scholarly journals NRF2 Is a Potential Modulator of Hyperresistance to Arsenic Toxicity in Stem-Like Keratinocytes

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Xiafang Wu ◽  
Bei Yang ◽  
Yuxin Hu ◽  
Ru Sun ◽  
Huihui Wang ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Antioxidant Defense ◽  
Arsenic Exposure ◽  
Human Keratinocytes ◽  
Related Factor ◽  
Nuclear Factor ◽  
Arsenic Toxicity ◽  
Human Carcinogen ◽  
Survival Selection ◽  
Underlying Mechanisms

Arsenic is a well-known human carcinogen. Stem cells are indicated to be involved in arsenic carcinogenesis and have a survival selection advantage during arsenic exposure with underlying mechanisms undefined. In the present study, we demonstrated that CD34high-enriched cells derived from HaCaT human keratinocytes showed stem-like phenotypes. These cells were more resistant to arsenic toxicity and had higher arsenic efflux ability than their mature compartments. The master transcription factor in antioxidant defense, nuclear factor erythroid 2-related factor 2 (NRF2) with its downstream genes, was highly expressed in CD34high-enriched cells. Stable knockdown ofNRF2abolished the hyperresistance to arsenic toxicity and holoclone-forming ability of CD34high-enriched cells. Our results suggest that skin epithelial stem/progenitor cells are more resistant to arsenic toxicity than mature cells, which is associated with the high innate expression ofNRF2in skin epithelial stem/progenitor cells.

scholarly journals Camu-Camu Fruit Extract Inhibits Oxidative Stress and Inflammatory Responses by Regulating NFAT and Nrf2 Signaling Pathways in High Glucose-Induced Human Keratinocytes

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3174
Author(s):  
Nhung Quynh Do ◽  
Shengdao Zheng ◽  
Bom Park ◽  
Quynh T. N. Nguyen ◽  
Bo-Ram Choi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathways ◽  
High Glucose ◽  
Skin Diseases ◽  
Inflammatory Responses ◽  
Human Keratinocytes ◽  
Related Factor ◽  
Nuclear Factor ◽  
Fruit Extract ◽  
Activated T Cells

Myrciaria dubia (HBK) McVaugh (camu-camu) belongs to the family Myrtaceae. Although camu-camu has received a great deal of attention for its potential pharmacological activities, there is little information on the anti-oxidative stress and anti-inflammatory effects of camu-camu fruit in skin diseases. In the present study, we investigated the preventative effect of 70% ethanol camu-camu fruit extract against high glucose-induced human keratinocytes. High glucose-induced overproduction of reactive oxygen species (ROS) was inhibited by camu-camu fruit treatment. In response to ROS reduction, camu-camu fruit modulated the mitogen-activated protein kinases (MAPK)/activator protein-1 (AP-1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and nuclear factor of activated T cells (NFAT) signaling pathways related to inflammation by downregulating the expression of proinflammatory cytokines and chemokines. Furthermore, camu-camu fruit treatment activated the expression of nuclear factor E2-related factor 2 (Nrf2) and subsequently increased the NAD(P)H:quinone oxidoreductase1 (NQO1) expression to protect keratinocytes against high-glucose-induced oxidative stress. These results indicate that camu-camu fruit is a promising material for preventing oxidative stress and skin inflammation induced by high glucose level.

scholarly journals The Protective Role of Feruloylserotonin in LPS-Induced HaCaT Cells

Molecules ◽  
2019 ◽  
Vol 24 (17) ◽  
pp. 3064 ◽  
Author(s):  
Yuzhu He ◽  
Byung-gook Kim ◽  
Hye-Eun Kim ◽  
Qiaochu Sun ◽  
Shuhan Shi ◽  
...  
Keyword(s):  
Antioxidant Activities ◽  
Protective Role ◽  
Related Factor ◽  
Nuclear Factor ◽  
Hacat Cells ◽  
Protective Effects ◽  
Hydroxycinnamic Acid Amides ◽  
Anti Inflammatory ◽  
Underlying Mechanisms

