The Natural Products Targeting on Allergic Rhinitis: From Traditional Medicine to Modern Drug Discovery

More than 500 million people suffer from allergic rhinitis (AR) in the world. Current treatments include oral antihistamines and intranasal corticosteroids; however, they often cause side effects and are unsuitable for long-term exposure. Natural products could work as a feasible alternative, and this study aimed to review the efficacies and mechanisms of natural substances in AR therapies by examining previous literature. Fifty-seven studies were collected and classified into plants, fungi, and minerals decoction; clinical trials were organized separately. The majority of the natural products showed their efficacies by two mechanisms: anti-inflammation regulating diverse mediators and anti-oxidation controlling the activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway stimulated by reactive oxygen species (ROS). The main AR factors modified by natural products included interleukin (IL)-4, IL-5, IL-13, interferon-gamma (IFN-γ), tumor necrosis factor-α (TNF-α), cyclooxygenase 2 (COX-2), and phospho-ERK1/2 (p-ERK1/2). Although further studies are required to verify their efficacies and safeties, natural products can significantly contribute to the treatment of AR.


Introduction
Allergic rhinitis (AR), also known as hay fever, is inflammation inside the nose stimulated by specific allergens, usually pollen or dust [1]. Due to its high prevalence and the negative impact on patients' quality of life, AR is regarded as a major chronic disease. More than 500 million people suffer from AR, and up to 40% of the global population is affected [2]. It is an immunoglobulin E (IgE)-mediated disorder in the nose and triggered by the interaction between specific mast cell IgE antibodies and allergens present in the air. The interaction causes the mast cells to release chemicals that act as inflammatory agents, thus resulting in inflamed marginal tissues [3]. Consequently, it is considered part of a systemic inflammatory process. The symptoms include rhinorrhea, nasal itching, sneezing, and nasal congestion, and are also associated with upper and lower airway membrane disorders: asthma, rhinosinusitis, conjunctivitis, and polyposis [4].
Histamine released from mast cells is the dominant factor of allergic reactions, and the secretion of interleukin (IL)-4 and IL-5 follows, generating T helper cell 2 (Th2) cytokine response. It is, therefore, crucial to control histamine pathways in treating AR. Current therapeutic interventions commonly used are oral antihistamines and intranasal corticosteroids [5]. Antihistamines block the binding of histamine to the H1 receptor, preventing the release of histamines [6]. Although second-generation antihistamines have fewer side effects, they are still sedating and may provoke psychomotor retardation and reduced academic performance [7,8]. Intranasal corticosteroids control inflammation by regulating mediator release [9]. However, long-term exposure may increase the risk of osteoporosis, fractures, cataracts, hyperglycemia, infection risk, slower wound healing, and headache [10]. Natural products could be plausible options for curing AR, as treatments that cover these adversaries and effectively maintain therapeutic efficacy are in need.
Plant extracts have been used as conventional treatment for thousands of years in many countries, including Korea, Japan, China, etc. [11,12]. Unlike synthetic drugs, they down-regulate harmful side effects and mitigate the damages of various therapy, such as onco-chemotherapy or radiotherapy [13,14]. Furthermore, they are capable of multitargeting the immune system since they consist of diverse molecules in nature. Many of the previous works of literature have demonstrated the individual efficacy of each product in treating allergic symptoms, but an overall review of these plant extracts is absent. This paper concentrated on plant extracts that have been tested as a remedy for allergic rhinitis and examined their mechanisms, aiming to invigorate the use of natural substances in AR therapies.

