Chronic coronary syndrome (CCS) is a newly proposed concept and is hallmarked by more long-term major adverse cardiovascular events (MACEs), calling for accurate prognostic biomarkers for initial risk Show more
Chronic coronary syndrome (CCS) is a newly proposed concept and is hallmarked by more long-term major adverse cardiovascular events (MACEs), calling for accurate prognostic biomarkers for initial risk stratification. Data-independent acquisition liquid chromatography tandem mass spectrometry (DIA LC-MS/MS) quantitative proteomics was performed on 38 patients with CCS; 19 in the CCS events group and 19 in the non-events group as the controls. We also developed a machine-learning-based pipeline to identify proteins as potential biomarkers and validated the target proteins by enzyme-linked immunosorbent assay in an independent prospective cohort. Fifty-seven differentially expressed proteins were identified by quantitative proteomics and three final biomarkers were preliminarily selected from the machine-learning-based pipeline. Further validation with the prospective cohort showed that endothelial protein C receptor (EPCR) and cholesteryl ester transfer protein (CETP) levels at admission were significantly higher in the CCS events group than they were in the non-events group, whereas the carboxypeptidase B2 (CPB2) level was similar in the two groups. In the Cox survival analysis, EPCR and CETP were independent risk factors for MACEs. We constructed a new prognostic model by combining the Framingham coronary heart disease (CHD) risk model with EPCR and CETP levels. This new model significantly improved the C-statistics for MACE prediction compared with that of the Framingham CHD risk model alone. Plasma proteomics was used to find biomarkers of predicting MACEs in patients with CCS. EPCR and CETP were identified as promising prognostic biomarkers for CCS. Show less
Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1), a negative regulator of oligodendrocyte differentiation and myelination, is associated with Show more
Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1), a negative regulator of oligodendrocyte differentiation and myelination, is associated with cognitive function, and its expression is highly upregulated in Alzheimer's disease (AD) patients. Anti-LINGO-1 antibody treatment can effectively antagonize the negative regulatory effect of LINGO-1. In this study, we aim to assess the effect of anti-LINGO-1 antibody treatment on cognition and hippocampal oligodendrocytes in an AD transgenic animal model. First, 10-month-old male amyloid-β (Aβ) protein precursor (APP)/presenilin 1 (PS1) mice were administered anti-LINGO-1 antibody for 8 weeks. Then, learning and memory abilities were assessed with the Morris water maze (MWM) and Y-maze tests, and Aβ deposition and hippocampal oligodendrocytes were investigated by immunohistochemistry, immunofluorescence, and stereology. We found that anti-LINGO-1 antibody alleviated the deficits in spatial learning and memory abilities and working and reference memory abilities, decreased the density of LINGO-1 positive cells, decreased Aβ deposition, significantly increased the number of mature oligodendrocytes and the density of myelin, reversed the abnormal increases in the number of oligodendrocyte lineage cells and the densities of oligodendrocytes precursor cells in APP/PS1 mice. Our results provide evidence that LINGO-1 might be involved in the process of oligodendrocyte dysmaturity in the hippocampus of AD mice, and that antagonizing LINGO-1 can alleviate cognitive deficits in APP/PS1 mice and decrease Aβ deposition and promote oligodendrocyte differentiation and maturation in the hippocampus of these mice. Our findings suggest that changes in LINGO-1 and oligodendrocytes in the hippocampus play important roles in the pathogenesis of AD and that antagonizing LINGO-1 might be a potential therapeutic strategy for AD. Show less
Although ovarian cancer, a gynecological malignancy, has the highest fatality rate, it still lacks highly specific biomarkers, and the differential diagnosis of ovarian masses remains difficult to det Show more
