Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Recent Progress in Traditional Chinese Medicines and Their Mechanism in the Treatment of Allergic Rhinitis

Recent Progress in Traditional Chinese Medicines and Their Mechanism in the Treatment of Allergic... Hindawi Journal of Healthcare Engineering Volume 2022, Article ID 3594210, 18 pages https://doi.org/10.1155/2022/3594210 Review Article Recent Progress in Traditional Chinese Medicines and Their Mechanism in the Treatment of Allergic Rhinitis Dehong Mao, Zhongmei He, Linglong Li, Yuting lei, Maodi Xiao, Huimin Zhang, and Feng Zhang Department of Otolaryngology, Yongchuan Hospital of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 402160, China Correspondence should be addressed to Feng Zhang; fengzhang06@yeah.net Received 18 February 2022; Accepted 17 March 2022; Published 11 April 2022 Academic Editor: Liaqat Ali Copyright © 2022 Dehong Mao et al. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. To conduct a systematic review on the mechanism of action and use of traditional Chinese medicines (TCM) in allergic rhinitis treatment. Background. Allergic rhinitis (AR) is a type I allergic disease of the immune system induced by immuno- globulin E mediated inflammation and is characterized by sneezing, nasal itching, paroxysmal nasal obstruction, mucosal edema, cough, and rhinorrhea. More than 500 million people have been affected by rhinitis worldwide in the past 20 years, leading to negative effects on health, quality of life, and social relationships. Currently, the trending medicines used in the case of AR include intranasal corticosteroids and oral H1 antihistamines, which are given as combinatorial medicines supplemented with immune therapy. +ese medications have been found to be very effective in either the short term or long term; however, they have been found to possess some serious side effects. Search Methodology. +e information in this article on classical and traditional Chinese medications used to treat AR was derived from original papers and reviews published in Chinese and English language journals. Two Chinese databases (Wanfang and CNKI) and three English databases (Cochrane Library, PubMed, and Embase) were utilized for data gathering. Results. Traditional Chinese remedies have been identified to influence the production of cytokines such as IL-5 and IL-6, which are key mediators of eosinophilic inflammation, TNF-α, which stimulates TH2 cells at the site of inflammation, and NF-lB, which is required for cytokine and IgE antibody production. TCM has also been shown to be successful in lowering histamine levels, preserving histological changes by decreasing the thickness of the lamina propria, and downregulating the expression of Orai1, STIM1, and TRYC1, showing low expression of Ca channel proteins. Conclusion. In this review, we discussed a series of classical, traditional Chinese medications, including Centipeda minima, Scutellaria baicalensis, licorice root (Glycyrrhiza uralensis), and others, as potential antiallergic agents and investigate their in vivo effect upon the production of cytokines and release of histamines for allergic rhinitis treatment. approximately 15–20% of the population around the globe is 1. Introduction affected by AR, with a dominating ratio in western countries Allergic rhinitis (AR) is usually a severe condition that [2, 3]. +e treatment of the condition potentially focuses on develops due to allergen exposure and results in IgE-me- alleviating the symptoms rather than addressing the root diated inflammation of the nasal membranes. +e common cause of the issue. Hence, patients are often recommended to symptoms found among patients with AR include sneezing, avoid direct contact with allergens such as pollen, dander, nasal obstruction, itching sensation in the nasal cavity, and dust mites, and cockroach infestations, which can potentially rhinorrhea. +ese major symptoms may often be accom- stimulate the arousal of rhinitis. Considerably, the first line panied by fatigue from nasal discomfort, itching sensation of treatment is solely based on (intranasal antihistamines, around the eyes, swelling of the nasal mucosal membranes, corticosteroids, and cromolyn) to reduce inflammation. postnasal dripping, and cough [1]. On the far current record, However, some cases might require surgical intervention [4]. 2 Journal of Healthcare Engineering combined drugs treatment has been recorded to date. Using the allergen challenge test at the molecular level, several researchers have established that people with AR Although the following TCM herbs are beneficial against allergic rhinitis, no comprehensive assessment of their anti- secrete mediators such as histamine and leukotriene (LT). +ese proinflammatory factors have been detected in nasal allergic-rhinitis mechanisms information from published secretions of the affected individuals upon exposure to al- scientific results has yet been undertaken. As a result, the lergens, but little has been known about their secretion in current study concentrated on using traditional Chinese natural conditions [5–7]. Previous studies have reported the medicinal herbs to treat AR. +is review will cover tradi- secretion of cytokine (IL-1α), a proinflammatory factor, tional Chinese medicines (TCM) that are widely used to treat upon exposure to allergens during the early or late phase of allergic rhinitis. Studies have demonstrated certain herbs to change bi- the reaction [8–10]. +ereby, it was suggested that the cy- tokine might have a crucial role in activating endothelial ological pathways implicated in allergic rhinitis, such as eosinophil cell death, adhesion molecule modulation, mast cells long with T-lymphocytes, further stimulating the cy- tokine release. Recent research has also discovered the cell generation, T /T imbalance, nuclear factor, che- H1 H2 presence of IL-1Ra, a naturally occurring inhibitor, in a mokine concentrations, and IgE regulation [12] (Table 1). higher molar concentration in the nasal discharges of AR Herbs that are frequently used to cure allergic rhinitis patients and controls [11]. +e antagonist (IL-1Ra) binds comprise Xanthium fruit, Scutellaria root (Scutellaria bai- with the IL-1 receptor, preventing the active (IL-1α) binding calensis), Centipeda herb (Centipeda minima), licorice root without affecting its respective biological response. Similar (Glycyrrhiza uralensis), and Astragalus roots (Astragalus to IL-1α, another chemokine of the interleukin-8 family, membranaceus). +ese herbs are the key components in interleukin-8 (IL-8), has been found to be elevated herbal prescription and other Chinese herbs [12]. throughout the late stages of the disease and is being in- vestigated as a possible candidate in eosinophil movement in 2. Xanthium Fructus certain conditions. According to a seasonal study conducted to assess the +e Xanthii fructus (XF) is a well-known dried fruit of effect of cytokines upon exposure to allergens, it was de- Xanthium strumarium, also called “Cang-Erzi” in Taiwan. It duced that a constant incline in the concentration of leu- has been used over the years to treat various diseases, in- kotriene and Eosinophil Cationic Protein (ECP) was cluding rheumatism, sinusitis, skin pruritus, and headaches prominent throughout the season. According to the find- (Figures 1(a) and 1(b)) [18]. +e Xanthii fructus has been ings, histamine concentrations only elevated late in the shown to reduce mast cell-mediated allergy reactions [19], season and postseasonally. Additionally, the cytokine IL-1β anti-inflammatory actions in lipopolysaccharide-stimulated and its natural antagonist, IL-1Ra, were assessed. Surpris- inflammatory responses [20], and prevention of β-cell ingly, there was a considerable rise in IL-1β concentrations damage in type 1 diabetes [21]. from early in the season to postseason, corroborating the As previously stated, allergic rhinitis can be divided into hypothesis of chronic proinflammatory upregulation in two stages: early and late. +e ailment manifests itself within seasonal allergic rhinitis. Additionally, the same study de- 5–30 minutes of exposure to the antigen, such as mold, dust, termined a considerable decrease in IL-1Ra concentrations or animal dander [22, 23]. Early symptoms following ex- during the early season, indicating dysregulation of the local posure typically include lacrimation, clear rhinorrhea, anti-inflammatory capacity. Similarly, nasal secretions itching, and sneezing, which are commonly triggered by the contained a significant rise in IL-1β concentration, con- production of mast cell secretions, including histamine [24]. firming the assumption of chronic proinflammatory On a molecular level, mast cells have been known to play a regulation. significant role in inflammatory processes, including the Along with IL-1β, the considerable downregulation of release of proinflammatory cytokines such as tumor necrosis IL-8 and myeloperoxidase indicates disruption of localized factor (TNF-α), interleukin-1β, interleukin-8, and inter- immunity, implying a substantial connection between the leukin-6 and inflammatory factors including serotonin and two variables. Myeloperoxidase is a marker of neutrophil histamine (Figure 2) [25–27]. activation, and its lower expression means reduced IL-8 Likewise, the late phase of allergic rhinitis is often secretion. Since neutrophils account for about 40%–60% of characterized by the recruitment of effector cells such as the cells on the mucosal surface and may operate similarly to basophils, eosinophils, and T-helper 2 (T ) lymphocytes, H2 macrophages, their dysregulation may increase susceptibility causing malaise, irritability, fatigue, and congestion within to infectious diseases. To summarize, allergic rhinitis does 6–24 hours after antigen exposure [28–32]. On the other certainly reflect chronic inflammation, as evidenced by hand, eosinophils have been revealed to play an essential eosinophil activity and prolonged elevation of the proin- part in the disease’s late stage. +e abundance of eosinophils flammatory cytokine IL-1α. As a result, the release of cy- in the nasal mucosa of the affected patients indicates the tokines continues for weeks after pollen contact is ceased in release of proinflammatory mediators such as cysteinyl persistent and seasonal allergic rhinitis. Numerous com- leukotrienes, eosinophil peroxidase, major basic protein ponents, targets, and mechanisms underlying allergen-in- cation in proteins. Presently, the common treatment of AR, duced inflammatory disorders remain unknown despite as mentioned earlier, includes the usage of corticosteroids, substantial research on allergic rhinitis. Due to the com- immunosuppressants, and antihistamines. However, their plexity of the disease, only symptomatic treatment or use is restricted due to various adverse effects, such as lipid Journal of Healthcare Engineering 3 Table 1: A cumulative representation of traditional Chinese medicines used to treat allergic rhinitis and the respective pathways and biomarkers regulated by them. Traditional Chinese Type of S. no. Status of biomarkers Techniques/assays used References medicine study TNF-α, IL-6, IL-5 ↓ Cytotoxicity assay IF-1β, MIP-1 ↓ Western blotting 01. Xanthi fructus MIP-2 ↓ In vivo Optical microscopy [13] Histamine, IgE ↓ ELISA Caspase-1 ↓ IFN-c ↑ Evans blue extravasion assay IgE, IgG ↓ ELISA assay Licorice root β-Hexosaminidase ↓ WST-8 assay 02. In vivo [14] (glycyrrhizic acid) IgE mediated Ca influx↓ β-Hex assay Orai1, STIM1 ↓ RT-PCR IP3R, TRYC1 ↓ Western blot Scutellaria baicalensis IL-6, TNF-α, IL-1β ↓ ELISA 03. In vivo [15] Georgi. STAT3 pathway ↓ Immunohistochemical staining TNF-α, IL-2, IL-4 ↓ In silico ELISA 04. Centipeda minima Immunohistochemical staining, H&E [16] PTGS2, MAPK ↓ In vivo staining PCA, histamine ↓ Evans blue extravasion assay LCT , PGD , LTC ↓ β-Hexosaminidase assay immunoblotting 4 2 4 β-Hex, Ca influx ↓ 5-LO, MAPK, cPLA2α ↓ 05. Emodin In vivo [17] PDG generation ↓ TNF-α, IL-6, NF-lB ↓ Syk, LAT, PLCɤ1 ↓ AKT pathway ↓ (a) Figure 1: Continued. 4 Journal of Healthcare Engineering (b) Figure 1: (a) and (b) Representation of the plant and fruit of Xanthium strumarium, also called “Cang-Erzi.” IL-4 IL-13 TSLP Histamine IgE Production Medicinal Plant Medicinal Allergic Rhinitis Medicinal Plant Plant Medicinal Plant T > T Mast cell activation H2 H1 Histamine Serotonin Leukotriene Figure 2: +e diagrammatic representation of biomarkers affected during allergic rhinitis. and glucose metabolism problems, osteoporosis, excessive histamine and TNF-α production in mast cell-mediated sedation, and hypertension [33–35]. allergic responses [19, 36]. We will cover a study paper in this Over the years, multiple studies have proven the me- section which examines the mechanism of XF effects by dicinal value of Xanthii fructus (XF) with its anti-inflam- looking at cytokine and caspase-1 levels, the thickness of matory properties. In a survey conducted by An et al., the nasal septum tissue, and the frequency of sneezing behavior anti-inflammatory role of XF has been reported on lip- in an in vivo AR model produced by ovalbumin (OVA). osaccharide-stimulated mouse peritoneal macrophages [20]. Additionally, the process by which XF inhibits NF-lB Another study discovered that XF extract shields pancreatic regulation has been explored. β-cells from cytokine-induced damage by inhibiting nuclear factor kappa-B (NK-lB) [21]. Another study has established 2.1. Effects of Xanthii fructus over Nasal Symptoms in Allergic that XF is responsible for inhibiting chronic inflammation found in airways among bronchial asthma patients. Addi- Rhinitis. As discussed earlier, the major symptoms of AR include rhinorrhea, itching, sneezing, and nasal congestion tionally, the extract was found to be effective against Journal of Healthcare Engineering 5 sensitized mast cell begins to degranulate, secreting newly [37]. An OVA-sensitized mouse model was considered to study XF’s potential in vivo anti-inflammatory effects. synthesized and preformed mediators including cytokines, histamines, cysteinyl leukotrienes, and prostaglandins Following sensitization, the extract of XF was injected with cetirizine (a positive control) to assess its anti-inflammatory [40, 41]. TNF-α is one of the cytokines that have been shown properties. Compared to OVA-sensitized mice, a model to have a significant role in allergic inflammation, as it is treated with XF had a considerably lower amount of required for +2 migration to the site of allergic inflam- sneezing (P< 0.01). mation and the generation of +2 cytokines [42]. IL-1β, which has mostly been found to be elevated after allergen exposure, activates endothelial cells and T-lymphocytes, 2.2. Effects of Xanthii fructus on Serum Levels of Histamine, leading to further production of cytokines [43]. Immunoglobulin E, and OVA-Specific IgE. To investigate the Similarly, IL-5 and IL-6 have been identified as major effects of XF, several mice (BALB/c) were injected with OVA mediators of eosinophilic inflammation leading to asthma injections causing a significant increase in OVA-specific IgE and are vital in developing nasal secretions, respectively [44]. and immunoglobulin E levels. As to our previous under- Asthma patients’ bronchoalveolar lavage fluid contains standing, overexpression of IgE is a prominent marker of greater levels of the chemokine MCP-1, associated with the allergic rhinitis. In OVA-sensitized models, blood levels of activation of eosinophils and basophils [45]. In the absence histamine and total and OVA-sensitized IgE were observed of an antigen or an anti-IgE antibody, histamine-releasing to be considerably raised with time. However, treatment of factors (HRFs) drive mast cells and basophils to release mice with XF extract resulted in a significant decrease histamine. (P< 0.05) in histamine and total and OVA-specific IgE. Eosinophils move from the blood to the site of in- flammation in allergic rhinitis because of the inflammatory stimulus (produced by antigen-presenting cells). +is is also 2.3. Cytokines and the Role of Xanthii fructus in Regulation. one of the main features of allergic rhinitis [46]. Inflam- As we previously understood, cytokines play a vital role in mation is frequently reduced when eosinophils are de- the course of inflammation. +e two groups taken under creased. Now that we know more about caspase-1, an study (i.e., OVA-sensitized mice and mice treated with XF) enzyme in the cysteine-protease family, we can better un- were observed to understand the trend in the serum level of derstand how it affects the development of the IL-1 family cytokines. +e concentration levels of TNF-α, IL-6, IL-5, IF- and how it affects disease-causing immune responses [47]. 1β, MIP-2, and MIP-1 significantly increased among OVA- +is thickness of the lamina propria in the nasal septum and sensitized mice. On the contrary, the XF-treated group infiltration of eosinophils has been found to be conspicu- presented an appreciable decline in the concentrations of ously reduced after treatment with XF. these cytokines, indicating its anti-inflammatory function +e expressions of all cytokines predominantly depend among AR models. on an active transcription factor, NF-lB [48]. +is activation requires phosphorylation and proteolysis and degradation of 2.4. Eosinophil Infiltration and Histological Alterations in the Il-Bα (an endogenous inhibitor of NF-lB) as its key Nasal Mucosa. OVA-sensitized mice groups had extensive component [49]. XF was also found to inhibit the phos- eosinophil infiltration in the entire area of the lamina phorylation and degradation of this transcription factor propria, increasing thickness to the nasal tissues, as per successfully. Hence, causing the inactivation of NF-lB leads histological analyses. However, XF-treated mice groups to a substantially low level of cytokines. +e treatment of AR showed a marked reduction in the thickness of the lamina has led to constructing an animal model in the current propria. research strategy. In comparison, periodic intranasal OVA treatment has induced typical AR symptoms on a physical and molecular 2.5. Impact of Xanthii fructus on the Expression of Caspase-1. level in the animal models (i.e., inflammatory mediators and Caspase-1 is a member of a protease family also known by IgE production) [48, 50, 51]. XF has drastically decreased the name of IL-1β-converting enzyme (IL-1, BCE, or ICE). levels and an antiallergic impact by blocking the generation +e enzyme contributes to immune-mediated inflammation of its mediators. Cetirizine, a metabolite that is a selective H1 by converting the precursor forms of interleukin-1β and receptor being used to treat angioedema, urticarial, and interleukin-18 into active molecules found in the extracel- allergies [52], has been taken as a positive control. +e lular compartment [38]. Following the same trend, a sig- scheme has also concluded that the effect of XF has been nificant increase in the expression of caspase-1 was observed found similar to that of cetirizine. among OVA-sensitized mice, whereas, upon treatment with XF, a prominent decrement was noted in the expression of 3. Licorice Root caspase-1. An allergic reaction is mostly regarded as a condition caused 2.6. Mechanism of Action. To our knowledge, allergic illness by hypersensitivity of the immune system to react with the is mediated by the increase of the +2 cell subset and the substances normally considered harmless in all age groups, production of particular IgE antibodies by B cells in response thereby leading to anaphylaxis [53]. +e condition is often to diverse allergens. [39]. In such response, the IgE- mediated by immunoglobulin E response with few 6 Journal of Healthcare Engineering medicines available to alleviate the allergic symptoms, in- studied compared to the controls (P< 0.05). +e results cluding antihistamine drugs (i.e., diphenhydramine, terfe- presented that only 100 mg/kg body weight of GA has nadine, and chlorpheniramine maleate), immune significantly decreased the production of OVA-sensitized suppressors (hydrocortisone, dexamethasone, and adrenal antibodies (P< 0.05). +e inhibition effect was found to be cortical hormones), and mast cells stabilizers (ketotifen, similar to that of hydrocortisone. Hence, GA was also found sodium hydroxypropyl cromate, and disodium cromogly- to influence OVA-sensitized antibody-producing B-cells cate). However, as with other drugs, most of these products have been shown to possess side effects. Similarly, symptom 3.3. Role of GA as a “Mast Cell Stabilizer”. According to our relapse has also been observed among patients. In this prior knowledge, Mast cells contribute to IgE-induced al- regard, a suitable alternative derived from food with no side lergy by producing different cytokines, a key cause of allergic effects may serve as a possible drug of interest to overcome conditions. Using passive cutaneous anaphylaxis (PCA) and allergic symptoms. RBL3-2H3 immunologic cell-based tests, it was further Glycyrrhiza is a plant with an ancient origin and has been explored if GA can also influence mast cell activation. used over history for herbal medicine and food (Figure 3) +e assay results indicate a substantial reduction in the [54]. Among other plant constituents, glycyrrhizic acid (GA) mast cell-dependent PCA reaction in the GA-treated group is considered one of the main components possessing several (in a dose-dependent manner). Similarly, the effect of GA on pharmacological properties. Numerous research have dis- degranulation was examined by quantifying β-hexosamin- covered that biologically active substances in organic foods, idase release in the absence and presence of GA. As for the such as polyphenols and flavonoids, which have anti-in- cytokines, glycyrrhizic acid was found to cause substantial flammatory or antioxidant properties, lead to antiallergic suppression in the release of β-hexosaminidase from 87.46% action. Clinical and experimental studies have revealed the to 45.23% with the increment of dosage from 100 to 1000µg/ application of glycyrrhizic acid (Figure 4) with its immu- mL (P< 0.05). nomodulatory [55] and anti-inflammatory [56] character- istics. A study reduced asthma-like symptoms in mice with a Balb/c model by taking GA (2.5–20 mg/kg body weight). 