目的通过检测NOD样受体蛋白3(NLRP3)/半胱氨酸天冬氨酸蛋白水解酶-1(Caspase-1)/消皮素D(GSDMD)通路,探讨阿霉素纳米凝胶载药(Nanogel drug loading,NG)对H22肝癌荷瘤小鼠的作用机制。方法将H22肝癌细胞珠每只1.25×10^(6)个/100μ...目的通过检测NOD样受体蛋白3(NLRP3)/半胱氨酸天冬氨酸蛋白水解酶-1(Caspase-1)/消皮素D(GSDMD)通路,探讨阿霉素纳米凝胶载药(Nanogel drug loading,NG)对H22肝癌荷瘤小鼠的作用机制。方法将H22肝癌细胞珠每只1.25×10^(6)个/100μl接种于Balb/c小鼠右前肢腋窝皮下,待肿瘤体积至50~60mm^(3)时,将40只Balb/c小鼠随机分为5组(n=8),分别为肿瘤对照组、阿霉素3mg组(DOX-3.0)、阿霉素6mg组(DOX-6.0)、阿霉素纳米凝胶载药3mg组(NG/DOX-3.0)和阿霉素纳米凝胶载药6mg组(NG/DOX-6.0)。各组均采用尾静脉注射给药治疗,分别给予生理盐水(5ml/kg)、DOX(3mg/kg)、DOX(6mg/kg)、NG/DOX(3mg/kg)和NG/DOX(6mg/kg),1次/3d,给药4次,于给药结束第3d处死动物取材。通过苏木精-伊红(hematoxylin-eosin,HE)染色,观察肿瘤生长情况和坏死面积;采用免疫组织化学染色检测NLRP3/Caspase-1/GSDMD凋亡基因的表达情况。结果HE染色与肿瘤对照组比较,各治疗组肿瘤生长状态较差,且DOX-3.0、NG/DOX-3.0、DOX-6.0、NG/DOX-6.0肿瘤坏死面积百分率依次增大,组间差异均有统计学意义(P<0.05);与肿瘤对照组比较,DOX-3.0、NG/DOX-3.0、DOX-6.0、NG/DOX-6.0组肿瘤组织中NLRP3、Caspase-1、GSDMD的蛋白阳性表达水平依次减弱,组间差异均有统计学意义(P<0.05),纳米凝胶载药组作用优于单纯阿霉素给药组。结论纳米凝胶载药组治疗H22肝癌的作用优于阿霉素单独用药,它能通过下调NLRP3/Caspase-1/GSDMD通路,有效抑制肿瘤生长、降低药物使用剂量及提高抗癌效果,具有良好发展前景,其作用机制有待于进一步探讨。展开更多
目的探究H型原发性高血压(高血压)患者血清诱骗受体3(decoy receptor 3,DcR3)、含1型血小板反应蛋白基序的去整合素金属蛋白酶13(A disintegrin and metalloproteinase with A thrombospondin type 1 motif member 13,ADAMTS13)浓度与...目的探究H型原发性高血压(高血压)患者血清诱骗受体3(decoy receptor 3,DcR3)、含1型血小板反应蛋白基序的去整合素金属蛋白酶13(A disintegrin and metalloproteinase with A thrombospondin type 1 motif member 13,ADAMTS13)浓度与其心血管功能及预后的关系。方法选取大庆市人民医院2020年6月至2022年6月收治的132例高血压患者作为观察对象,根据同型半胱氨酸(homocysteine,Hcy)浓度分为非H型高血压组40例和H型高血压组92例,根据预后情况将H型高血压患者分为预后良好组和预后不良组,并选择同期来大庆市人民医院健康体检的成年人70名作为对照组。采用酶联免疫吸附试验法检测受试者血清中DcR3、ADAMTS13浓度,Pearson法分析血清中DcR3、ADAMTS13浓度与心血管功能指标的相关性,多因素Logistic回归分析H型高血压患者1年预后不良的影响因素。绘制受试者工作特征曲线(receiver operating characteristic curve,ROC)分析血清DcR3、ADAMTS13浓度对H型高血压患者1年预后不良的预测价值。结果与对照组[(122.28±32.34)mmHg(1 mmHg=0.133 kPa)、(48.16±8.65)mmHg、(8.59±1.25)mm、(118.34±34.25)g/m2、(1.48±0.34)g/L、(57.15±14.94)mg/L、(1.45±0.31)、70.28%±15.21%]比较,H型高血压组患者的收缩压[(139.35±38.21)mmHg]、脉压[(57.37±11.75)mmHg]、左心室后壁厚度(posterior wall thickness,PWT)[(11.69±2.00)mm]以及左心室质量指数(left ventricular mass index,LVMI)[(148.54±38.22)g/m2]显著升高,DcR3[(0.74±0.19)g/L]、ADAMTS13浓度[(14.13±4.62)mg/L]、二尖瓣舒张早期血流峰值/二尖瓣舒张晚期血流峰值(E-peak to A-peak of the mitral flow spectrum,E/A)(0.65±0.13)、左心室射血分数(left ventricular ejection fraction,LVEF)(64.26%±12.75%)显著降低,差异有统计学意义(P<0.05);与非H型高血压组患者组比较,H型高血压组患者的DcR3、ADAMTS13浓度及E/A显著降低,LVMI显著升高,差异有统计学意义(P<0.05)。