Thirty years of NRF2: advances and therapeutic challenges

Nature Reviews Drug Discovery, Год журнала: 2025, Номер unknown

Опубликована: Март 4, 2025

Язык: Английский

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Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2

Free Radical Biology and Medicine, Год журнала: 2022, Номер 188, С. 221 - 261

Опубликована: Июнь 18, 2022

Non-alcoholic steatohepatitis (NASH) represents a global health concern. It is characterised by fatty liver, hepatocyte cell death and inflammation, which are associated with lipotoxicity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, iron overload oxidative stress. NF-E2 p45-related factor 2 (Nrf2) transcription that combats Remarkably, Nrf2 downregulated during the development of NASH, probably accelerates disease, whereas in pre-clinical studies upregulation inhibits NASH. We now review scientific literature proposes downregulation NASH involves its increased ubiquitylation proteasomal degradation, mediated Kelch-like ECH-associated protein 1 (Keap1) and/or β-transducin repeat-containing (β-TrCP) HMG-CoA reductase degradation (Hrd1, also called synoviolin (SYVN1)). Additionally, Nrf2-mediated may involve diminished recruitment coactivators Nrf2, due to levels activating 3 (ATF3) nuclear factor-kappaB (NF-κB) p65, or competition for promoter binding BTB CNC homology (Bach1). Many processes downregulate triggered transforming growth factor-beta (TGF-β), stress amplifying signalling. Oxidative increase suppression β-TrCP through facilitating formation DSGIS-containing phosphodegron glycogen synthase kinase-3. In animal models, knockout increases susceptibility while pharmacological activation inducing agents target Keap1 These counter affected β-TrCP, Hrd1/SYVN1, ATF3, NF-κB p65 Bach1, suppressing Activation likely inhibit ameliorating ER overload. Crucially, mice has already been established supresses liver steatosis inflammation. There therefore compelling evidence provides comprehensive multipronged strategy treat

Язык: Английский

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Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls

Antioxidants, Год журнала: 2022, Номер 11(6), С. 1112 - 1112

Опубликована: Июнь 3, 2022

The nuclear factor erythroid 2-related 2 (Nrf2) protects the cell against oxidative damage. Nrf2 system comprises a complex network that functions to ensure adequate responses redox perturbations, but also metabolic demands and cellular stresses. It must be kept within physiologic activity range. Oxidative stress alterations in Nrf2-system are central for chronic-kidney-disease (CKD) progression CKD-related morbidity. Activation of CKD is multiple ways related inflammation, kidney fibrosis, mitochondrial effects. In human CKD, both endogenous activation repression exist. state varies with cause disease, comorbidities, stage severity uremic toxin accumulation inflammation. An earlier stage, rapid inflammatory processes associated more robust activation. Advanced stronger repression. moderate kappa B (NF-κB) elevations. relates high NF-κB concentrations, may Kelch-like ECH-associated protein 1 (Keap1)-independent degradation. Furthermore, we review effects pharmacological by bardoxolone methyl, curcumin, resveratrol outline strategies how adapt future Nrf2-targeted therapies requirements patients CKD.

Язык: Английский

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Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes

Redox Biology, Год журнала: 2023, Номер 62, С. 102672 - 102672

Опубликована: Март 14, 2023

The transcription factor Nrf2 and its repressor Keap1 mediate cell stress adaptation by inducing expression of genes regulating cellular detoxification, antioxidant defence energy metabolism. Energy production employ NADH NADPH respectively as essential metabolic cofactors; both are generated in distinct pathways glucose metabolism, enhanced activation. Here, we examined the role on distribution interrelation between metabolism homeostasis using glio-neuronal cultures isolated from wild-type, Nrf2-knockout Keap1-knockdown mice. Employing advanced microscopy imaging single live cells, including multiphoton fluorescence lifetime (FLIM) to discriminate NADPH, found that activation increases uptake into neurons astrocytes. Glucose consumption is prioritized brain cells for mitochondrial production, with a smaller contribution synthesis pentose phosphate pathway redox reactions. As suppressed during neuronal development, this strategy leaves reliant astrocytic maintain balance homeostasis.

