Hepatic Reactive Oxygen Species Levels Research Articles

Sesamin Protects against APAP-Induced Acute Liver Injury by Inhibiting Oxidative Stress and Inflammatory Response via Deactivation of HMGB1/TLR4/NFκB Signal in Mice.

Acetaminophen (APAP) overdose would lead to liver toxicity and even acute liver failure in severe cases by triggering an inflammatory response and oxidative stress. Sesamin has been reported to possess anti-inflammatory and antioxidant actions in several animal disease models. In the present study, the effects and mechanisms of sesamin on APAP-induced acute liver injury (ALI) were explored. The results showed that pretreatment with sesamin significantly alleviated APAP-induced ALI, as indicated by decreased serum aminotransferase activities, hepatic pathological damages, and hepatic cellular apoptosis. But sesamin has no significant effects on the expression of cytochrome P450 2E1 (CYP2E1), APAP-cysteine adducts (APAP-CYS) production, and glutathione content in the liver of APAP-administered mice. Moreover, APAP-induced liver oxidative stress and inflammatory response also were remarkedly attenuated by sesamin, including reducing hepatic reactive oxygen species levels, promoting antioxidant generation, and inhibiting the expression of TNF-α and IL-1β, as well as decreasing inflammatory cell recruitment. Notably, sesamin inhibited serum high-mobility group box 1 (HMGB1) releases and blocked hepatic activation of Toll-like receptor 4 (TLR4)-interleukin 1 receptor-associated kinase 3-nuclear factor kappa B (NF-κB) signaling pathway in APAP-administered mice. These findings indicated that sesamin could mitigate APAP-induced ALI through suppression of oxidative stress and inflammatory response, which might be mediated by the deactivation of HMGB1/TLR4/NF-κB signaling in mice.

Fish exposed to eprinomectin show hepatic oxidative stress and impairment in enzymes of the phosphotransfer network

The objective of this study was to evaluate whether the antiparasitic drug eprinomectin causes hepatic oxidative stress and impairment of hepatic energetic metabolism in the silver catfish (Rhamdia quelen), in conditions of experimental aquatic contamination. The fish were exposed for 24 and 48 h at various concentrations of eprinomectin (0.0, 1.124, 1.809 and 3.976 μg L−1), followed by 48 h of recovery in eprinomectin-free water. We measured levels of reactive oxygen species (ROS) and lipoperoxidation (LOOH) in hepatic tissue, as well as levels of antioxidant capacity against peroxyl radicals (ACAP), and activities of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione S-transferase (GST), in addition to the activities of enzymes involved in energy metabolism, adenylate kinase (AK) and pyruvate kinase (PK). After 24 h, hepatic ROS levels increased in fish exposed to all concentrations of eprinomectin, and the same occurred with LOOH at the two highest concentrations of eprinomectin. ACAP levels decreased after 24 h of exposure to the highest concentration, also occurring with SOD activity at the two highest concentrations. Glutathione enzymes activities (GPx and GST) decreased after 48 h of exposure to the highest concentration. Fish transfer to eprinomectin-free water, with re-analysis after 48 h post-recovery, was unable to reverse ROS and LOOH increases, likewise with the reductions of ACAP, SOD, GPx and GST, especially at the two highest concentrations. AK and PK activities decreased after 48 h of exposure, AK decreased at the two highest concentrations and PK decreased at the highest concentration. AK activity remained lower after 48 h in eprinomectin-free water. PK activity returned to normal after 48 h in eprinomectin-free water. In summary, silver catfish exposed to aquatic contamination with the antiparasitic drug eprinomectin showed hepatic oxidative stress, possibly related to impairment of the phosphotransfer network and energy metabolism.

Frontline Science: Concanavalin A-induced acute hepatitis is attenuated in vitamin D receptor knockout mice with decreased immune cell function.

The vitamin D receptor (VDR) is a nuclear receptor for the active form of vitamin D, 1α,25-dihydroxyvitamin D3 , and regulates various physiologic processes, such as bone and calcium metabolism, cellular proliferation and differentiation, and immunity. VDR is highly expressed in the intestine, kidney, bone, and macrophages, but is expressed at a low level in the liver. The liver is a major metabolic organ and also acts as an immune gateway for dietary nutrients and xenobiotics. In this study, we investigated the function of VDR in hepatic immune cells, such as Kupffer cells/macrophages, utilizing VDR knockout (KO) mice. We showed that VDR is functionally expressed in hepatic mononuclear cells, specifically resident Kupffer cells. We examined the role of VDR in acute hepatitis induced by concanavalin A (Con-A) and found that Con-A-induced hepatitis is attenuated in VDR-KO mice compared to wild-type (WT) mice. Con-A-induced hepatitis is known to be mediated by NKT cell activation, cytokine production, and reactive oxygen species (ROS) production in Kupffer cells/macrophages. However, the proportions of Kupffer cells/macrophages and the NKT cell activation were similar in the liver of WT and VDR-KO mice and inflammatory cytokine gene expression was increased in VDR-KO mice. On the other hand, plasma and hepatic ROS levels were decreased in the liver of VDR-KO mice compared to WT mice. The phagocytic activity of resident Kupffer cells and hepatic neutrophils were also decreased in VDR-KO mice. Therefore, VDR is necessary for Con-A-induced acute hepatitis and plays an important role in hepatic immune cell functions.

