scholarly journals The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

2021 ◽  
Vol 22 (15) ◽  
pp. 7963
Author(s):  
Sonia Emanuele ◽  
Adriana Celesia ◽  
Antonella D’Anneo ◽  
Marianna Lauricella ◽  
Daniela Carlisi ◽  
...  
Keyword(s):  
Cell Fate ◽  
Viral Infections ◽  
Cell Transformation ◽  
Metabolic Reprogramming ◽  
Related Factor ◽  
Detoxifying Enzymes ◽  
Cancer Initiation ◽  
Genes Encoding ◽  
Complex Correlation ◽  
Molecular Aspects

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known transcription factor best recognised as one of the main regulators of the oxidative stress response. Beyond playing a crucial role in cell defence by transactivating cytoprotective genes encoding antioxidant and detoxifying enzymes, Nrf2 is also implicated in a wide network regulating anti-inflammatory response and metabolic reprogramming. Such a broad spectrum of actions renders the factor a key regulator of cell fate and a strategic player in the control of cell transformation and response to viral infections. The Nrf2 protective roles in normal cells account for its anti-tumour and anti-viral functions. However, Nrf2 overstimulation often occurs in tumour cells and a complex correlation of Nrf2 with cancer initiation and progression has been widely described. Therefore, if on one hand, Nrf2 has a dual role in cancer, on the other hand, the factor seems to display a univocal function in preventing inflammation and cytokine storm that occur under viral infections, specifically in coronavirus disease 19 (COVID-19). In such a variegate context, the present review aims to dissect the roles of Nrf2 in both cancer and COVID-19, two widespread diseases that represent a cause of major concern today. In particular, the review describes the molecular aspects of Nrf2 signalling in both pathological situations and the most recent findings about the advantages of Nrf2 inhibition or activation as possible strategies for cancer and COVID-19 treatment respectively.

scholarly journals Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

2021 ◽  
Vol 22 (8) ◽  
pp. 4256
Author(s):  
Lorenzo Maggi ◽  
Manolis Mavroidis ◽  
Stelios Psarras ◽  
Yassemi Capetanaki ◽  
Giovanna Lattanzi
Keyword(s):  
Muscular Dystrophy ◽  
Cardiac Muscle ◽  
Intermediate Filament ◽  
Striated Muscle ◽  
Congenital Muscular Dystrophy ◽  
Left Ventricular ◽  
Intermediate Filament Proteins ◽  
Muscle Disorders ◽  
Genes Encoding ◽  
Molecular Aspects

Intermediate filaments are major components of the cytoskeleton. Desmin and synemin, cytoplasmic intermediate filament proteins and A-type lamins, nuclear intermediate filament proteins, play key roles in skeletal and cardiac muscle. Desmin, encoded by the DES gene (OMIM *125660) and A-type lamins by the LMNA gene (OMIM *150330), have been involved in striated muscle disorders. Diseases include desmin-related myopathy and cardiomyopathy (desminopathy), which can be manifested with dilated, restrictive, hypertrophic, arrhythmogenic, or even left ventricular non-compaction cardiomyopathy, Emery–Dreifuss Muscular Dystrophy (EDMD2 and EDMD3, due to LMNA mutations), LMNA-related congenital Muscular Dystrophy (L-CMD) and LMNA-linked dilated cardiomyopathy with conduction system defects (CMD1A). Recently, mutations in synemin (SYNM gene, OMIM *606087) have been linked to cardiomyopathy. This review will summarize clinical and molecular aspects of desmin-, lamin- and synemin-related striated muscle disorders with focus on LMNA and DES-associated clinical entities and will suggest pathogenetic hypotheses based on the interplay of desmin and lamin A/C. In healthy muscle, such interplay is responsible for the involvement of this network in mechanosignaling, nuclear positioning and mitochondrial homeostasis, while in disease it is disturbed, leading to myocyte death and activation of inflammation and the associated secretome alterations.

