Chronic consumption of aflatoxin-contaminated foods is a global problem in both developing and developed countries especially where there is poor regulation of their levels in foods. In the body, aflatoxins (AFBs) mai...Chronic consumption of aflatoxin-contaminated foods is a global problem in both developing and developed countries especially where there is poor regulation of their levels in foods. In the body, aflatoxins (AFBs) mainly AFB1 are biotransformed to various metabolites especially the active AFB1-exo-8,9-epoxide (AFBO). The AFB, AFBO and other metabolites interact with various biomolecules in the body including nucleic acids such as DNA and RNA and the various metabolic pathways such as protein synthesis, glycolytic pathway and electron transport chain involved in ATP production in body cells. The AFB interacts with DNA to form AFB-DNA adducts causing DNA breakages. The AFB and its metabolites induce the up regulation of nuclear receptors such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR) through gene expression that regulates the metabolizing enzymes such as CYP450 involved in Phase I and Phase II metabolism of xenobiotics. AFB activates these nuclear receptors to produce the metabolizing enzymes. The AFB1 is metabolized in the body by cytochrome P450 (CYP450) enzyme isoforms such as CYP1A2, CYP1A2, CYP3A4/ CYP3A5, and CYP3A7 in fetus, glutathione S-transferase, aflatoxin B1-aldehyde reductase leading to reactive metabolites, some of which can be used as aflatoxin exposure biomarkers. These enzymes are involved in the Phase I and Phase II metabolic reactions of aflatoxins. The CYP1A2 is the principal metabolizer of aflatoxin at low concentrations while the reverse is true for CYP3A4. The accumulation of AFB and its metabolites in the body especially the AFB1-exo-8,9-epoxide depletes the glutathione (GSH) due to the formation of high amounts of epoxides and other reactive oxygen species (ROS). The AFB, AFB1-exo-8,9-epoxide and other metabolites also affect the epigenetic mechanisms including the DNA methylation, histone modifications, maturation of miRNAs as well as the daily formation of single nucleotide polymorphism (SNP) where AFB exposure may facilitat展开更多
Colorectal cancer(CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC(...Colorectal cancer(CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC(EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, Mut YH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach.展开更多
The growing and rapid development of high-throughput sequencing technologies have allowed a greater understanding of the mechanisms underlying gene expression regulation.Editing the epigenome and epitranscriptome dire...The growing and rapid development of high-throughput sequencing technologies have allowed a greater understanding of the mechanisms underlying gene expression regulation.Editing the epigenome and epitranscriptome directs the fate of the transcript influencing the functional outcome of each mRNA.In this context,non-coding RNAs play a decisive role in addressing the expression regulation at the gene and chromosomal levels.Long-noncoding RNAs,consisting of more than 200 nucleotides,have been shown to act as epigenetic regulators in several key molecular processes involving neurodegenerative disorders,such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis and Huntington’s disease.Long-noncoding RNAs are abundantly expressed in the central nervous system,suggesting that their deregulation could trigger neuronal degeneration through RNA modifications.The evaluation of their diagnostic significance and therapeutic potential could lead to new treatments for these diseases for which there is no cure.展开更多
