The urea cycle (UC) removes the excess nitrogen and ammonia generated by nitrogen-containing compound composites or protein breakdown in the human body. Research has shown that changes in UC enzymes a Show more
The urea cycle (UC) removes the excess nitrogen and ammonia generated by nitrogen-containing compound composites or protein breakdown in the human body. Research has shown that changes in UC enzymes are not only related to tumorigenesis and tumor development but also associated with poor survival in hepatocellular, breast, and colorectal cancers (CRC), etc. Cytoplasmic ornithine, the intermediate product of the urea cycle, is a specific substrate for ornithine decarboxylase (ODC, also known as ODC1) for the production of putrescine and is required for tumor growth. Polyamines (spermidine, spermine, and their precursor putrescine) play central roles in more than half of the steps of colorectal tumorigenesis. Given the close connection between polyamines and cancer, the regulation of polyamine metabolic pathways has attracted attention regarding the mechanisms of action of chemical drugs used to prevent CRC, as the drug most widely used for treating type 2 diabetes (T2D), metformin (Met) exhibits antitumor activity against a variety of cancer cells, with a vaguely defined mechanism. In addition, the influence of metformin on the UC and putrescine generation in colorectal cancer has remained unclear. In our study, we investigated the effect of metformin on the UC and putrescine generation of CRC in vivo and in vitro and elucidated the underlying mechanisms. In nude mice bearing HCT116 tumor xenografts, the administration of metformin inhibited tumor growth without affecting body weight. In addition, metformin treatment increased the expression of monophosphate (AMP)-activated protein kinase (AMPK) and p53 in both HCT116 xenografts and colorectal cancer cell lines and decreased the expression of the urea cycle enzymes, including carbamoyl phosphate synthase 1 (CPS1), arginase 1 (ARG1), ornithine trans-carbamylase (OTC), and ODC. The putrescine levels in both HCT116 xenografts and HCT116 cells decreased after metformin treatment. These results demonstrate that metformin inhibited CRC cell proliferation via activating AMPK/p53 and that there was an association between metformin, urea cycle inhibition and a reduction in putrescine generation. Show less
There are few studies on the role of iron metabolism genes in predicting the prognosis of lung adenocarcinoma (LUAD). Therefore, our research aims to screen key genes and to establish a prognostic sig Show more
There are few studies on the role of iron metabolism genes in predicting the prognosis of lung adenocarcinoma (LUAD). Therefore, our research aims to screen key genes and to establish a prognostic signature that can predict the overall survival rate of lung adenocarcinoma patients. RNA-Seq data and corresponding clinical materials of 594 adenocarcinoma patients from The Cancer Genome Atlas(TCGA) were downloaded. GSE42127 of Gene Expression Omnibus (GEO) database was further verified. The multi-gene prognostic signature was constructed by the Cox regression model of the Least Absolute Shrinkage and Selection Operator (LASSO). We constructed a prediction signature with 12 genes (HAVCR1, SPN, GAPDH, ANGPTL4, PRSS3, KRT8, LDHA, HMMR, SLC2A1, CYP24A1, LOXL2, TIMP1), and patients were split into high and low-risk groups. The survival graph results revealed that the survival prognosis between the high and low-risk groups was significantly different (TCGA: P < 0.001, GEO: P = 0.001). Univariate and multivariate Cox regression analysis confirmed that the risk value is a predictor of patient OS (P < 0.001). The area under the time-dependent ROC curve (AUC) indicated that our signature had a relatively high true positive rate when predicting the 1-year, 3-year, and 5-year OS of the TCGA cohort, which was 0.735, 0.711, and 0.601, respectively. In addition, immune-related pathways were highlighted in the functional enrichment analysis. In conclusion, we developed and verified a 12-gene prognostic signature, which may be help predict the prognosis of lung adenocarcinoma and offer a variety of targeted options for the precise treatment of lung cancer. Show less
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC is enriched with breast cancer stem cells (BCSCs), which are responsible for cancer initiation, cancer progre Show more
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC is enriched with breast cancer stem cells (BCSCs), which are responsible for cancer initiation, cancer progression and worse prognosis. Our previous study found that HES1 was overexpressed and promoted invasion in TNBC. However, the role of HES1 in modulating BCSC stemness of TNBC remains unclear. Here, we found that HES1 upregulates Slug both in transcriptional level and in protein level. HES1 also has a positive correlation with Slug expression in 150 TNBC patient samples. TNBC patients with high HES1 and Slug levels show worse prognosis in both progression-free survival and overall survival analyses. Survival analyses indicate that the effects of HES1 on survival prognosis may depend on Slug. Furthermore, we reveal that HES1 is a novel transcriptional activator for Slug through acting directly on its promoter. Meanwhile, HES1 knockdown reduces BCSC self-renewal, BCSC population, and cancer cell proliferation in TNBC, whereas overexpression of Slug restores the oncogenic function of HES1, both Show less
Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB). D Show more
Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB). DUB PSMD14 is reported to be a promising therapeutic target in various cancers. Here, we explored the antitumor activity of Thiolutin (THL), the PSMD14 inhibitor, as a new therapy strategy in ESCC. Show less
Homo- or heterodimerization of G protein-coupled receptors (GPCRs) generally alters the normal functioning of these receptors and mediates their responses to a variety of physiological stimuli in vivo Show more
Homo- or heterodimerization of G protein-coupled receptors (GPCRs) generally alters the normal functioning of these receptors and mediates their responses to a variety of physiological stimuli in vivo. It is well known that melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) are key regulators of appetite and energy homeostasis in the central nervous system (CNS). However, the GPCR partners of MC3R and MC4R are not well understood. Our objective is to analyze single cell RNA-seq datasets of the hypothalamus to explore and identify novel GPCR partners of MC3R and MC4R and examine the pharmacological effect on the downstream signal transduction and membrane translocation of melanocortin receptors. We conducted an integrative analysis of multiple single cell RNA-seq datasets to reveal the expression pattern and correlation of GPCR families in the mouse hypothalamus. The emerging GPCRs with important metabolic functions were selected for cloning and co-immunoprecipitation validation. The positive GPCR partners were then tested for the pharmacological activation, competitive binding assay and surface translocation ELISA experiments. Based on the expression pattern of GPCRs and their function enrichment results, we narrowed down the range of potential GPCR interaction with MC3R and MC4R for further confirmation. Co-immunoprecipitation assay verified 23 and 32 novel GPCR partners that interacted with MC3R and MC4R in vitro. The presence of these GPCR partners exhibited different effects in the physiological regulation and signal transduction of MC3R and MC4R. This work represented the first large-scale screen for the functional GPCR complex of central melanocortin receptors and defined a composite metabolic regulatory GPCR network of the hypothalamic nucleuses. 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
Right heart failure and right ventricular (RV) remodeling were the main reason for mortality of pulmonary hypertension (PH) patients. Apolipoprotein AV (ApoA5) is a key regulator of plasma triglycerid Show more
Right heart failure and right ventricular (RV) remodeling were the main reason for mortality of pulmonary hypertension (PH) patients. Apolipoprotein AV (ApoA5) is a key regulator of plasma triglyceride and have multifunction in several target organs. We detected decreased ApoA5 in serum of patients with PH and both in serum and RV of monocrotaline-induced PH model. Exogenously, overexpression ApoA5 by adenovirus showed protective effects on RV failure and RV fibrosis secondary to PH. In addition, in vitro experiments showed ApoA5 attenuated the activation of fibroblast induced by transforming growth factor β1 and synthesis and secretion of extracellular matrix by inhibiting focal adhesion kinase-c-Jun N-terminal kinase-Smad3 pathway. Finally, we suggest that ApoA5 may potentially be a pivotal target for RV failure and fibrosis secondary of PH. Show less
Anacetrapib is a novel, powerful cholesteryl ester transfer protein (CETP) inhibitor with bidirectional lipid regulation, which was developed for dyslipidemia. The aim of this study is to evaluate the Show more
Anacetrapib is a novel, powerful cholesteryl ester transfer protein (CETP) inhibitor with bidirectional lipid regulation, which was developed for dyslipidemia. The aim of this study is to evaluate the single- and multiple-dose pharmacokinetics (PK), safety and tolerability of anacetrapib in healthy Chinese subjects and assess the PK difference between Chinese and other populations. Forty subjects were enrolled in an open-label study consisting of three panels (50 mg single dose; 100 mg single dose followed by 100 mg once-daily multiple doses for 10 days; a 200 mg single dose). Safety and tolerability were evaluated by monitoring adverse events, laboratory safety tests, ECGs, vital signs and physical examination. PK were evaluated and compared with historical data in black and white subjects. Anacetrapib was absorbed after administration of a single oral dose, with a median T The PK properties of anacetrapib in Chinese subjects are comparable to those observed in the black population and in white subjects. Single and once-daily administration of anacetrapib was generally well tolerated in healthy Chinese subjects observed in this study. chinadrugtrials.org.cn identifier number CTR20130983. Show less
Macroautophagy/autophagy is a conserved catabolic pathway that targets cytoplasmic components for their degradation and recycling in an autophagosome-dependent lysosomal manner. Under physiological co Show more
