Grain size is one of the key agronomic traits that determine grain yield in crops. However, the mechanisms underlying grain size control in crops remain elusive. Here we demonstrate that the OsMKKK10-OsMKK4- OsMAPK6 s...Grain size is one of the key agronomic traits that determine grain yield in crops. However, the mechanisms underlying grain size control in crops remain elusive. Here we demonstrate that the OsMKKK10-OsMKK4- OsMAPK6 signaling pathway positively regulates grain size and weight in rice. In rice, loss of OsMKKKIO function results in small and light grains, short panicles, and semi-dwarf plants, while overexpression of constitutively active OsMKKK10 （CA-OsMKKK10） results in large and heavy grains, long panicles, and tall plants. OsMKKK10 interacts with and phosphorylates OsMKK4. We identified an OsMKK4 gain-of-func- tion mutant （large11-1D）that produces large and heavy grains. OsMKK4A227T encoded by the large11-1D allele has stronger kinase activity than OsMKK4. Plants overexpressing a constitutively active form of OsMKK4 （OsMKK4oDD） also produce large grains. Further biochemical and genetic analyses revealed that OsMKKK10, OsMKK4, and OsMAPK6 function in a common pathway to control grain size. Taken together, our study establishes an important genetic and molecular framework for OsMKKK10-OsMKK4- OsMAPK6 cascade-mediated control of grain size and weight in rice.展开更多
Nucleotide oligomerization domain 2(NOD2) is a major cytoplasmic sensor for pathogens and is critical for the clearance of cytosolic bacteria in mammals.However, studies regarding NOD2, especially the initiated signal...Nucleotide oligomerization domain 2(NOD2) is a major cytoplasmic sensor for pathogens and is critical for the clearance of cytosolic bacteria in mammals.However, studies regarding NOD2, especially the initiated signaling pathways, are scarce in teleost species. In this study, we identified a NOD2 molecule(PaNOD2) from ayu(Plecoglossus altivelis).Bioinformatics analysis showed the structure of NOD2 to be highly conserved during vertebrate evolution. Dual-luciferase reporter assays examined the activation of NF-κB signaling and Western blotting analysis detected the phosphorylation of three MAP kinases(p-38, Erk1/2, and JNK1/2).Functional study revealed that, like its mammalian counterparts, PaNOD2 was the receptor of the bacterial cell wall component muramyl dipeptide(MDP), and the leucine-rich repeat motif was responsible for the recognition and binding of Pa NOD2 with the ligand. Overexpression of PaNOD2 activated the NF-κB signaling pathway, leading to the upregulation of inflammatory cytokines, including TNF-α and IL-1β in HEK293 T cells and ayu head kidney-derived monocytes/macrophages(MO/MΦ).Particularly, we found that PaNOD2 activated the MAPK signaling pathways, as indicated by the increased phosphorylation of p-38, Erk1/2, and JNK1/2, which have not been characterized in any teleost species previously. Our findings proved that the NOD2 molecule and initiated pathways are conserved between mammals and ayu. Therefore, ayu could be used as an animal model to investigate NOD2-based diseases and therapeutic applications.展开更多
