels of corresponding genes and proteins. Show less
Yuan-Zhi Decoction (YZD) is a traditional Chinese medical formulation with demonstrated clinical benefits in Alzheimer's disease (AD). We used liquid chromatography coupled with mass spectrometry to i Show more
Yuan-Zhi Decoction (YZD) is a traditional Chinese medical formulation with demonstrated clinical benefits in Alzheimer's disease (AD). We used liquid chromatography coupled with mass spectrometry to identify 27 unique chemical components of YZD. Analyzing these using network pharmacology and molecular docking models identified 34 potential interacting molecular targets involved in 26 biochemical pathways. When tested in an animal model of AD, the APP/PS1 transgenic mice showed measurable improvements in spatial orientation and memory after the administration of YZD. These improvements coincided with significantly reduced deposition of Aβ plaques and tau protein in the hippocampi in the treated animals. In addition, a decreased BACE1 and beta-amyloid levels, a downregulation of the p-GSK-3β/GSK-3β, and an upregulation of the PI3K and p-AKT/AKT pathway was seen in YZD treated animals. These Show less
In this study, we evaluated the roles of heat-induced circEZH2 in the regulation of milk fat metabolism. CircEZH2 overexpression increased HC11 cell proliferation and decreased apoptosis. These change Show more
In this study, we evaluated the roles of heat-induced circEZH2 in the regulation of milk fat metabolism. CircEZH2 overexpression increased HC11 cell proliferation and decreased apoptosis. These changes were accompanied by increased expression of proliferation marker proteins (PCNA, Cyclin D, and Cyclin E) and the anti-apoptotic protein Bcl2, while expression of the pro-apoptotic proteins Bax and cleaved-caspase was reduced. SiRNA-mediated silencing of EZH2 in HC11 cells had the opposite effects. CircEZH2 overexpression promoted the uptake of a fluorescent fatty acid (Bodipy) as well as expression of the fatty acid transport-related protein CD36, lipolysis-related protein LPL, and unsaturated fatty acid metabolism-related proteins FADS1 and SCD1. Dual luciferase reporter assays verified the targeting relationship of the two ceRNA networks, circEZH2-miR378b-LPL and circEZH2-miR378b-CD36. This information provides further clarification of the role of circRNAs in milk fat regulation in addition to a theoretical basis for alleviating the effects of heat stress on milk production by dairy cows. Show less
Lung adenocarcinoma (LUAD) is one of the main causes of cancer-related mortality, with a strong tendency to metastasize early. Transforming growth factor-β (TGF-β) signaling is a powerful regulator to Show more
Lung adenocarcinoma (LUAD) is one of the main causes of cancer-related mortality, with a strong tendency to metastasize early. Transforming growth factor-β (TGF-β) signaling is a powerful regulator to promote metastasis of LUAD. Here, we screened long non-coding RNAs (lncRNAs) responsive to TGF-β and highly expressed in LUAD cells, and finally obtained our master molecular LINC00152. We proved that the TGF-β promoted transcription of LINC00152 through the classical TGF-β/SMAD3 signaling pathway and maintained its stability through the RNA-binding protein HuR. Moreover, LINC00152 increased ZEB1, SNAI1 and SNAI2 expression via increasing the interactions of HuR and these transcription factors, ultimately promoting epithelial-mesenchymal transition of LUAD cell and enhancing LUAD metastasis in vivo. These data provided evidence that LINC00152 induced by TGF-β promotes metastasis depending HuR in lung adenocarcinoma. Designing targeting LINC00152 and HuR inhibitors may therefore be an effective therapeutic strategy for LUAD treatment. Show less
Differentiation blockade is a hallmark of acute myeloid leukemia (AML). A strategy to overcome such a blockade is a promising approach against the disease. The lack of understanding of the underlying Show more
