Transforming Growth Factor-beta I Involved in the Pathogenesis of Endometriosis through Regulating Expression of Vascular Endothelial Growth Factor under Hypoxia

Background： Endometriosis （EMs） is a common gynecological disorder characterized by endometrial-like tissue outside the uterus. Hypoxia induces the expression of many important downstream genes to regulate the implantation, survival, and maintenance ofectopic endometriotic lesions. Transtbrming growth factor-beta I （TGF-β1） plays a major role in the etiology of EMs. We aimed to determine whether TGF-β1 affects EMs development and progression and its related mechanisms in hypoxic conditions. Methods： Endometrial tissue was obtained from women with or without EMs undergoing surgery from October, 2015 to October, 2016. Endometrial cells were cultured and then exposed to hypoxia and TGF-β1 or TGF-β1 inhibitors. The messenger RNA （mRNA） and protein expression levels ofTGF-β1, vascular endothelial growth fhctor （VEGF）, and hypoxia-inducible fhctor-Ic~ （HIF-β1） were measured. A DuaI-Luciferase Reporter Assay was used to examine the effect ofTGF-[31 and hypoxia on a VEGF promoter construct. Student＇s t-test was pertbrmed/br comparison among groups （one-sided or two-sided） and a value ofP 〈 0.05 was considered statistically significant. Results： TGF-β1, VEGF, HIF-β1 mRNA, and protein expression were significantly higher in EMs tissue than that in normal endometrial tissue （t = 2.16, P = 0.042）. EMs primary cultured cells exposed to hypoxia expressed 43.8% higher VEGF mRNA and protein （t = 6.84, P - 0.023）. VEGF mRNA levels increased 12.5% in response to TGF-β1, whereas the combined treatment of hypoxia/TGF-β1 resulted in a much higher production （87.5% increases） of VEGF. The luciferase activity of the VEGF promoter construct was increased in the presence of either TGF-β1 （2.6-fold, t = 6.08, P = 0.032） or hypoxia （11.2-fold, t = 32.70, P 〈 0.001 ）, whereas the simultaneous presence of both stimuli resulted in a significant cooperative effect （ 18.5-fold, t = 33.50, P 〈 0.001 ）. Conclusions： The data support the hypothesis that TGF-β1 is involved in the pathogenesis of EMs through regulating VEGF expression. An additive effect of TGF-[31 and hypoxia is taking place at the transcriptional level.

Stability analysis of Runge-Kutta methods for nonlinear neutral delay integro-differential equations

The sufficient conditions for the stability and asymptotic stability of Runge-Kutta methods for nonlinear neutral delay integro-differential equations are derived. A numerical test that confirms the theoretical results is given in the end.