Chamomile (Matricaria chamomilla L.): A Review of Ethnomedicinal Use, Phytochemistry and Pharmacological Uses

Matricaria chamomilla L. is a famous medicinal plant distributed worldwide. It is widely used in traditional medicine to treat all kinds of diseases, including infections, neuropsychiatric, respiratory, gastrointestinal, and liver disorders. It is also used as a sedative, antispasmodic, antiseptic, and antiemetic. In this review, reports on M. chamomilla taxonomy, botanical and ecology description, ethnomedicinal uses, phytochemistry, biological and pharmacological properties, possible application in different industries, and encapsulation were critically gathered and summarized. Scientific search engines such as Web of Science, PubMed, Wiley Online, SpringerLink, ScienceDirect, Scopus, and Google Scholar were used to gather data on M. chamomilla. The phytochemistry composition of essential oils and extracts of M. chamomilla has been widely analyzed, showing that the plant contains over 120 constituents. Essential oils are generally composed of terpenoids, such as α-bisabolol and its oxides A and B, bisabolone oxide A, chamazulene, and β-farnesene, among other compounds. On the other hand, M. chamomilla extracts were dominated by phenolic compounds, including phenolic acids, flavonoids, and coumarins. In addition, M. chamomilla demonstrated several biological properties such as antioxidant, antibacterial, antifungal, anti-parasitic, insecticidal, anti-diabetic, anti-cancer, and anti-inflammatory effects. These activities allow the application of M. chamomilla in the medicinal and veterinary field, food preservation, phytosanitary control, and as a surfactant and anti-corrosive agent. Finally, the encapsulation of M. chamomilla essential oils or extracts allows the enhancement of its biological activities and improvement of its applications. According to the findings, the pharmacological activities of M. chamomilla confirm its traditional uses. Indeed, M. chamomilla essential oils and extracts showed interesting antioxidant, antibacterial, antifungal, anticancer, antidiabetic, antiparasitic, anti-inflammatory, anti-depressant, anti-pyretic, anti-allergic, and analgesic activities. Moreover, the most important application of M. chamomilla was in the medicinal field on animals and humans.


Introduction
Matricaria chamomilla, usually referred to as chamomile, is a well-known medicinal plant from the Asteraceae family. It is an annual herb that grows on all soil types and is resistant to cold. M. chamomilla is native to southern and eastern Europe and northern and western Asia [1]. Nowadays, it is widely distributed all around the world [2]. M. chamomilla has been used traditionally in several countries to cure a number of diseases, including

Phytochemical Interest
The phytochemical composition of M. chamomilla EO and extracts has been widely investigated, and more than 120 constituents have been identified. Due to the large number of investigations found in this section, we have reported only the major studies reflecting the chemical composition in different environmental areas ( Table 2). The phytochemical screening of EO and extracts was carried out using chromatographic techniques and focused on the flowers since they are the most used plant organ. Generally, the chemical composition of EO and extracts showed the abundance of terpenoids ( Figure 2) and phenolic compounds, commonly phenolic acids (     Generally, the chemical composition varied significantly depending on the origin of the plants. The EO from Moroccan M. chamomilla obtained by microwave-assisted hydrodistillation showed 24 chemical components representing 98.49% of the total EO, with chamazulene (26.11%) as the main component, followed by cis-β-farnesene (11.64%) and eucalyptol (8.19%) [87]. In another study from Egypt, Abbas et al. [13] compared the chemical composition of EO obtained from fresh and dried flowers using different techniques (sunlight, shade, oven, solar dryer, and microwave). The findings of this work showed that the main component of all EO was α-bisabolol oxide A (33-50.5%). The drying methods used in this study significantly influenced the number of compounds identified, with 21 compounds found after solar drying and only 13 found after microwave drying.
Chromatographic analysis of the chemical composition of M. chamomilla extracts revealed the presence of phenolic acids, flavonoids, coumarin, and amino acids. In addition, the extracts contain sterols, triterpens, saponins, tannins, and alkaloids [55,101]. The work of Elsemelawy indicated that Egyptian M. chamomilla powder was rich in flavonoids (luteolin O-acylhexoside and quercetin) and phenolic acids (ellagic acid, catechol, and chlorogenic acid) [102]. Another study on aqueous extract showed that the main compounds were also flavonoids (myricetin, quercetin, and naringenin) and phenolic acids (benzoic and rosmarinic acids) [53]. In their study on M. chamomilla from Slovakia, Petrul'ová-Poracká et al. reported for the first time the presence of three coumarins in methanolic extract, skimmin (umbelliferone-7-O-β-D-glucoside), daphnin (daphnetin-7-O-β-D-glucoside), and daphnetin (7,8-dihydroxycoumarin) [103]. On the other hand, coumarin, phenolic acid, and flavonoids contents of leaves methanolic extract were influenced by ethephon treatment [17]. In addition, the investigation of Kováčik et al. showed that the phenolic acid content of leaf rosettes was influenced by exposure to cadmium and copper. The mineral content of leaf rosettes and roots was also affected [18]. On the other hand, the results of the methanolic extracts from Iran M. chamomilla showed the highest amounts of luteolin and apigenin [10]. In addition, Sayyar et al. reported n-heptacosane (33.53%), a higher alkane, as the main component of ethanol extract [104]. The HPLC technique was used to determine the caffeoylquinic acid content of 34 samples from different geographical areas of China [105]. The findings showed the presence of six phenolic acids dominated by isochlorogenic acid A. The extract of M. chamomilla can also contain amino acids, such as proline and alanine [106]. M. chamomilla extract from Pakistan showed the dominance of amino acids proline and asparagine [16].

