Computational prediction for the metabolism of human UDP-glucuronosyltransferase 1A1 substrates.

UDP-glucuronosyltransferase (UGT) 1A1, one of the most important isoforms in UGTs superfamily, has attracted increasing concerns for its special role in the clearance and detoxification of endogenous and exogenous substances. To avoid the clinical drug-drug interactions, it is of great importance to have the knowledge of the metabolic profile of UGT1A1 substrates early. Herein, we purposed to establish machine learning models to predict the metabolic propeties of UGT1A1 substrates. On the basis of the literature-derived substrates database of UGT1A1, automatic metabolism prediction models for the aromatic hydroxyl (ArOH) and carboxyl (COOH) groups were developed with eight machine learning methods, among which, three methods, i.e. Random Forest, Random Subspace and J48, illustrated the best performance either for the aromatic hydroxyl and the carboxyl model. The models illustrated good robustness when they were evaluated with functions like "Precision", "Recall", "F-Measure", "AUC", "MCC", etc. Nice accuracy was observed for the aromatic hydroxyl and carboxyl model of these methods, whose AUCs ranged from 0.901 to 0.997. Additionally, the ArOH model was applied to predict the UGT1A1-mediated metabolism of an external set. Two new unknown substrates, cytochrome P450 (CYPs)-mediated metabolites of gefitinib, were predicted and identified, which were validated by in vitro assays. In summary, this study provides a reliable and robust strategy to predict UGT1A1 metabolites, which will be helpful either in rational-optimization of drug metabolism or in avoiding drug-drug interactions in clinic.

Evaluating the long-term prognosis of coronary artery disease patients undergoing percutaneous coronary intervention by risk stratification with ACC/AHA classification of coronary lesions / 中华心血管病杂志

Objective: To evaluate the long-term prognosis of coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI) by risk stratification with American College of Cardiology (ACC)/American Heart Association (AHA) classification of coronary lesions. Methods: Data used in this study derived from the I-LOVE-IT 2 trial. I-LOVE-IT 2 trial was a prospective, multicenter, randomized, assessor-blinded, noninferiority study. A total of 1 255 patients in I-LOVE-IT 2 trial with only one lesion and underwent biodegradable polymer drug-eluting stent implantation were included and grouped according to ACC/AHA classification of coronary lesions, namely type A/B1 lesion group (n=184), type B2 lesion group (n=457) and type C lesion group (n=614). The primary endpoint was 48-month patient-oriented composite endpoint (PoCE), a composite of all-cause mortality, all myocardial infarction, stroke, and/or any revascularization. The secondary endpoints were target lesion failure (TLF), components of PoCE, major bleeding (bleeding academic research consortium(BARC) type 3-5) and definite/probable stent thrombosis within 48 months. The incidences of endpoint events were compared in the three groups. The multivariable Cox hazard ratio model was used to analyze the independent predictors of PoCE and TLF at 48 months. Results: Incidences of PoCE at 48 months were significantly higher in patients with type C lesion compared with patients with type A/B1 (24.43%(150/614) vs. 14.13%(26/184), P<0.05) or B2 lesion (24.43%(150/614) vs. 15.97%(73/457), P<0.05). The multivariable Cox hazard ratio model showed that the type C lesion were the independent predictors of 48-month PoCE (HR=1.59, 95%CI 1.21-2.08, P<0.001) and TLF (HR=2.31, 95%CI 1.53-3.49, P<0.001). After multivariable adjustment, the HRs of PoCE for patients with type C lesion versus type A/B1 and type B2 were 1.91 (95%CI 1.25-2.92, P=0.003) and 1.64 (95%CI 1.23-2.20, P<0.001), respectively. Meanwhile, the HRs of TLF for patients with type C lesion versus type A/B1 and type B2 were 2.45 (95%CI 1.29-4.64, P=0.006) and 2.55 (95%CI 1.62-4.02, P=0.001), respectively. Conclusions: The ACC/AHA classification of coronary lesions has good discrimination with long-term outcomes for CAD patients undergoing PCI. The type C lesion is associated with a worse prognosis, enough attention should be paid in these patients during routine clinical management.

Determination of six active ingredients in different parts of Belamcanda chinensis and Iris tectorum and their anti-inflammatory activity / 中国中药杂志

In order to explore the anti-inflammatory activity and active ingredient basis from the leaves of the Belamcanda chinensis and Iris tectorum, we established an HPLC method for simultaneous determination of six anti-inflammatory active ingredient contents in the root of the B. chinensis and I. tectorum as well as their leaves with different dry methods, and the anti-inflammatory effects of the extract were studied by the mouse ear swelling experiment. The HPLC analysis was performed on an Agilent WondaSil© C₁₈-WR(4.6 mm×250 mm，5 μm)，with isocratic elution of acetonitrile-0.1% ortho-phosphoric acid solution at a flow rate of 1. 0 mL·min⁻¹ and the detection was carried out at 265 nm. The chemical compositions of the B. chinensis and I. tectorum are similar but the contents of them are obviously different. Both rhizome and leaf extract of B. chinensis and I. tectorum had inhibitory effects on inflamed mice induced by dimethylbenzene and had anti-inflammatory effects by animal experiment, which could lay the material and active foundation for the development of the non-medicinal parts of the B. chinensis and I. tectorum.

The evaluation of structural remodeling of the left atrium in elderly patients with non-valvular atrial fibrillation / 中华老年医学杂志

Objective To assess the difference in left atrial properties between elderly and younger control subjects and the role of left atrium remodeling in patients of different ages with atrial fibrillation.Methods A total of 194 patients with non-valvular atrial fibrillation were enrolled from September 2014 to June 2016.Based on age,patients were divided into an elderly group (≥60 years,n=129) and a younger group (＜60 years,n=65).We evaluated remodeling parameters for the left atrium using an Ultrasound Cardiography (UCG) system in 125 elder subjects,together with 64 control subjects.All remodeling parameters were recorded,including left atrial diameter (LAD),left atrial square (LAS),left atrial pressure (LAP) and left ventricular end-diastolic dimension (LVEDD).Results The elderly group had more female patients and more patients with persistent atrial fibrillation.Meanwhile,scores of CHA2DS2Vsc and levels of N-terminal pro-brain natriuretic peptide (NT-ProBNP) were significantly increased in elderly patients (both P＜0.05).Moreover,the elderly group was associated with increased values of LAD and LAS[(39.1±4.4)mm vs.(37.1±5.3)mm,P＜0.01;and(23.3±4.5)cm2 vs.(21.4±4.8)cm2,P＜0.01;respectively],compared with those in the control group.Spearman's correlation analysis showed that LAD,LAS and LAP were all markedly related to age (r=0.213,P＜0.05;r=-0.175,P＜0.05;r=0.170,P＜0.05;respectively),persistent onset of atrial fibrillation (r=0.401,P＜0.05;r=0.446,P＜0.05;r=0.160,P＜0.05;respectively),and impaired heart function,measured by left ventricular ejection fraction (r=-0.4371,P＜0.05;r=-0.403,P＜0.05;r=-0.364,P＜0.05;respectively) and NT-ProBNP (r=0.485,P＜0.01;r=0.483,P＜ 0.01;r =0.293,P＜ 0.01;respectively).Conclusions Left atrial remodeling properties measured by the UCG system in the elderly with non-valvular atrial fibrillation are more serious than those in mid-aged and young subjects.As a convenient and accurate assessment of remodeling parameters,the UCG system is an excellent option for measuring left atrial remodeling in the elderly population.