An updated comprehensive review of the therapeutic properties of Chamomile (Matricaria chamomilla L.)

ABSTRACT

Neurological and cardiovascular illnesses, cancers, metabolic disorders, and microbial infections result in deaths of millions of people globally. Recent researches have intensely been directed at evaluating the therapeutic potential of herbal plants as alternative medicines. One such species is chamomile (Matricaria chamomilla), from the Asteraceae family. It elicits protective properties against inflammation and oxidative stress, bacterial and fungal infections, cancers, ulcers, neuropathologies, etc. The present review focuses on various medical/ethnomedicinal uses of chamomile. Moreover, we emphasize on the therapeutic actions of constituents from chamomile, along with their underlying mechanism(s). Literature was systematically searched on electronic databases using keywords; “Matricaria chamomilla/chamomile” in combination with “medicinal,” and “therapeutic.” Our analyses of the retrieved articles indicate tremendous therapeutic potential of chamomile, and establish it as an alternative multimodal herbal medicine. The individual active constituents (e.g., geraniol, caffeic acid, chlorogenic acid, umbelliferone, rutin) were also found to elicit significant beneficial properties in various disorders. Collectively, chamomile and its bioactive seem to hold great promises as miraculous herbal drugs with multiple medical uses. In conclusion, based upon its beneficial antibacterial, antioxidant and anti-inflammatory actions, Matricaria chamomilla is strongly implicated in protection against skin photo-damage, aging, neuropathologies and cancers.

GRAPHICAL ABSTRACT

KEYWORDS:

• Matricaria chamomilla
• natural compounds
• pharmacological actions
• traditional medicine
• herbal drugs

Introduction

The study of herbs dates back to over 5,000 years to the ancient Sumerians, who initiated the description of medicinal uses for plants. Since then, traditional medicine has been used to treat a variety of illnesses. Modern research has also been increasingly focused on the therapeutic potential of various traditional medicinal plants and their bioactives. One such plant is Matricaria chamomilla, a popular therapeutic plant species from the Asteraceae family (Figure 1). Its medicinal and fragrant qualities have earned it the nickname “the star of medical plants.” Due to its apple-like scent, it gets the name “chamomile” (the Greek word “chamaimlon” means “earth-apple”)^[1]. Chamomile was first mentioned in ancient Egyptian writings, wherein crushed chamomile flower heads were evidenced to be used in cosmetic formulations, and for the treatment skin conditions and dermatitis.^[2] Chamomile’s therapeutic potential has also been mentioned by Greek physicians, Asclepius, Hippocrates, and Galen.^{[3] .} Interestingly, chamomile was included as a member of the nine sacred herbs in Anglo-Saxon culture. Medieval Arab herbalists have also noted the numerous traditional remedies of chamomile based upon its hepatoprotective, anti-inflammatory, anti-flatulence, anti-diarrheal, spasmolytic, laxative and diuretic, and anti-epileptic properties.^[1]

Figure 1. (a) Matricaria chamomilla L. Habit (b) Flowers (c) Flower and Leaf Morphology.

Chamomile remains one of the most popular medicinal herbs used in the modern age. In fact, it is included in the pharmacopoeia of 26 countries.^[4] Interestingly, in 1987, Germany designated it as “the medicinal plant of the year.” Chamomile is cultivated commercially in many nations for the extraction of its blue essence, production of herbal tea, and for pharmacological and cosmeceutical uses.^[4] Its flower heads and essential oils are employed for anti-inflammatory, antibacterial, antiseptic, antispasmodic, and sedative uses.^[5] Herbal tea containing chamomile extract is regularly consumed by significant number of individuals across the globe. When the mucous membranes of the mouth and throat become inflamed, the tea infusion may be used as a wash or gargle. Chamomile flower in form of a tincture is used to treat diarrhea in children. In situations of external swelling, like facial swelling linked to an underlying illness or abscess, chamomile flowers are often used as a poultice or hot foment. Chamomile extract is also used in pharmacological formulations to to treat toothaches, earaches, and neuralgia.^[6] Additionally, it has been reported to be utilized as a bath addition and is suggested to reduce anogenital irritation.^[7] It is advised to breathe in the vaporized essential oils made from chamomile flowers to treat general sadness and anxiety. Chamomile oil is often used as a component in aromatherapy and hair care products.^[6]

While the traditional and modern medicinal uses of chamomile are well-known, researchers are only beginning to establish the molecular and cellular mechanisms of actions of the whole chamomile extract as well as its individual phytochemicals. Thus, studies have indicated their potent antioxidant functions of scavenging reactive oxygen species and inhibiting oxidative damage.^[8] The purpose of this timely review is to summarize the utilities of chamomile and its bioactives in the numerous pathological conditions, with a particular focus on the underlying mechanisms of action.

Chemical constituents of Matricaria chamomilla and their therapeutic potentials

Matricaria chamomilla includes various therapeutically valuable active chemical constituents. These include sesquiterpenes, flavonoids, coumarins, and polyacetylenes. Bioactive compounds of chamomile extract are summarized in Table 1. In the following sections, we discuss the therapeutic potential of the major active constituents of Matricaria chamomilla.

Table 1. Various bioactive chemical constituents of Matricaria chamomile.