Epidermal inflammation is caused by various bacterial infectious diseases that impair the skin health. Feruloylserotonin (FS) belongs to the hydroxycinnamic acid amides of serotonin, which mainly exists in safflower seeds and has been proven to have anti-inflammatory and antioxidant activities. Human epidermis mainly comprises keratinocytes whose inflammation causes skin problems. This study investigated the protective effects of FS on the keratinocyte with lipopolysaccharides (LPS)-induced human HaCaT cells and elucidated its underlying mechanisms of action. The mechanism was investigated by analyzing cell viability, PGE2 levels, cell apoptosis, nuclear factor erythroid 2-related factor 2 (Nrf2) translocation, and TLR4/NF-κB pathway. The anti-inflammatory effects of FS were assessed by inhibiting the inflammation via down-regulating the TLR4/NF-κB pathway. Additionally, FS promoted Nrf2 translocation to the nucleus, indicating that FS showed anti-oxidative activities. Furthermore, the antioxidative and anti-inflammatory effects of FS were found to benefit each other, but were independent. Thus, FS can be used as a component to manage epidermal inflammation due to its anti-inflammatory and anti-oxidative properties.

scholarly journals Loss of Sigma-1 Receptor Chaperone Promotes Astrocytosis and Enhances the Nrf2 Antioxidant Defense

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Tzu-Yu Weng ◽  
Denise T. Hung ◽  
Tsung-Ping Su ◽  
Shang-Yi A. Tsai
Keyword(s):  
Control Systems ◽  
Antioxidant Defense ◽  
Stress Condition ◽  
Expression Profiles ◽  
Related Factor ◽  
Nuclear Factor ◽  
Sigma 1 Receptor ◽  
Ubiquitinated Proteins ◽  
Brain Expression ◽  
Sigma 1

Sigma-1 receptor (Sig-1R) functions as a chaperon that interacts with multiple proteins and lipids and is implicated in neurodegenerative and psychiatric diseases. Here, we used Sig-1R KO mice to examine brain expression profiles of astrocytes and ubiquitinated proteins, which are both hallmarks of central nervous system (CNS) pathologies. Our results showed that Sig-1R KO induces increased glial fibrillary acidic protein (GFAP) expression in primary neuron-glia cultures and in the whole brain of fetus mice with concomitantly increased accumulations of ubiquitinated proteins. Astrogliosis was also observed in the neuron-glia culture. Upon proteasome or autophagy inhibitor treatments, the pronounced ubiquitinated proteins were further increased in Sig-1R KO neurons, indicating that the Sig-1R regulates both protein degradation and quality control systems. We found that Nrf2 (nuclear factor erythroid 2-related factor 2), which functions to overcome the stress condition, was enhanced in the Sig-1R KO systems especially when cells were under stressful conditions. Mutation or deficiency of Sig-1Rs has been observed in neurodegenerative models. Our study identifies the critical roles of Sig-1R in CNS homeostasis and supports the idea that functional complementation pathways are triggered in the Sig-1R KO pathology.

scholarly journals Autophagy inhibition enables Nrf2 to exaggerate the progression of diabetic cardiomyopathy in mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Huimei Zang ◽  
Weiwei Wu ◽  
Lei Qi ◽  
Wenbin Tan ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Antioxidant Defense ◽  
Myocardial Damage ◽  
Related Factor ◽  
Nrf2 Knockout ◽  
Underlying Mechanisms ◽  
Autophagy Inhibition ◽  
And Oxidative Stress

Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) may either ameliorate or worsen diabetic cardiomyopathy. However, the underlying mechanisms are poorly understood. Herein we report a novel mechanism of Nrf2-mediated myocardial damage in type 1 diabetes (T1D). Global Nrf2 knockout (Nrf2KO) hardly affected the onset of cardiac dysfunction induced by T1D but slowed down its progression in mice independent of sex. In addition, Nrf2KO inhibited cardiac pathological remodeling, apoptosis and oxidative stress associated with both onset and advancement of cardiac dysfunction in T1D. Such Nrf2-mediated progression of diabetic cardiomyopathy was confirmed by cardiomyocyte-restricted (CR) Nrf2 transgenic (Tg) approach in mice. Moreover, cardiac autophagy inhibition via CR KO of autophagy related 5 gene (CR-Atg5KO) led to early onset and accelerated development of cardiomyopathy in T1D, and CR-Atg5KO-induced adverse phenotypes were rescued by additional Nrf2KO. Mechanistically, chronic T1D leads to glucolipotoxicity inhibiting autolysosome efflux, which in turn intensifies Nrf2-driven transcription to fuel lipid peroxidation while inactivating Nrf2-mediated antioxidant defense and impairing Nrf2-coordinated iron metabolism, thereby leading to ferroptosis in cardiomyocytes. These results demonstrate that diabetes over time causes autophagy deficiency, which turns off Nrf2-mediated defense while switching on Nrf2-operated pathological program toward ferroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy.

