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 Molecular Mechanisms Underlying Hepatocellular Carcinoma Induction by Aberrant NRF2 Activation-Mediated Transcription Networks: Interaction of NRF2-KEAP1 Controls the Fate of Hepatocarcinogenesis

2020 ◽  
Vol 21 (15) ◽  
pp. 5378 ◽  
Author(s):  
Effi Haque ◽  
M. Rezaul Karim ◽  
Aamir Salam Teeli ◽  
Magdalena Śmiech ◽  
Paweł Leszczynski ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Leucine Zipper ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Precancerous Lesions ◽  
Redox Homeostasis ◽  
Detoxification Enzymes ◽  
Related Factor ◽  
Basic Leucine Zipper ◽  
Nrf2 Activation

NF-E2-related factor 2 (NRF2) is a basic leucine zipper transcription factor, a master regulator of redox homeostasis regulating a variety of genes for antioxidant and detoxification enzymes. NRF2 was, therefore, initially thought to protect the liver from oxidative stress. Recent studies, however, have revealed that mutations in NRF2 cause aberrant accumulation of NRF2 in the nucleus and exert the upregulation of NRF2 target genes. Moreover, among all molecular changes in hepatocellular carcinoma (HCC), NRF2 activation has been revealed as a more prominent pathway contributing to the progression of precancerous lesions to malignancy. Nevertheless, how its activation leads to poor prognosis in HCC patients remains unclear. In this review, we provide an overview of how aberrant activation of NRF2 triggers HCC development. We also summarize the emerging roles of other NRF family members in liver cancer development.

scholarly journals The Role of the Nrf2 Signaling in Obesity and Insulin Resistance

2020 ◽  
Vol 21 (18) ◽  
pp. 6973 ◽  
Author(s):  
Shiri Li ◽  
Natsuki Eguchi ◽  
Hien Lau ◽  
Hirohito Ichii
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Leucine Zipper ◽  
Close Association ◽  
Underlying Mechanism ◽  
Related Factor ◽  
Basic Leucine Zipper ◽  
State Of Research ◽  
And Oxidative Stress

Obesity, a metabolic disorder characterized by excessive accumulation of adipose tissue, has globally become an increasingly prevalent disease. Extensive studies have been conducted to elucidate the underlying mechanism of the development of obesity. In particular, the close association of inflammation and oxidative stress with obesity has become increasingly evident. Obesity has been shown to exhibit augmented levels of circulating proinflammatory cytokines, which have been associated with the activation of pathways linked with inflammation-induced insulin resistance, a major pathological component of obesity and several other metabolic disorders. Oxidative stress, in addition to its role in stimulating adipose differentiation, which directly triggers obesity, is considered to feed into this pathway, further aggravating insulin resistance. Nuclear factor E2 related factor 2 (Nrf2) is a basic leucine zipper transcription factor that is activated in response to inflammation and oxidative stress, and responds by increasing antioxidant transcription levels. Therefore, Nrf2 has emerged as a critical new target for combating insulin resistance and subsequently, obesity. However, the effects of Nrf2 on insulin resistance and obesity are controversial. This review focuses on the current state of research on the interplay of inflammation and oxidative stress in obesity, the role of the Nrf2 pathway in obesity and insulin resistance, and the potential use of Nrf2 activators for the treatment of insulin resistance.

scholarly journals Jun dimerization protein 2 is a critical component of the Nrf2/MafK complex regulating the response to ROS homeostasis

2013 ◽  
Vol 4 (11) ◽  
pp. e921-e921 ◽  
Author(s):  
S Tanigawa ◽  
C H Lee ◽  
C S Lin ◽  
C C Ku ◽  
H Hasegawa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcriptional Activation ◽  
Leucine Zipper ◽  
Target Genes ◽  
Critical Role ◽  
Notch Receptor ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mobility Shift ◽  
Basic Leucine Zipper