T Helper Cell Differentiation
There are several mechanisms of AR; Th cell differentiation can primarily lead to AR symptoms ( Figure 1). Allergens trigger IgE to bind to the high-affinity receptor on the surface of mast cells, and diverse mediators such as histamine, leukotrienes, and cytokines are subsequently released [15][16][17][18][19]. These agents create inflammation mostly in the nasal mucosa, causing mucus secretion, sneezing and sometimes reduce the size of airways by inducing vasodilation of blood vessels. Several mechanisms produce immune responses, thus leading to allergic reactions. IL-4 and IL-12 from the antigen-presenting cell (APC) initiate the manipulation of Th cells. Th cells differentiate from Th0 cells, a common precursor, into Th1, Th2, Th17, or regulatory T (Treg) cells. For Th1 cells to differentiate from Th0 cells, IL-12 activates T-box-expressed-in-T-cells (T-bet) through STAT4 [20]. Th1 cells immunize against pathogens invading into other cells by secreting mainly IL-2, IFN-γ, and TNF-α. Cytokines secreted by Th1, IL-2, IFN-γ, and transforming growth factor (TGF)-β, elicit immunoglobulin G2a (IgG2a) that reduces symptoms. IFN-γ is also responsible for cell-mediated immunity by instigating a macrophagic reaction, hence generating delayed-type hypersensitivity (DTH). IL-4 stimulates the activation of GATA binding protein 3 (GATA3) and signal transducer and activator of transcription 6 (STAT6), the factors related to Th2 cells differentiation, while suppressing T-bet and STAT4. Th2 cells produce IL-4, IL-10, and IL-13 for IgE and IgG1 promotion and IL-5 for eosinophil growth and differentiation. IgE production by B cells is followed by the release of the mediator, histamine, leukotrienes, prostaglandins, and cytokines, by mast cells. The products elicit acute symptoms, whereas the eosinophil is responsible for chronic symptoms. IgG1 from B cells is involved in defense against huge, extracellular pathogens. Substance P (SP) binding to the neurokinin-1 receptor (NK-1R) leads to vasodilation and the release of histamine from mast cells [21][22][23]. TGF-β and IL-6 together regulate STAT3 and retinoid-related orphan receptors (RoRyt). RoRyt secretes IL-23, which initiates the alteration of Th0 into Th17 cells. Th17 cells are accountable for cell-mediated inflammation and autoimmune diseases induced while protecting the host against extracellular pathogens and fungi. Lastly, Th0 cells are transited to Treg cells by activation of Forkhead box p3 (Foxp3). Treg cells secrete IL-10 and TGF-β, acting on B cells to produce IgG4 and IgA, respectively. IgG4 reduces symptoms, while IgA defends against infection by microorganisms.

Plant-Originated Natural Products
Plant-originated natural products are substances derived from herbs, flowers, trees, etc. They are naturally extracted rather than artificially synthesized. The efficacy of plants containing medical substances is principally descendent from the past, and sometimes they are newly discovered.

