本实验室前期研究表明,小菜蛾通过有丝分裂原激活的蛋白激酶(mitogen-activated protein kinase,MAPK)信号途径上游转录激活的关键基因MAP4K4反式调控多个中肠受体基因的表达,从而介导其对苏云金芽胞杆菌Bacillus thuringiensis(Bt)产生...本实验室前期研究表明,小菜蛾通过有丝分裂原激活的蛋白激酶(mitogen-activated protein kinase,MAPK)信号途径上游转录激活的关键基因MAP4K4反式调控多个中肠受体基因的表达,从而介导其对苏云金芽胞杆菌Bacillus thuringiensis(Bt)产生的Cry1Ac杀虫蛋白的高抗性。为进一步明确MAP4K4基因转录激活而过量表达的顺式调控机制,本文利用小菜蛾基因组数据库中MAP4K4基因序列信息,首先克隆了Bt Cry1Ac敏感小菜蛾种群MAP4K4基因上游5′-侧翼序列,得到了两种不同形式的5′-侧翼序列:MAP4K4-1和MAP4K4-2。随后,预测分析了其中的潜在功能顺式作用元件,同时发现其中核苷酸的转换会导致顺式作用元件的改变。本研究初步揭示了小菜蛾MAP4K4基因的5′-侧翼序列的遗传多样性,为后续明确MAP4K4的顺式调控机制奠定了基础。展开更多
Endothelial-mesenchymal transition(EndMT)disrupts vascular endothelial integrity and induces atherosclerosis.Active integrinβ1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endotheli...Endothelial-mesenchymal transition(EndMT)disrupts vascular endothelial integrity and induces atherosclerosis.Active integrinβ1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endothelial cells.Here,we report a novel anthraquinone compound,Kanglexin(KLX),which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrinβ1/TGFβsignaling.First,KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFβ1.Second,KLX suppressed TGFβ/Smad signaling by inactivating integrinβ1 and inhibiting the polymerization of TGFβR1/2.The underlying mechanism involved the activation of FGFR1 by KLX,resulting in the phosphorylation of MAP4K4 and Moesin,which led to integrinβ1 inactivation by displacing Talin from itsβ-tail.Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrinβ1,thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe^(-/-)mice.Notably,KLX(20 mg/kg)exhibited superior efficacy compared with atorvastatin,a clinically approved lipid-regulating drug.In conclusion,KLX exhibited potential in ameliorating EndMT and retarding the formation and progression of atherosclerosis through direct activation of FGFR1.Therefore,KLX is a promising candidate for the treatment of atherosclerosis to mitigate vascular endothelial injury.展开更多
文摘本实验室前期研究表明,小菜蛾通过有丝分裂原激活的蛋白激酶(mitogen-activated protein kinase,MAPK)信号途径上游转录激活的关键基因MAP4K4反式调控多个中肠受体基因的表达,从而介导其对苏云金芽胞杆菌Bacillus thuringiensis(Bt)产生的Cry1Ac杀虫蛋白的高抗性。为进一步明确MAP4K4基因转录激活而过量表达的顺式调控机制,本文利用小菜蛾基因组数据库中MAP4K4基因序列信息,首先克隆了Bt Cry1Ac敏感小菜蛾种群MAP4K4基因上游5′-侧翼序列,得到了两种不同形式的5′-侧翼序列:MAP4K4-1和MAP4K4-2。随后,预测分析了其中的潜在功能顺式作用元件,同时发现其中核苷酸的转换会导致顺式作用元件的改变。本研究初步揭示了小菜蛾MAP4K4基因的5′-侧翼序列的遗传多样性,为后续明确MAP4K4的顺式调控机制奠定了基础。
基金supported by the Basic Research Support Program for Outstanding Young Teachers of Heilongjiang Province(No.YQJH2023038)the National Natural Science foundation of China(Nos.82170431,82070312,82373868,82330011,and U21A20339)the Scientific Research Project of Provincial Scientific Research Institute of Heilongjiang Province(No.CZKYF2022-1-B007).
文摘Endothelial-mesenchymal transition(EndMT)disrupts vascular endothelial integrity and induces atherosclerosis.Active integrinβ1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endothelial cells.Here,we report a novel anthraquinone compound,Kanglexin(KLX),which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrinβ1/TGFβsignaling.First,KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFβ1.Second,KLX suppressed TGFβ/Smad signaling by inactivating integrinβ1 and inhibiting the polymerization of TGFβR1/2.The underlying mechanism involved the activation of FGFR1 by KLX,resulting in the phosphorylation of MAP4K4 and Moesin,which led to integrinβ1 inactivation by displacing Talin from itsβ-tail.Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrinβ1,thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe^(-/-)mice.Notably,KLX(20 mg/kg)exhibited superior efficacy compared with atorvastatin,a clinically approved lipid-regulating drug.In conclusion,KLX exhibited potential in ameliorating EndMT and retarding the formation and progression of atherosclerosis through direct activation of FGFR1.Therefore,KLX is a promising candidate for the treatment of atherosclerosis to mitigate vascular endothelial injury.
