An Updated Comprehensive Review of Plants and Herbal Compounds with Antiasthmatic Effect

Background Asthma is a common disease with rising prevalence worldwide, especially in industrialized countries. Current asthma therapy with traditional medicines lacks satisfactory success, hence the patients' search for alternative and complementary treatments for their diseases. Researchers have conducted many studies on plants with antiallergic and antiasthmatic effects in recent decades. Many of these plants are now used in clinics, and searching for their mechanism of action may result in creating new ideas for producing more effective drugs. Purpose The goal of this review was to provide a compilation of the findings on plants and their active agents with experimentally confirmed antiasthmatic effects. Study Design and Method. A literature search was conducted from 1986 to November 2023 in Scopus, Springer Link, EMBASE, Science Direct, PubMed, Google Scholar, and Web of Science to identify and report the accumulated knowledge on herbs and their compounds that may be effective in asthma treatment. Results The results revealed that 58 plants and 32 herbal extracted compounds had antiasthmatic activity. Also, 32 plants were shown to have anti-inflammatory and antioxidative effects or may act as bronchodilators and potentially have antiasthmatic effects, which must be investigated in future studies. Conclusion The ability of herbal medicine to improve asthma symptoms has been confirmed by clinical and preclinical studies, and such compounds may be used as a source for developing new antiasthmatic drugs. Moreover, this review suggests that many bioactive compounds have therapeutic potential against asthma.


Introduction
Asthma is a chronic infammatory change in the pulmonary system [1].Te airway hyperresponsiveness (AHR) that results from this chronic infammation leads to recurrent episodes of asthma symptoms, which can vary in intensity over time [1].Asthma is an obstructive pulmonary disease with diferent etiologies, afecting approximately 300 million people worldwide [2,3].By 2025, a further 100 million will be added to this estimate [4].In the USA alone, the annual cost of asthma is approximately $56 billion.Te signifcant impact of airway infammation in the pathophysiology of asthma has been confrmed by many clinical and basic studies [5].Te chronic airway remodeling, especially thickening of airway walls, and infammation is mediated by potent chemical mediators [6].Te disease progression and chronicity is further aggravated by the resulting narrowing of airways [7,8].Te primary goal of asthma management is the reduction of disease prevalence and mortality through maintaining control over the disease in order to prevent exacerbations.Terapy also aims to improve lung function and overall quality of life, normalize physical activity, reduce the necessity of medicine, and improve the symptoms in terms of quantity and quality [9].Medications that are currently used to relieve asthma symptoms in the clinic are inhaled corticosteroids (ICSs), leukotriene receptor antagonists (LTRAs), long-acting beta-agonists (LABAs) in combination with an ICS, long-acting muscarinic receptor antagonists (LAMAs), monoclonal antibody immunemodulating drugs, mast cell stabilizing medications, methylxanthine drugs, and biologic substances, such as anti-IL-5 therapy and anti-IgE therapy.Medications used for asthma relief include inhaled anticholinergic drugs and rapid-acting beta2-agonists [10].Te drugs that are currently prescribed have several side efects that can vary depending on the drug class, its dose, and how it is administered.Some side efects of beta-agonists include cough, headache, vomiting, fever, nausea, sweating, dyspepsia, and increased insomnia and nervousness in children [11].Te systemic anticholinergic activity of LAMAs causes side efects such as lower urinary tract symptoms and urinary retention, especially in older men, dizziness, and excessive dry mouth [12].Common side efects that may occur with ICSs include headache, throat irritation, dysphonia, cough, viral gastroenteritis, and back and oropharyngeal pain [13].LTRAs cause other issues, including abdominal pain, headache, dizziness, dyspepsia, elevated liver function indicators, and cholestatic hepatitis [11,13].Plants and natural sources contribute largely to the commercial drug preparations manufactured today [14][15][16].Traditional and plant-derived compounds are the treatment of choice for most (>80%) of the global population, and about 25% of prescriptions in the United States contain at least one plant-derived ingredient [17][18][19].Terefore, consumers should be given sciencebased information on dosage, contraindications, and efcacy [20][21][22].If sufcient scientifc evidence of the benefts of an herb is available, the benefts can be employed to promote public health and treat disease [23][24][25].Tere are recent reviews about herbal plants used for asthma control.However, these reviews generally focus on a specifc asthma model or class of herbs, such as traditional Chinese or Indian herbs [26].Since there is no defnite treatment for asthma and the drugs available in the clinic mostly relieve the symptoms of the disease and the drug's side efects, delineating the role of herbal compounds in improving and treating asthma can be helpful.In this comprehensive review, we searched the literature as far back as 37 years ago for information about herbal plants and herbal compounds that have shown real or potential antiasthmatic activity.Also, the studies that have pointed out these properties for each plant or compound are introduced along with the probable mechanisms of action to help the researchers continue the earlier studies towards producing new and efective drugs with fewer adverse efects against asthma.

Method
We used the searched terms "asthma," "the plants afecting the respiratory system," "phytomedicine," "herbal compounds," "alkaloids," "polyphenols," "favonoids," "medicinal plants/herbs," "plants," and "herbs," in the Scopus, Springer Link, EMBASE, Science Direct, PubMed, Google Scholar, and Web of Science databases.All the studies related to the above keywords were assessed.Articles published from 1986 to November 2023 were included.In this review, preclinical (animal studies, in vitro experiments) and clinical investigations (clinical trials) were considered.Te main criteria for selecting herbs and compounds were their anti-infammatory, antiasthmatic, antioxidative, antiremodeling, antihistaminic, and anticholinergic efects.Inclusion and exclusion criteria were established to select articles that met the specifc research question.Te titles and abstracts of the identifed articles were reviewed to identify those relevant to the research question.Te full texts of the selected articles were then carefully assessed to determine their inclusion in the review.Te search terms were clustered according to the PICO (Population, Phenomenon of Interest, Context) scheme to ensure a systematic approach.Tis allowed for the inclusion of research examining the impact of herbs or their active agents on asthma control and treatment.Nevertheless, because of large number of papers found, to reduce the length of the review, in cases where more than one paper reported an individual property of a plant (for example, the anti-infammatory efect), only the more recent/more comprehensive study was cited.

