scholarly journals Keap1 Cystenine 151 as a Potential Target for Artemisitene-Induced Nrf2 Activation

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Shanshan Liu ◽  
Shengmei Xu ◽  
Renrong Wei ◽  
Zhizhong Cui ◽  
Xiaoyun Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Lines ◽  
Underlying Mechanism ◽  
Nuclear Factor ◽  
Potential Target ◽  
Nrf2 Activation ◽  
Redox Sensors ◽  
Pharmacological Basis

Artemisitene (ATT) activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) by increasing its stabilization and reducing ubiquitination. The cysteine (Cys) residues of the cytosolic Nrf2 repressor Kelch-like ECH-associated protein-1 (Keap1) function as redox sensors and may be crucial in activating Nrf2. To determine whether ATT-induced Nrf2 activation is dependent on the modification of Keap1 and to elucidate the underlying mechanism, we transfected cell lines with six different Keap1 mutant constructs, each with a Cys (−77, −151, −257, −273, −288, and −297) to Ser substitution. Only the Cys151Ser mutant prevented ATT-mediated activation of Nrf2, indicating that the Cys151 residue of Keap1 likely interacts with ATT and is essential for Nrf2 stabilization and transcription of downstream genes. Our finding provides a pharmacological basis for using artemisitene against oxidative stress-related diseases.

scholarly journals Caffeine Modulates Cadmium-Induced Oxidative Stress, Neuroinflammation, and Cognitive Impairments by Regulating Nrf-2/HO-1 In Vivo and In Vitro

2019 ◽  
Vol 8 (5) ◽  
pp. 680 ◽  
Author(s):  
Amjad Khan ◽  
Muhammad Ikram ◽  
Tahir Muhammad ◽  
Junsung Park ◽  
Myeong Ok Kim
Keyword(s):  
Oxidative Stress ◽  
Cell Lines ◽  
Cognitive Deficits ◽  
Calcium Binding ◽  
Neuronal Loss ◽  
Treated Group ◽  
Nuclear Factor ◽  
Acute And Chronic Exposure

Cadmium (Cd), a nonbiodegradable heavy metal and one of the most neurotoxic environmental and industrial pollutants, promotes disturbances in major organs and tissues following both acute and chronic exposure. In this study, we assessed the neuroprotective potential of caffeine (30 mg/kg) against Cd (5 mg/kg)-induced oxidative stress-mediated neuroinflammation, neuronal apoptosis, and cognitive deficits in male C57BL/6N mice in vivo and in HT-22 and BV-2 cell lines in vitro. Interestingly, our findings indicate that caffeine markedly reduced reactive oxygen species (ROS) and lipid peroxidation (LPO) levels and enhanced the expression of nuclear factor-2 erythroid-2 (Nrf-2) and hemeoxygenase-1 (HO-1), which act as endogenous antioxidant regulators. Also, 8-dihydro-8-oxoguanine (8-OXO-G) expression was considerably reduced in the caffeine-treated group as compared to the Cd-treated group. Similarly, caffeine ameliorated Cd-mediated glial activation by reducing the expression of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), and other inflammatory mediators in the cortical and hippocampal regions of the mouse brain. Moreover, caffeine markedly attenuated Cd-induced neuronal loss, synaptic dysfunction, and learning and cognitive deficits. Of note, nuclear factor-2 erythroid-2 (Nrf-2) gene silencing and nuclear factor-κB (NF-κB) inhibition studies revealed that caffeine exerted neuroprotection via regulation of Nrf-2- and NF-κB-dependent mechanisms in the HT-22 and BV-2 cell lines, respectively. On the whole, these findings reveal that caffeine rescues Cd-induced oxidative stress-mediated neuroinflammation, neurodegeneration, and memory impairment. The present study suggests that caffeine might be a potential antioxidant and neuroprotective agent against Cd-induced neurodegeneration.

scholarly journals NRF2 as a regulator of cell metabolism and inflammation in cancer

2020 ◽  
Vol 41 (4) ◽  
pp. 405-416 ◽  
Author(s):  
Feng He ◽  
Laura Antonucci ◽  
Michael Karin
Keyword(s):  
Oxidative Stress ◽  
Cancer Risk ◽  
Poor Prognosis ◽  
Cell Metabolism ◽  
Transcriptional Regulator ◽  
Negative Control ◽  
Metabolic Reprogramming ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nrf2 Activation

Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of genes whose products defend our cells for toxic and oxidative insults. Although NRF2 activation may reduce cancer risk by suppressing oxidative stress and tumor-promoting inflammation, many cancers exhibit elevated NRF2 activity either due to mutations that disrupt the negative control of NRF2 activity or other factors. Importantly, NRF2 activation is associated with poor prognosis and NRF2 has turned out to be a key activator of cancer-supportive anabolic metabolism. In this review, we summarize the diverse roles played by NRF2 in cancer focusing on metabolic reprogramming and tumor-promoting inflammation.

