Food-Derived Pharmacological Modulators of the Nrf2/ARE Pathway: Their Role in the Treatment of Diseases

Oxidative stress, which refers to unbalanced accumulation of reactive oxygen species (ROS) levels in cells, has been linked to acute and chronic diseases. Nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway plays a vital role in regulating cytoprotective genes and enzymes in response to oxidative stress. Therefore, pharmacological regulation of Nrf2/ARE pathway is an effective method to treat several diseases that are mainly characterized by oxidative stress and inflammation. Natural products that counteract oxidative stress by modulating Nrf2 have contributed significantly to disease treatment. In this review, we focus on bioactive compounds derived from food that are Nrf2/ARE pathway regulators and describe the molecular mechanisms for regulating Nrf2 to exert favorable effects in experimental models of diseases.

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Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches – Pulmonary Disease/Asthma

Frontiers in Physiology ◽

10.3389/fphys.2021.727806 ◽

2021 ◽

Vol 12 ◽

Author(s):

Camille Audousset ◽

Toby McGovern ◽

James G. Martin

Keyword(s):

Oxidative Stress ◽

Pulmonary Disease ◽

Molecular Mechanisms ◽

Redox Homeostasis ◽

Antioxidant Response ◽

Protective Role ◽

Experimental Models ◽

Chronic Obstructive ◽

Related Factor ◽

Obstructive Pulmonary Disease

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor involved in redox homeostasis and in the response induced by oxidative injury. Nrf2 is present in an inactive state in the cytoplasm of cells. Its activation by internal or external stimuli, such as infections or pollution, leads to the transcription of more than 500 elements through its binding to the antioxidant response element. The lungs are particularly susceptible to factors that generate oxidative stress such as infections, allergens and hyperoxia. Nrf2 has a crucial protective role against these ROS. Oxidative stress and subsequent activation of Nrf2 have been demonstrated in many human respiratory diseases affecting the airways, including asthma and chronic obstructive pulmonary disease (COPD), or the pulmonary parenchyma such as acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Several compounds, both naturally occurring and synthetic, have been identified as Nrf2 inducers and enhance the activation of Nrf2 and expression of Nrf2-dependent genes. These inducers have proven particularly effective at reducing the severity of the oxidative stress-driven lung injury in various animal models. In humans, these compounds offer promise as potential therapeutic strategies for the management of respiratory pathologies associated with oxidative stress but there is thus far little evidence of efficacy through human trials. The purpose of this review is to summarize the involvement of Nrf2 and its inducers in ARDS, COPD, asthma and lung fibrosis in both human and in experimental models.

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Trilobatin Protects Cardiomyocytes from Hypoxia/ Reperfusion Injury by Regulating the Nuclear Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:133-138 ◽

2020 ◽

Vol 19 (2) ◽

pp. 133-138

Author(s):

Wenyu Chen ◽

Hui He

Keyword(s):

Heme Oxygenase ◽

Molecular Mechanisms ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Cellular Injury ◽

Nuclear Factor ◽

Oxygen Species ◽

H9c2 Cells ◽

Natural Plant ◽

Induced Changes

Trilobatin is a natural plant-derived glycosylated flavonoid that has been shown to exhibit multiple beneficial pharmacologic activities including protection of heart against H/R-induced cardiomyocyte injury. However, the molecular mechanisms underlying protection from H/R-induced cardiomyocyte injury remain unknown. Using H9C2 cells as a model, we examined the effect of trilobatin on H/R-induced cellular injury, apoptosis, and generation of reactive oxygen species. The results showed that trilobatin protected H9C2 cells not only from cell death and apoptosis, but also counteracted H/R-induced changes in malondialdehyde, superoxide dismutase, glutathione, and glutathione peroxidase. The evaluation of the mechanism underlying the effect of trilobatin on protection from H/R-induced cellular injury suggested changes in the regulation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway.

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Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

Antioxidants ◽

10.3390/antiox10010025 ◽

2020 ◽

Vol 10 (1) ◽

pp. 25

Author(s):

Lara Macchioni ◽

Davide Chiasserini ◽

Letizia Mezzasoma ◽

Magdalena Davidescu ◽

Pier Luigi Orvietani ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Age Related Macular Degeneration ◽

Inflammasome Activation ◽

Related Factor ◽

Nuclear Factor ◽

Rpe Cells ◽

Age Related ◽

Oxidative Insult

Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.

