Neuroprotective effect of the Nrf2/ARE/miRNA145-5p signaling pathway in the early phase of spinal cord injury

Ebrahimy, Nahal; Gasterich, Natalie; Behrens, Victoria; Amini, Javad; Fragoulis, Athanassios; Beyer, Cordian; Zhao, Weiyi; Sanadgol, Nima; Zendedel, Adib

doi:10.1016/j.lfs.2022.120726

Cited by 7 publications

(6 citation statements)

References 72 publications

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“…A nonparametric test (Kruskal-Wallis) was performed if the data were not distributed normally. Statistical differences between various groups and time points in WT animals and between WT and Lcn2 −/− animals were analyzed with a one-way analysis of variance (ANOVA) and two-way ANOVA, respectively, followed by a Bonferroni post hoc test (multiple comparison test) [55]. All data are given as mean ± standard error of the mean (SEM).…”

Section: Discussionmentioning

confidence: 99%

Lipocalin-2 Deficiency Diminishes Canonical NLRP3 Inflammasome Formation and IL-1β Production in the Subacute Phase of Spinal Cord Injury

Müller

Scheld

Voelz

et al. 2023

IJMS

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Spinal cord injury (SCI) results in the production of proinflammatory cytokines due to inflammasome activation. Lipocalin 2 (LCN2) is a small secretory glycoprotein upregulated by toll-like receptor (TLR) signaling in various cells and tissues. LCN2 secretion is induced by infection, injury, and metabolic disorders. In contrast, LCN2 has been implicated as an anti-inflammatory regulator. However, the role of LCN2 in inflammasome activation during SCI remains unknown. This study examined the role of Lcn2 deficiency in the NLRP3 inflammasome-dependent neuroinflammation in SCI. Lcn2−/− and wild-type (WT) mice were subjected to SCI, and locomotor function, formation of the inflammasome complex, and neuroinflammation were assessed. Our findings demonstrated that significant activation of the HMGB1/PYCARD/caspase-1 inflammatory axis was accompanied by the overexpression of LCN2 7 days after SCI in WT mice. This signal transduction results in the cleaving of the pyroptosis-inducing protein gasdermin D (GSDMD) and the maturation of the proinflammatory cytokine IL-1β. Furthermore, Lcn2−/− mice showed considerable downregulation in the HMGB1/NLRP3/PYCARD/caspase-1 axis, IL-1β production, pore formation, and improved locomotor function compared with WT. Our data suggest that LCN2 may play a role as a putative molecule for the induction of inflammasome-related neuroinflammation in SCI.

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Section: Discussionmentioning

confidence: 99%

Lipocalin-2 Deficiency Diminishes Canonical NLRP3 Inflammasome Formation and IL-1β Production in the Subacute Phase of Spinal Cord Injury

Müller

Scheld

Voelz

et al. 2023

IJMS

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“…The results of GO biological processes and KEGG pathways of hub genes were in line with many previous studies. Inflammation, oxidative stress, IL-17 signaling pathway, and so on were regarded as indispensable parts of specific mechanisms in SCI [43][44][45]. There are 93 molecules involved in IL-17 family signaling events in the IL-17 signaling pathway resource [46].…”

Section: Discussionmentioning

confidence: 99%

“…IL-17 signaling pathway contributes to immune response and inflammation in the body [47]. As a small class of short, single-chain, and noncoding RNA molecules, microRNA (miRNA) could posttranscriptionally regulate target genes and is involved in a variety of physiological and pathological disorders, including the development of SCI [45,48,49]. The top 10 predicted miRNAs-targeted hub genes were identified as specific miRNAs for a better understanding of SCI, as well as the treatment development.…”

Section: Discussionmentioning

confidence: 99%

Specific Blood RNA Profiles in Individuals with Acute Spinal Cord Injury as Compared with Trauma Controls

