Abstract
The treatment of allergic diseases, such as asthma, with both conventional and novel therapies presents a challenge both in terms of optimal effect and cost. On the other hand, traditional therapies utilizing natural products such as onion have been in use for centuries with demonstrated efficacy and safety but without much knowledge of their mechanims of action. In this study, we investigated if the anti-inflammatory effects of onion bulb extract (OBE) are mediated via the modulation of the EGFR/ERK1/2/AKT signaling pathway, and whether OBE can synergise with steroids to produce greater anti-inflammatory actions. Treatment with OBE inhibited the house dust mite (HDM)-induced increased phosphorylation of EGFR, ERK1/2 and AKT which resulted in the inhibition of HDM-induced increase in airway cellular influx, perivascular and peribronchial inflammation, goblet cell hyper/metaplasia, and also inhibited ex vivo eosinophil chemotaxis. Moreover, treatment with a combination of a low dose OBE and low dose dexamethasone resulted in a significant inhibition of the HDM-induced cellular influx, perivascular and peribronchial inflammation, goblet cell hyper/metaplasia, and increased the pERK1/2 levels, whereas neither treatment, when given alone, had any discernible effects. This study therefore shows that inhibition of the EGFR/ERK1/2/AKT-dependent signaling pathway is one of the key mechanisms by which OBE can mediate its anti-inflammatory effects in diseases such as asthma. Importantly, this study also demonstrates that combining OBE with steroids results in significantly enhanced anti-inflammatory effects. This action may have important potential implications for future asthma therapy.
Highlights
Natural products have been the cornerstone of therapeutic agents for millennia and more recently an important source of therapeutic drugs with unique structural diversity and pharmacological actions (Newman and Cragg, 2016)
In this study, using a clincially relevant allergen (HDM), we investigated 1) whether the EGFR/ERK1/2/AKT signaling pathway is modulated by onion bulb extract (OBE), and 2) if OBE synergizes with dexamethasone to result in a greater anti-inflammatory action
24 h after the last intranasal challenge, animals were sacrificed with an overdose of halothane; bronchoalveolar lavage (BAL) was performed to obtain BAL fluid, and the lungs were excised for preparation for histology, Western Blot (WB), and immunofluorescence (IF) studies
Summary
Natural products have been the cornerstone of therapeutic agents for millennia and more recently an important source of therapeutic drugs with unique structural diversity and pharmacological actions (Newman and Cragg, 2016). We have reported that ERK1/2 and AKT are downstream signaling molecules of EGFR activation (El-Hashim et al, 2017) Both clinical and preclinical studies clearly establish an important role for EGFR-dependent signaling in inflammatory-based diseases. Despite the recent market increase in therapeutic agents that selectively target specific molecules, it is unlikely that the blockade of individual mediator signaling pathways would result in optimal therapeutic outcomes in asthma, and monoclonal based therapy would certainly be beyond the financial reach of most asthma patients in the developing world due to their high cost. In this study, using a clincially relevant allergen (HDM), we investigated 1) whether the EGFR/ERK1/2/AKT signaling pathway is modulated by OBE, and 2) if OBE synergizes with dexamethasone to result in a greater anti-inflammatory action
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