1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demons...1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demonstrated receptor-interacting protein kinase 2(RIPK2)triggering immune evasion.Mechanistically,RIPK2 drives the desmoplastic tumor microenvironment(TME)and restricts the activation and density of tumor-infiltrating effector T cells by impairing the expression of major histocompatibility complex class I(MHC-I)[1].This process might be relevant in different solid cancer entities as illustrated by analyzing publicly available databases.展开更多
目的探讨受体相互作用丝氨酸/苏氨酸蛋白激酶2(RIPK2)参与免疫调控通路及临床预后的作用。方法通过TIMER、cBioPortal、Human Protein Atlas(HPA)和UALCAN和STRING等数据库对RIPK2在组织中的定位和表达,及其在肿瘤免疫浸润、免疫调控和...目的探讨受体相互作用丝氨酸/苏氨酸蛋白激酶2(RIPK2)参与免疫调控通路及临床预后的作用。方法通过TIMER、cBioPortal、Human Protein Atlas(HPA)和UALCAN和STRING等数据库对RIPK2在组织中的定位和表达,及其在肿瘤免疫浸润、免疫调控和生存预后中的作用进行分析。结果(1)RIPK2主要由激酶和CARD结构域构成,第18~298位氨基酸是其激酶结构,第435~526位氨基酸是CARD结构域;与正常组织细胞比较,RIPK2在大部分恶性肿瘤中高表达,其中在子宫内膜上皮癌和人黑色素瘤细胞系(hTERT-HME1)中表达最高。相比胶质瘤(GBM)和透明细胞癌(KIRC),在结肠癌(COAD)组织突变率和表达水平较高。(2)免疫组化和荧光染色结果显示,RIPK2定位在胞质,在不同肿瘤组织中RIPK2的表达和AIM2、CASP1、GSDMD、NLRP3、NOD1和NOD2蛋白表达呈正相关。(3)PPI网络图显示,RIPK2参与免疫调控,包括NOD样、NLRP3炎性小体、AIM2炎性小体和细胞焦亡相关通路。(4)RIPK2的表达与免疫渗漏和临床预后有关,在COAD和KIRC中,RIPK2的表达与CD_(8)^(+)、CD_(4)^(+)T细胞、Neutrophil细胞存在相关性。(5)生存分析曲线显示,RIPK2高表达与KIRC患者的预后生存相关,且高表达RIPK2的KIRC患者生存期缩短。结论RIPK2在COAD、GBM和KIRC等恶性肿瘤中高表达,参与调控免疫渗漏、预测肿瘤预后和生存分析,推测RIPK2可作为一个关键的候选基因,在免疫调控、指导临床预后和治疗恶性肿瘤中发挥重要作用。展开更多
Background:Gastric cancer(GC)is a prevalent cause of death.3,9-Di-O-methylnissolin(DOM)is a flavonoid isolated from Astragalus membranaceus.It has anticancer and anti-inflammatory effects,but its effect and mechanismo...Background:Gastric cancer(GC)is a prevalent cause of death.3,9-Di-O-methylnissolin(DOM)is a flavonoid isolated from Astragalus membranaceus.It has anticancer and anti-inflammatory effects,but its effect and mechanismof actiononGCarenot very clear.Methods:The appropriate concentration was selected after observing the effects of varying concentrations of DOM on the viability of GC cells,which was examined through the cell counting kit-8(CCK-8)assay.The receptor-interacting protein kinase 2(RIPK2)overexpression plasmid was transfected into GC cells,which were then treated with DOM.Cell cycle and proliferation,RIPK2 levels,and inflammatory factor levels were evaluated by flow cytometry,cell colony formation assay,Hoechst 33,258 fluorescence,5-ethynyl-2′-deoxyuridine(EdU)assay,Transwell assay,immunofluorescence,and enzyme-linked immunosorbent assay(ELISA),respectively.The nuclear factor kappa-B(NF-κB)pathway was detected using immunofluorescence andWestern blot.Results:The appropriate concentrations of DOM were found to be 200,400,and 800μg/mL.At these concentrations,in GC cells,DOMcould significantly reduce EdU-positive cells;decrease the colony formation,migration,and invasion rates;block the cell cycle;increase theHoechst 33,258 fluorescence intensity and apoptosis rate;andsignificantly reduce p-IκBαand p-NF-κB p65 expressions.Moreover,DOMnotably reduced the high level of RIPK2.After the overexpression of RIPK2,these effects were significantly reversed in GC cells,and interleukin(IL)-1βand IL-6 contents were clearly elevated.Conclusion:DOMcan suppress the level of RIPK2 and inhibit the activation of the NF-κB signaling,thereby reducing inflammation;inhibiting the malignant progression of GC cells;and promoting cycle arrest.展开更多
