Objectives:Pancreatic cancer(PC)is characterized by poor prognosis due to its limited treatment choices and delayed detection.S100A14 has been implicated in tumor progression,yet its regulatory hierarchy and functiona...Objectives:Pancreatic cancer(PC)is characterized by poor prognosis due to its limited treatment choices and delayed detection.S100A14 has been implicated in tumor progression,yet its regulatory hierarchy and functional interplay in PC remain unclear.This study aimed to define the role of S100A14 in PC progression.Methods:Integrated bioinformatic analyses of TCGA-PAAD and GSE22780 datasets identified candidate hub genes.Prognostic relevance was assessed via Kaplan-Meier and ROC analyses.Functional experiments were performed in PANC-1 and BxPC-3 cells,including qRT-PCR,CCK-8 assay,Western blotting,Transwell assay,and apoptosis assay.Co-immunoprecipitation(Co-IP)was used to verify S100A14-S100A16 interaction.CHX chase and dual-luciferase assays were employed to assess protein stability and transcriptional activity.Results:S100A14 was markedly upregulated in PC tissues and cell lines and identified as a key prognostic gene.Silencing S100A14 suppressed EMT,proliferation,invasion,and migration,while reversing S100A16-mediated p53 inhibition and enhancing apoptosis.Mechanistically,Co-IP assay confirmed the protein interaction between S100A14 and S100A16;S100A14 stabilized S100A16 protein through post-translational modification without transcriptional regulation;the S100A14/S100A16 axis reduced p53 protein stability and inhibited its transcriptional activity as well as the downstream p21 expression.Critically,knockdown of S100A14 abrogated the pro-metastatic phenotype of cancer cells.Conclusion:This study identifies S100A14 promotes PC progression by stabilizing S100A16 and suppressing the tumor-suppressive p53/p21 pathway;knockdown of S100A14 can reverse the above effects,restore p53 function,and enhance cancer cell apoptosis.Targeting the S100A14/S100A16/p53 regulatory axis could represent a promising therapeutic approach for PC.展开更多
Colitis-associated colorectal cancer(CAC)is a major contributor to cancer-related mortality worldwide.Titanium dioxide(TiO_(2),E171),a widely used food additive,has been insufficiently studied regarding its effects on...Colitis-associated colorectal cancer(CAC)is a major contributor to cancer-related mortality worldwide.Titanium dioxide(TiO_(2),E171),a widely used food additive,has been insufficiently studied regarding its effects on macrophages within colon tumors during CAC development.In this study,CAC mouse models were used to investigate the biological impact of dietary E171 on macrophages in vivo,while lipopolysaccharide(LPS)-stimulated RAW264.7 macrophage cell lines were employed to elucidate the underlying mechanisms in vitro.We found that dietary E171 intake accelerated CAC development,exacerbated inflammatory responses and oxidative stress,and upregulated CAC-associated genes,including S100a8,S100a9,Lcn2,S100a11,Cxcl2,and interleukin-1α(Il-1α).E171 also increased the expression of S100A8,S100A9,NOD-like receptor family pyrin domain-containing 3(NLRP3),and gasdermin-D Nterminal(GSDMD-N)in macrophages within colon tumors.In inflammatory macrophages,E171 exposure enhanced cell viability,increased reactive oxygen species(ROS)levels,and elevated the expression and secretion of S100A8 and S100A9,consistent with in vivo histological observations.Furthermore,E171-induced secretion of S100A8 and S100A9 in macrophages was suppressed by specific inhibitors,including N-acetylcysteine(NAC,ROS inhibitor),MCC950(NLRP3 inhibitor),Z-YVAD-FMK(caspase 1 inhibitor),disulfiram(GSDMD inhibitor),and transfection of NLRP3 small interfering ribonucleic acid(siRNA).These results indicate that dietary E171 promotes CAC development by activating macrophages,with S100A8 and S100A9 serving as key mediators,and the NLRP3/caspase 1/GSDMD pathway acting as a critical mechanism.展开更多
