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.

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 Redox for Repair: Cold Physical Plasmas and Nrf2 Signaling Promoting Wound Healing

Antioxidants ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 146 ◽  
Author(s):  
Anke Schmidt ◽  
Sander Bekeschus
Keyword(s):  
Wound Healing ◽  
Wound Closure ◽  
Chronic Wounds ◽  
Health Care Systems ◽  
Molecular Switches ◽  
Dermal Fibroblasts ◽  
Tissue Response ◽  
Related Factor ◽  
Plasma Effects ◽  
Care Systems

Chronic wounds and ulcers are major public health threats. Being a substantial burden for patients and health care systems alike, better understanding of wound pathophysiology and new avenues in the therapy of chronic wounds are urgently needed. Cold physical plasmas are particularly effective in promoting wound closure, irrespective of its etiology. These partially ionized gases deliver a therapeutic cocktail of reactive oxygen and nitrogen species safely at body temperature and without genotoxic side effects. This field of plasma medicine reanimates the idea of redox repair in physiological healing. This review compiles previous findings of plasma effects in wound healing. It discusses new links between plasma treatment of cells and tissues, and the perception and intracellular translation of plasma-derived reactive species via redox signaling pathways. Specifically, (i) molecular switches governing redox-mediated tissue response; (ii) the activation of the nuclear E2-related factor (Nrf2) signaling, together with antioxidative and immunomodulatory responses; and (iii) the stabilization of the scaffolding function and actin network in dermal fibroblasts are emphasized in the light of wound healing.

scholarly journals Progressive Rotavirus Infection Downregulates Redox-Sensitive Transcription Factor Nrf2 and Nrf2-Driven Transcription Units

2020 ◽  
Vol 2020 ◽  
pp. 1-48
Author(s):  
Upayan Patra ◽  
Urbi Mukhopadhyay ◽  
Arpita Mukherjee ◽  
Rakesh Sarkar ◽  
Mamta Chawla-Sarkar
Keyword(s):  
Transcription Factor ◽  
Stress Response ◽  
Antioxidant Defense ◽  
Cellular Stress Response ◽  
Erythroid Cell ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Defense System ◽  
Cellular Redox ◽  
Cellular Environment

Eukaryotic cells adopt highly tuned stress response physiology under threats of exogenous stressors including viruses to maintain cellular homeostasis. Not surprisingly, avoidance of cellular stress response pathways is an essential facet of virus-induced obligatory host reprogramming to invoke a cellular environment conducive to viral perpetuation. Adaptive cellular responses to oxidative and electrophilic stress are usually taken care of by an antioxidant defense system, core to which lies the redox-responsive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-driven transcriptional cascade. Deregulation of host redox balance and redox stress-sensitive Nrf2 antioxidant defense have been reported for many viruses. In the current study, we aimed to study the modulation of the Nrf2-based host cellular redox defense system in response to Rotavirus (RV) infection in vitro. Interestingly, we found that Nrf2 protein levels decline sharply with progression of RV infection beyond an initial upsurge. Moreover, Nrf2 decrease as a whole was found to be accompanied by active nuclear vacuity of Nrf2, resulting in lowered expression of stress-responsive Nrf2 target genes heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1, and superoxide dismutase 1 both in the presence and absence of Nrf2-driven transcriptional inducers. Initial induction of Nrf2 concurred with RV-induced early burst of oxidative stress and therefore was sensitive to treatments with antioxidants. Reduction of Nrf2 levels beyond initial hours, however, was found to be independent of the cellular redox status. Furthermore, increasing the half-life of Nrf2 through inhibition of the Kelch-like erythroid cell-derived protein with CNC homology- (ECH-) associated protein 1/Cullin3-RING Box1-based canonical Nrf2 turnover pathway could not restore Nrf2 levels post RV-SA11 infection. Depletion of the Nrf2/HO-1 axis was subsequently found to be sensitive to proteasome inhibition with concurrent observation of increased K48-linked ubiquitination associated with Nrf2. Together, the present study describes robust downregulation of Nrf2-dependent cellular redox defense beyond initial hours of RV infection, justifying our previous observation of potent antirotaviral implications of Nrf2 agonists.

scholarly journals Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

2016 ◽  
Vol 397 (5) ◽  
pp. 383-400 ◽  
Author(s):  
Noemí Esteras ◽  
Albena T. Dinkova-Kostova ◽  
Andrey Y. Abramov
Keyword(s):  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Related Factor ◽  
Mitochondrial Bioenergetics ◽  
Cytoprotective Activity ◽  
Nrf2 Activation ◽  
Potential Therapeutic Role ◽  
And Function

