scholarly journals A Nature-Inspired Nrf2 Activator Protects Retinal Explants from Oxidative Stress and Neurodegeneration

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1296
Author(s):  
Maria Grazia Rossino ◽  
Rosario Amato ◽  
Marialaura Amadio ◽  
Michela Rosini ◽  
Filippo Basagni ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nuclear Translocation ◽  
Apoptotic Cell ◽  
Antioxidant Properties ◽  
Antioxidant Response ◽  
Structural Features ◽  
Related Factor ◽  
Retinal Diseases ◽  
Protein Levels ◽  
Retinal Explants

Oxidative stress (OS) plays a key role in retinal dysfunctions and acts as a major trigger of inflammatory and neurodegenerative processes in several retinal diseases. To prevent OS-induced retinal damage, approaches based on the use of natural compounds are actively investigated. Recently, structural features from curcumin and diallyl sulfide have been combined in a nature-inspired hybrid (NIH1), which has been described to activate transcription nuclear factor erythroid-2-related factor-2 (Nrf2), the master regulator of the antioxidant response, in different cell lines. We tested the antioxidant properties of NIH1 in mouse retinal explants. NIH1 increased Nrf2 nuclear translocation, Nrf2 expression, and both antioxidant enzyme expression and protein levels after 24 h or six days of incubation. Possible toxic effects of NIH1 were excluded since it did not alter the expression of apoptotic or gliotic markers. In OS-treated retinal explants, NIH1 strengthened the antioxidant response inducing a massive and persistent expression of antioxidant enzymes up to six days of incubation. These effects resulted in prevention of the accumulation of reactive oxygen species, of apoptotic cell death, and of gliotic reactivity. Together, these data indicate that a strategy based on NIH1 to counteract OS could be effective for the treatment of retinal diseases.

scholarly journals Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Yasuhiro Nakagami
Keyword(s):  
Oxidative Stress ◽  
Neuronal Degeneration ◽  
Antioxidant Response ◽  
Related Factor ◽  
Retinal Diseases ◽  
Age Related ◽  
Nrf2 Signaling Pathway ◽  
Genes Encoding ◽  
Antioxidant Response Elements ◽  
Nrf2 Activator

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway.

Abstract 17514: Hydrogen Sulfide Levels and NRF2 Activity are Attenuated in the Setting of Critical Limb Ischemia (CLI)

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kazi N Islam ◽  
David J Polhemus ◽  
Erminia Donnarumma ◽  
Hiroyuki Otsuka ◽  
Shashi Bhushan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Hydrogen Sulfide ◽  
Limb Ischemia ◽  
Antioxidant Response ◽  
Protein Carbonyl ◽  
Related Factor ◽  
Mobility Shift ◽  
Protein Levels ◽  
Nrf2 Activation

Background: Cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST) are enzymatic sources of hydrogen sulfide (H2S). Functions of H2S are mediated by several targets including ion channels and signaling proteins. Nuclear factor-erythriod 2-related factor 2 (NRF2) is responsible for the expression of antioxidant response element (ARE)-regulated genes and is known to be upregulated by H2S. We examined the levels of H2S producing enzymes, H2S, and NRF2 activation status in skeletal muscle obtained from CLI patients. Methods: Gastrocnemius tissues were attained post amputation from human CLI and aged-matched control patients. Tissue H2S levels were measured using gas chromatography methods coupled with sulfur chemiluminescence. RT-qPCR, immunoblot, and electrophoretic mobility shift assay (EMSA) were used to analyze respective gene expression, protein levels, and DNA binding activity, respectively. Results: We found mRNA and protein levels of CSE, CBS, and 3-MST were significantly decreased in skeletal muscle of CLI (~2 fold, p < 0.05) patients as compared to control. H2S and sulfane sulfur levels were significantly decreased in skeletal muscle of CLI patients. We also observed significant reductions in NRF2 activation (2 fold, p < 0.05) as well as antioxidant proteins, such as CuZn-superoxide dismutase (2 fold, p < 0.05), catalase (2 fold, p < 0.05), and glutathione peroxidase (2 fold, p < 0.05) in skeletal muscle of CLI patients. Biomarkers of oxidative stress, such as malondialdehyde and protein carbonyl formation were significantly increased (2 fold, p < 0.05) in skeletal muscle of CLI patients as compared to age-matched controls. Conclusions: The data demonstrate that H2S bioavailability and NRF2 activation are both attenuated in CLI tissues concomitant with significantly increased oxidative stress. Reductions in the activity of H2S producing enzymes may contribute to the pathogenesis of CLI.