Results
Te results revealed that over 120 plants or their extracted compounds have shown antiasthmatic, antiremodeling, antiapoptotic, anti-infammatory, antioxidative, antihistaminic, anticholinergic, and bronchodilator activity.Te description of the herbs (58 herbs) or their compounds (32 compounds) found with antiasthmatic activity are presented in alphabetic order in the text.Te fndings are summarized in two tables at the end of the paper.Te efects on pulmonary function tests or the airway responsiveness corresponding to clinical studies are shown in Table 1, and the efects on infammatory, oxidative, remodeling, cholinergic, bronchodilatory, and histaminic characteristics corresponding to preclinical studies are shown in Table 2. Te pictures of the plants with verifed antiasthmatic activity are presented in Figure 1 (58 plants), and the pictures of those with potential antiasthmatic activity are presented in Figure 1 of the supplementary fle (available here) (32 plants).

Plants with Verifed Antiasthmatic Activity.
Plants that have shown antiasthmatic activity are described frst in alphabetic order.In many of these studies, the efects of plants have been compared with medicines currently used in the clinic.Tese plants are of diferent species, and the mechanism of action of most of them against asthma is to inhibit infammation and oxidative stress.

Adiantum capillus-veneris L. (Fern).
Te venus hair fern, maidenhair fern, black maidenhair fern, and southern maidenhair fern are species of ferns in genus Adiantum and family Pteridaceae distributed in subcosmopolitan areas worldwide.In general, the ameliorative efects of this plant have been shown in respiratory disorders, including asthma [147].It has been shown that its leaf ethanolic extract in concentrations of 250 and 500 mg/kg has antiasthmatic (H1 receptor antagonist) activity in experimental models of asthma [51].

2
Evidence-Based Complementary and Alternative Medicine

No.3.2.43 Pimpinella anisum
Bronchodilator activity [50] Te number in the frst column refers to the paragraph in the text describing the plant/compound characteristics.
Evidence-Based Complementary and Alternative Medicine  ↓ ICAM-1, VCAM-1 [37] No. Evidence-Based Complementary and Alternative Medicine    Evidence-Based Complementary and Alternative Medicine in albino rats [151].It has been shown that garlic's sulfur compounds beneft asthma patients in various ways, through the modulation of antiviral cytokines and infammation and other antiviral, antibacterial, and antioxidant mechanisms.
As the development of asthma is delayed this way, this treatment may be considered an alternative or coadjutants in the treatment of asthma [152].

Alnus hirsuta (Spach).
In Eastern Asia, alcoholism, diarrhea, and hemorrhage are treated with compounds derived from this member of the Betulaceae family.Using an ovalbumin-induced murine asthma model to compare Alnus hirsuta with dexamethasone (3 mg/kg), Lee et al. found that this plant alleviates mucus overproduction and airway infammation at the concentration of 50 mg/kg [153].

Anchomanes diformis (Blume).
In Delta State, Nigeria, herbal practitioners reportedly use Anchomanes diformis to treat asthma [154].Its leaf aqueous extract was compared with salbutamol as reference in guinea pigs, and the diference in antiasthmatic activity between the aqueous leaf extract (400 mg/kg) (32.7%) and salbutamol (32.5%) was not signifcant.Te experiment verifed the asthma-relieving efect and safety of A. diformis leaf extract [30,155].
3.1.9.Boswellia serrata (Frankincense).Indian frankincense is produced using this plant.A clinical study in 2010 demonstrated that the extract has a pronounced efect on managing bronchial asthma, signifcantly decreasing plasma NO, MDA, and LTC4 levels [62].In a randomized openlabel comparative clinical study, Boswellia signifcantly decreased asthmatic attack episodes and increased forced vital capacity (FVC) values and forced expiratory volume in the frst second (FEV1) [31,159].Tere are old placebocontrolled double-blind clinical studies where bronchial asthma patients were treated for six weeks, three times daily, with either lactose as placebo or gum resin (300 mg).Decrease in erythrocyte sedimentation rate (ESR) and eosinophilic count, elevation in peak expiratory fow rate, FVC, and FEV1, and alleviation of disease physical symptoms and signs (frequency of attacks, rhonchi, and dyspnea) were recorded in 70% of the treatment group but only in 27% of the placebo group [32,159].

Brassica napus (Rapeseed).
Rapeseed (Brassica napus subsp.napus) is a bright yellow fowering member of the family Brassicaceae (mustard or cabbage family), which naturally contains appreciable amounts of erucic acid.Neamati et al. disclosed that Brassica napus L. oil at 0.5 and 0.75 mg/kg could decrease lung eosinophil count and airway smooth muscle thickness in asthmatic rats [63].
3.1.12.Camellia sinensis (Tea).Te leaves and leaf buds of these small evergreen trees or shrubs of the Teaceae family are used to produce tea.Heo et al. demonstrated that the aqueous extract of Camellia sinensis at the concentration of 25 μg/ml exerts antiasthmatic activity by alleviating asthmarelated cytokine activity through increasing the expression of TGF-β, IFN-c, and IL-10 and by decreasing the expression of infammatory cytokines IL-4, IL-13, and IgE in 10 Evidence-Based Complementary and Alternative Medicine the lungs [65].Some studies have revealed that mucus hypersecretion and airway infammation are regulated by tea extract, improving allergic asthma induced by ovalbumin [160,161].