Antioxidant Activity
Several studies have investigated the antioxidant activity of M. chamomilla EO, extracts, and cell suspension culture (Table 3). These researches were carried out by several tests, including DPPH, ABTS, FRAP, β-carotene bleaching, ferrous ion chelating ability, and lipid peroxidation inhibition. The enzyme activities were also assessed for catalase, acetylcholine esterase, glutathione, peroxidase, ascorbate peroxidase, and superoxide dismutase.
DPPH assay is the most widely used to assess antioxidant activity. Using this test, M. chamomilla EOs showed the highest DPPH scavenging activity after 90 min of reaction [107]. On the other hand, M. chamomilla EOs had less activity than the used standards BHT and α-tocopherol in both DPPH and β-carotene bleaching tests, while it showed a comparable ferrous ion chelating ability than the citric acid standard [108]. The ABTS test was used to investigate the antioxidant power of EOs obtained by different extraction techniques (steam stripping, hydrodistillation, steam-dragging distillation with simultaneous steam extraction using an organic solvent, maceration, and supercritical fluid extraction) [109]. The results varied depending on the extraction technique, with the steam stripping technique providing the higher antioxidant activity in ABTS assay. This observation could be explained by the variation of EOs' chemical composition depending on the extraction methods.
In another study on 13 cultivated M. chamomilla, the EOs and methanol extracts exhibited an interesting antioxidant activity using DPPH and FRAP assays [92]. This activity varied depending on the environmental factors and the chemical composition. Indeed, the highest activity was obtained by EOs rich in oxygenated compounds and extracts with high phenolic content. Comparing EOs and extracts, the authors reported higher DPPH activity from extracts, while both had similar activity using the FRAP test. Moreover, ABTS assay was used to study the antioxidant activity of two extracts (ethyl acetate extract and aqueous extract) from different plant parts (flower, leaf, stem, and root) [110]. The results showed that hydrophilic antioxidant activity (HAA) was significantly higher than the lipophilic antioxidant activity (LAA).
Abdoul-Latif et al., using the DPPH test, found that methanolic extract exhibited higher activity than EO, while EO showed a higher relative antioxidant activity in βcarotene-linoleic acid assay [111]. Other studies also showed the antioxidant activity of methanolic extract [46,112]. In addition, the activity varied depending on plant organ/tissue used, with separated parts exhibiting sometimes higher activity than whole herb [113]. On the other hand, Munir et al. [114] reported higher antioxidant activity with methanolic extract compared to ethanolic extract using DPPH assay, showing the role of extraction solvent in the antioxidant activity [114]. In the same way, Roby et al. found that methanol extract had the strongest DPPH scavenging activity, followed closely by ethanol, then diethyl ether and hexane extracts [115]. On the other hand, M. chamomilla ethanolic extract was also able to scavenge DPPH radicals [49,116]. Using also DPPH assay, Molnar et al. found that hydroethanolic extract obtained from processing waste fraction using maceration method exhibited the highest antioxidant activity compared to other extracts from processed chamomile flowers first class, unprocessed chamomile flowers first class, and pulvis [20]. This shows that extract obtained from waste can also exhibit interesting antioxidant capacity. In addition, Cvetanović et al. investigated the antioxidant activity of extracts obtained by several extraction techniques (microwave-assisted, Soxhlet, and ultrasound-assisted extraction) using two solvents (ethanol and water) compared to subcritical water extraction [117]. In general, subcritical water extract had the strongest DPPH scavenging capacity and ability to reduce Fe 3+ to Fe 2+ compared to other extracts. Furthermore, the temperature selected during subcritical water extraction had an influence on the antioxidant power of M. chamomilla aqueous extracts [118]. Extracts obtained at a temperature of 210 • C demonstrated the strongest DPPH activity, while extraction at 150 • C gave extracts with the highest ABTS and hydroxyl radical scavenging activities and lipid peroxidation inhibition. In the same way, Sotiropoulou et al. [119] investigated the effect of extraction temperature (25, 80, and 100 • C) on aqueous extracts' DPPH capacity. The results showed that the extract at 80 • C had the highest activity, while no activity was reported by extract prepared at 25 • C. These results can be explained by the highest phenol content obtained at 80 • C compared to other temperatures. Indeed, high temperatures can allow the extraction of more polyphenols, but extremely high temperatures (100 • C) can lead to the loss of unstable ones. In addition, using a multivariate approach, Pereira et al. investigated the effect of several extraction parameters on the antioxidant capacity of hydroalcoholic extract obtained by dynamic maceration process. The results showed that extraction temperature, ratio of plant to solvent, and ethanol strength were the factors that exhibited most influence on the extract. Using the optimal conditions, the authors found that the extract was rich in flavonoids, apigenin, and apigenin-7-glycoside, and had high antioxidant activity close to the predicted results [120].