Epimedium koreanum Ameliorates Oxidative Stress-Mediated Liver Injury by Activating Nuclear Factor Erythroid 2-Related Factor 2

2018 ◽  
Vol 46 (02) ◽  
pp. 469-488 ◽  
Author(s):  
Ji Yun Jung ◽  
Sang Mi Park ◽  
Hae Li Ko ◽  
Jong Rok Lee ◽  
Chung A Park ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Hepg2 Cells ◽  
Liver Diseases ◽  
Caspase 3 ◽  
Glutathione Depletion ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nrf2 Activation ◽  
Anti Oxidant

Oxidative stress induced by reactive oxygen species is the main cause of various liver diseases. This study investigated the hepatoprotective effect of Epimedium koreanum Nakai water extract (EKE) against arachidonic acid (AA)[Formula: see text][Formula: see text][Formula: see text]iron-mediated cytotoxicity in HepG2 cells and carbon tetrachloride (CCl4-)-mediated acute liver injury in mice. Pretreatment with EKE (30 and 100[Formula: see text][Formula: see text]g/mL) significantly inhibited AA[Formula: see text][Formula: see text][Formula: see text]iron-mediated cytotoxicity in HepG2 cells by preventing changes in the expression of cleaved caspase-3 and poly(ADP-ribose) polymerase. EKE attenuated hydrogen peroxide production, glutathione depletion, and mitochondrial membrane dysfunction. EKE also increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), transactivated anti-oxidant response element harboring luciferase activity, and induced the expression of anti-oxidant genes. Furthermore, the cytoprotective effect of EKE against AA[Formula: see text][Formula: see text][Formula: see text]iron was blocked in Nrf2 knockout cells. Ultra-performance liquid chromatography analysis showed that EKE contained icariin, icaritin, and quercetin; icaritin and quercetin were both found to protect HepG2 cells from AA[Formula: see text][Formula: see text][Formula: see text]iron via Nrf2 activation. In a CCl4-induced mouse model of liver injury, pretreatment with EKE (300[Formula: see text]mg/kg) for four consecutive days ameliorated CCl4-mediated increases in serum aspartate aminotransferase activity, histological activity index, hepatic parenchyma degeneration, and inflammatory cell infiltration. EKE also decreased the number of nitrotyrosine-, 4-hydroxynonenal-, cleaved caspase-3-, and cleaved poly(ADP-ribose) polymerase-positive cells in hepatic tissues. These results suggest EKE is a promising candidate for the prevention or treatment of oxidative stress-related liver diseases via Nrf2 activation.

scholarly journals Therapeutic Effects of Specialized Pro-Resolving Lipids Mediators on Cardiac Fibrosis via NRF2 Activation

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1259
Author(s):  
Gyeoung Jin Kang ◽  
Eun Ji Kim ◽  
Chang Hoon Lee
Keyword(s):  
Oxidative Stress ◽  
Cardiac Fibrosis ◽  
Lipid Mediators ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Nuclear Factor ◽  
Docosahexanoic Acid ◽  
Nrf2 Activation ◽  
The World ◽  
Polyunsaturated Lipids

Heart disease is the number one mortality disease in the world. In particular, cardiac fibrosis is considered as a major factor causing myocardial infarction and heart failure. In particular, oxidative stress is a major cause of heart fibrosis. In order to control such oxidative stress, the importance of nuclear factor erythropoietin 2 related factor 2 (NRF2) has recently been highlighted. In this review, we will discuss the activation of NRF2 by docosahexanoic acid (DHA), eicosapentaenoic acid (EPA), and the specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated lipids, including DHA and EPA. Additionally, we will discuss their effects on cardiac fibrosis via NRF2 activation.

