Receptor Interaction Pathway Research Articles

Comparative transcriptomic analysis of porcine peripheral blood reveals differentially expressed genes from the cytokine-cytokine receptor interaction pathway related to health status.

While some research has looked into the host genetic response in pigs challenged with specific viruses or bacteria, few studies have explored the expression changes of transcripts in the peripheral blood of sick pigs that may be infected with multiple pathogens on farms. In this study, the architecture of the peripheral blood transcriptome of 64 Duroc sired commercial pigs, including 18 healthy animals at entry to a growing facility (set as a control) and 23 pairs of samples from healthy and sick pen mates, was generated using RNA-Seq technology. In total, 246 differentially expressed genes were identified to be specific to the sick animals. Functional enrichment analysis for those genes revealed that the over-represented gene ontology terms for the biological processes category were exclusively immune activity related. The cytokine-cytokine receptor interaction pathway was significantly enriched. Nine functional genes from this pathway encoding members (as well as their receptors) of the interleukins, chemokines, tumor necrosis factors, colony stimulating factors, activins, and interferons exhibited significant transcriptional alteration in sick animals. Our results suggest a subset of novel marker genes that may be useful candidate genes in the evaluation and prediction of health status in pigs under commercial production conditions.

Bioinformatics method identifies potential biomarkers of dilated cardiomyopathy in a human induced pluripotent stem cell-derived cardiomyocyte model.

Dilated cardiomyopathy (DCM) is the most common type of cardiomyopathy that account for the majority of heart failure cases. The present study aimed to reveal the underlying molecular mechanisms of DCM and provide potential biomarkers for detection of this condition. The public dataset of GSE35108 was downloaded, and 4 normal induced pluripotent stem cell (iPSC)-derived cardiomyocytes (N samples) and 4 DCM iPSC-derived cardiomyocytes (DCM samples) were utilized. Raw data were preprocessed, followed by identification of differentially expressed genes (DEGs) between N and DCM samples. Crucial functions and pathway enrichment analysis of DEGs were investigated, and protein-protein interaction (PPI) network analysis was conducted. Furthermore, a module network was extracted from the PPI network, followed by enrichment analysis. A set of 363 DEGs were identified, including 253 upregulated and 110 downregulated genes. Several biological processes (BPs), such as blood vessel development and vasculature development (FLT1 and MMP2), cell adhesion (CDH1, ITGB6, COL6A3, COL6A1 and LAMC2) and extracellular matrix (ECM)-receptor interaction pathway (CDH1, ITGB6, COL6A3, COL6A1 and LAMC2), were significantly enriched by these DEGs. Among them, MMP2, CDH1 and FLT1 were hub nodes in the PPI network, while COL6A3, COL6A1, LAMC2 and ITGB6 were highlighted in module 3 network. In addition, PENK and APLNR were two crucial nodes in module 2, which were linked to each other. In conclusion, several potential biomarkers for DCM were identified, such as MMP2, FLT1, CDH1, ITGB6, COL6A3, COL6A1, LAMC2, PENK and APLNR. These genes may serve significant roles in DCM via involvement of various BPs, such as blood vessel and vasculature development and cell adhesion, and the ECM-receptor interaction pathway.

Protein microarray analysis identifies key cytokines associated with malignant middle cerebral artery infarction.

