ABSTRACT
OBJECTIVE@#To identify the target genes mediating anti-tumor effect of sesquiterpenoids from Cryptoporus volvatus and explore the possible mechanism using molecular docking and molecular dynamics simulation.@*METHODS@#Based on the chemical structure of sesquiterpenes from C. volvatus, we explored the online reverse target finding websites PharmMapper, SEA, Target Hunter and related literature for preliminary prediction of possible anti-tumor targets. Discovery Studio 4.0 (Libdock function) and Maestro 12.3 were used to connect sesquiterpenes with the possible targets, and the potential targets were selected according to the scores. The interaction between the sesquiterpenes and the targets were analyzed using 2D interaction diagram, and the influence of different sesquiterpene skeletons on their activity was inferred based on their activity measurements in experiment. Kinetic simulation was performed for front-end protein sequence (1UNQ) of the Akt (protein kinase B) and for the complex formed by 1UNQ and compound 4 (which had the best cytotoxic activity in vitro) in its optimal conformation, and the root mean square deviation (RMSD) value and root mean square float (RMSF) value of the complex and 1UNQ were measured to evaluate the stability of the binding of compound 4 to the target.@*RESULTS@#The sesquiterpenes showed optimal binding with 1UNQ. Analysis of 2D interaction diagram suggested that the hydrogen bonding and electrostatic force were the most important forces mediating the interaction between the sesquiterpenes and 1UNQ. Analysis of the optimal 3D conformation showed that for different sesquiterpenes, a slight change of the molecular framework produced a steric hindrance effect and caused changes in their bioactivity. Kinetic simulation showed that the complex formed by compound 4 and1UNQ had a lower RMSD than the target pure protein sequence, indicating that compound 4 could stably bind to 1UNQ. The anti-tumor effect of the sesquiterpenoids from C. volvatus was associated with their ability to cause Lys-144 acetylation, which blocks Akt binding to the downstream PIP3 and thus affects the proliferation of tumor cells.@*CONCLUSION@#1UNQ is the target of sesquiterpenoids from C. volvatus, which affects the proliferation of tumor cells by acetylating Lys-14.
Subject(s)
Humans , Molecular Docking Simulation , Neoplasms , Polyporaceae , Sesquiterpenes/pharmacologyABSTRACT
AIM: To study the effects of polysaccharides of ferment cultured cryptoporus volvatus (CVPS) on release of leukotrienes from guinea pig lung and Schultz - Dale reaction. METHODS: The bioassay method and reversed phase high-performance liquid chromatography (RP-HPLC) were used to analyze SRS-A or LTD4 from sensitized or normal guinea pig, after challenged with antigen or A23187 respectively. The antiallergic effects of CVPS were evaluated with Schultz-Dale reaction. RESULTS: The release of SRS-A or LTD4 from sensitized or normal guinea pigs were greatly reduced by CVPS after antigen or A23187 challenge. The CVPS could also inhibit the Schultz-Dale reaction of sensitized guinea pig (IC50 = 0.49 g·L-1). CONCLUSION: The effects of CVPS involved in inhibiting release of leukotrienes from lung and antiallergy.
ABSTRACT
Objective To establish a model of asthma mice with spleen-deficiency syndrome (asthma-SDS) and to investigate the effects of Cryptoporus volvatus ferment substance (CVFS) on the airway hyperresponsiveness and inflammation in model mice. Methods An asthma-SDS model of mice was established by ovalbumin (OVA)-sensitized plus over-eating and over-exerting. The changes of lung resistance (R_L), inflammatory cells in bronchoalveolar lavage fluid (BALF), lung tissue pathology, and spleen index were observed. Results Compared with the simple asthma model of mice, the airway hyperresponsiveness, eosinophils number in the BALF, lung tissue pathology, and spleen index in the asthma-SDS model of mice showed a significant difference (P