Aflatoxin B_(1)(AFB_(1))is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin,particularly causing damages to kidney.Glomerular podocytes are terminally differentiated epithelial cells.AF...Aflatoxin B_(1)(AFB_(1))is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin,particularly causing damages to kidney.Glomerular podocytes are terminally differentiated epithelial cells.AFB_(1)induces podocyte inflammation,proteinuria and renal dysfunction.Studying the mechanism of AFB_(1)-induced podocyte inflammation and murine kidney dysfunction,we detected that AFB_(1)increased ubiquitindependent degradation of the transcription factor RelA through enhanced interaction of RelA with E3 ubiquitin ligase tripartite motif containing 7(TRIM7)in mouse podocyte clone-5(MPC-5)and mouse glomeruli.Reduction of RelA resulted in decreasing microRNA-9(miR-9)and activating the chemokine receptor 4(CXCR4),thioredoxin interacting protein(TXNIP),and NOD-like receptor pyrin domain-containing 3(NLRP3)signaling axis(CXCR4/TXNIP/NLRP3 pathway),leading to podocyte inflammation.We also determined that downregulation of miR-9 led to CXCR4 expression and the downstream TXNIP/NLRP3 pathway activation.Overexpression of miR-9 or deletion of CXCR4 suppressed AFB_(1)-induced CXCR4/TXNIP/NLRP3 pathway,resulting in alleviating podocyte inflammation and kidney dysfunction.Our findings indicated that ubiquitin-dependent proteolysis of RelA,downregulation of miR-9,and activation of CXCR4/TXNIP/NLRP3 pathway played an essential role in AFB_(1)-induced glomerular podocyte inflammation.Our study revealed a novel mechanism,via RelA,for the control of AFB_(1)’s nephrotoxicity,leading to an effective protection of food safety and public health.展开更多
AIM:To determine global DNA methylation in paired hepatocellular carcinoma(HCC) samples using several different assays and explore the correlations between hypomethylation and clinical parameters and biomarkers,includ...AIM:To determine global DNA methylation in paired hepatocellular carcinoma(HCC) samples using several different assays and explore the correlations between hypomethylation and clinical parameters and biomarkers,including that of aflatoxin B 1 exposure.METHODS:Using the radio labeled methyl acceptance assay as a measure of global hypomethylation,as well as two repetitive elements,including satellite 2(Sat2) by MethyLight and long interspersed nucleotide elements(LINE1),by pyrosequencing.RESULTS:By all three assays,mean methylation levels in tumor tissues were significantly lower than that in adjacent tissues.Methyl acceptance assay log(mean ± SD) disintegrations/min/ng DNA are 70.0 ± 54.8 and 32.4 ± 15.6,respectively,P = 0.040;percent methylation of Sat2 42.2 ± 55.1 and 117.9 ± 88.8,respectively,P < 0.0001 and percent methylation LINE1 48.6 ± 14.8 and 71.7 ± 1.4,respectively,P < 0.0001.Aflatoxin B 1 albumin(AFB 1-Alb) adducts,a measure of exposure to this dietary carcinogen,were inversely correlated with LINE1 methylation(r =-0.36,P = 0.034).CONCLUSION:Consistent hypomethylation in tumor compared to adjacent tissue was found by the three different methods.AFB 1 exposure is associated with DNA global hypomethylation,suggesting that chemical carcinogens may influence epigenetic changes in humans.展开更多
基金funded by Suzhou Science and Technology Council(SNG201907)Universities Natural Science Foundation of Jiangsu Province(20KJB330002)+6 种基金General Program of China Postdoctoral Science Foundation(2022M711369)the Startup Funding of Soochow University,Jiangsu Province-Suzhou Science and Technology Planning Project(SL T201917)National Natural Science Foundation of China(32172922,31972741)Natural Science Foundation of Jiangsu Province of China(BK20211216,BK20221091)the Startup Funding of Hefei University of Technology(1302003712022058)China-CEEC Joint University Education Project(202010)the Excellence Project PrF UHK(2217/2022-2023)。
文摘Aflatoxin B_(1)(AFB_(1))is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin,particularly causing damages to kidney.Glomerular podocytes are terminally differentiated epithelial cells.AFB_(1)induces podocyte inflammation,proteinuria and renal dysfunction.Studying the mechanism of AFB_(1)-induced podocyte inflammation and murine kidney dysfunction,we detected that AFB_(1)increased ubiquitindependent degradation of the transcription factor RelA through enhanced interaction of RelA with E3 ubiquitin ligase tripartite motif containing 7(TRIM7)in mouse podocyte clone-5(MPC-5)and mouse glomeruli.Reduction of RelA resulted in decreasing microRNA-9(miR-9)and activating the chemokine receptor 4(CXCR4),thioredoxin interacting protein(TXNIP),and NOD-like receptor pyrin domain-containing 3(NLRP3)signaling axis(CXCR4/TXNIP/NLRP3 pathway),leading to podocyte inflammation.We also determined that downregulation of miR-9 led to CXCR4 expression and the downstream TXNIP/NLRP3 pathway activation.Overexpression of miR-9 or deletion of CXCR4 suppressed AFB_(1)-induced CXCR4/TXNIP/NLRP3 pathway,resulting in alleviating podocyte inflammation and kidney dysfunction.Our findings indicated that ubiquitin-dependent proteolysis of RelA,downregulation of miR-9,and activation of CXCR4/TXNIP/NLRP3 pathway played an essential role in AFB_(1)-induced glomerular podocyte inflammation.Our study revealed a novel mechanism,via RelA,for the control of AFB_(1)’s nephrotoxicity,leading to an effective protection of food safety and public health.
基金Supported by A grant from the National Institute of Health,No. ES005116 and No.P30ES009089
文摘AIM:To determine global DNA methylation in paired hepatocellular carcinoma(HCC) samples using several different assays and explore the correlations between hypomethylation and clinical parameters and biomarkers,including that of aflatoxin B 1 exposure.METHODS:Using the radio labeled methyl acceptance assay as a measure of global hypomethylation,as well as two repetitive elements,including satellite 2(Sat2) by MethyLight and long interspersed nucleotide elements(LINE1),by pyrosequencing.RESULTS:By all three assays,mean methylation levels in tumor tissues were significantly lower than that in adjacent tissues.Methyl acceptance assay log(mean ± SD) disintegrations/min/ng DNA are 70.0 ± 54.8 and 32.4 ± 15.6,respectively,P = 0.040;percent methylation of Sat2 42.2 ± 55.1 and 117.9 ± 88.8,respectively,P < 0.0001 and percent methylation LINE1 48.6 ± 14.8 and 71.7 ± 1.4,respectively,P < 0.0001.Aflatoxin B 1 albumin(AFB 1-Alb) adducts,a measure of exposure to this dietary carcinogen,were inversely correlated with LINE1 methylation(r =-0.36,P = 0.034).CONCLUSION:Consistent hypomethylation in tumor compared to adjacent tissue was found by the three different methods.AFB 1 exposure is associated with DNA global hypomethylation,suggesting that chemical carcinogens may influence epigenetic changes in humans.
