Background:Breast cancer has become the most common malignant tumor in the world.It is vital to discover novel prognostic biomarkers despite the fact that the majority of breast cancer patients have a good prognosis b...Background:Breast cancer has become the most common malignant tumor in the world.It is vital to discover novel prognostic biomarkers despite the fact that the majority of breast cancer patients have a good prognosis because of the high heterogeneity of breast cancer,which causes the disparity in prognosis.Recently,inflammatory-related genes have been proven to play an important role in the development and progression of breast cancer,so we set out to investigate the predictive usefulness of inflammatory-related genes in breast malignancies.Methods:We assessed the connection between Inflammatory-Related Genes(IRGs)and breast cancer by studying the TCGA database.Following differential and univariate Cox regression analysis,prognosis-related differentially expressed inflammatory genes were estimated.The prognostic model was constructed through the Least Absolute Shrinkage and Selector Operation(LASSO)regression based on the IRGs.The accuracy of the prognostic model was then evaluated using the Kaplan-Meier and Receiver Operating Characteristic(ROC)curves.The nomogram model was established to predict the survival rate of breast cancer patients clinically.Based on the prognostic expression,we also looked at immune cell infiltration and the function of immune-related pathways.The CellMiner database was used to research drug sensitivity.Results:In this study,7 IRGs were selected to construct a prognostic risk model.Further research revealed a negative relationship between the risk score and the prognosis of breast cancer patients.The ROC curve proved the accuracy of the prognostic model,and the nomogram accurately predicted survival rate.The scores of tumorinfiltrating immune cells and immune-related pathways were utilized to calculate the differences between the low-and high-risk groups,and then explored the relationship between drug susceptibility and the genes that were included in the model.Conclusion:These findings contributed to a better understanding of the function of inflammatory-related genes in breast cancer,and the prognostic risk model provides a potentially promising prognostic strategy for breast cancer.展开更多
The immunoresponsive gene 1 （IRG 1） protein has crucial functions in embryonic implantation and neurodegeneration. IRG1 promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxyge...The immunoresponsive gene 1 （IRG 1） protein has crucial functions in embryonic implantation and neurodegeneration. IRG1 promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species （ROS）. The cytoprotective protein heme oxygenase-1 （HO-1）, which generates endogenous carbon monoxide （CO）, is expressed in the lung during Lipopolysaccharide （LPS） tolerance and cross tolerance. However, the detailed molecular mechanisms and functional links between IRG1 and HO-1 in the innate immune system remain unknown. In the present study, we found that the CO releasing molecule-2 （CORM-2） and chemical inducers of HO- 1 increased I RG 1 expression in a time- and dose-dependent fashion in RAW264.7 cells. Furthermore, inhibition of HO-1 activity by zinc protoporphyrin IX （ZnPP） and HO-1 siRNA significantly reduced expression of IRG1 under these conditions. In addition, treatment with CO and HO-1 induction significantly increased A20 expression, which was reversed by ZnPP and HO-1 siRNA. LPS-stimulated TNF-a was significantly decreased, whereas IRG1 and A20 were increased by CORM-2 application and HO-1 induction, which in turn were abrogated by ZnPP. Interestingly, siRNA against IRG1 and A20 reversed the effects of CO and HO-1 on LPS-stimulated TNF-a production. Additionally, CO and HO-1 inducers significantly increased IRG1 and A20 expression and downregulated TNF-a production in a LPS-stimulated sepsis mice model. Furthermore, the effects of CO and HO-1 on TNF-α production were significantly reversed when ZnPP was administered. In conclusion, CO and HO-1 induction regulates IRG1 and A20 expression, leading to inhibition of inflammation in vitroand in an in vivomice model.展开更多
Inflammatory bowel disease(IBD)is a chronic relapsing gastrointestinal disorder,while the treatment effect is not satisfactory.Immune responsive gene 1(IRG1)is a highly ex-pressed gene in macrophage in response to inf...Inflammatory bowel disease(IBD)is a chronic relapsing gastrointestinal disorder,while the treatment effect is not satisfactory.Immune responsive gene 1(IRG1)is a highly ex-pressed gene in macrophage in response to inflammatory response and catalyzes the production of itaconate.Studies have reported that IRG1/itaconate has a significant antioxidant effect.This study aimed to investigate the effect and mechanism of IRG1/itaconate on dextran sulfate so-dium(DSS)-induced colitis in vivo and in vitro.In vivo experiments,we found IRG1/itaconate ex-erted protective effects against acute colitis by increasing mice weight,the length of colon,reducing disease activity index and colonic inflammation.Meanwhile,IRG1 deletion aggravated the macrophages/CD4+/CD8+T-cell accumulation,and increased the release of interleukin(IL)-1b,tumor necrosis factor-a(TNF-a),IL-6,the activation of nuclear factor-kB(NF-kB)/mitogen-activated protein kinase(MAPK)signaling pathway,and gasdermin D(GSDMD)mediated pyrop-tosis.Four-octyl itaconate(4-OI),a derivative of itaconate,attenuated these changes,therefore relieved DSS-induced colitis.In vitro experiment,we found 4-OI inhibited the reactive oxygen species production,thereby inhibiting the activation of MAPK/NF-kB signaling pathway in RAW264.7 and murine bone-marrow-derived macrophages.Simultaneously,we found 4-OI inhib-ited caspase1/GSDMD-mediated pyroptosis to reduce the release of cytokines.Finally,we found anti-TNF-a agent reduced the severity of DSS-induced colitis and inhibited gasdermin E(GSDME)-mediated pyroptosis in vivo.Meanwhile,our study revealed that 4-OI inhibited caspase3/GSDME-mediated pyroptosis induced by TNF-a in vitro.Taken together,IRG1/itaconate exerted a pro-tective role in DSS-induced colitis by inhibiting inflammatory response and GSDMD/GSDME-medi-ated pyroptosis,which could be a promising candidate for IBD therapy.展开更多
基金supported by the Natural Science Foundation of Jiangsu Province(BK20171506).
