Mechanism of anti-hyperuricemia of isobavachin based on network pharmacology and molecular docking.

BACKGROUND: Hyperuricemia is a more popular metabolic disease caused by a disorder of purine metabolism. Our previous study firstly screened out a natural product Isobavachin as anti-hyperuricemia targeted hURAT1 from a Chinese medicine Haitongpi (Cortex Erythrinae). In view of Isobavachin's diverse pharmacological activities, similar to the Tranilast (as another hURAT1 inhibitor), our study focused on its potential targets and molecular mechanisms of Isobavachin anti-hyperuricemia based on network pharmacology and molecular docking. METHODS: First of all, the putative target genes of compounds were screen out based on the public databases with different methods, such as SwissTargetPerdiction, PharmMapper and TargetNet,etc. Then the compound-pathways were obtained by the compounds' targets gene from David database for Gene Ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis. The cross pathways of compound-pathways and the diseases pathways of hyperuricemia from Comparative Toxicogenomics Database were be considered as the compound-disease pathways. Next, based on the compound-disease pathways and the PPI network, the core targets were identified based on the retrieved disease-genes. Finally, the compound-target-pathway-disease network was constructed by Cytoscape and the mechanism of isobavachin anti-hyperuricemia was discussed based on the network analysis. RESULTS: Our study demonstrated that there were five pathways involved in Isobavachin against hyperuricemia, including Drug metabolism-other enzymes, Metabolic pathways, Bile secretion, Renin-angiotensin system and Renin secretion. Among the proteins involved in these pathways, HPRT1, REN and ABCG2 were identified as the core targets associated with hyperuricemia, which regulated the five pathways mentioned above. It is quite different from that of Tranilast, which involved in the same pathways except Bile secretion instead of purine metabolism. CONCLUSION: This study revealed Isobavachin could regulate the pathways including Drug metabolism-other enzymes, Metabolic pathways, Bile secretion, Renin-angiotensin system, Renin secretion by core targets HPRT1, REN and ABCG2, in the treatment of hyperuricemia effect. Among them, the Bile secretion regulated by ABCG2 probably would be a novel pathway. Our work provided a theoretical basis for the pharmacological study of Isobavachin in lowering uric acid and further basic research.

Novel natural scaffold as hURAT1 inhibitor identified by 3D-shape-based, docking-based virtual screening approach and biological evaluation.

As a promising therapeutic target for gout, hURAT1 has attracted increasing attention. In this work, we identified a novel scaffold of hURAT1 inhibitors from a personal natural product database of verified herb-treated gout. First, we constructed more than 800 natural compounds from Chinese medicine that were verified to treat gout. Following the application of both shape-based and docking-based virtual screening (VS) methods, taking into account the shape similarity and flexibility of the target, we identified isopentenyl dihydroflavones that might inhibit hURAT1. Specifically, 9 compounds with commercial availability were tested with biochemical assays for the inhibition of 14C-uric acid uptake in high-expression hURAT1 cells (HEK293-hURAT1), and their structure-activity relationship was evaluated. As a result, 8-isopentenyl dihydroflavone was identified as a novel scaffold of hURAT1 inhibitors since isobavachin (DHF3) inhibited hURAT1 with an IC50 value of 0.39 ± 0.17 µM, which was comparable to verinurad with an IC50 value of 0.32 ± 0.23 µM. Remarkably, isobavachin also displayed an eminent effect in the decline of serum uric acid in vivo experiments. Taken together, isobavachin is a promising candidate for the treatment of hyperuricemia and gout.

Practice Patterns and Guideline Non-Adherence in Surgical Management of Appendiceal Carcinoid Tumors.

BACKGROUND: Surgical management of appendiceal carcinoid tumors is heavily debated, despite National Comprehensive Cancer Network guidelines recommending aggressive resection of tumors >2 cm. We investigated national practice patterns and the predictors and impact of guideline non-adherence. STUDY DESIGN: The National Cancer Database was queried for cases of appendiceal carcinoids diagnosed from 2004 to 2015 treated with either appendectomy or hemicolectomy. Multivariable logistic regression, adjusted for demographic and clinical factors, identified associations with the procedure type among patients stratified by tumor size ≤2 cm and >2 cm. Cox Proportional Hazards then identified associations with overall survival among stratified patient groups. RESULTS: Of 3,198 cases of appendiceal carcinoids, 1,893 appendectomies and 1,305 hemicolectomies were identified. Contrary to National Comprehensive Cancer Network guidelines, 32.4% of tumors ≤2 cm were treated with hemicolectomy and 31.3% of tumors >2 cm were treated with definitive appendectomy. Hemicolectomy for small tumors was associated with age 65 years and older (odds ratio [OR] 2.4; 95% CI 1.7 to 3.3; reference group age 18 to 39 years), history of malignancy (OR 2.0; 95% CI 1.6 to 2.6), tumor size 1.1 to 2 cm (OR 2.8; 95% CI 2.3 to 3.4; reference group size ≤1 cm), and lymphovascular invasion (OR 2.2; 95% CI 1.6 to 3.2); appendectomy for large tumors was associated with age 65 years and older only (OR 2.2; 95% CI 1.1 to 4.2). Procedure type was not associated with survival for small or large tumors (hazard ratio 1.0; 95% CI 0.7 to 1.4 and hazard ratio 1.1; 95% CI 0.6 to 2.0, respectively). CONCLUSIONS: Despite well-known size-based treatment guidelines for appendiceal carcinoids, one-third of patients in the US undergo hemicolectomy for small tumors and appendectomy for large tumors. Guideline non-adherence, however, is not associated with overall survival. Reasons for these practice patterns should be explored, and guidelines revisited.

GaS and GaSe ultrathin layer transistors.

Room-temperature, bottom-gate, field-effect transistor characteristics of 2D ultrathin layer GaS and GaSe prepared from the bulk crystals using a micromechanical cleavage technique are reported. The transistors based on active GaS and GaSe ultrathin layers demonstrate typical n-and p-type conductance transistor operation along with a good ON/OFF ratio and electron differential mobility.