In Vitro Studies
There were eighteen in vitro studies of plant-originated natural products ( Table 1). The bark of Albizia lebbeck is an ingredient of Ayurvedic Kadha, which has been used for treating asthma for more than two thousand years [55]. Propidium Monoazide-treated HeLa cells were administered with 0.1, 1, and 10 µg/mL of Albizia lebbeck bark ethanol extract for 24 h. Additionally, histamine-treated HeLa cells were administered with 10 µg/mL of the same extract for 24 h. Both treatments were related to the degradation of IL-4, IL-5, IL-13, H1R, and HDC.
Brazilian green propolis (BGPP), mainly isolated from Baccharis dracunculifolia and produced in Southeast Brazil, has been extensively consumed as a dietary supplement. HeLa cells were administered with 25, 75, 100, 125, and 200 µg/mL of BGPP ethanol extract for 3 h [56]. Additionally, RBL-2H3 cells were treated with 25, 75, and 100 µg/mL of BGPP ethanol extract for 3 h. The first experiment degraded levels of H1R mRNA, p-PKCδ, and IL-9, and the second decreased levels of IL-9.
A combination of preparations from Citrus and Cydonia have been commonly used as injections or sprays to treat allergic patients during the past hundred years [59]. Citrus limon Burm. f. was stimulated on PBMCs at the amount of 0.01 g/mL for 7 days [60]. PBMCs were obtained from the blood of five grass pollen-allergic donors aged 18-40 and five healthy eligible participants who had no sign of allergic rhinitis. Citrus reduced Th2 pathway activation by ameliorating the level of IFN-γ and down-regulating TNF-α, IL-5 cytokines. By using the same method, Cydonia oblonga Mill. was stimulated. Cydonia was mainly concerned with increasing the innate related Th1 pathway activity by the induction of the IFN-γ cytokine.
Magnoliae Flos is an oriental herb commonly used in traditional Chinese and Korean medicine formulations [62]. It has been commonly used as a symptomatic relief to allergic rhinitis, sinusitis, and headache. Kim et al. administered 0.1, 0.3, and 1 mg/mL of FM ethanol extract (FM EtOH) to hANO1-transfected HEK293T cells for 600 s. Additionally, HEK293T and Calu-3 cells were treated with 30, 100, and 300 µg/mL of FM EtOH for 600 s. Gencydo ® , a combination of lemon (Citrus limon) juice and aqueous quince (Cydonia oblonga) extract has been used traditionally in anthroposophical medicine for treating patients with allergic rhinitis or asthma [63]. DNP-HSA-treated RBL-2H3 were treated with 0.2, 0.4, and 0.8 mg/mL of Genydo ® for 10 min, thus inhibiting the release of histamine and degranulation. Meanwhile, TNF-α/IL-4-exposed human bronchial epithelial cells, PMA/A23187-activated HMC, and granulocyte-macrophage colony-stimulating factor (GM-CSF)-treated human eosinophil granulocytes were treated with 0.2, 0.4, and 0.8 mg/mL of Gencydo ® for 24 h. Gencydo ® inhibited the release of eotaxin and restrained early and late-phase allergic reactions when injected into human bronchial epithelial cells and HMC, respectively. However, Gencydo ® had no impact on the state of GM-CSF-treated human eosinophils.
Lindera obtusiloba, a traditional Korean medicine, has been used in the treatment of inflammation and improvement of blood circulation [64]. Herbal infusions of Lindera obtusiloba have been used to treat chronic liver disease. PMACI-treated HMC-1, dinitrophenylhuman serum albumin (DNP-HSA)-treated RBL-2H3, and DNP-HSA-treated RPMCs were administered with 0.1, 1, 10, and 100 µg/mL of Lindera obtusiloba water extract for 30 min. Lindera obtusiloba water extract reduced histamine release and inhibited systemic and local allergic reactions.
Perilla frutescens is a dietary leaf herb that has been used for Chinese medicine, known for its anti-inflammatory activity [67]. Kamei et al. reported that Perilla-derived methoxyflavanone prevented passive cutaneous anaphylaxis and allergic rhinitis-like nasal symptoms. Perilla-derived methoxyflavanone was treated to anti-DNP IgE-sensitized RBL-2H3 cells. Representative indicators such as p-Akt and intracellular Ca 2+ influx were negatively regulated.
Effects and mechanism of 30% ethanol extract powder of Perilla frutescens var. acuta Kudo was observed [68]. It was treated to mouse mast cells and mouse eosinophils at a dose of 1 g/kg for 10 days. Additionally, PMACI-exposed HMC-1 was treated with 0.01, 0.1, and 1 mg/mL of EPPF for 1 h. The decoction initiated the degradation of IL-1β, IL-6, TNF-α, COX-2, and NF-κB.
Rosmarinic acid was treated to mouse mast cells and mouse eosinophils at a dose of 4 g/kg for 10 days, and 100 µM was treated to PMACI-exposed HMC-1 for 1 h [68]. The effects of rosmarinic acid were related to the degradation of IL-1β, IL-6, TNF-α IL-6, and NF-κB.
Spinacia oleracea Linn. extract was orally administered to Hydrogen peroxide-applied SH-SY5Y neuroblastoma cells at a dose of 25 µL/mL for 24 h [69]. Viable cell number recovery related to reduced levels of IL-4, IL-13, and Ig-E was observed.
Treatment of Ze339 at a dose of 3 µg/mg in human nasal epithelial cells from inferior turbinate of patients for 24 h inhibited the recruitment of inflammatory cells, proinflammatory cytokine, and chemokine response of viral mimics [70]. Ze339 increased the expression of granulocyte-colony stimulating factor (G-CSF) and decreased the expression of IL-8, chemokine (C-C motif) ligand 3 (CCL-3), IL-6, signal transducer, an activator of transcription 1 (STAT1), STAT3, and STAT6.