scholarly journals Autophagy inhibition enables Nrf2 to exaggerate the progression of diabetic cardiomyopathy in mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Huimei Zang ◽  
Weiwei Wu ◽  
Lei Qi ◽  
Wenbin Tan ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Antioxidant Defense ◽  
Myocardial Damage ◽  
Related Factor ◽  
Nrf2 Knockout ◽  
Underlying Mechanisms ◽  
Autophagy Inhibition ◽  
And Oxidative Stress

Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) may either ameliorate or worsen diabetic cardiomyopathy. However, the underlying mechanisms are poorly understood. Herein we report a novel mechanism of Nrf2-mediated myocardial damage in type 1 diabetes (T1D). Global Nrf2 knockout (Nrf2KO) hardly affected the onset of cardiac dysfunction induced by T1D but slowed down its progression in mice independent of sex. In addition, Nrf2KO inhibited cardiac pathological remodeling, apoptosis and oxidative stress associated with both onset and advancement of cardiac dysfunction in T1D. Such Nrf2-mediated progression of diabetic cardiomyopathy was confirmed by cardiomyocyte-restricted (CR) Nrf2 transgenic (Tg) approach in mice. Moreover, cardiac autophagy inhibition via CR KO of autophagy related 5 gene (CR-Atg5KO) led to early onset and accelerated development of cardiomyopathy in T1D, and CR-Atg5KO-induced adverse phenotypes were rescued by additional Nrf2KO. Mechanistically, chronic T1D leads to glucolipotoxicity inhibiting autolysosome efflux, which in turn intensifies Nrf2-driven transcription to fuel lipid peroxidation while inactivating Nrf2-mediated antioxidant defense and impairing Nrf2-coordinated iron metabolism, thereby leading to ferroptosis in cardiomyocytes. These results demonstrate that diabetes over time causes autophagy deficiency, which turns off Nrf2-mediated defense while switching on Nrf2-operated pathological program toward ferroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy.

scholarly journals Myocardial infarction-induced microRNA-enriched exosomes contribute to cardiac Nrf2 dysregulation in chronic heart failure

2018 ◽  
Vol 314 (5) ◽  
pp. H928-H939 ◽  
Author(s):  
Changhai Tian ◽  
Lie Gao ◽  
Matthew C. Zimmerman ◽  
Irving H. Zucker
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Chronic Heart Failure ◽  
Antioxidant Defense ◽  
Defense Mechanism ◽  
Pcr Analysis ◽  
Related Factor ◽  
Nuclear Factor ◽  
New Findings ◽  
Antioxidant Defense Systems

The imbalance between the synthesis of reactive oxygen species and their elimination by antioxidant defense systems results in macromolecular damage and disruption of cellular redox signaling, affecting cardiac structure and function, thus contributing to contractile dysfunction, myocardial hypertrophy, and fibrosis in chronic heart failure [chronic heart failure (CHF)]. The Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is an important antioxidant defense mechanism and is closely associated with oxidative stress-mediated cardiac remodeling in CHF. In the present study, we investigated the regulation of myocardial Nrf2 in the postmyocardial infarction (post-MI) state. Six weeks post-MI, Nrf2 protein was downregulated in the heart, resulting in a decrease of Nrf2-targeted antioxidant enzymes, whereas paradoxically the transcription of Nrf2 was increased, suggesting that translational inhibition of Nrf2 may contribute to the dysregulation in CHF. We therefore hypothesized that microRNAs may be involved in the translational repression of Nrf2 mRNA in the setting of CHF. Using quantitative real-time PCR analysis, we found that three microRNAs, including microRNA-27a, microRNA-28-3p, and microRNA-34a, were highly expressed in the left ventricle of infarcted hearts compared with other organs. Furthermore, in vitro analysis revealed that cultured cardiac myocytes and fibroblasts expressed these three microRNAs in response to TNF-α stimulation. These microRNAs were preferentially incorporated into exosomes and secreted into the extracellular space in which microRNA-enriched exosomes mediated intercellular communication and Nrf2 dysregulation. Taken together, these results suggest that increased local microRNAs induced by MI may contribute to oxidative stress by the inhibition of Nrf2 translation in CHF. NEW & NOTEWORTHY The results of this work provide a novel mechanism mediated by microRNA-enriched exosomes, contributing to the nuclear factor erythroid 2-related factor 2 dysregulation and subsequent oxidative stress. Importantly, these new findings will provide a promising strategy to improve the therapeutic efficacy through targeting nuclear factor erythroid 2-related factor 2-related microRNAs in the chronic heart failure state, which show potentially clinical applications.