Abstract Oxidative stress and reactive oxygen species (ROS) are associated with diseases such as cancer, cardiovascular complications, inflammation and neurodegeneration. Cellular defense systems must work constantly to control ROS levels and to prevent their accumulation. We report here that the Jun dimerization protein 2 (JDP2) has a critical role as a cofactor for transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and small Maf protein family K (MafK) in the regulation of the antioxidant-responsive element (ARE) and production of ROS. Chromatin immunoprecipitation–quantitative PCR (qPCR), electrophoresis mobility shift and ARE-driven reporter assays were carried out to examine the role of JDP2 in ROS production. JDP2 bound directly to the ARE core sequence, associated with Nrf2 and MafK (Nrf2–MafK) via basic leucine zipper domains, and increased DNA-binding activity of the Nrf2–MafK complex to the ARE and the transcription of ARE-dependent genes. In mouse embryonic fibroblasts from Jdp2-knockout (Jdp2 KO) mice, the coordinate transcriptional activation of several ARE-containing genes and the ability of Nrf2 to activate expression of target genes were impaired. Moreover, intracellular accumulation of ROS and increased thickness of the epidermis were detected in Jdp2 KO mice in response to oxidative stress-inducing reagents. These data suggest that JDP2 is required to protect against intracellular oxidation, ROS activation and DNA oxidation. qPCR demonstrated that several Nrf2 target genes such as heme oxygenase-1, glutamate–cysteine ligase catalytic and modifier subunits, the notch receptor ligand jagged 1 and NAD(P)H dehydrogenase quinone 1 are also dependent on JDP2 for full expression. Taken together, these results suggest that JDP2 is an integral component of the Nrf2–MafK complex and that it modulates antioxidant and detoxification programs by acting via the ARE.

scholarly journals The Role of Nrf2: Adipocyte Differentiation, Obesity, and Insulin Resistance

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Hyun-Ae Seo ◽  
In-Kyu Lee
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Energy Metabolism ◽  
Leucine Zipper ◽  
Adipocyte Differentiation ◽  
Metabolic Diseases ◽  
Related Factor ◽  
Basic Leucine Zipper ◽  
Cellular Defense

Metabolic diseases, such as type 2 diabetes and obesity, are increasing globally, and much work has been performed to elucidate the regulatory mechanisms of these diseases. Nuclear factor E2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor that serves as a primary cellular defense against the cytotoxic effects of oxidative stress. Recent studies have proposed a close relationship between oxidative stress and energy metabolism-associated disease. The Nrf2 pathway, as a master regulator of cellular defense against oxidative stress, has emerged as a critical target of energy metabolism; however, its effects are controversial. This review examines the current state of research on the role of Nrf2 on energy metabolism, specifically with respect to its participation in adipocyte differentiation, obesity, and insulin resistance, and discusses the possibility of using Nrf2 as a therapeutic target in the clinic.

scholarly journals Complexity of CNC Transcription Factors As Revealed by Gene Targeting of the Nrf3 Locus

2004 ◽  
Vol 24 (8) ◽  
pp. 3286-3294 ◽  
Author(s):  
Anna Derjuga ◽  
Tania S. Gourley ◽  
Teresa M. Holm ◽  
Henry H. Q. Heng ◽  
Ramesh A. Shivdasani ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Leucine Zipper ◽  
B Lymphocyte ◽  
Gross Anatomy ◽  
Related Factor ◽  
Wild Type ◽  
Basic Leucine Zipper ◽  
Mild Phenotype ◽  
Age Progression

ABSTRACT Cap'n'collar (CNC) family basic leucine zipper transcription factors play crucial roles in the regulation of mammalian gene expression and development. To determine the in vivo function of the CNC protein Nrf3 (NF-E2-related factor 3), we generated mice deficient in this transcription factor. We performed targeted disruption of two Nrf3 exons coding for CNC homology, basic DNA-binding, and leucine zipper dimerization domains. Nrf3 null mice developed normally and revealed no obvious phenotypic differences compared to wild-type animals. Nrf3 −/− mice were fertile, and gross anatomy as well as behavior appeared normal. The mice showed normal age progression and did not show any apparent additional phenotype during their life span. We observed no differences in various blood parameters and chemistry values. We infected wild-type and Nrf3 −/− mice with acute lymphocytic choriomeningitis virus and found no differences in these animals with respect to their number of virus-specific CD8 and CD4 T cells as well as their B-lymphocyte response. To determine whether the mild phenotype of Nrf3 null animals is due to functional redundancy, we generated mice deficient in multiple CNC factors. Contrary to our expectations, an absence of Nrf3 does not seem to cause additional lethality in compound Nrf3 −/−/Nrf2 −/− and Nrf3 −/−/p45 −/− mice. We hypothesize that the role of Nrf3 in vivo may become apparent only after appropriate challenge to the mice.