Abstract The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor well-known for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich’s ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

scholarly journals Nrf2 Transcription Factor, a Novel Target of Keratinocyte Growth Factor Action Which Regulates Gene Expression and Inflammation in the Healing Skin Wound

2002 ◽  
Vol 22 (15) ◽  
pp. 5492-5505 ◽  
Author(s):  
Susanne Braun ◽  
Christine Hanselmann ◽  
Marcus G. Gassmann ◽  
Ulrich auf dem Keller ◽  
Christiane Born-Berclaz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Wound Healing ◽  
Transcription Factor ◽  
Growth Factor ◽  
Wound Repair ◽  
Keratinocyte Growth Factor ◽  
Skin Wound ◽  
Related Factor ◽  
Control Of Gene Expression ◽  
Nrf2 Knockout

ABSTRACT Keratinocyte growth factor (KGF) is a potent mitogen for epithelial cells, and it promotes survival of these cells under stress conditions. In a search for KGF-regulated genes in keratinocytes, we identified the gene encoding the transcription factor NF-E2-related factor 2 (Nrf2). Nrf2 is a key player in the cellular stress response. This might be of particular importance during wound healing, where large amounts of reactive oxygen species are produced as a defense against invading bacteria. Therefore, we studied the wound repair process in Nrf2 knockout mice. Interestingly, the expression of various key players involved in wound healing was significantly reduced in early wounds of the Nrf2 knockout animals, and the late phase of repair was characterized by prolonged inflammation. However, these differences in gene expression were not reflected by obvious histological abnormalities. The normal healing rate appears to be at least partially due to an up-regulation of the related transcription factor Nrf3, which was also identified as a target of KGF and which was coexpressed with Nrf2 in the healing skin wound. Taken together, our results reveal novel roles of the KGF-regulated transcription factors Nrf2 and possibly Nrf3 in the control of gene expression and inflammation during cutaneous wound repair.

scholarly journals Polydopamine Antioxidant Hydrogels for Wound Healing Applications

Gels ◽  
2020 ◽  
Vol 6 (4) ◽  
pp. 39
Author(s):  
Naphtali A. O’Connor ◽  
Abdulhaq Syed ◽  
Madeline Wong ◽  
Josiah Hicks ◽  
Greisly Nunez ◽  
...  
Keyword(s):  
Wound Healing ◽  
Therapeutic Strategy ◽  
Chronic Wounds ◽  
Ex Vivo ◽  
Healing Process ◽  
Antioxidant Properties ◽  
Feed Ratio ◽  
Wound Healing Process ◽  
Wound Healing Assay ◽  
Hydrogel Synthesis

Antioxidants are known to improve the wound healing process and are researched as a therapeutic strategy to treat chronic wounds. Dopamine is a known neurotransmitter with antioxidant properties that can be polymerized to form polydopamine (PDA). Herein, polydopamine is demonstrated as an antioxidant biomaterial. In prior work, we developed methodology to prepare hydrogels by crosslinking polysaccharides with polyamines via epichlorohydrin and NaOH. Using this previously developed methodology, dextran hydrogels crosslinked with polydopamine were prepared. Darkening of the gels indicated the increasing incorporation of polydopamine within the hydrogels. In addition to basic pH, polydopamine can be formed by reaction with polyethylene imine (PEI), which results in PEI-PDA copolymer. Dextran was similarly crosslinked with the PEI-PDA copolymer and resulted in sturdier, darker gels, which had more polydopamine incorporated. Hydrogel morphology and strength were dependent on the feed ratios of dopamine. Antioxidant activity of polydopamine containing hydrogel was confirmed and shown to be dependent on the amount of dopamine used in hydrogel synthesis. Hydrogels with 0.5 dopamine to dextran feed ratio scavenged 78.8% of radicals in a 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) antioxidant assay while gels with no dopamine scavenged only 1.4% of radicals. An ex vivo wound healing assay showed considerable cell migration with the PEI-PDA containing hydrogel.

scholarly journals Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 481 ◽  
Author(s):  
Azhwar Raghunath ◽  
Kiruthika Sundarraj ◽  
Frank Arfuso ◽  
Gautam Sethi ◽  
Ekambaram Perumal
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcription Factor ◽  
Cancer Progression ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Related Factor ◽  
Liver Malignancy ◽  
Beneficial Effects ◽  
Nrf2 Activation ◽  
Key Factor

The liver executes versatile functions and is the chief organ for metabolism of toxicants/xenobiotics. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third foremost cause of cancer death worldwide. Oxidative stress is a key factor related with the development and progression of HCC. Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2) is a cytosolic transcription factor, which regulates redox homeostasis by activating the expression of an array of antioxidant response element-dependent genes. Nrf2 displays conflicting roles in normal, healthy liver and HCC; in the former, Nrf2 offers beneficial effects, whereas in the latter it causes detrimental effects favouring the proliferation and survival of HCC. Sustained Nrf2 activation has been observed in HCC and facilitates its progression and aggressiveness. This review summarizes the role and mechanism(s) of action of Nrf2 dysregulation in HCC and therapeutic options that can be employed to modulate this transcription factor.