The enzymatic treatment of M. chamomilla aqueous infusion by hesperidinase and β-galactosidase led to a small increase in the percentage of DPPH radical-scavenging activity even though several phenolic compounds were altered by the treatment [121]. Using chicken liver tissue, Singh et al. found that M. chamomilla tea extract exhibited great antioxidant activity in lipid peroxidation tests [122]. In addition, the lipid peroxidation inhibition was influenced by treatment with electron beam irradiation [123]. Indeed, this treatment used for plant microbial decontamination caused a decrease of antioxidant activity in a dose-dependent way. This result was explained by the decrease of plant chemical compounds content, including flavonoid, tannins, and polyphenolcarboxylic acids. On the other hand, Hassanpour and Niknam found that the treatment of M. chamomilla cell suspension culture with a static magnetic field ameliorated its antioxidant activity and flavonoid metabolism [124]. Moreover, cells culture under clino-rotation induced antioxidant enzyme activity leading to growth and cell division [19]. Consequently, the parameters of cell culture also influence the antioxidant activity.
M. chamomilla EOs and extracts possess antioxidant activity that allows their use to prevent or treat diseases. In male Wistar rats, the intake of hydroalcoholic extract prevented the increase of superoxide dismutase globule and plasma malondialdehyde caused by a high cholesterol diet [125]. Additionally, in diabetic rats, the treatment with 10 and 20% M. chamomilla powder significantly decreased lipid peroxidation and increased catalase, acetylcholine esterase, and glutathione levels in serum [19].

Antibacterial Activity
The antibacterial efficacy of M. chamomilla EOs and extracts was investigated by several studies (Table 4). Generally, the agar diffusion technique, using discs or wells, is the most used to screen the antibacterial activity of EOs and extracts. Using this technique, Stanojevic et al. [107] reported the antibacterial activity of M. chamomilla EO. The most sensitive strain was Staphylococcus aureus, while the most resistant one was Pseudomonas aeruginosa. Similarly, Owlia et al. [22] reported no activity against P. aeruginosa using the disc diffusion technique. However, the EO was able to reduce biofilm formation and alginate production, showing efficiency in controlling biofilm-producing bacteria. On the other hand, results of both diffusion and dilution techniques showed that Bacillus subtilis was the most sensitive bacteria to M. chamomilla EO from Morocco [87]. In addition, the EO showed the largest inhibition zone against B. cereus and the smallest MIC and MBC values against S. aureus [97]. Gram-positive bacteria also showed the smallest MIC values, as found by Silva et al. [126]. These results could be explained by differences in the cell wall structure since Gram-negative bacteria have a complex and rigid membrane rich in lipopolysaccharide, which limits the access of antimicrobial molecules [127]. In addition, the antibacterial activity of M. chamomilla EO was also reported against several Streptococcus species [128]. The commercial EO also showed antibacterial activity against several Gram-positive bacteria [129]. The results showed that the EO was more active against S. aureus MRSA compared to reference strains. On the other hand, P. aeruginosa was the most sensitive bacteria in both diffusion and micro-dilution assays [108,111], showing that Gram-negative bacteria could be more sensitive to EO compared to Gram-positive strains. In addition, Shakya et al. [130] found that M. chamomilla flower EO significantly reduced Enterococcus faecalis growth. More interestingly, Satyal et al. [131] reported that M. chamomilla EO exhibited the strongest activity against both S. aureus and P. aeruginosa. In addition, Hartmann and Onofre [132] reported the smallest MIC values against Escherichia coli, while no activity was found against P. aeruginosa. The largest inhibition zone was obtained against S. aureus, with the highest results when the EO was used without dilution (100%). Other factors can influence EO antibacterial activity, including plant origin, as found by Höferl et al. [27]. Indeed, the highest activity (MIC = 2000 µg/mL) was obtained against most bacteria by EO from South Africa (18.7% trans-β-farnesene) and Hungary (38.3% α-bisabolol).