H型高血压组患者血清中DcR3、ADAMTS13浓度均与收缩压、脉压和LVMI呈负相关(P<0.05),而与E/A、LVEF呈正相关(P<0.05)。预后不良组患者的年龄显著高于预后良好组,E/A(0.38±0.07)、DcR3[(0.45±0.13)g/L]、ADAMTS13浓度[(8.45±2.11)mg/L]显著低于预后良好组[0.75±0.11、(0.85±0.27)g/L、(16.25±4.85)mg/L],差异有统计学意义(P<0.05)。DcR3、ADAMTS13是H型高血压患者预后不良的保护因素(P<0.05)。血清DcR3、ADAMTS13浓度单独及二者联合预测H型高血压患者1年发生预后不良的曲线下面积(area under the curve,AUC)分别为0.906、0.844、0.950。结论H型高血压疾病患者血清DcR3、ADAMTS13浓度降低,与心血管功能及预后密切相关,对该疾病的预后评估有重要价值。展开更多
建立了一种简单、实用的光诱导一锅法高选择性N-甲基喹喔啉酮类化合物和苯乙酮类化合物合成一系列3-烷基化喹唑啉-2(1H)-酮类化合物的方法。该方法在室温条件下,以玫瑰红作为光催化剂,在18 W 460 nm的蓝色LED下照射8 h,通过直接C3-H活...建立了一种简单、实用的光诱导一锅法高选择性N-甲基喹喔啉酮类化合物和苯乙酮类化合物合成一系列3-烷基化喹唑啉-2(1H)-酮类化合物的方法。该方法在室温条件下,以玫瑰红作为光催化剂,在18 W 460 nm的蓝色LED下照射8 h,通过直接C3-H活化的方案,较好收率获得一系列相应的3-烷基化喹喔啉-2(1H)-酮类化合物,最高产率可达到76%。反应体系具有经济实用性和底物适用范围广的特点,为3-烷基化喹喔啉-2(1H)-酮类化合物类化合物的合成提供了一种简便经济的方法。展开更多
BACKGROUND Serpin peptidase inhibitor clade H member 1(SERPINH1)was initially recognized as an oncogene implicated in various human malignancies.Nevertheless,the clinical relevance and functional implications of SERPI...BACKGROUND Serpin peptidase inhibitor clade H member 1(SERPINH1)was initially recognized as an oncogene implicated in various human malignancies.Nevertheless,the clinical relevance and functional implications of SERPINH1 in colorectal cancer(CRC)remain largely elusive.AIM To investigate the effects of SERPINH1 on CRC cells and its specific mechanism.METHODS Quantitative real-time polymerase chain reaction,western blotting analysis,The Cancer Genome Atlas data mining and immunohistochemistry were employed to examine SERPINH1 expression in CRC cell lines and tissues.A series of in-vitro assays were performed to demonstrate the function of SERPINH1 and its possible mechanisms in CRC.RESULTS SERPINH1 demonstrated elevated expression levels in both CRC cells and tissues,manifested at both mRNA and protein tiers.Elevated SERPINH1 levels correlated closely with advanced T stage,lymph node involvement,and distant metastasis,exhibiting a significant association with poorer overall survival among CRC patients.Subsequent investigations unveiled that SERPINH1 overexpression notably bolstered CRC cell proliferation,invasion,and migration in vitro,while conversely,SERPINH1 knockdown elicited the opposite effects.Gene set enrichment analysis underscored a correlation between SERPINH1 upregulation and genes associated with cell cycle regulation.Our