目的:探讨滋养细胞STAT3基因介导表观遗传学调控对子痫前期(PE)发病中的影响机制。方法:收集30例正常(Con组)和30例子痫前期(PE组)产妇胎盘组织,采用Real time-PCR和Western blot检测DNMT1、STAT3、PTEN、TSC2 mRNA和蛋白表达水平,甲基...目的:探讨滋养细胞STAT3基因介导表观遗传学调控对子痫前期(PE)发病中的影响机制。方法:收集30例正常(Con组)和30例子痫前期(PE组)产妇胎盘组织,采用Real time-PCR和Western blot检测DNMT1、STAT3、PTEN、TSC2 mRNA和蛋白表达水平,甲基化DNA免疫共沉淀测序(MeDIP-Seq)检测甲基化程度差异。体外培养HTR8/Svneo、JEG-3、JAR、BeWo滋养细胞株,分为空白对照组(Con组)、STAT3沉默组(shSTAT3组)、STAT3过表达组(STAT3OE组)。应用去甲基药物(5-AZA-DC)处理,采用GST-pull down,染色质免疫共沉淀实验(CHIP),双荧光素酶报告基因,甲基化特异性PCR(MSP)和亚硫酸盐测序PCR(BSP)检测。结果:(1)在胎盘组织中,与Con组相比,PE组胎盘组织中DNMT1 mRNA和蛋白[(5.25±1.12 vs 8.02±0.67)ng/ml、(3.33±0.98 vs 7.31±0.55)μg/ml,P<0.05]表达升高,STAT3[(5.17±0.98 vs 2.27±0.33)ng/ml、(6.12±1.03 vs 2.59±0.43)μg/ml,P<0.05]、PTEN[(4.58±0.77 vs 1.97±0.28)ng/ml、(6.21±1.04 VS 2.28±0.36)μg/ml,P<0.05]、TSC2[(6.39±0.83 vs 3.16±0.52)ng/ml、(6.56±0.67 vs 3.03±0.17)μg/ml,P<0.05]mRNA和蛋白表达下降。MeDIP-Seq检测出PE组甲基化水平显著增高,其中STAT3、PTEN、TSC2基因为甲基化差异显著基因,差异有统计学意义(P<0.05)。(2)在细胞株中,与Con组相比,GST-pull down验证HTR8/Svneo细胞中STAT3与PTEN、TSC2蛋白体外相互作用,CHIP证实在HTR8/Svneo、JEG-3、JAR、BeWo细胞中STAT3能明显富集靶基因PTEN,双荧光素酶报告基因验证HTR8/Svneo、JEG-3、JAR、BeWo细胞中STAT3调控PTEN启动子活性,5-AZA-DC干预后显著改善,差异有统计学意义(P<0.05)。MSP和BSP检测HTR8/Svneo细胞中PTEN基因启动子区CpG岛DNA甲基化,5-AZA-DC干预前shSTAT3、STAT3OE组甲基化显著,干预后呈非甲基化,差异有统计学意义(P<0.05)。结论:STAT3基因是介导表观遗传学调控引起PE发病的重要基因,可作为子痫前期表观遗传学治疗的潜在靶点。展开更多
Epigenetic modifications alter chromatin structures and consequently affect transcription and cellular functions.Major epigenetic markers include DNA methylation and histone acetylation and methylation.The modificatio...Epigenetic modifications alter chromatin structures and consequently affect transcription and cellular functions.Major epigenetic markers include DNA methylation and histone acetylation and methylation.The modifications are reversible and are achieved in aid of relative enzymes.Much effort has been directed at the understanding of the chemical mechanisms of individual catalytic reactions,which can serve as a foundation for inhibitor development.Among the many methods deployed,structural studies have proven the most effective for understanding enzyme-mediated modifications and have provided support for the development of lead-candidate drug inhibitors.This review briefly summarizes the existing knowledge on the catalytic mechanisms of the major epigenetic modification enzymes,with an emphasis on the structural information and inhibitors of these enzymes.展开更多
泛素特异性蛋白酶22(ubiquitin specific protease 22,USP22)是一种组蛋白去泛素化酶,在核受体介导的基因转录调控中起增强转录活性的作用。USP22在肿瘤发生、发展中发挥着重要作用,影响癌基因c-Myc介导的基因转录,从而促进肿瘤的增殖...泛素特异性蛋白酶22(ubiquitin specific protease 22,USP22)是一种组蛋白去泛素化酶,在核受体介导的基因转录调控中起增强转录活性的作用。USP22在肿瘤发生、发展中发挥着重要作用,影响癌基因c-Myc介导的基因转录,从而促进肿瘤的增殖和生长;另一方面,USP22可改变远上游识别序列结合蛋白1(far upstream element-binding protein 1,FBP1)的泛素化水平,从而影响FBP1下游的抑癌基因p21的表达。USP22与胃癌、大肠癌、乳腺癌及膀胱癌等肿瘤的病理进程相关。此外,USP22在端粒稳态的维持中起作用。本文主要综述USP22参与核受体介导的基因转录调控的表观遗传学机制及其在肿瘤发生中的作用。展开更多
