👤 Jiaxin Lv

Agmatine, an endogenous biogenic amine, is considered to be a central neurotransmitter. And it plays an important role in mammal feeding behavior. However, there were few studies on the effect of agmatine on feeding behavior in fishes. Here, we investigated the impact of intracerebroventricular (ICV) injections of agmatine (1.25-20 nmol/fish) on food intake in mandarin fish (Siniperca chuatsi). At 1-h post-injection, food intake showed a significant decrease in agmatine-treated fishes compared with the saline treated. Furthermore, the food intake in agmatine treatment mostly did not differ from that in saline treatment at 4--24-h post-injection as well as the results of genes expression of neuropeptide Y (NPY), agouti-regulated peptide (AgRP), and anorexigenic melanocortin 4 receptor (MC4R). In accordance with the insulin level increasing in liver, the gene expression of insulin receptor substrate (IRS2) was significantly higher in agmatine treatment compared to saline treatment at 1-h post-injection. Thus, the anorexigenic effect of agmatine is likely to decrease NPY and AgRP expression levels and increase MC4R and IRS2 levels which was coupled with stimulation of insulin secretion. Although these initial findings are limited in dose, the data firstly provides evidence for the anorectic effects of agmatine in fish. Show less

Antipsychotic-induced metabolic disturbance (AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor (MC4R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4R in Chinese population by genotyping two SNPs (rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index (BMI), waist circumference (WC), glucose, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status (drug-naïve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-naïve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way. Show less

Caveolin-1 has been reported to play an important role in the pathogenesis of acute respiratory distress syndrome (ARDS). This study was designed to identify Caveolin-1-interacting proteins to reveal the molecular mechanisms of ARDS. Yeast two-hybrid screening was performed using Caveolin-1 as the bait, and Axin-1 was identified as a binding partner for Caveolin-1. Co-immunoprecipitation demonstrated that the binding domains were located in the N-terminal region (1-100 aa) of Caveolin-1 and the C-terminal region (710-797 aa) of Axin-1. Caveolin-1 gene knockout or Axin-1 knockdown significantly decreased the levels of TNF-α and IL-6 in the supernatants of alveolar type I (AT-I) epithelial cells treated with LPS. Disrupting the interaction between Caveolin-1 and Axin-1 using CRISPR/Cas9 technology led to a significant increase in TNF-α and IL-6 from AT-I cells, along with a significant reduction in β-catenin expression. In conclusion, Axin-1 functions as an adaptor of Caveolin-1 and affects the production of inflammatory cytokines in AT-I cells challenged with LPS via β-catenin-mediated negative regulation. Show less

Carbamoyl phosphate synthetase I (CPS1) deficiency (CPS1D), is a rare autosomal recessive disorder, characterized by life-threatening hyperammonemia. In this study, we presented the detailed clinical features and genetic analysis of two patients with neonatal-onset CPS1D carrying two compound heterozygous variants of c.1631C > T (p.T544M)/c.1981G > T (p.G661C), and c.2896G > T (p.E966X)/c622-3C > G in Show less

Hereditary multiple exostoses (HMEs) is an autosomal dominant skeletal disorder. Six probands of the 6 unrelated Han Chinese families were identified as having HME. These patients had exostoses at multiple sites and significantly affected joints malformation and movement. Hereditary multiple exostoses. To detect the genetic mechanism of HME in 6 unrelated Chinese families, whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were used after genomic DNA was isolated from peripheral blood leucocytes. Point mutations identified by these methods were verified by Sanger sequencing after PCR amplification. Six mutations in the EXT1 and EXT2 genes were identified, including a heterozygous deletion mutation from exon 2 to exon 8 (Family 1), a c.448C>T, p.(Gln150X) heterozygous nonsense mutation (Family 4), a c.1057-2A>T heterozygous splicing substitution (Family 5), and a c.1468dupC, p.(Leu490fs519X) (Family 6) heterozygous duplication mutation in the EXT1 gene in addition to a heterozygous deletion mutation from exon 2 to exon 3 (Family 2) and a c.1197C>G, p.(Tyr399X) heterozygous nonsense mutation (Family 3) in the EXT2 gene. Overall, we identified 5 novel mutations and 1 recurrent mutation in the EXT1 and EXT2 genes in 6 Chinese families with HME. Our findings expand the mutational spectrum of the EXT1 and EXT2 genes and are useful for genetic counseling and prenatal diagnosis. Show less

