Traditional Uses, Phytochemistry, and Bioactivities of Mesosphaerum suaveolens (L.) Kuntze.

Mesosphaerum suaveolens (L.) Kuntze is a species widely used traditionally in the treatment of ailments, such as stomach pain, hemorrhoids, cough, verminosis, ulcer, liver disease, fever, influenza, nasal congestion, and inflammation. This review aims to provide a survey of available information on seven international electronic databases (Google Scholar, Medline, ResearchGate, Web of Science, Scopus, Science Direct, and PubMed) about botanical aspects, traditional uses, phytochemistry, and biological activities of M. suaveolens. Mesosphaerum suaveolens is a tropical America native species, but it can be found in several parts of the world as a ruderal plant. The species is the most studied species of the genus Lamiaceae due its phytochemical aspect, especially regarding the chemical composition of its essential oil. Besides the essential oils, M. suaveolens is a source of numerous secondary compounds such as triterpenes, diterpenes, and phenolic compounds, which are related to its biological activities, such as allelopathic, antibacterial, antifungal, insecticidal, and larvicidal activities as described in the literature.

1. Introduction

Plant species, with medicinal properties that have always been part of human life, are being used both for the treatment of diseases as for food. For the treatment of diseases, they are accessible and culturally accepted, so their use is popular since ancient civilizations [1, 2]. The Lamiaceae family is one of the most diverse and widespread in terms of the ethnomedicinal value and variety of plants with biological and medical applications [3-8]. Regarding the genus Mesosphaerum, previous studies demonstrate the ethnomedicinal and pharmacological importance of some species that belong to it, such as Mesosphaerum sidifolium (L'Hérit.) Harley & J.F.B. Pastore, used to treat stomach disorders and headaches, as well as being used as an expectorant, carminative, and tonic. This species possesses in vivo antitumor activity against Ehrlich ascites carcinoma cells causing growth inhibition by inducing cell cycle arrest, besides not showing cytotoxicity [9]. Another species with several bioactivities is Mesosphaerum verticillatum (syn. Hyptis verticillata Jacq.) with anti-inflammatory, antimicrobial, and anticancer potentials, among other reports. Ethnomedicinal uses of this plant include cough, colds, asthma, fever, tonsillitis, uterine fibroids, bronchitis, and gastrointestinal problems [5].

In Northeast Brazil, the use of plant species as therapeutic resources is widespread, and one species present in this region is Mesosphaerum suaveolens (L.) Kuntze, known as “bamburral,” “erva-canudo,” or “alfazema-brava” [10]. Its leaves are mainly used to treat respiratory diseases (asthma, bronchitis, colds, and flu) and diseases related to the gastrointestinal tract [1]. Such medicinal uses are related to the chemical heterogeneity arising from the secondary metabolism of the species, a recurrent characteristic in species of the Lamiaceae family [6].

Several works in the literature indicate that M. suaveolens presents a high biotechnological potential, mainly regarding its essential oil [10]. In addition, a large number of studies have emphasized the biological activities of the essential oil and extracts of this species against pathogenic microorganisms to humans [6]. Taking into account that M. suaveolens is a medicinal species widely studied by the scientific community, the main objective of this work was to make a general review of the botanical aspects, traditional uses, phytochemistry, toxicity and biological, and pharmacological activities.

2. Materials and Methods

Methodologically, it was used the keywords “Mesosphaerum suaveolens” and its synonym “Hyptis suaveolens” associated to the terms “biological activity,” “bioactive,” “ethnomedicinal use,” “traditional use,” “ethnobotany,” “ethnopharmacology,” “toxicity,” “natural products,” “phytochemistry,” and “allelopathy” to collect information available on Google Scholar, Medline, ResearchGate, Web of Science, Scopus, ScienceDirect, and PubMed databases. The consideration insertion criteria of the articles were as follows: full article only, articles written in English and/or Portuguese languages, and all available and opened access articles, with no time limit determined.

It was obtained 190 articles dated between 1971 and 2021 which were grouped into some categories. (1) Botanical aspects, with information on description, classification, and geographical distribution; (2) phytochemistry; (3) ethnobotany; (4) biological activities; and (5) pharmacological activities. The trial process (collecting of the articles, reading of the abstracts, and checking the insertion criteria) took three months, and all the selected articles had been read completely and summarized in a table with the isolated chemical constituents and their respective biological activities.

3. Review

3.1. Botanical Aspects: Description, Classification, and Distribution

Mesosphaerum suaveolens (L.) Kuntze is an herbaceous plant belonging to the Lamiaceae family. The word “mesosphairon” comes from the Greek and Latin “mesosphaerum,” meaning “a type of tuberose with medium-sized leaves,” while its specific epithet suaveolens, means “with a sweet fragrance” due to the aroma of essential oils exhaled by the trichomes present on its leaves [11, 12].

Its vernacular name varies widely according to the region of occurrence. In the northeastern region of Brazil, the species is known as “bamburral” and “alfazema-brava” and in the southern region of the country, the herbaceous plant is called “erva-canudo” and “betônica-brava” [10]. In other parts of the world, such as in India, it is known as “pignut,” “beejabandha,” “sima tulasi,” “sakavong,” “pichi tulas,” and “bushmint” [13], while in Nigeria, it is known as “false buttonweed” and in Bangladesh as “tukma” [14]. In French-speaking countries, the species is called “horehound,” “pignut,” “wild spikenard,” “gros baume,” and “Hyptis à odeur.” In other languages, the plant is called “chao,” “hierba de las muelas,” “menta de campo” (Spanish), “wilaiti tulsi” (Hindi), “bhustrena,” “darp tulas,” “jungli tulas” (Marathi), “sirna tulasi” (Telugu), “bilati tulas” (Bengali), “ganga tulasi” (Ora), and “bhustrena” (Sanskrit) [13].

Taxonomically, M. suaveolens presents as botanical synonyms Ballota suaveolens L., Hyptis suaveolens (L.) Poit., Bystropogon suaveolens (L.) L'Hér., Bystropogon graveolens Blume, Hyptis congesta Leonard, Hyptis ebracteata R.Br., Hyptis plumierii Poit., and Marrubium indicum Blanco, with H. suaveolens as the most widespread synonym in scientific circles. However, the current circumscription of the genus Mesosphaerum P. Browne was recognized in 2012 after phylogenetic studies [15].

Morphologically, M. suaveolens is an erect herb or subshrub that measures up to 2 m in height. Its photosynthetic quadrangular stem is hairy with closely spaced branches and nodes. It has oval leaves, serrate or cordate margin, pilose limb, acute apex, and obtuse base with opposite crossed phyllotaxis. The petioles are short, canaliculate, as are its stems. Its inflorescences consist of up to 20 flowers located around the nodes and near the leaf axils. The flowers are pedunculate, with a persistent, tubular calyx, and 5 pointed sepals. The corolla is also tubular with five lilac petals, and the lobes are evident. Its fruits are dry, indehiscent, and uniseminated, originating from a bicarpellate gynoecium. Such fruits originate dimorphic seeds, two per fruit. Morphologically, such diaspores are elongated with dorsoventral flattening, longitudinal median ridge, starting near the hilum and extending to the apex of the seed with retusa boundary with black coloration (Figure 1) [16-18].

Figure 1

Mesosphaerum suaveolens (L.) Kuntze (Lamiaceae). (a) Leaves and stem. (b) Population of M. suaveolens in an area of Caatinga, a seasonally dry tropical forest, in Quixelô-CE, Brazil. (c) Prominence of flowers. (d) Leaves in senescence. Source: author (2018).

