scholarly journals Monocyte transcriptomes from patients with axial spondyloarthritis reveal dysregulated monocytopoiesis and a distinct inflammatory imprint

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Fabian Karow ◽  
Biljana Smiljanovic ◽  
Joachim R. Grün ◽  
Denis Poddubnyy ◽  
Fabian Proft ◽  
...  
Keyword(s):  
Disease Activity ◽  
Blood Cells ◽  
Axial Spondyloarthritis ◽  
Inflammatory Responses ◽  
Binding Protein ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Fatty Acid Binding ◽  
Gut Inflammation ◽  
Activated Monocytes

Abstract Background In patients with axial spondyloarthritis (axSpA), monocytes show a pre-activated phenotype. Gut inflammation is a trigger of monocyte activation and may also affect their development in the bone marrow (BM). As gut inflammation is commonly observed in axSpA patients, we performed a detailed analysis of monocyte transcriptomes of axSpA patients in two cohorts and searched for signs of activation and developmental adaptations as putative imprints of gut inflammation. Methods Transcriptomes of blood CD14+ monocytes of HLA-B27+ axSpA patients and healthy controls (HC) were generated by microarrays from cohort 1 and by RNA-sequencing from cohort 2. Differentially expressed genes from both analyses were subjected to gene set enrichment analysis (GSEA) and to co-expression analysis in reference transcriptomes from BM cells, blood cells and activated monocytes. As serological markers of translocation, 1,3 beta-glycan, intestinal fatty acid binding protein, and lipopolysaccharide binding protein (LBP) were determined by LAL and ELISA. Results Transcriptome analysis identified axSpA-specific monocyte signatures showing an imprint of LPS/cytokine-activated monocytes, late granulopoietic BM cells, blood neutrophils, and G-CSF-mobilized blood cells, which suggests LPS/TNF activation and more prominent BM adaptation promoting a neutrophil-like phenotype. GSEA mapped axSpA upregulated genes to inflammatory responses and TNFα signaling and downregulated probe-sets to metabolic pathways. Among translocation markers, LBP levels were significantly increased in axSpA patients vs. HC (p < 0.001). Stratified analysis by disease activity and stage identified an “active disease signature” (BASDAI ≥ 4) with an imprint of LPS/cytokine-activated monocytes and CD16+ monocyte subsets. The “AS signature” (vs. non-radiographic axSpA) showed a reinforced neutrophil-like phenotype due to deprivation of dendritic cell transcripts. Conclusions The neutrophil-like phenotype of axSpA monocytes points towards a biased monocytopoiesis from granulocyte-monocyte progenitors. This shift in monocytopoiesis and the LPS/cytokine imprint as well as the elevated LBP levels are indicators of systemic inflammation, which may result from bacterial translocation. The BM adaptation is most prominent in AS patients while disease activity appears to be linked to activation and trafficking of monocytes.

scholarly journals Identification of long noncoding RNAs reveals the effects of dinotefuran on the brain in Apis mellifera (Hymenopptera: Apidae)

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Minjie Huang ◽  
Jie Dong ◽  
Haikun Guo ◽  
Minghui Xiao ◽  
Deqian Wang
Keyword(s):  
Immune Response ◽  
Honey Bee ◽  
Honey Bees ◽  
Transforming Growth Factor ◽  
Sublethal Effects ◽  
Inflammatory Responses ◽  
Noncoding Rnas ◽  
Enrichment Analysis ◽  
Long Noncoding Rnas ◽  
Gene Set Enrichment Analysis

