Abstract
Spinal cord injury (SCI) is a neurological injury that can cause neuronal loss around the lesion site and leads to locomotive and sensory deficits. However, the underlying molecular mechanisms remain unclear. This study aimed to verify differential gene time-course expression in SCI and provide new insights for gene-level studies. We downloaded two rat expression profiles (GSE464 and GSE45006) from the Gene Expression Omnibus database, including 1 day, 3 days, 7 days, and 14 days post-SCI, along with thoracic spinal cord data for analysis. At each time point, gene integration was performed using “batch normalization.” The raw data were standardized, and differentially expressed genes at the different time points versus the control were analyzed by Gene Ontology enrichment analysis, the Kyoto Encyclopedia of Genes and Genomes pathway analysis, and gene set enrichment analysis. A protein-protein interaction network was then built and visualized. In addition, ten hub genes were identified at each time point. Among them, Gnb5, Gng8, Agt, Gnai1, and Psap lack correlation studies in SCI and deserve further investigation. Finally, we screened and analyzed genes for tissue repair, reconstruction, and regeneration and found that Anxa1, Snap25, and Spp1 were closely related to repair and regeneration after SCI. In conclusion, hub genes, signaling pathways, and regeneration genes involved in secondary SCI were identified in our study. These results may be useful for understanding SCI-related biological processes and the development of targeted intervention strategies.
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References
Huang H, Young W, Skaper S, Chen L, Moviglia G, Saberi H, al-Zoubi Z, Sharma HS et al (2020) Clinical neurorestorative therapeutic guidelines for spinal cord injury (IANR/CANR version 2019). J Orthop Transl 20:14–24. https://doi.org/10.1016/j.jot.2019.10.006
Alizadeh A, Dyck SM, Karimi-Abdolrezaee S (2019) Traumatic spinal cord injury: an overview of pathophysiology. Models and Acute Injury Mechanisms Front Neurol 10. https://doi.org/10.3389/fneur.2019.00282
Griffin JM, Bradke F (2020) Therapeutic repair for spinal cord injury: Combinatory approaches to address a multifaceted problem. EMBO Mol med 12:1–29. https://doi.org/10.15252/emmm.201911505
Baptiste DC, Fehlings MG (2006) Pharmacological approaches to repair the injured spinal cord. J Neurotrauma 23:318–334. https://doi.org/10.1089/neu.2006.23.318
Zhou X, Wahane S, Friedl MS, Kluge M, Friedel CC, Avrampou K, Zachariou V, Guo L et al (2020) Microglia and macrophages promote corralling, wound compaction and recovery after spinal cord injury via Plexin-B2. Nat Neurosci 23:337–350. https://doi.org/10.1038/s41593-020-0597-7
Zhaohui C, Shuihua W (2020) Protective effects of SIRT6 against inflammation, oxidative stress, and cell apoptosis in spinal cord injury. Inflammation 43:1751–1758. https://doi.org/10.1007/s10753-020-01249-2
Yi WY, Shen D, Jun ZL et al (2019) Sting is a critical regulator of spinal cord injury by regulating microglial inflammation via interacting with TBK1 in mice. Biochem Biophys Res Commun 517:741–748. https://doi.org/10.1016/j.bbrc.2019.07.125
Zhang XJ, Cheng X, Yan ZZ, Fang J, Wang X, Wang W, Liu ZY, Shen LJ et al (2018) An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury. Nat Med 24:73–83. https://doi.org/10.1038/nm.4451
