Trans-resveratrol mitigates miR-204-3p mediated progression of allergic rhinitis by regulating the EGLN3/HIF-1α/IL33/ST2 signalling pathway.

BACKGROUND

Allergic rhinitis (AR) is a multifactorial disease triggered by interactions between genes and the environment. Clinical evidence has shown that trans-resveratrol, a widely used drug, significantly ameliorates AR pathology. However, the precise mechanisms underlying this effect remain unclear.

PURPOSE

This study aimed to elucidate the pharmacological mechanisms of action of trans-resveratrol in patients with AR who exhibit hypoxic symptoms. This will be achieved through microRNA sequencing and signaling pathway screening combined with basic experiments to determine the effects of Trans-resveratrol intervention in this patient population.

METHODS

Network pharmacology was used to determine the therapeutic value of trans-resveratrol in AR. The micro-RNA miR-204-3p was pinpointed by sequencing. Quantitative reverse transcription polymerase chain reaction was used to quantify the expression levels. Haematoxylin and eosin, alcian blue-periodic acid-Schiff, and Masson's trichrome staining were used to assess the effects of hypoxia on nasal mucosa immunohistochemistry and immunofluorescence-localised target proteins. Egl nine homolog 3 (EGLN3) was screened using bioinformatics software. Protein expression was detected by western blotting. Cell growth and death were gauged via Cell Counting Kit-8 and terminal deoxynucleotidyl transferase dUTP nick end labelling staining, respectively. Cell migration was observed using a transwell assay. Enzyme-linked immunosorbent assay was used to measure interleukin (IL)33 levels in the cell supernatants. Flow cytometry was used to verify cell cycle and antigen levels. Electron microscopy was used to visualise the status of the nasal mucosa prior to in vivo expression analysis.

RESULTS

Patients with hypoxic AR demonstrated more pronounced nasal mucosal remodelling than that in patients with common AR. Sequencing results indicated that these patients had a reduced expression of miR-204-3p. Through a combination utilizing of bioinformatics analysis and experimental validation, EGLN3 has been identified as a direct target of HIF-1α. The low expression level of miR-204-3p represses EGLN3, resulting in the accumulation of HIF-1α and the activation of the IL33/ST2 signaling pathway. These stimulate the proliferation, survival, and migration of HNEpCs, ultimately contributing to mucosa remodeling and AR progression. Trans-resveratrol notably downregulated the levels of HIF-1α and IL33/ST2, while simultaneously increasing the expression of EGLN3.

CONCLUSIONS

Downregulation of miR-204-3p initiated a vicious cycle of hypoxic AR via EGLN3/HIF-1α/IL33/ST2. Trans-resveratrol reversed the pathological process of nasal mucosa remodeling of hypoxic AR by exhibiting anti-inflammatory and anti-angiogenic functions via the above signaling pathway. Our study uncovers the underlying mechanism by which hypoxia drives the progression of AR. It presents innovative strategies for addressing inflammatory and hypoxia-related diseases, bridging traditional and modern medicine, and highlighting the potential of natural compounds in clinical practice.