Identification of target genes in neuroinflammation and neurodegeneration after traumatic brain injury in rats

Background Traumatic brain injury (TBI) is a common neurological emergency observed in hospitals. A considerable number of patients suffer from long-term disabilities after TBI. This study aimed to identify altered gene expression signatures and mechanisms related to TBI-induced chronic neuroinflammation and neurodegeneration. Methods An integrated analysis was performed using published RNA-sequencing studies to determine TBI-induced differentially expressed genes (DEGs). Based on the DEG data, functional annotation, signal-net, and transcription factor analyses were conducted to understand the mechanism of chronic neuroinflammation and neurodegeneration induced after TBI. Results Two datasets were obtained using the Gene Expression Omnibus database, of which, 6,513 DEGs were identified (6,464 upregulated and 49 downregulated). Positive regulation of biological process, positive regulation of cellular process, nucleus, and heterocyclic compound binding were Gene Ontology terms significantly enriched in post-TBI rat models. Leukocyte transendothelial migration, chemokine signaling pathway, neurotrophin signaling pathway, and longevity-regulating pathway were significantly enriched after TBI. With regard to the signal-net analysis, FOXO3, DGKZ and ILK were considered the most critical genes derived using high–betweenness centrality calculation. A total of 44 TFs, including FOXO1, SRY and KLF4, were predicted to play an important role in the upregulation of gene expression. Using integrated bioinformatics analysis, TBI was found to be associated with a significant inflammatory response and neurodegeneration. FOXO3, apolipoprotein (APOE), microtubule-associated protein tau (MAPT), and TREM2 were probably associated with the TBI pathological process. The mitochondrial electron transport chain may be associated with neurodegeneration in patients with TBI, serving as a potential therapeutic target.

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Integrated analysis of cancer stem cells-associated lncRNA-miRNA-mRNA network for ovarian cancer via microarray and Gene Expression Omnibus database

10.21203/rs.3.rs-106454/v1 ◽

2020 ◽

Author(s):

Zheng Li ◽

Zhijiao Wang ◽

Yingying Zhou

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Signaling Pathway ◽

Gene Expression Omnibus ◽

Integrated Analysis ◽

Cerna Network ◽

Geo Database

Abstract Background: Cancer stem cells (CSCs) are associated with the recurrence, metastasis and chemoresistance of epithelial ovarian cancer. Competing endogenous RNAs (CeRNAs) play an important role in maintenance of ovarian cancer stem cell-like cells (OCSCs) characteristics. To construct a ceRNA regulatory network for OCSCs, microarray technology and Gene Expression Omnibus (GEO) database had been used. Human serous epithelial ovarian carcinoma cell line COC1 cells were treated with cisplatin and paclitaxel then maintained in stem cell conditions for 6 days to obtain CD117+/CD133+ cells (OCSCs). We identified the differentially expressed miRNAs (DEMs), lncRNA (DELs) and mRNA (DEGs) between OCSCs and COC1 by microarray and combined them with representative microarray profiles in GEO Database. Results: According to the combination, 28 DEMs were identified at first, and 452 DEGs were obtained combining with the predicted targets of these miRNAs and our mRNA microarray results. Up-regulated DEGs of them were significantly enriched in ‘p53 signaling pathway’, ‘FoxO signaling pathway’ and ‘MicroRNAs in cancer’, whereas down-regulated DEGs were significantly enriched in ‘Adherens junction’ and ‘Hepatitis C’ pathway. 29 transcripts of 17 lncRNAs should be the ceRNAs of 10 of these miRNAs according to bioinformatics predicted results and lncRNA microarray. Finally, we obtained ceRNA network with 10 DEMs, 21 DEGs, and 25 transcripts of 13 DELs which should play an important role in maintenance of OCSCs characteristics. LINC00665-miR-146a-5p-NRP2 should be one of ceRNA pathways of the network. The qPCR results indicated that the expression of miR-146a-5p in OCSCs was lower than that in COC1, and LINC00665 shows the opposite trend. These results were consistent with the results of microarray partially. When LINC00665 expression was up-regulated in COC1, the cell proliferation ability enhanced, apoptosis rate reduced, and the percentage of G2/M phase cells increased. Conclusions: The ceRNA network we constructed may be involved in the stem cell characteristics maintenance of OCSCs and provide directions for further OCSCs research in the future, so as to assist the development and treatment of ovarian cancer.