Name	Structure	IUPAC name	Molecular formula	Molecular weight	Sources & Yield	Therapeutic potential	References
Bisabolol		(2 R)-6-methyl-2-[(1 R)-4-methylcyclohex-3-en-1-yl]hept-5-en-2-ol	C15H26O	222.37	Leaves: α-bisabolol (4.8–11.3%), α-bisabolol oxides A (25.5–28.7%), and α-bisabolol oxides B (12.2–30.9%) Flower: α-bisabolol and its oxide (15.7%)	Anticancer, antinociceptive, neuroprotective, cardioprotective, and antimicrobial.	^[Citation9–12]
β-farnesene		(6E)-7,11-dimethyl-3-methylidenedodeca-1,6,10-triene	C15H24	204.35	Leaves: (E)-β-farnesene (42.2%), (E)-farnesene (4.9–8.1%), (E, E)-α-farnesene (8.3%), terpene alcohol (farnesol), Flower: β-farnesene (29.8%), α-farnesene (9.3%)	Anticancer, anti-inflammatory antimicrobial, antiviral, and skin permeation enhancer	^[Citation13,Citation14]
Germacrene D		(1E,6E,8S)-1-methyl-5-methylidene-8-propan-2-ylcyclodeca-1,6-diene	C15H24	204.35	Leaves: 3.41% Flower: 6.2%	Anticancer, antiulcer, hepatoprotective, anti-viral, anticonvulsant, antiarthritic activities	^[Citation15,Citation16]
Occidol acetate		2-(5,8-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-2-yl acetate	C17H24O2	260.40	Flower: 22.8%	Analgesic and anti-inflammatory activities	^[Citation17–19]
Chamazulene & Proazulene		7-ethyl-1,4-dimethylazulene	C14H16	184.28	Leaves: chamazulene (2.3–10.9%), Flower: Proazulene Flower: chamazulene (6.4%)	Anti-inflammatory, anti-bacterial and anti-spasmolytic, insecticidal, and anti-ulcer properties and are widely used in producing gastrointestinal drugs	^[Citation20–22]
Apigenin		5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one	C15H10O5	270.24	Flower: 0.3–0.5%	Beneficial effects in diabetes, amnesia, Alzheimer’s disease, depression, insomnia, and cancer	^[Citation23–25]
Geraniol		(2E)-3,7-dimethylocta-2,6-dien-1-ol	C10H18O	154.25	Flower: 27.6%	Antitumor and antimicrobial	^[Citation26–28]
Herniarin		7-methoxychromen-2-one	C10H8O3	176.17	Flower & leaves: 82.79 mg/100 g	Antioxidant activity as additives to different cosmetic products.	^[Citation29,Citation30]
Umbelliferone		7-hydroxychromen-2-one	C9H6O3	162.14	Flower & Leaves: 11.80 mg/100 g	Antioxidant activity as additives to different cosmetic products.	^[Citation30,Citation31]
Chlorogenic acid		(1S,3 R,4 R,5 R)-3-[(E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy-1,4,5-trihydroxycyclohexane-1-carboxylic acid	C16H18O9	354.31	Flower: 65.09 μmol/l	Anti-inflammatory, antimicrobial, antiviral, anxiolytic, and antidepressant agent	^[Citation32–34]
Caffeic acid		(E)-3-(3,4-dihydroxyphenyl)prop-2-enoic acid	C9H8O4	180.16	Flower: 4.12 μmol/l	Anti-inflammatory, antimicrobial, antiviral, anxiolytic, and antidepressant agent	^[Citation24,Citation32,Citation35]
Luteolin		2-(3,4-dihydroxyphenyl)-5,7-dihydroxychromen-4-one	C15H10O6	286.24	Flower: 2.09 μmol/l	Anti-AChE activity and cognitive-enhancing effects, anti-inflammatory, antimicrobial, antiviral, anxiolytic, and antidepressant agent	^[Citation32,Citation33]
Quercetin		2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one	C15H10O7	302.23	Flower: 1.42 μmol/l	Antiaging properties, anti-inflammatory activity, cardioprotective effects, antiviral activity, antibacterial activity, and antiparasitic activity	^[Citation33,Citation36,Citation37]
Rutin		2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3 R,4S,5S,6 R)-3,4,5-trihydroxy-6-[[(2 R,3 R,4 R,5 R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl] oxymethyl] oxan-2-yl] oxychromen-4-one	C27H30O16	610.5	Flower: 15.9 μmol/l)	Anti-inflammatory, antimicrobial, antiviral, anxiolytic, and antidepressant agent	^[Citation32,Citation33,Citation38]

α-bisabolol

Bisabolol is a sesquiterpene alcohol that was first isolated from Matricaria chamomilla in the 20^th century. Due to its low toxicity, the US Food and Drug Administration (FDA) has classified bisabolol as generally recognized as safe (GRAS) chemical, allowing it to be utilized as an active ingredient in a number of commercial products.^[12] Bisabolol has shown to harbor significant anti-inflammatory, analgesic, antibacterial, anticancer, antibacterial, antiseptic, and skin-soothing properties.^[39]

Gastroprotective actions

Bisabolol reduces pepsin levels without changing the pH of stomach acid, making it a great alternative for treating stomach and upper intestinal dysfunctions.^[3]

Leishmanicidal activities

Bisabolol has been shown to elicit strong leishmanicidal action, possibly via activation of programmed cell death in the promastigote stage of the parasite. It result in damages of cellular membranes and reduce mitochondrial membrane potential and ATP production in this parasite.^[40] Neuroprotective and cardioprotective actions: α-bisabolol has been shown to induce neuroprotection by preventing the formation of amyloid oligomers and prevent their fibrillization.^[41] Further, it can inhibit inflammatory signaling through the NLRP3 inflammasome and toll-like receptor-4/nuclear factor kappa B/mitogen-activated protein kinase (TLR4-NFκB/MAPK) pathway signalling, rectify lysosomal dysfunction, rescue dysregulations in autophagic flux, and mitigate oxidative stress.^[42]

Antioxidant functions

Antioxidant activity of α-bisabolol has been determined in both cell culture and cell-free systems. It has been reported that bisabolol robustly inhibits the formation of reactive oxygen species (ROS) and stimulates antioxidant systems.^[12] Nonetheless, the antioxidant mechanisms of bisabolol need to be further tested.

Anti-inflammatory

Bisabolol-enriched plant extract have been reported to elicit antiphlogistic effects because of their anti-inflammatory properties ^[40]. The traditional uses of α-bisabolol in treating various skin irritations including dermatitis and eczema may also depend, at least in part, on its anti-inflammatory actions of inhibiting leukotriene synthesis.^[12] This is confirmed by an in vitro study which showed that α-bisabolol inhibits 5-lipoxygenase (5-LOX).^[43]

Anticancer effects

α-Bisabolol may also harbor anti-tumorigenic effects by promoting apoptosis of cancer cells via modulation of kisspeptin receptor 1 signaling,^[10] however this needs to be further researched.

β-farnesene

β-farnesene is a sesquiterpenoid with several industrial applications and is commercially synthesized using engineered Saccharomyces cerevisiae strains.^[44]

Antioxidant actions

β-farnesene has been reported to show antioxidant free radical scavenging activity in in vitroiDPPH assays.^[45]

Antimicrobial potential

β-farnesene-enriched extracts have shown robust antibacterial activity against both gram-positive and gram-negative bacteria including Staphylococcus aureus.^[46] β-farnesene-mediated inhibition of Staphylococcus epidermidis and E. coli has also been reported in the literature.^[47]

Aphicidal activity

Aphids are a cause of concern for serious damage to agricultural products. β-farnesene is known as a biological agent in repellents for controlling aphids.^[48] In aphicidal bioassay systems, farnesene and its analogs have shown appreciable aphicidal activity against Myzus persicae^[49]. In silico analyses have been performed to evaluate the inhibitory mechanism of β-farnesene against molecular targets in aphids.^[50]

Germacrene D

Germacrene D is a flavorful chemical obtained from the flower of Matricaria chamomile. It is also extracted from herbs such as Artemisia annua and Hypericum .

Antimicrobial actions

Germacrene D containing essential oil extracted from Artemisia annua has been shown to elicit antimicrobial activity against Enterococcus hirae (gram-positive) and certain fungal species.^[51] Germacrene D also harbors potential for inhibiting gram-negative bacterial species such as Klebsiella pneumoniae, Salmonella enteritidis, gram-positive bacteria like Staphylococcus aureus and Bacillus subtilis, and fungi such as Aspergillus niger and Candida albicans.^[22,52]

Antioxidant potential

The extracted oil having Germacrene D as a major compound exhibits antioxidant activity using DPPH and showed inhibition compared with BHA and ascorbic acid moreover the compound was characterized by GC-MS analysis. Furthermore, the ABTS Assay also showed the inhibition of 28% measuring the absorbance by UV at 415 nm.^[53]

Anti-inflammatory activities

Germacrene D has been evidenced to show immunotherapeutic effects by modulatory neutrophil functions.^[54] Essential oil extracted from Verbesina macrophylla (Cass.) containing germacrene D as the major component was shown to beneficially alter the pro-inflammatory actions of immune mediators, tumor necrosis factor alfa (TNF-α) and interleukin 1 beta (IL-1β).^[55]

Occidol acetate

Occidol is another relevant bioactive which can be extracted from Matricaria chamomile. It is also enriched in dichloromethane extract of the Fagraea fragrans.

