Introduction Vascular endothelial (VE)-cadherin is localized to the endothelial borders and the adherens junctions,which are regulated by changes in mitogen activated protein kinases (MAPK),GTPases,and intracellular c...Introduction Vascular endothelial (VE)-cadherin is localized to the endothelial borders and the adherens junctions,which are regulated by changes in mitogen activated protein kinases (MAPK),GTPases,and intracellular calcium. We previously展开更多
We reported in this manuscript that TGF-beta1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly ...We reported in this manuscript that TGF-beta1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly inhibited the TGF-beta1-induced apoptosis and PAI-1 promoter activity. Treatment of cells with TGF-beta1 activates p38. Furthermore, over-expression of dominant negative mutant p38 also reduced the TGF-beta1-induced apoptosis. The data indicate that the activation of p38 is involved in TGF-beta1-mediated gene expression and apoptosis.展开更多
目的探讨利拉鲁肽通过沉默信息调节因子1(silent information regulator 1,SIRT1)/腺苷酸活化蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)通路改善小鼠肝脏脂质变性的机制。方法将24只健康雄性6周龄C57BL/6J小鼠...目的探讨利拉鲁肽通过沉默信息调节因子1(silent information regulator 1,SIRT1)/腺苷酸活化蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)通路改善小鼠肝脏脂质变性的机制。方法将24只健康雄性6周龄C57BL/6J小鼠随机分为对照组、模型组、模型+利拉鲁肽组、模型+SIRT1组、模型+SIRT1+利拉鲁肽组、模型+SIRT1-NC组,每组4只。对照组普通饲料饲养,予以等容积生理盐水皮下注射,模型组高脂饲养12周建立代谢相关脂肪性肝病(metabolic dysfunction-associated fatty liver disease,MAFLD)模型,之后3周尾静脉注射SIRT1干扰慢病毒及利拉鲁肽。检测各组小鼠血清甘油三酯和丙氨酸氨基转移酶(alanine aminotransferase,ALT)水平,采用HE染色和油红O染色观察肝组织病理,采用实时荧光定量RT-PCR检测AMPK、SIRT1、肝激酶B1(liver kinase B1,LKB1)和去乙酰化固醇调节元件结合蛋白(sterol regulatory element binding protein-1c,SREBP-1c)基因表达水平,采用Western blot检测蛋白表达水平。结果利拉鲁肽可降低高脂喂养的C57BL/6J小鼠体质量、肝湿重、血清甘油三酯及ALT水平,油红O染色可见肝细胞脂滴减少。与模型组相比,模型+利拉鲁肽组SIRT1(0.212±0.110比0.076±0.010)、AMPK(0.518±0.051比0.248±0.023)、LKB1(1.023±0.039比0.576±0.029)基因表达量和AMPK(0.212±0.026比0.100±0.006)、LKB1(0.413±0.016比0.221±0.015)蛋白表达水平均上调,而SREBP-1c基因(0.727±0.249比9.007±1.530)和蛋白(0.187±0.008比0.824±0.114)表达水平均下调(P均<0.05)。与模型组相比,模型+SIRT1组SIRT1(0.029±0.003比0.076±0.010)、AMPK(0.105±0.013比0.248±0.023)、LKB1(0.333±0.106比0.576±0.029)基因表达量均下调(P均<0.05)。与模型+SIRT1组相比,模型+SIRT1+利拉鲁肽组LKB1(0.945±0.110比0.333±0.106;0.380±0.004比0.145±0.014)、AMPK(0.319±0.051比0.105±0.013;0.181±0.039比0.051±0.012)基因表达量和蛋白表达量均上调,而SREBP-1c基因表达量(4.239±0.554比12.740±0.976)下调(P均<0.05)。结论利拉鲁肽改善C57BL/6J小鼠肝脏脂毒性可能通过直接上调SIRT1/AMPK通路信号分子基因和蛋白表达水平,或间接激活LKB1并增强AMPK基因和蛋白表达、拮抗SREBP-1c基因和蛋白表达,从而降低脂质合成相关分子水平,而干扰SIRT1表达削弱了利拉鲁肽上调SIRT1/AMPK通路改善肝脏脂肪变性的作用。展开更多
Being sessile,plants have evolved sophisticated mechanisms to balance between growth and defense to survive in the harsh environment.The transition from growth to defense is commonly achieved by factors,such as protei...Being sessile,plants have evolved sophisticated mechanisms to balance between growth and defense to survive in the harsh environment.The transition from growth to defense is commonly achieved by factors,such as protein kinases(PKs)and transcription factors,that initiate signal transduction and regulate specialized metabolism.Plants produce an array of lineage-specific specialized metabolites for chemical defense and stress tolerance.Some of these molecules are also used by humans as drugs.However,many of these defense-responsive metabolites are toxic to plant cells and inhibitory to growth and development.Plants have,thus,evolved complex regulatory networks to balance the accumulation of the toxic metabolites.Perception of external stimuli is a vital part of the regulatory network.Protein kinase-mediated signaling activates a series of defense responses by phosphorylating the target pro-teins and translating the stimulus into downstream cellular signaling.As biosynthesis of specialized metabolites is triggered when plants perceive stimuli,a possible connection between PKs and spe-cial ized meta bolism is well recognized.However,the roles of PKs in plant specialized metabolism have not received much attention until recently.Here,we summarize the recent advances in understanding PKs in plant specialized metabolism.We aim to highlight how the stimulatory signals are transduced,leading to the biosynthesis of corresponding metabolites.We discuss the post-translational regulation of specialized metabolism and provide insights into the mechanisms by which plants respond to the external signals.In addition,we propose possible strategies to increase the production of plant spe-cial ized metabolites in biotechnological applications using PKs.展开更多
