Chemical Composition and Biological Activities of Mentha Species

The genus Mentha L. (Lamiaceae) is distributed all over the world and can be found in many environments. Mentha species, one of the world’s oldest and most popular herbs, are widely used in cooking, in cosmetics, and as alternative or complementary therapy, mainly for the treatment of gastrointestinal disorders like flatulence, indigestion, nausea, vomiting, anorexia, and ulcerative colitis. Furthermore, it is well documented that the essential oil and extracts of Mentha species possess antimicrobial, fungicidal, antiviral, insecticidal, and antioxidant properties. The economic importance of mints is also evident; mint oil and its constituents and derivatives are used as flavoring agents throughout the world in food, pharmaceutical, herbal, perfumery, and flavoring industry. To provide a scientific basis for their traditional uses, several studies have been conducted to determine the chemical composition of mints and assess their biological activities. This chapter describes the therapeutic effects and uses of Mentha species and their constituents, particularly essential oils and phenolic compounds; some additional biological activities will also be considered.


Introduction
Mentha is a member of the Lamiaceae which was originally described and named by Jussieu (1789) who gave the family name Lamiaceae, due to the distinctive flowers with a prominent liplike lower petal. This family has almost cosmopolitan distribution, from temperate to tropical regions, but is primarily found in the Mediterranean Basin. Members of this family may be annual or perennial herbs, shrubs, and small trees. The Lamiaceae are closely allied and possibly M. longifolia are also of hybrid origin and incongruence of nuclear and plastid DNA-based phylogenies indicates that all species of this section may have experienced some extension of reticulate gene flow during their evolution [9].
Šarić-Kundalić et al. [9] suggest a differentiation of the section Mentha into three basic lines, capitatae, spicatae, and verticillatae, based on inflorescence characters. The line "capitatae" includes all species with compact, headlike inflorescence; the type of species is M. aquatica.
The "spicatae" species have a spike as shown by M. spicata, M. longifolia, and M. suaveolens. The third line is represented by M. arvensis having an inflorescence vertically partitioned into whorls.

Therapeutic effects and uses
Besides its culinary uses, mint is also used in traditional systems of medicine. Mints are mainly used to cure gastrointestinal disorders, but the spectrum of medical activities is broader [9]. Mint was originally used as a medicinal herb to treat stomachache and chest pains, and it is commonly used in the form of tea as a home remedy to stimulate digestion; alleviate stomach pain; and treat biliary disorders, dyspepsia, enteritis, flatulence, gastritis, gastric acidities, aerophagia, intestinal colic, and spasms of the bile duct, gallbladder, and gastrointestinal tract [7,10,11]. Mint also aids digestion, notably of fats; in recent years, it has been often recommended for treating obesity. Mint tea is also a strong diuretic [7].
The essential oil from Mentha spp. is used topically to treat oral mucosal inflammation and also an antimicrobial and an ingredient in many analgesic creams. Approved for internal use, the oil from Mentha spp. is also used to treat bile duct discomfort, irritable bowel syndrome, myalgia and neuralgia, inflammation of the oral mucosa, discomfort from menstrual cramps, secondary amenorrhea and oligomenorrhea, and diverticulitis and is used as an anti-inflammatory and expectorant [4,12].
Other therapeutic effects attributed to a series of Mentha species are summarized in Table 1.   [13] Morocco Leaf and stem infusion for headache and tiredness [14] India Stimulant, carminative, antispasmodic, fever, remedy in infantile troubles; the boiled leaves extract is used to relieve hiccup, flatulence, giddiness and as remedy for inflammation, bronchitis, to control vomiting during pregnancy [15] Turkey Three or four cups daily between meals can relieve gastrointestinal complaints. This herb is considered stimulant, carminative, antispasmodic, and antidote for poisons. It has been reported as a remedy for inflammation, fevers, bronchitis, infantile troubles, vomiting in pregnancy, and hysteria [16] India The boiled leave extract was counseled in the viral hepatitis, as analgesic known for its ability to enhance memory. Leaves are given for fever and bronchitis and are used as lotion in aphthae, as stomachic and diuretic, for gas pain, rheumatism, toothache, muscle pain, and mouthwash [11] France Acquires a very powerful action on the nervous system [17] India The plant is typically used in the treatment of loss of appetite, common cold, bronchitis, sinusitis, fever, nausea, and vomiting Mint is also used for buccodental prevention. During the middle ages, powdered mint leaves were used to whiten teeth [7]. Fresh mint leaves are used in chewing, for mouth burns; in decoction, it is used as mouthwashes to reduce gingival pain [29]. Mint is used in making oral dentifrices as it can provide overall freshness in breath. More studies are being done as to whether or not it directly contributes to preventing caries and plaque; however, it is confirmed that it does create an unfavorable environment for bacteria [23]. Moreover, peppermint applied to the gums of teething babies can help relieve distress and clean teeth [4].
Mint oil and its constituents and derivatives are also used as flavoring agents throughout the world in food, pharmaceutical, perfumery, and flavoring industry [23]. Essential oils isolated from Mentha plants have a long history of use as improving the flavor of foods like confectionaries (such as candies and chewing gums) and beverages. Mint flavor, which includes spearmint, peppermint, and corn mint, is probably the third most important flavor used after vanilla and citrus. As a result, Mentha plants are among the most important commercial herbs cultivated for dry leaf production in Germany, Spain, Poland, Bulgaria, Egypt, Morocco, Greece, Israel, United Kingdom, Turkey, Nigeria, and China [12,30].