scholarly journals Mortalin/glucose-regulated protein 75 promotes the cisplatin-resistance of gastric cancer via regulating anti-oxidation/apoptosis and metabolic reprogramming

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yi Dai ◽  
Fan Li ◽  
Yuwen Jiao ◽  
Guoguang Wang ◽  
Tian Zhan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cisplatin Resistance ◽  
Meta Analysis ◽  
Acquired Resistance ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Platinum Resistance ◽  
Related Factor ◽  
Platinum Drug ◽  
Glucose Regulated Protein

AbstractPlatinum drug treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). However, the therapeutic effect is less than satisfactory, largely due to the acquired resistance to platinum drugs. Therefore, a better understanding of the underlying mechanisms can greatly improve the therapeutic efficacy of GC. In this study, we aimed to investigate the chemo-resistance related functions/mechanisms and clinical significance of glucose-regulated protein 75 (GRP75) in GC. Here, our data showed that compared with SGC7901 cells, the expression of GRP75 was markedly higher in cisplatin-resistance cells (SGC7901CR). Knockdown of GRP75 abolished the maintenance of mitochondrial membrane potential (MMP) and inhibited the nuclear factor erythroid-2-related factor 2 (NRF2), phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), hypoxia-inducible factor 1α (HIF-1α), and c-myc, which resulted in blocking the activation of their downstream targets. These processes attenuated the anti-oxidation/apoptosis abilities and altered the metabolic reprogramming in SGC7901CR cells, leading to re-sensitizing these cells to cisplatin. However, overexpression of GRP75 in SGC7901 cells caused the opposite effects. A xenografts model confirmed the abovementioned results. In GC patients receiving platinum chemotherapy and a meta-analysis, a high level of GRP75 was positively associated with aggressive characteristics and poor prognosis including but not limited to gastrointestinal cancers, and was an independent predictor for overall survival. Collectively, our study indicated that GRP75 was involved in the cisplatin-resistance of GC and that GRP75 could be a potential therapeutic target for restoring the drug response in platinum-resistance cells and a useful additive prognostic tool in guiding clinical management of GC patients.

scholarly journals Induction of metallothionein I by phenolic antioxidants requires metal-activated transcription factor 1 (MTF-1) and zinc

2004 ◽  
Vol 380 (3) ◽  
pp. 695-703 ◽  
Author(s):  
Yongyi BI ◽  
Richard D. PALMITER ◽  
Kristi M. WOOD ◽  
Qiang MA
Keyword(s):  
Transcription Factor ◽  
Phase Ii ◽  
Leucine Zipper ◽  
Gene Promoter ◽  
Phenolic Antioxidants ◽  
Related Factor ◽  
Basic Leucine Zipper ◽  
Free Zinc ◽  
Genes Encoding ◽  
Transcription Factor 1

Phenolic antioxidants, such as tBHQ [2,5-di-(t-butyl)-1,4-hydroquinone], induce Mt1 (metallothionein 1) gene expression and accumulation of MT protein. Induction of Mt1 mRNA does not depend on protein synthesis, and correlates with oxidation–reduction functions of the antioxidants. In the present study, we analysed the biochemical pathway of the induction. Induction depends on the presence of MTF-1 (metal-activated transcription factor 1), a transcription factor that is required for metal-induced transcription of Mt1, but does not require nuclear factor erythroid 2-related factor 2, a tBHQ-activated CNC bZip (cap ‘n’ collar basic leucine zipper) protein, that is responsible for regulating genes encoding phase II drug-metabolizing enzymes. Moreover, tBHQ induces the expression of MRE-βGeo, a reporter gene driven by five metal response elements that constitute an optimal MTF-1 binding site. Reconstitution of Mtf1-null cells with MTF-1 restores induction by both zinc and tBHQ. Unlike activation of phase II genes by tBHQ, induction of Mt1 expression does not occur in the presence of EDTA, when cells are cultured in zinc-depleted medium, or in cells with reduced intracellular ‘free’ zinc due to overexpression of ZnT1, a zinc-efflux transporter, indicating that induction requires zinc. In addition, fluorescence imaging reveals that tBHQ increases cytoplasmic free zinc concentration by mobilizing intracellular zinc pools. These findings establish that phenolic antioxidants activate Mt1 transcription by a zinc-dependent mechanism, which involves MTF-1 binding to metal regulator elements in the Mt1 gene promoter.