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Systems spatiotemporal dynamics of traumatic brain injury at single cell resolution reveals humanin as a therapeutic target

10.21203/rs.3.rs-765030/v1 ◽

2021 ◽

Author(s):

Douglas Arneson ◽

Guanglin Zhang ◽

In Sook Ahn ◽

Zhe Ying ◽

Graciel Diamante ◽

...

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Frontal Cortex ◽

Single Cell ◽

Target Genes ◽

Expression Patterns ◽

Brain Regions ◽

Cellular Heterogeneity ◽

Blood Leukocytes

Abstract The etiology of mild traumatic brain injury (mTBI) remains elusive due to the tissue and cellular heterogeneity of the affected brain regions that underlie cognitive impairments and subsequent neurological disorders. This complexity is further exacerbated by disrupted circuits within and between cell populations across brain regions and the periphery, which occur at different timescales and in spatial domains. We profiled three tissues (hippocampus, frontal cortex, and blood leukocytes) at the acute (24hr) and chronic (7days) phases of mTBI at single cell resolution and demonstrated that the coordinated gene expression patterns across cell types were disrupted and re-organized by TBI at different timescales with distinct regional and cellular patterns. Gene expression-based network modeling identified astrocytes as a key regulator of the cell-cell coordination following mTBI in both hippocampus and frontal cortex across timepoints, and mt-Rnr2, which encodes the mitochondrial peptide humanin, as a potential target for intervention based on its broad regional and dynamic dysregulation following mTBI. Treatment of a murine mTBI model with humanin reversed cognitive impairment caused by mTBI through the restoration of metabolic pathways within astrocytes. Our results offer a systems-level understanding of the dynamic and spatial regulation of gene programs by mTBI and pinpoint key target genes, pathways, and cell circuits that are amenable to therapeutics.

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Systematic Analysis of tRNA-Derived Small RNAs Reveals Effects of Xuefu-Zhuyu Decoction on Hippocampus of Rats after Traumatic Brain Injury

10.21203/rs.3.rs-826529/v1 ◽

2021 ◽

Author(s):

Feng Dai ◽

Tao Tang ◽

Ruohuang Lu ◽

Pengfei Li ◽

Dandan Feng ◽

...

Keyword(s):

Experimental Data ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Signaling Pathway ◽

Rat Model ◽

Small Rnas ◽

Target Genes ◽

Cocaine Addiction ◽

Therapeutic Effects ◽

Xuefu Zhuyu Decoction

Abstract Background: Traumatic brain injury (TBI) is one of the most common neurosurgical diseases which refers to brain function impairment or brain pathological changes induced by external causes. A traditional Chinese medicine, Xuefu Zhuyu Decoction (XFZYD), has been indicated to harbor therapeutic property against TBI. Transfer RNA (tRNA)-derived small RNAs i.e., tsRNAs (a group of small RNAs derived from tRNAs) are multifunctional regulatory non-coding RNAs generated under pressure and implicated in the progression of TBI.Methods: TBI model was successfully constructed by using of rats. Further using sequencing and omics to identify novel tsRNAs as drug targets for XFZYD therapy against TBI in rat hippocampus. qPCR assay was used to further verify the experimental results. GO analyzed the signaling pathways of downstream target genes of tsRNA in XFZYD regulated TBI model. qPCR was used to detect the influence of over-expressed tsRNA mimic/inhibitor on their target genes in PC12 cell.Results: Our RNA-Seq data illustrates that 11 tsRNAs were mediated by the XFZYD. The experimental data revealed AS-tDR-002004 and AS-tDR-002583 as potential targets for XFZYD therapy and influenced TBI via the cadherin signaling pathway, cocaine addiction, circadian entrainment and nicotine pharmacodynamics pathway. We also confirm that Pi4kb, Mlh3, Pcdh9, and Ppp1cb were targets genes of 2 XFZYD regulated tsRNAs in hippocampus of rat model and PC12 cells. Furthermore, biological function analysis revealing potential therapeutic effects of tsRNAs, and results found Mapk1, Gnai1 was the related genes of for XFZYD therapy against TBI.Conclusion: Our work successfully illuminates the efficiency of XFZYD for the treatment of TBI. The experimental data revealed AS-tDR-002004 and AS-tDR-002583 as potential targets for XFZYD therapy and influenced TBI via the cadherin signaling pathway, cocaine addiction, circadian entrainment and nicotine pharmacodynamics pathway in TBI rat model.

