In this study, based on web database, 324 neurotoxic compounds and 234 non-neurotoxic compounds were selected as a data set for neurotoxicity discriminative model. 6 122 molecular descriptors, including charge distribution, physicochemical and geometrical descriptors,were calculated to characterize the molecular structure of neurotoxic compounds. The combination of Cfs Subset Evaluation and Best First-D1-N5 searching was used to select molecular descriptors. A discrimination model with high accuracy was built based on the support vector machine (SVM) approach. Meanwhile, the model accuracy, sensitivity and specificity were all above 80%. Besides, 30 traditional Chinese medicine compositions with neurotoxicity were set as external validation to further verify the model accuracy,with anaccuracy of 73.333%. Using the model, 13 potential neurotoxic compounds were screened from Sophorae subprostrate Radix,4 of them were verified by literatures. The results demonstrated that the discrimination model can be applied to screen neurotoxic compounds from Chinese medicinal materials.
Computer Simulation ; Drug Evaluation, Preclinical ; methods ; Medicine, Chinese Traditional ; methods ; Models, Theoretical ; Neurotoxins ; analysis ; chemistry ; Reproducibility of Results ; Support Vector Machine

On the basis of web databases, 111 compounds with nephrotoxicity and 90 compounds without nephrotoxicity were collected as data set of nephrotoxicity discrimination model, 39 compounds with tubular necrosis and 39 compounds without tubular necrosis were collected as data set of tubular necrosis discrimination model. The 6 122 molecular descriptors, including physicochemical, charge distribution and geometrical descriptors were calculated to characterize the molecular structure of the above-mentioned compounds. CfsSubsetEval valuation method and BestFirst-D1-N5 searching method were used to select molecular descriptors. Two models with high accuracy were built based on the support vector machine (SVM) approach, respectively. Accuracy, sensitivity, specificity and matthew's correlation coefficient of the two models were all above 70%. By using 22 nephrotoxicity compounds of Chinese medicine, the nephrotoxicity discrimination model was further verified with an accuracy of 72.73%. Using the tubular necrosis discrimination model, 10 potential compounds which can cause tubular necrosis were screened from the positive results of nephrotoxicity discrimination model, 6 of them have been verified by literatures. The results demonstrated that the discrimination models can be applied to screen nephrotoxic compounds from Chinese medicinal materials, and they also offer a new research idea for the further studies on the mechanism of nephrotoxicity.
Drugs, Chinese Herbal ; toxicity ; Nephrons ; drug effects ; Support Vector Machine ; Toxicity Tests ; instrumentation ; methods

Nicotinic acid could increase high density lipoprotein and reduce serum total cholesterol, low density lipoprotein cholesterol and triglycerides in human bodies, thus is frequently applied in treating low high-density lipoprotein cholesterol and hypertriglyceridemia in clinic. However, according to the findings, nicotinic acid could also cause adverse effects, such as skin flush, beside its curative effects. In this study, bioisosterism, fragment-based search and Lipinski's Rule of Five were used to preliminarily screen out potential TCM ingredients that may have similar pharmacological effects with nicotinic acid from Traditional Chinese medicine database (TCMD). Afterwards, homology modeling and flexible docking were used to further screen out potential nicotinic acid receptor agonists. As a result, eleven candidate compounds were derived from eight commonly used traditional Chinese medicines. Specifically, all of the candidate compounds' interaction with nicotinic acid receptor was similar to nicotinic acid, and their docking scores were all higher than that of nicotinic acid, but their druggability remained to be further studied. Some of the eight source traditional Chinese medicines were used to lower lipid according to literature studies, implying that they may show effect through above means. In summary, this study provides basis and reference for extracting new nicotinic acid receptor agonists from traditional Chinese medicines and improving the medication status of hyperlipidemia.
Drug Evaluation, Preclinical ; Drugs, Chinese Herbal ; chemistry ; Humans ; Models, Molecular ; Molecular Structure ; Nicotinic Acids ; chemistry ; Nicotinic Agonists ; chemistry ; Protein Binding ; Receptors, G-Protein-Coupled ; agonists ; chemistry ; Receptors, Nicotinic ; chemistry