OBJECTIVE Neuroinflammation is considered to be an important and inevitable pathological process associated with all types of damages to the central nervous system.The hallmark of neuroinflammation is the microglia ac...OBJECTIVE Neuroinflammation is considered to be an important and inevitable pathological process associated with all types of damages to the central nervous system.The hallmark of neuroinflammation is the microglia activation.In response to different micro-environmental disturbances,microglia could polarize into either an M1 pro-inflammatory phenotype,exacerbating neurotoxicity,or an M2 anti-inflammatory phenotype,exerting neuroprotection.Therefore,shifting the polarization of microglia toward the M2 phenotype could possess a more viable strategy for the neuroinflammatory disorders treatment.Naringenin(NAR) is natural y a grapefruit flavonoid and possesses various kinds of pharmacological activities,such as anti-inflammatory and neuroprotective activities.In the present study,we aimed to investigate the potential effects of NAR on microglial M1/M2 polarization and further reveal the underlying mechanisms of actions.METHODS BV-2 cells were pretreated with NAR(100 μmol·L^(-1)) for 1 h and then incubated with LPS(1 mg·L^(-1)) for 24 h.The effects of NAR on LPS-induced microglia activation,microglial M1/M2 polarization and MAPK pathways were detected.In addition,BV-2 cells were incubated with or without anisomycin(ANI,a selective agonist of JNK) to evaluate the role of JNK on microglia activation and microglia M1/M2 polarization.RESULTS First,NAR inhibited LPS-induced microglial activation.Then,NAR shifted the M1 pro-inflammatory microglia phenotype to the M2 anti-inflammatory M2 microglia state as demonstrated by the decreased expression of M1 markers,ie,inducible tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and the elevated expression of M2 markers(ie,arginase 1,IL-4 and IL-10).In addition,the effects of NAR on microglial polarization was dependent on MAPK signaling,particularly JNK inactivation,as evidenced by the fact that the selective activator of JNK abolished NAR-promoted M2 polarization and further NAR-inhibited microglial activation.CONCLUSION NAR promotes microglia M1/M2 polarization,thus con展开更多
Cigarette smoking is a known risk factor for the development of numerous diseases. The role of nicotine in the induction of pancreatic inflammation and pancreatic cancer as a result of cigarette smoking has been recog...Cigarette smoking is a known risk factor for the development of numerous diseases. The role of nicotine in the induction of pancreatic inflammation and pancreatic cancer as a result of cigarette smoking has been recognized and reported in the literature. The mechanism by which nicotine induces such pathologies is as yet unknown. An understanding of the proliferative potential of nicotine in primary and tumor cells of the pancreas will allow us to develop measures that will ultimately lead to intervention,prevention and treatment of these diseases. Studies show that nicotine can increase the cell numbers of certain cancer cell lines,suggesting that exposure to nicotine can lead to the disruption of the dynamic balance between cell death and proliferation,which is required for normal functioning of cells. We hypothesize that nicotine induces oxidative stress in pancreatic acinar cells and thus contributes to this disruption. We have used the AR42J cell line in our study because of its stability as an immortal tumor cell line and its known physiological similarity to primary acinar cells. Our studies show that mitogen activated protein kinase signaling is induced bynicotine in AR42J cells,causing an increase in lipid peroxidation and a subsequent decrease in cell function. Our data suggest that exposure to nicotine induces oxidative stress,leading to cell injury and compromised function,thus implicating cigarette smoking as a plausible mechanism.展开更多
