👤 Fenglei Gao

Dual activation of the glucagon-like peptide 1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor has potential as a novel strategy for treatment of diabesity. Here, we created a hybrid peptide which we named 19W, and show that it is more stable in presence of murine plasma than exendin-4 is. In vitro studies were performed to reveal that 19W could stimulate insulin secretion from INS-1 cells in a dose-dependent manner, just like the native peptide GIP and exendin-4 do. 19W effectively evoked dose-dependent cAMP production in cells targeting both GLP-1R and GIPR. In healthy C57BL/6J mice, the single administration of 19W significantly improved glucose tolerance. When administered in combination with sodium deoxycholate (SDC), its oral hypoglycemic activity was enhanced. Pharmacokinetics studies in Wistar rats revealed that 19W was absorbed following oral uptake, while SDC increased its bioavailability. A long-term (28 days) exposure study of twice-daily oral administration to high fat-fed (HFF) mice showed that 19W significantly reduced animal food intake, body weight, fasting blood glucose, total serum cholesterol (T-CHO), non-esterified free fatty acids (NEFA), and low-density lipoprotein cholesterol (LDL-C) levels. It also significantly improved glucose tolerance and the pancreatic β/α cell ratio, and decreased the area of liver fibrosis. These results clearly demonstrate the beneficial action of this novel oral GLP-1/GIP dual receptor agonist to reduce adiposity and hyperglycemia in diabetic mice and to ameliorate liver fibrosis associated with obesity. This dual-acting peptide can be considered a good candidate for novel oral therapy to treat obesity and diabetes. Show less

Dysregulation of metabolic regulatory hormones often occurs during the progress of obesity. Key regulatory hormone insulin-growth hormone (GH) balance has recently been proposed to maintain metabolism profiles. Time-restricted feeding (TRF) is an effective strategy against obesity without detailed research on pulsatile GH releasing patterns. TRF was performed in an over-eating melanocortin 4 receptor-knockout (MC4RKO) obese mouse model using normal food. Body weight and food intake were measured. Series of blood samples were collected for 6-h pulsatile GH profile, glucose tolerance test, and insulin tolerance test at 5, 8, and 9 weeks of TRF, respectively. Indirect calorimetric recordings were performed by the Phenomaster system at 6 weeks for 1 week, and body composition was measured by nuclear magnetic resonance spectroscopy (NMR). Substrate- and energy metabolism-related gene expressions were measured in terminal liver and subcutaneous white adipose tissues. TRF increased pulsatile GH secretion in dark phase and suppressed hyperinsulinemia in MC4RKO obese mice to reach a reduced insulin/GH ratio. This was accompanied by the improvement in insulin sensitivity, metabolic flexibility, glucose tolerance, and decreased glucose fluctuation, together with appropriate modification of gene expression involved in substrate metabolism and adipose tissue browning. NMR measurement showed that TRF decreased fat mass but increased lean mass. Indirect calorimeter recording indicated that TRF decreased the respiratory exchange ratio (RER) reflecting consumption of more fatty acid in energy production in light phase and increased the oxygen consumption during activities in dark phase. TRF effectively decreases hyperinsulinemia and restores pulsatile GH secretion in the overeating obese mice with significant improvement in substrate and energy metabolism and body composition without reducing total caloric intake. Show less

Berberine hydrochloride is the main effective component of Coptis spp. used in Chinese herbal medicine and its underlying molecular mechanisms, responsible for inducing effects in crustacean species, are not fully understood. In this study, the molecular response of the crab Charybdis japonica to berberine hydrochloride exposure was studied using transcriptome sequencing. The survival rate, gene expression and activities of several immune enzymes were measured after berberine hydrochloride treatments, with or without injection of the pathogenic bacterium Aeromonas hydrophila. A total of 962 differentially expressed genes (464 up-regulated and 498 down-regulated) were observed during exposure to 100 mg/L of berberine hydrochloride and in the control group after 48 h. Enrichment analysis revealed that these genes are involved in metabolism, cellular processes, signal transduction and immune functions, indicating that exposure to berberine hydrochloride activated the immune complement system. This bioactive compound simultaneously activated fibrinogen beta (FGB), fibrinogen alpha (FGA), alpha-2-macroglobulin (A2M), kininogen (KNG), fibrinogen gamma chain (FGB), alpha-2-HS-glycoprotein (AHSG), caspase-8 (CASP8), cathepsin L (CTSL), adenylate cyclase 3 (Adcy3) and MMP1. Its action could significantly increase the survival rate of the crabs injected with A. hydrophila and promote the activity of LZM, Caspas8, FGA, ACP and AKP in the hepatopancreas. When A. hydrophila was added, the neutralization of 300 mg/L berberine hydrochloride maximized the activities of Caspas8, LZM, ACP and AKP. Our results provide a new understanding of the potential effects of berberine hydrochloride on the immune system mechanisms in crustaceans. Show less