Macroautophagy/autophagy is a conserved catabolic pathway that targets cytoplasmic components for their degradation and recycling in an autophagosome-dependent lysosomal manner. Under physiological conditions, this process maintains cellular homeostasis. However, autophagy can be stimulated upon different forms of cellular stress, ranging from nutrient starvation to exposure to drugs. Thus, this pathway can be seen as a central component of the integrated and adaptive stress response. Here, we report that even brief induction of autophagy is coupled Show less
Microribonucleic acid-155 (microRNA155) and microRNA29 are reported to inhibit glucose metabolism in some cell and animal models, but no evidence from susceptible populations that examines the relatio Show more
Microribonucleic acid-155 (microRNA155) and microRNA29 are reported to inhibit glucose metabolism in some cell and animal models, but no evidence from susceptible populations that examines the relationship between microRNA155 or microRNA29 and type 2 diabetes mellitus currently exists. Furthermore, target genes regulated by microRNA155 and microRNA29 that affect glucose and lipid metabolism remain unknown. Human participants were divided into normal weight (n = 72), obesity (n = 120) and type 2 diabetes (n = 59) groups. The contents of microRNA155 and microRNA29 abundance in serum were measured, and candidate genes potentially related to glucose and lipid metabolism targeted by either microRNA155 or microRNA29 were screened. Overexpression of microRNA155 and microRNA29 in HepG2 cells was used to verify candidate gene expression, and measure the effects on glucose and lipid metabolism. Serum levels of microRNA155 and microRNA29 show a significant increase in individuals with obesity and type 2 diabetes compared with normal weight individuals. Identified target genes for microRNA155 were MAPK14, MAP3K10, DUSP14 and PRKAR2B. Identified target genes for microRNA29 were PEX11A and FADS1. Overexpression of microRNA155 or microRNA29 in HepG2 cells was found to downregulate the expression of identified target genes, and result in inhibition of triglyceride synthesis and glucose incorporation. MicroRNA155 and microRNA29 were significantly higher in type 2 diabetes patients compared with the control patients, their levels were also positively correlated with fasting plasma glucose levels, and over-expression of microRNA155 or microRNA29 were found to downregulate glucose and lipid metabolism target genes, and reduce lipid synthesis and glucose incorporation in HepG2 cells. Show less
Previous genotyping-based assays have identified non-coding variants of several interleukins (ILs) being associated with genetic susceptibility to leprosy. However, understanding of the involvement of Show more
Previous genotyping-based assays have identified non-coding variants of several interleukins (ILs) being associated with genetic susceptibility to leprosy. However, understanding of the involvement of coding variants within all IL family genes in leprosy was still limited. To obtain the full mutation spectrum of all ILs in leprosy, we performed a targeted deep sequencing of coding regions of 58 ILs genes in 798 leprosy patients (age 56.2 ± 14.4; female 31.5%) and 990 healthy controls (age 38.1 ± 14.0; female 44.3%) from Yunnan, Southwest China. mRNA expression alterations of ILs in leprosy skin lesions or in response to M. leprae treatment were estimated by using publicly available expression datasets. Two coding variants in IL27 (rs17855750, p.S59A, p = 4.02 × 10 Show less
Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the Unite Show more
Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors ( Show less
Myocardial hypertrophy is a pathological thickening of the myocardium, leading to various ailments, such as myocardial infarction and heart failure. RBM38 is critical in modulating mRNA translation fo Show more
Myocardial hypertrophy is a pathological thickening of the myocardium, leading to various ailments, such as myocardial infarction and heart failure. RBM38 is critical in modulating mRNA translation for multiple protective activities such as p53 tumor repressor and p21 kinase cell cycle inhibitors. Liver X receptors (LXR-α) agonists reduce cellular hypertrophy initiated by various hypertrophic stimuli as lipopolysaccharides and Ang II. This research investigates the possible cooperation between RBM38 and LXR-α and mechanisms in modulating myocardial hypertrophy. H9C2 cells were treated with PE, TNF-α, and AngII to induce myocardial hypertrophy. RBM38 and LXR- α were overexpressed or silenced in H9C2 cells, and hypertrophy markers (ANF and Myh7) were determined with Western blot and RT-qPCR. Binding assays were done through RNA immunoprecipitation. H&E and Rhodamine-labeled phalloidin staining assays were used to assess the relative cell surface change. The results demonstrated RBM38 downregulation in in vitro models of myocardial hypertrophy. Modulation of RBM38 expression also exerted inverse effects on myocardial hypertrophy markers. Further observations also showed that LXR-α expression regulates the myocardial hypertrophy markers in H9C2 cells and RBM38 binds with LXR-α mRNA, consequently inhibiting LXR-α expression. Finally, overexpression of RBM38 rescues Angiotensin II-induced myocardial hypertrophy by regulating LXR-α dependent lipogenesis pathway. In conclusion, RBM38 Overexpression rescues Angiotensin II-induced myocardial hypertrophy by regulating LXR-α dependent lipogenesis pathway. Show less
Ocular surface changes may develop in patients with chronic renal failure (CRF) undergoing hemodialysis. In recent years, an association of CRF with dry eye syndrome has been emphasized. However, tear Show more
