JNK在脑缺血再灌注损伤细胞凋亡中的作用
The Role of JNK in Apoptosis after Cerebral Ischemia-Reperfusion Injury
DOI: 10.12677/ACM.2021.115302, PDF,    科研立项经费支持
作者: 王海鹏:青岛大学青岛医学院,山东 青岛 ;于 群:潍坊医学院麻醉学院,山东 潍坊;王明山*:青岛大学附属青岛市市立医院麻醉科,山东 青岛
关键词: 脑缺血/再灌注损伤JNK信号通路细胞凋亡抑制剂Cerebral Ischemia/Reperfusion Injury JNK Signaling Pathway Apoptosis Inhibitor
摘要: 缺血性脑卒中发病率逐年增高,严重威胁人们的健康与生活质量,脑缺血/再灌注损伤(CIRI)是其发病及治疗过程中常见的不良后果之一。c-jun氨基末端激酶(JNK)信号转导通路在CIRI中起着重要的调控作用,参与介导了神经元凋亡等病理生理过程,是防治CIRI的重要靶点。许多研究提示,JNK抑制剂可以减少CIRI引起的细胞凋亡,发挥神经保护作用,可为临床上缺血性脑卒中的治疗提供新的思路,同时对寻找新的药物靶点和筛选新药都具有重要的理论意义。
Abstract: The incidence rate of ischemic stroke is increasing year by year, which seriously threatens people’s health and quality of life. Cerebral ischemia/reperfusion injury (CIRI) is one of the common adverse consequences in the course of its onset and treatment. C-Jun N-terminal kinase (JNK) signal transduction pathway plays an important role in the regulation of CIRI. It participates in the pathophysiological processes such as neuronal apoptosis, and is an important target for the prevention and treatment of CIRI. Many studies suggest that JNK inhibitors can reduce the apoptosis induced by CIRI and play a neuroprotective role, which can provide a new idea for the treatment of ischemic stroke in clinic. At the same time, it has important theoretical significance for finding new drug targets and screening new drugs.
文章引用:王海鹏, 于群, 王明山. JNK在脑缺血再灌注损伤细胞凋亡中的作用[J]. 临床医学进展, 2021, 11(5): 21111-2119. https://doi.org/10.12677/ACM.2021.115302

参考文献

[1] Feigin, V.L., Krishnamurthi, R.V., Parmar, P., Norrving, B., Mensah, G.A., Bennett, D.A., et al. (2015) Update On the Global Burden of Ischemic and Hemorrhagic Stroke in 1990-2013: The GBD 2013 Study. Neuroepidemiology, 45, 161-176. [Google Scholar] [CrossRef] [PubMed]
[2] Liu, L., Wang, D., Lawrence Wong, K.S. and Wang, Y. (2011) Stroke and Stroke Care in China: Huge Burden, Significant Workload, and a National Priority. Stroke, 42, 3651-3654. [Google Scholar] [CrossRef
[3] Wang, W., Jiang, B., Sun, H., Ru, X., Sun, D., Wang, L., et al. (2017) Prevalence, Incidence, and Mortality of Stroke in China: Results From a Nationwide Population-Based Survey of 480687 Adults. Circulation, 135, 759-771. [Google Scholar] [CrossRef
[4] Wang, D., Liu, J., Liu, M., Lu, C., Brainin, M. and Zhang, J. (2017) Patterns of Stroke between University Hospitals and Nonuniversity Hospitals in Mainland China: Prospective Multicenter Hospital-Based Registry Study. World Neurosurgery, 98, 258-265. [Google Scholar] [CrossRef] [PubMed]
[5] Eltzschig, H.K. and Eckle, T. (2011) Ischemia and Reperfusion—From Mechanism to Translation. Nature Medicine, 17, 1391-1401. [Google Scholar] [CrossRef] [PubMed]
[6] 王道合, 拜承萍, 赵秀丽. 脑缺血再灌注损伤的防治方法与机制研究进展[J]. 中国实用神经疾病杂志, 2019, 22(17): 1958-1965.