Villaseñor-Park J, Ortega-Loayza AG (2013) Microarray technique, analysis, and applications in dermatology. J Invest Dermatol 133:1–4. https://doi.org/10.1038/jid.2013.64
Jeon J, Noh J, Lee H et al (2020) RIP3 axis perturbation accelerates osteoarthritis pathogenesis:1–9. https://doi.org/10.1136/annrheumdis-2020-217904
Cheng Y, Wang K, Geng L, Sun J, Xu W, Liu D, Gong S, Zhu Y (2019) Identification of candidate diagnostic and prognostic biomarkers for pancreatic carcinoma. EBioMedicine 40:382–393. https://doi.org/10.1016/j.ebiom.2019.01.003
Karasinska JM, Topham JT, Kalloger SE, Jang GH, Denroche RE, Culibrk L, Williamson LM, Wong HL et al (2020) Altered gene expression along the glycolysis–cholesterol synthesis axis is associated with outcome in pancreatic cancer. Clin Cancer Res 26:135–146. https://doi.org/10.1158/1078-0432.CCR-19-1543
Zhou YY, Chen LP, Zhang Y, Hu SK, Dong ZJ, Wu M, Chen QX, Zhuang ZZ et al (2019) Integrated transcriptomic analysis reveals hub genes involved in diagnosis and prognosis of pancreatic cancer. Mol Med 25:1–13. https://doi.org/10.1186/s10020-019-0113-2
Li B, Cui Y, Nambiar DK, Sunwoo JB, Li R (2019) The immune subtypes and landscape of squamous cell carcinoma. Clin Cancer Res 25:3528–3537. https://doi.org/10.1158/1078-0432.CCR-18-4085
Li Z, Yu F, Yu X, Wang S (2020) Potential molecular mechanism and biomarker investigation for spinal cord injury based on bioinformatics analysis 1:
Yang Z, Lv Q, Wang Z, Dong X, Yang R, Zhao W (2017) Identification of crucial genes associated with rat traumatic spinal cord injury. Mol Med Rep 15:1997–2006. https://doi.org/10.3892/mmr.2017.6267
Wang T, Wu B, Zhang X, Zhang M, Zhang S, Huang W, Liu T, Yu W et al (2019) Identification of gene coexpression modules, hub genes, and pathways related to spinal cord injury using integrated bioinformatics methods. J Cell Biochem 120:6988–6997. https://doi.org/10.1002/jcb.27908
Liu Y, Han N, Li Q, Li Z (2016) Bioinformatics analysis of microRNA time-course expression in brown rat (rattus norvegicus) spinal cord injury self-repair. Spine (Phila Pa 1976) 41:97–103. https://doi.org/10.1097/BRS.0000000000001323
Li Z, Yu F, Yu X, Wang S (2020) Potential molecular mechanism and biomarker investigation for spinal cord injury based on bioinformatics analysis. J Mol Neurosci 70:1–1353. https://doi.org/10.1007/s12031-020-01549-0
Di Giovanni S, Knoblach SM, Brandoli C et al (2003) Gene profiling in spinal cord injury shows role of cell cycle neuronal death. Ann Neurol 53:454–468. https://doi.org/10.1002/ana.10472
Chamankhah M, Eftekharpour E, Karimi-Abdolrezaee S, Boutros PC, San-Marina S, Fehlings MG (2013) Genome-wide gene expression profiling of stress response in a spinal cord clip compression injury model. BMC Genomics 14:583. https://doi.org/10.1186/1471-2164-14-583
Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD (2012) The SVA package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28:882–883. https://doi.org/10.1093/bioinformatics/bts034
Guo Y, Huang P, Ning W, Zhang H, Yu C (2020) Identification of core genes and pathways in medulloblastoma by integrated bioinformatics analysis. J Mol Neurosci 70:1702–1712. https://doi.org/10.1007/s12031-020-01556-1
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47. https://doi.org/10.1093/nar/gkv007
Harris MA, Clark JI, Ireland A, et al (2006) go The gene ontology (GO) project in 2006. Nucleic Acids Res 34:D322–D326. https://doi.org/10.1093/nar/gkj021