IntroductionWe aimed to explore potential cytokines involved in the malignant middle cerebral artery infarction (MMI) and elucidate their underlying regulatory mechanisms.MethodsWe first developed a cytokine profile by Quantibody® Human Cytokine Antibody Array7000 using serum samples from eight patients with MMI and eight patients with non‐acute cerebral infarction (NACI). The differentially expressed cytokines were then identified in patients with MMI using two‐tailed Student's t‐test and Fisher's Exact Test compared with patients with NACI. Gene Ontology and pathway enrichment analyses were performed using DAVID. Protein–protein interaction (PPI) network was constructed based on STRING database.ResultsA total of 10 differentially expressed cytokines were identified from 320 unique inflammatory cytokines in serums. Among them, four cytokines, like NCAM1 (neural cell adhesion molecule 1), IGFBP‐6 (insulin‐like growth factor binding protein 6), LYVE1 (lymphatic vessel endothelial hyaluronan receptor 1), and LCN2 (Lipocalin2), were up‐regulated, while another six cytokines, such as TGFB1 (transforming growth factor, beta 1, also known as LAP), EGF (epidermal growth factor), PDGFA (platelet‐derived growth factor alpha polypeptide), MMP‐10 (matrix metallopeptidase 10), IL‐27 (interleukin 27), and CCL2 (chemokine (C‐C motif) receptor 2), were down‐regulated. Moreover, cytokine–cytokine receptor interaction pathway was significantly enriched.ConclusionsOur findings indicate that 10 differentially expressed cytokines, such as NCAM1, LCN2, IGFBP‐6, LYVE1, MMP‐10, IL‐27, PDGFA, EGF, CCL2, and TGFB1 may participate in the development of MMI. Moreover, cytokine–cytokine receptor interaction pathway may be an important mechanism involved in this disease. These differentially expressed cytokines may serve as diagnostic biomarkers or drug targets for MMI.

Abstract 2454: Genetic landscape of glioma reveals defective neuroactive ligand receptor interaction pathway as a poor prognosticator in glioblastoma patients

Abstract Glioblastoma (GBM; grade IV), is highly proliferative, infiltrative and treatment refractory. Hence, understanding the complete genetic alteration profile of GBM would help us in identifying molecules or pathways that have strong implications in GBM pathogenesis, thus opening up avenues for targeted therapy. Recent large scale studies suggest that three pathways - receptor-tyrosine kinase, TP53 and RB, are significantly altered in GBM. However, even with the tremendous increase in our understanding of the tumor, advancement in therapeutics is minimal and the median survival still remains at 15 months. Hence, we need to elucidate novel altered molecules and pathways in GBM progression such that more effective therapeutic options can be explored. Here, we have carried out whole exome sequencing of grade II, grade III and GBM samples which revealed the mutation spectrum of glioma from our patient set. Further, we performed integrative analysis of mutated genes from our patient cohort as well as TCGA cohort (The Cancer Genome Atlas) to find out mutated pathways that predict survival in GBM patients. The most significant pathway - neuroactive ligand-receptor interaction pathway was explored further. Patients with mutations in one or more genes of this pathway had poor survival. The pathway comprises of G-protein coupled receptors, ion channels and ligands which functions in modulation of neural plasticity, memory processes, behavior etc. Of the enriched genes belonging to this pathway, Calcitonin Receptor (CALCR), which was highest mutated in GBM (2.75%), was taken up for further investigation. CALCR was found to be downregulated in GBM and mutation or downregulation of the gene was found to predict poor survival in patients. Functional studies through cell-line based experiments revealed CALCR is a tumor suppressor in GBM. The peptide hormone calcitonin (CT), a high affinity CALCR ligand, inhibited proliferation, migration and anchorage-independent growth of glioma cells expressing CALCR with a concomitant decrease in the phosphorylation levels of ERK, AKT and JNK signaling molecules. However, CT failed to do these functions in CALCR silenced glioma cells. Exogenous overexpression of CALCR in glioma cells expressing low levels of the receptor was found to inhibit proliferation, migration and anchorage independent growth and this effect was further augmented when CT was added. Further, introduction of tumor-derived mutations in CALCR led to the abrogation of its tumor suppressor function. Studies are ongoing to demonstrate the tumor suppressive nature of CALCR using in vitro astrocyte transformation and intracranial orthotopic mouse glioma model. Thus, our study finds CT-CALCR signaling axis is an important tumor suppressor pathway in glioma development and underscores the importance of using CT as a novel therapeutic molecule for GBM treatment. Citation Format: Jagriti Pal, Vikas Patil, Anupam Kumar, Kavneet Kaur, Chitra Sarkar, Kumaravel Somasundaram. Genetic landscape of glioma reveals defective neuroactive ligand receptor interaction pathway as a poor prognosticator in glioblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2454. doi:10.1158/1538-7445.AM2017-2454