scholarly journals Ishige okamurae Ameliorates Methylglyoxal-Induced Nephrotoxicity via Reducing Oxidative Stress, RAGE Protein Expression, and Modulating MAPK, Nrf2/ARE Signaling Pathway in Mouse Glomerular Mesangial Cells

Foods ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2000
Author(s):  
Mingyeong Kim ◽  
Chiheung Cho ◽  
Changjun Lee ◽  
Bomi Ryu ◽  
Sera Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mesangial Cells ◽  
Apoptotic Cell ◽  
Antioxidant Response ◽  
Diabetic Complication ◽  
Related Factor ◽  
Glomerular Mesangial Cells ◽  
Ishige Okamurae ◽  
Age Related

Advanced glycation end-products (AGEs) such as methylglyoxal (MGO) play a vital role in the pathogenesis of nephropathy, a diabetic complication. In the present study, we evaluated the anti-glycation and renal protective properties of Ishige okamurae extract (IOE) against AGE-induced oxidative stress. HPLC analysis confirmed that bioactive phlorotannins such as diphlorethohydroxycarmalol and ishophloroglucin A are predominantly present in IOE. IOE showed strong anti-glycation activities via inhibition of AGE formation, inhibition of AGE–protein cross-linking, and breaking of AGE–protein cross-links. In addition, in vitro studies using mesangial cells demonstrated that IOE effectively suppressed intracellular reactive oxygen species production, intracellular MGO accumulation, and apoptotic cell death by MGO-induced oxidative stress, in addition to regulating the expression of proteins involved in the receptor for AGEs and nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signaling pathways. Therefore, IOE can serve as a natural therapeutic agent for the management of AGE-related nephropathy.

scholarly journals Role of Nrf2 in Synaptic Plasticity and Memory in Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1884
Author(s):  
Don A. Davies ◽  
Aida Adlimoghaddam ◽  
Benedict C. Albensi
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Neurodegenerative Disorders ◽  
Nuclear Translocation ◽  
Antioxidant Response ◽  
Related Factor ◽  
Amyloid Aβ ◽  
Novel Therapeutic

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that reduces oxidative stress. When reactive oxygen species (ROS) or reactive nitrogen species (RNS) are detected, Nrf2 translocates from the cytoplasm into the nucleus and binds to the antioxidant response element (ARE), which regulates the expression of antioxidant and anti-inflammatory genes. Nrf2 impairments are observed in the majority of neurodegenerative disorders, including Alzheimer’s disease (AD). The classic hallmarks of AD include β-amyloid (Aβ) plaques, and neurofibrillary tangles (NFTs). Oxidative stress is observed early in AD and is a novel therapeutic target for the treatment of AD. The nuclear translocation of Nrf2 is impaired in AD compared to controls. Increased oxidative stress is associated with impaired memory and synaptic plasticity. The administration of Nrf2 activators reverses memory and synaptic plasticity impairments in rodent models of AD. Therefore, Nrf2 activators are a potential novel therapeutic for neurodegenerative disorders including AD.

scholarly journals Ingredients from Litsea garrettii as Potential Preventive Agents against Oxidative Insult and Inflammatory Response

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Yan-Ru Li ◽  
Guo-Hui Li ◽  
Lin Sun ◽  
Lin Li ◽  
Yue Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nuclear Translocation ◽  
Regulatory Subunit ◽  
No Production ◽  
Related Factor ◽  
Etoh Extract ◽  
Protein Levels ◽  
Phytochemical Investigation ◽  
Nrf2 Activator ◽  
Oxidative Insult

