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Abstract Adaptive responses to environmental and physiological challenges, including exposure to low environmental temperature, require extensive structural, redox, and metabolic reprogramming. Detailed molecular mechanisms of suc...
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Abstract Adaptive responses to environmental and physiological challenges, including exposure to low environmental temperature, require extensive structural, redox, and metabolic reprogramming. Detailed molecular mechanisms of such processes in the skin are lacking, especially the role of nuclear factor erythroid 2‐related factor 2 (Nrf2) and other closely related redox‐sensitive transcription factors Nrf1, Nrf3, and nuclear respiratory factor (NRF1). To investigate the role of Nrf2, we examined redox and metabolic responses in the skin of wild‐type (WT) mice and mice lacking functional Nrf2 (Nrf2 KO) at room (RT, 24?±?1°C) and cold (4?±?1°C) temperature. Our results demonstrate distinct expression profiles of major enzymes involved in antioxidant defense and key metabolic and mitochondrial pathways in the skin, depending on the functional Nrf2 and/or cold stimulus. Nrf2 KO mice at RT displayed profound alterations in redox, mitochondrial and metabolic responses, generally akin to cold‐induced skin responses in WT mice. Immunohistochemical analyses of skin cell compartments (keratinocytes, fibroblasts, hair follicle, and sebaceous gland) and spatial locations (nucleus and cytoplasm) revealed synergistic interactions between members of the Nrf transcription factor family as part of redox‐metabolic reprogramming in WT mice upon cold acclimation. In contrast, Nrf2 KO mice at RT showed loss of NRF1 expression and a compensatory activation of Nrf1/Nrf3, which was abolished upon cold, concomitant with blunted redox‐metabolic responses. These data show for the first time a novel role for Nrf2 in skin physiology in response to low environmental temperature, with important implications in human connective tissue diseases with altered thermogenic responses.
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Nuclear factor E2-related factor 2 (NRF2) plays an important role in redox metabolism and antioxidant defense. Under normal conditions, NRF2 proteins are maintained at very low levels because of their ubiquitination and proteasoma...
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Nuclear factor E2-related factor 2 (NRF2) plays an important role in redox metabolism and antioxidant defense. Under normal conditions, NRF2 proteins are maintained at very low levels because of their ubiquitination and proteasomal degradation via binding to the kelch-like ECH associated protein 1 (KEAP1)-E3 ubiquitin ligase complex. However, oxidative and/or electrophilic stresses disrupt the KEAP1-NRF2 interaction, which leads to the accumulation and transactivation of NRF2. During recent decades, a growing body of evidence suggests that NRF2 is frequently activated in many types of cancer by multiple mechanisms, including the genetic mutations in the KEAP1-NRF2 pathway. This suggested that NRF2 inhibition is a promising strategy for cancer therapy. Recently, several NRF2 inhibitors have been reported with anti-tumor efficacy. Here, we review the mechanisms whereby NRF2 is dysregulated in cancer and its contribution to the tumor development and radiochemoresistance. In addition, among the NRF2 inhibitors reported so far, we summarize and discuss repurposed NRF2 inhibitors with their potential mechanisms and provide new insights to develop selective NRF2 inhibitors.
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To defend against a vast variety of challenges in oxygenated environments, all life forms have evolutionally established a set of antioxidants, detoxification, and cytoprotective systems during natural selection and adaptive survi...
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To defend against a vast variety of challenges in oxygenated environments, all life forms have evolutionally established a set of antioxidants, detoxification, and cytoprotective systems during natural selection and adaptive survival, to maintain cell redox homeostasis and organ integrity in the healthy development and growth. Such antioxidant defense systems are predominantly regulated by two key transcription factors Nrf1 and Nrf2, but the underlying mechanism(s) for their coordinated redox control remains elusive. Here, we found that loss of full-length Nrf1 led to a dramatic increase in reactive oxygen species (ROS) and oxidative damages in Nrf1α –∕– cells, and this increase was not eliminated by drastic elevation of Nrf2, even though the antioxidant systems were also substantially enhanced by hyperactive Nrf2. Further studies revealed that the increased ROS production in Nrf1α –∕– resulted from a striking impairment in the mitochondrial oxidative respiratory chain and its gene expression regulated by nuclear respiratory factors, called αPal NRF1 and GABP NRF2 . In addition to the antioxidant capacity of cells, glycolysis was greatly augmented by aberrantly-elevated Nrf2, so to partially relieve the cellular energy demands, but aggravate its mitochondrial stress. The generation of ROS was also differentially regulated by Nrf1 and Nrf2 through miR-195 and/or mIR-497-mediated UCP2 pathway. Consequently, the epithelial-mesenchymal transformation (EMT) of Nrf1α –∕– cells was activated by putative ROS-stimulated signaling via MAPK, HIF1α, NF-?B, PI3K and AKT, all players involved in cancer development and progression. Taken together, it is inferable that Nrf1 acts as a potent integrator of redox regulation by multi-hierarchical networks.