Elucidation of Gene Expression Patterns in the Brain after Spinal Cord Injury

Spinal cord injury (SCI) is a devastating neurological disease. The pathophysiological mechanisms of SCI have been reported to be relevant to central nervous system injury such as brain injury. In this study, gene expression of the brain after SCI was elucidated using transcriptome analysis to characterize the temporal changes in global gene expression patterns in a SCI mouse model. Subjects were randomly classified into 3 groups: sham control, acute (3 h post-injury), and subacute (2 wk post-injury) groups. We sought to confirm the genes differentially expressed between post-injured groups and sham control group. Therefore, we performed transcriptome analysis to investigate the enriched pathways associated with pathophysiology of the brain after SCI using Database for Annotation Visualization, and Integrated Discovery (DAVID), which yielded Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Following enriched pathways were found in the brain: oxidative phosphorylation pathway; inflammatory response pathways—cytokine–cytokine receptor interaction and chemokine signaling pathway; and endoplasmic reticulum (ER) stress-related pathways—antigen processing and presentation and mitogen-activated protein kinase signaling pathway. Oxidative phosphorylation pathway was identified at acute phase, while inflammation response and ER stress-related pathways were identified at subacute phase. Since the following pathways—oxidative phosphorylation pathway, inflammatory response pathways, and ER stress-related pathways—have been well known in the SCI, we suggested a link between SCI and brain injury. These mechanisms provide valuable reference data for better understanding pathophysiological processes in the brain after SCI.

SGBS cells as a model of human adipocyte browning: A comprehensive comparative study with primary human white subcutaneous adipocytes

The Simpson Golabi Behmel Syndrome (SGBS) pre-adipocyte cell strain is widely considered to be a representative in vitro model of human white pre-adipocytes. A recent study suggested that SGBS adipocytes exhibit an unexpected transient brown phenotype. Here, we comprehensively examined key differences between SGBS adipocytes and primary human white subcutaneous (PHWSC) adipocytes. RNA-Seq analysis revealed that extracellular matrix (ECM)-receptor interaction and metabolic pathways were the top two KEGG pathways significantly enriched in SGBS adipocytes, which included positively enriched mitochondrial respiration and oxidation pathways. Compared to PHWSC adipocytes, SGBS adipocytes showed not only greater induction of adipogenic gene expression during differentiation but also increased levels of UCP1 mRNA and protein expression. Functionally, SGBS adipocytes displayed higher ISO-induced basal leak respiration and overall oxygen consumption rate, along with increased triglyceride accumulation and insulin-stimulated glucose uptake. In conclusion, we confirmed that SGBS adipocytes, which are considered of white adipose tissue origin can shift towards a brown/beige adipocyte phenotype. These differences indicate SGBS cells may help to identify mechanisms leading to browning, and inform our understanding for the use of SGBS vis-à-vis primary human subcutaneous adipocytes as a human white adipocyte model, guiding the selection of appropriate cell models in future metabolic research.

Predicting miRNA targets for head and neck squamous cell carcinoma using an ensemble method.

This study aimed to uncover potential microRNA (miRNA) targets in head and neck squamous cell carcinoma (HNSCC) using an ensemble method which combined 3 different methods: Pearson's correlation coefficient (PCC), Lasso and a causal inference method (i.e., intervention calculus when the directed acyclic graph (DAG) is absent [IDA]), based on Borda count election. The Borda count election method was used to integrate the top 100 predicted targets of each miRNA generated by individual methods. Afterwards, to validate the performance ability of our method, we checked the TarBase v6.0, miRecords v2013, miRWalk v2.0 and miRTarBase v4.5 databases to validate predictions for miRNAs. Pathway enrichment analysis of target genes in the top 1,000 miRNA-messenger RNA (mRNA) interactions was conducted to focus on significant KEGG pathways. Finally, we extracted target genes based on occurrence frequency ≥3. Based on an absolute value of PCC >0.7, we found 33 miRNAs and 288 mRNAs for further analysis. We extracted 10 target genes with predicted frequencies not less than 3. The target gene MYO5C possessed the highest frequency, which was predicted by 7 different miRNAs. Significantly, a total of 8 pathways were identified; the pathways of cytokine-cytokine receptor interaction and chemokine signaling pathway were the most significant. We successfully predicted target genes and pathways for HNSCC relying on miRNA expression data, mRNA expression profile, an ensemble method and pathway information. Our results may offer new information for the diagnosis and estimation of the prognosis of HNSCC.