Differentiation blockade is a hallmark of acute myeloid leukemia (AML). A strategy to overcome such a blockade is a promising approach against the disease. The lack of understanding of the underlying mechanisms hampers development of such strategies. Dysregulated ribonucleotide reductase (RNR) is considered a druggable target in proliferative cancers susceptible to deoxynucleoside triphosphate (dNTP) depletion. Herein, we report an unanticipated discovery that hyperactivating RNR enables differentiation and decreases leukemia cell growth. We integrate pharmacogenomics and metabolomics analyses to identify that pharmacologically (eg, nelarabine) or genetically upregulating RNR subunit M2 (RRM2) creates a dNTP pool imbalance and overcomes differentiation arrest. Moreover, R-loop-mediated DNA replication stress signaling is responsible for RRM2 activation by nelarabine treatment. Further aggravating dNTP imbalance by depleting the dNTP hydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) enhances ablation of leukemia stem cells by RRM2 hyperactivation. Mechanistically, excessive activation of extracellular signal-regulated kinase (ERK) signaling downstream of the imbalance contributes to cellular outcomes of RNR hyperactivation. A CRISPR screen identifies a synthetic lethal interaction between loss of DUSP6, an ERK-negative regulator, and nelarabine treatment. These data demonstrate that dNTP homeostasis governs leukemia maintenance, and a combination of DUSP inhibition and nelarabine represents a therapeutic strategy. Show less
Circular RNAs (circRNAs) are non-coding RNAs with covalently closed structures that modulate the progression of hepatocellular carcinoma (HCC). Here, we explored whether circ₀₀₀₈₀₄₃ regulated the bio Show more
Circular RNAs (circRNAs) are non-coding RNAs with covalently closed structures that modulate the progression of hepatocellular carcinoma (HCC). Here, we explored whether circ₀₀₀₈₀₄₃ regulated the biological function of HCC cells. Quantitative real-time polymerase chain reaction (qPCR) was used to detect circ₀₀₀₈₀₄₃, microRNA (miR)-326, and RAB21 levels. Expression of E-cadherin, N-cadherin, and vimentin was assessed using qPCR. Cell proliferation, migration, and invasion were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation, and transwell assays. Xenograft tumors were used to evaluate cell growth Show less
Preeclampsia (PE) is the predominant medical condition leading to maternal and fetal mortality, and the lack of effective treatment increases its risk to the public health. Among the numerous predispo Show more
Preeclampsia (PE) is the predominant medical condition leading to maternal and fetal mortality, and the lack of effective treatment increases its risk to the public health. Among the numerous predisposing factors, the ineffectual remodeling of the uterine spiral arteries, which can induce abnormal placental angiogenesis, has been focused to solve the pathogenesis of PE. According to the preceding research results, abnormal expression of long non-coding RNAs (lncRNA)s could be associated with the pathological changes inducing PE. To be more specific, lncRNA Show less
Runs of heterozygosity (ROHet) and homozygosity (ROH) harbor useful information related to traits of interest. There is a lack of investigating the effect of ROHet and ROH on reproductive success and Show more
Runs of heterozygosity (ROHet) and homozygosity (ROH) harbor useful information related to traits of interest. There is a lack of investigating the effect of ROHet and ROH on reproductive success and the loss of reproduction in mammals. Here, we detected and characterized the ROHet and ROH patterns in the genomes of Chinese indigenous pigs (i.e., Jinhua, Chun'an, Longyou Black, and Shengxian Spotted pigs), revealing the similar genetic characteristics of indigenous pigs. Later, we highlighted the underlying litter traits-related ROHet and ROH using association analysis with linear model in these four indigenous pig breeds. To pinpoint the promising candidate genes associated with litter traits, we further in-depth explore the selection patterns of other five pig breeds (i.e., Erhualian, Meishan, Minzhu, Rongchang, and Diqing pigs) with different levels of reproduction performance at the underlying litter traits-related ROHet and ROH using Show less
The most hostile form of urologic cancer, clear cell renal cell carcinoma (ccRCC), has a high fatality rate and poor prognosis due to tumor metastasis at initial presentation. The complex process driv Show more