Yu G, Wang LG, Han Y, He QY (2012) ClusterProfiler: an R package for comparing biological themes among gene clusters. Omi A J Integr Biol 16:284–287. https://doi.org/10.1089/omi.2011.0118
Yi Y, Fang Y, Wu K, Liu Y, Zhang W (2020) Comprehensive gene and pathway analysis of cervical cancer progression. Oncol Lett 19:3316–3332. https://doi.org/10.3892/ol.2020.11439
Kanehisa M, Sato Y, Furumichi M, Morishima K, Tanabe M (2019) New approach for understanding genome variations in KEGG. Nucleic Acids Res 47:D590–D595. https://doi.org/10.1093/nar/gky962
Mathur R, Rotroff D, Ma J, Shojaie A, Motsinger-Reif A (2018) gsea Gene set analysis methods: a systematic comparison. BioData Min 11:1–19. https://doi.org/10.1186/s13040-018-0166-8
Peng S, Yang S, Bo X, Li F (2017) Paragsea: A scalable approach for large-scale gene expression profiling. Nucleic Acids Res 45:e155. https://doi.org/10.1093/nar/gkx679
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–15550. https://doi.org/10.1073/pnas.0506580102
Xu N, Cui Y, Dong J, Huang L (2020) Exploring the molecular mechanisms of pterygium by constructing lncRNA-miRNA-mRNA regulatory network. Invest Ophthalmol Vis Sci 61:12. https://doi.org/10.1167/iovs.61.8.12
Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT et al (2019) STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 47:D607–D613. https://doi.org/10.1093/nar/gky1131
Asgharzadeh MR, Pourseif MM, Barar J et al (2019) Functional expression and impact of testis-specific gene antigen 10 in breast cancer: a combined in vitro and in silico analysis. BioImpacts 9:145–159. https://doi.org/10.15171/bi.2019.19
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504. https://doi.org/10.1101/gr.1239303
Zhang J, Liu X, Zhou W, Cheng G, Wu J, Guo S, Jia S, Liu Y et al (2020) A bioinformatics investigation into molecular mechanism of Yinzhihuang granules for treating hepatitis B by network pharmacology and molecular docking verification. Sci Rep 10:1–13. https://doi.org/10.1038/s41598-020-68224-7
Cong R, Wang Y, Wang Y, Zhang Q, Zhou X, Ji C, Yao L, Song N et al (2020) Comprehensive analysis of lncRNA expression pattern and lncRNA–miRNA–mRNA network in a rat model with cavernous nerve injury erectile dysfunction. J Sex Med 17:1–15. https://doi.org/10.1016/j.jsxm.2020.05.008
Chin CH, Chen SH, Wu HH, Ho CW, Ko MT, Lin CY (2014) cytoHubba: Identifying hub objects and sub-networks from complex interactome. BMC Syst Biol 8:1–7. https://doi.org/10.1186/1752-0509-8-S4-S11
Zhang Y, Yang X, Zhu XL, Hao JQ, Bai H, Xiao YC, Wang ZZ, Hao CY et al (2020) Bioinformatics analysis of potential core genes for glioblastoma. Biosci Rep 40. https://doi.org/10.1042/BSR20201625
Li CY, Cai JH, Tsai JJP, Wang CCN (2020) Identification of hub genes associated with development of head and neck squamous cell carcinoma by integrated bioinformatics analysis. Front Oncol 10:1–12. https://doi.org/10.3389/fonc.2020.00681
Li T, Gu M, Deng A, Qian C (2020) Increased expression of YTHDF1 and HNRNPA2B1 as potent biomarkers for melanoma: a systematic analysis. Cancer Cell Int 20:1–14. https://doi.org/10.1186/s12935-020-01309-5
Fu H, Han G, Li H, Liang X, Hu D, Zhang L, Tang P (2019) Identification of key genes and pathways involved in the heterogeneity of intrinsic growth ability between neurons after spinal cord injury in adult zebrafish. Neurochem Res 44:2057–2067. https://doi.org/10.1007/s11064-019-02841-1
Walter W, Sánchez-Cabo F, Ricote M (2015) GOplot: an R package for visually combining expression data with functional analysis. Bioinformatics 31:2912–2914. https://doi.org/10.1093/bioinformatics/btv300
