Neferine Ameliorates Sepsis-Induced Myocardial Dysfunction Through Anti-Apoptotic and Antioxidative Effects by Regulating the PI3K/AKT/mTOR Signaling Pathway

Abstract

Septic cardiomyopathy is a common complication of severe sepsis, which is one of the leading causes of death in intensive care units. Therefore, finding an effective therapy target is urgent. Neferine is an alkaloid extracted from the green embryos of mature seeds of Nelumbo nucifera Gaertn., which has been reported to exhibit various biological activities and pharmacological properties. This study aims to explore the protective effects of neferine against lipopolysaccharide (LPS)-induced myocardial dysfunction and its mechanisms. The LPS-induced cardiac dysfunction mouse model was employed to investigate the protective effects of neferine. In this study, we demonstrated that neferine remarkably improved cardiac function and survival rate and ameliorated morphological damage to heart tissue in LPS-induced mice. Neferine also improved cell viability and mitochondrial function and reduced cell apoptosis and the production of reactive oxygen species in LPS-treated H9c2 cells. In addition, neferine significantly upregulated Bcl-2 expression and suppressed cleaved caspase 3 activity in LPS-induced mouse heart tissue and H9c2 cells. Furthermore, neferine also upregulated the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling pathway in vivo and in vitro. Conversely, LY294002 (a PI3K inhibitor) reversed the protective effect of neferine in LPS-induced H9c2 cells. Our findings thus demonstrate that neferine ameliorates LPS-induced cardiac dysfunction by activating the PI3K/AKT/mTOR signaling pathway and presents a promising therapeutic agent for the treatment of LPS-induced cardiac dysfunction.

Oxidant/Antioxidant Status Is Impaired in Sepsis and Is Related to Anti-Apoptotic, Inflammatory, and Innate Immunity Alterations

“…This is in agreement with the findings of a recent study, showing that seemingly antagonistic pathways of both pro- and anti-apoptotic genes are simultaneously upregulated early in the course of sepsis [ 29 ]. New therapeutic agents, increasing ATP production and the activities of mitochondrial complexes I and III in LPS-stimulated cardiomyocytes, have recently been found to reduce the LPS-induced levels of reactive oxygen species by suppressing cleaved caspase 3 activity [ 71 ] or by increasing the activities of antioxidant enzymes, glutathione peroxidase, superoxide dismutase, and GSH [ 72 ]. Similar scientific research, focused on the apoptotic/anti-apoptotic and oxidant/antioxidant pathways in sepsis, might reveal promising therapeutic targets and encourage novel interventions in the future.…”

The anticardiac fibrosis of total alkaloids of Plumula nelumbinis by regulating circulating lipidomic profile: In vivo study

“…The cardioprotective effect of neferine may be related to the regulation of PI3K/Akt/mTOR signaling pathway. In addition, neferine restores lipopolysaccharide‐induced myocardial dysfunction through antiapoptotic and antioxidant effects (Qi et al, 2021). Isoliensinine significantly suppressed bleomycin‐induced pulmonary fibrosis via inhibiting TNF‐α and TGF‐β expression (Xiao et al, 2005).…”

miR-340-5p Alleviates Oxidative Stress Injury by Targeting MyD88 in Sepsis-Induced Cardiomyopathy

“…As mentioned in previous studies [ 24 , 25 ], echocardiography was performed using the Vevo 3100 Imaging System (FUJIFILM VisualSonics, Toronto, Ontario, Canada) with an MX400 line ultrasound transducer (30 MHz). Firstly, the mice were fixed after 1.5% isopentane anesthesia.…”

“…Cellular ROS was evaluated with DCFH-DA (D6883; Sigma-Aldrich, MS, USA), a fluorescent probe [ 25 , 26 ]. DCFH-DA can enter living cells and transform them into nonfluorescent DCFH, and intracellular reactive oxygen species can convert DCFH into green fluorescent DCF.…”