The Drosophila orphan nuclear receptor seven-up requires the Ras pathway for its function in photoreceptor determination

Development ◽  
1995 ◽  
Vol 121 (1) ◽  
pp. 225-235 ◽  
Author(s):  
G. Begemann ◽  
A.M. Michon ◽  
L. vd Voorn ◽  
R. Wepf ◽  
M. Mlodzik
Keyword(s):  
Cell Fate ◽  
Nuclear Receptor ◽  
Egf Receptor ◽  
Cell Transformation ◽  
Orphan Nuclear Receptor ◽  
Loss Of Function ◽  
Cone Cell ◽  
Ras Pathway ◽  
Protein Levels ◽  
Cone Cells

The Drosophila seven-up (svp) gene specifies outer photoreceptor cell fate in eye development and encodes an orphan nuclear receptor with two isoforms. Transient expression under the sevenless enhancer of either svp isoform leads to a dosage-dependent transformation of cone cells into R7 photoreceptors, and at a lower frequency, R7 cells into outer photoreceptors. To investigate the cellular pathways involved, we have taken advantage of the dosage sensitivity and screened for genes that modify this svp-induced phenotype. We show that an active Ras pathway is essential for the function of both Svp isoforms. Loss-of-function mutations in components of the Ras signal transduction cascade act as dominant suppressors of the cone cell transformation, whilst loss-of-function mutations in negative regulators of Ras-activity act as dominant enhancers. Furthermore, Svp-mediated transformation of cone cells to outer photoreceptors, reminiscent of its wild-type function in specifying R3/4 and R1/6 identity, requires an activated Ras pathway in the same cells, or alternatively dramatic increase in ectopic Svp protein levels. Our results indicate that svp is only fully functional in conjunction with activated Ras. Since we find that mutations in the Egf-receptor are also among the strongest suppressors of svp-mediated cone cell transformation, we propose that the Ras activity in cone cells is due to low level Egfr signaling. Several models that could account for the observed svp regulation by the Ras pathway are discussed.

scholarly journals Small, Thin Graphene Oxide Is Anti-inflammatory Activating Nuclear Factor Erythroid 2-Related Factor 2 via Metabolic Reprogramming

ACS Nano ◽  
2018 ◽  
Vol 12 (12) ◽  
pp. 11949-11962 ◽  
Author(s):  
Christopher Hoyle ◽  
Jack Rivers-Auty ◽  
Eloïse Lemarchand ◽  
Sandra Vranic ◽  
Emily Wang ◽  
...  
Keyword(s):  
Graphene Oxide ◽  
Metabolic Reprogramming ◽  
Related Factor ◽  
Nuclear Factor ◽  
Anti Inflammatory

scholarly journals Autophagy in Viral Development and Progression of Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Alejandra Suares ◽  
María Victoria Medina ◽  
Omar Coso
Keyword(s):  
Cell Fate ◽  
Cell Transformation ◽  
Tumor Development ◽  
Lysosomal Hydrolases ◽  
Subsequent Degradation ◽  
Cellular Context ◽  
Tumor Transformation ◽  
Proliferation And Metastasis ◽  
Viral Development ◽  
Catabolic Process