Anti-microbial actions

Occidol has antibacterial activity against both gram-positive and -negative bacteria. Fagraea fragrans extract containing occidol acetate, as determined by GC-MS has been illustrated to show significant antibacterial activity against gram-negative bacteria, Serratia marcescens, Escherichia coli, and Salmonella typhi as well as gram-positive bacterial species, Micrococcus luteus, Staphylococcus aureus and Listeria monocytogenes.^[56]

Chamazulene

Chamazulene is derived from chamomile flower heads. It has been shown to elicit potent herbicidal effects and phytotoxic action against weed species, such as Amaranthus chlorostachys (A. cruentus), Chenopodium album, Cirsium arvense, Persicaria lapathifolia (Polygonum lapathifolium), Sonchus oleraceus, and Stellaria medium.^[57]

Antitumorigenic actions

Chamazulene showed anticancer activity through apoptotic pathway on cancerous cell.^[58] Other in vitro studies have also confirmed its robust antiproliferative and antitumorigenic actions.^[59]

Anti-inflammatory and anti-oxidant

Chamazulene is implicated as a potent anti-inflammatory agent.^[20] In addition, it is also an antioxidant and free radical scavenger, and can suppress leukotriene B4 synthesis.^[60,61] The sturdy anti-oxidant and anti-inflammatory properties of chamazulene have been proposed as mechanisms for treating osteoarthritis, as evidenced by animal studies.^[58]

Apigenin

Apigenin is a naturally occurring compound of the flavone family, sometimes referred to by its chemical name 4,’5,7-trihydroxyflavone. It is an aglycone derivative of many naturally occurring glycosides with the generic molecular formula C₁₅H₁₀O₅ and molecular weight 270.24. Numerous biological effects including antioxidant, anticancer, anti-inflammatory, anti-allergic, anti-genotoxic, cardioprotective, neuroprotective, and antibacterial have been shown for apigenin or and its synthetic flavone derivatives. Because of its yellow color, apigenin is also used as a dye for wool.^[62]

Anti-inflammatory and anti-oxidant actions

Apigenin can promote anti-inflammatory pathways such as p38/MAPK and PI3K/Akt, preventing IκB degradation and nuclear translocation of the NF-κB via inhibiting COX-2 activity.^[63,64] Apigenin also has the potential to increase the cellular antioxidant defense system via increasing activities of glutathione, catalase, and superoxide dismutase (SOD).^[65] Apigenin-7-glucoside (APG), a chemical constituent of Matricaria chamomilla, has been demonstrated to have anti-inflammatory properties by reducing TNF-α production in mouse macrophages.^[66]

Anti-diabetic potential

Apigenin has been reported to harbor significant anti-diabetic activities due to its ability to suppress α-glucosidase enzyme, boost insulin production,^[67] and neutralize ROS in the cell.^[68] Additionally, it reduced glycolysis and glucose uptake while boosting mitochondrial function.^[69] Apigenin has also provided endothelial cells with a modest amount of NO, reducing the risk of endothelial cell damage and dysfunction induced by hyperglycemia.^[70]

Anticancer properties

The anticancer properties of apigenin rely on its ability to arrest cell cycle progression and induce apoptosis.^[25,25,25] It causes cell cycle arrest at the G1/S and G2/M phases via altering the expression of cyclin dependent kinases (CDKs) and other cell cycle related genes.^[71–73] It also influences intrinsic apoptotic pathways by altering mitochondrial membrane potential, triggering cytoplasmic release of cytochrome c, and activating caspase 3.^[74] Additionally, it has been reported to modulate apoptotic pathways by activating caspase-8 and modulating the expression of various other proteins, including Bcl-2, Bax, STAT-3, and Akt, which drive death in cancer cells.^[75] Additionally, Chiang et al. showed that apigenin possesses anti-hepatoma properties through an apoptotic mechanism mediated by the p53-dependent pathway and the increase of p21 expression, which causes cell cycle arrest in the G2/M phase.^[76]

Neuroprotective properties

Apigenin has been implicated as a neuroprotectant. For instance, it can reduce GABA-activated chloride current in a dose-dependent manner in picrotoxin-induced convulsions.^[77] Apigenin has been proposed as a potential natural treatment for neuroinflammation-related diseases, including multiple sclerosis. Indeed, it was found that apigenin decreased neuroinflammatory signaling in LPS-treated dendritic cells (DCs) ^[69]. Further, apigenin may also be beneficial in ameliorating motor deficits by interacting with various neurotransmission systems.^[77,78] Figure 2 demonstrates the different mechanism(s) of apigenin.

Figure 2. Illustration of mechanism(s) of apigenin for its therapeutic potential.

The left panel describes the general mechanism for different actions of apigenin like cell-cycle arrest, apoptotic, anti-inflammatory, and antioxidant. The right panel describes the anti-diabetic action.

Geraniol (GE)

Geraniol is a monoterpene extracted from the shoot primordia of Matricaria chamomilla and possesses dose and time-dependent apoptosis-inducing activity.^[79] Its pharmacological properties include anticancer, anti-inflammatory, antioxidative, antibacterial activity, hepatoprotective, cardioprotective, and neuroprotective.^[80]

Anticancer functions

Geraniol possesses strong antitumorigenic and cytotoxic effects. For instance, in colon cancer colo-205 cells, geraniol suppresses cell growth and promotes apoptosis via upregulation of Bax and downregulation of Bcl-2, as well as by inducing DNA damage and cell cycle arrest.^[81,82] Geraniol may also inhibit transcription of K-ras, MAPK, PI3K, NF-κB, COX-2 and catenin while increasing the expression of phosphatase, PTEN, progesterone receptors and E-cadherin protein.^[83] It also has anti-angiogenic properties in the endothelioma eEND2 cells, which are probably mediated by decreases in PCNA production and inhibition of the VEGF/VEGFR-2 signaling pathway.^[84]

Anti-inflammatory and anti-oxidant actions

Inhibition of COX-2 and stimulation of IL-10 are thought to underlie the anti-inflammatory action of geraniol.^[85,86] Further, it has also been reported to increase glutathione levels, thus contributing to the endogenous anti-oxidant mechanisms.

Hepatoprotective functions

Geraniol has been reported to harbor significant hepatoprotective potential. It suppresses activity of alanine aminotransferase and aspartate aminotransferase.^[87] It is also reported to maintain hepatic mitochondrial function by decreasing hepatic mitochondrial ROS stimulating mitochondrial electron transport chain enzyme activity, and protecting mitochondrial DNA,^[88] Further, it can stimulate the production of iNOS and cytochrome P450 2E1 in hepatocytes, and reduce malondialdehyde and 3-nitrotyrosine synthesis.^[89] Furthermore, Geraniol also inhibits liver inflammation by inhibiting cytokines, TNF-α and IL-6.^[88] It also lowers blood fat levels by inhibiting lipogenesis and downregulating HMGCR, and LCAT lowers cholesterol esters levels and increases C-reactive protein (CRP) activity.^[88] Additionally, geraniol therapy also suppresses the synthesis of hepatic fatty acids, total lipids, and non-saponifiable lipids, lowering total cholesterol and triglyceride in the plasma. Geraniol can also induce production of LDL mRNA and VLDL receptor mRNA and promote blood LDL uptake. Finally, it reduces fatty acid production while suppressing triglyceride synthesis.^[90]

Anti-fungal actions

Studies indicate that geraniol is s robust antifungal agent. Treatment with geraniol has been shown to retard growth of Candida albicans and other Candida species,^[91] possibly by altering mitochondrial function, disrupting iron homeostasis, and reducing genotoxicity.^[92] It also disrupts cell wall function by lowering ergosterol levels and decreasing plasma membrane ATPase activity.^[93] Another study reported its antimycotic action in a concentration-dependent manner, with the lowest inhibitory concentration against C. albicans at 16 g/mL. In addition, GE also suppresses the growth of Pseudohyphae and Chlamydoconidia.^[94] Figure 3 summarizes the potential underlying mechanisms of apigenin-mediated therapeutic actions.

