REMOVED: Protein kinase inhibitors in traumatic brain injury and repair: New roles of nanomedicine

Sharma, Hari Shanker; Sahib, Seaab; Tian, Z. Ryan; Mureșanu, Dafin F.; Nozari, Ala; Castellani, Rudy J.; Lafuente, José Vicente; Wiklund, Lars; Sharma, Aruna

doi:10.1016/bs.pbr.2020.09.009

Cited by 12 publications

(3 citation statements)

References 299 publications

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“…The MAPK family in mammals consists of c-Jun N-terminal kinase, p38 MAPK, and extracellular signal-regulated kinase [28]. Previous findings suggested that inhibiting the activation of the MAPK signaling pathway might produce neuroprotective effects in TBI [29,30]. As a critical regulator of organismal growth and multiple cellular processes, the PI3K/Akt signaling pathway plays an important role under various pathophysiological conditions [31].…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

Zeng¹,

Zhao²,

Zhao³

et al. 2023

J. Integr. Neurosci.

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Background: Traumatic brain injury (TBI) is a common brain injury with a high morbidity and mortality. The complex injury cascade triggered by TBI can result in permanent neurological dysfunction such as cognitive impairment. In order to provide new insights for elucidating the underlying molecular mechanisms of TBI, this study systematically analyzed the transcriptome data of the rat hippocampus in the subacute phase of TBI. Methods: Two datasets (GSE111452 and GSE173975) were downloaded from the Gene Expression Omnibus (GEO) database. Systematic bioinformatics analyses were performed, including differentially expressed genes (DEGs) analysis, gene set enrichment analysis (GSEA), Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) network construction, and hub gene identification. In addition, hematoxylin and eosin (HE), Nissl, and immunohistochemical staining were performed to assess the injured hippocampus in a TBI rat model. The hub genes identified by bioinformatics analyses were verified at the mRNA expression level. Results: A total of 56 DEGs were shared in the two datasets. GSEA results suggested significant enrichment in the MAPK and PI3K/Akt pathways, focal adhesion, and cellular senescence. GO and KEGG analyses showed that the common DEGs were predominantly related to immune and inflammatory processes, including antigen processing and presentation, leukocyte-mediated immunity, adaptive immune response, lymphocyte-mediated immunity, phagosome, lysosome, and complement and coagulation cascades. A PPI network of the common DEGs was constructed, and 15 hub genes were identified. In the shared DEGs, we identified two transcription co-factors and 15 immune-related genes. The results of GO analysis indicated that these immune-related DEGs were mainly enriched in biological processes associated with the activation of multiple cells such as microglia, astrocytes, and macrophages. HE and Nissl staining results demonstrated overt hippocampal neuronal damage. Immunohistochemical staining revealed a marked increase in the number of Iba1-positive cells in the injured hippocampus. The mRNA expression levels of the hub genes were consistent with the transcriptome data. Conclusions: This study highlighted the potential pathological processes in TBI-related hippocampal impairment. The crucial genes identified in this study may serve as novel biomarkers and therapeutic targets, accelerating the pace of developing effective treatments for TBI-related hippocampal impairment.

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Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

Zeng¹,

Zhao²,

Zhao³

et al. 2023

J. Integr. Neurosci.

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“…Numerous studies have demonstrated that neuronal fate is determined by various cell signaling pathways, and the activation of MAPK pathway is the arbiter of neuronal fate [4]. The ERK, JNK and P38 MAPK pathways play key roles in the MAPK pathway, and they contribute to inflammation, oxidative stress and apoptosis in TBI [15]. With cellular stress, the up-regulation of p-ERK, p-JNK and p-P38 activates pro-caspase family [16].…”

Section: Discussionmentioning

confidence: 99%

Abietic acid ameliorates neuroinflammation and blood-brain barrier disruption in traumatic brain injury by inhibiting MAPK pathway

Xing¹,

Jiang²

2022

Trop. J. Pharm Res

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Purpose: To investigate the effects of abietic acid (AA) on traumatic brain injury (TBI) in a rat model, and the underlying mechanisms of action. Methods: Twenty male Sprague-Dawley (SD) rats were randomly divided into four groups of 5 animals each: Sham, TBI, TBI + AA (14 mg/kg), and TBI + AA (28 mg/kg). Controlled cortical impact (CCI) model was used to induce TBI in rats. Western blot was used to determine the protein levels of Claudin 3, Occludin, ZO-1, Bax, Bcl-2, cleaved-caspase3, p65 NF-κB, p-p65 NF-κB, ERK, p-ERK, JNK, p-JNK, p38 and p-p38, while the expressions of TNF-α, IL-6 and IL-1β were determined using the applicable assay kits. Neurological deficit was assessed based on mNSS and brain water content. Results: Treatment with AA significantly reduced TBI-induced blood-brain barrier (BBB) damage, as well as apoptosis and neuroinflammation in a concentration-dependent manner (p < 0.001). The neuroprotective effect of AA was associated with the inhibition of the MAPK signaling pathways and subsequent suppression of NF-κB (p < 0.001). Conclusion: Abietic acid serves as a potential novel candidate for the treatment of TBI, and its anti-inflammatory and anti-apoptotic effects are related to the suppression of MAPK signaling pathways. Therefore, abietic acid may serve as a novel candidate for the treatment of TBI in humans.

