BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against...BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.展开更多
目的观察玉屏风散对肺气虚模型大鼠Janus激酶1/信号转导及转录活化因子3(janus kinase 1/signal transducer and activator of transcription 3,JAK1/STAT3)信号通路及其上下游炎性因子的影响,探讨玉屏风散改善肺气虚证的作用机制。方...目的观察玉屏风散对肺气虚模型大鼠Janus激酶1/信号转导及转录活化因子3(janus kinase 1/signal transducer and activator of transcription 3,JAK1/STAT3)信号通路及其上下游炎性因子的影响,探讨玉屏风散改善肺气虚证的作用机制。方法60只Sprague Dawley(SD)大鼠随机分为空白组,模型组,玉屏风散高、中、低剂量组,阳性对照组,每组10只。除空白组外,其余各组大鼠均采用烟熏加脂多糖气管滴入方法建立肺气虚模型,造模开始灌胃给药,玉屏风散高、中、低剂量组分别予玉屏风散汤液[浓度分别为24、12、6 g/(kg·d)],阳性对照组予地塞米松[0.2 mg/(kg/d)],空白组、模型组给予等体积0.9%生理盐水,连续给药30 d。观察治疗前后各组大鼠症状和体征,肺组织形态学,血清中肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、白细胞介素-6(interleukin-6,IL-6)、白细胞介素-8(interleukin-8,IL-8)含量和肺组织中JAK1、STAT3、磷酸化信号转导及转录活化因子3(phosphorylation signal transducer and activator of transcription 3,p-STAT3)、基质金属蛋白酶-9(matrix metalloprotein-9,MMP-9)、组织金属蛋白酶抑制剂1(tissue inhibitor of matrix metalloproteinase 1,TIMP1)蛋白水平的变化。结果与空白组比较,模型组大鼠症状、体征和肺组织损伤状态严重,血清细胞因子TNF-α、IL-6、IL-8显著升高(P<0.01);模型组肺组织中JAK1、STAT3、p-STAT3、MMP-9平均光密度值(Integrated Optical Density,IOD)(P<0.01)和蛋白表达显著升高(P<0.01),TIMP1平均光密度值(P<0.01)和蛋白表达显著降低(P<0.01)。药物治疗后,与模型组比较,玉屏风高剂量组和阳性对照组症状、体征和肺组织损伤状态明显减轻,血清中TNF-α、IL-6、IL-8明显降低(P<0.01),肺组织中JAK1、STAT3、p-STAT3、MMP-9平均光密度值(P<0.01或P<0.05)和蛋白表达明显降低(P<0.01或P<0.05),TIMP1平均光密度值(P<0.01)和蛋白表达明显升高(P<0.01);玉屏风中剂量组症状、体征和肺组织损伤状态减轻,血清TNF-α、IL-6、IL-8降低(P<0.01或P<0.05),肺组织中JAK1、STAT3、p-STAT3、MMP-9平均光密度值明显降低(P<0.01),STAT3、MMP-9蛋白表达明显降低(P<0.01),TIMP1平均光密度值(P<0.01)和蛋白表达明显升高(P<0.01);玉屏风低剂量组症状、体征和肺组织损伤状态有所减轻,肺组织中STAT3、p-STAT3、MMP-9平均光密度值降低(P<0.01或P<0.05),STAT3、MMP-9蛋白表达降低(P<0.05),TIMP1平均光密度值(P<0.01)和蛋白表达升高(P<0.01)。总体上玉屏风散高剂量组疗效优于玉屏风散中剂量组和玉屏风散低剂量组,并与阳性对照组疗效持平。结论玉屏风散通过降低TNF-α、IL-6水平来调控JAK1/STAT3的信号转导,从而减少IL-8的产生,纠正MMP-9/TIMP-1平衡状态,达到抑制气道炎症反应和气道重塑的目的,从而改善肺气虚证的症状、体征和肺组织损伤状态。展开更多