scholarly journals Role of Nuclear Factor Erythroid 2-Related Factor 2 in Diabetic Nephropathy

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Wenpeng Cui ◽  
Xu Min ◽  
Xiaohong Xu ◽  
Bing Du ◽  
Ping Luo
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Cellular Response ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Nuclear Factor ◽  
Urinary Protein Level ◽  
Nrf2 Activation ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is manifested as increased urinary protein level, decreased glomerular filtration rate, and final renal dysfunction. DN is the leading cause of end-stage renal disease worldwide and causes a huge societal healthcare burden. Since satisfied treatments are still limited, exploring new strategies for the treatment of this disease is urgently needed. Oxidative stress takes part in the initiation and development of DN. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the cellular response to oxidative stress. Thus, activation of Nrf2 seems to be a new choice for the treatment of DN. In current review, we discussed and summarized the therapeutic effects of Nrf2 activation on DN from both basic and clinical studies.

scholarly journals Therapeutic Agents with AHR Inhibiting and NRF2 Activating Activity for Managing Chloracne

Antioxidants ◽  
2018 ◽  
Vol 7 (7) ◽  
pp. 90 ◽  
Author(s):  
Masutaka Furue ◽  
Yoko Fuyuno ◽  
Chikage Mitoma ◽  
Hiroshi Uchi ◽  
Gaku Tsuji
Keyword(s):  
Oxidative Stress ◽  
Therapeutic Agents ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Cytochrome P450 1A1 ◽  
Skin Symptom ◽  
Aryl Hydrocarbon ◽  
Nrf2 Activation ◽  
Dual Functions

Chloracne is the major skin symptom caused by dioxin intoxication. Dioxin activates the aryl hydrocarbon receptor (AHR)–cytochrome p450 1A1 (CYP1A1) system, generates oxidative stress, and induces hyperkeratinization of keratinocytes and sebocytes leading to chloracne. Nuclear factor-erythroid 2-related factor-2 (NRF2) is a master switch that induces the expression of various antioxidative enzymes, such as heme oxygenase-1. Cinnamaldehyde is an antioxidant phytochemical that inhibits AHR–CYP1A1 signaling and activates the NRF2–antioxidative axis. The cinnamaldehyde-containing Kampo herbal medicine Keishibukuryogan is capable of improving chloracne in Yusho patients who are highly contaminated with dioxin. Agents with dual functions in promoting AHR–CYP1A1 inhibition and NRF2 activation may be useful for managing dioxin-related health hazards.

Abstract 175: Activation of Nrf2 by Exercise Training and Curcumin Contributes to Sympatho-Inhibition in Heart Failure

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Karla K Haack ◽  
Amanda M Harlow ◽  
Hanjun Wang ◽  
Irving H Zucker
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Exercise Training ◽  
Western Blot ◽  
Related Factor ◽  
Nuclear Factor ◽  
Sympathetic Outflow ◽  
Post Surgery ◽  
Nrf2 Activation ◽  
And Oxidative Stress

Chronic Heart Failure (CHF) is a disease characterized by increased Angiotensin II type 1 receptor (AT1R) signaling, sympathetic outflow, and oxidative stress. In conditions of high oxidant stress, Nuclear factor erythroid 2 related factor 2 (Nrf2) is dissociated from Kelch-like ECH associated protein 1 (Keap1) to activate antioxidant response element (ARE)genes. Nuclear factor kappa B (NF-kB) is a transcription factor downstream of AT1R that inhibits ARE transcription . Exercise training (ExT) decreases sympathetic outflow and oxidative stress, but the mechanism(s) by which ExT is protective remain unclear. The aim of this study was to investigate if ExT indirectly activates Nrf2 and if direct Nrf2 activation by curcumin (Cur) in rats with CHF would decrease sympatho-excitation and normalize AT1R pathway overactivation. Rats were ExT for 4 weeks post-surgery on a treadmill at a final speed of 25 m/min for 60 minutes, 5 days a week for 6 weeks. Western blot analyses of RVLM micropunches are summarized in the Table. Briefly, in CHF, there was a significant upregulation in NF-kB and Keap1 and a decrease in Nrf2 protein compared to sham. ExT significantly increased Nrf2 expression compared to both sham and CHF groups but normalized NF-kB and AT1R expression in CHF animals. Oral Cur (200mg/kg/day) decreased resting HR, urinary norepinephrine excretion, and renal sympathetic nerve activity in CHF animals. Western blot analyses indicated that Cur increased Nrf2, decreased NF-kB and normalized AT1R expression in the RVLM (Table). Taken together, Nrf2 activation may be protective in normalizing AT1R expression in CHF and one of the mechanisms by which ExT exerts its beneficial effects.