Pathological hypertrophic myocardium under consistent adverse stimuli eventually can cause heart failure. This study aims to explore the role of BACH2, a member of the basic region leucine zipper transcription factor family, in cardiac hypertrophy and failure. Transverse aortic constriction surgery was operated to induce cardiac hypertrophy and failure in mice. BACH2 was overexpressed in mice through tail vein injection of AAV9- Show less

The domestic goose is an important economic animal in agriculture and its beak, a trait with high heritability, plays an important role in promoting food intake and defending against attacks. In this study, we sequenced 772 420-day-old Xingguo gray geese (XGG) using a low-depth (~1 ×) whole-genome resequencing strategy. We detected 12,490,912 single nucleotide polymorphisms (SNPs) using the standard GATK and imputed with STITCH. We then performed a genome-wide association study on the beak length trait in XGG. The results indicated that 57 SNPs reached genome-wide significance levels for the beak length trait and were assigned to seven genes, including Show less

Lung adenocarcinoma (LUAD) is a common malignant tumor with a poor prognosis. Recent studies have found that angiopoietin-like 4 (ANGPTL4) is abnormally expressed in many tumors, so it can serve as a potential prognostic marker and therapeutic target. However, its prognostic value in LUAD remains unclear. We downloaded RNA sequence data for LUAD from The Cancer Genome Atlas (TCGA) database, methylation data from the University of California Santa Cruz genome database, and clinical information. R software (version 4.1.1) was applied to analyze the ANGPTL4 expression in LUAD and nontumor samples, and the correlation with clinical characteristics to assess its prognostic and diagnostic value. In addition, we analyzed the relationship between the ANGPTL4 expression and methylation levels. Tumor IMmune Estimation Resource (TIMER) tool was taken for immune infiltration analysis, and two Gene Expression Omnibus (GEO) datasets were combined for meta-analysis. Finally, differentially expressed genes (DEGs) related to ANGPTL4 were analyzed to clarify its function. As shown in our results, ANGPTL4 was upregulated in LUAD and was an independent risk factor for the diagnosis and prognosis of LUAD. The general methylation level and eight ANGPTL4 methylation sites were significantly negatively correlated with the ANGPTL4 expression. Furthermore, we found that B cell infiltration was negatively correlated with ANGPTL4 expression and was an independent risk factor. Meta-analysis showed that the high expression of ANGPTL4 was closely associated with a poor prognosis. 153 DEGs, including the matrix metalloproteinase family, the chemokines subfamily, and the collagen family, were correlated with ANGPTL4. In this study, we found that ANGPTL4 was significantly elevated in LUAD and was closely associated with the development and poor prognosis of LUAD, suggesting that ANGPTL4 may be a prognostic biomarker and a potential therapeutic target for LUAD. Show less

Hypoxia is a risk factor for non-alcoholic fatty liver diseases, leading to permanent imbalance of liver lipid homeostasis and steatohepatitis. However, a detailed understanding of the metabolic genes and pathways involved remains elusive. In vivo experiments were designed to analyze body weight and lipid metabolism changes of rats under hypoxia. After this, we combined microarray analysis and gene overexpression experiments to validate the core mechanisms involved in the response to hypoxia. The hypobaric hypoxia treated rats exhibited significantly increased serum triglycerides (TG) (p < 0.05), despite no significant changes in serum alanine aminotransferase (ALT) and blood glucose (BG) were observed. In addition, serum high-density lipoprotein cholesterol (HDL-C) greatly increased after 3 days and then returned to normal level at 30 days. Interestingly, serum low-density lipoprotein cholesterol (LDL-C) showed an opposite pattern. Transcriptome analysis, qRT-PCR, ICC revealed that the genes PPARA, ANGPTL4, CPT-I, ACC and LPL play a crucial role in response to hypobaric hypoxia. IPA pathway analysis further confirmed that PPARA-mediated regulation of ANGPTL4 participated in TG clearance and lipoprotein metabolism. Finally, the PPARA-ANGPTL4 pathway was validated in rats and HL 7702 cells treated with Fenofibrate, a PPARA specific agonist. Our study showed this pathway plays an important role on lipid metabolism caused by hypobaric hypoxia and the potential target genes associated with oxygen-dependent lipid homeostasis in the liver. Show less