Comparing the antibacterial activity of M. chamomilla EO and four extracts, Roby et al. [115] found that EO had the highest activity against all tested bacteria. The antibacterial activity increased with increasing concentrations of both EO and extracts. Among tested extracts, diethyl ether extract had the lowest activity, showing the effect of extraction solvent on antibacterial activity. Similarly, Ismail et al. [133] found that methanol and ethanol extracts studied at different concentrations were only active at the highest concentration and only against S. aureus. In addition, the aqueous extract was inactive against all strains at all tested concentrations. On the contrary, the aqueous extract was the strongest extract against most strains studied by Boudıeb et al. [134], except Pseudomonas sp., which was more sensitive to methanol extract. In their study on methanol, ethanol, petroleum ether, and ethyl acetate extracts, Abdalla and Abdelgadir [101] found that petroleum ether extract exhibited the highest activity (diameter-Φ between 22 and 26 mm) while ethyl acetate extract showed no activity against all tested bacteria. On the other hand, the study of Mariod et al. [135] on methanol, n-hexane, chloroform, ethyl acetate, and aqueous extracts from Sudanese and Egyptian M. chamomilla confirmed the effect of extraction solvent and plant origin on antibacterial activity. Indeed, Sudanese methanolic extract showed the highest activity, with better effect against S. aureus (W17) at concentrations of 50, 100, and 200 mg/mL. In another study, ethyl acetate extract exhibited a higher inhibitory effect against Helicobacter pylori compared to ethanol extract [136]. In addition, MBC values varied depending on ethanol percentage used (MBC = 125 µg/mL with ethanol 99.8%). On the other hand, ethanolic extract was only active against P. aeruginosa, while cyclohexane extract exhibited no antibacterial activity against all tested bacteria [137].
Several studies reported the antibacterial activity of M. chamomilla ethanolic extracts [117,[138][139][140]. The results varied depending on the organ used [23][24][25]. Indeed, among 24 S. aureus MRSA studied, ethanolic extracts from flowers had an activity on 20 strains compared to 7 for leaf extracts [23]. The same results were found by Ahani Azari and Danesh [24] against MRSA strains. However, the authors found that ethanolic extract from leaves was the only one active against P. aeruginosa multidrug-resistant (16 strains). These findings were similar to the one found by Poudineh et al. [25]. On the other hand, methanol extracts also showed antibacterial activity [46,111,141,142]. The extract also exhibited an anti-adherence activity against all tested strains [26]. In addition, aqueous extracts have also demonstrated antibacterial activity [143,144] that varied depending on the plant organ used [145].

Antifungal Activity
The antifungal activities of EOs and extracts obtained from different parts of M. chamomilla have been reported in the literature, suggesting great efficacy against a variety of fungal strains (Table 5). Most studies investigated the effect of M. chamomilla EO on Candida sp. Höferl et al. found that EOs from different origins were able to inhibit C. albicans growth with MFC = 2000 µg/mL, except EOs obtained from cultivated Indian plants dominated by α-bisabolol oxide A (25%), which showed MFC of 4000 µg/mL [27]. This reflects the influence of plant origin and EO chemical composition on antifungal activity. In addition, fluconazole-resistant and susceptible C. albicans strains isolated from Human Immunodeficiency Virus (HIV) positive patients with oropharyngeal candidiasis were inhibited by M. chamomilla EO, with a better effect on susceptible strains [146]. Other studies proved that C. albicans is more sensitive to EO than Aspergillus sp. [111,131]. Moreover, EL-Hefny et al. [88] found that EO antifungal activity was dose-dependent, with the best results against A. niger. Similar to their results on antibacterial activity, Mekonnen et al. reported no effect of M. chamomilla EO from Ethiopia on two Aspergillus sp. and two Trichophyton sp. Strains [147].
Comparing the antifungal capacity of M. chamomilla EO and extracts, Abdoul-Latif et al. [111] found that EO had better activity than methanolic extract. On the other hand, Roby et al. found that EOs and different extracts (methanol, ethanol, diethyl ether, and hexane) had a dose-dependent activity [115]. Among chloroform, methanol, and aqueous extracts, only chloroform showed antifungal activity (Φ = 6 mm) against C. albicans and Fusarium sp. [134]. This shows the effect of extracts on antifungal activity. In another study, Hameed et al. found that methanolic plant extract had an activity on A. terreus [141], while Lavanya et al. reported no activity against four Candida sp. (C. albicans, C. tropicalis, C. parapsilosis, and C. krusei) [26]. On the other hand, ethanolic flower extract also showed an antifungal activity [117]. Moreover, hydroalcoholic extract of M. chamomilla caused a significant decrease in Saccharomyces cerevisiae growth and cell survival [148]. In addition, aqueous extracts also showed antifungal activity [143,144]. On the other hand, seed aqueous extracts obtained at different pH (acidic, neutral, and alkaline) exhibited the same antifungal activity against A. niger and P. citrinum [149]. In addition, their sulfated derivatives exhibited a close antifungal activity even though they had higher phenolic content. In another study, Seyedjavadi et al. [150] isolated a novel peptide (AMP1) from M. chamomilla, with antifungal activity against C. albicans and Aspergillus sp. This shows that M. chamomilla can be source of interesting antifungal molecules.

