Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, Republic of China.
Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, Republic of China.
Biochem Pharmacol. 2018 Sep;155:207-212. doi: 10.1016/j.bcp.2018.07.002. Epub 2018 Jul 3.
Despite great advances in contemporary medicine, brain death still remains enigmatic and its cellular and molecular mechanisms unsettled. This review summarizes recent findings that substantiate the notion that PTEN/FLJ10540/PI3K/Akt cascade, the classical tumorigenic signaling pathway, is actively engaged in experimental brain stem death. These results were based on a clinically relevant animal model that employs the pesticide mevinphos as the experimental insult in Sprague-Dawley rats to mimic brain stem death in patients died of organophosphate poisoning. The neural substrate investigated is the rostral ventrolateral medulla (RVLM), a brain stem site classically known to maintain arterial pressure (AP) and is established to be the origin of a "life-and-death" signal detected from AP, which reflects brain stem cardiovascular dysregulation that precedes death. Activation of PI3K/Akt signaling pathway in the RVLM upregulates the nuclear factor-κB/nitric oxide synthase II/peroxynitrite cascade, resulting in impairment of brain stem cardiovascular regulation that leads to the loss of the "life-and-death" signal in experimental brain stem death. This process is reinforced by FLJ10540, a PI3K-association protein; and is counteracted by PTEN, a negative regulator of PI3K/Akt signaling. The concept that a classical signaling pathway in tumorigenesis is also an active player in cardiovascular dysregulation in brain stem death provides new ramifications for translational medicine. It promulgates the concept that rather than focusing on a particular disease condition, a new vista for future therapeutic strategy against both fatal eventualities should target at this common cellular cascade.
尽管当代医学取得了巨大进步，但脑死亡仍然是一个谜，其细胞和分子机制尚未确定。这篇综述总结了最近的发现，这些发现证实了 PTEN/FLJ10540/PI3K/Akt 级联反应，即经典的致癌信号通路，积极参与实验性脑干死亡。这些结果基于一个临床相关的动物模型，该模型使用农药速灭磷作为实验性刺激物，在 Sprague-Dawley 大鼠中模拟有机磷中毒患者的脑干死亡。研究的神经基质是延髓腹外侧头端（RVLM），这是一个经典的维持动脉压（AP）的脑干部位，并且被确定为从 AP 检测到的“生死”信号的起源，该信号反映了脑干心血管调节失常，这是死亡的前兆。RVLM 中的 PI3K/Akt 信号通路的激活上调了核因子-κB/一氧化氮合酶 II/过氧亚硝酸盐级联反应，导致脑干心血管调节受损，导致实验性脑干死亡中的“生死”信号丧失。FLJ10540 是一种 PI3K 相关蛋白，增强了这一过程；PTEN 是 PI3K/Akt 信号的负调节剂，抵消了这一过程。在肿瘤发生中的经典信号通路也是脑干死亡中心血管失调的积极参与者的概念，为转化医学提供了新的启示。它宣扬了这样一种概念，即未来的治疗策略不应针对特定的疾病状况，而是应该针对这一共同的细胞级联反应，以预防这两种致命结局。