As for the geographical distribution, M. suaveolens is native to tropical America; however, as it is ruderal, it ended up invading natural ecosystems in tropical and subtropical regions of the globe, so that, due to this widespread occurrence, the species is considered a pantropical ruderal species [19-22]. In Brazil, M. suaveolens is present in almost the entire territory [23].

3.2. Phytochemistry

Mesosphaerum suaveolens is an important source of essential oils, alkaloids, flavonoids, phenols, saponins, triterpenes, and sterols [13, 24]. The essential oil of this species, obtained exclusively from its leaves, has already been chemically characterized in several studies. However, since this species exhibits a high level of genetic polymorphism and allows adaptation to changes in environmental characteristics, high variability in the composition and content of the major constituents (>20%) has been found [25]. In M. suaveolens extracts, terpenoids had a great predominance (mono, di, tri, and sesquiterpenes) (Table 1) (Table 1). Among the diterpenes, suaveolic acid stood out with recognized antimicrobial and allelopathic action [26]. Furthermore, phenolic acids, phenylpropanoids, flavonoids [10, 27], and fatty acids [28, 29] were also identified in different parts of M. suaveolens (Table 1).

Table 1

Identified constituents in Mesosphaerum suaveolens (L.) Kuntze (Lamiaceae).

Composite	Structure	Identification method	Part of the plant	Citation
Monoterpene
Sabinene		GC-MS	Leaves (essential oil)	[30–35]
Eucalyptol		GC-MS	Leaves (essential oil)	[35–37]
Sesquiterpene
E-Caryophyllene		GC-MS	Leaves (essential oil)	[38]
Germacrene D		GC-MS	Leaves (essential oil)	[38]
β-Caryophyllene		GC-MS	Leaves (essential oil)	[32, 33, 39, 40]
Diterpenes
Mellowolic acid		1H-NMR and 13C-NMR	Leaves and stem	[26, 41]
Suaveolol		1H-NMR and 13C-NMR	Leaves	[41–43]
Dehydroabietinol		GC-MS, 1H-NMR, and 13C-NMR	Leaves, stem, and flowers	[29, 44, 45]
9α,13α-Epi-dioxiabiet-8(14)-en-18-ol		1H-NMR and 13C-NMR	Leaves	[46]
Methyl suaveolate		1H-NMR and 13C-NMR	Leaves	[42]
Ácido 8α,9α-epoxysuaveolic		1H-NMR and 13C-NMR	Leaves and stem	[43]
4α-Hydroperoxy-5-enovatodiolide		1H-NMR and 13C-NMR	Flowers	[47]
4-Methylene-5β-hydroperoxy ovatodiolide		1H-NMR and 13C-NMR	Flowers	[47]
Ovatodiolide		1H-NMR and 13C-NMR	Flowers	[47]
4α-Hydroxy-5-enovatodiolide		1H-NMR and 13C-NMR	Flowers	[47]
Phytol		GC-MS	Flowers	[29]
Triterpenes and steroids
α-Peltoboikinolic acid		1H-NMR and 13C-NMR	Root	[48]
Oleanolic acid		1H-NMR and 13C-NMR	Root	[48]
Bacosine		1H-NMR and 13C-NMR	Root	[49]
Betulinic acid		1H-NMR and 13C-NMR	Root	[49]
Ursolic acid		1H-NMR and 13C-NMR	Root, leaves, and stem	[49, 50]
α-Amyrin		1H-NMR and 13C-NMR	Root	[51]
3β-Hydroxylup-20(29)-en-28-oic acid		1H-NMR and 13C-NMR	Root	[51]
Urs-12-en-3β-ol-29-oic acid		1H-NMR and 13C-NMR	Leaves and stem	[53]
Lupeol		1H-NMR and 13C-NMR	Leaves	[50]
Rotundic acid		1H-NMR and 13C-NMR	Leaves and stem	[50]
β-Sitosterol		1H-NMR and 13C-NMR	Leaves and stem	[50]
Hyptadienoic acid		1H-NMR and 13C-NMR	Leaves and stem	[53]
Phenolics
Gallic acid		HPLC-DAD and HPTLC	Leaves and stem	[10, 27]
Ellagic acid		HPLC-DAD	Leaves and aerial parts	[6]
Ferulic acid		HPTLC	Leaves and stem	[27]
Caffeic acid		HPLC-DAD and UPLC-MS	Leaves	[6, 10, 54]
Chlorogenic acid		HPLC-DAD and HPTLC	Leaves and stem	[6, 10, 27]
Apigenin		HPLC-DAD	Leaves	[6, 10]
Catechin		HPLC-DAD	Leaves	[6, 10]
Rutin		HPLC-DAD and UPLC-MS	Leaves	[6, 10, 54]
Quercetin		HPLC-DAD and UPLC-MS	Leaves and stem	[6, 10, 27, 54]
Rosmarinic acid		UPLC-MS	Leaves	[54]
Ethyl caffeate		UPLC-MS	Leaves	[54]
Sagerinic acid		UPLC-MS	Leaves	[54]
Isoquercetin		UPLC-MS	Leaves	[54]
Syringic acid		UPLC-MS	Leaves	[54]
Yunnaneic acid		UPLC-MS	Leaves	[54]
Secoiridoid
Oleoside dimethyl ester		UPLC-MS	Leaves	[54]
Fatty acids
Linoleic acid		GC-MS	Seeds	[28]
Palmitic acid		GC-MS	Seeds and leaves	[28, 29]
Oleic acid		GC-MS	Seeds	[28]
Stearic acid		GC-MS	Seeds	[28]
Palmitoleic acid		GC-MS	Seeds	[28]
Undecanoic acid		GC-MS	Leaves	[29]
Octanoic acid		GC-MS	Leaves	[29]
n-Decanoic acid		GC-MS	Leaves	[29]
Tetradecanoic acid		GC-MS	Leaves	[29]
Myristic acid ethyl ester		GC-MS	Aerial parts	[55]

3.3. Ethnobotany

Traditionally, M. suaveolens is taken to treat ailments in Brazil, Benin, India, Nigeria, Thailand, and Togo. In Brazil, the leaves in the form of infusions, decoctions, teas, and syrups are used to treat ulcers, inflammation, respiratory diseases (asthma, bronchitis, colds, flu, and sinusitis), diseases related to the gastrointestinal tract, pain, dizziness, nausea, nervousness, and constipation [1, 56–64]. The leaves are also used to treat headaches [65], malaria [14, 66], fever [67, 68], and used to reduce labor time and labor pain [69]. The flowers of M. suaveolens are employed as therapeutic resources against dysmenorrhea, respiratory diseases, and as a febrifuge [70, 71].

In the Asian continent, more specifically in India, the leaves, stems, inflorescence, and roots are used to treat urinary calculi [72], stomach pain [73], healing, itching [74], boil, eczema, diabetes [75], pneumonia [76], and fever [77]. Besides that, the seeds of M. suaveolens are used to treat gynecological disorders such as menorrhagia, leucorrhea, and rheumatism [78, 79]. The fresh poultice of the leaves is applied to snake bites, wounds, and mycoses [80], while the paste of the fresh leaves is also indicated for skin diseases [81].

In South Asia, in Bangladesh, traditional communities use the seeds in juice preparations to treat constipation and weakness [82, 83]; in addition, the seeds are consumed along with roots of Bombax ceiba to treat gonorrhea [84, 85], and the paste of the leaves is used to treat skin infections [86]. In Togo, the leaves of the species are spent in decoction form for the treatment of gynecological disorders [87], while in Thailand, the decoction of the roots is indicated in cases of food poisoning [88]. On the African continent, more specifically in Benin and Nigeria, the whole plant of M. suaveolens is used for the treatment of candidiasis and as a blood tonic [89, 90].