Although ovarian cancer, a gynecological malignancy, has the highest fatality rate, it still lacks highly specific biomarkers, and the differential diagnosis of ovarian masses remains difficult to determine for gynecologists. Our study aimed to obtain ovarian cancer-specific protein candidates from the circulating small extracellular vesicles (sEVs) and develop a protein panel for ovarian cancer screening and differential diagnosis of ovarian masses. In our study, sEVs derived from the serum of healthy controls and patients with cystadenoma and ovarian cancer were investigated to obtain a cancer-specific proteomic profile. In a discovery cohort, 1119 proteins were identified, and significant differences in the protein profiles of EVs were observed among groups. Then, 23 differentially expressed proteins were assessed using the parallel reaction monitoring in a validation cohort. Through univariate and multivariate logistic regression analyses, a novel model comprising three proteins (fibrinogen gamma gene (FGG), mucin 16 (MUC16), and apolipoprotein (APOA4)) was established to screen patients with ovarian cancer. This model exhibited an area under the receiver operating characteristic curve (AUC) of 0.936 (95% CI, 0.888-0.984) with 92.0% sensitivity and 82.9% specificity. Another panel comprising serum CA125, sEV-APOA4, and sEV-CD5L showed excellent performance (AUC 0.945 (95% CI, 0.890-1.000), sensitivity of 88.0%, specificity of 93.3%, and accuracy of 89.2%) to distinguish malignancy from benign ovarian masses. Altogether, our study provided a proteomic signature of circulating sEVs in ovarian cancer. The diagnostic proteomic panel may complement current clinical diagnostic measures for screening ovarian cancer in the general population and the differential diagnosis of ovarian masses. Show less
Treatments for giant congenital melanocytic nevi (GCMN) are extremely limited. Thus, there is an urgent need for development of relevant targeted therapies. However, current lack of preclinical cell m Show more
Treatments for giant congenital melanocytic nevi (GCMN) are extremely limited. Thus, there is an urgent need for development of relevant targeted therapies. However, current lack of preclinical cell models restricts progress in GCMN research. In this study, we aimed to establish and characterize an immortalized GCMN cell line. GCMN cells were successfully immortalized by means of lentivirus-mediated simian virus 40 large T transfection. The immortalized GNC cell line (ImGNC) showed lower proliferation rate and higher melanin content than primary melanocytes. Expression levels of the differentiation gene MITF and stemness genes TWIST1, SNAI1, and FOXD3 were elevated in ImGNCs; however, the established ImGNC cell line was immortalized but not transformed. Sanger sequencing detected the heterozygous NRAS Show less
Osteosarcoma (OS) is a disease with high mortality in children and adolescents, and metastasis is one of its important clinical features. However, the molecular mechanism of OS occurrence is not compl Show more
Osteosarcoma (OS) is a disease with high mortality in children and adolescents, and metastasis is one of its important clinical features. However, the molecular mechanism of OS occurrence is not completely clear. Thus, we screened potential biomarkers of OS and analyze their prognostic value. The Cancer Genome Atlas (TCGA) datasets were used to analyze the differential lncRNAs in patients with OS of different immune score and the lncRNAs expressed by immune cells. Cox regression was used to develop the prognosis prediction model and specify the prognosis outcomes. Risk-proportional regression model was constructed, and the samples were divided into high and low groups based on the risk scores for the survival analysis. The areas under the receiver operating characteristic (ROC) curve were calculated and the risk-score model was verified. Finally, using 4 gene sets (comprising chemokines, immune checkpoint blockades, immune activity-related genes, and immune cells), and 4 analysis tools (CIBERSORT, TIMER, XCELL and MCP) to evaluated tumor immune infiltration. Twenty-nine long non-coding ribonucleic acids (lncRNAs) were obtained from the intersection of the screened lncRNAs. Caspase recruitment domain-containing protein 8-antisense RNA 1 (CARD8-AS1), lncRNA five prime to Xist (FTX), KAT8 regulatory NSL complex unit 1-antisense RNA 1 (KANSL1-AS1), Neuroplastin Intronic Transcript 1 (NPTN-IT1), oligodendrocyte maturation-associated long intervening non-coding RNA (OLMALINC) and RPARP Antisense RNA 1 (RPARP-AS1) were found to be correlated with survival. Univariate and multivariate regression analysis showed risk score [HR (hazard ratio) 3.5, P value 0.0043; HR 3.7, P value 0.0033] and metastasis (HR 4.7, P value 6.60E-05; HR 4.8, P value 8.36E-05) were the key factors of patients with OS. The areas under curves (AUCs) of the 1-, 3-, and 5-year ROC curves of the prognostic model were 0.715, 0.729, and 0.771. The low-risk patients tended to have a high abundance of immune cells. This study showed that a risk score based on 6 lncRNAs has potential value in the prognosis of OS, and patients with low-risk scores have high immune cell infiltration and good prognosis. This study may enrich understandings of underlying mechanisms related to the occurrence and development of OS. Show less