Adverse and toxic effects
Although some healthcare professionals believe that herbal medicines, such as the essential oil from Mentha spp., are relatively safe as they are "natural," recent publications have highlighted potentially severe side effects [4]. Contact allergy to the leaves of Mentha spicata has been reported, and cases of contact cheilitis from its essential oil, as toothpaste flavoring, have been described. The main allergens appear to be carvone and limonene. Spearmint and peppermint tea can cause iron deficiency anemia [16]. Besides, the essential oil from peppermint is associated with adverse effects such as heartburn, nausea, vomiting, allergic reactions, flushing, and headaches [4]. Potentially toxic compounds in peppermint are pulegone and menthol. Pulegone and its metabolite menthofuran, the probable hepatotoxic compounds in pennyroyal mint (Mentha pulegium L.), are also found in peppermint in much smaller proportions [23].

M. arvensis
India Possess abortifacient property [10] M. australis Australia Decoctions were used to treat colds and coughs while inhaling the crushed mint to relieve headaches; the plant is also used as an abortifacient [26] M. haplocalyx China Various parts of the plant are used to treat sores and rashes on the skin, headache, red eyes, common cold, superficial visual obstructions, sore throat, mouth ulcers, and distension and oppression in the chest and the hypochondrium [27,28]  On the basis of recent rodent chronic studies [31], target organs for pulegone and menthofuran are the liver and kidney, and a plausible mechanism for toxicity is the formation of reactive metabolites, which is also supported by in vitro experimental data. According to the Committee of Experts on Flavoring Substances (CEFS), provisional consumption limits were established for pulegone at 20 mg/kg in food and beverages [32].
Menthol causes hepatocellular changes in rats. Inhalation of menthol can cause apnea and laryngeal constriction, a risk for infants. Contact sensitivity to menthol and peppermint with oral symptoms including burning mouth syndrome, recurrent oral ulceration, or a lichenoid reaction has been reported. The excessive inhalation of mentholated preparation has caused reversible nausea, anorexia, cardiac problems, ataxia, and other central nervous system (CNS) problems. Peppermint oil is contraindicated in obstruction of the bile ducts, gallbladder inflammation, and severe liver failure [23].
Dose-dependent hepatotoxicity and nephrotoxicity were reported for M. piperita and M. spicata in rats as well as decreased plasma testosterone and increased plasma LH and FSH levels affecting spermatogenetic activity; extensive degenerative changes in germinal epithelium and spermatogenesis arrest were observed in testicular biopsies. The exact Mentha compounds that cause these effects are not known [33].
In Wistar rats, depending on dosage, the M. longifolia leaves' essential oil increased the population of neutrophils, monocytes, and large unstained cells; the liver-body weight ratio; and the serum cholesterol, HDL cholesterol, triglyceride, inorganic phosphate, total and conjugated bilirubin, alkaline phosphatase activity, total proteins, and albumin; it reduced the serum urea and atherogenic index. The oil, at 500 μL/kg of body weight, also increased the kidney-body weight ratio [22].
Due to the major decrease of the potentially harmful pulegone and menthone by oven-drying, it is recommended that this herb should be oven-dried or cooked before consumption in order to reduce toxicity. Eating of the raw plant should be discouraged, particularly in patients with a history of liver disease or those taking cytochrome P450-inducing drugs [22].

