【目的】人体中丝裂原激活蛋白激酶14(Mitogen-activated protein kinase 14,MAPK14,又称p38α)主要调控应激和免疫反应。在皮肤组织中,MAPK14信号通路是维护角质形成细胞稳定状态的关键因素,因此需进一步探索MAPK14在皮肤组织中的表达...【目的】人体中丝裂原激活蛋白激酶14(Mitogen-activated protein kinase 14,MAPK14,又称p38α)主要调控应激和免疫反应。在皮肤组织中,MAPK14信号通路是维护角质形成细胞稳定状态的关键因素,因此需进一步探索MAPK14在皮肤组织中的表达状况。【方法】采用互补脱氧核糖核酸末端快速扩增技术和实时荧光定量逆转录聚合酶链式反应技术对该基因的表达进行深度分析。【结果】在来源于婴儿包皮的角质形成细胞中发现了2个MAPK14新型剪接体,即MAPK14-v2a(Genbank注册登记号为OM256527)和MAPK14-v2b(Genbank注册登记号为OM256528)。实时荧光定量逆转录聚合酶链式反应技术的分析结果表明,除皮肤组织外这2个新型剪接体还在其他组织器官中广泛存在,如肾脏、子宫、唾液腺和正常黏膜等。在生长分化期中,发现MAPK14-v2a的表达量逐天显著提高,而MAPK14-v2b的表达则相对稳定;同时还发现,MAPK14-v2a在基底细胞癌患者的病变组织中表达量显著提高。【结论】本研究发现了2种MAPK14新型剪接体,它们是MAPK14在皮肤组织中的表达形式,其中MAPK14-v2a与角质细胞增殖分化呈正相关,并有潜力作为基底细胞癌诊断的分子标记。展开更多
Dysregulation of mi R-124 has been reported to be involved in the pathophysiology of depression. Chaihu-Shugan-San, a traditional Chinese medicine, has antidepressive activity; however, the underlying mechanisms remai...Dysregulation of mi R-124 has been reported to be involved in the pathophysiology of depression. Chaihu-Shugan-San, a traditional Chinese medicine, has antidepressive activity; however, the underlying mechanisms remain unclear. In this study, to generate a rodent model of depression, rats were subjected to a combination of solitary confinement and chronic unpredictable mild stress for 28 days. Rats were intragastrically administered Chaihu-Shugan-San（2.835 m L/kg/d） for 4 weeks, once a day. Real-time reverse-transcription quantitative polymerase chain reaction, mi RNA microarray, western blot assay and transmission electron microscopy demonstrated that ChaihuShugan-San downregulated mi R-124 expression and upregulated the m RNA and protein levels of mitogen-activated protein kinase 14（MAPK14） and glutamate receptor subunit 3（Gria3）. Chaihu-Shugan-San also promoted synapse formation in the hippocampus. The open field test, sucrose consumption test and forced swimming test were used to assess depression-like behavior. After intragastric administration of Chaihu-Shugan-San, sucrose consumption increased, while the depressive behaviors were substantially reduced. Together, these findings suggest that Chaihu-Shugan-San exerts an antidepressant-like effect by downregulating mi R-124 expression and by releasing the inhibition of the MAPK14 and Gria3 signaling pathways.展开更多
Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases.However,the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unkn...Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases.However,the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown.In this study,we demonstrated that S-nitrosoglutathione reductase(GSNOR)deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1βexpression levels and interleukin-1β(IL-1β)secretion in response to NLRP3 inflammasome stimulation.Furthermore,in vivo experiments utilizing Gsnor^(−/−)mice revealed increased disease severity in both lipopolysaccharide(LPS)-induced septic shock and dextran sodium sulfate(DSS)-induced colitis models.Additionally,we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor^(−/−)Nlrp3^(−/−)double-knockout(DKO)mice.Mechanistically,GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14(MAPK14)at the Cys211 residue and augments MAPK14 kinase activity,thereby promoting Nlrp3 and Il-1βtranscription and stimulating NLRP3 inflammasome activity.Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation.展开更多
