2. Academic Validation
  3. Bidirectional crosstalk of the cAMP/ROS-dependent signaling pathways in inflammatory macrophage: An activation of formononetin

Bidirectional crosstalk of the cAMP/ROS-dependent signaling pathways in inflammatory macrophage: An activation of formononetin

  • Toxicol Appl Pharmacol. 2023 Jun 1;116571. doi: 10.1016/j.taap.2023.116571.
Lan-Fang Zhang 1,  Xiao-Yan Zhang 2,  Ai-Cheng Wang 1,  Yi-Jia Feng 1,  Xiao-Ming Qi 3,  Yuan-Lin Zhang 4,  Qing-Fang Li 1,  Yuan-Biao Qiao 5,  Qing-Shan Li 6
Affiliations

Affiliations

  • 1 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, TaiYuan, Shanxi 030619, China.
  • 2 Fenyang College of Shanxi Medical University, Fenyang, Shanxi 032200, China.
  • 3 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, TaiYuan, Shanxi 030619, China. Electronic address: qxm871001@sxtcm.edu.cn.
  • 4 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, TaiYuan, Shanxi 030619, China. Electronic address: zhangyl@sxtcm.edu.cn.
  • 5 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, TaiYuan, Shanxi 030619, China. Electronic address: qiaoyb@sxtcm.edu.cn.
  • 6 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, TaiYuan, Shanxi 030619, China. Electronic address: sxlqs0501@sxtcm.edu.cn.
PMID: 37269934 DOI: 10.1016/j.taap.2023.116571
Abstract

Bacterial lipopolysaccharide (LPS) is a toxic stimulant to macrophage inflammation. Inflammation intersects cell metabolism and often directs host immunopathogenesis stress. We aim here at pharmacological discovering of formononetin (FMN) action, to which anti-inflammatory signaling spans across immune membrane receptors and second messenger metabolites. In ANA-1 macrophage stimulated by LPS, and simultaneous treatment with FMN, results show the Toll-like Receptor 4 (TLR4) and Estrogen Receptor (ER) signals, in concert with Reactive Oxygen Species (ROS) and cyclic adenosine monophosphate (cAMP), respectively. LPS stimulates inactivation of the ROS-dependent nuclear factor erythroid 2-related factor 2 (Nrf2) by upregulating TLR4, but it does not affect cAMP. However, FMN treatment not only activates Nrf2 signaling by TLR4 inhibition, but also it activates cAMP-dependent protein kinase activities by upregulating ER. The cAMP activity gives rise to phosphorylation (p-) of protein kinase A, liver kinase B1 and 5'-AMP activated protein kinase (AMPK). Moreover, bidirectional signal crosstalk is amplified between p-AMPK and ROS, as FMN combinational validation with AMPK Activator/inhibitor/target small-interfering RNA or ROS scavenger. The signal crosstalk is well positioned serving as the 'plug-in' knot for rather long signaling axis, and the immune-to-metabolic circuit via ER/TLR4 signal transduction. Collectively, convergence of the FMN-activated signals drives significant reduction of cyclooxygenase-2, interleukin-6 and NLR family pyrin domain-containing protein 3, in LPS-stimulated cell. Although anti-inflammatory signaling is specifically related to the immune-type macrophage, the p-AMPK antagonizing effect arises from FMN combination with ROS scavenger H-bond donors. Information of our work assists in predictive traits against macrophage inflammatory challenges, using phytoestrogen discoveries.

Keywords

AMPK/Nrf2 signaling; Bidirectional crosstalk; Formononetin; Inflammation; Second messenger.

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