Oxidative stress contributes to the pathogenesis of neurodegenerative diseases.With the aim to find reagents that reduce oxidative stress,a phage display library was screened for peptides mimicking a2,6-sialyllactose(...Oxidative stress contributes to the pathogenesis of neurodegenerative diseases.With the aim to find reagents that reduce oxidative stress,a phage display library was screened for peptides mimicking a2,6-sialyllactose(6'-SL),which is known to beneficially influence neural functions.Using Sambucus nigra lectin,which specifically binds to 6'-SL,we screened a phage display library and found a peptide comprising identical sequences of 12 amino acids.Mimetic peptide,reverse peptide and scrambled peptide were tested for inhibition of 6'-SL binding to the lectin.Indeed,lectin binding to 6'-SL was inhibited by the most frequently identified mimetic peptide,but not by the reverse or scrambled peptides,showing that this peptide mimics 6'-SL.Functionally,mimetic peptide,but not the reverse or scrambled peptides,increased viability and expression of neural cell adhesion molecule L1 in SK-N-SH human neuroblastoma cells,and promoted survival and neurite outgrowth of cultured mouse cerebellar granule neurons challenged by H_20_2-induced oxidative stress.The combined results indicate that the 6'-SL mimetic peptide promotes neuronal survival and neuritogenesis,thus raising hopes for the treatment of neurodegenerative diseases.This study was approved by the Medical Ethics Committee of Shantou University Medical College,China(approval No.SUMC 2014-004)on February 20,2014.展开更多
Insulin is a protein hormone secreted by pancreatic β cells. One of its main functions is to keep the balance of glucose inside the body by regulating the absorption and metabolism of glucose in the periphery tissue,...Insulin is a protein hormone secreted by pancreatic β cells. One of its main functions is to keep the balance of glucose inside the body by regulating the absorption and metabolism of glucose in the periphery tissue, as well as the production and storage of hepatic glycogen. The insulin receptor is a transmembrane glycoprotein in which two a subunits with a molecular weight of 135 kD and two,8 subunits with a molecular weight of 95 kD are joined by a disulfide bond to form a β-α-α-β structure. The extracellular a subunit, especially, its three domains near the N-terminal are partially responsible for signal transduction or ligand-binding, as indicated by the experiments. The extracellular α subunits are involved in binding the ligands. The experimental results indicate that the three domains of the N-terminal of the a subunits are the main determinative parts of the insulin receptor to bind the insulin or mimetic peptide. We employed the extracellular domain（ PDBID： 1IGR） of the insulin-like growth factor-1 receptor （IGF-1R） as the template to simulate and optimize the spatial structures of the three domains in the extracellular domain of the insulin receptor, which includes 468 residues. The work was accomplished by making use of the homology program in the Insight Ⅱ package on an Origin3800 server. The docking calculations of the insulin receptor obtained by homology with hexapeptides were carried out by means of the program Affinity. The analysis indicated that there were hydrogen bonding, and electrostatic and hydrophobic effects in the docking complex of the insulin receptor with hexapeptides. Moreover, we described the spatial orientation of a mimetic peptide with agonist activity in the docking complex. We obtained a rough model of binding of DLAPSQ or STIVYS with the insulin receptor, which provides the powerful theoretical support for designing the minimal insulin mimetic peptide with agonist activity, making it possible to develop oral small molecular hypoglycemic drugs.展开更多
血管新生能够有效改善缺血性心脏病的病生理进程,以促进血管新生为目的的治疗可能是缺血性心脏病的有效方法。正常高密度脂蛋白(high density lipoprotein,HDL)在机体内起着逆转运胆固醇、抗炎、抗氧化和促进血管新生等保护心血管的作...血管新生能够有效改善缺血性心脏病的病生理进程,以促进血管新生为目的的治疗可能是缺血性心脏病的有效方法。正常高密度脂蛋白(high density lipoprotein,HDL)在机体内起着逆转运胆固醇、抗炎、抗氧化和促进血管新生等保护心血管的作用。作为HDL的主要功能蛋白,载脂蛋白A-I(apolipoprotein A-I,ApoA-I)在HDL的各种功能活动中起关键作用。根据ApoA-I的两亲性α-螺旋结构特点,研究人员设计了一系列旨在模拟ApoA-I功能的模拟肽。ApoA-I模拟肽在体内外实验中显示出一定的促进血管新生的能力,但其机制尚不完全清楚。对ApoA-I模拟肽在血管新生中的进一步研究可能给缺血性心脏病带来新的治疗方法。展开更多