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus. DN is the main cause of end-stage renal disease (ESRD). SIRT6 becomes the important target of DN. Diosgenin (a monomer from Chinese herbs) is probable to bind to SIRT6. Based on studies presented in the literature on kidney injuries plus screening for the binding effects of the drug to Sirt6, we aimed to carry out the study to assess the effects of diosgenin involved in improving podocyte damage in the early phase of DN.. DN model was established in spontaneous diabetic db/db mice. Animal experiment was in two parts. The first part includes four groups consisting of control (Con) group, model (Mod) group, low dose of diosgenin (DL) group and high dose of diosgenin (DH) group. The second part includes four groups consisting of control group, model group, DH+OSS₁₂₈₁₆₇ (OSS, inhibitor of SIRT6) group, MDL800 (agonist of SIRT6) group. MPC5 cell line was selected in cell experiment, which was mainly composed of six groups including Con group, palmitic acid (PA) group, PA+DL group, PA+DH group, PA+DH+OSS group, PA+MDL800 group. Some procedures such as transcriptomics, RT-qPCR and so on were used in the study to explore and verify the mechanism. The abnormal changes of mesangial matrix expansion, glomerular basement membrane (GBM) thickness, foot process (FP) width, urine albumin/creatinine (UACR), DESMIN, ADRP, NEPHRIN, PODOCIN, SIRT6 in Mod group were alleviated in DH group rather than DL group in the first part of animal experiment. The effect in DH group could be reversed in DH+OSS group and the same effect was observed in MDL800 group in the second part of animal experiment. The same results were also found in cell experiment. Protein level and mRNA expression of pyruvate dehydrogenase kinase 4 (PDK4) and Angiopoietin-like-4 (ANGPTL4) were increased in PA group, which could be alleviated in DH group, MDL800 group rather than DH+OSS group. Diosgenin could protect against podocyte injury in early phase of diabetic nephropathy by regulating SIRT6. Show less

Podocyte pyroptosis is an inflammatory form of cell death associated with Diabetic nephropathy (DN). It is reported that hyposialylated Angiopoietin-like-4 (Angptl4) secreted by glomerular podocytes plays an important role in the formation of proteinuria. Previous study indicated that supplementation of sialic acid precursor N-acetylmannosamine (ManNAc) could inhibit podocyte apoptosis and actin cytoskeleton rearrangement. Nevertheless, whether ManNAc could improve diabetic kidney damage by inhibiting podocyte pyroptosis remains unclear. This study aimed to explore the effect of ManNAc therapy on alleviating diabetic renal injury and podocyte pyroptosis, and its possible mechanism was also figured out. The male 8-week-old C57BL/6 mice were divided into three groups: control group, Streptozocin (STZ)-induced DN group, and ManNAc treated diabetic group. Then, the changes in renal function, renal histopathology, podocyte pyroptosis, reactive oxygen species (ROS), and mitochondrial dysfunction were measured. Herein, we observed that the upregulated expression of Angptl4 was involved in podocyte injury. ManNAc treatment ameliorated podocyte ultrastructure, renal function, and renal histopathology in STZ-induced DN mice. In addition, ManNAc administration attenuated podocyte cell death and suppressed the activation of Nucleotide leukin-rich polypeptide 3 (NLRP3), caspase-1, and interleukin-1β (IL-1β), and the cleavage of gasdermin-D (GSDMD). Moreover, ManNAc inhibited ROS production and restored mitochondrial morphology in vivo and vitro. Further, ManNAc administration significantly alleviated podocyte pyroptosis through inhibiting ROS/NLRP3 signaling pathway. Therefore, these results elucidated that the upregulated expression of Angptl4 was involved in podocyte injury and ManNAc treatment protected against podocyte pyroptosis via inhibiting mitochondrial injury and ROS/NLRP3 signaling pathway in DN mice. Show less