目的胃癌放疗抵抗是绝大多数胃癌患者在治疗过程中所面临的一大难题,探讨其关键基因靶点与潜在机制,对指导临床胃癌患者放射治疗及预后分析有着深远意义。本研究旨在分析丝裂原活化蛋白激酶14(mitogen-activated protein kinase 14,MAPK...目的胃癌放疗抵抗是绝大多数胃癌患者在治疗过程中所面临的一大难题,探讨其关键基因靶点与潜在机制,对指导临床胃癌患者放射治疗及预后分析有着深远意义。本研究旨在分析丝裂原活化蛋白激酶14(mitogen-activated protein kinase 14,MAPK14)在胃癌放疗抵抗患者及胃癌放疗抵抗细胞株中的表达,探究其在胃癌放疗抵抗中的潜在作用。方法采用the Cancer Genome Atlas(TCGA)数据库获得416例胃癌患者MAPK14的mRNA表达水平,Kaplan Meier生存曲线分析MAPK14表达与胃癌患者生存的关联性;建立胃癌放疗抵抗细胞株(放抗株)SGC-7901-R,通过克隆形成实验鉴定其放射线抗性,流式细胞术检测其细胞凋亡、细胞周期改变,蛋白质印迹分析放疗抵抗细胞株(放抗株)SGC-7901-R与亲本胃癌细胞株SGC-7901的MAPK14蛋白表达差异;免疫组化技术验证胃癌放疗抵抗患者与胃癌放疗敏感患者的MAPK14蛋白表达差异。结果 Kaplan-Meier生存曲线分析显示,MAPK14低表达组患者的总生存期优于MAPK14高表达组,中位生存期分别为57.39和19.32个月,两者的预后差异有统计学意义(χ2=14.96,P=0.000 1)。克隆形成实验表明,在4Gy放射线的作用下,放抗株SGC-7901-R的克隆形成能力高于亲本胃癌细胞株SGC-7901,差异有统计学意义,t=41.99,P<0.001。流式检测显示,经4Gy放射线处理后,SGC-7901-R的细胞凋亡率低于SGC-7901细胞,差异有统计学意义,t=8.88,P=0.000 9;与SGC-7901细胞相比,SGC-7901-R的细胞周期阻滞在G2/M期,差异有统计学意义,t=3.011,P=0.039 5。蛋白质印迹结果证实,放抗株SGC-7901-R的MAPK14蛋白表达量高于亲本SGC-7901细胞(1.09±0.07 vs 0.59±0.11),差异有统计学意义,t=3.869,P=0.018。免疫组化结果显示,与胃癌放疗敏感患者相比,胃癌放疗抵抗患者肿瘤组织中MAPK14蛋白表达水平上调,差异有统计学意义,t=26.27,P<0.001。结论 MAPK14异常高表达介导胃癌放疗抵抗且与胃癌患者不良预后相关,其潜在机制与MAPK14影响肿瘤细胞凋亡及细胞周期再分布有关。展开更多
Background:1,2,3,4,6-penta-O-galloyl-beta-D-glucose(PGG)is a natural polyphenolic compound derived from multiple medicinal plants with favorable anticancer activity.Methods:In this study,the mechanisms of PGG against ...Background:1,2,3,4,6-penta-O-galloyl-beta-D-glucose(PGG)is a natural polyphenolic compound derived from multiple medicinal plants with favorable anticancer activity.Methods:In this study,the mechanisms of PGG against gastric cancer were explored through network pharmacology and molecular docking.First,the targets of PGG were searched in the Herbal Ingredients’Targets(HIT),Similarity Ensemble Approach(SEA),and Super-PRED databases.The potential targets related to gastric cancer were predicted from the Human Gene Database(GeneCards)and DisGeNET databases.The intersecting targets of PGG and gastric cancer were obtained by Venn diagram and then subjected to protein-protein interaction analysis to screen hub targets.Functional and pathway enrichment of hub targets were analyzed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases.The differential expression and survival analysis of hub targets in gastric cancer were performed based on The Cancer Genome Atlas database.Finally,the affinity of PGG with hub targets was visualized by molecular docking.Results:Three hub targets were screened,including mitogen-activated protein kinase 14(MAPK14),BCL2 like 1(BCL2L1),and vascular endothelial growth factor A(VEGFA).MAPK14 had a higher expression,while BCL2L1 and VEGFA had lower expression in gastric cancer than in normal conditions.Enrichment analysis indicated enrichment of these hub targets in MAPK,neurotrophin,programmed death-ligand 1(PD-L1)checkpoint,phosphatidylinositol 3-kinases/protein kinase B(PI3K-Akt),Ras,and hypoxia-inducible factor-1(HIF-1)signaling pathways.Conclusion:Therefore,network pharmacology and molecular docking analyses revealed that PGG exerts a therapeutic efficacy on gastric cancer by multiple targets(MAPK14,BCL2L1,and VEGFA)and pathways(MAPK,PD-L1 checkpoint,PI3K-Akt,Ras,and HIF-1 pathways).展开更多