目的:系统评价两种选择性Janus激酶1(JAK-1)抑制药Upadacitinib和Filgotinib治疗类风湿性关节炎的疗效和安全性,为临床治疗提供循证参考。方法:计算机检索PubMed、Medline、Embase、Cochrane图书馆、中国生物医学文献数据库、中国期刊...目的:系统评价两种选择性Janus激酶1(JAK-1)抑制药Upadacitinib和Filgotinib治疗类风湿性关节炎的疗效和安全性,为临床治疗提供循证参考。方法:计算机检索PubMed、Medline、Embase、Cochrane图书馆、中国生物医学文献数据库、中国期刊全文数据库、万方数据和中文科技期刊数据库,检索时限均为自建库起至2019年1月,收集在甲氨蝶呤或其他抗风湿类药物的基础上,安慰剂(对照组)对比Upadacitinib或Filgotinib(试验组)治疗类风湿性关节炎的随机对照试验(RCT),进行资料提取并采用Cochrane系统评价员手册5.1.0进行质量评价后,采用Rev Man 5.3统计软件对疗效[按美国风湿病协会标准判断病情缓解20%的患者比例(ACR20)、ACR50、ACR70、28个关节疾病活动度评分(DAS28)<3.2的患者比例]和安全性[不良事件(AE)发生率、严重不良事件(SAE)发生率、感染发生率、严重感染发生率、带状疱疹发生率、肝损害发生率]进行Meta分析。结果:共纳入8项RCT,合计2 738例患者。Meta分析结果显示,试验组患者ACR20[OR=3.37,95%CI(2.80,4.05),P<0.001]、ACR50[OR=3.78,95%CI(2.98,4.78),P<0.001]、ACR70[OR=4.31,95%CI(3.05,6.09),P<0.001]、DAS28<3.2分的患者比例[OR=3.86,95%CI(2.98,5.00),P<0.001]、AE发生率[OR=1.33,95%CI(1.11,1.61),P=0.002]和感染发生率[OR=1.43,95%CI(1.12,1.81),P=0.004]均显著高于对照组,其余指标比较差异均无统计学意义(P>0.05)。结论:JAK-1抑制药Upadacitinib和Filgotinib在提高类风湿性关节炎患者的ACR20、ACR50、ACR70、DAS28<3.2的患者比例等疗效指标方面较好;不会增加SAE、严重感染、带状疱疹与肝损害的发生率,但会增加患者AE与感染的风险。展开更多
文摘BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.
文摘目的观察玉屏风散对肺气虚模型大鼠Janus激酶1/信号转导及转录活化因子3(janus kinase 1/signal transducer and activator of transcription 3,JAK1/STAT3)信号通路及其上下游炎性因子的影响,探讨玉屏风散改善肺气虚证的作用机制。方法60只Sprague Dawley(SD)大鼠随机分为空白组,模型组,玉屏风散高、中、低剂量组,阳性对照组,每组10只。除空白组外,其余各组大鼠均采用烟熏加脂多糖气管滴入方法建立肺气虚模型,造模开始灌胃给药,玉屏风散高、中、低剂量组分别予玉屏风散汤液[浓度分别为24、12、6 g/(kg·d)],阳性对照组予地塞米松[0.2 mg/(kg/d)],空白组、模型组给予等体积0.9%生理盐水,连续给药30 d。观察治疗前后各组大鼠症状和体征,肺组织形态学,血清中肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、白细胞介素-6(interleukin-6,IL-6)、白细胞介素-8(interleukin-8,IL-8)含量和肺组织中JAK1、STAT3、磷酸化信号转导及转录活化因子3(phosphorylation signal transducer and activator of transcription 3,p-STAT3)、基质金属蛋白酶-9(matrix metalloprotein-9,MMP-9)、组织金属蛋白酶抑制剂1(tissue inhibitor of matrix metalloproteinase 1,TIMP1)蛋白水平的变化。