In Vivo Studies
There were 25 in vivo studies of plant-originated natural products (Table 2). Nurul et al. orally administered 200 mg of powdered Albizia lebbeck bark ethanol extract to toluene-2, 4-diisocyanate (TDI)-sensitized allergy rats once a day for 3 weeks [55]. IL-4, IL-5, and IL-13 were decreased. Albizia lebbeck reduced the amount of sneezing and nasal rubbing, thus alleviating nasal symptoms.
Artemisia vulgaris water extract was orally administered in a mugwort pollen-sensitized AR BALB/c mouse model for 15 days [71]. Except for the control group, each group was treated with 10, 50, and 100 µg/mL of the extract, respectively. Artemisia vulgaris water extract significantly declined the level of IgE. It also controlled the imbalance between T helper cell 1 (Th1) and T helper cell 2 (Th2) cytokines by increasing IL-12 and decreasing IL-4 and IL-5. The extract attenuated the symptoms of allergic rhinitis in a dose-dependent manner.
Awa-tea inhibited allergic diseases as well as stimulating anti-obesity and anti-oxidant activity [72]. TDI-sensitized rats were treated with 40 mg/kg of Awa-tea leaf hot-water extract once a day for 3 weeks. Decreased levels of IL-9 and IL-4 were observed.
Berberine, originated from Berberis, has been widely used in China as a gastrointestinal remedy and is known for its antibacterial, antifungal, and anti-inflammatory properties [73][74][75][76]. Dermatophagoides farinae (Derf)-induced AR BALB/c mice were orally administered 10 µg/mL of berberine for 5 days [77]. Serum IgE, GATA3 mRNA levels, and tissue eosinophil counts decreased, while Foxp3 increased compared with the control group. Berberine showed anti-inflammatory activity regarding allergic rhinitis through regulating the mechanism and function of diverse cells.
Cinnamomum zeylanicum bark hydroalcoholic extract has a long history of having been used as a traditional medicine to cure autoimmune diseases and cold in diverse regions such as India, China, Egypt, and Europe [80][81][82]. Aswar et al. induced AR in BALB/c mice by intranasal challenging OVA and injected 3, 10, and 30 µg/kg of Cinnamomum zeylanicum bark hydroalcoholic extract for 8 days [83]. The primary result was mast cell stabilization and subsequent prevention of IgE and histamine, which indicates that the extract effectively ameliorates nasal inflammation.
Dryopteris crassirhizoma (DC) is commonly used in Korea, Japan, and China to treat the common cold, tapeworm infection, and bacterial and inflammatory diseases [84]. OVA-induced AR BALB/c mice were treated with 100, 200, and 400 mg/kg of Dryopteris crassirhizoma ethanol extracts by oral gavage for 11 days [85]. DC increased the level of Treg cytokines in nasal fluid but decreased the activity of IgE, Immunoglobulin G1 (IgG1), and Immunoglobulin G2 (IgG2) cytokines in the blood. DC significantly prevented the occurrence of nasal allergic symptoms and the internal work of histamine.
Various kinds of literature have already found that soybean suppressed the development of chronic diseases, as it contains cancer risk-reducing properties [87,88]. Glycine max water extract, obtained from dried green soybean powder, was administered in the TDI-induced guinea pig rhinitis model at the concentrations of 30, 150, and 300 µg/kg for 28 days [89]. Green soybean extracts decreased levels of IgE serum, IL-4, B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL) production. It effectively acted as an immune modulator of allergic rhinitis, preventing nasal mucosa secretions and allergic symptoms.
Lindera obtusiloba water extract was intraperitoneally administered to compound 48/80-induced systemic allergy mice at doses of 1, 10, and 100 mg/kg one hour before the challenge [64]. The anti-allergic effects of the extract were related to reduced TNF-α, IL-6, IκBα, and NF-κB.