Background The extracellular signal-regulated kinase （ERK） is widely expressed in mammal cells and involved in airway proliferation and remodeling in asthma. In this study, we intend to explore the role of ERK in th...Background The extracellular signal-regulated kinase （ERK） is widely expressed in mammal cells and involved in airway proliferation and remodeling in asthma. In this study, we intend to explore the role of ERK in the expression of the Th2 cytokine, interleukin 13 （IL-13） in lymphocytes in asthma. Methods Forty Sprague-Dawley rats were randomly divided into two groups： normal control and asthmatic groups. Peripheral blood lymphocytes were isolated and purified from the blood of each rat and divided into five groups： control, asthmatic lymphocytes, asthmatic cells stimulated with ERK activator epidermal growth factor （EGF）, or with ERK inhibitor PD98059, or with EGF and PD98059 together. The expression of phosphorylated-ERK （p-ERK） was observed by immunocytochemical staining, the expression of ERK mRNA was determined by reverse transcriptase-PCR, IL-13 protein in supernatants was measured by ELISA. Results （1） The ERK mRNA level and the percentage of cells with p-ERK in lymphocytes from asthmatic rats were significantly higher than those in normal controls, and were significantly increased by EGF administration. This effect of EGF was significantly inhibited by PD98059 pretreatment. （2） IL-13 protein in supernatants of asthmatic lymphocytes was higher than that produced by normal control lymphocytes, and was significantly increased by EGF treatment. This EGF effect was partly blocked by PD98059 pretreatment. （3） There was a significant positive correlation between the percentage of cells with p-ERK in peripheral blood lymphocytes and IL-13 protein in supernatants of lymphocytes from asthmatic rats. Conclusions In asthma the ERK expression and activation levels were increased, as was the protein level of IL-13. The ERK signaling pathway may be involved in the increased expression of the Th2 cytokine IL-13 in asthma.展开更多
Cardiovascular diseases(CVDs)and metabolic disorders are major components of noncommunicable diseases,causing an enormous health and economic burden worldwide.There are common risk factors and developmental mechanisms...Cardiovascular diseases(CVDs)and metabolic disorders are major components of noncommunicable diseases,causing an enormous health and economic burden worldwide.There are common risk factors and developmental mechanisms among them,indicating the far-reaching significance in exploring the corresponding therapeutic targets.MST1/2 kinases are well-established proapoptotic effectors that also bidirectionally regulate autophagic activity.Recent studies have demonstrated that MST1/2 influence the outcome of cardiovascular and metabolic diseases by regulating immune inflammation.In addition,drug development against them is in full swing.In this review,we mainly describe the roles and mechanisms of MST1/2 in apoptosis and autophagy in cardiovascular and metabolic events as well as emphasis on the existing evidence for their involvement in immune inflammation.Moreover,we summarize the latest progress of pharmacotherapy targeting MST1/2 and propose a new mode of drug combination therapy,which may be beneficial to seek more effective strategies to prevent and treat CVDs and metabolic disorders.展开更多
基金supported by grants from NIH CA-125707 NSF CBET-0729091 (C D ),as well as NIH AI-065566 (A A )
文摘Introduction Vascular endothelial (VE)-cadherin is localized to the endothelial borders and the adherens junctions,which are regulated by changes in mitogen activated protein kinases (MAPK),GTPases,and intracellular calcium. We previously
文摘目的 :探讨组蛋白去甲基化酶JMJD2B影响人结直肠癌细胞恶性表型所介导的信号通路。方法 :以RNA干扰技术靶向沉默人结直肠癌细胞HCT116和SW480中JMJD2B的表达,采用蛋白质印迹法检测人结直肠癌细胞ERK-MAPK信号通路的变化,并分别采用CCK-8、流式细胞分析检测细胞增殖和细胞周期分布、凋亡情况。结果:转染JMJD2B si RNA能特异性抑制JMJD2B的表达并导致ERK2表达下调,其磷酸化水平也降低,肿瘤细胞发生G2/M或G0/G1期阻滞,细胞凋亡比例增加,增殖显著受抑(P<0.05)。结论:抑制JMJD2B可通过阻断ERK-MAPK信号转导而抑制人结直肠癌细胞的恶性表型。
基金grants fromthe Chinese Academy of Sciences (No. KJ951-BI608), the National Natural Sciences FOundation ofChina (No. 39625007 and
文摘We reported in this manuscript that TGF-beta1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly inhibited the TGF-beta1-induced apoptosis and PAI-1 promoter activity. Treatment of cells with TGF-beta1 activates p38. Furthermore, over-expression of dominant negative mutant p38 also reduced the TGF-beta1-induced apoptosis. The data indicate that the activation of p38 is involved in TGF-beta1-mediated gene expression and apoptosis.