结果与空白组比较,模型组大鼠症状、体征和肺组织损伤状态严重,血清细胞因子TNF-α、IL-6、IL-8显著升高(P<0.01);模型组肺组织中JAK1、STAT3、p-STAT3、MMP-9平均光密度值(Integrated Optical Density,IOD)(P<0.01)和蛋白表达显著升高(P<0.01),TIMP1平均光密度值(P<0.01)和蛋白表达显著降低(P<0.01)。药物治疗后,与模型组比较,玉屏风高剂量组和阳性对照组症状、体征和肺组织损伤状态明显减轻,血清中TNF-α、IL-6、IL-8明显降低(P<0.01),肺组织中JAK1、STAT3、p-STAT3、MMP-9平均光密度值(P<0.01或P<0.05)和蛋白表达明显降低(P<0.01或P<0.05),TIMP1平均光密度值(P<0.01)和蛋白表达明显升高(P<0.01);玉屏风中剂量组症状、体征和肺组织损伤状态减轻,血清TNF-α、IL-6、IL-8降低(P<0.01或P<0.05),肺组织中JAK1、STAT3、p-STAT3、MMP-9平均光密度值明显降低(P<0.01),STAT3、MMP-9蛋白表达明显降低(P<0.01),TIMP1平均光密度值(P<0.01)和蛋白表达明显升高(P<0.01);玉屏风低剂量组症状、体征和肺组织损伤状态有所减轻,肺组织中STAT3、p-STAT3、MMP-9平均光密度值降低(P<0.01或P<0.05),STAT3、MMP-9蛋白表达降低(P<0.05),TIMP1平均光密度值(P<0.01)和蛋白表达升高(P<0.01)。总体上玉屏风散高剂量组疗效优于玉屏风散中剂量组和玉屏风散低剂量组,并与阳性对照组疗效持平。结论玉屏风散通过降低TNF-α、IL-6水平来调控JAK1/STAT3的信号转导,从而减少IL-8的产生,纠正MMP-9/TIMP-1平衡状态,达到抑制气道炎症反应和气道重塑的目的,从而改善肺气虚证的症状、体征和肺组织损伤状态。
文摘目的:系统评价两种选择性Janus激酶1(JAK-1)抑制药Upadacitinib和Filgotinib治疗类风湿性关节炎的疗效和安全性,为临床治疗提供循证参考。方法:计算机检索PubMed、Medline、Embase、Cochrane图书馆、中国生物医学文献数据库、中国期刊全文数据库、万方数据和中文科技期刊数据库,检索时限均为自建库起至2019年1月,收集在甲氨蝶呤或其他抗风湿类药物的基础上,安慰剂(对照组)对比Upadacitinib或Filgotinib(试验组)治疗类风湿性关节炎的随机对照试验(RCT),进行资料提取并采用Cochrane系统评价员手册5.1.0进行质量评价后,采用Rev Man 5.3统计软件对疗效[按美国风湿病协会标准判断病情缓解20%的患者比例(ACR20)、ACR50、ACR70、28个关节疾病活动度评分(DAS28)<3.2的患者比例]和安全性[不良事件(AE)发生率、严重不良事件(SAE)发生率、感染发生率、严重感染发生率、带状疱疹发生率、肝损害发生率]进行Meta分析。结果:共纳入8项RCT,合计2 738例患者。Meta分析结果显示,试验组患者ACR20[OR=3.37,95%CI(2.80,4.05),P<0.001]、ACR50[OR=3.78,95%CI(2.98,4.78),P<0.001]、ACR70[OR=4.31,95%CI(3.05,6.09),P<0.001]、DAS28<3.2分的患者比例[OR=3.86,95%CI(2.98,5.00),P<0.001]、AE发生率[OR=1.33,95%CI(1.11,1.61),P=0.002]和感染发生率[OR=1.43,95%CI(1.12,1.81),P=0.004]均显著高于对照组,其余指标比较差异均无统计学意义(P>0.05)。结论:JAK-1抑制药Upadacitinib和Filgotinib在提高类风湿性关节炎患者的ACR20、ACR50、ACR70、DAS28<3.2的患者比例等疗效指标方面较好;不会增加SAE、严重感染、带状疱疹与肝损害的发生率,但会增加患者AE与感染的风险。