Carum copticum (Ajwain).
Te seed of Ajwain is a member of the Apiaceae family, believed to have a hot humor, and is commonly used in Indian cuisine [33].Te strong bronchodilatory efect of 0.125 and 0.25 ml/kg C. copticum on asthmatic airways was demonstrated in a clinical study by Boskabady et al., an efect comparable with that of theophylline (6 mg/kg) [162].Tey reported a signifcant increase in lung function tests (sGaw, MEF25, MEF50, MEF75, MMEF, PEF, and FEV1) between 30 and 150 min post administration of high concentrations of its boiled extract [162].

Crataegus pinnatifda (Mountain Hawthorn).
Administration of Crataegus pinnatifda ethanolic extract at concentrations of 100 and 200 mg/kg in the murine asthma model signifcantly reduces infammatory cells, especially eosinophils in the lung tissue and BALF and decreases AHR, OVA-specifc IgG levels, OVA-specifc IgE, and total IgE in the serum and also eotaxin, IL-13, IL-5, and IL-4 after OVA challenge in BALF in comparison with montelukast (30 mg/ kg).Tese fndings indicate that Crataegus pinnatifda ethanolic extract may be efective in inhibiting the development of airway infammation in allergic asthma.In addition, the alcoholic extract of Crataegus pinnatifda exerts its anti-infammatory efect partially through downregulating MMP-9, leading to a decrease in the expression of VCAM-1 and ICAM-1 [37].

Crocus sativus (Safron).
Pharmacological investigations have confrmed that the extract or the constituents of this stemless perennial member of the Iridaceae family [169] have free radical-scavenging efects and antioxidant properties [170], and relaxant efects on tracheal smooth muscles [70,170].Previous studies have shown that this plant inhibits histamine (H1) receptors [71] and stimulates β-adrenoceptors [171].Mahmoudabady et al.
showed the ability of C. sativus extract to reduce eosinophils and other infammatory cells in the lung lavage of sensitized animals [172].Safranal, the main constituent of C. sativus, attenuates AHR and airway structural changes during allergic asthma and decreases IL-13 and IL-5 and other infammatory cytokines in mouse lungs [38].It has been shown that safranal and safron alleviate OVA-induced asthma, inhibit mast cell activation, and reduce serum endothelin [173].[176].Gao et al. revealed that after eight weeks of treatment with curcumin, at a concentration of 200 mg/kg, brought about signifcant improvement in the areas of the aortic root that had lesions, and the T17 and T2 cells that had been elevated showed signifcant decrease [177].According to another study, postbronchodilator FEV1 in atopic asthma patients was not signifcantly afected by oral curcumin administration [40].It has been shown that curcumin administered intranasally modulates MAPK signaling and NF-κB activation, regulating chronic asthma in mice as a result [178,179].In contrast, Abidi et al. revealed that curcumin is efective and safe as an add-on therapy for the treatment of bronchial asthma [180].Curcumin administered intranasally prevented remodeling related to chronic asthma, structural alterations, airway infammatory cell accumulation, and mucus secretion in the OVA-induced murine model of chronic asthma, along with a decrease in IL-5, IL-4, and IgE levels [74,181].[190].
3.1.24.Ganoderma lucidum.Liu et al. showed that ganoderic acid C1 (GAC1) isolated from G. lucidum inhibits TNF-α production in asthma patients' peripheral blood mononuclear cells (PBMCs) and in murine macrophages stimulated by LPS and associated this efect with NF-κB signaling pathway suppression and, in part, with MAPK and AP1 pathway suppression.Infammatory diseases such as TNF-α-associated asthma may be treatable by GAC1 as a novel therapy [193].
3.1.25.Ginkgo biloba.Ginkgo biloba, commonly known as ginkgo or gingko, is the only living species in the division Ginkgophyta, all others having gone extinct [88].According to the results of animal studies, administration of G. biloba at concentrations of 100 and 150 mg/kg diminishes the number of goblet cells and mast cells, epithelium thickness, subepithelial smooth muscle thickness, and basement membrane thickness in asthmatic mice [89], and reduces IL-4 and IgE levels at 12.5 mg/kg in asthmatic rabbits (compared with 0.5 mg/kg prednisolone) [90].It also decreases leukocytes, eosinophils, IL-4, IL-13, and TNF-α levels in the BALF of asthmatic mice [91].Chu et al. found that at 40 mg/kg dose, ginkgolide B inhibited the ERK/MAPK signaling pathway, exerting anti-infammatory efects in asthma [194].A clinical study showed that treatment with Ginkgo biloba extract results in reduced blood platelet activating factor in asthmatic children and improves asthma symptoms [195].Zheng et al. showed that Ginkgo biloba tablets added to routine therapy can improve lung function (FEV1/FVC) in steroid-dependent asthma patients [196].Yijune et al. in a clinical study reported that the Ginkgo biloba extract could signifcantly decrease the infltration of infammatory cells in the asthmatic airways, and it may be used as a complement to glucocorticosteroid therapy [197].[198].Chen et al. showed the efect of glycyrrhizic acid loaded on PLGA nanoparticles in treating allergic asthma [199].A clinical study showed that aqueous liquorice extract capsules signifcantly improve pulmonary function tests (increase in FVC% and FEV1%) in asthmatic patients [200].

Hedera helix (Ivy)
. Hedera helix, the common ivy, is a member of the Araliaceae family [201].Zeil et al. have demonstrated that the lung function parameters of children with uncontrolled, persistent, mild asthma experience signifcant improvement after combined therapy of ivy leaf extract and inhaled corticosteroids (budesonide) [201].Babayigit Hocaoglu et al. showed that Hedera helix administration at the concentration of 100 mg/kg reduces goblet cell numbers and thickness of basement membrane in the lung of asthmatic mice, comparable to 1 mg/kg dexamethasone [202].A systematic review in 2011 by Holzinger et al. approved the efectiveness of ivy leaves for treating acute upper respiratory tract infections [203].Another clinical study revealed that ivy leaf extract improves the respiratory functions of children with chronic asthma [204].