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are crucial regulators affecting the progression of human cancers. Recently, lncRNA downregulated in liver cancer stem cells (lnc-DILC) was identified to function as a tumor suppressor inhibiting the tumorigenesis and metastasis in liver cancer and colorectal cancer. However, to date, little is known about the functional roles of lnc-DILC in modulating malignant phenotypes of clear cell renal cell carcinoma (ccRCC) cells. lnc-DILC expression in human ccRCC tissues was detected by qRT-PCR. Overexpression and knockdown experiments were carried out to determine the effects of lnc-DILC on ccRCC cell proliferation, migration and invasion. To reveal the underlying mechanisms of lnc-DILC functions in ccRCC cells. RNA immunoprecipitation, RNA pull-down, in vivo ubiquitination, co-immunoprecipitation and western blot assays were performed. Here, we identified that lnc-DILC levels were dramatically downregulated in ccRCC tissues. Loss of lnc-DILC expression was correlated with larger tumor size, advanced tumor grade and lymph node metastasis, and also predicted worse prognosis in patients with ccRCC. Functionally, knockdown and overexpression experiments demonstrated that lnc-DILC inhibited cell proliferation, migration and invasion in ccRCC cells. Mechanistic investigation revealed that lnc-DILC bound to tumor suppressor PTEN and suppressed its degradation. lnc-DILC repressed the PTEN ubiquitination through blocking the interaction between PTEN and E3 ubiquitin ligase WWP2 and recruiting the deubiquitinase USP11 to PTEN. Moreover, we demonstrated that PTEN-AKT signaling was crucial for lnc-DILC-mediated suppressive effects. In summary, our research revealed a novel mechanism by which lnc-DILC regulates PTEN stability via WWP2 and USP11, and shed light on potential therapeutic strategies by the restoration of lnc-DILC expression in patients with ccRCC. Show less

Gastric cancer has become a serious disease in the past decade. It has the second highest mortality rate among the four most common cancer types, leading to ~700,000 mortalities annually. Previous studies have attempted to elucidate the underlying biological mechanisms of gastric cancer. The present study aimed to obtain useful biomarkers and to improve the understanding of gastric cancer mechanisms at the genetic level. The present study used bioinformatics analysis to identify 1,829 differentially expressed genes (DEGs) which were obtained from the GSE54129 dataset. Using protein‑protein interaction information from the Search Tool for the Retrieval of Interacting Genes database, disease modules were constructed for gastric cancer using Cytoscape software. In the Gene Ontology analysis of biology processes, upregulated genes were significantly enriched in 'extracellular matrix organization', 'cell adhesion' and 'inflammatory response', whereas downregulated DEGs were significantly enriched in 'xenobiotic metabolic process', 'oxidation‑reduction process' and 'steroid metabolic process'. During Kyoto Encyclopedia of Genes and Genomes analysis, upregulated DEGs were significantly enriched in 'extracellular matrix‑receptor interaction', 'focal adhesion' and 'PI3K‑Akt signaling pathway', whereas the downregulated DEGs were significantly enriched in 'chemical carcinogenesis', 'metabolism of xenobiotics by cytochrome P450' and 'peroxisome'. The present study additionally identified 10 hub genes from the DEGs: Tumor protein p53 (TP53), C‑X‑C motif chemokine ligand 8 (CXCL8), tetraspanin 4 (TSPAN4), lysophosphatidic acid receptor 2 (LPAR2), adenylate cyclase 3 (ADCY3), phosphoinositide‑3‑kinase regulatory subunit 1 (PIK3R1), neuromedin U (NMU), C‑X‑C motif chemokine ligand (CXCL12), fos proto‑oncogene, AP‑1 transcription factor subunit (FOS) and sphingosine‑1‑phosphate receptor 1 (S1PR1), which have high degrees with other DEGs. The survival analysis revealed that the high expression of ADCY3, LPAR2, S1PR1, TP53 and TSPAN4 was associated with a lower survival rate, whereas high expression of CXCL8, FOS, NMU and PIK3R1 was associated with a higher survival rate. No significant association was identified between CXCL12 and survival rate. Additionally, TSPAN1 and TSPAN8 appeared in the top 100 DEGs. Finally, it was observed that 4 hub genes were highly expressed in gastric cancer tissue compared with para‑carcinoma tissue in the 12 patients; the increased TSPAN4 was significant (>5‑fold). Tetraspanin family genes may be novel biomarkers of gastric cancer. The findings of the present study may improve the understanding of the molecular mechanisms underlying the development of gastric cancer. Show less

This study aims to explore the effects of miR-539 on osteoblast proliferation and differentiation and osteoclast apoptosis in a rat model of osteoporosis, and its mechanism involving the regulation of the AXIN1-mediated wingless-Int (Wnt) signaling pathway. A rat model of osteoporosis was successfully established by ovariectomy. With osteoblasts and osteoclasts of rats not receiving ovariectomy in the sham group as control, those of osteoporotic rats were treated with miR-539 inhibitor, miR-539 mimic, and AXIN1 shRNA. The expression of miR-53, AXIN1, the Wnt pathway related-genes, apoptosis related-genes, and osteogenic markers were measured by RT-qPCR and Western blot analysis, respectively. Alkaline phosphatase (ALP) activity in osteoblast and tartrate-resistant acid phosphatase (TRAP) activity in osteoclasts were determined after cell transfection. Osteoblast and osteoclast viability was assayed by CCK-8 assay. Cell cycle and apoptosis of osteoblasts and osteoclasts were detected by flow cytometry. Lastly, alizarin red S staining was used to detect mineralized nodules of osteoblasts. Firstly, we determined that miR-539 was down-regulated in osteoblast and osteoclast of osteoporotic rats and AXIN1 was negatively regulated by miR-539. Additionally, overexpression of miR-539 increased the expressions of β-catenin, LEF1, c-myc, cyclin D1, RUNX2, BGP, BMP-2 in osteoblast as well as β-catenin, RhoA, caspase-3, and Bcl-2 in osteoclasts. Finally, overexpression of miR-539 elevated ALP activity, proliferation, and mineralized nodules in osteoblast and osteoclast apoptosis, with reduced TRAP activity in osteoclasts. Our results demonstrate that miR-539 promotes osteoblast proliferation and differentiation as well as osteoclast apoptosis through the AXIN1-dependent Wnt signaling pathway in osteoporotic rats. Show less