Synaptic plasticity is known to regulate and support signal transduction between neurons, while synaptic dysfunction contributes to multiple neurological and other brain disorders;however, the specific mechanism under...Synaptic plasticity is known to regulate and support signal transduction between neurons, while synaptic dysfunction contributes to multiple neurological and other brain disorders;however, the specific mechanism underlying this process remains unclear. In the present study, abnormal neural and dendritic morphology was observed in the hippocampus following knockout of Atpllb both in vitro and in vivo. Moreover, ATP11B modified synaptic ultrastructure and promoted spine remodeling via the asymmetrical distribution of phosphatidylserine and enhancement of glutamate release, glutamate receptor expression, and intracellular Ca^2+ concentration. Fuithermoe experimental results also indicate that ATP11B regulated synaptic plasticity in hippocampal neurons through the MAPK14 signaling pathway. In conclusion, our data shed light on the possible mechanisms underlying the regulation of synaptic plasticity and lay the foundation for the exploration of proteins involved in signal transduction during this process.展开更多
文摘【目的】人体中丝裂原激活蛋白激酶14(Mitogen-activated protein kinase 14,MAPK14,又称p38α)主要调控应激和免疫反应。在皮肤组织中,MAPK14信号通路是维护角质形成细胞稳定状态的关键因素,因此需进一步探索MAPK14在皮肤组织中的表达状况。【方法】采用互补脱氧核糖核酸末端快速扩增技术和实时荧光定量逆转录聚合酶链式反应技术对该基因的表达进行深度分析。【结果】在来源于婴儿包皮的角质形成细胞中发现了2个MAPK14新型剪接体,即MAPK14-v2a(Genbank注册登记号为OM256527)和MAPK14-v2b(Genbank注册登记号为OM256528)。实时荧光定量逆转录聚合酶链式反应技术的分析结果表明,除皮肤组织外这2个新型剪接体还在其他组织器官中广泛存在,如肾脏、子宫、唾液腺和正常黏膜等。在生长分化期中,发现MAPK14-v2a的表达量逐天显著提高,而MAPK14-v2b的表达则相对稳定;同时还发现,MAPK14-v2a在基底细胞癌患者的病变组织中表达量显著提高。【结论】本研究发现了2种MAPK14新型剪接体,它们是MAPK14在皮肤组织中的表达形式,其中MAPK14-v2a与角质细胞增殖分化呈正相关,并有潜力作为基底细胞癌诊断的分子标记。
基金supported by the National Natural Science Foundation of China,No.81503415,81574038,81603671the China Postdoctoral Science Foundation Grant,No.2016M600709+1 种基金a grant from the Science and Technology Planning Project of Guangdong Province of China,No.2014A020221062a grant from the Science and Technology Planning Project of Shenzhen City of China,No.JCYJ20150401170235349,JCYJ20160428105749954
文摘Dysregulation of mi R-124 has been reported to be involved in the pathophysiology of depression. Chaihu-Shugan-San, a traditional Chinese medicine, has antidepressive activity; however, the underlying mechanisms remain unclear. In this study, to generate a rodent model of depression, rats were subjected to a combination of solitary confinement and chronic unpredictable mild stress for 28 days. Rats were intragastrically administered Chaihu-Shugan-San（2.835 m L/kg/d） for 4 weeks, once a day. Real-time reverse-transcription quantitative polymerase chain reaction, mi RNA microarray, western blot assay and transmission electron microscopy demonstrated that ChaihuShugan-San downregulated mi R-124 expression and upregulated the m RNA and protein levels of mitogen-activated protein kinase 14（MAPK14） and glutamate receptor subunit 3（Gria3）. Chaihu-Shugan-San also promoted synapse formation in the hippocampus. The open field test, sucrose consumption test and forced swimming test were used to assess depression-like behavior. After intragastric administration of Chaihu-Shugan-San, sucrose consumption increased, while the depressive behaviors were substantially reduced. Together, these findings suggest that Chaihu-Shugan-San exerts an antidepressant-like effect by downregulating mi R-124 expression and by releasing the inhibition of the MAPK14 and Gria3 signaling pathways.