The most hostile form of urologic cancer, clear cell renal cell carcinoma (ccRCC), has a high fatality rate and poor prognosis due to tumor metastasis at initial presentation. The complex process driving ccRCC metastasis is still unknown, though. In this study, we demonstrate that Spindle and kinetochore-associated protein 1 (SKA1) expression is significantly upregulated in ccRCC tissues and associated with aggressive clinicopathologic characteristics. Functionally, SKA1 knockdown on ccRCC cells reduced cancer cell motility both Show less
Childhood overweight and obesity (OW/OB) is a worldwide public health problem, and its genetic risks remain unclear. To investigate risks of OW/OB associated with genetic variances in We conducted a c Show more
Childhood overweight and obesity (OW/OB) is a worldwide public health problem, and its genetic risks remain unclear. To investigate risks of OW/OB associated with genetic variances in We conducted a case-control study with 734 infants included at delivery and followed up to 12-month old. The classification and regression tree analysis were used to generate the structure of the gene-gene interactions, while the unconditional multivariate logistic regression models were applied to analyze the single SNP, gene-gene interactions, and cumulative effects of the genotypes on OW/OB, adjusted for potential confounders. There were 219 (29.84%) OW/OB infants. Rs543874 G allele and rs11030104 AA genotype increased the risk of OW/OB in 12-month-old infants ( Rs543874, rs11030104, and rs11191580 were associated with OW/OB in 12-month-old Chinese infants, and the three SNPs together with rs10913469 and rs11165675 had a combined effect on OW/OB. Show less
Nausea is a discomforting sensation of gut malaise that remains a major clinical challenge. Several visceral poisons induce nausea through the area postrema, a sensory circumventricular organ that det Show more
Nausea is a discomforting sensation of gut malaise that remains a major clinical challenge. Several visceral poisons induce nausea through the area postrema, a sensory circumventricular organ that detects bloodborne factors. Here, we use genetic approaches based on an area postrema cell atlas to reveal inhibitory neurons that counteract nausea-associated poison responses. The gut hormone glucose insulinotropic peptide (GIP) activates area postrema inhibitory neurons that project locally and elicit inhibitory currents in nausea-promoting excitatory neurons through γ-aminobutyric acid (GABA) receptors. Moreover, GIP blocks behavioral responses to poisons in wild-type mice, with protection eliminated by targeted area postrema neuron ablation. These findings provide insights into the basic organization of nausea-associated brainstem circuits and reveal that area postrema inhibitory neurons are an effective pharmacological target for nausea intervention. Show less
This study aims to investigate the pathogenic gene variant in a family with hypertrophic cardiomyopathy by using whole-exome sequencing and to explore the relationship between the gene variant and cli Show more
This study aims to investigate the pathogenic gene variant in a family with hypertrophic cardiomyopathy by using whole-exome sequencing and to explore the relationship between the gene variant and clinical phenotype. Peripheral blood was collected from a family with hypertrophic cardiomyopathy, and deoxyribonucleic acid was extracted. The possible pathogenic genes were detected by whole-exome sequencing, and the variant was verified by Sanger sequencing. Functional change in the variant was predicted by bioinformatics software. Clinical data of the family members are analysed simultaneously. The proband carries a novel heterozygous nonsense variant of MYBPC3:c.2731G > T (p.E911X). The analysis of amino acid conservation suggests that the variation is highly conserved. The three-dimensional protein structure shows that the variant in MYBPC3 results in the incompleteness of the fibronectintype-III2 (p872-967) domain and deletion of Ig-like C2-type 6 (p971-1065) and fibronectin type-III 3 and Ig-like C2-type 7 (p1181-1274) domains, in which p1253-1268 is predicted to have a transmembrane helix structure. Clinical data indicate that the phenotypes of variant carriers with hypertrophic cardiomyopathy are diverse, suggesting the functional damages to the protein of MYBPC3. The phenotypes of variant carriers with hypertrophic cardiomyopathy caused by the novel variant in MYBPC3: c.2731G > T (p.E911X) exhibit variable severity and clinical manifestations. Whole-exome sequencing can be used to comprehensive screen hypertrophic cardiomyopathy genes and provide a strong basis for early screening and accurate diagnosis and treatment of hypertrophic cardiomyopathy in children. Show less