Epigenetic modifiers have emerged as critical factors governing the biology of different cancers. Herein we show that FBXL10 (also called KDM2B or JHDM1B), an important member of Polycomb repressive complexes, is overexpressed in human diffuse large B-cell lymphoma (DLBCL) tissues and the derived cell lines. Knocking down FBXL10 by specific short hairpin RNAs in DLBCL cells inhibits cell proliferation and induces apoptosis in vitro. Moreover, FBXL10 depletion in DLBCL cells abrogates tumor growth in mouse xenograft models. Through the analysis of RNA sequencing, we find that one of the key derepressed genes by depletion of FBXL10 is DUSP6, encoding a phosphatase for ERK1/2. Mechanistically FBXL10 maintains the silencing of DUSP6 expression via recruitment of Polycomb group proteins and deposition of repressive histone modifications at the DUSP6 promoter. Consistently, FBXL10 is required for ERK1/2 phosphorylation in DLBCL cells. Furthermore, we show that ERK1/2 activation and the proliferation rate of FBXL10-depleted cells can be rescued by downregulation of DUSP6 expression. These findings indicate that FBXL10 may be a promising therapeutic target in DLBCL and establish a link of epigenetic regulators to kinase signaling pathways. Show less

B-cell translocation gene 3 (BTG3) has been identified as a candidate driver gene for various cancers, but its specific role in colorectal cancer (CRC) is poorly understood. We aimed to investigate the relationship between expression of BTG3 and clinicopathological features and prognosis, as well as to explore the effects and the role of a possible BTG3 molecular mechanism on aggressive colorectal cancer behavior. BTG3 expression was assessed by immunohistochemistry (IHC) on specimens from 140 patients with CRC. The association of BTG3 expression with clinicopathological features was examined. To confirm the biological role of BTG3 in CRC, two CRC cell lines expressing BTG3 were used and BTG3 expression was knocked down by shRNA. CCK-8, cell cycle, apoptosis, migration, and invasion assays were performed. The influence of BTG3 knockdown was further investigated by genomic microarray to uncover the potential molecular mechanisms underlying BTG3-mediated CRC development and progression. BTG3 was downregulated in colorectal cancer tissues and positively correlated with pathological classification (p = 0.037), depth of invasion (p = 0.016), distant metastasis (p = 0.024), TNM stage (p = 0.007), and overall survival (OS) and disease-free survival (DFS). BTG3 knockdown promoted cell proliferation, migration, invasion, relieved G2 arrest, and inhibited apoptosis in HCT116 and LoVo cells. A genomic microarray analysis showed that numerous tumor-associated signaling pathways and oncogenes were altered by BTG3 knockdown. At the mRNA level, nine genes referred to the extracellular-regulated kinase/mitogen-activated protein kinase pathway were differentially expressed. Western blotting revealed that BTG3 knockdown upregulated PAK2, RPS6KA5, YWHAB, and signal transducer and activator of transcription (STAT)3 protein levels, but downregulated RAP1A, DUSP6, and STAT1 protein expression, which was consistent with the genomic microarray data. BTG3 expression might contribute to CRC carcinogenesis. BTG3 knockdown might strengthen the aggressive colorectal cancer behavior. Show less

Acute myeloid leukemia can develop as myoblasts infiltrate into organs and tissues anywhere other than the bone marrow, which called extramedullary infiltration (EMI), indicating a poor prognosis. Circular RNAs (circRNAs) are a novel class of non-coding RNAs that feature covalently closed continuous loops, suggesting their potential as micro RNA (miRNA) "sponges" that can participate in biological processes and pathogenesis. However, investigations on circRNAs in EMI were conducted rarely. In this study, the overall alterations of circRNAs and their regulatory network between EMI and non-EMI AML were delineated. CircRNA and whole genome microarrays derived from EMI and non-EMI AML bone marrow mononuclear cells were carried out. Functional analysis was performed via Gene Ontology and KEGG test methods. The speculated functional roles of circRNAs were based on mRNAs and predicted miRNAs that played intermediate roles. Integrated bioinformatic analysis was conducted to further characterize the circRNA/miRNA/mRNA regulatory network and identify the functions of distinct circRNAs. The Cancer Genome Atlas (TCGA) data were acquired to evaluate the poor prognosis of distinct target genes of circRNAs. Reverse transcription-quantitative polymerase chain reaction was conducted to identify the expression of has_circRNA₀₀₀₄₅₂₀. Connectivity map (CMap) analysis was further performed to predict potential therapeutic agents for EMI. 253 circRNAs and 663 genes were upregulated and 259 circRNAs and 838 genes were downregulated in EMI compared to non-EMI AML samples. GO pathways were enriched in progress including cell adhesion (GO:0030155; GO:0007155), migration (GO:0016477; GO:0030334), signal transduction (GO:0009966; GO:0007165) and cell-cell communication. Overlapping circRNAs envolved in pathways related to regulate cell-cell crosstalk, 17 circRNAs were chosen based on their putative roles. 7 target genes of 17 circRNAs (LRRK1, PLXNB2, OLFML2A, LYPD5, APOL3, ZNF511, and ASB2) indicated a poor prognosis, while overexpression of PAPLN and NRXN3 indicated a better one based on data from TCGA. LY-294002, trichostatin A and SB-202190 were identified as therapeutic candidates for EMI by the CMap analysis. Taken together, this study reveals the overall alterations of circRNA and mRNA involved in EMI and suggests potential circRNAs may act as biomarkers and targets for early diagnosis and treatment of EMI. Show less