Objective To investigate the expression levels and the roles of heme oxygenase-1(HO-1) in rat kidney after interruption of blood flow and the following ischemia-reperfusion(IR)injury.Methods Rats were divided into 3 groups: interruptions(5,15,30 min),IR group(2,5,8,24,48,72 h),and control group.They were killed at different time points.Kidney tissue samples were studied by immuneohistochemical method.Results The expressions of HO-1 raised significantly in both ischemia group of 30 min((P

Objective To illustrate the expressional distribution of heat shock protein 70(HSP 70) in the kidney of acute renal injury rats caused by gentamicin.Methods One hundred and fifty rats were randomly divided into 3 groups: group A (normal group), group B [80 mg/(kg?d) gentamicin to be injected], group C [160 mg/(kg?d) gentamicin to be given]. The variations of renal pathology were observed at different time phasess by light scope and electromicroscope. Simultaneously, the expression of HSP 70 in kidney was evaluated by immunohistochemistry.Results HSP 70 distributed in epithelial cells of renal tubular in acute injury rats. The expression of HSP 70 increased markedly from the 6th hour after injection, peaked at the 12th hour and lasted for 48 hours. The expression of HSP 70 in group C was higher than that in group B(P

Objective To investigate the relationship between esophageal motility and distal latency (DL) in gastroesophageal reflux disease (GERD) using high resolution manometry (HRM).Methods A total of 51 GERD patients underwent HRM and 24 h-esophageal pH monitoring.According to the HRM topography (characterized as either break peristalsis or normal esophageal movement),all GERD patients were divided into two groups:hypomotility group (n =28) and normal group (n =23).Fourteen non-GERD controls were enrolled.The monitoring results were analyzed.Results The HRM DL of 28 esophageal hypomotility patients(54.9％,28/51) were the longest (7.27 ± 1.44) s.Patients with normal peristalsis also had longer latency (6.70 ± 1.41)s than the non-GERD controls (5.86 ± 0.96)s.All the differences were statistically significant (P ＜ 0.01).DCI of hypotensive peristalsis patients (712.49 ± 703.10) mmHg · s · cm was lower compared with the other groups [(1 285.85 ± 850.83) mmHg · s · cm,(1 109.74 ± 611.70) mmHg · s · cm] (P ＜0.O1).Other indicators such as LES pressure,CFV and IBP showed no significant differences among groups (P ＞ 0.05).Conclusion Esophageal manometry of GERD patients indicates that esophageal hypomotility is accompanied with prolonged DL.Because DL of all GERD sufferers are extended,esophageal dysmotility has great implications for GERD's development.

Traditional Chinese medicine (TCM) has definitely clinical effect in treating hyperlipidemia, but the action mechanism still need to be explored. Based on consulting Chinese Pharmacopoeia (2010), all the lipid-lowering Chinese patent medicines were analyzed by associated rules data mining method to explore high frequency herb pairs. The top three couplet medicines with high support degree were Puerariae Lobatae Radix-Crataegi Fructus, Salviae Miltiorrhizae Radix et Rhizoma-Crataegi Fructus, and Polygoni Multiflori Radix-Crataegi Fructus. The 20 main ingredients were selected from the herb pairs and docked with 3 key hyperlipidemia targets, namely 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), peroxisome proliferator activated receptor-α (PPAR-α ) and niemann-pick C1 like 1 (NPC1L1) to further discuss the molecular mechanism of the high frequency herb pairs, by using the docking program, LibDock. To construct evaluation rules for the ingredients of herb pairs, the root-mean-square deviation (RMSD) value between computed and initial complexes was first calculated to validate the fitness of LibDock models. Then, the key residues were also confirmed by analyzing the interactions of those 3 proteins and corresponding marketed drugs. The docking results showed that hyperin, puerarin, salvianolic acid A and polydatin can interact with two targets, and the other five compounds may be potent for at least one of the three targets. In this study, the multi-target effect of high frequency herb pairs for lipid-lowering was discussed on the molecular level, which can help further researching new multi-target anti-hyperlipidemia drug.
Asteraceae ; chemistry ; Drugs, Chinese Herbal ; chemistry ; metabolism ; Humans ; Hydroxymethylglutaryl CoA Reductases ; chemistry ; genetics ; metabolism ; Hyperlipidemias ; drug therapy ; enzymology ; genetics ; metabolism ; Hypolipidemic Agents ; chemistry ; metabolism ; Membrane Proteins ; chemistry ; genetics ; metabolism ; Molecular Docking Simulation ; PPAR alpha ; chemistry ; genetics ; metabolism ; Protein Binding ; Pueraria ; chemistry

