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Research Article
2026
:38;
13012025
doi:
10.25259/JKSUS_1301_2025

Anti-airway inflammatory effects of a complex from Scutellaria baicalensis, Nelumbinis semen, and Mori cortex extracts in an ovalbumin-induced allergic asthma model

, , , , , ,
aIINVIVO Co. Ltd., 121, Deahak-ro, Nonsan, Chungnam, 32992, Republic of Korea
bDepartment of Pathology, College of Korean Medicine, Wonkwang University, 460, Iksan, Jeonbuk, 54538, Republic of Korea
cCentral Research and Development, Hanpoong Pharm & Foods Co., Ltd., Wanju-gun, Jeonbuk, 55316, Republic of Korea
dKorea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo, Wanju-gun, Jeonbuk, 55365, Republic of Korea

* Corresponding author: E-mail address: jsbae78@wku.ac.kr (JS Bae)

Received: , Accepted: ,
© 2026 Journal of King Saud University – Science - Published by Scientific Scholar
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This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Abstract

Allergic asthma is a chronic inflammatory disease characterized by T helper 2 (Th2)-mediated immune responses that lead to airway inflammation and structural remodeling. Despite existing treatments, limitations, such as drug resistance and adverse effects, necessitate alternative approaches. In this study, we examined the effects of the SNM complex, a combination of Scutellaria baicalensis (SB), Nelumbinis semen (NS), and Mori Cortex (MC) extracts, on allergic asthma. The anti-inflammatory potential of SNM was investigated in H292 cells stimulated with lipopolysaccharide and in mouse models of ovalbumen-induced asthma. Key parameters such as Th2 cytokines, leukotrienes, and nuclear factor-kappa B (NF)-κB activation were evaluated using enzyme-linked immunosorbent assay (ELISA) and western blot analysis. Histological analyses of the lung tissues were performed to examine structural changes. SNM significantly reduced the levels of Th2 cytokines (interleukin (IL)-4, IL-5, and IL-13), leukotrienes (LTB4, LTC4, and LTD4), and immunoglobulin E (IgE) in a dose-dependent manner, and the high-dose group showed similar reductions in IL-4 and LTB4 levels to the positive control (montelukast) group. Treatment with SNM significantly decreased the phosphorylation level of NF-κB. Histological analysis revealed that airway thickening and inflammatory cell infiltration were decreased in SNM-treated mice. These findings suggest that the SNM complex may represent a potential therapeutic approach for allergic asthma by improving airway inflammation and remodeling. However, further preclinical studies are needed to translate these findings into clinical applications.

Keywords

Asthma
Mori cortex
Nelumbinis semen
Scutellaria baicalensis
Th2 cytokines

1. Introduction

Allergic asthma, a chronic respiratory disease caused by allergens such as pollen, dust, and air pollutants, has become one of the most rapidly growing disorders, affecting one-third of the global population and contributing to millions of deaths annually (Levy et al., 2023; Rehman et al., 2018). Asthma is a chronic inflammatory disease of the airways characterized by mucus overproduction and goblet cell hyperplasia, leading to airflow obstruction and heightened airway responsiveness (Fahy, 2015; Ye et al., 2017). T helper 2 (Th2) cells are crucial mediators of allergic airway inflammation by inducing allergen-specific IgE production, promoting eosinophil recruitment, and secreting cytokines such as IL-4, IL-5, and IL-13 (Lee et al., 2011; Mizusaki et al., 2017; Lee et al., 2019; Lee et al., 2020).

Nuclear factor-kappa B (NF-κB) and leukotrienes are critical molecular mediators in asthma pathogenesis (Barnes, 2006). NF-κB regulates innate immune responses, promoting inflammatory cell infiltration and cytokine production, including tumor necrosis factor (TNF-α) and IL-1β (Lawrence, 2009). Ovalbumin (OVA)-induced asthma models demonstrate increased NF-κB activity and inflammatory cell infiltration (Edwards et al., 2009).

Leukotrienes, including Leukotriene B4 (LTB4), LTC4, and LTD4, also contribute by promoting neutrophil activation, bronchoconstriction, and mucus secretion (Peters-Golden and Henderson, 2007; Liu and Yokomizo, 2015). Inhibiting the leukotriene pathway is thus a promising strategy for asthma therapy.

Scutellaria baicalensis (SB), a traditional herbal medicine with a long history of use, has been reported to exert anti-inflammatory and anti-allergic effects. Its main active components, including baicalin, baicalein, and wogonin, have been shown to inhibit the NF-κB pathway and reduce the expression of inflammatory cytokines (Liu et al., 2016; Xu et al., 2019; Shin et al., 2014). In particular, baicalin is known to suppress the expression of IL-4 and IL-13, which are key drivers of airway inflammation, and has been observed to reduce inflammatory cell infiltration in asthma models (Liu et al., 2016).

Nelumbo nucifera (NN) is a herbal medicine with potent antioxidant, anti-inflammatory, and immunomodulatory properties. Its main components, flavonoids and polysaccharides, effectively suppress cytokine expression and mitigate oxidative stress (Chen et al., 2019). NN extracts have been shown to suppress inflammatory cell activation and attenuate airway hyper-responsiveness under experimental airway inflammation (Yang et al., 2017). Moreover, the seeds of NN (Nelumbinis semen, NS) are also traditionally used to treat various conditions, including inflammation, cancer, and chronic diarrhea (Mukherjee et al., 2009). Specifically, β-sitosterol, a bioactive component of NS extract, has been shown to attenuate airway inflammatory responses (Rossi et al., 2023; Xu et al., 2023).