Ortho-vanillic acid was orally administered to OVA-induced active systemic anaphylaxis (ASA) mice at doses of 2, 10, and 50 mg/kg for 14 days [65]. Furthermore, IgEmediated passive cutaneous anaphylaxis (PCA) mice were orally treated with 50 mg/kg of saline-dissolved ortho-vanillic acid for 1 h. Kim et al. concluded that ortho-vanillic acid attenuated the OVA-induced active systemic anaphylaxis and lessened IgE-mediated cutaneous allergic reactions.
Efficacy of Osterici Radix (OR) root methanol extract was demonstrated by orally administering OVA-induced allergic rhinitis BALB/c mice with doses of 50 or 100 mg/kg from day 28 to day 34 [66]. OR extract attenuated disease progression, which is determined by nasal symptoms and histological changes of the nasal mucosa. Degradation of OVAspecific IgE and Il-4 and the elevation of IFN-γ were related to the effects.
Piper nigrum L. ethanol extract (PNE), originated from Piperine, is widely used for treating bacteria-induced illnesses, tumors, diabetes, and inflammation [90][91][92]. OVAinduced AR BALB/c mice were orally administered with 50, 100, and 200 mg/kg PNE or 2.5 mg/kg Dexamethasone (Dex) for 13 days, respectively [93]. Piper nigrum L. ethanol extract positively inhibited nasal symptoms by suppressing the accumulation of inflammatory cells. The activation of inflammation-related cytokines signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells protein 65 (NFκBp65) were inhibited, and the action of anti-inflammatory cytokine Th1 was elevated. PNE showed significant differences compared with the naïve group and had a similar effect when compared with the Dex group.
Another study was conducted to determine the effect of Piper nigrum L. in treating allergic rhinitis. OVA-induced AR Swiss albino mice were treated with either 10, 20, or 40 mg/kg of Piper nigrum L. extract or 10 mg/kg of montelukast for 7 days [94]. The extract reduced the expression of IL-6, IL-1β, and IgE in contrast with the control group.
Propolis is a transformed form of plant resin produced by honey bees and has been used to treat burns and wounds, gastric ulcers, and prostate hyperplasia [95,96]. It is widely known for its diverse anti-microbial, anti-viral, and anti-inflammatory functions [97][98][99][100]. Yasar et al. orally applied 200 mg/kg of propolis to a group of Sprague Dawley (SD) rats, while the other groups were given mometasone furoate, ketotifen, and saline (sham treatment) [101]. Propolis, mometasone furoate, and ketotifen similarly down-regulated ciliary loss, inflammation, number of goblet cells, vascular proliferation, eosinophil count, and allergic symptoms scores. In the long-term, the observation results of symptom scores implied that propolis had a more powerful efficacy of inhibiting allergic reactions than sham medicines.
Spinacia oleracea Linn. aqueous extract, which is well-known for its vitamin content, improved the asthmatic symptoms induced by the OVA challenge and reduced the BAL's eosinophil expression [69]. OVA-challenge asthmatic mice were orally treated with Spinacia oleracea Linn. extract at a dose of 25 µL/mL for 24 h.
Syzygium formosum (Wall.) Masam. leaves have been routinely used among indigenous Vietnamese people to treat various allergic symptoms, including dermatitis and rhinitis [104]. They also improved food allergy symptoms and inflammatory lesions in the gut. Syzygium formosum leaves extract was orally administered to chicken ovalbumin (cOVA)-induced food allergy mice at doses of 80 and 200 mg/kg for 13 days. T helper 2 cell cytokines (Th2 cytokines) (e.g., IL-4, IL-5, IL-10), and multiple c2 domains and transmembrane region proteins-1 (MCTP-1) were significantly decreased.
Wild grape (Ampelopsis glandulosa) has been reported to have anti-inflammatory, antihepatotoxic, and anti-osteoclastogenesis activity [72]. Islam et al. demonstrated that wild grape hot-water extract alleviated nasal symptoms and eosinophilic inflammation. The extract was orally treated to TDI-sensitized rats at doses of 25 and 50 mg/kg once a day, for 3 weeks. It inhibited the expression of p-PKCδ, H 1 R, IL-9, IL-4, IL-5, and IL-33.

