Ethyl Pyruvate Induces Heme Oxygenase-1 Through p38 Mitogen-Activated Protein Kinase Activation by Depletion of Glutathione in RAW 264.7 Cells and Improves Survival in Septic Animals

Abstract

Aims: We investigated the molecular mechanism by which ethyl pyruvate (EP) induces heme oxygenase-1 (HO-1) in RAW 264.7 cells and its effect on survival rate in cecal ligation and puncture (CLP)-induced wild-type (WT) and HO-1 knockout (HO-1 -/ -) septic mice. Results: EP induced HO-1 in a dose-and time-dependent manner, which was mediated through p38 mitogen-activated protein kinase (MAPK) and NF-E2-related factor 2 (Nrf2) signaling cascade in RAW 264.7 cells. EP significantly inhibited the lipopolysaccharide (LPS)-stimulated inducible nitric oxide synthase (iNOS) expression and high-mobility group box 1 (HMGB1) release in RAW 264.7 cells. The inhibitory effect of EP on LPS-stimulated iNOS expression and HMGB1 release was reversed by transfection with siHO-1RNA in RAW 264.7 cells, but EP failed to reduce them in HO-1 -/ -peritoneal macrophages treated with LPS. Moreover, treatment of cells with glutathione ethyl ester (GSH-Et), SB203580 (p38 MAPK inhibitor), siHO-1, or p38-siRNA transfection inhibited anti-inflammatory effect of EP. Interestingly, both HO-1 induction and phosphorylation of p38 by EP were reversed by GSH-Et, and antioxidant redox elementluciferase activity by EP was reversed by SB203580 in LPS-activated cells. EP increased survival and decreased serum HMGB1 in CLP-WT mice, whereas it did not increase survival or decrease circulating HMGB1 in HO-1 -/ -CLP-mice. Innovation and Conclusion: Our work provides new insights into the understanding the molecular mechanism by showing that EP induces HO-1 through a p38 MAPK-and NRF2-dependent pathway by decreasing GSH cellular levels. We conclude that EP inhibits proinflammatory response to LPS in macrophages and increases survival in CLP-induced septic mice by upregulation of HO-1 level, in which p38 MAPK and Nrf2 play an important role. Antioxid. Redox Signal. 17, 878-889.

Wuzhi Tablet (Schisandra SphenantheraExtract) Protects against Acetaminophen-Induced Hepatotoxicity by Inhibition of CYP-Mediated Bioactivation and Regulation of NRF2-ARE and p53/p21 Pathways

“…Additionally, previously published studies demonstrated that p38 MAPK triggered activation of NRF2 resulting in induction of the Ho-1 gene (Jang et al, 2012;Park et al, 2013), suggesting that WZ pretreatment seemed to activate NRF2-ARE pathway via p38 MAPK. ALR is identified to promote liver regeneration after partial hepatectomy and to augment hepatocyte proliferation (Polimeno et al, 2011).…”

Absence of pyruvate anti-oxidant effect on granulocytes stimulated toll-like receptors

“…2,25 The anti-inflammatory activities of pyruvate have been associated with i) the inhibition of cellular adhesion to the endothelium, 3 ii) the inhibition of NADPH-oxidase in kidney lesion, 2 iii) the association between the up-regulation of HO-1 and the inhibition of nitric oxide synthase expression associated with high-mobility group box 1 (HMGB-1) release in RAW 264.7 cells, 7 and iv) the down-regulation of oxidative stress and HMGB-1 expression during lung injury in C57BL/mice. 25 The results obtained in the present study demonstrate the effects of pyruvate on ROS generation during phagocytosis or toll-like receptor activation.…”

“…Glucose metabolism through the pentose phosphate pathway provides NADPH to maintain glutathione in the reduced state. 27,28 Jang et al 7 demonstrated that glutathione ethyl ester (GSH-Et), SB203580 (p38 MAPK inhibitor), siHO-1, or p38-siRNA transfection abolished the anti-inflammatory effect of ethyl pyruvate. Kamata et al, 29 showed…”

“…3e6 The antiinflammatory effect of ethyl pyruvate was inhibited through treatment with glutathione ethyl ester (GSH-Et) or SB203580 (p38 MAPK inhibitor). 7 However, it has also been demonstrated that hyperglycemic diabetes, as a consequence of direct osmolarity and/or alterations in signaling pathways, induces several modifications in cellular reactivity, tissue damage, inflammation, pyruvate dehydrogenase inhibition, increased ROS generation and the formation of advanced glycation end products (AGEs). AGEs interact with their respective receptors (RAGEs) to induce a cascade of metabolic responses leading to the production and secretion of proinflammatory cytokines.…”

Acteoside Improves Survival in Cecal Ligation an Puncture-Induced Septic Mice via Blocking of High Mobility Group Box 1 Release

“…Anti-HMGB1 antibodies and HMGB1 inhibitors significantly improve survival in septic animals, suggesting that HMGB1 is a possible therapeutic target in sepsis (Barnay-Verdier et al, 2011;Sama et al, 2004). Heme oxygenase-1 (HO-1), a stress-responsive protein induced by stimulants (inflammatory cytokines, heat shock, heavy metals, and oxidants) (Jang et al, 2012;Tsoyi et al, 2009) decreases circulating HMGB1 levels in animal models of sepsis and improves patient survival, demonstrating its therapeutic potential in inflammatory disorders . In addition, it is well known that the inducers of HO-1 expression inhibits the expression of the inflammatory genes (cyclooxygenase-2 and inducible nitric oxide synthase), and subsequently decreases PGE 2 and NO production (Oh et al, 2006;Suh et al, 2006).…”