3.4. Impact of GA upon Expression of Calcium Channel +is was found to be an effective way to treat the mice’s Proteins. According to the available literature, degranula- asthma, simultaneously preventing the reduction in total +2 tion of RBL-2H3 cells is dependent on the release of Ca IgG2a and interferon-gamma (INF-c) levels. Furthermore, ions from the endoplasmic reticulum (ER) and the Ca ion GA (10 mg/kg body weight) has been proven to block the influx mediated by calcium release-activated calcium activation of NF-lB and STAT-317, hence reducing the channels (CRAC) [57]. Hence, the effect of GA on the influx onset of acute inflammation. In this section, we will discuss +2 of Ca ions was taken under investigation. +e intracellular the antiallergic effects of glycyrrhizic acid along with its Ca ion concentration was determined using Fluo-3 AM possible underlying mechanisms. +2 (a fluorescent Ca ion indicator). GA at a 1000µg/mL concentration prevented Ca influx mediated by IgE/Ag. +e activation of Ca influx-mediated proteins such as 3.1. <rough T-Helper Cell Development, GA Plays a Role in stromal interacting molecule 1 (STIM1), Inositol 1,4,5 tri- OVA-Induced Systemic Allergy Reactions. +e antiallergic phosphate receptor (IP3R), calcium release-activated cal- activity of GA was evaluated in an OVA-induced active cium channel protein 1 (Orai1), and transient receptor systemic allergic response. Conspicuously, multiple allergic potential channel 1 (TRPC1) was also studied. On a similar symptoms were prominent in the sensitization group, in- note, there was a significant decrease in the expressions of cluding labored respiration, scratching, and a total decrease in Orai1, STIM1, IP3R, and TRPC1 upon treatment with GA. rectal temperature by −1.60± 0.1 C. However, the 100 mg/kg +ese findings show that GA has no role in the depletion of body weight group treated with GA showed substantial the ER Ca reservoir; instead, the stability of mast cells is suppression of allergic symptoms and a net decrease of ° predicated on Ca influx inhibition due to decreased Orai1, −0.9± 0.1 C in rectal temperature. STIM1, and TRPC1) expression. +e rate of inhibition observed by 100 mg/kg of GA is comparable to that of hydrocortisone, a standard allergy treatment. As for the levels of cytokines, a significant in- 3.5. Mechanism of Action. Glycyrrhizic acid (GA) has been crease was noted among T cytokine IL-4, whereas a de- H2 reported to have similar effects on the immune system of creasing trend was prominent among +1 cytokines (IFN-c) Balb/c mice as other natural triterpenoids [58]. +ese may among the OVA-sensitized group. However, after treatment include anti-inflammatory, antineoplastic, antiviral, im- with 100 mg/kg, a significant increase in the level of IFN-c mune-regulatory, pharmacological, and antiallergic effects. was observed. +ese findings indicated that an oral dose of +e three major mechanisms by which antiallergic effect 100 mg/kg GA might influence +1/+2, resulting in an comes into play are (i) a potential role as a mast cell sta- attenuation of allergic reactions. bilizer, to reduce the secretion of mediators via imparting inhibitory effect over Ca influx, (ii) modulation of TH cell 3.2. Inhibition of OVA-Specific IgE and IgG1 Production via development to limit cytokine (IL-4) release from T cells, H2 B-Cells. Additionally, the effect of GA on the generation of and (iii) influencing OVA-specific antibody-producing IgG1 and IgE antibodies in the OVA-sensitized group was B-cells (Figure 5). Journal of Healthcare Engineering 7 Figure 3: Presentation of a licorice plant [17]. COOH HOOC OH HO HOOC OH HO OH Figure 4: Structure of glycyrrhizic acid. According to our previous understanding, GA can de- GA treatment has led to the significant reduction of the crease serum total IgE and OVA-specific IgE levels [14]. In intracellular Ca levels. As a result, the extracellular process allergic rhinitis mice models, GA has been shown to elicit a of Ca influxes is inhibited. However, no variation in considerable reduction of OVA-specific IgE antibodies in a mRNA expression of inositol-3-phosphate receptor was dose-dependent way. +is significant reduction could be identified in the absence or presence of GA, indicating that caused by blocking T /T differentiation and maturation, GA did not affect endoplasmic reticulum (ER) storage. On H1 H2 which would impede the production of IL-4. Furthermore, the other hand, the expressions of Orai1, STIM1, and GA has also been found to suppress IgG1, later leading to TRYC1 were significantly reduced, suggesting that GA may inhibition of basophil activation [59]. Likewise, the study has regulate Ca degranulation via decreasing calcium channel also presented the role of GA as a mast cell stabilizer, where expression levels. Degranulation 8 Journal of Healthcare Engineering Glycyrrhizic acid Stabilizes mast cells Ag Modulates T 1/T 2 H H or basophils by subset balance blocking Ca influx Basophils Secretion of Modulates T 1/T 2 H H subset balance PAF Dendritic cells Mast cells T-helper cell Synthesis of antibodies Ex Ca influx through Calcium channel T 1 cells T 2 cells H H protein IgG IgE Recruitment and activation of T 2 cells Binds to FcγRIII Figure 5: +e mechanism through which GA exerts its antiallergic impact on IgE-mediated allergic reactions [13]. obstruction, sneezing, congestion, and rhinorrhea, which 4. Scutellariae Radix can lead to ear and nasal abnormalities if left untreated [74]. Scutellariae Radix (RS), also referred to as huangqin in A complicated allergen-induced inflammatory process Chinese, is the dry root of the Labiatae plant Scutellaria within the nasal mucosa causes the condition. On a mo- baicalensis Georgi. [60]. In English, the plant is also known lecular level, such a process causes the release of histamine as Baikal skullcap or Chinese skullcap, and it is endemic to and a variety of cytokines and proinflammatory substances, Asia, particularly Far East Russia, Mongolia, Siberia, East which can trigger vascular dilatation and tear secretion [75]. Asia, and China (Figure 6). +e plant is frequently used in Among all other activities, the release of IgE has been de- traditional Chinese medicine to treat cardiovascular and termined to have a significant part in the overproduction of respiratory disorders, gastrointestinal infections, inflam- basophils, eosinophils, and mast cells, as discussed in various mation, and other diseases [61]. Regardless of the whole sections [76]. plant, the usage of RS is more extensive in Japanese and Among the various flavonoids mentioned above, bai- Chinese pharmacopeia with a broad range of therapeutic calein is one of the major constituents of RS found to effects, including detoxifying toxicosis, preventing bleeding regulate T /T balance and adjust histamine release from H1 H2 and miscarriage, clearing away heat, and moistening aridity the mast cells [77]. Several research groups have reported the [62, 63]. Anti-inflammatory properties of RS have been well anti-inflammatory role of baicalein in mouse models, alle- documented in in vivo and in vitro investigations, including viating colitis, liver, and vascular inflammation [78, 79] inhibition of chemokine, cytokine, and growth factor pro- induced by dextran sulfate sodium (DSS) and 2,4,6-trini- duction from macrophages [64–69], exhibiting potential trobenzene sulfonic acid (TNBS) [79, 80]. +rough an OVA- treatment of colon cancer [70], stroke [71], and colitis [72]. induced AR animal model, we will explain the regulating +e major biological compounds isolated from RS efficacy of baicalein derived from RS on clinical symptoms of include phenylethanoid glycosides, flavonoids, diterpenes, AR, mucosal histological alterations, and inflammation in triterpenes, phytosterols, polysaccharides, and iridoid vivo. glycosides [73]. Among these, over 40 flavonoids along with the form of glycosides have been identified as most abundant [73], which include the key bioactive compo- 4.1. Baicalein’s Anti-Inflammatory Properties in AR-Infected nents oroxylin A-7-glucuronide (OAG), oroxylin A (OA), Rats. Two major characteristic features, body weight and wogonoside (wogonin-7-glucuronide, WG), baicalein (B), mass of the vital organs, were considered in OVA group, wogonin (W), and baicalin (baicalein-7-glucuronide, BG) OVA + baicalein group, and OVA + clarityne group. In [61] (Figure 7). terms of body weight, there was no statistically significant As previously mentioned, AR is a condition marked by difference between the two groups. After 30 minutes of OVA significant pain and other symptoms such as respiratory stimulation, the frequency of nasal scratching, degree of IL-4 Differentiation Binds to FcR1 IL-4 Journal of Healthcare Engineering 9 Figure 6: A pictorial presentation of a traditional Chinese medicine herb, Scutellariae Radix [15]. COOH HO O O OH HO OH OH O OH O · Baicalin (R =OH, R =H) · Baicalein (R =OH, R =H) 1 2 1 2 · Wogonin(R =H, R =OMe) · Wogonoside (R =H, R =OMe) 1 2 1 2 · Oroxylin A(R =OMe, R =H) · Oroxylin A7-0-glucuronide (R =OMe, R =H) 1 2 1 2 Figure 7: Active components obtained from Scutellariae Radix, including flavonoids and glycosides. nasal outflow, and sneezing pattern in each group were OVA-induced (AR model) and baicalein-treated groups recorded and then overlapped to analyze the findings. better to understand the role of baicalein in inflammatory It is worth noting that the OVA-treated group had more factor production. In the AR model, there was a considerable sneezing and nasal scratching than the control group. Fur- increase in IL-6, TNF-α, and IL-1β, which gradually de- thermore, a significant reduction in the frequency of sneeze and creased after treatment with baicalein. nasal grating was found after baicalein treatment, but the in- hibition mechanism is still unknown. +e primary organ masses 4.3. Baicalein’s Effect on Inflammatory Cell Infiltration in the (including the spleen, kidney, liver, and heart) were also iden- tified in the OVA-induced, OVA + baicalein-treated, and control NasalMucosaandLungTissue. Allergen-induced rhinitis, as groups. +e spleen in the OVA-induced group was significantly we all know, results in inflammatory infiltration of the lamina propria. +ree groups have been identified based on heavier in comparison to the control group (P< 0.05), while the spleen in the baicalein treatment group was considerably lighter histological findings using H&E staining. Inflammatory cells were not found in the nasal cavity, lateral nasal walls, or nasal in comparison to the OVA-induced group (P< 0.05). septum in the healthy one. In addition, no signs of vascular congestion or proliferation were observed while presenting 4.2. <e Effect of Baicalein on Inflammatory Variables in AR normal tissue structure and mucosal glands. However, in the Rats’ Nasal Lavage Fluid and Serum. Levels of inflammatory second group (AR model), characteristic changes were factors such as IL-6, TNF-α, and IL-1β were assessed in the present in the histological parameters, including many 10 Journal of Healthcare Engineering inflammatory cells (eosinophils, basophils, and mast cells) inside the nasal mucosa. On the other hand, the same feature was significantly reduced in the baicalein-treated group, demonstrating a significant ability to prevent inflammatory cell formation. Additionally, lung tissue compounds were examined, with pertinent sections stained with H&E to ascertain the extent of lung injury. Damage was visible on the surface, with interstitial edema, thickening, and infiltration of neutrophils into the alveolar wall, as well as the formation of a necrotizing ulcer. However, baicalein was found to alle- viate these symptoms significantly. Figure 8: +e plant of Centipeda minima [85]. 4.4.Baicalein’sEffectonp-STAT3ExpressioninNasalMucosa Tissues. To further validate the impact of baicalein over the inhibition of relevant pathways, the STAT3 signaling demonstrated in studies to decrease eosinophil and mast cell pathway was brought into the investigation. According to activation, diminish degenerative alterations in nasal mu- the findings, baicalein inhibited the phosphorylation of the cosal tissues, lower histamine levels, and minimize nasal STAT3 signaling pathway in OVA-induced rats. As dis- stiffness [87]. cussed earlier, AR can be categorized into two distinct +is section will explain the experimental investigation phases. An early stage is usually characterized by IgE-in- conducted to extract volatile oil components from duced activation of inflammatory cells, including neutro- C. minima gathered from seven different geographical sites phils, eosinophils, and lymphocytes, along with the throughout China and the optimal steam distillation ex- production of related cytokines (IL1β, IL-6, and TNF-α). traction settings. +e volatile oil composition of C. minima Similarly, the late phase of the condition involves the was determined using gas chromatography-mass spec- recruitment of other inflammatory cells such as mast trometry (GC-MS) after extraction. Component-related cells and basophils, in addition to the release of che- molecular targets were investigated using network phar- mokines, histamine, and leukotrienes accounting for the macology analysis. +e primary pathways and key targets of anaphylactic shock [81–84]. Typical AR symptoms were C. minima components were identified, as well as the overall reported in this study starting on day 15 and gradually amount of protein-disease connection. +e best volatile oil faded after 1.5 hours. According to the present findings, extraction yield from C. minima was obtained at 300 C baicalein reduced the frequency of nasal itching and through a 10-mesh sieve. sneezing in AR rats. 5.1. Fingerprint and Cluster Analysis. +e volatile oil-related 5. Centipeda minima GC-MS data from C. minima were integrated into the Centipeda minima (L.) A. Braun et Aschers (Compositae), traditional Chinese medicine chromatographic fingerprints sometimes known as coriander, is an annual herbaceous similarity evaluation method. +e data reveal minor changes plant native to eastern tropical zones, Taiwan, and China in the makeup of C. minima samples taken from seven (Figure 8). +e plant, also known as chickweed, is drought- different geographic locations. tolerant and spreads throughout China. C. minima has been +e findings reveal that plants collected in Jiangxi, known to possess a spicy taste. It has been traditionally used Hubei, Shanxi, and Sichuan have high similarities. We in Chinese folk medicine to treat sinusitis, relieve pain, discovered roughly 30 additional volatile oil C. minima reduce swelling rhinitis, and treat cancer for a very long time compounds for each location, 15 of which were identical [86]. Medicinally, the plant has also been used to minimize across all plants. cough and nasal secretions associated with respiratory complications [16]. To our current understanding, the main medicinal constituents of C. minima involved in treatment 5.2. C. minima and Allergic Rhinitis Target Prediction and include polysaccharides, flavonoids, and volatile oils. Mapping. +e Venny software tool collected the 15 volatile Pharmacological studies of the plant represent that these oil components isolated from C. minima specimens in seven therapeutic components have been conventionally used to geographic areas. 343 relevant targets for 15 components treat antitumor, antiprotozoal, and allergic rhinitis-associ- and 2155 diseases targets were identified following a data- ated headaches. base search. +e Venny software was used to import the As previously described, allergic rhinitis is a noninfec- obtained component targets and disease-related targets. As a tious inflammation of the nasal mucosa. Symptoms include result, 117 genes with known intersections were identified. nasal congestion, runny and itchy nose, and recurrent 172 intersection targets were imported into the STRING sneezing episodes. Work and other daily activities may be platform to study protein interactions. +e circle’s diameter harmed due to these difficulties. C. minima has been fluctuates according to each protein’s degree value, with a Journal of Healthcare Engineering 11 that the IL-2 content in the model group was significantly higher degree value suggesting that a protein interacts with more pathways. +ree proteins were chosen based on their lower than that in the blank group (P< 0.01). +ere was a statistically significant difference (P< 0.01) between the degree and centrality values: mitogen-activated protein ki- nase 3 (MAPK3), prostaglandin-endoperoxide synthase 2 treatment and the model groups in IL-2 levels. (PTGS2), and tumor necrosis factor (TNF). +e model group’s IL-4 levels were considerably higher (P< 0.001). +e level of IL-4 in the treatment group was substantially lower than that in the model group (P< 0.001). 5.3.KEGGandGOAnalysis. +e KEGG and GO analyses of According to the IgE study, the model group had consid- the intersection targets were performed using the R package erably more IgE than the blank group (P< 0.001). Compared clusterProfiler. According to the findings of the GO analysis, to the model group, the treatment group had dramatically the biological process (BP) was linked to 1753 pathways, reduced levels of IgE (P< 0.01). Because of this, C. minima including response to a bacterial molecule, regulation of the can reduce inflammatory responses while increasing anti- inflammatory response, and cellular calcium ion homeo- inflammatory responses. +is effect indicates the plant’s stasis, indicating that these genes are involved in related ability to alleviate the symptoms of allergic rhinitis. biological processes in vivo and collaborate in the treatment of allergic rhinitis. Our study data revealed 37 cellular components (CC) pathways, including the membrane re- 5.6. Immunochemistry. Immunohistochemistry results gion, an important part of the resynaptic membrane tran- showed that the expression rates of PTGS2 and MAPK3 in scription regulator complex, and other pathways that play a inflamed tissues were much greater than those in normal role in allergic rhinitis pathology. KEGG analysis found 137 tissues. Compared to the control group, the model group’s pathways that were connected. 