Hepatic Reactive Oxygen Species Production Research Articles

Targeting hepatic oxidative stress rescues bone loss in liver fibrosis

ObjectiveChronic liver diseases often involve metabolic damage to the skeletal system. The underlying mechanism of bone loss in chronic liver diseases remains unclear, and appropriate therapeutic options, except for orthotopic liver transplantation, have proved insufficient for these patients. This study aimed to investigate the efficacy and mechanism of transplantation of immature hepatocyte-like cells converted from stem cells from human exfoliated deciduous teeth (SHED-Heps) in bone loss of chronic liver fibrosis. MethodsMice that were chronically treated with CCl4 received SHED-Heps, and trabecular bone density, reactive oxygen species (ROS), and osteoclast activity were subsequently analyzed in vivo and in vitro. The effects of stanniocalcin 1 (STC1) knockdown in SHED-Heps were also evaluated in chronically CCl4 treated mice. ResultsSHED-Hep transplantation (SHED-HepTx) improved trabecular bone loss and liver fibrosis in chronic CCl4-treated mice. SHED-HepTx reduced hepatic ROS production and interleukin 17 (Il-17) expression under chronic CCl4 damage. SHED-HepTx reduced the expression of both Il-17 and tumor necrosis factor receptor superfamily 11A (Tnfrsf11a) and ameliorated the imbalance of osteoclast and osteoblast activities in the bone marrow of CCl4-treated mice. Functional knockdown of STC1 in SHED-Heps attenuated the benefit of SHED-HepTx including anti-bone loss effect by suppressing osteoclast differentiation through TNFSF11–TNFRSF11A signaling and enhancing osteoblast differentiation in the bone marrow, as well as anti-fibrotic and anti-ROS effects in the CCl4-injured livers. ConclusionsThese findings suggest that targeting hepatic ROS provides a novel approach to treat bone loss resulting from chronic liver diseases.

DDIT4 S-Nitrosylation Aids p38-MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production.

Mitogen‐activated protein kinase (MAPK) signaling plays a significant role in reactive oxygen species (ROS) production. The authors have previously shown that Brahma‐related gene 1 (BRG1), a chromatin remodeling protein, contributes to hepatic ROS accumulation in multiple animal and cellular models of liver injury. Here it is reported that DNA damage‐induced transcript 4 (DDIT4) is identified as a direct transcriptional target for BRG1. DDIT4 overexpression overcomes BRG1 deficiency to restore ROS production whereas DDIT4 knockdown phenocopies BRG1 deficiency in suppressing ROS production in vitro and in vivo. Mechanistically, DDIT4 coordinates the assembly of the p38‐MAPK signaling complex to drive ROS production in an S‐nitrosylation dependent manner. Molecular docking identifies several bioactive DDIT4‐inteacting compounds including imatinib, nilotinib, and nateglinide, all of which are confirmed to attenuate hepatic ROS production, dampen p38‐MAPK signaling, and ameliorate liver injury by influencing DDIT4 S‐nitrosylation. Importantly, positive correlation between ROS levels and BRG1/DDIT4/S‐nitrosylated DDIT4 levels is detected in human liver biopsy specimens. In conclusion, the data reveal a transcription‐based signaling cascade that contributes to ROS production in liver injury.

Redox Control of Integrin-Mediated Hepatic Inflammation in Systemic Autoimmunity.

Significance: Systemic autoimmunity affects 3%-5% of the population worldwide. Systemic lupus erythematosus (SLE) is a prototypical form of such condition, which affects 20-150 of 100,000 people globally. Liver dysfunction, defined by increased immune cell infiltration into the hepatic parenchyma, is an understudied manifestation that affects up to 20% of SLE patients. Autoimmunity in SLE involves proinflammatory lineage specification in the immune system that occurs with oxidative stress and profound changes in cellular metabolism. As the primary metabolic organ of the body, the liver is uniquely capable to encounter oxidative stress through first-pass derivatization and filtering of waste products. Recent Advances: The traffic of immune cells from their development through recirculation in the liver is guided by cell adhesion molecules (CAMs) and integrins, cell surface proteins that tightly anchor cells together. The surface expression of CAMs and integrins is regulated via endocytic traffic that is sensitive to oxidative stress. Reactive oxygen species (ROS) that elicit oxidative stress in the liver may originate from the mitochondria, the cytosol, or the cell membrane. Critical Issues: While hepatic ROS production is a source of vulnerability, it also modulates the development and function of the immune system. In turn, the liver employs antioxidant defense mechanisms to protect itself from damage that can be harnessed to serve as therapeutic mechanisms against autoimmunity, inflammation, and development of hepatocellular carcinoma. Future Directions: This review is aimed at delineating redox control of integrin signaling in the liver and checkpoints of regulatory impact that can be targeted for treatment of inflammation in systemic autoimmunity. Antioxid. Redox Signal. 36, 367-388.