Hyssopus ofcinalis (Zufa). Te medicinal plant
Hyssopus ofcinalis L., which belongs to the family Lamiaceae, is widely cultivated in Asia, Europe, and temperate regions of America [97].Ma et al. showed that Hyssopus ofcinalis at concentrations of 0.04 g/kg and 1.6 g/kg regulates the MMP-9/TIMP-1 ratio via afecting the expressions of some cytokines (such as IL-1, IL-17, and TNF-α) and improves airway remodeling in asthmatic mice compared to dexamethasone (5 mg/kg) [98].Another study showed that Hyssopus ofcinalis could inhibit the secretion of IL-17 in serum and solve T1/T2 cytokine (IL-4 and IFN-c) imbalance in asthmatic rats [205].A clinical study showed that Hyssopus ofcinalis efectively relieves the signs and symptoms of bronchial asthma [100].Fengjuan et al. showed that JAX2, an ethanol extract of hyssop, could reduce BALF IgE, TNF-α, IL-17, IL-6, and IL-4 and inhibit MAPK/NF-κB infammatory signaling, resulting in the prevention of bronchial asthma in rats [206].[217].In animal models, mechanisms such as the alleviation of imbalance between the T1 and T2 cytokines [115] and inhibition of histamine release from mast cells [116] have been shown.Boskabady et al. showed that asthma symptoms such as night wheezing and coughing and exercise wheezing and coughing in patients improve after three months' treatment with Nigella sativa seed extract.Pulmonary function tests improve after 45 days of treatment [117,218].Te antiasthmatic efects of Nigella sativa and its constituents have been reviewed in more detail [218].

Plants with Potentially Antiasthmatic Efects.
Tere are herbs whose efects on asthma have not been directly studied, but due to their anti-infammatory, antioxidative, and bronchodilatory efects, they may have antiasthmatic efects to be investigated in future studies.We found 32 of these plants in our literature review.To reduce the length of this review, the studies related to these plants are described in the supplementary fle.

Herbal Bioactive Compounds with Antiasthmatic Efects.
Researchers have tried isolating the active ingredients from the plants, showing antiasthmatic activity.In the following section, we have reviewed the literature concerning the efect of these herbal compounds on asthmatic animal models or their use in clinical trials.Baicalin is a favone glycoside and a natural product from traditional Chinese medication.Xu et al. revealed baicalin at concentrations of 10, 25, and 65 mg/kg decreases OVA + LPS-induced organ coefcient (organ weight (mg)/ body weight (g)) of lungs, inhibits IL-6 and IL-17A in BALF and IgE in the serum.It also alleviates airway mucus secretion and lung tissue infammatory responses and increases IL-10 in BALF in allergic asthma induced by OVA + LPS in mice.Moreover, baicalin increases FOXP3 expression and inhibits STAT3 expression in the mouse lung tissues comparable with 1 mg/kg budesonide [55].Liu et al. showed that 10, 25, and 50 mg/kg baicalin attenuates infammation in mice with OVA-induced asthma by inhibiting NF-κB and suppressing CCR7/CCL19/CCL21 in comparison to dexamethasone (0.085 mg/kg) [56].Also, another study showed that baicalin mediates the TLR4/NF-κB pathway and upregulates microRNA-103, regulating asthma development in children [57].Hu et al. found that 50, 100, and 200 mg/kg baicalin modulates the RAS signaling pathway, reducing the proliferation of airway smooth muscle cells in murine asthmatic airways in comparison with dexamethasone (1 mg) [245].
Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in Berberis vulgaris (barberry) and Berberis aristata (turmeric tree).Saadat et al. reported the potent relaxant efect of berberine on tracheal smooth muscles through histamine (H1) receptor blockade and inhibition of COX pathways and NO formation [58].It has been shown that berberine regulates MAPK signaling and FcεRI mediation, reducing allergic responses mediated by mast cells [59].One study found that 0.1, 1, and 10 μM berberine modulates the STAT6 pathway in bronchial epithelial cells in humans, suppressing the production of proinfammatory CCL11 and IL-6 induced by cytokines [60].Carvacrol is a monoterpenoid phenol present in the essential oil of Origanum vulgare (oregano), oil of thyme, oil of pepperwort, and wild bergamot [246].Khalaf et al. demonstrated that at a concentration of 15 mg/kg, carvacrol diminishes infammation in bronchial asthma via reducing tissue MDA and BALF TNF-α, IFN-c, and iNOS levels and increasing SOD and GSH compared to dexamethasone (1 mg/kg) [66].Boskabady et al. showed a preventive efect of carvacrol, as potent as dexamethasone, on tracheal responsiveness at 40, 80, and 160 μg/mL [67].Also, they reported that carvacrol attenuates serum levels of total protein, phospholipase A2, and histamine in asthmatic guinea pigs [247].Some clinical investigations have shown improvement in respiratory symptoms, pulmonary function tests, and FEV1 values and alleviation of lung wheezing in asthmatic patients following treatment for two months.Also, in a randomized, double-masked clinical trial, carvacrol improved pulmonary function tests, oxidant/antioxidant parameters, and cytokine levels in asthmatic patients [34].A phenol antioxidant naturally occurring in various vegetables and fruits is ellagic acid.Ellagic acid has been found to possess antioxidant and antiproliferative efects [79].Alves et al. revealed that ellagic acid decreases eosinophil recruitment and airway mucus metaplasia and promotes the resolution of airway allergen clearance [80,81].Zhou et al. reported that ellagic acid at concentrations of 2.5, 5, or 10 mg/kg attenuates airway infammation, release of T2 cytokines into the airways, goblet cell hyperplasia, OVA-specifc IgE levels in the serum, and AHR in an OVAinduced asthmatic mouse model compared to dexamethasone [248].