目的:探讨雷公藤多苷(multi-glycoside of Tripterygium wilfordii,GTW)在体内改善糖尿病肾病(diabetic nephropathy,DN)模型鼠肾小球炎症性损伤的作用和机制。方法:采用单侧肾切除联合腹腔注射链脲佐菌素(streptozotocin,STZ)建立DN模...目的:探讨雷公藤多苷(multi-glycoside of Tripterygium wilfordii,GTW)在体内改善糖尿病肾病(diabetic nephropathy,DN)模型鼠肾小球炎症性损伤的作用和机制。方法:采用单侧肾切除联合腹腔注射链脲佐菌素(streptozotocin,STZ)建立DN模型。将大鼠随机分为3组:假手术组、对照组、GTW组,各5只。大鼠在造模成功后分别经灌胃给予蒸馏水(2 m L)或GTW悬浊液(50 mg·kg-1·d-1),每日1次,连续8周。各组大鼠自给药开始计时,第8周末处死。采集血液、尿液样本和肾组织,观察各组大鼠尿白蛋白、肾功能、肾小球形态特征、巨噬细胞(ED1+细胞)浸润以及肾组织肿瘤坏死因子(tumor necrosis factor,TNF)-α,白介素(interleukin,IL)-1β,p38丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK),磷酸化p38MAPK(phosphorylated p38,p-p38MAPK),转化生长因子(transforming growth factor,TGF)-β1的蛋白表达水平。结果:GTW能改善DN模型鼠一般情况、体重,减少尿白蛋白,减轻肾小球硬化,抑制肾小球ED1+细胞浸润,下调肾组织TNF-α,IL-1β,p-p38MAPK,TGF-β1蛋白表达水平。结论:GTW在体内具有抑制炎症细胞浸润和炎症因子表达,减轻肾组织炎症性损伤的作用;GTW通过下调肾组织p38MAPK信号通路中关键信号分子——p-p38MAPK蛋白表达水平,抑制炎症信号通路活性,减少TGF-β1表达,从而,改善肾组织炎症性损伤。展开更多
综述中药干预丝裂素活化蛋白激酶(mitogen-activated protein kinase,MAPK)通路治疗支气管哮喘的实验研究进展。MAPK信号转导途径是参与支气管哮喘发病及进展的一条重要通路,通过调控免疫/炎症细胞和气道结构细胞,引起气道高反应和气道...综述中药干预丝裂素活化蛋白激酶(mitogen-activated protein kinase,MAPK)通路治疗支气管哮喘的实验研究进展。MAPK信号转导途径是参与支气管哮喘发病及进展的一条重要通路,通过调控免疫/炎症细胞和气道结构细胞,引起气道高反应和气道重塑,造成Th1/Th2免疫应答失衡,最终诱发支气管哮喘。相关调控因子包括c-Jun氨基端激酶(JNK)、p38和细胞外信号调节激酶(ERK)等。近年来实验研究显示,多种中药复方(止哮汤、柴朴汤等)、中药单味药及其提取物(川贝母、黄芪多糖等)和中药单体(姜黄素、欧前胡素等)可通过抑制MAPK通路,改善哮喘症状,减轻气道炎症,逆转气道重塑,调节Th1/Th2平衡,在防治支气管哮喘方面取得显著疗效。展开更多
基金This work was supported by grants from the National Basic Research Program of China （2016YFD0100402 2016YFD0100501+6 种基金 2017YFD0101701 2013CBA01401）, the National Natural Science Foundation of China （91735302 31771340 31500976 91535203 31425004 31400249）, the Chinese Academy of Sciences （XDA08020108）, the Ministry of Agriculture of China （2014ZX08009-003）, and the strategic pdodty research program ＂Molecular Mechanism of Plant Growth and Development＂ （XDBP401）.
文摘Grain size is one of the key agronomic traits that determine grain yield in crops. However, the mechanisms underlying grain size control in crops remain elusive. Here we demonstrate that the OsMKKK10-OsMKK4- OsMAPK6 signaling pathway positively regulates grain size and weight in rice. In rice, loss of OsMKKKIO function results in small and light grains, short panicles, and semi-dwarf plants, while overexpression of constitutively active OsMKKK10 （CA-OsMKKK10） results in large and heavy grains, long panicles, and tall plants. OsMKKK10 interacts with and phosphorylates OsMKK4. We identified an OsMKK4 gain-of-func- tion mutant （large11-1D）that produces large and heavy grains. OsMKK4A227T encoded by the large11-1D allele has stronger kinase activity than OsMKK4. Plants overexpressing a constitutively active form of OsMKK4 （OsMKK4oDD） also produce large grains. Further biochemical and genetic analyses revealed that OsMKKK10, OsMKK4, and OsMAPK6 function in a common pathway to control grain size. Taken together, our study establishes an important genetic and molecular framework for OsMKKK10-OsMKK4- OsMAPK6 cascade-mediated control of grain size and weight in rice.