Meta-analysis of genome-wide SNP- and pathway-based associations for facets of neuroticism

Neuroticism is a heritable personality trait that is comprised of distinct sub-factors, or facets. Sub-factors of neuroticism are linked to different emotional states or psychiatric symptoms and studying the genetic variants associated with these facets may help reveal the biological mechanisms underlying psychiatric disorders. In the present study, a meta-analysis of genome-wide association studies for six facets of neuroticism was performed in 5584 participants from three cohorts. Additionally, a Gene Set Enrichment Analysis was conducted to find biological pathways associated with each facet. Six neuroticism facets (N1: anxiety, N2: angry hostility, N3: depression, N4: self-consciousness, N5: impulsivity and N6: vulnerability) were assessed using the Korean version of the Revised NEO Personality Inventory. In the single-nucleotide polymorphism-based analysis, results showed genome-wide significance for N2 within the MIR548H3 gene (rs1360001, P=4.14 × 10−9). Notable genes with suggestive associations (P<1.0 × 10−6) were ITPR1 for N1, WNT7A for N2, FGF10 and FHIT for N3, DDR1 for N4, VGLL4 for N5 and PTPRD for N6. In the pathway-based analysis, the axon guidance pathway was identified to be associated with multiple facets of neuroticism (N2, N4 and N6). The focal adhesion and extracellular matrix receptor interaction pathways were significantly associated with N2 and N3. Our findings revealed genetic influences and biological pathways that are associated with facets of neuroticism.

GRIK3: A novel oncogenic protein related to tumor TNM stage, lymph node metastasis, and poor prognosis of GC.

Glutamate receptor, ionotropic, kainate 3 (GRIK3), as a member of the glutamate kainate receptor family, mainly participated in neuroactive ligand receptor interaction pathway. Other members of GRIK family were previously reported to regulate cellular migration, transformation, and proliferation in tumor. However, the mechanism of GRIK3 in tumor is still unclear. Therefore, the purpose of our study was to reveal the expression and clinical significance of GRIK3 in gastric cancer (GC). First, we performed the expression analysis and survival analysis of GRIK3 using The Cancer Genome Atlas (TCGA) database, and the results showed that the GRIK3 expressed differentially between gastric cancer tissues and the adjacent normal tissues and that higher expression of GRIK3 was associated with poor survival outcomes. And the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that GRIK3 mainly took part in cancer-related process. Subsequently, the validated immunohistochemistry showed that GRIK3 expressed higher in the GC tissues than in the matched normal tissues and the patients with overexpressed GRIK3 had worse survival outcomes. The univariate and multivariate analyses suggested that the expression of GRIK3 was an independent prognostic factor to predict GC prognosis. Furthermore, additional experiment showed that the lymph node metastasis tissues had higher GRIK3 expression than their matched primary GC tissues. These findings suggested that elevated GRIK3 expression could serve as an independent prognostic biomarker and a novel potential treatment target for patients with GC.

Abnormal expression of long non-coding RNAs in myocardial infarction.

Myocardial infarction (MI) is the leading cause of fatality worldwide. Our study aimed to investigate the dysregulated long non-coding RNA (lncRNA) in MI and elucidate the mechanism of it in MI. The lncRNA and mRNA expression profiling of the whole left ventricular tissue of MI mice model (8 mice) and Sham group (8 mice) was obtained based on microarray analysis. Differentially expressed lnRNAs/mRNA (DELs/DEMs) were identified in MI. DELs/DEMs co-expression network construction, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to predict the biological functions of DEMs. Quantitative real-time polymerase chain reaction (qRT-PCR) was subjected to validate the abnormally expressed DELs in left ventricular tissues of MI mice model. Total of 168 DELs (37 up- and 131 down-regulated) and 126 DEMs (87 up- and 39 down-regulated) were identified in MI compared with Sham group. The co-expression network of candidate DELs and DEMs was constructed, which covered 219 nodes and 1775 edges. The qRT-PCR validation results indicated that ENSMUST00000124047 was significantly down-regulated in MI group and AK166279 was significantly up-regulated in MI group. ENSMUST00000121611 and NR_015515 had the up-regulated tendency in MI group compared with Sham group. The DEMs in MI were significantly enriched in 41 signaling pathways including complement and coagulation cascades, cytokine-cytokine receptor interaction and chemokine signaling pathway. The expression profiling of dysregulated DELs in MI was identified. Our results might provide useful information for exploring the pathogenesis mechanism of MI.

