The impact of metabolic factors on inflammatory mrna expression profiles: Findings from the MAMI study

2021 ◽  
Vol 331 ◽  
pp. e91
Author(s):  
R. Attard ◽  
P. Dingli ◽  
A.C. Spek ◽  
K. Cassar ◽  
R. Farrugia ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Expression Profiles ◽  
Metabolic Factors ◽  
The Impact

scholarly journals Differential Expression of Neuroinflammatory mRNAs in the Rat Sciatic Nerve Following Chronic Constriction Injury and Pain-Relieving Nanoemulsion NSAID Delivery to Infiltrating Macrophages

2019 ◽  
Vol 20 (21) ◽  
pp. 5269 ◽  
Author(s):  
Andrea M. Stevens ◽  
Lu Liu ◽  
Dylan Bertovich ◽  
Jelena M. Janjic ◽  
John A. Pollock
Keyword(s):  
Gene Expression ◽  
Chronic Pain ◽  
Pain Relief ◽  
Sciatic Nerve ◽  
Mrna Expression ◽  
Chronic Constriction Injury ◽  
Expression Profiles ◽  
Nerve Tissue ◽  
Rat Sciatic Nerve ◽  
The Impact

The neuroinflammatory response to peripheral nerve injury is associated with chronic pain and significant changes in the molecular expression profiles of mRNAs in neurons, glia and infiltrating immune cells. Chronic constriction injury (CCI) of the rat sciatic nerve provides an opportunity to mimic neuropathic injury and quantitatively assess behavior and differential gene expression in individual animals. Previously, we have shown that a single intravenous injection of nanoemulsion containing celecoxib (0.24 mg/kg) reduces inflammation of the sciatic nerve and relieves pain-like behavior for up to 6 days. Here, we use this targeted therapy to explore the impact on mRNA expression changes in both pain and pain-relieved states. Sciatic nerve tissue recovered from CCI animals is used to evaluate the mRNA expression profiles utilizing quantitative PCR. We observe mRNA changes consistent with the reduced recruitment of macrophages evident by a reduction in chemokine and cytokine expression. Furthermore, genes associated with adhesion of macrophages, as well as changes in the neuronal and glial mRNAs are observed. Moreover, genes associated with neuropathic pain including Maob, Grin2b/NMDAR2b, TrpV3, IL-6, Cacna1b/Cav2.2, Itgam/Cd11b, Scn9a/Nav1.7, and Tac1 were all found to respond to the celecoxib loaded nanoemulsion during pain relief as compared to those animals that received drug-free vehicle. These results demonstrate that by targeting macrophage production of PGE2 at the site of injury, pain relief includes partial reversal of the gene expression profiles associated with chronic pain.

scholarly journals Tet2 Deficiency Leads to an Increased Inflammatory Phenotype in Murine Macrophages

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 708-708 ◽  
Author(s):  
Alyssa Cull ◽  
Brooke Snetsinger ◽  
Michael J. Rauh
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Binding Sites ◽  
Expression Profiles ◽  
Raw264.7 Cells ◽  
Signalling Pathways ◽  
Mrna Levels ◽  
Anti Inflammatory ◽  
The Impact ◽  
Lps Treatment