From a veterinary point of view, M. suaveolens has also been used for the treatment of diseases in animals. Such use is reported in India for the treatment of inflammation in cattle, with the juice of the leaves being applied to the animal's eyes [91]. In Brazil, the species is employed against diarrhea [92]. In the African continent, more specifically in Kenya, the aerial parts of the plant are utilized as a repellent for the mosquito Anopheles gambiae Giles, 1926 (Diptera: Culicidae) [93, 94].

3.4. Biological Activities

3.4.1. Allelopathic Activity

According to Sharma et al. [95], after the establishment of M. suaveolens in an area, it becomes evident that the species imposes a profound impact on the local vegetation, as the number of species, richness, diversity, and uniformity is severely reduced. Although M. suaveolens is native to the Brazilian territory, it is distributed in different ecosystems, such as Caatinga, a seasonally dry tropical forest [20].

Mesosphaerum suaveolens produces numerous seeds of rapid germination and subsequent growth and thus manages to occupy and dominate environments because of its allelopathic action [96]. Islam et al. [26], for example, isolated suaveolic acid from M. suaveolens and demonstrated in bioassays that this diterpene exhibits allelopathic action, interfering with the growth of the caulicle and radicle of Lepidium sativum L. (Brassicaceae), Lactuca sativa L. (Asteraceae), Lolium multiflorum Lam. (Poaceae), and Echinochloa crus-galli (L.). P. Beauv. (Poaceae). Their extracts present allelopathic action against Echinochloa crus-galli (L.) P. Beauv. [97], Sorghum vulgare Pers., Raphanus sativus L., and Lactuca sativa L. [98].

Allelochemicals present in the species have been reported to act by causing oxidative stress, reduction in chlorophyll content, and inducing the formation of chromosomal aberrations [99, 100]. Such damage may occur in response to the synergistic action of the constituents.

In addition to heterotoxicity, M. suaveolens has been found to exhibit autotoxicity; however, its constituents affect other species more than itself [101]. Thus, the low amounts of allelochemicals released by M. suaveolens affect the ecological succession of other species, but do not affect the species itself as much.

Despite reports of the allelopathic action of M. suaveolens, it is worth noting that most of these studies were conducted under laboratory conditions and with extracts of the plant, so these actions do not match the allelopathic actions found in the environment. Thus, it is necessary to conduct studies that simulate as much as possible the natural conditions, to affirm whether one species can affect another. Only Kapoor [99] evaluated the allelopathic action of M. suaveolens in conditions similar to those found in the environment, demonstrating in fact that the species has allelopathic action on Parthenium hysterophorus L. (Asteraceae).

M. suaveolens has allelochemicals from its secondary metabolism, which compromise the structure and plant diversity [102].

3.4.2. Antimicrobial Activity

Teas of M. suaveolens are used to treat diseases related to the gastrointestinal and respiratory tracts [1], so numerous researchers have hypothesized that the species exhibits biological activity against strains of pathogenic microorganisms.

Cyrille et al. [103] evaluated the antibacterial action of the hydroethanolic extract (70%) of the leaves and found that the species presented low antibacterial activity since an MIC of 3.12 mg/ml was observed against Staphylococcus aureus (Rosenbach, 1884) (Staphylococaceae) ATCC 25923 and Pseudomonas aeruginosa (Schroeter, 1872) (Pseudomonadaceae) ATCC 27853 strains. It is worth noting that MIC values obtained above 1 mg/ml (1000 μg/ml) do not reflect clinically notable activity (Van Vuuren, 2008) (Table 2).

Table 2

Antimicrobial activities of Mesosphaerum suaveolens (L.) Kuntze (Lamiaceae).

