BACKGROUND Colorectal cancer(CRC)is among the most prevalent and life-threatening malignancies worldwide.Syndecan-2 methylation(mSDC2)testing has emerged as a widely used biomarker for early detection of CRC in stool ...BACKGROUND Colorectal cancer(CRC)is among the most prevalent and life-threatening malignancies worldwide.Syndecan-2 methylation(mSDC2)testing has emerged as a widely used biomarker for early detection of CRC in stool and serum samples.Cancer(CRC)is among the most prevalent and life-threatening malignancies worldwide.mSDC2 testing has emerged as a widely used biomarker for early detection of CRC in stool and serum samples.AIM To validate the effectiveness of fecal DNA mSDC2 testing in the detection of CRC among a high-risk Chinese population to provide evidence-based data for the development of diagnostic and/or screening guidelines for CRC in China.METHODS A high-risk Chinese cohort consisting of 1130 individuals aged 40-79 years was selected for evaluation via fecal mSDC2 testing.Sensitivity and specificity for CRC,advanced adenoma(AA)and advanced colorectal neoplasia(ACN)were determined.High-risk factors for the incidence of colorectal lesions were determined and a logistic regression model was constructed to reflect the efficacy of the test.RESULTS A total of 1035 high-risk individuals were included in this study according to established criteria.Among them,16 suffered from CRC(1.55%),65 from AA(6.28%)and 189 from non-AAs(18.26%);150 patients were diagnosed with polyps(14.49%).Diagnoses were established based upon colonoscopic and pathological examinations.Sensitivities of the mSDC2 test for CRC and AA were 87.50%and 40.00%,respectively;specificities were 95.61%for other groups.Positive predictive values of the mSDC2 test for CRC,AA and ACN were 16.09%,29.89%and 45.98%,respectively;the negative predictive value for CRC was 99.79%.After adjusting for other high-risk covariates,mSDC2 test positivity was found to be a significant risk factor for the occurrence of ACN(P<0.001).CONCLUSION Our findings confirmed that offering fecal mSDC2 testing and colonoscopy in combination for CRC screening is effective for earlier detection of malignant colorectal lesions in a high-risk Chinese population.展开更多
BACKGROUND Early detection of colorectal cancer(CRC)is essential to reduce cancer-related morbidity and mortality.Stool DNA(sDNA)testing is an emerging method for early CRC detection.Syndecan-2(SDC2)methylation is a p...BACKGROUND Early detection of colorectal cancer(CRC)is essential to reduce cancer-related morbidity and mortality.Stool DNA(sDNA)testing is an emerging method for early CRC detection.Syndecan-2(SDC2)methylation is a potential biomarker for the sDNA testing.Aberrant DNA methylation is an early epigenetic event during tumorigenesis and can occur in the normal colonic mucosa during aging,which can compromise the sDNA test results.METHODS In this prospective study,we enrolled 151 patients with CRC who underwent curative surgical resection between September 2016 and May 2020.Preoperative stool samples were collected from 123 patients and postoperative samples were collected from 122 patients.A total of 104 samples were collected from both preoperative and postoperative patients.Aberrant promoter methylation of SDC2 in sDNA was assessed using linear target enrichment quantitative methylation-specific real-time polymerase chain reaction.Clinicopathological parameters were analyzed using the results of SDC2 methylation.RESULTS Detection rates of SDC2 methylation in the preoperative and postoperative stool samples were 88.6%and 19.7%,respectively.Large tumor size(3 cm,P=0.019)and advanced T stage(T3–T4,P=0.033)were positively associated with the detection rate of SDC2 methylation before surgery.Female sex was associated with false positives after surgery(P=0.030).Cycle threshold(CT)values were significantly decreased postoperatively compared with preoperative values(P<0.001).The postoperative negative conversion rate for preoperatively methylated SDC2 was 79.3%(73/92).CONCLUSION Our results suggested that the SDC2 methylation test for sDNA has acceptable sensitivity and specificity.However,small size and early T stage tumors are associated with a low detection rate of SDC2 methylation.As the cycle threshold values significantly decreased after surgery,SDC2 methylation test for sDNA might have a diagnostic value for CRC.展开更多
