scholarly journals Astaxanthin as a Modulator of Nrf2, NF-κB, and Their Crosstalk: Molecular Mechanisms and Possible Clinical Applications

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 502
Author(s):  
Sergio Davinelli ◽  
Luciano Saso ◽  
Floriana D’Angeli ◽  
Vittorio Calabrese ◽  
Mariano Intrieri ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Nuclear Factor Κb ◽  
Protective Role ◽  
Related Factor ◽  
Nuclear Factor ◽  
Molecular Features ◽  
Wide Range ◽  
Pharmaceutical Industries

Astaxanthin (AST) is a dietary xanthophyll predominantly found in marine organisms and seafood. Due to its unique molecular features, AST has an excellent antioxidant activity with a wide range of applications in the nutraceutical and pharmaceutical industries. In the past decade, mounting evidence has suggested a protective role for AST against a wide range of diseases where oxidative stress and inflammation participate in a self-perpetuating cycle. Here, we review the underlying molecular mechanisms by which AST regulates two relevant redox-sensitive transcription factors, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor κB (NF-κB). Nrf2 is a cellular sensor of electrophilic stress that coordinates the expression of a battery of defensive genes encoding antioxidant proteins and detoxifying enzymes. Likewise, NF-κB acts as a mediator of cellular stress and induces the expression of various pro-inflammatory genes, including those encoding cytokines, chemokines, and adhesion molecules. The effects of AST on the crosstalk between these transcription factors have also been discussed. Besides this, we summarize the current clinical studies elucidating how AST may alleviate the etiopathogenesis of oxidative stress and inflammation.

scholarly journals Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-ҡB and p53 Pathways in Neurodegeneration

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1628
Author(s):  
Maja Jazvinšćak Jembrek ◽  
Nada Oršolić ◽  
Lucija Mandić ◽  
Anja Sadžak ◽  
Suzana Šegota
Keyword(s):  
Transcription Factors ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Nuclear Factor Κb ◽  
Related Factor ◽  
Nuclear Factor ◽  
Anti Inflammatory ◽  
New Treatments ◽  
Apoptotic Effects

Neurodegenerative diseases are one of the leading causes of disability and death worldwide. Intracellular transduction pathways that end in the activation of specific transcription factors are highly implicated in the onset and progression of pathological changes related to neurodegeneration, of which those related to oxidative stress (OS) and neuroinflammation are particularly important. Here, we provide a brief overview of the key concepts related to OS- and neuroinflammation-mediated neuropathological changes in neurodegeneration, together with the role of transcription factors nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB). This review is focused on the transcription factor p53 that coordinates the cellular response to diverse genotoxic stimuli, determining neuronal death or survival. As current pharmacological options in the treatment of neurodegenerative disease are only symptomatic, many research efforts are aimed at uncovering efficient disease-modifying agents. Natural polyphenolic compounds demonstrate powerful anti-oxidative, anti-inflammatory and anti-apoptotic effects, partially acting as modulators of signaling pathways. Herein, we review the current understanding of the therapeutic potential and limitations of flavonols in neuroprotection, with emphasis on their anti-oxidative, anti-inflammatory and anti-apoptotic effects along the Nrf2, NF-κB and p53 pathways. A better understanding of cellular and molecular mechanisms of their action may pave the way toward new treatments.

scholarly journals The Protective Effects of Flavonoids in Cataract Formation through the Activation of Nrf2 and the Inhibition of MMP-9

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3651
Author(s):  
Aaron Hilliard ◽  
Patricia Mendonca ◽  
Tanya D. Russell ◽  
Karam F. A. Soliman
Keyword(s):  
Oxidative Stress ◽  
Redox Homeostasis ◽  
Nuclear Factor Κb ◽  
Protective Role ◽  
Related Factor ◽  
Nuclear Factor ◽  
Protective Effects ◽  
Cataract Formation ◽  
Contributing Factors ◽  
Cataract Development