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The Potential of Lactobacillus spp. for Modulating Oxidative Stress in the Gastrointestinal Tract

Antioxidants ◽

10.3390/antiox9070610 ◽

2020 ◽

Vol 9 (7) ◽

pp. 610 ◽

Cited By ~ 4

Author(s):

Yanzhuo Kong ◽

Kenneth J. Olejar ◽

Stephen L. W. On ◽

Venkata Chelikani

Keyword(s):

Oxidative Stress ◽

Nuclear Factor Kappa B ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Mechanisms Of Action ◽

Related Factor ◽

Nuclear Factor ◽

Oxygen Species ◽

Pathogenic Microorganisms ◽

Gi Tract ◽

Lactobacillus Spp

The gastrointestinal (GI) tract is crucial for food digestion and nutrient absorption in humans. However, the GI tract is usually challenged with oxidative stress that can be induced by various factors, such as exogenous pathogenic microorganisms and dietary alterations. As a part of gut microbiota, Lactobacillus spp. play an important role in modulating oxidative stress in cells and tissues, especially in the GI tract. Oxidative stress is linked with excessive reactive oxygen species (ROS) that can be formed by a few enzymes, such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs). The redox mechanisms of Lactobacillus spp. may contribute to the downregulation of these ROS-forming enzymes. In addition, nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf-2) and nuclear factor kappa B (NF-κB) are two common transcription factors, through which Lactobacillus spp. modulate oxidative stress as well. As oxidative stress is closely associated with inflammation and certain diseases, Lactobacillus spp. could potentially be applied for early treatment and amelioration of these diseases, either individually or together with prebiotics. However, further research is required for revealing their mechanisms of action as well as their extensive application in the future.

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NRF2 Regulation by Noncoding RNAs in Cancers: The Present Knowledge and the Way Forward

Cancers ◽

10.3390/cancers12123621 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3621

Author(s):

Federico Pio Fabrizio ◽

Angelo Sparaneo ◽

Lucia Anna Muscarella

Keyword(s):

Noncoding Rna ◽

Gene Network ◽

Noncoding Rnas ◽

Antioxidant Response ◽

Present Knowledge ◽

Cellular Damage ◽

Related Factor ◽

Nuclear Factor ◽

Oxygen Species ◽

Cellular Mechanisms

Nuclear factor erythroid 2-related factor 2 (NRF2) is the key transcription factor triggered by oxidative stress that moves in cells of the antioxidant response element (ARE)-antioxidant gene network against reactive oxygen species (ROS) cellular damage. In tumors, the NRF2 pathway represents one of the most intriguing pathways that promotes chemo- and radioresistance of neoplastic cells and its activity is regulated by genetic and epigenetic mechanisms; some of these being poorly investigated in cancer. The noncoding RNA (ncRNA) network is governed by microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) and modulates a variety of cellular mechanisms linked to cancer onset and progression, both at transcriptional and post-transcriptional levels. In recent years, the scientific findings about the effects of ncRNA landscape variations on NRF2 machines are rapidly increasing and need to be continuously updated. Here, we review the latest knowledge about the link between NRF2 and ncRNA networks in cancer, thus focusing on their potential translational significance as key tumor biomarkers.

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Differential Yet Integral Contributions of Nrf1 and Nrf2 in the Human HepG2 Cells on Antioxidant Cytoprotective Response against Tert-Butylhydroquinone as a Pro-Oxidative Stressor

Antioxidants ◽

10.3390/antiox10101610 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1610

Author(s):

Reziyamu Wufuer ◽

Zhuo Fan ◽

Keli Liu ◽

Yiguo Zhang

Keyword(s):

Oxidative Stress ◽

Regulatory Networks ◽

Substantial Reduction ◽

Normal Growth ◽

Antioxidant Response ◽

Related Factor ◽

Nuclear Factor ◽

Expression Levels ◽

Hormetic Effect ◽

Cytoprotective Response

In the past 25 years, Nrf2 (nuclear factor erythroid 2-related factor 2, also called NFE2L2) had been preferentially parsed as a master hub of regulating antioxidant, detoxification, and cytoprotective genes; albeit as a matter of fact that Nrf1 (nuclear factor erythroid 2-related factor 1, also called NFE2L1)—rather than Nrf2—is indispensable for cell homeostasis and organ integrity during normal growth and development. Herein, distinct genotypic cell lines (i.e., Nrf1α−/−, Nrf2−/−ΔTA, and caNrf2ΔN) are employed to determine differential yet integral roles of Nrf1 and Nrf2 in mediating antioxidant responsive genes to tert-butylhydroquinone (tBHQ) serving as a pro-oxidative stressor. In Nrf1α−/− cells, Nrf2 was highly accumulated but also could not fully compensate specific loss of Nrf1α’s function in its basal cytoprotective response against endogenous oxidative stress, though it exerted partially inducible antioxidant response, as the hormetic effect of tBHQ, against apoptotic damages. By contrast, Nrf2−/−ΔTA cells gave rise to a substantial reduction of Nrf1 in both basal and tBHQ-stimulated expression levels and hence resulted in obvious oxidative stress, but it can still be allowed to mediate a potent antioxidant response, as accompanied by a significantly decreased ratio of GSSG (oxidized glutathione) to GSH (reduced glutathione). Conversely, a remarkable increase of Nrf1 expression resulted from the constitutive active caNrf2ΔN cells, which were not manifested with oxidative stress, whether or not it was intervened with tBHQ. Such inter-regulatory effects of Nrf1 and Nrf2 on the antioxidant and detoxification genes (encoding HO-1, NQO1, GCLC, GCLM, GSR, GPX1, TALDO, MT1E, and MT2), as well on the ROS (reactive oxygen species)-scavenging activities of SOD (superoxide dismutase) and CAT (catalase), were further investigated. The collective results unraveled that Nrf1 and Nrf2 make distinctive yet cooperative contributions to finely tuning basal constitutive and/or tBHQ-inducible expression levels of antioxidant cytoprotective genes in the inter-regulatory networks. Overall, Nrf1 acts as a brake control for Nrf2’s functionality to be confined within a certain extent, whilst its transcription is regulated by Nrf2.

