Peripheral nerve injury (PNI) is a public health concern that results in sensory and motor disorders as well as neuropathic pain and secondary lesions. Currently, effective treatments for PNI are still limited. For example, while nerve growth factor (NGF) is widely used in the treatment of PNI to promote nerve regeneration, it also induces pain. Maresin 1 (MaR1) is an anti-inflammatory and proresolving mediator that has the potential to regenerate tissue. We determined whether MaR1 is able to promote nerve regeneration as well as alleviating neuropathic pain, and to be considered as a putative therapeutic agent for treating PNI.PNI models were constructed with 8-week-old adult male ICR mice and treated with NGF, MaR1 or saline by local application, intrathecal injection or intraplantar injection. Behavioral analysis and muscle atrophy test were assessed after treatment. Immunofluorescence assay was performed to examine the expression of ATF-3, GFAP, IBA1, and NF200. The expression transcript levels of inflammatory factors IL1β, IL-6, and TNF-α were detected by quantitative real-time RT-PCR. AKT, ERK, mTOR, PI3K, phosphorylated AKT, phosphorylated ERK, phosphorylated mTOR, and phosphorylated PI3K levels were examined by western blot analysis. Whole-cell patch-clamp recordings were executed to detect transient receptor potential vanilloid 1 (TRPV1) currents.MaR1 demonstrated a more robust ability to promote sensory and motor function recovery in mice after sciatic nerve crush injury than NGF. Immunohistochemistry analyses showed that the administration of MaR1 to mice with nerve crush injury reduced the number of damaged DRG neurons, promoted injured nerve regeneration and inhibited gastrocnemius muscle atrophy. Western blot analysis of ND7/23 cells cultured with MaR1 or DRG neurons collected from MaR1 treated mice revealed that MaR1 regulated neurite outgrowth through the PI3K-AKT-mTOR signaling pathway. Moreover, MaR1 dose-dependently attenuated the mechanical allodynia and thermal hyperalgesia induced by nerve injury. Consistent with the analgesic effect, MaR1 inhibited capsaicin-elicited TRPV1 currents, repressed the nerve injury-induced activation of spinal microglia and astrocytes and reduced the production of proinflammatory cytokines in the spinal cord dorsal horn in PNI mice.Application of MaR1 to PNI mice significantly promoted nerve regeneration and alleviated neuropathic pain, suggesting that MaR1 is a promising therapeutic agent for PNI. 

/pdf/maresin-1-promotes-nerve-regeneration-and-alleviates-3mn0fw0z.pdf

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

RNA modifications are dynamic and reversible chemical modifications on substrate RNA that are regulated by specific modifying enzymes. They play important roles in the regulation of many biological processes in various diseases, such as the development of cancer and other diseases. With the help of advanced sequencing technologies, the role of RNA modifications has caught increasing attention in human diseases in scientific research. In this review, we briefly summarized the basic mechanisms of several common RNA modifications, including m6A, m5C, m1A, m7G, Ψ, A-to-I editing and ac4C. Importantly, we discussed their potential functions in human diseases, including cancer, neurological disorders, cardiovascular diseases, metabolic diseases, genetic and developmental diseases, as well as immune disorders. Through the "writing-erasing-reading" mechanisms, RNA modifications regulate the stability, translation, and localization of pivotal disease-related mRNAs to manipulate disease development. Moreover, we also highlighted in this review all currently available RNA-modifier-targeting small molecular inhibitors or activators, most of which are designed against m6A-related enzymes, such as METTL3, FTO and ALKBH5. This review provides clues for potential clinical therapy as well as future study directions in the RNA modification field. More in-depth studies on RNA modifications, their roles in human diseases and further development of their inhibitors or activators are needed for a thorough understanding of epitranscriptomics as well as diagnosis, treatment, and prognosis of human diseases. 

RNA modification: mechanisms and therapeutic targets

In recent years, N7-methylguanosine (m7G) methylation, originally considered as messenger RNA (mRNA) 5' caps modifications, has been identified at defined internal positions within multiple types of RNAs, including transfer RNAs, ribosomal RNAs, miRNA, and mRNAs. Scientists have put substantial efforts to discover m7G methyltransferases and methylated sites in RNAs to unveil the essential roles of m7G modifications in the regulation of gene expression and determine the association of m7G dysregulation in various diseases, including neurological disorders. Here, we review recent findings regarding the distribution, abundance, biogenesis, modifiers, and functions of m7G modifications. We also provide an up-to-date summary of m7G detection and profile mapping techniques, databases for validated and predicted m7G RNA sites, and web servers for m7G methylation prediction. Furthermore, we discuss the pathological roles of METTL1/WDR-driven m7G methylation in neurological disorders. Last, we outline a roadmap for future directions and trends of m7G modification research, particularly in the central nervous system. 

