Search

Current treatments for neurodegenerative diseases and neural injuries face major challenges, primarily due to the diminished regenerative capacity of neurons in the mammalian CNS as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulating mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons following peripheral nerve injury to facilitate spontaneous axon regeneration. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via both histone methylation-dependent and -independent mechanisms. Further investigation revealed that Ezh2 fostered axon regeneration by orchestrating the transcriptional silencing of genes governing synaptic function and those inhibiting axon regeneration, while concurrently activating various factors that support axon regeneration. Notably, we demonstrated that GABA transporter 2, encoded by Slc6a13, acted downstream of Ezh2 to control axon regeneration. Overall, our study underscores the potential of modulating chromatin accessibility as a promising strategy for promoting CNS axon regeneration., Introduction Axon degeneration and neuronal cell death are common consequences of neurodegenerative diseases and neural injuries. Unfortunately, current clinical therapeutics for neural injuries and neurodegenerative diseases still fall short of [...]

Epigenetic regulation of neuronal transcriptomic landscape is emerging to be a key coordinator of mammalian neural regeneration. Here we investigated roles of two histone 3 lysine 27 (H3K27) demethylases Kdm6a/b in controlling neuroprotection and axon regeneration. Deleting either Kdm6a or Kdm6b led to enhanced sensory axon regeneration in PNS, whereas in the CNS only deleting Kdm6a in retinal ganglion cells (RGCs) significantly enhanced optic nerve regeneration. Moreover, both Kdm6a and Kdm6b functioned to regulate RGC survival but with different mechanisms. Mechanistically, Kdm6a regulates RGC regeneration via distinct pathway from that of Pten and co-deleting Kdm6a and Pten resulted in long distance optic nerve regeneration passing the optic chiasm. In addition, RNA-seq profiling revealed that Kdm6a deletion switched the RGC transcriptomics into a developmental-like state and suppressed several known repressors of neural regeneration. Klf4 was identified as a direct downstream target of Kdm6a-H3K27me3 signaling in both sensory neurons and RGCs to regulate axon regeneration. These findings not only revealed different roles of Kdm6a and Kdm6b in regulation of neural regeneration and their underlying mechanisms, but also identified Kdm6a-mediated histone demethylation signaling as a novel epigenetic target for supporting CNS neural regeneration.

Glycogen synthase kinase 3 (GSK3) signaling plays important and broad roles in regulating neural development in vitro and in vivo. Here, we reviewed recent findings of GSK3-regulated axon regeneration in vivo in both the peripheral and central nervous systems and discussed a few controversial findings in the field. Overall, current evidence indicates that GSK3β signaling serves as an important downstream mediator of the PI3K-AKT pathway to regulate axon regeneration in parallel with the mTORC1 pathway. Specifically, the mTORC1 pathway supports axon regeneration mainly through its role in regulating cap-dependent protein translation, whereas GSK3β signaling might be involved in regulating N6-methyladenosine mRNA methylation-mediated, cap-independent protein translation. In addition, GSK3 signaling also plays a key role in reshaping the neuronal transcriptomic landscape during neural regeneration. Finally, we proposed some research directions to further elucidate the molecular mechanisms underlying the regulatory function of GSK3 signaling and discover novel GSK3 signaling-related therapeutic targets. Together, we hope to provide an updated and insightful overview of how GSK3 signaling regulates neural regeneration in vivo., (© The Author(s) (2023). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

Most current studies quantify axon regeneration by immunostaining regeneration-associated proteins, representing indirect measurement of axon lengths from both sensory neurons in the dorsal root ganglia and motor neurons in the spinal cord. Our recently developed method of in vivo electroporation of plasmid DNA encoding for enhanced green fluorescent protein into adult sensory neurons in the dorsal root ganglia provides a way to directly and specifically measure regenerating sensory axon lengths in whole-mount nerves. A mouse model of sciatic nerve compression was established by squeezing the sciatic nerve with tweezers. Plasmid DNA carrying enhanced green fluorescent protein was transfected by ipsilateral dorsal root ganglion electroporation 2 or 3 days before injury. Fluorescence distribution of dorsal root or sciatic nerve was observed by confocal microscopy. At 12 and 18 hours, and 1, 2, 3, 4, 5, and 6 days of injury, lengths of regenerated axons after sciatic nerve compression were measured using green fluorescence images. Apoptosis-related protein caspase-3 expression in dorsal root ganglia was determined by western blot assay. We found that in vivo electroporation did not affect caspase-3 expression in dorsal root ganglia. Dorsal root ganglia and sciatic nerves were successfully removed and subjected to a rapid tissue clearing technique. Neuronal soma in dorsal root ganglia expressing enhanced green fluorescent protein or fluorescent dye-labeled microRNAs were imaged after tissue clearing. The results facilitate direct time course analysis of peripheral nerve axon regeneration. This study was approved by the Institutional Animal Care and Use Committee of Guilin Medical University, China (approval No. GLMC201503010) on March 7, 2014., Competing Interests: None

Aim: To investigate the efficacy and safety of ulinastatin for patients with acute lung injury (ALI) and those with acute respiratory distress syndrome (ARDS)., Methods: A systematic review of randomized controlled trials (RCTs) of ulinastatin for ALI/ARDS was conducted. Oxygenation index, mortality rate [intensive care unit (ICU) mortality rate, 28-d mortality rate] and length of ICU stay were compared between ulinastatin group and conventional therapy group. Meta-analysis was performed by using Rev Man 5.1., Results: Twenty-nine RCTs with 1726 participants were totally included, the basic conditions of which were similar. No studies discussed adverse effect. Oxygenation index was reported in twenty-six studies (1552 patients). Ulinastatin had a significant effect in improving oxygenation [standard mean difference (SMD) = 1.85, 95%CI: 1.42-2.29, P < 0.00001, I(2) = 92%]. ICU mortality and 28-d mortality were respectively reported in eighteen studies (987 patients) and three studies (196 patients). We found that ulinastatin significantly decreased the ICU mortality [I(2) = 0%, RR = 0.48, 95%CI: 0.38-0.59, number needed to treat (NNT) = 5.06, P < 0.00001], while the 28-d mortality was not significantly affected (I(2) = 0%, RR = 0.78, 95%CI: 0.51-1.19, NNT = 12.66, P = 0.24). The length of ICU stay (six studies, 364 patients) in the ulinastatin group was significantly lower than that in the control group (SMD = -0.97, 95%CI: -1.20--0.75, P < 0.00001, I(2) = 86%)., Conclusion: Ulinastatin seems to be effective for ALI and ARDS though most trials included were of poor quality and no information on safety was provided.