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Isoliquiritigenin Confers Neuroprotection and Alleviates Amyloid-β42-Induced Neuroinflammation in Microglia by Regulating the Nrf2/NF-κB Signaling

Frontiers in Neuroscience ◽

10.3389/fnins.2021.638772 ◽

2021 ◽

Vol 15 ◽

Author(s):

Yue Fu ◽

Jianping Jia

Keyword(s):

Oxidative Stress ◽

Inflammatory Response ◽

Molecular Mechanisms ◽

Morphological Changes ◽

No Production ◽

Related Factor ◽

Nuclear Factor ◽

Qrt Pcr ◽

Bv2 Cells ◽

And Oxidative Stress

BackgroundNeuroinflammation and oxidative stress are two major pathological characteristics of Alzheimer’s disease (AD). Amyloid-β oligomers (AβO), a toxic form of Aβ, promote the neuroinflammation and oxidative stress in the development of AD. Isoliquiritigenin (ISL), a natural flavonoid isolated from the root of liquorice, has been shown to exert inhibitory effects on inflammatory response and oxidative stress.ObjectivesThe main purpose of this study is to assess the influence of ISL on inflammatory response and oxidative stress in BV2 cells stimulated with AβO, and to explore the underlying molecular mechanisms.Methods3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H- tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) cytotoxicity assays were used to assess the toxic or protective effects of ISL. The expression levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assays. Morphological changes in BV2 cells were assessed by immunofluorescence method. Nitric oxide (NO) assay kit was used to determinate the NO production. Western blot, qRT-PCR and immunofluorescence were used to explore the underlying molecular mechanisms.ResultsISL treatment reduced the production of inflammatory cytokines and NO, and alleviated the morphological changes in BV2 cells induced by AβO. ISL treatment further protected N2a cells from the toxic medium of AβO-stimulated BV2 cells. ISL activated nuclear factor erythroid-2 related factor 2 (Nrf2) signaling and suppressed nuclear factor-κB (NF-κB) signaling in BV2 cells.ConclusionISL suppresses AβO-induced inflammation and oxidative stress in BV2 cells via the regulation of Nrf2/NF-κB signaling. Therefore, ISL indirectly protects neurons from the damage of toxic conditioned media.

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Xanthohumol inhibits PRRSV proliferation and alleviates oxidative stress induced by PRRSV via the Nrf2–HMOX1 axis

Veterinary Research ◽

10.1186/s13567-019-0679-2 ◽

2019 ◽

Vol 50 (1) ◽

Cited By ~ 3

Author(s):

Xuewei Liu ◽

Zhongbao Song ◽

Juan Bai ◽

Hans Nauwynck ◽

Yongxiang Zhao ◽

...

Keyword(s):

Oxidative Stress ◽

Therapeutic Strategy ◽

Antioxidant Response ◽

Economic Losses ◽

Respiratory Syndrome Virus ◽

Related Factor ◽

Nuclear Factor ◽

Swine Industry ◽

Therapeutic Drugs ◽

Swine Pathogen

Abstract Porcine reproductive and respiratory syndrome virus (PRRSV) is a prevalent and endemic swine pathogen that causes significant economic losses in the global swine industry. Commercial vaccines provide limited protection against this virus, and no highly effective therapeutic drugs are yet available. In this study, we first screened a library of 386 natural products and found that xanthohumol (Xn), a prenylated flavonoid found in hops, displayed high anti-PRRSV activity by inhibiting PRRSV adsorption onto and internalization into cells. Transcriptome sequencing revealed that Xn treatment stimulates genes associated with the antioxidant response in the nuclear factor-erythroid 2-related factor 2 (Nrf2) signalling pathway. Xn causes increased expression of Nrf2, HMOX1, GCLC, GCLM, and NQO1 in Marc-145 cells. The action of Xn against PRRSV proliferation depends on Nrf2 in Marc-145 cells and porcine alveolar macrophages (PAMs). This finding suggests that Xn significantly inhibits PRRSV proliferation and decreases viral-induced oxidative stress by activating the Nrf2–HMOX1 pathway. This information should be helpful for developing a novel prophylactic and therapeutic strategy against PRRSV infection.