Ocular surface changes may develop in patients with chronic renal failure (CRF) undergoing hemodialysis. In recent years, an association of CRF with dry eye syndrome has been emphasized. However, tear proteomics of CRF patients has not been analyzed. Here, we performed systematic profiling of the tear film proteins in CRF patients through use of isobaric tags for relative and absolute quantitative (iTRAQ) MS/MS, aiming to identify associations between dry eye symptoms and expression of tear proteomic changes in patients with CRF undergoing hemodialysis. Twenty CRF patients and ten healthy subjects underwent a series of ophthalmic examinations. Tear samples from the participants were analyzed by iTRAQ approach. A total of 1139 tear proteins were screened, and 212 differentially expressed proteins were identified. The pattern changes included 77 whose expression levels were upregulated (fold increase >1.2) whereas 135 others that were downregulated (fold decrease <1/1.2). Bioinformatics analysis showed that these proteins were significantly enriched in lipid metabolism, inflammatory, and immune response pathways. Furthermore, APOA1, APOA4, APOB, APOE, S100A8, S100A9, S100A4, HSP90B and other molecules were significantly changed. Our study elucidated the characteristics of tear dynamics and protein markers in CRF patients undergoing hemodialysis. Significance: Despite the association of chronic renal failure (CRF) with dry eye disease, there are no reports describing potentially important differentially expressed tear proteins in CRF patients undergoing hemodialysis. It is still a challenge to obtain a comprehensive description of the pathogenesis of dry eye in CRF patients which hinders establishing a patient specific therapeutic scheme. Our study is the first iTRAQ proteomics analysis of the tears of patients with CRF, which reveals the changes in the protein expression profile in CRF patients afflicted with dry eye disease. The identity was verified of some relevant differentially expressed proteins, and they may be candidate diagnostic markers of dry eye disease in patients with CRF. These tear film protein constituents found in hemodialysis patients can be of important clinical significance in treating this condition. SIGNIFICANCE: Despite the association of chronic renal failure (CRF) with dry eye disease, there are no reports describing potentially important differentially expressed tear proteins in CRF patients undergoing hemodialysis. It is still a challenge to obtain a comprehensive description of the pathogenesis of dry eye in CRF patients which hinders establishing a patient specific therapeutic scheme. Our study is the first iTRAQ proteomics analysis of the tears of patients with CRF, which reveals the changes in the protein expression profile in CRF patients afflicted with dry eye disease. The identity was verified of some relevant differentially expressed proteins, and they may be candidate diagnostic markers of dry eye disease in patients with CRF. These tear film protein constituents found in hemodialysis patients can be of important clinical significance in treating this condition. Show less
The prognosis‑associated genes of urinary bladder cancer have been systematically investigated in the Pathology Atlas project based on The Cancer Genome Atlas data. However, the biological functions o Show more
The prognosis‑associated genes of urinary bladder cancer have been systematically investigated in the Pathology Atlas project based on The Cancer Genome Atlas data. However, the biological functions of most genes in bladder cancer remain unknown. The present study investigated the biological function of 12 of the most significant survival‑associated genes (ABRACL, MITD1, ZNF524, EMP1, HSPB6, CXorf38, TRIM38, ZNF182, ZNF195, SPRN, PTPN6 and LIPT1) in urothelial cancer reported by the Pathology Atlas project, with respect to cell proliferation and migration. In vitro, proliferation and migration analyses of T24 cells were performed following the transfection of the 12 prognostic genes. The results were validated with a small interfering (si)RNA library. Immunohistochemistry (IHC) analysis of clinical samples was performed to determine the association between gene expression and tumor metastasis. Furthermore, RNA sequencing was used to investigate the downstream signals. Among the 12 prognostic genes, MIT‑domain containing protein 1 (MITD1) transfection was demonstrated to inhibit T24 cell migration to a certain degree. Experiments performed with a 7‑gene siRNA library demonstrated that MITD1 knockdown markedly upregulated cell migratory abilities. Mechanistically, the influence of MITD1 on cell signal transduction was assessed via RNA sequencing. Cell migration‑associated genes, including KISS1, SPANXB1, SPINT1, PIWIL2, SNAI1, APLN and CTHRC1 were dysregulated. IHC analysis demonstrated that MITD1 protein expression was notably lower in metastatic lymph nodes compared with the primary tumors. Taken together, the results of the present study suggest that the prognostic gene, MITD1 may serve as a migration inhibitor, and be developed as a potential therapeutic target for improving the prognosis of bladder cancer. Show less
Digestive system carcinoma is one of the most devastating diseases worldwide. Lack of valid clinicopathological parameters as prognostic factors needs more accurate and effective biomarkers for high-c Show more
