scholarly journals Electrophiles against (Skin) Diseases: More Than Nrf2

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 271 ◽  
Author(s):  
Paulina Hennig ◽  
Gabriele Fenini ◽  
Michela Di Filippo ◽  
Hans-Dietmar Beer
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Skin Diseases ◽  
Inflammatory Diseases ◽  
Protein Complexes ◽  
Dimethyl Fumarate ◽  
Inflammatory Conditions ◽  
Nrf2 Activation ◽  
Nrf2 Activator

The skin represents an indispensable barrier between the organism and the environment and is the first line of defense against exogenous insults. The transcription factor NRF2 is a central regulator of cytoprotection and stress resistance. NRF2 is activated in response to oxidative stress by reactive oxygen species (ROS) and electrophiles. These electrophiles oxidize specific cysteine residues of the NRF2 inhibitor KEAP1, leading to KEAP1 inactivation and, subsequently, NRF2 activation. As oxidative stress is associated with inflammation, the NRF2 pathway plays important roles in the pathogenesis of common inflammatory diseases and cancer in many tissues and organs, including the skin. The electrophile and NRF2 activator dimethyl fumarate (DMF) is an established and efficient drug for patients suffering from the common inflammatory skin disease psoriasis and the neuro-inflammatory disease multiple sclerosis (MS). In this review, we discuss possible molecular mechanisms underlying the therapeutic activity of DMF and other NRF2 activators. Recent evidence suggests that electrophiles not only activate NRF2, but also target other inflammation-associated pathways including the transcription factor NF-κB and the multi-protein complexes termed inflammasomes. Inflammasomes are central regulators of inflammation and are involved in many inflammatory conditions. Most importantly, the NRF2 and inflammasome pathways are connected at different levels, mainly antagonistically.

scholarly journals Evaluation of antioxidant activation by potential nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Keap1 complex inhibitors

2021 ◽  
Vol 20 (9) ◽  
pp. 1861-1873
Author(s):  
Inas Saleh Almazari ◽  
Shada Youssef Elhayek
Keyword(s):  
Oxidative Stress ◽  
Stress Disorders ◽  
Binding Affinities ◽  
Pathway Activation ◽  
Nrf2 Activation ◽  
Glutamylcysteine Synthetase ◽  
Nrf2 Activator ◽  
Nrf2 Expression ◽  
Activation Capacity ◽  
Mcf 7

Purpose: To investigate the binding affinities of forty-one (41) National Cancer Institute (NCI)-generated compounds, to the Nrf2 ligand, and possible activation of Nrf2 in the MCF-7 cell line.Methods: To investigate the inhibition of the Nrf2/Keap1 complex, the MCF-7 cell line was treated with each of the 41 compounds, at a working concentration of 30 μM. The extent of Nrf2 activation and corresponding Nrf2/Keap1 complex inhibition was evaluated in terms of Nrf2 expression and its antioxidant-associated enzyme gamma-glutamylcysteine synthetase (GCS), using western blotanalysis.Results: Twenty-nine compounds out of the 41 targeted compounds activated GCS, and some showed comparable or greater activation capacity than the standard Nrf2 activator tBHQ. To confirm that the activation of GCS was mediated via Nrf2 activation, cell lysates were tested for their Nrf2 protein expression, and it was found that Nrf2 was activated by the examined compounds for more than 24 h, indicating that the effect of the chosen compounds were not transient.Conclusion: These results might be useful for identifying better targets for cytoprotection, and for oxidative stress alleviation through Nrf2 pathway activation. Further studies are required on the effects of these targets on the prevention and treatment of various oxidative stress disorders, including cancer.

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 Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1

2015 ◽  
Vol 112 (25) ◽  
pp. E3246-E3254 ◽  
Author(s):  
Yayi Gao ◽  
Jiayou Tang ◽  
Weiqian Chen ◽  
Qiang Li ◽  
Jia Nie ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Function ◽  
Inflammatory Diseases ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Autoimmune Encephalomyelitis ◽  
Inflammatory Conditions ◽  
Forkhead Box ◽  
Binding Partners ◽  
And Function

Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells’ signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex. We found that DBC1 interacts physically with FOXP3, and depletion of DBC1 attenuates FOXP3 degradation in inflammatory conditions. Treg cells from Dbc1-deficient mice were more resistant to inflammation-mediated abrogation of Foxp3 expression and function and delayed the onset and severity of experimental autoimmune encephalomyelitis and colitis in mice. These findings establish a previously unidentified mechanism regulating FOXP3 stability during inflammation and reveal a pathway for potential therapeutic modulation and intervention in inflammatory diseases.

scholarly journals Aldosterone Negatively Regulates Nrf2 Activity: An Additional Mechanism Contributing to Oxidative Stress and Vascular Dysfunction by Aldosterone

2021 ◽  
Vol 22 (11) ◽  
pp. 6154
Author(s):  
Daniel Rodrigues ◽  
Tiago J. Costa ◽  
Josiane F. Silva ◽  
José Teles de Oliveira Neto ◽  
Juliano V. Alves ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Injury ◽  
Vascular Dysfunction ◽  
Nuclear Accumulation ◽  
Ros Generation ◽  
Antioxidant Responses ◽  
Nrf2 Activation ◽  
Ros Scavenger ◽  
Ea.Hy926 Cells ◽  
Nrf2 Activator

High levels of aldosterone (Aldo) trigger oxidative stress and vascular dysfunction independent of effects on blood pressure. We sought to determine whether Aldo disrupts Nrf2 signaling, the main transcriptional factor involved in antioxidant responses that aggravate cell injury. Thoracic aorta from male C57Bl/6J mice and cultured human endothelial cells (EA.hy926) were stimulated with Aldo (100 nM) in the presence of tiron [reactive oxygen species (ROS) scavenger, eplerenone [mineralocorticoid receptor (MR) antagonist], and L-sulforaphane (SFN; Nrf2 activator). Thoracic aortas were also isolated from mice infused with Aldo (600 μg/kg per day) for 14 days. Aldo decreased endothelium-dependent vasorelaxation and increased ROS generation, effects prevented by tiron and MR blockade. Pharmacological activation of Nrf2 with SFN abrogated Aldo-induced vascular dysfunction and ROS generation. In EA.hy926 cells, Aldo increased ROS generation, which was prevented by eplerenone, tiron, and SFN. At short times, Aldo-induced ROS generation was linked to increased Nrf2 activation. However, after three hours, Aldo decreased the nuclear accumulation of Nrf2. Increased Keap1 protein expression, but not activation of p38 MAPK, was linked to Aldo-induced reduced Nrf2 activity. Arteries from Aldo-infused mice also exhibited decreased nuclear Nrf2 and increased Keap1 expression. Our findings suggest that Aldo reduces vascular Nrf2 transcriptional activity by Keap1-dependent mechanisms, contributing to mineralocorticoid-induced vascular dysfunction.

scholarly journals Control of Oxidative Stress and Inflammation in Sickle Cell Disease with the Nrf2 Activator Dimethyl Fumarate

2017 ◽  
Vol 26 (14) ◽  
pp. 748-762 ◽  
Author(s):  
John D. Belcher ◽  
Chunsheng Chen ◽  
Julia Nguyen ◽  
Ping Zhang ◽  
Fuad Abdulla ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Dimethyl Fumarate ◽  
Cell Disease ◽  
Nrf2 Activator

scholarly journals Interleukin-36 Cytokines in Infectious and Non-Infectious Lung Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Hernán F. Peñaloza ◽  
Rick van der Geest ◽  
Joel A. Ybe ◽  
Theodore J. Standiford ◽  
Janet S. Lee
Keyword(s):  
Infectious Diseases ◽  
Lung Diseases ◽  
Skin Diseases ◽  
Inflammatory Diseases ◽  
Lymphoid Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Inflammatory Conditions ◽  
Inflammatory Processes

The IL-36 family of cytokines were identified in the early 2000’s as a new subfamily of the IL-1 cytokine family, and since then, the role of IL-36 cytokines during various inflammatory processes has been characterized. While most of the research has focused on the role of these cytokines in autoimmune skin diseases such as psoriasis and dermatitis, recent studies have also shown the importance of IL-36 cytokines in the lung inflammatory response during infectious and non-infectious diseases. In this review, we discuss the biology of IL-36 cytokines in terms of how they are produced and activated, as well as their effects on myeloid and lymphoid cells during inflammation. We also discuss the role of these cytokines during lung infectious diseases caused by bacteria and influenza virus, as well as other inflammatory conditions in the lungs such as allergic asthma, lung fibrosis, chronic obstructive pulmonary disease, cystic fibrosis and cancer. Finally, we discuss the current therapeutic advances that target the IL-36 pathway and the possibility to extend these tools to treat lung inflammatory diseases.