The molecular mechanism of in hyperlipidemia-induced renal injury has not been elucidated. Angiogenin-like protein 4 (ANGPTL4) is a key regulator of lipid metabolism. The role of ANGPTL4 hyperlipidemia-induced renal injury has not been reported. Wild type C57 mice and gene angptl4 knockout mice were fed with 60% high fat diet or normal diet respectively. The serum lipid, urinary albumin and renal pathology were tested at the 9th, 13th, 17th and 21st week with high fat diet. Elevated blood lipids in the wild-type mice with high-fat diet were found at 9th week. At the 17th week, the level of urinary albumin in high-fat fed wild type mice were significantly higher than which with normal diet, correspondingly, segmental fusion of podocyte foot process in kidney could be observed in these hyperlipidemia mice. IHC showed that the expression of ANGPTL4 in glomeruli of high-fat fed wild type mice began significant elevated since the 9th week. When given high fat diet, compared to the wild type, the gene angptl4 knockout mice showed significantly alleviated the levels of hyperlipidemia, proteinuria and effacement of podocyte foot process. Finally, the expression of ACTN4 showed remarkably lower in glomeruli podocyte of wild type mice fed high fat diet than that of wild type mice with normal diet at each time-point (P < 0.01). Differently, the expression of ACTN4 in gene angptl4 knockout mice did not happen significantly weaken when given the same dose of high fat diet. ANGPTL4 could play a role in hyperlipidemic-induced renal injury via down-regulating the expression of ACTN4 in kidney podocyte. 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 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

Hepatic steatosis and insulin resistance (IR) are risk factors for many metabolic syndromes such as NAFLD and T2DM. ApoA4 improves glucose hemostasis by increasing glucose-stimulated insulin secretion and glucose uptake via PI3K-Akt activation in adipocytes. However, whether ApoA4 has an effect on hepatic steatosis or IR remains unclear. ApoA4-knockout (KO) aggravates diet-induced obesity, hepatic steatosis, and IR in mice promoted by increased hepatic lipogenesis gene expression based on RNA-seq data. Conversely, liver-specific overexpression of ApoA4 via AAV-ApoA4 transduction reverses the effect in ApoA4-KO mice, accompanied by suppressed hepatic lipogenesis, increased lipolysis, and fatty acid oxidation. Short-term treatment with recombinant ApoA4 protein improves glucose clearance and liver insulin sensitivity, and reduces hepatic lipogenesis gene expression in the absence of insulin. Moreover, in primary hepatocytes and a hepatic cell line, ApoA4 improves hepatic glucose uptake via IRS-PI3K-Akt signaling and decreases fat deposition and hepatic lipogenesis gene expression by inhibiting SREBF1 activity. ApoA4 restricts hepatic steatosis by inhibiting SREBF1-mediated lipogenesis and improves insulin sensitivity and glucose uptake via IRS-PI3K-Akt signaling in the liver. These findings indicate that ApoA4 may serve as a therapeutic target for obesity-associated NAFLD. Show less

A new label-free method was developed for SERS detection of human apolipoprotein A4. Rolling circle amplification (RCA) was used, which could induce the production of AuNPs (poly adenine and adsorption gold nanoparticles). When there were two DNA labeled antibodies and target protein, MB1 (molecular beacon 1) was unfolded and the substrate was modified in the homogeneous solution, and the proximate complex was formed. The unfolded molecular beacon worked as a primer in the hybridization with the RCA template to start RCA, which could produce many long sequences of DNA containing amounts of adenines. The AuNPs were bound with the long-repeated adenine in the RCA product, causing accumulation of AuNPs on the surface of the electrode. It was indicated that the spectral characteristics of adenine at 736 cm Show less