Identification of aberrantly expressed long non-coding RNAs in stomach adenocarcinoma.

AimStomach adenocarcinoma (STAD) is a common malignancy worldwide. This study aimed to identify the aberrantly expressed long non-coding RNAs (lncRNAs) in STAD.ResultsTotal of 74 DElncRNAs and 449 DEmRNAs were identified in STAD compared with paired non-tumor tissues. The DElncRNA/DEmRNA co-expression network was constructed, which covered 519 nodes and 2993 edges. The qRT-PCR validation results of DElncRNAs were consistent with our bioinformatics analysis based on RNA-sequencing. The DEmRNAs co-expressed with DElncRNAs were significantly enriched in gastric acid secretion, complement and coagulation cascades, pancreatic secretion, cytokine-cytokine receptor interaction and Jak-STAT signaling pathway. The expression levels of the nine candidate DElncRNAs in TCGA database were compatible with our RNA-sequencing. FEZF1-AS1, HOTAIR and LINC01234 had the potential diagnosis value for STAD.Materials and MethodsThe lncRNA and mRNA expression profile of 3 STAD tissues and 3 matched adjacent non-tumor tissues was obtained through high-throughput RNA-sequencing. Differentially expressed lncRNAs/mRNAs (DElncRNAs/DEmRNAs) were identified in STAD. DElncRNA/DEmRNA co-expression network construction, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to predict the biological functions of DElncRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was subjected to validate the expression levels of DEmRNAs and DElncRNAs. Moreover, the expression of DElncRNAs was validated through The Cancer Genome Atlas (TCGA) database. The diagnosis value of candidate DElncRNAs was accessed by receiver operating characteristic (ROC) analysis.ConclusionsOur work might provide useful information for exploring the tumorigenesis mechanism of STAD and pave the road for identification of diagnostic biomarkers in STAD.

Identification of key genes associated with Schmid-type metaphyseal chondrodysplasia based on microarray data.

This study aimed to gain a better understanding of the molecular circuitry of Schmid-type metaphyseal chondrodysplasia (SMCD), and to identify more potential genes associated with the pathogenesis of SMCD. Microarray data from GSE72261 were downloaded from the NCBI GEO database, including collagen X p.Asn617Lys knock-in mutation (ColXN617K), ablated XBP1 activity (Xbp1CartΔEx2), compound mutant (C/X), and wild-type (WT) specimens. Differentially expressed genes (DEGs) were screened in Xbp1 vs. WT, Col vs. WT and CX vs. WT, respectively. Pathway enrichment analysis of these DEGs was performed. Transcription factors (TFs) of the overlapping DEGs were identified. Weighted correlation network analysis (WGCNA) was performed to find modules of DEGs with high correlations, followed by gene function analysis and a protein-protein interaction network construction. In total, 481, 1,530 and 1,214 DEGs were identified in Xbp1 vs. WT, Col vs. WT and CX vs. WT, respectively. These DEGs were enriched in different pathways, such as extracellular matrix (ECM)-receptor interaction and metabolism-related pathways. A total of 7 TFs were found to regulate 19 common upregulated genes, and 4 TFs were identified to regulate 21 common downregulated genes. Two significant gene co-expression modules were enriched and DEGs in the 2 modules were mainly enriched in different biological processes, such as ribosome biogenesis. Moreover, Kras (downregulated), Col5a1 (upregulated) and Furin (upregulated) were both identified in the regulatory networks and protein-protein interaction (PPI) network. On the whole, our findings indicate that the Kras, Col5a1 and Furin genes may play essential roles in the molecular mechanisms of SMCD, which warrants further investigation.

Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors.

