The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones

Chalcones have shown a broad spectrum of biological activities with clinical potential against various diseases. The biological activities are mainly attributed to the presence in the chalcones of the α,β-unsaturated carbonyl system, perceived as a potential Michael acceptor. Chalcones could activate the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway through a Michael addition reaction with the cysteines of Keap1, which acts as a redox sensor and negative regulator of Nrf2. This modification allows the dissociation of Nrf2 from the cytoplasmic complex with Keap1 and its nuclear translocation. At this level, Nrf2 binds to the antioxidant response element (ARE) and activates the expression of several detoxification, antioxidant and anti-inflammatory genes as well as genes involved in the clearance of damaged proteins. In this regard, the Keap1/Nrf2–ARE pathway is a new potential pharmacological target for the treatment of many chronic diseases. In this review we summarize the current progress in the study of Keap1/Nrf2–ARE pathway activation by natural and synthetic chalcones and their potential pharmacological applications. Among the pharmacological activities highlighted, anti-inflammatory activity was more evident than others, suggesting a multi-target Michael acceptor mechanism for the chalcones involving key regulators of the Nrf2 and nuclear factor- κB (NF-κB) pathways.

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Mokko Lactone Attenuates Doxorubicin-Induced Hepatotoxicity in Rats: Emphasis on Sirt-1/FOXO1/NF-κB Axis

Nutrients ◽

10.3390/nu13114142 ◽

2021 ◽

Vol 13 (11) ◽

pp. 4142

Author(s):

Alaa Sirwi ◽

Rasheed A. Shaik ◽

Abdulmohsin J. Alamoudi ◽

Basma G. Eid ◽

Ahmed K. Kammoun ◽

...

Keyword(s):

Nuclear Translocation ◽

Biological Activities ◽

Nuclear Factor Κb ◽

Glutathione Depletion ◽

Related Factor ◽

Protective Effects ◽

Pathological Alteration ◽

Enhanced Expression ◽

Factor Α ◽

Apoptotic Effects

Doxorubicin (DOX), a common chemotherapeutic agent, suffers serious adverse effects including hepatotoxicity. Mokko lactone (ML) is a guainolide sesquiterpene with promising biological activities. The study aimed to evaluate the protection offered by ML against hepatotoxicity induced by DOX in rats. Our data indicated ML exhibited protective effects as evidenced by ameliorating the rise in serum activities of alanine transaminase, aspartate transaminase and alkaline phosphatase. This was confirmed histologically as ML prevented DOX-induced pathological alteration in liver architecture. Further, ML administration significantly prevented malondialdehyde accumulation, glutathione depletion and superoxide dismutase and catalase exhaustion. Antioxidant action of ML was associated with enhanced expression of the nuclear translocation of NF-E2-related factor 2 (Nrf2) and a lower expression of forkhead box protein O1 (FOXO1). Also, ML showed potent anti-inflammatory activities highlighted by decreased expression of interleukin 6, tumor necrosis factor α and nuclear factor κB (NF-κB). The anti-apoptotic effects of ML were associated with decreased Bax and enhanced Bcl-2 mRNA expression in liver tissues. ML caused a significant up-regulation in the expression of silent information regulator 1 (Sirt-1). Therefore, it can be concluded that ML prevents liver injury caused by DOX. This could partially be due to the ML regulatory activities on Sirt-1/FOXO1/NF-κB axis.

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Anti-Inflammatory and Antioxidant Effects of Anthocyanins of Trifolium pratense (Red Clover) in Lipopolysaccharide-Stimulated RAW-267.4 Macrophages

Nutrients ◽

10.3390/nu12041089 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1089 ◽

Cited By ~ 9

Author(s):

Sang Gil Lee ◽

Cindi R. Brownmiller ◽

Sun-Ok Lee ◽

Hye Won Kang

Keyword(s):