[7] Coffey, E.T. (2014) Nuclear and Cytosolic JNK Signalling in Neurons. Nature Reviews. Neuroscience, 15, 285-299. [Google Scholar] [CrossRef] [PubMed]
[8] Cargnello, M. and Roux, P.P. (2011) Activation and Function of the MAPKs and their Substrates, the MAPK-activated Protein Kinases. Microbiology and Molecular Biology Reviews, 75, 50-83. [Google Scholar] [CrossRef
[9] Haeusgen, W., Herdegen, T. and Waetzig, V. (2011) The Bottleneck of JNK Signaling: Molecular and Functional Characteristics of MKK4 and MKK7. European Journal of Cell Biology, 90, 536-544. [Google Scholar] [CrossRef] [PubMed]
[10] Patterson, K.I., Brummer, T., O’Brien, P.M. and Daly, R.J. (2009) Dual-Specificity Phosphatases: Critical Regulators with Diverse Cellular Targets. The Biochemical Journal, 418, 475-489. [Google Scholar] [CrossRef
[11] Engström, W., Ward, A. and Moorwood, K. (2010) The Role of Scaffold Proteins in JNK Signalling. Cell Proliferation, 43, 56-66. [Google Scholar] [CrossRef] [PubMed]
[12] Sabapathy, K. (2012) Role of the JNK Pathway in Human Diseases. Progress in Molecular Biology and Translational Science, 106, 145-169. [Google Scholar] [CrossRef
[13] Ma, S., Liu, X., Cheng, B., Jia, Z., Hua, H. and Xin, Y. (2019) Chemical Characterization of Polysaccharides Isolated From Scrophularia Ningpoensis and its Protective Effect on the Cerebral Ischemia/Reperfusin Injury in Rat Model. International Journal of Biological Macromolecules, 139, 955-966. [Google Scholar] [CrossRef] [PubMed]
[14] Zhu, Q.J., Xu, Y., Du, C.P. and Hou, X.-Y. (2012) SUMOylation of the Kainate Receptor Subunit GluK2 Contributes to the Activation of the MLK3-JNK3 Pathway Following Kainate Stimulation. FEBS Letters, 586, 1259-1264. [Google Scholar] [CrossRef] [PubMed]
[15] Zhen, Y., Ding, C., Sun, J., Wang, Y., Li, S. and Dong, L. (2016) Activation of the Calcium-Sensing Receptor Promotes Apoptosis by Modulating the JNK/p38 MAPK Pathway in Focal Cerebral Ischemia-Reperfusion in Mice. American Journal of Translational Research, 8, 911-921.
[16] Wang, X.T., Pei, D.S., Xu, J., Guan, Q.-H., Sun, Y.-F., Liu, X.-M., et al. (2007) Opposing Effects of Bad Phosphorylation at Two Distinct Sites by Akt1 and JNK1/2 on Ischemic Brain Injury. Cellular Signaling, 19, 1844-1856. [Google Scholar] [CrossRef] [PubMed]
[17] Cho, Y.S., Shin, M.S., Ko, I.G., Kim, S.‑E., Kim, C.‑J., Sung, Y.‑H., et al. (2015) Ulinastatin Inhibits Cerebral Ischemia-Induced Apoptosis in the Hippocampus of Gerbils. Molecular Medicine Reports, 12, 1796-1802. [Google Scholar] [CrossRef] [PubMed]
[18] Zhang, J., Xia, Y., Xu, Z. and Deng, X. (2016) Propofol Suppressed Hypoxia/Reoxygenation-Induced Apoptosis in HBVSMC by Regulation of the Expression of Bcl-2, Bax, Caspase3, Kir6.1, and p-JNK. Oxidative Medicine and Cellular Longevity, 2016, Article ID: 1518738. [Google Scholar] [CrossRef] [PubMed]
[19] Yu, C.Z., Li, C., Pei, D.S., Zong, Y.-Y., Shi, Q., Wen, X.-R., et al. (2009) Neuroprotection against Transient Focal Cerebral Ischemia and Oxygen-Glucose Deprivation by Interference with GluR6-PSD95 Protein Interaction. Neurochemical Research, 34, 2008-2021. [Google Scholar] [CrossRef] [PubMed]