Abstract Background Dinotefuran (CAS No. 165252–70-0), a neonicotinoid insecticide, has been used to protect various crops against invertebrate pests and has been associated with numerous negative sublethal effects on honey bees. Long noncoding RNAs (lncRNAs) play important roles in mediating various biological and pathological processes, involving transcriptional and gene regulation. The effects of dinotefuran on lncRNA expression and lncRNA function in the honey bee brain are still obscure. Results Through RNA sequencing, a comprehensive analysis of lncRNAs and mRNAs was performed following exposure to 0.01 mg/L dinotefuran for 1, 5, and 10 d. In total, 312 lncRNAs and 1341 mRNAs, 347 lncRNAs and 1458 mRNAs, and 345 lncRNAs and 1155 mRNAs were found to be differentially expressed (DE) on days 1, 5 and 10, respectively. Gene set enrichment analysis (GSEA) indicated that the dinotefuran-treated group showed enrichment in carbohydrate and protein metabolism and immune-inflammatory responses such as glycine, serine and threonine metabolism, pentose and glucuronate interconversion, and Hippo and transforming growth factor-β (TGF-β) signaling pathways. Moreover, the DE lncRNA TCONS_00086519 was shown by fluorescence in situ hybridization (FISH) to be distributed mainly in the cytoplasm, suggesting that it may serve as a competing endogenous RNA and a regulatory factor in the immune response to dinotefuran. Conclusion This study characterized the expression profile of lncRNAs upon exposure to neonicotinoid insecticides in young adult honey bees and provided a framework for further study of the role of lncRNAs in honey bee growth and the immune response.

scholarly journals Electrospun Scaffold Micro-Architecture Induces an Activated Transcriptional Phenotype within Tendon Fibroblasts

2022 ◽  
Vol 9 ◽  
Author(s):  
Mathew J. Baldwin ◽  
Jolet Y. Mimpen ◽  
Adam P. Cribbs ◽  
Edward Stace ◽  
Martin Philpott ◽  
...  
Keyword(s):  
Rotator Cuff ◽  
Inflammatory Responses ◽  
Large Diameter ◽  
Transcriptional Response ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Type Iii Collagen ◽  
Tissue Remodelling ◽  
Cellular Replication ◽  
Cellular Phenotypes

Biomaterial augmentation of surgically repaired rotator cuff tendon tears aims to improve the high failure rates (∼40%) of traditional repairs. Biomaterials that can alter cellular phenotypes through the provision of microscale topographical cues are now under development. We aimed to systematically evaluate the effect of topographic architecture on the cellular phenotype of fibroblasts from healthy and diseased tendons. Electrospun polydioxanone scaffolds with fiber diameters ranging from 300 to 4000 nm, in either a highly aligned or random configuration, were produced. Healthy tendon fibroblasts cultured for 7 days on scaffolds with highly aligned fibers demonstrated a distinctive elongated morphology, whilst those cultured on randomly configured fibers demonstrated a flattened and spread morphology. The effect of scaffold micro-architecture on the transcriptome of both healthy and diseased tendon fibroblasts was assessed with bulk RNA-seq. Both healthy (n = 3) and diseased tendon cells (n = 3) demonstrated a similar transcriptional response to architectural variants. Gene set enrichment analysis revealed that large diameter (≥2000 nm) aligned scaffolds induced an upregulation of genes involved in cellular replication and a downregulation of genes defining inflammatory responses and cell adhesion. Similarly, PDPN and CD248, markers of inflammatory or “activated” fibroblasts, were downregulated during culture of both healthy and diseased fibroblasts on aligned scaffolds with large (≥2000 nm) fiber diameters. In conclusion scaffold architectures resembling that of disordered type III collagen, typically present during the earlier phases of wound healing, resulted in tendon fibroblast activation. Conversely, scaffolds mimicking aligned diameter collagen I fibrils, present during tissue remodelling, did not activate tendon derived fibroblasts. This has implications for the design of scaffolds used during rotator cuff repair augmentation.

scholarly journals Expression Profile and Prognostic Value of CXCR Family Members in Head and Neck Squamous Cell Carcinoma