Emodin.
Abundant in the roots of knotgrass, knotweed, and Chinese rhubarb, emodin is a compound in the anthraquinone family.Miao et al. reported that emodin inhibits the NF-κB signaling pathway, protecting obese asthmatic rats from pathological damage via visfatin [249].

Gallic Acid.
O HO HO OH OH Classifed as a phenolic acid, gallic acid is a trihydroxy benzoic acid [41].Fan et al. demonstrated that oral gallic acid signifcantly attenuates infammation of airways in an airway infammation model induced by OVA.Kim et al. disclosed that gallic acid at 0.1, 1, and 10 μM inhibits histamine release and proinfammatory cytokine (IL-6 and TNF-α) production in mast cells [253].Te efects of gallic acid are probably connected to inactivated ILC2s and suppressed release of IL-13 and IL-5 via the IL-33/MyD88/NF-κB signaling pathway [254].

OH HO O O OH
Structurally a member of isofavone compounds, genistein occurs naturally in plants [255].Liu et al. showed that genistein can inhibit the translocation of NF-κB and hypersecretion of TNF-α in PBMCs of asthma patients.However, the efects were weaker than those of dexamethasone [86].Another study revealed that genistein modulates the transcription factors STAT6, GATA3, and Tbet, attenuating airway allergic infammation in a murine asthma model [87].Duan et al. also showed antiinfammatory efects for 15 mg/kg genistein in a guinea pig asthma model as a tyrosine kinase inhibitor [256].Hesperetin is a naturally occurring favanone glycoside [94], which selectively inhibits phosphodiesterase four and efectively suppresses OVA-induced AHR [95].In a clinical study, Gu et al. disclosed that hesperetin inhibits the maturation and function of monocyte-derived dendritic cells from patients with asthma by suppressing the activation of NF-κB, reducing IL-4, increasing IFN-c levels [45], ameliorating airway infammation, remodeling, and decreasing airway fbrosis and mucus plug formation [257].AHR Alleviation, BALF T2 cytokine level enhancement, infammatory cell reduction, goblet cell hyperplasia attenuation, and airway luminal narrowing are the other antiasthmatic mechanisms of hesperetin [99].Kaempferol is a natural favonol found in various plants and plant-derived foods, including kale, beans, tea, spinach, and broccoli [260].Molitorisova et al. revealed that long-term use of kaempferol at concentrations of 2, 6, or 20 mg/kg attenuates the progression of chronic infammation by decreasing the amount of proinfammatory cytokines IL-5, IL-13, GM-CSF, and eosinophils in the BALF compared to budesonide [101].In addition, kaempferol attenuates TNF-α-induced expression of epithelial ICAM-1, integrin β2, and MCP-1 transcription and ameliorates allergic and infammatory airway diseases [261].Medeiros et al. showed that kaempferol treatment (both preventive or curative) exerts a profound inhibitory efect on airway infammation and hyperresponsiveness in a murine asthmatic model by suppressing the T2 cytokine profle via reducing IL-5 and IL-13 [262].Xu et al. showed that kaempferol (20 mg/kg) inhibits airway infammation induced by allergic asthma through NOX4-mediated autophagy [263].
Ligustrazine is an alkaloid derivative of the Chuanxiong rhizome (Ligusticum chuanxiong Hort).Wang et al. disclosed that in an asthma model, infammation and hyperresponsivity induced by allergens in the lungs is reduced signifcantly by ligustrazine.Treatment with ligustrazine has been connected to decreased PDE expression, including the expression of PDE4, in the rat lungs [266].

Limonene.
Limonene is a colorless liquid aliphatic hydrocarbon, classifed as a cyclic monoterpene, a signifcant component in the oil of citrus fruit peels.Rajalingam et al. reported that limonene reduces tracheal and vascular reactivity in a mouse asthmatic model [267].Patel et al. revealed that limoneneinduced activation of A2AARs reduces airway infammation and reactivity in a mouse asthmatic model via reducing infammatory cells and IgE in the BALF [268].Common guava (Psidium guajava) leaves, old fustic (Maclura tinctorial), and Osage orange (Maclura pomifera) can be used to isolate the yellow compound called morin [269].Franova et al. revealed morin's bronchodilator, antiinfammatory, and antitussive efects at 30 mg/kg in experimentally induced allergic asthma via reducing airway resistance, number of cough eforts, and the concentration of IL-4, IL-5, and IL-13 in the BALF of asthmatic guinea pigs compared to dexamethasone [107].Kandhare et al. found that morin possesses antiasthmatic qualities mediated by the reduction of oxidative airway infammation and stress through modulating the BLT2/NF-κB and SUMF2/IL-13 signaling pathways and downregulating the expression of LTB-4, IL-6, IL-4, COX-2, and IgE [108] in OVA-induced allergic asthma [270].demonstrated that myrtenol exerts antiremodeling efects in asthmatic rats' lungs by reducing the remodeling process in the airways.Also, they showed myrtenol's oxidation-and infammation-reducing efects at 50 mg/kg through diminishing MDA, TNF, and IL-1β and increasing BALF SOD, GPX, IFN, and IL-10 [111].In another study, Rajizadeh et al. revealed that myrtenol at 50 mg/kg can reduce infammation and tissue damage in asthmatic rats compared to dexamethasone (2.5 mg/kg) [112].Our recent investigations revealed the oxidation-and infammation-reducing efects of the inhaled niosomal form of myrtenol in asthmatic rats [274,275] Naringenin is a colorless, favorless favonoid predominantly found in grapefruit and other fruits and herbs [113].A study showed that consumption of hesperetinnaringenin is associated with substantial amelioration of airway structural changes and provided signifcant insight into the role of orange juice or grapefruit juice in decreasing airway fbrosis and mucus plug formation in an asthma model [257].Shi et al. reported that naringenin at 25, 50, and 100 mg/kg inhibits allergen-induced airway infammation by reducing serum IgE, infammatory cells, CCL11, CCL5, IL-4, and IL-13 in BALF.It also ameliorates airway responsiveness and airway remodeling and decreases NF-κB activity in asthma [114,277].Jasemi et al. revealed that the antioxidant and anti-infammatory efects of naringenin improve the allergic asthma induced by ovalbumin in rats [278].20 Evidence-Based Complementary and Alternative Medicine 3.3.23.Osthole.

