|
|
生酮饮食治疗脊髓损伤关键基因的筛选及潜在中药预测
|
Abstract:
目的：利用生物信息学技术分析生酮饮食对治疗脊髓损伤的潜在分子靶点和相关通路，同时通过靶基因预测潜在的中药药物用于治疗脊髓损伤。在GEO数据库中提取与脊髓损伤治疗相关的生酮饮食芯片组数据，并利用R语言软件对芯片数据进行分析，找出差异表达的基因。然后对这些差异基因进行功能富集分析，以获取与差异基因相关的信号通路和分子功能。并构建基因–蛋白网络，然后使用Cytoscape对该网络进行分析，以获取治疗脊髓损伤的关键基因。接着将这些基因映射到CTD数据库获得的脊髓损伤疾病基因网络中，以确定生酮饮食治疗脊髓损伤过程中的核心基因。最后，通过将核心基因与医学本体信息检索平台(Coremine Medical)相互映射，筛选出治疗脊髓损伤的中药。结果：GEO芯片组数据分析得出生酮饮食治疗脊髓损伤的差异基因有237个，最后筛选出10个核心基因包括LCN2、TTR、ORM1、ATP6V0D2、TNS1、HTR2C、ACTRT2、UOX、KCNAB3、RAB9B。治疗脊髓损伤的潜在中药药物有：大黄、三七、黄芪、充蔚子。
Objective: To analyze potential molecular targets and related pathways of ketogenic diet in the treatment of spinal cord injury using bioinformatics techniques, and predict potential Chinese herbal medicines for the treatment of spinal cord injury through target gene analysis. Method: Mi-croarray data of ketogenic diet treatment for spinal cord injury in the GEO database were extracted, and differentially expressed genes were obtained through analysis using R software. Functional en-richment analysis was performed on the differentially expressed genes to identify related signaling pathways and molecular functions. Using STING, a protein-protein interaction network of the genes was constructed, and Cytoscape was used to analyze the network and identify key genes in the treatment of spinal cord injury. The identified genes were mapped to the spinal cord injury disease gene network obtained from the CTD database, and core genes of the ketogenic diet treatment pro-cess for spinal cord injury were obtained. Finally, using Coremine Medical, the core genes were mapped to the medical ontology information retrieval platform to screen potential Chinese herbal medicines for the treatment of spinal cord injury. Results: Analysis of GEO microarray data revealed 237 differentially expressed genes associated with ketogenic diet treatment for spinal cord injury. Ten core genes, including LCN2, TTR, ORM1, ATP6V0D2, TNS1, HTR2C, ACTRT2, UOX, KCNAB3 and RAB9B, were selected. Potential Chinese herbal medicines for the treatment of spinal cord injury included Rhubarb, Sanqi, Astragalus and Chongweizi.
| [1] | 刘俊, 高峰, 李建军. 创伤性脊髓损伤患者的流行病学及住院费用影响因素研究[J]. 中国康复, 2020, 35(3): 139-142. |
| [2] | 蔡志威. 区域性创伤性脊髓损伤流行病学调查研究[D]: [硕士学位论文]. 天津: 天津医科大学, 2019. |
| [3] | Nie, B.X., Zhao, G., Yuan, X.F., et al. (2022) Inhibition of CDK1 Attenuates Neuronal Apoptosis and Au-tophagy and Confers Neuroprotection after Chronic Spinal Cord Injury in Vivo. Journal of Chemical Neuroanatomy, 119, Article ID: 1020533. |
| [4] | Veyrat-Durebex, C., Reynier, P., Procaccio, V., et al. (2018) How Can a Ketogenic Diet Im-prove Motor Function? Frontiers in Molecular Neuroscience, 11, Article 315811. https://doi.org/10.3389/fnmol.2018.00015 |
| [5] | Keene, L.D. (2006) A Systematic Review of the Use of the Keto-genic Diet in Childhood Epilepsy. Pediatric Neurology, 35, 1-5. https://doi.org/10.1016/j.pediatrneurol.2006.01.005 |
| [6] | Pani, G. (2015) Neuroprotective Effects of Dietary Re-striction: Evidence and Mechanisms. Seminars in Cell and Developmental Biology, 40, 106-114. https://doi.org/10.1016/j.semcdb.2015.03.004 |
| [7] | Streijger, F., Plunet, T.W., Lee, T.H.J., et al. (2017) Ketogenic Diet Improves Forelimb Motor Function after Spinal Cord Injury in Rodents. PLOS ONE, 8, e78765. https://doi.org/10.1371/journal.pone.0078765 |
| [8] | Tan, B.T., Jiang, H., Moulson, A.J., et al. (2020) Neuroprotec-tive Effects of a Ketogenic Diet in Combination with Exogenous Ketone Salts following Acute Spinal Cord Injury. Neu-ral Regeneration Research, 15, 1912-1919.