Antiparasitic and Insecticidal Activities
Several studies have investigated the capacity of M. chamomilla EOs and extracts to inhibit the growth of a wide range of parasites and insects. An in vitro evaluation of the leishmanicidal activity of Tunisian M. chamomilla EOs was carried out [151]. The results showed that EOs exhibited a good activity on the promastigotes (an extracellular and motile form) of Leishmania amazonensis (IC 50 = 10.8 µg/mL after 96 h) and L. infantum (IC 50 = 10.4 µg/mL after 96 h), while α-bisabolol was able to activate programmed cell death effects in the promastigote. In another study by Hajaji et al., the activity of α-bisabolol against Acanthamoeba castellani has been investigated. The results showed that α-bisabolol has amoebicidal activity with IC 50 = 20.83 µg/mL and IC 90 = 46.60 µg/mL, and it was able to increase the plasmatic membrane permeability and to decrease ATP levels [152].
The anti-Acanthamoeba activity of flower extracts of Tunisian M. chamomilla was evaluated on Acanthamoeba castellanii [158]. The methanolic extract has shown a potent anti-acanthamoeba activity (IC 50 = 66.23 µg/mL) which is attributed to a coumarin mixture. The anti-helminthic activity of the extracts from M. chamomilla flowers was evaluated on the egg and adult stages of Haemonchus contortus, which is a gastrointestinal parasite of small ruminants [159]. Methanolic and aqueous extracts showed higher inhibitory effects on egg hatching (IC 50 of 1.52 and 2.55 mg/mL, respectively). After 8 h, methanolic extract induced 91.77% mortality at the highest concentration tested (8 mg/mL), while the aqueous extract induced only 75.05% mortality at the same concentration. Another study showed that methanol extract (at 1024 µg/mL) was the most active as an anti-helminthic against Haemonchus contortus [159]. The percentage of ovicidal activity was 37.5% for the egg hatch test, and the percentage of larvicidal activity was 84% for the larval development test. Concerning the mosquitocidal activity, Al-Mekhlafi et al.have tested the larvicidal and ovicidal effects of the combination of M. chamomilla and Foeniculum vulgare hexane extracts against Culex pipiens. The mixture obtained showed a larvicidal activity with LC 50 of 100.3 mg/mL after 72 h exposure [28]. In addition, an ovicidal activity was reported with a decrease in egg hatchability from 95 to 15% at doses ranging from 62.5 to 500 mg/mL. The larval mortality ranged from 13.33 to 93.33% at doses ranging from 31.25 to 250 mg/mL. In another study, M. chamomilla ethyl acetate extract showed the most promising larvicidal activity against Culex pipiens, with 90% mortality at concentration 358.9 µg/mL after 48 h of exposure [160]. Treatment of eggs with concentration of 240 µg/mL showed 86.49% hatchability, and the life cycle could not be completed because all the larvae were dead (100% mortality).

Antidiabetic Activity
The activity of M. chamomilla extract and isolated apigenin, apigenin-7-O-glucoside, cis and trans-2-hydroxy-4-methoxycinnamic acid glucosides against α-amylase and maltase have been tested [29,161]. The results showed that the extract and the compounds exhibited a concentration-dependent inhibition on both enzyme activities. The highest α-amylase and maltase inhibition was obtained by apigenin and apigenin-7-O-glucoside, respectively. Furthermore, these two flavonoids were able to restrict sucrose and glucose transports and regulate sugar absorption. Moreover, another study reported that M. chamomilla hydro-methanolic extract and some isolated compounds inhibited rat lens aldose reductase activity [162]. In addition, 3,5-O-di-caffeoylquinic acid and luteolin-7-O-β-D-glucuronide suppressed sorbitol accumulation in rat lens under high-glucose conditions, while luteolin-7-O-β-D-glucuronide and luteolin suppressed advanced glycation end products formation. Furthermore, M. chamomilla ethanolic extract demonstrated anti-glycation properties with IC 50 of 264.2 µg/mL for lipase inhibition activity [163].