Fatty acid composition contributes greatly to the nutritional value of meat, and breeds/strains are important factors affecting the composition of fatty acid. Recently, few studies have focused on the Show more
Fatty acid composition contributes greatly to the nutritional value of meat, and breeds/strains are important factors affecting the composition of fatty acid. Recently, few studies have focused on the fatty acid composition in breast muscle of different duck breeds. Therefore, the objective of the present study was to compare the fatty acid composition and lipid metabolism-related genes expression in breast muscle of Jianchang duck (J), Cherry Verry duck (CV) and 3 crossbred strains (BH1, BH2 and MC♂ × (BGF2♂ × GF2♀)♀ (MBG)). Our results showed that the breast muscle of J had the highest contents of C22:1(n-9) but the lowest ratios of Ʃ-omega 6 (Ʃn-6)/Ʃ-omega 3 (Ʃn-3), Ʃ-mono-unsaturated fatty acid (ƩMUFA)/Ʃ-saturated fatty acid (ƩSFA) and Ʃ-polyunsaturated fatty acid (ƩPUFA)/ƩSFA. The ƩPUFA/ƩSFA ratio was higher in breast muscle of MBG than in that of BH2 and CV, and the contents of C22:1(n-9), ƩMUFA and ƩPUFA were higher in BH1 than in BH2 and CV. Furthermore, the mRNA levels of SCD1, FADS2, ELOVL2, and ELOVL5 were significantly higher in MBG (P < 0.05), while those of FASD1 and ACACA were significantly higher in BH1 than in BH2 and CV (P < 0.05). Principal component analysis showed that fatty acids variation exhibited extensive positive loading on principal components (PCs). Correlation analysis showed that PC1 and PC3 of BH1, as well as PC1 of MBG were correlated with the mRNA levels of ACACA and FABP3, respectively. Thus, it could be concluded that the breast muscles of MBG and BH1 have better fatty acid composition, which was closely related to the increased expression levels of SCD1, FADS2, ELOVL2, and ELOVL5 genes in MBG but FADS1 and ACACA in BH1. Moreover, these results also showed that crossbreeding could optimize the composition of fatty acid in breast muscle of ducks. Show less
The endothelial glycocalyx regulates vascular permeability, inflammation, and coagulation, and acts as a mechanosensor. The loss of glycocalyx can cause endothelial injury and contribute to several mi Show more
The endothelial glycocalyx regulates vascular permeability, inflammation, and coagulation, and acts as a mechanosensor. The loss of glycocalyx can cause endothelial injury and contribute to several microvascular complications and, therefore, may promote diabetic retinopathy. Studies have shown a partial loss of retinal glycocalyx in diabetes, but with few molecular details of the changes in glycosaminoglycan (GAG) composition. Therefore, the purpose of our study was to investigate the effect of hyperglycemia on GAGs of the retinal endothelial glycocalyx. GAGs were isolated from rat retinal microvascular endothelial cells (RRMECs), media, and retinas, followed by liquid chromatography-mass spectrometry assays. Quantitative real-time polymerase chain reaction was used to study mRNA transcripts of the enzymes involved in GAG biosynthesis. Hyperglycemia significantly increased the shedding of heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA). There were no changes to the levels of HS in RRMEC monolayers grown in high-glucose media, but the levels of CS and HA decreased dramatically. Similarly, while HA decreased in the retinas of diabetic rats, the total GAG and CS levels increased. Hyperglycemia in RRMECs caused a significant increase in the mRNA levels of the enzymes involved in GAG biosynthesis (including EXTL-1,2,3, EXT-1,2, ChSY-1,3, and HAS-2,3), with these increases potentially being compensatory responses to overall glycocalyx loss. Both RRMECs and retinas of diabetic rats exhibited glucose-induced alterations in the disaccharide compositions and sulfation of HS and CS, with the changes in sulfation including N,6-O-sulfation on HS and 4-O-sulfation on CS. Show less
The heterogeneity of hepatocellular carcinoma (HCC) highlights the importance of precision therapy. In recent years, single-cell RNA sequencing has been used to reveal the expression of genes at the s Show more