ApoC3 plays a central role in the hydrolysis process of triglyceride (TG)-rich lipoproteins mediated by lipoprotein lipase (LPL), which levels are positively associated with the incidence of cardiovascular disease (CVD). Although targeting ApoC3 by antisense oligonucleotide (ASO), Volanesorsen markedly reduces plasma TG level and increase high-density lipoprotein cholesterol (HDL-C) in patients with hypertriglyceridemia (HTG), the cholesterol-lowering effect of ApoC3 inhibition and then the consequential outcome of atherosclerotic cardiovascular disease (ASCVD) have not been reported in patients of familial hypercholesterolemia (FH) with severe refractory hypercholesterolemia yet. To investigate the precise effects of depleting ApoC3 on refractory hypercholesterolemia and atherosclerosis, we crossed ApoC3-deficient hamsters with a background of LDLR deficiency to generate a double knockout (DKO) hamster model (LDLR On the standard laboratory diet, DKO hamsters had reduced levels of plasma TG and total cholesterol (TC) relative to LDLR In this study, our novel findings provide new insight into the application of ApoC3 inhibition for severe refractory hypercholesterolemia and ASCVD. Show less

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are prevalent diseases with similar pathophysiological characteristics and genetic predispositions. Polyunsaturated fatty acids (PUFAs) are essential in maintaining normal brain function. However, little is known about the effect of dietary n-6/n-3 PUFA ratio on AD-like pathology, particularly in high-fat diet (HFD)-fed AD model mice. In the present study, the APP/PS1 mice were fed with 60 % HFD for 3.5 months to induce insulin resistance. After that, 45 % HFD with various n-6/n-3 PUFA ratios (n-6/n-3 = 1:1, 5:1 or 16:1) was applied for an additional 3.5 months of treatment. The behavior of mice was observed using the water maze after dietary intervention. The animals were euthanized after behavioral testing, and serum and tissue samples were collected for biochemical, histological, and pathological tests and evaluation. HFD caused insulin resistance, increased serum IL-6 and TNF-α levels, cortical soluble Aβ Show less

Alzheimer's disease (AD) is a common neurodegenerative disease that often occurs in the elderly population. At present, most drugs for AD on the market are single-target drugs, which have achieved certain success in the treatment of AD. However, the efficacy and safety of single-target drugs have not achieved the expected results because AD is a multifactorial disease. Multi-targeted drugs act on multiple factors of the disease network to improve efficacy and reduce adverse reactions. Therefore, the search for effective dual-target or even multi-target drugs has become a new research trend. Many of results found that the dual-target inhibitors of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and acetylcholinesterase (AChE) found from traditional Chinese medicine have a good inhibitory effect on AD with fewer side effects. This article reviews sixty-six compounds extracted from Chinese medicinal herbs, which have inhibitory activity on BACE1 and AChE. This provides a theoretical basis for the further development of these compounds as dual-target inhibitors for the treatment of AD. Show less

Diabetic encephalopathy (DE), a chronic complication of diabetes, is characterized by decline of cognitive function. The molecular mechanism of DE remains unclear. The purpose of this study is to evaluate the roles of advanced glycation end products (AGEs) in the pathogenesis of DE and investigate its underlying mechanisms in this process. DE rats were developed by incorporating a high-fat diet and streptozotocin injection followed by the Morris Water Maze test. HT-22 cells were used to mimic the in vitro neuronal injuries of DE. Expression levels of long non-coding RNA H19, miR-15b and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) mRNA in the hippocampus of DE rats or HT-22 cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The levels of BACE1 proteins were analyzed by western blotting or immunohistochemical staining. The contents of Aβ We found that the accumulation of Aβ These results suggested that AGEs induced Aβ Show less

Alzheimer's disease (AD), as a progressive and irreversible brain disorder, remains the most universal neurodegenerative disease. No effective therapeutic methods are established yet due to the hindrance of the blood-brain barrier (BBB) and the complex pathological condition of AD.  Therefore, a multifunctional nanocarrier (Rapa@DAK/siRNA) for AD treatment is constructed to achieve small interfering RNA of β-site precursor protein (APP) cleaving enzyme-1 (BACE1 siRNA) and rapamycin co-delivery into the brain, based on Aleuria aurantia lectin (AAL) and β-amyploid (Aβ)-binding peptides (KLVFF) modified PEGylated dendrigraft poly-l-lysines (DGLs) via intranasal administration. Nasal administration provides an effective way to deliver drugs directly into the brain through the nose-to-brain pathway. AAL, specifically binding to L-fucose located in the olfactory epithelium, endows Rapa@DAK/siRNA with high brain entry efficiency through intranasal administration. KLVFF peptide as an Aβ targeting ligand and aggregation inhibitor enables nanoparticles to bind with Aβ, inhibit Aβ aggregation, and reduce toxicity. Meanwhile, the release of BACE1 siRNA and rapamycin is confirmed to reduce BACE1 expression, promote autophagy, and reduce Aβ deposition. Rapa@DAK/siRNA is verified to improve the cognition of transgenic AD mice after intranasal administration. Collectively, the multifunctional nanocarrier provides an effective and potential intranasal avenue for combination therapy of AD. Show less