findings underscored the capacity of heightened SERPINH1 levels to expedite G1/S phase cell cycle progression via phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway activation,thereby facilitating CRC cell invasion and migration.CONCLUSION These findings imply a crucial involvement of SERPINH1 in the advancement and escalation of CRC,potentially positioning it as a novel candidate for prognostic assessment and therapeutic intervention in CRC management.展开更多
Isocitrate dehydrogenase 2(IDH2)and glutamate dehydrogenase 1(GLUD1)are key enzymes involved in the production ofα-ketoglutarate(α-KG),a metabolite central to the tricarboxylic acid cycle and glutamine metabolism.In...Isocitrate dehydrogenase 2(IDH2)and glutamate dehydrogenase 1(GLUD1)are key enzymes involved in the production ofα-ketoglutarate(α-KG),a metabolite central to the tricarboxylic acid cycle and glutamine metabolism.In this study,we investigated the impact of IDH2 and GLUD1 on early porcine embryonic development following IDH2 and GLUD1 knockdown(KD)via doublestranded RNA(dsRNA)microinjection.Results showed that KD reducedα-KG levels,leading to delayed embryonic development,decreased blastocyst formation,increased apoptosis,reduced blastomere proliferation,and pluripotency.Additionally,IDH2 and GLUD1 KD induced abnormally high levels of trimethylation of lysine 20 of histone H4(H4K20me3)at the 4-cell stage,likely resulting in transcriptional repression of embryonic genome activation(EGA)-related genes.Notably,KD of lysine methyltransferase 5C(KMT5C)and supplementation with exogenousα-KG reduced H4K20me3 expression and partially rescued these defects,suggesting a critical role of IDH2 and GLUD1 in the epigenetic regulation and proper development of porcine embryos.Overall,this study highlights the significance of IDH2 and GLUD1 in maintaining normal embryonic development through their influence onα-KG production and subsequent epigenetic modifications.展开更多
文摘目的通过检测NOD样受体蛋白3(NLRP3)/半胱氨酸天冬氨酸蛋白水解酶-1(Caspase-1)/消皮素D(GSDMD)通路,探讨阿霉素纳米凝胶载药(Nanogel drug loading,NG)对H22肝癌荷瘤小鼠的作用机制。方法将H22肝癌细胞珠每只1.25×10^(6)个/100μl接种于Balb/c小鼠右前肢腋窝皮下,待肿瘤体积至50~60mm^(3)时,将40只Balb/c小鼠随机分为5组(n=8),分别为肿瘤对照组、阿霉素3mg组(DOX-3.0)、阿霉素6mg组(DOX-6.0)、阿霉素纳米凝胶载药3mg组(NG/DOX-3.0)和阿霉素纳米凝胶载药6mg组(NG/DOX-6.0)。各组均采用尾静脉注射给药治疗,分别给予生理盐水(5ml/kg)、DOX(3mg/kg)、DOX(6mg/kg)、NG/DOX(3mg/kg)和NG/DOX(6mg/kg),1次/3d,给药4次,于给药结束第3d处死动物取材。