Autophagy is a complex degradative process by which eukaryotic cells capture cytoplasmic components for subsequent degradation through lysosomal hydrolases. Although this catabolic process can be triggered by a great variety of stimuli, action in cells varies according to cellular context. Autophagy has been previously linked to disease development modulation, including cancer. Autophagy helps suppress cancer cell advancement in tumor transformation early stages, while promoting proliferation and metastasis in advanced settings. Oncoviruses are a particular type of virus that directly contribute to cell transformation and tumor development. Extensive molecular studies have revealed complex ways in which autophagy can suppress or improve oncovirus fitness while still regulating viral replication and determining host cell fate. This review includes recent advances in autophagic cellular function and emphasizes its antagonistic role in cancer cells.

scholarly journals Phenotypic Plasticity and Cell Fate Decisions in Cancer: Insights from Dynamical Systems Theory

2017 ◽  
Author(s):  
Dongya Jia ◽  
Mohit Kumar Jolly ◽  
Prakash Kulkarni ◽  
Herbert Levine
Keyword(s):  
Phenotypic Plasticity ◽  
Dynamical Systems ◽  
Cancer Cells ◽  
Cell Fate ◽  
Conformational Dynamics ◽  
Metabolic Reprogramming ◽  
Disordered Proteins ◽  
Cell Phenotype ◽  
Cell Fate Decisions ◽  
Multiple Variables

Waddington’s epigenetic landscape, a famous metaphor in developmental biology, depicts how a stem cell progresses from an undifferentiated phenotype to a differentiated one. The concept of “landscape” in the context of dynamical system theory represents a high-dimensional cell state space, in which each cell phenotype is considered as an “attractor” that is determined by interactions among multiple variables (molecular players), and is buffered against environmental fluctuations. Further, biological noise is thought to play an important role during these cell-fate decisions and in fact controls transitions between different phenotypes. Here, we discuss these phenotypic transitions in cancer from a dynamical systems perspective and invoke the concept of “cancer attractors” – hidden stable states of the underlying regulatory network that are not occupied by normal cells. Using epithelial-to-mesenchymal transition (EMT), cancer stem-like properties, metabolic reprogramming and the emergence of drug/hormone resistance as examples, we illustrate how phenotypic plasticity in cancer cells enables them to acquire hybrid phenotypes (such as hybrid epithelial/mesenchymal and hybrid metabolic phenotypes) that tend to be more aggressive and notoriously resilient to drug/hormone treatment. Furthermore, we highlight multiple factors that may give rise to phenotypic plasticity in cancer cells, such as (a) multi-stability or oscillatory behaviors governed by underlying regulatory networks involved in cell-fate decisions in cancer cells, and (b) network rewiring due to conformational dynamics of intrinsically disordered proteins (IDPs) that are highly enriched in cancer cells. We conclude by discussing why a therapeutic approach that promotes ‘recanalization’, i.e. the exit from “cancer attractors” and re-entry into “normal attractors”, is more likely to succeed rather than a conventional approach that targets individual molecules/pathways.

scholarly journals The role of Nrf2 in acute and chronic muscle injury

2020 ◽  
Author(s):  
Iwona Bronisz-Budzyńska ◽  
Magdalena Kozakowska ◽  
Paulina Podkalicka ◽  
Neli Kachamakova-Trojanowska ◽  
Agnieszka Łoboda ◽  
...  
Keyword(s):  
Muscle Damage ◽  
Muscle Injury ◽  
Experimental Models ◽  
Muscle Pathology ◽  
Related Factor ◽  
Chronic Injury ◽  
Inflammatory Infiltration ◽  
Genes Encoding ◽  
Fibrotic Scar