Acute liver injury(ALI)serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders.The prevention and treatment of ALI is still a serious glob...Acute liver injury(ALI)serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders.The prevention and treatment of ALI is still a serious global challenge.Given the limited therapeutic options for ALI,exploring novel targeted therapeutic agents becomes imperative.The potential therapeutic efficacy of inhibiting RIPK2 is highlighted,as it may provide significant benefits by attenuating the MAPK pathway and NF-κB signaling.Herein,we propose a CMD-OPT model,a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties.Compound RP20,which targets the ATP binding site,demonstrated excellent kinase specificity,ideal oral pharmacokinetics,and superior therapeutic effects in a model of APAP-induced ALI,positioning RP20 as a promising preclinical candidate.This marks the first application of RIPK2 inhibitors in ALI treatment,opening a novel therapeutic pathway for clinical applications.These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules,showcasing its significant potential in drug discovery.展开更多
Acetaminophen(APAP)overdose remains a leading cause of acute liver injury(ALI)worldwide,with limited therapeutic options except for N-acetylcysteine(NAC),whose efficacy is hampered by short half-life and suboptimal bi...Acetaminophen(APAP)overdose remains a leading cause of acute liver injury(ALI)worldwide,with limited therapeutic options except for N-acetylcysteine(NAC),whose efficacy is hampered by short half-life and suboptimal bioavailability^(1,2,3).Inflammation driven by MAPK and NF-κB pathways exacerbates hepatocellular damage,positioning receptor-interacting serine/threonine kinase 2(RIPK2)as an attractive target to attenuate pro-inflammatory signaling and apoptosis^(4,5).Early RIPK2 inhibitors such as GSK2983559 advanced into clinical trials for inflammatory bowel disease but faltered due to safety and pharmacokinetic drawbacks6.Addressing these challenges,Chen et al.7 introduce a two-stage,transformer-based CMD-OPT model to refine scaffold design and ADME properties of lead RIPK2 inhibitors,culminating in compound RP20-a selective,orally bioavailable preclinical candidate exhibiting robust hepatoprotective effects in APAP-induced ALI models.展开更多
文摘1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demonstrated receptor-interacting protein kinase 2(RIPK2)triggering immune evasion.Mechanistically,RIPK2 drives the desmoplastic tumor microenvironment(TME)and restricts the activation and density of tumor-infiltrating effector T cells by impairing the expression of major histocompatibility complex class I(MHC-I)[1].This process might be relevant in different solid cancer entities as illustrated by analyzing publicly available databases.
文摘目的探讨受体相互作用丝氨酸/苏氨酸蛋白激酶2(RIPK2)参与免疫调控通路及临床预后的作用。方法通过TIMER、cBioPortal、Human Protein Atlas(HPA)和UALCAN和STRING等数据库对RIPK2在组织中的定位和表达,及其在肿瘤免疫浸润、免疫调控和生存预后中的作用进行分析。结果(1)RIPK2主要由激酶和CARD结构域构成,第18~298位氨基酸是其激酶结构,第435~526位氨基酸是CARD结构域;与正常组织细胞比较,RIPK2在大部分恶性肿瘤中高表达,其中在子宫内膜上皮癌和人黑色素瘤细胞系(hTERT-HME1)中表达最高。相比胶质瘤(GBM)和透明细胞癌(KIRC),在结肠癌(COAD)组织突变率和表达水平较高。(2)免疫组化和荧光染色结果显示,RIPK2定位在胞质,在不同肿瘤组织中RIPK2的表达和AIM2、CASP1、GSDMD、NLRP3、NOD1和NOD2蛋白表达呈正相关。(3)PPI网络图显示,RIPK2参与免疫调控,包括NOD样、NLRP3炎性小体、AIM2炎性小体和细胞焦亡相关通路。(4)RIPK2的表达与免疫渗漏和临床预后有关,在COAD和KIRC中,RIPK2的表达与CD_(8)^(+)、CD_(4)^(+)T细胞、Neutrophil细胞存在相关性。(5)生存分析曲线显示,RIPK2高表达与KIRC患者的预后生存相关,且高表达RIPK2的KIRC患者生存期缩短。结论RIPK2在COAD、GBM和KIRC等恶性肿瘤中高表达,参与调控免疫渗漏、预测肿瘤预后和生存分析,推测RIPK2可作为一个关键的候选基因,在免疫调控、指导临床预后和治疗恶性肿瘤中发挥重要作用。
基金funded by the Hospital Fund of The First Hospital of Lanzhou University(grant number ldyyyyn2023-46)the Science and Technology Project of Gansu Province Key Research and Development Program(grant number 21YF5FA120)+1 种基金the Gansu Province Health Industry Research Project(grant number GSWSKY2020-12)the National Natural Science Foundation of China(grant number 82160498).