scholarly journals Fucoxanthin Inhibits Lipopolysaccharide-Induced Inflammation and Oxidative Stress by Activating Nuclear Factor E2-Related Factor 2 in Macrophages

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 116-116
Author(s):  
Mi-Bo Kim ◽  
Hyunju Kang ◽  
Ji-Young Lee
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Capacity ◽  
Nuclear Translocation ◽  
Radical Scavenging ◽  
Raw 264.7 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Underlying Mechanisms ◽  
Antioxidant Effects ◽  
And Oxidative Stress

Abstract Objectives Anti-inflammatory and antioxidant effects of fucoxanthin (FCX), a carotenoid present in edible brown seaweeds, have been suggested. However, the underlying mechanisms have not been fully understood. The objectives of this study were to determine whether FCX can inhibit lipopolysaccharide (LPS)-induced inflammation and oxidative stress and to elucidate the underlying mechanisms in macrophages. Methods Cytotoxicity of FCX (0–15 μM) was measured in RAW 264.7 macrophage. The effects of the FCX on LPS-induced inflammatory cytokine and antioxidant gene expression were determined in RAW 264.7 macrophages by quantitative realtime PCR, Western blot, and enzyme-linked immunosorbent assays. Cellular reactive oxygen species (ROS) accumulation was measured in LPS-induced RAW 264.7 macrophage. The antioxidant capacity was also determined by 2,2′-azinobis (3-ethylbenzothiazoline 6-sulfonate) (ABTS) radical scavenging activity expressed by trolox equivalent antioxidant capacity (TEAC). Also, a potential role of phosphatidylinositol 3-kinase (PI3K)/nuclear factor E2-related factor 2 (NRF2) axis, a crucial pathway in endogenous antioxidant defense, in the FCX effects was evaluated. Results Cells treated with 5 μM FCX were 90%<viable. LPS significantly increased mRNA levels of interleukin (Il)-6, Il-1β, and tumor necrosis factor α (Tnf) as well as TNFα secretion, which were significantly decreased by FCX. Elevated levels of cellular ROS levels by LPS were abolished by FCX with a concomitant increase in the expression of antioxidant enzymes. ABTS assay demonstrated that FCX had a stronger free radical scavenging property (57.6 TEAC μM/100 μM). Also, FCX significantly increased Nrf2 and heme oxygenase 1 expression compared to LPS control. LPS increased the nuclear translocation of NRF2, which was further increased by FCX. Interestingly, LY294002, an inhibitor of PI3K, noticeably decreased the effect of FCX on NRF2 nuclear translocation. Conclusions FCX exerts anti-inflammatory and antioxidant effects by the activation of NRF2 in LPS-induced macrophages. The increase in NRF2 nuclear translocation is mediated, at least in part, through the PI3K pathway. Funding Sources This study was supported by National Research Foundation of Korea (2019R1A6A3A03032678).

scholarly journals Nuclear Factor-Erythroid 2-Related Factor 2 (Nrf2) and Mitochondrial Dynamics/Mitophagy in Neurological Diseases

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 617 ◽  
Author(s):  
Tae-Cheon Kang
Keyword(s):  
Quality Control ◽  
Antioxidant Defense ◽  
Mitochondrial Dynamics ◽  
Neurological Diseases ◽  
Redox Homeostasis ◽  
Related Factor ◽  
Nuclear Factor ◽  
Antioxidant Defense Enzymes ◽  
Antioxidant Defense Systems ◽  
The Relationship

Mitochondria play an essential role in bioenergetics and respiratory functions for cell viability through numerous biochemical processes. To maintain mitochondria quality control and homeostasis, mitochondrial morphologies change rapidly in response to external insults and changes in metabolic status through fusion and fission (so called mitochondrial dynamics). Furthermore, damaged mitochondria are removed via a selective autophagosomal process, referred to as mitophagy. Although mitochondria are one of the sources of reactive oxygen species (ROS), they are themselves vulnerable to oxidative stress. Thus, endogenous antioxidant defense systems play an important role in cell survival under physiological and pathological conditions. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that maintains redox homeostasis by regulating antioxidant-response element (ARE)-dependent transcription and the expression of antioxidant defense enzymes. Although the Nrf2 system is positively associated with mitochondrial biogenesis and mitochondrial quality control, the relationship between Nrf2 signaling and mitochondrial dynamics/mitophagy has not been sufficiently addressed in the literature. This review article describes recent clinical and experimental observations on the relationship between Nrf2 and mitochondrial dynamics/mitophagy in various neurological diseases.

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