Methamphetamine (Meth), a central nervous system (CNS) stimulant with strong neurotoxicity, causes progressive cognitive impairment with characterized neurodegenerative changes. However, the mechanism underlying Meth-induced pathological changes remains poorly understood. In the current study, Meth elicited a striking accumulation of the pathological proteins hyperphosphorylated tau (p-tau) and amyloid beta (A Show less

To evaluate the correlation of circulating C1q tumor necrosis factor-related protein 4 (CTRP4) with coronary artery disease (CAD) in type 2 diabetes mellitus patients. A total of 240 individuals with type 2 diabetes mellitus were enrolled in our center between January 2020 and December 2020. They were assigned into two groups, including the CAD and non-CAD groups, based on coronary angiography or computed tomography angiography findings. Serum CTRP4 levels were detected by an enzyme-linked immunosorbent assay kit. The association of CTRP4 with CAD was determined by logistic regression analysis. The predictive value of CTRP4 for CAD was calculated by receiver operating characteristic curve analysis. Median serum CTRP4 amounts were markedly elevated in the CAD group in comparison with the non-CAD group (10.37 vs 3.75 ng/mL, P < 0.01). Binary logistic regression showed that CTRP4 was associated with CAD and even the amount of coronary artery lesions (P < 0.05). In receiver operating characteristic curve analysis, the area under the receiver operating characteristic curve was greater for CTRP4 compared with HbA1c or CRP (0.87 vs 0.74, 0.87 vs 0.80, P < 0.01). The area under the curve for CTRP4 and glycated hemoglobin in combination was larger than that obtained for CTRP4 combined with CRP (0.91 vs 0.87, P < 0.01). According to the maximum Youden index criteria, the optimal cut-off of CTRP4 was 5.42 ng/mL, which yielded a sensitivity of 84.4% and a specificity of 76.7% in predicting CAD in type 2 diabetes mellitus patients. Serum CTRP4 levels are positively correlated with CAD occurrence and severity. Combining CTRP4 and glycated hemoglobin has a better predictive value for CAD in type 2 diabetes mellitus patients. Show less

Esophageal cancer (ESCA), one of the most aggressive malignant tumors, has been announced to be the ninth most common cancer and the sixth leading cause of cancer-related death in the world. Chromobox family members (CBXs) are important epigenetic regulators which are related with the transcription of target genes. The role of CBXs in carcinomas has been reported in many studies. However, the function and prognostic value of different CBXs in ESCA are still largely unknown. In this article, we first performed differential expression analysis through several methods including Oncomine and Gene Expression Profiling Interactive Analysis. The results led us to determine the differential expression of CBXs in pan-cancer, especially ESCA. Then we evaluated the prognostic value of different CBX messenger RNA (mRNA) expression in patients with ESCA through the Kaplan-Meier plotter and the Human Protein Atlas database. In addition, we used cBioPortal to explore all genetic alterations and mutations in the CBXs in ESCA. Simultaneously, the correlation between its expression and the level of immune infiltration of ESCA was visualized by TIMER. Finally, the biological function of CBXs in ESCA is obtained through Biological Enrichment Analysis including gene ontology and Kyoto Encyclopedia of Genes and Genomes. The expression levels of CBX3/4/5 and CBX8 in ESCA tissues increased significantly and the expression level of CBX7 decreased through differential expression analysis. Additionally, CBX1 is significantly related to the clinical cancer stage and disease-free survival of ESCA patients. The high mRNA expression of CBX4 is related to the short overall survival of patients with esophageal squamous cell carcinoma, and the high mRNA expression of CBX3/7/8 is related to the short overall survival of patients with esophageal adenocarcinoma, indicating that CBX1/3/4/7/8 may be a potential prognostic biomarker for the survival of ESCA patients. Besides, the expression of CBXs is significantly related to the infiltration of a variety of immune cells, including six types of CD4-positive T-lymphocytes, macrophages, neutrophils, bursindependentlymphocyte, CD8-positive T-lymphocytes cells and dendritic cells in ESCA. Moreover, we found that CBXs are mainly associated with the inhibition of cell cycle and apoptosis pathway. Further, enrichment analysis indicated that CBXs and correlated genes were enriched in mismatch repair, DNA replication, cancer pathways, and spliceosomes. Our research may provide new insights into the choice of prognosis biomarkers of the CBXs in ESCA. Show less