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Gene expression following traumatic brain injury in humans: analysis by microarray

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2004.11.003 ◽

2005 ◽

Vol 12 (3) ◽

pp. 284-290 ◽

Cited By ~ 43

Author(s):

Daniel B. Michael ◽

Donna M. Byers ◽

Louis N. Irwin

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Brain Injury

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The role of salivary vesicles as a potential inflammatory biomarker to detect traumatic brain injury in mixed martial artists

Scientific Reports ◽

10.1038/s41598-021-87180-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rani Matuk ◽

Mandy Pereira ◽

Janette Baird ◽

Mark Dooner ◽

Yan Cheng ◽

...

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Head Injury ◽

Injury Severity ◽

Expression Profiles ◽

High Impact ◽

Impact Mechanism ◽

Inflammatory Biomarker ◽

Potential Biomarker

AbstractTraumatic brain injury (TBI) is of significant concern in the realm of high impact contact sports, including mixed martial arts (MMA). Extracellular vesicles (EVs) travel between the brain and oral cavity and may be isolated from salivary samples as a noninvasive biomarker of TBI. Salivary EVs may highlight acute neurocognitive or neuropathological changes, which may be particularly useful as a biomarker in high impact sports. Pre and post-fight samples of saliva were isolated from 8 MMA fighters and 7 from controls. Real-time PCR of salivary EVs was done using the TaqMan Human Inflammatory array. Gene expression profiles were compared pre-fight to post-fight as well as pre-fight to controls. Largest signals were noted for fighters sustaining a loss by technical knockout (higher impact mechanism of injury) or a full match culminating in referee decision (longer length of fight), while smaller signals were noted for fighters winning by joint or choke submission (lower impact mechanism as well as less time). A correlation was observed between absolute gene information signals and fight related markers of head injury severity. Gene expression was also significantly different in MMA fighters pre-fight compared to controls. Our findings suggest that salivary EVs as a potential biomarker in the acute period following head injury to identify injury severity and can help elucidate pathophysiological processes involved in TBI.

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Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01226-2 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Amer Toutonji ◽

Mamatha Mandava ◽

Silvia Guglietta ◽

Stephen Tomlinson

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Complement System ◽

Classical Pathway ◽

Post Injury ◽

Complement Inhibition ◽

Time Points ◽

Complement Gene ◽

The Complement System

AbstractActivation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of C2, C3 and C4 expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.

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Effect of Xenon Treatment on Gene Expression in Brain Tissue after Traumatic Brain Injury in Rats

Brain Sciences ◽

10.3390/brainsci11070889 ◽

2021 ◽

Vol 11 (7) ◽

pp. 889

Author(s):

Anton D. Filev ◽

Denis N. Silachev ◽

Ivan A. Ryzhkov ◽

Konstantin N. Lapin ◽

Anastasiya S. Babkina ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Tissue ◽

Target Genes ◽

Neural Function ◽

Stress Genes ◽

Expression Of Genes ◽

Delayed Recovery ◽

The Brain ◽

Lower Expression

The overactivation of inflammatory pathways and/or a deficiency of neuroplasticity may result in the delayed recovery of neural function in traumatic brain injury (TBI). A promising approach to protecting the brain tissue in TBI is xenon (Xe) treatment. However, xenon’s mechanisms of action remain poorly clarified. In this study, the early-onset expression of 91 target genes was investigated in the damaged and in the contralateral brain areas (sensorimotor cortex region) 6 and 24 h after injury in a TBI rat model. The expression of genes involved in inflammation, oxidation, antioxidation, neurogenesis and neuroplasticity, apoptosis, DNA repair, autophagy, and mitophagy was assessed. The animals inhaled a gas mixture containing xenon and oxygen (ϕXe = 70%; ϕO2 25–30% 60 min) 15–30 min after TBI. The data showed that, in the contralateral area, xenon treatment induced the expression of stress genes (Irf1, Hmox1, S100A8, and S100A9). In the damaged area, a trend towards lower expression of the inflammatory gene Irf1 was observed. Thus, our results suggest that xenon exerts a mild stressor effect in healthy brain tissue and has a tendency to decrease the inflammation following damage, which might contribute to reducing the damage and activating the early compensatory processes in the brain post-TBI.