scholarly journals Nuclear factor erythroid 2-related factor 2 activation mediates hyperhomocysteinemia-associated lipolysis suppression in adipocytes

2018 ◽  
Vol 243 (11) ◽  
pp. 926-933 ◽  
Author(s):  
Xin Li ◽  
Yuhong Cheng ◽  
Xiuli Zhong ◽  
Bing Zhang ◽  
Zhiwei Bao ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Epigallocatechin Gallate ◽  
Underlying Mechanism ◽  
Control Group ◽  
Related Factor ◽  
Nuclear Factor ◽  
Glycerol Release ◽  
Nrf2 Activation

Hyperhomocysteinemia (HHcy) is associated with suppressed lipolytic response in adipocytes/adipose tissue, however, the underlying mechanism remains to be extensively studied. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcriptional factor regulating antioxidant generation, has been recently reported to mediate lipid metabolism. Employing both fully differentiated 3T3-L1 adipocytes and male C57BL/6 mice, in the present study, we investigated the potential involvement of Nrf2 activation in HHcy-mediated lipolytic suppression. Our results showed that homocysteine (Hcy) treatment resulted in suppressed lipolysis, evidenced by increased intracellular triglyceride (TG) accumulation, decreased glycerol and free fatty acid (FFA) in fully differentiated 3T3-L1 adipocytes. Interestingly, Hcy exposure was associated with Nrf2 activation in adipocytes. Further studies showed that Nrf2 knockdown via siRNA transfection ameliorated Hcy-induced glycerol release in adipocytes. On the contrary, Nrf2 activators, epigallocatechin gallate (EGCG) and tert-butylhydroquinone (t-BHQ), increased intracellular TG content and decreased glycerol release in adipocytes. Importantly, our in vitro observations were corroborated by our in vivo findings, in which Hcy feeding (0.1% wt/vol) for four weeks induced Nrf2 expression in adipose tissue and lowered circulating FFA and glycerol levels in mice. Furthermore, EGCG injection (5 mg/kg/d) decreased circulating glycerol levels in comparison to the control group in mice. In conclusion, these results indicated that Nrf2 activation in response to HHcy plays an important role in mediating Hcy-suppressed lipolysis in adipocytes.

scholarly journals Prodigiosin Promotes Nrf2 Activation to Inhibit Oxidative Stress Induced by Microcystin-LR in HepG2 Cells

Toxins ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 403 ◽  
Author(s):  
Jihua Chen ◽  
Yuji Li ◽  
Fuqiang Liu ◽  
De-Xing Hou ◽  
Jingjing Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepg2 Cells ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Anticancer Properties ◽  
Nrf2 Activation ◽  
Nrf2 Protein ◽  
Related Phase

Microcystin-LR (MC-LR), a cyanotoxin produced by cyanobacteria, induces oxidative stress in various types of cells. Prodigiosin, a red linear tripyrrole pigment, has been recently reported to have antimicrobial, antioxidative, and anticancer properties. How prodigiosin reacts to reactive oxygen species (ROS) induced by MC-LR is still undetermined. This study aimed to examine the effect of prodigiosin against oxidative stress induced by MC-LR in HepG2 cells. Ros was generated after cells were treated with MC-LR and was significantly inhibited with treatment of prodigiosin. In prodigiosin-treated cells, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-related phase II enzyme heme oxygenase-1 (HO-1) were increased. Besides, prodigiosin contributed to enhance nuclear Nrf2 level and repressed ubiquitination. Furthermore, prodigiosin promoted Nrf2 protein level and inhibited ROS in Nrf2 knocked down HepG2 cells. Results indicated that prodigiosin reduced ROS induced by MC-LR by enhancing Nrf2 translocation into the nucleus in HepG2 cells. The finding presents new clues for the potential clinical applications of prodigiosin for inhibiting MC-LR-induced oxidative injury in the future.

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