Mori cortex (MC), traditionally used for its antipyretic and sedative effects, has also been reported to reduce inflammation and alleviate allergic responses (Batiha et al., 2023; Li et al., 2018; Lee et al., 2016). Its main active components include quercetin, morin, rutin, moracin M, and mulberrofuran G. Notably, polyphenols like moracin M and quercetin have been shown to suppress the Th2 immune response, reduce IL-4 and IL-5 expression, and effectively ameliorate airway inflammation (Lee et al., 2016; Park et al., 2009; Lim et al., 2013).

Despite current asthma treatments, issues like drug resistance and side effects drive interest in safer alternatives. Natural extracts, especially in combination, offer promising therapeutic potential. While SB, NS, and MC extracts show individual anti-inflammatory effects, their combined impact (SNM) on allergic asthma remains unknown. This study evaluates SNM’s anti-airway inflammatory effects in lipopolysaccharide (LPS)-stimulated cells and an OVA-induced asthma model.

2. Materials and Methods

2.1 Samples

SB (the root of Scutellaria baicalensis Georgi (Labiatae)) and NS (the seed of Nelumbo nucifera Gaertner (Nymphaeaceae)) were purchased from CK PHARM Co., LTD. (Seoul, Korea). MC (the root bark of Morus alba Linné (Moraceae)) were purchased from Entap Herb Co., Ltd (Yangju, Korea). The SNM complex was prepared by mixing 70% ethanol extracts of SB, NS, and MC in a 1:1:1 (w/w/w) ratio. A total of 400 g of SB was subjected to two rounds of extraction with 10 volumes of 70% ethanol (v/v) at 80-90°C for 3 h. The solution was then filtered, concentrated under vacuum at 60°C using a rotary evaporator (EYELA N-1200B, Tokyo Rikakikai Co., Tokyo, Japan), and dried under reduced pressure to obtain 160 g of extract. The same extraction procedure was applied to NS (400 g) and MC (400 g), yielding 57.2 g and 40.0 g of extract, respectively. Montelukast (MTK) was obtained from Sigma-Aldrich (St. Louis, MO, USA). MTK, commonly prescribed for asthma and allergic rhinitis, served as the positive control in this study.

2.2 HPLC analysis

High-performance liquid chromatography (HPLC) was used to quantify the SNM complex (SHIMADZU I-series LC-2030C, Shimadzu, Kyoto, Japan). The primary compounds analyzed in the SNM complex were baicalin, baicalein, wogonin, β-sitosterol, moracin M, and mulberrofuran G (Fig. S1). Analysis of these compounds was performed using two types of HPLC columns: For baicalin, baicalein, wogonin, and β-sitosterol, a Discovery C18 column (250 × 3.0 mm I.D., 5 μm; injection volume: 10 μL; run time: 40 min; Sigma Aldrich) was used. The mobile phase consisted of acetonitrile (solvent A) and methanol (solvent B), with a flow rate of 0.8 mL/min at 25°C. The gradient program was as follows: solvent B was decreased from 100% to 97% over 30 min, followed by re-equilibration at the initial condition (100% solvent B) from 31 to 40 min. Detection was carried out using a PDA detector at 206 nm. For moracin M and mulberrofuran G, an Xbridge RP18 C18 column (150 × 4.6 mm I.D., 3.5 μm; injection volume: 10 μL; run time: 60 min; Waters, Milford, MA, USA) was used. The HPLC mobile phase comprised 0.1% formic acid (v/v, solvent A) and acetonitrile (solvent B), with a flow rate of 0.5 mL/min, and the column was maintained at 35°C. The gradient program was as follows: solvent B was increased from 10% to 30% during the first 10 min, further increased to 40% at 25 min, to 60% at 50 min, and then returned to the initial condition (10% solvent B) from 51 to 60 min. Detection was performed using a PDA detector at 320 nm. Each sample was prepared in triplicate, and the results are presented as the mean ± SD.

Fig. S1

2.3 Cell culture and viability assay

Human pulmonary epithelial NCI-H292 (H292) cells were acquired from the American Type Culture Collection (ATCC, Rockville, MD, USA) and maintained in RPMI-1640 medium (Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (Gibco BRL, Gaithersburg, MD, USA) and 1% penicillin/streptomycin. Cells were maintained at 37°C in a humidified incubator with 5% CO₂. For cell viability analysis, H292 cells (1 × 104 cells/90 µL/well) were seeded in a 96-well plate and treated with SNM (1, 3, 5, 10, 30, 50, 100, 300, 500, 1000, and 3000 μg/mL) or MTK (0.1, 0.5, 1, 10, and 50 μM) at various concentrations, followed by incubation for 24 h at 37°C with 5% CO2. Thereafter, 10 µL of WST-1 solution (ITSBio, Seoul, Korea) was added to 100 µL of the cell culture medium, and incubated for 1 h. Absorbance was measured at 450 nm using a microplate reader (Infinite 200, TECAN Group Ltd., Switzerland). The control group was treated with the solvent corresponding to the highest concentration used in the experimental group. Cell viability was assessed in at least three independent experiments (n = 3).

2.4 Inflammatory mediator measurement in H292 cells

H292 cells were plated at a density of 5 × 105 cells per well in 12-well plates. After 24 h, the cells were washed with 1 mL of PBS and incubated with 100 µg of SNM or 10 µM of MTK for 3 h to measure phosphodiesterase 4 (PDE4), leukotriene B4 (LTB4), and leukotriene E4 (LTE4) levels. Subsequently, cells were stimulated with 10 µg/mL LPS and incubated for 24 h. For PDE4 analysis, cells were lysed in PBS via repeated freeze-thaw cycles, and the lysates were centrifuged at 2,000 rpm for 20 min to obtain supernatants. The culture medium for LTB4 and LTE4 measurements was processed similarly to remove residual cells. All supernatants were stored at -20°C until analysis. Levels of PDE4, LTB4, and LTE4 were quantified using ELISA kits (MybioSource, San Diego, CA, USA) following the manufacturer’s instructions. Experiments were conducted in at least three independent replicates (n = 3).

