scholarly journals Nrf2 Activation and Its Coordination with the Protective Defense Systems in Response to Electrophilic Stress

2020 ◽  
Vol 21 (2) ◽  
pp. 545 ◽  
Author(s):  
Takamitsu Unoki ◽  
Masahiro Akiyama ◽  
Yoshito Kumagai
Keyword(s):  
Related Factor ◽  
Sulfur Species ◽  
Molecular Responses ◽  
Nrf2 Pathway ◽  
Defense Systems ◽  
Nrf2 Activation ◽  
Sensor Protein ◽  
Electrophilic Stress ◽  
Essential Function ◽  
Sensor Proteins

Molecular responses mediated by sensor proteins are important for biological defense against electrophilic stresses, such as xenobiotic electrophile exposure. NF-E2-related factor 2 (Nrf2) has an essential function as a master regulator of such cytoprotective molecular responses along with sensor protein Kelch-like ECH-associated protein 1. This review focuses on Nrf2 activation and its involvement with the protective defense systems under electrophilic stresses integrated with our recent findings that reactive sulfur species (RSS) mediate detoxification of electrophiles. The Nrf2 pathway does not function redundantly with the RSS-generating cystathionine γ-lyase pathway, and vice versa.

scholarly journals The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials

2021 ◽  
Author(s):  
Tom Clifford ◽  
Jarred P. Acton ◽  
Stuart P. Cocksedge ◽  
Kelly A. Bowden Davies ◽  
Stephen J. Bailey
Keyword(s):  
Systematic Review ◽  
Assessment Tool ◽  
Cochrane Collaboration ◽  
Risk Of Bias ◽  
Related Factor ◽  
Human Intervention ◽  
Nrf2 Activation ◽  
Dietary Phytochemicals ◽  
Intervention Trials

AbstractWe conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans. Well controlled human intervention trials are needed to corroborate the findings from in vitro and animal studies.

scholarly journals Delivery of Cinnamic Aldehyde Antioxidant Response Activating nanoParticles (ARAPas) for Vascular Applications

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 709
Author(s):  
Ana E. Cartaya ◽  
Halle Lutz ◽  
Sophie Maiocchi ◽  
Morgan Nalesnik ◽  
Edward M. Bahnson
Keyword(s):  
Ex Vivo ◽  
Antioxidant Response ◽  
Related Factor ◽  
Cinnamic Aldehyde ◽  
Vsmc Proliferation ◽  
Nrf2 Activation ◽  
Selective Delivery ◽  
And Migration ◽  
Inner Vessel ◽  
Macrophage Uptake

Selective delivery of nuclear factor erythroid 2-related factor 2 (Nrf2) activators to the injured vasculature at the time of vascular surgical intervention has the potential to attenuate oxidative stress and decrease vascular smooth muscle cell (VSMC) hyperproliferation and migration towards the inner vessel wall. To this end, we developed a nanoformulation of cinnamic aldehyde (CA), termed Antioxidant Response Activating nanoParticles (ARAPas), that can be readily loaded into macrophages ex vivo. The CA-ARAPas-macrophage system was used to study the effects of CA on VSMC in culture. CA was encapsulated into a pluronic micelle that was readily loaded into both murine and human macrophages. CA-ARAPas inhibits VSMC proliferation and migration, and activates Nrf2. Macrophage-mediated transfer of CA-ARAPas to VSMC is evident after 12 h, and Nrf2 activation is apparent after 24 h. This is the first report, to the best of our knowledge, of CA encapsulation in pluronic micelles for macrophage-mediated delivery studies. The results of this study highlight the feasibility of CA encapsulation and subsequent macrophage uptake for delivery of cargo into other pertinent cells, such as VSMC.

scholarly journals Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma

2020 ◽  
Vol 318 (3) ◽  
pp. G419-G427 ◽  
Author(s):  
Tatsuhide Nabeshima ◽  
Shin Hamada ◽  
Keiko Taguchi ◽  
Yu Tanaka ◽  
Ryotaro Matsumoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cancer Progression ◽  
Stress Responses ◽  
Target Genes ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Related Factor ◽  
Loss Of Function ◽  
P53 Expression ◽  
Nrf2 Activation

The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/ p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/ p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/ p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma. NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.

scholarly journals Sulforaphane Protects against Cardiovascular Disease via Nrf2 Activation