文摘Background:Breast cancer has become the most common malignant tumor in the world.It is vital to discover novel prognostic biomarkers despite the fact that the majority of breast cancer patients have a good prognosis because of the high heterogeneity of breast cancer,which causes the disparity in prognosis.Recently,inflammatory-related genes have been proven to play an important role in the development and progression of breast cancer,so we set out to investigate the predictive usefulness of inflammatory-related genes in breast malignancies.Methods:We assessed the connection between Inflammatory-Related Genes(IRGs)and breast cancer by studying the TCGA database.Following differential and univariate Cox regression analysis,prognosis-related differentially expressed inflammatory genes were estimated.The prognostic model was constructed through the Least Absolute Shrinkage and Selector Operation(LASSO)regression based on the IRGs.The accuracy of the prognostic model was then evaluated using the Kaplan-Meier and Receiver Operating Characteristic(ROC)curves.The nomogram model was established to predict the survival rate of breast cancer patients clinically.Based on the prognostic expression,we also looked at immune cell infiltration and the function of immune-related pathways.The CellMiner database was used to research drug sensitivity.Results:In this study,7 IRGs were selected to construct a prognostic risk model.Further research revealed a negative relationship between the risk score and the prognosis of breast cancer patients.The ROC curve proved the accuracy of the prognostic model,and the nomogram accurately predicted survival rate.The scores of tumorinfiltrating immune cells and immune-related pathways were utilized to calculate the differences between the low-and high-risk groups,and then explored the relationship between drug susceptibility and the genes that were included in the model.Conclusion:These findings contributed to a better understanding of the function of inflammatory-related genes in breast cancer,and the prognostic risk model provides a potentially promising prognostic strategy for breast cancer.
文摘The immunoresponsive gene 1 （IRG 1） protein has crucial functions in embryonic implantation and neurodegeneration. IRG1 promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species （ROS）. The cytoprotective protein heme oxygenase-1 （HO-1）, which generates endogenous carbon monoxide （CO）, is expressed in the lung during Lipopolysaccharide （LPS） tolerance and cross tolerance. However, the detailed molecular mechanisms and functional links between IRG1 and HO-1 in the innate immune system remain unknown. In the present study, we found that the CO releasing molecule-2 （CORM-2） and chemical inducers of HO- 1 increased I RG 1 expression in a time- and dose-dependent fashion in RAW264.7 cells. Furthermore, inhibition of HO-1 activity by zinc protoporphyrin IX （ZnPP） and HO-1 siRNA significantly reduced expression of IRG1 under these conditions. In addition, treatment with CO and HO-1 induction significantly increased A20 expression, which was reversed by ZnPP and HO-1 siRNA. LPS-stimulated TNF-a was significantly decreased, whereas IRG1 and A20 were increased by CORM-2 application and HO-1 induction, which in turn were abrogated by ZnPP. Interestingly, siRNA against IRG1 and A20 reversed the effects of CO and HO-1 on LPS-stimulated TNF-a production. Additionally, CO and HO-1 inducers significantly increased IRG1 and A20 expression and downregulated TNF-a production in a LPS-stimulated sepsis mice model. Furthermore, the effects of CO and HO-1 on TNF-α production were significantly reversed when ZnPP was administered. In conclusion, CO and HO-1 induction regulates IRG1 and A20 expression, leading to inhibition of inflammation in vitroand in an in vivomice model.
基金supported by the National Natural Science Foundation of China(No.81701883,82072736,82172171)。
文摘Inflammatory bowel disease(IBD)is a chronic relapsing gastrointestinal disorder,while the treatment effect is not satisfactory.Immune responsive gene 1(IRG1)is a highly ex-pressed gene in macrophage in response to inflammatory response and catalyzes the production of itaconate.Studies have reported that IRG1/itaconate has a significant antioxidant effect.This study aimed to investigate the effect and mechanism of IRG1/itaconate on dextran sulfate so-dium(DSS)-induced colitis in vivo and in vitro.In vivo experiments,we found IRG1/itaconate ex-erted protective effects against acute colitis by increasing mice weight,the length of colon,reducing disease activity index and colonic inflammation.Meanwhile,IRG1 deletion aggravated the macrophages/CD4+/CD8+T-cell accumulation,and increased the release of interleukin(IL)-1b,tumor necrosis factor-a(TNF-a),IL-6,the activation of nuclear factor-kB(NF-kB)/mitogen-activated protein kinase(MAPK)signaling pathway,and gasdermin D(GSDMD)mediated pyrop-tosis.Four-octyl itaconate(4-OI),a derivative of itaconate,attenuated these changes,therefore relieved DSS-induced colitis.In vitro experiment,we found 4-OI inhibited the reactive oxygen species production,thereby inhibiting the activation of MAPK/NF-kB signaling pathway in RAW264.7 and murine bone-marrow-derived macrophages.Simultaneously,we found 4-OI inhib-ited caspase1/GSDMD-mediated pyroptosis to reduce the release of cytokines.Finally,we found anti-TNF-a agent reduced the severity of DSS-induced colitis and inhibited gasdermin E(GSDME)-mediated pyroptosis in vivo.Meanwhile,our study revealed that 4-OI inhibited caspase3/GSDME-mediated pyroptosis induced by TNF-a in vitro.Taken together,IRG1/itaconate exerted a pro-tective role in DSS-induced colitis by inhibiting inflammatory response and GSDMD/GSDME-medi-ated pyroptosis,which could be a promising candidate for IBD therapy.