28 of the target proteins were average optical density of PTGS2 and MAPK3 proteins was found to play a role in neuroactive ligand-receptor inter- significantly higher (P< 0.01). +ere was a big difference in action, 15 of the target proteins are involved in +17 cell the PTGS2 and MAPK3 proteins in the volatile oil-treated differentiation, and 12 of the target proteins are involved in group compared to the model group (P< 0.05). the VEGF signaling process. +e data analysis shows that C. minima active ingredients are linked to several possible 6. Xanthium Fruit: Emodin allergic rhinitis pathways. People who have allergic rhinitis are more likely to get it if they go through the second +17 As discussed previously, chronic T allergic inflammation H2 cell differentiation process, according to the results of the such as rhinitis, asthma, and atopic dermatitis affects up to enrichment analysis and the literature. 300 million people worldwide [88, 89]. With the current expansion in urbanization, there is a rise in the number of patients suffering from allergic reactions. +ere is an urgent 5.4.H&EStaining. Tissue analysis in rats demonstrated that need to discover alternative antiallergic medicines that can the nasal mucosa epithelium in the “blank controls” was increase the quality of life while also being safer to use. unaffected. +ere was no inflammatory cell infiltration in the Mast cells have long been recognized as a critical player submucosa of control rats. Cilia were also lost in the disease in allergic diseases, where the aggregation of high-affinity model group, and the nasal epithelium was damaged. In IgE receptors (FceRI) on mast cells stimulates the secretion tissue samples from infected mice, interstitial edema and of both preformed (e.g., proteases and histamine) and newly interstitial inflammatory cell infiltration were observed, as synthesized mediators such as prostaglandin D2 (PGD2) well as gland hyperplasia and swelling. C. minima extract- and leukotriene C4 (LTC4) [90, 91]. Signaling cascades are treated rats had much less damage to their nasal mucosa, initiated when a cognate antigen (Ag) binds to FceRI. +e with less glandular hyperplasia and less inflammatory cell stimulation of receptor-proximal tyrosine kinases such as infiltration into the interstitial cell layers in their noses. Syk, Lyn, Fyn, and Btk and the phosphorylation of other adaptor molecules are examples of these pathways. Syk is 5.5. ELISA. Immune cells can be activated and regulated by essential for the activation of IgE-dependent mast cells. Once interleukins as second messengers, activating and regulating active, Syk phosphorylates adaptor proteins such as the several inflammatory processes, such as +17 cell differ- linker for activation of T cells (LAT), resulting in the for- entiation. Cell proliferation and differentiation can be mation of a macromolecular signaling complex that allows boosted by TNF, for example. IgE serves as a reference for the diversity of downstream signaling required for the measure for the onset and progression of allergic rhinitis as a creation of various proinflammatory mediators [92–95]. key inflammatory factor. Further, we measured the amounts Signaling pathways of such a kind include Ca ion of inflammatory and anti-inflammatory elements (IL-4, mobilization mediated through phospholipase C (PLC ), a g g TNF-α, and IgE) in the serum to verify the network phar- prerequisite step for LTC generation and subsequent de- macology’s pathway and targets. TNF, IL-2, IgE, and IL-4 granulation [94]. As a result, inhibiting Syk kinase may limit were measured in rat serum using ELISA. TNF levels in the the release of various granule-stored and newly produced model group were substantially higher than those in the mediators [92]. Additionally, crosslinking of FceR1 has been control group (P< 0.001). shown to activate the mitogen-activated protein kinase TNF levels were considerably lower in the treatment (MAPK), phosphoinositol-3-kinase/Akt (PI3K/Akt), and group compared to the model group (p 0.01). It was found nuclear factor-lB signaling pathways. As a result, several 12 Journal of Healthcare Engineering proinflammatory genes, such as those encoding cyclo- OH OOH oxygenase (COX-2) and proinflammatory cytokines, are expressed [95]. Polygonum multiflorum +unberg, Rheum officinale Bail, Polygoni cuspidati (P. cuspidati), radix, and Cassia obtusi- folia seed have been utilized in traditional medicines in Eastern Asia for numerous centuries. +ese oriental plants H C OH contain various pharmacological properties, including anti- inflammatory and antiallergic properties [96–99]. Emodin O (1,3,8-trihydroxy-6-methylanthraquinone), a compound Figure 9: Structure of Emodin. found in these herbs, has been demonstrated to have a variety of biological actions (i.e., immunosuppressive, an- timicrobial, anti-inflammatory, antidiabetic, and anti- A substantial suppression of β-hex was observed in a atherosclerotic activities) (Figure 9) [100–104]. Additionally, dose-dependent manner (P< 0.01). Moreover, the produc- Emodin has been shown to inhibit the oncogenic trans- tion of cytosolic Ca was considered, acknowledging that formation of lung and breast cancer by inhibiting HER2/neu the release of Ca is a key factor in mast cell degranulation tyrosine kinase activity, indicating its anticancer potential. [107]. Interestingly, 20 mM of Emodin completely inhibited We will address the antiallergic properties of Emodin and its IgE/Ag-stimulated Ca influx (P< 0.01). possible use as a natural remedy for allergic diseases in this part. 6.3. Effect of Emodin on the Generation of Leukotriene-C (LTC ) from Mast Cells. According to our present under- 6.1. Effect of Emodin on Anaphylactic Reaction in Mice. standing, LTC4 production is regulated in two phases (i.e., We understand that anaphylaxis is a profound allergic re- cPLA liberation of arachidonic acid (AA) from membrane 2α action induced by crosslinking specific IgE bound to FceR1. phospholipids and 5-lipooxygenase oxygenation of free +is interaction between FceR1 and IgE stimulates the arachidonic acid). In response to increased Ca levels, both mediator release from mast cells, causing anaphylaxis molecules (cPLA and 5-LO) translocate from the cytosol to 2α [30, 105, 106]. Passive cutaneous anaphylaxis (PCA) and the perinuclear membrane [108, 109]. passive systemic anaphylaxis (PSA) were used to assess Furthermore, mitogen-activated kinases (MAPK) Emodin’s antiallergic activity. PCA was considered in sensi- phosphorylate cPLA2α, a mechanism necessary for opti- tized mice following oral treatment of 25 mg/kg and 50 mg/kg mum arachidonic acid secretion. Further, to assess the mode Emodin and 50 mg/kg fexofenadine-HCl for 1 h, via IV of action of Emodin, an immunoblot of cPLA2α, MAPK, challenge with Ag (di-nitrophenyl-human serum albumin in and 5-LO was performed after treatment with IgE/IgA in the 1% Evans blue dye). presence and absence of Emodin. +e obtained results Emodin effectively inhibited the mast cell-dependent presented that the majority of cPLA2α was still in the cytosol PCA reaction in a dose-dependent manner (n � 9), sup- regardless of the IgE/Ag stimulation. However, a pool pressing it by 48% (P< 0.001) and 55% (P< 0.001) at 25 and of phosphorylated cPLA2α was detected in the nuclear 50 mg/kg, respectively. PSA levels were determined in mice (N-p-cPLA2α) and cytosolic (C-p-cPLA2α) regions of the sensitized with IgE or control saline through IV injection activated cells where LTC4 was generated. Under these and challenged 24 hours later with an i.v. injection of DNP- circumstances, no change was observed in the Lamin B and HSA. Emodin dose-dependently decreased serum hista- B-actin (internal control for nuclear and cytosolic fractions, mine, LTC4, and PGD2 levels (n � 9), suppressing LTC4 respectively). +e IgE/Ag-dependent presence of N-p-cPLA2α generation by 38% (P< 0.05) and 70% (P< 0.05), PGD2 and C-p-cPLA2α was substantially suppressed by Emodin, generation by 41% (P< 0.01) and 48% (P< 0.01), and his- indicating the potential role of Emodin in the blockage of tamine release by 13.6% (P< 0.05) and 34.7% (P< 0.01), Ca -dependent translocation of cPLA2α as well as MAPKs respectively. (i.e., ERK1/2) dependent phosphorylation. Similarly, whereas the majority of 5-LO was found in the 6.2. Effect of Emodin on Ca Ion Mobilization and Mast Cell cytosol (C-5-LO), a small amount was translocated into the Degranulation. +e effect of Emodin on the degranulation nucleus fraction (N-5-LO) upon cell activation, resulting in of mast cells was also examined, considering them to play a the formation of LC4. Emodin and each MAPK inhibitor major role in anaphylaxis. Initially, the cytotoxic effects of suppressed 5-LO’s nuclear translocation effectively. Emodin on bone marrow mast cells (BMMCs) were ex- Immunoblot densitometric measurements have further amined using MTT assay, and no significant effects on cell demonstrated that Emodin reduced the Ag-dependent viability even at 40 mM were observed. As a result, addi- translocation of cPLA2a and 5-LO from the cytosolic to 2+ tional studies were conducted at a concentration of<20 mM. nuclear fractions. Studies have shown that intracellular Ca To further study the impact of Emodin on IgE/Ag-induced influx helps regulate 5-LO translocation on multiple occa- 2+ BMMC degranulation, the synthesis of β-hexosaminidase sions [108, 109] and Ca -independent 5-LO translocation (β-hex) was evaluated in the presence and absence of into the nucleus [40]. +ough 5-LO can be activated and Emodin. phosphorylated by MAPKs, [110], it is unclear how MAPK Journal of Healthcare Engineering 13 FcεR1 LAT NTAL α γ PI3K Emodin Grb2 SYK PLCγ1 AKT MAPK IKK Ca cPLAα2 ions IκB Degradation NF κB 5-LO Degranulation NF κB LTC IL-6, TNF-α, COX-2 Figure 10: Emodin might stop mast cells from getting activated by FceRI. +e activation of Syk, a receptor-proximal tyrosine kinase, happens when FceRI comes into contact with the right antigen. A protein called NTAL, which acts as an adaptor, helps Syk control how the PI3K pathway works. +is is important because it allows NF-lB to make COX-2 and other proinflammatory cytokines. Syk also phosphorylates LAT, which leads to the formation of a macromolecular signaling complex that allows for a wide range of downstream 2+ signalings, like PLC1 and Grb2. Activated PLC1 is important for Ca responses and activation of PKCs, which are important for de- granulation and the movement of cPLA2α and 5-LO to the perinuclear membrane and the direction of cPLA2α and 5-LO to the perinuclear membrane. +e Grb2-mediated pathway is important for cPLA2α to be activated properly, leading to eicosanoid hormones [17]. inhibitors prevented 5-LO translocation in IgE/Ag-stimu- the initial phase [17, 85]. IgE-sensitized BMMCs were lated BMMCs. +ere is some preliminary evidence to show pretreated with aspirin to eliminate any previous COX-1 that IgE/Ag-activated BMMCs are resistant to intracellular activity, followed by a brief wash, and then stimulated Ca2+ influx when treated with inhibitors of p38 and ERK. with Ag for 7 hours with or without Emodin to examine if COX-2-mediated delayed PGD Densitometric research indicated that Emodin reduced the production was occur- activation of all MAPKs evoked by IgE/Ag. ring. Emodin suppressed delayed PGD production dose- dependently, with a corresponding decrease in COX-2 protein. Since all MAPK inhibitors wiped out COX-2 ex- 6.4.InMastCells,EmodinSuppressesDelayedPGD Synthesis pression, Emodin’s inhibitory impact on MAPKs may be andCytokineProduction. As we are already familiar with the responsible for suppressing COX-2 induction. metabolism of arachidonic acid (AA) inside mast cells, the Emodin also reduced TNF-α and IL-6 production in a molecule can also opt to alternate COX pathway and thus get dose-dependent manner. It has been found that the NF-lB is metabolism into prostaglandin D (PGD ). PGD synthesis, a key regulator of COX-2 and cytokine expression [111, 112]. 2 2 2 in contrast to LTC synthesis, is a biphasic process. LTC +e effect of Emodin on the NF-lB pathway was studied; 4 4 output and PGD production occur within a few minutes of results indicated that Emodin significantly inhibited the each other in the immediate phase of PGD . NF-lB pathway by phosphorylating IkappaB kinase (IKK- +e second phase of PGD synthesis, which lasts for 2–10 dependent phosphorylation) and degrading the inhibitory hours and is dependent on de novo-induced COX-2, follows Il-B effects on NF-lB nuclear translocation. 14 Journal of Healthcare Engineering After IgE/Ag activation, phosphorylation of the IKK Data Availability complex (p-IlKa/b) and IlBa (p-IlBa) increased, resulting All the data are included in the main text. in a decrease in overall IlBa protein and nuclear translo- cation of NF-lB (N-NF-lB). Emodin inhibited p-IlKa/b and p-IlBa from increasing, IlBa from decreasing, and Conflicts of Interest N-NF-lB from developing. Because Emodin influencess gene transcription in activated mast cells, its effect on the +e authors declare no conflicts of interest. PI3K/Akt pathway was also studied. Emodin inhibited these reactions after IgE/Ag stimulation enhanced the phos- References phorylation forms of Akt. [1] D. V. Wallace, M. S. Dykewicz, D. I. Bernstein et al., “+e diagnosis and management of rhinitis: an updated practice 6.5. Emodin Inhibits Syk Activation. As previously stated, parameter,” <e Journal of Allergy and Clinical Immunology, Emodin has demonstrated a highly effective reaction to vol. 122, pp. S1–S84, 2008. various mast cell functions. +us, it would be noteworthy [2] A Noor, “A data-driven medical decision framework for to assess whether it can inhibit an early regulatory step of associating adverse drug events with drug-drug interaction mechanisms,” Journal of Healthcare Engineering, vol. 2022, FceRI signaling. As we know, spleen tyrosine kinase (Syk) Article ID 9132477, 7 pages, 2022 Mar 3. plays a key role in initiating FceRI-dependent signaling [3] R. A Settipane, “Demographics and epidemiology of allergic [92, 93, 95]. +erefore, it would be essential to note and nonallergic rhinitis,” Allergy and Asthma Proceedings, whether Emodin affects the inhibition of Syk vol. 22, p. 185, 2001. [96, 113, 114]. In addition, phosphorylated forms of LAT [4] K. Okubo, Y. Kurono, K. Ichimura et al., “Japanese (linker of activated T-cells) and PLCɤ1 (phospholipase C Guidelines for Allergic Rhinitis,” Allergology International, gamma 1) were also considered. +ese molecules lie vol. 69, pp. 331–345, 2017. downstream of the Syk [115]. +e experiment significantly [5] S. N. Shah, R. S. Gammal, M. G. Amato et al., “Clinical utility inhibited Syk, LAT, and PLC ɤ1 by Emodin. Because of pharmacogenomic data collected by a health-system PLCg1 phosphorylation is required for inositol phos- Biobank to predict and prevent adverse drug events,” Drug 2+ pholipid breakdown and subsequent Ca signaling [116], Safety, vol. 44, no. 5, pp. 601–607, 2021 May. 2+ the observed suppression of Ca influx by Emodin is most [6] D. A. Nguyen, C. H. Nguyen, and H. Mamitsuka, “A survey on adverse drug reaction studies: data, tasks and machine likely due to its inhibitory action on the Syk-dependent learning methods,” Briefings in Bioinformatics, vol. 22, no. 1, activation of PLC1 (Figure 10). pp. 164–177, 2021 Jan. Lastly, to determine if Emodin may also inhibit human [7] C. Y. Lee and Y.-P. P. Chen, “Prediction of drug adverse mast cell activation, we evaluated its effect on the IgE/Ag- events using deep learning in pharmaceutical discovery,” dependent phosphorylation of Syk, PLCɤ1, and LAT in Briefings in Bioinformatics, vol. 22, no. 2, pp. 1884–1901, 2021 HMC-1 cells. Emodin efficiently suppressed these receptor- Mar. proximal events in HMC-1 cells. [8] A. Noor and A. Assiri, “A novel computational drug repurposing approach for Systemic Lupus Erythematosus (SLE) treatment using Semantic Web technologies,” Saudi 7. Conclusion Journal of Biological Sciences, vol. 28, no. 7, pp. 3886–3892, 2021 Jul. +e current review entails a detailed discussion regarding [9] H. Cao, Y. Rao, L. Liu et al., “+e efficacy and safety of traditional Chinese medicines used to treat allergic rhinitis. leflunomide for the treatment of lupus nephritis in Chinese +e study also outlines the limitation of the currently patients: systematic review and meta-analysis,” PLoS One, marketed drugs such as intranasal antihistamines and vol. 10, no. 12, Article ID e0144548, 2015 Dec 15. corticosteroids, which have been shown to possess multiple [10] R. Naclerio, I. J. Ansotegui, J. Bousquet et al., “International side effects. On the contrary, Chinese traditional medicines expert consensus on the management of allergic rhinitis have been found to regulate the production of cytokines, (AR) aggravated by air pollutants,” World Allergy Organi- including IL-5 and IL-6, which are the major mediators of zation Journal, vol. 13, no. 3, Article ID 100106, 2020 Mar 1. eosinophilic inflammation, TNF-α which recruits T cells [11] J Cheng, W. J Cai, and X. M Zhang, “Study on characteristic H2 at the site of inflammation, and NF-lB which is needed for of syndrome differentiation and therapeutic methods of traditional Chinese medicine on allergic rhinitis,” China J the production of cytokines and IgE antibodies. Tradit Chin Med Pharm, vol. 27, no. 7, pp. 1947–1950, 2012. Similarly, traditional Chinese medicines (TCM) have [12] L Du, X Ye, M Li et al., “Mechanisms of traditional Chinese also been effective in reducing histamine concentration, medicines in the treatment of allergic rhinitis using a net- maintaining histological changes by reducing the thickness work biology approach,” J Tradit Chinese Med Sci, vol. 8, of the lamina propria, and downregulating the expressions pp. 82–89, 2021. of Orai1, STIM1, and TRYC1, indicating the low expres- [13] R. P Siraganian, J Zhang, K Suzuki, and K Sada, “Protein sion of Ca channel proteins. Keeping in view the tyrosine kinase Syk in mast cell signaling,” Molecular Im- promising results obtained from TCM, there is a dire need munology, vol. 38, pp. 1229–1233, 2002. to extend these medications to clinical trials further to [14] R. A Isbrucker and G. A Burdock, “Risk and safety assess- reduce the risk ratio of the disease and contribute to ment on the consumption of Licorice root (Glycyrrhiza sp.), society. its extract and powder as a food ingredient, with emphasis on Journal of Healthcare Engineering 15 the pharmacology and toxicology of glycyrrhizin,” Regula- [30] T. Wynn, “Cellular and molecular mechanisms of fibrosis,” tory Toxicology and Pharmacology, vol. 46, pp. 167–192, 2006. <e Journal of Pathology, vol. 214, no. 2, pp. 199–210, 2008 [15] G Ciprandi, M. A Tosca, C Cosentino, A. M Riccio, Jan. G Passalacqua, and G. W Canonica, “Effects of fexofenadine [31] B Royer, S Varadaradjalou, P Saas et al., “Autocrine regu- and other antihistamines on components of the allergic lation of cord blood-derived human mast cell activation by response: adhesion molecules,” <e Journal of Allergy and IL-10,” <e Journal of Allergy and Clinical Immunology, Clinical Immunology, vol. 112, pp. S78–S82, 2003. vol. 108, pp. 80–86, 2001. [16] F Xu, S Yu, M Qin et al., “Hydrogen-Rich Saline Ameliorates [32] M Stassen, C Muller, ¨ M Arnold et al., “IL-9 and IL-13 Allergic Rhinitis by Reversing the Imbalance of +1/+2 and production by activated mast cells is strongly enhanced in the Up-Regulation of CD4+CD25+Foxp3+Regulatory T Cells, presence of lipopolysaccharide: NF-κB is decisively involved Interleukin-10, and Membrane-Bound Transforming in the expression of IL-9,” <e Journal of Immunology, Growth Factor-β in Guinea Pigs,” Inflammation, vol. 41, vol. 166, no. 7, pp. 4391–4398, 2001. pp. 81–92, 2018. [33] D. P Skoner, “Allergic rhinitis: definition, epidemiology, [17] N Flamand, J Lefebvre, M. E Surette, S Picard, and P Borgeat, pathophysiology, detection, and diagnosis,” <e Journal of “Arachidonic acid regulates the translocation of 5-lip- Allergy and Clinical Immunology, vol. 108, no. 1, pp. S2–S8, oxygenase to the nuclear membranes in human neutrophils,” Journal of Biological Chemistry, vol. 281, pp. 129–136, 2006. [34] L Borish, “Allergic rhinitis: systemic inflammation and [18] N.