测定5-氯-2戊酮和环丙基甲基酮的物化性质:密度、黏度、摩尔体积、热膨胀系数和表面张力。测定5-氯-2-戊酮(1)+环丙基甲基酮(2)二元体系的汽液相平衡(VLE),并应用Aspen Plus V11中Van Laar方程、Wilson方程和NRTL方程对实验数据进行关联...测定5-氯-2戊酮和环丙基甲基酮的物化性质:密度、黏度、摩尔体积、热膨胀系数和表面张力。测定5-氯-2-戊酮(1)+环丙基甲基酮(2)二元体系的汽液相平衡(VLE),并应用Aspen Plus V11中Van Laar方程、Wilson方程和NRTL方程对实验数据进行关联,回归得到二元交互参数。实验结果通过热力学一致性检查。该研究不仅补充了汽液相平衡数据库,也为5-氯-2-戊酮与环丙基甲基酮的分离提供热力学数据。展开更多
背景甲基化CpG结合蛋白2(methyl-CpG-binding protein 2,MeCP2)在基因转录调控中发挥重要作用,研究表明MeCP2可能是胶质瘤治疗的一个新靶点,但其在胶质瘤中的表达与患者预后的关系尚不清楚。目的探讨MeCP2在胶质瘤中的表达与患者手术后...背景甲基化CpG结合蛋白2(methyl-CpG-binding protein 2,MeCP2)在基因转录调控中发挥重要作用,研究表明MeCP2可能是胶质瘤治疗的一个新靶点,但其在胶质瘤中的表达与患者预后的关系尚不清楚。目的探讨MeCP2在胶质瘤中的表达与患者手术后临床预后的关系。方法选择2016年1月—2018年10月在贵阳市第二人民医院神经外科手术治疗的临床病理资料完整的96例胶质瘤患者,应用免疫组织化学方法检测肿瘤组织和正常脑组织中MeCP2的表达,随访患者生存情况。采用Kaplan-Meier法进行生存分析;采用Cox单因素和多因素风险回归模型分析MeCP2表达水平及相关临床病理因素与患者生存预后的关系。结果96例患者获得随访,其中男51例,女45例,年龄7~79岁,平均年龄(44.9±18.3)岁。免疫组化结果显示胶质瘤组织中MeCP2阳性表达率高于正常脑组织(75.0%vs 30.0%,P<0.05)。MeCP2表达的阳性率在WHOⅠ~Ⅳ级胶质瘤组织中分别为20.0%、66.7%、75.0%、90.6%(1/5、18/27、24/32、29/32),在高级别胶质瘤(WHOⅢ、Ⅳ级)中的阳性表达率高于低级别胶质瘤(WHOⅠ、Ⅱ级),差异有统计学意义(P<0.05)。70例出现肿瘤复发,59例死亡,中位无进展生存期(progression-free survival,PFS)和总生存期(overall survival,OS)分别为(10.7±1.7)个月和(24.1±2.9)个月。Kaplan-Meier生存分析显示,胶质瘤患者中MeCP2高表达组的中位PFS和OS显著低于低表达组[PFS:(15.6±1.8)个月vs(28.0±2.6)个月,P=0.026;OS:(16.1±2.0)个月vs(28.3±5.8)个月,P=0.022]。Cox回归分析显示,MeCP2高表达(HR:1.705,95%CI:1.019~2.854)、肿瘤病变多发(HR:2.727,95%CI:1.453~5.120)、单纯采用手术治疗(HR:1.704,95%CI:1.015~2.861)、高病理级别(WHOⅢ、Ⅳ级)(HR:3.294,95%CI:2.317~4.683)是胶质瘤患者预后不良的独立危险因素。结论MeCP2在胶质瘤手术患者中表达水平上调,且高表达水平与胶质瘤患者术后不良预后相关。展开更多
Inflammation is closely related to stroke prognosis, and high inflammation status leads to poor functional outcome in stroke. DNA methylation is involved in the pathogenesis and prognosis of stroke. However, the effec...Inflammation is closely related to stroke prognosis, and high inflammation status leads to poor functional outcome in stroke. DNA methylation is involved in the pathogenesis and prognosis of stroke. However, the effect of DNA methylation on stroke at high levels of inflammation is unclear. In this study, we constructed a hyperinflammatory cerebral ischemia mouse model and investigated the effect of hypomethylation and hypermethylation on the functional outcome. We constructed a mouse model of transient middle cerebral artery occlusion and treated the mice with lipopolysaccharide to induce a hyperinflammatory state. To investigate the effect of DNA methylation on stroke, we used small molecule inhibitors to restrain the function of key DNA methylation and demethylation enzymes. 2,3,5-Triphenyltetrazolium chloride staining, neurological function scores, neurobehavioral tests, enzyme-linked immunosorbent assay, quantitative reverse transcription PCR and western blot assay were used to evaluate the effects after stroke in mice. We assessed changes in the global methylation status by measuring DNA 5-mc and DNA 5-hmc levels in peripheral blood after the use of the inhibitor. In the group treated with the DNA methylation inhibitor, brain tissue 2,3,5-triphenyltetrazolium chloride staining showed an increase in infarct volume, which was accompanied by a decrease in neurological scores and worsening of neurobehavioral performance. The levels of inflammatory factors interleukin 6 and interleukin-1 beta in ischemic brain tissue and plasma were elevated, indicating increased inflammation. Related inflammatory pathway exploration showed significant overactivation of nuclear factor kappa B. These results suggested that inhibiting DNA methylation led to poor functional outcome in mice with high inflammation following stroke. Further, the effects were reversed by inhibition of DNA demethylation. Our findings suggest that DNA methylation regulates the inflammatory response in stroke and has an important role in the functional outcome of hyperinflammatory stroke.展开更多