Trifolium Pratense ◽

Nuclear Translocation ◽

Red Clover ◽

Related Factor ◽

Nuclear Factor ◽

Expression Of Genes ◽

Nadph Oxidase 1 ◽

Anti Inflammatory ◽

Antioxidant Effects

Red clover (Trifolium pratense) possesses various dietary compounds that improve human health. However, the functions of anthocyanins in red clover remain unclear. Here we examined anti-inflammatory and antioxidant effects of red clover extract (RC) and red clover anthocyanins fraction (RCA) using lipopolysaccharide (LPS)-treated RAW 264.7 macrophages and identified dietary compounds. RC and RCA suppressed LPS-induced expression of genes such as tumor necrosis factor (TNF)α, interleukin (IL)1β, inducible nitric oxide synthase (iNOS), monocyte chemoattractant protein (MCP)1, and cyclooxygenase (COX)2. LPS-stimulated intracellular reactive oxygen species (ROS) production also was prevented by both RC and RCA. NADPH oxidase 1 (NOX1) gene and phosphorylation of p47phox of NOX1 that were increased by LPS were inhibited in the cells treated with RCA. LPS-stimulated nuclear factor erythroid 2-related factor 2 (NRF2) gene expression and nuclear translocation of nuclear factor kappa B (NF-kB) subunit p65 were suppressed together with reduced iNOS and COX2 proteins by RCA. Additionally, 27 polyphenols and 7 anthocyanins from RC were identified and quantified. In conclusion, RC, especially RCA, exerted anti-inflammatory and anti-oxidative activities in vitro by regulating NF-κB and NRF2 signaling pathways, suggesting that anthocyanins in red clover are the potential candidates to reduce inflammation and oxidative stress.

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β-Adrenergic agonists exert their “anti-inflammatory” effects in monocytic cells through the IκB/NF-κB pathway

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2000.279.4.l675 ◽

2000 ◽

Vol 279 (4) ◽

pp. L675-L682 ◽

Cited By ~ 134

Author(s):

Pierre Farmer ◽

Jérôme Pugin

Keyword(s):

Mononuclear Cells ◽

Nuclear Translocation ◽

Nuclear Factor Κb ◽

Late Time ◽

Nuclear Factor ◽

Adrenergic Agonists ◽

Time Points ◽

Human Mononuclear Cells ◽

Anti Inflammatory ◽

Factor Α

In addition to their well-studied bronchodilatory and cardiotonic effects, β-adrenergic agonists carry anti-inflammatory properties by inhibiting cytokine production by human mononuclear cells. In a model of human promonocytic THP-1 cells stimulated with lipopolysaccharide (LPS), we showed that β-agonists inhibited tumor necrosis factor-α and interleukin-8 production predominantly via the β2-adrenergic receptor through the generation of cAMP and activation of protein kinase A. This effect was reproduced by other cAMP-elevating agents such as prostaglandins and cAMP analogs. Activation and nuclear translocation of the transcription factor nuclear factor-κB induced by LPS were inhibited with treatment with β-agonists, an effect that was prominent at late time points (>1 h). Although the initial IκB-α degradation induced by LPS was minimally affected by β-agonists, the latter induced a marked rebound of the cytosolic IκB-α levels at later time points (>1 h), accompanied by an increased IκB-α cytoplasmic half-life. This potentially accounts for the observed nuclear factor-κB sequestration in the cytoplasmic compartment. We postulate that the anti-inflammatory effects of β-agonists reside in their capacity to increase cytoplasmic concentrations of IκB-α, possibly by decreasing its degradation.

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Antioxidant and Anti-Inflammatory Effects of Bischofia javanica (Blume) Leaf Methanol Extracts through the Regulation of Nrf2 and TAK1

Antioxidants ◽

10.3390/antiox10081295 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1295

Author(s):

Sewoong Lee ◽

Jain Ha ◽

Jiyoung Park ◽

Eunjeong Kang ◽

Sung-Hyun Jeon ◽

...

Keyword(s):

Molecular Mechanisms ◽

Nuclear Translocation ◽

The Philippines ◽

No Production ◽

Related Factor ◽

Nuclear Factor ◽

Antioxidant Genes ◽

Methanol Extracts ◽

Anti Inflammatory ◽

Bischofia Javanica

Bischofia javanica (Blume) has been traditionally used to treat inflammatory diseases such as tonsillitis and ulcers throughout Asia, including China, Indonesia, and the Philippines: however, the molecular mechanisms by which B. javanica exerts its antioxidant and anti-inflammatory properties remain largely unknown. In this study, we analyzed the antioxidant and anti-inflammatory mechanisms of methanol extracts of B. javanica leaves (MBJ) in vitro and in vivo. MBJ decreased nitric oxide (NO) production and the expression of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, in lipopolysaccharide (LPS)-treated RAW 264.7 cells. The observed suppression of inflammatory responses by MBJ was correlated with an inhibition of the nuclear factor-κB (NF-κB) and the mitogen-activated protein kinase (MAPK) pathways. Additionally, MBJ induced nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that upregulates the expression of anti-inflammatory and antioxidant genes. Furthermore, MBJ exhibited antioxidant and anti-inflammatory effects in an acute hepatitis mouse model. In conclusion, our results confirm the medicinal properties of B. javanica, and therefore MBJ could be applied to improve inflammatory and redox imbalances in different types of pathologies.