Язык: Английский

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Itaconate: A Potent Macrophage Immunomodulator

Inflammation, Год журнала: 2023, Номер 46(4), С. 1177 - 1191

Опубликована: Май 4, 2023

Язык: Английский

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Antiviral, anti-inflammatory and antioxidant effects of curcumin and curcuminoids in SH-SY5Y cells infected by SARS-CoV-2

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Май 10, 2024

COVID-19, caused by SARS-CoV-2, affects neuronal cells, causing several symptoms such as memory loss, anosmia and brain inflammation. Curcuminoids (Me08 e Me23) curcumin (CUR) are derived from Curcuma Longa extract (EXT). Many therapeutic actions have been linked to these compounds, including antiviral action. Given the severe implications of especially within central nervous system, our study aims shed light on potential curcuminoids against SARS-CoV-2 infection, particularly in cells. Here, we investigated effects CUR, EXT, Me08 Me23 human neuroblastoma SH-SY5Y. We observed that significantly decreased expression plasma membrane-associated transmembrane protease serine 2 (TMPRSS2) TMPRSS11D, consequently mitigating elevated ROS levels induced SARS-CoV-2. Furthermore, exhibited antioxidative properties increasing NRF2 gene restoring NQO1 activity following infection. Both effectively reduced replication SH-SY5Y cells overexpressing ACE2 (SH-ACE2). Additionally, all compounds demonstrated ability decrease proinflammatory cytokines IL-6, TNF-α, IL-17, while specifically INF-γ levels. Our findings suggest curcuminoid could serve a agent for impact context system involvement.

Язык: Английский

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Metabolic regulation of type I interferon production

Immunological Reviews, Год журнала: 2024, Номер 323(1), С. 276 - 287

Опубликована: Март 11, 2024

Summary Over the past decade, there has been a surge in discoveries of how metabolic pathways regulate immune cell function health and disease, establishing field immunometabolism. Specifically, such as glycolysis, tricarboxylic acid (TCA) cycle, those involving lipid metabolism have implicated regulating function. Viral infections cause immunometabolic changes which lead to antiviral immunity, but little is known about interferon responses. Interferons are critical cytokines host defense, rapidly induced upon pathogen recognition, also involved autoimmune diseases. This review summarizes change impacts production. We describe (specifically eicosanoids cholesterol), TCA cycle‐linked intermediates itaconate fumarate impact type I interferons. Targeting these presents new therapeutic possibilities modulate interferons during defense or disorders.

Язык: Английский

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Cocoa flavanols, Nrf2 activation, and oxidative stress in peripheral artery disease: mechanistic findings in muscle based on outcomes from a randomized trial

AJP Cell Physiology, Год журнала: 2024, Номер 326(2), С. C589 - C605

Опубликована: Янв. 8, 2024

The current study supports the hypothesis that in people with PAD, cocoa flavanols activate Nrf2, thereby increasing antioxidant protein levels, protecting against skeletal muscle damage, and mitochondrial abundance. These results suggest Nrf2 activation may be an important therapeutic target for improving walking performance PAD.

Язык: Английский

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Regulation of metabolic microenvironment with a nanocomposite hydrogel for improved bone fracture healing

Bioactive Materials, Год журнала: 2024, Номер 37, С. 424 - 438

Опубликована: Апрель 24, 2024

Bone nonunion poses an urgent clinical challenge that needs to be addressed. Recent studies have revealed the metabolic microenvironment plays a vital role in fracture healing. Macrophages and bone marrow-derived mesenchymal stromal cells (BMSCs) are important targets for therapeutic interventions fractures. Itaconate is TCA cycle metabolite has emerged as potent macrophage immunomodulator limits inflammatory response. During osteogenic differentiation, BMSCs tend undergo aerobic glycolysis metabolize glucose lactate. Copper ion (Cu2+) essential trace element participates metabolism may stimulate promote osteogenesis. In this study, we develop 4-octyl itaconate (4-OI)@Cu@Gel nanocomposite hydrogel can effectively deliver release 4-OI Cu2+ modulate improve functions of involved healing process. The findings reveal burst reduces response, promotes M2 polarization, alleviates oxidative stress, while sustained stimulates BMSC differentiation enhances endothelial cell angiogenesis. Consequently, 4-OI@Cu@Gel system achieves rapid mice. Thus, study proposes promising regenerative strategy expedite through reprogramming macrophages BMSCs.

Язык: Английский

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Itaconate modulates immune responses via inhibition of peroxiredoxin 5

Nature Metabolism, Год журнала: 2025, Номер unknown

Опубликована: Апрель 18, 2025

Язык: Английский

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