galangin and Asthma

Atopic diseases (atopic dermatitis, asthma and allergic rhinitis) affects a huge number of people around the world and their incidence rate is on rise. Atopic dermatitis (AD) is more prevalent in paediatric population which sensitizes an individual to develop allergic rhinitis and asthma later in life. The complex pathogenesis of these allergic diseases though involves numerous cellular signalling pathways but redox imbalance has been reported to be critical for induction/perpetuation of inflammatory process under such conditions. The realm of complementary and alternative medicine has gained greater attention because of the reported anti-oxidant/anti-inflammatory properties. Several case studies of treating atopic diseases with homeopathic remedies have provided positive results. Likewise, pre-clinical studies suggest that various natural compounds suppress allergic response via exhibiting their anti-oxidant potential. Despite the reported beneficial effects of phytochemicals in experimental model system, the clinical success has not been documented so far. It appears that poor absorption and bioavailability of natural compounds may be one of the reasons for realizing their full potential. The current paper throws light on impact of phytochemicals in the redox linked cellular and signalling pathways that may be critical in manifestation of atopic diseases. Further, an effort has been made to identify the gaps in the area so that future strategies could be evolved to exploit the medicinal value of various phytochemicals for an improved efficiency.

Topics: Asthma; Catechols; Curcumin; Dermatitis, Atopic; Fatty Alcohols; Flavonoids; Ginsenosides; Humans; Hypersensitivity; Molecular Structure; Phytochemicals; Resveratrol

Peroxisome proliferator-activated receptor gamma (PPARγ) is a multifaceted ligand-activated transcription factor that regulates inflammatory responses in asthma pathophysiology. The present study corroborates PPARγ-mediated anti-asthmatic action of the flavonoid, galangin (norizalpinin). In silico molecular interactions reveal that galangin formed three H-bonds (Glu291, Leu340 and Ser342) and a π-sigma bond (Arg288) with PPARγ, contributing to the binding affinity and stability of the complex. In vivo studies explore the role of galangin as a propitious PPARγ agonist in mitigating airway inflammation, thereby excluding ligand-independent action of PPARγ. Accordingly, oral administration of galangin significantly ameliorated airway hyperresponsiveness, inflammation and goblet cell hyperplasia by the suppression of IL-4, 5, 13, 17, TNF-α, NO, ROS, EPO, IgE and increase of IFN-γ in ovalbumin-induced allergic asthma model. PPARγ expression (mRNA and protein) studies were performed to elucidate a possible mechanism by which galangin modulates. Furthermore, to eliminate PPARγ-independent effects of galangin, a specific PPARγ antagonist (GW9662) was administered, which dramatically reversed the effects of galangin on PPARγ up-regulation, confirming the pleiotropic role of galangin as a PPARγ agonist in asthma therapeutics. Taken together, our findings communicate that PPARγ plays as a master regulator in the anti-asthmatic action of galangin.

Topics: Amino Acid Sequence; Anilides; Animals; Anti-Asthmatic Agents; Asthma; Binding Sites; Biomechanical Phenomena; Female; Flavonoids; Gene Expression Regulation; Humans; Hydrogen Bonding; Interleukins; Lung; Mice, Inbred BALB C; Molecular Docking Simulation; Ovalbumin; PPAR gamma; Protein Binding; Protein Conformation; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha

Enhanced contractility of airway smooth muscle (ASM) is a major pathophysiological characteristic of asthma. Expanding the therapeutic armamentarium beyond β-agonists that target ASM hypercontractility would substantially improve treatment options. Recent studies have identified naturally occurring phytochemicals as candidates for acute ASM relaxation. Several flavonoids were evaluated for their ability to acutely relax human and murine ASM ex vivo and murine airways in vivo and were evaluated for their ability to inhibit procontractile signaling pathways in human ASM (hASM) cells. Two members of the flavonol subfamily, galangin and fisetin, significantly relaxed acetylcholine-precontracted murine tracheal rings ex vivo (n = 4 and n = 5, respectively, P < 0.001). Galangin and fisetin also relaxed acetylcholine-precontracted hASM strips ex vivo (n = 6-8, P < 0.001). Functional respiratory in vivo murine studies demonstrated that inhaled galangin attenuated the increase in lung resistance induced by inhaled methacholine (n = 6, P < 0.01). Both flavonols, galangin and fisetin, significantly inhibited purified phosphodiesterase-4 (PDE4) (n = 7, P < 0.05; n = 7, P < 0.05, respectively), and PLCβ enzymes (n = 6, P < 0.001 and n = 6, P < 0.001, respectively) attenuated procontractile Gq agonists' increase in intracellular calcium (n = 11, P < 0.001), acetylcholine-induced increases in inositol phosphates, and CPI-17 phosphorylation (n = 9, P < 0.01) in hASM cells. The prorelaxant effect retained in these structurally similar flavonols provides a novel pharmacological method for dual inhibition of PLCβ and PDE4 and therefore may serve as a potential treatment option for acute ASM constriction.

Topics: Animals; Aorta; Asthma; Bronchoconstriction; Calcium Signaling; Cyclic Nucleotide Phosphodiesterases, Type 4; Drug Evaluation, Preclinical; Flavonoids; Flavonols; Humans; Inositol 1,4,5-Trisphosphate; Male; Mice; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Phosphodiesterase 4 Inhibitors; Phospholipase C beta

Galangin, a natural flavonol, has attracted much attention for its potential anti-inflammatory properties. However, its role in the regulation of airway remodelling in asthma has not been explored. The present study aimed to elucidate the effects of galangin on chronic inflammation and airway remodelling and to investigate the underlying mechanisms both in vivo and in vitro. Ovalbumin (OVA)-sensitised mice were administered with galangin 30 min before challenge. Our results showed that severe inflammatory responses and airway remodelling occurred in OVA-induced mice. Treatment with galangin markedly attenuated the leakage of inflammatory cells into bronchoalveolar lavage fluid (BALF) and decreased the level of OVA-specific IgE in serum. Galangin significantly inhibited goblet cell hyperplasia, collagen deposition and α-SMA expression. Lowered level of TGF-β1 and suppressed expression of VEGF and MMP-9 were observed in BALF or lung tissue, implying that galangin has an optimal anti-remodelling effect in vivo. Consistently, the TGF-β1-induced proliferation of airway smooth muscle cells was reduced by galangin in vitro, which might be due to the alleviation of ROS levels and inhibition of MAPK pathway. Taken together, the present findings highlight a novel role for galangin as a promising anti-remodelling agent in asthma, which likely involves the TGF-β1-ROS-MAPK pathway.

Topics: Actins; Airway Remodeling; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Proliferation; Collagen; Disease Models, Animal; Female; Fibrosis; Flavonoids; Goblet Cells; Humans; Hyperplasia; Immunoglobulin E; Matrix Metalloproteinase 9; Mice; Mitogen-Activated Protein Kinases; Myocytes, Smooth Muscle; Ovalbumin; Oxidation-Reduction; Phosphorylation; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A