2.5 Animal and experimental design

Six-week-old, specific-pathogen-free (SPF) male BALB/c mice obtained from Orient Bio (Gyeonggi, Korea) were used in the experiments following a one-week adaptation period. The adapting environment was maintained at a temperature of 23 ± 1°C, humidity of 50 ± 5%, noise level below 60 phon, a 12 h light/dark cycle (08:00 to 20:00), illuminance of 150 to 300 lx, and ventilation of 10-12 air changes per hour. During the rearing period, the animals were provided with standard solid feed (Samtako, Gyeonggi, Korea), and drinking water was replaced daily with sterilized water supplied ad libitum. Following a 7-day acclimation period, BALB/c mice were randomly assigned to six groups of 10 animals each using a randomized block design: normal group (normal), OVA-induced respiratory disease model group (control), OVA + SNM group (SNM 50, 100, and 200 mg/kg), and OVA + MTK group (MTK 30 mg/kg). To establish the OVA-induced respiratory disease model, systemic sensitization was achieved by intraperitoneal injection of 200 µL OVA solution (10 µg in PBS with 2 mg Al(OH)₃) on days 1 and 14. Mice were subsequently challenged by intranasal administration of 3% OVA solution once daily on days 21, 22, and 23. SNM (50, 100, or 200 mg/kg) or MTK (30 mg/kg) were suspended in sterilized water (vehicle) and administered orally by gavage once daily from day 9 to day 23. The administered volume was set at 5 mL/kg according to the body weight of each mouse, and all doses were delivered at approximately the same time each morning. All animals were sacrificed on day 24. An overview of the experimental procedure has been provided in Supplementary Fig. S2. All animal experiments were conducted following approval from the Institutional Animal Care and Use Committee of INVIVO Co., Ltd. (approval no. IV-RA-27-2305-12).

Fig. S2

2.6 Bronchoalveolar lavage fluid analysis

During the autopsy of mice anesthetized by inhalation (Isoflurane, USP), the trachea were incised, and 1 mL of sterile saline solution to 4°C was instilled into the trachea via a catheter. Thereafter, the injected saline solution was left for approximately 30 seconds, and the saline solution was collected and stored at 4°C. The total cell counts were determined using an automated cell counter (Model R1; Olympus, Tokyo, Japan). The immune cell count in BALF was assessed using Diff-Quik staining (Sysmex Co., Japan). Cell counts were performed under a light microscope at 40x magnification using a hemocytometer. For image-based analysis, each image was segmented into four representative areas, and the cells in each region were enumerated to estimate the total cell count per sample. Immune cell subtypes were identified based on morphological characteristics: macrophages by their large size, asymmetric nuclei, and abundant cytoplasm; lymphocytes by their small size and centrally located large nuclei; neutrophils by their multilobed nuclei; and eosinophils by their bilobed nuclei and eosinophilic staining. To analyze cytokine and inflammatory factor levels, the BALF samples were centrifuged at 3,000 rpm for 10 minutes at 4°C to remove cells. Levels of TNF-α, IL-4, IL-5, IL-13, IgE, and leukotrienes (LTB4, LTC4, LTD4) in the cell-free BALF were quantified using ELISA kits (MyBioSource) following the manufacturer’s instructions.

2.7 Western blot analysis

Briefly, Lung tissues were homogenized and lysed in a protein extraction buffer (iNtRON, Seongnam, Korea). Lysates were centrifuged at 14,000 rpm for 10 min at 4°C, and protein concentrations were determined using the Bradford assay (Bio-Rad, Hercules, CA, USA). Proteins were separated by SDS-PAGE and transferred onto PVDF membranes. The membranes were incubated with primary antibodies (Supplementary Table 1) against phospho-NF-κB (Cell Signaling Technology, Danvers, MA, USA) and NF-κB (Cell Signaling Technology) at 4°C overnight, followed by incubation with horseradish peroxidase (HRP)-conjugated secondary antibodies at room temperature for 1 h. Protein detection was performed using an enhanced chemiluminescence kit (EZ-Western Lumi Pico, DoGen, Korea) and imaged with a c-Digit Western scanner (LI-COR, Lincoln, NE, USA). GAPDH served as the loading control, and band intensities were quantified using ImageJ software (version 1.8.0; NIH, Bethesda, MD, USA). NF-κB phosphorylation levels were expressed as the ratio of phosphorylated NF-κB to total NF-κB.

Table S1

2.8 Histological analysis

After the experiment, lung samples were collected, fixed in 10% formalin, dehydrated, and embedded in paraffin. Sections of 4 μm thickness were prepared and deparaffinized with xylene. The tissue slices were stained with hematoxylin and eosin (H&E) for histological evaluation, scanned using a Motic Easyscan device (Motic, China), and inflammatory cell infiltration was assessed by optical microscopy. All slides were interpreted by a pathologist under blinded conditions to prevent bias and ensure that the experimental groups were not known during the evaluation.

2.9 Statistical analysis

Data are presented as the mean ± standard error of the mean (SEM). Differences among groups were assessed by one-way ANOVA followed by Duncan’s multiple-range test. All statistical analyses were performed using SPSS version 23.0 (SPSS Inc., Chicago, IL, USA). Each value represents the mean of at least three independent experiments per group. Statistical significance was set at p < 0.05. Superscript letters indicate differences among groups: groups sharing the same letter are not significantly different, whereas groups with different letters are significantly different.

