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
Objective: To investigate the effects of Yanghe Pingchuan Granules on airway remodeling in asthmatic rats, and to explore the mechanism of Interleukin-6/Janus kinase 2/ Signal transducing activator of transcription 3(...Objective: To investigate the effects of Yanghe Pingchuan Granules on airway remodeling in asthmatic rats, and to explore the mechanism of Interleukin-6/Janus kinase 2/ Signal transducing activator of transcription 3(IL-6/JAK2/STAT3) signal axis. Methods: We separated 42 healthy male SD rats into two groups, a control group (7) and a model group (35).The model group was sensitized with a combination of ovalbumin (OVA) and aluminum hydroxide for 2 weeks, while the control group was given an equal amount of physiological saline.After 2 weeks, the modeling group was randomly divided into Model group, Yanghe Pingchuan Granules high, medium and low dose groups and Dexamethasone group, each group consisted of 7 animals. After 4 weeks, OVA atomization and gavage were used for stimulation and treatment. Yanghe Pingchuan Granules high, middle and low groups were given 15.48, 7.74, 3.87 g∙kg-1 Yanghe Pingchuan Granules daily, dexamethasone group was given 0.0625 mg∙kg-1 dexamethasone daily, and the other groups were given the same amount of normal saline. HE, PAS and Masson staining were used to observe the lung histopathological changes in rats. The levels of interleukin-6, IL-23 and IL-17A were detected by ELISA. The expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 in lung tissues were detected by Western blot. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels of IL-6, JAK2 and STAT3 in rat lung tissue. Results: The lung tissue structure of the model group was severely damaged compared to the control group, accompanied by a great many of inflammatory cell infiltration, goblet cell hyperplasia, subepithelial collagen fiber deposition and airway epithelial thickening were more obvious. The expressions of IL-6, IL- 23 and IL-17A in serum were significantly increased (P<0.01), the protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and the mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly increased (P<0.01);Compared with the model group, inflammatory cell infiltration, goblet cell proliferation, subepithelial collagen fiber deposition and airway epithelial thickening were significantly reduced in each administration group, and the expressions of IL-6, IL-23 and IL-17A in serum were significantly decreased (P< 0.01). The protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly decreased (P<0.01). Conclusion: Yanghe Pingchuan Granules can significantly alleviate airway remodeling in asthmatic rats, and its mechanism may be through inhibiting the IL-6/JAK2/STAT3 signal axis.展开更多
就近年来白细胞介素6/非受体酪氨酸蛋白激酶/信号转导和转录激活因子3(interleukin-6/janus activated kinase/signal transducer and activator of transcription 3,IL-6/JAK/STAT3)信号通路在多种消化系统肿瘤中发挥的效应、中药单体...就近年来白细胞介素6/非受体酪氨酸蛋白激酶/信号转导和转录激活因子3(interleukin-6/janus activated kinase/signal transducer and activator of transcription 3,IL-6/JAK/STAT3)信号通路在多种消化系统肿瘤中发挥的效应、中药单体及其活性成分、中药复方对与IL-6/JAK/STAT3信号通路调控有关的消化系统肿瘤中的防治作用进行综述,探究中医药在延缓、阻抑甚至逆转炎-癌转化中发挥的作用,为防治肿瘤提供更有力的理论指导。展开更多
The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of it...The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of its elements are compared for normal cholangiocytes, cholangiocarcinoma predisposition and development. Prolactin and interleukin-6 are described in detail as the best studied examples. In addition, the non-classical nuclear translocation of cytokine receptors is discussed in terms of its possible implication to cholangiocarcinoma development.展开更多
