The c-Jun N-terminal kinase signaling pathway in epilepsy: activation, regulation, and therapeutics

Zhang, Wuqiong; Wang, Xue; Yu, Miaomiao; Li, Jiaai; Meng, Hongmei

doi:10.1080/10799893.2019.1590410

Cited by 10 publications

(5 citation statements)

References 63 publications

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“…MAPK (mitogen-activated protein kinase) is involved in reaction to physiological and pathological stimuli, such as cytokines, neurotransmitters, hypoxia, and hypoglycemia [53]. MAPK3 (MAP kinase ERK1) and MAPK1 (MAP kinase ERK2) form ERK1/2, a subfamily of MAPK.…”

Section: Discussionmentioning

confidence: 99%

[Retracted] A Network Pharmacology to Explore the Mechanism of Calculus Bovis in the Treatment of Ischemic Stroke

Liu

Chen

et al. 2021

BioMed Research International

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Background. Calculus Bovis is a valuable Chinese medicine, which is widely used in the clinical treatment of ischemic stroke. The present study is aimed at investigating its target and the mechanism involved in ischemic stroke treatment by network pharmacology. Methods. Effective compounds of Calculus Bovis were collected using methods of network pharmacology and using the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) and the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Potential compound targets were searched in the TCMSP and SwissTargetPrediction databases. Ischemic stroke-related disease targets were searched in the Drugbank, DisGeNet, OMIM, and TTD databases. These two types of targets were uploaded to the STRING database, and a network of their interaction (PPI) was built with its characteristics calculated, aiming to reveal a number of key targets. Hub genes were selected using a plug-in of the Cytoscape software, and Gene Ontology (GO) biological processes and pathway enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted using the clusterProfiler package of R language. Results. Among 12 compounds, deoxycorticosterone, methyl cholate, and biliverdin were potentially effective components. A total of 344 Calculus Bovis compound targets and 590 ischemic stroke targets were found with 92 overlapping targets, including hub genes such as TP53, AKT, PIK2CA, MAPK3, MMP9, and MMP2. Biological functions of Calculus Bovis are associated with protein hydrolyzation, phosphorylation of serine/threonine residues of protein substrates, peptide bond hydrolyzation of peptides and proteins, hydrolyzation of intracellular second messengers, antioxidation and reduction, RNA transcription, and other biological processes. Conclusion. Calculus Bovis may play a role in ischemic stroke by activating PI3K-AKT and MAPK signaling pathways, which are involved in regulating inflammatory response, cell apoptosis, and proliferation.

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Section: Discussionmentioning

confidence: 99%

[Retracted] A Network Pharmacology to Explore the Mechanism of Calculus Bovis in the Treatment of Ischemic Stroke

Liu

Chen

et al. 2021

BioMed Research International

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“…The activation of JNK/MAPK signaling pathway occurs at both acute and chronic stages of epileptic development. It participates in astrocyte activation, neuronal death and mossy fiber sprouting [67]. The MAPK signaling pathway regulates RNA-binding proteins (RBPs), which are responsible for mRNA translation.…”

Section: Mapk Signaling Pathwaymentioning

confidence: 99%

The role of the TNFα-mediated astrocyte signaling pathway in epilepsy

Chen

Xue

Hölscher

2021

Acta Epileptologica

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Epilepsy is a common disease in the central nervous system. There is growing evidence that epilepsy is associated with glial cells, including astrocytes. Tumor necrosis factor α (TNFα) is a “master regulator” of proinflammatory cytokine production and is secreted by microglia and astrocytes. TNFα secreted by microglia can activate astrocytes. Additionally, TNFα can regulate neuron activity and induce epilepsy by increasing the glutamate release, reducing the expression of γ-aminobutyric acid, inducing neuroinflammation and affecting the synaptic function in astrocytes. This review summarizes the signaling pathways and receptors of TNFα acting on astrocytes that are related to epilepsy and provides insights into the potential therapeutic strategies of epilepsy for clinical practice.

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“…Blocking ERK1/2 signaling prevented epileptiform behavior in rats [ 51 , 52 ]. Additionally, several studies have shown that JNK is abnormally activated in epileptic models and is related to cell death [ 53 , 54 ]. The p38 inhibitor SB203580 decreased pathological damage to the hippocampus and reduced the epileptic frequency [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Calcium‐/Calmodulin‐Dependent Protein Kinase II (CaMKII) Inhibition Induces Learning and Memory Impairment and Apoptosis

Wang

Jia

et al. 2021

Oxidative Medicine and Cellular Longevity

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Objectives. Inhibition of calcium-/calmodulin- (CaM-) dependent kinase II (CaMKII) is correlated with epilepsy. However, the specific mechanism that underlies learning and memory impairment and neuronal death by CaMKII inhibition remains unclear. Materials and Methods. In this study, KN93, a CaMKII inhibitor, was used to investigate the role of CaMKII during epileptogenesis. We first identified differentially expressed genes (DEGs) in primary cultured hippocampal neurons with or without KN93 treatment using RNA-sequencing. Then, the impairment of learning and memory by KN93-induced CaMKII inhibition was assessed using the Morris water maze test. In addition, Western blotting, immunohistochemistry, and TUNEL staining were performed to determine neuronal death, apoptosis, and the relative signaling pathway. Results. KN93-induced CaMKII inhibition decreased cAMP response element-binding (CREB) protein activity and impaired learning and memory in Wistar and tremor (TRM) rats, an animal model of genetic epilepsy. CaMKII inhibition also induced neuronal death and reactive astrocyte activation in both the Wistar and TRM hippocampi, deregulating mitogen-activated protein kinases. Meanwhile, neuronal death and neuron apoptosis were observed in PC12 and primary cultured hippocampal neurons after exposure to KN93, which was reversed by SP600125, an inhibitor of c-Jun N-terminal kinase (JNK). Conclusions. CaMKII inhibition caused learning and memory impairment and apoptosis, which might be related to dysregulated JNK signaling.

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The c-Jun N-terminal kinase signaling pathway in epilepsy: activation, regulation, and therapeutics

Cited by 10 publications

References 63 publications

[Retracted] A Network Pharmacology to Explore the Mechanism of Calculus Bovis in the Treatment of Ischemic Stroke

[Retracted] A Network Pharmacology to Explore the Mechanism of Calculus Bovis in the Treatment of Ischemic Stroke

The role of the TNFα-mediated astrocyte signaling pathway in epilepsy

Calcium‐/Calmodulin‐Dependent Protein Kinase II (CaMKII) Inhibition Induces Learning and Memory Impairment and Apoptosis

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