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
目的:观察蒲公英多糖(dandelion polysaccharide,DP)对大鼠多器官功能障碍综合征(multiple organ dysfunction syndrome,MODS)肺、小肠组织炎症反应及S100钙结合蛋白A8/A9(S100 calcium-binding protein A8/A9,S100A8/A9)表达的影响。方...目的:观察蒲公英多糖(dandelion polysaccharide,DP)对大鼠多器官功能障碍综合征(multiple organ dysfunction syndrome,MODS)肺、小肠组织炎症反应及S100钙结合蛋白A8/A9(S100 calcium-binding protein A8/A9,S100A8/A9)表达的影响。方法:应用失血性休克及腹腔注射脂多糖“二次打击”的方法,构建大鼠MODS模型,分为假手术组、模型组、DP低剂量组、DP高剂量组。观察各组大鼠肺和小肠脏器系数及湿/干重比值;苏木精-伊红(hematoxylin-eosinstaining,HE)染色观察肺和小肠组织病理形态学改变;免疫组织化学染色观察肺和小肠组织白细胞介素(interleukin,IL)1β、IL-6、IL-10的表达;蛋白质免疫印迹法(Western blot)检测肺和小肠组织S100A8/A9蛋白表达变化。结果:与假手术组相比,模型组大鼠肺脏系数(5.849±0.824)、湿/干重比值(6.556±0.631)和小肠湿/干重比值(6.356±0.535)、湿重/长度比值(73.950±5.569)均上升。HE染色显示肺泡腔及肺间质可见大量炎细胞浸润,肺泡壁增厚;小肠绒毛崩解碎裂,可见炎细胞浸润及节段性集合淋巴滤泡增生。S100A8/A9主要表达于中性粒细胞和巨噬细胞,大鼠肺和小肠组织S100A8/A9、IL-1β、IL-6表达上调,IL-10表达下调。给予高剂量DP治疗后,大鼠肺脏系数(4.297±0.462)、湿/干重比值(5.313±0.495)和小肠湿/干重比值(5.398±0.388)、湿重/长度比值(59.417±2.891)均下降。肺和小肠组织病理损伤减轻,肺和小肠组织S100A8/A9、IL-1β、IL-6表达下调,IL-10表达上调。结论:DP可能通过抑制S100A8/A9的表达,减轻大鼠MODS肺和小肠组织损伤的炎症反应。展开更多
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.
文摘目的:观察蒲公英多糖(dandelion polysaccharide,DP)对大鼠多器官功能障碍综合征(multiple organ dysfunction syndrome,MODS)肺、小肠组织炎症反应及S100钙结合蛋白A8/A9(S100 calcium-binding protein A8/A9,S100A8/A9)表达的影响。方法:应用失血性休克及腹腔注射脂多糖“二次打击”的方法,构建大鼠MODS模型,分为假手术组、模型组、DP低剂量组、DP高剂量组。观察各组大鼠肺和小肠脏器系数及湿/干重比值;苏木精-伊红(hematoxylin-eosinstaining,HE)染色观察肺和小肠组织病理形态学改变;免疫组织化学染色观察肺和小肠组织白细胞介素(interleukin,IL)1β、IL-6、IL-10的表达;蛋白质免疫印迹法(Western blot)检测肺和小肠组织S100A8/A9蛋白表达变化。结果:与假手术组相比,模型组大鼠肺脏系数(5.849±0.824)、湿/干重比值(6.556±0.631)和小肠湿/干重比值(6.356±0.535)、湿重/长度比值(73.950±5.569)均上升。HE染色显示肺泡腔及肺间质可见大量炎细胞浸润,肺泡壁增厚;小肠绒毛崩解碎裂,可见炎细胞浸润及节段性集合淋巴滤泡增生。S100A8/A9主要表达于中性粒细胞和巨噬细胞,大鼠肺和小肠组织S100A8/A9、IL-1β、IL-6表达上调,IL-10表达下调。给予高剂量DP治疗后,大鼠肺脏系数(4.297±0.462)、湿/干重比值(5.313±0.495)和小肠湿/干重比值(5.398±0.388)、湿重/长度比值(59.417±2.891)均下降。肺和小肠组织病理损伤减轻,肺和小肠组织S100A8/A9、IL-1β、IL-6表达下调,IL-10表达上调。结论:DP可能通过抑制S100A8/A9的表达,减轻大鼠MODS肺和小肠组织损伤的炎症反应。