[20] Xiao, B., Bi, F.F., Hu, Y.Q., Tian, F.-F., Wu, Z.-G., Mujlli, H.M., et al. (2007) Edaravone Neuroprotection Effected by Suppressing the Gene Expression of the FAS Signal Pathway Following Transient Focal Ischemia in Rats. Neurotoxicity Research, 12, 155-162. [Google Scholar] [CrossRef
[21] Guan, Q.H., Pei, D.S., Xu, T.L. and Zhang, G.-Y. (2006) Brain Ischemia/Reperfusion-Induced Expression of DP5 and Its Interaction with Bcl-2, Thus Freeing Bax From Bcl-2/Bax Dimmers Are Mediated by c-Jun N-terminal Kinase (JNK) Pathway. Neuroscience Letters, 393, 226-230. [Google Scholar] [CrossRef] [PubMed]
[22] Almanza, A., Carlesso, A., Chintha, C., Creedican, S., Doultsinos, D., Leuzzi, B., et al. (2019) Endoplasmic Reticulum Stress Signalling—From Basic Mechanisms to Clinical Applications. The FEBS Journal, 286, 241-278. [Google Scholar] [CrossRef] [PubMed]
[23] Zhao, Y.N., Li, J.M., Chen, C.X., Zhang, P. and Li, S.X. (2015) Hypertension-Mediated Enhancement of JNK Activation in Association with Endoplasmic Reticulum Stress in Rat Model Hippocampus with Cerebral Ischemia-Reperfusion. Genetics and Molecular Research, 14, 10980-10990. [Google Scholar] [CrossRef
[24] Chen, H., Yang, H., Pan, L., Wang, W., Liu, X., Ren, X., et al. (2016) The Molecular Mechanisms of XBP-1 Gene Silencing On IRE1α-TRAF2-ASK1-JNK Pathways in Oral Squamous Cell Carcinoma Under Endoplasmic Reticulum Stress. Biomedicine & Pharmacotherapy, 77, 108-113. [Google Scholar] [CrossRef] [PubMed]
[25] Chen, J.H., Kuo, H.C., Lee, K.F. and Tsai, T.-H. (2015) Global Proteomic Analysis of Brain Tissues in Transient Ischemia Brain Damage in Rats. International Journal of Molecular Sciences, 16, 11873-11891. [Google Scholar] [CrossRef] [PubMed]
[26] Ye, Z., Wang, N., Xia, P., Wang, E., Liao, J. and Guo, Q. (2013) Parecoxib Suppresses CHOP and Foxo1 Nuclear Translocation, but Increases GRP78 Levels in a Rat Model of Focal Ischemia. Neurochemical Research, 38, 686-693. [Google Scholar] [CrossRef] [PubMed]
[27] Kaufman, R.J., Scheuner, D., Schröder, M., Shen, X., Lee, K., Liu, C.Y., et al. (2002) The Unfolded Protein Response in Nutrient Sensing and Differentiation. Nature Reviews. Molecular Cell Biology, 3, 411-421. [Google Scholar] [CrossRef] [PubMed]
[28] 李建民, 赵雅宁, 刘乐, 常学优, 陈长香, 李淑杏. 高血压大鼠全脑缺血再灌注后海马区c-Jun氨基末端激酶激活与GRP78表达的关系[J]. 医学研究生学报, 2014, 27(5): 473-477.
[29] Gao, Y., Signore, A.P., Yin, W., Cao, G., Yin, X.-M., Sun, F., et al. (2005) Neuroprotection against Focal Ischemic Brain Injury by Inhibition of c-Jun N-terminal Kinase and Attenuation of the Mitochondrial Apoptosis-Signaling Pathway. Journal of Cerebral Blood Flow and Metabolism, 25, 694-712. [Google Scholar] [CrossRef] [PubMed]
[30] Guan, Q.H., Pei, D.S., Zhang, Q.G., Hao, Z.-B., Xu, T.-L. and Zhang, G.-Y. (2005) The Neuroprotective Action of SP600125, a New Inhibitor of JNK, On Transient Brain Ischemia/Reperfusion-Induced Neuronal Death in Rat Hippocampal CA1 via Nuclear and Non-Nuclear Pathways. Brain Research, 1035, 51-59. [Google Scholar] [CrossRef] [PubMed]
[31] Murata, Y., Fujiwara, N., Seo, J.H., Yan, F., Liu, X., Terasaki, Y., et al. (2012) Delayed Inhibition of c-Jun N-terminal Kinase Worsens Outcomes after Focal Cerebral Ischemia. The Journal of Neuroscience, 32, 8112-8115. [Google Scholar] [CrossRef