https://doi.org/10.1016/j.omtn.2023.01.003

Internal m7G methylation: A novel epitranscriptomic contributor in brain development and diseases


 Background: Peripheral nerve injury (PNI) is a public health concern that results in sensory and motor disorders as well as neuropathic pain and secondary lesions. Currently, effective treatments for PNI are still limited. For example, while nerve growth factor (NGF) is widely used in the treatment of PNI to promote nerve regeneration, it also induces pain. Maresin 1 (MaR1) is an anti-inflammatory and proresolving mediator that has the potential to regenerate tissue. We determined whether MaR1 is able to promote nerve regeneration as well as alleviating neuropathic pain, and to be considered as a putative therapeutic agent for treating PNI.Methods: PNI models were constructed with eight-week-old adult male ICR mice and treated with NGF, MaR1 or saline by local application, intrathecal injection or intraplantar injection. Behavioral analysis and muscle atrophy test were assessed after treatment. Immunofluorescence assay was performed to examine the expression of ATF-3, GFAP, IBA1, and NF200. The expression transcript levels of inflammatory factors IL1β, IL-6, and TNF-α were detected by quantitative real-time RT-PCR. AKT, ERK, mTOR, PI3K, phosphorylated AKT, phosphorylated ERK, phosphorylated mTOR, and phosphorylated PI3K levels were examined by western blot analysis. Whole-cell patch-clamp recordings were executed to detect transient receptor potential vanilloid 1 (TRPV1) currents.Results: MaR1 demonstrated a more robust ability to promote sensory and motor function recovery in mice after sciatic nerve crush injury than NGF. Immunohistochemistry analyses showed that the administration of MaR1 to mice with nerve crush injury reduced the number of damaged DRG neurons, promoted injured nerve regeneration and inhibited gastrocnemius muscle atrophy. Western blot analysis of ND7/23 cells cultured with MaR1 revealed that MaR1 regulated neurite outgrowth through the PI3K-AKT-mTOR signaling pathway. Moreover, MaR1 dose-dependently attenuated the mechanical allodynia and thermal hyperalgesia induced by nerve injury. Consistent with the analgesic effect, MaR1 inhibited capsaicin-elicited TRPV1 currents, repressed the nerve injury-induced activation of spinal microglia and astrocytes and reduced the production of proinflammatory cytokines in the spinal cord dorsal horn in PNI mice.Conclusions: Application of MaR1 to PNI mice significantly promoted nerve regeneration and alleviated neuropathic pain, suggesting that MaR1 is a promising therapeutic agent for PNI.

/pdf/maresin-1-promotes-nerve-regeneration-and-alleviates-2xdjsc2otu.pdf

Neurotoxicity of nanoparticles: Insight from studies in zebrafish.

RNA methylation is involved in multiple physiological and pathological processes. However, the role of RNA methylation in spinal cord regeneration has not been reported. In this study, we find an altered m6A (N6-methyladenosine) RNA methylation profiling following zebrafish spinal cord injury (SCI), in line with an altered transcription level of the m6A methylase Mettl3. Interestingly, many of the differential m6A-tagged genes associated with neural regeneration are hypomethylated, but their transcription levels are upregulated in SCI. Moreover, we find that METTL3 may be important for spinal cord regeneration. We also show a conserved feature of METTL3 changes in mouse SCI model, in which the expression of METTL3 is increased in both astrocytes and neural stem cells. Together, our results indicate that m6A RNA methylation is dynamic and conserved following SCI and may contribute to spinal cord regeneration.

Epitranscriptomic m6A regulation following spinal cord injury

After spinal cord injury (SCI), the irreversible loss of neurons and the dense glial scar are two of the leading causes of axon regeneration failure. The adult mammalian spinal cord lacks the ability to spontaneously produce new neurons, making it a key challenge to provide new neurons for spinal cord regeneration. Additionally, the dual role of the glial scar (both inhibitory and protective) makes it difficult to manipulate it for therapeutic purposes. In this study, using a single transcription factor Sry-related HMG-box 2 (Sox2) delivered by adeno-associated virus (AAV), we reprogrammed some of the astrocytes targeted by the viral vectors in the glial scar into neurons in a severe SCI model. We show that this astrocytic reprogramming alone can propel axon regeneration by not only replenishing the lost neurons, but also moderately reducing the density of the glial scar without interrupting its integrity. Beyond that, astrocytic reprogramming can significantly improve functional recovery when combined with running wheel rehabilitation, which provides use-dependent plasticity. These findings may provide us with a new idea for how to manipulate the glial scar and a promising therapeutic strategy that combines biological intervention with a rehabilitation strategy.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.202001657RR

Astrocytic reprogramming combined with rehabilitation strategy improves recovery from spinal cord injury.

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Epitranscriptomic m6A regulation following spinal cord injury

Astrocytic reprogramming combined with rehabilitation strategy improves recovery from spinal cord injury.