Little is known about differentially expressed genes (DEGs) and alternative splicing (AS) landscapes in congenital lung malformations (CLMs). We applied reference-based assembly of sequencing reads fr Show more
Little is known about differentially expressed genes (DEGs) and alternative splicing (AS) landscapes in congenital lung malformations (CLMs). We applied reference-based assembly of sequencing reads from RNA sequencing (RNA-seq) libraries to identify DEGs and AS landscapes in the lesions and normal lung tissue from the most common types of CLMs, including congenital pulmonary airway malformation-Ⅰ (CPAM-Ⅰ), CPAM-Ⅱ, intralobar sequestration (ILS), and ILS with CPAM (ILS-CPAM). We analyzed the expression profiles and related biological functions of AS events (ASEs). We further constructed a co-expression regulatory network between RNA binding protein (RBP) genes and corresponding ASEs to explore the related pathways in the regulated network. Ten DEGs were identified in the four types of CLMs, including eight upregulated genes and two downregulated genes. Additionally, 16 differential ASEs were detected, including the genes MACF1, RFX2, and FBXL4. Gene ontology (GO) enrichment was mainly observed in embryonic visual malformation and apoptotic process, and the KEGG pathway mainly enriched in the PI3K/AKT signaling pathway. We also detected 13 differentially expressed RBPs among 1979 DEGs in CPAM-I, in which ASEs in the MACF1 gene and RBP genes TLR8 and PTRH1 were closely associated. Moreover, we confirmed that the expression levels of PTRH1, NSUN7, and DZIP1L abundantly increased and the expression levels of TLR8, MEF2A, and NIPBL decreased in the CPAM-I lung tissue compared with the controls. It is suggested that ASEs in different types of CLMs is prominently different from normal controls, and ASEs differences occurring in CPAM-I malformation tissue are dramatically different from other types, which demonstrates the complex pathogenesis of CLMs and provides foundations for future studies to elucidate the mechanisms of developing CLMs. 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
Post-translational modifications (PTMs) are a covalent processing process of proteins after translation. Proteins are capable of playing their roles only after being modified, so as to maintain the no Show more
Post-translational modifications (PTMs) are a covalent processing process of proteins after translation. Proteins are capable of playing their roles only after being modified, so as to maintain the normal physiological function of cells. As a key modification of protein post-translational modification, ubiquitination is an essential element, which forms an enzyme-linked reaction through ubiquitin-activating enzyme, ubiquitin binding enzyme, and ubiquitin ligase, aiming to regulate the expression level and function of cellular proteins. Nedd4 family is the largest group of ubiquitin ligases, including 9 members, such as Nedd4-1, Nedd4L (Nedd4-2), WWP1, WWP2, ITCH, etc. They could bind to substrate proteins through their WW domain and play a dominant role in the ubiquitination process, and then participate in various pathophysiological processes of cardiovascular diseases (such as hypertension, myocardial hypertrophy, heart failure, etc.). At present, the role of Nedd4L in the cardiovascular field is not fully understood. This review aims to summarize the progress and mechanism of Nedd4L in cardiovascular diseases, and provide potential perspective for the clinical treatment or prevention of related cardiovascular diseases by targeting Nedd4L. Show less
Many studies show that genetics play a major contribution to the onset of obesity. Human genome-wide association studies (GWASs) have identified hundreds of genes that are associated with obesity. How Show more
Many studies show that genetics play a major contribution to the onset of obesity. Human genome-wide association studies (GWASs) have identified hundreds of genes that are associated with obesity. However, the majority of them have not been functionally validated. Show less
To detect whether Danlou Tablet (DLT) regulates the hypoxia-induced factor (HIF)-1α-angiopoietin-like 4 (Angptl4) mRNA signaling pathway and explore the role of DLT in treating chronic intermittent hy Show more