scholarly journals Role of Oxidative Stress and Nrf2/KEAP1 Signaling in Colorectal Cancer: Mechanisms and Therapeutic Perspectives with Phytochemicals

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 743
Author(s):  
Da-Young Lee ◽  
Moon-Young Song ◽  
Eun-Hee Kim
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Transcription Factor ◽  
Cancer Progression ◽  
Inflammatory Diseases ◽  
Negative Regulator ◽  
Related Factor ◽  
Cancer Society ◽  
Incidence And Mortality

Colorectal cancer still has a high incidence and mortality rate, according to a report from the American Cancer Society. Colorectal cancer has a high prevalence in patients with inflammatory bowel disease. Oxidative stress, including reactive oxygen species (ROS) and lipid peroxidation, has been known to cause inflammatory diseases and malignant disorders. In particular, the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-related protein 1 (KEAP1) pathway is well known to protect cells from oxidative stress and inflammation. Nrf2 was first found in the homolog of the hematopoietic transcription factor p45 NF-E2, and the transcription factor Nrf2 is a member of the Cap ‘N’ Collar family. KEAP1 is well known as a negative regulator that rapidly degrades Nrf2 through the proteasome system. A range of evidence has shown that consumption of phytochemicals has a preventive or inhibitory effect on cancer progression or proliferation, depending on the stage of colorectal cancer. Therefore, the discovery of phytochemicals regulating the Nrf2/KEAP1 axis and verification of their efficacy have attracted scientific attention. In this review, we summarize the role of oxidative stress and the Nrf2/KEAP1 signaling pathway in colorectal cancer, and the possible utility of phytochemicals with respect to the regulation of the Nrf2/KEAP1 axis in colorectal cancer.

scholarly journals Cytoprotection against Oxidative Stress by Methylnissolin-3-O-β-D-glucopyranoside from Astragalus membranaceus Mainly via the Activation of the Nrf2/HO-1 Pathway

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3852
Author(s):  
Xiaohua Wu ◽  
Jian Xu ◽  
Yousheng Cai ◽  
Yuejun Yang ◽  
Yuancai Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Food Plants ◽  
Astragalus Membranaceus ◽  
Ros Generation ◽  
Induced Expression ◽  
Akt Phosphorylation ◽  
Intracellular Ros ◽  
Nrf2 Activation ◽  
Ea.Hy926 Cells ◽  
Nrf2 Activator

Astragalus membranaceus is a famous herb found among medicinal and food plants in East and Southeastern Asia. The Nrf2-ARE assay-guided separation of an extract from Jing liqueur led to the identification of a nontoxic Nrf2 activator, methylnissolin-3-O-β-D-glucopyranoside (MNG, a component of A. membranaceus). Nrf2 activation by MNG has not been reported before. Using Western Blot, RT-qPCR and imaging, we investigated the cytoprotective effect of MNG against hydrogen peroxide-induced oxidative stress. MNG induced the expression of Nrf2, HO-1 and NQO1, accelerated the translocation of Nrf2 into nuclei, and enhanced the phosphorylation of AKT. The MNG-induced expression of Nrf2, HO-1, and NQO1 were abolished by Nrf2 siRNA, while the MNG-induced expression of Nrf2 and HO-1 was abated and the AKT phosphorylation was blocked by LY294002 (a PI3K inhibitor). MNG reduced intracellular ROS generation. However, the protection of MNG against the H2O2 insult was reversed by Nrf2 siRNA with decreased cell viability. The enhancement of Nrf2 and HO-1 by MNG upon H2O2 injury was reduced by LY294002. These data showed that MNG protected EA.hy926 cells against oxidative damage through the Nrf2/HO-1 and at least partially the PI3K/Akt pathways.