The heterogeneity of hepatocellular carcinoma (HCC) highlights the importance of precision therapy. In recent years, single-cell RNA sequencing has been used to reveal the expression of genes at the single-cell level and comprehensively study cell heterogeneity. This study combined big data analytics and single-cell data mining to study the influence of genes on HCC prognosis. The cells and genes closely related to the HCC were screened through single-cell RNA sequencing (71,915 cells, including 34,414 tumor cells) and big data analysis. Comprehensive bioinformatics analysis of the key genes of HCC was conducted for molecular classification and multi-dimensional correlation analyses, and a prognostic model for HCC was established. Finally, the correlation between the prognostic model and clinicopathological features was analyzed. 16,880 specific cells, screened from the single-cell expression profile matrix, were divided into 20 sub-clusters. Cell typing revealed that 97% of these cells corresponded to HCC cell lines, demonstrating the high specificity of cells derived from single-cell sequencing. 2,038 genes with high variability were obtained. The 371 HCC samples were divided into two molecular clusters. Cluster 1 (C1) was associated with tumorigenesis, high immune score, immunotherapy targets (PD-L1 and CYLA-4), high pathological stage, and poor prognosis. Cluster 2 (C2) was related to metabolic and immune function, low immune score, low pathological stage, and good prognosis. Seven differentially expressed genes (CYP3A4, NR1I2, CYP2C9, TTR, APOC3, CYP1A2, and AFP) identified between the two molecular clusters were used to construct a prognostic model. We further validated the correlation between the seven key genes and clinical features, and the established prognostic model could effectively predict HCC prognosis. Our study identified seven key genes related to HCC that were used to construct a prognostic model through single-cell sequencing and big data analytics. This study provides new insights for further research on clinical targets of HCC and new biomarkers for clinical application. Show less
Recent studies have revealed the close correlation between microRNAs (miRs) and Parkinson's disease (PD). Here, we aimed to investigate the neuroprotective effect of miR-124 in a PD mouse model. MiR-1 Show more
Recent studies have revealed the close correlation between microRNAs (miRs) and Parkinson's disease (PD). Here, we aimed to investigate the neuroprotective effect of miR-124 in a PD mouse model. MiR-124 expression in human plasma was detected by qRT-PCR. PD mouse model was established by stereotactic injection of 6-hydroxydopmine. Lentivirus were used to deliver and overexpress miR-124 and Axin1 into the substantia nigra. Multiple behavioral tests and oxidative stress assays were carried out to access the protective effect of miR-124 against PD. Western blot and luciferase assay were conducted to dissect the underlying molecular mechanisms. MiR-124 expression was decreased in PD patients. Overexpression of miR-124 in PD mice could improve motor defects, ameliorate dopaminergic neurons loss, and reduce oxidative stress. Mechanistically, miR-124 targeted Axin1 directly, and then attenuated PD progression via suppressing Axin1 and activating the Wnt/β-catenin pathways in PD mice. MiR-124 is an important neuroprotective factor, which suppresses Axin1 and activates Wnt/β-catenin signaling pathways in PD mice. Show less
Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-o Show more
Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-occurs with DON as its glucosylated form and is another emerging food safety issue in recent years. However, the toxicity of D3G is not fully understood compared to DON, especially in emetic potency. The goals of this research were to (1) compare emetic effects to D3G by oral and intraperitoneal (IP) routes and relate emetic effects to brain-gut peptides glucose-dependent insulinotropic polypeptide (GIP) and substance P (SP) in mink; (2) determine the roles of calcium-sensing receptor (CaSR) and transient receptor potential (TRP) channel in D3G's emetic effect. Both oral and IP exposure to D3G elicited marked emetic events. This emetic response corresponded to an elevation of GIP and SP. Blocking the GIP receptor (GIPR) diminished emetic response induction by GIP and D3G. The neurokinin 1 receptor (NK-1R) inhibitor Emend Show less