3. Results

3.1 Effects of SNM complex-mediated cell proliferation in H292 cells

To determine the non-toxic concentrations of SNM or MTK in H292 cells, we first performed cell proliferation assays. Cytotoxicity was evaluated in H292 cells treated with SNM at concentrations ranging from 1 μg/mL to 3,000 μg/mL and with MTK at concentrations ranging from 0.1 μM to 50 μM. After 24 h, the cell viability percentages for SNM, compared to the untreated control group (100.0 ± 0.0%), were as follows: 1 μg/mL (98.5 ± 2.9%), 3 μg/mL (99.9 ± 2.7%), 5 μg/mL (98.8 ± 1.4%), 10 μg/mL (100.0 ± 1.6%), 30 μg/mL (98.3 ± 2.3%), 50 μg/mL (98.6 ± 3.4%), 100 μg/mL (97.3 ± 2.8%), 300 μg/mL (86.0 ± 1.9%) (p < 0.001), 500 μg/mL (77.0 ± 2.6%) (p < 0.001), 1,000 μg/mL (58.4 ± 1.3%) (p < 0.001), and 3,000 μg/mL (18.6 ± 0.6%) (p < 0.001) (Fig. 1a). The positive control, MTK, displayed viabilities of 98.5 ± 1.2% at 0.1 μM, 98.1 ± 1.6% at 0.5 μM, 98.4 ± 2.2% at 1 μM, 99.8 ± 0.8% at 10 μM, and 89.8 ± 1.1% at 50 μM (p < 0.001) (Fig. 1b). SNM complexes exhibited significant cytotoxic effects at concentrations exceeding 300 μg/mL (IC50 = 1109.4 ± 54.7 μg/mL), while the MTK demonstrated cytotoxicity at 50 μM. Therefore, the non-toxic concentrations of SNM were established at 100 μg/mL, and the concentration of MTK was set at 10 μM. These concentrations were subsequently used to measure the phosphodiesterase 4 (PDE4), leukotriene B4 (LTB4), and LTE4 levels.

Cell viability of H292 cells (human lung epithelial cells) after treatment with SB, NS, and MC. SNM complex or montelukast (MTK). H292 cells (1 × 104 cells/well) were seeded in 96-well plates and treated with (A) SNM or (B) MTK at various concentrations for 24 h, respectively. After 24 h, cell viability was measured using the WST-1 assay. Bars labeled with different superscripts indicate significant differences (p < 0.001, vs. control). The results are expressed as mean ± standard error of the mean (SEM) of at least three independent experiments (n = 3).
Fig. 1.
Cell viability of H292 cells (human lung epithelial cells) after treatment with SB, NS, and MC. SNM complex or montelukast (MTK). H292 cells (1 × 104 cells/well) were seeded in 96-well plates and treated with (A) SNM or (B) MTK at various concentrations for 24 h, respectively. After 24 h, cell viability was measured using the WST-1 assay. Bars labeled with different superscripts indicate significant differences (p < 0.001, vs. control). The results are expressed as mean ± standard error of the mean (SEM) of at least three independent experiments (n = 3).

3.2 Effects of SNM complex on inflammatory mediator in H292 cells

In this study, we evaluated the inhibitory effects of the SNM complexes on leukotriene production in H292 cells. We assessed its effects on PDE4, a critical regulator of leukotriene synthesis. In the 10 μg/mL LPS-treated group (control; 1112.61 ± 16.90 nmol/mL) (p < 0.001), PDE4 activity significantly increased compared to the untreated group (Normal; 747.61 ± 7.15 nmol/mL). Treatment with the SNM (100 μg/mL) (p < 0.001) significantly inhibited PDE4 activity compared to the control group and showed an inhibitory effect similar to that of the positive control, MTK (10 μM) (p < 0.001) (Fig. 2a). Subsequently, we evaluated the effects of the SNM complexes on LTB4 and LTE4 production. In the control group, LTB4 and LTE4 levels increased significantly to 55.04 ± 3.82 pg/mL (p < 0.001) and 4262.67 ± 28.04 pg/mL (p < 0.001) compared to the normal group (30.63 ± 1.47 pg/mL and 1369.33 ± 73.96 pg/mL). The SNM groups showed significantly inhibited LTB4 and LTE4 production compared to the control group (p < 0.001) (Figs. 2b and c). Furthermore, PDE4, LTB4, and LTE4 concentrations were markedly reduced in the MTK-treated group compared with the control group (p < 0.001). Based on these findings, an in vivo study was conducted to assess the effects of SNM complexes in a mouse model of OVA-induced allergic asthma.

Effect of SNM complex on the expression of inflammatory mediators in LPS-treated H292 cells. H292 cells (5 × 105 cells/well) were seeded in 12-well plates, and pre-treated with SNM (100 µg/mL) or MTK (10 µM) for 3 h. Subsequently, LPS (10 µg/mL) was added and incubated for an additional 24 h. The concentrations of (A) phosphodiesterase 4 (PDE4), (B) leukotrienes (LT)B4, and (C) LTE4 in the supernatant were measured using an ELISA kit. The experiments were conducted in triplicate, and the error bars represent the SEM. Significant differences between the SNM and control groups are indicated (p < 0.001).
Fig. 2.
Effect of SNM complex on the expression of inflammatory mediators in LPS-treated H292 cells. H292 cells (5 × 105 cells/well) were seeded in 12-well plates, and pre-treated with SNM (100 µg/mL) or MTK (10 µM) for 3 h. Subsequently, LPS (10 µg/mL) was added and incubated for an additional 24 h. The concentrations of (A) phosphodiesterase 4 (PDE4), (B) leukotrienes (LT)B4, and (C) LTE4 in the supernatant were measured using an ELISA kit. The experiments were conducted in triplicate, and the error bars represent the SEM. Significant differences between the SNM and control groups are indicated (p < 0.001).