Extract/parts of the plant	Assay	Antimicrobial activity	Citation
Methanolic extract of the aerial parts	Disk diffusion test	Candida albicans (7 mm)	[105]
Essential oil from the leaves	Disk diffusion test	Staphylococcus aureus ATCC 29213 (27 mm)Escherichia coli ATCC 25922 (22 mm)Trichophyton mentagrophytes (15 mm)Trichophyton rubrum (24 mm)	[106]
Essential oil from the leaves	Dilution method	Staphylococcus aureus ATCC 29213 (MIC 8.82 mg/ml)Streptococcus pyogenes P183 (MIC 4.41 mg/ml)Streptococcus pyogenes P31 P183 (MIC 4.41 mg/ml)	[106]
Essential oil from the leaves	Disk diffusion test	Bacillus subtilis (MIC 16.67 μl/ml)Staphylococcus aureus (MIC 1.56 μl/ml)Escherichia coli (MIC 6.25 μl/ml)Proteus vulgaris (MIC 50 μl/ml)Pseudomonas aeruginosa (MIC 25 μl/ml)	[107]
Essential oil from the leaves	Disk diffusion test and dilution method	Erwinia herbicola MTCC 3609 (MIC 2 μl/ml)Pseudomonas putida MTCC 1190 (MIC 8 μl/ml)	[108]
Essential oil from the aerial parts	Microdilution method	Staphylococcus aureus CMCC 26001 (MIC 50 μg/ml)Bacillus subtilis CMCC 63501 (MIC 25 μg/ml)Pseudomonas aeruginosa CMCC 10104 (MIC 50 μg/ml)Escherichia coli CMCC 44102 (MIC 25 μg/ml)Fusarium graminearum (MIC 50 μg/ml)Botrytis cinerea (MIC 25 μg/ml)Exerohilum turcicum (MIC 50 μg/ml)Lecanosticta acicola (MIC 50 μg/ml)	[104]
Ethanolic extract of the aerial parts	Disk diffusion test	Aeromonas caviae (0.1 mm)Aeromonas hydrophila (0.1 mm)Ralstonia spp. (0.17 mm)Shigella spp. (0.23 mm)	[109]
Aerial parts essential oil	Disk diffusion test	Trichophyton mentagrophyte (15.7 mm)Trichophyton rubrum (14.7 mm)Microsporum gypeum (13.3 mm)Candida albicans (13.7 mm)	[110]
Blossoms essential oil	Disk diffusion test	Escherichia coli ATCC 25922 (MIC 350 μl/ml)Klebsiella pneumoniae ATCC 23357 (MIC 400 μl/ml)Salmonella typhi CDC57 (MIC 450 μl/ml)	[111]
Flower essential oil	Disk diffusion test	Escherichia coli ATCC 25922 (MIC 350 μl/ml)Klebsiella pneumoniae ATCC 23357 (MIC 400 μl/ml)Salmonella typhi CDC57 (MIC 450 μl/ml)	[111]
Leaf hydroethanolic extract (70%)	Agar diffusion method	Staphylococcus aureus Meti-R (MIC 3.12 mg/ml)Pseudomonas aeruginosa Cefta/Imp-R (MIC 12.5 mg/ml)Staphylococcus aureus ATCC 25923 (MIC 3.12 mg/ml)Pseudomonas aeruginosa ATCC 27853 (MIC 3.12 mg/ml)	[103]
Leaves essential oil	Agar diffusion method	Staphylococcus aureus Meti-R (MIC 5.37 mg/ml)Pseudomonas aeruginosa Cefta/Imp-R (MIC 10.75 mg/ml)Staphylococcus aureus ATCC 25923 (MIC 5.37 mg/ml)Pseudomonas aeruginosa ATCC 27853 (MIC 10.75 mg/ml)	[103]
Seed fixed oil	Dilution method	Escherichia coli MTCC 443 (MIC 0.5 mg/ml)Salmonella typhi MTCC 531 (MIC 0.125 mg/ml)Shigella flexneri MTCC 1457 (MIC 0.5 mg/ml)Vibrio vulnificus MTCC 1145 (MIC 0.5 mg/ml)Pseudomonas aeruginosa MTCC 424 (MIC 0.125 mg/ml)Lactobacillus plantarum MTCC 2621 (MIC 0.125 mg/ml)Lactobacillus leishmanii MTCC 911 (MIC 0.25 mg/ml)Staphylococcus aureus MTCC 737 (MIC 0.25 mg/ml)Candida tropicalis MTCC 227 (MIC 0.125 mg/ml)Candida albicans MTCC 227 (MTCC 0.25 mg/ml)	[112]
Essential oil from leaves	Disc diffusion method	Escherichia coli ATCC 25922 (MIC 350 μl/ml)Klebsiella pneumoniae ATCC 23357 (MIC 300 μl/ml)Salmonella typhi CDC57 (MIC 400 μl/ml)	[111]
Hexanic extract from the seeds	Microdilution method	Staphylococcus aureus Meti-R (MIC 0.375 mg/ml)Enterococcus faecalis ATCC 29212 (MIC 0.1875 mg/ml)Escherichia coli ATCC 25922 (MIC 0.1875 mg/ml)Pseudomonas aeruginosa ATCC 15442 (MIC 0.375 mg/ml)Klebsiella pneumoniae (MIC 0.375 mg/ml)Acinetobacter baumannii (MIC 0.375 mg/ml)	[113]
Aqueous extract from the leaves	Microdilution method	Candida albicans 77 (IC50 266.4 μg/ml)Candida albicans 40006 (IC50 300.4 μg/ml)Candida tropicalis 23 (IC50 359.9 μg/ml)Candida tropicalis 40042 (IC50 640.3 μg/ml)	[6]
Aqueous extract from aerial parts	Microdilution method	Candida albicans 77 (IC50 18.5 μg/ml)Candida albicans 40006 (IC50 526.4 μg/ml)Candida tropicalis 23 (IC50 25 μg/ml)Candida tropicalis 40042 (IC50 58.62 μg/ml)	[6]
Essential oil from the leaves	Disk diffusion test	Staphylococcus aureus UCH 511 (14 mm)Bacillus cereus (10 mm)Escherichia coli NCTC 7001 (12 mm)Pseudomonas aeruginosa UCH 655 (14 mm)Candida albicans (16 mm)	[114]
Leaf ethanolic extract	Disk diffusion test	Sclerotium rolfsii (MIC 2000 mg/ml)	[115]
Leaf hydroethanolic extract (70%)	Disk diffusion test	Staphylococcus aureus Meti-R (24 mm)Staphylococcus aureus ATCC 25923 (24 mm)Pseudomonas aeruginosa Ceft/Imp-R (16 mm)Pseudomonas aeruginosa ATCC 27853 (20 mm)	[116]
Leaf essential oil	Disk diffusion test	Staphylococcus aureus Meti-R (13 mm)Staphylococcus aureus ATCC 25923 (16 mm)Pseudomonas aeruginosa Ceft/Imp-R (0 mm)Pseudomonas aeruginosa ATCC 27853 (0 mm)	[116]
Leaf essential oil	Disk diffusion test	Staphylococcus aureus (MIC 30 μg/ml)Bacillus subtilis (MIC 26 μg/ml)Proteus vulgaris (MIC 15 μg/ml)Candida albicans (MIC 10 μg/ml)Aspergillus niger (MIC 40 μg/ml)Pseudomonas aeruginosa (MIC 28 μg/ml)Trichophyton mentagrophytes (MIC > 100 μg/ml)Escherichia coli (MIC 26 μg/ml)Klebsiella pneumoniae (MIC 37 μg/ml)Yersinia enterocolitica (MIC > 100 μg/ml)	[117]
Essential oil from the leaves	Disk diffusion test	Aspergillus flavus (MIC 93.8 μl/ml)	[118]
Essential oil from the leaves	Disk diffusion test	Escherichia coli (7 mm)Bacillus subtilis (8 mm)Vibrio cholerae (9 mm)Shigella dysenteriae (9 mm)Corynebacterium diphtheriae (10 mm)Salmonella typhi (9 mm)Streptococcus faecalis (9 mm)Bacillus pumilus (9 mm)Streptococcus pyogenes (8 mm)Micrococcus (8 mm)Pseudomonas solanacearum (10 mm)	[119]
Crushed leaves	Disk diffusion test	Aspergillus flavus (56% inhibition at 5% concentration)	[120]
Methanolic extract from the leaves	Disk diffusion test	Bacillus cereus (9 mm)Bacillus subtilis (3 mm)Bacillus megaterium (1 mm)Staphylococcus aureus (6 mm)Enterococcus faecalis (7 mm)Escherichia coli (12 mm)Salmonella typhi (6 mm)Salmonella paratyphi (5 mm)Pseudomonas aeruginosa (3 mm)Klebsiella pneumoniae (4 mm)	[121]
Essential oil from the leaves	Microdilution method	Saccharomyces cerevisiae (IC50 1000 μg/ml)Fusarium moniliforme 7075 (IC50 > 1500 μg/ml)Mucor sp. (IC50 750 μg/ml)	[122]
Whole plant aqueous extract	Disk diffusion test	Candida albicans (0 mm)Colletotrichum capsici (10 mm)Fusarium oxysporum F.sp. lycopersici (5 mm)Klebsiella pneumoniae (14 mm)Escherichia coli (12 mm)Staphylococcus aureus (0 mm)Pseudomonas aeruginosa (0 mm)	[123]
Whole plant ethanolic extract	Disk diffusion test	Candida albicans (19 mm)Colletotrichum capsici (20 mm)Fusarium oxysporum F.sp. lycopersici (18 mm)Klebsiella pneumoniae (22 mm)Escherichia coli (18 mm)Staphylococcus aureus (29 mm)Pseudomonas aeruginosa (12 mm)	[123]
Ethanolic (1), chloroform (2), methanolic (3), petroleum ether (4), and aqueous (5) extracts of the whole plant	Disk diffusion test	Aspergillus niger:1: 6 mm2: 11 mm3: 0.5 mm4: 7 mm5: 12 mmCandida albicans:1: 10 mm2: 10.5 mm3: 3.5 mm4: 8.5 mm5: 8 mmFusarium sp.:1: 12 mm2: 11 mm3: 3 mm4: 12 mm5: 19 mm	[124]
Essential oil from the leaves	Microdilution method	Aspergillus fumigatus ATCC 40640 (MIC 40 μl/ml)Aspergillus parasiticus ATCC 15517 (MIC 40 μl/ml)	[36]
Essential oil from the leaves	Microdilution method	Trichophyton mentagrophytes (MIC 640 μl/ml)Staphylococcus aureus (MIC 160 μl/ml)Streptococcus suis (MIC 160 μl/ml)Erysipelothrix rhusiopathiae (MIC 80 μl/ml)Actinomyces pyogenes (MIC 80 μl/ml)Pasteurella multocida (MIC 80 μl/ml)Pseudomonas aeruginosa (MIC 20 μl/ml)Escherichia coli (MIC 20 μl/ml)	[125]
Essential oil from the leaves	Disk diffusion test	Rhizoctonia solani (MIC 4000 μl/l)Pythium debaryanum (MIC 300 μl/l)Pythium aphanidermatum (MIC 300 μl/l)	[126]
Aqueous extract of the leaves	Microdilution method	Trichoderma viride (IC50 > 500 μl/l)Alternaria porri (IC50 > 500 μl/l)Aspergillus parasiticus (IC50 > 500 μl/l)Aspergillus fumigatus (IC50 > 500 μl/l)Fusarium lini (IC50 > 500 μl/l)Alternaria brassicae (IC50 > 500 μl/l)Colletotrichum sp. (IC50 > 500 μl/l)Fusarium sesami (IC50 > 500 μl/l)Fusarium nivale (IC50 > 500 μl/l)Alternoria solani (IC50 > 500 μl/l)Fusarium oxysporum f. sp. ciceri (IC50 > 393.4 μl/l)Aspergillus niger (IC50 > 244.7 μl/l)Aspergillus sulphureus (IC50 > 475.4 μl/l)Helminthosporium oryzae (IC50 > 197.7 μl/l)Alternoria alternata (IC50 > 475.5 μl/l)Alternoria tenuissima (IC50 >  321.1 μl/l)Fusarium semitectum (IC50 >  243.5 μl/l)Cladosporium cladosporioides (IC50 >  228.6 μl/l)Drechslera aunti (IC50 >  411 μl/l)Penicillium citrinum (IC50 >  446.7 μl/l)	[127]
Methanolic extract of the leaves	Disk diffusion test	Staphylococcus aureus (6 mm)Bacillus subtilis (9 mm)	[128]
Hexanic extract of the leaves	Microdilution method	Escherichia coli ATCC 10536 (IC50 ≅ 200 μg/ml)Proteus mirabilis ATCC 7002 (IC50 ≅ 200 μg/ml)Klebsiella pneumoniae ATCC 10031 (IC50 ≅ 400 μg/ml)Proteus vulgaris ATCC 49132 (IC50 ≅ 100 μg/ml)Serratia marcescens FJ584421 (IC50 ≅ 50 μg/ml)	[29]
Petroleum ether (1), chloroform (2), methanolic (3), and aqueous (4) extracts of the leaves	Disk diffusion test	Staphylococcus aureus ATCC 29213:1: 13 mm2: 8 mm3: 8 mm4: 12 mmListeria monocytogenes ATCC 19115:1: 0 mm2: 7 mm3: 5 mm4: 0 mmEscherichia coli ATCC 25922:1: 7 mm2: 10 mm3: 0 mm4: 0 mmSerratia marcescens ATCC 21074:1: 18 mm2: 0 mm3: 8 mm4: 0 mmAspergillus flavus ATCC 32612:1: 18 mm2: 0 mm3: 0 mm4: 14 mm	[129]
Leaf essential oil	Disk diffusion test	Fusarium oxysporum f. sp. gladioli MPPLU 01 (MIC 0.6 μl/ml)	[130]
Leaf essential oil	Disk diffusion test	Rhizoctonia solani (MIC 5.000 μg/ml)Sclerotinia sclerotiorum (MIC 5.000 μg/ml)Sclerotium rolfsii (MIC 5.000 μg/ml)	[131]
Leaf methanolic extract	Disk diffusion test	Klebsiella pneumoniae MTCC 109 (7.5 mm)Bacillus subtilis MTCC 121 (8 mm)Salmonella typhi MTCC 733 (7 mm)	[132]
Leaf essential oil	Disk diffusion test	Fusarium oxysporum f.sp. gladioli MPPLU 01 (MIC 0.998 μg/ml)	[133]
Aerial parts methanolic extract	Disk diffusion test	Candida albicans (7 mm)	[105]
Leaf essential oil	Disk diffusion test	Microsporum gypseum (MIC 625 μg/ml)Aureobasidium pullulans (MIC 5.000 μg/ml)Candida albicans (MIC 10.000 μg/ml)Aspergillus flavus (MIC 10.000 μg/ml)Trichophyton rubrum (MIC 156 μg/ml)Cryptococcus neoformans (MIC 5.000 μg/ml)	[134]
Essential oil from the leaves	Microdilution method	Staphylococcus aureus (MIC 64 and 256 μg/ml)Candida albicans (IC50 18.15 μg/ml)Candida tropicalis (IC50 40.4 μg/ml)	[135]
Leaf hydroethanolic extract	Disk diffusion test	Staphylococcus aureus (0.7 cm)Salmonella typhi (0.52 cm)Escherichia coli (0.25 cm)	[136]
Leaf essential oil	Microdilution method	Enterococcus faecalis (IC50 5.78 μg/ml)Staphylococcus aureus (IC50 68.98 μg/ml)Bacillus cereus (IC50 9.35 μg/ml)Candida albicans (IC50 6.78 μg/ml)	[137]