Protective Effects of Taraxasterol against Ethanol-Induced Liver Injury by Regulating CYP2E1/Nrf2/HO-1 and NF-κB Signaling Pathways in Mice.

Taraxasterol, a pentacyclic-triterpene compound, is one of the main active components isolated from the traditional Chinese medicinal herb Taraxacum. The objective of this study is to evaluate the protective effects of taraxasterol and its possible underlying mechanisms against ethanol-induced liver injury in mice. ICR mice were fed with Lieber-DeCarli diet containing 5% ethanol for 10 d and then challenged with a single dose of 20% ethanol (5 g/kg BW) by intragastric administration. The mice were intragastrically treated daily with taraxasterol (2.5, 5, and 10 mg/kg). Tiopronin was used as a positive control. The liver index was calculated, and the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in sera were detected. The contents of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) and the activity of superoxide dismutase (SOD) in the livers were measured. The histopathological changes of liver tissues were observed by hematoxylin and eosin (H&E) staining. The protein expression levels of hepatic cytochrome P450 2E1 (CYP2E1), nuclear factor erythroid 2-related factor 2 (Nrf2), antioxidant protein heme oxygenase-1 (HO-1), and nuclear factor-kappa B (NF-κB) signaling pathway in liver tissues were detected by immunohistochemistry and Western blot methods. Taraxasterol significantly reduced the ethanol-induced increases of liver index, ALT, AST, and TG levels in sera and TG and MDA contents in the livers and hepatic ROS production and suppressed the ethanol-induced decreases of hepatic GSH level and SOD activity. Taraxasterol also significantly inhibited the secretion of proinflammatory cytokines TNF-α and IL-6 induced by ethanol. In addition, taraxasterol improved the liver histopathological changes in mice with ethanol-induced liver injury. Further studies revealed that taraxasterol significantly inhibited the ethanol-induced upregulation of CYP2E1, increased the ethanol-induced downregulation of Nrf2 and HO-1, and inhibited the degradation of inhibitory kappa Bα (IκBα) and the expression level of NF-κB p65 in liver tissues of ethanol-induced mice. These findings suggest that taraxasterol possesses the potential protective effects against ethanol-induced liver injury in mice by exerting antioxidative stress and anti-inflammatory response via CYP2E1/Nrf2/HO-1 and NF-κB signaling pathways.

Deficiency of DJ-1 Ameliorates Liver Fibrosis through Inhibition of Hepatic ROS Production and Inflammation.

Liver fibrosis is a global health problem and previous studies have demonstrated that reactive oxygen species (ROS) play important roles in fibrogenesis. Parkinson disease (autosomal recessive, early onset) 7 (Park7) also called DJ-1 has an essential role in modulating cellular ROS levels. DJ-1 therefore may play functions in liver fibrogenesis and modulation of DJ-1 may be a promising therapeutic approach. Here, wild-type (WT) and DJ-1 knockout (DJ-1 KO) mice were administrated with carbon tetrachloride (CCl4) to induce liver fibrosis or acute liver injury. Results showed that DJ-1 depletion significantly blunted liver fibrosis, accompanied by marked reductions in liver injury and ROS production. In the acute CCl4 model, deficiency of DJ-1 showed hepatic protective functions as evidenced by decreased hepatic damage, reduced ROS levels, diminished hepatic inflammation and hepatocyte proliferation compared to WT mice. In vitro hepatic stellate cells (HSCs) activation assays indicated that DJ-1 has no direct effect on the activation of HSCs in the context of with or without TGFβ treatment. Thus our present study demonstrates that in CCl4-induced liver fibrosis, DJ-1 deficiency attenuates mice fibrosis by inhibiting ROS production and liver injury, and further indirectly affecting the activation of HSCs. These results are in line with previous studies that ROS promote HSC activation and fibrosis development, and suggest the therapeutic value of DJ-1 in treatment of liver fibrosis.