Fungi and Minerals-Originated Natural Products
Although plant-derived natural products are the most abundant materials for AR treatments, several studies cover compounds derived from fungi and minerals.

Decoctions of Natural Products
A decoction is an extract obtained by boiling one or more herbal materials for medical purposes. Various studies reported that decoctions have anti-AR effects in several experimental models.

In Vivo Studies
There were seventeen in vivo studies of decoctions (Table 6). Biyeom-Tang has been used to treat allergic rhinitis (AR) traditionally [115]. The ethanol extract of Biyeom-Tang inhibited allergic and inflammatory responses. The decoction suppressed β-hexosaminidase (β-Hex) when treated to BMMC from BALB/c mice at doses of 12.5, 25, or 50 µg/mL for an hour. Ethanol extract of Biyeom-Tang also suppressed the production of prostaglandin D 2 (PGD 2 ) and LTC 4 on BMMC in BALB/c mice when the mice were treated with 6.3, 12.5, or 25 µg/mL of the extract for one hour. Additionally, the extract was orally administered with doses of 50, 100, or 200 mg/kg to OVA-induced AR BALB/c mice for 7 days. It was found that levels of IL-4, IL-5, IL-10, and IL-13 decreased.
Hyeonggaeyeongyo-Tang is a traditional treatment for otolaryngology symptoms [118]. The decoction suppressed the progression of AR by decreasing IL-4, IL-13, and leukemia inhibitory factor (LIF). OVA-induced AR BALB/c mice were orally administered Hyeonggaeyeongyo-Tang at doses of 101, 202, or 404 mg/kg for 14 days.
In another study, 500 mg/kg of KOB03 was orally injected into OVA-induced AR BALB/c mice for 8 consecutive days [123]. KOB03 controlled the levels of IgE, LTC 4 , IL-4, and IL-1β, thus significantly increasing Th1 cytokine and down-regulating Th2 cytokine. KOB03 showed its efficacy in inhibiting nasal inflammation by controlling diverse allergic mediators and Th1/Th2 balance.
Senn-kinn-naidaku-sann alleviated the symptoms of AR in OVA-induced AR C3H/HeN mice by increasing IFN-γ and decreasing IgE, immunoglobulin G1 (IgG1), IL-4, and IL-5 [113]. The mice were orally administered with 100 and 1000 mg/kg of the decoction for 7 days. The same dose had no enhancement of AR in OVA-induced AR C3H/HeJ mice.
Tong Qiao is new Chinese medicine developed by Chengdu Huashen Zhiyao, Ltd. Co., [129]. OVA-induced AR SD rats were given intranasal drops of Tong Qiao, 10 µL/kg per nostril per treatment, three times a day, for 7 or 15 days. Tong Qiao alleviated the symptoms of AR by suppressing eotaxin, IL-5, and IL-13.
Xingbi gel is a traditional application prescribed for the cure of allergic rhinitis [130]. OVA-induced AR guinea pig models were sensitized with 50 µL/kg of Xingbi gel for 12 days. Xingbi gel regulated the secretion of Leukotriene E4 (LTE 4 ) and IgE, which led to the decreased production of inflammatory mediators and cytokines.
Yiqi Wenyang Fang is known to treat AR patients with a cold deficiency in the lung and spleen [131]. Yiqi Wenyang Fang inhibited inflammatory response and alleviated the symptoms of AR in OVA-induced AR SD rats by decreasing IL-10, transforming growth factor-beta 1 (TGF-β1), IL-4, and IL-13. The rats were given 1.6 g/mL of Yiqi Wenyang Fang per day, by gavage, for 28 days.