Single nucleotide polymorphisms that affect RNA modification (RNAm-SNPs) may have functional roles in coronary artery disease (CAD). The aim of this study was to identify RNAm-SNPs in CAD susceptibili Show more
Single nucleotide polymorphisms that affect RNA modification (RNAm-SNPs) may have functional roles in coronary artery disease (CAD). The aim of this study was to identify RNAm-SNPs in CAD susceptibility loci and highlight potential risk factors. CAD-associated RNAm-SNPs were identified in the CARDIoGRAMplusC4D and UK Biobank genome-wide association studies. Gene expression and circulating protein levels affected by the RNAm-SNPs were identified by QTL analyses. Cell experiments and Mendelian randomization (MR) methods were applied to test whether the gene expression levels were associated with CAD. We identified 81 RNAm-SNPs that were associated with CAD or acute myocardial infarction (AMI), including m The present study identified RNAm-SNPs in CAD susceptibility genes, gene expression and circulating proteins as risk factors for CAD and suggested that RNA modification may play a role in the pathogenesis of CAD. Show less
Cardiac dysfunction resulting from sepsis causes high morbidity and mortality. Silibinin (SIL) is a secondary metabolite isolated from the seed extract of the milk thistle plant with various propertie Show more
Cardiac dysfunction resulting from sepsis causes high morbidity and mortality. Silibinin (SIL) is a secondary metabolite isolated from the seed extract of the milk thistle plant with various properties, including anti-inflammatory, anti-fibrotic, and anti-oxidative activities. This study, for the first time, examined the effects and mechanisms of SIL pretreatment, posttreatment and in combination with classical antibiotics in septic myocardial injury. The survival rate, sepsis score, anal temperature, routine blood parameters, blood biochemical parameters, cardiac function indicators, pathological indicators of myocardial injury, NR1H3 signaling pathway, and several sepsis-related signaling pathways were detected 8 h following cecal ligation and puncture (CLP). Our results showed that SIL pretreatment showed a significant protective effect on sepsis and septic myocardial injury, which was explained by the attenuation of inflammation, inhibition of oxidative stress, improvement of mitochondrial function, regulation of endoplasmic reticulum stress (ERS), and activation of the NR1H3 pathway. SIL posttreatment and the combination of SIL and azithromycin (AZI) showed a certain therapeutic effect. RNA-seq detection further clarified the myocardial protective mechanisms of SIL. Taken together, this study provides a theoretical basis for the application strategy and combination of SIL in septic myocardial injury. Show less
Metastasis is the dominant cause of cancer-related mortality. Metastasis-associated with colon cancer protein 1 (MACC1) has been proven to play a critical role in cancer metastasis. However, the prome Show more
Metastasis is the dominant cause of cancer-related mortality. Metastasis-associated with colon cancer protein 1 (MACC1) has been proven to play a critical role in cancer metastasis. However, the prometastatic role of MACC1 in regulating the pancreatic cancer (PC) metastatic phenotype remains elusive. Here, we report that MACC1 is highly expressed in The Cancer Genome Atlas (TCGA) and tissue microarray (TMA) and identified as a good indicator for poor prognosis. Overexpression or knockdown of MACC1 in PC cells correspondingly promoted or inhibited pancreatic cancer cell migration and invasion in a MET proto-oncogene receptor tyrosine kinase (MET)-independent manner. Notably, knockdown of MACC1 in PC cells markedly decreased the liver metastatic lesions in a liver metastasis model. Mechanistically, MACC1 binds to the epithelial-mesenchymal transition (EMT) regulator snail family transcriptional repressor 1 (SNAI1) to drive EMT via upregulating the transcriptional activity of SNAI1, leading to the transactivation of fibronectin 1 (FN1) and the trans-repression of cadherin 1 (CDH1). Collectively, our results unveil a new mechanism by which MACC1 drives pancreatic cancer cell metastasis and suggest that the MACC1-SNAI1 complex-mediated mesenchymal transition may be a therapeutic target in pancreatic cancer. Show less
