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
This review briefly describes the origin,chemistry,molecular mechanism of action,pharmacology,toxicology,and ecotoxicology of palytoxin and its analogues. Palytoxin and its analogues are produced by marine dinoflagell...This review briefly describes the origin,chemistry,molecular mechanism of action,pharmacology,toxicology,and ecotoxicology of palytoxin and its analogues. Palytoxin and its analogues are produced by marine dinoflagellates. Palytoxin is also produced by Zoanthids(i.e. Palythoa),and Cyanobacteria(Trichodesmium). Palytoxin is a very large,non-proteinaceous molecule with a complex chemical structure having both lipophilic and hydrophilic moieties. Palytoxin is one of the most potent marine toxins with an LD50 of 150 ng/kg body weight in mice exposed intravenously. Pharmacological and electrophysiological studies have demonstrated that palytoxin acts as a hemolysin and alters the function of excitable cells through multiple mechanisms of action. Palytoxin selectively binds to Na+/K+-ATPase with a Kd of 20 p M and transforms the pump into a channel permeable to monovalent cations with a single-channel conductance of 10 p S. This mechanism of action could have multiple effects on cells. Evaluation of palytoxin toxicity using various animal models revealed that palytoxin is an extremely potent neurotoxin following an intravenous,intraperitoneal,intramuscular,subcutaneous or intratracheal route of exposure. Palytoxin also causes non-lethal,yet serious toxic effects following dermal or ocular exposure. Most incidents of palytoxin poisoning have manifested after oral intake of contaminated seafood. Poisonings in humans have also been noted after inhalation,cutaneous/systemic exposures with direct contact of aerosolized seawater during Ostreopsis blooms and/or through maintaining aquaria containing Cnidarian zoanthids. Palytoxin has a strong potential for toxicity in humans and animals,and currently this toxin is of great concern worldwide.展开更多
Mycotoxins can cause body poisoning and induce carcinogenesis,often with a high mortality rate.Therefore,it is of great significance to seek new targets that indicate mycotoxin activity and to diagnose and intervene i...Mycotoxins can cause body poisoning and induce carcinogenesis,often with a high mortality rate.Therefore,it is of great significance to seek new targets that indicate mycotoxin activity and to diagnose and intervene in mycotoxin-induced diseases in their early stages.MicroRNAs(miRNAs)are physiological regulators whose dysregulation is closely related to the development of diseases.They are thus important markers for the occurrence and development of diseases.In this review,consideration is given to the toxicological mechanisms associated with four major mycotoxins(ochratoxin A,aflatoxin B1,deoxynivalenol,and zearalenone).The roles that miRNAs play in these mechanisms and the interactions between them and their target genes are explained,and summarize the important role of histone modifications in their toxicity.As a result,the ways that miRNAs are regulated in the pathogenicity signaling pathways are revealed which highlights the roles played by miRNAs in preventing and controlling the harmful effects of the mycotoxins.It is hoped that this review will provide a theoretical basis for the prevention and control of the damage caused by these mycotoxins.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Project(2102–2020)supported by the SPEV Project,University of Hradec Kralove,FIM,Czech RepublicProject(Vot-20H04)supported by Universiti Teknologi Malaysia(UTM)+1 种基金Project(Vot 4L876)supported by Malaysia Research University Network(MRUN)Project(Vot 5F073)supported by the Fundamental Research Grant Scheme(FRGS),Ministry of Education Malaysia。
基金supported by Long Term Development Plan of University Hospital Hradec Kralove and University of Hradec Kralove,the Project of Excellence FIM UHK,as well as,Yangtze Youth Talents Fund(Yangtze University)
文摘This review briefly describes the origin,chemistry,molecular mechanism of action,pharmacology,toxicology,and ecotoxicology of palytoxin and its analogues. Palytoxin and its analogues are produced by marine dinoflagellates. Palytoxin is also produced by Zoanthids(i.e. Palythoa),and Cyanobacteria(Trichodesmium). Palytoxin is a very large,non-proteinaceous molecule with a complex chemical structure having both lipophilic and hydrophilic moieties. Palytoxin is one of the most potent marine toxins with an LD50 of 150 ng/kg body weight in mice exposed intravenously. Pharmacological and electrophysiological studies have demonstrated that palytoxin acts as a hemolysin and alters the function of excitable cells through multiple mechanisms of action. Palytoxin selectively binds to Na+/K+-ATPase with a Kd of 20 p M and transforms the pump into a channel permeable to monovalent cations with a single-channel conductance of 10 p S. This mechanism of action could have multiple effects on cells. Evaluation of palytoxin toxicity using various animal models revealed that palytoxin is an extremely potent neurotoxin following an intravenous,intraperitoneal,intramuscular,subcutaneous or intratracheal route of exposure. Palytoxin also causes non-lethal,yet serious toxic effects following dermal or ocular exposure. Most incidents of palytoxin poisoning have manifested after oral intake of contaminated seafood. Poisonings in humans have also been noted after inhalation,cutaneous/systemic exposures with direct contact of aerosolized seawater during Ostreopsis blooms and/or through maintaining aquaria containing Cnidarian zoanthids. Palytoxin has a strong potential for toxicity in humans and animals,and currently this toxin is of great concern worldwide.
基金funded by the National Key Research and Development Program of China (2017YFC1600304)the National Natural Science Foundation of China (grants No. 31872538+4 种基金grants No. 31972746grants No.31772809)Liaoning Provincial Natural Fund Guidance Program Project(2019-ZD-0708)China Postdoctoral Science Foundation (2016 T90477)PAPD,Project UHK VT2019–2021 and and MH CZ–DRO (UHHK, 00179906)
文摘Mycotoxins can cause body poisoning and induce carcinogenesis,often with a high mortality rate.Therefore,it is of great significance to seek new targets that indicate mycotoxin activity and to diagnose and intervene in mycotoxin-induced diseases in their early stages.MicroRNAs(miRNAs)are physiological regulators whose dysregulation is closely related to the development of diseases.They are thus important markers for the occurrence and development of diseases.In this review,consideration is given to the toxicological mechanisms associated with four major mycotoxins(ochratoxin A,aflatoxin B1,deoxynivalenol,and zearalenone).The roles that miRNAs play in these mechanisms and the interactions between them and their target genes are explained,and summarize the important role of histone modifications in their toxicity.As a result,the ways that miRNAs are regulated in the pathogenicity signaling pathways are revealed which highlights the roles played by miRNAs in preventing and controlling the harmful effects of the mycotoxins.It is hoped that this review will provide a theoretical basis for the prevention and control of the damage caused by these mycotoxins.