通过苏木精-伊红(hematoxylin-eosin,HE)染色,观察肿瘤生长情况和坏死面积;采用免疫组织化学染色检测NLRP3/Caspase-1/GSDMD凋亡基因的表达情况。结果HE染色与肿瘤对照组比较,各治疗组肿瘤生长状态较差,且DOX-3.0、NG/DOX-3.0、DOX-6.0、NG/DOX-6.0肿瘤坏死面积百分率依次增大,组间差异均有统计学意义(P<0.05);与肿瘤对照组比较,DOX-3.0、NG/DOX-3.0、DOX-6.0、NG/DOX-6.0组肿瘤组织中NLRP3、Caspase-1、GSDMD的蛋白阳性表达水平依次减弱,组间差异均有统计学意义(P<0.05),纳米凝胶载药组作用优于单纯阿霉素给药组。结论纳米凝胶载药组治疗H22肝癌的作用优于阿霉素单独用药,它能通过下调NLRP3/Caspase-1/GSDMD通路,有效抑制肿瘤生长、降低药物使用剂量及提高抗癌效果,具有良好发展前景,其作用机制有待于进一步探讨。
文摘目的探究H型原发性高血压(高血压)患者血清诱骗受体3(decoy receptor 3,DcR3)、含1型血小板反应蛋白基序的去整合素金属蛋白酶13(A disintegrin and metalloproteinase with A thrombospondin type 1 motif member 13,ADAMTS13)浓度与其心血管功能及预后的关系。方法选取大庆市人民医院2020年6月至2022年6月收治的132例高血压患者作为观察对象,根据同型半胱氨酸(homocysteine,Hcy)浓度分为非H型高血压组40例和H型高血压组92例,根据预后情况将H型高血压患者分为预后良好组和预后不良组,并选择同期来大庆市人民医院健康体检的成年人70名作为对照组。采用酶联免疫吸附试验法检测受试者血清中DcR3、ADAMTS13浓度,Pearson法分析血清中DcR3、ADAMTS13浓度与心血管功能指标的相关性,多因素Logistic回归分析H型高血压患者1年预后不良的影响因素。绘制受试者工作特征曲线(receiver operating characteristic curve,ROC)分析血清DcR3、ADAMTS13浓度对H型高血压患者1年预后不良的预测价值。结果与对照组[(122.28±32.34)mmHg(1 mmHg=0.133 kPa)、(48.16±8.65)mmHg、(8.59±1.25)mm、(118.34±34.25)g/m2、(1.48±0.34)g/L、(57.15±14.94)mg/L、(1.45±0.31)、70.28%±15.21%]比较,H型高血压组患者的收缩压[(139.35±38.21)mmHg]、脉压[(57.37±11.75)mmHg]、左心室后壁厚度(posterior wall thickness,PWT)[(11.69±2.00)mm]以及左心室质量指数(left ventricular mass index,LVMI)[(148.54±38.22)g/m2]显著升高,DcR3[(0.74±0.19)g/L]、ADAMTS13浓度[(14.13±4.62)mg/L]、二尖瓣舒张早期血流峰值/二尖瓣舒张晚期血流峰值(E-peak to A-peak of the mitral flow spectrum,E/A)(0.65±0.13)、左心室射血分数(left ventricular ejection fraction,LVEF)(64.26%±12.75%)显著降低,差异有统计学意义(P<0.05);与非H型高血压组患者组比较,H型高血压组患者的DcR3、ADAMTS13浓度及E/A显著降低,LVMI显著升高,差异有统计学意义(P<0.05)。H型高血压组患者血清中DcR3、ADAMTS13浓度均与收缩压、脉压和LVMI呈负相关(P<0.05),而与E/A、LVEF呈正相关(P<0.05)。预后不良组患者的年龄显著高于预后良好组,E/A(0.38±0.07)、DcR3[(0.45±0.13)g/L]、ADAMTS13浓度[(8.45±2.11)mg/L]显著低于预后良好组[0.75±0.11、(0.85±0.27)g/L、(16.25±4.85)mg/L],差异有统计学意义(P<0.05)。DcR3、ADAMTS13是H型高血压患者预后不良的保护因素(P<0.05)。血清DcR3、ADAMTS13浓度单独及二者联合预测H型高血压患者1年发生预后不良的曲线下面积(area under the curve,AUC)分别为0.906、0.844、0.950。结论H型高血压疾病患者血清DcR3、ADAMTS13浓度降低,与心血管功能及预后密切相关,对该疾病的预后评估有重要价值。
文摘建立了一种简单、实用的光诱导一锅法高选择性N-甲基喹喔啉酮类化合物和苯乙酮类化合物合成一系列3-烷基化喹唑啉-2(1H)-酮类化合物的方法。该方法在室温条件下,以玫瑰红作为光催化剂,在18 W 460 nm的蓝色LED下照射8 h,通过直接C3-H活化的方案,较好收率获得一系列相应的3-烷基化喹喔啉-2(1H)-酮类化合物,最高产率可达到76%。反应体系具有经济实用性和底物适用范围广的特点,为3-烷基化喹喔啉-2(1H)-酮类化合物类化合物的合成提供了一种简便经济的方法。
基金Supported by Ruian Natural Science Foundation,No.MS2021008.