Clinical Trials
Several clinical trials with natural products from plants and animals were conducted (Table 7). Depigoid 50% Grasses/50% Olea europaea or Depigoid 50% Grasses/50% Parietaria judaica were administered to patients with allergic rhinitis or rhinoconjunctivitis with or without seasonal asthma [132]. This trial was a phase II, prospective, open uncontrolled, and non-randomized study. The study evaluated the safety and tolerance of a rush build-up of administration of Depigoid forte pollen with the first maintenance dose administered 4 weeks later. OVA-induced AR SD rats    MK-3641 12 Amb a 1-U (short ragweed extract) and MK-7243 2800 BAU (timothy grass extract) were co-administered to patients [133]. Patients at least 18 years of age with ragweed and grass pollen-induced allergic rhinitis with or without conjunctivitis were recruited. After administration, the percentages of participants who experienced at least one event of local swelling were measured. During periods I, II, and III, they were 13.7%, 21.6%, and 14.7%, respectively. These results indicated that MK-3641 12 Amb a 1-U and MK-7243 2800 BAU are safe substances to treat AR.
The efficacy and safety of short ragweed pollen allergen extract sublingual immunotherapy tablets were assessed in children with ragweed-induced rhinoconjunctivitis with or without asthma [134]. The primary outcome was measured as the total combined score (TCS) during the peak ragweed season (RS). TCS is a daily symptom score (DSS) plus daily medication score (DMS), while RS means 15 consecutive days with the highest average pollen count. TCS could range from 0 to 38, and a lower score indicates fewer RC symptoms and medication use. TCS of short ragweed pollen allergen extract was 4.39 while the placebo was 7.12, thus implying short ragweed pollen allergen extract can be an effective treatment option for patients with rhinitis.
The optimal effective dose of SUBLIVAC FIX Birch was determined based on a decrease of upper airways reactivity after 5 months of treatment with different dosages of SUBLIVAC FIX Birch compared with placebo [135]. SUBLIVAC FIX Birch was administered in patients with allergic rhinitis/rhinoconjunctivitis caused by birch pollen. In all treatment groups, post-treatment symptom scores compared with baseline were improved. After active treatment, peak nasal inspiratory flow and serum IgG levels increased compared with placebo. All active dosages produced more adverse reactions than placebo, but those reactions were mainly mild and well-controlled.
Patients with allergic rhinitis/rhinoconjunctivitis caused by grass pollen were treated with SUBLIVAC FIX Phleum pratense [136]. This was a phase II, randomized, doubleblind, and placebo-controlled study. The optimal effective dose of SUBLIVAC FIX Phleum pratense was determined with the same method as for SUBLIVAC FIX Birch. The dosages of five different pratense were 0, 3333, 10,000, 20,000, and 40,000 AUN/mL respectively.
After 10 months, a study about SUBLIVAC FIX Phleum Pratense for grass pollenallergic patients with IgE-mediated seasonal allergic rhinoconjunctivitis (ARC) was conducted. [137]. The safety and tolerability of the pratense were assessed, and the doseresponse signal was measured by using the total symptom score (TSS). The TSS of SUB-LIVAC FIX Phleum Pratense (SP) 10,000, 40,000, and 80,000 AUN/mL were 8.06, 8.19, and 7.69 while the score of placebo was 10.01, demonstrating that SP could be effective in relieving total symptoms of ARC.
A trial tested cockroach subcutaneous immunotherapy (SCIT) safety in cockroachsensitive adults with asthma and/or perennial allergic rhinitis. (ICAC-18) [138]. No severe adverse effects related to treatment were reported.
Mouse allergenic extract, called mouse epithelial extract or allergenic extract of Mus musculus, was administered by subcutaneous injection in mouse-sensitive adults with asthma or/and perennial allergic rhinitis (ICAC-26) [139]. The primary objective of this study was to assess whether treatment with mouse subcutaneous immunotherapy (SCIT) is safe. A total of nine adverse events (AEs) were reported, and no serious adverse events (SAEs) were reported. Although further studies are required to ensure the safety of mouse allergenic extract, perhaps the number of adverse events shows that the extract treats rhinitis safely. Diverse studies referred to T helper cell differentiation when discussing the process of how the target extract works to treat allergic rhinitis (Figure 2). There were twenty five plantoriginated natural products and fourteen decoctions modulating T helper cell differentiation.  IL-12, which is a Th1-related cytokine, was up-regulated by Artemisia vulgaris water extract, BCE, and RMFE [71,79,103]. Citrus, BCE, Ostericum koreanum root methanol extract, and Bu-Zhong-Yi-Qi-Tang showed their effects by increasing another Th1 cytokine, IFNγ [60,66,79,117]. TNF-α is associated predominantly with Th1-mediated inflammation and is essential for the production of Th2 cytokines such as IL-4 and IL-12 [140]. The release of TNF-α was reduced by Chrysin, Citrus, Elsholtzia ciliate water extract, Gencydo ® , Ostericum koreanum root methanol extract, Lindera obtusiloba water extract, Rosmarinic acid, Biyuanling, and KOB03 [58,60,61,63,64,66,68,116,122].