文摘Being sessile,plants have evolved sophisticated mechanisms to balance between growth and defense to survive in the harsh environment.The transition from growth to defense is commonly achieved by factors,such as protein kinases(PKs)and transcription factors,that initiate signal transduction and regulate specialized metabolism.Plants produce an array of lineage-specific specialized metabolites for chemical defense and stress tolerance.Some of these molecules are also used by humans as drugs.However,many of these defense-responsive metabolites are toxic to plant cells and inhibitory to growth and development.Plants have,thus,evolved complex regulatory networks to balance the accumulation of the toxic metabolites.Perception of external stimuli is a vital part of the regulatory network.Protein kinase-mediated signaling activates a series of defense responses by phosphorylating the target pro-teins and translating the stimulus into downstream cellular signaling.As biosynthesis of specialized metabolites is triggered when plants perceive stimuli,a possible connection between PKs and spe-cial ized meta bolism is well recognized.However,the roles of PKs in plant specialized metabolism have not received much attention until recently.Here,we summarize the recent advances in understanding PKs in plant specialized metabolism.We aim to highlight how the stimulatory signals are transduced,leading to the biosynthesis of corresponding metabolites.We discuss the post-translational regulation of specialized metabolism and provide insights into the mechanisms by which plants respond to the external signals.In addition,we propose possible strategies to increase the production of plant spe-cial ized metabolites in biotechnological applications using PKs.
文摘Background The extracellular signal-regulated kinase （ERK） is widely expressed in mammal cells and involved in airway proliferation and remodeling in asthma. In this study, we intend to explore the role of ERK in the expression of the Th2 cytokine, interleukin 13 （IL-13） in lymphocytes in asthma. Methods Forty Sprague-Dawley rats were randomly divided into two groups： normal control and asthmatic groups. Peripheral blood lymphocytes were isolated and purified from the blood of each rat and divided into five groups： control, asthmatic lymphocytes, asthmatic cells stimulated with ERK activator epidermal growth factor （EGF）, or with ERK inhibitor PD98059, or with EGF and PD98059 together. The expression of phosphorylated-ERK （p-ERK） was observed by immunocytochemical staining, the expression of ERK mRNA was determined by reverse transcriptase-PCR, IL-13 protein in supernatants was measured by ELISA. Results （1） The ERK mRNA level and the percentage of cells with p-ERK in lymphocytes from asthmatic rats were significantly higher than those in normal controls, and were significantly increased by EGF administration. This effect of EGF was significantly inhibited by PD98059 pretreatment. （2） IL-13 protein in supernatants of asthmatic lymphocytes was higher than that produced by normal control lymphocytes, and was significantly increased by EGF treatment. This EGF effect was partly blocked by PD98059 pretreatment. （3） There was a significant positive correlation between the percentage of cells with p-ERK in peripheral blood lymphocytes and IL-13 protein in supernatants of lymphocytes from asthmatic rats. Conclusions In asthma the ERK expression and activation levels were increased, as was the protein level of IL-13. The ERK signaling pathway may be involved in the increased expression of the Th2 cytokine IL-13 in asthma.
基金grants from the National Natural Science Foundation of China(Nos.81770327 and 81100173)Jiangsu Province Health Care Development Special Fund(M2022038,China)。
文摘Cardiovascular diseases(CVDs)and metabolic disorders are major components of noncommunicable diseases,causing an enormous health and economic burden worldwide.There are common risk factors and developmental mechanisms among them,indicating the far-reaching significance in exploring the corresponding therapeutic targets.MST1/2 kinases are well-established proapoptotic effectors that also bidirectionally regulate autophagic activity.Recent studies have demonstrated that MST1/2 influence the outcome of cardiovascular and metabolic diseases by regulating immune inflammation.In addition,drug development against them is in full swing.In this review,we mainly describe the roles and mechanisms of MST1/2 in apoptosis and autophagy in cardiovascular and metabolic events as well as emphasis on the existing evidence for their involvement in immune inflammation.Moreover,we summarize the latest progress of pharmacotherapy targeting MST1/2 and propose a new mode of drug combination therapy,which may be beneficial to seek more effective strategies to prevent and treat CVDs and metabolic disorders.