Sicyos angulatus ameliorates acute liver injury by inhibiting oxidative stress via upregulation of anti-oxidant enzymes

ABSTRACTObjective: We aimed to investigate the effect of Sicyos angulatus (SA) ethanolic extracts as antioxidants and potential treatments for liver disease.Methods: To establish a mouse model of liver injury, C57BL/6 male mice were injected via the caudal vein with a single dose of concanavalin A (Con A, 15 mg kg−1). SA extracts were administered once by oral gavage 30 min before Con A injection.Results: In vitro studies showed that SA decreased tert-butyl hydroperoxide (t-BHP)-induced reactive oxygen species (ROS) production. SA administration reduced plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, as well as hepatic ROS levels, in a dose-dependent manner. Moreover, SA increased the activities of the hepatic antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase in a dose-dependent manner. Furthermore, SA treatment reduced pro-apoptotic protein levels. Con A-mediated cytosolic release of Smac/DIABLO and apoptosis-inducing factor (AIF), which are markers of necrosis, were dramatically decreased in HepG2 cells treated with SA.Conclusion: SA ameliorated liver injury and might be a good strategy for the treatment of liver injury.

Interleukin‐37 reduces liver inflammatory injury via effects on hepatocytes and non‐parenchymal cells

The purpose of the present study was to determine the effects of interleukin-37 (IL-37) on liver cells and on liver inflammation induced by hepatic ischemia/reperfusion (I/R). Mice were subjected to I/R. Some mice received recombinant IL-37 (IL-37) at the time of reperfusion. Serum levels of alanine aminotransferase, and liver myeloperoxidase content were assessed. Serum and liver tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-2 (MIP-2) and keratinocyte chemokine (KC) were also assessed. Hepatic reactive oxygen species (ROS) levels were assessed. For in vitro experiments, isolated hepatocytes and Kupffer cells were treated with IL-37 and inflammatory stimulants. Cytokine and chemokine production by these cells were assessed. Primary hepatocytes underwent induced cell injury and were treated with IL-37 concurrently. Hepatocyte cytotoxicity and Bcl-2 expression were determined. Isolated neutrophils were treated with TNF-α and IL-37 and neutrophil activation and respiratory burst were assessed. IL-37 reduced hepatocyte injury and neutrophil accumulation in the liver after I/R. These effects were accompanied by reduced serum levels of TNF-α and MIP-2 and hepatic ROS levels. IL-37 significantly reduced MIP-2 and KC productions from lipopolysaccharide-stimulated hepatocytes and Kupffer cells. IL-37 significantly reduced cell death and increased Bcl-2 expression in hepatocytes. IL-37 significantly suppressed TNF-α-induced neutrophil activation. IL-37 is protective against hepatic I/R injury. These effects are related to the ability of IL-37 to reduce proinflammatory cytokine and chemokine production by hepatocytes and Kupffer cells as well as having a direct protective effect on hepatocytes. In addition, IL-37 contributes to reduce liver injury through suppression of neutrophil activity.

EFFECTS OF ETHANOL TREATMENT UPON SOURCES OF REACTWE OXYGEN SPECIES IN BRAIN AND LIVER

Sources of reactive oxygen species (ROS) generation have been compared in microsomal and mitochondrial fractions of brain and liver from ethanol-treated and control rats. Rates of ROS generation were quantitated with the fluorescent probe precursor, 2'7'-dihydrochloroflurescin diacetate, whose validity has been previously established. The production of active pro-oxidant species was measured in the presence of various selective inhibitors of enzymes potentially able to contribute to oxidative events. Several steps in the arachidonic acid cascade appeared to constitute a large fraction of total ROS generating capacity. Chelation of intrinsic iron with desferoxamine greatly reduced such capacity, especially in cerebral tissue. Aldehyde oxidases were active in generating ROS in both tissues. Inhibition of catalase dramatically enhanced ROS in liver but not in brain microsomes. While no ethanol-treatment effects were found in brain, there was evidence that ethanol consumption decreased hepatic levels of catalase, aldehyde oxidases and cyclooxygenase. However, despite these reductions, total basal ROS production was elevated in liver but not brain fractions from treated animals. The addition of an exogenous iron salt enhanced ROS formation to a lesser extent in ethanol-consuming rats than in controls. The elevation of basal hepatic ROS levels in ethanol-treated rats may thus be compatible with the release of cytosolic low molecular weight free iron compounds into the cytosol.