Carvedilol may attenuate liver cirrhosis by inhibiting angiogenesis through the VEGF-Src-ERK signaling pathway

AIM: To investigate the effect of carvedilol on angiogenesis and the underlying signaling pathways.METHODS: The effect of carvedilol on angiogenesis was examined using a human umbilical vascular endothelial cell(HUVEC) model. The effect of carvedilol on cell viability was measured by CCK8 assay. Flow cytometry was used to assess the effect of carvedilol on cell cycle progression. Cell migration, transwell migration and tube formation assays were performed to analyze the effect of carvedilol on HUVEC function. Vascular endothelial growth factor(VEGF) induced activation of HUVECs, which were pretreated with different carvedilol concentrations or none. Western blot analysis detected the phosphorylation levels of three cell signaling pathway proteins, VEGFR-2, Src, and extracellular signal-regulated kinase(ERK). The specific Src inhibitor PP2 was used to assess the role of Src in the VEGF-induced angiogenic pathway.RESULTS: Carvedilol inhibited HUVEC proliferation in a dose-dependent manner(IC50 = 38.5 mmol/L). The distribution of cells in the S phase decreased from 43.6% to 37.2%, 35.6% and 17.8% by 1, 5 and 10 μmol/L carvedilol for 24 h, respectively. Carvedilol(10 μmol/L) reduced VEGF-induced HUVEC migration from 67.54 ± 7.83 to 37.11 ± 3.533(P < 0.001). Carvedilol concentrations of 5 μmol/L and 10 μmol/L reduced cell invasion from 196.3% ± 18.76% to 114.0% ± 12.20% and 51.68% ± 8.28%, respectively. VEGFinduced tube formation was also reduced significantly by 5 μmol/L and 10 μmol/L carvedilol from 286.0 ± 36.72 to 135.7 ± 18.13(P < 0.05) and 80.27 ± 11.16(P < 0.01) respectively. We investigated several intracellular protein levels to determine the reason for these reductions. Treatment with 10 μmol/L carvedilol reduced VEGF-induced tyrosine phosphorylation of VEGFR-2 from 175.5% ± 8.54% to 52.67% ± 5.33%(P < 0.01). Additionally, 10 μmol/L carvedilol reduced VEGF-induced ERK 1/2 phosphorylation from 181.9% ± 18.61% to 56.45% ± 7.64%(P < 0.01). The VEGFinduced increase in Src kinase activity was alleviated by carvedilol [decreased from 141.8% ± 15.37% to 53.57 ± 7.18%(P < 0.01) and 47.04% ± 9.74%(P < 0.01) at concentrations of 5 and 10 μmol/L, respectively]. Pretreatment of HUVECs with Src kinase inhibitor almost completely prevented the VEGF-induced ERK upregulation [decreased from 213.2% ± 27.68% to 90.96% ± 17.16%(P < 0.01)].CONCLUSION: Carvedilol has an anti-angiogenic effect on HUVECs. This inhibitory effect is mediated by VEGF-induced Src-ERK signaling pathways.

Stress concentration factor expression for tension strip with eccentric elliptical hole

Two explicit expressions of the stress concentration factor for a tension finite-width strip with a central elliptical hole and an eccentric elliptical hole, respectively, are formulated by using a semi-analytical and semi-empiricai method. Accuracy of the results obtained from these expressions is better, and application scope is wider, than the results of Durelli＇s photo-elastic experiment and Isida＇s formula. When eccentricity of the elliptical hole is within a certain range, the error is less than 8%. Based on the relation between the stress concentration factor and the stress intensity factor, a stress intensity factor expression for tension strips with a center or an eccentric crack is derived with the obtained stress concentration factor expressions. Compared with the existing formulae and the finite element analysis, this stress intensity factor expression also has sufficient accuracy.

A New Sesquiterpenoid Glycoside from Rhizomes of Atractylodes lancea

Objective To study the water-soluble chemical constituents from the rhizomes of Atratylodes lancea. Methods Two sesquiterpenoid glycosides were purified by column chromatography and their structures were determined by spectroscopic analysis. They were also evaluated for anti-inflammatory activity by determining the inhibitory activity on LPS-induced NO and PGE2 generation in RAW 264.7 cell lines. Results Compound 1 was a new sesquiterpenoid glycoside, named as（1S,4S,5R,7R,10S）-4,11,14-trihydroxyguai-3-one-11-O-β-D-glucopyranoside, but exhibited no appreciable activity. Compound 2 was atractyloside A and showed weak activity. Conclusion The hydroxyl group at C-10 of guaiol-type glycoside could be important for anti-inflammatory activity.