P2X7 Receptor as a Key Player in Oxidative Stress-Driven Cell Fate in Nonalcoholic Steatohepatitis

Incidences of nonalcoholic fatty liver disease parallels increase in the global obesity epidemic. NAFLD has been shown to be associated with risks of cardiometabolic disorders and kidney disturbances. It is accompanied by insulin and leptin resistance that complicate the diagnosis and treatment of this public health menace. Though significant research is underway for understanding the molecular mechanisms of NAFLD and its subsequent inflammatory and fibrotic manifestations like nonalcoholic steatohepatitis, the role of purinergic receptors has been unclear. It is increasingly being recognized that damage associated molecular patterns like NAD and ATP that are released from injured cells via hepatocellular injury either by oxidative stress or lipotoxicity from steatosis activate the purinergic receptor. Based on evidence from inflammatory responses in the airways and vasculature and autoimmune complications in humans and rodents, it is beyond doubt that hepatocellular inflammation such as that seen in NASH can result from the activation of purinergic receptors. This event can result in the formation of inflammasomes and can be an important pathway for the progression of NASH. The present review evaluates the current knowledge of the role of oxidative stress and its signaling via P2X7 receptors in hepatocellular injury that might contribute to the NASH pathophysiology.

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Deficiency of the Purinergic Receptor 2X7 Attenuates Nonalcoholic Steatohepatitis Induced by High-Fat Diet: Possible Role of the NLRP3 Inflammasome

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/8962458 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

Claudia Blasetti Fantauzzi ◽

Stefano Menini ◽

Carla Iacobini ◽

Chiara Rossi ◽

Eleonora Santini ◽

...

Keyword(s):

Nonalcoholic Steatohepatitis ◽

Nlrp3 Inflammasome ◽

High Fat Diet ◽

Molecular Mechanisms ◽

Purinergic Receptor ◽

High Fat ◽

Liver Sinusoidal Endothelial Cells ◽

Nonalcoholic Fatty Liver ◽

Markers Of Inflammation

Molecular mechanisms driving transition from simple steatosis to nonalcoholic steatohepatitis (NASH), a critical step in the progression of nonalcoholic fatty liver disease (NAFLD) to cirrhosis, are poorly defined. This study aimed at investigating the role of the purinergic receptor 2X7 (PR2X7), through the NLRP3 inflammasome, in the development of NASH. To this end, mice knockout for the Pr2x7 gene (Pr2x7−/−) and coeval wild-type (WT) mice were fed a high-fat diet (HFD) or normal-fat diet for 16 weeks. NAFLD grade and stage were lower in Pr2x7−/− than WT mice, and only 1/7 Pr2x7−/− animals showed evidence of NASH, as compared with 4/7 WT mice. Molecular markers of inflammation, oxidative stress, and fibrosis were markedly increased in WT-HFD mice, whereas no or significantly reduced increments were detected in Pr2x7−/− animals, which showed also decreased modulation of genes of lipid metabolism. Deletion of Pr2x7 gene was associated with blunted or abolished activation of NLRP3 inflammasome and expression of its components, which were induced in liver sinusoidal endothelial cells challenged with appropriate stimuli. These data show that Pr2x7 gene deletion protects mice from HFD-induced NASH, possibly through blunted activation of NLRP3 inflammasome, suggesting that PR2X7 and NLRP3 may represent novel therapeutic targets.

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Micro-RNA 21 inhibition of SMAD7 enhances fibrogenesis via leptin-mediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00346.2014 ◽

2015 ◽

Vol 308 (4) ◽

pp. G298-G312 ◽

Cited By ~ 72

Author(s):

Diptadip Dattaroy ◽

Sahar Pourhoseini ◽

Suvarthi Das ◽

Firas Alhasson ◽

Ratanesh Kumar Seth ◽

...