Inhibitor of DNA binding (Id) proteins, including Id1-4, are transcriptional regulators involved in promoting cell proliferation and survival in various cell types. Although upregulation of Id proteins is associated with a broad spectrum of tumors, recent studies have identified that Id3 plays a tumor-suppressor role in the development of Burkitt's lymphoma in humans and hepatosplenic T cell lymphomas in mice. In this article, we report rapid lymphoma development in Id2/Id3 double-knockout mice that is caused by unchecked expansion of invariant NKT (iNKT) cells or a unique subset of innate-like CD1d-independent T cells. These populations began to expand in neonatal mice and, upon malignant transformation, resulted in mortality between 3 and 11 mo of age. The malignant cells also gave rise to lymphomas upon transfer to Rag-deficient and wild-type hosts, reaffirming their inherent tumorigenic potential. Microarray analysis revealed a significantly modified program in these neonatal iNKT cells that ultimately led to their malignant transformation. The lymphoma cells demonstrated chromosome instability along with upregulation of several signaling pathways, including the cytokine-cytokine receptor interaction pathway, which can promote their expansion and migration. Dysregulation of genes with reported driver mutations and the NF-κB pathway were found to be shared between Id2/Id3 double-knockout lymphomas and human NKT tumors. Our work identifies a distinct premalignant state and multiple tumorigenic pathways caused by loss of function of Id2 and Id3. Thus, conditional deletion of Id2 and Id3 in developing T cells establishes a unique animal model for iNKT and relevant innate-like lymphomas.

Bioinformatics analysis of gene expression alterations in microRNA‑122 knockout mice with hepatocellular carcinoma.

Reduced microRNA (miR)-122 expression levels are frequently observed in hepatocellular carcinoma (HCC). The present study was conducted to investigate potential targets of miR-122 and determine the underlying regulatory mechanisms of miR-122 in HCC development. The public dataset GSE31731 was utilized, consisting of 8 miR-122 knockout (KO) mice (miR-122 KO) and 8 age-matched wild-type mice (WT group). Following data preprocessing, the differentially expressed genes (DEGs) were selected, followed by enrichment analysis. A protein-protein interaction (PPI) network was established, and a module network was further extracted. Combining the DEGs with microRNA targeting databases permitted the screening of the overlapping targets of miR-122. Furthermore, previously reported genes were screened out by literature mining. Transcription factors (TFs) of the targets were subsequently investigated. DEGs between miR-122 KO and WT groups were selected, including 713 upregulated and 395 downregulated genes. Of these, upregulated genes were enriched in cell cycle-associated processes [including nucleolar and spindle associated protein 1 (NUSAP1)], the cytokine-cytokine receptor interaction pathway [including C-X-C motif chemokine receptor 4 (CXCR4) and C-C motif chemokine receptor 2 (CCR2)], and the extracellular matrix-receptor interaction pathway [including integrin subunit alpha V (ITGAV)]. In addition, multiple overlapping targets were highlighted in the PPI network, including NUSAP1, CXCR4, CCR2 and ITGAV. Notably, CXCR4 and CCR2 were linked in module C, enriched in the cytokine-cytokine receptor interaction pathway. Furthermore, upregulated sex determining region Y-box 4 (SOX4) was identified as a TF. The results of the present study may provide a theoretical basis for further studies on the mechanisms of miR-122 in the development of HCC.

Apigenin Modulation of Whole Transcriptome Patterns of TNFα ‐ Induced Changes in Triple Negative Breast Cancer Cells, MDA‐MB‐231