Digestive system carcinoma is one of the most devastating diseases worldwide. Lack of valid clinicopathological parameters as prognostic factors needs more accurate and effective biomarkers for high-confidence prognosis that guide decision-making for optimal treatment of digestive system carcinoma. The aim of the present study was to establish a novel model to improve prognosis prediction of digestive system carcinoma, with a particular interest in transcription factors (TFs). A TF-related prognosis model of digestive system carcinoma with data from TCGA database successively were processed by univariate and multivariate Cox regression analyses. Then, for evaluating the prognostic prediction value of the model, ROC curve and survival analysis were performed by external data from GEO database. Furthermore, we verified the expression of TFs expression by qPCR in digestive system carcinoma tissue. Finally, we constructed a TF clinical characteristics nomogram to furtherly predict digestive system carcinoma patient survival probability with TCGA database. By Cox regression analysis, a panel of 17 TFs (NFIC, YBX2, ZBTB47, ZNF367, CREB3L3, HEYL, FOXD1, TIGD1, SNAI1, HSF4, CENPA, ETS2, FOXM1, ETV4, MYBL2, FOXQ1, ZNF589) was identified to present with powerful predictive performance for overall survival of digestive system carcinoma patients based on TCGA database. A nomogram that integrates TFs was established, allowing efficient prediction of survival probabilities and displaying higher clinical utility. The 17-TF panel is an independent prognostic factor for digestive system carcinoma, and 17 TFs based nomogram might provide implication an effective approach for digestive system carcinoma patient management and treatment. Show less
The etiology of hypertriglyceridemia (HTG) and acute pancreatitis (AP) is complex. Herein, we dissected the underlying etiology in a patient with HTG and AP. The patient had a 20-year history of heavy Show more
The etiology of hypertriglyceridemia (HTG) and acute pancreatitis (AP) is complex. Herein, we dissected the underlying etiology in a patient with HTG and AP. The patient had a 20-year history of heavy alcohol consumption and an 8-year history of mild HTG. He was hospitalized for alcohol-triggered AP, with a plasma triglyceride (TG) level up to 21.4 mmol/L. A temporary rise in post-heparin LPL concentration (1.5-2.5 times of controls) was noted during the early days of AP whilst LPL activity was consistently low (50∼70% of controls). His TG level rapidly decreased to normal in response to treatment, and remained normal to borderline high during a ∼3-year follow-up period during which he had abstained completely from alcohol. Sequencing of the five primary HTG genes (i.e., Show less
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, by increasing hepatic low density lipoprotein (LDL) receptor (LDLR) levels, has emerged as a strategy to reduce atherosclerosis by low Show more
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, by increasing hepatic low density lipoprotein (LDL) receptor (LDLR) levels, has emerged as a strategy to reduce atherosclerosis by lowering circulating very low density lipoprotein (VLDL)-cholesterol. We hypothesized that the therapeutic effectiveness of PCSK9 inhibition can be increased by accelerating the generation of VLDL remnants, which typically have a high affinity for the LDLR. Therefore, we aimed to investigate whether accelerating lipolytic processing of VLDL by brown fat activation can further lower (V)LDL and reduce atherosclerosis on top of PCSK9 inhibition. APOE*3-Leiden.CETP mice were fed a Western-type diet and treated with the anti-PCSK9 antibody alirocumab or saline. After 2 weeks, both groups of mice were randomized to receive either the selective β3-adrenergic receptor (AR) agonist CL316,243 to activate brown fat or saline for 3 additional weeks to evaluate VLDL clearance or 12 additional weeks to analyze atherosclerosis development. β3-AR agonism and alirocumab combined decreased (V)LDL-cholesterol compared to alirocumab alone, which was explained by an accelerated plasma clearance of VLDL-cholesteryl esters that were mainly taken up by the liver. In addition, the combination promoted the transfer of VLDL-phospholipids to HDL to a higher extent than alirocumab alone, accompanied by higher plasma HDL-cholesterol levels and increased cholesterol efflux capacity. Consequently, combination treatment largely reduced atherosclerotic lesion area compared to vehicle. Together, β3-AR agonism enhances the lipoprotein-modulating effects of alirocumab to further improve dyslipidemia and non-significantly further attenuate atherosclerosis development. Our findings demonstrate that brown fat activation may enhance the therapeutic effects of PCSK9 inhibition in dyslipidemia. Show less
Asprosin, coiled-coil domain-containing 80(CCDC80) and angiopoietin-like4(ANGPTL4) are newly discovered adipocytokine that affects glucose tolerance, insulin resistance and cardiovascular diseases. Th Show more