The works evaluating the antimicrobial action of the species highlight the use of the volatile terpenes (essential oils) of the leaves (Table 2). Xu et al. [104] demonstrated that the oil of M. suaveolens showed antimicrobial action through the microdilution technique with MIC values of great clinical relevance, notably against Bacillus subtilis (Cohn, 1872) (Bacillaceae) CMCC 63501, Escherichia coli (T. Escherich, 1885) (Enterobacteriaceae) CMCC 44102, and Botrytis cinerea (De Bary) Whetzel, 1945 (Sclerotiniaceae). The oil was also very active against S. aureus CMCC 26001, P. aeruginosa CMCC 10104, Fusarium graminearum Schwabe, 1839 (Nectriaceae), Exerohilum turcicum (Pass.) K.J. Leonard & Suggs, 1974 (Pleosporaceae), and Lecanosticta acicola (Thüm.) Syd., 1924 (Mycosphaerellaceae).

Besides the essential oil, the fixed oil from M. suaveolens seeds showed activities of clinical relevance against E. coli MTCC 443 (MIC 0.5 mg/ml), Salmonella typhi Typhi (Enterobacteriaceae) MTCC 531 (MIC 0.125 mg/ml), Shigella flexneri Castellani & Chalmers, 1919 (Enterobacteriaceae) MTCC 1457 (MIC 0.5 mg/ml), Vibrio vulnificus (Reichelt et al.) Farmer, 1980 (Vibrionaceae) MTCC 1145 (MIC 0.5 mg/ml), P. aeruginosa MTCC 424 (MIC 0.125 mg/ml), Lactobacillus plantarum (Orla-Jensen) Bergey et al., 1923 (Lactobacillaceae) MTCC 2621 (MIC 0.125 mg/ml), Lactobacillus leishmanii (Henneberg) Bergey et al. 1923 (Lactobacillaceae) MTCC 911 (MIC 0.25 mg/mL), S. aureus MTCC 737 (MIC 0.25 mg/ml), Candida tropicalis Berkhout, 1923 (Saccharomycetaceae) MTCC 227 (MIC 0.125 mg/ml), and Candida albicans Berkhout, 1923 (Saccharomycetaceae) MTCC 227 (MIC 0.25 mg/ml) (Table 2).

3.4.3. Insecticidal Activity

Popularly, in Kenya, the aerial parts of M. suaveolens are burned to repel mosquitoes of the species Anopheles gambiae [84, 94]. Subsequently, other researchers have highlighted that the oil has biological action against various insects, such as A. gambiae itself (Table 3).

Table 3

Insecticidal activities of Mesosphaerum suaveolens (L.) Kuntze (Lamiaceae).

