ovalbumin and fisetin

Fisetin is isolated from many fruits and vegetables and has been confirmed to improve airway hyperresponsiveness in asthmatic mice. However, whether fisetin reduces inflammatory response and oxidative stress in bronchial epithelial cells is unclear. Here, BEAS-2B human bronchial epithelial cells were treated with various concentrations of fisetin and then stimulated with tumor necrosis factor-α (TNF-α) or TNF-α/interleukin-4. In addition, ovalbumin-sensitized mice were treated with fisetin to detect inflammatory mediators and oxidative stress expression. Fisetin significantly reduced the levels of inflammatory cytokines and chemokines in TNF-α-stimulated BEAS-2B cells. Fisetin also attenuated intercellular adhesion molecule-1 expression in TNF-α-stimulated BEAS-2B cells, suppressing THP-1 monocyte adhesion. Furthermore, fisetin significantly suppressed airway hyperresponsiveness in the lungs and decreased eosinophil numbers in the bronchoalveolar lavage fluid of asthmatic mice. Fisetin decreased cyclooxygenase-2 expression, promoted glutathione levels, and decreased malondialdehyde levels in the lungs of asthmatic mice. Our findings indicate that fisetin is a potential immunomodulator that can improve the pathological features of asthma by decreasing oxidative stress and inflammation.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Epithelial Cells; Flavonols; Mice; Mice, Inbred BALB C; Ovalbumin; Oxidative Stress; Respiratory Hypersensitivity; Tumor Necrosis Factor-alpha

Asthma is a common chronic airway inflammation disease and is considered as a major public health problem. Fisetin (3,3',4',7-tetrahydroxyflavone) is a naturally occurring flavonoid abundantly found in different vegetables and fruits. Fisetin has been reported to exhibit various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. We evaluated the effects of fisetin on allergic asthma regulation in mice. Mice were first sensitized, then airway-challenged with ovalbumin (OVA). Whether fisetin treatment attenuated OVA-induced airway inflammation was examined via inflammation inhibition through MyD88-related NF-κB (p65) signaling pathway. Mice were divided into the control (Con), OVA-induced asthma (Mod), 40 (FL) and 50 (FH) mg/kg fisetin-treated OVA-induced asthma groups. Our results found that OVA-induced airway inflammation in mice caused a significant inflammatory response via the activation of MyD88 and NF-κB signaling pathways, leading to release of pro-inflammatory cytokines. In contrast, fisetin-treated mice after OVA induction inhibited activation of MyD88 and NF-κB signaling pathways, resulting in downregulation of pro-inflammatory cytokine secretion. Further, fisetin significantly ameliorated the airway hyperresponsiveness (AHR) towards methacholine (Mch). In addition, fisetin reduced the number of eosinophil, monocyte, neutrophil and total white blood cell in the bronchoalveolar lavage fluid (BALF) of OVA-induced mice. The serum and BALF samples obtained from the OVA-induced mice with fisetin showed lower levels of pro-inflammatory cytokines. The results of our study illustrated that fisetin may be a new promising candidate to inhibit airway inflammation response induced by OVA.

Topics: Airway Resistance; Animals; Asthma; Bronchial Hyperreactivity; Cell Count; Cytokines; Disease Models, Animal; Flavonoids; Flavonols; Inflammation Mediators; Lipopolysaccharides; Lung; Male; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; NF-kappa B; Ovalbumin; Pneumonia; Signal Transduction; Toll-Like Receptor 5

Persistent activation of nuclear factor-κB (NF-κB) has been associated with the development of asthma. Fisetin (3,7,3',4'-tetrahydroxyflavone), a naturally occurring bioactive flavonol, has been shown to inhibit NF-κB activity. We hypothesized that fisetin may attenuate allergic asthma via negative regulation of the NF-κB activity. Female BALB/c mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Fisetin dose-dependently inhibited ovalbumin-induced increases in total cell count, eosinophil count, and IL-4, IL-5 and IL-13 levels recovered in bronchoalveolar lavage fluid. It attenuated ovalbumin-induced lung tissue eosinophilia and airway mucus production, mRNA expression of adhesion molecules, chitinase, IL-17, IL-33, Muc5ac and inducible nitric oxide synthase in lung tissues, and airway hyperresponsiveness to methacholine. Fisetin blocked NF-κB subunit p65 nuclear translocation and DNA-binding activity in the nuclear extracts from lung tissues of ovalbumin-challenged mice. In normal human bronchial epithelial cells, fisetin repressed TNF-α-induced NF-κB-dependent reporter gene expression. Our findings implicate a potential therapeutic value of fisetin in the treatment of asthma through negative regulation of NF-κB pathway.