Keyword(s):

Oxidative Stress ◽

Nadph Oxidase ◽

Nonalcoholic Steatohepatitis ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Micro Rna ◽

Protein Levels ◽

Significant Research ◽

Human Livers

Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) is the common pathophysiological process resulting from chronic liver inflammation and oxidative stress. Although significant research has been carried out on the role of leptin-induced NADPH oxidase in fibrogenesis, the molecular mechanisms that connect the leptin-NADPH oxidase axis in upregulation of transforming growth factor (TGF)-β signaling have been unclear. We aimed to investigate the role of leptin-mediated upregulation of NADPH oxidase and its subsequent induction of micro-RNA 21 (miR21) in fibrogenesis. Human NASH livers and a high-fat (60% kcal) diet-fed chronic mouse model, where hepatotoxin bromodichloromethane was used to induce NASH, were used for this study. To prove the role of the leptin-NADPH oxidase-miR21 axis, mice deficient in genes for leptin, p47phox, and miR21 were used. Results showed that wild-type mice and human livers with NASH had increased oxidative stress, increased p47phox expression, augmented NF-κB activation, and increased miR21 levels. These mice and human livers showed increased TGF-β, SMAD2/3-SMAD4 colocalizations in the nucleus, increased immunoreactivity against Col1α, and α-SMA with a concomitant decrease in protein levels of SMAD7. Mice that were deficient in leptin or p47phox had decreased activated NF-κB and miR21 levels, suggesting the role of leptin and NADPH oxidase in inducing NF-κB-mediated miR21 expression. Further miR21 knockout mice had decreased colocalization events of SMAD2/3-SMAD4 in the nucleus, increased SMAD7 levels, and decreased fibrogenesis. Taken together, the studies show the novel role of leptin-NADPH oxidase induction of miR21 as a key regulator of TGF-β signaling and fibrogenesis in experimental and human NASH.

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Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00235.2013 ◽

2013 ◽

Vol 305 (12) ◽

pp. G950-G963 ◽

Cited By ~ 34

Author(s):

Suvarthi Das ◽

Ratanesh Kumar Seth ◽

Ashutosh Kumar ◽

Maria B. Kadiiska ◽

Gregory Michelotti ◽

...

Keyword(s):

Oxidative Stress ◽

Nonalcoholic Steatohepatitis ◽

P2x7 Receptor ◽

Molecular Mechanisms ◽

Purinergic Receptor ◽

Receptor Gene ◽

Receptor Expression ◽

Histopathological Analysis ◽

Protein Levels ◽

Metabolic Oxidative Stress

Recent studies indicate that metabolic oxidative stress, autophagy, and inflammation are hallmarks of nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanisms that link these important events in NASH remain unclear. In this study, we investigated the mechanistic role of purinergic receptor X7 (P2X7) in modulating autophagy and resultant inflammation in NASH in response to metabolic oxidative stress. The study uses two rodent models of NASH. In one of them, a CYP2E1 substrate bromodichloromethane is used to induce metabolic oxidative stress and NASH. Methyl choline-deficient diet feeding is used for the other NASH model. CYP2E1 and P2X7 receptor gene-deleted mice are used to establish their roles in regulating metabolic oxidative stress and autophagy. Autophagy gene expression, protein levels, confocal microscopy based-immunolocalization of lysosome-associated membrane protein (LAMP)2A and histopathological analysis were performed. CYP2E1-dependent metabolic oxidative stress induced increases in P2X7 receptor expression and chaperone-mediated autophagy markers LAMP2A and heat shock cognate 70 but caused depletion of light chain 3 isoform B (LC3B) protein levels. P2X7 receptor gene deletion significantly decreased LAMP2A and inflammatory indicators while significantly increasing LC3B protein levels compared with wild-type mice treated with bromodichloromethane. P2X7 receptor-deleted mice were also protected from NASH pathology as evidenced by decreased inflammation and fibrosis. Our studies establish that P2X7 receptor is a key regulator of autophagy induced by metabolic oxidative stress in NASH, thereby modulating hepatic inflammation. Furthermore, our findings presented here form a basis for P2X7 receptor as a potential therapeutic target in the treatment for NASH.