基金Yunnan Fundamental Research Project(202305AH340006)National Natural Science Foundation of China(32201018)+1 种基金Basic Research Program and Key Project of Yunnan Province(202301AW070013 and 202003AD150009)Youth Innovation Promotion Association(2023403).
文摘Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases.However,the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown.In this study,we demonstrated that S-nitrosoglutathione reductase(GSNOR)deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1βexpression levels and interleukin-1β(IL-1β)secretion in response to NLRP3 inflammasome stimulation.Furthermore,in vivo experiments utilizing Gsnor^(−/−)mice revealed increased disease severity in both lipopolysaccharide(LPS)-induced septic shock and dextran sodium sulfate(DSS)-induced colitis models.Additionally,we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor^(−/−)Nlrp3^(−/−)double-knockout(DKO)mice.Mechanistically,GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14(MAPK14)at the Cys211 residue and augments MAPK14 kinase activity,thereby promoting Nlrp3 and Il-1βtranscription and stimulating NLRP3 inflammasome activity.Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation.
文摘目的胃癌放疗抵抗是绝大多数胃癌患者在治疗过程中所面临的一大难题,探讨其关键基因靶点与潜在机制,对指导临床胃癌患者放射治疗及预后分析有着深远意义。本研究旨在分析丝裂原活化蛋白激酶14(mitogen-activated protein kinase 14,MAPK14)在胃癌放疗抵抗患者及胃癌放疗抵抗细胞株中的表达,探究其在胃癌放疗抵抗中的潜在作用。方法采用the Cancer Genome Atlas(TCGA)数据库获得416例胃癌患者MAPK14的mRNA表达水平,Kaplan Meier生存曲线分析MAPK14表达与胃癌患者生存的关联性;建立胃癌放疗抵抗细胞株(放抗株)SGC-7901-R,通过克隆形成实验鉴定其放射线抗性,流式细胞术检测其细胞凋亡、细胞周期改变,蛋白质印迹分析放疗抵抗细胞株(放抗株)SGC-7901-R与亲本胃癌细胞株SGC-7901的MAPK14蛋白表达差异;免疫组化技术验证胃癌放疗抵抗患者与胃癌放疗敏感患者的MAPK14蛋白表达差异。结果 Kaplan-Meier生存曲线分析显示,MAPK14低表达组患者的总生存期优于MAPK14高表达组,中位生存期分别为57.39和19.32个月,两者的预后差异有统计学意义(χ2=14.96,P=0.000 1)。克隆形成实验表明,在4Gy放射线的作用下,放抗株SGC-7901-R的克隆形成能力高于亲本胃癌细胞株SGC-7901,差异有统计学意义,t=41.99,P<0.001。流式检测显示,经4Gy放射线处理后,SGC-7901-R的细胞凋亡率低于SGC-7901细胞,差异有统计学意义,t=8.88,P=0.000 9;与SGC-7901细胞相比,SGC-7901-R的细胞周期阻滞在G2/M期,差异有统计学意义,t=3.011,P=0.039 5。蛋白质印迹结果证实,放抗株SGC-7901-R的MAPK14蛋白表达量高于亲本SGC-7901细胞(1.09±0.07 vs 0.59±0.11),差异有统计学意义,t=3.869,P=0.018。免疫组化结果显示,与胃癌放疗敏感患者相比,胃癌放疗抵抗患者肿瘤组织中MAPK14蛋白表达水平上调,差异有统计学意义,t=26.27,P<0.001。结论 MAPK14异常高表达介导胃癌放疗抵抗且与胃癌患者不良预后相关,其潜在机制与MAPK14影响肿瘤细胞凋亡及细胞周期再分布有关。
基金supported by the Natural Science Foundation of Gansu Province[Grant Numbers 22JR5RA930,22JR5RA894]the Talent Project of Lanzhou Science and Technology Bureau[Grant Number 2022-3-44]+1 种基金the projects managed by the Administration of Traditional Chinese Medicine[Grant Number GZKG-2022-54]Intra Hospital Fund of the First Hospital of Lanzhou University[Grant Number ldyyyn2021101].