Asprosin, coiled-coil domain-containing 80(CCDC80) and angiopoietin-like4(ANGPTL4) are newly discovered adipocytokine that affects glucose tolerance, insulin resistance and cardiovascular diseases. The goal of this study was to investigate if a relationship exists among asprosin, CCDC80 and ANGPTL4 and inflammatory bowel disease (IBD). Fifty subjects with newly diagnosed IBD and fifty healthy individuals were enrolled. Patients were treated with standard therapies for 3 months. Plasma asprosin, CCDC80 and ANGPTL4 levels were measured with enzyme-linked immunosorbent assay. High resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperemia (flow-mediated dilation, FMD) and after sublingual glyceryltrinitrate.Compare with healthy individuals, plasma CCDC80,erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels and homeostasis modelassessment of insulin resistance (HOMA-IR) were significantly higher (p < 0.05, respectively), whereas plasma asprosin,ANGPTL4 levels and FMD were significantly lower inboth UC and CD patients(p <0.05). Plasma CCDC80 levels were significantly higher in patients with CD (p<0.05), while plasma asprosin and ANGPTL4 levels were lower (p<0.05) as compared with those in patients with UC. Standard therapies increased plasma asprosin, ANGPTL4 levels and FMD in both UC and CD (p<0.05),UC and CD patientswhile decreased plasma CCDC80, ESR, CRP levels and HOMA-IR (p<0.05). The changes in HOMA-IR and FMD were correlated with the changes in plasma asprosin, CCDC80 and ANGPTL4 levels over the study period (p<0.05). Plasma asprosin, CCDC80 and ANGPTL4 levels may be applied as a significant marker for early stage of insulin resistance and atherosclerosis in IBD, especially of CD. Show less
The biological functions of circular RNAs in liver tumorigenesis have been well demonstrated by a number of studies. Nevertheless, to the best of our knowledge, the role and mechanism of action of hsa Show more
The biological functions of circular RNAs in liver tumorigenesis have been well demonstrated by a number of studies. Nevertheless, to the best of our knowledge, the role and mechanism of action of hsa_circ₀₀₀₈₅₃₇ (circ₀₀₀₈₅₃₇₎ in liver cancer pathogenesis remain undetermined. In the present study, circ₀₀₀₈₅₃₇ expression was associated with the GLI3 gene and was markedly increased in liver cancer tissue specimens and cells. High expression levels of circ₀₀₀₈₅₃₇ exhibited a poor prognosis. In addition, circ₀₀₀₈₅₃₇ overexpression resulted in an increased proliferation, migration and invasion of liver cancer cells, whereas circ₀₀₀₈₅₃₇ knockdown exhibited opposite effects. circ₀₀₀₈₅₃₇ acted as a sponge of microRNA‑153‑3p (miR‑153‑3p), and a negative correlation was observed between circ₀₀₀₈₅₃₇ and miR‑153‑3p expression in liver cancer. Transfection with miR‑153‑3p further abolished the effects of circ₀₀₀₈₅₃₇ on the malignant behavior of liver cancer cells. Furthermore, circ₀₀₀₈₅₃₇ indirectly affected the expression levels of pro‑survival protein myeloid cell leukemia 1 (MCL1) and snail family zinc finger 1 (Snail1) via miR‑153‑3p in liver cancer cells. In conclusion, the data indicated that circ₀₀₀₈₅₃₇ facilitated liver carcinogenesis by indirectly regulating miR‑153‑3p and leading to the release of MCL1 and Snail1. Show less
Gastric cancer (GC) is one of the most common cancers, with most patients often succumbing to death as a result of tumor metastasis. Recent work has demonstrated that gastrin is closely associated wit Show more
Gastric cancer (GC) is one of the most common cancers, with most patients often succumbing to death as a result of tumor metastasis. Recent work has demonstrated that gastrin is closely associated with GC metastasis. However, the specific molecular mechanisms underlying this relationship remain to be unveiled. In this study, we assessed the impact of gastrin and the Wnt/β-catenin inhibitor XAV939 on the epithelial-mesenchymal transition (EMT) of the SGC-7901 and MKN45 GC cell lines, and we determined that gastrin-17 significantly decreased E-cadherin expression and upregulated the expression of Snail1 and N-cadherin in GC cells. In addition, gastrin 17 also significantly increased the expression of Wnt3α in a dose-dependent manner. Consistent with these results, gastrin-17 promoted GC cell invasion, proliferation, and migration in a dose-dependent fashion, and these effects were inhibited by XAV939. Together, these results indicated that gastrin-17 induced GC cell EMT, migration, and invasion via the Wnt/β-catenin signaling pathway, which suggests that this gastrin/Wnt/β-catenin signaling axis may represent a therapeutic target for the prevention of GC metastasis. Show less
The study aimed to investigate the roles of potassium voltage-gated channel subfamily D member 2 (KCND2) in lung adenocarcinoma (AD). RNA sequencing data from The Cancer Genome Atlas (TCGA) database s Show more
The study aimed to investigate the roles of potassium voltage-gated channel subfamily D member 2 (KCND2) in lung adenocarcinoma (AD). RNA sequencing data from The Cancer Genome Atlas (TCGA) database showed that the expression of KCND2 was elevated in lung AD samples compared to the normal samples, and its upregulation was significantly associated with the unfavorable clinic outcome of lung AD patients. Cell proliferation and transwell assays revealed that the growth, migration, and invasion of lung AD cells, which was crucial to cancer aggressiveness, were markedly inhibited after the depletion of KCND2. Importantly, we demonstrated that the depletion of KCND2 suppressed the biological behaviors of lung AD cells via restraining the expression of four tumor-related genes including PCNA, CDH2, SNAI1, and MMP2. Overall, KCND2 promotes the aggressiveness of lung AD and can be considered as a potential predictor of the prognosis of lung AD patients. Downregulation of KCND2 may contribute to the therapy of lung AD. Show less