The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centere...The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression.The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus.Notably,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal cortex.Further,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory processes.The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns.Despite the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology.Future research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.展开更多
Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environme...Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.展开更多
基金Supported by the Science and Technology Program of Panyu Central Hospital,No.PY-2023-003the Science and Technology Program of Panyu,No.2020-Z04-054+4 种基金the Science and Technology Project of the Guangzhou Health Commission,No.20211A011114the Science and Technology Program of Guangzhou,No.202002020023the General University Youth Innovative Talent Project of Guangdong Province,No.2022KQNCX281the Guangdong Provincial Key Field Special Project for Ordinary Colleges and Universities,No.2023ZDZX2097the Foshan Engineering Technology Research Center for Prepared Food Processing and Quality Evaluation,No.2022-KJZX113.
文摘BACKGROUND Colorectal cancer(CRC)is among the most prevalent and life-threatening malignancies worldwide.Syndecan-2 methylation(mSDC2)testing has emerged as a widely used biomarker for early detection of CRC in stool and serum samples.Cancer(CRC)is among the most prevalent and life-threatening malignancies worldwide.mSDC2 testing has emerged as a widely used biomarker for early detection of CRC in stool and serum samples.AIM To validate the effectiveness of fecal DNA mSDC2 testing in the detection of CRC among a high-risk Chinese population to provide evidence-based data for the development of diagnostic and/or screening guidelines for CRC in China.METHODS A high-risk Chinese cohort consisting of 1130 individuals aged 40-79 years was selected for evaluation via fecal mSDC2 testing.Sensitivity and specificity for CRC,advanced adenoma(AA)and advanced colorectal neoplasia(ACN)were determined.High-risk factors for the incidence of colorectal lesions were determined and a logistic regression model was constructed to reflect the efficacy of the test.RESULTS A total of 1035 high-risk individuals were included in this study according to established criteria.Among them,16 suffered from CRC(1.55%),65 from AA(6.28%)and 189 from non-AAs(18.26%);150 patients were diagnosed with polyps(14.49%).Diagnoses were established based upon colonoscopic and pathological examinations.Sensitivities of the mSDC2 test for CRC and AA were 87.50%and 40.00%,respectively;specificities were 95.61%for other groups.Positive predictive values of the mSDC2 test for CRC,AA and ACN were 16.09%,29.89%and 45.98%,respectively;the negative predictive value for CRC was 99.79%.After adjusting for other high-risk covariates,mSDC2 test positivity was found to be a significant risk factor for the occurrence of ACN(P<0.001).CONCLUSION Our findings confirmed that offering fecal mSDC2 testing and colonoscopy in combination for CRC screening is effective for earlier detection of malignant colorectal lesions in a high-risk Chinese population.
基金Supported by the Research Fund of Chungnam National University,No.2018-0626-01.
