1. Agmatine Protects Against the Progression of Sepsis Through the Imidazoline I2 Receptor-Ribosomal S6 Kinase 2-Nuclear Factor-κB Signaling Pathway.
- Author
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Li X, Zhu J, Tian L, Ma X, Fan X, Luo L, Yu J, Sun Y, Yang X, Tang W, Ma W, Yan J, Xu X, and Liang H
- Subjects
- Agmatine pharmacology, Animals, Cells, Cultured, Disease Progression, Humans, Imidazoline Receptors drug effects, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear physiology, Macrophages drug effects, Macrophages physiology, Mice, Mice, Inbred C57BL, NF-kappa B drug effects, Ribosomal Protein S6 Kinases, 90-kDa drug effects, Signal Transduction drug effects, Agmatine therapeutic use, Imidazoline Receptors physiology, NF-kappa B physiology, Ribosomal Protein S6 Kinases, 90-kDa physiology, Sepsis drug therapy, Signal Transduction physiology
- Abstract
Objectives: The knowledge that agmatine is found in the human body has existed for several years; however, its role in sepsis has not yet been studied. In the present study, we investigate the role of agmatine in the progression and treatment of sepsis., Design: Clinical/laboratory investigations., Setting: Medical centers/University-based research laboratory., Subjects: Elective ICU patients with severe sepsis and healthy volunteers; C57BL/6 mice weighing 18-22 g., Interventions: Serum agmatine level and its associations with inflammatory markers were assessed in patients with sepsis. Agmatine was administered intraperitoneally to mice before a lipopolysaccharide challenge. Human peripheral blood mononuclear cells and murine macrophages were pretreated with agmatine followed by lipopolysaccharide stimulation., Measurements and Main Results: Serum agmatine levels were significantly decreased in patients with sepsis and lipopolysaccharide-induced mice, and correlated with Acute Physiology and Chronic Health Evaluation II score, procalcitonin, tumor necrosis factor-α, and interleukin-6 levels. In a therapeutic experiment, exogenous agmatine attenuated the cytokine production of peripheral blood mononuclear cells from patients with sepsis and healthy controls. Agmatine also exerted a significant beneficial effect in the inflammatory response and organ damage and reduced the death rate in lipopolysaccharide-induced mice. Imidazoline I2 receptor agonist 2-benzofuran-2-yl blocked the pharmacological action of agmatine; whereas, other imidazoline receptor ligands did not. Furthermore, agmatine significantly impaired the inflammatory response by inactivating nuclear factor-κB, but not protein 38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and inducible nitric oxide synthase signaling in macrophages. Activation of imidazoline I2 receptor or knockdown of ribosomal S6 kinase 2 counteracted the effects of agmatine on phosphorylation and degradation of inhibitor of nuclear factor-κBα., Conclusions: Endogenous agmatine metabolism correlated with the progression of sepsis. Supplemental exogenous agmatine could ameliorate the lipopolysaccharide-induced systemic inflammatory responses and multiple organ injuries through the imidazoline I2 receptor-ribosomal S6 kinase 2-nuclear factor-κB pathway. Agmatine could be used as both a clinical biomarker and a promising pharmaconutrient in patients with severe sepsis.
- Published
- 2020
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