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The Underlying Role of Oxidative Stress in Neurodegeneration: A Mechanistic Review

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180425122557 ◽

2018 ◽

Vol 17 (3) ◽

pp. 207-215 ◽

Cited By ~ 30

Author(s):

Habib Yaribeygi ◽

Yunes Panahi ◽

Behjat Javadi ◽

Amirhossein Sahebkar

Keyword(s):

Oxidative Stress ◽

Neurodegenerative Diseases ◽

Cell Activation ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Amyloid Β ◽

Nerve Degeneration ◽

Future Research ◽

Key Words Oxidative Stress

Background: Neurodegeneration is a condition in which progressive loss of function and structure of neurons occurs. Several lines of evidence suggest that oxidative stress has a central role in neurodegenerative diseases. Objective: The aim was to survey molecular mechanisms underlying the involvement of oxidative stress in developing different neurodegenerative diseases. Methods: Original and review articles were retrieved through a PubMed and Google scholar search (from 1989 to 2015) using the following key words: “oxidative stress”, “nerve degeneration” and “neurodegenerative diseases”. Results: A comprehensive analysis of the obtained articles confirmed strong involvement of oxidative stress in the pathophysiology of neurodegenerative diseases through a variety of mechanisms including induction of oxidation of nucleic acids, proteins and lipids, formation of advanced glycation end products, mitochondrial dysfunction, glial cell activation, amyloid β deposition and plaque formation, apoptosis, cytokine production and inflammatory responses, and proteasome dysfunction. Conclusion: Regarding the pivotal role of oxidative stress in neurodegeneration, modulation of free radical production or alleviating their harmful effects can be considered as a potential therapeutic strategy for preventing and controlling neurodegenerative diseases. Accordingly; boosting endogenous antioxidant capacity besides providing exogenous sources of antioxidants merits future research in order to discover new therapeutic agents.

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LncRNA SNHG12 Improves Cerebral Ischemic-reperfusion Injury by Activating SIRT1/FOXO3a Pathway through I nhibition of Autophagy and Oxidative Stress

Current Neurovascular Research ◽

10.2174/1567202617666200727142019 ◽

2020 ◽

Vol 17 (4) ◽

pp. 394-401

Author(s):

Yuanhua Wu ◽

Yuan Huang ◽

Jing Cai ◽

Donglan Zhang ◽

Shixi Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Ischemia Reperfusion ◽

Critical Role ◽

Cell Activity ◽

Ht22 Cells ◽

Cerebral Ischemic ◽

Cerebral Ischemic Reperfusion ◽

And Oxidative Stress

Background: Ischemia/reperfusion (I/R) injury involves complex biological processes and molecular mechanisms such as autophagy. Oxidative stress plays a critical role in the pathogenesis of I/R injury. LncRNAs are the regulatory factor of cerebral I/R injury. Methods: This study constructs cerebral I/R model to investigate role of autophagy and oxidative stress in cerebral I/R injury and the underline regulatory mechanism of SIRT1/ FOXO3a pathway. In this study, lncRNA SNHG12 and FOXO3a expression was up-regulated and SIRT1 expression was down-regulated in HT22 cells of I/R model. Results: Overexpression of lncRNA SNHG12 significantly increased the cell viability and inhibited cerebral ischemicreperfusion injury induced by I/Rthrough inhibition of autophagy. In addition, the transfected p-SIRT1 significantly suppressed the release of LDH and SOD compared with cells co-transfected with SIRT1 and FOXO3a group and cells induced by I/R and transfected with p-SNHG12 group and overexpression of cells co-transfected with SIRT1 and FOXO3 further decreased the I/R induced release of ROS and MDA. Conclusion: In conclusion, lncRNA SNHG12 increased cell activity and inhibited oxidative stress through inhibition of SIRT1/FOXO3a signaling-mediated autophagy in HT22 cells of I/R model. This study might provide new potential therapeutic targets for further investigating the mechanisms in cerebral I/R injury and provide.