Oxidative stress and inflammation undoubtedly contribute to the pathogenesis of many human diseases. The nuclear transcription factor erythroid 2-related factor (Nrf2) and the nuclear factor κB (NF-κB) play central roles in regulation of oxidative stress and inflammation and thus are targets for developing agents against oxidative stress- and inflammation-related diseases. Our previous study indicated that the EtOH extract of Litsea garrettii protected human bronchial epithelial cells against oxidative insult via the activation of Nrf2. In the present study, a systemic phytochemical investigation of L. garrettii led to the isolation of twenty-one chemical ingredients, which were further evaluated for their inhibitions on oxidative stress and inflammation using NAD(P)H:quinone reductase (QR) assay and nitric oxide (NO) production assay. Of these ingredients, 3-methoxy-5-pentyl-phenol (MPP, 5) was identified as an Nrf2 activator and an NF-κB inhibitor. Further studies demonstrated the following: (i) MPP upregulated the protein levels of Nrf2, NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase regulatory subunit (GCLM); enhanced the nuclear translocation and stabilization of Nrf2; and inhibited arsenic [As(III)]-induced oxidative insult in normal human lung epithelial Beas-2B cells. And (ii) MPP suppressed the nuclear translocation of NF-κB p65 subunit; inhibited the lipopolysaccharide- (LPS-) stimulated increases of NF-κB p65 subunit, COX-2, iNOS, TNF-α, and IL-1β; and blocked the LPS-induced biodegrade of IκB-α in RAW 264.7 murine macrophages. Taken together, MPP displayed potential preventive effects against inflammation- and oxidative stress-related diseases.

scholarly journals 7,8-Dihydroxyflavone Suppresses Oxidative Stress-Induced Base Modification in DNA via Induction of the Repair Enzyme 8-Oxoguanine DNA Glycosylase-1

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Ki Cheon Kim ◽  
In Kyung Lee ◽  
Kyoung Ah Kang ◽  
Ji Won Cha ◽  
Suk Ju Cho ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nuclear Translocation ◽  
Antioxidant Response ◽  
Dna Glycosylase ◽  
Lung Fibroblasts ◽  
Related Factor ◽  
Protective Effects ◽  
Akt Inhibitor ◽  
Phosphorylated Akt ◽  
Nuclear Levels

The modified guanine base 8-oxoguanine (8-oxoG) is abundantly produced by oxidative stress, can contribute to carcinogenesis, and can be removed from DNA by 8-oxoguanine DNA glycosylase-1 (OGG1), which acts as an 8-oxoG glycosylase and endonuclease. This study investigated the mechanism by which 7,8-dihydroxyflavone (DHF) inhibits oxidative stress-induced 8-oxoG formation in hamster lung fibroblasts (V79-4). DHF significantly reduced the amount of 8-oxoG induced by hydrogen peroxide (H2O2) and elevated the levels of OGG1 mRNA and protein. DHF increased the binding of nuclear factor erythroid 2-related factor 2 (Nrf2) to antioxidant response element sequences in the upstream promoter region of OGG1. Moreover, DHF increased the nuclear levels of Nrf2, small Maf proteins, and the Nrf2/small Maf complex, all of which are decreased by H2O2treatment. Likewise, the level of phosphorylated Akt, which activates Nrf2, was decreased by H2O2treatment but restored by DHF treatment. The levels of OGG1 and nuclear translocation of Nrf2 protein were decreased upon treatment with PI3K inhibitor or Akt inhibitor, and DHF treatment did not restore OGG1 and nuclear Nrf2 levels in these inhibitor-treated cells. Furthermore, PI3K and Akt inhibitors abolished the protective effects of DHF in cells undergoing oxidative stress. These data indicate that DHF induces OGG1 expression via the PI3K-Akt pathway and protects cells against oxidative DNA base damage by activating DNA repair systems.

scholarly journals Protective Effects of GYY4137 on Renal Ischaemia/Reperfusion Injury through Nrf2-Mediated Antioxidant Defence

2021 ◽  
pp. 1-9
Author(s):  
Hongmei Zhao ◽  
Yun Qiu ◽  
Yichen Wu ◽  
Hong Sun ◽  
Sumin Gao
Keyword(s):  
Oxidative Stress ◽  
Reperfusion Injury ◽  
Nuclear Translocation ◽  
Organ Damage ◽  
Related Factor ◽  
Protective Effects ◽  
Ischaemia Reperfusion Injury ◽  
Renal Ischaemia ◽  
Ischaemia Reperfusion ◽  
Renal Histology