2021 ◽  
Author(s):  
Yiming Shen ◽  
Chongchang Zhou ◽  
Yujie Cao ◽  
Qun Li ◽  
Hongxia Deng ◽  
...  
Keyword(s):  
Head And Neck ◽  
Expression Profile ◽  
Prognostic Value ◽  
Inflammatory Responses ◽  
Receptor Gene ◽  
Family Members ◽  
Enrichment Analysis ◽  
Progression Free Survival ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas

Abstract Background: CXC chemokine receptor gene family consists of seven well-established members which are broadly involved in biological functions of various cancers. Currently, limited studies have shed light on the expression profile of CXCR family members (CXCRs), as well as their prognostic value, in head and neck squamous cells carcinoma (HNSCC). Methods: The data for this study were retrieved from the Cancer Genome Atlas database and other publicly available databases, including gene expression, methylation profiles, clinical information, immunological features and prognoses. The expression pattern and prognostic values of CXCRs were identified, and the potential mechanism underlying CXCRs function in HNSCC was investigated by gene set enrichment analysis (GSEA). Results: CXCRs were differentially expressed in HNSCC. As shown by Kaplan Meier analysis, high CXCR3-6 expression was significantly associated with better prognostic outcomes of HNSCC patients, including overall survival and progression-free survival. According to the results of univariate and multivariate Cox proportional risk regression analysis, it was demonstrated that upregulation of CXCR3-6 was an independent factor for better prognosis, while the two other clinical features, age and stage, were factors for worse prognosis. A significant positive correlation between CXCR3-6 and tumor-infiltrated immune cells was revealed by results from Tumor Immune Estimation Resource and CIBERSORT analysis database. The main involvement of CXCRs in immune and inflammatory responses was further confirmed by GSEA. Conclusions: Overall, this study provided a rationale for targeting CXCRs as a promising therapeutic strategy of HNSCC.

Gene Expression Profiling of Age-Related Epstein-Barr Virus (EBV)-Associated B-Cell Lymphoproliferative Disorder Uncovers Alterations in Immune and Inflammatory Genes: Possible Implications for Pathogenesis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3448-3448
Author(s):  
Harumi Kato ◽  
Kazuhito Yamamoto ◽  
Kennosuke Karube ◽  
Miyuki Katayama ◽  
Shinobu Tsuzuki ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Enrichment Score ◽  
P Value ◽  
Toll Like Receptor ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Age Related ◽  
Gene Sets