-G Gwak, E.-Y Kim, B Lee et al., “Xanthii Fructus inhibits implications for management,” <e Journal of Allergy and allergic response in the ovalbumin-sensitized mouse allergic Clinical Immunology, vol. 112, no. 6, pp. 1021–1031, 2003. rhinitis model,” Pharmacognosy Magazine, vol. 11, p. 352, [35] S. J Galli, M Tsai, and A. M Piliponsky, “+e development of 2015. allergic inflammation,” Nature, vol. 454, pp. 445–454, 2008. [19] S Han, L Sun, F He, and H Che, “Anti-Allergic activity of [36] E. W Gelfand, “Inflammatory mediators in allergic rhinitis,” glycyrrhizic acid on IgE-mediated allergic reaction by reg- <e Journal of Allergy and Clinical Immunology, vol. 114, ulation of allergy-related immune cells,” Scientific Reports, no. 5, pp. S135–S138, 2004. vol. 7, pp. 1–9, 2017. [37] a Jr Jc, N York, and G Science, “+e Structure of a Typical [20] T Liu, J Xu, Y Wu et al., “Beneficial effects of Baicalein on a Antibody Molecule,” Immunobiology, 2001. model of allergic rhinitis,” Acta Pharm, vol. 70, pp. 35–47, [38] H Schacke, ¨ W. D Docke, ¨ and K Asadullah, “Mechanisms 2020. involved in the side effects of glucocorticoids,” Pharmacology [21] Y Jia, J Zou, Y Wang et al., “Mechanism of allergic rhinitis & <erapeutics, vol. 96, pp. 23–43, 2002. treated by Centipeda minima from different geographic [39] S. K Wise, S. Y Lin, E Toskala et al., “International consensus areas,” Pharmacien Biologiste, vol. 59, no. 1, pp. 604–616, statement on allergy and rhinology: allergic rhinitis,” In- 2021. ternational forum of allergy & rhinology, vol. 8, no. 2, [22] Y. Lu, J. H. Yang, X. Li et al., “Emodin, a naturally occurring pp. 108–352, 2018. anthraquinone derivative, suppresses IgE-mediated ana- [40] K Rifai, G. I Kirchner, M. J Bahr et al., “A new side effect of phylactic reaction and mast cell activation,” Biochemical immunosuppression: high incidence of hearing impairment Pharmacology, vol. 82, no. 11, pp. 1700–1708, 2011 Dec 1. after liver transplantation,” Liver Transplantation, vol. 12, [23] S. Zhao and R. Iyengar, “Systems pharmacology: network no. 3, pp. 411–415, 2006. analysis to identify multiscale mechanisms of drug action,” [41] H. H Zhu, Y. P Chen, J. E Yu, M Wu, and Z Li, “+erapeutic Annual Review of Pharmacology and Toxicology, vol. 52, Effect of Xincang Decoction on Chronic Airway Inflam- no. 1, pp. 505–521, 2012 Feb 10. mation in Children with Bronchial Asthma in Remission [24] S. H Hong, H. J Jeong, and H. M Kim, “Inhibitory effects of Stage,” Journal of Chinese Integrative Medicine, vol. 3, Xanthii fructus extract on mast cell-mediated allergic re- pp. 23–27, 2005. action in murine model,” Journal of Ethnopharmacology, [42] J Bousquet, P Van Cauwenberge, and N Khaltaev, “Allergic vol. 88, no. 2-3, pp. 229–234, 2003. rhinitis and its impact on asthma,” <e Journal of Allergy and [25] H. J An, H. J Jeong, E. H Lee et al., “Xanthii Fructus Inhibits Clinical Immunology, vol. 108, pp. S147–S334, 2001. Inflammatory Responses in LPS-Stimulated Mouse Perito- [43] T. M Cunha, J Talbot, L. G Pinto et al., “Caspase-1 is involved neal Macrophages,” Inflammation, vol. 28, no. 5, in the genesis of inflammatory hypernociception by con- pp. 263–270, 2004. tributing to peripheral IL-1β maturation,” Molecular Pain, [26] M. Y Song, E. K Kim, H. J Lee et al., “Fructus Xanthii extract vol. 6, pp. 1744–8069, 2010. protects against cytokine-induced damage in pancreatic [44] S. N Georas, J Guo, U De Fanis, and V Casolaro, “T-helper β-cells through suppression of NF-κB activation,” Interna- cell type-2 regulation in allergic disease,” European Respi- tional Journal of Molecular Medicine, vol. 23, no. 4, ratory Journal, vol. 26, pp. 1119–1137, 2005. pp. 547–553, 2009. [45] S. T Holgate and R Polosa, “Treatment strategies for allergy [27] C Bachert, M Jorissen, B Bertrand, N Khaltaev, and and asthma,” Nature Reviews Immunology, vol. 8, no. 3, 2008. J Bousquet, “Allergic Rhinitis and its Impact on Asthma [46] S. A Quraishi, M. J Davies, and T. J Craig, “Inflammatory Update (ARIA 2008),” <e Belgian Perspective. Acta oto- responses in allergic rhinitis: traditional approaches and rhino-laryngologica belgica, vol. 4, no. 4, p. 253, 2008. novel treatment strategies,” Journal of the American Osteo- [28] T. Taylor-Clark, “Histamine in allergic rhinitis,” Advances in pathic Association, vol. 104, pp. S7–15, 2004. Experimental Medicine & Biology, vol. 709, 2010. [47] M. A. McGuckin, S. K. Lind´en, P. Sutton, and T. H. Florin, [29] M. F Kramer, T. R Jordan, C Klemens et al., “Factors “Mucin dynamics and enteric pathogens,” Nature Reviews contributing to nasal allergic late phase eosinophilia,” Am Microbiology, vol. 9, no. 4, pp. 265–278, 2011 Apr. J Otolaryngol - Head Neck Med Surg, vol. 27, no. 3, [48] E. Compalati, E. Ridolo, G. Passalacqua, F. Braido, E. Villa, pp. 190–199, 2006. and G. W. Canonica, “+e link between allergic rhinitis and 16 Journal of Healthcare Engineering asthma: the united airways disease,” Expert Review of Clinical [65] C. Li, G. Lin, and Z. Zuo, “Pharmacological effects and Immunology, vol. 6, no. 3, pp. 413–423, 2010 May 1. pharmacokinetics properties of Radix Scutellariae and its [49] S. Yezli and J. A. Otter, “Minimum infective dose of the bioactive flavones,” Biopharmaceutics & Drug Disposition, major human respiratory and enteric viruses transmitted vol. 32, no. 8, pp. 427–445, 2011 Nov. through food and the environment,” Food and Environ- [66] H. B. Li and F Chen, “Isolation and purification of Baicalein, mental Virology, vol. 3, no. 1, pp. 1–30, 2011 Mar. wogonin and oroxylin A from the medicinal plant Scutellaria [50] S. J. Galli and M. Tsai, “IgE and mast cells in allergic disease,” baicalensis by high-speed counter-current chromatography,” Nature Medicine, vol. 18, no. 5, pp. 693–704, 2012 May. Journal of Chromatography A, vol. 1074, pp. 107–110, 2005. [51] Y. H Kim, C. S Park, D. H Lim et al., “Anti-allergic effect of [67] J Ming, L Zhuoneng, and Z Guangxun, “Protective role of anti-Siglec-F through reduction of eosinophilic inflamma- flavonoid baicalin from Scutellaria baicalensis in periodontal tion in murine allergic rhinitis,” Am J Rhinol Allergy, vol. 27, disease pathogenesis: a literature review,” Complementary pp. 187–191, 2013. <erapies in Medicine, vol. 38, pp. 11–18, 2018. [52] A Stutz, D. T Golenbock, and E Latz, “Inflammasomes: too [68] S. B. Yoon, Y. J Lee, S. K Park et al., “Anti-inflammatory big to miss,” Journal of Clinical Investigation, vol. 119, effects of Scutellaria baicalensis water extract on LPS-acti- pp. 3502–3511, 2009. vated RAW 264.7 macrophages,” Journal of Ethno- [53] A. Noor, A. Assiri, S. Ayvaz, C. Clark, and M. Dumontier, pharmacology, vol. 125, pp. 286–290, 2009. “Drug-drug interaction discovery and demystification using [69] C. S Chen, N. J Chen, L. W Lin, C. C Hsieh, G. W Chen, and Semantic Web technologies,” Journal of the American M. T Hsieh, “Effects of Scutellariae Radix on gene expression Medical Informatics Association, vol. 24, no. 3, pp. 556–564, in HEK 293 cells using cDNA microarray,” Journal of 2017 May 1. Ethnopharmacology, vol. 105, pp. 346–351, 2006. [54] A Azzolina, A Bongiovanni, and N Lampiasi, “Substance P [70] J Choi, C. C Conrad, C. A Malakowsky, J. M Talent, induces TNF-α and IL-6 production through NFκB in C. S Yuan, and R. W Gracy, “Flavones from Scutellaria peritoneal mast cells,” Biochimica et Biophysica Acta (BBA) - baicalensis Georgi attenuate apoptosis and protein oxidation Molecular Cell Research, vol. 1643, pp. 75–83, 2003. in neuronal cell lines,” Biochimica et Biophysica Acta (BBA) - [55] F. J Zhang, Q Wang, Y Wang, and M. L Guo, “Anti-allergic General Subjects, vol. 1571, pp. 201–210, 2002. effects of total bakkenolides from Petasites tricholobus in [71] K Kang, Y. K Oh, R Choue, and S. J Kang, “Scutellariae radix ovalbumin-sensitized rats,” Phyther Res, vol. 25, pp. 116–121, extracts suppress ethanol-induced caspase-11 expression and cell death in N2a cells,” Molecular Brain Research, vol. 142, [56] S. I Mayr, R. I Zuberi, and F. T Liu, “Role of immunoglobulin pp. 139–145, 2005. E and mast cells in murine models of asthma,” Brazilian [72] G. R Schinella, H. A Tournier, J. M Prieto, P Mordujovich Journal of Medical and Biological Research, vol. 36, De Buschiazzo, and J. L R´ıos, “Antioxidant activity of pp. 821–827, 2003. antiinflammatory plant extracts,” Life Sciences, vol. 70, [57] J. M Lehman and M. S Blaiss, “Selecting the Optimal Oral pp. 1023–1033, 2002. Antihistamine for Patients with Allergic Rhinitis,” Drugs, [73] J. Zielonka and B. Kalyanaraman, “Hydroethidine- and vol. 66, pp. 2309–2319, 2006. MitoSOX-derived red fluorescence is not a reliable indicator [58] S. H. Sicherer and H. A. Sampson, “Food allergy: a review of intracellular superoxide formation: another inconvenient and update on epidemiology, pathogenesis, diagnosis, pre- truth,” Free Radical Biology and Medicine, vol. 48, no. 8, vention, and management,” <e Journal of Allergy and pp. 983–1001, 2010 Apr 15. Clinical Immunology, vol. 141, no. 1, pp. 41–58, 2018 Jan 1. [74] C.-L. Kuo, C.-W. Chi, and T.-Y. Liu, “+e anti-inflammatory [59] T Tokiwa, K Harada, T Matsumura, and T Tukiyama, potential of berberine in vitro and in vivo,” Cancer Letters, “Oriental medicinal herb, Periploca sepium, extract inhibits vol. 203, no. 2, pp. 127–137, 2004 Jan 1. growth and IL-6 production of human synovial fibroblast- [75] W Tang, X Sun, J. S Fang, M Zhang, and N. J Sucher, like cells,” Biological and Pharmaceutical Bulletin, vol. 27, “Flavonoids from Radix Scutellariae as Potential Stroke pp. 1691–1693, 2004. +erapeutic Agents by Targeting the Second Postsynaptic [60] T. J Raphael and G Kuttan, “Effect of Naturally Occurring Density 95 (PSD-95)/disc Large/zonula Occludens-1 (PDZ) Triterpenoids Glycyrrhizic Acid, Ursolic Acid, Oleanolic Domain of PSD-95,” Phytomedicine, vol. 11, pp. 277–284, Acid and Nomilin on the Immune System,” Phytomedicine, vol. 10, pp. 483–489, 2003. [76] H. L Chung, G. G. L Yue, K. F To, Y. L Su, Y Huang, and [61] M Vig and J. P Kinet, “Calcium signaling in immune cells,” W. H Ko, “Effect of Scutellariae Radix extract on experi- Nature Immunology, vol. 10, pp. 21–27, 2009. mental dextran-sulfate sodium-induced colitis in rats,” [62] E Gumpricht, R Dahl, M. W Devereaux, and R. J Sokol, World Journal of Gastroenterology, vol. 13, p. 5605, 2007. “Licorice compounds glycyrrhizin and 18β-glycyrrhetinic [77] X. Shang, X. He, X. He et al., “+e genus Scutellaria an acid are potent modulators of bile acid-induced cytotoxicity ethnopharmacological and phytochemical review,” Journal in rat hepatocytes,” Journal of Biological Chemistry, vol. 280, of Ethnopharmacology, vol. 128, no. 2, pp. 279–313, 2010 Mar pp. 10556–10563, 2005. [63] Y Tsujimura, K Obata, K Mukai et al., “Basophils play a [78] P. W Hellings and W. J Fokkens, “Allergic rhinitis and its pivotal role in immunoglobulin-G-mediated but not im- munoglobulin-E-mediated systemic anaphylaxis,” Immu- impact on otorhinolaryngology,” Allergy Eur J Allergy Clin nity, vol. 28, pp. 581–589, 2008. Immunol, vol. 61, pp. 656–664, 2006. [79] P. C Bahekar, J. H Shah, U. B Ayer, S. N Mandhane, and [64] M Bruno, F Piozzi, and S Rosselli, “Natural and hemi- R +ennati, “Validation of Guinea pig model of allergic synthetic neoclerodane diterpenoids from Scutellaria and their antifeedant activity,” Natural Product Reports, vol. 19, rhinitis by oral and topical drugs,” International Immuno- pp. 357–378, 2002. pharmacology, vol. 8, pp. 1540–1551, 2008. Journal of Healthcare Engineering 17 [80] C Cuppari, S Leonardi, S Manti et al., “Allergen immuno- [98] “Proximal signaling events in FcεRI-mediated mast cell therapy, routes of administration and cytokine networks: an activation,” <e Journal of Allergy and Clinical Immunology, update,” Immunotherapy, vol. 6, pp. 775–786, 2014. vol. 119, pp. 544–552, 2007. [81] T. T Bui, C. H Piao, C. H Song, C. H Lee, H. S Shin, and [99] O. L Beong, H. L Jun, Y. K Na et al., “Polygoni Cuspidati O. H Chai, “Baicalein, wogonin, and Scutellaria baicalensis radix inhibits the activation of syk kinase in mast cells for ethanol extract alleviate ovalbumin-induced allergic airway anti-allergic activity,” Experimental Biology and Medicine, vol. 232, pp. 1425–1431, 2007. inflammation and mast cell-mediated anaphylactic shock by regulation of +1/+2 imbalance and histamine release,” [100] B. Yu, J. Sun, and X. Yang, “Assembly of naturally occurring glycosides, evolved tactics, and glycosylation methods,” Anat Cell Biol, vol. 50, pp. 124–134, 2017. [82] S. K Ku and J. S Bae, “Baicalin, Baicalein and wogonin in- Accounts of Chemical Research, vol. 45, no. 8, pp. 1227–1236, hibits high glucose-induced vascular inflammation in vitro 2012 Aug 21. and in vivo,” BMB Rep, vol. 48, p. 519, 2015. [101] Z. P Liu, W. X Li, B Yu et al., “Effects of trans-resveratrol [83] Y Kim, S. B Kim, Y. J You, and B. Z Ahn, “Deoxy- from Polygonum cuspidatum on bone loss using the podophyllotoxin; the cytotoxic and antiangiogenic compo- ovariectomized rat model,” Journal of Medicinal Food, vol. 8, nent from Pulsatilla koreana,” Planta Med, vol. 68, pp. 14–19, 2005. [102] Z Zhang and B Yu, “Total synthesis of the anti-allergic pp. 271–274, 2002. [84] X Luo, Z Yu, C Deng et al., “Baicalein ameliorates naphtho-α-pyrone tetraglucoside, cassiaside C2, isolated from Cassia seeds,” Journal of Organic Chemistry, vol. 68, TNBS-induced colitis by suppressing TLR4/MyD88 signaling cascade and NLRP3 inflammasome activation pp. 6309–6313, 2003. [103] Y. S Lee, O. H Kang, J. G Choi et al., “Synergistic effect of in mice,” Scientific Reports, vol. 7, pp. 1–14, 2017. [85] E. Z. M. da Silva, M. C. Jamur, and C. Oliver, “Mast cell Emodin in combination with ampicillin or oxacillin against function,” Journal of Histochemistry and Cytochemistry, methicillin-resistant Staphylococcus aureus,” Pharmacien vol. 62, no. 10, pp. 698–738, 2014 Oct. Biologiste, vol. 48, pp. 1285–1290, 2010. [86] X. L Fan, Q. X Zeng, X Li et al., “Induced pluripotent stem [104] S. K Heo, H. J Yun, W. H Park, and S. D Park, “Emodin inhibits TNF-α-induced human aortic smooth-muscle cell cell-derived mesenchymal stem cells activate quiescent T cells and elevate regulatory T cell response via NF-κB in proliferation via caspase- and mitochondrial-dependent apoptosis,” Journal of Cellular Biochemistry, vol. 105, allergic rhinitis patients,” Stem Cell Research & <erapy, vol. 9, 2018. pp. 70–80, 2008. [105] S. Z Lin, K. J Chen, H. F Tong, H Jing, H Li, and S Zheng, [87] T Iinuma, Y Okamoto, Y Morimoto et al., “Pathogenicity of memory +2 cells is linked to stage of allergic rhinitis,” “Emodin attenuates acute rejection of liver allografts by Allergy Eur J Allergy Clin Immunol, vol. 73, pp. 479–489, inhibiting hepatocellular apoptosis and modulating the +1/ +2 balance in rats,” Clinical and Experimental Pharma- [88] R Noble and D Noble, “Harnessing Stochasticity: How Do cology and Physiology, vol. 37, pp. 790–794, 2010. [106] G Meng, Y Liu, C Lou, and H Yang, “Emodin suppresses Organisms Make Choices?” Chaos: An Interdisciplinary Journal of Nonlinear Science, vol. 28, Article ID 106309, 2018. lipopolysaccharide-induced pro-inflammatory responses and NF-κB activation by disrupting lipid rafts in CD14- [89] J Cao and G Li, “Chemical constituents of Centipeda minima,” China Journal of Chinese Materia Medica, vol. 37, negative endothelial cells,” British Journal of Pharmacology, no. 15, 2012. vol. 161, pp. 1628–1644, 2010. [90] Z. G Liu, H. M Yu, S. L Wen, and Y. L Liu, “Histopathological [107] Y Feng, S. L Huang, W Dou et al., “Emodin, a natural study on allergic rhinitis treated with Centipeda minima,” product, selectively inhibits 11β-hydroxysteroid dehydro- Zhongguo Zhongyao Zazhi, vol. 30, pp. 292–294, 2005. genase type 1 and ameliorates metabolic disorder in diet- [91] I. V. Yang, C. A. Lozupone, and D. A. Schwartz, “+e induced obese mice,” British Journal of Pharmacology, environment, epigenome, and asthma,” <e Journal vol. 61, p. 113, 2010. of Allergy and Clinical Immunology, vol. 140, no. 1, [108] L. A Samayawardhena and C. J Pallen, “PTPα activates Lyn and Fyn and suppresses hck to negatively regulate FcεRI- pp. 14–23, 2017 Jul 1. [92] H. Lehman and C. Gordon, “+e skin as a window into dependent mast cell activation and allergic responses,” <e primary immune deficiency diseases: atopic dermatitis and Journal of Immunology, vol. 185, pp. 5993–6002, 2010. chronic mucocutaneous candidiasis,” Journal of Allergy and [109] D. D Metcalfe, R. D Peavy, and A. M Gilfillan, “Mechanisms Clinical Immunology: In Practice, vol. 7, no. 3, pp. 788–798, of mast cell signaling in anaphylaxis,” <e Journal of Allergy 2019 Mar 1. and Clinical Immunology, vol. 124, pp. 639–646, 2009. [93] K. Amin, “+e role of mast cells in allergic inflammation,” [110] L Fischer, D Poeckel, E Buerkert, D Steinhilber, and O Werz, “Inhibitors of actin polymerization stimulate arachidonic Respiratory Medicine, vol. 106, no. 1, pp. 9–14, 2012 Jan 1. [94] M Murakami and I Kudo, “Diversity and regulatory func- acid release and 5-lipoxygenase activation by upregulation of Ca2+ mobilization in polymorphonuclear leukocytes in- tions of mammalian secretory phospholipase A2s,” Advances in Immunology, vol. 77, pp. 163–194, 2001. volving Src family kinases,” Biochimica et Biophysica Acta [95] E. S Masuda and J Schmitz, “Syk inhibitors as treatment for (BBA) - Molecular and Cell Biology of Lipids, vol. 1736, allergic rhinitis,” Pulmonary Pharmacology & <erapeutics, pp. 109–119, 2005. vol. 21, pp. 461–467, 2008. [111] O Werz, E Burkert, ¨ B Samuelsson, O Radmark, ˚ and [96] R. P Siraganian, “Mast cell signal transduction from the high- D Steinhilber, “Activation of 5-lipoxygenase by cell stress is affinity IgE receptor,” Current Opinion in Immunology, calcium independent in human polymorphonuclear leuko- vol. 15, pp. 639–646, 2003. cytes,” Blood, vol. 99, pp. 1044–1052, 2002. [97] C Tkaczyk and A. M Gilfillan, “FcεRI-dependent signaling [112] J. K Son, M. J Son, E Lee et al., “Ginkgetin, a biflavone pathways in human mast cells,” Clinical Immunology and from Ginko biloba leaves, inhibits cyclooxygenases-2 and Immunopathology, vol. 99, pp. 198–210, 2001. 5-lipoxygenase in mouse bone marrow-derived mast 18 Journal of Healthcare Engineering cells,” Biological and Pharmaceutical Bulletin, vol. 28, pp. 2181–2184, 2005. [113] Y. Pylayeva-Gupta, E. Grabocka, and D. Bar-Sagi, “RAS oncogenes: weaving a tumorigenic web,” Nature Reviews Cancer, vol. 11, no. 11, pp. 761–774, 2011 Nov. [114] P. P Tak and G. S Firestein, “NF-κB: a key role in inflam- matory diseases,” Journal of Clinical Investigation, vol. 107, pp. 7–11, 2001. [115] J. Jia, F. Zhu, X. Ma, Z. W. Cao, Y. X. Li, and Y. Z. Chen, “Mechanisms of drug combinations: interaction and net- work perspectives,” Nature Reviews Drug Discovery, vol. 8, no. 2, pp. 111–128, 2009 Feb. [116] Y. Lin, R. Shi, X. Wang, and H.-M. Shen, “Luteolin, a fla- vonoid with potential for cancer prevention and therapy,” Current Cancer Drug Targets, vol. 8, no. 7, pp. 634–646, 2008 Nov 1. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Healthcare Engineering Hindawi Publishing Corporation

Recent Progress in Traditional Chinese Medicines and Their Mechanism in the Treatment of Allergic Rhinitis

Loading next page...