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NF-E2-related factor 2 (Nrf2) protein is a basic-region leucine zipper transcription factor that defends against endogenous or exogenous stressors. By inducing several cytoprotective and detoxifying gene expressions, Nrf2 can incr...
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NF-E2-related factor 2 (Nrf2) protein is a basic-region leucine zipper transcription factor that defends against endogenous or exogenous stressors. By inducing several cytoprotective and detoxifying gene expressions, Nrf2 can increase the sensitivity of the cells to oxidants and electrophiles. Transient Nrf2 activation, by its specific activators, has protective roles against carcinogenesis and cancer development. However, permanent activation of Nrf2 promotes various cancer properties, comprising malignant progression, chemo/radio resistance, and poor patient prognosis. Taken together, these findings suggest that reaching an optimal balance between paradoxical functions of Nrf2 in malignancy may render a selective improvement to identify therapeutic strategies in cancer treatment. In this review, we describe lately discovered Nrf2 inducers and inhibitors, and their chemopreventive and/or anticancer activities. The Nrf2 pathway signifies one of the most significant cell defense procedures against exogenous or endogenous stressors. Certainly, by increasing the expression of several cytoprotective genes, the transcription factor Nrf2 can shelter cells and tissues from multiple sources of damage including electrophilic, xenobiotic, metabolic, and oxidative stress. Notably, the aberrant activation or accumulation of Nrf2, a common event in many tumors, confers a selective advantage to cancer cells and is connected to malignant progression, therapy resistance, and poor prognosis. Therefore, lately, Nrf2 has arisen as a hopeful target in treatment of cancer, and many struggles have been made to detect therapeutic strategies intended at disrupting its pro-oncogenic role. By summarizing the outcomes from past and recent studies, this review provided an overview concerning the Nrf2 pathway and the molecular mechanisms causing Nrf2 hyperactivation in cancer cells. Finally, this paper?also described some of the most promising therapeutic approaches that have been successfully employed to counteract Nrf2 activity in tumors, with a particular emphasis on the development of natural compounds and the adoption of drug repurposing strategies.
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Nuclear factor, erythroid 2 like 2 (Nfe2l2 or Nrf2), is a transcription factor that protects cells by maintaining a homeostatic redox state during stress. The constitutive expression of Nrf2 (CaNrf2-TG) was previously shown to be ...
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Nuclear factor, erythroid 2 like 2 (Nfe2l2 or Nrf2), is a transcription factor that protects cells by maintaining a homeostatic redox state during stress. The constitutive expression of Nrf2 (CaNrf2-TG) was previously shown to be pathological to the heart over time. We tested a hypothesis that the cardiac-specific expression of full length Nrf2 (mNrf2-TG) would moderately increase the basal antioxidant defense, triggering a pro-reductive environment leading to adaptive cardiac remodeling. Transgenic and non-transgenic (NTG) mice at 7–8 months of age were used to analyze the myocardial transcriptome, structure, and function. Next generation sequencing (NGS) for RNA profiling and qPCR-based validation of the NGS data, myocardial redox levels, and imaging (echocardiography) were performed. Transcriptomic analysis revealed that out of 14,665 identified mRNAs, 680 were differently expressed (DEG) in TG hearts. Of 680 DEGs, 429 were upregulated and 251 were downregulated significantly (FC > 2.0, p < 0.05). Gene set enrichment analysis revealed that the top altered pathways were (a) Nrf2 signaling, (b) glutathione metabolism and (c) ROS scavenging. A comparative analysis of the glutathione redox state in the hearts demonstrated significant differences between pro-reductive vs. hyper-reductive conditions (233 ± 36.7 and 380 ± 68.7 vs. 139 ± 8.6 μM/mg protein in mNrf2-TG and CaNrf2-TG vs. NTG). Genes involved in fetal development, hypertrophy, cytoskeletal rearrangement, histone deacetylases (HDACs), and GATA transcription factors were moderately increased in mNrf2-TG compared to CaNrf2-TG. Non-invasive echocardiography analysis revealed an increase in systolic function (ejection fraction) in mNrf2-TG, suggesting an adaptation, as opposed to pathological remodeling in CaNrf2-TG mice experiencing a hyper-reductive stress, leading to reduced survival (40% at 60 weeks). The effects of excess Nrf2-driven antioxidant transcriptome revealed a pro-reductive condition in the myocardium leading to an adaptive cardiac remodeling. While pre-conditioning the myocardial redox with excess antioxidants (i.e., pro-reductive state) could be beneficial against oxidative stress, a chronic pro-reductive environment in the myocardium might transition the adaptation to pathological remodeling.
