Background:Inhibitor of NF-κB kinase-interacting protein(IKIP)is known to promote proliferation of glioblastoma(GBM)cells,but how it affects migration and invasion by those cells is unclear.Methods:We compared levels...Background:Inhibitor of NF-κB kinase-interacting protein(IKIP)is known to promote proliferation of glioblastoma(GBM)cells,but how it affects migration and invasion by those cells is unclear.Methods:We compared levels of IKIP between glioma tissues and normal brain tissue in clinical samples and public databases.We examined the effects of IKIP overexpression and knockdown on the migration and invasion of GBM using transwell and wound healing assays,and we compared the transcriptomes under these different conditions to identify the molecular mechanisms involved.Results:Based on data from our clinical samples and from public databases,IKIP was overexpressed in GBM tumors,and its expression level correlated inversely with survival.IKIP overexpression in GBM cells inhibited migration and invasion in transwell and wound healing assays,whereas IKIP knockdown exerted the opposite effects.IKIP overexpression in GBM cells that were injected into mouse brain promoted tumor growth but inhibited tumor invasion of surrounding tissue.The effects of IKIP were associated with downregulation of THBS1 mRNA and concomitant inhibition of THBS1/FAK signaling.Conclusions:IKIP inhibits THBS1/FAK signaling to suppress migration and invasion of GBM cells.展开更多
目的:观察解毒化瘀健脾方对胃黏膜异型增生模型大鼠血小板反应蛋白1基因(thrombospondin 1,Thbs1)甲基化状态的影响,并探讨解毒化瘀健脾方治疗胃黏膜异型增生的可能机制.方法:将实验性胃黏膜异型增生病变模型大鼠分为:模型对照组(model ...目的:观察解毒化瘀健脾方对胃黏膜异型增生模型大鼠血小板反应蛋白1基因(thrombospondin 1,Thbs1)甲基化状态的影响,并探讨解毒化瘀健脾方治疗胃黏膜异型增生的可能机制.方法:将实验性胃黏膜异型增生病变模型大鼠分为:模型对照组(model control group,M G)、阳性对照组(positive control group,PCG)-西药维甲酸治疗组、解毒化瘀健脾方治疗组(Jiedu Huayu Jianpi Fang treatment group,A),并以健康大鼠为对照组(control group,CG),进行相应的药物干预;取胃黏膜组织,应用甲基化特异PCR技术检测Thbs1基因甲基化状态;HE染色观察各处理组胃黏膜组织结构变化差异.结果:CG组10只健康大鼠胃黏膜经检测Thbs1基因均未发生甲基化,胃黏膜异型增生MG组大鼠T h b s1基因的甲基化阳性检出率为33.33%(6/18);PCG组-西药维甲酸组同正常大鼠相同,Thbs1基因甲基化检出率为0.00%;A组治疗大鼠Thbs1基因甲基化比率(20.00%),相比MG组显著降低(P=0.0198).HE染色结果显示MG、PCG、A组呈现中轻度胃黏膜异型增生症状,经治疗后PCG、A组异型增生趋于正常.结论:解毒化瘀健脾方对发生异型增生的胃黏膜组织Thbs1基因具有显著地去甲基化作用.解毒化瘀健脾方治疗胃黏膜异型增生可能与该药物使Thbs1基因甲基化程度显著降低有关.展开更多
Preeclampsia is a pregnancy complication which threatens the survival of mothers and fetuses.It originates from abnormal placentation,especially insufficient fusion of the cytotrophoblast cells to form the syncytiotro...Preeclampsia is a pregnancy complication which threatens the survival of mothers and fetuses.It originates from abnormal placentation,especially insufficient fusion of the cytotrophoblast cells to form the syncytiotrophoblast.In this study,we found that THBS1,a matricellular protein that mediates cell-to-cell and cell-to-matrix interactions,is downregulated during the fusion of primary cytotrophoblast and BeWo cells,but upregulated in the placenta of pregnancies complicated by preeclampsia.Also,THBS1 was observed to interact with CD36,a membrane signal receptor and activator of the cAMP signaling pathway,to regulate the fusion of cytotrophoblast cells.Overexpression of THBS1 inhibited the cAMP signaling pathway and reduced the BeWo cells fusion ratio,while the effects of THBS1 were abolished by a CD36-blocking antibody.Our results suggest that THBS1 signals through a CD36-mediated cAMP pathway to regulate syncytialization of the cytotrophoblast cells,and that its upregulation impairs placental formation to cause preeclampsia.Thus,THBS1 can serve as a therapeutic target regarding the mitigation of abnormal syncytialization and preeclampsia.展开更多
Hepatocellular carcinoma(HCC),a prevalent solid carcinoma of significant concern,is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes.The etiology and pathologi...Hepatocellular carcinoma(HCC),a prevalent solid carcinoma of significant concern,is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes.The etiology and pathological progression of non-alcoholic steatohepatitis(NASH)-related HCC is multifactorial and multistage.However,no single animal model can accurately mimic the full NASH-related HCC pathological progression,posing considerable challenges to transition and mechanistic studies.Herein,a novel conditional inducible wild-type human HRAS overexpressed mouse model(HRAS-HCC)was established,demonstrating 100%morbidity and mortality within approximately one month under normal dietary and lifestyle conditions.Advanced symptoms of HCC such as ascites,thrombus,internal hemorrhage,jaundice,and lung metastasis were successfully replicated in mice.In-depth pathological features of NASH-related HCC were demonstrated by pathological staining,biochemical analyses,and typical marker gene detections.Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival,further confirming the accuracy and reliability of the model.Based on protein-protein interaction(PPI)network and RNA sequencing analyses,we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis,with subsequent progression to HCC.Collectively,our study successfully duplicated natural sequential progression in a single murine model over a very short period,providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.展开更多
基金supported by the National Natural Science Foundation of China(82002638)the National Natural Science Foundation of Sichuan Province(2023NSFSC0734).