Anti-Tumoral Activity
M. chamomilla extracts and EOs have also been studied for their anti-tumoral properties on several cancer cell lines. The anticancer activity of M. chamomilla EO was evaluated on human breast carcinoma (MCF-7) cell line by Ali [30]. The results showed that EOs inhibited the cell proliferation in a dose-dependent manner, with 89% inhibition after 24 h exposure at the highest concentration, 640 µg/mL. On the other hand, EO anticancer activity against two species of human promyelocytic leukemia cell lines (HL-60 and NB4) was tested [164]. The EOs were able to inhibit both cell lines growth, with higher dead percentages against NB4 cells (86.03% at 200 µg/mL) compared to HL-60 cells (78.4% at 200 µg/mL). In addition, M. chamomilla hydroalcoholic extracts from aerial parts or roots revealed an anti-proliferative effect on human breast cancer cells [31,165]. The IC 50 was 785 g/mL against MDA-MB-468 and 921 g/mL against MCF-7 for aerial parts extracts and 1560 g/mL against MCF-7 for root extracts. The methanolic extract of M. chamomilla has been tested by Fraihat et al. [166] on two solid human melanocyte tumor cell lines, A375.S2 and WM1361A. In this study, results showed an inhibition only in the proliferation of the melanotic WM1361A cell line (IC 50 = 25.2 g/mL). On the other hand, Cvetanović et al. [117] found that the extraction method impacted the anticancer efficacy of M. chamomilla extracts. Indeed, subcritical water extracts revealed the most effective cytotoxic activity against murine fibroblast cell line (IC 50 = 19.65 µg/mL), human cervical carcinoma cell line Hep2c (IC 50 = 20.54 µg/mL), and human rhabdomyosarcoma cell line (IC 50 = 30.54 µg/mL). Antitumor potentials of water extracts of M. chamomilla seeds obtained at different pH conditions and their corresponding sulfated derivatives against the Ehrlich ascites carcinoma cells were evaluated by [167]. All extracts slightly inhibited the growth of the Ehrlich ascites carcinoma cell line at 3 different concentrations (300, 600, and 900 µg/mL). The anticancer properties of M. chamomilla appear to be linked to apoptosis and necrosis, as well as to a decrease in migration and invasion capacities of oncogenic cells [31,167].

Anti-Inflammatory Activity
The anti-inflammatory effect of M. chamomilla extracts has been reported [32]. According to the findings of this study, the anti-inflammatory activity of M. chamomilla ethanolic extract on macrophages was associated with a decrease in nitric oxide production and cell viability, while on lymphocytes, it was related to the induction of anti-inflammatory cytokine production (IL-10) and the decrease in cell viability. On the other hand, M. chamomilla aqueous extract caused a reduction of nitric oxide production and an increase in cell viability in macrophages, while it was an effective T helper Th2 suppressor by disrupting the Th1/Th2 balance. The difference between these two extracts could be attributed to the presence of different active compounds. In another study, Singh et al. investigated the anti-inflammatory properties of M. chamomilla tea extract. The results showed that extract caused inhibition of protein denaturation and stabilization of human red blood cell membrane, indicating its anti-inflammatory properties [122].
The anti-inflammatory activity of M. chamomilla was also investigated in animal models. According to Wu et al., the volatile and non-volatile components of M. chamomilla, essential oil, flower water, and aqueous extract, can all significantly inhibit swelling of mouse ears caused by xylene, pedal swelling caused by carrageenan in rats, and the increase of celiac capillary vessel permeability in mice. They also had a significant inhibitory effect on the increase in prostaglandin E2 and nitric oxide levels in rat pedal edema caused by carrageenan [168]. Furthermore, the effects of M. chamomilla hydroalcoholic extract on the level of inflammatory blood indicators were investigated on rats by Nargesi et al. [125]. Treatment with 110 mg/kg hydroalcoholic extract prevented a significant increase in serum levels of Tumor Necrosis Factor-α (TNF-α), C-Reactive Protein (CRP), Interleukin 6 (IL-6), and fibrinogen. On the other hand, the combination of ethanolic extract and diclofenac or indomethacin, two non-steroidal anti-inflammatory drugs, showed interesting synergic anti-inflammatory effects on carrageenan-induced paw inflammation and stomach damage in rats [169].

Phyotherapeutical Applications
Traditionally, M. chamomilla has been used to treat several diseases. Nowadays, studies have demonstrated the therapeutic potential of this plant in animal and human studies. Indeed, M. chamomilla showed an interesting effect on the nervous system of rats by improving learning, memory [104,116,170,171], and motor function [172]. In mice, Can et al. [173] found that EOs had a stimulant effect on the central nervous system similar to that of caffeine. In a clinical study, the oral administration of M. chamomilla extract caused a sedative effect on elderly people, improving their sleep quality [174]. In another study, EOs reduced crying and fussing in breastfed colicky infants [175]. In addition, M. chamomilla EOs can exhibit sedative effects against withdrawal syndrome in narcotics anonymous [176]. On the other hand, clinical studies showed that M. chamomilla could be used to treat anxiety and depression [177,178], including anxiety before esophagogastroduodenoscopy [179].