Figure 3. Beneficial effects of geraniol and its mechanisms of action.

Herniarin

Herniarin is chemically known as 7-methoxycoumarin and is natural coumarin derivative found in various plant species.

Antioxidant and anti-inflammatory actions

Herniarin provides beneficial effects in the middle cerebral artery occlusion (MCAO) ischemic model in rats, reducing IL-1 and TNF-α and inhibiting oxidative stress and inflammation.^[95] It has also been shown to robustly reduce oxidative stress and damage in streptozotocin-induced diabetic neuropathy.^[96]

Anti-cytotoxicity actions

Herniarin also elicits significant chemoprotection against cisplatin-induced genotoxicity. In bone marrow cells, it reduced the proportion of apoptotic and necrotic cells as well as attenuates generation of ROS.^[97]

Umbelliferone

Umbelliferone is chemically known as 7-hydroxycoumarin and is present in multiple plant species including chamomile, bitter orange, carrot and golden apple. It has potent antioxidant, anticancer and antidiabetic properties.^[98]

Antioxidant activities

In aqueous environment, umbelliferone elicits significant antioxidant actions.^[99] In addition, it is also known to stimulate SOD activities, which complement its antioxidant potency.^[98] Further, umbelliferone mitigates lead-induced testicular toxicity by suppressing oxidative damage, inflammation, and cell death and increasing endogenous antioxidant defense systems via nuclear factor erythroid-2 related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling^[100]

Anti-inflammatory actions

Umbelliferone has been shown to regulate hyperactivated inflammatory signaling in LPS-induced model of acute lung injury by regulating the TLR4/MyD88/NF-κB signaling axis. Thus, it significantly reduces infiltration of immune cells in the lung tissues, represses the levels of proinflammatory mediators, myeloperoxidase monocyte chemoattractant protein-1 (MCP-1), IL-1, and 6, TNF-α, in bronchoalveolar lavage fluid, diminishes oxidative damage and the formation of malondialdehyde^[101,102]

Antitumorigenic functions

Umbelliferone has shown anticancer activity in form of a mesoporous silica nanoparticle (MSN) containing pH-sensitive poly acrylic acid (PAA). This formulation has demonstrated robust cytotoxic activity in human breast cancer cell MCF-7.^[103]

Nephroprotective potential

Umbelliferone is thought to attenuate kidney dysfunction. It exhibits nephroprotective benefits possibly by inhibiting the pro-inflammatory and pro-apoptotic NF-κB, TLR-4, NLRP3 inflammasome, JAK1/STAT3, and caspase-3 pathways. It may also have significant modulatory effects on the ERK1/ERK2 and p38MAPK cell signaling pathways.^[101] Umbelliferone was recently shown to significantly improve gentamicin-induced renal damage. The nephroprotective effects mediated by umbelliferone may be ascribed to their anti-inflammatory properties and capacity to inhibit TLR-4/NF-κB/NLRP-3 inflammasome and activate the JAK1/STAT3 pathway.^[104] Figure 4 presents the mechanisms of action behind the therapeutic actions of umbelliferone.

Figure 4. Representation of different biological activity and its associated molecular pathways of umbelliferone.

Chlorogenic acid (CA)

Chlorogenic acid is another interesting phenolic phytochemical isolated from the Matricaria chamomilla. It is also present in coffee, hawthorn, honeysuckle, Chrysanthemum and Eucommia.^[105]

Antioxidant actions

Chlorogenic acid is an important antioxidant component of the Matricaria chamomilla extract and has been implicated in protecting cells from oxidative damage and lipid peroxidation.^[106,107] It has also been evidenced to beneficially modulate gut bacteria homeostasis, thereby affecting multiple aspects of the host metabolism pathophysiology.^[108]

Cardioprotective and antiobesity functions

Chlorogenic acid has been shown to rescue elevated systolic blood pressure and attenuate left ventricular diastolic stiffness in obese conditions, probably by reducing deposition of collagen proteins and preventing infiltration of inflammatory cells infiltration.^[109] In rat models, it reduces inflammation and fat deposition in the liver and attenuation dysregulation of plasma liver enzymes.^[109,110] Dihydrocaffeic acid, a metabolite of chlorogenic acid, also possesses antioxidant, cardioprotective, neuroprotective, and anticancer action.

Anticancer effects

Chlorogenic acid robustly suppresses tumor cell mitochondrial ATP synthesis, proliferation, motility, and invasiveness in solid tumors.^[111] It has also been shown to enhance the stability and expression of the mRNA coding for small ubiquitin-like modifier (SUMO1), resulting in SUMOylation of c-Myc. It further regulates the c-Myc SUMOylation/miR-17/p21 signaling axis downregulates the expression of miR-20a, miR-93, and miR-106b, with consequent enhancement of p21 expression leading to attenuation of cancer cell malignancy and reduction of tumor load.^[111] Chlorogenic acid may also drastically decrease tissue inflammation and death in DSS-induced ulcerative colitis in rodents, via its effects on MAPK/ERK/JNK cellular signaling pathway, thereby rescuing colonic mucosal damage and inflammation, oxidative stress, and cellular apoptosis.^[111] Lastly, dihydrocaffeic acid, a chlorogenic acid derivative has been elicited to harbor potent anticancer activities in cancer cell lines, MCF-7, Hep-G2, PC-3, and HCT-116.^[112]

Neuroprotective potential

Chlorogenic acid has been demonstrated to have neuroprotective properties in both in vitro and in vivo studies. For instance, it reduces ROS generation and restores mitochondrial membrane potential via activating the endogenous enzyme antioxidant systems and regulating intracellular Ca²⁺ concentrations in a glutamate-induced excitotoxicity model.^[113] Further, it has been implicated as a an antioxidant and cognition-stimulating agent for protection against neurodegenerative pathologies.^[114] It’s neuroprotective potential has also been reported neurotoxicity induced by 6-hydroxydopamine (6-OHDA), a catecholaminergic neurotoxin.^[115] Further, chlorogenic acid may also protect against cerebral ischemia/reperfusion injury. Thus, it has been reported that chlorogenic acid decreases cerebral infarction area, mitigated Evans blue extravasation, and restores cerebral water content. These effects may be dependent on anti-inflammatory and antiapoptotic actions of chlorogenic acid and its ability to modulate signaling via the cellular mediators, TNF-α, iNOS, and caspase-3.^[116,117] Figure 5 represents the potential molecular targets and pathways of chlorogenic acid-mediated therapy against different pathologies.

Figure 5. Therapeutic targets and mechanisms of chlorogenic acid.