Comparison Analysis
Some compounds or extracts were examined in more than one study. There were two different studies about BGPP. The studies differed in experimental subjects, dose, duration, mechanism, and efficacy of the extract. Shaha et al. used HeLa cells, RBL-2H3 cells, and a TDI-sensitized rat model, while Tani et al. used Cry j1-treated PBMCs and Cry j1-treated peripheral leukocytes of allergic patients [56,57]. The former study showed the relationship between improvement of nasal symptoms and degradation of H1R mRNA, p-PKCδ, IL-9, IL-4, and IL-5; the latter explained that nasal obstruction preventing property of BGPP was related to degradation of IL-5, IL-14, and CysLTs. Two different studies examined the extract of Piper nigrum L. (PNE) as AR treatment in vivo [90,93]. Bui et al. and Bang et al. both used OVA-induced AR mice, but the species differed-BALB/c mice and Swiss albino mice, respectively. The former administered 50, 100, and 200 mg/kg of PNE and the latter 10, 20, and 40 mg/kg. Bui et al. compared the efficacy of PNE with that of Dex, while Bang et al. did so with montelukast. Different mechanisms related to AR symptoms were investigated: the former focused on the inhibition of STAT3 and NFκBp65 plus the elevation of Th1, whereas the latter focused on the inhibition of IL-6, IL-1β, and IgE. KOB03 was examined by various methods [122,141]. OVA-induced AR BALB/c mice and SD rats were administered with 100 or 200 mg/kg of KOB03 for 7 days. The efficacy of the decoction was generated by inhibiting TNF-α, IL-1β, IL-6, and IL-8. In comparison, only OVA-induced AR BALB/c mice were administered with a higher dose, 5 mg/kg, for 8 days. As a result, the decrease of IgE, LTC 4 , IL-4, and IL-1β inhibited nasal inflammation.

Limitations
The reviewed studies had some limitations. There were experiments with high doses (over 60 µg/mL in vitro) of the compound or extract [56,57,61,62,111,114]. Some experiments were conducted only in in vitro [57,58,[60][61][62][63]66,67,70,106]. The nasal symptoms and pathogenesis observed in the studies using the TDI-sensitized rhinitis model may differ from AR, an IgE mediated disease, as TDI-sensitized rhinitis is a non-IgE mediated disease [55,56,72,89,116,142]. Furthermore, this paper had shortcomings that should be remedied in the following studies. The papers are predominantly about compounds and extracts that originated from plants. Clinical trials lack quantity compared with in vivo and in vitro experiments, eight to a total of forty-nine. Additionally, this review was limited to studies published in the last 10 years and written in English. Above all, although a variety of compounds and extracts were included, examination for each of them was insufficient.

Significance
This review included specific mechanisms of AR and its treatment, examined the result of diverse research, and contains specific figures of AR mechanisms. As various compounds and extracts were reviewed, this paper details the potential for the widespread use of natural products in treating AR. Further studies about toxicity, stability, and pharmacokinetics based on this review could be conducted to confirm their possibilities.

Methods
Relevant articles published between 2009 and 2019 regarding the therapeutic effect of plant extracts on allergic rhinitis were collected from PUBMED, the Google Scholar database, and the Web of Science. The search algorithm was designed by entering related keywords such as 'allergic rhinitis', 'natural product', 'herbal medicine', 'decoction', 'tang', 'extract', and 'clinical trial'. We only reviewed articles written in English and excluded duplicates and studies with English abstracts but non-English articles. The papers were first classified into two categories based on the form of the experimental model: in vivo and in vitro. Then, we reclassified in vitro studies into three categories according to the kinds of natural resources used in the experiment: plant, etc., and decoction. "Etc." includes animal and fungi, which were very few in number to be exclusively classified. For data unity and a better understanding of the influence of compounds on allergic rhinitis, we only considered single compounds except for decoction. Decoctions were included for the inclusiveness of the study; plant extracts are frequently used in clinical situations in the form of decoction or tang. Overall, fifty-seven studies demonstrating the efficacy of using plant extracts in treating nasal inflammation were reviewed.

Conclusions
Natural products can be used as an effective treatment for AR. In most of the studies reviewed, they showed positive effects on relieving the symptoms of AR, such as rubbing of the nose and sneezing, or inhibiting inflammation in vivo and in vitro. The results of clinical trials showed that the treatments were effective and safe. Therefore, natural products could be attractive candidates for drug development for treating AR.