To detect whether Danlou Tablet (DLT) regulates the hypoxia-induced factor (HIF)-1α-angiopoietin-like 4 (Angptl4) mRNA signaling pathway and explore the role of DLT in treating chronic intermittent hypoxia (CIH)-induced dyslipidemia and arteriosclerosis. The mature adipocytes were obtained from 3T3-L1 cell culturation and allocated into 8 groups including control groups (Groups 1 and 5, 0.1 mL of cell culture grade water); DLT groups (Groups 2 and 6, 0.1 mL of 1,000 µg/mL DLT submicron powder solution); dimethyloxalylglycine (DMOG) groups (Groups 3 and 7, DMOG and 0.1 mL of cell culture grade water); DMOG plus DLT groups (Groups 4 and 8, DMOG and 0.1 mL of 1,000 µg/mL DLT submicron powder solution). Groups 1-4 used mature adipocytes and groups 5-8 used HIF-1 α-siRNA lentivirus-transfected mature adipocytes. After 24-h treatment, real-time polymerase chain reaction and Western blot were employed to determine the mRNA and protein expression levels of HIF-1 α and Angptl4. In animal experiments, the CIH model in ApoE Angptl4 expression was dependent on HIF-1 α, with a reduction in mRNA expression and no response in protein level to DMOG or DLT treatment in relation to siHIF-1 α -transfected cells. DLT inhibited HIF-1 α and Angptl4 mRNA expression (P<0.05 or P<0.01) and reduced HIF-1 α and Angptl4 protein expressions with DMOG in mature adipocytes (all P<0.01), as the effect on HIF-1 α protein also existed in the presence of siHIF-1 α (P<0.01). ApoE DLT had positive effects in improving dyslipidemia and arteriosclerosis by inhibiting Angptl4 protein level through HIF-1 α-Angptl4 mRNA signaling pathway. 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
To investigate the treating effect of Yiqi-Bushen-Tiaozhi (YBT) recipe on nonalcoholic steatohepatitis (NASH) mice, determine whether the outcome was associated with gut microbiota, and clarify the re Show more
To investigate the treating effect of Yiqi-Bushen-Tiaozhi (YBT) recipe on nonalcoholic steatohepatitis (NASH) mice, determine whether the outcome was associated with gut microbiota, and clarify the regulating mechanism. NASH mice were induced by high-fat and high-fructose diets (HFFD). In the fifth week, mice in the YBT group were orally administrated YBT (22.12g·kg Results of the pathological and biochemical index showed that YBT could improve NASH mice. Compared with improving inflammation and hepatocyte damage, YBT may be more focused on enhancing metabolic disorders in mice, such as increasing HDL-c level. The diversity and richness of the gut microbiota of NASH mice induced by HFFD are significantly different from the normal control (NC) group. After YBT treatment, the diversity and richness of the mice microbiota will be increased to similar NC mice. YBT could treat NASH mice by improving the diversity and richness of gut microbiota and further the improvement of ALA metabolism. Show less
Ying Wang, Jun Liu, Chizuru Akatsu+18 more · 2022 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains Show more
Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways. LAPTM5 causes BCR internalization, resulting in decreased phosphorylation of SYK and ERK. In addition, LAPTM5 targets the E3 ubiquitin ligase WWP2 for lysosomal degradation, resulting in the accumulation of its substrate PTEN. Elevated PTEN levels suppress AKT phosphorylation, leading to increased FOXO1 expression and up-regulation of the cell cycle inhibitor p27Kip1 and the proapoptotic molecule BIM. In vivo, LAPTM5 is involved in the elimination of autoreactive B cells and its deficiency exacerbates autoantibody production. Our results reveal a previously unidentified mechanism that contributes to immature B cell apoptosis and B cell tolerance. Show less
Kidney cancer is one of the most common urological cancers worldwide, and kidney renal clear cell cancer (KIRC) is the major histologic subtype. Our previous study found that von-Hippel Lindau (VHL) g Show more
