Glioblastoma is acknowledged as the most aggressive cerebral tumor in adults.However,the efficacy of current standard therapy is seriously undermined by drug resistance and suppressive immune microenvironment.Ferropto...Glioblastoma is acknowledged as the most aggressive cerebral tumor in adults.However,the efficacy of current standard therapy is seriously undermined by drug resistance and suppressive immune microenvironment.Ferroptosis is a recently discovered form of iron-dependent cell death that may have excellent prospect as chemosensitizer.The utilization of ferropotosis inducer Erastin could significantly mediate chemotherapy sensitization of Temozolomide and exert anti-tumor effects in glioblastoma.In this study,a combination of hydrogel-liposome nanoplatform encapsulatedwith Temozolomide and ferroptosis inducer Erastin was constructed.Theαvβ3 integrin-binding peptide cyclic RGD was utilized to modify codelivery system to achieve glioblastoma targeting strategy.As biocompatible drug reservoirs,cross-linked GelMA(gelatin methacrylamide)hydrogel and cRGD-coated liposome realized the sustained release of internal contents.In the modified intracranial tumor resection model,GelMA-liposome system achieved slow release of Temozolomide and Erastin in situ for more than 14 d.The results indicated that nanoplatform(T+E@LPs-cRGD+GelMA)improved glioblastoma sensitivity to chemotherapeutic temozolomide and exerted satisfactory anti-tumor effects.It was demonstrated that the induction of ferroptosis could be utilized as a therapeutic strategy to overcome drug resistance.Furthermore,transcriptome sequencing was conducted to reveal the underlying mechanism that the nanoplatform(T+E@LPs-cRGD+GelMA)implicated in.It is suggested that GelMA-liposome system participated in the immune response and immunomodulation of glioblastoma via interferon/PD-L1 pathway.Collectively,this study proposed a potential combinatory therapeutic strategy for glioblastoma treatment.展开更多
目的利用基因芯片和生物信息学的分析方法,筛选与恶性周围神经鞘瘤(MPNSTs)发生发展有关的差异表达基因(DEGs)和信号通路,为进一步研究和治疗MPNSTs提供新的粑点和方向。方法在GE0数据库下载基因表达数据集GSE66743,通过分析良性神经纤...目的利用基因芯片和生物信息学的分析方法,筛选与恶性周围神经鞘瘤(MPNSTs)发生发展有关的差异表达基因(DEGs)和信号通路,为进一步研究和治疗MPNSTs提供新的粑点和方向。方法在GE0数据库下载基因表达数据集GSE66743,通过分析良性神经纤维瘤和MPNSTs的基因表达,获得DEGs。随后,使用DAVID数据库进行基因本体论(GO)功能注释和京都基因与基因组百科全书(KEGG)富集分析。使用STRING蛋白质相互作用(PPI)数据库对DEGs进行PPI网络的构建,并应用Cytoscape软件从P P I网络中识别核心基因。最后使用Cytoscope软件对PPI网络进行核心模块的筛选并对模块设计DEGs进行KEGG富集分析。结果共鉴定出上调基因493个,下调基因362个。GO分析表明DEGs主要参与细胞周期、染色体分离、有丝分裂细胞周期过程、分子功能调节和酶调节活性等;KEGG主要富集在补体和凝血级联、癌症中的蛋白多糖、酪氨酸代谢、肿瘤坏死因子(TNF)信号通路和趋化因子信号通路、细胞周期、蛋白质消化吸收、细胞外基质(ECM)-受体相互作用和范科尼贫血途径;PPI网络筛选得到了10个核心基因,对前3个核心模块所涉及基因的富集分析表明,DEGs主要与细胞周期、系统性红斑狼疮以及补体和凝血级联相关。结论GO功能注释和KEGG富集分析揭示了MPNSTs潜在的发病机制,筛选得到的核心基因和通路为MPNSTs提供了潜在的诊断和治疗靶点。展开更多
基金supported by Natural Science Foundation of China(Grant NO.81972340,82173140,81871196)Shandong Provincial Natural Science Foundation,China(Grant No.ZR202010300086)Academic promotion program of Shandong First Medical University(Grant NO.2019LJ005)。
文摘Glioblastoma is acknowledged as the most aggressive cerebral tumor in adults.However,the efficacy of current standard therapy is seriously undermined by drug resistance and suppressive immune microenvironment.Ferroptosis is a recently discovered form of iron-dependent cell death that may have excellent prospect as chemosensitizer.The utilization of ferropotosis inducer Erastin could significantly mediate chemotherapy sensitization of Temozolomide and exert anti-tumor effects in glioblastoma.In this study,a combination of hydrogel-liposome nanoplatform encapsulatedwith Temozolomide and ferroptosis inducer Erastin was constructed.Theαvβ3 integrin-binding peptide cyclic RGD was utilized to modify codelivery system to achieve glioblastoma targeting strategy.As biocompatible drug reservoirs,cross-linked GelMA(gelatin methacrylamide)hydrogel and cRGD-coated liposome realized the sustained release of internal contents.In the modified intracranial tumor resection model,GelMA-liposome system achieved slow release of Temozolomide and Erastin in situ for more than 14 d.The results indicated that nanoplatform(T+E@LPs-cRGD+GelMA)improved glioblastoma sensitivity to chemotherapeutic temozolomide and exerted satisfactory anti-tumor effects.It was demonstrated that the induction of ferroptosis could be utilized as a therapeutic strategy to overcome drug resistance.Furthermore,transcriptome sequencing was conducted to reveal the underlying mechanism that the nanoplatform(T+E@LPs-cRGD+GelMA)implicated in.It is suggested that GelMA-liposome system participated in the immune response and immunomodulation of glioblastoma via interferon/PD-L1 pathway.Collectively,this study proposed a potential combinatory therapeutic strategy for glioblastoma treatment.
文摘目的利用基因芯片和生物信息学的分析方法,筛选与恶性周围神经鞘瘤(MPNSTs)发生发展有关的差异表达基因(DEGs)和信号通路,为进一步研究和治疗MPNSTs提供新的粑点和方向。方法在GE0数据库下载基因表达数据集GSE66743,通过分析良性神经纤维瘤和MPNSTs的基因表达,获得DEGs。随后,使用DAVID数据库进行基因本体论(GO)功能注释和京都基因与基因组百科全书(KEGG)富集分析。使用STRING蛋白质相互作用(PPI)数据库对DEGs进行PPI网络的构建,并应用Cytoscape软件从P P I网络中识别核心基因。最后使用Cytoscope软件对PPI网络进行核心模块的筛选并对模块设计DEGs进行KEGG富集分析。结果共鉴定出上调基因493个,下调基因362个。GO分析表明DEGs主要参与细胞周期、染色体分离、有丝分裂细胞周期过程、分子功能调节和酶调节活性等;KEGG主要富集在补体和凝血级联、癌症中的蛋白多糖、酪氨酸代谢、肿瘤坏死因子(TNF)信号通路和趋化因子信号通路、细胞周期、蛋白质消化吸收、细胞外基质(ECM)-受体相互作用和范科尼贫血途径;PPI网络筛选得到了10个核心基因,对前3个核心模块所涉及基因的富集分析表明,DEGs主要与细胞周期、系统性红斑狼疮以及补体和凝血级联相关。结论GO功能注释和KEGG富集分析揭示了MPNSTs潜在的发病机制,筛选得到的核心基因和通路为MPNSTs提供了潜在的诊断和治疗靶点。
