Neferine Exerts Antioxidant and Anti-Inflammatory Effects on Carbon Tetrachloride-Induced Liver Fibrosis by Inhibiting the MAPK and NF-κB/IκBα Pathways.

Yuanyuan Wang,Rong Wang,Yongfang Yuan,Shengnan Li,Shaozhan Wang,Armando Zarrelli

doi:10.1155/2021/4136019

Yuanyuan Wang, Rong Wang + Show 4 more

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https://doi.org/10.1155/2021/4136019

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Abstract

Reversible liver fibrosis is the consequence of diverse liver injuries. Oxidative stress combined with inflammation is the primary cause of carbon tetrachloride- (CCl4-) induced liver fibrosis. Neferine is a bibenzyl isoquinoline alkaloid, which has strong anti-inflammatory and antioxidant properties. The present study attempted to find its antiliver fibrosis effect and explore the potential mechanism to relieve oxidative stress and inflammation in rats with CCl4-induced liver fibrosis. Herein, we found that neferine noticeably mitigated fibrosis and improved liver function. Furthermore, neferine increased the activity of antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and catalase (CAT), but decreased the level of malondialdehyde (MDA). Neferine also decreased the levels of alpha-smooth muscle actin (α-SMA), transforming growth factor β1 (TGF-β1), and inflammatory factors. These results may demonstrate that neferine could effectively inhibit oxidative stress and inflammation in liver fibrosis. To account for the potential mechanism by which neferine relieves oxidative stress and inflammation in liver fibrosis rats, immunohistochemistry analyses and western blotting were performed. The results showed that neferine inhibited the mitogen-activated protein kinase (MAPK) pathway, as evidenced by the reduced phosphorylation of p38 MAPK, ERK 1/2, and JNK. And it inhibited the nuclear factor- (NF-) κB/IκBα pathway, as evidenced by preventing the translocation of NF-κB into nuclei. Our findings indicated a protective role for neferine, acting as an antioxidant and anti-inflammatory agent in CCl4-induced liver fibrosis.

Highlights

Liver fibrosis characterized by hepatic stellate cell (HSC) activation and extracellular matrix (ECM) deposition involves inflammatory factors, growth factors, chemokines, and oxidative stress-related molecules at the molecular regulation level [1,2,3]
It has recently become clear that oxidative stress, inflammation, and cytokines are the major stimulus factors in the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. e three main pathways, p38 MAPK, Jun N-terminal kinase (JNK), and extracellular signal-regulated protein kinase 1/2 (ERK 1/2), are the most studied and, together with the nuclear factor-κB (NF-κB) pathway, are crucial for oxidative stress and inflammation responses as they are involved in the regulation of inflammatory cytokines and reactive oxygen species (ROS) [9]
232 118 112 256 index of rats were monitored. e results of statistical analysis shown in Figure 1(a) demonstrated that the body weight significantly decreased, while the liver weight and liver index significantly increased in model group as compared to those in normal group

Summary

Introduction

Liver fibrosis characterized by hepatic stellate cell (HSC) activation and extracellular matrix (ECM) deposition involves inflammatory factors, growth factors, chemokines, and oxidative stress-related molecules at the molecular regulation level [1,2,3]. MAPK), c-Jun N-terminal kinase (JNK), and extracellular signal-regulated protein kinase 1/2 (ERK 1/2), is an important signaling pathway associated with cell growth and differentiation and contributes to the regulation of many human diseases, including cancer, Alzheimer’s disease (AD), and liver fibrosis [7, 8]. E three main pathways, p38 MAPK, JNK, and ERK 1/2, are the most studied and, together with the nuclear factor-κB (NF-κB) pathway, are crucial for oxidative stress and inflammation responses as they are involved in the regulation of inflammatory cytokines and reactive oxygen species (ROS) [9]. NF-κB plays an important role in the Evidence-Based Complementary and Alternative Medicine inflammatory process; the members of the NF-κB family include RelA (p65), RelB, c-Rel, p50, and p52 in which the activation of the p65 subunit of NF-κB is mostly involved in the regulation of inflammatory response through the NF-κB/ IκBα signaling pathway [10]. After IκB kinase (IKK) activation, which induces the phosphorylation and ubiquitin-dependent degradation of IκB, NF-κB is activated and translocated in the nucleus where it undergoes combination with target gene sequence, starting the subsequent gene transcription [11]

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