Cataracts account for over half of global blindness. Cataracts formations occur mainly due to aging and to the direct insults of oxidative stress and inflammation to the eye lens. The nuclear factor-erythroid-2-related factor 2 (Nrf2), a transcriptional factor for cell cytoprotection, is known as the master regulator of redox homeostasis. Nrf2 regulates nearly 600 genes involved in cellular protection against contributing factors of oxidative stress, including aging, disease, and inflammation. Nrf2 was reported to disrupt the oxidative stress that activates Nuclear factor-κB (NFκB) and proinflammatory cytokines. One of these cytokines is matrix metalloproteinase 9 (MMP-9), which participates in the decomposition of lens epithelial cells (LECs) extracellular matrix and has been correlated with cataract development. Thus, during inflammatory processes, MMP production may be attenuated by the Nrf2 pathway or by the Nrf2 inhibition of NFκB pathway activation. Moreover, plant-based polyphenols have garnered attention due to their presumed safety and efficacy, nutritional, and antioxidant effects. Polyphenol compounds can activate Nrf2 and inhibit MMP-9. Therefore, this review focuses on discussing Nrf2’s role in oxidative stress and cataract formation, epigenetic effect in Nrf2 activity, and the association between Nrf2 and MMP-9 in cataract development. Moreover, we describe the protective role of flavonoids in cataract formation, targeting Nrf2 activation and MMP-9 synthesis inhibition as potential molecular targets in preventing cataracts.

scholarly journals Molecular Mechanisms That Link Oxidative Stress, Inflammation, and Fibrosis in the Liver

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1279
Author(s):  
Erika Ramos-Tovar ◽  
Pablo Muriel
Keyword(s):  
Oxidative Stress ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Nuclear Factor Κb ◽  
Receptor Protein ◽  
Related Factor ◽  
Nuclear Factor ◽  
Interacting Protein ◽  
Caspase 1 ◽  
Ecm Proteins

Activated hepatic stellate cells (HSCs) and myofibroblasts are the main producers of extracellular matrix (ECM) proteins that form the fibrotic tissue that leads to hepatic fibrosis. Reactive oxygen species (ROS) can directly activate HSCs or induce inflammation or programmed cell death, especially pyroptosis, in hepatocytes, which in turn activates HSCs and fibroblasts to produce ECM proteins. Therefore, antioxidants and the nuclear factor E2-related factor-2 signaling pathway play critical roles in modulating the profibrogenic response. The master proinflammatory factors nuclear factor-κB (NF-κB) and the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome may coordinate to produce and activate profibrogenic molecules such as interleukins 1β and 18, which effectively activate HSCs, to produce large amounts of fibrotic proteins. Furthermore, the NLRP3 inflammasome activates pro-caspase 1, which is upregulated by NF-κB, to produce caspase 1, which induces pyroptosis via gasdermin and the activation of HSCs. ROS play central roles in the activation of the NF-κB and NLRP3 signaling pathways via IκB (an inhibitor of NF-κB) and thioredoxin-interacting protein, respectively, thereby linking the molecular mechanisms of oxidative stress, inflammation and fibrosis. Elucidating these molecular pathways may pave the way for the development of therapeutic tools to interfere with specific targets.

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

Antioxidants ◽  
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.

scholarly journals (–)-Loliolide Isolated from Sargassum horneri Suppressed Oxidative Stress and Inflammation by Activating Nrf2/HO-1 Signaling in IFN-γ/TNF-α-Stimulated HaCaT Keratinocytes

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 856
Author(s):  
Eui-Jeong Han ◽  
Ilekuttige Priyan Shanura Fernando ◽  
Hyun-Soo Kim ◽  
Dae-Sung Lee ◽  
Areum Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nuclear Factor Κb ◽  
Sargassum Horneri ◽  
Mitogen Activated Protein Kinase ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Hacat Keratinocytes ◽  
Tnf Α ◽  
Ifn Γ