Gut morphology and hepatic oxidative status of European sea bass (Dicentrarchus labrax) juveniles fed plant feedstuffs or fishmeal-based diets supplemented with short-chain fructo-oligosaccharides and xylo-oligosaccharides.

The effects of short-chain fructo-oligosaccharides (scFOS) and xylo-oligosaccharides (XOS) on gut morphology and hepatic oxidative status were studied in European sea bass juveniles weighing 60 g. Fish were fed diets including fishmeal (FM diets) or plant feedstuffs (PF diets; 30 FM:70 PF) as main protein sources (control diets). Four other diets were formulated similar to the control diets but including 1 % scFOS or 1 % XOS. At the end of the trial, fish fed PF-based diets presented histomorphological alterations in the distal intestine, whereas only transient alterations were observed in the pyloric caeca. Comparatively to fish fed FM-based diets, fish fed PF diets had higher liver lipid peroxidation (LPO), superoxide dismutase (SOD) and catalase (CAT) activities, and lower glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenase activities. In fish fed the PF diets, prebiotic supplementation decreased SOD activity and XOS supplementation further decreased CAT activity. In fish fed the FM diets, XOS supplementation promoted a reduction of all antioxidant enzyme activities. Overall, dietary XOS and scFOS supplementation had only minor effects on gut morphology or LPO levels. However, dietary XOS reduced antioxidant enzymatic activity in both PF and FM diets, which indicate a positive effect on reduction of hepatic reactive oxygen species production.

Enhanced stem cell engraftment and modulation of hepatic reactive oxygen species production in diet‐induced obesity

The impact of dietary-induced obesity (DIO) on stem cell engraftment and the respective therapeutic potential of stem cell engraftment in DIO have not been reported. The objectives of this study were to examine the impact of DIO on the survival and efficacy of intravenous bone marrow-derived mesenchymal stem cell (MSC) administration in the conscious C57BL/6 mouse. Male mice consumed either a chow (CH) or high fat (HF, 60% kcal) diet for 18 weeks and were subsequently treated with MSC over a 6-day period. Key measurements included tissue-specific cell engraftment, glucose and insulin sensitivity, inflammation, and oxidative stress. MSC administration had no effect on inflammatory markers, glucose, or insulin sensitivity. DIO mice showed increases in MSC engraftment in multiple tissues compared with their CH counterparts. Engraftment was increased in the HF liver where MSC administration attenuated DIO-induced oxidative stress. These liver-specific alterations in HF-MSC were associated with increases in stanniocalcin-1 (STC1) and uncoupling protein 2 (UCP2), which contribute to cell survival and modulate mitochondrial bioenergetics. Results suggest that MSC administration in DIO promotes engraftment and mitigates hepatic oxidative stress. These data invite further exploration into the therapeutic potential of stem cells for the treatment of DIO oxidative stress in the liver.

Hepatoprotective effect of the selective mineralocorticoid receptor antagonist, eplerenone against carbon tetrachloride-induced liver injury in rats

Background. Eplerenone is a selective mineralocorticoid receptor (MR) antagonist, and its potential protective role in cardiovascular injury has been reported by several studies. However, whether and how this drug can ameliorate hepatic injury in rats is unknown.Material and methods. The present study was conducted to investigate effect of eplerenone against liver injury induced by carbon tetrachloride (CCl4) in rats. The biochemical liver function tests and oxidative stress parameters including malondialdehyde (MDA), reactive oxygen species (ROS), in addition to the reduced glutathione (GSH) levels were evaluated. Moreover, serum tumor necrotic factors (TNF-α) level and histopathological changes were examined.Results. Our results show that pre-treatment with eplerenone (4 mg/kg per day for 4 weeks) revealed attenuation in serum activities of alanine aminotransferase (ALT), aspartate aminotransferase, (AST), alkaline phosphatase (ALP) and bilirubin levels that were enhanced by CCl4. Further, pre-treatment with eplerenone inhibited the elevated hepatic MDA content and restored hepatic GSH to its normal level. The enhanced hepatic ROS production in CCl4-treated group was markedly decreased by eplerenone administration. Eple-renone pre-treatment significantly attenuated the inflammatory responses caused by CCl4 as evident by the decreased serum TNF-α level. Histopathological studies showed that eplerenone alleviated the liver damage and reduced the lesions caused by CCl4.Conclusion. Collectively, the present study provides a proof to hepatoprotective actions of eplerenone via reducing oxidative stress and inflammatory responses in CCl4-induced liver damage in rat model.