3.3 Effect of SNM complex on inflammatory cell recruitment in BALF

Based on the results of the in vitro study, the therapeutic effects of the SNM complexes were investigated using a mouse model of allergic asthma induced by OVA. Bronchoalveolar lavage fluid (BALF) contains a variety of airway-derived components, including living cells, proteins, and enzymes, that provide valuable information on the immune and inflammatory mechanisms underlying various respiratory diseases. To assess the changes in inflammatory cell counts between the control and experimental groups, BALF samples were obtained 24 hours following the final intranasal administration of OVA, and inflammatory cell counts were quantified. The total cell count in the BALF was significantly higher in the control group (5.79 ± 0.16 × 10⁶/mL) (p < 0.001) compared to the normal group (0.93 ± 0.04 × 10⁶/mL). In the SNM-treated groups, the total cell count was 4.64 ± 0.18 × 10⁶/mL in the low-dose group (SNM 50 mg/kg) (p < 0.001), 4.65 ± 0.38 × 10⁶/mL in the medium-dose group (SNM 100 mg/kg) (p < 0.001), and 4.45 ± 0.16 × 10⁶/mL in the high-dose group (SNM 200 mg/kg) (p < 0.001), all of which were significantly reduced compared with the control group. The positive control group (MTK 30 mg/kg) exhibited the lowest total cell count among all experimental groups (2.96 ± 0.25 × 10⁶/mL) (p < 0.001) (Fig. 3a). Microscopic examination of the BALF revealed significant increases in the counts of eosinophils, neutrophils, lymphocytes, and macrophages in the control group compared to those in the normal group. However, the SNM-treated group exhibited a marked decrease in neutrophil numbers relative to the control group, while eosinophil, lymphocyte, and macrophage counts remained comparable between the two groups. In addition, a decrease in neutrophil count, similar to that observed in the SNM treatment group, was confirmed in the MTK group, which served as the positive control (Figs. 3b-g, Table 1).

Effect of the SNM complex on inflammatory cell recruitment in BALF of ovalbumin (OVA)-induced mice. Sixty BALB/c mice were divided into six groups (10 mice per group): normal control group (Normal), OVA-induced allergic asthma group (Control), OVA + SNM 50 mg/kg group (SNM 50), OVA + SNM 100 mg/kg group (SNM 100), OVA + SNM 200 mg/kg group (SNM 200), and OVA + MTK 30 mg/kg group (MTK 30). An OVA-induced allergic asthma model was established by intraperitoneal (IP) injection of OVA (10 µg) with Al(OH)3 on days 1 and 14, followed by 3% OVA inhalation on days 21–23. SNM (50, 100, 200 mg/kg) and MTK (30 mg/kg) were administered orally for 2 weeks. To determine the differences in the number of inflammatory cells between the control and experimental groups in BALF, BALF was collected 24 h after the last OVA intranasal injection. (a) Total cell counts were determined using an automated cell counter. (B-G) The number of immune cells in BALF were determined using Diff-Quik staining and counted under a light microscope at 40× magnification: (b) Normal, (c) Control, (d) SNM 50, (e) SNM 100, (f) SNM 200, and (g) MTK 30. Values are presented as mean ± SEM (n = 10). Values in the row with different superscript letters are significantly different, p < 0.001. Scale bar: 20 µm.
Fig. 3.
Effect of the SNM complex on inflammatory cell recruitment in BALF of ovalbumin (OVA)-induced mice. Sixty BALB/c mice were divided into six groups (10 mice per group): normal control group (Normal), OVA-induced allergic asthma group (Control), OVA + SNM 50 mg/kg group (SNM 50), OVA + SNM 100 mg/kg group (SNM 100), OVA + SNM 200 mg/kg group (SNM 200), and OVA + MTK 30 mg/kg group (MTK 30). An OVA-induced allergic asthma model was established by intraperitoneal (IP) injection of OVA (10 µg) with Al(OH)3 on days 1 and 14, followed by 3% OVA inhalation on days 21–23. SNM (50, 100, 200 mg/kg) and MTK (30 mg/kg) were administered orally for 2 weeks. To determine the differences in the number of inflammatory cells between the control and experimental groups in BALF, BALF was collected 24 h after the last OVA intranasal injection. (a) Total cell counts were determined using an automated cell counter. (B-G) The number of immune cells in BALF were determined using Diff-Quik staining and counted under a light microscope at 40× magnification: (b) Normal, (c) Control, (d) SNM 50, (e) SNM 100, (f) SNM 200, and (g) MTK 30. Values are presented as mean ± SEM (n = 10). Values in the row with different superscript letters are significantly different, p < 0.001. Scale bar: 20 µm.
Table 1. Effects of SNM complex on BALF cell changes in an OVA-induced asthma model.
Group Eosinophil Neutrophil Lymphocyte

(×105/mL)

Macrophage
Normal N.D.a N.D.a 1.13 ± 0.23a 13.50 ± 1.07a
Control 10.63 ± 1.40c 1.65 ± 7.43e 10.50 ± 1.27b 30.63 ± 5.39b
SNM 50 10.00 ± 1.05c 0.99 ± 2.38b 13.25 ± 1.83bc 33.38 ± 1.96b
SNM 100 9.13 ± 1.34c 1.07 ± 3.93bc 11.75 ± 0.56b 48.25 ± 6.23c
SNM 200 10.25 ± 1.61c 1.28 ± 6.45d 16.13 ± 1.81c 45.38 ± 5.39c
MTK 30 5.75 ± 0.70b 1.19 ± 4.82cd 11.75 ± 1.46b 29.38 ± 1.81b
* N.D. : Not detected
* Values in rows with different superscript letters are significantly different, P < 0.001.