scholarly journals miRNA Influences in NRF2 Pathway Interactions within Cancer Models

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Duncan Ayers ◽  
Byron Baron ◽  
Therese Hunter
Keyword(s):  
Transcription Factor ◽  
Cross Talk ◽  
Drug Targets ◽  
Wide Spectrum ◽  
Clinical Importance ◽  
Regulatory Control ◽  
Related Factor ◽  
Cellular Interactions ◽  
Cancer Models ◽  
Nrf2 Transcription Factor

The NRF2 transcription factor (nuclear factor-erythroid 2 p45-related factor 2) has been identified as a key molecular player in orchestrating adaptive cellular interactions following a wide spectrum of cellular stress conditions that could be either extracellular or intracellular. Dysregulation of the NRF2 system is implicated in various disease states, including inflammatory conditions. The NRF2 transcription factor is also known to permit cross talk with several other essential cellular signaling pathways. Recent literature has also elucidated the potential influences of miRNA activity over modulations of the NRF2 signalling network. Consequently, further delving into the knowledge regarding the extent of miRNA-induced epigenetic gene regulatory control on key elements of the NRF2 signalling pathway and its cross talk, particularly within the context of cancer models, can prove to be of high clinical importance. This is so since such miRNAs, once identified and validated, can be potentially exploited as novel drug targets for emerging translational medicine-based therapies.

scholarly journals Regulatory Role of Nrf2 Signaling Pathway in Wound Healing Process

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2424
Author(s):  
Ipek Süntar ◽  
Sümeyra Çetinkaya ◽  
Emiliano Panieri ◽  
Sarmistha Saha ◽  
Brigitta Buttari ◽  
...  
Keyword(s):  
Wound Healing ◽  
Signaling Pathway ◽  
Bioactive Compounds ◽  
Wound Repair ◽  
Chronic Wounds ◽  
Healing Process ◽  
Wound Healing Process ◽  
Related Factor ◽  
Nrf2 Signaling Pathway

Wound healing involves a series of cellular events in damaged cells and tissues initiated with hemostasis and finally culminating with the formation of a fibrin clot. However, delay in the normal wound healing process during pathological conditions due to reactive oxygen species, inflammation and immune suppression at the wound site represents a medical challenge. So far, many therapeutic strategies have been developed to improve cellular homeostasis and chronic wounds in order to accelerate wound repair. In this context, the role of Nuclear factor erythroid 2-related factor 2 (Nrf2) during the wound healing process has been a stimulating research topic for therapeutic perspectives. Nrf2 is the main regulator of intracellular redox homeostasis. It increases cytoprotective gene expression and the antioxidant capacity of mammalian cells. It has been reported that some bioactive compounds attenuate cellular stress and thus accelerate cell proliferation, neovascularization and repair of damaged tissues by promoting Nrf2 activation. This review highlights the importance of the Nrf2 signaling pathway in wound healing strategies and the role of bioactive compounds that support wound repair through the modulation of this crucial transcription factor.

scholarly journals NRF2, a Transcription Factor for Stress Response and Beyond

2020 ◽  
Vol 21 (13) ◽  
pp. 4777 ◽  
Author(s):  
Feng He ◽  
Xiaoli Ru ◽  
Tao Wen
Keyword(s):  
Transcription Factor ◽  
Stress Response ◽  
Regulatory Network ◽  
Metabolic Reprogramming ◽  
Related Factor ◽  
Genetic Manipulations ◽  
Cellular Processes ◽  
Expression Of Genes ◽  
Nrf2 Activation ◽  
Complex Regulatory Network

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of genes involved in oxidative stress response and drug detoxification. NRF2 activation renders cells resistant to chemical carcinogens and inflammatory challenges. In addition to antioxidant responses, NRF2 is involved in many other cellular processes, including metabolism and inflammation, and its functions are beyond the originally envisioned. NRF2 activity is tightly regulated through a complex transcriptional and post-translational network that enables it to orchestrate the cell’s response and adaptation to various pathological stressors for the homeostasis maintenance. Elevated or decreased NRF2 activity by pharmacological and genetic manipulations of NRF2 activation is associated with many metabolism- or inflammation-related diseases. Emerging evidence shows that NRF2 lies at the center of a complex regulatory network and establishes NRF2 as a truly pleiotropic transcription factor. Here we summarize the complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity.

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