 
/lp/hindawi-publishing-corporation/recent-progress-in-traditional-chinese-medicines-and-their-mechanism-bKraBebXcW
Publisher
Hindawi Publishing Corporation
Copyright
Copyright © 2022 Dehong Mao et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN
2040-2295
eISSN
2040-2309
DOI
10.1155/2022/3594210
Publisher site
See Article on Publisher Site

Abstract

Hindawi Journal of Healthcare Engineering Volume 2022, Article ID 3594210, 18 pages https://doi.org/10.1155/2022/3594210 Review Article Recent Progress in Traditional Chinese Medicines and Their Mechanism in the Treatment of Allergic Rhinitis Dehong Mao, Zhongmei He, Linglong Li, Yuting lei, Maodi Xiao, Huimin Zhang, and Feng Zhang Department of Otolaryngology, Yongchuan Hospital of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 402160, China Correspondence should be addressed to Feng Zhang; fengzhang06@yeah.net Received 18 February 2022; Accepted 17 March 2022; Published 11 April 2022 Academic Editor: Liaqat Ali Copyright © 2022 Dehong Mao et al. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. To conduct a systematic review on the mechanism of action and use of traditional Chinese medicines (TCM) in allergic rhinitis treatment. Background. Allergic rhinitis (AR) is a type I allergic disease of the immune system induced by immuno- globulin E mediated inflammation and is characterized by sneezing, nasal itching, paroxysmal nasal obstruction, mucosal edema, cough, and rhinorrhea. More than 500 million people have been affected by rhinitis worldwide in the past 20 years, leading to negative effects on health, quality of life, and social relationships. Currently, the trending medicines used in the case of AR include intranasal corticosteroids and oral H1 antihistamines, which are given as combinatorial medicines supplemented with immune therapy. +ese medications have been found to be very effective in either the short term or long term; however, they have been found to possess some serious side effects. Search Methodology. +e information in this article on classical and traditional Chinese medications used to treat AR was derived from original papers and reviews published in Chinese and English language journals. Two Chinese databases (Wanfang and CNKI) and three English databases (Cochrane Library, PubMed, and Embase) were utilized for data gathering. Results. Traditional Chinese remedies have been identified to influence the production of cytokines such as IL-5 and IL-6, which are key mediators of eosinophilic inflammation, TNF-α, which stimulates TH2 cells at the site of inflammation, and NF-lB, which is required for cytokine and IgE antibody production. TCM has also been shown to be successful in lowering histamine levels, preserving histological changes by decreasing the thickness of the lamina propria, and downregulating the expression of Orai1, STIM1, and TRYC1, showing low expression of Ca channel proteins. Conclusion. In this review, we discussed a series of classical, traditional Chinese medications, including Centipeda minima, Scutellaria baicalensis, licorice root (Glycyrrhiza uralensis), and others, as potential antiallergic agents and investigate their in vivo effect upon the production of cytokines and release of histamines for allergic rhinitis treatment. approximately 15–20% of the population around the globe is 1. Introduction affected by AR, with a dominating ratio in western countries Allergic rhinitis (AR) is usually a severe condition that [2, 3]. +e treatment of the condition potentially focuses on develops due to allergen exposure and results in IgE-me- alleviating the symptoms rather than addressing the root diated inflammation of the nasal membranes. +e common cause of the issue. Hence, patients are often recommended to symptoms found among patients with AR include sneezing, avoid direct contact with allergens such as pollen, dander, nasal obstruction, itching sensation in the nasal cavity, and dust mites, and cockroach infestations, which can potentially rhinorrhea. +ese major symptoms may often be accom- stimulate the arousal of rhinitis. Considerably, the first line panied by fatigue from nasal discomfort, itching sensation of treatment is solely based on (intranasal antihistamines, around the eyes, swelling of the nasal mucosal membranes, corticosteroids, and cromolyn) to reduce inflammation. postnasal dripping, and cough [1]. On the far current record, However, some cases might require surgical intervention [4]. 2 Journal of Healthcare Engineering combined drugs treatment has been recorded to date. Using the allergen challenge test at the molecular level, several researchers have established that people with AR Although the following TCM herbs are beneficial against allergic rhinitis, no comprehensive assessment of their anti- secrete mediators such as histamine and leukotriene (LT). +ese proinflammatory factors have been detected in nasal allergic-rhinitis mechanisms information from published secretions of the affected individuals upon exposure to al- scientific results has yet been undertaken. As a result, the lergens, but little has been known about their secretion in current study concentrated on using traditional Chinese natural conditions [5–7]. Previous studies have reported the medicinal herbs to treat AR. +is review will cover tradi- secretion of cytokine (IL-1α), a proinflammatory factor, tional Chinese medicines (TCM) that are widely used to treat upon exposure to allergens during the early or late phase of allergic rhinitis. Studies have demonstrated certain herbs to change bi- the reaction [8–10]. +ereby, it was suggested that the cy- tokine might have a crucial role in activating endothelial ological pathways implicated in allergic rhinitis, such as eosinophil cell death, adhesion molecule modulation, mast cells long with T-lymphocytes, further stimulating the cy- tokine release. Recent research has also discovered the cell generation, T /T imbalance, nuclear factor, che- H1 H2 presence of IL-1Ra, a naturally occurring inhibitor, in a mokine concentrations, and IgE regulation [12] (Table 1). higher molar concentration in the nasal discharges of AR Herbs that are frequently used to cure allergic rhinitis patients and controls [11]. +e antagonist (IL-1Ra) binds comprise Xanthium fruit, Scutellaria root (Scutellaria bai- with the IL-1 receptor, preventing the active (IL-1α) binding calensis), Centipeda herb (Centipeda minima), licorice root without affecting its respective biological response. Similar (Glycyrrhiza uralensis), and Astragalus roots (Astragalus to IL-1α, another chemokine of the interleukin-8 family, membranaceus). +ese herbs are the key components in interleukin-8 (IL-8), has been found to be elevated herbal prescription and other Chinese herbs [12]. throughout the late stages of the disease and is being in- vestigated as a possible candidate in eosinophil movement in 2. Xanthium Fructus certain conditions. According to a seasonal study conducted to assess the +e Xanthii fructus (XF) is a well-known dried fruit of effect of cytokines upon exposure to allergens, it was de- Xanthium strumarium, also called “Cang-Erzi” in Taiwan. It duced that a constant incline in the concentration of leu- has been used over the years to treat various diseases, in- kotriene and Eosinophil Cationic Protein (ECP) was cluding rheumatism, sinusitis, skin pruritus, and headaches prominent throughout the season. According to the find- (Figures 1(a) and 1(b)) [18]. +e Xanthii fructus has been ings, histamine concentrations only elevated late in the shown to reduce mast cell-mediated allergy reactions [19], season and postseasonally. Additionally, the cytokine IL-1β anti-inflammatory actions in lipopolysaccharide-stimulated and its natural antagonist, IL-1Ra, were assessed. Surpris- inflammatory responses [20], and prevention of β-cell ingly, there was a considerable rise in IL-1β concentrations damage in type 1 diabetes [21]. from early in the season to postseason, corroborating the As previously stated, allergic rhinitis can be divided into hypothesis of chronic proinflammatory upregulation in two stages: early and late. +e ailment manifests itself within seasonal allergic rhinitis. Additionally, the same study de- 5–30 minutes of exposure to the antigen, such as mold, dust, termined a considerable decrease in IL-1Ra concentrations or animal dander [22, 23]. Early symptoms following ex- during the early season, indicating dysregulation of the local posure typically include lacrimation, clear rhinorrhea, anti-inflammatory capacity. Similarly, nasal secretions itching, and sneezing, which are commonly triggered by the contained a significant rise in IL-1β concentration, con- production of mast cell secretions, including histamine [24]. firming the assumption of chronic proinflammatory On a molecular level, mast cells have been known to play a regulation. significant role in inflammatory processes, including the Along with IL-1β, the considerable downregulation of release of proinflammatory cytokines such as tumor necrosis IL-8 and myeloperoxidase indicates disruption of localized factor (TNF-α), interleukin-1β, interleukin-8, and inter- immunity, implying a substantial connection between the leukin-6 and inflammatory factors including serotonin and two variables. Myeloperoxidase is a marker of neutrophil histamine (Figure 2) [25–27]. activation, and its lower expression means reduced IL-8 Likewise, the late phase of allergic rhinitis is often secretion. Since neutrophils account for about 40%–60% of characterized by the recruitment of effector cells such as the cells on the mucosal surface and may operate similarly to basophils, eosinophils, and T-helper 2 (T ) lymphocytes, H2 macrophages, their dysregulation may increase susceptibility causing malaise, irritability, fatigue, and congestion within to infectious diseases. To summarize, allergic rhinitis does 6–24 hours after antigen exposure [28–32]. On the other certainly reflect chronic inflammation, as evidenced by hand, eosinophils have been revealed to play an essential eosinophil activity and prolonged elevation of the proin- part in the disease’s late stage. +e abundance of eosinophils flammatory cytokine IL-1α. As a result, the release of cy- in the nasal mucosa of the affected patients indicates the tokines continues for weeks after pollen contact is ceased in release of proinflammatory mediators such as cysteinyl persistent and seasonal allergic rhinitis. Numerous com- leukotrienes, eosinophil peroxidase, major basic protein ponents, targets, and mechanisms underlying allergen-in- cation in proteins. Presently, the common treatment of AR, duced inflammatory disorders remain unknown despite as mentioned earlier, includes the usage of corticosteroids, substantial research on allergic rhinitis. Due to the com- immunosuppressants, and antihistamines. However, their plexity of the disease, only symptomatic treatment or use is restricted due to various adverse effects, such as lipid Journal of Healthcare Engineering 3 Table 1: A cumulative representation of traditional Chinese medicines used to treat allergic rhinitis and the respective pathways and biomarkers regulated by them. Traditional Chinese Type of S. no. Status of biomarkers Techniques/assays used References medicine study TNF-α, IL-6, IL-5 ↓ Cytotoxicity assay IF-1β, MIP-1 ↓ Western blotting 01. Xanthi fructus MIP-2 ↓ In vivo Optical microscopy [13] Histamine, IgE ↓ ELISA Caspase-1 ↓ IFN-c ↑ Evans blue extravasion assay IgE, IgG ↓ ELISA assay Licorice root β-Hexosaminidase ↓ WST-8 assay 02. In vivo [14] (glycyrrhizic acid) IgE mediated Ca influx↓ β-Hex assay Orai1, STIM1 ↓ RT-PCR IP3R, TRYC1 ↓ Western blot Scutellaria baicalensis IL-6, TNF-α, IL-1β ↓ ELISA 03. In vivo [15] Georgi. STAT3 pathway ↓ Immunohistochemical staining TNF-α, IL-2, IL-4 ↓ In silico ELISA 04. Centipeda minima Immunohistochemical staining, H&E [16] PTGS2, MAPK ↓ In vivo staining PCA, histamine ↓ Evans blue extravasion assay LCT , PGD , LTC ↓ β-Hexosaminidase assay immunoblotting 4 2 4 β-Hex, Ca influx ↓ 5-LO, MAPK, cPLA2α ↓ 05. Emodin In vivo [17] PDG generation ↓ TNF-α, IL-6, NF-lB ↓ Syk, LAT, PLCɤ1 ↓ AKT pathway ↓ (a) Figure 1: Continued. 4 Journal of Healthcare Engineering (b) Figure 1: (a) and (b) Representation of the plant and fruit of Xanthium strumarium, also called “Cang-Erzi.” IL-4 IL-13 TSLP Histamine IgE Production Medicinal Plant Medicinal Allergic Rhinitis Medicinal Plant Plant Medicinal Plant T > T Mast cell activation H2 H1 Histamine Serotonin Leukotriene Figure 2: +e diagrammatic representation of biomarkers affected during allergic rhinitis. and glucose metabolism problems, osteoporosis, excessive histamine and TNF-α production in mast cell-mediated sedation, and hypertension [33–35]. allergic responses [19, 36]. We will cover a study paper in this Over the years, multiple studies have proven the me- section which examines the mechanism of XF effects by dicinal value of Xanthii fructus (XF) with its anti-inflam- looking at cytokine and caspase-1 levels, the thickness of matory properties. In a survey conducted by An et al., the nasal septum tissue, and the frequency of sneezing behavior anti-inflammatory role of XF has been reported on lip- in an in vivo AR model produced by ovalbumin (OVA). osaccharide-stimulated mouse peritoneal macrophages [20]. Additionally, the process by which XF inhibits NF-lB Another study discovered that XF extract shields pancreatic regulation has been explored. β-cells from cytokine-induced damage by inhibiting nuclear factor kappa-B (NK-lB) [21]. Another study has established 2.1. Effects of Xanthii fructus over Nasal Symptoms in Allergic that XF is responsible for inhibiting chronic inflammation found in airways among bronchial asthma patients. Addi- Rhinitis. As discussed earlier, the major symptoms of AR include rhinorrhea, itching, sneezing, and nasal congestion tionally, the extract was found to be effective against Journal of Healthcare Engineering 5 sensitized mast cell begins to degranulate, secreting newly [37]. An OVA-sensitized mouse model was considered to study XF’s potential in vivo anti-inflammatory effects. synthesized and preformed mediators including cytokines, histamines, cysteinyl leukotrienes, and prostaglandins Following sensitization, the extract of XF was injected with cetirizine (a positive control) to assess its anti-inflammatory [40, 41]. TNF-α is one of the cytokines that have been shown properties. Compared to OVA-sensitized mice, a model to have a significant role in allergic inflammation, as it is treated with XF had a considerably lower amount of required for +2 migration to the site of allergic inflam- sneezing (P< 0.01). mation and the generation of +2 cytokines [42]. IL-1β, which has mostly been found to be elevated after allergen exposure, activates endothelial cells and T-lymphocytes, 2.2. Effects of Xanthii fructus on Serum Levels of Histamine, leading to further production of cytokines [43]. Immunoglobulin E, and OVA-Specific IgE. To investigate the Similarly, IL-5 and IL-6 have been identified as major effects of XF, several mice (BALB/c) were injected with OVA mediators of eosinophilic inflammation leading to asthma injections causing a significant increase in OVA-specific IgE and are vital in developing nasal secretions, respectively [44]. and immunoglobulin E levels. As to our previous under- Asthma patients’ bronchoalveolar lavage fluid contains standing, overexpression of IgE is a prominent marker of greater levels of the chemokine MCP-1, associated with the allergic rhinitis. In OVA-sensitized models, blood levels of activation of eosinophils and basophils [45]. In the absence histamine and total and OVA-sensitized IgE were observed of an antigen or an anti-IgE antibody, histamine-releasing to be considerably raised with time. However, treatment of factors (HRFs) drive mast cells and basophils to release mice with XF extract resulted in a significant decrease histamine. (P< 0.05) in histamine and total and OVA-specific IgE. Eosinophils move from the blood to the site of in- flammation in allergic rhinitis because of the inflammatory stimulus (produced by antigen-presenting cells). +is is also 2.3. Cytokines and the Role of Xanthii fructus in Regulation. one of the main features of allergic rhinitis [46]. Inflam- As we previously understood, cytokines play a vital role in mation is frequently reduced when eosinophils are de- the course of inflammation. +e two groups taken under creased. Now that we know more about caspase-1, an study (i.e., OVA-sensitized mice and mice treated with XF) enzyme in the cysteine-protease family, we can better un- were observed to understand the trend in the serum level of derstand how it affects the development of the IL-1 family cytokines. +e concentration levels of TNF-α, IL-6, IL-5, IF- and how it affects disease-causing immune responses [47]. 1β, MIP-2, and MIP-1 significantly increased among OVA- +is thickness of the lamina propria in the nasal septum and sensitized mice. On the contrary, the XF-treated group infiltration of eosinophils has been found to be conspicu- presented an appreciable decline in the concentrations of ously reduced after treatment with XF. these cytokines, indicating its anti-inflammatory function +e expressions of all cytokines predominantly depend among AR models. on an active transcription factor, NF-lB [48]. +is activation requires phosphorylation and proteolysis and degradation of 2.4. Eosinophil Infiltration and Histological Alterations in the Il-Bα (an endogenous inhibitor of NF-lB) as its key Nasal Mucosa. OVA-sensitized mice groups had extensive component [49]. XF was also found to inhibit the phos- eosinophil infiltration in the entire area of the lamina phorylation and degradation of this transcription factor propria, increasing thickness to the nasal tissues, as per successfully. Hence, causing the inactivation of NF-lB leads histological analyses. However, XF-treated mice groups to a substantially low level of cytokines. +e treatment of AR showed a marked reduction in the thickness of the lamina has led to constructing an animal model in the current propria. research strategy. In comparison, periodic intranasal OVA treatment has induced typical AR symptoms on a physical and molecular 2.5. Impact of Xanthii fructus on the Expression of Caspase-1. level in the animal models (i.e., inflammatory mediators and Caspase-1 is a member of a protease family also known by IgE production) [48, 50, 51]. XF has drastically decreased the name of IL-1β-converting enzyme (IL-1, BCE, or ICE). levels and an antiallergic impact by blocking the generation +e enzyme contributes to immune-mediated inflammation of its mediators. Cetirizine, a metabolite that is a selective H1 by converting the precursor forms of interleukin-1β and receptor being used to treat angioedema, urticarial, and interleukin-18 into active molecules found in the extracel- allergies [52], has been taken as a positive control. +e lular compartment [38]. Following the same trend, a sig- scheme has also concluded that the effect of XF has been nificant increase in the expression of caspase-1 was observed found similar to that of cetirizine. among OVA-sensitized mice, whereas, upon treatment with XF, a prominent decrement was noted in the expression of 3. Licorice Root caspase-1. An allergic reaction is mostly regarded as a condition caused 2.6. Mechanism of Action. To our knowledge, allergic illness by hypersensitivity of the immune system to react with the is mediated by the increase of the +2 cell subset and the substances normally considered harmless in all age groups, production of particular IgE antibodies by B cells in response thereby leading to anaphylaxis [53]. +e condition is often to diverse allergens. [39]. In such response, the IgE- mediated by immunoglobulin E response with few 6 Journal of Healthcare Engineering medicines available to alleviate the allergic symptoms, in- studied compared to the controls (P< 0.05). +e results cluding antihistamine drugs (i.e., diphenhydramine, terfe- presented that only 100 mg/kg body weight of GA has nadine, and chlorpheniramine maleate), immune significantly decreased the production of OVA-sensitized suppressors (hydrocortisone, dexamethasone, and adrenal antibodies (P< 0.05). +e inhibition effect was found to be cortical hormones), and mast cells stabilizers (ketotifen, similar to that of hydrocortisone. Hence, GA was also found sodium hydroxypropyl cromate, and disodium cromogly- to influence OVA-sensitized antibody-producing B-cells cate). However, as with other drugs, most of these products have been shown to possess side effects. Similarly, symptom 3.3. Role of GA as a “Mast Cell Stabilizer”. According to our relapse has also been observed among patients. In this prior knowledge, Mast cells contribute to IgE-induced al- regard, a suitable alternative derived from food with no side lergy by producing different cytokines, a key cause of allergic effects may serve as a possible drug of interest to overcome conditions. Using passive cutaneous anaphylaxis (PCA) and allergic symptoms. RBL3-2H3 immunologic cell-based tests, it was further Glycyrrhiza is a plant with an ancient origin and has been explored if GA can also influence mast cell activation. used over history for herbal medicine and food (Figure 3) +e assay results indicate a substantial reduction in the [54]. Among other plant constituents, glycyrrhizic acid (GA) mast cell-dependent PCA reaction in the GA-treated group is considered one of the main components possessing several (in a dose-dependent manner). Similarly, the effect of GA on pharmacological properties. Numerous research have dis- degranulation was examined by quantifying β-hexosamin- covered that biologically active substances in organic foods, idase release in the absence and presence of GA. As for the such as polyphenols and flavonoids, which have anti-in- cytokines, glycyrrhizic acid was found to cause substantial flammatory or antioxidant properties, lead to antiallergic suppression in the release of β-hexosaminidase from 87.46% action. Clinical and experimental studies have revealed the to 45.23% with the increment of dosage from 100 to 1000µg/ application of glycyrrhizic acid (Figure 4) with its immu- mL (P< 0.05). nomodulatory [55] and anti-inflammatory [56] character- istics. A study reduced asthma-like symptoms in mice with a Balb/c model by taking GA (2.5–20 mg/kg body weight). 