https://doi.org/10.4103/1673-5374.280327 |
| [9] | Wang, X., Wu, X., Liu, Q., et al. (2017) Ketogenic Metabolism In-hibits Histone Deacetylase (HDAC) and Reduces Oxidative Stress after Spinal Cord Injury in Rats. Neuroscience, 366, 1912-1919.
https://doi.org/10.1016/j.neuroscience.2017.09.056 |
| [10] | Wang, X.M., Wu, X.L., Liu, Q., et al. (2017) The Ketone Metabolite β-Hydroxybutyrate Attenuates Oxidative Stress in Spinal Cord Injury by Suppression of Class I Histone Deacetylases. Journal of Neurotrauma, 34, 2645-2655.
https://doi.org/10.1089/neu.2017.5192 |
| [11] | Yu, G.C., Wang, L.G., Han, Y.Y. and He, Q.Y. (2012) ClusterProfiler: An R Package for Comparing Biological Themes among Gene Clusters. OMICS: A Journal of Integrative Biology, 16, 284-287.
https://doi.org/10.1089/omi.2011.0118 |
| [12] | Szklarczyk, D., Gable, A.L., Nastou, K.C., et al. (2021) The STRING Database in 2021: Customizable Protein-Protein Networks, and Functional Characterization of User-Uploaded Gene/Measurement Sets. Nucleic Acids Research, 49, D605-D612. https://doi.org/10.1093/nar/gkaa1074 |
| [13] | Davis, A.P., Grondin, C.J., Johnson, R.J., et al. (2019) The Comparative Toxicogenomics Database: Update 2019. Nucleic Acids Research, 47, D948-D954. https://doi.org/10.1093/nar/gky868 |
| [14] | Arsalan, A., Matthew, S.D. and Soheila, K. (2019) Traumatic Spinal Cord Injury: An Overview of Pathophysiology, Models and Acute Injury Mechanisms. Frontiers in Neurology, 10, Article 441408.
https://doi.org/10.3389/fneur.2019.00282 |
| [15] | Miller, V.J., Villamena, F.A. and Volek, J.S. (2018) Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health. Journal of Nutrition and Metabolism, 2018, Article ID: 5157645.
https://doi.org/10.1155/2018/5157645 |
| [16] | Carrì, M.T., Polster, B.M. and Beart, P.M. (2018) Mitochondria in the Nervous System: From Health to Disease, Part II. Neurochemistry International, 117, 1-4. https://doi.org/10.1016/j.neuint.2018.04.006 |
| [17] | Polster, B.M., Carrì, M.T. and Beart, P.M. (2017) Mitochondria in the Nervous System: From Health to Disease, Part I. Neurochemistry International, 109, 1-4. https://doi.org/10.1016/j.neuint.2017.09.006 |
| [18] | Bratic, I. and Trifunovic, A. (2010) Mitochondrial Energy Me-tabolism and Ageing. Biochimica et Biophysica Acta (BBA)—Bioenergetics, 1797, 961-967. https://doi.org/10.1016/j.bbabio.2010.01.004 |
| [19] | Musatov, A. and Robinson, N.C. (2012) Susceptibility of Mito-chondrial Electron-Transport Complexes to Oxidative Damage. Focus on Cytochrome c Oxidase. Free Radical Research, 46, 1313-1326.
https://doi.org/10.3109/10715762.2012.717273 |
| [20] | Cronin, S.J.F., Seehus, C., Weidinger, A., et al. (2019) Pub-lisher Correction: The Metabolite BH4 Controls T Cell Proliferation in Autoimmunity and Cancer. Nature, 572, E18. |
| [21] | Lu, F., Inoue, K., Kato, J., et al. (2019) Functions and Regulation of Lipocalin-2 in Gut-Origin Sepsis: A Narrative Review. Critical Care, 23, Article No. 269. https://doi.org/10.1186/s13054-019-2550-2 |
| [22] | Kim, J.H., Ko, P.W., Lee, H.W., et al. (2017) Astrocyte-Derived Lipocalin-2 Mediates Hippocampal Damage and Cognitive Deficits in Experimental Models of Vascular Dementia. Glia, 65, 1471-1490.