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Oxidative stress is well recognized to contribute to the cause of a wide range of diseases, such as cancer, diabetes, Alzheimer's disease, arteriosclerosis, and inflammation. The Keap1-Nrf2-ARE pathway plays a critical regulatory ...
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Oxidative stress is well recognized to contribute to the cause of a wide range of diseases, such as cancer, diabetes, Alzheimer's disease, arteriosclerosis, and inflammation. The Keap1-Nrf2-ARE pathway plays a critical regulatory role and can protect cells from oxidative stress through activating Nrf2 to induce its downstream phase II enzymes. Nrf2 activation through the covalent inactivation of Keap1 may cause unpredictable side effects. Non-covalent disruption of the Keap1-Nrf2 protein-protein interactions is an alternative strategy for Nrf2 activation, potentially with reduced risk of toxicity. Efforts have been made in recent years to develop peptide- and small molecule-based Keap1-Nrf2 PPI inhibitors via different approaches, including high-throughput screening, target-based virtual screening, structure-based optimization, and fragment-based drug design. This review aims to highlight the recently discovered smallmolecule inhibitors as well as their therapeutic potential.
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Purpose: The purpose of this investigation was to determine the impact of post-exercise environmental cold exposure on muscle glycogen, PGC-1α, and downstream transcription factors. Methods: Eight males cycled for 1h and recovere...
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Purpose: The purpose of this investigation was to determine the impact of post-exercise environmental cold exposure on muscle glycogen, PGC-1α, and downstream transcription factors. Methods: Eight males cycled for 1h and recovered in either 7°C (cold) or 20°C (room temp) environment for 4h. Muscle biopsies were obtained pre, post, and 4h post exercise for the analysis of muscle glycogen and mRNA. During recovery participants consumed 1.8gkg-1 of body weight of an oral dextrose solution immediately following the post biopsy and 2h into recovery. Blood samples were obtained post exercise and at 30, 60, 120, 150, 180, and 240min post exercise for the analysis of serum glucose and insulin AUC. Results: Oxygen uptake was lower during room temp than during cold recovery (0.40±0.05L x min-1 vs. 0.80±0.12 L x min-1; p<0.01). There was no effect of temperature on muscle glycogen recovery or glucose AUC. However, insulin AUC was greater during the room temp trial compared to the cold trial (5139±1412 vs. 4318±1272, respectively; p=0.025). PGC-1α gene expression was higher (p=0.029), but ERRα and NRF2 were lower (p=0.019 and p=0.046, respectively) after recovery in the cold. There were no differences in NRF1 (p=.173) or TFAM (p=0.694). Conclusions: This investigation shows no effect of a cold recovery environment on glycogen re-synthesis but does demonstrate reduced ERRα and NRF2 mRNA despite elevations in PGC-1α mRNA when recovery post-exercise takes place in a cold environment.
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Nrf2 is the major transcription factor that regulates many of the cytoprotective enzymes involved in the adaptive stress response. Modulation of Nrf2 could be therapeutically useful in a number of disease states. Activation can oc...
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Nrf2 is the major transcription factor that regulates many of the cytoprotective enzymes involved in the adaptive stress response. Modulation of Nrf2 could be therapeutically useful in a number of disease states. Activation can occur through either an electrophilic or non-electrophilic mechanism. To date, most of the research has focused on electrophilic Nrf2 activators, but there is increasing interest in non-electrophilic modulators of Nrf2. This Digest examines the current selection of small molecules that modulate Nrf2 through non-electrophilic mechanisms, and it highlights new opportunities for this important therapeutic target. (C) 2015 Elsevier Ltd. All rights reserved.
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