腺苷酸激活蛋白激酶(AMP-activated protein kinase,AMPK)作为重要的能量代谢激酶,广泛存在于真核生物,在能量代谢调控中起重要作用。肝脏激酶B1(Liver kinase B1,LKB1)和钙调素依赖蛋白激酶(Calmodulin-dependent protein kinasesβ,Ca...腺苷酸激活蛋白激酶(AMP-activated protein kinase,AMPK)作为重要的能量代谢激酶,广泛存在于真核生物,在能量代谢调控中起重要作用。肝脏激酶B1(Liver kinase B1,LKB1)和钙调素依赖蛋白激酶(Calmodulin-dependent protein kinasesβ,Ca MKKβ)可激活AMPK。激活的AMPK通过对脂肪、蛋白质和糖类代谢的调控维持体内能量平衡。另外,AMPK调控因子激活剂与抑制剂、细胞因子可通过上调或下调AMPK表达,调控能量物质代谢。展开更多
Drug repurposing offers an efficient approach to therapeutic development.In this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gas...Drug repurposing offers an efficient approach to therapeutic development.In this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gastrointestinal ulcers.We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity,insulin resistance,and hepatic stea-tosis in mice.Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes,and induced cold tolerance in cold-exposed mice,suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism.Mechanistically,LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1(PHOSPHOI)and produces metabolic benefits in a PHOS-PHO1-dependent manner.Our results suggested that LPZ may stimulate adipose thermogenesis by inhi-biting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid(2-AG-LPA)to 2-arachidonoylglycerol(2-AG)and reduce the activity of the thermogenic-suppressive cannabinoid recep-tor signaling.In summary,we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome,and identified a potential metabolic basis by which LPZ improves energy metabolism.展开更多
Alternative mechanisms of toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin（TCDD）, instead of the binding to aryl hydrocarbon receptor（AhR）, have been taken into consideration. It has been recently show...Alternative mechanisms of toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin（TCDD）, instead of the binding to aryl hydrocarbon receptor（AhR）, have been taken into consideration. It has been recently shown that TCDD reduces rapidly the activity of CK2（casein kinase II） both in vivo and in vitro. It is found that TCDD has high molecular similarities to the known inhibitors of CK2 catalytic subunit（CK2a）. This suggests that TCDD could also be an ATP-competitive inhibitor of CK2a. In this work, docking TCDD to CK2 was carried out based on the two structures of CK2a from maize and human, respectively. The binding free energies of the predicted CK2a-TCDD complexes estimated by the molecular mechanics/Poisson-Boltzmann surface area（MM/PBSA） method are from -85.1 kJ/mol to -114.3 kJ/mol for maize and are from -96.1 kJ/mol to -118.2 kJ/mol for human, which are comparable to those estimated for the known inhibitor and also ATP with CK2a. The energetic analysis also reveals that the van der Waals interaction is the dominant contribution to the binding free energy. These results are also useful for designing new drugs for a target of overexpressing CK2 in cancers.展开更多
采用分子动力学方法研究激酶ABL与ATP位点小分子imatinib、P16及变构位点小分子STJ、MS7、MS9、3YY、MYR等的结合,并用GBSA(generalized Born surface area)方法将结合自由能分解到各残基.自山能计算结果表明,小分子STJ、MS7、MS9有利于...采用分子动力学方法研究激酶ABL与ATP位点小分子imatinib、P16及变构位点小分子STJ、MS7、MS9、3YY、MYR等的结合,并用GBSA(generalized Born surface area)方法将结合自由能分解到各残基.自山能计算结果表明,小分子STJ、MS7、MS9有利于imatinib与ABL结合;小分子STJ、MS7、MS9与激酶ABL的结合自由能接近,绝对值均大于ABL与3YY、MYR的结合自由能.能量分解表明,ABL残基ILE502、VAL506、LEU510与STJ和MYR的相互作用是αl螺旋处于弯曲状态的重要原因.模拟过程中ABL肉豆蔻酰口袋残基均方根偏差(RMSD)变化值表明,STJ等小分子抑制剂与ABL结合后降低了肉豆蔻酰口袋残基的柔性.展开更多
文摘腺苷酸激活蛋白激酶(AMP-activated protein kinase,AMPK)作为重要的能量代谢激酶,广泛存在于真核生物,在能量代谢调控中起重要作用。肝脏激酶B1(Liver kinase B1,LKB1)和钙调素依赖蛋白激酶(Calmodulin-dependent protein kinasesβ,Ca MKKβ)可激活AMPK。激活的AMPK通过对脂肪、蛋白质和糖类代谢的调控维持体内能量平衡。另外,AMPK调控因子激活剂与抑制剂、细胞因子可通过上调或下调AMPK表达,调控能量物质代谢。
基金This work was supported by the Beijing Municipal Natural Science Foundation Grant 7212148(to Mengxi Jiang,China)the National Natural Science Foundation of China Grant 82000807(to Mengxi Jiang,China)the Beijing Municipal Education Commission Grant KM202110025023(to Mengxi Jiang,China).