Molecular variation between geographical populations and subtypes indicate potential genomic heterogeneity and novel genomic features within CCA. Here, we analyze exome-sequencing data of 87 perihilar Show more
Molecular variation between geographical populations and subtypes indicate potential genomic heterogeneity and novel genomic features within CCA. Here, we analyze exome-sequencing data of 87 perihilar cholangiocarcinoma (pCCA) and 261 intrahepatic cholangiocarcinoma (iCCA) cases from 3 Asian centers (including 43 pCCAs and 24 iCCAs from our center). iCCA tumours demonstrate a higher tumor mutation burden and copy number alteration burden (CNAB) than pCCA tumours, and high CNAB indicates a poorer pCCA prognosis. We identify 12 significantly mutated genes and 5 focal CNA regions, and demonstrate common mutations in post-transcriptional modification-related potential driver genes METTL14 and RBM10 in pCCA tumours. Finally we demonstrate the tumour-suppressive role of METTL14, a major RNA N6-adenosine methyltransferase (m6A), and illustrate that its loss-of-function mutation R298H may act through m6A modification on potential driver gene MACF1. Our results may be valuable for better understanding of how post-transcriptional modification can affect CCA development, and highlight both similarities and differences between pCCA and iCCA. Show less
Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been appli Show more
Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been applied to ameliorate cognitive impairment in mild-to-moderate AD patients. However, the overall molecular mechanism of SQYG in treating AD has not been clarified. This study aimed to investigate the molecular mechanism of SQYG on AD using an integration strategy of network pharmacology and molecular docking. The active compounds of SQYG and common targets between SQYG and AD were screened from databases. The herb-compound network, compound-target network, and protein-protein interaction network were constructed. The enrichment analysis of common targets and molecular docking were performed. 816 compounds and 307 common targets between SQYG and AD were screened. KEGG analysis revealed that common targets were mainly enriched in lipid metabolism, metal ion metabolism, IL-17 signaling pathway, GABA receptor signaling, and neuroactive ligand-receptor interaction. Molecular docking analysis showed high binding affinity between ginsenoside Rg1 and A The therapeutic mechanisms of SQYG on AD were associated with regulating lipid metabolism, metal ion metabolism, IL-17 signaling pathway, and GABA receptor signaling. Ginsenoside Rg1, tanshinone IIA, baicalin, astragaloside IV, and folic acid may play an important role in AD treatment. Show less
Hypoxia can cause Epithelial-mesenchymal transition (EMT) in renal tubular cells, and in turn, renal fibrosis. We tested the expression of TRIM46, a member of tripartite motif-containing (TRIM) family Show more
Hypoxia can cause Epithelial-mesenchymal transition (EMT) in renal tubular cells, and in turn, renal fibrosis. We tested the expression of TRIM46, a member of tripartite motif-containing (TRIM) family proteins, and mesenchymal markers under hypoxia. Our results showed that hypoxia significantly enhanced expression of TRIM46 in HK2 human renal proximal tubular epithelial cells. Our data further showed that hypoxia led to upregulated expression of mesenchymal markers including α-smooth muscle actin, vimentin, and Snail, and downregulated expression of epithelial marker E-cadherin, coupled with an increased abundance of nuclear β-catenin. However, such effects were reversed when TRIM46 expression was knocked down. TRIM46 overexpression had similar effects as hypoxia exposure, and such effects were reversed when cells were treated with XAV-939, a selective inhibitor for β-catenin. Furthermore, we found that TRIM46 promoted ubiquitination and proteasomal degradation of Axin1 protein, a robust negative regulator of Wnt/β-catenin signaling activity. Finally, increased TRIM46 coupled with decreased Axin1 was observed in a rat renal fibrosis model. These data suggest a novel mechanism contributing to EMT that mediates hypoxia-induced renal fibrosis. Our results suggest that selectively inhibiting this pathway that activates fibrosis in human kidney may lead to development of a novel therapeutic approach for managing this disease. Show less