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

Antioxidants ◽

10.3390/antiox10101628 ◽

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.

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Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats

Human & Experimental Toxicology ◽

10.1177/0960327114532381 ◽

2014 ◽

Vol 34 (1) ◽

pp. 32-43 ◽

Cited By ~ 6

Author(s):

G-L Hong ◽

Q-Q Cai ◽

J-P Tan ◽

X-Z Jiang ◽

G-J Zhao ◽

...

Keyword(s):

Lung Injury ◽

Recombinant Adenovirus ◽

Antioxidant Response ◽

Nuclear Factor Κb ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Dependent Manner ◽

Nuclear Factor ◽

Quinone Oxidoreductase ◽

Protein Levels

Objective: To investigate the effects of overexpression of nuclear factor E2-related factor-2 (NRF2) on lung injury in rats exposed to paraquat (PQ) poisoning. Methods: A mifepristone (RU486)-inducible recombinant adenoviral vector carrying the human NRF2 gene (Ad-RUNRF2) was constructed and transfected via airway into the rats 7 days before the administration of RU486. Rats were orally challenged with PQ at 20 mg/kg 24 h after the injection of RU486. On days 0.5, 3 and 21 after PQ poisoning, the expressions of NRF2 and cytokines related to inflammation and oxidation in lung tissue were examined. Results: RU486 remarkably enhanced NRF2 mRNA and NRF2 protein levels in Ad-RUNRF2-transfected rats in a dose-dependent manner ( p < 0.01). PQ stimulated compensatory overexpression of NRF2, heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO-1) in lungs on days 0.5 and 3 after exposure ( p < 0.05), but depleted the expression of catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH), with an increased malondialdehyde (MDA) ( p < 0.05). However, pretreatment with Ad-RUNRF2 and RU486 strongly enhanced the expression levels of NRF2, HO-1, NQO-1, CAT and GSH-Px in the lungs of PQ intoxicated rats, with increased GSH and decreased MDA ( p < 0.05). Pretreatment with Ad-RUNRF2 and RU486 also strongly suppressed the PQ-induced activation of nuclear factor κB (NF-κB) and decreased the levels of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). In addition, Ad-RUNRF2 and RU486 induction significantly reduced PQ-induced pathological changes in lungs and attenuated lung oedema and protein leakage caused by PQ ( p < 0.05). Conclusion: RU486-induced overexpression of NRF2 in lungs transfected with Ad-RUNRF2 can ameliorate PQ-induced lung injury by the activation of the NRF2-antioxidant response element (ARE) pathway.

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Lutonarin from Barley Seedlings Inhibits the Lipopolysacchride-Stimulated Inflammatory Response of RAW 264.7 Macrophages by Suppressing Nuclear Factor-κB Signaling

Molecules ◽

10.3390/molecules26061571 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1571

Author(s):

Ji Yeong Yang ◽

So-Yeun Woo ◽

Mi Ja Lee ◽

Hyun Young Kim ◽

Jin Hwan Lee ◽

...

Keyword(s):

Nuclear Translocation ◽

Nuclear Factor Κb ◽

Ultra Performance Liquid Chromatography ◽

Raw 264.7 ◽

Nuclear Factor ◽

Raw 264.7 Macrophages ◽

Tnf Α ◽

Anti Inflammatory ◽

Oxide Synthase ◽

Necrosis Factor

Extracts from barley seedlings (BS) have known antioxidant and anti-inflammatory activities. The flavonoid lutonarin (LN) is a component of BS extract and has several known bioactivities. Here, we evaluated LN anti-inflammatory efficacy against lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Lutonarin was isolated from BS by methanol extraction and characterized by ultra-performance liquid chromatography and quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Lutonarin did not reduce the viability or enhance the apoptosis rate of RAW 264.7 macrophages at concentrations up to 150 µM. Concentrations within 20–60 µM dose-dependently suppressed the LPS-induced expression, phosphorylation, and nuclear translocation of the inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Furthermore, LN suppressed the LPS-induced upregulation of proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α and of the inflammatory enzyme cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Lutonarin may be a safe and effective therapeutic agent for alleviation of pathological inflammation.

