Targeting the Dvl-1/β-arrestin2/JNK3 interaction disrupts Wnt5a-JNK3 signaling and protects hippocampal CA1 neurons during cerebral ischemia reperfusion

Wei, Xuewen; Gong, Juanjuan; Ma, Juyun; Zhang, Taiyu; Lan, Ting; Guo, Peng; Qi, Suhua

doi:10.1016/j.neuropharm.2018.03.006

Cited by 15 publications

(20 citation statements)

References 60 publications

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“…Since miRNAs do not code for proteins, the protective effect of miR-374 on cerebral IR injury is assumed to be exerted via the regulation of its targets. A previous study showed that suppression of Wnt5a is neuroprotective after cerebral ischemia [23]. In the present study, in database predicted, we experimentally confirmed that Wnt5a transcripts are targets of miR-374, which was predicted by TargetScan and the Starbase database.…”

Section: Discussionsupporting

confidence: 85%

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miR-374 improves cerebral ischemia reperfusion injury by targeting <i>Wnt5a</i>

et al. 2021

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To date, studies have demonstrated the potential functions of microRNAs in cerebral ischemia reperfusion (IR) injury. Herein, we established a middle cerebral artery occlusion (MCAO) model in rats and then subjected them to reperfusion to explore the role of microRNA-374 (miR-374) in cerebral IR injury. After reperfusion, the endogenous miR-374 level decreased, and the expression of its target gene, Wnt5a, increased in brain tissues. Intracerebral pretreatment of miR-374 agomir attenuated cerebral damage induced by IR, including neurobehavioral deficits, infarction, cerebral edema and blood-brain barrier disruption. Moreover, rats pretreated with miR-374 agomir showed a remarkable decrease in apoptotic neurons, which was further confirmed by reduced BAX expression as well as increased BCL-2 and BCL-XL expression. A dual-luciferase reporter assay substantiated that Wnt5a was the target gene of miR-374. miR-374 might protect against brain injury by downregulating Wnt5a in rats after IR. Thus, our study provided a novel mechanism of cerebral IR injury from the perspective of miRNA regulation.

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Section: Discussionsupporting

confidence: 85%

“…Furthermore, Wnt5a has been reported to play a crucial role in stroke. Both in vitro and in vivo studies have shown that inhibition of Wnt5a could alleviate cerebral IR injury, which provided a novel target for stroke therapy [23].…”

Section: Introductionmentioning

confidence: 99%

miR-374 improves cerebral ischemia reperfusion injury by targeting <i>Wnt5a</i>

et al. 2021

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“…JNK3 has a key role in cerebral ischemia/reperfusion, in particular through the assembly of the Dvl-1-β-arrestin-2-JNK3 signaling module [ 104 ], and it has been proved that inhibiting JNK3 through Akt1 has a neuroprotective effect on the hippocampal CA1 pyramidal neurons after the induction of transient global brain ischemia [ 105 , 106 ]. Other studies have shown that the activation of the JNK3 pathway, after brain ischemia, can also occur through the assembly of an MLK3-MKK7-JNK3 signaling module, scaffolded by JIP-1; disrupting the interaction between the members of this module protects neurons against ischemic injury [ 107 ].…”

Section: Jnk3 In Brain Diseasesmentioning

confidence: 99%

JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

Musi

Agrò

Santarella

et al. 2020

Cells

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The c-Jun N-terminal kinase 3 (JNK3) is the JNK isoform mainly expressed in the brain. It is the most responsive to many stress stimuli in the central nervous system from ischemia to Aβ oligomers toxicity. JNK3 activity is spatial and temporal organized by its scaffold protein, in particular JIP-1 and β-arrestin-2, which play a crucial role in regulating different cellular functions in different cellular districts. Extensive evidence has highlighted the possibility of exploiting these adaptors to interfere with JNK3 signaling in order to block its action. JNK plays a key role in the first neurodegenerative event, the perturbation of physiological synapse structure and function, known as synaptic dysfunction. Importantly, this is a common mechanism in many different brain pathologies. Synaptic dysfunction and spine loss have been reported to be pharmacologically reversible, opening new therapeutic directions in brain diseases. Being JNK3-detectable at the peripheral level, it could be used as a disease biomarker with the ultimate aim of allowing an early diagnosis of neurodegenerative and neurodevelopment diseases in a still prodromal phase.

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“…Beyond that, signal transduction (Wei et al, 2018;Armstead et al, 2019), immunes response (Famakin, 2014), apoptosis and survival (Sun et al, 2018), transport , and transcription, which existed in both BJ and JU groups, were also closely related to stroke. For example, during brain ischemia/reperfusion, intracellular signaling cascades were FIGURE 6 | Active patterns of p53 under different treatment conditions.…”

Section: The Common Functions Of Bj and Ju Concentrating On Central Nmentioning

confidence: 99%

Divergence and Convergence of Cerebral Ischemia Pathways Profile Deciphers Differential Pure Additive and Synergistic Mechanisms

Wei

Wang

et al. 2020

Front. Pharmacol.

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The variable mechanisms on additive and synergistic effects of jasminoidin (JA)-Baicalin (BA) combination and JA-ursodeoxycholic acid (UA) combination in treating cerebral ischemia are not completely understood. In this study, we explored the differential pure mechanisms of additive and synergistic effects based on pathway analysis that excluded ineffective interference. Methods: The MCAO mice were divided into eight groups: sham, vehicle, BA, JA, UA, Concha Margaritifera (CM), BA-JA combination (BJ), and JA-UA combination (JU). The additive and synergistic effects of combination groups were identified by cerebral infarct volume calculation. The differentially expressed genes based on a microarray chip containing 16,463 oligoclones were uploaded to GeneGo MetaCore software for pathway analyses and function catalogue. The comparison of specific pathways and functions crosstalk between different groups were analyzed to reveal the underlying additive and synergistic pharmacological variations. Results: Additive BJ and synergistic JU were more effective than monotherapies of BA, JA, and UA, while CM was ineffective. Compared with monotherapies, 43 pathways and six functions were found uniquely in BJ group, with 33 pathways and three functions in JU group. We found six overlapping pathways and six overlapping functions between BJ and JU groups, which mainly involved central nervous system development. Thirty-seven specific pathways and 10 functions were activated by additive BJ, which were mainly related to cell adhesion and G-protein signaling; and 27 specific pathways and three functions of synergistic JU were associated with regulation of metabolism, DNA damage, and translation. The overlapping and distinct pathways and functions may contribute to different additive and synergistic effects. Conclusion: The divergence pathways of pure additive effect of BJ were mainly related to cell adhesion and G-protein signaling, while the pure synergistic mechanism of JU depended on metabolism, translation and DNA damage. Such a systematic analysis of

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Targeting the Dvl-1/β-arrestin2/JNK3 interaction disrupts Wnt5a-JNK3 signaling and protects hippocampal CA1 neurons during cerebral ischemia reperfusion

Cited by 15 publications

References 60 publications

miR-374 improves cerebral ischemia reperfusion injury by targeting <i>Wnt5a</i>

miR-374 improves cerebral ischemia reperfusion injury by targeting <i>Wnt5a</i>

JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

Divergence and Convergence of Cerebral Ischemia Pathways Profile Deciphers Differential Pure Additive and Synergistic Mechanisms

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