M. chamomilla tea was effective in reducing pain in patients after orthopedic surgery [45]. In addition, dermal application of flower EOs by patients with knee osteoarthritis decreased their need for analgesic acetaminophen and ameliorated physical function and stiffness [180]. In another clinical trial, Zargaran et al. found that M. chamomilla oleogel can be used to relieve pain in patients with migraine without aura [181]. Additionally, clinical studies demonstrated that M. chamomilla could exhibit an interesting analgesic effect on women during childbirth [182,183]. The plant was also efficient in relieving the pain of mild to moderate mastalgia, breast pain often preceding the menstrual period [184]. In addition, some reviews gathered studies on the use of M. chamomilla in the treatment of premenstrual syndrome [185], primary dysmenorrhea, and reducing menstrual bleeding [186]. On the other hand, M. chamomilla extracts can exhibit an effect on male and female reproductive systems of rats by influencing sexual hormones level [34,187]. Moreover, the extract showed a protective effect against formaldehyde in male rats' reproductive system [49] and against torsion/detorsion-induced damages on adult rat testis tissue [188] and ovary tissue [189]. On the other hand, M. chamomilla extracts showed a therapeutic effect against thyroid damage [190] and kidney dysfunction [191] associated with polycystic ovary syndrome in female rats.
Other studies showed the protective effect of M. chamomilla on kidney and liver in animal models [47,192,193]. In animal models, several studies showed that M. chamomilla could be used to treat diabetes [102,[194][195][196][197]. In a clinical trial on patients with type 2 diabetes, Rafraf et al. [35] found that short-term intake of M. chamomilla tea can control fatty acids and blood sugar levels and increase insulin sensitivity. In their review, Bayliak et al. [36] reported the possible use of M. chamomilla to treat obesity and related metabolic disorders. Moreover, in both animal and clinical studies, Awaad et al. [37] found that M. chamomilla had anti-hypertensive activity, decreasing the risk for various cardiovascular diseases.
In addition to anti-cancer activity reported before, M. chamomilla can also be used as a chemo-preventive agent [198]. Indeed, the findings showed that aqueous extract had a protective effect against 1,2-dimethylhydrazine that induced colorectal cancer in mice. Moreover, M. chamomilla showed antinociceptive effects against vincristine [199] and formalin [200] in animal models, showing its possible use to treat or attenuate negative side effects of chemotherapy. Clinical studies also showed the ability of M. chamomilla to reduce nausea [201], anxiety, and depression [202] in patients undergoing chemotherapy.
In rats, M. chamomilla exhibited therapeutic gastrointestinal effects on diarrhea [40] and gastric ulcer [39]. In addition, M. chamomilla showed a gastroprotective effect against alcohol-induced ulcer injury in rat gastric mucosa [48]. On the other hand, a traditional Brazilian herbal medicine (Arthur de Carvalho Drops ® ), prepared from plants extracts including M. chamomilla, showed beneficial effects for the treatment of gastrointestinal disorders in rats [38]. In a randomized controlled trial, Khadem et al. [203] found that the topical application of M. chamomilla EOs on the abdominal region of patients after cesarean section ameliorated their postoperative bowel activity.
In their study, Park et al. [204] reported that ethanol extract of M. chamomilla was efficient in treating muscle wasting in mice with dexamethasone-induced muscle atrophy. On the other hand, M. chamomilla methanol extract showed anti-allergic activity against compound 48/80 by reducing scratching behavior in mice [41]. This result was explained by the extract's ability to inhibit histamine release from mast cells. In addition, M. chamomilla extract showed potential to heal wound [46] and atopic dermatitis-like lesions [205] in animal models. Among Matricaria genus is one of the most used in treating skin diseases. A number of patents and medicines have been developed using M. chamomilla EOs and extracts to treat skin diseases [42]. In addition, it has been used for the preparation of skincare formulations [206]. On the other hand, Jiménez Delgado et al. [207] found that M. chamomilla infusion can help reduce the dark rings under the eyes and periocular zone swelling. A commercial eye drop (Dacriovis™), containing extracts from M. chamomilla and Euphrasia officinalis, was found to exhibit a protective effect on human corneal epithelial cells from Ultraviolet B exposure [43]. Indeed, the eye drop showed antioxidant and antiinflammatory activities, allowing it to provide protection against cell death and ameliorate wound healing. On the other hand, M. chamomilla can also be used to treat a number of oral diseases. As a saliva substitute, this plant was clinically used against burning mouth syndrome [44] and xerostomia (dry mouth sensation) [208]. As a mouthwash, M. chamomilla was used to treat gingivitis, allowing the decrease of biofilm accumulation and gingival bleeding [209]. In addition, Braga et al. [210] found that a mouth rinse containing M. chamomilla aqueous extract showed an anti-caries effect. An orabase containing chamomile extract relieved pain in patients with oral mucosal minor aphthous stomatitis [211].