The ability of liver to respond to changes in nutrient availability is essential for the maintenance of metabolic homeostasis. Autophagy encompasses mechanisms of cell survival, including capturing, degrading, and recycling of intracellular proteins and organelles in lysosomes. During negative nutrient status, autophagy provides substrates to sustain cellular metabolism and hence, tissue function. Severe negative energy balance in dairy cows is associated with fatty liver. The aim of this study was to investigate the hepatic autophagy status in dairy cows with severe fatty liver and to determine associations with biomarkers of liver function and inflammation. Liver and blood samples were collected from multiparous cows diagnosed as clinically healthy (n = 15) or with severe fatty liver (n = 15) at 3 to 9 d in milk. Liver tissue was biopsied by needle puncture, and serum samples were collected on 3 consecutive days via jugular venipuncture. Concentrations of free fatty acids and β-hydroxybutyrate were greater in cows with severe fatty liver. Milk production, dry matter intake, and concentration of glucose were all lower in cows with severe fatty liver. Activities of serum aspartate aminotransferase, alanine aminotransferase, glutamate dehydrogenase, and γ-glutamyl transferase were all greater in cows with severe fatty liver. Serum concentrations of haptoglobin and serum amyloid A were also markedly greater in cows with severe fatty liver. The mRNA expression of autophagosome formation-related gene ULK1 was lower in the liver of dairy cows with severe fatty liver. However, the expression of other autophagosome formation-related genes, beclin 1 (BECN1), phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3), autophagy-related gene (ATG) 3, ATG5, and ATG12, did not differ. More important, ubiquitinated proteins, protein expression of sequestosome-1 (SQSTM1, also called p62), and microtubule-associated protein 1 light chain 3 (MAP1LC3, also called LC3)-II was greater in cows with severe fatty liver. Transmission electron microscopy revealed an increased number of autophagosomes in the liver of dairy cows with severe fatty liver. Taken together, these results indicate that excessive lipid infiltration of the liver impairs autophagic activity that may lead to cellular damage and inflammation. Show less

Metabolic syndrome (MetS), a cluster of metabolic disturbances that increase the risk for cardiovascular disease and diabetes, was because of genetic susceptibility and environmental risk factors. To identify the genetic variants associated with MetS and metabolic components, we conducted a genome-wide association study followed by replications in totally 12,720 participants from the north, north-eastern and eastern China. In combined analyses, independent of the top known signal at rs651821 on APOA5, we newly identified a secondary triglyceride-associated signal at rs180326 on BUD13 (P Show less

The objective of this study was to observe the infection of human cytomegalovirus (HCMV) to human umbilical vein endothelial cells, and its effect on the expression of single-stranded DNA-binding protein (SSBP1) and on lipid metabolism in endothelial cells. We screened the differential expression of mRNAs after HCMV infection by suppression subtractive hybridization and the expression levels of SSBP1 mRNA and protein after HCMV infection by real-time PCR and western blot. After verification of successful infection by indirect immunofluorescent staining and RT-PCR, we found a differential expression of lipid metabolism-related genes including LDLR, SCARB, CETP, HMGCR, ApoB and LPL induced by HCMV infection. The expression levels of SSBP1 mRNA and protein after HCMV infection were significantly down-regulated. Furthermore, we found that upregulation of SSBP1 inhibited the expression of atherosclerosis-associated LDLR, SCARB, HMGCR, CETP as well as the accumulation of lipids in the cells. The results showed that the inhibition of SSBP1 by HCMV infection promotes lipid accumulation in the cells. Show less

Genome-wide association studies have struggled to identify functional genes and variants underlying complex phenotypes. We recruited a multi-ethnic cohort of healthy volunteers (n = 91) and used their tissue to generate induced pluripotent stem cells (iPSCs) and hepatocyte-like cells (HLCs) for genome-wide mapping of expression quantitative trait loci (eQTLs) and allele-specific expression (ASE). We identified many eQTL genes (eGenes) not observed in the comparably sized Genotype-Tissue Expression project's human liver cohort (n = 96). Focusing on blood lipid-associated loci, we performed massively parallel reporter assays to screen candidate functional variants and used genome-edited stem cells, CRISPR interference, and mouse modeling to establish rs2277862-CPNE1, rs10889356-DOCK7, rs10889356-ANGPTL3, and rs10872142-FRK as functional SNP-gene sets. We demonstrated HLC eGenes CPNE1, VKORC1, UBE2L3, and ANGPTL3 and HLC ASE gene ACAA2 to be lipid-functional genes in mouse models. These findings endorse an iPSC-based experimental framework to discover functional variants and genes contributing to complex human traits. Show less