基金supported by the National Natural Science Foundation of China(31772876,31702374)Natural Science Foundation of Zhejiang Province(LZ18C190001,LQ17C190001)+1 种基金Zhejiang Xinmiao Talents Program(2017R405023)K.C.Wong Magna Fund in Ningbo University
文摘Nucleotide oligomerization domain 2(NOD2) is a major cytoplasmic sensor for pathogens and is critical for the clearance of cytosolic bacteria in mammals.However, studies regarding NOD2, especially the initiated signaling pathways, are scarce in teleost species. In this study, we identified a NOD2 molecule(PaNOD2) from ayu(Plecoglossus altivelis).Bioinformatics analysis showed the structure of NOD2 to be highly conserved during vertebrate evolution. Dual-luciferase reporter assays examined the activation of NF-κB signaling and Western blotting analysis detected the phosphorylation of three MAP kinases(p-38, Erk1/2, and JNK1/2).Functional study revealed that, like its mammalian counterparts, PaNOD2 was the receptor of the bacterial cell wall component muramyl dipeptide(MDP), and the leucine-rich repeat motif was responsible for the recognition and binding of Pa NOD2 with the ligand. Overexpression of PaNOD2 activated the NF-κB signaling pathway, leading to the upregulation of inflammatory cytokines, including TNF-α and IL-1β in HEK293 T cells and ayu head kidney-derived monocytes/macrophages(MO/MΦ).Particularly, we found that PaNOD2 activated the MAPK signaling pathways, as indicated by the increased phosphorylation of p-38, Erk1/2, and JNK1/2, which have not been characterized in any teleost species previously. Our findings proved that the NOD2 molecule and initiated pathways are conserved between mammals and ayu. Therefore, ayu could be used as an animal model to investigate NOD2-based diseases and therapeutic applications.
基金National Natural Science Foundation of China(8146055681760658)+2 种基金Foundation for High-level Innovative Talents of Guizhou Province(20164027)Innovation Research Group Projectof Education Department of Guizhou Province(2016038)Foundation for ExcellentYoung
文摘OBJECTIVE Neuroinflammation is considered to be an important and inevitable pathological process associated with all types of damages to the central nervous system.The hallmark of neuroinflammation is the microglia activation.In response to different micro-environmental disturbances,microglia could polarize into either an M1 pro-inflammatory phenotype,exacerbating neurotoxicity,or an M2 anti-inflammatory phenotype,exerting neuroprotection.Therefore,shifting the polarization of microglia toward the M2 phenotype could possess a more viable strategy for the neuroinflammatory disorders treatment.Naringenin(NAR) is natural y a grapefruit flavonoid and possesses various kinds of pharmacological activities,such as anti-inflammatory and neuroprotective activities.In the present study,we aimed to investigate the potential effects of NAR on microglial M1/M2 polarization and further reveal the underlying mechanisms of actions.METHODS BV-2 cells were pretreated with NAR(100 μmol·L^(-1)) for 1 h and then incubated with LPS(1 mg·L^(-1)) for 24 h.The effects of NAR on LPS-induced microglia activation,microglial M1/M2 polarization and MAPK pathways were detected.In addition,BV-2 cells were incubated with or without anisomycin(ANI,a selective agonist of JNK) to evaluate the role of JNK on microglia activation and