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Anemopsis californica Attenuates Photoaging by Regulating MAPK, NRF2, and NFATc1 Signaling Pathways

Antioxidants ◽

10.3390/antiox10121882 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1882

Author(s):

Quynh T. N. Nguyen ◽

Minzhe Fang ◽

Nhung Quynh Do ◽

Jeehaeng Jeong ◽

Sarang Oh ◽

...

Keyword(s):

Oxidative Stress ◽

Chronic Inflammation ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Biological Effects ◽

Dermal Fibroblasts ◽

Related Factor ◽

Mrna Levels ◽

Nuclear Factor ◽

Anemopsis Californica

Long-term exposure of the skin to solar radiation causes chronic inflammation and oxidative stress, which accelerates collagen degradation. This contributes to the formation of wrinkles and dark spots, skin fragility, and even skin cancer. In this study, Anemopsis californica (AC), a herb from North America that is well known for treating microorganism infection and promoting wound healing, was investigated for its photoprotective effects. The biological effects of AC were studied on two in vitro models, namely, lipopolysaccharide (LPS)-induced macrophages and ultraviolet B (UVB)-irradiated dermal fibroblasts, to characterize its underlying molecular mechanisms. The results showed that AC decreased the mRNA levels of inflammatory mediators in sensitized macrophages, including cytokines, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX-2). Moreover, AC alleviated UVB-induced photoaging in dermal fibroblasts by restoring procollagen synthesis. This resulted from the regulation of excessive reactive oxygen species (ROS) by AC, which was mediated by the activation of the antioxidative system nuclear factor erythroid 2-related factor 2 (NRF2). AC also alleviated oxidative stress and inflammatory responses by inhibiting the phosphorylation of mitogen-activated protein kinase (MAPK) and interfering with the nuclear translocation of the immune regulator nuclear factor of activated T-cells 1 (NFATc1). In conclusion, the protective effects of AC on skin cellular components suggested that it has the potential for use in the development of drugs and cosmetics that protect the skin from UVB-induced chronic inflammation and aging.

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Effects of Lespedeza Bicolor Extract on Regulation of AMPK Associated Hepatic Lipid Metabolism in Type 2 Diabetic Mice

Antioxidants ◽

10.3390/antiox8120599 ◽

2019 ◽

Vol 8 (12) ◽

pp. 599 ◽

Cited By ~ 3

Author(s):

Younmi Kim ◽

Heaji Lee ◽

Sun Yeou Kim ◽

Yunsook Lim

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Smooth Muscle Actin ◽

Lipid Synthesis ◽

Hepatic Damage ◽

Related Factor ◽

Nuclear Factor ◽

Diabetic Mice ◽

Lespedeza Bicolor

Lespedeza bicolor (LB) is one of the ornamental plants used for the treatment of inflammation caused by oxidative damage. However, its beneficial effects on hyperglycemia-induced hepatic damage and the related molecular mechanisms remain unclear. We hypothesized that Lespedeza bicolor extract (LBE) would attenuate hyperglycemia-induced liver injury in type 2 diabetes mellitus (T2DM). Diabetes was induced by a low dosage of streptozotocin (STZ) injection (30 mg/kg) with a high fat diet in male C57BL/6J mice. LBE was administered orally at 100 mg/kg or 250 mg/kg for 12 weeks. LBE supplementation regardless of dosage ameliorated plasma levels of hemoglobin A1c (HbA1c) in diabetic mice. Moreover, both LBE supplementations upregulated AMP-activation kinase (AMPK), which may activate sirtuin1 (SIRT) associated pathway accompanied by decreased lipid synthesis at low dose of LBE supplementation. These changes were in part explained by reduced protein levels of oxidative stress (nuclear factor erythroid 2-related factor 2 (Nrf2) and catalase), inflammation (nuclear factor kappa B (NF-κB), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide synthases (iNOS)), and fibrosis (α-smooth muscle actin (α-SMA) and protein kinase C (PKC)) in diabetic liver. Taken together, LBE might be a potential nutraceutical to ameliorate hepatic damage by regulation of AMPK associated pathway via oxidative stress, inflammation, and fibrosis in T2DM.

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