https://doi.org/10.1002/glia.23174 |
| [23] | Zhang, Y., Liu, J., Yang, B., et al. (2018) Ginkgo Biloba Extract Inhibits Astrocytic Lipocalin-2 Expression and Alleviates Neuroinflammatory Injury via the JAK2/STAT3 Pathway after Is-chemic Brain Stroke. Frontiers in Pharmacology, 9, Article 356208. https://doi.org/10.3389/fphar.2018.00518 |
| [24] | 梁修梓, 陈勇军. TTR基因突变致神经系统损害的研究进展[J]. 中南医学科学杂志, 2020, 48(6): 565-568, 575. |
| [25] | 王玥, 周玥, 赵丽. 缺血性脑卒中关键基因的筛选及治疗药物的预测[J]. 科技导报, 2023, 41(9): 89-97. |
| [26] | 夏宇. 巨噬细胞ATP6V0d2通过促进自噬体-溶酶体融合抑制炎症小体活化和相关炎症性疾病[D]: [博士学位论文]. 武汉: 华中科技大学, 2018. |
| [27] | Wang, Z.H., Ye, J.X., Dong, F.R., et al. (2022) TNS1: Emerging Insights into Its Domain Function, Biological Roles, and Tumors. Biology, 11, Article 1571. https://doi.org/10.3390/biology11111571 |
| [28] | Ding, J., Miao, Q.F., Zhang, J.W., et al. (2020) H258R Mutation in KCNAB3 Gene in a Family with Genetic Epilepsy and Febrile Seizures Plus. Brain and Behavior, 10, e01859. https://doi.org/10.1002/brb3.1859 |
| [29] | Yuko, H., Shun-ichi, Y., Yusuke, K., et al. (2015) Mitophagy Is Primarily Due to Alternative Autophagy and Requires the MAPK1 and MAPK14 Signaling Pathways. Autophagy, 11, 332-343.
https://doi.org/10.1080/15548627.2015.1023047 |
| [30] | Giannandrea, M., Bianchi, V., Mignogna, L.M., et al. (2010) Mutations in the Small GTPase Gene RAB39B Are Responsible for X-linked Mental Retardation Associated with Au-tism, Epilepsy, and Macrocephaly. The American Journal of Human Genetics, 86, 185-195. https://doi.org/10.1016/j.ajhg.2010.01.011 |
| [31] | Jin, Z., Gan, C., Luo, G., et al. (2021) Notoginsenoside R1 Protects Hypoxia-Reoxygenation Deprivation-Induced Injury by Upregulation of miR-132 in H9c2 Cells. Human & Experimental Toxicology, 40, S29-S38.
https://doi.org/10.1177/09603271211025589 |
| [32] | 罗鸿波, 周明建, 陈宇鑫. 三七皂苷R1对大鼠脊髓损伤后线粒体功能和神经炎症的作用及相关机制研究[J]. 中国脊柱脊髓杂志, 2022, 32(9): 823-833. |
| [33] | Shang, H., Jia, X.H., Liu, H.M., et al. (2022) A Comprehensive Review of Emodin in Fibrosis Treatment. Fitoterapia, 165, Article ID: 105358. https://doi.org/10.1016/j.fitote.2022.105358 |
| [34] | 曾欢欢, 黄英如, 李子健, 等. 大黄素对大鼠急性脊髓损伤后氧化应激和炎症反应的影响研究[J]. 中国中药杂志, 2018, 43(9): 1886-1893. |
| [35] | Costa, I.M., Lima, F.O.V., Fernandes, L.C.B., et al. (2019) Astragaloside IV Supplementation Promotes A Neuroprotective Effect in Ex-perimental Models of Neurological Disorders: A Systematic Review. Current Neuropharmacology, 17, 648-665. https://doi.org/10.2174/1570159X16666180911123341 |
| [36] | 冯韬, 吕烨华, 王盛, 等. 黄芪注射液对大鼠急性脊髓损伤的神经保护作用及机制研究[J]. 南京中医药大学学报, 2022, 38(12): 1128-1136. |
