Maresin 1 promotes nerve regeneration and alleviates neuropathic pain after nerve injury

Wei, Jin; Chen, Gang; Su, Wenfeng; Zhao, Yayu; Wei, Zhongya; Hua, Yimin; Xue, Peng; Chen, Ying

doi:10.21203/rs.3.rs-448859/v1

Cited by 3 publications

(3 citation statements)

References 34 publications

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“…Curcumin-and lipopolysaccharide-activated olfactory ensheathing cells were found to provide proangiogenic effects through the PI3K-AKT signaling pathway 44 . Another study veri ed that activating the PI3K-AKT signaling pathway facilitated nerve reconstruction and attenuated neuropathic pain after peripheral nerve injury 45 . The NF-kappa B pathway is a classical pathway involved in in ammatory and immune responses.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of m6A methylation modification in chronic spinal cord injury in mice

Liu

Zhao

Qin

et al. 2022

Journal Orthopaedic Research

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Chronic spinal cord injury (CSCI) is a catastrophic disease of the central nervous system (CNS), resulting in partial or complete loss of neurological function. N6-methyladenosine (m6A) is the most common form of reversible posttranslational modi cation at the RNA level. However, the role of m6A modi cation in CSCI remains unknown. In this study, we established a CSCI model using a water-absorbable polyurethane polymer, with behavioral assessment, electrophysiological analysis, and histochemical staining for validation. Methylated RNA immunoprecipitation sequencing (meRIP-seq) and mRNA sequencing (mRNA-seq) were jointly explored to compare the differences in CSCI spinal tissue and normal spinal tissue. Furthermore, qRT-PCR, western blotting, and immuno uorescence staining were used to analyze m6A modi cation-related proteins. We found that water-absorbable polyurethane polymer well simulated chronic spinal cord compression. BMS scores and electrophysiological analysis showed continuous neurological function decline after chronic compression of the spinal cord. meRIP-seq identi ed 642 differentially modi ed m6A genes, among which 263 genes were downregulated and 379 genes were upregulated. mRNA-seq showed that 1544 genes were upregulated and 290 genes were downregulated after CSCI. Gene Ontology (GO) terms and enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were also identi ed. qRT-PCR, western blotting, and immuno uorescence staining showed that Mettl14 was signi cantly upregulated after CSCI. Our study revealed a comprehensive pro le of m6A modi cations in CSCI and may provide a valuable tool for further research on CSCI. study showed that mettl14 was signi cantly overexpressed after CSCI and mainly expressed in neurons, which was further validated by qRT-PCR, western blotting, and immuno uorescence.Our study is not without limitations. First, we obtained whole spinal tissue for meRIP-seq and mRNA-seq. Although the total m6A modi cations were assessed, it was di cult to distinguish m6A methylation changes in speci c cell types. In further in-depth research, extracting speci c cells for veri cation of m6A modi cation and exploring its function would be meaningful. Second, we performed preliminary analyses of differentially expressed genes and enriched GO and KEGG pathways, but their roles in CSCI require further validation through extensive experiments.Collectively, our study analyzed m6A methylation modi cations in spinal cord tissue after CSCI. The results indicated that m6A plays an important role in the process of CSCI. Our research may provide new insights for further study of the CSCI pathological process and potential treatment options. DeclarationsAuthor contributions JH, YC and HL designed the study. CL and JZ carried out most of the experiments and data analysis. YJ, TQ, CD and TW assisted in experiments and data analysis. CL drafted the manuscript, and JH and YC revised the manuscript.