基金supported by the National Natural Science Foundation of China,No.81471279 and No.81171138(to WJZ)Talent Support Grant from Shantou University Medical College,China,No.2501220118(to WJZ)the Li Kashing Foundation,No.LD030302(to MS)
文摘Oxidative stress contributes to the pathogenesis of neurodegenerative diseases.With the aim to find reagents that reduce oxidative stress,a phage display library was screened for peptides mimicking a2,6-sialyllactose(6'-SL),which is known to beneficially influence neural functions.Using Sambucus nigra lectin,which specifically binds to 6'-SL,we screened a phage display library and found a peptide comprising identical sequences of 12 amino acids.Mimetic peptide,reverse peptide and scrambled peptide were tested for inhibition of 6'-SL binding to the lectin.Indeed,lectin binding to 6'-SL was inhibited by the most frequently identified mimetic peptide,but not by the reverse or scrambled peptides,showing that this peptide mimics 6'-SL.Functionally,mimetic peptide,but not the reverse or scrambled peptides,increased viability and expression of neural cell adhesion molecule L1 in SK-N-SH human neuroblastoma cells,and promoted survival and neurite outgrowth of cultured mouse cerebellar granule neurons challenged by H_20_2-induced oxidative stress.The combined results indicate that the 6'-SL mimetic peptide promotes neuronal survival and neuritogenesis,thus raising hopes for the treatment of neurodegenerative diseases.This study was approved by the Medical Ethics Committee of Shantou University Medical College,China(approval No.SUMC 2014-004)on February 20,2014.
文摘Insulin is a protein hormone secreted by pancreatic β cells. One of its main functions is to keep the balance of glucose inside the body by regulating the absorption and metabolism of glucose in the periphery tissue, as well as the production and storage of hepatic glycogen. The insulin receptor is a transmembrane glycoprotein in which two a subunits with a molecular weight of 135 kD and two,8 subunits with a molecular weight of 95 kD are joined by a disulfide bond to form a β-α-α-β structure. The extracellular a subunit, especially, its three domains near the N-terminal are partially responsible for signal transduction or ligand-binding, as indicated by the experiments. The extracellular α subunits are involved in binding the ligands. The experimental results indicate that the three domains of the N-terminal of the a subunits are the main determinative parts of the insulin receptor to bind the insulin or mimetic peptide. We employed the extracellular domain（ PDBID： 1IGR） of the insulin-like growth factor-1 receptor （IGF-1R） as the template to simulate and optimize the spatial structures of the three domains in the extracellular domain of the insulin receptor, which includes 468 residues. The work was accomplished by making use of the homology program in the Insight Ⅱ package on an Origin3800 server. The docking calculations of the insulin receptor obtained by homology with hexapeptides were carried out by means of the program Affinity. The analysis indicated that there were hydrogen bonding, and electrostatic and hydrophobic effects in the docking complex of the insulin receptor with hexapeptides. Moreover, we described the spatial orientation of a mimetic peptide with agonist activity in the docking complex. We obtained a rough model of binding of DLAPSQ or STIVYS with the insulin receptor, which provides the powerful theoretical support for designing the minimal insulin mimetic peptide with agonist activity, making it possible to develop oral small molecular hypoglycemic drugs.
文摘血管新生能够有效改善缺血性心脏病的病生理进程,以促进血管新生为目的的治疗可能是缺血性心脏病的有效方法。正常高密度脂蛋白(high density lipoprotein,HDL)在机体内起着逆转运胆固醇、抗炎、抗氧化和促进血管新生等保护心血管的作用。作为HDL的主要功能蛋白,载脂蛋白A-I(apolipoprotein A-I,ApoA-I)在HDL的各种功能活动中起关键作用。根据ApoA-I的两亲性α-螺旋结构特点,研究人员设计了一系列旨在模拟ApoA-I功能的模拟肽。ApoA-I模拟肽在体内外实验中显示出一定的促进血管新生的能力,但其机制尚不完全清楚。对ApoA-I模拟肽在血管新生中的进一步研究可能给缺血性心脏病带来新的治疗方法。