Extract/parts of the plant	Assay	Insecticidal activity	Citation
Leaf essential oil	FumigationIngestionContact toxicity	Ceratitis capitata Fumigation: CL50 18.37 μl/lIngestion: CL50 13.041 μl/lContact toxicity: CL50 0.066 μl/l	[30]
Leaf essential oil	Fumigation	Callosobruchus maculatus (CL50 4.7 μg/ml)Rhyzopertha dominica (CL50 12 μg/ml)Sitophilus oryzae (CL50 10.6 μg/ml)Tribolium castaneum (CL50 23.2 μg/ml)Callosobruchus maculatus (CL50 57 μg/mg)Rhyzopertha dominica (CL50 126 μg/mg)Sitophilus oryzae (CL50 101 μg/mg)Tribolium castaneum (CL50 167 μg/mg)	[34]
Leaf essential oil	Contact toxicity	Sitophilus granarius (CL50 0.251 μL/insect)	[138]
Leaf essential oil	Ingestion	Bactrocera oleae (CL50 4.9 mg/ml)	[139]
Leaf methanolic extract	Contact	Sitophilus oryzae (CL50 475.9 μl/ml)Sitophilus zeamais CL50 707.4 μl/ml)Callosobruchus maculatus (CL50 451.2 μl/ml)	[140]
Leaf essential oil	Fumigation	Tribolium castaneum (CL50 229.33 μg/ml)	[141]
Leaf essential oil	Fumigation	Drosophila melanogaster (CL50 15.5 μg/ml)	[10]
Leaf infusion	Ingestion	Drosophila melanogaster (CL50  >  30.3 μg/ml)	[10]
Leaf essential oil	Fumigation	Anopheles gambiae (CL50 1.86 μg/ml)	[35]
Leaf essential oil	Contact toxicity	Tenebroides mauritanicus (CL50 0.35 μl/g)	[142]
Leaf essential oil	Toxicity by ingestion	Apis mellifera (CL50 43.03%)	[143]
Leaf ethanolic extract	Fumigation	Callosobruchus maculatus (100% mortality (at 10% concentration)	[144]
Crushed leaves	Ingestion toxicity	Callosobruchus maculatus (CL50 73 mg/g)	[145]
Crushed leaves and flowers	Ingestion toxicity	Callosobruchus maculatus (20.1% of mortality)	[146]
Crushed leaves	Ingestion toxicity	Callosobruchus maculatus (96.6% of mortality in the concentration 43.75 mg/g)Sitophilus zeamais (30% of mortality in the concentration 43.75 mg/g)	[147]
Leaf essential oil	Fumigation	Callosobruchus maculatus (CL50: 1.3 μl/l)	[148]
Leaf essential oil	Fumigation	Callosobruchus maculatus (CL50: >20 μl/l)	[149]
Leaf essential oil	Fumigation	Callosobruchus maculatus (CL50: >2.6 μl/ml)	[150]
Leaf essential oil	Fumigation	Nauphoeta cinerea (did not show insecticidal action)	[151]

Works evaluating the insecticidal action showed that the essential oil of M. suaveolens by fumigation showed the effect against Callosobruchus maculatus (Fabricius 1775; Coleoptera: Chrysomelidae) (CL50 4.7 μg/ml), Rhyzopertha dominica (Fabricius 1972; Coleoptera: Bostrichidae) (CL50 12 μg/ml), Sitophilus oryzae (Linnaeus 1763; Coleoptera: Curculionidae) (CL50 10.6 μg/ml), Tribolium castaneum (Herbst 1932; Coleoptera: Tenebrionidae) (CL50 23.2 μg/ml) (Tripathi; Upadhyay 2009), and Sitophilus granarius (Linnaeus, 1758) (CL50 0.251 μl/insect) [138].

Mesosphaerum suaveolens oil showed toxicity through contact and ingestion against Mediterranean flies (Ceratitis capitata (Wiedemann, 1824) (Diptera: Tephritidae)) with CL50 13.041 μl/l through ingestion and CL50 0.066 μl/l through contact [30]. Canale et al. [139], when evaluating the toxicity of the oil against Bactrocera oleae (Rossi, 1790) (Diptera: Tephritidae), demonstrated that, by ingestion, the product showed a CL50 of 4.9 mg/ml. Bezerra et al. [10] evaluated by fumigation the action of the oil and highlighted that it presents great insecticidal action with CL50 of 15.5 μg/ml against adults of Drosophila melanogaster (Meigen, 1830) (Diptera: Drosophilidae). Also, via the fumigation test, Wangrawa et al. [35] found a CL50 of 1.86 μg/ml (oil/air) against A. gambiae. Recently, Adjou et al. (2019) found the insecticidal action of M. suaveolens oil against Tenebroides mauritanicus (Linnaeus, 1758) (Coleoptera: Trogossitidae) with a CL50 0.35 μl/g.

3.4.4. Repellent Activity

Besides causing mortality in insects, the products of M. suaveolens, especially the essential oil of the leaves, can repel insects and arachnids of public health and economic interests (Table 4). As for Diptera, the essential oil by fumigation and the fresh leaves by contact were able to repel mosquitoes of the species Anopheles gambiae, malaria vector, with the former showing an effective rate of 98% repellency at a low concentration (6%) [152], while the leaves when rubbed on the body had a rate of 66.5% [153]. Besides this Diptera, Aedes aegypti vector of arboviruses, such as dengue, yellow fever, chikungunya, and zika, was also repelled when in contact with the ethyl acetate extract of the leaves.

Table 4

Repellent activities of Mesosphaerum suaveolens (L.) Kuntze (Lamiaceae).

Extract/parts of the plant	Assay	Insecticidal activity	Citation
Aerial parts essential oil	Contact	Amblyomma cajennense (EC50 0.55 mg/cm²)	[23]
Crushed leaves	Fumigation	Callosobruchus maculatus (repellency from 5 minutes of exposure)	[146]
Leaf essential oil	Fumigation	Anopheles gambiae (98% repellency rate at 6% concentration)	[152]
Fresh leaves	Contact	Anopheles gambiae (repellency rate 66.5%)	[153]
Leaf essential oil	Fumigation	Sitophilus granarius (repellency rate 40% at 100% concentration)	[154]
Leaf ethyl acetate extract	Contact	Aedes aegypti (repellency rate of 78.8% for 500 μl)	[155]
Crushed leaves (1) and twigs (2)	Contact	Callosobruchus maculatus:1: repellency index: 0.112: repellency index: 0.2	[156]
Leaf essential oil	Fumigation	Anopheles sp. (67% repellency rate at 6.3 μg/ml concentration)	[157]
Leaf essential oil	Fumigation	Ixodes ricinus (repellency rate 93% at 10% concentration)	[158]

As for insects of economic interest, the leaves of M. suaveolens showed that the phytochemicals released by the leaves can repel two species of coleoptera, being Sitophilus granarius and Callosobruchus maculatus. As for arachnid repellency, the essential oil was able to repel Amblyomma cajennense and Ixodes ricinus.

3.4.5. Larvicidal Activity

Besides microbiological and insecticidal activities, apolar and polar extracts of M. suaveolens showed larvicidal action in some studies (Table 5). Its oil, for example, showed activity against Aedes albopictus (Skuse, 1894) (Diptera: Culicidae) (CL50 240.3 μg/ml) [159], Aedes aegypti (Linnaeus, 1762) (Diptera: Culicidae) (CL50 0.4 μL/ml) [160], Artemia salina (Linnaeus, 1758) (Anostraca: Artemiidae) (CL50 49.72 μg/ml) [10], and Chrysodeixis chalcites (Esper, 1789) (Lepidoptera: Noctuidae) (CL50 2.42 μg/ml) [32].

Table 5

Larvicidal activities of Mesosphaerum suaveolens (L.) Kuntze (Lamiaceae).