In-Chern-Hau-Tang and Genipin Reduces Acute Urinary Bladder Distension Evoked Sympathetic Activation-Induced Hepatic Dysfunction in Rats

Increased norepinephrine production by acute urine retention (AUR) induced sympathetic activation may contribute to acute liver injury (ALI) via the action of hepatic vasoconstriction and increased reactive oxygen species (ROS) production. We evaluated whether In-Chern-Hau-Tang, a hepatoprotective herb medicine, and its major ingredient genipin, may ameliorate norepinephrine-induced liver injury in the rat. We determined the effects of In-Chern-Hau-Tang and genipin on norepinephrine-induced oxidative stress in the Kupffer and endothelial cells and AUR-induced ALI in the rat via a chemiluminescence analyzer, physiologic and biochemical determination and western blot. The results of in vitro study showed that genipin with efficient H(2)O(2) and HOCl scavenging activities decreased norepinephrine-enhanced ROS production in the Kupffer cell and endothelial cell cultures. AUR activated hepatic sympathetic nervous activity lead to a hepatic hypoxia/hypoperfusion, and a reduction in bile flow. AUR increased intercellular adhesion molecular 1 (ICAM-1) protein expression, and hepatic ROS production from the activated leukocyte NADPH oxidase activity subsequently leading to plasma aspartate aminotransferase (AST) elevation. Hepatic sympathetic denervation, or oral pretreatment of In-Chern-Hau-Tang or genipin for 1 week ameliorated the level in AUR-induced hepatic hypoxia/hypoperfusion, and bile stasis. Hepatic denervation, In-Chern-Hau-Yang and genipin inhibited AUR-enhanced hepatic ICAM-1 expression, hepatic ROS production, leukocyte NADPH oxidase activity and plasma AST activity. In conclusion, In-Chern-Hau-Tang along with its active component, genipin, can ameliorate AUR-induced ALI via the alleviation of oxidative stress possibly by the inhibition of sympathetic induced hypoxia/hypoperfusion and leukocyte NADPH oxidase activity.

Dose‐Dependent Effect of Ethanol on Hepatic Oxidative Stress and Interleukin‐6 Production After Burn Injury in the Mouse

Burned patients with detectable blood alcohol levels (BAL) show an elevated mortality rate. Interleukin (IL)-6 and reactive oxygen species (ROS) production is stimulated independently by alcohol and burn injury. The aim of the study was to determine whether increasing levels of alcohol differentially enhance the hepatic production of IL-6 and ROS after burn in a murine model of dorsal scald injury. Groups of mice received either saline or alcohol intraperitoneally to reach a BAL of 100 mg/dl or 300 mg/dl at the time of burn (15% total body surface scald) or sham injury. Burn injury alone resulted in a low mortality rate at 24 hr after injury as did the burn group with a BAL of 100 mg/dl (15%), whereas 57% of the mice burned with a BAL of 300 mg/dl did not survive (p = 0.02). Twenty-four hours after burn or sham injury, IL-6 levels were measured by enzyme-linked immunosorbent assay in serum and liver. In the saline-treated group, IL-6 circulating and hepatic levels rose after burn injury (p < 0.03). Circulating IL-6 levels in sham mice increased 1.5-fold in the group with a BAL of 100 mg/dl and 3-fold in those with a BAL of 300 mg/ml (p = 0.005 versus burn-injured, saline-treated). IL-6 hepatic production after burn injury was higher in the mice with a BAL of 300 mg/dl than in those with a BAL of 100 mg/dl and the saline-treated group (p = 0.001). Among the burned mice, alcohol exposure increased hepatic ROS production, measured by lipid peroxidation and protein oxidation, in a dose-dependent manner. Alcohol enhances in a dose-dependent manner the hepatic production of IL-6 induced by burn injury through the modulation of oxidative stress. The increased mortality rate of mice exposed to alcohol and burn injury may be due to the adverse effect on immune function induced by IL-6 elevation.