Chen

Wang

et al. 2023

Oxidative Medicine and Cellular Longevity

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Background. Spinal cord injury (SCI) is known to cause a more robust systemic inflammatory response than general trauma without CNS injury, inducing severe secondary organ damage, especially the lung and liver. Related studies are principally focused on the mechanisms underlying repair and regeneration in the injured spinal cord tissue. However, the specific mechanism of secondary injury after acute SCI is widely overlooked, compared with general trauma. Methods. Two datasets of GSE151371 and GSE45376 related to the blood samples and spinal cord after acute SCI were selected to identify the differentially expressed genes (DEGs). In GSE151371, functional enrichment analysis on specific DEGs of blood samples was performed. And the top 15 specific hub genes were identified from intersectional genes between the specific upregulated DEGs of blood samples in GSE151371 and the upregulated DEGs of the spinal cord in GSE45376. The specific functional enrichment analysis and the drug candidates of the hub genes and the miRNAs-targeted hub genes were also analyzed and predicted. Results. DEGs were identified, and a total of 64 specific genes were the intersection of upregulated genes of the spinal cord in GSE45376 and upregulated genes of human blood samples in GSE151371. The top 15 hub genes including HP, LCN2, DLGAP5, CEP55, HMMR, CDKN3, PRTN3, SKA3, MPO, LTF, CDC25C, MMP9, NEIL3, NUSAP1, and CD163 were calculated from the 64 specific genes. Functional enrichment analysis of the top 15 hub genes revealed inflammation-related pathways. The predicted miRNAs-targeted hub genes and drug candidates of hub genes were also performed to put forward reasonable treatment strategies. Conclusion. The specific hub genes of acute SCI as compared with trauma without CNS injury were identified. The functional enrichment analysis of hub genes showed a specific immune response. Several predicted drugs of hub genes were also obtained. The hub genes and the predicted miRNAs may be potential biomarkers and therapeutic targets and require further validation.

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“…Under normal physiological conditions, Nrf2 can form a dimer with Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm, resulting in the inhibition of Nrf2 activity ( 37 ). The Nrf2/ARE signaling pathway plays an important neuroprotective role in the early stage of SCI ( 38 ). After being activated by ROS, the Nrf2-Keap1 dimer dissociates, leading to Nrf2 phosphorylation and translocation into the cell nucleus, inducing the expression of a series of antioxidant enzyme genes such as heme oxygenase-1 (HO-1), NAD(P) H quinone oxidoreductase 1 (NQO1), and superoxide dismutase (SOD), directly or indirectly clearing free radicals, thus reducing or eliminating ROS, reducing cell oxidative stress ( 39 ).…”

Section: The Relationship Between Sci With Oxidative Stressmentioning

confidence: 99%

Research progress on the inhibition of oxidative stress by teriparatide in spinal cord injury

Ai,

Xiong,

Deng

et al. 2024

Front. Neurol.

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Spinal cord injury (SCI) is currently a highly disabling disease, which poses serious harm to patients and their families. Due to the fact that primary SCI is caused by direct external force, current research on SCI mainly focuses on the treatment and prevention of secondary SCI. Oxidative stress is one of the important pathogenic mechanisms of SCI, and intervention of oxidative stress may be a potential treatment option for SCI. Teriparatide is a drug that regulates bone metabolism, and recent studies have found that it has the ability to counteract oxidative stress and is closely related to SCI. This article summarizes the main pathological mechanisms of oxidative stress in SCI, as well as the relationship between them with teriparatide, and explores the therapeutic potential of teriparatide in SCI.

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Neuroprotective effect of the Nrf2/ARE/miRNA145-5p signaling pathway in the early phase of spinal cord injury

Cited by 7 publications

References 72 publications

Lipocalin-2 Deficiency Diminishes Canonical NLRP3 Inflammasome Formation and IL-1β Production in the Subacute Phase of Spinal Cord Injury

Lipocalin-2 Deficiency Diminishes Canonical NLRP3 Inflammasome Formation and IL-1β Production in the Subacute Phase of Spinal Cord Injury

Specific Blood RNA Profiles in Individuals with Acute Spinal Cord Injury as Compared with Trauma Controls

Research progress on the inhibition of oxidative stress by teriparatide in spinal cord injury

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