To develop a cost-effective molecular regulator to improve growth metabolism and immunity of animals, a recombinant plasmid co-expressing fatty acid desaturase (mFat-1) and pig insulin growth like factor 1 (IGF-1) genes was constructed by the 2 A self-cleavage technique. After entrapment within modified chitosan nanoparticles (chitosan modified with polyethyleneglycol-polyethylenimine, CPP), the recombinant plasmid was injected intramuscularly into mice. Compared with controls, co-expression of mFat-1 and IGF-1 significantly raised the level of serum IGF-1, and increased the liver and muscle docosa hexaenoic acid (DHA) content. Th and Tc cell levels were also elevated, as were expression levels of serum IL-4 and IL-6 genes. These results demonstrate that the immunity and metabolism of an animal can be effectively improved by co-expression of mFat-1 and IGF-1 genes in vivo, which may contribute to further development of novel immunomodulators with beneficial effects on growth metabolism and immunity. Show less

Liver X receptor (LXR), a member of the nuclear receptor superfamily, is known to induce the expression of SREBP-1c and ChREBP, two master regulators of hepatic lipogenesis. Histone deacyetylases (HDACs) have been shown to play critical roles in glucose and lipids metabolism. However, the exact role of HDAC5 in lipogenesis remains elusive. mRNA and protein levels of HDAC5 were analyzed by quantitative real-time PCR and Western blots in high-fat-diet-induced and leptin receptor deficiency-induced obese mice. HDAC5 was overexpressed or depleted in HepG2 cells, followed by analysis of cellular triglycerides contents. Quantitative real-time PCR was used to detect the expression levels of lipogenic genes. Luciferase reporter assay was used to determine the regulation of HDAC on the transcriptional activity of LXR. Co-immunoprecipitation experiment was used to determine the interaction between HDAC5 and LXR. We found that mRNA and protein expression levels of hepatic HDAC5 were reduced in high-fat-diet-induced and leptin receptor deficiency-induced obese mice. In vitro studies further demonstrated that knockdown of HDAC5 promoted cellular triglycerides accumulation, accompanied with up-regulation of lipogenic genes. At the molecular level, HDAC5 was shown to interact with LXR, thereby attenuating its transcriptional activity. Overall, our data suggest that hepatic HDAC5 is an important regulator of lipogenesis. Show less

Salvianolic acid A (SalA), one of the most efficacious polyphenol compounds extracted from Radix Salvia miltiorrhiza (Danshen), has been shown to possess many potential pharmacological activities. This study aimed to investigate whether SalA has hepatoprotective effects against high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and to further explore the mechanism underlying this process. SalA treatment significantly attenuated HFD-induced obesity and liver injury, and markedly decreased lipid accumulation in HFD-fed rat livers. Moreover, SalA treatment ameliorated HFD-induced hepatic inflammation and oxidative stress by decreasing hepatotoxic levels of cytokines, suppressing the overproduction of reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) and preventing the decreased expression of superoxide dismutase (SOD). Importantly, SalA reversed the HFD- or palmitic acid (PA)-induced activation of the NLRP3 inflammasome, the nuclear translocation of ChREBP and the up-regulation of FAS, and these effects were accompanied by TXNIP down-regulation. However, TXNIP siRNA treatment partially abrogated the above-mentioned effects of SalA in PA-treated HepG2 cells. Together, our results demonstrated, for the first time, that SalA protects against HFD-induced NAFLD by ameliorating hepatic lipid accumulation and inflammation, and these protective effects may partially due to regulation of the TXNIP/NLRP3 and TXNIP/ChREBP pathways. Show less

Perfluorooctane sulfonate (PFOS), one persistent organic pollutant, has been widely detected in the environment, wildlife and human. Currently few studies have documented the effects of chronic PFOS exposure on lipid metabolism, especially in aquatic organisms. The underlying mechanisms of hepatotoxicity induced by chronic PFOS exposure are still largely unknown. The present study defined the effects of chronic exposure to low level of PFOS on lipid metabolism using zebrafish as a model system. Our findings revealed a severe hepatic steatosis in the liver of males treated with 0.5μM PFOS as evidenced by hepatosomatic index, histological assessment and liver lipid profiles. Quantitative PCR assay further indicated that PFOS significantly increase the transcriptional expression of nuclear receptors (nr1h3, rara, rxrgb, nr1l2) and the genes associated with fatty acid oxidation (acox1, acadm, cpt1a). In addition, chronic PFOS exposure significantly decreased liver ATP content and serum level of VLDL/LDL lipoprotein in males. Taken together, these findings suggest that chronic PFOS exposure induces hepatic steatosis in zebrafish via disturbing lipid biosynthesis, fatty acid β-oxidation and excretion of VLDL/LDL lipoprotein, and also demonstrate the validity of using zebrafish as an alternative model for PFOS chronic toxicity screening. Show less