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Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

Cells ◽

10.3390/cells10030629 ◽

2021 ◽

Vol 10 (3) ◽

pp. 629

Author(s):

Jorge Gutiérrez-Cuevas ◽

Ana Sandoval-Rodriguez ◽

Alejandra Meza-Rios ◽

Hugo Christian Monroy-Ramírez ◽

Marina Galicia-Moreno ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Dysfunction ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Peroxisome Proliferator ◽

White Adipocyte ◽

Peroxisome Proliferator Activated Receptors ◽

And Oxidative Stress

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

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Insights in the Role of Lipids, Oxidative Stress and Inflammation in Rheumatoid Arthritis Unveiled by New Trends in Lipidomic Investigations

Antioxidants ◽

10.3390/antiox10010045 ◽

2021 ◽

Vol 10 (1) ◽

pp. 45

Author(s):

Helena Beatriz Ferreira ◽

Tânia Melo ◽

Artur Paiva ◽

Maria do Rosário Domingues

Keyword(s):

Rheumatoid Arthritis ◽

Oxidative Stress ◽

Lipid Peroxidation ◽

Lipid Profile ◽

Inflammatory Responses ◽

Molecular Level ◽

Lipid Hydroperoxides ◽

Lipid Species ◽

Inflammatory Autoimmune Disease

Rheumatoid arthritis (RA) is a highly debilitating chronic inflammatory autoimmune disease most prevalent in women. The true etiology of this disease is complex, multifactorial, and is yet to be completely elucidated. However, oxidative stress and lipid peroxidation are associated with the development and pathogenesis of RA. In this case, oxidative damage biomarkers have been found to be significantly higher in RA patients, associated with the oxidation of biomolecules and the stimulation of inflammatory responses. Lipid peroxidation is one of the major consequences of oxidative stress, with the formation of deleterious lipid hydroperoxides and electrophilic reactive lipid species. Additionally, changes in the lipoprotein profile seem to be common in RA, contributing to cardiovascular diseases and a chronic inflammatory environment. Nevertheless, changes in the lipid profile at a molecular level in RA are still poorly understood. Therefore, the goal of this review was to gather all the information regarding lipid alterations in RA analyzed by mass spectrometry. Studies on the variation of lipid profile in RA using lipidomics showed that fatty acid and phospholipid metabolisms, especially in phosphatidylcholine and phosphatidylethanolamine, are affected in this disease. These promising results could lead to the discovery of new diagnostic lipid biomarkers for early diagnosis of RA and targets for personalized medicine.

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Enhancing the Nrf2 Antioxidant Signaling Provides Protection Against Trichloroethene-mediated Inflammation and Autoimmune Response

Toxicological Sciences ◽

10.1093/toxsci/kfaa022 ◽

2020 ◽

Vol 175 (1) ◽

pp. 64-74 ◽

Cited By ~ 3

Author(s):

Nivedita Banerjee ◽

Hui Wang ◽

Gangduo Wang ◽

M Firoze Khan

Keyword(s):

Oxidative Stress ◽

T Cells ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Autoimmune Response ◽

Mediated Effects ◽

Antioxidant Gene Expression ◽

Responsive Element

Abstract Trichloroethene (trichloroethylene, TCE) and one of its reactive metabolites dichloroacetyl chloride (DCAC) are associated with the induction of autoimmunity in MRL+/+ mice. Although oxidative stress plays a major role in TCE-/DCAC-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Nuclear factor (erythroid-derived 2)-like2 (Nrf2) is an oxidative stress-responsive transcription factor that binds to antioxidant responsive element (ARE) and provides protection by regulating cytoprotective and antioxidant gene expression. However, the potential of Nrf2 in the regulation of TCE-/DCAC-mediated autoimmunity is not known. This study thus focused on establishing the role of Nrf2 and consequent inflammatory responses in TCE-/DCAC-mediated autoimmunity. To achieve this, we pretreated Kupffer cells (KCs) or T cells with/without tert-butylhydroquinone (tBHQ) followed by treatment with DCAC. In both KCs and T cells, DCAC treatment significantly downregulated Nrf2 and HO-1 expression along with induction of Keap-1 and caspase-3, NF-κB (p65), TNF-α, and iNOS, whereas pretreatment of these cells with tBHQ attenuated these responses. The in vitro findings were further verified in vivo by treating female MRL+/+ mice with TCE along with/without sulforaphane. TCE exposure in mice also led to reduction in Nrf2 and HO-1 but increased phospho-NF-κB (p-p65) and iNOS along with increased anti-dsDNA antibodies. Interestingly, sulforaphane treatment led to amelioration of TCE-mediated effects, resulting in Nrf2 activation and reduction in inflammatory and autoimmune responses. Our results show that TCE/DCAC mediates an impairment in Nrf2 regulation. Attenuation of TCE-mediated autoimmunity via activation of Nrf2 supports that antioxidants sulforaphane/tBHQ could be potential therapeutic agents for autoimmune diseases.