Composition of Mentha species
The majority of studies on mint constituents focus on essential oils. Indeed, these compounds are widely used in different industries. Moreover, major polyphenols have also been investigated for interesting biological properties.

Essential oils
Essential oils are natural and volatile secondary metabolites characterized by a strong odor and a complex composition. They are usually obtained by steam or hydro-distillation from various aromatic plants, generally localized in temperate to warm countries like Mediterranean and tropical countries where they represent an important part of the traditional pharmacopoeia [34]. Several species of Mentha are cultivated for the production of essential oil. Indeed, mint oils are among the most important essential oils produced in the world, and their values are exceeding 400 million of US dollar/year. For instance, M. canadensis L. produces corn mint oil which represents the most important source of (-) menthol; M. piperita L. produces peppermint oil, constituted of menthol, menthone, and menthyl acetate as main components; M. spicata ssp., M. viridis (native spearmint), and M. gracilis (scotch spearmint) produce mostly carvone-rich oils, although different compositions have been reported; M. citrata is a source of linalool and linalyl acetate; M. pulegium produces the so-called pennyroyal oil, which is a pulegone-rich oil; the composition of M. aquatica oils is dominated by menthofuran [21]; M. haplocalyx could be classified into six chemotypes, including linalool, pulegone, menthone, carvone, menthol, and piperitenone oxide [35].

Phenolic compounds
Phenolic compounds, secondary metabolites ubiquitously distributed in plants, include a large group of biologically active compounds, with over 8000 molecules, either small or large and complex molecules, presenting at least one aromatic ring with one or more hydroxyl groups attached. These compounds often appear in their natural sources as esters and glycosides [94].
Species of the genus Mentha have been reported to contain a range of components, including cinnamic acids and aglycon, glycoside, and/or acylated flavonoids [95]. Triantaphyllou et al. [96] reported that water extracts from Mentha contain esters of phenolic acids and flavonoid derivatives and glycosidic flavonoids hydroxylated in position 3 or 5.
In an older study, external lipophilic methylated flavonoids have been extracted from dried The phenolic composition of other species of different origins is summarized in Table 3. Rutin, quercetin, luteolin Greece [110] Aromatic and Medicinal Plants -Back to Nature 56

Other compounds
Various other classes of compounds have been characterized and quantified in the mints.
M. spicata and M. piperita contain different trace elements [46,131]. Maffei and Scannerini [132] studied the variability of the triacylglycerol, diacylglycerol, and free fatty acids in some Mentha species. They found a high level of C 18   leaves are fatty acids such as linoleic, linolenic, and palmitic acid [98]. In addition, recent studies identified two new ceramides from the methanolic extract of M. longifolia, longifoamides A and B [10].
Mint was also reported to contain sugars, saponins, alkaloids, anthraquinones, and quinines [136], but these absolutely surprising HPTLC-based phytochemical data as well as the identity/purity of investigated samples should be thoroughly verified.

Biological activities
The research over the past several years has shown that mint and its constituents possess different biological activities including antioxidant, antimicrobial, insecticidal, anticancer, and anti-inflammatory properties [10].

