The Effect of Structural Diversity on Ligand Specificity and Resulting Signaling Differences of Estrogen Receptor α.

Numerous chemicals have been reported to exert estrogen-like endocrine disrupting effects via a receptor binding mechanism that directly interacts with the ligand binding domain of estrogen receptor α (ERα). However, not only their binding affinities to ERα but also their interference in specific cell and tissue functions are clearly different. In this regard, significant regulation differences among three representative estrogenic chemicals (diethylstilbestrol (DES), bisphenol A (BPA), and diarylpropionitrile (DPN)), well-known ERα agonists with very similar structures, have been observed. Molecular dynamics simulation is used to explore the underlying mechanism of different regulation effects induced by the similar estrogen-like chemicals. The DES-induced 12 Å motion of the H9-H10 loop markedly expands the negative electrostatic potential surface of the AF-2 domain, which is consistent with the over-regulation effect of the agonist. In comparison, the 3 Å motion induced by BPA and DPN corresponds to the low-regulation effect of the chemicals. Cross-correlation analysis indicates that the different ERα motions and resulting surface feature of AF-2 domain are brought by the distinguished binding modes of the agonists. Moreover, only hydrophobic DES with estrogen-like size and flexibility has a high binding affinity of -23.47 kcal/mol binding free energy. Both the hydrophilic group in DPN and the small molecular size of BPA dramatically decrease the agonist binding ability, and their binding free energies are only -12.43 kcal/mol and -11.82 kcal/mol, respectively. Our study demonstrates that similar chemicals interact differently with ERα and induce different allosteric effects, which explains the observed regulation diversity.

Low-power Helium-Neon laser irradiation enhances the expression of VEGF in murine myocardium.

BACKGROUND: Low-power helium-neon (He-Ne) lasers have been increasingly widely applied in the treatment of cardiovascular diseases, and its vasodilation effect has been proven. The aim of this study was to determine the effects of low-power He-Ne laser irradiation directed at the precardial region of Wistar rats on capillary permeability in the myocardium and the expression of myocardial vascular endothelial growth factor (VEGF). METHODS: Sixteen rats were divided randomly into control and irradiated groups (n = 8, each). A He-Ne laser (632.8 nm) was applied to the irradiated group with a dose of 60.5 J/cm(2). Ferritin was perfused into the left femoral vein and capillary permeability was examined under an electron microscope. VEGF expression in the myocardium was investigated by immunohistochemical methods, RT-PCR, and image analysis. RESULTS: The ultrastructures of the myocardial capillaries were examined. Compared to the control group, more high-density granules (ferritin), which were present within the capillary endothelium and the mitochondrions of myocardial cells in the internal layer of the myocardium, were observed in the irradiated group. VEGF staining of the myocardium was stronger in the irradiated group than that in the control group. The optic density of the irradiated group (0.246 +/- 0.015) was significantly higher than that of the control group (0.218 +/- 0.012, P < 0.05). Finally, the levels of RT-PCR products of VEGF165 mRNA were 2.79 times higher in irradiated rats than in the control rats. CONCLUSIONS: Our study demonstrates that He-Ne laser irradiation (in doses of 60.5 J/cm(2)) increases myocardial capillary permeability and the production of VEGF in myocardial microvessels and in myocardium. Our study provides experimental morphological evidence that myocardial microcirculation can be improved using He-Ne laser irradiation.