Extract/parts of the plant	Assay	Larvicidal activity	Citation
Leaf essential oil	Acute toxicity	Artemia salina (CL50 49.72 μg/ml)	[10]
Leaf infusion	Acute toxicity	Artemia salina (CL50 > 1000 μg/ml)	[10]
Leaf essential oil	Acute toxicity	Chrysodeixis chalcites (CL50 2.42 μg/ml)	[32]
Essential oil from leaves	Acute toxicity	Aedes albopictus (CL50 240.3 μg/ml)	[159]
Leaf essential oil	Acute toxicity	Aedes aegypti (CL50 0.4 μL/ml)	[160]
Hexanic extract (1), diethyl ether (2), dichloromethane (3), and ethyl acetate (4) from leaves	Acute toxicity	Aedes aegypti 1: CL50 543.66 μg/ml2: CL50 1443.53 μg/ml3: CL50 1292.36 μg/ml4: CL50 853.04 μg/ml	[161]
Hexanic extract (1), diethyl ether (2), dichloromethane (3), and ethyl acetate (4) from aerial parts	Acute toxicity	Anopheles stephensi 1: CL50 1.52 mg/ml2: CL50 1.49 mg/ml3: CL50 1.39 mg/ml4: CL50 0.94 mg/ml	[162]
Hexanic (1), isopropanolic (2), methanolic (3), acetone (4), and dimethyl sulfoxide (5) extract from the leaves	Acute toxicity	Aedes albopictus 1: CL50 1.52 mg/ml2: CL50 1.52 mg/ml3: CL50 1.52 mg/ml4: CL50 1.52 mg/ml5: CL50 1.52 mg/ml	[163]
Isopropanolic (1), methanolic (2), acetonic (3), dimethyl sulfoxide (4), and aqueous extract from the leaves (5)	Acute toxicity	Aedes albopictus 1: CL50 900 μg/ml2: CL50 940 μg/ml3: CL50 820 μg/ml4: CL50 1590 μg/ml5: CL50 1560 μg/ml	[163]
Aqueous leaf extract	Acute toxicity	Anopheles stephensi (CL50 26.08 mg/ml)Aedes aegypti (CL50 17.6 mg/ml)Culex quinquefasciatus (CL50 33.68 mg/ml)	[164]
Methanolic (1), chloroform (2), and petroleum ether (3) extracts of the leaves	Acute toxicity	Culex quinquefasciatus:1: CL50 > 300 μg/ml2: CL50 41.93 μg/ml3: CL50 38.39 μg/mlAedes aegypti:1: CL50 > 300 μg/ml2: CL50 > 300 μg/ml3: CL50 64.49 μg/ml	[165]
Dichloromethane extract from the aerial parts	Acute toxicity	Anopheles gambiae (CL50 63.5 mg/ml)	[166]
Aqueous extract from aerial parts	Spraying	Sesamia calamistis (37.85% motility (300 mg/ml))	[167]
Aqueous extract from leaves and fruits	Contact toxicity	Mussidia nigrivenella (49% motility (200 mg/g))Sesamia calamistis (37% motility (200 mg/g))Eldana saccharina (41% motility (200 mg/g))	[168]
Hexanic (1), chloroform (2), ethyl acetate (3), and methanolic (4) extract from the aerial parts	Acute toxicity	Culex quinquefasciatus:1: CL50 213.09 μg/ml2: CL50 217.64 μg/ml3: CL50 167.59 μg/ml4: CL50 86.93 μg/ml	[169]
Crushed aerial parts	Contact toxicity	Helicoverpa armigera (66.7% mortality at 20% concentration)	[170]
Essential oil from leaves	Ingestion toxicity	Spodoptera frugiperda (CL50 600 μg/ml)	[171]
Hexanic extract (1), chloroform (2), and ethyl acetate (3) from leaves	Ingestion toxicity	Helicoverpa armigera:1: mortality of 31.68% (concentration: 1%)2: mortality of 65.28% (concentration: 1%)3: mortality of 72.87% (concentration: 1%)Spodoptera litura:1: mortality of 34.09% (concentration: 1%)2: mortality of 63.62% (concentration: 1%)3: mortality of 74.56% (concentration: 1%)Earias vittella:1: mortality of 44.37% (concentration: 1%)2: mortality of 69.28% (concentration: 1%)3: mortality of 73.40% (concentration: 1%)Leucinodes orbonalis:1: mortality of 37.57% (concentration: 1%)2: mortality of 67.62% (concentration: 1%)3: mortality of 78.28% (concentration: 1%)	[172]
Essential oil from leaves (1) and crushed leaves (2)	Contact toxicity	Dinarmus basalis:1: CL50 7.76 μl2: CL50 14.06 g	[173]
Leaf essential oil	Acute toxicity	Aedes aegypti (CL50 139.07 μg/ml)	[174]

3.4.6. Cytotoxic Activity

Besides microbiological and insecticidal activities, it was evidenced that M. suaveolens products present biologically active compounds against cancer cells (Table 6). The activities evaluated using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay demonstrated that the leaves are the source of the anticancer compounds against some cell types. Among these, Lautié et al. [175] evaluated the bioactivities of chlorophore and butanolic extracts against MCF-7 cell lines and showed that such products have low IC50 (12 and 2.8 μg/ml, respectively). Besides these cell lines, activities were demonstrated against EAC (Ehrlich ascites carcinoma), human breast epithelial adenocarcinoma (MDA-MB-231), and T-lymphocyte leukemia cells.

Table 6

Cytotoxic activities of Mesosphaerum suaveolens (L.) Kuntze (Lamiaceae).

Extract/parts of the plant	Assay	Cytotoxic activity	Citation
Chloroform (1) and butanolic (2) extract from the leaves	MTT assay	MCF-7 cell lines1: IC50 12 μg/ml2: IC50 2.8 μg/ml	[175]
Ethanolic (1) and aqueous (2) extracts of the leaves	MTT assay	Human T-lymphocyte leukemia:1: IC50 553.52 μg/ml2: IC50 1356.17 μg/ml	[176]
Ethanolic extract of the aerial parts	MTT assay	EAC cells (IC50 10.63 μg/ml)	[177]
Leaf callus	MTT assay	Human breast epithelial adenocarcinoma (MDA-MB-231)IC50 74.66 μg/mlProstate cancer (PC-3)IC50 173.21 μg/ml	[178]
Silver nanoparticles from the leaves	MTT assay	Human breast epithelial adenocarcinoma (MDA-MB-231)IC50 63.16 μg/mlProstate cancer (PC-3)IC50 52.49 μg/ml	[179]

Among the studies against cancer cell lines, only the aqueous extract of the leaves showed low cytotoxicity (IC50 1,356.17 μg/ml) when evaluated against T-lymphocyte leukemia-causing cells [176]. Concomitantly in the same study, the ethanolic extract of the same organs had moderate cytotoxicity (IC50 553.52 μg/ml); such fact is explained by the variation of solvent used for the extraction of the compounds.

3.4.7. Other Biological Activities (Antiarachnidic, Antiparasitic, and Molluscicides)

In addition to the aforementioned activities, the herbaceous species present bioactive compounds against other biological organisms. Among these were highlighted parasitic organisms of humans, as reported by Shittu et al. [180], in which evaluating the trypanocidal action (Trypanosoma brucei brucei) in vivo of gold nanoparticles from M. suaveolens demonstrated that the species can cause a complete clearance of the parasite after seven days of infection. As well as in insecticidal action against malaria vectors (Anopheles spp.), M. suaveolens exhibits antiplasmodial activity (Plasmodium falciparum 3D7) [45, 46, 181]. Noronha et al. [181] evaluated the antiparasitic action of the methanolic extract of M. suaveolens leaves and observed that the natural product has an IC50 of 3.906 μg/ml against chloroquine-sensitive Plasmodium falciparum strains. In the study by Ziegler et al. [45], the researchers isolated a diterpene (dehydroabietinol) from the leaves and observed that the compound was able to inhibit 50% of parasite growth at a low concentration of 7.3 μg/ml. Similarly, Chukwujekwu et al. [46] demonstrated that another diterpene (13α-epi-dioxiabiet-8(14)-en-18-ol) isolated from the same organ showed an IC50 of 0.11 μg/ml, against P. falciparum D10, being of great clinical interest.