The present study evaluated the effects of (–)-loliolide isolated from Sargassum horneri (S. horneri) against oxidative stress and inflammation, and its biological mechanism in interferon (IFN)-γ/tumor necrosis factor (TNF)-α-stimulated HaCaT keratinocytes. The results showed that (–)-loliolide improved the cell viability by reducing the production of intracellular reactive oxygen species (ROS) in IFN-γ/TNF-α-stimulated HaCaT keratinocytes. In addition, (–)-loliolide effectively decreased the expression of inflammatory cytokines (interleukin (IL)-4 IL-6, IL-13, IFN-γ and TNF-α) and chemokines (CCL11 (Eotaxin), macrophage-derived chemokine (MDC), regulated on activation, normal T cell expressed and secreted (RANTES), and thymus and activation-regulated chemokine (TARC)), by downregulating the expression of epidermal-derived initial cytokines (IL-25, IL-33 and thymic stromal lymphopoietin (TSLP)). Furthermore, (–)-loliolide suppressed the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling, whereas it activated nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Interestingly, the cytoprotective effects of (–)-loliolide against IFN-γ/TNF-α stimulation were significantly blocked upon inhibition of HO-1. Taken together, these results suggest that (–)-loliolide effectively suppressed the oxidative stress and inflammation by activating the Nrf2/HO-1 signaling in IFN-γ/TNF-α-stimulated HaCaT keratinocytes.

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

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.

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

Antioxidants ◽  
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.

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

Antioxidants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 599 ◽  
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.

scholarly journals New targets of urocortin-mediated cardioprotection

2010 ◽  
Vol 45 (2) ◽  
pp. 69-85 ◽  
Author(s):  
Seán P Barry ◽  
Kevin M Lawrence ◽  
James McCormick ◽  
Surinder M Soond ◽  
Mike Hubank ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Related Factor ◽  
Nuclear Factor ◽  
Free Radical Damage ◽  
Apoptosis Protein ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Crh Receptors

The urocortin (UCN) hormones UCN1 and UCN2 have been shown previously to confer significant protection against myocardial ischaemia/reperfusion (I/R) injury; however, the molecular mechanisms underlying their action are poorly understood. To further define the transcriptional effect of UCNs that underpins their cardioprotective activity, a microarray analysis was carried out using an in vivo rat coronary occlusion model of I/R injury. Infusion of UCN1 or UCN2 before the onset of reperfusion resulted in the differential regulation of 66 and 141 genes respectively, the majority of which have not been described previously. Functional analysis demonstrated that UCN-regulated genes are involved in a wide range of biological responses, including cell death (e.g. X-linked inhibitor of apoptosis protein), oxidative stress (e.g. nuclear factor erythroid derived 2-related factor 1/nuclear factor erythroid derived 2-like 1) and metabolism (e.g. Prkaa2/AMPK). In addition, both UCN1 and UCN2 were found to modulate the expression of a host of genes involved in G-protein-coupled receptor (GPCR) signalling including Rac2, Gnb1, Dab2ip (AIP1), Ralgds, Rnd3, Rap1a and PKA, thereby revealing previously unrecognised signalling intermediates downstream of CRH receptors. Moreover, several of these GPCR-related genes have been shown previously to be involved in mitogen-activated protein kinase (MAPK) activation, suggesting a link between CRH receptors and induction of MAPKs. In addition, we have shown that both UCN1 and UCN2 significantly reduce free radical damage following myocardial infarction, and comparison of the UCN gene signatures with that of the anti-oxidant tempol revealed a significant overlap. These data uncover novel gene expression changes induced by UCNs, which will serve as a platform to further understand their mechanism of action in normal physiology and cardioprotection.

GLUTATHIONE TRANSFERASES

2005 ◽  
Vol 45 (1) ◽  
pp. 51-88 ◽  
Author(s):  
John D. Hayes ◽  
Jack U. Flanagan ◽  
Ian R. Jowsey
Keyword(s):  
Oxidative Stress ◽  
Antitumor Agents ◽  
Glutathione Transferase ◽  
Degradation Products ◽  
Nuclear Factor Κb ◽  
Peroxisome Proliferator ◽  
Related Factor ◽  
Nuclear Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Increased Risk

This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous α,β-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor γ (PPARγ) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-κB (NF-κB). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.

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