Mammalian milk is a key source of lipids, providing not only important calories but also essential fatty acids. Veterinary medicine and omics systems sciences intersection, termed as "veterinomics" here, has received little attention to date but stands to offer much promise for building bridges between human and animal health. We determined the changes in porcine mammary genes and proteomics expression associated with milk triacylglycerol (TAG) synthesis and secretion from late pregnancy to lactation. TAG content and fatty acid (FA) composition were determined in porcine colostrum (the 1st day of lactation) and milk (the 17th day of lactation). The mammary transcriptome for 70 genes and 13 proteins involved in TAG synthesis and secretion from six sows, each at d -17(late pregnancy), d 1(early lactation), and d 17 (peak lactation) relative to parturition were analyzed using quantitative real-time PCR and Western blot analyses. The TAG content and the concentrations of de novo synthesized FAs, saturated FAs, and monounsaturated FAs were higher in milk than in colostrum (p<0.05). Robust upregulation with high relative mRNA abundance was evident during lactation for genes associated with FA uptake (VLDLR, LPL, CD36), FA activation (ACSS2, ACSL3), and intracellar transport (FABP3), de novo FA synthesis (ACACA, FASN), FA elongation (ELOVL1), FA desaturation (SCD, FADS1), TAG synthesis (GPAM, AGPAT1, LPIN1, DGAT1), lipid droplet formation (BTN2A1, XDH, PLIN2), and transcription factors and nuclear receptors (SREBP1, SCAP, INSIG1/2). In conclusion, a wide variety of lipogenic genes and proteins regulate the channeling of FAs towards milk TAG synthesis and secretion in porcine mammary gland tissue. These findings inform future omics strategies to increase milk fat production and lipid profile and attest to the rise of both veterinomics and lipidomics in postgenomics life sciences. Show less

Previous studies suggested that dietary fatty acids could affect blood lipids by interacting with genetic variations in fatty acid desaturase 1 (FADS1). However, little is known about their direct effects on coronary artery disease (CAD). The aim of this study was to evaluate whether dietary n-3 long-chain polyunsaturated fatty acids (LCPUFAs)-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) could modulate the effect of FADS1 rs174547 polymorphism on CAD. FADS1 single-nucleotide polymorphisms rs174547 genotypes were measured in 440 CAD patients and 838 healthy controls. Dietary EPA and DHA intakes were assessed with a validated quantitative frequency food questionnaire. The association between FADS1 rs174547 and CAD was estimated using logistic regression under both dominant and additive genetic models. The interactions between rs174547 polymorphism and LCPUFAs were analyzed by using multiple logistic regression and the "genotype × n-3 LCPUFAs" interaction term was included into the model. We found that the minor T allele of FADS1 rs174547 increased CAD risk (OR = 1.36, 95%CIs 1.03-1.80), and observed significant interaction between rs174547 and dietary EPA intakes on CAD (P-interaction = 0.028). The T-allele was only associated with higher CAD risk among individuals with lower dietary EPA intakes, but not in those with higher EPA intakes. Similarly, significant interaction was also observed between rs174547 and dietary DHA intakes on CAD (P-interaction = 0.020). Dietary n-3 LCPUFA intakes could modulate the association between FADS1 rs174547 polymorphism and CAD. High dietary n-3 LCPUFA intakes could negate the unfavorable effect of genetic variation in FADS1 on CAD in middle-aged and elderly Chinese population. Show less

Both genetic predisposition and lifestyle factors are associated with the risk for obesity. Multiple obesity loci have been identified using genome-wide association studies mainly in European populations. The aims of this study were to examine the associations of these loci with obesity and gene×dietary behavior interactions among Chinese children and adolescents. Nineteen candidate SNPs were genotyped using Sequenom technology in the Chinese children (N=2977, 853 obese and 2124 controls, aged 7-17). Dietary behaviors were assessed using self-administered questionnaires. After adjusting for age, sex and multiple testing, MC4R rs17782313, SEC16B rs543874, MAP2K5 rs2241423 and KCTD15 rs11084753 were associated with obesity and obesity-related traits (all P<0.005), with odd ratios ranging from 1.22 to 2.15. Dose-response association was significant between genetic risk score, which was calculated by summing the risk alleles, and the risk of obesity (P<0.001). Multiplicative interaction was found between rs543874 and salt preference on obesity with an OR of 4.40 (95% CI, 1.12-17.30). Additive interactions with salt preference were found in rs17782313 and rs11084753. Our findings indicated that rs17782313, rs543874, rs2241423 and rs11084753 were associated with the risk for children obesity in China, and interaction of genetic variants with diet behaviors on obesity. Show less