Acute ischemic stroke is a highly prevalent and disabling disease with poor prognosis.Neuronal death is a major feature after a stroke.PANoptosis is a newly reported pattern of cell death,characterized by pyroptosis,a...Acute ischemic stroke is a highly prevalent and disabling disease with poor prognosis.Neuronal death is a major feature after a stroke.PANoptosis is a newly reported pattern of cell death,characterized by pyroptosis,apoptosis,and necroptosis,that plays an important role in the pathophysiological process after ischemic brain injury.However,its precise underlying mechanisms have not yet been fully elucidated.This study aimed to clarify the function of S100 calcium-binding protein A10 in neuronal PANoptosis after ischemic brain damage and to investigate the impact and mechanism of sonic hedgehog and S100 calcium-binding protein A10 on PANoptosis.The results showed that S100 calcium-binding protein A10 was significantly upregulated in both cellular and animal models of ischemic stroke.Knockdown of S100 calcium-binding protein A10 exacerbated PANoptosis and the levels of PANoptosis-related proteins following cerebral ischemia damage.Sonic hedgehog treatment increased S100 calcium-binding protein A10 and inhibited the increase in PANoptosis induced by S100 calcium-binding protein A10 knockdown.The findings suggest that sonic hedgehog intervention mitigated neuronal PANoptosis ensuing from ischemic stroke.The combination of S100 calcium-binding protein A10 and sonic hedgehog demonstrated promise for developing an effective therapy against cerebral ischemic stroke,which would have significant potential for future clinical applications.展开更多
目的研究布地奈德(BUD)对S100钙结合蛋白A4(S100A4)诱导的肥大细胞活化、炎性因子释放及受体表达的影响。方法8~10周龄野生型(WT)的C57BL/6健康雄性小鼠2只,取胫骨与股骨提取骨髓进行骨髓源肥大细胞(BMMCs)培养,将5 mL PBS注射至小鼠腹...目的研究布地奈德(BUD)对S100钙结合蛋白A4(S100A4)诱导的肥大细胞活化、炎性因子释放及受体表达的影响。方法8~10周龄野生型(WT)的C57BL/6健康雄性小鼠2只,取胫骨与股骨提取骨髓进行骨髓源肥大细胞(BMMCs)培养,将5 mL PBS注射至小鼠腹腔,取腹腔灌洗液以获取腹膜来源的肥大细胞(PMCs);采用S100A4蛋白与BUD处理小鼠BMMCs和PMCs,实验分为PBS组、S100A4组、BUD组及S100A4+BUD组;β-己糖胺酶(β-hex)释放实验检测细胞脱颗粒指标β-hex、ELISA测定细胞活化介质类胰蛋白酶、糜蛋白酶及白三烯B4的释放,流式细胞术编码微球芯片技术(CBA)法检测炎性因子(IL-5、IL-6、IL-13和TNF-α)分泌水平以及Toll样受体4(TLR4)和晚期糖基化终产物受体(RAGE)的表达。结果在BMMCs与PMCs中,与PBS组相比,S100A4组培养上清中β-hex、类胰蛋白酶、白三烯B4及相关炎性因子IL-5、IL-6、IL-13和TNF-α的释放增加,细胞上TLR4和RAGE的表达上调(P<0.05);与S100A4组相比,S100A4+BUD组肥大细胞活化及炎性因子分泌明显被抑制,同时TLR4的表达下调(P<0.05),而RAGE的表达无显著变化(P>0.05)。结论BUD能够抑制S100A4介导的肥大细胞活化及炎性因子释放,并下调TLR4的表达,但不影响RAGE的表达,BUD可能通过TLR-4受体发挥其功能,为BUD在过敏性炎症中的应用提供新的理论依据。展开更多
基金supported by the Yunnan Province Liu Liang Expert Workstation(No.202305AF150148)Famous Doctor Projects of Yunnan Province(No.XDYC-MY-2022-0032)+1 种基金Yunnan Health Training Project of High Level Talents(No.L-2024029)Innovation Team Special Program of Yunnan(No.202505AS350004).
文摘Objectives:Pancreatic cancer(PC)is characterized by poor prognosis due to its limited treatment choices and delayed detection.S100A14 has been implicated in tumor progression,yet its regulatory hierarchy and functional interplay in PC remain unclear.This study aimed to define the role of S100A14 in PC progression.Methods:Integrated bioinformatic analyses of TCGA-PAAD and GSE22780 datasets identified candidate hub genes.Prognostic relevance was assessed via Kaplan-Meier and ROC analyses.Functional experiments were performed in PANC-1 and BxPC-3 cells,including qRT-PCR,CCK-8 assay,Western blotting,Transwell assay,and apoptosis assay.Co-immunoprecipitation(Co-IP)was used to verify S100A14-S100A16 interaction.CHX chase and dual-luciferase assays were employed to assess protein stability and transcriptional activity.Results:S100A14 was markedly upregulated in PC tissues and cell lines and identified as a key prognostic gene.Silencing S100A14 suppressed EMT,proliferation,invasion,and migration,while reversing S100A16-mediated p53 inhibition and enhancing apoptosis.Mechanistically,Co-IP assay confirmed the protein interaction between S100A14 and S100A16;S100A14 stabilized S100A16 protein through post-translational modification without transcriptional regulation;the S100A14/S100A16 axis reduced p53 protein stability and inhibited its transcriptional activity as well as the downstream p21 expression.Critically,knockdown of S100A14 abrogated the pro-metastatic phenotype of cancer cells.Conclusion:This study identifies S100A14 promotes PC progression by stabilizing S100A16 and suppressing the tumor-suppressive p53/p21 pathway;knockdown of S100A14 can reverse the above effects,restore p53 function,and enhance cancer cell apoptosis.Targeting the S100A14/S100A16/p53 regulatory axis could represent a promising therapeutic approach for PC.