文摘Chronic consumption of aflatoxin-contaminated foods is a global problem in both developing and developed countries especially where there is poor regulation of their levels in foods. In the body, aflatoxins (AFBs) mainly AFB1 are biotransformed to various metabolites especially the active AFB1-exo-8,9-epoxide (AFBO). The AFB, AFBO and other metabolites interact with various biomolecules in the body including nucleic acids such as DNA and RNA and the various metabolic pathways such as protein synthesis, glycolytic pathway and electron transport chain involved in ATP production in body cells. The AFB interacts with DNA to form AFB-DNA adducts causing DNA breakages. The AFB and its metabolites induce the up regulation of nuclear receptors such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR) through gene expression that regulates the metabolizing enzymes such as CYP450 involved in Phase I and Phase II metabolism of xenobiotics. AFB activates these nuclear receptors to produce the metabolizing enzymes. The AFB1 is metabolized in the body by cytochrome P450 (CYP450) enzyme isoforms such as CYP1A2, CYP1A2, CYP3A4/ CYP3A5, and CYP3A7 in fetus, glutathione S-transferase, aflatoxin B1-aldehyde reductase leading to reactive metabolites, some of which can be used as aflatoxin exposure biomarkers. These enzymes are involved in the Phase I and Phase II metabolic reactions of aflatoxins. The CYP1A2 is the principal metabolizer of aflatoxin at low concentrations while the reverse is true for CYP3A4. The accumulation of AFB and its metabolites in the body especially the AFB1-exo-8,9-epoxide depletes the glutathione (GSH) due to the formation of high amounts of epoxides and other reactive oxygen species (ROS). The AFB, AFB1-exo-8,9-epoxide and other metabolites also affect the epigenetic mechanisms including the DNA methylation, histone modifications, maturation of miRNAs as well as the daily formation of single nucleotide polymorphism (SNP) where AFB exposure may facilitat
文摘Colorectal cancer(CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC(EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, Mut YH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach.
基金funded by a special award to the Department of Pharmacy,Health and Nutritional Sciences of University of Calabria(Italy)(Department of Excellence,Italian Law232/2016)from the Italian Ministry of Research and University(MIUR)to FLC.
文摘The growing and rapid development of high-throughput sequencing technologies have allowed a greater understanding of the mechanisms underlying gene expression regulation.Editing the epigenome and epitranscriptome directs the fate of the transcript influencing the functional outcome of each mRNA.In this context,non-coding RNAs play a decisive role in addressing the expression regulation at the gene and chromosomal levels.Long-noncoding RNAs,consisting of more than 200 nucleotides,have been shown to act as epigenetic regulators in several key molecular processes involving neurodegenerative disorders,such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis and Huntington’s disease.Long-noncoding RNAs are abundantly expressed in the central nervous system,suggesting that their deregulation could trigger neuronal degeneration through RNA modifications.The evaluation of their diagnostic significance and therapeutic potential could lead to new treatments for these diseases for which there is no cure.