Caffeic acid

Caffeic acid is a well-known therapeutic phytochemical which is also present in Matricaria chamomilla. Multiple in vitro and in vivo studies have provided irrefutable evidences supporting its actions as a treatment agency for a variety of malignancies.^[118]

Antibacterial activities

Caffeic acid elicits strong antibacterial potency against S. aureus strains with minimum inhibitory concentration (MIC) between 256 g/mL to 1024 g/mL. Further, it enhances the bactericidal efficiencies of antibiotics such as erythromycin, clindamycin, and cefoxitin. Caffeic-acid’s synergy with antibiotics highlights its promise as an effective new antibacterial strategy against multidrug-resistant bacteria.^[119]

Anticancer functions

Caffeic acid has been illustrated to induce toxicity and promote intrinsic apoptotic signaling pathways in breast cancer cells, by influencing the expression levels apoptotic genes, p53, p21 and myeloid cell leukemia sequence 1 (Mcl-1) activated the.^[120] In its esterified caffeic acid phenethyl ester (CAPE) form, it has been reported to retard metabolic activity and biofilm formation of S. mutans. CAPE may also block critical virulence factors of S. mutans which are associated with carcinogenicity, such as acid tolerance and generation of extracellular polysaccharides. Indeed, because of its ability to inhibit cariogenic bacteria, CAPE has been implicated a potent anticariogenic drug.^[121]

Antiviral potential

Interestingly, caffeic-acid derivatives have been proposed as antagonists of SARS-CoV-2 viral proteins responsible for the viral infectivity^[122] In silico analyses of molecular interaction and dynamics with open and closed states of the SARS-CoV-2 spike S2 subunit have uncovered khainaoside C, 6-O-caffeoylarbutin, khainaoside B, khainaoside C and vitexfolin A as the most potent inhibitors of the SARS-CoV-2 virus.^[123]

Luteolin

Luteolin is a yellow colored bioactive dye which is chemically recognized as 2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-4 H–1-benzopyran-4-one.

Anticancer actions

Luteolin has been shown to inhibit epithelial-to-mesenchymal transition by promoting the expression of epithelial marker protein; E-cadherin, altering cytoskeletal organization, and down-regulating mesenchymal marker proteins; N-cadherin, snail, and vimentin. In glioblastoma cells, it has been evidenced to increase intracellular reactive oxygen species (ROS) levels by activating endoplasmic reticulum stress response systems and inducing mitochondrial dysfunction.It also acts as an antiproliferative agent by inhibiting receptor tyrosine-kinase and PI3K/Akt signaling pathways in breast cancer cells.^[124] Luteolin has also shown anti-cancer potential in human hepatoma HepG2 cells by initiating G1 cell cycle arrest, triggering apoptosis, and modulating the expression levels of p21, Bax, and caspase-3.^[125] Further, its anticancer benefits in colorectal cancer have been proposed to be mediated by the Wnt/catenin signaling pathway.^[126]

Cardioprotective effects

Luteolin also elicits significant cardioprotective effects by preventing ROS generation, and mitigating mitochondrial membrane potential loss.^[127] It has been revealed that among the multiple bioactives present in methanolic extract of chamomile, luteolin and apigenin have the highest capacity for stimulating angiogenesis.^[128]

Anti-inflammatory activities

Luteolin can reduce negative photobiological effects on the skin keratinocytes, fibroblasts, and immunological cells by acting as a potent anti-oxidant and anti-inflammatory agent. It inhibits proinflammatory mediators, including IL-1, IL-6, IL-8, IL-17, IL-22, TNF-α, and COX-2, and regulating cellular signaling through NF-κB, JAK-STAT, and TLR pathways.^[129]

Neuroprotective functions

Lastly, luteolin is implicated as a neuroprotective agent as it has been shown to retard neuroinflammatory responses, attenuate glial activation, and control oxidative stress and damage in pathologies such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and traumatic brain injury.^[130] Figure 6 summarizes the therapeutic actions of luteolin at the molecular and cellular levels.

Figure 6. Representation of different biological activity and its associated molecular pathways of Luteolin.

Quercetin

Quercetin can be utilized as a nutraceutical for various ailments. It is beneficial in treating and preventing human illnesses principally because it beneficially affects redox and cell signal transduction pathways.^[131] Quercetin has been proposed to serve as a promising lead compound for synthetic analogues in medical research programs.^[132]

Antioxidant and anti-inflammatory actions

Upon its supplementation, quercetin and its metabolites in systemic circulation following operate as powerful antioxidants and anti-inflammatory agents, indicating the benefits of a quercetin-rich diet.^[133] Quercetin and its six derivatives (quercetin-3-O-glucuronide, tamarixetin, isorhamnetin, isorhamnetin-3-O-glucoside, quercetin-3,4′-di-O-glucoside, quercetin-3,5,7,3′,4′-pentamethylether) have been recently proposed to elicit significant antioxidant and anti-inflammatory activity.^[134] Interestingly, while the antioxidant actions of quercetin are reduced upon derivatization of its hydroxyl groups, the number of free hydroxyl groups in quercetin do not alter its anti-inflammatory functions.^[135]

Cardioprotective potential

Several lines of evidences have implicated quercetin as a robust therapeutic drug for the treatment of cardiovascular illnesses with the abilities to modulate the effects of aging, hypertension, angiotensin-converting enzyme, and endothelial-dependent and independent pathways.^[132]

Antitumorigenic actions

The tremendous antioxidant capacity of quercetin is thought to drive its preventive actions in several human malignancies. Further, quercetin has direct proapoptotic effects on tumor cells, retarding the progression of cancers. Indeed, its anticancer functions have been demonstrated in several investigations using a variety of cell lines and animal models.^[136]

Neuroprotective actions

Lastly, the protective effects of quercetin against neuropathologies such as Alzheimer’s disease may be because of its multimodal abilities to regulate neuroinflammatory, cell signaling kinase, and redox pathways.^[137]

Rutin

Rutin is also known as rutoside, quercetin-3-O-rutinoside, and sophorin. It is a flavonoid found in chamomile, Asparagus, buckwheat, apricots, apples, cherries, grapes, grapefruit, plums, oranges and tea.^[138]

Antioxidant and anti-inflammatory functions

Rutin acts as an therapeutic agent by reducing the levels of proinflammatory cytokines, stimulating antioxidant enzyme activities, activating MAPK cascade, downregulating expression of cell death and proapoptotic genes, upregulating cell survival and antiapoptotic genes, and restoring mitochondrial bioenergetic activities.^[139] In wound healing models, rutin has also been proposed to promote neovascularization, reduce oxidative stress, and decrease inflammation.^[139,140] Its downstream targets include antioxidant enzymes induced by NRF2, matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF).^[139]

Anticancer actions

Rutin’s abilities to regulate cellular signaling pathways such as Wnt/β-catenin, PI3K/Akt, JAK/STAT, MAPK, p53 and NF-cascades have been hypothesized to contribute to its anti-tumorigenic actions.^[141] Indeed, it has been shown that rutin modulates a plethora of pathophysiological aspects of inflammatory, apoptotic, autophagic, and angiogenic signaling in cancer progression.^[138]

Neuroprotective potential

Rutin has also been implicated as a viable pharmacological option for the treatment of neurodegenerative conditions such as Alzheimer’s disease due to its protective effects against Aβ and tau pathologies, and its antioxidant and anti-inflammatory actions.^[139,142]

Medicinal uses of Matricaria Chamomilla extracts

Antibacterial functions

In Europe, Latin America, Asia, Nepal, and Africa, Matricaria species are frequently used to treat the signs and symptoms of bacterial infections against Bacillus cereus, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger.^[143] Inhalational and oral treatments are used to treat respiratory infections, whereas topical applications are used to treat skin infections. Although the genus has a wide range of therapeutic applications, the species are most commonly used for treating gastrointestinal diseases. Interestingly, Matricaria chamomilla extracts have antimicrobial properties with the minimum inhibitory concentration (MIC) which are amongst the lowest for plant-based formulations (Table 2).^[144]

Table 2. Minimum inhibitory concentration (MIC) of Chamomile extract.