3.4. Impact of GA upon Expression of Calcium Channel +is was found to be an effective way to treat the mice’s Proteins. According to the available literature, degranula- asthma, simultaneously preventing the reduction in total +2 tion of RBL-2H3 cells is dependent on the release of Ca IgG2a and interferon-gamma (INF-c) levels. Furthermore, ions from the endoplasmic reticulum (ER) and the Ca ion GA (10 mg/kg body weight) has been proven to block the influx mediated by calcium release-activated calcium activation of NF-lB and STAT-317, hence reducing the channels (CRAC) [57]. Hence, the effect of GA on the influx onset of acute inflammation. In this section, we will discuss +2 of Ca ions was taken under investigation. +e intracellular the antiallergic effects of glycyrrhizic acid along with its Ca ion concentration was determined using Fluo-3 AM possible underlying mechanisms. +2 (a fluorescent Ca ion indicator). GA at a 1000µg/mL concentration prevented Ca influx mediated by IgE/Ag. +e activation of Ca influx-mediated proteins such as 3.1. <rough T-Helper Cell Development, GA Plays a Role in stromal interacting molecule 1 (STIM1), Inositol 1,4,5 tri- OVA-Induced Systemic Allergy Reactions. +e antiallergic phosphate receptor (IP3R), calcium release-activated cal- activity of GA was evaluated in an OVA-induced active cium channel protein 1 (Orai1), and transient receptor systemic allergic response. Conspicuously, multiple allergic potential channel 1 (TRPC1) was also studied. On a similar symptoms were prominent in the sensitization group, in- note, there was a significant decrease in the expressions of cluding labored respiration, scratching, and a total decrease in Orai1, STIM1, IP3R, and TRPC1 upon treatment with GA. rectal temperature by −1.60± 0.1 C. However, the 100 mg/kg +ese findings show that GA has no role in the depletion of body weight group treated with GA showed substantial the ER Ca reservoir; instead, the stability of mast cells is suppression of allergic symptoms and a net decrease of ° predicated on Ca influx inhibition due to decreased Orai1, −0.9± 0.1 C in rectal temperature. STIM1, and TRPC1) expression. +e rate of inhibition observed by 100 mg/kg of GA is comparable to that of hydrocortisone, a standard allergy treatment. As for the levels of cytokines, a significant in- 3.5. Mechanism of Action. Glycyrrhizic acid (GA) has been crease was noted among T cytokine IL-4, whereas a de- H2 reported to have similar effects on the immune system of creasing trend was prominent among +1 cytokines (IFN-c) Balb/c mice as other natural triterpenoids [58]. +ese may among the OVA-sensitized group. However, after treatment include anti-inflammatory, antineoplastic, antiviral, im- with 100 mg/kg, a significant increase in the level of IFN-c mune-regulatory, pharmacological, and antiallergic effects. was observed. +ese findings indicated that an oral dose of +e three major mechanisms by which antiallergic effect 100 mg/kg GA might influence +1/+2, resulting in an comes into play are (i) a potential role as a mast cell sta- attenuation of allergic reactions. bilizer, to reduce the secretion of mediators via imparting inhibitory effect over Ca influx, (ii) modulation of TH cell 3.2. Inhibition of OVA-Specific IgE and IgG1 Production via development to limit cytokine (IL-4) release from T cells, H2 B-Cells. Additionally, the effect of GA on the generation of and (iii) influencing OVA-specific antibody-producing IgG1 and IgE antibodies in the OVA-sensitized group was B-cells (Figure 5). Journal of Healthcare Engineering 7 Figure 3: Presentation of a licorice plant [17]. COOH HOOC OH HO HOOC OH HO OH Figure 4: Structure of glycyrrhizic acid. According to our previous understanding, GA can de- GA treatment has led to the significant reduction of the crease serum total IgE and OVA-specific IgE levels [14]. In intracellular Ca levels. As a result, the extracellular process allergic rhinitis mice models, GA has been shown to elicit a of Ca influxes is inhibited. However, no variation in considerable reduction of OVA-specific IgE antibodies in a mRNA expression of inositol-3-phosphate receptor was dose-dependent way. +is significant reduction could be identified in the absence or presence of GA, indicating that caused by blocking T /T differentiation and maturation, GA did not affect endoplasmic reticulum (ER) storage. On H1 H2 which would impede the production of IL-4. Furthermore, the other hand, the expressions of Orai1, STIM1, and GA has also been found to suppress IgG1, later leading to TRYC1 were significantly reduced, suggesting that GA may inhibition of basophil activation [59]. Likewise, the study has regulate Ca degranulation via decreasing calcium channel also presented the role of GA as a mast cell stabilizer, where expression levels. Degranulation 8 Journal of Healthcare Engineering Glycyrrhizic acid Stabilizes mast cells Ag Modulates T 1/T 2 H H or basophils by subset balance blocking Ca influx Basophils Secretion of Modulates T 1/T 2 H H subset balance PAF Dendritic cells Mast cells T-helper cell Synthesis of antibodies Ex Ca influx through Calcium channel T 1 cells T 2 cells H H protein IgG IgE Recruitment and activation of T 2 cells Binds to FcγRIII Figure 5: +e mechanism through which GA exerts its antiallergic impact on IgE-mediated allergic reactions [13]. obstruction, sneezing, congestion, and rhinorrhea, which 4. Scutellariae Radix can lead to ear and nasal abnormalities if left untreated [74]. Scutellariae Radix (RS), also referred to as huangqin in A complicated allergen-induced inflammatory process Chinese, is the dry root of the Labiatae plant Scutellaria within the nasal mucosa causes the condition. On a mo- baicalensis Georgi. [60]. In English, the plant is also known lecular level, such a process causes the release of histamine as Baikal skullcap or Chinese skullcap, and it is endemic to and a variety of cytokines and proinflammatory substances, Asia, particularly Far East Russia, Mongolia, Siberia, East which can trigger vascular dilatation and tear secretion [75]. Asia, and China (Figure 6). +e plant is frequently used in Among all other activities, the release of IgE has been de- traditional Chinese medicine to treat cardiovascular and termined to have a significant part in the overproduction of respiratory disorders, gastrointestinal infections, inflam- basophils, eosinophils, and mast cells, as discussed in various mation, and other diseases [61]. Regardless of the whole sections [76]. plant, the usage of RS is more extensive in Japanese and Among the various flavonoids mentioned above, bai- Chinese pharmacopeia with a broad range of therapeutic calein is one of the major constituents of RS found to effects, including detoxifying toxicosis, preventing bleeding regulate T /T balance and adjust histamine release from H1 H2 and miscarriage, clearing away heat, and moistening aridity the mast cells [77]. Several research groups have reported the [62, 63]. Anti-inflammatory properties of RS have been well anti-inflammatory role of baicalein in mouse models, alle- documented in in vivo and in vitro investigations, including viating colitis, liver, and vascular inflammation [78, 79] inhibition of chemokine, cytokine, and growth factor pro- induced by dextran sulfate sodium (DSS) and 2,4,6-trini- duction from macrophages [64–69], exhibiting potential trobenzene sulfonic acid (TNBS) [79, 80]. +rough an OVA- treatment of colon cancer [70], stroke [71], and colitis [72]. induced AR animal model, we will explain the regulating +e major biological compounds isolated from RS efficacy of baicalein derived from RS on clinical symptoms of include phenylethanoid glycosides, flavonoids, diterpenes, AR, mucosal histological alterations, and inflammation in triterpenes, phytosterols, polysaccharides, and iridoid vivo. glycosides [73]. Among these, over 40 flavonoids along with the form of glycosides have been identified as most abundant [73], which include the key bioactive compo- 4.1. Baicalein’s Anti-Inflammatory Properties in AR-Infected nents oroxylin A-7-glucuronide (OAG), oroxylin A (OA), Rats. Two major characteristic features, body weight and wogonoside (wogonin-7-glucuronide, WG), baicalein (B), mass of the vital organs, were considered in OVA group, wogonin (W), and baicalin (baicalein-7-glucuronide, BG) OVA + baicalein group, and OVA + clarityne group. In [61] (Figure 7). terms of body weight, there was no statistically significant As previously mentioned, AR is a condition marked by difference between the two groups. After 30 minutes of OVA significant pain and other symptoms such as respiratory stimulation, the frequency of nasal scratching, degree of IL-4 Differentiation Binds to FcR1 IL-4 Journal of Healthcare Engineering 9 Figure 6: A pictorial presentation of a traditional Chinese medicine herb, Scutellariae Radix [15]. COOH HO O O OH HO OH OH O OH O · Baicalin (R =OH, R =H) · Baicalein (R =OH, R =H) 1 2 1 2 · Wogonin(R =H, R =OMe) · Wogonoside (R =H, R =OMe) 1 2 1 2 · Oroxylin A(R =OMe, R =H) · Oroxylin A7-0-glucuronide (R =OMe, R =H) 1 2 1 2 Figure 7: Active components obtained from Scutellariae Radix, including flavonoids and glycosides. nasal outflow, and sneezing pattern in each group were OVA-induced (AR model) and baicalein-treated groups recorded and then overlapped to analyze the findings. better to understand the role of baicalein in inflammatory It is worth noting that the OVA-treated group had more factor production. In the AR model, there was a considerable sneezing and nasal scratching than the control group. Fur- increase in IL-6, TNF-α, and IL-1β, which gradually de- thermore, a significant reduction in the frequency of sneeze and creased after treatment with baicalein. nasal grating was found after baicalein treatment, but the in- hibition mechanism is still unknown. +e primary organ masses 4.3. Baicalein’s Effect on Inflammatory Cell Infiltration in the (including the spleen, kidney, liver, and heart) were also iden- tified in the OVA-induced, OVA + baicalein-treated, and control NasalMucosaandLungTissue. Allergen-induced rhinitis, as groups. +e spleen in the OVA-induced group was significantly we all know, results in inflammatory infiltration of the lamina propria. +ree groups have been identified based on heavier in comparison to the control group (P< 0.05), while the spleen in the baicalein treatment group was considerably lighter histological findings using H&E staining. Inflammatory cells were not found in the nasal cavity, lateral nasal walls, or nasal in comparison to the OVA-induced group (P< 0.05). septum in the healthy one. In addition, no signs of vascular congestion or proliferation were observed while presenting 4.2. <e Effect of Baicalein on Inflammatory Variables in AR normal tissue structure and mucosal glands. However, in the Rats’ Nasal Lavage Fluid and Serum. Levels of inflammatory second group (AR model), characteristic changes were factors such as IL-6, TNF-α, and IL-1β were assessed in the present in the histological parameters, including many 10 Journal of Healthcare Engineering inflammatory cells (eosinophils, basophils, and mast cells) inside the nasal mucosa. On the other hand, the same feature was significantly reduced in the baicalein-treated group, demonstrating a significant ability to prevent inflammatory cell formation. Additionally, lung tissue compounds were examined, with pertinent sections stained with H&E to ascertain the extent of lung injury. Damage was visible on the surface, with interstitial edema, thickening, and infiltration of neutrophils into the alveolar wall, as well as the formation of a necrotizing ulcer. However, baicalein was found to alle- viate these symptoms significantly. Figure 8: +e plant of Centipeda minima [85]. 4.4.Baicalein’sEffectonp-STAT3ExpressioninNasalMucosa Tissues. To further validate the impact of baicalein over the inhibition of relevant pathways, the STAT3 signaling demonstrated in studies to decrease eosinophil and mast cell pathway was brought into the investigation. According to activation, diminish degenerative alterations in nasal mu- the findings, baicalein inhibited the phosphorylation of the cosal tissues, lower histamine levels, and minimize nasal STAT3 signaling pathway in OVA-induced rats. As dis- stiffness [87]. cussed earlier, AR can be categorized into two distinct +is section will explain the experimental investigation phases. An early stage is usually characterized by IgE-in- conducted to extract volatile oil components from duced activation of inflammatory cells, including neutro- C. minima gathered from seven different geographical sites phils, eosinophils, and lymphocytes, along with the throughout China and the optimal steam distillation ex- production of related cytokines (IL1β, IL-6, and TNF-α). traction settings. +e volatile oil composition of C. minima Similarly, the late phase of the condition involves the was determined using gas chromatography-mass spec- recruitment of other inflammatory cells such as mast trometry (GC-MS) after extraction. Component-related cells and basophils, in addition to the release of che- molecular targets were investigated using network phar- mokines, histamine, and leukotrienes accounting for the macology analysis. +e primary pathways and key targets of anaphylactic shock [81–84]. Typical AR symptoms were C. minima components were identified, as well as the overall reported in this study starting on day 15 and gradually amount of protein-disease connection. +e best volatile oil faded after 1.5 hours. According to the present findings, extraction yield from C. minima was obtained at 300 C baicalein reduced the frequency of nasal itching and through a 10-mesh sieve. sneezing in AR rats. 5.1. Fingerprint and Cluster Analysis. +e volatile oil-related 5. Centipeda minima GC-MS data from C. minima were integrated into the Centipeda minima (L.) A. Braun et Aschers (Compositae), traditional Chinese medicine chromatographic fingerprints sometimes known as coriander, is an annual herbaceous similarity evaluation method. +e data reveal minor changes plant native to eastern tropical zones, Taiwan, and China in the makeup of C. minima samples taken from seven (Figure 8). +e plant, also known as chickweed, is drought- different geographic locations. tolerant and spreads throughout China. C. minima has been +e findings reveal that plants collected in Jiangxi, known to possess a spicy taste. It has been traditionally used Hubei, Shanxi, and Sichuan have high similarities. We in Chinese folk medicine to treat sinusitis, relieve pain, discovered roughly 30 additional volatile oil C. minima reduce swelling rhinitis, and treat cancer for a very long time compounds for each location, 15 of which were identical [86]. Medicinally, the plant has also been used to minimize across all plants. cough and nasal secretions associated with respiratory complications [16]. To our current understanding, the main medicinal constituents of C. minima involved in treatment 5.2. C. minima and Allergic Rhinitis Target Prediction and include polysaccharides, flavonoids, and volatile oils. Mapping. +e Venny software tool collected the 15 volatile Pharmacological studies of the plant represent that these oil components isolated from C. minima specimens in seven therapeutic components have been conventionally used to geographic areas. 343 relevant targets for 15 components treat antitumor, antiprotozoal, and allergic rhinitis-associ- and 2155 diseases targets were identified following a data- ated headaches. base search. +e Venny software was used to import the As previously described, allergic rhinitis is a noninfec- obtained component targets and disease-related targets. As a tious inflammation of the nasal mucosa. Symptoms include result, 117 genes with known intersections were identified. nasal congestion, runny and itchy nose, and recurrent 172 intersection targets were imported into the STRING sneezing episodes. Work and other daily activities may be platform to study protein interactions. +e circle’s diameter harmed due to these difficulties. C. minima has been fluctuates according to each protein’s degree value, with a Journal of Healthcare Engineering 11 that the IL-2 content in the model group was significantly higher degree value suggesting that a protein interacts with more pathways. +ree proteins were chosen based on their lower than that in the blank group (P< 0.01). +ere was a statistically significant difference (P< 0.01) between the degree and centrality values: mitogen-activated protein ki- nase 3 (MAPK3), prostaglandin-endoperoxide synthase 2 treatment and the model groups in IL-2 levels. (PTGS2), and tumor necrosis factor (TNF). +e model group’s IL-4 levels were considerably higher (P< 0.001). +e level of IL-4 in the treatment group was substantially lower than that in the model group (P< 0.001). 5.3.KEGGandGOAnalysis. +e KEGG and GO analyses of According to the IgE study, the model group had consid- the intersection targets were performed using the R package erably more IgE than the blank group (P< 0.001). Compared clusterProfiler. According to the findings of the GO analysis, to the model group, the treatment group had dramatically the biological process (BP) was linked to 1753 pathways, reduced levels of IgE (P< 0.01). Because of this, C. minima including response to a bacterial molecule, regulation of the can reduce inflammatory responses while increasing anti- inflammatory response, and cellular calcium ion homeo- inflammatory responses. +is effect indicates the plant’s stasis, indicating that these genes are involved in related ability to alleviate the symptoms of allergic rhinitis. biological processes in vivo and collaborate in the treatment of allergic rhinitis. Our study data revealed 37 cellular components (CC) pathways, including the membrane re- 5.6. Immunochemistry. Immunohistochemistry results gion, an important part of the resynaptic membrane tran- showed that the expression rates of PTGS2 and MAPK3 in scription regulator complex, and other pathways that play a inflamed tissues were much greater than those in normal role in allergic rhinitis pathology. KEGG analysis found 137 tissues. Compared to the control group, the model group’s pathways that were connected. 