Mortality associated with breast cancer is primarily attributable to metastasis, of which TNFα plays a central orchestrating role. TNFα acts on the breast tumor TNF receptors evoking the release of chemotactic proteins (e.g. MCP‐1/CCL2). These proteins directs massive inward infiltration/migration of tumor‐associated macrophages (TAMs), tumor‐associated neutrophils (TANs), myeloid‐derived suppressor cells (MDSCs), T‐regulatory cells (Tregs), T helper IL‐17‐producing cells (Th17s), metastasis‐associated macrophages (MAMs) and cancer‐associated fibroblasts (CAFs). These tumor embedded infiltrates collectively enable immune evasion, tumor growth, angiogenesis, and metastasis. In the current study, we investigated the potential of apigenin, a known anti‐inflammatory constituent of parsley, to alter the transcriptome patterns in TNFα treated triple negative breast cancer cells (MDA‐MB‐231). Whole genome expression profiling was carried out on Agilent Human 4 × 44 k arrays. The findings show TNFα mediated upregulation and apigenin downregulation of transcription patterns for the following genes: LAMC2, TMEM132A, TNFAIIP2, ICAM1, TLR2, IL32, IL4l1, CTSS, NEURL3, GBP5, IDO1, C3, EB13, ANO09, C1QTNF1‐AS1, BMPER, TNFSF15, IL 24, LINC00996, TRA2A, MAP3K5, LRG1, NEDD4l and PDA15. Pathway analysis shows the primary pathway involved in the effects of TNF were in the cytokine‐cytokine receptor interaction pathway, with sub‐categorical targets within the family of chemokines, TNF family and TGF‐Beta families. These data provide a general transcriptome pattern changes influence by TNFα, and modulated by apigenin in human breast cancer cellsSupport or Funding InformationThis research was supported by the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant Number G12 MD007582 and Grant Number P20 MD006738.

The single and joint toxicity effects of chlorpyrifos and beta-cypermethrin in zebrafish (Danio rerio) early life stages

Water environment pollution caused by the widespread application of beta-cypermethrin (BCP) and chlorpyrifos (CPF) in agriculture has attracted extensive concern of the world. In this study, zebrafish was used as a model to investigate the individual and joint toxicity of BCP and CPF. In the acute toxicity test, 3 hpf embryos were exposed to various concentrations of CPF, BCP and their binary mixtures (MIX) for 96h. The results indicated that these two pesticides and mixtures induced malformation and death in larvae, and affected hatchability. These two pesticides in mixtures were verified to act together in a synergistic manner under experimental conditions. Oxidative stress assaying manifested that CPF, BCP and MIX altered CAT, SOD and GST activities and MDA content, resulting in oxidative damage in larvae. By pathology analysis, CPF (236μg/L), BCP (5.9μg/L) and MIX (236μg/L CPF+5.9μg/L BCP) were found to trigger liver lesions and promote apoptosis in tissues. The transcriptome sequencing suggested that ECM- receptor interaction, focal adhesion, cell cycle, DNA replication, phototransduction and adherens junction pathways were closely associated with the toxicity of these two pesticides.

Bioinformatic analysis of computational identified differentially expressed genes in tumor stoma of pregnancy‑associated breast cancer.

The present study aimed to screen the differentially expressed genes (DEGs) in tumor‑associated stroma of pregnancy‑associated breast cancer (PABC). By analyzing Affymetrix microarray data (GSE31192) from the Gene Expression Omnibus database, DEGs between tumor asso-ciated stromal cells and normal stromal cells in PABC were identified. Gene Ontology (GO) function and pathway enrichment analyses for the DEGs were then performed, followed by construction of a protein‑protein interaction (PPI) network. A total of 94 upregulated and 386 downregulated DEGs were identified between tumor associated stromal cells and normal stromal cells in patients with PABC. The upregulated DEGs were primarily enriched in the cytokine‑cytokine receptor interaction pathway and GO terms associated with the immune response, which included the DEGs of interleukin 18 (IL18) and cluster of differentiation 274 (CD274). The downregulated DEGs were primarily involved in GO terms associated with cell surface receptor linked signal transduction and pathways of focal adhesion and pathways in cancer. In the PPI network, nodes of jun proto‑oncogene (JUN), FBJ murine osteosarcoma viral oncogene homolog (FOS), V‑myc avian myelocytomatosis viral oncogene homolog (MYC), and alpha‑smooth muscle actin (ACTA2) had higher degrees. The hub genes of JUN, FOS, MYC and ACTA2, as well as the DEGs IL18 and CD274 that were associated with the immune response in GO terms may exert important functions in the molecular mechanisms of PABC. These genes may be used as new molecular targets in the treatment of this disease.

