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OBJECTIVE:To study 3D-QSAR of pyridine heterocyclic ring PI3K inhibitor as anti-renal cancer drug,and to provide reference for the design and R&D of new anti-renal cancer inhibitors. METHODS:The data of structure and active value (pIC50) of 30 pyridine heterocyclic ring PI3K inhibitors were collected. After Sybyl-X 1.1 software used for molecular superimposition, CoMFA and CoMSIA model were established to investigate three dimensional field, electrostatic field, hydrophobic field,hydrogen bond donor site and hydrogen bond acceptor field of PI3K inhibitor molecule. Sybyl-X 1.1 software was used for molecular docking,and the mechanism of PI3K inhibitor molecule and receptor target protein were analyzed. PyMOL V1.5 software was used to design new PI3K inhibitor molecules. The activity of inhibitor molecules was predicted with CoMFA and CoMSIA model. RESULTS:The cross validation coefficients of CoMFA and CoMSIA model were 0.617 and 0.601, fitting validation coefficients were 0.969 and 0.974,and external predictive correlation coefficients were 0.656 and 0.670, respectively. In CoMFA model, contributions of three dimensional field and electrostatic field were 56.2% and 43.8%respectively. In CoMSIA model,contributions of three dimensional field,electrostatic field,hydrophobic field,hydrogen bond donor site and hydrogen bond acceptor field were 41.0%,31.3%,21.1%,2.4%,4.2%. After molecular superimposition,small steric hindrance,strong positive and hydrophilic groups introduced nearby R1 group of common skeleton could help to enhance the activity of molecules. The results of molecular docking showed that PI3K inhibitor molecule formed three hydrogen bonds with the key amino acids ALA805,VAL882 and THR887 of receptor target protein,with the length of 1.84,1.99,1.99 ?. According to above information,6 new molecules were designed,among which predicted pIC50 of 2 molecules with higher activity were 3.211,3.247(CoMFA method)and 3.238,3.222(CoMSIA method). CONCLUSIONS:Established new CoMFA and CoMSIA model have good prediction ability and statistical stability. Contribution of three dimensional field is higher than that of electrostatic field,and the influence of hydrophobic field on molecular activity can not be ignored. Pyridine heterocyclic ring PI3K inhibitors have strong hydrogen bonding role with receptor target protein. 3D-QSAR can provide reference for the design,reconstruction and drug R&D of new PI3K inhibitor molecule.
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Objective To assess the differences in nutrient composition by chemical analysis method and weighing method,A corps of armed police forces daily dietary nutrient intakes were investigated in Tianjin,to understand the status of the actual intakes of dietary nutrient.Methods A dietary survey was performed using the weighing method and with ref-erence to China food composition database in 2002.The intake of each nutrient was calculated through chemical analysis;Nutritional analysis was used in the collection of duplicate food portions during the dietary survey.Results For most of the main dietary nutrients(protein,fat and carbohydrates),minerals (Na,K,Mg,Ca,Zn,Cu and Se)and vitamins (β-car-otene,vitamin E,thiamine,riboflavin,vitamin C,niacin,and vitamin A),the calculated values of intakes were found to exceed those obtained via chemical analysis.Conclusion Differences of the two methods of dietary survey were ultimately due to the analysed values were below the calculated ones.So it is necessary to improve methods of food storage and trans-portation in order to obtain adequate nutrition and to improve the health of troops.
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Objective To investigate the effects of oxidative stress on homocysteine and related amino acids metabolism in methionine-loading BRL rat hepatocytes.Methods Cultured BRL rat hepatocytes were divided into control and oxidatively stressed group(100 μmol/L H2O2 was added in culture medium for 2 hours),methionine group(50 mmol/L methionine was added in culture medium for 1 hour),and oxidatively stressed + methionine group(100 μmol/L H2O2 was added in culture medium for 2 hours + 50 mmol/L methionine was added in culture medium for 1 hour).At the end of the experiment,culture fluid was collected.Homocysteine,cysteine,and glutathione were measured by high-performance liquid chromatography,and amino acids were assayed by amino acids analyzer.Results Compared with the control group,the contents of homocysteine[(3.76 ± 0.22)vs.(1.54±0.05)μmol/L,P=0.000]and cysteine[(199.80 ±8.75)vs.(99.11 ±2.47)μmol/L,P=0.000]significantly increased in methionine group,and the contents of homocysteine[(3.84 ± 0.34)vs.(1.54 ±0.05)μmol/L,P=0.000]and cysteine[(200.66±8.60)vs.(99.11 ±2.47)μ mol/L,P=0.000]also increased in oxidatively stressed + methionine group.Compared with oxidatively stressed group,the concentrations of homocysteine[(3.76 ± 0.22)vs.(1.67 ± 0.13)μmol/L,P =0.000],cysteine[(199.80 ± 8.75)vs.(82.64±15.88)μmol/L,P=0.000],and glutathione[(1.50 ±0.14)vs.(1.00 ±0.11)μ mol/L,P=0.011)]significantly increased in methionine group,and the concentrations of homocysteine[(3.84 ± 0.34)vs.(1.67±0.13)μmol/L,P=0.000],cysteine[(200.66±8.60)vs.(82.64±15.88)μmol/L,P=0.000]and glutathione[(1.40 ± 0.30)vs.(1.00 ± 0.11)μmol/L,P =0.028]significantly increased in oxidatively stressed + methionine groups.Compared with the control group,the contents of serine[(12.41 ± 1.51)vs.(24.00 ±2.54)mg/L,P =0.000],glutamate[(33.31 ±0.17)vs.(43.10 ±0.52)mg/L,P =0.000]and glycine[(6.23 ± 0.18)vs.(24.66 ± 10.87)mg/L,P =0.000]significantly decreased,while taurine [(7.99 ±0.16)vs.(6.17 ±0.15)mg/L,P =0.000]increased significantly in oxidatively stressed group.Compared with the oxidatively stressed group,the concentrations of serine[(16.98 ± 0.39)vs.(12.41 ± 1.51)mg/L,P=0.006)]and glutamate[(35.44 ±0.82)vs.(33.31 ±0.17)mg/L,P =0.002]in methionine group significantly increased,while taurine[(3.77 ±0.16)vs.(7.99 ±0.16)mg/L,P =0.000]significantly decreased in methionine group.Compared with the methionine group,the contents of serine[(12.59 ± 0.66)vs.(16.98±0.39)mg/L,P=0.008],glutamate[(30.87±0.60)vs.(35.44±0.82)mg/L,P=0.000]significantly decreased while taurine[(4.37 ± 0.12)vs.(3.77 ± 0.16)mg/L,P =0.001]in oxidatively stressed + methionine group significantly increased.Conclusion Oxidative stress can somehow promote homocysteine production in methionine loading BRL rat hepatocytes,but it is not the main effects.
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HPLC method is quick,accurate,and sensitive,and can be applied to the determination of riboflavin in hepatic tissue.