28 of the target proteins were average optical density of PTGS2 and MAPK3 proteins was found to play a role in neuroactive ligand-receptor inter- significantly higher (P< 0.01). +ere was a big difference in action, 15 of the target proteins are involved in +17 cell the PTGS2 and MAPK3 proteins in the volatile oil-treated differentiation, and 12 of the target proteins are involved in group compared to the model group (P< 0.05). the VEGF signaling process. +e data analysis shows that C. minima active ingredients are linked to several possible 6. Xanthium Fruit: Emodin allergic rhinitis pathways. People who have allergic rhinitis are more likely to get it if they go through the second +17 As discussed previously, chronic T allergic inflammation H2 cell differentiation process, according to the results of the such as rhinitis, asthma, and atopic dermatitis affects up to enrichment analysis and the literature. 300 million people worldwide [88, 89]. With the current expansion in urbanization, there is a rise in the number of patients suffering from allergic reactions. +ere is an urgent 5.4.H&EStaining. Tissue analysis in rats demonstrated that need to discover alternative antiallergic medicines that can the nasal mucosa epithelium in the “blank controls” was increase the quality of life while also being safer to use. unaffected. +ere was no inflammatory cell infiltration in the Mast cells have long been recognized as a critical player submucosa of control rats. Cilia were also lost in the disease in allergic diseases, where the aggregation of high-affinity model group, and the nasal epithelium was damaged. In IgE receptors (FceRI) on mast cells stimulates the secretion tissue samples from infected mice, interstitial edema and of both preformed (e.g., proteases and histamine) and newly interstitial inflammatory cell infiltration were observed, as synthesized mediators such as prostaglandin D2 (PGD2) well as gland hyperplasia and swelling. C. minima extract- and leukotriene C4 (LTC4) [90, 91]. Signaling cascades are treated rats had much less damage to their nasal mucosa, initiated when a cognate antigen (Ag) binds to FceRI. +e with less glandular hyperplasia and less inflammatory cell stimulation of receptor-proximal tyrosine kinases such as infiltration into the interstitial cell layers in their noses. Syk, Lyn, Fyn, and Btk and the phosphorylation of other adaptor molecules are examples of these pathways. Syk is 5.5. ELISA. Immune cells can be activated and regulated by essential for the activation of IgE-dependent mast cells. Once interleukins as second messengers, activating and regulating active, Syk phosphorylates adaptor proteins such as the several inflammatory processes, such as +17 cell differ- linker for activation of T cells (LAT), resulting in the for- entiation. Cell proliferation and differentiation can be mation of a macromolecular signaling complex that allows boosted by TNF, for example. IgE serves as a reference for the diversity of downstream signaling required for the measure for the onset and progression of allergic rhinitis as a creation of various proinflammatory mediators [92–95]. key inflammatory factor. Further, we measured the amounts Signaling pathways of such a kind include Ca ion of inflammatory and anti-inflammatory elements (IL-4, mobilization mediated through phospholipase C (PLC ), a g g TNF-α, and IgE) in the serum to verify the network phar- prerequisite step for LTC generation and subsequent de- macology’s pathway and targets. TNF, IL-2, IgE, and IL-4 granulation [94]. As a result, inhibiting Syk kinase may limit were measured in rat serum using ELISA. TNF levels in the the release of various granule-stored and newly produced model group were substantially higher than those in the mediators [92]. Additionally, crosslinking of FceR1 has been control group (P< 0.001). shown to activate the mitogen-activated protein kinase TNF levels were considerably lower in the treatment (MAPK), phosphoinositol-3-kinase/Akt (PI3K/Akt), and group compared to the model group (p 0.01). It was found nuclear factor-lB signaling pathways. As a result, several 12 Journal of Healthcare Engineering proinflammatory genes, such as those encoding cyclo- OH OOH oxygenase (COX-2) and proinflammatory cytokines, are expressed [95]. Polygonum multiflorum +unberg, Rheum officinale Bail, Polygoni cuspidati (P. cuspidati), radix, and Cassia obtusi- folia seed have been utilized in traditional medicines in Eastern Asia for numerous centuries. +ese oriental plants H C OH contain various pharmacological properties, including anti- inflammatory and antiallergic properties [96–99]. Emodin O (1,3,8-trihydroxy-6-methylanthraquinone), a compound Figure 9: Structure of Emodin. found in these herbs, has been demonstrated to have a variety of biological actions (i.e., immunosuppressive, an- timicrobial, anti-inflammatory, antidiabetic, and anti- A substantial suppression of β-hex was observed in a atherosclerotic activities) (Figure 9) [100–104]. Additionally, dose-dependent manner (P< 0.01). Moreover, the produc- Emodin has been shown to inhibit the oncogenic trans- tion of cytosolic Ca was considered, acknowledging that formation of lung and breast cancer by inhibiting HER2/neu the release of Ca is a key factor in mast cell degranulation tyrosine kinase activity, indicating its anticancer potential. [107]. Interestingly, 20 mM of Emodin completely inhibited We will address the antiallergic properties of Emodin and its IgE/Ag-stimulated Ca influx (P< 0.01). possible use as a natural remedy for allergic diseases in this part. 6.3. Effect of Emodin on the Generation of Leukotriene-C (LTC ) from Mast Cells. According to our present under- 6.1. Effect of Emodin on Anaphylactic Reaction in Mice. standing, LTC4 production is regulated in two phases (i.e., We understand that anaphylaxis is a profound allergic re- cPLA liberation of arachidonic acid (AA) from membrane 2α action induced by crosslinking specific IgE bound to FceR1. phospholipids and 5-lipooxygenase oxygenation of free +is interaction between FceR1 and IgE stimulates the arachidonic acid). In response to increased Ca levels, both mediator release from mast cells, causing anaphylaxis molecules (cPLA and 5-LO) translocate from the cytosol to 2α [30, 105, 106]. Passive cutaneous anaphylaxis (PCA) and the perinuclear membrane [108, 109]. passive systemic anaphylaxis (PSA) were used to assess Furthermore, mitogen-activated kinases (MAPK) Emodin’s antiallergic activity. PCA was considered in sensi- phosphorylate cPLA2α, a mechanism necessary for opti- tized mice following oral treatment of 25 mg/kg and 50 mg/kg mum arachidonic acid secretion. Further, to assess the mode Emodin and 50 mg/kg fexofenadine-HCl for 1 h, via IV of action of Emodin, an immunoblot of cPLA2α, MAPK, challenge with Ag (di-nitrophenyl-human serum albumin in and 5-LO was performed after treatment with IgE/IgA in the 1% Evans blue dye). presence and absence of Emodin. +e obtained results Emodin effectively inhibited the mast cell-dependent presented that the majority of cPLA2α was still in the cytosol PCA reaction in a dose-dependent manner (n � 9), sup- regardless of the IgE/Ag stimulation. However, a pool pressing it by 48% (P< 0.001) and 55% (P< 0.001) at 25 and of phosphorylated cPLA2α was detected in the nuclear 50 mg/kg, respectively. PSA levels were determined in mice (N-p-cPLA2α) and cytosolic (C-p-cPLA2α) regions of the sensitized with IgE or control saline through IV injection activated cells where LTC4 was generated. Under these and challenged 24 hours later with an i.v. injection of DNP- circumstances, no change was observed in the Lamin B and HSA. Emodin dose-dependently decreased serum hista- B-actin (internal control for nuclear and cytosolic fractions, mine, LTC4, and PGD2 levels (n � 9), suppressing LTC4 respectively). +e IgE/Ag-dependent presence of N-p-cPLA2α generation by 38% (P< 0.05) and 70% (P< 0.05), PGD2 and C-p-cPLA2α was substantially suppressed by Emodin, generation by 41% (P< 0.01) and 48% (P< 0.01), and his- indicating the potential role of Emodin in the blockage of tamine release by 13.6% (P< 0.05) and 34.7% (P< 0.01), Ca -dependent translocation of cPLA2α as well as MAPKs respectively. (i.e., ERK1/2) dependent phosphorylation. Similarly, whereas the majority of 5-LO was found in the 6.2. Effect of Emodin on Ca Ion Mobilization and Mast Cell cytosol (C-5-LO), a small amount was translocated into the Degranulation. +e effect of Emodin on the degranulation nucleus fraction (N-5-LO) upon cell activation, resulting in of mast cells was also examined, considering them to play a the formation of LC4. Emodin and each MAPK inhibitor major role in anaphylaxis. Initially, the cytotoxic effects of suppressed 5-LO’s nuclear translocation effectively. Emodin on bone marrow mast cells (BMMCs) were ex- Immunoblot densitometric measurements have further amined using MTT assay, and no significant effects on cell demonstrated that Emodin reduced the Ag-dependent viability even at 40 mM were observed. As a result, addi- translocation of cPLA2a and 5-LO from the cytosolic to 2+ tional studies were conducted at a concentration of<20 mM. nuclear fractions. Studies have shown that intracellular Ca To further study the impact of Emodin on IgE/Ag-induced influx helps regulate 5-LO translocation on multiple occa- 2+ BMMC degranulation, the synthesis of β-hexosaminidase sions [108, 109] and Ca -independent 5-LO translocation (β-hex) was evaluated in the presence and absence of into the nucleus [40]. +ough 5-LO can be activated and Emodin. phosphorylated by MAPKs, [110], it is unclear how MAPK Journal of Healthcare Engineering 13 FcεR1 LAT NTAL α γ PI3K Emodin Grb2 SYK PLCγ1 AKT MAPK IKK Ca cPLAα2 ions IκB Degradation NF κB 5-LO Degranulation NF κB LTC IL-6, TNF-α, COX-2 Figure 10: Emodin might stop mast cells from getting activated by FceRI. +e activation of Syk, a receptor-proximal tyrosine kinase, happens when FceRI comes into contact with the right antigen. A protein called NTAL, which acts as an adaptor, helps Syk control how the PI3K pathway works. +is is important because it allows NF-lB to make COX-2 and other proinflammatory cytokines. Syk also phosphorylates LAT, which leads to the formation of a macromolecular signaling complex that allows for a wide range of downstream 2+ signalings, like PLC1 and Grb2. Activated PLC1 is important for Ca responses and activation of PKCs, which are important for de- granulation and the movement of cPLA2α and 5-LO to the perinuclear membrane and the direction of cPLA2α and 5-LO to the perinuclear membrane. +e Grb2-mediated pathway is important for cPLA2α to be activated properly, leading to eicosanoid hormones [17]. inhibitors prevented 5-LO translocation in IgE/Ag-stimu- the initial phase [17, 85]. IgE-sensitized BMMCs were lated BMMCs. +ere is some preliminary evidence to show pretreated with aspirin to eliminate any previous COX-1 that IgE/Ag-activated BMMCs are resistant to intracellular activity, followed by a brief wash, and then stimulated Ca2+ influx when treated with inhibitors of p38 and ERK. with Ag for 7 hours with or without Emodin to examine if COX-2-mediated delayed PGD Densitometric research indicated that Emodin reduced the production was occur- activation of all MAPKs evoked by IgE/Ag. ring. Emodin suppressed delayed PGD production dose- dependently, with a corresponding decrease in COX-2 protein. Since all MAPK inhibitors wiped out COX-2 ex- 6.4.InMastCells,EmodinSuppressesDelayedPGD Synthesis pression, Emodin’s inhibitory impact on MAPKs may be andCytokineProduction. As we are already familiar with the responsible for suppressing COX-2 induction. metabolism of arachidonic acid (AA) inside mast cells, the Emodin also reduced TNF-α and IL-6 production in a molecule can also opt to alternate COX pathway and thus get dose-dependent manner. It has been found that the NF-lB is metabolism into prostaglandin D (PGD ). PGD synthesis, a key regulator of COX-2 and cytokine expression [111, 112]. 2 2 2 in contrast to LTC synthesis, is a biphasic process. LTC +e effect of Emodin on the NF-lB pathway was studied; 4 4 output and PGD production occur within a few minutes of results indicated that Emodin significantly inhibited the each other in the immediate phase of PGD . NF-lB pathway by phosphorylating IkappaB kinase (IKK- +e second phase of PGD synthesis, which lasts for 2–10 dependent phosphorylation) and degrading the inhibitory hours and is dependent on de novo-induced COX-2, follows Il-B effects on NF-lB nuclear translocation. 14 Journal of Healthcare Engineering After IgE/Ag activation, phosphorylation of the IKK Data Availability complex (p-IlKa/b) and IlBa (p-IlBa) increased, resulting All the data are included in the main text. in a decrease in overall IlBa protein and nuclear translo- cation of NF-lB (N-NF-lB). Emodin inhibited p-IlKa/b and p-IlBa from increasing, IlBa from decreasing, and Conflicts of Interest N-NF-lB from developing. Because Emodin influencess gene transcription in activated mast cells, its effect on the +e authors declare no conflicts of interest. PI3K/Akt pathway was also studied. Emodin inhibited these reactions after IgE/Ag stimulation enhanced the phos- References phorylation forms of Akt. [1] D. V. Wallace, M. S. Dykewicz, D. I. Bernstein et al., “+e diagnosis and management of rhinitis: an updated practice 6.5. Emodin Inhibits Syk Activation. As previously stated, parameter,” <e Journal of Allergy and Clinical Immunology, Emodin has demonstrated a highly effective reaction to vol. 122, pp. S1–S84, 2008. various mast cell functions. +us, it would be noteworthy [2] A Noor, “A data-driven medical decision framework for to assess whether it can inhibit an early regulatory step of associating adverse drug events with drug-drug interaction mechanisms,” Journal of Healthcare Engineering, vol. 2022, FceRI signaling. As we know, spleen tyrosine kinase (Syk) Article ID 9132477, 7 pages, 2022 Mar 3. plays a key role in initiating FceRI-dependent signaling [3] R. A Settipane, “Demographics and epidemiology of allergic [92, 93, 95]. +erefore, it would be essential to note and nonallergic rhinitis,” Allergy and Asthma Proceedings, whether Emodin affects the inhibition of Syk vol. 22, p. 185, 2001. [96, 113, 114]. In addition, phosphorylated forms of LAT [4] K. Okubo, Y. Kurono, K. Ichimura et al., “Japanese (linker of activated T-cells) and PLCɤ1 (phospholipase C Guidelines for Allergic Rhinitis,” Allergology International, gamma 1) were also considered. +ese molecules lie vol. 69, pp. 331–345, 2017. downstream of the Syk [115]. +e experiment significantly [5] S. N. Shah, R. S. Gammal, M. G. Amato et al., “Clinical utility inhibited Syk, LAT, and PLC ɤ1 by Emodin. Because of pharmacogenomic data collected by a health-system PLCg1 phosphorylation is required for inositol phos- Biobank to predict and prevent adverse drug events,” Drug 2+ pholipid breakdown and subsequent Ca signaling [116], Safety, vol. 44, no. 5, pp. 601–607, 2021 May. 2+ the observed suppression of Ca influx by Emodin is most [6] D. A. Nguyen, C. H. Nguyen, and H. Mamitsuka, “A survey on adverse drug reaction studies: data, tasks and machine likely due to its inhibitory action on the Syk-dependent learning methods,” Briefings in Bioinformatics, vol. 22, no. 1, activation of PLC1 (Figure 10). pp. 164–177, 2021 Jan. Lastly, to determine if Emodin may also inhibit human [7] C. Y. Lee and Y.-P. P. Chen, “Prediction of drug adverse mast cell activation, we evaluated its effect on the IgE/Ag- events using deep learning in pharmaceutical discovery,” dependent phosphorylation of Syk, PLCɤ1, and LAT in Briefings in Bioinformatics, vol. 22, no. 2, pp. 1884–1901, 2021 HMC-1 cells. Emodin efficiently suppressed these receptor- Mar. proximal events in HMC-1 cells. [8] A. Noor and A. Assiri, “A novel computational drug repurposing approach for Systemic Lupus Erythematosus (SLE) treatment using Semantic Web technologies,” Saudi 7. Conclusion Journal of Biological Sciences, vol. 28, no. 7, pp. 3886–3892, 2021 Jul. +e current review entails a detailed discussion regarding [9] H. Cao, Y. Rao, L. Liu et al., “+e efficacy and safety of traditional Chinese medicines used to treat allergic rhinitis. leflunomide for the treatment of lupus nephritis in Chinese +e study also outlines the limitation of the currently patients: systematic review and meta-analysis,” PLoS One, marketed drugs such as intranasal antihistamines and vol. 10, no. 12, Article ID e0144548, 2015 Dec 15. corticosteroids, which have been shown to possess multiple [10] R. Naclerio, I. J. Ansotegui, J. Bousquet et al., “International side effects. On the contrary, Chinese traditional medicines expert consensus on the management of allergic rhinitis have been found to regulate the production of cytokines, (AR) aggravated by air pollutants,” World Allergy Organi- including IL-5 and IL-6, which are the major mediators of zation Journal, vol. 13, no. 3, Article ID 100106, 2020 Mar 1. eosinophilic inflammation, TNF-α which recruits T cells [11] J Cheng, W. J Cai, and X. M Zhang, “Study on characteristic H2 at the site of inflammation, and NF-lB which is needed for of syndrome differentiation and therapeutic methods of traditional Chinese medicine on allergic rhinitis,” China J the production of cytokines and IgE antibodies. Tradit Chin Med Pharm, vol. 27, no. 7, pp. 1947–1950, 2012. Similarly, traditional Chinese medicines (TCM) have [12] L Du, X Ye, M Li et al., “Mechanisms of traditional Chinese also been effective in reducing histamine concentration, medicines in the treatment of allergic rhinitis using a net- maintaining histological changes by reducing the thickness work biology approach,” J Tradit Chinese Med Sci, vol. 8, of the lamina propria, and downregulating the expressions pp. 82–89, 2021. of Orai1, STIM1, and TRYC1, indicating the low expres- [13] R. P Siraganian, J Zhang, K Suzuki, and K Sada, “Protein sion of Ca channel proteins. Keeping in view the tyrosine kinase Syk in mast cell signaling,” Molecular Im- promising results obtained from TCM, there is a dire need munology, vol. 38, pp. 1229–1233, 2002. to extend these medications to clinical trials further to [14] R. A Isbrucker and G. A Burdock, “Risk and safety assess- reduce the risk ratio of the disease and contribute to ment on the consumption of Licorice root (Glycyrrhiza sp.), society. its extract and powder as a food ingredient, with emphasis on Journal of Healthcare Engineering 15 the pharmacology and toxicology of glycyrrhizin,” Regula- [30] T. Wynn, “Cellular and molecular mechanisms of fibrosis,” tory Toxicology and Pharmacology, vol. 46, pp. 167–192, 2006. <e Journal of Pathology, vol. 214, no. 2, pp. 199–210, 2008 [15] G Ciprandi, M. A Tosca, C Cosentino, A. M Riccio, Jan. G Passalacqua, and G. W Canonica, “Effects of fexofenadine [31] B Royer, S Varadaradjalou, P Saas et al., “Autocrine regu- and other antihistamines on components of the allergic lation of cord blood-derived human mast cell activation by response: adhesion molecules,” <e Journal of Allergy and IL-10,” <e Journal of Allergy and Clinical Immunology, Clinical Immunology, vol. 112, pp. S78–S82, 2003. vol. 108, pp. 80–86, 2001. [16] F Xu, S Yu, M Qin et al., “Hydrogen-Rich Saline Ameliorates [32] M Stassen, C Muller, ¨ M Arnold et al., “IL-9 and IL-13 Allergic Rhinitis by Reversing the Imbalance of +1/+2 and production by activated mast cells is strongly enhanced in the Up-Regulation of CD4+CD25+Foxp3+Regulatory T Cells, presence of lipopolysaccharide: NF-κB is decisively involved Interleukin-10, and Membrane-Bound Transforming in the expression of IL-9,” <e Journal of Immunology, Growth Factor-β in Guinea Pigs,” Inflammation, vol. 41, vol. 166, no. 7, pp. 4391–4398, 2001. pp. 81–92, 2018. [33] D. P Skoner, “Allergic rhinitis: definition, epidemiology, [17] N Flamand, J Lefebvre, M. E Surette, S Picard, and P Borgeat, pathophysiology, detection, and diagnosis,” <e Journal of “Arachidonic acid regulates the translocation of 5-lip- Allergy and Clinical Immunology, vol. 108, no. 1, pp. S2–S8, oxygenase to the nuclear membranes in human neutrophils,” Journal of Biological Chemistry, vol. 281, pp. 129–136, 2006. [34] L Borish, “Allergic rhinitis: systemic inflammation and [18] N.