Kim GT, Siregar AS, Kim EJ, Lee ES, Nyiramana MM, Woo MS, Hah YS, Han J et al (2020) Upregulation of tresk channels contributes to motor and sensory recovery after spinal cord injury. Int J Mol Sci 21:1–15. https://doi.org/10.3390/ijms21238997
Han X, Chen Y, Liu Y, Wang Z, Tang G, Tian W (2018) HIF-1α promotes bone marrow stromal cell migration to the injury site and enhances functional recovery after spinal cord injury in rats. J Gene Med 20:e3062. https://doi.org/10.1002/jgm.3062
Luo Z, Wu F, Xue E et al (2019) Hypoxia preconditioning promotes bone marrow mesenchymal stem cells survival by inducing HIF-1α in injured neuronal cells derived exosomes culture system. Cell Death Dis 10. https://doi.org/10.1038/s41419-019-1410-y
Batty NJ, Fenrich KK, Fouad K (2017) The role of cAMP and its downstream targets in neurite growth in the adult nervous system. Neurosci Lett 652:56–63. https://doi.org/10.1016/j.neulet.2016.12.033
Ávila-Mendoza J, Subramani A, Denver RJ (2020) Krüppel-like factors 9 and 13 block axon growth by transcriptional repression of key components of the cAMP signaling pathway. Front Mol Neurosci 13:1–17. https://doi.org/10.3389/fnmol.2020.602638
Li H, Huang Y, Ma C, Yu X, Zhang Z, Shen L (2015) MiR-203 involves in neuropathic pain development and represses rap1a expression in nerve growth factor differentiated neuronal PC12 cells. Clin J Pain 31:36–43. https://doi.org/10.1097/AJP.0000000000000070
Gao L, Pu X, Huang Y, Huang J (2019) MicroRNA-340-5p relieved chronic constriction injury-induced neuropathic pain by targeting Rap1A in rat model. Genes and Genomics 0:0. https://doi.org/10.1007/s13258-019-00802-0, 41, 713, 721
Shi LL, Zhang N, Xie XM, Chen YJ, Wang R, Shen L, Zhou JS, Hu JG et al (2017) Transcriptome profile of rat genes in injured spinal cord at different stages by RNA-sequencing. BMC Genomics 18:1–14. https://doi.org/10.1186/s12864-017-3532-x
Xia Y, Xia H, Chen D, Liao Z, Yan Y (2017) Mechanisms of autophagy and apoptosis mediated by JAK2 signaling pathway after spinal cord injury of rats. Exp Ther Med 14:1589–1593. https://doi.org/10.3892/etm.2017.4674
Kang MK, Kang SK (2008) Interleukin-6 induces proliferation in adult spinal cord-derived neural progenitors via the JAK2/STAT3 pathway with EGF-induced MAPK phosphorylation. Cell Prolif 41:377–392. https://doi.org/10.1111/j.1365-2184.2008.00537.x
Li Z, Chen T, Cao Y, Jiang X, Lin H, Zhang J, Chen Z (2019) Pros and cons: autophagy in acute spinal cord injury. Neurosci Bull 35:941–945. https://doi.org/10.1007/s12264-019-00368-7
Li H, Wang Y, Hu X, Ma B, Zhang H (2019) Thymosin beta 4 attenuates oxidative stress-induced injury of spinal cord-derived neural stem/progenitor cells through the TLR4/MyD88 pathway. Gene 707:136–142. https://doi.org/10.1016/j.gene.2019.04.083
Xu S, Wang J, Jiang J, Song J, Zhu W, Zhang F, Shao M, Xu H et al (2020) TLR4 promotes microglial pyroptosis via lncRNA-F630028O10Rik by activating PI3K/AKT pathway after spinal cord injury. Cell Death Dis 11:693. https://doi.org/10.1038/s41419-020-02824-z
Wan G, An Y, Tao J, Wang Y, Zhou Q, Yang R, Liang Q (2020) MicroRNA-129-5p alleviates spinal cord injury in mice via suppressing the apoptosis and inflammatory response through HMGB1/TLR4/NF-κB pathway. Biosci Rep 40:1–15. https://doi.org/10.1042/BSR20193315