Myrtenol.
Osthole, one of the most essential coumarin compounds isolated from the ripe fruit, is derived from the plant Cnidium monnieri (L.) Cuss.Tong et al. disclosed the ameliorating role of osthole on TGF-β-induced lung epithelium apoptosis and epithelial-mesenchymal transition-mediated airway remodeling in pediatric asthma [279].
3.3.24.Qingfei Yihuo Wan.Jing et al. revealed that qingfei liquid administered orally at the concentration of 6.36 g/kg alleviates AHR and mucus hypersecretion via TRPV1 signaling in RSV-infected asthmatic mice.Tey reported that qingfei ameliorates airway resistance and lung compliance and reduces serum levels of IL-4, IL-5, IL-13, and IL-1β compared to dexamethasone [129].Yu et al. demonstrated that qingfei oral liquid inhibits autophagy via the mTOR signaling pathway in RSV-infected asthmatic mice [130].Another study showed that long-term use of qingfei reduces the risk of asthma hospitalization in school-age children [280].A plant favonol, quercetin belongs to the favonoid polyphenols group [281].Rogerio and colleagues showed the anti-infammatory efect of quercetin-loaded microemulsion by reduction of eosinophil recruitment and IL-4 and IL-5 levels in the BALF and P-selectin expression and mucus secretion in the lung 1 and 10 mg/kg in the airways of an allergic infammatory model in mice in comparison to dexamethasone (1 mg/kg) [125,282].Park et al. revealed that quercetin decreases the expression of T-bet and suppresses GATA3, reducing hyperresponsiveness and infammation of allergic airways and regulating the T1/T2 balance in a murine asthma model [126].Another study confrmed that quercetin acts as an acute bronchodilator in experimental allergic asthma [283].Ravikumar and Kavitha revealed the immunomodulatory efect of quercetin on dysregulated T1/T2 cytokine balance in mice with both type 1 diabetes and allergic asthma [127].In another study, Sozmen et al. demonstrated how treatment with quercetin afects epithelial cell apoptosis and epithelium-derived cytokines in a mouse allergic airway infammation model [128].Our previous study showed quercetin's oxidation-and infammation-reducing efects in asthmatic rats by reducing GATA3 and increasing T-bet expression [284].Also, Fang et al. demonstrated that quercetin alleviates asthma-induced airway infammation and remodeling through downregulating periostin via blocking the TGF-β1/Smad pathway [285].

Resveratrol.
HO OH OH Peanuts, raspberries, blueberries, mulberries, and the skin of grapes contain resveratrol [131,132].Antioxidant and anti-infammatory efects, reduction of airway remolding and TNF-α, TGF-β, IL-17, and IL-6 in the BALF of asthmatic mouse model [286], attenuation of experimental allergic asthma, restoration of mitochondrial function, inhibition of PI3K-Akt signaling, and reduced calpain activity in mice are among the antiasthmatic actions of resveratrol [133].Moreover, the oral administration of resveratrol suppresses the asthmaassociated immune response mediated by the upregulation of FOXP3 and downregulation of miR-34a [287].Chen et al. confrmed the antiasthmatic efects of resveratrol at 30 mg/kg in a mouse OVA-induced asthma model compared to dexamethasone (5 mg/kg) [288].Hu et al. showed the efective suppression of eosinophil proliferation by resveratrol treatment in asthmatic patients [289].[135].Shakeri et al. showed that at concentrations of 0.125, 0.25, and 0.50 mg/ml (1.25 μg/ml), similar to dexamethasone, rosmarinic acid improves immunological and infammatory mediator levels by reducing IL-4, PLA2, TP, and IgE and increasing IFN-c in BALF and ameliorates lung pathological insults in asthmatic rats [290].Liang et al. revealed that rosmarinic acid treatment at the concentration of 20 mg/kg results in a signifcant reduction in the mRNA expression of AMCase, CCL11, CCR3, Ym2, and Eselectin in the lung tissue of asthmatic rats [291].Our previous study revealed that the inhalation of Salvia rosmarinus Spenn.has oxidation-and infammation-reducing efects in asthmatic rats [292].Ruscogenin is one of the major active compounds in Ophiopogon japonicus, which has been shown to exert antiinfammatory, antioxidant, and antiapoptotic efects.Zhan et al. demonstrated that 10 mg/kg ruscogenin inhibits mitochondrial calcium handling and VDAC1 expression, reducing apoptosis and oxidative stress in the airway epithelium [293].