microglia M1/M2 polarization.RESULTS First,NAR inhibited LPS-induced microglial activation.Then,NAR shifted the M1 pro-inflammatory microglia phenotype to the M2 anti-inflammatory M2 microglia state as demonstrated by the decreased expression of M1 markers,ie,inducible tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and the elevated expression of M2 markers(ie,arginase 1,IL-4 and IL-10).In addition,the effects of NAR on microglial polarization was dependent on MAPK signaling,particularly JNK inactivation,as evidenced by the fact that the selective activator of JNK abolished NAR-promoted M2 polarization and further NAR-inhibited microglial activation.CONCLUSION NAR promotes microglia M1/M2 polarization,thus con
基金Supported by the Earlier Grants from NIH and a Grant through University of Arkansas for Medical Sciences
文摘Cigarette smoking is a known risk factor for the development of numerous diseases. The role of nicotine in the induction of pancreatic inflammation and pancreatic cancer as a result of cigarette smoking has been recognized and reported in the literature. The mechanism by which nicotine induces such pathologies is as yet unknown. An understanding of the proliferative potential of nicotine in primary and tumor cells of the pancreas will allow us to develop measures that will ultimately lead to intervention,prevention and treatment of these diseases. Studies show that nicotine can increase the cell numbers of certain cancer cell lines,suggesting that exposure to nicotine can lead to the disruption of the dynamic balance between cell death and proliferation,which is required for normal functioning of cells. We hypothesize that nicotine induces oxidative stress in pancreatic acinar cells and thus contributes to this disruption. We have used the AR42J cell line in our study because of its stability as an immortal tumor cell line and its known physiological similarity to primary acinar cells. Our studies show that mitogen activated protein kinase signaling is induced bynicotine in AR42J cells,causing an increase in lipid peroxidation and a subsequent decrease in cell function. Our data suggest that exposure to nicotine induces oxidative stress,leading to cell injury and compromised function,thus implicating cigarette smoking as a plausible mechanism.
文摘目的:探讨雷公藤多苷(multi-glycoside of Tripterygium wilfordii,GTW)在体内改善糖尿病肾病(diabetic nephropathy,DN)模型鼠肾小球炎症性损伤的作用和机制。方法:采用单侧肾切除联合腹腔注射链脲佐菌素(streptozotocin,STZ)建立DN模型。将大鼠随机分为3组:假手术组、对照组、GTW组,各5只。大鼠在造模成功后分别经灌胃给予蒸馏水(2 m L)或GTW悬浊液(50 mg·kg-1·d-1),每日1次,连续8周。各组大鼠自给药开始计时,第8周末处死。采集血液、尿液样本和肾组织,观察各组大鼠尿白蛋白、肾功能、肾小球形态特征、巨噬细胞(ED1+细胞)浸润以及肾组织肿瘤坏死因子(tumor necrosis factor,TNF)-α,白介素(interleukin,IL)-1β,p38丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK),磷酸化p38MAPK(phosphorylated p38,p-p38MAPK),转化生长因子(transforming growth factor,TGF)-β1的蛋白表达水平。结果:GTW能改善DN模型鼠一般情况、体重,减少尿白蛋白,减轻肾小球硬化,抑制肾小球ED1+细胞浸润,下调肾组织TNF-α,IL-1β,p-p38MAPK,TGF-β1蛋白表达水平。结论:GTW在体内具有抑制炎症细胞浸润和炎症因子表达,减轻肾组织炎症性损伤的作用;GTW通过下调肾组织p38MAPK信号通路中关键信号分子——p-p38MAPK蛋白表达水平,抑制炎症信号通路活性,减少TGF-β1表达,从而,改善肾组织炎症性损伤。
文摘综述中药干预丝裂素活化蛋白激酶(mitogen-activated protein kinase,MAPK)通路治疗支气管哮喘的实验研究进展。MAPK信号转导途径是参与支气管哮喘发病及进展的一条重要通路,通过调控免疫/炎症细胞和气道结构细胞,引起气道高反应和气道重塑,造成Th1/Th2免疫应答失衡,最终诱发支气管哮喘。相关调控因子包括c-Jun氨基端激酶(JNK)、p38和细胞外信号调节激酶(ERK)等。近年来实验研究显示,多种中药复方(止哮汤、柴朴汤等)、中药单味药及其提取物(川贝母、黄芪多糖等)和中药单体(姜黄素、欧前胡素等)可通过抑制MAPK通路,改善哮喘症状,减轻气道炎症,逆转气道重塑,调节Th1/Th2平衡,在防治支气管哮喘方面取得显著疗效。