Kidney cancer is one of the most common urological cancers worldwide, and kidney renal clear cell cancer (KIRC) is the major histologic subtype. Our previous study found that von-Hippel Lindau (VHL) gene mutation, the dominant reason for sporadic KIRC and hereditary kidney cancer-VHL syndrome, could affect VHL disease-related cancers development by inducing telomere shortening. However, the prognosis role of telomere-related genes in kidney cancer has not been well discussed. In this study, we obtained the telomere-related genes (TRGs) from TelNet. We obtained the clinical information and TRGs expression status of kidney cancer patients in The Cancer Genome Atlas (TCGA) database, The International Cancer Genome Consortium (ICGC) database, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Totally 353 TRGs were differential between tumor and normal tissues in the TCGA-KIRC dataset. The total TCGA cohort was divided into discovery and validation TCGA cohorts and then using univariate cox regression, lasso regression, and multivariate cox regression method to conduct data analysis sequentially, ten TRGs (ISG15, RFC2, TRIM15, NEK6, PRKCQ, ATP1A1, ELOVL3, TUBB2B, PLCL1, NR1H3) risk model had been constructed finally. The kidney patients in the high TRGs risk group represented a worse outcome in the discovery TCGA cohort (p<0.001), and the result was validated by these four cohorts (validation TCGA cohort, total TCGA cohort, ICGC cohort, and CPTAC cohort). In addition, the TRGs risk score is an independent risk factor for kidney cancer in all these five cohorts. And the high TRGs risk group correlated with worse immune subtypes and higher tumor mutation burden in cancer tissues. In addition, the high TRGs risk group might benefit from receiving immune checkpoint inhibitors and targeted therapy agents. Moreover, the proteins NEK6, RF2, and ISG15 were upregulated in tumors both at the RNA and protein levels, while PLCL1 and PRKCQ were downregulated. The other five genes may display the contrary expression status at the RNA and protein levels. In conclusion, we have constructed a telomere-related genes risk model for predicting the outcomes of kidney cancer patients, and the model may be helpful in selecting treatment agents for kidney cancer patients. Show less
In day-to-day life, we often must choose between pursuing familiar behaviors or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for arbi Show more
In day-to-day life, we often must choose between pursuing familiar behaviors or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for arbitrating between old and new action strategies. To uncover molecular mechanisms, we trained mice to generate nose poke responses for food, then uncoupled the predictive relationship between one action and its outcome. We then bred the mice that failed to rapidly modify responding. This breeding created offspring with the same tendencies, failing to inhibit behaviors that were not reinforced. These mice had less post-synaptic density protein 95 in the DMS. Also, densities of the melanocortin-4 receptor (MC4R), a high-affinity receptor for α-melanocyte-stimulating hormone, predicted individuals' response strategies. Specifically, high MC4R levels were associated with poor response inhibition. We next found that reducing Mc4r in the DMS in otherwise typical mice expedited response inhibition, allowing mice to modify behavior when rewards were unavailable or lost value. This process required inputs from the orbitofrontal cortex, a brain region canonically associated with response strategy switching. Thus, MC4R in the DMS appears to propel reward-seeking behavior, even when it is not fruitful, while moderating MC4R presence increases the capacity of mice to inhibit such behaviors. Show less
Metastasis is the leading cause of death in patients with colorectal cancer (CRC). The 5-year survival rate of CRC patients in whom the cancer has spread to distant sites is 13.5%. The most common sit Show more
Metastasis is the leading cause of death in patients with colorectal cancer (CRC). The 5-year survival rate of CRC patients in whom the cancer has spread to distant sites is 13.5%. The most common sites of CRC metastasis are liver and lung. The principal therapies for CRC metastatic disease are surgery, but its benefits are limited. This study aimed to reveal the regulatory mechanism of berberine on secondary homing of CRC cells to form metastatic focus. This was more valuable than the previous direct study of the migration and metastasis characteristics of CRC cells. In this study, we used the functional enrichment analysis of differentially expressed genes after berberine treatment and investigated co-expression modules related with CRC metastasis by WGCNA. PPI and survival analyses of significant modules were also conducted. The biological functions of berberine in CRC lung and liver metastasis were investigated by a series of in vitro and in vivo experiments: MTT, colony formation and mouse tail vein injection. And we scanned through the entire extracellular domain of HEY2 protein for autodocking analysis with