Abstract Abstract 3448 Age-related EBV-associated B-cell lymphoproliferative disorder (AR-EBLPD) is classified as a subtype of diffuse large cell lymphoma (DLBCL) according to the WHO classification. However, molecular genetic characterization of AR-EBLPD remains largely unknown. We studied expression profiles of 5 AR-EBLPD and 8 EB-negative DLBCL samples using the Agilent 44K human oligonucleotide microarray. Total RNA was extracted from fresh-frozen tumor samples. Each microarray slide was converted into datasets using the Agilent Micro Array Scanner and Feature extractions. Data was standardized with Z-scores. Differences in mRNA expression levels between two sample groups were calculated using a two-sided t-test. A total of 1973 probes showed a p-value less than 0.05 with less than a 25% false discovery rate (FDR). These probes included 1688 genes. The number of probes showing high expression in AR-EBLPD and EB-negative DLBCL was 804 (693 genes) and 1169 (995 genes), respectively. First, we selected the top 300 differentially expressed genes. Genes highly expressed in AR-EBLPD included IL6, TNFAIP3, HOPX, and SLAMF1. IL6 is known as a gene encoding a cytokine which functions in inflammation and the maturation of B lymphocytes, and TNFAIP3 is known as a negative regulatory gene of the NF-kB pathway. HOPX and SLAMF1 are reported as genes related to lymphocyte function or the immune system (Schwartzberg et al. Nature immunology 2009, Hawiger et al. Nature immunology 2011). For better characterization, we next performed Gene Ontology Analysis using the WEB-based GEne SeT AnaLysis Toolkit and found that categories of external stimulus and inflammatory responses were enriched in AR-EBLPD. The Kyoto Encyclopedia of Genes and Genomes (KEGG)-signaling analyses showed that pathways of the NOD-like receptor (p-value =1.30e-06), JAK-STAT (p-value =9.01e-06), and Toll-like receptor (p-value =0.0002) were characteristic of AR-EBLPD. These results implied that inflammation would be prominent in AR-EBLPD cases. For validation, we next performed Gene Set Enrichment Analysis (GSEA) using all the database of KEGG pathways (186 gene sets). Dominant gene sets in AR-EBLPD included the cytokine-cytokine receptor interaction [Normalized Enrichment Score (NES) =2.66, p-value<0.001], NOD-like receptor pathway (NES =2.26, p-value<0.001), TOLL-like receptor pathway (NES =2.14, p-value<0.001), and JAK-STAT pathway (NES =1.79, p-value<0.001). Since all the pathways were related to the NF-kB pathway, inflammatory responses were suggested to activate the NF-kB pathway or vice versa. For confirmation, we finally performed GSEA using gene sets of the NF-kB pathway, which were obtained from a gene set reported by an NIH group (Puente et al. Nature 2011) and 30 gene sets in the GSEA database, and found that the gene sets of the NF-kB pathway were enriched in AR-EBLPD (Figure 1). Our results suggested that the inflammatory and immune-related genes were enriched in AR-EBLPD and that activation of the genes may be associated with NF-kB activation. Aberrant immune and inflammatory responses could define the clinical presentations of AR-EBLPD cases. (Figure 1) Gene Set Enrichment Analysis of 5 AR-EBLPD and 8 EB-negative DLBCL samples. The NF-kB signature reported from an NIH group (Puente et al. Nature 2011) was enriched in AR-EBLPD [Normalized Enrichment Score (NES) =2.20, p-value<0.001]. Disclosures: No relevant conflicts of interest to declare.

Genome-wide methylation profiles in coronary artery ectasia

2017 ◽  
Vol 131 (7) ◽  
pp. 583-594 ◽  
Author(s):  
Tzu-Pin Lu ◽  
Nai-Chen Chuang ◽  
Chin-Yu Cheng ◽  
Cheng-An Hsu ◽  
Yi-Chih Wang ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Coronary Arteries ◽  
Inflammatory Responses ◽  
Functional Characterization ◽  
Enrichment Analysis ◽  
Systematic Investigation ◽  
Gene Set Enrichment Analysis ◽  
Coronary Artery Ectasia ◽  
Protein Levels ◽  
Genome Wide

Coronary artery ectasia (CAE) is a disease characterized by abnormally dilated coronary arteries. The mechanism of CAE remains unclear, and its treatment is limited. Previous studies have shown that risk factors for CAE were related to changes in DNA methylation. However, no systematic investigation of methylation profiles has been performed. Therefore, we compared methylation profiles between 12 CAE patients and 12 propensity-matched individuals with normal coronary arteries using microarrays. Wilcoxon's rank sum tests revealed 89 genes with significantly different methylation levels (P<0.05 and Δβ > |0.1|). Functional characterization using the DAVID database and gene set enrichment analysis indicated that these genes were involved in immune and inflammatory responses. Of these genes 6 were validated in 29 CAE patients and 87 matched individuals with CAE, using pyro-sequencing. TLR6 and NOTCH4 showed significant differences in methylation between the two groups, and lower protein levels of toll-like receptor 6 (TLR6) were detected in CAE patients. In conclusion, this genome-wide analysis of methylation profiles in CAE patients showed that significant changes in both methylation and expression of TLR6 deserve further study to elucidate their roles in CAE.

scholarly journals Comprehensive Analysis to Identify Key Genes Involved in Advanced Atherosclerosis

2021 ◽  
Vol 2021 ◽  
pp. 1-25
Author(s):  
Tian-ming Huo ◽  
Zhi-wei Wang
Keyword(s):  
Gene Expression ◽  
Network Analysis ◽  
Lupus Erythematosus ◽  
Inflammatory Responses ◽  
Therapeutic Targets ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Hub Genes ◽  
Key Genes

