Syo-seiryu-to (SST) is a traditional herbal medicine that has been used clinically to treat allergic rhinitis (AR) in Japan. SST improves acute symptoms, such as sneezing and rhinorrhea, as well as chronic symptoms, such as nasal obstruction, in patients with AR. However, its therapeutic mechanisms remain unknown. We examined the effects of SST and eight constituent crude drugs on phorbol 12-myristate-13-acetate (PMA)-induced gene up-regulation of IL-33 and histamine H1 receptor (H1R), which are responsible for the pathogenesis of AR. We found that SST and its crude drugs, except for Pinellia tuber, significantly and dose-dependently suppressed PMA-induced both IL-33 and H1R mRNA up-regulation in vitro. The half-maximal inhibitory concentration values of the seven crude drugs to inhibit PMA-induced IL-33 mRNA up-regulation were correlated with those related to H1R mRNA up-regulation, suggesting that they act on a common signal molecule. These results suggest that SST improves nasal congestion that is induced by IL-33-related eosinophil infiltration and inhibits sneezing and rhinorrhea that are induced by H1R-mediated histamine signaling in the nasal mucosa of AR patients through its inhibition of a common molecule in the gene expression pathways of IL-33 and H1R. The results could explain the advantages of traditional herbal medicine, in which mixing various crude drugs not only acts on a common target to enhance its pharmacological action, similar to the effect of a high concentration of a single crude extract but also has the benefit of reducing the side effects of each crude drug.

H1-antihistamines antagonize histamine and prevent it from binding to the histamine H1 receptor (H1R). Some of them also act as inverse agonists, which are more potent than pure antagonists because they suppress the constitutive H1R activity. Bilastine is a non-sedative antihistamine which is one of the most satisfy the requirements for oral antihistamines. However, there is no information to show the inverse agonist activity of bilastine including inositol phosphates accumulation, and its inverse agonist activity is yet to be elucidated. Here we evaluated whether bilastine has inverse agonist activity or not. Intracellular calcium concentration was measured using Fluo-8. Inositol phosphates accumulation was assayed using [3H]myo-inositol. The H1R mRNA level was measured using real-time RT-PCR. At rest, Ca2+ oscillation was observed, indicating that H1R has intrinsic activity. Bilastine attenuated this fluorescence oscillation. Bilastine suppressed the increase in IPs formation in a dose-dependent manner and it was about 80% of the control level at the dose of 3 μM. Bilastine also suppressed histamine-induced increase in IPs formation to the control level. Furthermore, bilastine suppressed basal H1R gene expression in a dose-dependent manner. Data suggest that bilastine is an inverse agonist. Preseasonal prophylactic administration with bilastine could down-regulate basal H1R gene expression in the nasal mucosa and ameliorate the nasal symptoms during the peak pollen period.

Background Phototherapy with narrow‐band ultraviolet B (narrow‐band UVB) is clinically effective treatment for atopic dermatitis. In the present study, we examined the effects of intranasal irradiation with narrow‐band UVB on nasal symptom, upregulation of histamine H1 receptor (H1R) gene expression and induction of DNA damage in the nasal mucosa of allergic rhinitis (AR) model rat. Methods AR model rats were intranasally irradiated with 310 nm of narrow‐band UVB. Nasal mucosal levels of H1R mRNA were measured using real‐time quantitative reverse transcriptase (RT)‐PCR. DNA damage was evaluated using cyclobutane pyrimidine dimer (CPD) immunostaining. Results In toluene 2,4‐diisocyanate (TDI)‐sensitized rats, TDI provoked sneezes and H1R gene expression in the nasal mucosa. Intranasal pre‐irradiation with 310 nm narrow‐band UVB at doses of 600 and 1400, but not 200 mJ/cm2 significantly inhibited the number of sneezes and upregulation of H1R gene expression provoked by TDI. CPD‐positive cells appeared in the nasal mucosa after intranasal narrow‐band UVB irradiation at a dose of 1400, but not 200 and 600 mJ/cm2. The suppression of TDI‐provoked sneezes and upregulation of H1R gene expression lasted 24 hours, but not 48 hours, after narrow‐band UVB irradiation with a dose of 600 mJ/cm2. Conclusions Intranasal pre‐irradiation with narrow‐band UVB dose‐dependently inhibited sneezes and upregulation of H1R gene expression of the nasal mucosa in AR model rats, suggesting that the inhibition of nasal upregulation of H1R gene expression suppressed nasal symptom. The suppression after narrow‐band UVB irradiation at a dose of 600 mJ/cm2 was reversible without induction of DNA damage. These findings indicated that low‐dose narrow‐band UVB phototherapy could be effectively and safely used for AR treatment in a clinical setting. Level of Evidence NA.