Other Applications
The possible use of M. chamomilla as an anesthetic agent in aquaculture was reported [50,212]. In addition, the plant has been used by farmers as supplementary animal feeds. In rabbits, Alsaadi et al. [51] reported that aqueous flower extract promoted animal growth and had a positive effect on biochemical and hematological parameters. In another study, the use of M. chamomilla as a feed supplement positively influenced the intake of Juniperus phoenicea by goats [213]. M. chamomilla extracts have also been investigated as a food preservative in cottage cheese [59,214], yogurts [63], and biscuits [52]. On the other hand, the antifungal potential of M. chamomilla allows its use as an agricultural tool. In the greenhouse, Ghoniem et al. [53] reported the possible use of M. chamomilla aqueous extract to control Pythium ultimum fungus in bean crops. In addition, the possible use of M. chamomilla as a natural surfactant was studied. Shadizadeh and Kharrat [54] found that hydroglycolic extract can be used as a surfactant for a chemical enhanced oil recovery process since it decreased the oil-water interfacial tension. In another study, Ugi et al. [55] used M. chamomilla as an environmentally friendly inhibitor for the management of water corrosion of federated mild steel.
Although EOs and extracts have several biological activities, their application in industrial fields is limited by their low stability, low solubility, and high evaporation. The encapsulation allows the protection and target delivery and can also enhance biological activities [215]. Some studies incorporated M. chamomilla EOs and extracts into nanoparticles in order to improve their pharmacological properties. Indeed, Das et al. [56] prepared a Pickering emulsion of M. chamomilla EOs stabilized with modified Stöber silica nanoparticles. The Pickering nanoemulsions showed higher antibacterial and antifungal activities than that of emulsion stabilized with Tween 80 and ethanolic solution. The nanoparticles acted as a stabilizer, allowing the controlled release of EOs from the emulsion system. On the other hand, M. chamomilla extracts incorporated in silver nanoparticles demonstrated higher antibacterial and antifungal activities, explained by the synergistic effect between nanoparticles and extract, high localized concentration of extract, and size-specific nanoparticle efficacy [62]. In addition, Negahdary et al. [216] reported good activity of M. chamomilla silver nanoparticles against S. aureus growth and C. albicans biofilm. In another study, silver nanoparticles also exhibited higher activity on bacteria from dairy products [57]. In addition, silver nanoparticles prepared with M. chamomilla aqueous extract exhibited anticancer activity against human lung adenocarcinoma cell line (A549) [60]. On the other hand, silver nanoparticles containing aqueous extract exhibited catalytic activity against Rhodamine B under UV irradiation and thus can be considered a promising solution for wastewater treatment [61]. In their study, Karam et al. [58] found that chitosan nanocapsules containing M. chamomilla EOs had activity against Leishmania amazonensis , allowing its use to treat leishmaniasis. In addition, EO nanocapsules showed a significant reduction in cytotoxicity against mammalian cells compared to free EOs. In another study, M. chamomilla aqueous extract microencapsulated in alginate exhibited higher antioxidant activity when incorporated into cottage cheese [59]. However, other reviews on M. chamomilla highlighting several aspects of great interest can be consulted [217,218].

Conclusions
In this current review about M. chamomilla, we reported taxonomy and synonym, botanical and ecology description, geographic distribution, ethnomedicinal use, phytochemistry, pharmacological properties, medicinal and other applications, and encapsulation solutions. Traditionally, M. chamomilla was used to treat a variety of diseases, including diabetes, nervous disorders, diarrhea, angina, canker sore, abscess, microbial infections, painful menstruation, antiseptic, anti-inflammatory, sciatic pain, throat, ear, and skin, and stomach disorder. Moreover, antioxidant, antibacterial, antifungal, anticancer, antidiabetic, antiparasitic, antipyretic, anti-inflammatory, anti-osteoporosis, and analgesic activities of M. chamomilla EOs and extracts have been identified in in vitro and in vivo studies. The chemical composition of this plant from different countries of the world also has been reported in this work. Almost all studies have concentrated on the plant's flower components. The abundance of terpenoids present in EOs and phenolic compounds present in extracts of M. chamomilla has been shown through the phytochemical screening of EOs and extracts by chromatographic techniques (GC-MS, HPLC, LC-MS). There are also coumarin and amino acids. Depending on the origin of the plants, the concentration and structure of the predominant chemicals vary significantly from one sample to another, establishing different chemotypes.
The pharmacological investigation of M. chamomilla was attributed to the chemical composition, containing numerous biocompound types.
The most important application of M. chamomilla was in the medicinal field on animal models and on human patients; the results showed the therapeutic effect of this plant on a wide range of diseases, including nervous cardiovascular, gastrointestinal, skin and reproductive diseases, obesity and related metabolic disorders, allergies, eye dysfunctions, acting as a protective agent in kidney, liver, among other systems.  Acknowledgments: The Portuguese "Fundação para a Ciência e Tecnologia" (FCT) is acknowledged for funding the R&D Unit CIQUP (project UIDB/00081/2020).

Conflicts of Interest:
The authors declare no conflict of interest.