S. No.	Chamomile extract	Strain name with MIC values (μg/ml)					Reference
		A. flavus	B. cereus	E. coli	S. aureus	S. typhi
	Methanol	12.5	12.5	15	12.5	15	^[Citation144]
	Ethanol	15	12.5	15	12.5	15
	Diethyl ether	17.5	15	17.5	15	15
	Hexane	12.5	12.5	15	10	15
	Essential oil	12.5	10	15	10	12.5

Antifungal activity

Antimicrobial peptides from Matricaria chamomilla have been reported to have significant antifungal potential against Candida albicans and Aspergillus species. Since the antifungal activity remains stable at high temperatures (30–50°C) and pH (7–11), these peptides may have notable therapeutic applications.^[145] Matricaria chamomilla flower’s essential oil has demonstrated antifungal action against Aspergillus niger, preventing fungal contamination and destruction of stored food and other vulnerable materials.^[146] Similarly, Matricaria chamomilla has also shown strong antifungal potential against Aspergillus flavus, a common food contaminant, possibly via inhibiting the synthesis of aflatoxin B1 which is also known for its carcinogen activities.^[147] Matricaria chamomilla has a wide range of antifungal potency as evidenced by its actions against development of fungal molds in museum gypsum board antiques (Aspergillus flavus), archeological manuscripts (Aspergillus niger), museum organic materials (Fusarium culmorum), and museum archeological tissues (Aspergillus terreus).^[148]

Anti-cancer actions

Several studies indicate the potency of Matricaria chamomilla extracts as a potent therapeutic agent for oncological uses. When combined with silver nanoparticles, phytochemicals in Matricaria chamomilla have been found to be efficient in retarding the tumorigenicity of lung cancer A549 cells in a dose- and time-dependent manner.^[149] Similarly, hydroalcoholic extract inhibits cellular motility and colonization of human breast cancer cell lines, MCF-7 and MDA-MB-468. The extract contains anti-cancer bioactives such as bisabolol, germacrene D, β-farnesene, and geraniol.^[150,151] Organic solubilized extracts of Matricaria chamomilla have been found to effectively inhibited Caco-2 colon cancer cell migration, possibly in a VEGFR2-dependent manner.^[152] Methanolic extract of M. chamomilla inhibits the growth of several human cancer cell lines, including PZ-HPV-7, LNCaP, and PC-3, at the concentration of 100–400 μg/ml.^[6] As an essential oil, Matricaria chamomilla strongly inhibits the growth of cancer cell lines such as HCT116 and human colon carcinoma.^[153] Matricaria chamomilla is a powerful nutritional chemoprotective agent for colorectal cancer induced by 1,2-dimethylhydrazine.^[154] In agreement, Matricaria chamomilla and its chief chemical constituents, such as apigenin and luteolin, have shown protective effects against carcinogenic agent 1,2-dimethylhydrazine.^[155] Apigenin may rely on its ability to regulate Wnt/catenin signaling pathway for its anti-cancer actions.^[155] All these beneficial outcomes suggest the potential applications of using Matricaria chamomilla for preventing and retarding the progression of different cancer types.

Antioxidant and anti-inflammatory activities

Aqueous extraction of Matricaria chamomilla at 80°C is a reasonable health-promoting agent because of its maximal antioxidant actions, however its use should be limited to guarantee safe consumption.^[105] Other in vivo and in vitro studies have confirmed the antioxidant properties of Matricaria chamomilla extract. For example, in adherent cells, chamomile reduces oxidative stress and enhances cell growth and division.^[156] It is also known to prevent oxidative damage in paraquat-induced lung injury.^[157] Further, glycoconjugates of Matricaria chamomilla are advocated as novel natural-based pharmaceuticals and nutritional supplements for the prevention and treatment of oxidative stress-related illnesses.^[158] In rats, Matricaria chamomilla extract decreases tissue oxidative stress and damage induced by carbon tetrachloride toxicity. It may also elicit beneficial effects on lipid peroxidation, antioxidant enzymes (SOD, glutathione synthetase, and glutathione peroxidase), and liver enzymes (aspartate aminotransferase; AST, and alanine aminotransferase; ALT).^[159] Active ingredients of Matricaria chamomilla, such as fraxidin, matriisobenzofuran, apigenin, scopoletin, palmatoside A, apigenin 7-O-b-glucopyranoside, and p-hydroxyacetophenone, have been reported to regulate glutathione S-transferase (GST) activity, thereby contributing to the redox-associated GSH signaling.^[160] Lastly, scavenging of 2,2-diphenyl-1-picrylhydrazylhydrate (DPPH) radical has been shown to be effectively performed by various Matricaria chamomilla extracts, most effectively by its methanolic extract.^[144]

Co-administration of non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac and indomethacin in complementation with an ethanolic extract of Matricaria chamomilla extract has been shown to elicit strong synergistic anti-inflammatory efficacies in a carrageenan-induced paw inflammation and stomach damage rat model.^[161] An independent study has confirmed the anti-inflammatory actions of Matricaria chamomilla in another rodent model of carrageenan-induced pedal edema, possibly by regulating the levels of inflammatory mediators, prostaglandin E2 (PGE2) and nitric oxide (NO).^[162,163] Further, Matricaria chamomilla also attenuated xylol-induced ear edema\and HAC-induced celiac capillary vascular permeability in mice.

Neuroprotective potential

Numerous neuropharmacological agents and strategies have been proposed against central nervous system (CNS) illnesses, but most of these only offer symptomatic alleviation. Another drawback in neuropharmacological applications is the inability of the drugs to effectively pass the blood brain barrier (BBB). In these regards, researchers have proposed the usage of bioactives from natural sources such as medicinal plants like Matricaria chamomilla . Indeed, ethanolic extract of Matricaria chamomilla has been evidenced to enhance memory and cognition by stimulating cholinergic activity, retarding neuroinflammation and inducing antioxidant systems in the rat hippocampus.^[32] Similar results have reported in a model of formaldehyde-induced memory loss.^[164] Additionally, Matricaria chamomilla extract prevents scopolamine-induced oxidative damage to hippocampal neuronal morpho-functional characteristics.^[165] Morris water maze and passive avoidance tests have revealed that supplementation of Matricaria chamomilla ethanolic extract has free radical scavenging and memory-boosting actions, indicating that it may be a feasible treatment option against AD pathogenesis.^[166]

