Combining metformin and esomeprazole is additive in reducing sFlt-1 secretion and decreasing endothelial dysfunction - implications for treating preeclampsia.
Combining metformin and esomeprazole is additive in reducing sFlt-1 secretion and decreasing endothelial dysfunction - implications for treating preeclampsia.
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DOI：
10.1371/journal.pone.0188845
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Hannan NJ
中科院分区：
文献类型：
--
作者：
Kaitu'u-Lino TJ;Brownfoot FC;Beard S;Cannon P;Hastie R;Nguyen TV;Binder NK;Tong S;Hannan NJ
预防或治疗先兆子痫的新疗法的发现将是一个重大进展。抗血管生成因子可溶性fms样酪氨酸激酶-1（sFlt-1）和可溶性内皮糖蛋白（sENG）从胎盘过量分泌，引起高血压、内皮功能障碍和多器官损伤。我们最近发现二甲双胍和埃索美拉唑作为潜在的治疗先兆子痫。两者均减少sFlt-1和可溶性内皮糖蛋白的胎盘和内皮分泌，并减少内皮功能障碍。我们开始评估二甲双胍和埃索美拉唑联合是否会增加sFlt-1和可溶性内皮糖蛋白分泌并减少内皮功能障碍（与单独药物相比）。将二甲双胍和埃索美拉唑加入到原代胎盘细胞和组织中，并在体外评估内皮细胞及其对sFlt-1和可溶性内皮糖蛋白分泌的影响。肿瘤坏死因子-α（TNF-α）加入到内皮细胞中，以诱导体外功能障碍。我们检测了二甲双胍+埃索美拉唑挽救TNF-α诱导的血管细胞粘附分子-1（VCAM-1）和内皮素-1（ET-1）表达、白细胞粘附（内皮功能障碍的标志物）的能力。二甲双胍和埃索美拉唑联合使用可增加sFlt-1的分泌，并降低原代细胞滋养层、胎盘外植体和内皮细胞中sFlt-1 e15 a mRNA亚型的表达。相比之下，二甲双胍和埃索美拉唑联合给药时未观察到sENG的叠加性降低。低剂量二甲双胍+埃索美拉唑联合用药可额外降低TNF-α诱导的VCAM-1 mRNA表达，但不降低VCAM-1蛋白表达。二甲双胍和埃索美拉唑联合用药对TNF-α诱导的PBMC与内皮细胞的粘附无叠加性降低。然而，二甲双胍和埃索美拉唑联合使用可额外降低ET-1 mRNA表达。总之，二甲双胍和埃索美拉唑联合使用可额外减少sFlt-1的分泌和内皮功能障碍的标志物。二甲双胍和埃索美拉唑的组合可以提供一个更有效的治疗或预防先兆子痫相比，作为单一的药物。
The discovery of new treatments that prevent or treat preeclampsia would be a major advance. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. We recently identified metformin and esomeprazole as potential treatments for preeclampsia. Both reduce placental and endothelial secretion of sFlt-1 and soluble endoglin, and reduce endothelial dysfunction. We set out to assess whether combining metformin and esomeprazole would additively reduce sFlt-1 and soluble endoglin secretion and reduce endothelial dysfunction (verses drug alone). Metformin and esomeprazole were added to primary placental cells and tissues, and endothelial cells and their effects on sFlt-1 and soluble endoglin secretion were assessed in vitro. Tumor necrosis factor-α (TNF-α) was added to endothelial cells to induce dysfunction in vitro. We examined the ability of metformin + esomeprazole to rescue TNF-α induced vascular cell adhesion molecule-1 (VCAM-1) and Endothelin-1 (ET-1) expression, leukocyte adhesion (markers of endothelial dysfunction). Combining metformin and esomeprazole was additive at reducing sFlt-1 secretion and expression of sFlt-1 e15a mRNA isoform in primary cytotrophoblast, placental explants and endothelial cells. In contrast, no additive reduction in sENG was observed with combined metformin and esomeprazole. The low-dose combination of metformin + esomeprazole additively reduced TNF-α-induced VCAM-1 mRNA, but not VCAM-1 protein expression. There was no additive reduction when combining metformin and esomeprazole on TNF-α induced PBMC adhesion to endothelial cells. However, combining metformin and esomeprazole additively reduced ET-1 mRNA expression. In conclusion combining metformin and esomeprazole additively reduced secretion of sFlt-1, and markers of endothelial dysfunction. The combination of metformin and esomeprazole may provide a more effective treatment or prevention for preeclampsia compared to either as single agents.
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影响因子：
9.8
作者：
Labarrere CA;DiCarlo HL;Bammerlin E;Hardin JW;Kim YM;Chaemsaithong P;Haas DM;Kassab GS;Romero R
通讯作者：
Romero R
影响因子：
2.6
作者：
Gong L;Goswami S;Giacomini KM;Altman RB;Klein TE
通讯作者：
Klein TE
DOI：
10.1038/nrneph.2014.102
发表时间：
2014-08
期刊：
Nature reviews. Nephrology
影响因子：
--
作者：
Chaiworapongsa T;Chaemsaithong P;Yeo L;Romero R
通讯作者：
Romero R
影响因子：
9.8
作者：
Dhulkotia, Jaya Saxena;Ola, Bolarinde;Farrell, Tom
通讯作者：
Farrell, Tom
DOI：
10.1016/j.preghy.2014.09.003
发表时间：
2014-10-01
影响因子：
2.2
作者：
Kaitu'u-Lino, Tu'uhevaha J.;Tong, Stephen;Hannan, Natalie J.
通讯作者：
Hannan, Natalie J.