[32] Carboni, S., Hiver, A., Szyndralewiez, C., Gaillard, P., Gotteland, J.-P. and Vitte, P.-A. (2004) AS601245 (1,3-Benzo- thiazol-2-Yl (2-[[2-(3-Pyridinyl) Ethyl] Amino]-4 Pyrimidinyl) Acetonitrile): A c-Jun NH2-terminal Protein Kinase Inhibitor with Neuroprotective Properties. The Journal of Pharmacology and Experimental Therapeutics, 310, 25-32. [Google Scholar] [CrossRef] [PubMed]
[33] Carboni, S., Antonsson, B., Gaillard, P., Gotteland, J.-P., Gillon, J.-Y. and Vitte, P.-A. (2005) Control of Death Receptor and Mitochondrial-Dependent Apoptosis by c-Jun N-terminal Kinase in Hippocampal CA1 Neurones Following Global Transient Ischaemia. Journal of Neurochemistry, 92, 1054-1060. [Google Scholar] [CrossRef] [PubMed]
[34] Carboni, S., Boschert, U., Gaillard, P., Gotteland, J.-P., Gillon, J.-Y. and Vitte, P.-A. (2008) AS601245, a c-Jun NH2- Terminal Kinase (JNK) Inhibitor, Reduces Axon/Dendrite Damage and Cognitive Deficits after Global Cerebral Ischaemia in Gerbils. British Journal of Pharmacology, 153, 157-163. [Google Scholar] [CrossRef] [PubMed]
[35] Li, D., Li, X., Wu, J., Li, J., Zhang, L., Xiong, T., et al. (2015) Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic-Ischemic Brain Damage in Neonatal Rats. PLoS ONE, 10, e0132998. [Google Scholar] [CrossRef] [PubMed]
[36] Hu, S.Q., Ye, J.S., Zong, Y.Y., Sun, C.-C., Liu, D.-H., Wu, Y.-P., et al. (2012) S-Nitrosylation of Mixed Lineage Kinase 3 Contributes to its Activation after Cerebral Ischemia. The Journal of Biological Chemistry, 287, 2364-2377. [Google Scholar] [CrossRef
[37] Liu, D.H., Yuan, F.G., Hu, S.Q., Diao, F., Wu, Y.-P., Zong, Y.-Y., et al. (2013) Endogenous Nitric Oxide Induces Activation of Apoptosis Signal-Regulating Kinase 1 via S-Nitrosylation in Rat Hippocampus during Cerebral Ischemia- Reperfusion. Neuroscience, 229, 36-48. [Google Scholar] [CrossRef] [PubMed]
[38] Pei, D.S., Song, Y.J., Yu, H.M., Hu, W.-W., Du, Y. and Zhang, G.-Y. (2008) Exogenous Nitric Oxide Negatively Regulates c-Jun N-terminal Kinase Activation via Inhibiting Endogenous NO-Induced S-Nitrosylation during Cerebral Ischemia and Reperfusion in Rat Hippocampus. Journal of Neurochemistry, 106, 1952-1963. [Google Scholar] [CrossRef] [PubMed]
[39] Schepetkin, I.A., Kirpotina, L.N., Khlebnikov, A.I., Hanks, T.S., Kochetkova, I., Pascual, D.W., et al. (2012) Identification and Characterization of a Novel Class of c-Jun N-terminal Kinase Inhibitors. Molecular Pharmacology, 81, 832-845. [Google Scholar] [CrossRef] [PubMed]
[40] Atochin, D.N., Schepetkin, I.A., Khlebnikov, A.I., Seledtsov, V.I., Swanson, H., Quinn, M.T., et al. (2016) A Novel Dual NO-Donating Oxime and c-Jun N-terminal Kinase Inhibitor Protects Against Cerebral Ischemia-Reperfusion Injury in Mice. Neuroscience Letters, 618, 45-49. [Google Scholar] [CrossRef] [PubMed]
[41] Plotnikov, M.B., Chernysheva, G.A., Aliev, O.I., Smol’iakova, V.I., Fomina, T.I., Osipenko, A.N., et al. (2019) Protective Effects of a New C-Jun N-Terminal Kinase Inhibitor in the Model of Global Cerebral Ischemia in Rats. Molecules, 24, Article No. 1722. [Google Scholar] [CrossRef] [PubMed]