MicroRNA-452 (miRNA-452) was overexpressed in docetaxel-resistant human breast cancer MCF-7 cells (MCF-7/DOC). However, its role in modulating the sensitivity of breast cancer cells to docetaxel (DOC) remains unclear. The aim of this study is to investigate the role of miRNA-452 in the sensitivity of breast cancer cells to DOC.Real-time quantitative PCR (RT-qPCR) were used to identify the differential expression of miRNA-452 between MCF-7/DOC and MCF-7 cells. MiRNA-452 mimic was transfected into MCF-7 cells and miRNA-452 inhibitor was transfected into MCF-7/DOC cells. The role of miRNA-452 in these transfected cells was evaluated using RT-qPCR, MTT assay, and flow cytometry assay. The relationship of miRNA-452 and its predictive target gene "anaphase-promoting complex 4" (APC4) was analyzed by RT-qPCR and Western blot.MiRNA-452 showed significantly higher expression (78.9-folds) in MCF-7/DOC cells compared to parental MCF-7 cells. The expression of miRNA-452 in the mimic transfected MCF-7 cells was upregulated 212.2-folds (P < 0.05) compared to its negative control (NC), and the half maximal inhibitory concentration (IC50) value of DOC (1.98 ± 0.15 μM) was significantly higher than that in its NC (0.85 ± 0.08 μM, P < 0.05) or blank control (1.01 ± 0.19 μM, P < 0.05). Furthermore, its apoptotic rate (6.3 ± 1.3 %) was distinctly decreased compared with that in its NC (23.8 ± 6.6 %, P < 0.05) or blank control (18.6 ± 4.7 %, P < 0.05). In contrast, the expression of miRNA-452 in the inhibitor-transfected MCF-7/DOC cells was downregulated 0.58-fold (P < 0.05) compared to its NC, the IC50 value of DOC (44.5 ± 3.2 μM) was significantly lower than that in its NC (107.3 ± 6.63 μM, P < 0.05) or blank control (102.22 ± 11.34 μM, P < 0.05), and the apoptotic rate (45.5 ± 10.8 %) was distinctly increased compared with its NC (9.9 ± 2.2 %, P < 0.05) and blank control (9.4 ± 2.5 %, P < 0.05). Further, there was an inverse association between miRNA-452 and APC4 expression in breast cancer cells in vitro.Dysregulation of miRNA-452 involved in the DOC resistance formation of breast cancer cells may be, in part, via targeting APC4. Show less

Previous studies suggested that apolipoprotein A5 (ApoA5) genetic polymorphisms (SNPs) may result in lipid metabolism disorders. Therefore, genetic polymorphisms in ApoA5 may be associated with the occurrence of osteonecrosis of femoral head (ONFH). We designed a case-control study including 223 patients of osteonecrosis and 201 age- and sex-matched control subjects to analyze the association between ApoA5 polymorphisms and susceptibility of steroid-induced ONFH. We utilized polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to genotype two SNPs (rs662799 and rs3135506) in ApoA5 gene. We found both rs662799 and rs3135506 were associated with the risk of ONFH in codominant, dominant, and recessive model, respectively. Haplotype analyses suggested that T-C haplotype was associated with decreased risk of ONFH, whereas the haplotype C-C was significantly associated with an increased risk of ONFH. Our study suggested that ApoA5 genetic polymorphisms were associated with susceptibility to ONFH in Chinese population. However, our results need further investigation with large sample size and various populations. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000₂₀₁₄₂₂₉. Show less

Although the association between the apolipoprotein A5 (APOA5) genetic variants and hypertriglyceridemia has been extensively studied, there have been few studies, particularly in children and adolescents, on the association between APOA5 genetic variants and obesity or non-high-density lipoprotein cholesterol (non-HDL-C) levels. The objective of this study was to examine whether APOA5 gene polymorphisms affect body mass index (BMI) or plasma non-HDL-C levels in Chinese child population. This was a case-control study. Single nucleotide polymorphisms (SNPs) were genotyped using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry for an association study in 569 obese or overweight and 194 healthy Chinese children and adolescents. Genotype distributions for all polymorphisms in both cohorts were in accordance with the Hardy-Weinberg distribution. The frequencies of the risk alleles in rs662799 and rs651821 SNPs in APOA5 gene were all increased in obese or overweight patients compared to the controls. After adjusted for age and sex, C carriers in rs662799 had a 1.496-fold [95% confidence interval (CI): 1.074-2.084, P = 0.017] higher risk for developing obesity or overweight than subjects with TT genotype, while C carriers in rs651821 had a 1.515-fold higher risk than subjects with TT genotype (95% CI: 1.088-2.100, P = 0.014). Triglyceride (TG) and non-HDL-C concentrations were significantly different among rs662799 variants and both were higher in carriers of minor allele than in noncarriers for TG (1.64 ± 0.96 vs. 1.33 ± 0.67 mmol/L) (P < 0.001), and for non-HDL-C (3.23 ± 0.92 vs. 3.02 ± 0.80 mmol/L) (P = 0.005), respectively. There was also a trend towards increased TG and non-high-density lipoprotein cholesterol levels for rs651821 C carriers (P < 0.001 and P = 0.002, respectively). Furthermore, to confirm the independence of the associations between APOA5 gene and TG or non-HDL-C levels, multiple linear regression analysis was performed and the relationships were not eliminated by adjustment for age, sex and BMI. These findings suggest the TG-raising genetic variants in the APOA5 gene may influence the susceptibility of the individual to obesity, which may also contribute to an increased risk of high non-HDL-C levels in Chinese obese children and adolescents. Show less

