Fisetin, a bioactive flavonol, attenuates allergic airway inflammation through negative regulation of NF-κB

Goh, Fera Y.; Upton, Nadine; Guan, Sheng-Uei; Chang, Cheng; Shanmugam, Muthu K.; Sethi, Gautam; Leung, Bernard P.; Wong, W.S. Fred

doi:10.1016/j.ejphar.2012.01.002

Cited by 86 publications

(54 citation statements)

References 51 publications

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“…Cells were cultured at 2 3 10 6 cells/ml in complete RPMI 1640 medium supplemented with 10% heat-inactivated FCS (Invitrogen). Cells were exposed to 100 mg/ml OVA or 5 mg/ml Con A for 72 h (18). Supernatants from parallel triplicate cultures were analyzed for cytokine levels by ELISA.…”

Section: Lymph Node Cell Culturesmentioning

confidence: 99%

“…Lungs were fixed in 10% neutral formalin, paraffinized, cut into 5-mm sections, and stained with H&E for examining cell infiltration and with periodic acid-fluorescence Schiff stain for mucus production (18). Periodic acid-fluorescence Schiff stain allows visualization of mucus through covalent bonding of sulfited acriflavine to mucin glycoconjugates.…”

Section: Histologic Analysismentioning

confidence: 99%

“…Mice were anesthetized 24 h after the last OVA challenge, and bronchoalveolar lavage (BAL) was performed, as described (18). BAL fluid total and differential cell counts and cytokine and chemokine levels were determined, as described (18).…”

Section: Bronchoalveolar Lavage Fluid and Serum Analysesmentioning

confidence: 99%

“…BAL fluid total and differential cell counts and cytokine and chemokine levels were determined, as described (18). Blood was collected by cardiac puncture, and serum levels of total IgE and OVA-specific IgE were determined, as described (6).…”

Section: Bronchoalveolar Lavage Fluid and Serum Analysesmentioning

confidence: 99%

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Receptor-Interacting Protein 2 Gene Silencing Attenuates Allergic Airway Inflammation

Goh

Cook

Upton

et al. 2013

The Journal of Immunology

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Persistent activation of NF-κB has been associated with the development of asthma. Receptor-interacting protein 2 (Rip2) is a transcriptional product of NF-κB activation. It is an adaptor protein with serine/threonine kinase activity and has been shown to positively regulate NF-κB activity. We investigated potential protective effects of Rip2 gene silencing using small interfering RNA (siRNA) in an OVA-induced mouse asthma model. Rip2 protein level was found to be upregulated in allergic airway inflammation. A potent and selective Rip2 siRNA given intratracheally knocked down Rip2 expression in OVA-challenged lungs and reduced OVA-induced increases in total and eosinophil counts, and IL-4, IL-5, IL-13, IL-1β, IL-33, and eotaxin levels in bronchoalveolar lavage fluid. Rip2 silencing blocked OVA-induced inflammatory cell infiltration and mucus hypersecretion as observed in lung sections, and mRNA expression of ICAM-1, VCAM-1, E-selectin, RANTES, IL-17, IL-33, thymic stromal lymphopoietin, inducible NO synthase, and MUC5ac in lung tissues. In addition, elevation of serum OVA-specific IgE level in mouse asthma model was markedly suppressed by Rip2 siRNA, together with reduced IL-4, IL-5, and IL-13 production in lymph node cultures. Furthermore, Rip2 siRNA-treated mice produced significantly less airway hyperresponsiveness induced by methacholine. Mechanistically, Rip2 siRNA was found to enhance cytosolic level of IκBα and block p65 nuclear translocation and DNA-binding activity in lung tissues from OVA-challenged mice. Taken together, our findings clearly show that knockdown of Rip2 by gene silencing ameliorates experimental allergic airway inflammation, probably via interruption of NF-κB activity, confirming Rip2 a novel therapeutic target for the treatment of allergic asthma.

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Section: Lymph Node Cell Culturesmentioning

confidence: 99%

Section: Histologic Analysismentioning

confidence: 99%

Section: Bronchoalveolar Lavage Fluid and Serum Analysesmentioning

confidence: 99%

Section: Bronchoalveolar Lavage Fluid and Serum Analysesmentioning

confidence: 99%

See 2 more Smart Citations

Receptor-Interacting Protein 2 Gene Silencing Attenuates Allergic Airway Inflammation

Goh

Cook

Upton

et al. 2013

The Journal of Immunology

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“…At present, fisetin has shown multiple biological activities including anti-proliferative (7,8), pro-apoptotic (9-13), neuroprotective (14) and anti-oxidative activities (15). Moreover, fisetin has been shown to suppress the proliferation of a wide variety of tumor cell, including prostate cancer (16), liver cancer (17), colon cancer (18) and leukemia (19) cells, and inhibit the mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB signaling pathways in various type of cancer cell, such as colon and pancreatic cancer (14,(20)(21)(22)(23)(24). Fisetin was also reported to reduce the invasive and migratory capacity of the A549 human lung cancer cell line via the extracellular signal-regulated kinase (ERK) signaling pathway (25).…”