3.4 Effect of SNM complex on inflammatory cytokines and mediators in BALF

To evaluate the effects of the SNM complex on the inflammatory response in a mouse model of respiratory disease, IL-4, IL-5, and IL-13 concentrations in BALF were determined via ELISA. The data revealed that these cytokine levels were significantly higher in the control group than in the normal group (p < 0.001), indicating an inflammatory response triggered by OVA exposure. In the SNM-treated groups, the levels of these cytokines decreased significantly in a dose-dependent manner compared to those in the control group, with IL-4 levels in the high-dose SNM group comparable to those in the normal group (p < 0.001). The MTK group showed markedly decreased IL-4, IL-5, and IL-13 concentrations, approaching the levels observed in the normal group (p < 0.001) (Figs. 4a-c). BALF TNF-α levels were significantly elevated in the control group (157.32 ± 11.30 pg/mL) compared with the normal group (115.85 ± 6.94 pg/mL) (p < 0.001), whereas the SNM-treated groups did not show significant differences relative to the control group (Fig. 4d). The positive control group treated with MTK showed a TNF-α level (117.42 ± 11.20 pg/mL) comparable to that of the normal group (p < 0.001). IgE levels in the BALF were also assessed. The control group (7907.50 ± 289.17 pg/mL) had significantly elevated IgE levels compared to the normal group (6183.12 ± 357.46 pg/mL) (p < 0.001). Among the experimental groups, only the high-dose SNM group (200 mg/kg) and the MTK-treated group showed significantly reduced IgE levels relative to the control group (p < 0.001) (Fig. 4e). Finally, the effects of the SNM complex on LTB4, LTC4, and LTD4 levels in BALF were analyzed. The levels of these leukotrienes were significantly elevated in the control group compared with those in the normal group (p < 0.001). SNM treatment reduced LTB4, LTC4, and LTD4 levels in a dose-dependent manner, with LTB4 levels in the medium- and high-dose SNM groups comparable to those in the MTK group (p < 0.001) (Figs. 4f-h).

Effect of SNM complex on inflammatory cytokines and mediators in BALF of OVA-induced mice. For analysis of inflammatory cytokines and mediators in BALF, the separated BALF was analyzed for (a) interleukin (IL)-4, (b) IL-5, (c) IL-13, (d) tumor necrosis factor (TNF)-α, (e) immunoglobulin E (IgE), (f) LTB4, (g) LTC4, and (h) LTD4 levels using an ELISA kit. Bars labeled with different superscript letters indicate p < 0.001. Data are expressed as mean ± SEM (n = 10).
Fig. 4.
Effect of SNM complex on inflammatory cytokines and mediators in BALF of OVA-induced mice. For analysis of inflammatory cytokines and mediators in BALF, the separated BALF was analyzed for (a) interleukin (IL)-4, (b) IL-5, (c) IL-13, (d) tumor necrosis factor (TNF)-α, (e) immunoglobulin E (IgE), (f) LTB4, (g) LTC4, and (h) LTD4 levels using an ELISA kit. Bars labeled with different superscript letters indicate p < 0.001. Data are expressed as mean ± SEM (n = 10).

3.5 Activation of NF-κB proteins by SNM complex in lung tissues

In this study, the effect of the SNM complex on NF-κB activation, a key target in respiratory disease, was evaluated in lung tissue from the OVA-induced allergic asthma model. Phosphorylated NF-κB (p-NF-κB) expression was significantly increased in the OVA-induced allergic asthma group (Control) compared to the normal group (p < 0.001). In contrast, p-NF-κB expression in the SNM-treated groups was significantly reduced in a dose-dependent manner compared to the control group (p < 0.001) (Fig. 5a). Additionally, p-NF-κB protein levels in the MTK group (30 mg/kg) were lower than those in the normal group. After normalization to the control protein, relative protein expression levels were determined (Fig. 5b).

Changes in nuclear factor-kappa B (NF-κB) protein activation by the SNM complex in OVA-induced mouse lung tissue. After excising lung tissue from OVA-induced mice, proteins were isolated using a series of processes. (A) Protein expression levels were analyzed by western blotting using anti-NF-κB and p-NF-κB antibodies. (B) Band intensities were quantified using ImageJ software. Data are presented as mean ± SEM (n = 3). Bars labeled with different superscript letters indicate p < 0.001.
Fig. 5.
Changes in nuclear factor-kappa B (NF-κB) protein activation by the SNM complex in OVA-induced mouse lung tissue. After excising lung tissue from OVA-induced mice, proteins were isolated using a series of processes. (A) Protein expression levels were analyzed by western blotting using anti-NF-κB and p-NF-κB antibodies. (B) Band intensities were quantified using ImageJ software. Data are presented as mean ± SEM (n = 3). Bars labeled with different superscript letters indicate p < 0.001.

3.6 Effect of SNM complex on histopathological changes of lung tissues

In this study, H&E staining was performed to evaluate the effects of SNM complex on lung tissues in an OVA-induced allergic asthma model. The normal group (Normal) exhibited a well-preserved lung architecture, characterized by thin airway walls, regular alveolar lumens, and the absence of inflammatory cell infiltration. In contrast, the control group (Control) displayed significant pathological changes, including airway narrowing, thickening of the airway walls, irregular alveolar size, and marked infiltration of inflammatory cells. In the experimental groups treated with SNM, a dose-dependent reduction in airway narrowing and airway wall thickness was observed compared with that in the control group. Notably, in the high-dose SNM group (200 mg/kg), mild local airway wall thickening was observed; however, the airway lumen was significantly enlarged and cellular damage was markedly reduced, demonstrating recovery comparable to that of the MTK group (30 mg/kg) (Fig. 6).

