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人源性激肽释放酶结合蛋白(Kallistatin,Kal)是一种负性急性期内源性蛋白,与多种内皮相关性生理和病理过程密切相关,如血管生成及损伤修复、炎症、心功能不全、肾损伤、糖尿病等。炎症和氧化应激可引起内皮功能障碍,而Kal可抑制肿瘤坏死因子α引起的内皮细胞活化,通过KLF4-eNOS、PI3K-AKT-eNOS和AKT-FOXO1等信号通路,增加内皮细胞NO合酶的表达和NO生成,抑制内皮细胞损伤和凋亡。动物实验显示,Kal表达增加可减弱氧化应激诱导的细胞凋亡和器官损伤。基于内皮细胞所处的状态或来源,如健康或损伤情况,成熟内皮细胞或内皮祖细胞,Kal的作用可能有所区别。内皮细胞是参与肿瘤生长与转移的关键因素已达成共识,但肿瘤新生血管形成的机制尚待确认。Kal可诱导肿瘤内皮细胞凋亡,抑制肿瘤新生血管生成和肿瘤生长的能力已被证实。临床前研究结果表明,Kal具有多种药理作用,对氧化应激相关性疾病,特别是肿瘤治疗具有应用前景,但其药理作用的分子机制仍需深入探讨。
Human kallikrein (Kallistatin, Kal) is a negative acute endogenous protein that is closely related to a variety of endothelial-related physiological and pathological processes such as angiogenesis and injury repair, inflammation, cardiac function Incomplete, kidney damage, diabetes and so on. Inflammation and oxidative stress can cause endothelial dysfunction. However, Kal inhibits the activation of endothelial cells induced by tumor necrosis factor-α. The increase of endothelial nitric oxide synthase (NO synthase) through the signaling pathways of KLF4-eNOS, PI3K-AKT-eNOS and AKT-FOXO1 Expression and NO production, inhibiting endothelial cell injury and apoptosis. Animal experiments show that increased Kal expression attenuates oxidative stress-induced apoptosis and organ damage. The effect of Kal may be differentiated based on the state or source of endothelial cells, such as health or injury, mature endothelial cells, or endothelial progenitor cells. Endothelial cells are the key factors involved in tumor growth and metastasis. However, the mechanism of neovascularization has yet to be confirmed. The ability of Kal to induce tumor endothelial cell apoptosis and inhibit tumor angiogenesis and tumor growth has been demonstrated. Preclinical studies have shown that Kal has a variety of pharmacological effects, and has potential applications in the treatment of oxidative stress-related diseases, especially oncological treatment. However, the molecular mechanism of pharmacological action remains to be further explored.