ABSTRACT
OBJECTIVE Only limited number of drugs are currently available for treating ischemic stroke. Therapeu?tic angiogenesis has recently emerged as one of the most promising therapies for cerebral ischemic injury. Isopropyl-β-(3,4-dihydroxyphenyl)-α-hydroxypropanoate (IDHP) is a metabolite derived from the botanical formulation for Dantonic?. Here, we investigated the angiogenic efficacy of IDHP in cerebral ischemia. METHODS The in vivo effects of IDHP were evaluated in the C57BL/6 mouse Matrigel plug and rat transient middle cerebral artery occlusion (tMCAO) models. Primary human umbilical vein endothelial cells (HUVEC) and human brain microvascular endothelial cells (HBMEC) were used to explore the effects of IDHP on stimulating proliferation, migration and tube formation in vitro. ELISA and Western blotting were used to quantitate the release and expression of relevant target molecules and signaling path?ways. RESULTS IDHP reduced infarct volume and improved sensorimotor function in rats subjected to tMCAO by pro?moting angiogenesis, and promoted Matrigel neovascularization in mice. Moreover, IDHP produced a biphasic modula?tion on proliferation and migration both in HUVEC and HBMEC. It also induced tube formation in a 12-day HUVEC-HDF co-culture model and in Matrigel assays. IDHP-induced angiogenesis was accompanied by increased levels of p-AMPKα (Thr172) and p-eNOS (Ser1177) both in vitro and in vivo, and the decreased level of VEGF in rat brains on day 1 whereas enhanced level of VEGF on day 3 and 7 after tMCAO. Mechanistically, AMPK knockdown or pharmacologi?cally inhibiting AMPK and its upstream kinases (CaMKKβ) inhibited the eNOS phosphorylation induced by IDHP in HUVEC. Furthermore, selective eNOS inhibitor (L-NIO), selective CaMKKβ inhibitor (STO) and AMPKa inhibitor (Com?pound C) blocked the capillary-like tube formation in the co-culture model induced by IDHP (10 nmol · L-1). CONCLU?SION Collectively, these findings showed that IDHP protected rats from cerebral ischemia-reperfusion injury by promot?ing angiogenesis via activating CaMKKβ/AMPK(Thr172)/eNOS(Ser1177) signaling, and suggest it to be a promising new drug candidate for the prevention and/or treatment of cerebral ischemia and other vascular occlusive diseases.
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Objective To investigate the temporal and spatial distribution characteristics of non-syndromic cleft lip with or without palate (NSCLP) who born in Gansu Province from 2010 to 2016, and to establish a predictive model for developing the strategies for the prevention and control of NSCLP. Methods Spatial epidemiological research method and geographical information systems (GIS) were used to conduct thematic mapping, spatial correlation analysis, high/low clustering analysis, hotspot analysis and Kirging interpolation prediction for NSCLP patients in Gansu Province from 2010 to 2016. Results From 2010 to 2016, the aggregation trend of NSCLP incidence in 89 counties in Gansu Province was different obviously, the southeast area was high and the northwest was low. Based on the data of the cumulative incidence of NSCLP from 2010 to 2016 in Gansu, the spatial distribution of NSCLP presented positive spatial correlation (Moran’I=0.274，Z=7.814，P<0.001) and the aggregation type was high-high cluster(Getis Gi=0.000 003，Z=4.381，P<0.001), with 22 hot spots. The Kirging interpolation prediction results showed that the main prevalence trend of NSCLP in Gansu extended from Longdong to Longxi and Longnan areas. Conclusions The geographical distribution of NSCLP had a positive spatial correlation and a high-high aggregation type in Gansu from 2010 to 2016. The high aggregation area is concentrated in Longdong, Longxi and Longnan of Gansu, which suggest that it is essential to focus on prevention and control in these areas.
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Objective To explore changes in the vascular-protecting function of HDL in patients with diabetic retinopathy (DR).Methods Together 23 patients with diabetic retinopathy (DR,DR group) and 21 normal subjects (normal control group)were recruited,and the 2 mL blood were collected from each of these subjects for isolating high-density lipoprotein (HDL).And then human umbilical vein endothelial cells (HUVECs) treated with harvested HDL and PBS (blank control group) were used for detection of cell proliferation and migration in the three groups.Results Compared with the blank control group,HDL in the normal control can significantly promote the proliferation and migration of HUVECs;but when compared with the normal control group,the ability of HDL to promote cell proliferation and migration significantly decreased in the DR group,in which the proliferative capacity of the cells decreased by approximately 14.8％ (P =0.027 1),and the migration ability decreased by about 49.3％ (P =0.009 6).Conclusion HDL from DR patients is dysfunctional in stimulating endothelial cell migration and proliferation,which means that vascular-protecting function of HDL in patients with DR is abnormal.