Obesity is a global epidemic elevating the risk of various metabolic disorders. As there is a lack of effective drugs to treat obesity, we combined bioinformatics and reverse network pharmacology in this study to identify effective herbs to treat obesity. We identified 1011 differentially expressed genes (DEGs) of adipose tissue after weight loss by analyzing five expression profiles (GSE103766, GSE35411, GSE112307, GSE43471, and GSE35710) from the Gene Expression Omnibus (GEO) database. We identified 27 hub genes from the protein-protein interaction (PPI) network by performing MCODE using the Search Tool for the Retrieval of Interacting Genes (STRING) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed that these hub genes have roles in the extracellular matrix-receptor interaction, cholesterol metabolism, PI3K-Akt signaling pathway, etc. Ten herbs (Aloe, Portulacae Herba, Mori Follum, Silybum Marianum, Phyllanthi Fructus, Pollen Typhae, Ginkgo Semen, Leonuri Herba, Eriobotryae Folium, and Litseae Fructus) targeting the nine hub genes (COL1A1, MMP2, MMP9, SPP1, DNMT3B, MMP7, CETP, COL1A2, and MUC1) using six ingredients were identified as the key herbs. Quercetin and (-)-epigallocatechin-3-gallate were determined to be the key ingredients. Lastly, Ingredients-Targets, Herbs-Ingredients-Targets, and Herbs-Taste-Meridian Tropism networks were constructed using Cytoscape to elucidate this complex relationship. This study could help identify promising therapeutic targets and drugs to treat obesity. Show less

Nuclear Factor I B (NFIB) has been reported to promote tumor growth, metastasis, and liver regeneration, but its mechanism in liver cancer is not fully elucidated. The present study aims to reveal the role of NFIB in hepatocellular carcinogenesis. In our study, we constructed hepatocyte-specific NFIB gene knockout mice with CRISPR/Cas9 technology (Nfib Show less

Dual-specificity phosphatase 6 (DUSP6) serves a specific and conserved function on the dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). We previously identified Dusp6 as a regenerative repressor during zebrafish heart regeneration, therefore we propose to investigate the role of this repressor in mammalian cardiac repair. Utilizing a rat strain harboring Dusp6 nonsense mutation, rat neutrophil-cardiomyocyte co-culture, bone marrow transplanted rats and neutrophil-specific Dusp6 knockout mice, we find that Dusp6 deficiency improves cardiac outcomes by predominantly attenuating neutrophil-mediated myocardial damage in acute inflammatory phase after myocardial infarction. Mechanistically, Dusp6 is transcriptionally activated by p38-C/EBPβ signaling and acts as an effector for maintaining p-p38 activity by down-regulating pERK and p38-targeting phosphatases DUSP1/DUSP16. Our findings provide robust animal models and novel insights for neutrophil-mediated cardiac damage and demonstrate the potential of DUSP6 as a therapeutic target for post-MI cardiac remodeling and other relevant inflammatory diseases. Show less