berberine. We found the differentially expressed genes (DEGs) after berberine treatment were related with cancer progression and metastasis related pathways. Through WGCNA analysis, four cancer progression and metastasis related modules were detected. After PPI and survival analysis, we identified and validated HEY2 as a hub gene, high expression and poor survival at the metastatic stage. Functionally, berberine inhibited the survival, invasion and migration of CRC cells in vitro and in vivo. Mechanistically, berberine treatment down-regulated the expression of HEY2, metastasis related protein E-cadherin, β-catenin and Cyclin D1 during Mesenchymal epithelial transformation (MET). Berberine and HEY2 showed a significant interaction, and berberine binded to HEY2 protein at the residue HIS-99 interface with a hydrogen-bond distance of 1.9A. We revealed that berberine could significantly inhibit the expression of hub gene HEY2 and metastasis related proteins E-cadherin and β-catenin and Cyclin D1 during MET in CRC lung and liver metastases. In total, HEY2 was a promising candidate biomarker for prognosis and molecular characteristics in CRC metastasis. 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
Breast cancer is the most common malignancy among women across the globe. Recent studies have revealed that many long non-coding RNAs (lncRNAs) regulate the Wnt/β-catenin signaling pathway in several Show more
Breast cancer is the most common malignancy among women across the globe. Recent studies have revealed that many long non-coding RNAs (lncRNAs) regulate the Wnt/β-catenin signaling pathway in several types of cancer. Hyperactivation of the Wnt/β-catenin pathway has been extensively presented in breast cancer and is involved in breast cancer progression. However, the underlying molecular mechanism remains elusive. In the current study, we found lncRNA RBM5-AS1 was remarkably upregulated in breast cancer cells and tissues. Overexpression of RBM5-AS1 facilitated proliferation, migration, invasion, EMT, and stemness maintenance of breast cancer cells in vitro and in vivo. Mechanism studies suggested that RBM5-AS1 could be transcriptionally activated by hypoxia-induced RUNX2. Upregulated RBM5-AS1 further activated the Wnt/β-catenin signaling by preventing β-catenin degradation and by helping organize β-catenin-TCF4 transcriptional complex. These findings suggested that RBM5-AS1, a regulator of Wnt/β-catenin signaling, plays a vital role in breast cancer initiation and progression, implicating its potential as a new target for breast cancer treatment. Show less
Fat deposition is a complex economic trait regulated by polygenic genetic basis and environmental factors. Therefore, integrating multi-omics data to uncover its internal regulatory mechanism has attr Show more
Fat deposition is a complex economic trait regulated by polygenic genetic basis and environmental factors. Therefore, integrating multi-omics data to uncover its internal regulatory mechanism has attracted extensive attention. Here, we performed genomics and transcriptomics analysis to detect candidates affecting subcutaneous fat (SCF) deposition in beef cattle. The association of 770K SNPs with the backfat thickness captured nine significant SNPs within or near 11 genes. Additionally, 13 overlapping genes regarding fat deposition were determined via the analysis of differentially expressed genes and weighted gene co-expression network analysis (WGCNA). We then calculated the correlations of these genes with BFT and constructed their interaction network. Finally, seven biomarkers including ACACA, SCD, FASN, ACOX1, ELOVL5, HACD2, and HSD17B12 were screened. Notably, ACACA, identified by the integration of genomics and transcriptomics, was more likely to exert profound effects on SCF deposition. These findings provided novel insights into the regulation mechanism underlying bovine fat accumulation. 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
Increasing evidence shows that autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural Show more
Increasing evidence shows that autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural alkaloid named corynoxine B (Cory B) as a neuronal autophagy inducer. However, its brain permeability is relatively low, which hinders its potential use in treating PD. Thus we synthesized various derivatives of Cory B to find more potent autophagy inducers with improved brain bioavailability. In this study, we evaluated the autophagy-enhancing effect of CB6 derivative and its neuroprotective action against PD in vitro and in vivo. We showed that CB6 (5-40 μM) dose-dependently accelerated autophagy flux in cultured N2a neural cells through activating the PIK3C3 complex and promoting PI3P production. In MPP 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
