Abstract
We aim to investigate the effect and mechanism of dehydrocorydaline (Deh), an alkaloidal component isolated from Rhizoma corydalis, in the treatment of sepsis-mediated myocardial injury. Lipopolysaccharide (LPS) was taken to construct an in-vitro sepsis-myocardial injury models H9C2 cardiomyocytes. The in-vivo model of sepsis in C57BL/6 mice was induced by intraperitoneal injection of Escherichia coli (E. coli). The in-vitro and in-vivo models were treated with Deh in different concentrations, respectively. Hematoxylin-eosin (HE) staining, Masson staining, and immunohistochemistry (IHC) staining were taken to evaluate the histopathological changes of the heart. ELISA was applied to evaluate the levels of inflammatory factors, including IL-6, IL-1β, TNFα, IFNγ, and oxidized factors SOD, GSH-PX in the plasma or culture medium. Western blot was used to measure the expressions of Bax, Bcl2, Caspase3, iNOS, Nrf2, HO-1, TRAF6, NF-κB in heart tissues and cells. The viability of H9C2 cardiomyocytes was detected by the CCK8 method and BrdU assay. The ROS level in the H9C2 cardiomyocytes were determined using immunofluorescence. As a result, Deh treatment improved the survival of sepsis mice, reduced TUNEL-labeled apoptosis of cardiomyocytes. In vitro, Deh enhanced the viability of LPS-induced H9C2 cardiomyocytes and inhibited cell apoptosis. Additionally, Deh showed significant anti-inflammatory and anti-oxidative stress functions via decreasing IL-1β, IL-6, TNFα, and IFNγ levels, mitigating ROS level, up-regulating Nrf2/HO-1, SOD, and GSH-PX expressions dose-dependently. Mechanistically, Deh inhibited TRAF6 expression and the phosphorylation of NF-κB p65. The intervention with a specific inhibitor of TRAF6 (C25-140) or NF-κB inhibitor (BAY 11-7082) markedly repressed the protective effects mediated by Deh. In conclusion, Deh restrains sepsis-induced cardiomyocyte injury by inhibiting the TRAF6/NF-κB pathway.
Highlights
Sepsis is a clinical syndrome that mainly manifests as a systemic inflammatory response caused by infection, and has a high mortality rate in countries around the world (Innocenti et al, 2020)
The present study revealed that Deh enhanced the viability of cardiomyocytes in an Escherichia coli (E. coli)- or LPS-induced sepsis model, inhibited cell apoptosis, reduced IL-1β and TNFα levels, and upregulated the expressions of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in the plasma and culture medium
The present study explored the therapeutic effects of Deh in an LPS-induced sepsis model
Summary
Sepsis is a clinical syndrome that mainly manifests as a systemic inflammatory response caused by infection, and has a high mortality rate in countries around the world (Innocenti et al, 2020). The crucial factors of myocardial damage are changes in hemodynamics, inflammation, mitochondrial damage and oxidative stress induced by sepsis (Lewis et al, 2012). On the other hand, unbalanced oxidative stress following sepsis contributes to the damage of mitochondrion functions, which leads to the insufficient production of mitochondrial ATP, resulting in fatal energy failure of the cardiomyocytes, and leads to myocardial injury (Rocha et al, 2012). Studying the mechanism of sepsis-induced inflammation and oxidative stress helps the treatment of sepsis-induced myocardial injury. Clemastine Fumarate contributes to the prevention of myocardial ischemiareperfusion injury by regulating the TLR4/PI3K/Akt signaling pathway (Yuan et al, 2020). Ginsenoside Rg1 alleviates myocardial cell apoptosis and inflammation by inhibiting the TLR4/NF-κB/NLR family pyrin domain containing three signaling pathway (Luo et al, 2020)
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