Activator protein-1 (AP-1) plays a decisive role in cell proliferation, apoptosis, and inflammation under hypoxia; thus, AP-1 subunits or dimers could be modulated for a desired phenomenon in a cell using a suitable compound of therapeutic potential. Herein, we used Tanshinone-IIA as an AP-1 (subunits) modulator, and the purpose of the study was to investigate the signaling mechanism exhibited by Tan-IIA in facilitating tolerance to hypoxia. A549 cells were pretreated with Tan-IIA and exposed to hypoxia for 6, 12, 24, and 48 h. Biochemical and molecular parameters were assessed in order to trace the signaling pathway. Tan-IIA attenuated hypoxia-induced oxidative stress by modulating the expression of AP-1 subunits (via. MAPK) and Nrf2 transcription factor, which in turn were responsible for maintaining the higher levels of antioxidant enzymes and genes (HO). Tan-IIA increased the cell survival. This could be attributed to an increased NO level via iNOS gene and activated JNK, ERK pathway that induced c-jun/c-fos, c-jun/fosB, junD/c-fos, and junD/fosB heterodimers. This in turn leads to the cell cycle progression by activating cyclins (D and B). This was further confirmed by the lower levels of p53 and their downstream genes (p16, p21, p27). In addition, Tan-IIA decreased pro-inflammatory cytokine levels by inhibiting the formation of junB/fra-1 heterodimer regulated by p38. Tan-IIA increased cell survival to hypoxia by maintaining the higher levels of cellular iNOS, HO-1, jun-D, c-jun, fos B via Nrf2-AP-1.

中文翻译：

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丹参酮IIA预处理可通过AP-1-Nrf2转录因子促进低氧条件下人肺上皮细胞的细胞存活。

活化蛋白1（AP-1）在缺氧条件下对细胞增殖，凋亡和炎症起决定性作用。因此，可以使用治疗潜力的合适化合物，针对细胞中的期望现象调节AP-1亚基或二聚体。在本文中，我们使用丹参酮-IIA作为AP-1（亚基）调节剂，并且该研究的目的是研究Tan-IIA在促进耐缺氧性方面表现出的信号传导机制。用Tan-IIA预处理A549细胞，使其缺氧6、12、24和48小时。评估生化和分子参数以追踪信号传导途径。Tan-IIA通过调节AP-1亚基（通过MAPK）和Nrf2转录因子的表达来减轻缺氧诱导的氧化应激，反过来又负责维持较高水平的抗氧化酶和基因（HO）。Tan-IIA增加了细胞存活率。这可能归因于通过iNOS基因和激活的JNK，ERK途径诱导的c-jun / c-fos，c-jun / fosB，junD / c-fos和junD / fosB异二聚体的NO水平升高。这进而通过激活细胞周期蛋白（D和B）导致细胞周期进程。p53及其下游基因（p16，p21，p27）的水平较低进一步证实了这一点。另外，Tan-IIA通过抑制p38调控的junB / fra-1异二聚体的形成来降低促炎细胞因子水平。Tan-IIA通过维持较高水平的细胞iNOS，HO-1，jun-D，c-jun，fos B的水平，通过Nrf2-AP-1来提高细胞存活率。这可能归因于通过iNOS基因和激活的JNK，ERK途径诱导的c-jun / c-fos，c-jun / fosB，junD / c-fos和junD / fosB异二聚体的NO水平升高。这进而通过激活细胞周期蛋白（D和B）导致细胞周期进程。p53及其下游基因（p16，p21，p27）的水平较低进一步证实了这一点。另外，Tan-IIA通过抑制p38调控的junB / fra-1异二聚体的形成来降低促炎细胞因子水平。Tan-IIA通过维持较高水平的细胞iNOS，HO-1，jun-D，c-jun，fos B的水平，通过Nrf2-AP-1来提高细胞存活率。这可能归因于通过iNOS基因和激活的JNK，ERK途径诱导的c-jun / c-fos，c-jun / fosB，junD / c-fos和junD / fosB异二聚体的NO水平升高。这进而通过激活细胞周期蛋白（D和B）导致细胞周期进程。p53及其下游基因（p16，p21，p27）的水平较低进一步证实了这一点。另外，Tan-IIA通过抑制p38调控的junB / fra-1异二聚体的形成来降低促炎细胞因子水平。Tan-IIA通过维持较高水平的细胞iNOS，HO-1，jun-D，c-jun，fos B的水平，通过Nrf2-AP-1来提高细胞存活率。p53及其下游基因（p16，p21，p27）的水平较低进一步证实了这一点。另外，Tan-IIA通过抑制p38调控的junB / fra-1异二聚体的形成来降低促炎细胞因子水平。Tan-IIA通过维持较高水平的细胞iNOS，HO-1，jun-D，c-jun，fos B的水平，通过Nrf2-AP-1来提高细胞存活率。p53及其下游基因（p16，p21，p27）的水平较低进一步证实了这一点。另外，Tan-IIA通过抑制p38调控的junB / fra-1异二聚体的形成来降低促炎细胞因子水平。Tan-IIA通过维持较高水平的细胞iNOS，HO-1，jun-D，c-jun，fos B的水平，通过Nrf2-AP-1来提高细胞存活率。