Discussion
In this comprehensive review, we conducted a survey of 37 years of literature on herbs and their compounds used in the treatment of asthma.We found more than a hundred and twenty plants and herbal derivatives that were either benefcial for treating asthma or could potentially treat asthma.Te main mechanism of action in these plants is their anti-infammatory activity.Nevertheless, other important antiasthmatic mechanisms include antioxidant, antihistaminic, and antiallergic activities, inhibition of airway remodeling, and tracheal smooth muscle relaxation (see Figure 2).Tese results will help researchers isolate and identify the phytochemicals with antiasthmatic properties in these plants for the development of novel antiasthmatic medications.Te bioactive ingredients' synergistic and additive qualities are also a possible research feld for producing more efective compound formulas.
We acknowledge some limitations in our work.Tis review mostly looks at the mechanism of action of various plants or herbal compounds against asthma.To avoid lengthening the text, because of the large number of items found, we did not include detailed information about the route of administration, the part of the plant used, and the method of preparing the extracts.Te readers may refer to the references cited for each case for more detailed information if they are interested.Also, because of the plant's anti-infammatory, antioxidative, and bronchodilatory properties that may have antiasthmatic efects, they are described in a supplementary fle.Moreover, in cases where more than one paper reported an individual property of a plant (for example, the anti-infammatory efect), only the more recent/more comprehensive study was cited.
Most clinical trials resulted in ameliorated respiration and led to desirable outcomes (i.e., decrease in severity and frequency of symptoms) following herbal medicine administration in asthma treatment.However, due to the limited number and reliability of fndings, this review calls for further studies to identify the antiasthmatic efect and the suitable dosage for relieving the disease symptoms.At this time, given the limited scientifc evidence, we cannot confdently decide how efective the plant-based medications are in asthma treatment.Nevertheless, these treatment options are worth considering.High-quality studies on the longterm safety and efcacy of phytochemicals used for asthma treatment are still necessary.Furthermore, the unknown consequences of combining herbal medicine with other undeclared chemicals, toxic contamination of herbs, the use of the wrong plant species, and misuse by healthcare providers or consumers are among the reasons for experiencing adverse events arising from the consumption of herbal medicines [300].
Since the pharmacokinetic and pharmacodynamic characteristics of most herbal and other dietary supplements are only partially recognized, potential interactions are often  Evidence-Based Complementary and Alternative Medicine not avoidable.Potential interactions are likely to occur with drugs with narrow therapeutic indices.Despite these warnings, almost all studies that have investigated the efects of herbal medicine on asthma have reported desirable effects.Terefore, the results of this feld are promising.

Conclusion
Among all mentioned plants and compounds that have verifed ameliorative efects on asthma, the main mechanism of action of these herbs is their anti-infammatory efects.Te inhibition of airway remodeling, relaxation of tracheal smooth muscles, antihistaminic properties, alleviation of airway hyperresponsiveness, and antioxidant activities are also critical antiasthmatic mechanisms of action.Tese results can be helpful for the researchers to identify phytochemicals present in each plant or familiarize themselves with herbal compounds to develop new antiasthmatic drugs.
Along with investigating the safety and adverse efects of the mentioned plants and compounds, assessing the additive/ synergistic efects of combinations of diferent bioactive ingredients for the production of more efective formulas with fewer side efects can become the future felds of research in order to pave the path of using herbal treatments in the clinic.

Practical Recommendations for Healthcare Practitioners.
Based on the fndings of this review, healthcare practitioners are advised to pay attention to herbal and traditional medicine to treat asthma with a positive outlook.Since herbal medicine has fewer side efects and is cheaper than the existing drugs, prescribing herbal medicine to asthma patients can help the economics of treatment.However, it is recommended that possible toxicities (e.g., in the nerves, liver, and kidneys) and drug interactions be carefully considered before prescribing herbs and herbal compounds to treat patients.Reactive oxygen species SOD:

Figure 1 :
Figure 1: Pictures of plants with verifed antiasthmatic efects.Te plant names are arranged in alphabetical order.Te same ordering method is used in the text when describing the plant characteristics.

H
True myrtle or the common myrtle, is a fowering member of the Myrtaceae family[271][272][273].Bejeshk et al.
is a compound from Rosmarinus ofcinalis L. (rosemary), which is a medicinal plant native to the Mediterranean region and cultivated around the Evidence-Based Complementary and Alternative Medicine world syringin is a phenylpropanoid glycoside extracted from Eleutherococcus senticosus, Jasminum mesnyi, Edgeworthia chrysantha Lindl., and Acanthopanax senticosus[294].Dai et al. revealed that syringin uses the NF-κB signaling pathway to reduce infammation of the lungs induced by ovalbumin in a BALB/c mouse asthmatic model[295].

Figure 2 :
Figure 2: Factors involved in asthma induction (left) and the signs and symptoms of disease (middle), along with the mechanisms of antiasthmatic efects of plants or their compounds (right).GERD (gastroesophageal refux disease), AHR (airway hyperresponsiveness), ROS (reactive oxygen species), and RNS (reactive nitrogen species).

Table 1 :
Te plants or herbal compounds that have shown antiasthmatic efects in clinical studies and their mechanism of action.

Table 2 :
Plants or herbal compounds with verifed preclinical (animal/organ/tissue) antiasthmatic efects and related mechanisms.