Section: Introductionmentioning

confidence: 99%

Fisetin inhibits the growth and migration in the A549 human lung cancer cell line via the ERK1/2 pathway

Wang

Huang

2017

Exp Ther Med

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Abstract. Lung cancer is the most prevalent malignant tumor type in the developed world and the discovery of novel anti-tumor drugs is a research hotspot. Fisetin, a naturally occurring flavonoid, has been reported to have anti-cancer effects in multiple tumor types. The present study found that fisetin inhibited the growth and migration of non-small cell lung cancer in vitro. MTT, wound-healing, cell-matrix adhesion and Transwell assays were performed and demonstrated that fisetin suppressed proliferation, migration, adhesion and invasion, respectively. Flow cytometric analysis indicated that fisetin induced apoptosis in the A549 cell line by decreasing the expression of c-myc, cyclin-D1, cyclooxygenase-2, B cell lymphoma-2, CXC chemokine receptor type 4, cluster of differentiation 44 and metalloproteinase-2/9, increasing the expression of cyclin dependent kinase inhibitor (CDKN) 1A/B, CDKN2D and E-cadherin and increasing the activity of caspase-3/9 via targeting the extracellular signal-regulated kinase signaling pathway. The results provided comprehensive evidence for the anti-tumor effects of fisetin in non-small cell lung cancer in vitro, which may provide a novel approach for clinical treatment.

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Flavonoids as Cytokine Immunomodulators to Reduce Airway Inflammation via Inhibition of the NF‐κB Signalling Pathway: A Systematic Overview

Gandhi¹,

Dhanabalan²,

Vasconcelos³

et al. 2020

Encyclopedia of Life Sciences

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Asthma is a chronic inflammatory respiratory disease with increasing prevalence which has been linked to the interaction of genetic and environmental factors. Specific types of infections and environmental exposure, alongside a predisposed set of genes, can lead to a systemic propensity for allergic T‐helper (Th) type 2 cells to induce cytokine responses, resulting in allergic airway inflammation. The key event in the pathogenesis of asthma is infiltration of inflammatory cells into the airways and lungs, resulting in mucus hypersecretion and intermittent obstructive events. Cytokines play a vital role in the pathogenesis of immune responses and also have a complex mode of action in inflammatory processes. Peer‐reviewed articles investigating flavonoids with therapeutic evidence for the management of asthma were acquired from Pubmed, Embase, Scopus and Web of Science. We provide an extensive overview of the modulation of cytokines by flavonoids to assess how these natural products trigger immune responses, modulate immunity and lower airway inflammation. Seventeen flavonoids were reported as cytokine modulators of nuclear transcription factor kappa B (NF‐κB) signalling in the identified articles. These flavonoids predominantly modulated the release of the production and expressions of the pro‐ and anti‐inflammatory cytokines TNF‐α, IL‐1β, IL‐8, Th17 (IL‐17), Th1 (IFN‐γ, IL‐2 and IL‐12) and Th2 (IL‐4, IL‐5, IL‐6 and IL‐13), inhibited eosinophil infiltration and decreased the activity and expression of NF‐κB. Key Concepts Bronchial asthma is a chronic inflammatory airway syndrome which endangers human health. Corticosteroids and β2‐agonists are effective drugs for asthma; however, their prolonged use is associated with side effects such as drug tolerance, osteoporosis and immune suppression. Asthma increases the number of inflammatory cells such as eosinophils and lymphocytes in peripheral blood, bronchoalveolar lavage fluid (BALF) and lung tissue and immunoglobulin E (IgE). Flavonoids are plant‐derived active compounds reputed to have therapeutic potential. The use of flavonoids in experimentally induced asthma models is associated with lower levels of Th2 cytokines such as IL‐4, IL‐5, IL‐6 and IL‐13 and modulation of pro‐inflammatory cytokines such as TNF‐α, IL‐1β and IL‐8. Flavonoids generally inhibit pulmonary nuclear transcription factor kappa‐B (NF‐κB) or mitogen‐activated protein kinase (MAPK) signalling pathways and reduce airway inflammation in experimental models. Flavonoids reduce airway hyperresponsiveness, mucus cell hyperplasia and fixed airway flow obstruction. Flavonoids demonstrated significant in vitro and in vivo properties in animal models on homeostasis within the immune system and on the inflammatory response.

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Fisetin, a bioactive flavonol, attenuates allergic airway inflammation through negative regulation of NF-κB

Cited by 86 publications

References 51 publications

Receptor-Interacting Protein 2 Gene Silencing Attenuates Allergic Airway Inflammation

Receptor-Interacting Protein 2 Gene Silencing Attenuates Allergic Airway Inflammation

Fisetin inhibits the growth and migration in the A549 human lung cancer cell line via the ERK1/2 pathway

Flavonoids as Cytokine Immunomodulators to Reduce Airway Inflammation via Inhibition of the NF‐κB Signalling Pathway: A Systematic Overview

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