基金supported by grants from the National Natural Science Foundation of China (No. 81570728)the Natural Science Foundation of Hebei Province,China (No. H2018206358)。
文摘目的:探讨滋养细胞STAT3基因介导表观遗传学调控对子痫前期(PE)发病中的影响机制。方法:收集30例正常(Con组)和30例子痫前期(PE组)产妇胎盘组织,采用Real time-PCR和Western blot检测DNMT1、STAT3、PTEN、TSC2 mRNA和蛋白表达水平,甲基化DNA免疫共沉淀测序(MeDIP-Seq)检测甲基化程度差异。体外培养HTR8/Svneo、JEG-3、JAR、BeWo滋养细胞株,分为空白对照组(Con组)、STAT3沉默组(shSTAT3组)、STAT3过表达组(STAT3OE组)。应用去甲基药物(5-AZA-DC)处理,采用GST-pull down,染色质免疫共沉淀实验(CHIP),双荧光素酶报告基因,甲基化特异性PCR(MSP)和亚硫酸盐测序PCR(BSP)检测。结果:(1)在胎盘组织中,与Con组相比,PE组胎盘组织中DNMT1 mRNA和蛋白[(5.25±1.12 vs 8.02±0.67)ng/ml、(3.33±0.98 vs 7.31±0.55)μg/ml,P<0.05]表达升高,STAT3[(5.17±0.98 vs 2.27±0.33)ng/ml、(6.12±1.03 vs 2.59±0.43)μg/ml,P<0.05]、PTEN[(4.58±0.77 vs 1.97±0.28)ng/ml、(6.21±1.04 VS 2.28±0.36)μg/ml,P<0.05]、TSC2[(6.39±0.83 vs 3.16±0.52)ng/ml、(6.56±0.67 vs 3.03±0.17)μg/ml,P<0.05]mRNA和蛋白表达下降。MeDIP-Seq检测出PE组甲基化水平显著增高,其中STAT3、PTEN、TSC2基因为甲基化差异显著基因,差异有统计学意义(P<0.05)。(2)在细胞株中,与Con组相比,GST-pull down验证HTR8/Svneo细胞中STAT3与PTEN、TSC2蛋白体外相互作用,CHIP证实在HTR8/Svneo、JEG-3、JAR、BeWo细胞中STAT3能明显富集靶基因PTEN,双荧光素酶报告基因验证HTR8/Svneo、JEG-3、JAR、BeWo细胞中STAT3调控PTEN启动子活性,5-AZA-DC干预后显著改善,差异有统计学意义(P<0.05)。MSP和BSP检测HTR8/Svneo细胞中PTEN基因启动子区CpG岛DNA甲基化,5-AZA-DC干预前shSTAT3、STAT3OE组甲基化显著,干预后呈非甲基化,差异有统计学意义(P<0.05)。结论:STAT3基因是介导表观遗传学调控引起PE发病的重要基因,可作为子痫前期表观遗传学治疗的潜在靶点。
文摘Epigenetic modifications alter chromatin structures and consequently affect transcription and cellular functions.Major epigenetic markers include DNA methylation and histone acetylation and methylation.The modifications are reversible and are achieved in aid of relative enzymes.Much effort has been directed at the understanding of the chemical mechanisms of individual catalytic reactions,which can serve as a foundation for inhibitor development.Among the many methods deployed,structural studies have proven the most effective for understanding enzyme-mediated modifications and have provided support for the development of lead-candidate drug inhibitors.This review briefly summarizes the existing knowledge on the catalytic mechanisms of the major epigenetic modification enzymes,with an emphasis on the structural information and inhibitors of these enzymes.
文摘泛素特异性蛋白酶22(ubiquitin specific protease 22,USP22)是一种组蛋白去泛素化酶,在核受体介导的基因转录调控中起增强转录活性的作用。USP22在肿瘤发生、发展中发挥着重要作用,影响癌基因c-Myc介导的基因转录,从而促进肿瘤的增殖和生长;另一方面,USP22可改变远上游识别序列结合蛋白1(far upstream element-binding protein 1,FBP1)的泛素化水平,从而影响FBP1下游的抑癌基因p21的表达。USP22与胃癌、大肠癌、乳腺癌及膀胱癌等肿瘤的病理进程相关。此外,USP22在端粒稳态的维持中起作用。本文主要综述USP22参与核受体介导的基因转录调控的表观遗传学机制及其在肿瘤发生中的作用。