基金supported by the National Natural Science Foundation of China(Nos.81974441 and 82203619)the Science and Technology Planning Project of Shenzhen Municipality(Nos.JCYJ20190814105619048 and JCYJ20220530154202005)。
文摘Colitis-associated colorectal cancer(CAC)is a major contributor to cancer-related mortality worldwide.Titanium dioxide(TiO_(2),E171),a widely used food additive,has been insufficiently studied regarding its effects on macrophages within colon tumors during CAC development.In this study,CAC mouse models were used to investigate the biological impact of dietary E171 on macrophages in vivo,while lipopolysaccharide(LPS)-stimulated RAW264.7 macrophage cell lines were employed to elucidate the underlying mechanisms in vitro.We found that dietary E171 intake accelerated CAC development,exacerbated inflammatory responses and oxidative stress,and upregulated CAC-associated genes,including S100a8,S100a9,Lcn2,S100a11,Cxcl2,and interleukin-1α(Il-1α).E171 also increased the expression of S100A8,S100A9,NOD-like receptor family pyrin domain-containing 3(NLRP3),and gasdermin-D Nterminal(GSDMD-N)in macrophages within colon tumors.In inflammatory macrophages,E171 exposure enhanced cell viability,increased reactive oxygen species(ROS)levels,and elevated the expression and secretion of S100A8 and S100A9,consistent with in vivo histological observations.Furthermore,E171-induced secretion of S100A8 and S100A9 in macrophages was suppressed by specific inhibitors,including N-acetylcysteine(NAC,ROS inhibitor),MCC950(NLRP3 inhibitor),Z-YVAD-FMK(caspase 1 inhibitor),disulfiram(GSDMD inhibitor),and transfection of NLRP3 small interfering ribonucleic acid(siRNA).These results indicate that dietary E171 promotes CAC development by activating macrophages,with S100A8 and S100A9 serving as key mediators,and the NLRP3/caspase 1/GSDMD pathway acting as a critical mechanism.
基金supported by the National Natural Science Foundation of China,Nos.82171456(to QY),and 81971229(to QY)the Natural Science Foundation of Chongqing,No.CSTC2021JCYJ-MSXMX0263(to QY)Doctoral Innovation Project of The First Affiliated Hospital of Chongqing Medical University,Nos.CYYY-BSYJSCXXM-202318(to JW)and CYYY-BSYJSCXXM-202327(to HT).
文摘Acute ischemic stroke is a highly prevalent and disabling disease with poor prognosis.Neuronal death is a major feature after a stroke.PANoptosis is a newly reported pattern of cell death,characterized by pyroptosis,apoptosis,and necroptosis,that plays an important role in the pathophysiological process after ischemic brain injury.However,its precise underlying mechanisms have not yet been fully elucidated.This study aimed to clarify the function of S100 calcium-binding protein A10 in neuronal PANoptosis after ischemic brain damage and to investigate the impact and mechanism of sonic hedgehog and S100 calcium-binding protein A10 on PANoptosis.The results showed that S100 calcium-binding protein A10 was significantly upregulated in both cellular and animal models of ischemic stroke.Knockdown of S100 calcium-binding protein A10 exacerbated PANoptosis and the levels of PANoptosis-related proteins following cerebral ischemia damage.Sonic hedgehog treatment increased S100 calcium-binding protein A10 and inhibited the increase in PANoptosis induced by S100 calcium-binding protein A10 knockdown.The findings suggest that sonic hedgehog intervention mitigated neuronal PANoptosis ensuing from ischemic stroke.The combination of S100 calcium-binding protein A10 and sonic hedgehog demonstrated promise for developing an effective therapy against cerebral ischemic stroke,which would have significant potential for future clinical applications.
文摘目的研究布地奈德(BUD)对S100钙结合蛋白A4(S100A4)诱导的肥大细胞活化、炎性因子释放及受体表达的影响。方法8~10周龄野生型(WT)的C57BL/6健康雄性小鼠2只,取胫骨与股骨提取骨髓进行骨髓源肥大细胞(BMMCs)培养,将5 mL PBS注射至小鼠腹腔,取腹腔灌洗液以获取腹膜来源的肥大细胞(PMCs);采用S100A4蛋白与BUD处理小鼠BMMCs和PMCs,实验分为PBS组、S100A4组、BUD组及S100A4+BUD组;β-己糖胺酶(β-hex)释放实验检测细胞脱颗粒指标β-hex、ELISA测定细胞活化介质类胰蛋白酶、糜蛋白酶及白三烯B4的释放,流式细胞术编码微球芯片技术(CBA)法检测炎性因子(IL-5、IL-6、IL-13和TNF-α)分泌水平以及Toll样受体4(TLR4)和晚期糖基化终产物受体(RAGE)的表达。结果在BMMCs与PMCs中,与PBS组相比,S100A4组培养上清中β-hex、类胰蛋白酶、白三烯B4及相关炎性因子IL-5、IL-6、IL-13和TNF-α的释放增加,细胞上TLR4和RAGE的表达上调(P<0.05);与S100A4组相比,S100A4+BUD组肥大细胞活化及炎性因子分泌明显被抑制,同时TLR4的表达下调(P<0.05),而RAGE的表达无显著变化(P>0.05)。结论BUD能够抑制S100A4介导的肥大细胞活化及炎性因子释放,并下调TLR4的表达,但不影响RAGE的表达,BUD可能通过TLR-4受体发挥其功能,为BUD在过敏性炎症中的应用提供新的理论依据。