文摘Background:1,2,3,4,6-penta-O-galloyl-beta-D-glucose(PGG)is a natural polyphenolic compound derived from multiple medicinal plants with favorable anticancer activity.Methods:In this study,the mechanisms of PGG against gastric cancer were explored through network pharmacology and molecular docking.First,the targets of PGG were searched in the Herbal Ingredients’Targets(HIT),Similarity Ensemble Approach(SEA),and Super-PRED databases.The potential targets related to gastric cancer were predicted from the Human Gene Database(GeneCards)and DisGeNET databases.The intersecting targets of PGG and gastric cancer were obtained by Venn diagram and then subjected to protein-protein interaction analysis to screen hub targets.Functional and pathway enrichment of hub targets were analyzed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases.The differential expression and survival analysis of hub targets in gastric cancer were performed based on The Cancer Genome Atlas database.Finally,the affinity of PGG with hub targets was visualized by molecular docking.Results:Three hub targets were screened,including mitogen-activated protein kinase 14(MAPK14),BCL2 like 1(BCL2L1),and vascular endothelial growth factor A(VEGFA).MAPK14 had a higher expression,while BCL2L1 and VEGFA had lower expression in gastric cancer than in normal conditions.Enrichment analysis indicated enrichment of these hub targets in MAPK,neurotrophin,programmed death-ligand 1(PD-L1)checkpoint,phosphatidylinositol 3-kinases/protein kinase B(PI3K-Akt),Ras,and hypoxia-inducible factor-1(HIF-1)signaling pathways.Conclusion:Therefore,network pharmacology and molecular docking analyses revealed that PGG exerts a therapeutic efficacy on gastric cancer by multiple targets(MAPK14,BCL2L1,and VEGFA)and pathways(MAPK,PD-L1 checkpoint,PI3K-Akt,Ras,and HIF-1 pathways).
基金This work was supported bythe National Natural Science Foundation of China (31500827,81471162,and 61873156)Young Eastern Scholar (QD2015033)+1 种基金the Science and Technology Commission of Shanghai (14JC1402400)the Natural Science Foundation of Shanghai (17ZR1409900).
文摘Synaptic plasticity is known to regulate and support signal transduction between neurons, while synaptic dysfunction contributes to multiple neurological and other brain disorders;however, the specific mechanism underlying this process remains unclear. In the present study, abnormal neural and dendritic morphology was observed in the hippocampus following knockout of Atpllb both in vitro and in vivo. Moreover, ATP11B modified synaptic ultrastructure and promoted spine remodeling via the asymmetrical distribution of phosphatidylserine and enhancement of glutamate release, glutamate receptor expression, and intracellular Ca^2+ concentration. Fuithermoe experimental results also indicate that ATP11B regulated synaptic plasticity in hippocampal neurons through the MAPK14 signaling pathway. In conclusion, our data shed light on the possible mechanisms underlying the regulation of synaptic plasticity and lay the foundation for the exploration of proteins involved in signal transduction during this process.