文摘Background:Gastric cancer(GC)is a prevalent cause of death.3,9-Di-O-methylnissolin(DOM)is a flavonoid isolated from Astragalus membranaceus.It has anticancer and anti-inflammatory effects,but its effect and mechanismof actiononGCarenot very clear.Methods:The appropriate concentration was selected after observing the effects of varying concentrations of DOM on the viability of GC cells,which was examined through the cell counting kit-8(CCK-8)assay.The receptor-interacting protein kinase 2(RIPK2)overexpression plasmid was transfected into GC cells,which were then treated with DOM.Cell cycle and proliferation,RIPK2 levels,and inflammatory factor levels were evaluated by flow cytometry,cell colony formation assay,Hoechst 33,258 fluorescence,5-ethynyl-2′-deoxyuridine(EdU)assay,Transwell assay,immunofluorescence,and enzyme-linked immunosorbent assay(ELISA),respectively.The nuclear factor kappa-B(NF-κB)pathway was detected using immunofluorescence andWestern blot.Results:The appropriate concentrations of DOM were found to be 200,400,and 800μg/mL.At these concentrations,in GC cells,DOMcould significantly reduce EdU-positive cells;decrease the colony formation,migration,and invasion rates;block the cell cycle;increase theHoechst 33,258 fluorescence intensity and apoptosis rate;andsignificantly reduce p-IκBαand p-NF-κB p65 expressions.Moreover,DOMnotably reduced the high level of RIPK2.After the overexpression of RIPK2,these effects were significantly reversed in GC cells,and interleukin(IL)-1βand IL-6 contents were clearly elevated.Conclusion:DOMcan suppress the level of RIPK2 and inhibit the activation of the NF-κB signaling,thereby reducing inflammation;inhibiting the malignant progression of GC cells;and promoting cycle arrest.
基金supported by the National Natural Science Foundation of China(82304282 and T2221004)the Natural Science Foundation of Sichuan,China(2024NSFSC1733)the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD23020).
文摘Acute liver injury(ALI)serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders.The prevention and treatment of ALI is still a serious global challenge.Given the limited therapeutic options for ALI,exploring novel targeted therapeutic agents becomes imperative.The potential therapeutic efficacy of inhibiting RIPK2 is highlighted,as it may provide significant benefits by attenuating the MAPK pathway and NF-κB signaling.Herein,we propose a CMD-OPT model,a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties.Compound RP20,which targets the ATP binding site,demonstrated excellent kinase specificity,ideal oral pharmacokinetics,and superior therapeutic effects in a model of APAP-induced ALI,positioning RP20 as a promising preclinical candidate.This marks the first application of RIPK2 inhibitors in ALI treatment,opening a novel therapeutic pathway for clinical applications.These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules,showcasing its significant potential in drug discovery.
文摘Acetaminophen(APAP)overdose remains a leading cause of acute liver injury(ALI)worldwide,with limited therapeutic options except for N-acetylcysteine(NAC),whose efficacy is hampered by short half-life and suboptimal bioavailability^(1,2,3).Inflammation driven by MAPK and NF-κB pathways exacerbates hepatocellular damage,positioning receptor-interacting serine/threonine kinase 2(RIPK2)as an attractive target to attenuate pro-inflammatory signaling and apoptosis^(4,5).Early RIPK2 inhibitors such as GSK2983559 advanced into clinical trials for inflammatory bowel disease but faltered due to safety and pharmacokinetic drawbacks6.Addressing these challenges,Chen et al.7 introduce a two-stage,transformer-based CMD-OPT model to refine scaffold design and ADME properties of lead RIPK2 inhibitors,culminating in compound RP20-a selective,orally bioavailable preclinical candidate exhibiting robust hepatoprotective effects in APAP-induced ALI models.