As the expression level of allergic disease sensitive genes are correlated with the severity of allergic symptoms, suppression of these gene expressions could be promising therapeutics. We demonstrated that protein kinase Cδ / heat shock protein 90-mediated H1R gene expression signaling and nuclear factor of activated T-cells (NFAT)-mediated IL-9 gene expression signaling are responsible for the pathogenesis of pollinosis. Treatment with Awa-tea combined with wild grape hot water extract suppressed these signaling and alleviated nasal symptoms in toluene-2,4-diisocyanate (TDI)-sensitized rats. However, the underlying mechanism of its anti-allergic activity is not elucidated yet. Here, we sought to identify an anti-allergic compound from Awa-tea and pyrogallol was identified as an active compound. Pyrogallol strongly suppressed ionomycin-induced up-regulation of IL-9 gene expression in RBL-2H3 cells. Treatment with pyrogallol in combination with epinastine alleviated nasal symptoms and suppressed up-regulation of IL-9 gene expression in TDI-sensitized rats. Pyrogallol itself did not inhibit calcineurin phosphatase activity. However, pyrogallol suppressed ionomycin-induced dephosphorylation and nuclear translocation of NFAT. These data suggest pyrogallol is an anti-allergic compound in Awa-tea and it suppressed NFAT-mediated IL-9 gene expression through the inhibition of dephosphorylation of NFAT. This might be the underlying mechanism of the therapeutic effects of combined therapy of pyrogallol with antihistamine.

AimHistamine H1 receptor (H1R) gene is up‐regulated in the nasal mucosa of patients with pollinosis, and its expression level is strongly correlated with the severity of allergic symptoms. However, suppression of H1R mRNA to the basal level by antihistamine failed to alleviate nasal symptoms completely, and nuclear factor of activated T‐cells (NFAT) signalling was demonstrated to be the additional signalling responsible for the pathogenesis of allergic rhinitis (AR). Lotus Root (LR) has been traditionally used to improve the allergic symptoms; however, the underlying mechanism of its anti‐allergic activity is unknown. Here, we show that the LR aequeous extract suppressed ionomycin‐induced NFAT signalling‐mediated IL‐9 mRNA up‐regulation in RBL‐2H3 cells and toluene‐2,4‐diisocyanate (TDI)‐sensitised rats.MethodsAn active compound from LR was purified by aequeous extraction and ethanol precipitation followed by column chromatography, and its structure was resolved using thiol degradation followed by 1H‐NMR (nuclear magnetic resonance) and 13C‐NMR. The mRNA levels of H1R and IL‐9 were measured using real‐time reverse transcription‐polymerase chain reaction (RT‐PCR).ResultsWe isolated and identified proanthocyanidin containing gallocatechin tetramer as an active compound. LR‐derived proanthocyanidin (LRPC) suppressed IL‐9 mRNA up‐regulation both in RBL‐2H3 cells and TDI‐sensitised rats. Combination therapy of LRPC with antihistamine markedly alleviated allergic symptoms.ConclusionData suggest that LRPC alleviated nasal symptoms through the inhibition of IL‐9 mRNA up‐regulation, possibly through the inhibition of NFAT signalling, and that combination therapy of LRPC with antihistamine could be effective in advanced treatment for AR.