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Yang Bai ◽  
Xiaolu Wang ◽  
Song Zhao ◽  
Chunye Ma ◽  
Jiuwei Cui ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Disease ◽  
Leucine Zipper ◽  
Defense Mechanism ◽  
Myocardial Damage ◽  
Related Factor ◽  
Anticancer Activities ◽  
Basic Leucine Zipper ◽  
Nrf2 Activation

Cardiovascular disease (CVD) causes an unparalleled proportion of the global burden of disease and will remain the main cause of mortality for the near future. Oxidative stress plays a major role in the pathophysiology of cardiac disorders. Several studies have highlighted the cardinal role played by the overproduction of reactive oxygen or nitrogen species in the pathogenesis of ischemic myocardial damage and consequent cardiac dysfunction. Isothiocyanates (ITC) are sulfur-containing compounds that are broadly distributed among cruciferous vegetables. Sulforaphane (SFN) is an ITC shown to possess anticancer activities by bothin vivoand epidemiological studies. Recent data have indicated that the beneficial effects of SFN in CVD are due to its antioxidant and anti-inflammatory properties. SFN activates NF-E2-related factor 2 (Nrf2), a basic leucine zipper transcription factor that serves as a defense mechanism against oxidative stress and electrophilic toxicants by inducing more than a hundred cytoprotective proteins, including antioxidants and phase II detoxifying enzymes. This review will summarize the evidence from clinical studies and animal experiments relating to the potential mechanisms by which SFN modulates Nrf2 activation and protects against CVD.

scholarly journals Luteolin Confers Cerebroprotection after Subarachnoid Hemorrhage by Suppression of NLPR3 Inflammasome Activation through Nrf2-Dependent Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Zi-Huan Zhang ◽  
Jia-Qiang Liu ◽  
Cheng-Di Hu ◽  
Xin-Tong Zhao ◽  
Fei-Yun Qin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Subarachnoid Hemorrhage ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Neuronal Degeneration ◽  
Antioxidant Systems ◽  
Inflammasome Activation ◽  
Related Factor ◽  
Beneficial Effects ◽  
Nrf2 Activation

Luteolin (LUT) possesses multiple biologic functions and has beneficial effects for cardiovascular and cerebral vascular diseases. Here, we investigated the protective effects of LUT against subarachnoid hemorrhage (SAH) and the involvement of underlying molecular mechanisms. In a rat model of SAH, LUT significantly inhibited SAH-induced neuroinflammation as evidenced by reduced microglia activation, decreased neutrophil infiltration, and suppressed proinflammatory cytokine release. In addition, LUT markedly ameliorated SAH-induced oxidative damage and restored the endogenous antioxidant systems. Concomitant with the suppressed oxidative stress and neuroinflammation, LUT significantly improved neurologic function and reduced neuronal cell death after SAH. Mechanistically, LUT treatment significantly enhanced the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), while it downregulated nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation. Inhibition of Nrf2 by ML385 dramatically abrogated LUT-induced Nrf2 activation and NLRP3 suppression and reversed the beneficial effects of LUT against SAH. In neurons and microglia coculture system, LUT also mitigated oxidative stress, inflammatory response, and neuronal degeneration. These beneficial effects were associated with activation of the Nrf2 and inhibitory effects on NLRP3 inflammasome and were reversed by ML385 treatment. Taken together, this present study reveals that LUT confers protection against SAH by inhibiting NLRP3 inflammasome signaling pathway, which may be modulated by Nrf2 activation.

scholarly journals NBR1-mediated p62-liquid droplets enhance the Keap1-Nrf2 system

2019 ◽  
Author(s):  
Pablo Sánchez-Martín ◽  
Yu-shin Sou ◽  
Shun Kageyama ◽  
Masaaki Komatsu
Keyword(s):  
Oxidative Stress ◽  
Liquid Droplet ◽  
Brca1 Gene ◽  
Droplet Formation ◽  
Receptor Protein ◽  
Liquid Droplets ◽  
Nrf2 Pathway ◽  
Selective Degradation ◽  
System A ◽  
Nrf2 Activation