Organotropism during cancer metastasis occurs frequently but the underlying mechanism remains poorly understood. Here, we show that lysosomal protein transmembrane 5 (LAPTM5) promotes lung-specific me Show more
Organotropism during cancer metastasis occurs frequently but the underlying mechanism remains poorly understood. Here, we show that lysosomal protein transmembrane 5 (LAPTM5) promotes lung-specific metastasis in renal cancer. LAPTM5 sustains self-renewal and cancer stem cell-like traits of renal cancer cells by blocking the function of lung-derived bone morphogenetic proteins (BMPs). Mechanistic investigations showed that LAPTM5 recruits WWP2, which binds to the BMP receptor BMPR1A and mediates its lysosomal sorting, ubiquitination and ultimate degradation. BMPR1A expression was restored by the lysosomal inhibitor chloroquine. LAPTM5 expression could also serve as an independent predictor of lung metastasis in renal cancer. Lastly, elevation of LAPTM5 expression in lung metastases is a common phenomenon in multiple cancer types. Our results reveal a molecular mechanism underlying lung-specific metastasis and identify LAPTM5 as a potential therapeutic target for cancers with lung metastasis. Show less
Colitis-associated cancer (CAC) is a subtype of inflammatory bowel disease (IBD)-associated colorectal cancer. Huoxiang Zhengqi (HXZQ) is a classical Chinese herbal medicine and has been used to treat Show more
Colitis-associated cancer (CAC) is a subtype of inflammatory bowel disease (IBD)-associated colorectal cancer. Huoxiang Zhengqi (HXZQ) is a classical Chinese herbal medicine and has been used to treat intestinal disorders, however, anti-CAC effects and underlying mechanisms of HXZQ have not been reported. An azoxymethane/dextran sulfate sodium-induced CAC mice model was used to investigate the anti-CAC effect of HXZQ. HXZQ significantly reduced colonic inflammation, suppressed the size and number of tumors, and reduced the levels of pro-inflammatory cytokines (interleukin [IL]-1α, IL-1β, IL-6, IL-17A, IL-21, IL-23, granulocyte macrophage-colony stimulating factor, and tumor necrosis factor-α) and oxidative stress markers (reactive oxygen species and malondialdehyde), and increased the levels of anti-inflammatory cytokines (IL-10 and IL-27) in CAC mice. Intestinal microbiota and serum metabolomics analyses indicated that HXZQ altered the gut microbial composition and the abundance of 29 serum metabolites in CAC mice. Additionally, HXZQ activated the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) signaling pathway and increased the levels of antioxidants such as catalase (CAT), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductases-1 (NQO-1), and superoxide dismutase-1 (SOD-1). HXZQ inhibited the activation of the nuclear factor kappa-B (NF-κB) signaling pathway and decreased the expression of NLR family pyrin domain containing 3 (NLRP3) by inhibiting the phosphorylation of inhibitor of nuclear factor kappa-B (IκB), inhibitor of nuclear factor kappa-B kinase (IKK), and NF-κB. In conclusion, HXZQ alleviated CAC in mice by modulating the intestinal microbiota and metabolism, activating Nrf2-mediated antioxidant response, and inhibiting NF-κB-mediated NLRP3 inflammasome activation against inflammation. The present data provide a reference for the use of HXZQ as a therapeutic or combination agent for clinical CAC treatment. Show less
Liver cancer is the fifth most prevalent malignant tumor, while hepatocellular carcinoma represents the most prevalent subtype worldwide. Previous studies have associated the chromobox family, critica Show more
Liver cancer is the fifth most prevalent malignant tumor, while hepatocellular carcinoma represents the most prevalent subtype worldwide. Previous studies have associated the chromobox family, critical components of epigenetic regulatory complexes, with development of many malignancies owing to their role in inhibiting differentiation and promoting proliferation of cancer cells. However, little is known regarding their function in development and progression of hepatocellular carcinoma. In the present study, we analyzed differential expression, prognostic value, immune cell infiltration, and gene pathway enrichment of chromobox family in hepatocellular carcinoma patients. Next, we performed Pearson's correlation