Ribeiro P, Castro MV, Perez M, Cartarozzi LP, Spejo AB, Chiarotto GB, Augusto TM, Oliveira ALR (2020) Toll-like receptor 4 (TLR4) influences the glial reaction in the spinal cord and the neural response to injury following peripheral nerve crush. Brain Res Bull 155:67–80. https://doi.org/10.1016/j.brainresbull.2019.11.008
Gaojian T, Dingfei Q, Linwei L, Xiaowei W, Zheng Z, Wei L, Tong Z, Benxiang N et al (2020) Parthenolide promotes the repair of spinal cord injury by modulating M1/M2 polarization via the NF-κB and STAT 1/3 signaling pathway. Cell Death Discov 6:97. https://doi.org/10.1038/s41420-020-00333-8
Ji Z, Jiang X, Li Y, Song J, Chai C, Lu X (2020) Neural stem cells induce M2 polarization of macrophages through the upregulation of interleukin-4. Exp Ther Med 20:1–9. https://doi.org/10.3892/etm.2020.9277
Zhang T, Li K, Zhang ZL, Gao K, Lv CL (2021) LncRNA Airsci increases the inflammatory response after spinal cord injury in rats through the nuclear factor kappa B signaling pathway. Neural Regen Res 16:772–777. https://doi.org/10.4103/1673-5374.295335
Wang B, Shen PF, Qu YX et al (2019) MiR-940 promotes spinal cord injury recovery by inhibiting TLR4/NF-κB pathway-mediated inflammation. Eur Rev Med Pharmacol Sci 23:3190–3197. https://doi.org/10.26355/eurrev_201904_17677
Su Y, Zong S, Wei C, Song F, Feng H, Qin A, Lian Z, Fu F et al (2019) Salidroside promotes rat spinal cord injury recovery by inhibiting inflammatory cytokine expression and NF-κB and MAPK signaling pathways. J Cell Physiol 234:14259–14269. https://doi.org/10.1002/jcp.28124
Qian Z, Chang J, Jiang F, Ge D, Yang L, Li Y, Chen H, Cao X (2020) Excess administration of miR-340-5p ameliorates spinal cord injury-induced neuroinflammation and apoptosis by modulating the P38-MAPK signaling pathway. Brain Behav Immun 87:531–542. https://doi.org/10.1016/j.bbi.2020.01.025
Ye J, Xue R, Ji ZY et al (2020) Effect of NT-3 on repair of spinal cord injury through the MAPK signaling pathway. Eur Rev Med Pharmacol Sci 24:2165–2172. https://doi.org/10.26355/eurrev_202003_20481
Ni Y, Gu J, Wu J, Xu L, Rui Y (2020) MGMT-mediated neuron apoptosis in injured rat spinal cord. Tissue Cell 62:101311. https://doi.org/10.1016/j.tice.2019.101311
Yu X, Zhang S, Zhao D, Zhang X, Xia C, Wang T, Zhang M, Liu T et al (2019) SIRT1 inhibits apoptosis in in vivo and in vitro models of spinal cord injury via microRNA-494. Int J Mol Med 43:1758–1768. https://doi.org/10.3892/ijmm.2019.4106
Li Y, Guo Y, Fan Y, Tian H, Li K, Mei X (2019) Melatonin enhances autophagy and reduces apoptosis to promote locomotor recovery in spinal cord injury via the PI3K/AKT/mTOR signaling pathway. Neurochem Res 44:2007–2019. https://doi.org/10.1007/s11064-019-02838-w
Tang J, Guo WC, Hu JF, Yu L (2019) Let-7 participates in the regulation of inflammatory response in spinal cord injury through PI3K/Akt signaling pathway. Eur Rev Med Pharmacol Sci 23:6767–6773. https://doi.org/10.26355/eurrev_201908_18714
Ding B, Lin C, Liu Q, He Y, Ruganzu JB, Jin H, Peng X, Ji S et al (2020) Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro. J Neuroinflammation 17:1–17. https://doi.org/10.1186/s12974-020-01981-4
Kong Y, Wang F, Wang J, Liu C, Zhou Y, Xu Z, Zhang C, Sun B et al (2020) Pathological mechanisms linking diabetes mellitus and Alzheimer’s disease: the receptor for advanced glycation end products (RAGE). Front Aging Neurosci 12:1–10. https://doi.org/10.3389/fnagi.2020.00217
