Non-human primate monkey model of myocardial ischemic infarction is precious for translational medicine research. Ligation of the left anterior descending (LAD) artery is a common procedure to induce myocardial ischemic infarction. However, the consistency of the myocardial infarction thus generated remains problematic. The present study was undertaken to critically evaluate the monkey model of myocardial ischemic infarction to develop a procedure for a consistent cross-study comparison. Forty male Rhesus monkeys were divided into 4 groups and subjected to LAD artery ligation at different levels along the artery. In addition, the major diagonal branch was selectively ligated parallel to the ligation site of the LAD artery according to the diagonal branch distribution. Analyses of MRI, echocardiography, cardiac hemodynamics, electrocardiography, histopathology, and cardiac injury biomarkers were undertaken to characterize the monkeys with myocardial infarction. Ligation at 40% of the total length of the artery, measured from the apex end, produced variable infarct areas with inconsistent functional alterations. Ligation at 60% or above coupled with selective ligation of diagonal branches produced a consistent myocardial infarction with uniform dysfunction. However, ligation at 70% caused a lethal threat. After a thorough analysis, it is concluded that ligation at 60% of the total length coupled with selective ligation of diagonal branches, enables standardization of the location of occlusion and the subsequent ischemic area, as well as avoids the influence of the diagonal branches, are ideal to produce a consistent monkey model of myocardial ischemic infarction.

Myocardial ischemia leads to cardiac fibrosis along with copper (Cu) loss. Cu repletion diminishes myocardial fibrosis and improves cardiac function. The transformation of fibroblasts to myofibroblasts is highly responsible for the pathogenesis of cardiac fibrosis. This study was undertaken to test the hypothesis that Cu inhibition of cardiac fibrosis results from suppression of myofibroblasts. Rhesus monkeys 4-5 years old were subjected to coronary artery ligation to induce myocardial infarction (MI). At the end of the fourth week after the surgery, an ultrasound-directed Cu-albumin microbubble organ-specific Cu delivery technique was used to treat the ischemia-infarcted monkey hearts twice a week for 4 weeks. This treatment increased Cu concentrations in the infarct area, loosened the collagen cross-linking network, restored blood vessel density, and improved cardiac contractility. Total fibroblasts labeled with vimentin were increased in the infarct area, and Cu repletion did not alter this increase. Myofibroblasts, dually labeled with vimentin and α-smooth muscle actin (α-SMA), were also significantly increased in the infarct area but were significantly reduced by Cu repletion. Correspondingly, the products of myofibroblasts, type I and III collagens and inhibitors of collagenases were significantly reduced. In contrast, metalloproteinase-1 (MMP-1) and MMP-1 producing fibroblasts (vimentin+ and MMP-1+ cells) were significantly increased. These results suggest that Cu inhibits the transformation of fibroblasts to myofibroblasts, leading to a pro-fibrinolytic switch and an improvement in cardiac function.

Background The FGF/FGFR system may affect tumor cells and stromal microenvironment through autocrine and paracrine stimulation, thereby significantly promoting oncogene transformation and tumor growth. Abnormal expression of FGFR1 in cells is considered to be the main cause of tumorigenesis and a potential target for the treatment of cancer. Methods The known inhibitors were collected to construct 3D-QSAR pharmacophore model, which was verified by cost analysis, test set validation and Fischer test. Virtual screening of zinc database based on pharmacophore was carried out. FGFR1 crystal complex was downloaded from the protein database to dock with the compound. Finally, the absorption, distribution, metabolism and excretion (ADME) characteristics and toxicity of a series of potential inhibitors were studied. Results It was found that the constructed pharmacophore had a good ability to predict the activity. 2763 compounds in the database could hit well and the predicted activity value was less than 1 µM. Through molecular docking, we found that six compounds can bind to protein stably and inhibit the activity of FGFR1 through hydrogen bond interaction. In ADME and toxicity studies, we have successfully screened out a compound with a new structure scaffold, and found that it has good oral bioavailability and non-toxic. Conclusions This study screened out a new potential drug for cancer treatment, which can be further studied to explore its better therapeutic effect.