Neuregulin-1β Protects the Rat Diaphragm during Sepsis against Oxidative Stress and Inflammation by Activating the PI3K/Akt Pathway

Abstract

Sepsis-induced diaphragm dysfunction (SIDD) which is mainly characterized by decrease in diaphragmatic contractility has been identified to cause great harms to patients. Therefore, there is an important and pressing need to find effective treatments for improving SIDD. In addition, acetylcholinesterase (AChE) activity is a vital property of the diaphragm, so we evaluated both diaphragmatic contractility and AChE activity. Though neuregulin-1β (NRG-1β) is known to exert organ-protective effects in some inflammatory diseases, little is known about the potential of NRG-1β therapy in the diaphragm during sepsis. Our study was aimed at exploring the effects of NRG-1β application on diaphragmatic contractility and AChE activity during sepsis. Proinflammatory cytokines, muscle injury biomarkers in serum, contractile force, AChE activity, proinflammatory cytokines, oxidative parameters, histological condition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) signaling proteins in the diaphragm were measured and compared between nonseptic and septic groups with or without NRG-1β treatment. In vitro, the effects of NRG-1β on reactive oxygen species (ROS) production in the lipopolysaccharide- (LPS-) stimulated L6 rat muscle skeletal cells with or without the Akt inhibitor MK-2206 were detected. NRG-1β inhibited proinflammatory cytokine release and muscle injury biomarkers soaring in serum and improved the sepsis-induced diaphragm dysfunction and AChE activity decrease significantly during sepsis. Meanwhile, the inflammatory response, oxidative stress, pathological impairment, and cell apoptosis in the diaphragm were mitigated by NRG-1β. And NRG-1β activated the PI3K/Akt signaling in the diaphragm of septic rats. Elevated ROS production in the LPS-stimulated L6 rat skeletal muscle cells was reduced after treatment with NRG-1β, while MK-2206 blocked these effects of NRG-1β. In conclusion, our findings underlined that NRG-1β could reduce circulating levels of proinflammatory cytokines in rats with sepsis, adjust diaphragmatic proinflammatory cytokine level, mitigate diaphragmatic oxidative injury, and lessen diaphragm cell apoptosis, thereby improving diaphragmatic function, and play a role in diaphragmatic protection by activating PI3K/Akt signaling.

Utilising Network Pharmacology to Explore Underlying Mechanism of Astragalus membranaceus in Improving Sepsis-Induced Inflammatory Response by Regulating the Balance of IκBα and NF-κB in Rats

“…The PI3K (phosphatidylinositol-3-kinase) pathway is a crucial signaling pathway in the body, and it maintains tissue homeostasis by regulating protein phosphorylation, methylation, and ubiquitination [ 44 ]. In sepsis, activation of the PI3K pathway can reduce damage to the diaphragm [ 46 ], myocardium [ 47 ], lung [ 48 ], and other tissues and organs by inhibiting the degradation of I κ B α . Mitogen-activated protein kinase (MAPK) is an essential member of the intracellular signaling protein network that mediates extracellular stimuli to intracellular responses.…”

CYP4A11/20-HETE induces oxidative stress and inhibits trophoblast proliferation via the PI3K/AKT signaling pathway during preeclampsia

“…found that CYP4A suppression by HET0016 (a selective CYP450 inhibitor) or siRNAs alleviates myocardial oxidative injury and apoptosis by activating the AKT signaling pathway 42 . Liu et al also discovered that the activated PI3K/AKT signaling pathway can reduce the level of cellular oxidative stress injury and inhibit the generation and secretion of various proin ammatory cytokines, thereby ameliorating the symptoms of chronic kidney disease 43,44 . Consistent with the aforementioned studies, our results con rmed that CYP4A11/20-HETE caused its deleterious effects on excessively increasing oxidative stress and inhibiting proliferation both in vitro and in a pregnant mouse model by decreasing the levels of phosphorylated PI3K and AKT.…”

Neuregulin-1, a potential therapeutic target for cardiac repair

“…NRG1β is expressed in the cardiac microvascular endothelium, and promotes the growth and survival of cardiac myocytes in culture through the activation of ErbB2 and ErbB4 receptor tyrosine kinases ( Fukazawa et al, 2003 ). On the one hand, NRG1 β could reduce circulating levels of proinflammatory cytokines in rats with sepsis, adjust diaphragmatic proinflammatory cytokine level, mitigate diaphragmatic oxidative injury, and lessen diaphragm cell apoptosis, improving the function of the diaphragm and playing a role in the protection of the diaphragm by activating the signalling of PI3K/Akt ( Liu et al, 2020 ). On the other hand, expression of NRG1 and recombinant NRG1β protects myocytes from anthracycline and β-adrenergic receptor-induced cell injury and death ( Zhao et al, 1998 ; Sawyer et al, 2002 ; Fukazawa et al, 2003 ; Kuramochi et al, 2004b ).…”