Antioxidant activity
Various types of compounds from aromatic and medicinal plants are receiving particular attention due to their radical scavenging properties. Reactive oxygen species (ROS) are chemical species formed in the body during metabolism that are highly reactive and may have one or more unpaired electrons. Oxidative stress, i.e., an imbalance between ROS and antioxidant defenses, has deleterious effects, such as the peroxidation of membrane lipids and the attack on biomolecules (proteins, membrane enzymes, carbohydrates, and DNA) [137].
Mentha extracts are widely known to act as free radical scavengers in vitro. The acetonic extract and essential oil of peppermint act as scavengers of hydroxyl radical (•OH) [25,138], the hydroalcoholic extract of M. piperita [139] and peppermint essential oil [140] as scavengers of nitric oxide (•NO), and the ethanolic and water extracts of M. pulegium [141] as scavengers of hydrogen peroxide (H 2 O 2 ). Besides, different fractions of the ethanol extract of M. spicata [142]; the ethanolic extracts from M. spicata, M. pulegium, and M. rotundifolia [99]; the methanolic extract of M. pulegium [68,143] and M. longifolia [68] were shown to quench superoxide (O 2 • − ) radicals.
Other tests are less used in literature to evaluate the antioxidant potential/radical scavenger capacity of Mentha species polar extracts and essential oils (  [95,99,144,149]. The antioxidant compounds present in these extracts act as hydrogen-or electron-donating agents and/or metal chelators. Moreover, as expected from their composition, the polar extracts of Mentha species showed much better activity than the essential oils [6,41,69,93].

Antimicrobial activity
The antibacterial and antifungal activities of Mentha species have been studied on various bacteria and fungi [30]. These studies indicate that essential oils are more efficient antifungals and antibacterials compared to the polar extracts [6,68,73]. Mentha essential oils showed remarkable antimicrobial activity against bacteria and other microorganisms, such as yeasts and periodontopathogens [4], mainly due to the presence of oxygenated monoterpenes in their chemical compositions [22]. Bactericidal and bacteriostatic activities are observed in the 1/1 to 1/1000 (V/V) and 1-5 mg/mL concentration ranges, respectively.
M. pulegium presents an appreciable activity toward all microorganisms (five Gram + , five Gram − , and six fungal strains) tested by Hadjlaoui et al. [68] and Streptococcus pyogenes [47]. Similarly, they showed the best bacteriostatic and bactericidal effect compared to tested medicinal and aromatic plants from other genera [70]. Besides, the essential oil of the flowering aerial parts of M. pulegium showed a significant activity against microorganisms especially Gram-positive bacteria [19].
The essential oil of M. spicata has an appreciable activity against Streptococcus pyogenes [47], E. coli, S. aureus, S. pyogenes [46], and C. albicans [46,51]. Oils of Mentha longifolia showed strong antimicrobial activity against all 16 microorganisms tested by Hadjlaoui et al. [68] and against Escherichia coli, Shigella sonnei, and Micrococcus flavus. These bacteria were also inhibited by the essential oils from M. aquatica and M. piperita [92]. Of the Mentha essential oils tested by Hussain et al., the oil from M. arvensis showed relatively higher antimicrobial activity [45]; the essential oils of Mentha officinalis totally inhibited E. coli, Bacillus aureus, Streptococcus lactis, and S. aureus [153].
Besides, the essential oils from Mentha spp. have been considered a safe ingredient for the development of antibiofilm agents that could find a role in the pharmaceutical industry [4].
The antibacterial or antifungal activity of Mentha plant polar extracts have been studied to a much lesser extent; bactericidal and bacteriostatic activities are observed in the 2-4 mg/mL and 100-250 μg/mL concentration ranges, respectively, and at 6 μg/disk. The extracts were shown to possess antibacterial and antifungal activity [30]. Methanolic extracts of M. viridis and M. pulegium showed slight antimicrobial capacity against S. enteritidis and E. coli, respectively [104]; infusions of M. piperita and M. spicata were active on Vibrio parahaemolyticus [154]. Fractions from M. spicata ethanol extract showed effective antibacterial activity against Escherichia coli, Salmonella paratyphi, Shigella boydii, Staphylococcus aureus, and Vibrio cholerae [142]. Peppermint tea extracts were active against Chlamydia pneumoniae [24].