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“…For the miRNAs differentially expressed in DepTBI vs. ComC ( Table 2A ) there were 11 overlapping canonical pathways ( Figure 5A ), 4 of which are relevant to TBI: ephrin receptor, axonal guidance, BMP, and RhoA signaling ( Frugier et al, 2012 ; Patel et al, 2017 ; Bi et al, 2019 ; Divolis et al, 2019 ; Zhao et al, 2019 ; Greer et al, 2020 ; Mulherkar and Tolias, 2020 ; Duman et al, 2021 ). Likewise, for the miRNAs differentially expressed in DepTBI vs. DepC ( Table 2C ) there were 20 overlapping canonical pathways ( Figure 5C ), 8 of which are relevant to TBI: ERK/MAPK, TGF-β, senescence, reelin signaling in neurons, Wnt/β-catenin, eIF4 and p70S6K, PAK, and cyclins and cell cycle regulation ( Di Giovanni et al, 2005 ; Chen et al, 2007 ; Zhao et al, 2011 ; Salehi et al, 2018 ; Divolis et al, 2019 ; Sen, 2019 ; Dal Pozzo et al, 2020 ; Hascup and Hascup, 2020 ; Sharma et al, 2020 ; Tan et al, 2020 ; Schwab et al, 2021 ). Interestingly, many of these pathways are inter-related.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid MicroRNA Changes in Cognitively Normal Veterans With a History of Deployment-Associated Mild Traumatic Brain Injury

et al. 2021

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A history of traumatic brain injury (TBI) increases the odds of developing Alzheimer’s disease (AD). The long latent period between injury and dementia makes it difficult to study molecular changes initiated by TBI that may increase the risk of developing AD. MicroRNA (miRNA) levels are altered in TBI at acute times post-injury (<4 weeks), and in AD. We hypothesized that miRNA levels in cerebrospinal fluid (CSF) following TBI in veterans may be indicative of increased risk for developing AD. Our population of interest is cognitively normal veterans with a history of one or more mild TBI (mTBI) at a chronic time following TBI. We measured miRNA levels in CSF from three groups of participants: (1) community controls with no lifetime history of TBI (ComC); (2) deployed Iraq/Afghanistan veterans with no lifetime history of TBI (DepC), and (3) deployed Iraq/Afghanistan veterans with a history of repetitive blast mTBI (DepTBI). CSF samples were collected at the baseline visit in a longitudinal, multimodal assessment of Gulf War veterans, and represent a heterogenous group of male veterans and community controls. The average time since the last blast mTBI experienced was 4.7 ± 2.2 years [1.5 – 11.5]. Statistical analysis of TaqManTM miRNA array data revealed 18 miRNAs with significant differential expression in the group comparisons: 10 between DepTBI and ComC, 7 between DepC and ComC, and 8 between DepTBI and DepC. We also identified 8 miRNAs with significant differential detection in the group comparisons: 5 in DepTBI vs. ComC, 3 in DepC vs. ComC, and 2 in DepTBI vs. DepC. When we applied our previously developed multivariable dependence analysis, we found 13 miRNAs (6 of which are altered in levels or detection) that show dependencies with participant phenotypes, e.g., ApoE. Target prediction and pathway analysis with miRNAs differentially expressed in DepTBI vs. either DepC or ComC identified canonical pathways highly relevant to TBI including senescence and ephrin receptor signaling, respectively. This study shows that both TBI and deployment result in persistent changes in CSF miRNA levels that are relevant to known miRNA-mediated AD pathology, and which may reflect early events in AD.

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REMOVED: Protein kinase inhibitors in traumatic brain injury and repair: New roles of nanomedicine

Cited by 12 publications

References 299 publications

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

Abietic acid ameliorates neuroinflammation and blood-brain barrier disruption in traumatic brain injury by inhibiting MAPK pathway

Cerebrospinal Fluid MicroRNA Changes in Cognitively Normal Veterans With a History of Deployment-Associated Mild Traumatic Brain Injury

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