目的基于酪氨酸激酶/信号传导及转录激活蛋白(Janus kinase/signal transducer and activator of transcription,JAK/STAT)信号通路与免疫缺陷性疾病中CD4^(+)T细胞占比减少的相关性,探讨免疫缺陷大鼠CD4^(+)T淋巴细胞分化的机制。方法...目的基于酪氨酸激酶/信号传导及转录激活蛋白(Janus kinase/signal transducer and activator of transcription,JAK/STAT)信号通路与免疫缺陷性疾病中CD4^(+)T细胞占比减少的相关性,探讨免疫缺陷大鼠CD4^(+)T淋巴细胞分化的机制。方法将SPF级SD大鼠48只,随机分为正常大鼠(24只)和模型大鼠(24只),采用环孢素制备免疫缺陷模型。每组随机选6只验证造模效果,将剩余36只大鼠分为正常组、低鲁组、高鲁组、模型组、模型低鲁组、模型高鲁组,每组6只。低鲁组和模型低鲁组分别注射1.75 mg·kg^(-1)鲁索利替尼,高鲁组和模型高鲁组分别注射3.5 mg·kg^(-1)鲁索利替尼,正常组和模型组注射1.75 mg·kg^(-1)生理盐水,隔日1次,共注射6次。采用流式细胞术检测CD4^(+)T和CD8^(+)T淋巴细胞百分比,计算大鼠脾脏和胸腺指数,HE染色法观察脾脏和胸腺病理改变,ELISA检测白细胞介素-2(interleukin-2,IL-2)、γ-干扰素(interferon-γ,IFN-γ)、白细胞介素-12(interleukin-12,IL-12)、白细胞介素-4(interleukin-4,IL-4)、白细胞介素-6(interleukin-6,IL-6)、白细胞介素-10(interleukin-10,IL-10)细胞因子表达量,Western blot检测脾脏组织中酪氨酸激酶2(Janus kinase 2,JAK2)、T盒家族转录因子表达蛋白(T-box family transcription factor expression protein,T-bet)、信号传导及转录激活蛋白4(signal transducer and activator of transcription 4,STAT4)、信号传导及转录激活蛋白6(signal transducer and activator of transcription 6,STAT6)和GATA结合蛋白-3(GATA-binding protein-3,GATA3)蛋白表达量。结果模型组大鼠CD4^(+)T淋巴细胞百分比、胸腺指数较正常组明显下降(P<0.05)。与正常组比较,模型组CD4^(+)T淋巴细胞百分比减少(P<0.05),IL-2、IFN-γ和IL-12表达量下降(P<0.01),IL-10表达量升高(P<0.05);与模型组相比,模型高鲁组CD4^(+)T淋巴细胞百分比、胸腺和脾脏指数、IL-2、IFN-γ显著下降(P<0.05),而GATA3、STAT6蛋白表达量升高(P<0.05),IL-6、IL-10表达量明显增加(P<0.05,P<0.01)。结论免疫缺陷疾病以CD4^(+)T淋巴细胞减少为主要特征,CD4^(+)T细胞亚群失调与JAK/STAT信号通路表达失衡有关,其机制可能与IL-12/STAT4通路表达下调和IL-4/STAT6通路表达上调有关,CD4^(+)T淋巴细胞分化由辅助性T细胞1(helper T cell 1,Th1)向辅助性T细胞2(helper T cell 2,Th2)漂移,造成Th1/Th2失衡,引发免疫缺陷。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.
基金The Sixth Batch of Special Support Plans in Anhui Province(No.dlPtzjh20200050)Key Natural Science Research Project of Higher Education Institutions in Anhui Province(No.KJ2020A0426)。
文摘Objective: To investigate the effects of Yanghe Pingchuan Granules on airway remodeling in asthmatic rats, and to explore the mechanism of Interleukin-6/Janus kinase 2/ Signal transducing activator of transcription 3(IL-6/JAK2/STAT3) signal axis. Methods: We separated 42 healthy male SD rats into two groups, a control group (7) and a model group (35).The model group was sensitized with a combination of ovalbumin (OVA) and aluminum hydroxide for 2 weeks, while the control group was given an equal amount of physiological saline.After 2 weeks, the modeling group was randomly divided into Model group, Yanghe Pingchuan Granules high, medium and low dose groups and Dexamethasone group, each group consisted of 7 animals. After 4 weeks, OVA atomization and gavage were used for stimulation and treatment. Yanghe Pingchuan Granules high, middle and low groups were given 15.48, 7.74, 3.87 g∙kg-1 Yanghe Pingchuan Granules daily, dexamethasone group was given 0.0625 mg∙kg-1 dexamethasone daily, and the other groups were given the same amount of normal saline. HE, PAS and Masson staining were used to observe the lung histopathological changes in rats. The levels of interleukin-6, IL-23 and IL-17A were detected by ELISA. The expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 in lung tissues were detected by Western blot. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels of IL-6, JAK2 and STAT3 in rat lung tissue. Results: The lung tissue structure of the model group was severely damaged compared to the control group, accompanied by a great many of inflammatory cell infiltration, goblet cell hyperplasia, subepithelial collagen fiber deposition and airway epithelial thickening were more obvious. The expressions of IL-6, IL- 23 and IL-17A in serum were significantly increased (P<0.01), the protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and the mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly increased (P<0.01);Compared with the model group, inflammatory cell infiltration, goblet cell proliferation, subepithelial collagen fiber deposition and airway epithelial thickening were significantly reduced in each administration group, and the expressions of IL-6, IL-23 and IL-17A in serum were significantly decreased (P< 0.01). The protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly decreased (P<0.01). Conclusion: Yanghe Pingchuan Granules can significantly alleviate airway remodeling in asthmatic rats, and its mechanism may be through inhibiting the IL-6/JAK2/STAT3 signal axis.