Abbaszadeh F, Fakhri S, Khan H (2020) Targeting apoptosis and autophagy following spinal cord injury: therapeutic approaches to polyphenols and candidate phytochemicals. Pharmacol Res 160:105069. https://doi.org/10.1016/j.phrs.2020.105069
Yagura K, Ohtaki H, Tsumuraya T, Sato A, Miyamoto K, Kawada N, Suzuki K, Nakamura M et al (2020) The enhancement of CCL2 and CCL5 by human bone marrow-derived mesenchymal stem/stromal cells might contribute to inflammatory suppression and axonal extension after spinal cord injury. PLoS One 15:1–23. https://doi.org/10.1371/journal.pone.0230080
Longhi-Balbinot DT, Rossaneis AC, Pinho-Ribeiro FA, Bertozzi MM, Cunha FQ, Alves-Filho JC, Cunha TM, Peron JPS et al (2016) The nitroxyl donor, Angeli’s salt, reduces chronic constriction injury-induced neuropathic pain. Chem Biol Interact 256:1–8. https://doi.org/10.1016/j.cbi.2016.06.009
Hyochol Ahn, et al 2017 (2017) HHS Public Access Author manuscript Trends Immunol. Author manuscript; available in PMC 2018 May 01. Published in final edited form as: Trends Immunol. 2017 May ; 38(5): 310–322. doi:https://doi.org/10.1016/j.it.2017.01.006. IL-17 signaling: the yin and the yang Nilesh H. Physiol Behav 176:139–148. https://doi.org/10.1016/j.it.2017.01.006.IL-17
Liu NK, Zhang YP, Han S, Pei J, Xu LY, Lu PH, Shields CB, Xu XM (2007) Annexin A1 reduces inflammatory reaction and tissue damage through inhibition of phospholipase A2 activation in adult rats following spinal cord injury. J Neuropathol Exp Neurol 66:932–943. https://doi.org/10.1097/nen.0b013e3181567d59
Brennan FH, Jogia T, Gillespie ER, Blomster LV, Li XX, Nowlan B, Williams GM, Jacobson E et al (2019) Complement receptor C3aR1 controls neutrophil mobilization following spinal cord injury through physiological antagonism of CXCR2. JCI Insight 4:1–18. https://doi.org/10.1172/jci.insight.98254
Li L, Xiong Z yong, Qian ZM, et al (2014) Complement C5a is detrimental to histological and functional locomotor recovery after spinal cord injury in mice. Neurobiol Dis 66:74–82. https://doi.org/10.1016/j.nbd.2014.02.008
Hiraizumi Y, Fujimaki E, Transfeldt EE, Kawahara N, Fiegel VD, Knighton D, Sung JH (1996) The effect of the platelet derived wound healing formula and the nerve growth factor on the experimentally injured spinal cord. Spinal Cord 34:394–402. https://doi.org/10.1038/sc.1996.71
Biggins PJC, Brennan FH, Taylor SM, Woodruff TM, Ruitenberg MJ (2017) The alternative receptor for complement component 5a, C5aR2, conveys neuroprotection in traumatic spinal cord injury. J Neurotrauma 34:2075–2085. https://doi.org/10.1089/neu.2016.4701
Elujoba-Bridenstine A, Shao L, Zink K, Sanchez L, Cox B, Pajcini K, Tamplin OJ (2019) The neurotransmitter receptor Gabbr1 regulates proliferation and function of hematopoietic stem and progenitor cells. Blood 134:3707–3707. https://doi.org/10.1182/blood-2019-130627
Pineau I, Sun L, Bastien D, Lacroix S (2010) Astrocytes initiate inflammation in the injured mouse spinal cord by promoting the entry of neutrophils and inflammatory monocytes in an IL-1 receptor/MyD88-dependent fashion. Brain Behav Immun 24:540–553. https://doi.org/10.1016/j.bbi.2009.11.007
Francos-Quijorna I, Santos-Nogueira E, Gronert K, Sullivan AB, Kopp MA, Brommer B, David S, Schwab JM et al (2017) Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after spinal cord injury. J Neurosci 37:11731–11743. https://doi.org/10.1523/JNEUROSCI.1395-17.2017
Boomkamp SD, McGrath MA, Houslay MD, Barnett SC (2014) Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model. Br J Pharmacol 171:2385–2398. https://doi.org/10.1111/bph.12588
