| Background:Spinal cord injury(SCI)is a very important neurological disease that can cause severe sensory,motor and autonomic dysfunctions.Meanwhile,SCI is also a destructive disease,causing great damage to the nervous system and resulting in a poor quality of life.SCI causes significant physical,emotional,social and economic burdens to millions of people.Although our understanding of the pathophysiology and secondary injury mechanisms of SCI has improved,there are currently few treatments for this disease.However,with the development of new therapies and the emergence of key treatment methods,the field is evolving rapidly.There are two damage mechanisms after SCI: primary mechanical damage and secondary damage caused by various reasons,including temporary changes in gene expression.Studies have shown that many changes in gene expression play an important role in the pathogenesis of secondary SCI.Micro RNA(miRNA),a small non-coding RNA,controls the expression of target m RNA,protein synthesis and cell function by silencing or degrading the target m RNA,and the consequence of reduced protein production depends on the function of the target m RNA.At the same time,many secondary damage responses of SCI including oxidative stress,inflammatory response and apoptosis,involve the expression of miRNA,which participate in and regulate the expression of the target genes of miRNA.Micro RNAs are important players in the regulatory circuitry of the neural repair in SCI.In the past ten years,miRNA has attracted great attention from the biology and biomedical research community.So far,more than 1,900 miRNAs have been found in humans,many of which have been associated with common human diseases.Many biological processes are controlled by miRNA,which can affect the activity of more than 50% of protein-coding genes in mammals.According to previous studies,non-coding miRNAs are closely related to the occurrence,development and prognosis of almost all diseases.However,most micro RNAs remain uncharacterized.Among them,micro RNA-145(miR-145)is about 4.09 kb in length,and its coding gene is located in human chromosome 5,zone 3,zone 2(5q32),and 5q32 contains a highly conserved non-coding single-stranded miRNA.The precursor of miR-145 has a stem-loop structure,and after digestion,mature miR-145 composed of 23 bases is formed.Lagos-Quintana et al.found the presence of miR-145 in the cardiomyocytes of mice for the first time.Since then,in the human colon and rectum,Micheal and others have also proved the existence of miR-145.In this study,we have investigated the neuroprotection function of miR-145 after SCI in vivo and in vitro.Methods:KDM6A was identified as the target gene of miR-145 through bioinformatic analysis.Rat SCI model was established by weight drop,and lipopolysaccharide(LPS)-induced PC12 cell inflammatory injury model was also established.We manipulated the expression of miR-145 and/or KDM6 A in both in vivo and in vitro models to explore their roles in rat neurological function repair as well as inflammation and other cellular activities in PC12 cells.Most importantly,we delineated the mechanistic involvement of NOTCH2 and Abcb1 a in the neuroprotection of miR-145.Results:MiR-145 was poorly expressed and KDM6 A was highly expressed in spinal cord tissue of SCI rat model and LPS-induced PC12 cells.Overexpression of miR-145 protects PC12 cells from LPS-induced cell damage and expedites neurological function repair of SCI in rats.Mi R-145 was validated to target and downregulate the demethylase KDM6 A expression,which subsequently abrogated the expression of Abcb1 a by promoting the methylation of NOTCH2.Additionally,in vivo investigation confirmed that miR-145 expedited neuroprotection after SCI by regulating the KDM6A/NOTCH2/Abcb1 a axis.Conclusion:Taken together,miR-145 confers neuroprotective effects and enhances neural repair after SCI through KDM6A-mediated NOTCH2/Abcb1 a axis. |
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