文摘Drug repurposing offers an efficient approach to therapeutic development.In this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gastrointestinal ulcers.We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity,insulin resistance,and hepatic stea-tosis in mice.Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes,and induced cold tolerance in cold-exposed mice,suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism.Mechanistically,LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1(PHOSPHOI)and produces metabolic benefits in a PHOS-PHO1-dependent manner.Our results suggested that LPZ may stimulate adipose thermogenesis by inhi-biting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid(2-AG-LPA)to 2-arachidonoylglycerol(2-AG)and reduce the activity of the thermogenic-suppressive cannabinoid recep-tor signaling.In summary,we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome,and identified a potential metabolic basis by which LPZ improves energy metabolism.
基金Supported by the International Science and Technology Cooperation Program of China（No.2010DFA31710）, the National Natural Science Foundation of China（No.10974008）, the Doctoral Fund of Innovation from Beijing University of Technology （China）, and the Project from the Italian Association for Cancer Research（No.IG10412）.
文摘Alternative mechanisms of toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin（TCDD）, instead of the binding to aryl hydrocarbon receptor（AhR）, have been taken into consideration. It has been recently shown that TCDD reduces rapidly the activity of CK2（casein kinase II） both in vivo and in vitro. It is found that TCDD has high molecular similarities to the known inhibitors of CK2 catalytic subunit（CK2a）. This suggests that TCDD could also be an ATP-competitive inhibitor of CK2a. In this work, docking TCDD to CK2 was carried out based on the two structures of CK2a from maize and human, respectively. The binding free energies of the predicted CK2a-TCDD complexes estimated by the molecular mechanics/Poisson-Boltzmann surface area（MM/PBSA） method are from -85.1 kJ/mol to -114.3 kJ/mol for maize and are from -96.1 kJ/mol to -118.2 kJ/mol for human, which are comparable to those estimated for the known inhibitor and also ATP with CK2a. The energetic analysis also reveals that the van der Waals interaction is the dominant contribution to the binding free energy. These results are also useful for designing new drugs for a target of overexpressing CK2 in cancers.
文摘采用分子动力学方法研究激酶ABL与ATP位点小分子imatinib、P16及变构位点小分子STJ、MS7、MS9、3YY、MYR等的结合,并用GBSA(generalized Born surface area)方法将结合自由能分解到各残基.自山能计算结果表明,小分子STJ、MS7、MS9有利于imatinib与ABL结合;小分子STJ、MS7、MS9与激酶ABL的结合自由能接近,绝对值均大于ABL与3YY、MYR的结合自由能.能量分解表明,ABL残基ILE502、VAL506、LEU510与STJ和MYR的相互作用是αl螺旋处于弯曲状态的重要原因.模拟过程中ABL肉豆蔻酰口袋残基均方根偏差(RMSD)变化值表明,STJ等小分子抑制剂与ABL结合后降低了肉豆蔻酰口袋残基的柔性.