Watanabe S, Uchida K, Nakajima H, Matsuo H, Sugita D, Yoshida A, Honjoh K, Johnson WEB et al (2015) Early transplantation of mesenchymal stem cells after spinal cord injury relieves pain hypersensitivity through suppression of pain-related signaling cascades and reduced inflammatory cell recruitment. Stem Cells 33:1902–1914. https://doi.org/10.1002/stem.2006
Chen G, Zhou Z, Sha W, Wang L, Yan F, Yang X, Qin X, Wu M et al (2020) A novel CX3CR1 inhibitor AZD8797 facilitates early recovery of rat acute spinal cord injury by inhibiting inflammation and apoptosis. Int J Mol Med 45:1373–1384. https://doi.org/10.3892/ijmm.2020.4509
Poniatowski ŁA, Wojdasiewicz P, Krawczyk M, Szukiewicz D, Gasik R, Kubaszewski Ł, Kurkowska-Jastrzębska I (2017) Analysis of the role of CX3CL1 (fractalkine) and its receptor CX3CR1 in traumatic brain and spinal cord injury: Insight into recent advances in actions of neurochemokine agents. Mol Neurobiol 54:2167–2188. https://doi.org/10.1007/s12035-016-9787-4
Sun JF, Yang HL, Huang YH, Chen Q, Cao XB, Li DP, Shu HM, Jiang RY (2017) CaSR and calpain contribute to the ischemia reperfusion injury of spinal cord. Neurosci Lett 646:49–55. https://doi.org/10.1016/j.neulet.2017.03.009
Sapio MR, Iadarola MJ, Loydpierson AJ, Kim JJ, Thierry-Mieg D, Thierry-Mieg J, Maric D, Mannes AJ (2020) Dynorphin and enkephalin opioid peptides and transcripts in spinal cord and dorsal root ganglion during peripheral inflammatory hyperalgesia and allodynia. J Pain 21:988–1004. https://doi.org/10.1016/j.jpain.2020.01.001
Rojewska E, Wawrzczak-Bargiela A, Szucs E, Benyhe S, Starnowska J, Mika J, Przewlocki R, Przewlocka B (2018) Alterations in the activity of spinal and thalamic opioid systems in a mice neuropathic pain model. Neuroscience 390:293–302. https://doi.org/10.1016/j.neuroscience.2018.08.013
Shamseldin HE, Masuho I, Alenizi A, Alyamani S, Patil DN, Ibrahim N, Martemyanov KA, Alkuraya FS (2016) GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition. Genome Biol 17:1–9. https://doi.org/10.1186/s13059-016-1061-6
Ju LH, Choi TI, Kim YM et al (2020) Regulation of habenular G-protein gamma 8 on learning and memory via modulation of the central acetylcholine system. Mol Psychiatry. https://doi.org/10.1038/s41380-020-00893-2
Li Z, Wystrach L, Bernstein A et al (2020) The tissue-renin-angiotensin system of the human intervertebral disc. Eur Cells Mater 40:115–132. https://doi.org/10.22203/eCM.v040a07
Li ZW, Sun B, Gong T, Guo S, Zhang J, Wang J, Sugawara A, Jiang M et al (2019) GNAI1 and GNAI3 reduce colitis-associated tumorigenesis in mice by blocking IL6 signaling and down-regulating expression of GNAI2. Gastroenterology 156:2297–2312. https://doi.org/10.1053/j.gastro.2019.02.040
Mendsaikhan A, Tooyama I, Bellier JP, Serrano GE, Sue LI, Lue LF, Beach TG, Walker DG (2019) Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer’s disease and aged brains: increased levels correlate with neuropathology. Acta Neuropathol Commun 7:1–26. https://doi.org/10.1186/s40478-019-0862-8
Nakamura M, Okada S, Toyama Y, Okano H (2005) Role of IL-6 in spinal cord injury in a mouse model. Clin Rev Allergy Immunol 28:197–203. https://doi.org/10.1385/CRIAI:28:3:197
Alizadeh A, Dyck SM, Karimi-Abdolrezaee S (2015) Myelin damage and repair in pathologic CNS: challenges and prospects. Front Mol Neurosci 8:1–27. https://doi.org/10.3389/fnmol.2015.00035