-G Gwak, E.-Y Kim, B Lee et al., “Xanthii Fructus inhibits implications for management,” <e Journal of Allergy and allergic response in the ovalbumin-sensitized mouse allergic Clinical Immunology, vol. 112, no. 6, pp. 1021–1031, 2003. rhinitis model,” Pharmacognosy Magazine, vol. 11, p. 352, [35] S. J Galli, M Tsai, and A. M Piliponsky, “+e development of 2015. allergic inflammation,” Nature, vol. 454, pp. 445–454, 2008. [19] S Han, L Sun, F He, and H Che, “Anti-Allergic activity of [36] E. W Gelfand, “Inflammatory mediators in allergic rhinitis,” glycyrrhizic acid on IgE-mediated allergic reaction by reg- <e Journal of Allergy and Clinical Immunology, vol. 114, ulation of allergy-related immune cells,” Scientific Reports, no. 5, pp. S135–S138, 2004. vol. 7, pp. 1–9, 2017. [37] a Jr Jc, N York, and G Science, “+e Structure of a Typical [20] T Liu, J Xu, Y Wu et al., “Beneficial effects of Baicalein on a Antibody Molecule,” Immunobiology, 2001. model of allergic rhinitis,” Acta Pharm, vol. 70, pp. 35–47, [38] H Schacke, ¨ W. D Docke, ¨ and K Asadullah, “Mechanisms 2020. involved in the side effects of glucocorticoids,” Pharmacology [21] Y Jia, J Zou, Y Wang et al., “Mechanism of allergic rhinitis & <erapeutics, vol. 96, pp. 23–43, 2002. treated by Centipeda minima from different geographic [39] S. K Wise, S. Y Lin, E Toskala et al., “International consensus areas,” Pharmacien Biologiste, vol. 59, no. 1, pp. 604–616, statement on allergy and rhinology: allergic rhinitis,” In- 2021. ternational forum of allergy & rhinology, vol. 8, no. 2, [22] Y. Lu, J. H. Yang, X. Li et al., “Emodin, a naturally occurring pp. 108–352, 2018. anthraquinone derivative, suppresses IgE-mediated ana- [40] K Rifai, G. I Kirchner, M. J Bahr et al., “A new side effect of phylactic reaction and mast cell activation,” Biochemical immunosuppression: high incidence of hearing impairment Pharmacology, vol. 82, no. 11, pp. 1700–1708, 2011 Dec 1. after liver transplantation,” Liver Transplantation, vol. 12, [23] S. Zhao and R. Iyengar, “Systems pharmacology: network no. 3, pp. 411–415, 2006. analysis to identify multiscale mechanisms of drug action,” [41] H. H Zhu, Y. P Chen, J. E Yu, M Wu, and Z Li, “+erapeutic Annual Review of Pharmacology and Toxicology, vol. 52, Effect of Xincang Decoction on Chronic Airway Inflam- no. 1, pp. 505–521, 2012 Feb 10. mation in Children with Bronchial Asthma in Remission [24] S. H Hong, H. J Jeong, and H. M Kim, “Inhibitory effects of Stage,” Journal of Chinese Integrative Medicine, vol. 3, Xanthii fructus extract on mast cell-mediated allergic re- pp. 23–27, 2005. action in murine model,” Journal of Ethnopharmacology, [42] J Bousquet, P Van Cauwenberge, and N Khaltaev, “Allergic vol. 88, no. 2-3, pp. 229–234, 2003. rhinitis and its impact on asthma,” <e Journal of Allergy and [25] H. J An, H. J Jeong, E. H Lee et al., “Xanthii Fructus Inhibits Clinical Immunology, vol. 108, pp. S147–S334, 2001. Inflammatory Responses in LPS-Stimulated Mouse Perito- [43] T. M Cunha, J Talbot, L. G Pinto et al., “Caspase-1 is involved neal Macrophages,” Inflammation, vol. 28, no. 5, in the genesis of inflammatory hypernociception by con- pp. 263–270, 2004. tributing to peripheral IL-1β maturation,” Molecular Pain, [26] M. Y Song, E. K Kim, H. J Lee et al., “Fructus Xanthii extract vol. 6, pp. 1744–8069, 2010. protects against cytokine-induced damage in pancreatic [44] S. N Georas, J Guo, U De Fanis, and V Casolaro, “T-helper β-cells through suppression of NF-κB activation,” Interna- cell type-2 regulation in allergic disease,” European Respi- tional Journal of Molecular Medicine, vol. 23, no. 4, ratory Journal, vol. 26, pp. 1119–1137, 2005. pp. 547–553, 2009. [45] S. T Holgate and R Polosa, “Treatment strategies for allergy [27] C Bachert, M Jorissen, B Bertrand, N Khaltaev, and and asthma,” Nature Reviews Immunology, vol. 8, no. 3, 2008. J Bousquet, “Allergic Rhinitis and its Impact on Asthma [46] S. A Quraishi, M. J Davies, and T. J Craig, “Inflammatory Update (ARIA 2008),” <e Belgian Perspective. Acta oto- responses in allergic rhinitis: traditional approaches and rhino-laryngologica belgica, vol. 4, no. 4, p. 253, 2008. novel treatment strategies,” Journal of the American Osteo- [28] T. Taylor-Clark, “Histamine in allergic rhinitis,” Advances in pathic Association, vol. 104, pp. S7–15, 2004. Experimental Medicine & Biology, vol. 709, 2010. [47] M. A. McGuckin, S. K. Lind´en, P. Sutton, and T. H. Florin, [29] M. F Kramer, T. R Jordan, C Klemens et al., “Factors “Mucin dynamics and enteric pathogens,” Nature Reviews contributing to nasal allergic late phase eosinophilia,” Am Microbiology, vol. 9, no. 4, pp. 265–278, 2011 Apr. J Otolaryngol - Head Neck Med Surg, vol. 27, no. 3, [48] E. Compalati, E. Ridolo, G. Passalacqua, F. Braido, E. Villa, pp. 190–199, 2006. and G. W. Canonica, “+e link between allergic rhinitis and 16 Journal of Healthcare Engineering asthma: the united airways disease,” Expert Review of Clinical [65] C. Li, G. Lin, and Z. Zuo, “Pharmacological effects and Immunology, vol. 6, no. 3, pp. 413–423, 2010 May 1. pharmacokinetics properties of Radix Scutellariae and its [49] S. Yezli and J. A. Otter, “Minimum infective dose of the bioactive flavones,” Biopharmaceutics & Drug Disposition, major human respiratory and enteric viruses transmitted vol. 32, no. 8, pp. 427–445, 2011 Nov. through food and the environment,” Food and Environ- [66] H. B. Li and F Chen, “Isolation and purification of Baicalein, mental Virology, vol. 3, no. 1, pp. 1–30, 2011 Mar. wogonin and oroxylin A from the medicinal plant Scutellaria [50] S. J. Galli and M. Tsai, “IgE and mast cells in allergic disease,” baicalensis by high-speed counter-current chromatography,” Nature Medicine, vol. 18, no. 5, pp. 693–704, 2012 May. Journal of Chromatography A, vol. 1074, pp. 107–110, 2005. [51] Y. H Kim, C. S Park, D. H Lim et al., “Anti-allergic effect of [67] J Ming, L Zhuoneng, and Z Guangxun, “Protective role of anti-Siglec-F through reduction of eosinophilic inflamma- flavonoid baicalin from Scutellaria baicalensis in periodontal tion in murine allergic rhinitis,” Am J Rhinol Allergy, vol. 27, disease pathogenesis: a literature review,” Complementary pp. 187–191, 2013. <erapies in Medicine, vol. 38, pp. 11–18, 2018. [52] A Stutz, D. T Golenbock, and E Latz, “Inflammasomes: too [68] S. B. Yoon, Y. J Lee, S. K Park et al., “Anti-inflammatory big to miss,” Journal of Clinical Investigation, vol. 119, effects of Scutellaria baicalensis water extract on LPS-acti- pp. 3502–3511, 2009. vated RAW 264.7 macrophages,” Journal of Ethno- [53] A. Noor, A. Assiri, S. Ayvaz, C. Clark, and M. Dumontier, pharmacology, vol. 125, pp. 286–290, 2009. “Drug-drug interaction discovery and demystification using [69] C. S Chen, N. J Chen, L. W Lin, C. C Hsieh, G. W Chen, and Semantic Web technologies,” Journal of the American M. T Hsieh, “Effects of Scutellariae Radix on gene expression Medical Informatics Association, vol. 24, no. 3, pp. 556–564, in HEK 293 cells using cDNA microarray,” Journal of 2017 May 1. Ethnopharmacology, vol. 105, pp. 346–351, 2006. [54] A Azzolina, A Bongiovanni, and N Lampiasi, “Substance P [70] J Choi, C. C Conrad, C. A Malakowsky, J. M Talent, induces TNF-α and IL-6 production through NFκB in C. S Yuan, and R. W Gracy, “Flavones from Scutellaria peritoneal mast cells,” Biochimica et Biophysica Acta (BBA) - baicalensis Georgi attenuate apoptosis and protein oxidation Molecular Cell Research, vol. 1643, pp. 75–83, 2003. in neuronal cell lines,” Biochimica et Biophysica Acta (BBA) - [55] F. J Zhang, Q Wang, Y Wang, and M. L Guo, “Anti-allergic General Subjects, vol. 1571, pp. 201–210, 2002. effects of total bakkenolides from Petasites tricholobus in [71] K Kang, Y. K Oh, R Choue, and S. J Kang, “Scutellariae radix ovalbumin-sensitized rats,” Phyther Res, vol. 25, pp. 116–121, extracts suppress ethanol-induced caspase-11 expression and cell death in N2a cells,” Molecular Brain Research, vol. 142, [56] S. I Mayr, R. I Zuberi, and F. T Liu, “Role of immunoglobulin pp. 139–145, 2005. E and mast cells in murine models of asthma,” Brazilian [72] G. R Schinella, H. A Tournier, J. M Prieto, P Mordujovich Journal of Medical and Biological Research, vol. 36, De Buschiazzo, and J. L R´ıos, “Antioxidant activity of pp. 821–827, 2003. antiinflammatory plant extracts,” Life Sciences, vol. 70, [57] J. M Lehman and M. S Blaiss, “Selecting the Optimal Oral pp. 1023–1033, 2002. Antihistamine for Patients with Allergic Rhinitis,” Drugs, [73] J. Zielonka and B. Kalyanaraman, “Hydroethidine- and vol. 66, pp. 2309–2319, 2006. MitoSOX-derived red fluorescence is not a reliable indicator [58] S. H. Sicherer and H. A. Sampson, “Food allergy: a review of intracellular superoxide formation: another inconvenient and update on epidemiology, pathogenesis, diagnosis, pre- truth,” Free Radical Biology and Medicine, vol. 48, no. 8, vention, and management,” <e Journal of Allergy and pp. 983–1001, 2010 Apr 15. Clinical Immunology, vol. 141, no. 1, pp. 41–58, 2018 Jan 1. [74] C.-L. Kuo, C.-W. Chi, and T.-Y. Liu, “+e anti-inflammatory [59] T Tokiwa, K Harada, T Matsumura, and T Tukiyama, potential of berberine in vitro and in vivo,” Cancer Letters, “Oriental medicinal herb, Periploca sepium, extract inhibits vol. 203, no. 2, pp. 127–137, 2004 Jan 1. growth and IL-6 production of human synovial fibroblast- [75] W Tang, X Sun, J. S Fang, M Zhang, and N. J Sucher, like cells,” Biological and Pharmaceutical Bulletin, vol. 27, “Flavonoids from Radix Scutellariae as Potential Stroke pp. 1691–1693, 2004. +erapeutic Agents by Targeting the Second Postsynaptic [60] T. J Raphael and G Kuttan, “Effect of Naturally Occurring Density 95 (PSD-95)/disc Large/zonula Occludens-1 (PDZ) Triterpenoids Glycyrrhizic Acid, Ursolic Acid, Oleanolic Domain of PSD-95,” Phytomedicine, vol. 11, pp. 277–284, Acid and Nomilin on the Immune System,” Phytomedicine, vol. 10, pp. 483–489, 2003. [76] H. L Chung, G. G. L Yue, K. F To, Y. L Su, Y Huang, and [61] M Vig and J. P Kinet, “Calcium signaling in immune cells,” W. H Ko, “Effect of Scutellariae Radix extract on experi- Nature Immunology, vol. 10, pp. 21–27, 2009. mental dextran-sulfate sodium-induced colitis in rats,” [62] E Gumpricht, R Dahl, M. W Devereaux, and R. J Sokol, World Journal of Gastroenterology, vol. 13, p. 5605, 2007. “Licorice compounds glycyrrhizin and 18β-glycyrrhetinic [77] X. Shang, X. He, X. He et al., “+e genus Scutellaria an acid are potent modulators of bile acid-induced cytotoxicity ethnopharmacological and phytochemical review,” Journal in rat hepatocytes,” Journal of Biological Chemistry, vol. 280, of Ethnopharmacology, vol. 128, no. 2, pp. 279–313, 2010 Mar pp. 10556–10563, 2005. [63] Y Tsujimura, K Obata, K Mukai et al., “Basophils play a [78] P. W Hellings and W. J Fokkens, “Allergic rhinitis and its pivotal role in immunoglobulin-G-mediated but not im- munoglobulin-E-mediated systemic anaphylaxis,” Immu- impact on otorhinolaryngology,” Allergy Eur J Allergy Clin nity, vol. 28, pp. 581–589, 2008. Immunol, vol. 61, pp. 656–664, 2006. [79] P. C Bahekar, J. H Shah, U. B Ayer, S. N Mandhane, and [64] M Bruno, F Piozzi, and S Rosselli, “Natural and hemi- R +ennati, “Validation of Guinea pig model of allergic synthetic neoclerodane diterpenoids from Scutellaria and their antifeedant activity,” Natural Product Reports, vol. 19, rhinitis by oral and topical drugs,” International Immuno- pp. 357–378, 2002. pharmacology, vol. 8, pp. 1540–1551, 2008. Journal of Healthcare Engineering 17 [80] C Cuppari, S Leonardi, S Manti et al., “Allergen immuno- [98] “Proximal signaling events in FcεRI-mediated mast cell therapy, routes of administration and cytokine networks: an activation,” <e Journal of Allergy and Clinical Immunology, update,” Immunotherapy, vol. 6, pp. 775–786, 2014. vol. 119, pp. 544–552, 2007. [81] T. T Bui, C. H Piao, C. H Song, C. H Lee, H. S Shin, and [99] O. L Beong, H. L Jun, Y. K Na et al., “Polygoni Cuspidati O. H Chai, “Baicalein, wogonin, and Scutellaria baicalensis radix inhibits the activation of syk kinase in mast cells for ethanol extract alleviate ovalbumin-induced allergic airway anti-allergic activity,” Experimental Biology and Medicine, vol. 232, pp. 1425–1431, 2007. inflammation and mast cell-mediated anaphylactic shock by regulation of +1/+2 imbalance and histamine release,” [100] B. Yu, J. Sun, and X. Yang, “Assembly of naturally occurring glycosides, evolved tactics, and glycosylation methods,” Anat Cell Biol, vol. 50, pp. 124–134, 2017. [82] S. K Ku and J. S Bae, “Baicalin, Baicalein and wogonin in- Accounts of Chemical Research, vol. 45, no. 8, pp. 1227–1236, hibits high glucose-induced vascular inflammation in vitro 2012 Aug 21. and in vivo,” BMB Rep, vol. 48, p. 519, 2015. [101] Z. P Liu, W. X Li, B Yu et al., “Effects of trans-resveratrol [83] Y Kim, S. B Kim, Y. J You, and B. Z Ahn, “Deoxy- from Polygonum cuspidatum on bone loss using the podophyllotoxin; the cytotoxic and antiangiogenic compo- ovariectomized rat model,” Journal of Medicinal Food, vol. 8, nent from Pulsatilla koreana,” Planta Med, vol. 68, pp. 14–19, 2005. [102] Z Zhang and B Yu, “Total synthesis of the anti-allergic pp. 271–274, 2002. [84] X Luo, Z Yu, C Deng et al., “Baicalein ameliorates naphtho-α-pyrone tetraglucoside, cassiaside C2, isolated from Cassia seeds,” Journal of Organic Chemistry, vol. 68, TNBS-induced colitis by suppressing TLR4/MyD88 signaling cascade and NLRP3 inflammasome activation pp. 6309–6313, 2003. [103] Y. S Lee, O. H Kang, J. G Choi et al., “Synergistic effect of in mice,” Scientific Reports, vol. 7, pp. 1–14, 2017. [85] E. Z. M. da Silva, M. C. Jamur, and C. Oliver, “Mast cell Emodin in combination with ampicillin or oxacillin against function,” Journal of Histochemistry and Cytochemistry, methicillin-resistant Staphylococcus aureus,” Pharmacien vol. 62, no. 10, pp. 698–738, 2014 Oct. Biologiste, vol. 48, pp. 1285–1290, 2010. [86] X. L Fan, Q. X Zeng, X Li et al., “Induced pluripotent stem [104] S. K Heo, H. J Yun, W. H Park, and S. D Park, “Emodin inhibits TNF-α-induced human aortic smooth-muscle cell cell-derived mesenchymal stem cells activate quiescent T cells and elevate regulatory T cell response via NF-κB in proliferation via caspase- and mitochondrial-dependent apoptosis,” Journal of Cellular Biochemistry, vol. 105, allergic rhinitis patients,” Stem Cell Research & <erapy, vol. 9, 2018. pp. 70–80, 2008. [105] S. Z Lin, K. J Chen, H. F Tong, H Jing, H Li, and S Zheng, [87] T Iinuma, Y Okamoto, Y Morimoto et al., “Pathogenicity of memory +2 cells is linked to stage of allergic rhinitis,” “Emodin attenuates acute rejection of liver allografts by Allergy Eur J Allergy Clin Immunol, vol. 73, pp. 479–489, inhibiting hepatocellular apoptosis and modulating the +1/ +2 balance in rats,” Clinical and Experimental Pharma- [88] R Noble and D Noble, “Harnessing Stochasticity: How Do cology and Physiology, vol. 37, pp. 790–794, 2010. [106] G Meng, Y Liu, C Lou, and H Yang, “Emodin suppresses Organisms Make Choices?” Chaos: An Interdisciplinary Journal of Nonlinear Science, vol. 28, Article ID 106309, 2018. lipopolysaccharide-induced pro-inflammatory responses and NF-κB activation by disrupting lipid rafts in CD14- [89] J Cao and G Li, “Chemical constituents of Centipeda minima,” China Journal of Chinese Materia Medica, vol. 37, negative endothelial cells,” British Journal of Pharmacology, no. 15, 2012. vol. 161, pp. 1628–1644, 2010. [90] Z. G Liu, H. M Yu, S. L Wen, and Y. L Liu, “Histopathological [107] Y Feng, S. L Huang, W Dou et al., “Emodin, a natural study on allergic rhinitis treated with Centipeda minima,” product, selectively inhibits 11β-hydroxysteroid dehydro- Zhongguo Zhongyao Zazhi, vol. 30, pp. 292–294, 2005. genase type 1 and ameliorates metabolic disorder in diet- [91] I. V. Yang, C. A. Lozupone, and D. A. Schwartz, “+e induced obese mice,” British Journal of Pharmacology, environment, epigenome, and asthma,” <e Journal vol. 61, p. 113, 2010. of Allergy and Clinical Immunology, vol. 140, no. 1, [108] L. A Samayawardhena and C. J Pallen, “PTPα activates Lyn and Fyn and suppresses hck to negatively regulate FcεRI- pp. 14–23, 2017 Jul 1. [92] H. Lehman and C. Gordon, “+e skin as a window into dependent mast cell activation and allergic responses,” <e primary immune deficiency diseases: atopic dermatitis and Journal of Immunology, vol. 185, pp. 5993–6002, 2010. chronic mucocutaneous candidiasis,” Journal of Allergy and [109] D. D Metcalfe, R. D Peavy, and A. M Gilfillan, “Mechanisms Clinical Immunology: In Practice, vol. 7, no. 3, pp. 788–798, of mast cell signaling in anaphylaxis,” <e Journal of Allergy 2019 Mar 1. and Clinical Immunology, vol. 124, pp. 639–646, 2009. [93] K. Amin, “+e role of mast cells in allergic inflammation,” [110] L Fischer, D Poeckel, E Buerkert, D Steinhilber, and O Werz, “Inhibitors of actin polymerization stimulate arachidonic Respiratory Medicine, vol. 106, no. 1, pp. 9–14, 2012 Jan 1. [94] M Murakami and I Kudo, “Diversity and regulatory func- acid release and 5-lipoxygenase activation by upregulation of Ca2+ mobilization in polymorphonuclear leukocytes in- tions of mammalian secretory phospholipase A2s,” Advances in Immunology, vol. 77, pp. 163–194, 2001. volving Src family kinases,” Biochimica et Biophysica Acta [95] E. S Masuda and J Schmitz, “Syk inhibitors as treatment for (BBA) - Molecular and Cell Biology of Lipids, vol. 1736, allergic rhinitis,” Pulmonary Pharmacology & <erapeutics, pp. 109–119, 2005. vol. 21, pp. 461–467, 2008. [111] O Werz, E Burkert, ¨ B Samuelsson, O Radmark, ˚ and [96] R. P Siraganian, “Mast cell signal transduction from the high- D Steinhilber, “Activation of 5-lipoxygenase by cell stress is affinity IgE receptor,” Current Opinion in Immunology, calcium independent in human polymorphonuclear leuko- vol. 15, pp. 639–646, 2003. cytes,” Blood, vol. 99, pp. 1044–1052, 2002. [97] C Tkaczyk and A. M Gilfillan, “FcεRI-dependent signaling [112] J. K Son, M. J Son, E Lee et al., “Ginkgetin, a biflavone pathways in human mast cells,” Clinical Immunology and from Ginko biloba leaves, inhibits cyclooxygenases-2 and Immunopathology, vol. 99, pp. 198–210, 2001. 5-lipoxygenase in mouse bone marrow-derived mast 18 Journal of Healthcare Engineering cells,” Biological and Pharmaceutical Bulletin, vol. 28, pp. 2181–2184, 2005. [113] Y. Pylayeva-Gupta, E. Grabocka, and D. Bar-Sagi, “RAS oncogenes: weaving a tumorigenic web,” Nature Reviews Cancer, vol. 11, no. 11, pp. 761–774, 2011 Nov. [114] P. P Tak and G. S Firestein, “NF-κB: a key role in inflam- matory diseases,” Journal of Clinical Investigation, vol. 107, pp. 7–11, 2001. [115] J. Jia, F. Zhu, X. Ma, Z. W. Cao, Y. X. Li, and Y. Z. Chen, “Mechanisms of drug combinations: interaction and net- work perspectives,” Nature Reviews Drug Discovery, vol. 8, no. 2, pp. 111–128, 2009 Feb. [116] Y. Lin, R. Shi, X. Wang, and H.-M. Shen, “Luteolin, a fla- vonoid with potential for cancer prevention and therapy,” Current Cancer Drug Targets, vol. 8, no. 7, pp. 634–646, 2008 Nov 1.

Journal

Journal of Healthcare EngineeringHindawi Publishing Corporation

Published: Apr 11, 2022

References