<b><i>Introduction/Aims:</i></b> Hydrogen sulfide (H<sub>2</sub>S) is considered to be the third most important endogenous gasotransmitter in organisms. GYY4137 is a long-acting donor for H<sub>2</sub>S, a gas transmitter that has been shown to prevent multi-organ damage in animal studies. We previously reported the effect of GYY4137 on cardiac ischaemia reperfusion injury (IRI) in diabetic mice. However, the role and mechanism of GYY4137 in renal IRI are poorly understood. The aims of this study were to determine whether GYY4137 can effectively alleviate the injury induced by renal ischaemia reperfusion and to explore its possible mechanism. <b><i>Methods:</i></b> Mice received right nephrectomy and clipping of the left renal pedicle for 45 min. GYY4137 was administered by intraperitoneal injection for 2 consecutive days before the operation. The model of hypoxia/reoxygenation injury was established in HK-2 cells, which were pre-treated with or without GYY4137. Renal histology, function, apoptosis, and oxidative stress were measured. Western blot was used to measure the target ­protein after renal IRI. <b><i>Results:</i></b> The results indicated that GYY4137 had a clear protective effect on renal IRI as reflected by the attenuation of renal dysfunction, renal tubule injury, and apoptosis. Moreover, GYY4137 remarkably reduced renal IRI-induced oxidative stress. GYY4137 significantly elevated the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nrf2) and the expression of antioxidant enzymes regulated by Nrf2, including SOD, HO-1, and NQO-1. <b><i>Conclusions:</i></b> GYY4137 alleviates ischaemia reperfusion-induced renal injury through activating the antioxidant effect mediated by Nrf2 signalling.

scholarly journals Anti-Inflammatory and Antioxidant Effects of Soroseris hirsuta Extract by regulating iNOS/NF-κB and NRF2/HO-1 Pathways in Murine Macrophage RAW 264.7 Cells

2021 ◽  
Vol 11 (10) ◽  
pp. 4711
Author(s):  
Woo Jin Lee ◽  
Wan Yi Li ◽  
Sang Woo Lee ◽  
Sung Keun Jung
Keyword(s):  
Nitric Oxide ◽  
Nuclear Translocation ◽  
Antioxidant Properties ◽  
Raw 264.7 Cells ◽  
Heme Oxygenase 1 ◽  
Raw 264.7 ◽  
Related Factor ◽  
Iκb Kinase ◽  
Anti Inflammatory ◽  
Antioxidant Effects

Until now, the physiological effects of Soroseris hirsuta were primarily unknown. Here we have evaluated the anti-inflammatory and antioxidant effects of Soroseris hirsuta extract (SHE) on lipopolysaccharide (LPS)-activated murine macrophages RAW 264.7 cells. SHE inhibited nitric oxide expression and inducible nitric oxide synthase expression in RAW 264.7 cells treated with LPS. Moreover, SHE suppressed LPS-induced phosphorylation of IκB kinase, inhibitor of kappa B, p65, p38, and c-JUN N-terminal kinase. Western blot and immunofluorescence analyses showed that SHE suppressed p65 nuclear translocation induced by LPS. Furthermore, SHE inhibited the reactive oxygen species in LPS-treated RAW 264.7 cells. SHE significantly increased heme oxygenase-1 expression and the nuclear translocation of nuclear factor erythroid 2-related factor 2. SHE suppressed LPS-induced interleukin-1β mRNA expression in RAW 264.7 cells. Thus, SHE is a promising nutraceutical as it displays anti-inflammatory and antioxidant properties.

scholarly journals Floridoside Exhibits Antioxidant Properties by Activating HO-1 Expression via p38/ERK MAPK Pathway