Abstract The nuclear factor erythroid 2-related factor 2 (Nrf2) is considered as a master cytoprotective factor regulating the expression of genes encoding anti-oxidant, anti-inflammatory, and detoxifying proteins. The role of Nrf2 in the pathophysiology of skeletal muscles has been evaluated in different experimental models, however, due to inconsistent data, we aimed to investigate how Nrf2 transcriptional deficiency (Nrf2tKO) affects muscle functions both in an acute and chronic injury. The acute muscle damage was induced in mice of two genotypes – WT and Nrf2tKO mice by cardiotoxin (CTX) injection. To investigate the role of Nrf2 in chronic muscle pathology, mdx mice that share genetic, biochemical, and histopathological features with Duchenne muscular dystrophy (DMD) were crossed with mice lacking transcriptionally active Nrf2 and double knockouts (mdx/Nrf2tKO) were generated. To worsen the dystrophic phenotype, the analysis of disease pathology was also performed in aggravated conditions, by applying a long-term treadmill test.We have observed slightly increased muscle damage in Nrf2tKO mice after CTX injection. Nevertheless, transcriptional ablation of Nrf2 in mdx mice did not significantly aggravate the most deleterious, pathological hallmarks of DMD related to degeneration, inflammation, fibrotic scar formation, angiogenesis, and the number and proliferation of satellite cells in non-exercised conditions. On the other hand, upon chronic exercises, the degeneration and inflammatory infiltration of the gastrocnemius muscle, but not diaphragm, turned to be increased in Nrf2tKOmdx in comparison to mdx mice. In conclusion, the lack of transcriptionally active Nrf2 influences moderately muscle pathology in acute CTX-induced muscle injury and chronic DMD mouse model, without affecting muscle functionality. Hence, in general, we demonstrated that the deficiency of Nrf2 transcriptional activity has no profound impact on muscle pathology in various models of muscle injury.

scholarly journals Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Yasuhiro Nakagami
Keyword(s):  
Oxidative Stress ◽  
Neuronal Degeneration ◽  
Antioxidant Response ◽  
Related Factor ◽  
Retinal Diseases ◽  
Age Related ◽  
Nrf2 Signaling Pathway ◽  
Genes Encoding ◽  
Antioxidant Response Elements ◽  
Nrf2 Activator

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway.

scholarly journals Minimization of energy transduction confers resistance to phosphine in the rice weevil, Sitophilus oryzae

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kyeongnam Kim ◽  
Jeong Oh Yang ◽  
Jae-Yoon Sung ◽  
Ji-Young Lee ◽  
Jeong Sun Park ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Insect Pests ◽  
Sitophilus Oryzae ◽  
Resistance Mechanism ◽  
Energy Transduction ◽  
Metabolic Reprogramming ◽  
Rice Weevil ◽  
Altered Expression ◽  
Synonymous Mutations ◽  
Genes Encoding

Abstract Infestation of phosphine (PH3) resistant insects threatens global grain reserves. PH3 fumigation controls rice weevil (Sitophilus oryzae) but not highly resistant insect pests. Here, we investigated naturally occurring strains of S. oryzae that were moderately resistant (MR), strongly resistant (SR), or susceptible (wild-type; WT) to PH3 using global proteome analysis and mitochondrial DNA sequencing. Both PH3 resistant (PH3–R) strains exhibited higher susceptibility to ethyl formate-mediated inhibition of cytochrome c oxidase than the WT strain, whereas the disinfectant PH3 concentration time of the SR strain was much longer than that of the MR strain. Unlike the MR strain, which showed altered expression levels of genes encoding metabolic enzymes involved in catabolic pathways that minimize metabolic burden, the SR strain showed changes in the mitochondrial respiratory chain. Our results suggest that the acquisition of strong PH3 resistance necessitates the avoidance of oxidative phosphorylation through the accumulation of a few non-synonymous mutations in mitochondrial genes encoding complex I subunits as well as nuclear genes encoding dihydrolipoamide dehydrogenase, concomitant with metabolic reprogramming, a recognized hallmark of cancer metabolism. Taken together, our data suggest that reprogrammed metabolism represents a survival strategy of SR insect pests for the compensation of minimized energy transduction under anoxic conditions. Therefore, understanding the resistance mechanism of PH3–R strains will support the development of new strategies to control insect pests.

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