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Taraxacum officinale Wigg. Attenuates Inflammatory Responses in Murine Microglia through the Nrf2/HO-1 and NF-κB Signaling Pathways

The American Journal of Chinese Medicine ◽

10.1142/s0192415x20500238 ◽

2020 ◽

Vol 48 (02) ◽

pp. 445-462

Author(s):

Linsha Dong ◽

Zhuoma Dongzhi ◽

Yonglong Jin ◽

Youn-Chul Kim ◽

Dong-Sung Lee ◽

...

Keyword(s):

Nuclear Translocation ◽

Inflammatory Responses ◽

Taraxacum Officinale ◽

Related Factor ◽

Nuclear Factor ◽

Proinflammatory Mediators ◽

Bv2 Cells ◽

Murine Microglia ◽

Anti Inflammatory ◽

Ethanol Extracts

As a long-established medicinal and edible homologous plant, Taraxacum officinale Wigg. is widely distributed in Asia, Europe, and other parts of the world. T. officinale is reported to exert a variety of biological and pharmacological activities, including anticancer, hepatoprotective, and anti-obesity effects. In this study, we evaluated the anti-inflammatory effects of ethanol extracts of T. officinale (A-TOW) by examining the suppression of proinflammatory mediators in LPS-stimulated BV2 and mouse hippocampus. Furthermore, A-TOW also inhibited the nuclear translocation of nuclear factor [Formula: see text]B p65 caused by stimulation with LPS. In addition, A-TOW regulates heme oxygenase (HO)-1 expression through the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in BV2 cells. The effects of A-TOW on the over-expression of proinflammatory mediators were partially reversed by transfection of the cells with HO-1 siRNA. These findings suggest that the potent anti-inflammatory activity of T. officinale, possibly through the regulation of Nrf2/HO-1 and NF-[Formula: see text]B signaling pathway.

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The Protective Roles and Molecular Mechanisms of Troxerutin (Vitamin P4) for the Treatment of Chronic Diseases: A Mechanistic Review

Current Neuropharmacology ◽

10.2174/1570159x18666200510020744 ◽

2020 ◽

Vol 19 (1) ◽

pp. 97-110

Author(s):

Mohammad Zamanian ◽

Gholamreza Bazmandegan ◽

Antoni Sureda ◽

Eduardo Sobarzo-Sanchez ◽

Hasan Yousefi-Manesh ◽

...

Keyword(s):

Molecular Mechanisms ◽

Nuclear Translocation ◽

Therapeutic Potential ◽

Acetylcholinesterase Activity ◽

Nuclear Factor Κb ◽

In Vivo Studies ◽

Related Factor ◽

Nuclear Factor

: Troxerutin (TRX), a semi-synthetic bioflavonoid derived from rutin, has been reported to exert several pharmacological effects including antioxidant, anti-inflammatory, antihyperlipidemic, and nephroprotective. However, the related molecular details and its mechanisms remain poorly understood. In the present review, we presented evidences from the diversity in vitro and in vivo studies on the therapeutic potential of TRX against neurodegenerative, diabetes, cancer and cardiovascular diseases with the purpose to find molecular pathways related to the treatment efficacy. TRX has a beneficial role in many diseases through multiple mechanisms including, increasing antioxidant enzymes and reducing oxidative damage, decreasing in proapoptotic proteins (APAF-1, BAX, caspases-9 and-3) and increasing the antiapoptotic BCL-2, increasing the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and downregulating the nuclear factor κB (NFκ). TRX also reduces acetylcholinesterase activity and upregulates phosphoinositide 3- kinase/Akt signaling pathway in Alzheimer’s disease models. Natural products such as TRX may develop numerous and intracellular pathways at several steps in the treatment of many diseases. Molecular mechanisms of action are revealing novel, possible combinational beneficial approaches to treat multiple pathological conditions.

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