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of m6A methylation modification in chronic spinal cord injury in mice

Liu

Zhao

Qin

et al. 2022

Journal Orthopaedic Research

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“…Astrocytes mediate intercellular communication within the nervous system through the production and secretion of neuroactive substances [15,16,17]. Injury signals drive phenotypic transformation of astrocytes and the release of inflammatory mediators, playing roles in central and peripheral sensitization and participating in the progression of NPP.…”

Section: Introductionmentioning

confidence: 99%

Rab8a/SNARE complex activation promotes vesicle anchoring and transport in spinal astrocytes to drive neuropathic pain

Xiao,

Wang,

et al. 2024

Biomol Biomed

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Neuropathic pain (NPP) remains a clinically challenging condition, driven by the activation of spinal astrocytes and the complex release of inflammatory mediators. This study aimed to examine the roles of Rab8a and SNARE complex proteins in activated astrocytes to uncover the underlying mechanisms of NPP. The research was conducted using a rat model with chronic constriction injury (CCI) of the sciatic nerve and primary astrocytes treated with lipopolysaccharide. Enhanced expression of Rab8a was noted specifically in spinal dorsal horn astrocytes through immunofluorescence. Electron microscopy observations showed increased vesicular transport and exocytic activity in activated astrocytes, which was corroborated by elevated levels of inflammatory cytokines such as IL-1β and TNF-α detected through quantitative PCR. Western blot analyses confirmed significant upregulation of Rab8a, VAMP2, and Syntaxin16 in these cells. Furthermore, the application of botulinum neurotoxin type A (BONT/A) reduced the levels of vesicle transport-associated proteins, inhibiting vesicular transport in activated astrocytes. These findings suggest that the Rab8a/SNARE pathway in astrocytes enhances vesicle transport and anchoring, increasing the secretion of bioactive molecules that may play a crucial role in the pathophysiology of NPP. Inhibiting this pathway with BONT/A offers a novel therapeutic target for managing NPP, highlighting its potential utility in clinical interventions.

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“…For instance, different metabolites have been previously explored for their analgesic roles. In particular, endocannabinoids 24 , protectins 25, 26 , maresins 27, 28 , resolvins 28 , and lipoxins 29 , among others, have been shown to have anti-nociceptive properties by directly acting on nociceptor neurons.…”

Section: Introductionmentioning

confidence: 99%

Leishmania mexicanaPromotes Pain-reducing Metabolomic Reprogramming In Cutaneous Lesions

Volpedo

Oljuskin

Cox

et al. 2022

Preprint

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Cutaneous leishmaniasis (CL) is characterized by extensive skin lesions associated with an aggressive inflammatory reaction. Despite the extensive inflammation, CL lesions are usually painless, indicating that Leishmania infection may trigger anti-nociceptive activities in the infected tissues. To this date, the molecular mechanisms responsible for this clinical phenomenon have not been identified. Through an untargeted metabolomic analysis by mass spectrometry, we found enriched anti-nociceptive metabolic pathways in mice infected with Leishmania (L.) mexicana. In particular, endogenous purines were elevated at the lesion site during chronic infection, as well as in vitro in infected macrophages, compared to non-infected mice. These purines have known anti-inflammatory and analgesic properties by acting through adenosine receptors and inhibiting transient receptor potential channels of the vanilloid subtype 1 (TRPV1). Additionally, purine metabolites can promote interleukin (IL)-10 production, with a subsequent decrease in inflammation and pain sensitivity. We also found arachidonic acid metabolism enriched in the ear lesions compared to the non-infected controls. Arachidonic acid is a metabolite of anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These endocannabinoids act on cannabinoid receptors 1 and 2 and TRPV1 channels to exert anti-inflammatory and analgesic effects. Our study provides the first evidence of metabolic pathways upregulated during L. mexicana infection that may mediate anti-nociceptive effects experienced by CL patients and identifies macrophages as a source of these metabolites.

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Maresin 1 promotes nerve regeneration and alleviates neuropathic pain after nerve injury

Cited by 3 publications

References 34 publications

Comprehensive analysis of m6A methylation modification in chronic spinal cord injury in mice

Comprehensive analysis of m6A methylation modification in chronic spinal cord injury in mice

Rab8a/SNARE complex activation promotes vesicle anchoring and transport in spinal astrocytes to drive neuropathic pain

Leishmania mexicanaPromotes Pain-reducing Metabolomic Reprogramming In Cutaneous Lesions

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