Molecular mechanisms of the glucocorticoid receptor in steroid therapy – lessons from transgenic mice

2012 ◽  
Vol 3 (3) ◽  
pp. 241-253 ◽  
Author(s):  
Sabine Hübner ◽  
Jan Tuckermann
Keyword(s):  
Side Effects ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Pathological Condition ◽  
Cell Types ◽  
Therapeutic Effects ◽  
Gene Promoters ◽  
Inflammatory Conditions ◽  
Anti Inflammatory ◽  
And Function

AbstractGlucocorticoids (GCs) are potent anti-inflammatory agents that are used to treat chronic inflammatory diseases, allergic conditions, and some cancers. However, their therapeutic effects are hampered by severe side effects, such as muscle weakness, insulin resistance, fat redistribution, and osteoporosis. GCs act on many cell types that express the GC receptor (GR) via several modes of action. One of them includes GR homodimers recognizing binding sequences in the DNA of gene promoters. Another mode involves the modulation of other DNA-bound transcription factors via dimer-independent mechanisms. To what extent these mechanisms contribute to GC-mediated effects is currently being elucidated from analyses of mice with conditional and function-selective mutations of the GR and is summarized in this review. Whether GR homodimerization or its monomer activity is decisive in the therapeutic effectiveness and associated side effects of GCs for the treatment of inflammatory conditions depends on the type of the pathological condition. Thus, the classic criterion for selective GR modulators, discrimination between GR dimer- and GR monomer-dependent protein-protein interaction, will not help in any condition to avoid side effects and maintain anti-inflammatory activity. Rather, novel criteria for selective GR modulators have to be defined that take into consideration the tissue-specific mechanisms of the GR to achieve optimized anti-inflammatory therapies with reduced side effects. In the case of avoiding osteoporosis as a side effect, a first example of such optimized compounds can be provided.

scholarly journals The Transcription Factor MAFF Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism

Circulation ◽  
2021 ◽  
Author(s):  
Moritz von Scheidt ◽  
Yuqi Zhao ◽  
Thomas Q. de Aguiar Vallim ◽  
Nam Che ◽  
Michael Wierer ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Prediction Models ◽  
Cholesterol Metabolism ◽  
Association Studies ◽  
Experimental Studies ◽  
Genome Wide Association Studies ◽  
Inflammatory Conditions

Background: Coronary artery disease (CAD) is a multifactorial condition with both genetic and exogenous causes. The contribution of tissue specific functional networks to the development of atherosclerosis remains largely unclear. The aim of this study was to identify and characterise central regulators and networks leading to atherosclerosis. Methods: Based on several hundred genes known to affect atherosclerosis risk in mouse (as demonstrated in knock-out models) and human (as shown by genome-wide association studies (GWAS)) liver gene regulatory networks were modeled. The hierarchical order and regulatory directions of genes within the network were based on Bayesian prediction models as well as experimental studies including chromatin immunoprecipitation DNA-Sequencing (ChIP-Seq), ChIP mass spectrometry (ChIP-MS), overexpression, siRNA knockdown in mouse and human liver cells, and knockout mouse experiments. Bioinformatics and correlation analyses were used to clarify associations between central genes and CAD phenotypes in both human and mouse. Results: The transcription factor MAFF interacted as a key driver of a liver network with three human genes at CAD GWAS loci and eleven atherosclerotic murine genes. Most importantly, expression levels of the low-density lipoprotein receptor ( LDLR ) gene correlated with MAFF in 600 CAD patients undergoing bypass surgery (STARNET) and a hybrid mouse diversity panel involving 105 different inbred mouse strains. Molecular mechanisms of MAFF were tested under non-inflammatory conditions showing a positive correlation between MAFF and LDLR in vitro and in vivo . Interestingly, after LPS stimulation (inflammatory conditions) an inverse correlation between MAFF and LDLR in vitro and in vivo was observed. ChIP-MS revealed that the human CAD GWAS candidate BACH1 assists MAFF in the presence of LPS stimulation with respective heterodimers binding at the MAF recognition element (MARE) of the LDLR promoter to transcriptionally downregulate LDLR expression. Conclusions: The transcription factor MAFF was identified as a novel central regulator of an atherosclerosis/CAD relevant liver network. MAFF triggered context specific expression of LDLR and other genes known to affect CAD risk. Our results suggest that MAFF is a missing link between inflammation, lipid and lipoprotein metabolism and a possible treatment target.

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