Table 2 :
[150]nued.NO 3 , and total protein in rats[149].Te extract has been shown to reduce the number of bronchus mast cells of an asthmatic model caused by ovalbumin at 140 mg/kg[150].
choalveolar lavage fuid (BALF) IL-13, IL-5, and IL-4 [53].Shakeri et al. showed the antiasthmatic efects of this plant at the concentration of 0.7 mg/ml by inhibiting MDA, NO 2 , [43]d Complementary and Alternative Medicine changes of the lung, comparable with dexamethasone (1 mg/ kg)[44].A clinical study showed that oral administration of 50 mg soft-gelatin capsules of licorice extract (6.5% glycyrrhizin) three times a day for four weeks efectively reduces frequency and severity of asthma attacks[62].Ram et al.showed that Glycyrrhiza glabra at concentrations of 2.5, 5, 10, and 20 mg/kg signifcantly alleviates the asthmatic symptoms by an increase in IFN-c and reduction in BALF eosinophil count, IL-5, and IL-4 in comparison with dexamethasone (1 mg/kg)[93].Khattab et al. found that licorice extract at the concentration of 40 mg/kg prevents the production of T2 cytokines and free radicals induced by ovalbumin in mice via raising CAT and SOD levels and reducing IgE, IL-5, IL-13, NO, and MDA levels in plasma and BALF in comparison to montelukast (30 mg/kg)[43].Yang et al. demonstrated the synergistic antiasthmatic efects of glycyrrhizinand salbutamol (β2-agonist) in the treatment of asthma 122]26.Glycirizine glabra.Liquorice is the common name of Glycyrrhiza glabra, a fowering plant of the bean family, Fabaceae[92].Hocauglu et al. demonstrated that glycyrrhizin diminishes goblet cells and mast cells, epithelium thickness, subepithelial smooth muscle thickness, and basement membrane thickness at 10 mg/kg in the mouse asthma model, benefting all long-term histopathologic12Evidence- [209]208]glans regia.Also known as white or English walnut, Juglans regia is used by Palestinians to treat asthma and diabetes.Sharif et al.showed that by upregulating aquaporin-5 and aquaporin-1 and downregulating infammatory cytokines, Juglans regia ameliorates allergic asthma caused by ovalbumin exposure in mice[207].3.1.30.Lavandula stoechas.Known as French lavender (U.K.) or topped or Spanish lavender (U.S.), Lavandula stoechas is a member of the Lamiaceae family.Almohawes et al. confrmed that Lavandula at the concentration of 300 mg/kg has antiasthma, anti-infammatory, and antioxidant activity through reducing serum IgE and IgG concentration, diminishing MDA, and increasing SOD in asthmatic guinea pigs[104,208].Khodadoost et al. revealed the alleviating efects of Lavandula aqueous extract at the concentration of 833 mg/kg on asthma complications via reducing eosinophils and IL-5, IL-33, and IL-13 concentration in BALF in a mouse model in comparison to budesonide (5 mg/kg)[209].
3.1.31.Lignosus rhinocerotis.Lignosus rhinocerotis Cooke is a medicinal mushroom traditionally used by indigenous communities in Malaysia to treat asthma and several other diseases.It has been shown that Lignosus rhinocerotis Cooke reduces airway hyperresponsiveness, hypersecretion of mucus, and infammation of airways at the concentration of 125 mg/kg in a murine asthmatic model compared to the dexamethasone (3 mg/kg) [210].3.1.35.Mentha piperita.Tis plant has dry and warm nature and numerous medical features.Te green-formulated gold nanoparticles of Mentha piperita possess immunomodulatory [144]bady et al.revealed the antiinfammatory and immunomodulatory efects of the P. oleracea extract at concentrations of 1, 2, and 4 mg/ml in a rat asthma model.Its reduction of the BALF levels of PLA2, TP, and IgE suggests that the plant extract can have therapeutic efects on asthma, comparable with 1.25 μg/ml dexamethasone[124].Te common grape vine is native to Southwestern Asia (East to Northern Iran), Central Europe, and the Mediterranean region.Arora et al. demonstrated that the dried fruits of Vitis vinifera have antiasthmatic efects at concentrations of 31 and 42.5 mg/kg compared to dexamethasone (2.5 mg/kg) in an animal model of bronchial asthma.Vitis vinifera reduced respiratory rate, improved tidal volume, and diminished infammatory cells and interleukins LTD-4, IgE, NO, nitrite, and histamine levels in the serum and BALF[144].
[225]22]hysalis angulata Linn.Traditional medicine utilizes P. angulata to treat malaria, infammatory diseases, and asthma.Te alcoholic root extract of P. angulata was investigated for its antiasthmatic activity in asthmatic albino mice.Te extract reduced the release of infammatory mediators, preventing OVA-induced asthma[30,223].3.1.43.Pimpinella anisum.Pimpinella anisum (anise), also called aniseed or rarely anix, is a fowering plant in the family Apiaceae.Several studies have reported the bronchodilator efects of the essential oil and alcoholic and aqueous extracts of P. anisum.Te essential oils reduce proinfammatory cytokines, stimulating the secretion of mucus in the epithelial cell lines of the trachea and bronchi through diminishing IL-8 and IL-1β levels[224]and relaxes the guinea pig's tracheal chain[50,122].Dargahi et al. showed the anti-infammatory efect of Pimpinella anisum extract in a mouse model of allergic asthma[225].3.1.45.Portulaca oleracea (Purslane).Portulaca oleracea (common purslane, also known as duckweed, little hogweed, or parsley) is an annual succulent in the family 14 Evidence-Based Complementary and Alternative Medicine Portulacaceae.3.1.48.Sesamum indicum (Sesame).Benne or sesame is a fowering plant in the genus Sesamum.Hsu et al. edible bean.Cho et al. reported that treatment with soy isofavone signifcantly reduced severe asthma fareups in asthmatic patients with high PAI-1-producing genotypes partly by decreasing the generation of PAI-1 in airway epithelial cells using genistein [234].Bao et al. demonstrated that soy isofavone successfully decreased AHR, airway remodeling, mucus hypersecretion, MMP-9 expression in 3.1.52.Tridax procumbens.High anti-infammatory activity and active phytoconstituent content make this plant interesting to traditional medicine.Devi et al. demonstrated that Tridax procumbens alcoholic extract improved pulmonary infammation in an allergic asthma model by the inhibition of NF-κB/p65/ERK-mediated signaling [237].3.1.53.Urtica dioica.Tis is a species from the Urticaceae family.Zemmouri et al. showed that 1.5 g/kg Urtica dioica, Linn. is used in folk medicine to treat respiratory disorders.Tirpude et al. found that Vitex negundo Linn.extract at the concentration of 100 μg/ml activates macrophages and modulates the TGF-β/Smad/Bcl2/caspase/LC3 and AMPK/ PI3K/Akt/p38-NF-κB cascades, improving lung injury and infammatory aggravation in a murine allergic asthma model induced by OVA-LPS [241].Evidence-Based Complementary and Alternative Medicine 3.1.57.Vitis vinifera.Also, Zhu et al. demonstrated the protective role of zingerone in a murine asthma model via activation of the AMPK/Nrf2/HO-1 pathway [243].Jedli et al. showed the ameliorative function of Zingiber ofcinale on asthma via an increase in antioxidant potential and modulation of the STAT6 and TNF-α pathways [244]. A. .