Poly(A)-binding protein-interacting protein 1 (Paip1) stimulates translational initiation by inducing the circularization of mRNA. However, the mechanisms underlying Paip1 regulation, particularly its protein stability, are still unclear. Here, we show that the E6AP carboxyl terminus (HECT)-type ubiquitin ligase WW domain-containing protein 2 (WWP2), a homolog of the HECT-type ubiquitin ligase WWP1, interacts with and targets Paip1 for ubiquitination and proteasomal degradation. Mapping of the region including the WW domain of WWP2 revealed the interaction between WWP2 and the PABP-binding motif 2 (PAM2) of Paip1. The two consecutive PXXY motifs in PAM2 are required for WWP2-mediated ubiquitination and degradation. Furthermore, ectopic expression of WWP2 decreases translational stimulatory activity with the degradation of Paip1. We therefore provide evidence that the stability of Paip1 can be regulated by ubiquitin-mediated degradation, thus highlighting the importance of WWP2 as a suppressor of translation. Show less

Recent researches have implicated that mutations in the neurexin-3 (NRXN3) gene on chromosome 14q24.3-q31.1 might play a role in addiction, autism, and obesity. In order to explore the association of NRXN3 polymorphisms with schizophrenia, we examined seven single nucleotide polymorphisms (SNPs) in NRXN3 spanning 1.33 Mb of this gene, in a Chinese Han sample of 1214 schizophrenic patients and 1517 healthy control subjects. Our results showed that three SNPs were associated with schizophrenia (rs7157669: A>C, p=0.006; rs724373: C>T, p=0.014; rs7154021: C>T, p=0.018). After being corrected for multiple tests, the association of rs7157669 remained significant but those for two others were modest. According to the linkage disequilibrium pattern, the 7 SNPs may construct 3 haplotype blocks. Several haplotypes were significantly associated with schizophrenia, constructed by rs11624704-rs7157669-rs724373 (AAC, p=0.003; ACT, p=0.007, both remained significant after permutation tests), rs7154021-rs7142344 (TT, p=0.024; CT, p=0.012), respectively. Among the patients, 326 ones at first onset have received 6-week monotherapy of risperidone. Further analyses showed that two SNPs were associated with percentage of bodyweight gain following a 6-week therapy of risperidone (rs11624704: p=0.03; rs7154021: p=0.008) and rs7154021 remained significant after permutation test. Our findings suggested that NRXN3 might represent a major susceptibility gene for schizophrenia and have a role in bodyweight gain related to therapy of risperidone in Chinese Han population. Show less

MESP2, HES7 and DUSP6 genes have been proved to be involved in the etiopathogenesis of congenital scoliosis (CS) in animal embryo studies, however, whether this association was detected in human CS patients also remains unknown. One hundred sporadic and non-syndromic CS patients and 100 age-matched normal controls were included in this study. Mutation screening of gene exons were performed by DNA sequencing. However, no mutation or new single nucleotide polymorphism was found in the exons of MESP2, HES7 and DUSP6 genes in CS patients and normal controls. MESP2, HES7 and DUSP6 genes may not be involved in the etiopathogenesis of sporadic and non-syndromic CS in Chinese Han population. Show less

Pregnancy-associated plasma protein-A (PAPP-A) has been involved in the atherosclerotic process through regulation of local expression of IGF-1 that mediates the activation of the phosphatidylinositol-3 (PI3-K) and Akt kinase (Akt) signaling cascades which lead to constitutive nitric oxide formation, with its attending vasodilator, antiplatelet and insulin-sensitizing actions. In addition, IGF-1 may decreased cholesterol efflux through reductions of expression in ABCA1 and SR-B1 by the PI3-K/Akt signaling pathway. In the current study, we examined whether PAPP-A was involved in LXRα regulation and in expression of ABCA1, ABCG1 or SR-B1 through the IGF-I-mediated signaling pathway (IGF/PI3-K/Akt). Results showed that PAPP-A significantly decreased expression of ABCA1, ABCG1 and SR-BI at both transcriptional and translational levels in a dose-dependent and time-dependent manner. Cellular cholesterol content was increased while cholesterol efflux was decreased by PAPP-A treatment. Moreover, LXRα which can regulate the expression of ABCA1, ABCG1 and SR-B1, was also down-regulated by PAPP-A treatment. LXRα-specific activation by LXRα agonist almost rescued the down-regulation of ABCA1, ABCG1 and SR-B1 expression by PAPP-A. In addition, PAPP-A can induce the IGF-1/PI3-K/Akt pathway in macrophages. Furthermore, our results indicate that the decreased levels observed in LXRα, ABCA1, ABCG1 and SR-B1 mRNA and protein levels upon treating cells with PAPP-A were strongly impaired with the PI3-K inhibitors or IGF-1R siRNA while the MAPK cascade inhibitor did not execute this effect, indicating that the process of ABCA1, ABCG1 and SR-BI degradation by PAPP-A involves the IGF-1/PI3-K/Akt pathway. In conclusion, PAPP-A may first down-regulate expression of LXRα through the IGF-1/PI3-K/Akt signaling pathway and then decrease expression of ABCA1, ABCG1, SR-B1 and cholesterol efflux in THP-1 macrophage-derived foam cells. Therefore, our study provided one of the mechanisms for understanding the critical effect of PAPP-A in pathogenesis of atherosclerosis. Show less