Interestingly, Matricaria chamomilla has been proposed to elicit significant anxiolytic and antidepressant actions in patients with generalized anxiety disorder and concomitant depression.^[167] Chamomile supplementation also decreases irregular sleep patterns in postmenopausal women, possibly due to the high content of apigenin which acts as a sedative and sleep-promoting compound.^[168] Matricaria chamomilla extract has also been evidenced to greatly lower neuropathic pain associated with chemotherapeutics such as cisplatin and vincristine.^[169] In agreement, Matricaria chamomilla and morphine show synergistic analgesic effects in a mouse model of vincristine-induced peripheral neuropathy.^[170] Likely, in a scopolamine-induced toxicity model in rats, chamomile extract administration serves as an anxiolytic and antidepressant agent, possibly via its cholinergic stimulatory actions.^[171] Matricaria chamomilla-based therapeutic formulation (CH₁₂) has been utilized in bovine species to decrease stress and prevent cortisol production, as well as to induce relaxation.^[172] Lastly, Matricaria chamomilla is also implicating as a stimulant of neuromuscular circuitry, indicating its potential in improving motor coordination in neuropathological states.^[165]

Antiparasitic activity

Due to high cost and severity, leishmaniasis is a parasitic illness with few therapies.^[173] Chitosan nano capsules containing essential oil of Matricaria chamomilla from oil-in-water emulsions modified with tetradecyl chains hold great potential as anti-leishmanial therapy.^[174] Anti-parasitic actions of Matricaria chamomilla have been confirmed in Leishmania promastigotes and axenic amastigotes,^[175] mite Psoroptes cuniculi,^[176] and Limnatis nilotica.^[177]

Beneficial actions in dysmenorrhea or endocrinal deregulation

Chamomile has been demonstrated to inhibit cyclooxygenase and stop the formation of prostaglandins and leukotrienes, decreasing pain and inflammation. A study in female students using the premenstrual syndrome symptoms screening questionnaire revealed that supplementation of chamomile powder for 7 days before menstruation effectively reduces the intensity of menstrual pain, with consequent reductions in physical and psychological deficits. Phytoestrogens in chamomile appear to neutralize estrogen’s detrimental effects on endorphin levels by binding to estrogen receptors and lowering its actions, which may underlie chamomile’s beneficial actions in enhancing mood.^[178] Matricaria chamomilla flower extract has been observed to modulate testosterone secretion in rats.^[179] In male adult rats, Matricaria chamomilla extract can reduce spermatozoa count and motility, spermatozoon tail length, serum testosterone, and serum estradiol level.^[180]

Amelioration of skin inflammation, eczema and physical injuries

Generation of cytokines and eicosanoids are the major cause of eczema. These are inhibited by Matricaria chamomilla and are instrumental in preventing inflammatory reaction cascade associated with skin burn, itching, and abrasion.^[181] The stimulatory effects of chamomile extract on leukocytes, such as macrophages and B lymphocytes, has been hypothesized to treat eczema and skin irritation.^[182] Topically, it is used to cure swelling, dermatitis, and infectious diseases as rubs, while its oily formulation has been utilized for healing burn wounds.^[2] A herbal cream-based formulation containing extracts from marshmallow (Althaea officinalis), chamomile (Matricaria chamomilla), walnuts (Juglans regia), and fenugreek (Trigonella foenum) has been shown to considerably reduce the symptoms of itching, burning, bumps, redness, fissures, and scaling in eczema, notably with minimum side effects.^[183] In conclusion, natural therapies for many skin diseases, including wound healing, include Matricaria chamomilla, as a prominent natural therapeutic with potent anti-inflammatory and antioxidant effects.^[184] Anti-inflammatory and antioxidant actions of Matricaria chamomilla have also been utilized for the protection of testis tissue from torsion/detorsion-induced injury.^[185] Similarly, chamomile extract in rubbing oil formulation speeds up burn wound healing.^[186]

Treatment of diabetes mellitus

Ethanolic extract of Matricaria chamomilla shows significant antihyperglycemic activities, indicating that it can serve as a powerful agent to regulate blood glucose levels.^[187] Simultaneous antioxidant and anti-hyperglycemic actions of Matricaria chamomilla have also been reported in a rodent model of streptozotocin-induced diabetes.^[188] In diabetic rats, Matricaria chamomilla has shown substantial hypoglycemic impact, lowering blood levels of glucose, urea, creatinine, uric acid, AST, and ALT, among other metabolites.^[189] In concurrence, Matricaria chamomilla has been elicited to significantly improve diabetes-associated cardiac complications by decreasing lipid peroxidation, oxidative stress, and blood glucose levels.^[190] Synergistic application of endurance training and Matricaria chamomilla has been reported to improve diabetic symptoms and memory functions in a rodent model of hyperglycemia.^[191] In conclusion, chamomile extracts enriched in terpenoid and phenolic compounds are more effective against chronic conditions of hyperglycemia and oxidative injury in diabetes mellitus, as confirmed by a systemic review of literature.^[192]

Hepatoprotective functions

As a natural antioxidant, Matricaria chamomilla may be useful in preventing oxidative liver damage in paraquat poisoning.^[193] The anti-tumorigenic, anti-inflammatory and antioxidant nature of phytochemicals present in Matricaria chamomilla extract may also contribute to its hepatoprotective actions against dimethylhydrazine-induced carcinogenic liver damage.^[155] Matricaria chamomilla has been demonstrated to have significant hepatoprotective impacts in a chemically induced model of liver injury and oxidative stress, by positively affecting the endogenous antioxidant enzyme systems.^[194] Aqueous extract of Matricaria chamomilla has similarly shown attenuation of liver tissue damage caused by methomyl as evidenced by rescue of weight loss and liver enzyme activities.^[195]

Nephroprotective functions

Matricaria chamomilla is a potential nephroprotective molecule that reduces cisplatin-induced nephrotoxicity by inhibiting gamma-glutamyl transferase (GGT) and stimulating endogenous antioxidant pathways. It boosts body weight, normalizes renal functions, improves apoptotic indicators, decreases oxidative stress markers, and rectifies hypocalcemic conditions caused by cisplatin-induced nephrotoxicity.^[196] ‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬ Moreover, co-supplementation of Matricaria chamomilla and Nigella sativa has been proposed to harbor significantly improved nephroprotective properties and attenuating cisplatin-induced toxicity, most likely via stimulation of antioxidant and anti-apoptotic pathways.^[197] ‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬

Treatment of colic pain, diarrhea and intestinal worm infestation

In vivo studies show that Matricaria chamomilla has antidiarrheal and antispasmodic effects, presumably mediated its ion modulation of K⁺ and Ca²⁺ ions.^[198] Matricaria chamomilla essential oil and its two components, chamazulene and α-bisabolol inhibit the growth of nematode larvae, resulting in their enhanced mortality.^[199] Similarly, the anti-helminthic potency of Matricaria chamomilla is well-known. An investigation of the effects of Matricaria chamomilla on ostertagia infection in lambs indicated its robust actions in promoting weight gain as an antihelminthic agent.^[200] Likewise, Matricaria chamomilla flower’s extracts elicit potent inhibitory actions against the intestinal parasitic helminths, Acanthamoeba castellanii^[201] and Haemonchus contortus.^[162,202]

Antiulcer activity

Matricaria chamomilla’s antiulcerogenic effects on ethanol-induced stomach mucosal lesions are mediated via positive regulation of antioxidant systems and concomitant reduction of oxidative stress and damage.^[203] In mice, supplementation of Matricaria Chamomilla results in a dose-dependent attenuation of stomach ulcer.^[204] Oral treatment of Matricaria chamomilla extract has been found to inhibit stomach ulcers.^[205] Similarly, ingestion of an aqueous extract of Matricaria chamomilla flowers is associated with antiulcer activity against stress-induced stomach ulceration in rabbits.^[206] Moreover, its flower head extracts were found to have antiulcer efficacy in rats with indomethacin-induced ulcers.^[207] The beneficial effects of different Matricaria chamomilla extracts are summarized in Table 3.