Effect of SNM complex on histopathological changes of OVA-induced mouse lung tissue. Histological changes were assessed using hematoxylin & eosin (H&E) staining: Normal, Control, SNM 50 (SNM 50 mg/kg), SNM 100 (SNM 100 mg/kg), SNM 200 (SNM 200 mg/kg), and MTK (MTK 30 mg/kg). Histological analysis result image magnification (scale bar) = 2X (500 µm), 5X (200 µm), and 10X (100 μm), respectively.
Fig. 6.
Effect of SNM complex on histopathological changes of OVA-induced mouse lung tissue. Histological changes were assessed using hematoxylin & eosin (H&E) staining: Normal, Control, SNM 50 (SNM 50 mg/kg), SNM 100 (SNM 100 mg/kg), SNM 200 (SNM 200 mg/kg), and MTK (MTK 30 mg/kg). Histological analysis result image magnification (scale bar) = 2X (500 µm), 5X (200 µm), and 10X (100 μm), respectively.

4. Discussion

This study revealed that the SNM complex, a combination of extracts from SB, NS, and MC, has therapeutic potential for managing allergic asthma. Our findings indicated that the SNM complex significantly alleviated airway inflammation by reducing Th2 cytokines (IL-4, IL-5, and IL-13), and decreasing leukotriene (LTB4, LTC4, and LTD4) and IgE levels in an OVA-induced allergic asthma model. In addition, the SNM complex reduced the phosphorylation of NF-κB and ameliorated the structural remodeling of the airways. These findings suggested that the SNM complex acts on multiple pathophysiological pathways in asthma, providing a comprehensive therapeutic strategy against this disease.

Th2-mediated immune responses play a central role in allergic asthma, leading to elevated cytokines, including IL-4, IL-5, IL-13, and IL-17, which promote eosinophilic and neutrophilic inflammation, mucus overproduction, and airway remodeling. IL-4 is a key regulator of IgE production, which triggers mast cells activation and release inflammatory mediators, including histamine and leukotrienes, following allergen exposure (Lee et al., 2019; Pelaia et al., 2022). Our results demonstrated that SNM treatment significantly reduced IL-4, IL-5, and IL-13 concentrations in a manner proportional to the administered dose, with the highest dose group showing IL-4 levels similar to those in the normal group. This result aligns with studies on baicalin, baicalein, β-sitosterol, moracin M, and quercetin, components of SB, NS, and MC, respectively, which have been shown to suppress Th2 cytokine expression (Xu et al., 2023; Lee et al., 2016; Tanaka and Takahashi, 2013; Zeng et al., 2025; Bae et al., 2016; Mahajan and Mehta, 2011; Jafarinia et al., 2020). In addition, we confirmed that IgE expression was reduced in the high-dose SNM treatment group. The components of the SB, NS, and MC extracts enhance their ability to reduce IgE levels in BALF, thereby improving their capacity to modulate the allergic sensitization pathway, a key step in the pathogenesis of asthma (Mukherjee et al., 2009; Lee et al., 2016; Tanaka and Takahashi, 2013; Zeng et al., 2025; Bae et al., 2016; Mahajan and Mehta, 2011; Jafarinia et al., 2020; Bui et al., 2017)​. Interestingly, while the SNM complex effectively reduced IL-4, IL-5, and IL-13 levels, its impact on TNF-α was limited, suggesting a more selective effect on Th2-mediated inflammation rather than general pro-inflammatory cytokine pathways (Bui et al., 2017). This specificity could be advantageous because it minimizes potential systemic side effects while targeting the key mechanisms of allergic inflammation​.

Leukotrienes, including LTB4, LTC4, and LTD4, are key mediators of asthma and promote bronchoconstriction, mucus hypersecretion, and inflammatory cell recruitment. Allergen exposure triggers the release of leukotrienes and histamines from mast cells, leading to acute and chronic airway inflammation (Jafarinia et al., 2020; Fanta, 2009; Brady et al., 2024). Our results revealed that the SNM complex significantly reduced the LTB4, LTC4, or LTD4 levels in a dose-dependent manner. In particular, in the high-dose SNM group, LTB4 levels were significantly suppressed to levels similar to those induced by the leukotriene receptor antagonist MTK. Additionally, the SNM complex reduced the number of inflammatory cells and, in particular, the number of neutrophils. LTB4 is a potent neutrophil-activating factor that induces the chemotaxis of neutrophils and promotes their migration and activation to sites of inflammation (Afonso et al., 2012). Although the SNM complex significantly reduced neutrophil counts and suppressed Th2-associated cytokines (IL-4, IL-5, IL-13), it did not lead to a significant reduction in eosinophil counts in BALF. This finding suggests that SNM primarily attenuates the neutrophilic component of airway inflammation while only partially modulating the eosinophilic response. The discrepancy between reduced IL-5 levels and persistent eosinophilia implies that SNM may be more effective in suppressing upstream cytokine production than in influencing the survival of already infiltrated eosinophils. Moreover, these results indicate that Th2-independent chemotactic pathways, such as those mediated by eotaxins (CCL11, CCL24, CCL26), might not be sufficiently suppressed by SNM, thereby allowing eosinophils to persist in the airway. Collectlly, these results suggest that the SNM complex may play a role in suppressing neutrophilic inflammation, which is increasingly being recognized in severe asthma, by inhibiting LTB4, LTC4, or LTD4. In this study, the SNM complex inhibited leukotrienes and significantly reduced PDE4, an upstream regulator of leukotrienes, in LPS-treated H292 cells. These findings suggest that the SNM complex plays a role in modulating the inflammatory response in severe asthma and suppressing neutrophilic inflammation, which has gained increasing recognition as a critical feature of asthma pathogenesis (Jafarinia et al., 2020; Park et al., 2016). ​