文摘Background:Inhibitor of NF-κB kinase-interacting protein(IKIP)is known to promote proliferation of glioblastoma(GBM)cells,but how it affects migration and invasion by those cells is unclear.Methods:We compared levels of IKIP between glioma tissues and normal brain tissue in clinical samples and public databases.We examined the effects of IKIP overexpression and knockdown on the migration and invasion of GBM using transwell and wound healing assays,and we compared the transcriptomes under these different conditions to identify the molecular mechanisms involved.Results:Based on data from our clinical samples and from public databases,IKIP was overexpressed in GBM tumors,and its expression level correlated inversely with survival.IKIP overexpression in GBM cells inhibited migration and invasion in transwell and wound healing assays,whereas IKIP knockdown exerted the opposite effects.IKIP overexpression in GBM cells that were injected into mouse brain promoted tumor growth but inhibited tumor invasion of surrounding tissue.The effects of IKIP were associated with downregulation of THBS1 mRNA and concomitant inhibition of THBS1/FAK signaling.Conclusions:IKIP inhibits THBS1/FAK signaling to suppress migration and invasion of GBM cells.
文摘目的:观察解毒化瘀健脾方对胃黏膜异型增生模型大鼠血小板反应蛋白1基因(thrombospondin 1,Thbs1)甲基化状态的影响,并探讨解毒化瘀健脾方治疗胃黏膜异型增生的可能机制.方法:将实验性胃黏膜异型增生病变模型大鼠分为:模型对照组(model control group,M G)、阳性对照组(positive control group,PCG)-西药维甲酸治疗组、解毒化瘀健脾方治疗组(Jiedu Huayu Jianpi Fang treatment group,A),并以健康大鼠为对照组(control group,CG),进行相应的药物干预;取胃黏膜组织,应用甲基化特异PCR技术检测Thbs1基因甲基化状态;HE染色观察各处理组胃黏膜组织结构变化差异.结果:CG组10只健康大鼠胃黏膜经检测Thbs1基因均未发生甲基化,胃黏膜异型增生MG组大鼠T h b s1基因的甲基化阳性检出率为33.33%(6/18);PCG组-西药维甲酸组同正常大鼠相同,Thbs1基因甲基化检出率为0.00%;A组治疗大鼠Thbs1基因甲基化比率(20.00%),相比MG组显著降低(P=0.0198).HE染色结果显示MG、PCG、A组呈现中轻度胃黏膜异型增生症状,经治疗后PCG、A组异型增生趋于正常.结论:解毒化瘀健脾方对发生异型增生的胃黏膜组织Thbs1基因具有显著地去甲基化作用.解毒化瘀健脾方治疗胃黏膜异型增生可能与该药物使Thbs1基因甲基化程度显著降低有关.
基金This work was funded by the National Natural Science Foundation of China:[grant numbers 81671493,81801458]Chongqing Science and Technology Commission[grant number cstc2017jcyJAX0410].
文摘Preeclampsia is a pregnancy complication which threatens the survival of mothers and fetuses.It originates from abnormal placentation,especially insufficient fusion of the cytotrophoblast cells to form the syncytiotrophoblast.In this study,we found that THBS1,a matricellular protein that mediates cell-to-cell and cell-to-matrix interactions,is downregulated during the fusion of primary cytotrophoblast and BeWo cells,but upregulated in the placenta of pregnancies complicated by preeclampsia.Also,THBS1 was observed to interact with CD36,a membrane signal receptor and activator of the cAMP signaling pathway,to regulate the fusion of cytotrophoblast cells.Overexpression of THBS1 inhibited the cAMP signaling pathway and reduced the BeWo cells fusion ratio,while the effects of THBS1 were abolished by a CD36-blocking antibody.Our results suggest that THBS1 signals through a CD36-mediated cAMP pathway to regulate syncytialization of the cytotrophoblast cells,and that its upregulation impairs placental formation to cause preeclampsia.Thus,THBS1 can serve as a therapeutic target regarding the mitigation of abnormal syncytialization and preeclampsia.
基金supported by the National Institutes for Food and Drug Control,State Key Laboratory of Drug Regulatory Science。
文摘Hepatocellular carcinoma(HCC),a prevalent solid carcinoma of significant concern,is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes.The etiology and pathological progression of non-alcoholic steatohepatitis(NASH)-related HCC is multifactorial and multistage.However,no single animal model can accurately mimic the full NASH-related HCC pathological progression,posing considerable challenges to transition and mechanistic studies.Herein,a novel conditional inducible wild-type human HRAS overexpressed mouse model(HRAS-HCC)was established,demonstrating 100%morbidity and mortality within approximately one month under normal dietary and lifestyle conditions.Advanced symptoms of HCC such as ascites,thrombus,internal hemorrhage,jaundice,and lung metastasis were successfully replicated in mice.In-depth pathological features of NASH-related HCC were demonstrated by pathological staining,biochemical analyses,and typical marker gene detections.Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival,further confirming the accuracy and reliability of the model.Based on protein-protein interaction(PPI)network and RNA sequencing analyses,we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis,with subsequent progression to HCC.Collectively,our study successfully duplicated natural sequential progression in a single murine model over a very short period,providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.