Table 3. Various studies with different extract of Matricaria chamomilla and their beneficial outcomes.

Drug Name	Animal	Dose, Route, and Duration of treatment	Inducing drug	Outcomes	Reference
Ethanolic extract of Matricaria chamomilla	Rat	200 and 500 mg/kg/day intraperitoneally for 20–30 days	Formaldehyde-induced memory loss	Neuroprotective	^[Citation164]
Matricaria chamomilla ethanolic extract		200 and 500 mg/kg/day intraperitoneally for 15 days	Scopolamine-induced lipid peroxidation in the brain	Antioxidant properties and improved motor coordination	^[Citation165]
			Scopolamine-induced memory deficient	Memory enhancing activity	^[Citation166]
Matricaria chamomilla hydroalcoholic extract		25 and 75 mg/kg once daily intraperitoneally for 21 days	Scopolamine-induced depressive and anxiety-like behavior	Anxiolytic and antidepressant	^[Citation171]
Matricaria chamomilla hydroalcoholic extract		25 and 75 mg/kg once daily intraperitoneally for 7 days	Scopolamine-induced memory impairment	Neuroprotective	^[Citation32]
		300 mg/kg once daily intraperitoneally for 7 days	Torsion or detorsion-induced oxidative stress and tissue damage	Protect testicular damage	^[Citation185]
Matricaria chamomilla flower hydroalcoholic extract		10, 20, and 40 mg/kg, once daily intraperitoneally for 14 days	–	Reduce testosterone secretion	^[Citation179]
		400 mg/kg once daily oral for 8 weeks	–	Decreased spermatozoa count and motility, spermatozoon tail length, serum testosterone level, and increased serum estradiol level	^[Citation180]
Hydroalcoholic extract of Matricaria CHAMOMILLA	Mice	25 mg/kg intraperitoneally for 4 days	Cisplatin and vincristine-induced neuropathic pain	Protect form Neuropathy	^[Citation169]
Matricaria chamomilla flowers hydroethanolic extract	Rat	200 mg/kg/day oral for 12 weeks	Nicotinamide and Streptozotocin-induced diabetes	Antidiabetic	^[Citation191]
Leaves extract of Matricaria chamomilla		200 mg/kg/day once daily oral for 21 days	Streptozocin-induced diabetes	Antidiabetic	^[Citation189]
Matricaria chamomilla ethanolic extract (MCE)		20, 50, 100 mg/kg oral for 14 days			^[Citation187]
Aqueous extract Matricaria chamomilla		50 mg/kg/day, oral for 7 days	Paraquat-induced hepatotoxicity	Hepatoprotective	^[Citation193]
Matricaria chamomilla extract		25 mg/kg/day, intraperitoneally for 7 days	Morphine and naloxone-induced Withdrawal manifestations and weight loss	Withdrawal behavioral manifestations and weight loss	^[Citation208]
Matricaria chamomilla CH12	Nelore calves	2 gm/day, oral for 60 days	–	Inhibiting cortisol production and anxiolytic effects	^[Citation172]
Matricaria chamomilla extract	Rat	100 gm applied topically for 67 days	–	Good potential for acceleration of burn wound healing	^[Citation186]
Matricaria chamomilla		50 mg/kg, intraperitoneally for 5 days	Cisplatin-induced nephrotoxicity	Nephroprotective	‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬^[Citation196]
Matricaria chamomilla CH12	Nelore calves	2 g/day, oral for 60 days	–	Humoral immune response	^[Citation209]
Aqueous-methanolic extract of Matricaria chamomilla	Mice	150 and 300 mg/kg, oral for 7 days	Castor oil-induced diarrhea and fluid accumulation in the intestine	Antidiarrheal activity	^[Citation198]
Hydroalcoholic extract Matricaria chamomilla	Rat	50 mg/kg/day, oral for 7 days	Paraquat-induced lung injury	Antioxidant activity against lung injury	^[Citation157]
Matricaria chamomilla essential oil		46.9 mg/kg/day, oral for 7 days	–	Larvicidal activity	^[Citation199]
Chamomile flower (Matricaria chamomilla) extract and powder	Chicken	2 and 4 g/kg powder and 1.8 and 3.6 ml/l extract orally for 42 days	–	Growth performance	^[Citation210]
Matricaria chamomilla. extract	Lamb	5 ml/kg, oral for 10 weeks	Ostertagia ostertagi parasites induced helminth	Antihelmintic	^[Citation200]
Matricaria chamomilla (Compositae) hydroalcoholic extract (MCE)	Rat	25, 50, 100, 200, and 400 mg/kg, oral for 10 days	Ethanol-induced ulcers and free radicals	Antiulcerogenic and antioxidant activity	^[Citation203]
Matricaria chamomilla extract		250 and 500 mg/kg daily, oral for 10 days	Ibuprofen-induced gastric ulcer	Gastric ulcer healing effect	^[Citation204]
Ethanolic extract of Matricaria chamomilla extract		560, 1000, 1800, and 3000 mg/kg, oral for 10 days	Carrageenan-induced inflammation	Anti-inflammatory activity	^[Citation161]
Matricaria chamomilla hydroalcoholic extract	Mice	25 mg/kg, intraperitoneally for 12 days	Vincristine-induced nociception	Antinociceptive effect	^[Citation170]

Future perspectives and conclusion

Matricaria chamomilla has been used as an herbal medication since ancient times. It is still popular today and probably will continue to be used in the future as it contains various bioactive phytochemicals with potent multimodal therapeutic activities. In light of this, therapies against the various human pathological conditions such as cancers, ulcers, inflammation, microbial infections, diabetes, and neurological illnesses may be suitably directed utilizing Matricaria chamomilla and its phytotherapeutics, either alone or in complementation of standard agents. However, there are certain concerns which must be addressed in order to establish Chamomilla as a clinically relevant therapeutic agent. First, protocols for the production of Matricaria chamomilla extract and the purification of its active ingredients must be standardized. Second, assessment of the molecular and cellular mechanisms underlying the therapeutic actions of Matricaria chamomilla in a disease-specific manner must be further extended. Moreover, animal and cellular studies can be used for repurposing Matricaria chamomilla as a treatment alternative for related diseases with overlapping etiologies. The initial information of the appropriate dosages requirement must also be addressed using animal studies. Finally, clinical trials for the utilities of Matricaria chamomilla and its phytotherapeutics against human disease-specific cases are warrantied. Indeed, randomized clinical trials are absolutely required to validate Matricaria chamomilla as a multimodal diet-based therapeutic intervention. In conclusion, while the present review concludes that Matricaria chamomilla is a safe dietary herbal therapeutic agent that shows multifaceted beneficial activities with minimal side effects in numerous pathologies, more studies, particularly in human subjects are required to demonstrate its actual clinical potential.

Ethical statement

There are no ethical requirements for this article as it does not involve primary research on animals or humans.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the VIT University.