Background. The study was aimed at finding accurate and effective therapeutic targets and deepening our understanding of the mechanisms of advanced atherosclerosis (AA). Methods. We downloaded the gene expression datasets GSE28829, GSE120521, and GSE43292 from Gene Expression Omnibus. Weighted gene coexpression network analysis (WGCNA) was performed for GSE28829, and functional enrichment analysis and protein–protein interaction network analysis were conducted on the key module. Significant genes in the key module were analyzed by molecular complex detection, and genes in the most important subnetwork were defined as hub genes. Multiple dataset analyses for hub genes were conducted. Genes that overlapped between hub genes and differentially expressed genes (DEGs) of GSE28829 and GSE120521 were defined as key genes. Further validation for key genes was performed using GSE28829 and GSE43292. Gene set enrichment analysis (GSEA) was applied to key genes. Results. A total of 77 significant genes in the key module of GSE28829 were screened out that were mainly associated with inflammation and immunity. The subnetwork was obtained from significant genes, and 18 genes in this module were defined as hub genes, which were related to immunity and expressed in multiple diseases, particularly systemic lupus erythematosus. Some hub genes were regulated by SPI1 and associated with the blood, spleen, and lung. After overlapping with DEGs of GSE28829 and GSE120521, a total of 10 genes (HCK, ITGAM, CTSS, TYROBP, LAPTM5, FCER1G, ITGB2, NCF2, AIF1, and CD86) were identified as key genes. All key genes were validated and evaluated successfully and were related to immune response pathways. Conclusion. Our study suggests that the key genes related to immune and inflammatory responses are involved in the development of AA. This may deepen our understanding of the mechanisms of and provide valuable therapeutic targets for AA.

scholarly journals Adipocyte Fatty Acid-Binding Protein, Cardiovascular Diseases and Mortality

2021 ◽  
Vol 12 ◽  
Author(s):  
Chi-Ho Lee ◽  
David T. W. Lui ◽  
Karen S. L. Lam
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Visceral Fat ◽  
Fatty Acid Binding Protein ◽  
Inflammatory Responses ◽  
Binding Protein ◽  
Fatty Acid Binding ◽  
Fat Depots ◽  
Acid Binding Protein

It has been increasingly recognized that inflammation plays an important role in the pathogenesis of cardiovascular disease (CVD). In obesity, adipose tissue inflammation, especially in the visceral fat depots, contributes to systemic inflammation and promotes the development of atherosclerosis. Adipocyte fatty acid-binding protein (AFABP), a lipid chaperone abundantly secreted from the adipocytes and macrophages, is one of the key players mediating this adipose-vascular cross-talk, in part via its interaction with c-Jun NH2-terminal kinase (JNK) and activator protein-1 (AP-1) to form a positive feedback loop, and perpetuate inflammatory responses. In mice, selective JNK inactivation in the adipose tissue significantly reduced the expression of AFABP in their adipose tissue, as well as circulating AFABP levels. Importantly, fat transplant experiments showed that adipose-specific JNK inactivation in the visceral fat was sufficient to protect mice with apoE deficiency from atherosclerosis, with the beneficial effects attenuated by the continuous infusion of recombinant AFABP, supporting the role of AFABP as the link between visceral fat inflammation and atherosclerosis. In humans, raised circulating AFABP levels are associated with incident metabolic syndrome, type 2 diabetes and CVD, as well as non-alcoholic steatohepatitis, diabetic nephropathy and adverse renal outcomes, all being conditions closely related to inflammation and enhanced CV mortality. Collectively, these clinical data have provided support to AFABP as an important adipokine linking obesity, inflammation and CVD. This review will discuss recent findings on the role of AFABP in CVD and mortality, the possible underlying mechanisms, and pharmacological inhibition of AFABP as a potential strategy to combat CVD.

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