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Effects of AAV-mediated knockdown of nNOS and GPx-1 gene expression in rat hippocampus after traumatic brain injury

PLoS ONE ◽

10.1371/journal.pone.0185943 ◽

2017 ◽

Vol 12 (10) ◽

pp. e0185943 ◽

Cited By ~ 5

Author(s):

Deborah R. Boone ◽

Jeanna M. Leek ◽

Michael T. Falduto ◽

Karen E. O. Torres ◽

Stacy L. Sell ◽

...

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Rat Hippocampus

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miR-29a-5p Alleviates Traumatic Brain Injury (TBI)-Induced Permeability Disruption Via Regulating NLRP3 Pathway

10.21203/rs.3.rs-334899/v1 ◽

2021 ◽

Author(s):

Aijun Zhang ◽

Youming Lu ◽

Lei Yuan ◽

Pengqi Zhang ◽

Dongdong Zou ◽

...

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Endothelial Cell ◽

Brain Injury ◽

Inflammasome Activation ◽

Caspase 1 ◽

Promising Strategy ◽

Pathway Activation ◽

Nlrp3 Expression

Abstract Blood-brain barrier (BBB) dysfunction is presented during traumatic brain injury (TBI) and is dependent upon the activation of the NLRP3/Caspase-1 inflammasome pathway. MicroRNA (miRNA) was proved to inhibit signaling pathway activation by targeting gene expression and we predicated in the database that miR-29a targets to NLRP3. Herein, this study aims to define the regulating role of miR-29a in NLRP3 expression and NLRP3/Caspase-1 inflammasome activation in TBI-induced BBB dysfunction. Our results indicated that miR-29a-5p alleviates TBI-induced the increased permeability of endothelial cell and BBB via suppressing NLRP3 expression and NLRP3/Caspase-1 inflammasome activation, providing a promising strategy for relieving TBI via inhibiting NLRP3/Caspase-1 inflammasome activation.

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Noncanonical NF-κB Signaling Upregulation in Inflammatory Bowel Disease Patients is Associated With Loss of Response to Anti-TNF Agents

Frontiers in Pharmacology ◽

10.3389/fphar.2021.655887 ◽

2021 ◽

Vol 12 ◽

Author(s):

Vu Q. Nguyen ◽

Kristin Eden ◽

Holly A. Morrison ◽

Megan B. Sammons ◽

Kristin K. Knight ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Signaling Pathway ◽

Bowel Disease ◽

Target Genes ◽

Preliminary Evidence ◽

Lymphocyte Migration ◽

Clinical Criteria ◽

Number Of Patients ◽

Effective Therapeutic Strategy ◽

Inflammatory Bowel

Objectives: Targeting tumor necrosis factor (TNF) with biologic agents, such as infliximab and adalimumab, is a widely used and effective therapeutic strategy in inflammatory bowel disease (IBD). Unfortunately, a significant number of patients fail to respond or lose response over time to these agents. Previous studies have defined multiple complex roles for canonical NF-κB signaling in the pathogenesis of IBD. However, preliminary evidence suggests that the lesser defined noncanonical NF-κB signaling pathway also contributes to disease pathogenesis and response to anti-TNF agents. The objective of this study was to evaluate this hypothesis in Crohn’s disease (CD) and ulcerative colitis (UC) patients.Design: A total of 27 subjects with IBD (19 with CD and 8 with UC) and 15 control subjects were tested. Clinical criteria, patient history, and endoscopic disease activity were factors used to categorize patients and define therapeutic response. Biopsy specimens were collected during colonoscopy and expression was determined for 88 target genes known to be associated with noncanonical NF-κB signaling and IBD.Results: Noncanonical NF-κB signaling was significantly upregulated in IBD patients and was associated with increased gastrointestinal inflammation, epithelial cell death, lymphocyte migration, and Nod-like receptor signaling. Furthermore, noncanonical NF-κB signaling was further upregulated in patients unresponsive to anti-TNF agents and was suppressed in responsive patients. MAP3K14, NFKB2, CCL19, CXCL12, and CXCL13 were significantly dysregulated, as were genes that encode pathway regulators, such as CYLD, NLRP12, and BIRC2/3.Conclusion: Our study identifies a previously uncharacterized role for the understudied noncanonical NF-κB signaling pathway in the pathogenesis of IBD and anti-TNF therapy responsiveness. The genes and pathways identified may ultimately prove useful in IBD management and could potentially be used as biomarkers of drug response.

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