Topics: Airway Resistance; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Adhesion Molecules; Cell Count; Chemokines; Chitinases; Cytokines; Disease Models, Animal; DNA-Binding Proteins; Dose-Response Relationship, Drug; Female; Flavonoids; Flavonols; Genes, Reporter; Inflammation; Inflammation Mediators; Lung; Methacholine Chloride; Mice; Mice, Inbred BALB C; Mucin 5AC; Mucus; NF-kappa B; Nitric Oxide Synthase Type II; Ovalbumin; Protein Transport; Tumor Necrosis Factor-alpha

Fisetin, a flavonoid compound commonly present in fruits and vegetables, can exert anti-inflammation activities via inhibition of the NF-κB-signaling pathway. This study aims to evaluate the antiasthma activity of fisetin and investigate its possible molecular mechanisms. We found that fisetin attenuated lung inflammation, goblet cell hyperplasia, and airway hyperresponsiveness in ovalbumin-induced asthma and decreased eosinophils and lymphocytes in bronchoalveolar lavage fluid. Fisetin treatment reduced expression of the key initiators of allergic airway inflammation (eotaxin-1 and TSLP), Th2-associated cytokines (IL-4, IL-5, and IL-13) in lungs, and Th2-predominant transcription factor GATA-3 and cytokines in thoracic lymph node cells and splenocytes. Notably, fisetin treatment impaired NF-κB activation in OVA-stimulated lung tissues and TNF-α-stimulated bronchial epithelial cells. Collectively, this study demonstrated the beneficial effect of fisetin in the amelioration of asthmatic phenotypes. The antiasthma activity of fisetin is associated with reduction of Th2 responses as well as suppression of NF-κB and its downstream chemokines.

Topics: Animals; Asthma; Bronchi; Cell Line, Transformed; Chemokines; Cytokines; Epithelial Cells; Flavonoids; Flavonols; Goblet Cells; Humans; Immunosuppressive Agents; Lung; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Ovalbumin

We previously reported that quercetin and rutin have potent, anti-asthmatic activity, but the structure-activity relationships of flavonoids and anti-asthmatic agents are still poorly understood. In the current study, the effects of kaempferol, fisetin, and morin on the immediate-phase response (IAR) and late-phase response (LAR) caused by exposure to aerosolized-ovalbumin (OA) in OA-sensitized guinea pigs were evaluated by determining the specific airway resistance (sRaw), recruitment of leukocytes and chemical mediators in bronchoalveolar lavage fluid (BALF), histopathological surveys, and determination of neutrophil chemotaxis. Fisetin and kaempherol (30 mg/kg, p.o.) significantly (P<0.01) inhibited sRaw by 47.93% and 30.05% in IAR, and 54.45% and 40.50% in LAR, when compared to vehicle control, respectively. Furthermore, all three studied flavonols (30 mg/kg, p.o.) significantly (P<0.05) inhibited the recruitment of total, as well as subtypes of, leukocytes into the lung BALF. This recruitment inhibition corresponded to the inhibition of leukocyte infiltration, particularly of eosinophils and neutrophils, into the lung in pathological surveys and formly-methionyl-leucyl-phenylalanine (FMLP)-induced neutrophil chemotaxis studies. Kaempferol inhibited FMLP-induced neutrophil chemotaxis in a concentration-dependent manner in a tested range of 1-100 μM. Fisetin inhibited histamine content and peroxidase (EPO) activity in BALF in a dose-dependent manner. All three tested flavonols significantly (P<0.01) inhibited histamine content at 10 mg/kg, and phospholipase A(2) (PLA(2)) and EPO activities at 30 mg/kg (p.o.) in BALF. Kaempherol had a greater anti-asthmatic effect than other flavonols. Fisetin demonstrated the greatest inhibition of sRaw, whereas morin had lesser effects. These results indicate that the lower the molecular weight, the greater the anti-asthmatic activities of these compounds.

Topics: Administration, Inhalation; Aerosols; Airway Resistance; Animals; Anti-Asthmatic Agents; Bronchoalveolar Lavage; Chemotaxis, Leukocyte; Dose-Response Relationship, Drug; Eosinophils; Flavonoids; Flavonols; Guinea Pigs; Histamine; Kaempferols; Leukocytes; Lung; Male; Molecular Weight; N-Formylmethionine Leucyl-Phenylalanine; Neutrophil Infiltration; Neutrophils; Ovalbumin; Peroxidase; Phospholipases A2; Plant Extracts; Respiratory Mechanics