文摘BACKGROUND Serpin peptidase inhibitor clade H member 1(SERPINH1)was initially recognized as an oncogene implicated in various human malignancies.Nevertheless,the clinical relevance and functional implications of SERPINH1 in colorectal cancer(CRC)remain largely elusive.AIM To investigate the effects of SERPINH1 on CRC cells and its specific mechanism.METHODS Quantitative real-time polymerase chain reaction,western blotting analysis,The Cancer Genome Atlas data mining and immunohistochemistry were employed to examine SERPINH1 expression in CRC cell lines and tissues.A series of in-vitro assays were performed to demonstrate the function of SERPINH1 and its possible mechanisms in CRC.RESULTS SERPINH1 demonstrated elevated expression levels in both CRC cells and tissues,manifested at both mRNA and protein tiers.Elevated SERPINH1 levels correlated closely with advanced T stage,lymph node involvement,and distant metastasis,exhibiting a significant association with poorer overall survival among CRC patients.Subsequent investigations unveiled that SERPINH1 overexpression notably bolstered CRC cell proliferation,invasion,and migration in vitro,while conversely,SERPINH1 knockdown elicited the opposite effects.Gene set enrichment analysis underscored a correlation between SERPINH1 upregulation and genes associated with cell cycle regulation.Our findings underscored the capacity of heightened SERPINH1 levels to expedite G1/S phase cell cycle progression via phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway activation,thereby facilitating CRC cell invasion and migration.CONCLUSION These findings imply a crucial involvement of SERPINH1 in the advancement and escalation of CRC,potentially positioning it as a novel candidate for prognostic assessment and therapeutic intervention in CRC management.
基金supported by the National Research Foundation(NRF)of Korea grant funded by the Korean government(MSIT)(2022R1A2C300769),Republic of Korea。
文摘Isocitrate dehydrogenase 2(IDH2)and glutamate dehydrogenase 1(GLUD1)are key enzymes involved in the production ofα-ketoglutarate(α-KG),a metabolite central to the tricarboxylic acid cycle and glutamine metabolism.In this study,we investigated the impact of IDH2 and GLUD1 on early porcine embryonic development following IDH2 and GLUD1 knockdown(KD)via doublestranded RNA(dsRNA)microinjection.Results showed that KD reducedα-KG levels,leading to delayed embryonic development,decreased blastocyst formation,increased apoptosis,reduced blastomere proliferation,and pluripotency.Additionally,IDH2 and GLUD1 KD induced abnormally high levels of trimethylation of lysine 20 of histone H4(H4K20me3)at the 4-cell stage,likely resulting in transcriptional repression of embryonic genome activation(EGA)-related genes.Notably,KD of lysine methyltransferase 5C(KMT5C)and supplementation with exogenousα-KG reduced H4K20me3 expression and partially rescued these defects,suggesting a critical role of IDH2 and GLUD1 in the epigenetic regulation and proper development of porcine embryos.Overall,this study highlights the significance of IDH2 and GLUD1 in maintaining normal embryonic development through their influence onα-KG production and subsequent epigenetic modifications.