Marine Drugs ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 105 ◽  
Author(s):  
Tingting Niu ◽  
Gaoqing Fu ◽  
Jiawei Zhou ◽  
Hui Han ◽  
Juanjuan Chen ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Mapk Pathway ◽  
Antioxidant Properties ◽  
Human Hepatocyte ◽  
Related Factor ◽  
Nrf2 Pathway ◽  
Erk Mapk ◽  
Antioxidant Mechanism ◽  
Extracellular Signal ◽  
Inhibitor Treatment

Floridoside is a low-molecular-weight organic compound, which can be accumulated by red algae under stressful conditions to protect cells via its excellent antioxidant properties. In the present study, we investigated the antioxidant mechanism of floridoside toward human hepatocyte L-02 cells. We found that floridoside had no toxicity to L-02 cells, and no reactive oxidative species were induced by it either. However, the expression of hemoxygenase-1 (HO-1) protein was up-regulated upon exposure to floridoside, and two antioxidant enzymes, superoxide dismutase (SOD) and GSH-Px, were activated by floridoside. Moreover, we investigated the pathway involved in the production of these antioxidants, p38/extracellular signal-regulated kinase (ERK) MAPK-nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway. ERK1/2 and p38 phosphorylation, nuclear translocation of Nrf2, and activation of ARE luciferase activity were observed upon exposure to floridoside. siRNA interference and inhibitor treatment suppressed the HO-1 expression and the phosphorylation of ERK1/2 and p38, respectively. These results indicated that floridoside exerted its antioxidant activity by activating HO-1 expression via p38/ERK MAPK-Nrf2 pathway in human hepatocyte L-02 cells.

scholarly journals Nicotinamide Riboside Inhibits Alcohol-Induced Inflammation and Oxidative Stress in Macrophages

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 410-410
Author(s):  
Hyunju Kang ◽  
Young-Ki Park ◽  
Ji-Young Lee
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Mitochondrial Respiration ◽  
Nuclear Translocation ◽  
Antioxidant Properties ◽  
Sirtuin 1 ◽  
Mouse Bone Marrow ◽  
Nicotinamide Riboside ◽  
Mitochondrial Dna Copy Number ◽  
And Oxidative Stress

Abstract Objectives Macrophages play an essential role in the development of alcohol-induced inflammation. The objective of this study was to investigate whether nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD+) precursor naturally found in milk, can attenuate alcohol-induced inflammation and oxidative stress in macrophages with the elucidation of mechanisms of action. Methods RAW 264.7 macrophages and mouse bone marrow-derived macrophages (BMDMs) were stimulated with 80 mM ethanol with or without 1 mM of NR for 72 h. Expression of genes associated with inflammation and oxidative stress and cellular reactive oxygen species (ROS) accumulation were measured. Also, to evaluate the contribution of sirtuin 1 (SIRT1) to the NR's effect, cellular NAD + level (a cofactor of SIRT1), SIRT1 activity, and mitochondrial DNA copy number were measured. SIRT1 activity was inhibited or activated by sirtinol and resveratrol, respectively, to confirm SIRT1 functions further. Parameters related to mitochondrial respiration were determined using a Seahorse XFe24 Extracellular Flux analyzer. Results NR significantly decreased ethanol-induced inflammatory gene expression, with a concomitant decrease in nuclear translocation of nuclear factor kB p65 in macrophages. Increased cellular ROS levels by ethanol were also attenuated concomitantly with decreased expression of NADPH oxidase 2, a ROS-producing enzyme, by NR in both macrophage cell types. Ethanol decreased SIRT1 mRNA, protein and activity, cellular NAD + level, and mitochondrial DNA, all of which were markedly attenuated by NR. SIRT1 inhibition by sirtinol augmented the inflammatory effects of ethanol, while SIRT1 activation by resveratrol elicited the opposing results. Ethanol increased mitochondrial respiration, ATP production, and proton leak, but decreased maximal respiration and spare respiratory capacity. The ethanol-induced changes in mitochondrial respiration were abolished by NR. Conclusions NR showed anti-inflammatory and antioxidant properties in ethanol-treated macrophages by counteracting the effect of ethanol on lowering SIRT1 expression and cellular NAD+ levels. Therefore, NR may be a potential therapeutic agent for alcohol-induced inflammation and oxidative stress. Funding Sources This work is supported by the NIH 3R01DK108254-04S1.

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