Pancreatic cancer is one of the most lethal neoplasms with high metastatic potential and is resistant to almost all current therapies.Epalrestat is an aldo-keto reductase family 1 member B1(AKR1B1)inhibitor for the tr...Pancreatic cancer is one of the most lethal neoplasms with high metastatic potential and is resistant to almost all current therapies.Epalrestat is an aldo-keto reductase family 1 member B1(AKR1B1)inhibitor for the treatment of diabetic neuropathy,but its potential application in cancer treatment and the underlying mechanism are largely unknown.Here,we found that AKR1B1 is upregulated in pancreatic cancer and is positively associated with metastasis.Upregulated AKR1B1 promoted exosome secretion,accelerating cell migration in pancreatic cancer cells.Further analysis indicated that AKR1B1 negatively regulated lysosomal function and multivesicular body(MVB)degradation in lysosomes.However,AKR1B1 had a minimal role in the generation of MVBs.Transcription factor EB(TFEB)and MVB-expressed RAB7A were two molecular targets that are negatively regulated by AKR1B1.These results uncovered a critical role for AKR1B1 in the regulation of lysosomal function and exosome secretion.Pharmacological targeting of AKR1B1 by clinically used medicines,such as Epalrestat,might represent an efficient way to inhibit pancreatic growth and metastasis.展开更多
Subject Code:H16With the support by the National Natural Science Foundation of China,a study by the research groups led by Prof.Dong Chenfang(董辰方)from Zhejiang University School of Medicine demonstrates that AKR1B1...Subject Code:H16With the support by the National Natural Science Foundation of China,a study by the research groups led by Prof.Dong Chenfang(董辰方)from Zhejiang University School of Medicine demonstrates that AKR1B1promotes basal-like breast cancer progression by apositive feedback loop that activates the展开更多
●AIM:To investigate the association between a set of six candidate genes and the risk of diabetic retinopathy(DR)in an urban community cohort of Chinese patients with type 2 diabetes mellitus(T2 DM).●METHODS:A popul...●AIM:To investigate the association between a set of six candidate genes and the risk of diabetic retinopathy(DR)in an urban community cohort of Chinese patients with type 2 diabetes mellitus(T2 DM).●METHODS:A population-based cross-sectional study.The diabetic subjects were recruited from an urban community in Beijing and categorized into groups of proliferative diabetic retinopathy(PDR),non-proliferative diabetic retinopathy(NPDR),or diabetic without any retinopathy(DWR)based on the fundus photography and duration of diabetes.Six candidate genes,including advanced glycation end product specific receptor(AGER),aldose reductase(AKR1 B1),inducible nitric oxide synthase(i NOS),pigment epithelium derived factor(PEDF),tumor necrosis factor-alpha(TNF-α),and paraoxonase 1(PON1),were chosen based on Meta-analysis of genetic association studies for DR and biochemical pathways implicated in DR progression.The allele and genotype distribution of 21 functional singlenucleotide polymorphisms(SNPs)in those 6 candidate genes were investigated using MassARRAY genotyping system.●RESULTS:Among 1461 diabetic patients recruited from community,569 were selected in following genotyping analysis,including 97 patients with PDR,217 with NPDR,and 255 with DWR.For the promoter variant rs1051993 in AGER gene,the distribution of allele and genotype in PDR group differed from that in DWR group(allele:P=0.011;genotype:P=0.01).Compared with DWR,patients with PDR had lower frequencies of heterozygous genotype GT(9.8%for DWR,1%for PDR,OR:0.10,95%CI:0.01-0.72)and minor allele T(4.9%for DWR,0.5%for PDR,OR:0.10,95%CI:0.01-0.75).In multivariate model,the distribution of genotype for rs1051993 in PDR group was significantly different from that in DWR group(GT vs GG:OR:0.07,95%CI:0.01-0.61,P<0.001).No association with DR was observed in other genotyped SNPs.●CONCLUSION:The data suggest a significant association of the promoter variant rs1051993 in AGER gene with PDR in Chinese cohort with T2DM.展开更多
基金supported by grants from the National Natural Science Foundation(No.81702419)the National Science Fund for Distinguished Young Scholars(No.82000497)+4 种基金the Key Research and Development Plan of Jiangsu Province(Nos.BE2019692 and BE2020668)the Natural Science Foundation of Jiangsu Province(Nos.BK20211105 and BK20200965)the Postdoctoral Science Foundation of China(No.2019M661909)the Social Development Foundation of Nantong City(Nos.MS22020005 and MSZ20076)the Postgraduate Research&Practice Innovation Program of Jiangsu Province(Nos.KYCX20_2681,KYCX20_2673,and KYCX21_3112).
