With the increase of complexity and risk in drug discovery processes, human intestinal absorption (HIA) prediction has become more and more important. Up to now, some predictive models have been constructed to estimate HIA of new drug-like compounds with acceptable accuracies, but there are still some issues to be explored including the limited and unbalanced HIA data, the performance of different types of descriptors and the application domain issues of published models. To address these problems, in this study, we collected a relatively large dataset consisting of 970 compounds, and 9 different types of descriptors were calculated for further modeling. For all the modeling processes, a parameter named samplesize in the random forest (RF) method was applied to balance the dataset. And then, classification models were established based on different training sets and different combinations of descriptors. published models, our model exhibits some advantages in data size, model accuracy and model practicability to some extent. This structure-activity relationship model is necessary and useful for HIA prediction and it could be a convenient tool for virtual screening in the early stage of drug development.
BackgroundThrombotic diseases are a group of prevalent and life-threatening diseases. Selective inhibition of pathological thrombosis holds the key to treat variety of thrombotic diseases. The pathological thrombosis can be induced by either tissue necrosis and deregulated inflammation. HMGB1, as an important proinflammatory cytokine and a late mediator, also involves on thrombosis disease. However, the underlying mechanisms are not fully understood.MethodsImmunofluorescence, ELISA assay, Platelet Aggregation, Thromboelastogram (TEG) analyzes. Flow cytometric analysis and Western blot analysis were used to investigated the role of HMGB1 in platelet aggregation and obtained following observations.ResultsBy doing so, we obtained the following observations: i) Highly purified HMGB1 recombinant protein induces platelet aggregation and secretion in a dose-dependent manner in the presence of serum. ii) Low concentration of extracellular HMGB1 could synergistically promote subthreshold concentration of collagen or thrombin induced platelet aggregation. iii) Extracellular HMGB1 promoted platelet aggregation in a platelet-expressed GPIIb/IIIa-dependent manner. iv) We proposed that extracellular HMGB1 seems to promote the phosphorylation of GPIIb/IIIa and subsequent platelet aggregation via TLR4/NF-κB and cGMP pathway.ConclusionsIn this study, we provide evidence for the hypothesis that HMGB1 interact with platelet might play an important role in the haemostasis and thrombotic diseases. Our research might be provide an interesting avenue for the treatment of thrombotic diseases in the future.
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