文摘就近年来白细胞介素6/非受体酪氨酸蛋白激酶/信号转导和转录激活因子3(interleukin-6/janus activated kinase/signal transducer and activator of transcription 3,IL-6/JAK/STAT3)信号通路在多种消化系统肿瘤中发挥的效应、中药单体及其活性成分、中药复方对与IL-6/JAK/STAT3信号通路调控有关的消化系统肿瘤中的防治作用进行综述,探究中医药在延缓、阻抑甚至逆转炎-癌转化中发挥的作用,为防治肿瘤提供更有力的理论指导。
文摘The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of its elements are compared for normal cholangiocytes, cholangiocarcinoma predisposition and development. Prolactin and interleukin-6 are described in detail as the best studied examples. In addition, the non-classical nuclear translocation of cytokine receptors is discussed in terms of its possible implication to cholangiocarcinoma development.
文摘目的基于酪氨酸激酶/信号传导及转录激活蛋白(Janus kinase/signal transducer and activator of transcription,JAK/STAT)信号通路与免疫缺陷性疾病中CD4^(+)T细胞占比减少的相关性,探讨免疫缺陷大鼠CD4^(+)T淋巴细胞分化的机制。方法将SPF级SD大鼠48只,随机分为正常大鼠(24只)和模型大鼠(24只),采用环孢素制备免疫缺陷模型。每组随机选6只验证造模效果,将剩余36只大鼠分为正常组、低鲁组、高鲁组、模型组、模型低鲁组、模型高鲁组,每组6只。低鲁组和模型低鲁组分别注射1.75 mg·kg^(-1)鲁索利替尼,高鲁组和模型高鲁组分别注射3.5 mg·kg^(-1)鲁索利替尼,正常组和模型组注射1.75 mg·kg^(-1)生理盐水,隔日1次,共注射6次。采用流式细胞术检测CD4^(+)T和CD8^(+)T淋巴细胞百分比,计算大鼠脾脏和胸腺指数,HE染色法观察脾脏和胸腺病理改变,ELISA检测白细胞介素-2(interleukin-2,IL-2)、γ-干扰素(interferon-γ,IFN-γ)、白细胞介素-12(interleukin-12,IL-12)、白细胞介素-4(interleukin-4,IL-4)、白细胞介素-6(interleukin-6,IL-6)、白细胞介素-10(interleukin-10,IL-10)细胞因子表达量,Western blot检测脾脏组织中酪氨酸激酶2(Janus kinase 2,JAK2)、T盒家族转录因子表达蛋白(T-box family transcription factor expression protein,T-bet)、信号传导及转录激活蛋白4(signal transducer and activator of transcription 4,STAT4)、信号传导及转录激活蛋白6(signal transducer and activator of transcription 6,STAT6)和GATA结合蛋白-3(GATA-binding protein-3,GATA3)蛋白表达量。结果模型组大鼠CD4^(+)T淋巴细胞百分比、胸腺指数较正常组明显下降(P<0.05)。与正常组比较,模型组CD4^(+)T淋巴细胞百分比减少(P<0.05),IL-2、IFN-γ和IL-12表达量下降(P<0.01),IL-10表达量升高(P<0.05);与模型组相比,模型高鲁组CD4^(+)T淋巴细胞百分比、胸腺和脾脏指数、IL-2、IFN-γ显著下降(P<0.05),而GATA3、STAT6蛋白表达量升高(P<0.05),IL-6、IL-10表达量明显增加(P<0.05,P<0.01)。结论免疫缺陷疾病以CD4^(+)T淋巴细胞减少为主要特征,CD4^(+)T细胞亚群失调与JAK/STAT信号通路表达失衡有关,其机制可能与IL-12/STAT4通路表达下调和IL-4/STAT6通路表达上调有关,CD4^(+)T淋巴细胞分化由辅助性T细胞1(helper T cell 1,Th1)向辅助性T细胞2(helper T cell 2,Th2)漂移,造成Th1/Th2失衡,引发免疫缺陷。