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Critical Role of Zinc as Either an Antioxidant or a Prooxidant in Cellular Systems

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/9156285 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 48

Author(s):

Sung Ryul Lee

Keyword(s):

Oxidative Stress ◽

Zinc Deficiency ◽

Metal Binding ◽

Inflammatory Responses ◽

Binding Capacity ◽

Critical Role ◽

Cellular Systems ◽

Oxidative Stresses ◽

Dual Action

Zinc is recognized as an essential trace metal required for human health; its deficiency is strongly associated with neuronal and immune system defects. Although zinc is a redox-inert metal, it functions as an antioxidant through the catalytic action of copper/zinc-superoxide dismutase, stabilization of membrane structure, protection of the protein sulfhydryl groups, and upregulation of the expression of metallothionein, which possesses a metal-binding capacity and also exhibits antioxidant functions. In addition, zinc suppresses anti-inflammatory responses that would otherwise augment oxidative stress. The actions of zinc are not straightforward owing to its numerous roles in biological systems. It has been shown that zinc deficiency and zinc excess cause cellular oxidative stress. To gain insights into the dual action of zinc, as either an antioxidant or a prooxidant, and the conditions under which each role is performed, the oxidative stresses that occur in zinc deficiency and zinc overload in conjunction with the intracellular regulation of free zinc are summarized. Additionally, the regulatory role of zinc in mitochondrial homeostasis and its impact on oxidative stress are briefly addressed.

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Micronized Palmitoylethanolamide Ameliorates Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis via Inhibiting Inflammation and Restoring Autophagy

Frontiers in Pharmacology ◽

10.3389/fphar.2021.744483 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiaji Hu ◽

Hanglu Ying ◽

Jie Yao ◽

Longhe Yang ◽

Wenhui Jin ◽

...

Keyword(s):

Nonalcoholic Steatohepatitis ◽

Underlying Mechanism ◽

Protective Role ◽

Hepatocellular Injury ◽

Deficient Diet ◽

Neuroprotective Effects ◽

Pathway Activation ◽

Elevated Expression ◽

Anti Inflammatory

Nonalcoholic steatohepatitis (NASH) has become one of the serious causes of chronic liver diseases, characterized by hepatic steatosis, hepatocellular injury, inflammation and fibrosis, and lack of efficient therapeutic agents. Palmitoylethanolamide (PEA) is an endogenous bioactive lipid with various pharmacological activities, including anti-inflammatory, analgesic, and neuroprotective effects. However, the effect of PEA on nonalcoholic steatohepatitis is still unknown. Our study aims to explore the potential protective role of PEA on NASH and to reveal the underlying mechanism. In this study, the C57BL/6 mice were used to establish the NASH model through methionine- and choline-deficient (MCD) diet feeding. Here, we found that PEA treatment significantly improved liver function, alleviated hepatic pathological changes, and attenuated the lipid accumulation and hepatic fibrosis in NASH mice induced by MCD diet feeding. Mechanistically, the anti-steatosis effect of PEA may be due to the suppressed expression of ACC1 and CD36, elevated expression of PPAR-α, and the phosphorylation levels of AMPK. In addition, hepatic oxidative stress was greatly inhibited in MCD-fed mice treated with PEA via enhancing the expression and activities of antioxidant enzymes, including GSH-px and SOD. Moreover, PEA exerted a clear anti-inflammatory effect though ameliorating the expression of inflammatory mediators and suppressing the NLRP3 inflammasome pathway activation. Furthermore, the impaired autophagy in MCD-induced mice was reactivated with PEA treatment. Taken together, our research suggested that PEA protects against NASH through the inhibition of inflammation and restoration of autophagy. Thus, PEA may represent an efficient therapeutic agent to treat NASH.

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