Systemic flavonoid exposure and NF-κB mediated suppression of Th2 responses by Ziziphus spina-christi attenuate...

Ziziphus spina-christi is a medicinal plant native to arid regions of the UAE and has been used in folk medicine to treat respiratory diseases, but its efficacy in asthma triggered by allergens remains to be confirmed.

To investigate the therapeutic potential of Z. spina-christi in modulating immune responses in allergic asthma and to confirm the systemic bioavailability of its major phytochemicals.

The major flavonoids in Z. spina-christi were identified using an untargeted metabolite profiling, followed by pharmacokinetic analysis in rats to evaluate their systemic bioavailability. The anti-asthmatic effect was assessed in an HDM-induced asthma model in BALB/c mice (n = 8 per group). FlexiVent was used to assess airway hyperresponsiveness (AHR), and H&E staining was used to evaluate lung inflammation. Flow cytometry was used to quantify eosinophils in bronchoalveolar lavage fluid (BALF). Cytokine expression in lung homogenates and cytokine levels in BALF were measured by qPCR and ELISA, respectively. NF- κB pathway activation was assessed by western blotting.

Quercetin, kaempferol, myricetin, and luteolin were identified by metabolic profiling. A pharmacokinetic study confirmed the systemic absorption of these flavonoids. Treatment with Ziziphus spina-christi reduced AHR, inflammatory cell infiltration in the lungs, and eosinophil counts. It also significantly reduced the levels of IL-17A, IFN-γ, IL-4, IL-5, and IL-13. Treatment with Z. spina-christi reduced p-IkB expression and consequently inhibited the NF-κB pathway.

These findings show that Z. spina-christi suppresses allergic airway inflammation by modulating Th2/Th17 immune responses and inhibiting NF-κB-mediated inflammatory pathways. These findings are consistent with the systemic availability of major flavonoid constituents of the extract. This integrated approach linking phytochemical characterisation, pharmacokinetics and mechanistic in vivo assessments highlights the therapeutic potential of Z. spina-christi derived flavonoids as natural modulators of allergic airway inflammation.