文摘BACKGROUND Early detection of colorectal cancer(CRC)is essential to reduce cancer-related morbidity and mortality.Stool DNA(sDNA)testing is an emerging method for early CRC detection.Syndecan-2(SDC2)methylation is a potential biomarker for the sDNA testing.Aberrant DNA methylation is an early epigenetic event during tumorigenesis and can occur in the normal colonic mucosa during aging,which can compromise the sDNA test results.METHODS In this prospective study,we enrolled 151 patients with CRC who underwent curative surgical resection between September 2016 and May 2020.Preoperative stool samples were collected from 123 patients and postoperative samples were collected from 122 patients.A total of 104 samples were collected from both preoperative and postoperative patients.Aberrant promoter methylation of SDC2 in sDNA was assessed using linear target enrichment quantitative methylation-specific real-time polymerase chain reaction.Clinicopathological parameters were analyzed using the results of SDC2 methylation.RESULTS Detection rates of SDC2 methylation in the preoperative and postoperative stool samples were 88.6%and 19.7%,respectively.Large tumor size(3 cm,P=0.019)and advanced T stage(T3–T4,P=0.033)were positively associated with the detection rate of SDC2 methylation before surgery.Female sex was associated with false positives after surgery(P=0.030).Cycle threshold(CT)values were significantly decreased postoperatively compared with preoperative values(P<0.001).The postoperative negative conversion rate for preoperatively methylated SDC2 was 79.3%(73/92).CONCLUSION Our results suggested that the SDC2 methylation test for sDNA has acceptable sensitivity and specificity.However,small size and early T stage tumors are associated with a low detection rate of SDC2 methylation.As the cycle threshold values significantly decreased after surgery,SDC2 methylation test for sDNA might have a diagnostic value for CRC.
文摘测定5-氯-2戊酮和环丙基甲基酮的物化性质:密度、黏度、摩尔体积、热膨胀系数和表面张力。测定5-氯-2-戊酮(1)+环丙基甲基酮(2)二元体系的汽液相平衡(VLE),并应用Aspen Plus V11中Van Laar方程、Wilson方程和NRTL方程对实验数据进行关联,回归得到二元交互参数。实验结果通过热力学一致性检查。该研究不仅补充了汽液相平衡数据库,也为5-氯-2-戊酮与环丙基甲基酮的分离提供热力学数据。
基金supported by the National Natural Science Foundation of China,No.82171270 (to ZL)Public Service Platform for Artificial In telligence Screening and Auxiliary Diagnosis for the Medical and Health Industry,Ministry of Industry and Information Technology of the People's Republic of China,No.2020-0103-3-1 (to ZL)+3 种基金the Natural Science Foundation of Beijing,No.Z200016 (to ZL)Beijing Talents Project,No.2018000021223ZK03 (to ZL)Beijing Municipal Committee of Science and Technology,No.Z201 100005620010 (to ZL)CAMS Innovation Fund for Medical Sciences,No.2019-I2M-5-029 (to YongW)。
文摘Inflammation is closely related to stroke prognosis, and high inflammation status leads to poor functional outcome in stroke. DNA methylation is involved in the pathogenesis and prognosis of stroke. However, the effect of DNA methylation on stroke at high levels of inflammation is unclear. In this study, we constructed a hyperinflammatory cerebral ischemia mouse model and investigated the effect of hypomethylation and hypermethylation on the functional outcome. We constructed a mouse model of transient middle cerebral artery occlusion and treated the mice with lipopolysaccharide to induce a hyperinflammatory state. To investigate the effect of DNA methylation on stroke, we used small molecule inhibitors to restrain the function of key DNA methylation and demethylation enzymes. 2,3,5-Triphenyltetrazolium chloride staining, neurological function scores, neurobehavioral tests, enzyme-linked immunosorbent assay, quantitative reverse transcription PCR and western blot assay were used to evaluate the effects after stroke in mice. We assessed changes in the global methylation status by measuring DNA 5-mc and DNA 5-hmc levels in peripheral blood after the use of the inhibitor. In the group treated with the DNA methylation inhibitor, brain tissue 2,3,5-triphenyltetrazolium chloride staining showed an increase in infarct volume, which was accompanied by a decrease in neurological scores and worsening of neurobehavioral performance. The levels of inflammatory factors interleukin 6 and interleukin-1 beta in ischemic brain tissue and plasma were elevated, indicating increased inflammation. Related inflammatory pathway exploration showed significant overactivation of nuclear factor kappa B. These results suggested that inhibiting DNA methylation led to poor functional outcome in mice with high inflammation following stroke. Further, the effects were reversed by inhibition of DNA demethylation. Our findings suggest that DNA methylation regulates the inflammatory response in stroke and has an important role in the functional outcome of hyperinflammatory stroke.
文摘The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression.The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus.Notably,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal cortex.Further,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory processes.The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns.Despite the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology.Future research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.
基金supported by the National Natural Science Foundation of China,Nos.82271283(to XC),91854115(to JW),31970044(to JW)the Natural Science Foundation of Beijing,No.7202001(to XC)the Scientific Research Project of Beijing Educational Committee,No.KM202010005022(to XC)。
文摘Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.