scholarly journals The Nrf2–ARE cytoprotective pathway in astrocytes

2009 ◽  
Vol 11 ◽  
Author(s):  
Marcelo R. Vargas ◽  
Jeffrey A. Johnson
Keyword(s):  
Leucine Zipper ◽  
Neuronal Excitability ◽  
Neuronal Damage ◽  
Regulatory Element ◽  
Current Data ◽  
Related Factor ◽  
Antioxidant Defences ◽  
Basic Leucine Zipper

The expression of phase-II detoxification and antioxidant enzymes is governed by a cis-acting regulatory element named the antioxidant response element (ARE). ARE-containing genes are regulated by the nuclear factor erythroid-2-related factor 2 (Nrf2), a member of the Cap'n'Collar basic-leucine-zipper family of transcription factors. ARE-regulated genes are preferentially activated in astrocytes, which consequently have more efficient detoxification and antioxidant defences than neurons. Astrocytes closely interact with neurons to provide structural, metabolic and trophic support, as well as actively participating in the modulation of neuronal excitability and neurotransmission. Therefore, functional alterations in astrocytes can shape the interaction with surrounding cells, such as neurons and microglia. Activation of Nrf2 in astrocytes protects neurons from a wide array of insults in different in vitro and in vivo paradigms, confirming the role of astrocytes in determining the vulnerability of neurons to noxious stimuli. Here, we review the current data supporting Nrf2 activation in astrocytes as a viable therapeutic approach, not only in acute neuronal damage, but also in chronic neurodegeneration related to oxidative stress.

Nfe2l3 (Nrf3) deficiency predisposes mice to T-cell lymphoblastic lymphoma

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 2005-2008 ◽  
Author(s):  
Grégory Chevillard ◽  
Marilene Paquet ◽  
Volker Blank
Keyword(s):  
T Cell ◽  
Leucine Zipper ◽  
Tumor Development ◽  
Lymphocytic Infiltration ◽  
Protective Role ◽  
Lymphoblastic Lymphoma ◽  
Related Factor ◽  
Basic Leucine Zipper ◽  
Affected Tissue

Abstract We have previously generated mice deficient for Nfe213 (NF-E2 p45 related factor 3 or Nrf3), a member of the cap ‘n’ collar family of basic-leucine zipper transcription factors. To examine whether Nrf3 is involved in chemical-induced carcinogenesis, we exposed the mice to benzo[a]pyrene (B[a]P), a carcinogen found in cigarette smoke. Contrary to wild-type mice, Nrf3-null animals are highly susceptible to B[a]P, exhibiting significantly increased mortality. Pathology analysis of affected tissue sections revealed a high incidence of T-cell lymphoblastic lymphoma in B[a]P-treated Nrf3−/− mice. Lymphoblastic lymphoma occasionally metastasized into the lung as demonstrated by perivascular malignant lymphocytic infiltration. Together, our studies show that the absence of Nrf3 predisposes mice to lymphoma development, suggesting a protective role of this transcription factor in hematopoietic malignancies. Our data demonstrate the first in vivo function of Nrf3 and its link to tumor development. Nrf3-deficient mice may serve as a preclinical mouse model to study carcinogen-induced lymphomagenesis.

scholarly journals Functional and Placental Expression Analysis of the Human NRF3 Transcription Factor

2005 ◽  
Vol 19 (1) ◽  
pp. 125-137 ◽  
Author(s):  
Benoı̂t Chénais ◽  
Anna Derjuga ◽  
Wael Massrieh ◽  
Kristy Red-Horse ◽  
Valerie Bellingard ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Leucine Zipper ◽  
Related Factor ◽  
Nuclear Factor ◽  
Basic Leucine Zipper ◽  
Transcriptional Activation Domain ◽  
Functional Studies ◽  
Recognition Element ◽  
Protein Levels