analysis to determine the relationships between chromobox family proteins with tumor-immune infiltration. Results revealed that high expression of CBX1, CBX2, CBX3, CBX6, and CBX8 was associated with poor survival rates of hepatocellular carcinoma patients. These five factors were used to build prognostic gene models using LASSO Cox regression analysis. Results indicated that high expression of CBX2 and CBX3 proteins was significantly associated with poor prognosis for hepatocellular carcinoma patients. The resulting nomogram revealed that CBX3 and T stages were significantly correlated with prognosis of hepatocellular carcinoma patients. Notably, predictive CBX3 was strongly correlated with immune cell infiltration. Furthermore, results from functional enrichment analysis revealed that CBX3 was mainly involved in regulation of methylation of Histone H3-K27. Collectively, these findings suggest that CBX3 could be a biomarker for predicting prognosis of hepatocellular carcinoma patients. Show less
Few intravenously administered mesenchymal stromal cells (MSCs) engraft to the injured myocardium, thereby limiting their therapeutic efficacy for the treatment of ischemic heart injury. Here, it is f Show more
Few intravenously administered mesenchymal stromal cells (MSCs) engraft to the injured myocardium, thereby limiting their therapeutic efficacy for the treatment of ischemic heart injury. Here, it is found that irisin pretreatment increases the cardiac homing of adipose tissue-derived MSCs (ADSCs) administered by single and multiple intravenous injections to mice with MI/R by more than fivefold, which subsequently increases their antiapoptotic, proangiogenic, and antifibrotic effects in rats and mice that underwent MI/R. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis, and loss-of-function studies identified CSF2RB as a cytokine receptor that facilitates the chemotaxis of irisin-treated ADSCs in the presence of CSF2, a chemokine that is significantly upregulated in the ischemic heart. Cardiac-specific CSF2 knockdown blocked the cardiac homing and cardioprotection abilities of intravenously injected irisin-treated ADSCs in mice subjected to MI/R. Moreover, irisin pretreatment reduced the apoptosis of hydrogen peroxide-induced ADSCs and increased the paracrine proangiogenic effect of ADSCs. ERK1/2-SOD2, and ERK1/2-ANGPTL4 are responsible for the antiapoptotic and paracrine angiogenic effects of irisin-treated ADSCs, respectively. Integrin αV/β5 is identified as the irisin receptor in ADSCs. These results provide compelling evidence that irisin pretreatment can be an effective means to optimize intravenously delivered MSCs as therapy for ischemic heart injury. Show less
Idiopathic pulmonary fibrosis (IPF) is characterized by lung scarring and has no effective treatment. Fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration are majo Show more
Idiopathic pulmonary fibrosis (IPF) is characterized by lung scarring and has no effective treatment. Fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration are major clinical manifestations of this disease; hence, blocking these processes is a practical treatment strategy. Here, highly upregulated Show less
Macroautophagy/autophagy is a highly conserved process in eukaryotic cells. It plays a critical role in cellular homeostasis by delivering cytoplasmic cargos to lysosomes for selective degradation. OP Show more
Macroautophagy/autophagy is a highly conserved process in eukaryotic cells. It plays a critical role in cellular homeostasis by delivering cytoplasmic cargos to lysosomes for selective degradation. OPTN (optineurin), a well-recognized autophagy receptor, has received considerable attention due to its multiple roles in the autophagic process. OPTN is associated with many human disorders that are closely related to autophagy, such as rheumatoid arthritis, osteoporosis, and nephropathy. Here, we review the function of OPTN as an autophagy receptor at different stages of autophagy, focusing on cargo recognition, autophagosome formation, autophagosome maturation, and lysosomal quality control. OPTN tends to be protective in most autophagy associated diseases, though the molecular mechanism of OPTN regulation in these diseases is not well understood. A comprehensive review of the function of OPTN in autophagy provides valuable insight into the pathogenesis of human diseases related to OPTN and facilitates the discovery of potential key regulators and novel therapeutic targets for disease intervention in patients with autophagic diseases. Show less