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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; firstname.lastname@example.org 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 . On the far current record, However, some cases might require surgical intervention . 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  (Table 1). higher molar concentration in the nasal discharges of AR Herbs that are frequently used to cure allergic rhinitis patients and controls . +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 . 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)) . +e Xanthii fructus has been ings, histamine concentrations only elevated late in the shown to reduce mast cell-mediated allergy reactions , 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 , and prevention of β-cell ingly, there was a considerable rise in IL-1β concentrations damage in type 1 diabetes . 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 . 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  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  (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  Georgi. STAT3 pathway ↓ Immunohistochemical staining TNF-α, IL-2, IL-4 ↓ In silico ELISA 04. Centipeda minima Immunohistochemical staining, H&E  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  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 . 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) . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . +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 . 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 , has been taken as a positive control. +e lular compartment . 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 . +e condition is often to diverse allergens. . 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 . 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  and anti-inﬂammatory  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) . 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 . +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 . 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 . 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 . 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 . obstruction, sneezing, congestion, and rhinorrhea, which 4. Scutellariae Radix can lead to ear and nasal abnormalities if left untreated . 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. . 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 . 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 . Regardless of the whole sections . 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 . 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 , stroke , and colitis . 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 . Among these, over 40 ﬂavonoids along with the form of glycosides have been identiﬁed as most abundant , 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  (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 . 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 . 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 . 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 . Medicinally, the plant has also been used to minimize across all plants. cough and nasal secretions associated with respiratory complications . 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 . 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 . 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 . 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. . 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 . +ough 5-LO can be activated and Emodin. phosphorylated by MAPKs, , 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 . 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.  D. V. Wallace, M. S. 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