Abstract Members of the Maf protooncogene and cap’n’ collar families of basic-leucine zipper transcription factors play important roles in development, differentiation, oncogenesis, and stress signaling. In this study, we performed an in vivo protein-protein interaction screen to search for novel partners of the small Maf proteins. Using full-length human MAFG protein as bait, we identified the human basic-leucine zipper protein NRF3 [NF-E2 (nuclear factor erythroid 2)-related factor 3] as an interaction partner. Transfection studies confirmed that NRF3 is able to dimerize with MAFG. The resulting NRF3/MAFG heterodimer recognizes nuclear factor-erythroid 2/Maf recognition element-type DNA-binding motifs. Functional analysis revealed the presence of a strong transcriptional activation domain in the center region of the NRF3 protein. We found that NRF3 transcripts are present in placental chorionic villi from at least week 12 of gestation on through term. In particular, NRF3 is highly expressed in primary placental cytotrophoblasts, but not in placental fibroblasts. The human choriocarcinoma cell lines BeWo and JAR, derived from trophoblastic tumors of the placenta, also strongly express NRF3 transcripts. We generated a NRF3-specific antiserum and identified NRF3 protein in placental choriocarcinoma cells. Furthermore, we showed that NRF3 transcript and protein levels are induced by TNF-α in JAR cells. Our functional studies suggest that human NRF3 is a potent transcriptional activator. Finally, our expression and induction analyses hint at a possible role of Nrf3 in placental gene expression and development.

scholarly journals NRF2: A potential target for the treatment of diabetic nephropathy

2021 ◽  
Vol 1 (1) ◽  
pp. 27-32
Author(s):  
Jiahui Zhang ◽  
Fnu Anshul ◽  
Joshua D. Breidenbach ◽  
Jing Liu ◽  
James Shaffner
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Defense Mechanism ◽  
Cardiovascular Effects ◽  
Related Factor ◽  
Cytotoxic Effects ◽  
Promising Target ◽  
Nrf2 Activation ◽  
Clinical Models ◽  
Inflammatory Molecules

Abstract One of the major complications of diabetes mellitus is diabetic nephropathy (DN), the pathogenesis of which is primarily driven by oxidative stress. As a major regulator of antioxidant responses, the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) has recently attracted much interest. NRF2 is a primary defense mechanism against the cytotoxic effects of oxidative stress, involving heterogeneous detoxification, the production of antioxidants and anti-inflammatory molecules, DNA repair, nuclear chaperones, and proteasome systems. A myriad of studies in pre-clinical models of DN have consistently demonstrated a beneficial effect of NRF2 activation, suggesting that NRF2 is likely a promising target for treating DN. This has been further supported by findings from clinical trials of bardoxolone methyl, an activator of NRF2, despite the unexpected adverse cardiovascular effects. This review summarizes the support for therapeutic targeting of NRF2 in DN and emphasizes the need for the optimization of NRF2-based treatment with the minimization of potential adverse effects.

scholarly journals Diallyl Trisulfide Protects Rat Brain Tissue against the Damage Induced by Ischemia-Reperfusion through the Nrf2 Pathway

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 410 ◽  
Author(s):  
Carlos A. Silva-Islas ◽  
María E. Chánez-Cárdenas ◽  
Diana Barrera-Oviedo ◽  
Alma Ortiz-Plata ◽  
José Pedraza-Chaverri ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Protective Effect ◽  
Ischemia Reperfusion ◽  
Public Health Problem ◽  
Related Factor ◽  
Diallyl Trisulfide ◽  
In Vivo Models ◽  
Nrf2 Activation

Stroke is a public health problem due to its high mortality and disability rates; despite these, the pharmacological treatments are limited. Oxidative stress plays an important role in cerebral damage in stroke and the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) confers protection against oxidative stress. Different compounds, such as diallyl trisulfide (DATS), have the ability to activate Nrf2. DATS protects against the damage induced in oxygen-glucose deprivation in neuronal cells; however, in in vivo models of cerebral ischemia, DATS has not been evaluated. Male Wistar rats were subjected to 1 h of ischemia and seven days of reperfusion and the protective effect of DATS was evaluated. DATS administration (IR + DATS) decreased the infarct area and brain damage in the striatum and cortex; improved neurological function; decreased malondialdehyde and metalloproteinase-9 levels; increased Nrf2 activation in the cortex and the expression of superoxide dismutase 1 (SOD1) in the nucleus, SOD2 and glutathione S-transferase (GST) in the striatum and cortex; and increased the activity of catalase (CAT) in the striatum and glutathione peroxidase (GPx) in the cortex. Our results demonstrate the protective effect of DATS in an in vivo model of cerebral ischemia that involves Nrf2 activation.

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