The establishment of porcine pluripotent stem cells (piPSCs) is critical but remains challenging. All piPSCs are extremely sensitive to minor perturbations of culture conditions and signaling network. Show more
The establishment of porcine pluripotent stem cells (piPSCs) is critical but remains challenging. All piPSCs are extremely sensitive to minor perturbations of culture conditions and signaling network. Inhibitors, such as CHIR99021 and XAV939 targeting the WNT signaling pathway, have been added in a culture medium to modify the cell regulatory network. However, potential side effects of inhibitors could confine the pluripotency and practicability of piPSCs. This study aimed to investigate the roles of AXIN, one component of the WNT pathway in piPSCs. Here, porcine AXIN1 and AXIN2 genes were knocked-down or overexpressed. Digital RNA-seq was performed to explore the mechanism of cell proliferation and apoptosis. We found that (1) overexpression of the porcine AXIN2 gene significantly reduced survival and negatively impacted the pluripotency of piPSCs, and (2) knockdown of AXIN2, a negative effector of the WNT signaling pathway, enhanced the expression of genes involved in cell cycle but reduced the expression of genes related to cell differentiation, death, and apoptosis. Show less
Sleeve gastrectomy (SG) is the most widely used bariatric procedures globally, which could improve glucose and lipid metabolism dramatically. Circular RNAs (circRNAs) are being increasingly implicated Show more
Sleeve gastrectomy (SG) is the most widely used bariatric procedures globally, which could improve glucose and lipid metabolism dramatically. Circular RNAs (circRNAs) are being increasingly implicated in numerous pathophysiological processes. However, for diabetes mellitus (DM), the expression and function of circRNAs remain largely undetermined, in particular, whether circRNAs mediate the amelioration of DM observed after SG. Using a diabetic rat model, we subjected liver tissue from SG and sham-operated rats to RNA sequencing. Amongst the 103 differentially regulated circRNAs identified in diabetic rats after SG, we focused on circDOCK7, a highly expressed circRNA derived from the back-splicing of the DOCK7 gene. Silencing of circDOCK7 significantly inhibited cellular proliferation and induction of apoptosis in insulin-resistant rat hepatocytes. Further analysis indicated circDOCK7 harbored binding sites for miR-139-3p and regulated the expression of minichromosome maintenance 3 (MCM3) through sequestration of miR-139-3p. Our findings therefore demonstrate a novel regulatory pathway involving circDOCK7 that regulates cellular proliferation and apoptosis through increasing the expression of MCM3. Overall, our study establishes a list of specific circRNAs expressed in diabetic rat liver after SG including circDOCK7 which serve as potential biomarkers and treatment targets for DM patients. Show less
Danhong injection (DHI) is a Chinese medical injection applied to the clinical treatment of cardiovascular diseases that has anti-inflammatory, antiplatelet aggregation and antithrombotic effects. Thi Show more
Danhong injection (DHI) is a Chinese medical injection applied to the clinical treatment of cardiovascular diseases that has anti-inflammatory, antiplatelet aggregation and antithrombotic effects. This study aimed to explore the effects of DHI on dyslipidemia and cholesterol metabolism in high-fat diet-fed rats. Sprague Dawley (SD) rats were randomly divided into six groups: normal group (Normal); hyperlipidemia model group (Model); DHI-treated groups at doses of 1.0 mL/kg, 2.0 mL/kg, 4.0 mL/kg; and simvastatin positive control group (2.0 mg/kg). The hypolipidemic effects of DHI were evaluated by measuring serum lipid levels, hepatic function and oxidative stress, respectively. And pathological changes in liver tissues were determined using hematoxylin-eosin (H&E) and oil red O staining. Moreover, the mRNA and protein expression levels of cholesterol metabolism related genes were detected by real-time PCR (RT-PCR) and Western blot. Compared with the Model group, DHI treatment markedly decreased the liver index and improved the pathological morphology of liver tissues. DHI treatment dose-dependently decreased the levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), malondialdehyde (MDA), and free fatty acids (FFA) in serum or liver tissues (P < 0.01 or P < 0.05), and increased the high-density lipoprotein cholesterol (HDL-C) and tripeptide glutathione (GSH) (P < 0.01 or P < 0.05). The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were increased in the DHI-treated groups (P < 0.01 or P < 0.05), while the alanine transaminase (ALT) and aspartate transaminase (AST) were decreased (P < 0.01 or P < 0.05). Furthermore, the expression levels of LDL receptor (LDLR), cholesterol 7-α-hydroxylase (CYP7A1), liver X receptor α (LXRα), and peroxisome proliferator-activated receptor α (PPARα) were dose-dependently upregulated in the DHI-treated groups, whereas the expression of sterol regulatory element-binding protein-2 (SREBP-2) was downregulated. Our study demonstrated that DHI markedly ameliorated hyperlipidemia rats by regulating serum lipid levels, inhibiting hepatic lipid accumulation and steatosis, improving hepatic dysfunction, and reducing oxidative stress. The potential mechanism was also tentatively investigated and may be related to the promotion of bile acid synthesis via activation of the PPARα-LXRα-CYP7A1 pathway. Therefore, DHI could be regarded as a potential hypolipidemic drug for the treatment of hyperlipidemia. Show less
LINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, m Show more
LINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, middle cerebral artery occlusion/reperfusion (MACO/R) mice model and HT22 cell oxygen-glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of cerebral ischemia in vivo and in vitro and to detect the relevant mechanism. We found that LINGO-1 mRNA and protein were upregulated in mice and cell models. Down-regulation LINGO-1 improved the neurological symptoms and reduced pathological changes and the infarct size of the mice after MACO/R. In addition, LINGO-1 interference alleviated apoptosis and promoted cell proliferation in HT22 of OGD/R. Moreover, down-regulation of LINGO-1 proved to inhibit nuclear translocation of p-NF-κB and reduce the expression level of p-JAK2 and p-STAT3. In conclusion, our data suggest that shLINGO-1 attenuated ischemic injury by negatively regulating NF-KB and JAK2/STAT3 pathways, highlighting a novel therapeutic target for ischemic stroke. Show less
The objective was to perform a proof-of-principle study to evaluate the effects of methionine (Met) and arginine (Arg) supply on protein abundance of amino acid, insulin signaling, and glutathione met Show more
The objective was to perform a proof-of-principle study to evaluate the effects of methionine (Met) and arginine (Arg) supply on protein abundance of amino acid, insulin signaling, and glutathione metabolism-related proteins in subcutaneous adipose tissue (SAT) explants under ceramide (Ce) challenge. SAT from four lactating Holstein cows was incubated with one of the following media: ideal profile of amino acid as the control (IPAA; Lys:Met 2.9:1, Lys:Arg 2:1), increased Met (incMet; Lys:Met 2.5:1), increased Arg (incArg; Lys:Arg 1:1), or incMet plus incArg (Lys:Met 2.5:1 Lys:Arg 1:1) with or without 100 μM exogenous cell-permeable Ce ( Show less
Emerging evidence suggests the involvement of caudal-related homoeobox transcription factor 2 (CDX2) in tumorigenesis of various cancers. Although CDX2 functions in cancer invasion and metastasis, few Show more
Emerging evidence suggests the involvement of caudal-related homoeobox transcription factor 2 (CDX2) in tumorigenesis of various cancers. Although CDX2 functions in cancer invasion and metastasis, fewer studies focus on the role of CDX2 during the induction of epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC). Immunohistochemical analysis of CDX2 was performed. A series of in vitro and in vivo experiments were conducted to reveal the role of CDX2 in the invasion and metastasis of CRC. CDX2 was downregulated in CRC tissues and reduced CDX2 correlated with poor prognosis. Knockdown of CDX2 promoted colon cancer cell invasion in vitro and facilitated liver metastasis in vivo with inducing EMT phenotypes. Further investigation indicated that CDX2 retarded Akt and GSK-3β phosphorylation, and thereby diminished Snail expression, β-catenin stabilisation and nuclear translocation. The depletion of β-catenin neutralised the regulation of Slug and ZEB1 by CDX2 knockdown. Mechanistically, CDX2 antagonised PI3K/Akt activity in CRC by modulating PTEN expression. CDX2 directly bound to the promoter of PTEN and transactivated its expression. Our study first uncovered that CDX2 inhibits EMT and metastasis of CRC by regulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression. Show less
F-box and leucine-rich repeat protein 10 (FBXL10) has been reported to play a regulatory role in the initiation and development of breast cancer. Bioinformatics analyses revealed that FBXL10 may invol Show more
F-box and leucine-rich repeat protein 10 (FBXL10) has been reported to play a regulatory role in the initiation and development of breast cancer. Bioinformatics analyses revealed that FBXL10 may involve in the process of cytoskeleton organization. This research aimed to investigate the function of FBXL10 in epithelial-mesenchymal transition (EMT) and metastasis of breast cancer, and tried to reveal the molecular mechanism involved in this issue. Functional experiments in vitro revealed that FBXL10 promoted the migration and invasion of breast cancer cells through inhibiting E-cadherin expression and inducing EMT. Mechanical studies revealed that FBXL10 could specifically interact with SNAI1, but not Slug or ZEB1. And it promoted the transcriptional repression activity of SNAI1 on CDH1 in breast cancer cells. Furthermore, FBXL10 had a positive role for the deacetylation of SNAI1 by facilitating the interaction between SNAI1 and HDAC1, a dominating deacetylase of SNAI1. And the deacetylated SNAI1 showed a more suppressive ability to inhibit the transcription of E-cadherin. Moreover, mouse models were also conducted to confirm the effect of FBXL10 on the lung metastasis of breast cancer in vivo. Totally, our data revealed that FBXL10 served as a pro-metastatic factor in breast cancer via repressing the expression of E-cadherin and inducing EMT. It may provide a novel regulatory axis in the EMT of breast cancer. Show less