Bendix PM, Simonsen AC, Florentsen CD, Häger SC, Mularski A, Zanjani AAH, Moreno-Pescador G, Klenow MB et al (2020) Interdisciplinary synergy to reveal mechanisms of annexin-mediated plasma membrane shaping and repair. Cells 9:1–12. https://doi.org/10.3390/cells9041029
McArthur S, Juban G, Gobbetti T, Desgeorges T, Theret M, Gondin J, Toller-Kawahisa JE, Reutelingsperger CP et al (2020) Annexin A1 drives macrophage skewing to accelerate muscle regeneration through AMPK activation. J Clin Invest 130:1156–1167. https://doi.org/10.1172/JCI124635
Chen J, Cui Z, Yang S, Wu C, Li W, Bao G, Xu G, Sun Y et al (2017) The upregulation of annexin A2 after spinal cord injury in rats may have implication for astrocyte proliferation. Neuropeptides 61:67–76. https://doi.org/10.1016/j.npep.2016.10.007
Zhong ZQ, Xiang Y, Hu X et al (2017) Synaptosomal-associated protein 25 may be an intervention target for improving sensory and locomotor functions after spinal cord contusion. Neural Regen Res 12:969–976. https://doi.org/10.4103/1673-5374.208592
Liu X, Sun Y, Li H, Li Y, Li M, Yuan Y, Cui S, Yao D (2017) Effect of Spp1 on nerve degeneration and regeneration after rat sciatic nerve injury. BMC Neurosci 18:1–10. https://doi.org/10.1186/s12868-017-0348-1
Liu Y, Wang X, Li W et al (2017) A sensitized IGF1 treatment restores corticospinal axon-dependent functions. Neuron 95:817-833.e4. https://doi.org/10.1016/j.neuron.2017.07.037
Fu Y, Hashimoto M, Ino H, Murakami M, Yamazaki M, Moriya H (2004) Spinal root avulsion-induced upregulation of osteopontin expression in the adult rat spinal cord. Acta Neuropathol 107:8–16. https://doi.org/10.1007/s00401-003-0775-1
Hashimoto M, Sun D, Rittling SR, Denhardt DT, Young W (2007) Osteopontin-deficient mice exhibit less inflammation, greater tissue damage, and impaired locomotor recovery from spinal cord injury compared with wild-type controls. J Neurosci 27:3603–3611. https://doi.org/10.1523/JNEUROSCI.4805-06.2007
Kyyriäinen J, Tapiala J, Lipponen A, Ekolle Ndode-Ekane X, Pitkänen A (2020) Plau/Plaur double-deficiency did not worsen lesion severity or vascular integrity after traumatic brain injury. Neurosci Lett 729:134935. https://doi.org/10.1016/j.neulet.2020.134935
Freeman (2018) Endothelial cell-specific deletion of P2Y2 receptor promotes plaque stability in atherosclerosis-susceptible ApoE-null mice. Physiol Behav 176:139–148. https://doi.org/10.1117/12.2549369.Hyperspectral
Acknowledgements
We thank Dr. Xiao Fang of the Department of Burns (The First Affiliated Hospital of Anhui Medical University) for his help in programming and graphing in computer R language.
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This study was supported by the National Natural Science Foundation of China, Nos. 81871785 and 81672161.
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Sheng Fang conceived the original idea and designed the outlines of the study. Lin Zhong and An-quan Wang Helped collect, organize, and check the data. Hui Zhang and Zong-Sheng Yin aided in revising the manuscript. All authors have read and approved the final manuscript.
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Fang, S., Zhong, L., Wang, Aq. et al. Identification of Regeneration and Hub Genes and Pathways at Different Time Points after Spinal Cord Injury. Mol Neurobiol 58, 2643–2662 (2021). https://doi.org/10.1007/s12035-021-02289-x
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DOI: https://doi.org/10.1007/s12035-021-02289-x