Objective To study expressions of heme oxygenase-1 mRNA and protein in rat hippocampus after hypoxic-ischemia brain damage(HIBD) as well as the relationship with apoptosis in brain.Methods Seven-day-old SD rats were randomly divided into hypoxic-ischemia brain damage group and sham control group.Expressions of HO-1 protein and mRNA as welll as the relationship with apoptosis after HIBD in neonatal rat were determined by immunohisochemistry and in situs hybridizaion as well as terminal deoxynucleotidy transferase mediated UTP-biotin nick end labeling(TUNEL).Results 1.In the right hippocampus,expression of HO-1 gene increased sharply at 4 h (P

Objective To study changes of phosphorylated cyclic adenosine monophosphate(c-AMP) response element binding protein in hippocampus(CA1) of neonatal rats after cerebral hypoxic-ischemia(HI)and effects of gangliosides (GM1)on the p-CREB.Methods An animal model of neonatal hypoxic-ischemia brain damage was established. Changes of p-CREB in hippocampal CA1 was detected with immunohistochemical methods.Results The p-CREB levels in the CA1 of HI and GM1 groups increased transiently and then decreased quickly, but there was no significant difference between HI and GM1 group.Conclusion The p-CREB levels in the CA1 of HI group increase transiently and then decrease quickly after HI ;GM1 has little effect on p-CREB in the CA1 after HI.

Objective To investigate the clinical characteristics of severe patients with influenza A H1N1. Methods Fifteen prenant pneumonia patients with influenza A H1N1 were selected from November 26 to December 20,2009. Results The average age of all patients was 24 years old,with an average gestational age of 32 weeks. Leukopenia was observed in 13. 3% of IS patients,and lymphopenia in 86. 7%. Data on the ratio of CD4 cells to CD8 cells were available for 12 patients,54. 5% of whom had an abnormal CD4:CD8 ratio(< 1. 4). Ten of the 14 patients(71. 4%)had increased serum lactate dehydrogenase levels,which were above 245 U per liter. Four patients (26. 6%) had elevated creatine kinase levels at admission. 4 cases of 15 patients (26. 7%) had decreased serum potassium levels,which were below 3.5 mmol per liter. Four patients (33. 3%)had C4 levels higer than 36 g per liter,and 4 cases had C3 less than 0.75 g per liter. All 15 patients had radiologically confirmed pneumonia with bilateral patchy alveolar opacities, affecting three or four lung quadrants. Findings on chest radiographs were consistent with the acute respiratory distress syndrome in all patients requiring mechanical ventilation. 4 cases were found a small amount of pleural effusion, of which 1 case was combined a small amount of pericardial effusion. Respiratory distress requiring intubation and mechanical ventilation developed in 9 patients within the first 24 hours after admission, who were all pregnant women. Two of them in the third trimester died, and 7 cases who were timely terminated pregnancy were in stable condition. Conclusions Pandemic influenza A(HIM) may pose an increased risk of severe illness in pregnant women, and it is easy to develop rapidly into adult respiratory distress syndrome. The pregnancy immunological tolerance may be involved in the severe lung injury process of H1N1 influenza pneumonia.