Exploration of lead compounds against Parkinson's disease (PD), a neurodegenerative disease, is of great important. Dioscin, a bioactive natural product, shows various pharmacological effects. However, the activities and mechanisms of dioscin against PD have not been well investigated. In this study, the tests on 6-hydroxydopamine (6-OHDA)-induced PC12 cells and rats were carried out. The results showed that dioscin dramatically improved cell viability, decreased reactive oxygen species (ROS) levels, improved motor behavior and tyrosine hydroxylase(TH) levels and restored the levels of glutathione (GSH) and malondialdehyde (MDA) in rats. Mechanism investigation showed that dioscin not only markedly increased the expression level of dual- specificity phosphatase 6 (DUSP6) by 1.87-fold in cells and 2.56-fold in rats, and decreased phospho-extracellular regulated protein kinases (p-ERK) level by 2.12-fold in cells and 2.34-fold in rats, but also increased the levels of nuclear factor erythroid2-related factor 2 (Nrf2), hemeoxygenase-1 (HO-1), superoxide dismutase (SOD) and decreased the levels of kelch-1ike ECH-associated protein l (Keap1) in vitro and in vivo. Furthermore, DUSP6 siRNA transfection experiment in PC12 cells validated the protective effects of dioscin against PD via regulating DUSP6 to adjust the Keap1/Nrf2 pathway. Our data supported that dioscin has protection against PD in regulating oxidative stress via DUSP6 signal, which should be considered as an efficient candidate for the treatment of PD in the future. Show less

MicroRNAs (miRNAs) are a group of regulatory noncoding RNAs, serving as major regulators with a sequence-specific manner in multifarious biological processes. Although a series of viral families have been proved to encode miRNAs, few reports were available regarding the function of ALV-J-encoded miRNA. Here, we reported a novel miRNA (designated ALV-miRNA-p19-01) in ALV-J-infected DF-1 cells. We found that ALV-miRNA-p19-01 is encoded by the genome of the ALV-J SCAU1903 strain (located at nucleotides site 779 to 801) in a classic miRNA biogenesis manner. The transfection of DF-1 cells with ALV-miRNA-p19-01 enhanced ALV-J replication, while the blockage of ALV-miRNA-p19-01 suppressed ALV-J replication. Furthermore, our data showed that ALV-miRNA-p19-01 promotes ALV-J replication by directly targeting the cellular gene dual specificity phosphatase 6 through regulating ERK2 activity. Show less

Airway epithelial cell (AEC) dysfunction has been proven to be involved in the pathogenesis of asthma, which may be induced by the use of dexamethasone (Dex). The altered expression of microRNAs (miRNAs/miRs) has been found in asthma. However, the detailed mechanisms responsible for the effects of miR‑375 on Dex‑induced AEC dysfunction remain elusive. Thus, the present study aimed to elucidate these mechanisms. Following treatment with Dex for 0, 6, 12 and 24 h, AEC viability, migration, invasion and apoptosis were examined using Cell Counting Kit‑8 (CCK‑8), wound healing and Transwell assays, and flow cytometry, respectively. The expression levels of miR‑375, dual specificity phosphatase 6 (DUSP6) and apoptosis‑related proteins (Bcl‑2, Bax, cleaved caspase‑3) were measured using reverse transcription‑quantitative polymerase chain reaction and western blot analysis. The target genes and potential binding sites of miR‑375 and DUSP6 were predicted using TargetScan and confirmed using dual‑luciferase reporter assay. The viability, migration, invasion and apoptosis of Dex‑treated AECs were further assessed with or without miR‑375 and DUSP6. In the AECs (9HTE cells), Dex treatment suppressed cell viability and miR‑375 expression, whereas it promoted cell apoptosis and the expression of DUSP6, the target gene of miR‑375. The overexpression of miR‑375 reversed the effects of Dex treatment on miR‑375 expression, cell viability, migration and invasion, and apoptosis‑related protein expression; in turn, these effects were reversed by the overexpression of DUSP6, with the exception of miR‑375 expression. On the whole, the present study demonstrates that the overexpression of miR‑375 counteracts the effects of Dex treatment on AEC viability, migration, invasion and apoptosis by targeting DUSP6. Thus, it was suggested that the downregulated expression of miR‑375 may be a therapeutic target for AEC dysfunction. Show less

Several studies have found that pathological imbalance of alterative splicing (AS) events is associated with cancer susceptibility. carcinogenicity. Nevertheless, the relationship between heritable variation in AS events and carcinogenicity has not been extensively explored. Here, we downloaded AS event signatures, transcriptome profiles, and matched clinical information from The Cancer Genome Atlas (TCGA) database, identified the prognostic AS-related events Show less