Alcohol abuse can lead to alcoholic hepatitis (AH), a worldwide public health issue with high morbidity and mortality. Here, we identified apolipoprotein A-IV (APOA4) as a biomarker and potential ther Show more
Alcohol abuse can lead to alcoholic hepatitis (AH), a worldwide public health issue with high morbidity and mortality. Here, we identified apolipoprotein A-IV (APOA4) as a biomarker and potential therapeutic target for AH. APOA4 expression was detected by Gene Expression Omnibus (GEO) databases, Immunohistochemistry, and qRT-PCR in AH. Bioinformatics Methods (protein-protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Set Enrichment Analysis (GSEA) were used to show down-stream gene and pathways of APOA4 in AH. AML-12 cells were used to evaluate the biological function of APOA4 using an ELISA kit (AST, ALT, and IL-1β) and flow cytometry (ROS activity). Both in vivo and in vitro, APOA4 expression was significantly elevated in the AH model induced by alcohol (ETOH). AML-12 cell damage was specifically repaired by APOA4 deficiency, while AST, ALT, and IL-1β activity that was increased by ETOH (200 µmol, 12 h) were suppressed. APOA4 inhibition increased intracellular ROS induced by ETOH, which was detected by flow cytometry. Functional and PPI network analyses showed Fcgamma receptor (FCGR) and platelet activation signaling were potential downstream pathways. We identified Show less
Lung cancer is one of the top causes of cancer-related death worldwide. Cellular senescence is a characteristic of cell cycle arrest that plays a role in carcinogenesis and immune microenvironment mod Show more
Lung cancer is one of the top causes of cancer-related death worldwide. Cellular senescence is a characteristic of cell cycle arrest that plays a role in carcinogenesis and immune microenvironment modulation. Despite this, the clinical and immune cell infiltration features of senescence in lung squamous cell carcinoma (LUSC) are unknown. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were used to get RNA-seq data and clinical information for LUSC. The least absolute shrinkage and selection operator (LASSO)-Cox regression, receiver operating characteristic (ROC), and Kaplan-Meier analysis were used to evaluate a risk model for predicting overall survival based on six differentially expressed genes. The tumor microenvironment (TME) and immunotherapy response were also studied. To discriminate LUSC into high- and low-risk subgroups, a risk model comprised of six cellular senescence-related genes (CDKN1A, CEBPB, MDH1, SIX1, SNAI1, and SOX5) was developed. The model could stratify patients into high-risk and low-risk groups, according to ROC and Kaplan-Meier analysis. In the TCGA-LUSC and GSE73403 cohorts, the high-risk group had a worse prognosis (P<0.05), and was associated with immune cell inactivation and being insensitive to immunotherapy in IMvigor210. We discovered a new LUSC classification based on six cellular senescence-related genes, which will aid in identifying patients who will benefit from anti-PD-1 treatment. Targeting senescence-related genes appears to be another option for improving clinical therapy for LUSC. Show less
Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can Show more
Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can make the treatment of these conditions more difficult. Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family and plays a critical role in glucose metabolism. Previous research has demonstrated the multiple roles of GIP in both physiological and pathological processes. In the central nervous system (CNS), studies of GIP are mainly focused on neurodegenerative diseases; hence, little is known about the functions of GIP in chronic pain and pain-related anxiety disorders. The chronic inflammatory pain model was established by hind paw injection with complete Freund's adjuvant (CFA) in C57BL/6 mice. GIP receptor (GIPR) agonist (D-Ala In the present study, we found that hind paw injection with CFA induced pain sensitization and anxiety-like behaviors in mice. The expression of GIPR in the ACC was significantly higher in CFA-injected mice. D-Ala GIPR activation was found to produce analgesic and anxiolytic effects, which were partially due to attenuation of neuroinflammation and inhibition of excitatory transmission in the ACC. GIPR may be a suitable target for treatment of chronic inflammatory pain and pain-related anxiety. Show less