NF-κB is a critical regulator of inflammatory responses in asthma and other respiratory diseases, activated by airway epithelial cell damage induced by allergens or oxidative stress. TNF-α and IL-1β serve as primary activators, leading to the expression of various inflammatory mediators, inflammatory cell infiltration, and the release of proteolytic enzymes and reactive oxygen species. These processes contribute to lung damage and highlight the clinical relevance of NF-κB in allergic and chronic inflammatory conditions (Greenfeder et al., 2001). Western blot analysis confirmed that SNM treatment significantly reduced NF-κB phosphorylation in lung tissues from OVA-induced asthmatic mice, with the effects most pronounced in the high-dose SNM group. Our findings align with prior reports indicating that baicalin, wogonin, moracin M, and quercetin, which are well known to inhibit NF-κB activation, suppress inflammation and airway inflammation through NF-κB signaling (Xu et al., 2019; Lee et al., 2016; Jafarinia et al., 2020; Bui et al., 2017; Zeng et al., 2020). Interestingly, inhibition of NF-κB activity by the SNM complex is correlated with reduced airway inflammation and structural remodeling, suggesting that this pathway may be a key target for the anti-asthmatic effects of SNM (Liu et al., 2016; Xu et al., 2019; Lee et al., 2016; Bui et al., 2017; Feng et al., 2019). These results indicate that NF-κB may serve as a promising therapeutic target for the management of airway inflammation and remodeling.

In this study, histological analysis showed that SNM complex treatment significantly improved lung pathological features in OVA-induced asthmatic mouse models. In the high-dose SNM group, reductions in airway wall thickening and inflammatory cell infiltration were observed, comparable to those observed in the MTK-treated group. These findings suggest that the SNM complex effectively prevents structural remodeling, which is a hallmark of allergic asthma. Additionally, the enlargement of airway lumens and decreased mucus secretion in the SNM complex-treated groups indicated improved airway patency and a reduced risk of airway obstruction. The histological improvements observed with SNM complex treatment were consistent with those of previous studies, which attributed these effects to reductions in Th2 cytokines and leukotrienes (Xu et al., 2019; Mahajan and Mehta, 2011; Jafarinia et al., 2020).

The findings of this study confirmed the potential efficacy of the SNM complex as a natural extract combination therapy for allergic asthma. By modulating Th2 cytokine production, leukotriene synthesis, and NF-κB activation, the SNM complex addresses both the inflammatory and structural components of asthma.

However, this study has some limitations, including its reliance on a single OVA-induced asthma model, which primarily reflects Th2-driven mechanisms and may not fully capture the complexity of asthma, such as neutrophilic or mixed-type phenotypes. Additionally, IgE levels were assessed only in BALF. While BALF IgE provides important information on local airway inflammation, serum total IgE and OVA-specific IgE are critical markers of systemic immune responses in OVA-induced asthma models. The lack of serum IgE data limits the translational relevance of our findings, and future studies should include serum measurements. Furthermore, the pharmacokinetics and metabolism of the SNM complex components remain unclear and require further study to elucidate their in vivo actions. Future studies should explore the effects of the active ingredients of the SNM complex and their associated signaling pathways. Ultimately, human clinical studies are necessary to evaluate the safety, bioavailability, and therapeutic efficacy of SNM complexes in patients with asthma.

5. Conclusions

The SNM complex exhibited potent anti-inflammatory, anti-leukotriene, and airway-protective effects in in vitro and in vivo models of allergic asthma. The SNM complex significantly decreased the levels of Th2 cytokines (IL-4, IL-5, and IL-13), leukotrienes (LTB4, LTC4, and LTD4), and IgE. The SNM complex significantly reduced neutrophil counts but did not reduce eosinophil numbers in the BALF. In addition, the SNM complex reduced the phosphorylation of NF-κB. Histologically, the SNM complex improved airway inflammation and lung tissue damage. In conclusion, our findings demonstrate that the SNM complex exhibits a selective anti-inflammatory effect by significantly decreasing the neutrophilic component of airway inflammation, which is consistent with its inhibitory effect on LTB4. This targeted action, combined with a partial modulation of the Th2-driven eosinophilic response, suggests that the SNM complex holds potential as a therapeutic strategy for the treatment of allergic asthma by alleviating airway inflammation and structural remodeling.

Acknowledgment

This work was supported by the Food Functionality Evaluation Program [GE240200-01] under the Ministry of Agriculture, Food, and Rural Affairs and The Research Program [E0220602-04] of the Korea Food Research Institute under the Ministry of Science and ICT.

CRediT authorship contribution statement

Young Mi Park: Conceptualization, investigation, methodology, writing – original draft. Hak Yong Lee: Conceptualization, data curation, methodology, resources. Jin Joo Yoo: Data curation, methodology. Dae Sung Kim: Investigation, methodology. Min Jung Kim: Data curation, validation. Hye Jeong Yang: Data curation, validation. Jun Sang Bae: Conceptualization, supervision, resources, writing – original draft, writing – review & editing.

Declaration of competing interest

The authors declare that they have no competing financial interests or personal relationships that could have influenced the work presented in this paper.

Data availability

The data are available from the corresponding author upon reasonable request.

Declaration of Generative AI and AI-assisted technologies in the writing process

The authors confirm that there was no use of Artificial Intelligence (AI)-Assisted Technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Supplementary data

Supplementary material to this article can be found online at https://dx.doi.org/10.25259/JKSUS_1301_2025.

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