Abstract Introduction: In the context of MDS and CMML, little is known about the underlying causes of aberrant immune modulation, particularly with respect to the contribution of recurrently mutated genes. Inactivatingmutations in Tet methylcytosine dioxygenase 2 (TET2) cause loss of hydroxymethylation and a corresponding enrichment of 5-methylcytosine marks, changes which are thought to precipitate clonal dominance and monocytic skewing. Currently, the impact of TET2 loss on the properties of disease-relevant monocytes/macrophages (MΦs) is poorly understood. Therefore, our goals were to (1) characterize Tet2 expression during MΦ LPS and interferon gamma (IFNγ) treatment, (2) determine the effect of Tet2-deficiency on LPS signaling in these cells, and (3) explore how the demethylating agent 5-azacytidine (AZA) impacts abnormally expressed genes in Tet2-knockout MΦs. Methods: Peritoneal (PMΦ) and bone marrow-derived (BMMΦ) MΦs were obtained from Vav1-Cre-driven Tet2 knockout (Tet2-/-) mice in accordance with Queen's Animal Care protocols. Gene expression profiling was performed using the NanoString nCounter Mouse Immunology Gene Expression CodeSet plus 30 custom targets (591 candidate genes in total). Results: Previously, our group reported that Tet2 expression was induced 3h after LPS treatment in both primary PMΦ and BMMΦ cultures as well as RAW264.7 monocytic cells (Cull et al. Blood Abstract 2015: 646). To further understand the signalling pathways underpinning this induction, RAW264.7 cells were treated for 3h with 100ng/mL LPS alone, 10ng/mL IFNγ alone or a combination of LPS and IFNγ, as IFNγ is known to potentiate LPS signalling. As expected, LPS alone caused Tet2 mRNA levels to increase by 4- to 6-fold. The combined treatment of LPS and IFNγ lead to a 5- to 8-fold induction whereas IFNγ alone failed to increase Tet2 expression, suggesting that Tet2 induction is mainly IFNγ-independent. To evaluate relevant TLR4 signalling pathways, RAW264.7 cells were pretreated with the inhibitor compounds SP600125, BAY11-7082 and PD184352 prior to 3h LPS stimulation. Tet2 induction was abolished in cells pretreated with BAY 11-7082, an NF-κB inhibitor. Mining human ChIP-seq data from the ENCODE database indicated a number of NF-κB (p65) binding sites within the putative TET2 promoter and regulatory regions, some of which are conserved in the murine locus. ChIP studies are currently underway to evaluate binding sites of interest. We have previously reported that untreated Tet2-/- PMΦs constitutively overexpress a variety of genes involved in LPS-mediated inflammatory signalling (Cull et al. Blood Abstract 2015: 646). Based on these findings, we used NanoString gene expression analysis to evaluate the status of Tet2-/- versus Tet2f/f BMMΦs (n=3/genotype). We found gene expression in Tet2-/- BMMΦs to be very similar to control cells. In addition, early (3h) LPS gene expression profiles did not differ appreciably between Tet2-/- and Tet2f/f BMMΦs (n=3/genotype). However, at 12-24h following LPS treatment, Il1b, Il6 and Arg1 mRNA expression were significantly elevated in Tet2-/- BMMΦs. Given that IL-1β and IL-6 are both potent pro-inflammatory cytokines whereas Arg1 is associated with anti-inflammatory alternatively activated MΦfunctions (AAMΦ), we hypothesize that Tet2-/- BMMΦs are unable to resolve inflammation and compensate through overexpression of anti-inflammatory genes such as Arg1. Finally, we determined the effect that the hypomethylating agent AZA had on the mRNA expression of Il1b, Il6 and Arg1 in BMMΦs. In a pilot experiment, pooled Tet2-/- BMMΦs (n=3) were treated with 5μM AZA for 24h prior to 12h LPS stimulation. Compared to LPS alone, AZA pretreatment and subsequent LPS stimulation lead to a reduction in Arg1 (0.47-fold) and Il6 (0.65-fold) levels in Tet2-/- BMMΦs, whereas Il1b expression remained similar (0.97-fold). Based on these initial results, we hypothesize that AZA treatment leads to demethylation of genomic regions that have been enriched in methylation marks due to Tet2 loss, leading to the repression of promoters such as Arg1 and Il6. Further studies are underway to address these questions. Conclusions: In summary, we have demonstrated that Tet2 loss in MΦs leads to overexpression of genes involved in LPS signalling and LPS-related inflammation, suggesting that these cells may contribute to the abnormal immune environment found in myeloid cancers. Disclosures No relevant conflicts of interest to declare.