Aberrant Epicardial Adipose Tissue Extracellular Matrix Remodeling in Patients with Severe Ischemic Cardiomyopathy: Insight from Comparative Quantitative Proteomics

There is ample evidence indicating that epicardial adipose tissue (EAT) volume and thickness is positively associated with coronary artery disease (CAD). However, the exact pathological changes in the human EAT after myocardial ischemia remains largely unclear. In the current study, we applied a comparative quantitative proteomics to elucidate the altered biological processes in the EAT of ischemic cardiomyopathy (ICM) patients. A total of 1649 proteins were successfully quantified in our study, among which 165 proteins were significantly changed (ratio <0.8 or >1.2 fold and p < 0.05 in both repetitions) in EAT of ICM individuals. Gene ontology (GO) enrichment analysis revealed that cardiac structure and cellular metabolism were over-represented among these regulated proteins. The hypertrophic cardiomyopathy, adrenergic signaling in cardiomyocytes, extracellular matrix (ECM)-receptor interaction, phagosome, Glycolysis/Gluconeogenesis, and PPAR signaling pathway were highlighted by the KEGG PATHWAY analysis. More importantly, we found that the proteins responsible for extracellular matrix organization were dramatically increased in EAT of ICM patients. In addition, the picrosirius red (PSR) staining results showed that the collagen fiber content was prominently increased, which indicated the EAT of ICM individuals underwent extracellular matrix remodeling and ERK1/2 activation maybe responsible for these pathological changes partially.

Integrated Analysis of LncRNA-mRNA Co-Expression Profiles in Patients with Moyamoya Disease

Moyamoya disease (MMD) is an idiopathic disease associated with recurrent stroke. However, the pathogenesis of MMD remains unknown. Therefore, we performed long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in blood samples from MMD patients (N = 15) and healthy controls (N = 10). A total of 880 differentially expressed lncRNAs (3649 probes) and 2624 differentially expressed mRNAs (2880 probes) were obtained from the microarrays of MMD patients and healthy controls (P < 0.05; Fold Change >2.0). Gene ontology (GO) and pathway analyses showed that upregulated mRNAs were enriched for inflammatory response, Toll-like receptor signaling pathway, chemokine signaling pathway and mitogen-activated protein kinase (MAPK) signaling pathway among others, while the downregulated mRNAs were enriched for neurological system process, digestion, drug metabolism, retinol metabolism and others. Our results showed that the integrated analysis of lncRNA-mRNA co-expression networks were linked to inflammatory response, Toll-like signaling pathway, cytokine-cytokine receptor interaction and MAPK signaling pathway. These findings may elucidate the pathogenesis of MMD, and the differentially expressed genes could provide clues to find key components in the MMD pathway.

Genome-scale analysis identifies GJB2 and ERO1LB as prognosis markers in patients with pancreatic cancer.

Pancreatic cancer is a complex and heterogeneous disease with the etiology largely unknown. The deadly nature of pancreatic cancer, with an extremely low 5-year survival rate, renders urgent a better understanding of the molecular events underlying it. The aim of this study is to investigate the gene expression module of pancreatic adenocarcinoma and to identify differentially expressed genes (DEGs) with prognostic potentials. Transcriptome microarray data of five GEO datasets (GSE15471, GSE16515, GSE18670, GSE32676, GSE71989), including 117 primary tumor samples and 73 normal pancreatic tissue samples, were utilized to identify DEGs. The five sets of DEGs had an overlapping subset consisting of 98 genes (90 up-regulated and 8 down-regulated), which were probably common to pancreatic cancer. Gene ontology (GO) analysis of the 98 DEGs showed that cell cycle and cell adhesion were the major enriched processes, and extracellular matrix (ECM)-receptor interaction and p53 signaling pathway were the most enriched pathways according to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Elevated expression of gap junction protein beta 2 (GJB2) and reduced endoplasmic reticulum oxidoreductase 1-like beta (ERO1LB) expression were validated in an independent cohort. Kaplan-Meier survival analysis revealed that GJB2 and ERO1LB levels were significantly associated with the overall survival of pancreatic cancer patients. GJB2 and ERO1LB are implicated in pancreatic cancer progression and can be used to predict patient survival. Therapeutic strategies targeting GJB2 and facilitating ERO1LB expression may deserve evaluation to improve prognosis of pancreatic cancer patients.