Abstractp62/SQSTM1 is a multivalent protein that has an ability to cause a liquid-liquid phase separation and serves as a receptor protein that participates in cargo isolation during selective autophagy. This protein is also involved in the non-canonical activation of the Keap1-Nrf2 system, a major oxidative stress response pathway. Here we show a role of Neighbor of BRCA1 gene 1 (NBR1), an autophagy receptor structurally similar to p62/SQSTM1, in the p62-liquid droplet formation and the Keap1-Nrf2 pathway. The overexpression of NBR1 blocked selective degradation of p62/SQSTM1 through autophagy and promoted the accumulation and phosphorylation of p62/SQSTM1 in liquid-like bodies, which is required for the activation of Nrf2. NBR1 was induced in response to oxidative stress, and then the p62-mediated Nrf2 activation was up-regulated. Conversely, loss of Nbr1 suppresses not only the formation of p62/SQSTM1-liquid droplets but also p62-dependent Nrf2 activation during oxidative stress. Taken together, our results show that NBR1 mediates p62/SQSTM1-liquid droplet formation to activate the Keap1-Nrf2 pathway.

Sodium tanshinone IIA sulfate protects myocardium against paraquat-induced toxicity through activating the Nrf2 signaling pathway in rats

2018 ◽  
Vol 38 (2) ◽  
pp. 247-254 ◽  
Author(s):  
WX Zhang ◽  
XY Xiao ◽  
CG Peng ◽  
WL Chen ◽  
S Xie ◽  
...  
Keyword(s):  
Tanshinone Iia ◽  
Control Group ◽  
Heme Oxygenase 1 ◽  
Intragastric Administration ◽  
Related Factor ◽  
Dependent Manner ◽  
Myocardial Cells ◽  
Sprague Dawley ◽  
Nrf2 Pathway ◽  
Nrf2 Signaling Pathway

Objective: To investigate the therapeutic effect and mechanism of sodium tanshinone IIA sulfate (STS) on paraquat (PQ)-induced myocardial injuries in a rat model. Methods: Healthy adult Sprague Dawley rats were randomly divided into normal control, PQ, and PQ + STS groups. PQ group was given a single intragastric administration of PQ (80 mg/kg). PQ + STS group was intraperitoneally injected with STS (1 ml/kg) at 30 min following PQ exposure. Rats in control and PQ groups were injected with equal amount of saline. After 12, 24, 48, and 72 h, rats were killed, and the apoptosis of myocardial cells was detected. Myocardial expression of Bax and Bcl-2 was measured. The activity of the nuclear erythroid 2-related factor 2 (Nrf2) pathway was assessed by Western blot. Results: The apoptotic cells in PQ group were significantly increased in a time-dependent manner compared with the control group ( p < 0.01). The rats in PQ group exhibited significantly lower Bcl-2 expression, but notably higher Bax expression at 12, 24, 48, and 72 h after PQ exposure ( p < 0.05 or 0.01). STS intervention markedly reduced the proportion of apoptotic myocardial cells, increased Bcl-2 expression, and decreased Bax expression at 24, 48, and 72 h after treatment ( p < 0.05 or 0.01). The expression of phosphorylated Nrf2 and heme oxygenase 1 in PQ + STS group was significantly increased compared with PQ and control groups ( p < 0.05 or 0.01). Conclusion: STS effectively inhibits PQ-induced myocardial cell apoptosis in rats via modulating the Nrf2 pathway, suggesting its potential as a promising therapeutic agent for PQ-induced myocardium damage.

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 Regulation of Wound Healing by the NRF2 Transcription Factor—More Than Cytoprotection

2019 ◽  
Vol 20 (16) ◽  
pp. 3856 ◽  
Author(s):  
Paul Hiebert ◽  
Sabine Werner
Keyword(s):  
Wound Healing ◽  
Transcription Factor ◽  
Chronic Wounds ◽  
Antioxidant Properties ◽  
Cellular Stress Response ◽  
Related Factor ◽  
Loss Of Function ◽  
Nrf2 Activation ◽  
Nrf2 Transcription Factor ◽  
Made In

The nuclear factor-erythroid 2-related factor 2 (NRF2) transcription factor plays a central role in mediating the cellular stress response. Due to their antioxidant properties, compounds activating NRF2 have received much attention as potential medications for disease prevention, or even for therapy. Accumulating evidence suggests that activation of the NRF2 pathway also has a major impact on wound healing and may be beneficial in the treatment of chronic wounds, which remain a considerable health and economic burden. While NRF2 activation indeed shows promise, important considerations need to be made in light of corresponding evidence that also points towards pro-tumorigenic effects of NRF2. In this review, we discuss the evidence to date, highlighting recent advances using gain- and loss-of-function animal models and how these data fit with observations in humans.

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