Integrated analysis of non-coding RNA and mRNA expression profiles of 2 pig breeds differing in muscle traits

2017 ◽  
Vol 95 (3) ◽  
pp. 1092 ◽  
Author(s):  
J. Sun ◽  
M. Xie ◽  
Z. Huang ◽  
H. Li ◽  
T. chen ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Expression Profiles ◽  
Integrated Analysis ◽  
Pig Breeds ◽  
Non Coding Rna

The Predominant microRNAs in β-cell Clusters for Insulin Regulation and Diabetic Control

2020 ◽  
Vol 21 (7) ◽  
pp. 722-734
Author(s):  
Adele Soltani ◽  
Arefeh Jafarian ◽  
Abdolamir Allameh
Keyword(s):  
Mirna Expression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Diabetic Control ◽  
In Vitro Proliferation ◽  
Cell Functions ◽  
Mirna Expression Profiles ◽  
Multiple Processes ◽  
The Impact

micro (mi)-RNAs are vital regulators of multiple processes including insulin signaling pathways and glucose metabolism. Pancreatic β-cells function is dependent on some miRNAs and their target mRNA, which together form a complex regulative network. Several miRNAs are known to be directly involved in β-cells functions such as insulin expression and secretion. These small RNAs may also play significant roles in the fate of β-cells such as proliferation, differentiation, survival and apoptosis. Among the miRNAs, miR-7, miR-9, miR-375, miR-130 and miR-124 are of particular interest due to being highly expressed in these cells. Under diabetic conditions, although no specific miRNA profile has been noticed, the expression of some miRNAs and their target mRNAs are altered by posttranscriptional mechanisms, exerting diverse signs in the pathobiology of various diabetic complications. The aim of this review article is to discuss miRNAs involved in the process of stem cells differentiation into β-cells, resulting in enhanced β-cell functions with respect to diabetic disorders. This paper will also look into the impact of miRNA expression patterns on in vitro proliferation and differentiation of β-cells. The efficacy of the computational genomics and biochemical analysis to link the changes in miRNA expression profiles of stem cell-derived β-cells to therapeutically relevant outputs will be discussed as well.

scholarly journals Integrative Analysis of miRNA and mRNA Expression Profiles in Mammary Glands of Holstein Cows Artificially Infected with Staphylococcus aureus

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 506
Author(s):  
Xiaolong Wang ◽  
Yongliang Fan ◽  
Yifan He ◽  
Ziyin Han ◽  
Zaicheng Gong ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mrna Expression ◽  
Calcium Binding ◽  
Expression Profiles ◽  
Bovine Mastitis ◽  
Mammary Glands ◽  
Integrative Analysis ◽  
Differentially Expressed ◽  
Future Application ◽  
Collagen Type Iv

Staphylococcus aureus- induced mastitis is one of the most intractable problems for the dairy industry, which causes loss of milk yield and early slaughter of cows worldwide. Few studies have used a comprehensive approach based on the integrative analysis of miRNA and mRNA expression profiles to explore molecular mechanism in bovine mastitis caused by S. aureus. In this study, S. aureus (A1, B1 and C1) and sterile phosphate buffered saline (PBS) (A2, B2 and C2) were introduced to different udder quarters of three individual cows, and transcriptome sequencing and microarrays were utilized to detected miRNA and gene expression in mammary glands from the challenged and control groups. A total of 77 differentially expressed microRNAs (DE miRNAs) and 1625 differentially expressed genes (DEGs) were identified. Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that multiple DEGs were enriched in significant terms and pathways associated with immunity and inflammation. Integrative analysis between DE miRNAs and DEGs proved that miR-664b, miR-23b-3p, miR-331-5p, miR-19b and miR-2431-3p were potential factors regulating the expression levels of CD14 Molecule (CD14), G protein subunit gamma 2 (GNG2), interleukin 17A (IL17A), collagen type IV alpha 1 chain (COL4A1), microtubule associated protein RP/EB family member 2 (MAPRE2), member of RAS oncogene family (RAP1B), LDOC1 regulator of NFKB signaling (LDOC1), low-density lipoprotein receptor (LDLR) and S100 calcium binding protein A9 (S100A9) in bovine mastitis caused by S. aureus. These findings could enhance the understanding of the underlying immune response in bovine mammary glands against S. aureus infection and provide a useful foundation for future application of the miRNA–mRNA-based genetic regulatory network in the breeding cows resistant to S. aureus.

scholarly journals SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Qiao Li ◽  
Manran Liu ◽  
Yan Sun ◽  
Ting Jin ◽  
Pengpeng Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Histological Grade ◽  
Metabolic Adaptation ◽  
Mitochondrial Activity ◽  
Cell Viability Assay ◽  
Ki 67 ◽  
The Impact

Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with poor prognosis and limited treatment options. Hypoxia is a key hallmark of TNBC. Metabolic adaptation promotes progression of TNBC cells that are located within the hypoxic tumor regions. However, it is not well understood regarding the precise molecular mechanisms underlying the regulation of metabolic adaptions by hypoxia. Methods RNA sequencing was performed to analyze the gene expression profiles in MDA-MB-231 cell line (20% O2 and 1% O2). Expressions of Slc6a8, which encodes the creatine transporter protein, were detected in breast cancer cells and tissues by quantitative real-time PCR. Immunohistochemistry was performed to detect SLC6A8 protein abundances in tumor tissues. Clinicopathologic correlation and overall survival were evaluated by chi-square test and Kaplan-Meier analysis, respectively. Cell viability assay and flow cytometry analysis with Annexin V/PI double staining were performed to investigate the impact of SLC6A8-mediated uptake of creatine on viability of hypoxic TNBC cells. TNBC orthotopic mouse model was used to evaluate the effects of creatine in vivo. Results SLC6A8 was aberrantly upregulated in TNBC cells in hypoxia. SLC6A8 was drastically overexpressed in TNBC tissues and its level was tightly associated with advanced TNM stage, higher histological grade and worse overall survival of TNBC patients. We found that SLC6A8 was transcriptionally upregulated by p65/NF-κB and mediated accumulation of intracellular creatine in hypoxia. SLC6A8-mediated accumulation of creatine promoted survival and suppressed apoptosis via maintaining redox homeostasis in hypoxic TNBC cells. Furthermore, creatine was required to facilitate tumor growth in xenograft mouse models. Mechanistically, intracellular creatine bolstered cell antioxidant defense by reducing mitochondrial activity and oxygen consumption rates to reduce accumulation of intracellular reactive oxygen species, ultimately activating AKT-ERK signaling, the activation of which protected the viability of hypoxic TNBC cells via mediating the upregulation of Ki-67 and Bcl-2, and the downregulation of Bax and cleaved Caspase-3. Conclusions Our study indicates that SLC6A8-mediated creatine accumulation plays an important role in promoting TNBC progression, and may provide a potential therapeutic strategy option for treatment of SLC6A8 high expressed TNBC.

scholarly journals Heme Biosynthesis mRNA Expression Signature: Towards a Novel Prognostic Biomarker in Patients with Diffusely Infiltrating Gliomas

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 662
Author(s):  
Mario Mischkulnig ◽  
Barbara Kiesel ◽  
Daniela Lötsch ◽  
Thomas Roetzer ◽  
Martin Borkovec ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mrna Expression ◽  
Postoperative Management ◽  
Heme Biosynthesis ◽  
The Cancer Genome Atlas ◽  
Sequencing Data ◽  
Who Grade ◽  
Expression Signature ◽  
Cancer Genome Atlas ◽  
The Impact

Diffusely infiltrating gliomas are characterized by a variable clinical course, and thus novel prognostic biomarkers are needed. The heme biosynthesis cycle constitutes a fundamental metabolic pathway and might play a crucial role in glioma biology. The aim of this study was thus to investigate the role of the heme biosynthesis mRNA expression signature on prognosis in a large glioma patient cohort. Glioma patients with available sequencing data on heme biosynthesis expression were retrieved from The Cancer Genome Atlas (TCGA). In each patient, the heme biosynthesis mRNA expression signature was calculated and categorized into low, medium, and high expression subgroups. Differences in progression-free and overall survival between these subgroups were investigated including a multivariate analysis correcting for WHO grade, tumor subtype, and patient age and sex. In a total of 693 patients, progression-free and overall survival showed a strictly monotonical decrease with increasing mRNA expression signature subgroups. In detail, median overall survival was 134.2 months in the low, 79.9 months in the intermediate, and 16.5 months in the high mRNA expression signature subgroups, respectively. The impact of mRNA expression signature on progression-free and overall survival was independent of the other analyzed prognostic factors. Our data indicate that the heme biosynthesis mRNA expression signature might serve as an additional novel prognostic marker in patients with diffusely infiltrating gliomas to optimize postoperative management.

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