文摘Pancreatic cancer is one of the most lethal neoplasms with high metastatic potential and is resistant to almost all current therapies.Epalrestat is an aldo-keto reductase family 1 member B1(AKR1B1)inhibitor for the treatment of diabetic neuropathy,but its potential application in cancer treatment and the underlying mechanism are largely unknown.Here,we found that AKR1B1 is upregulated in pancreatic cancer and is positively associated with metastasis.Upregulated AKR1B1 promoted exosome secretion,accelerating cell migration in pancreatic cancer cells.Further analysis indicated that AKR1B1 negatively regulated lysosomal function and multivesicular body(MVB)degradation in lysosomes.However,AKR1B1 had a minimal role in the generation of MVBs.Transcription factor EB(TFEB)and MVB-expressed RAB7A were two molecular targets that are negatively regulated by AKR1B1.These results uncovered a critical role for AKR1B1 in the regulation of lysosomal function and exosome secretion.Pharmacological targeting of AKR1B1 by clinically used medicines,such as Epalrestat,might represent an efficient way to inhibit pancreatic growth and metastasis.
文摘Subject Code:H16With the support by the National Natural Science Foundation of China,a study by the research groups led by Prof.Dong Chenfang(董辰方)from Zhejiang University School of Medicine demonstrates that AKR1B1promotes basal-like breast cancer progression by apositive feedback loop that activates the
基金Supported by the National Basic Research Program of China(973 Program)Grant(No.2007CB512201)the Beijing Municipal Health Bureau Grant(No.2009208).
文摘●AIM:To investigate the association between a set of six candidate genes and the risk of diabetic retinopathy(DR)in an urban community cohort of Chinese patients with type 2 diabetes mellitus(T2 DM).●METHODS:A population-based cross-sectional study.The diabetic subjects were recruited from an urban community in Beijing and categorized into groups of proliferative diabetic retinopathy(PDR),non-proliferative diabetic retinopathy(NPDR),or diabetic without any retinopathy(DWR)based on the fundus photography and duration of diabetes.Six candidate genes,including advanced glycation end product specific receptor(AGER),aldose reductase(AKR1 B1),inducible nitric oxide synthase(i NOS),pigment epithelium derived factor(PEDF),tumor necrosis factor-alpha(TNF-α),and paraoxonase 1(PON1),were chosen based on Meta-analysis of genetic association studies for DR and biochemical pathways implicated in DR progression.The allele and genotype distribution of 21 functional singlenucleotide polymorphisms(SNPs)in those 6 candidate genes were investigated using MassARRAY genotyping system.●RESULTS:Among 1461 diabetic patients recruited from community,569 were selected in following genotyping analysis,including 97 patients with PDR,217 with NPDR,and 255 with DWR.For the promoter variant rs1051993 in AGER gene,the distribution of allele and genotype in PDR group differed from that in DWR group(allele:P=0.011;genotype:P=0.01).Compared with DWR,patients with PDR had lower frequencies of heterozygous genotype GT(9.8%for DWR,1%for PDR,OR:0.10,95%CI:0.01-0.72)and minor allele T(4.9%for DWR,0.5%for PDR,OR:0.10,95%CI:0.01-0.75).In multivariate model,the distribution of genotype for rs1051993 in PDR group was significantly different from that in DWR group(GT vs GG:OR:0.07,95%CI:0.01-0.61,P<0.001).No association with DR was observed in other genotyped SNPs.●CONCLUSION:The data suggest a significant association of the promoter variant rs1051993 in AGER gene with PDR in Chinese cohort with T2DM.