Insecticidal activity
Mint is also known to exhibit insecticidal activity against a wide variety of insects. Mentha has been used as insecticides mainly in the form of essential oils [155]. M. spicata, M. pulegium, and M. rotundifolia oils demonstrated insecticidal properties against adults of Rhyzopertha dominica, in contact and fumigation bioassays and repellency [51,71]. M. pulegium and M. rotundifolia oils were also very toxic in the first 24 h in a contact toxicity bioassay against the same pest [156].  [157,158]. Similarly, the essential oil of M. microphylla gave remarkable activity against this insect (LC 50 , 0.2 μL/L) in fumigation bioassays and in contact bioassays (24 h; LC 50 , 0.01 mg/cm 2 ) [159], and the ethanolic extract of M. longifolia was also efficient against it (24.2% repellency) [160]. Additionally, M. pulegium oil was toxic against Sitophilus granarius (contact LD 50 , 9.1 μL/mL) [72], and M. longifolia essential oil has 100% repellence against Sitophilus zeamais [22].
Varma and Dubey [158] reported complete inhibition of Tribolium castaneum, through the treatment of wheat samples with M. arvensis essential oil. The essential oil of M. microphylla gave remarkable activity against adults of this insect (LC 50 , 4.5 μL/L) in fumigation bioassays [159]. Furthermore, the insecticidal properties of M. longifolia essential oil against this pest have been attributed to piperitenone oxide (LC 50 , 9.95 mg/L) [22]. In another study, Lee et al. [157] observed that M. piperita (LD 50 , 25.8 μL/L) was a slightly better fumigant than M. spicata (LD 50 , 33.1 μL/L) against T. castaneum. Besides, in both contact and fumigation assays, the M. rotundifolia oil samples rich in pulegone and menthone, compared to other chemotypes, exhibited superior insecticidal activity against the adults of the same insect [161].
In another study, aqueous extract of M. spicata significantly reduced the proliferation of Wehi-164 and U937 cells dose and time dependently (LD 50 s ranging from 4.63 to 5.97 mg/mL) [169]. Jain et al. [170] examined the possible molecular mechanisms underlying the cytotoxicity and anticarcinogenic potential of Mentha piperita leaf extracts on six human cancer (HeLa, MCF-7, Jurkat, T24, HT-29, MIA PaCa-2). The chloroform and ethyl acetate extracts showed significant dose-and time-dependent anticarcinogenic activity, leading to G1 cell cycle arrest and mitochondrial-mediated apoptosis, perturbation of oxidative balance, upregulation of Bax gene, elevated expression of p53 and p21 in the treated cells, and acquisition of senescence phenotype (effective doses ranging from 10 × (10 μg/μL) to 100 × (100 μg/μL)).
Lv et al. [25] also evaluated the antiproliferative activity of a peppermint extract against the human tumor cell line HT-29 (effective doses 250 and 500 μg/mL). Similarly, the cytotoxic effect of Mentha piperita essential oil was assessed against four human cancer cells. It was found to be significantly active against human lung carcinoma SPC-A1, human leukemia K562, and human gastric cancer SGC-7901 cells, with IC 50 values of 10.9, 16.2, and 38.8 μg/mL, respectively [138].

Anti-inflammatory properties
Mentha extracts contain numerous constituents which could have anti-inflammatory effects.
In vivo, pretreatment of albino mice and female Wistar rats with M. suaveolens methanol extract induced an anti-inflammatory effect [173]. The anti-inflammatory effects of aqueous, chloroform, ethyl acetate, and hexane extracts of M. spicata ethyl acetate and aqueous fractions were both effective in reducing the chronic and acute inflammation of Wistar albino rats [11]. In addition, edema reduction was also observed by topic use of M. aquatica L. alcohol extract on Male CD-1 mice [174]. The M. piperita essential oil exhibited potent anti-inflammatory activities in a croton oil-induced mouse ear edema model. The oil reduced the edematous response by 5.77, 7.37, and 30.24% at the dose of 200, 400, and 800 μg, respectively [138].