Research involving the extracts and essential oil of M. suaveolens focus on insecticidal activities, so only one work aimed to evaluate the bioactive potential against Arachnida species [182]. In this study, the authors demonstrated that the essential oil of the leaves at the concentration of 31.3 mg/ml can cause 50% mortality of Rhipicephalus (Boophilus) microplus for engorged females, while for juvenile forms of the tick, CL50 is 51.6 mg/mL, demonstrating that females are more susceptible to the oil.

Salawu and Odaibo [182] evaluated the molluscicide action of the ethanolic extract of M. suaveolens against Bulinus globosus, found that the product presents both lethality in adult individuals (LC50 77 μg/ml), and also presents an ovicidal potential (LC50 614 μg/ml).

3.5. Pharmacological Activities

3.5.1. Antioxidant Activity

Narayanaswamy and Balakrishnan [84] evaluated the extracts of thirteen plants of ethnomedicinal importance and identified that M. suaveolens species among all had the highest activity in both aqueous and ethanolic extracts evaluated. Thus, it demonstrates that the species is a source of compounds of pharmacological interest for the development of natural antioxidant products.

Agarwal [183] showed that the methanolic extract of M. suaveolens leaves has potent antioxidant activity evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method with IC50 value = 40.91 μg/ml, and there is about 69% free radical inhibition capacity at the highest concentration (100 μg/ml). It was also found that the percentage of inhibition is concentration dependent, the higher the concentration the greater the inhibition of free radicals, and that the main phytochemicals involved in this activity may be phenols and flavonoids. The methanolic extract also demonstrated antioxidant activity with assays other than DPPH, such as ferric reducing antioxidant power (FRAP) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) [184].

Other studies have also evaluated the free radical scavenging potential by the DPPH method. Gavani and Paarakh [185] evaluated the methanolic extract of M. suaveolens leaves and obtained an IC50 of 14.04 μg/ml. The aqueous and ethanolic extracts of the fresh leaves of M. suaveolens demonstrated high antioxidant activity. The former product had an IC50 = 20.32 μg/ml, while the ethanolic extract had a statistically equal result to the positive control, ascorbic acid, with IC50 of 7.06 ± 0.82 and 6.69 ± 0.85 μg/mL, respectively [186]. Such results are attributed to the phenolic compounds present in such extracts.

Iqbal et al. [187] reported that the methanolic extract of the seeds of M. suaveolens showed better antioxidant activity by the DPPH method (IC50 = 72 ± 0.45 μg/ml) when compared to the methanolic extracts of the stem (IC50 = 250 ± 5.46 μg/ml) and root (IC50 = 143 ± 2.15 μg/ml).

In the work of Priyadharshini and Sujatha [188], four types of leaf extracts were evaluated; in the DPPH assay, three of the extracts had significant results, the best of them being the ethyl acetate extract with a percentage of inhibition (IC50 = 137 μg) very close to that of the standard used, ascorbic acid (IC50 = 127 μg). In this same study, the acetate extract also stood out with other tests; in the superoxide anion radical scavenging assay, the IC50 value = 22.94 μg, and the standard had a value of 21.47 μg.

In addition to leaves, antioxidant potentials of other organs such as flowers were investigated in the study by Banerjee and De [189]. However, the results were not promising, as the extract of the reproductive parts exhibited an IC50 of 1690.21 μg/ml against DPPH. Antioxidant studies involving M. suaveolens are not restricted to extracts only. Nantitanon et al. [126] evaluated the effect of the essential oil from the leaves; however, it showed low potential to reduce free radicals (IC50 of 3.7200 mg/ml). Hsu et al. [190] demonstrated that the seeds also exhibit antioxidant action, as they showed moderate inhibitory activity against xanthine oxidase. In a study conducted by Lima et al. [191], it was observed that the essential oil from M. suaveolens leaves showed moderate Fe2+ chelating activity at the concentration of 480 μg/ml.

3.5.2. Healing Potential

The healing potential of M. suaveolens leaves was evaluated by three types of extracts (petroleum ether, ethanolic, and aqueous) in different wound models (excision, incision, and healing) using albino Wistar rats [192]. In this study, it was revealed that the extract using petroleum ether had the greatest significant effect on wound healing in murine wounds. Shirwaikar et al. [193] evaluated the ethanolic extract on these same three types of wounds, also obtaining significant results which were justified by the free radical scavenging action of this species.

3.5.3. Neuroprotective Activity

Ghaffari et al. [184] determined the neuroprotective potential of the methanolic extract of the aerial parts of M. suaveolens on mouse N2A neuroblastoma cells, in which they observed that the natural product inhibits hydrogen peroxide (H2O2)-induced neuronal death. The authors justified this effect by the fact that the extract can regulate the activation of antioxidant and protective genes of the nerve cells. These results are promising, and the methanolic extract can be employed to treat stress-induced neurodegeneration.

3.5.4. Anti-Inflammatory Activity

Shenoy and Shirwaikar [194] evaluated the anti-inflammatory potential of ethanolic extract of the leaves against inflammation induced by carrageenan in albino rats; the extract showed significant results when compared to standard ibuprofen; this result is justified by the good antioxidant activity of this extract. In the study by Grassi et al. [42], two diterpenes (C20) isolated from M. suaveolens, suaveolol and methyl suaveolate, showed anti-inflammatory potential when evaluated regarding the reduction of ear edema in rats. In such research, it was observed that the compounds reduced inflammation with ID50 = 0.71 μmol/cm2 (dose giving 50% edema inhibition) for suaveolol and ID50 = 0.60 μmol/cm2; however, despite the pharmacological effect, the results were only two to three times less active than the standard drug used in the study indomethacin (ID50 = 0.26 μmol/cm2).

3.5.5. Antiulcer Activity

Mesosphaerum suaveolens leaves are popularly used for the treatment of gastric ulcers; however, no active ingredient had been identified. The first study evaluating such an effect was by Vera-Arvaze et al. [43], in which such authors isolated the diterpene suaveolol from the leaves and evaluated it against an induced experimental model; the results presented indicated that this compound had a gastroprotective effect of more than 70%.

One year after the publication of the mentioned study, Jesus et al. [195] using the ethnopharmacological approach of M. suaveolens evaluated its antiulcer potential through the ethanolic extract and its fractions. The results for all products had high significance, p > 0.001, with the hexanic fraction of the extract being the most effective with 74% inhibition of induced gastric ulcer at a dose of 500 mg/kg.

3.5.6. Antidiarrheal Activity

Although M. suaveolens is popularly used to treat gastrointestinal disorders such as diarrhea, only the work of Shaikat et al. [196] evaluated its antidiarrheal potential. The researchers prepared ethanolic extracts of the leaves and based on the popular use, evaluated against an experimental model of diarrhea induced in mice; the results obtained show that this species presents compounds with the antidiarrheal effect (p > 0.001) that may be acting in an isolated or synergistic way.

3.5.7. Antihyperglycemic Activity

The ethanolic extract of M. suaveolens leaves was evaluated in the in vivo experimental model of streptozotocin-induced diabetes. The extract at doses of 250 and 500 mg/kg bodyweight was administered orally over 21 days; at the end of the treatment, a decrease in the levels of triglycerides, total cholesterol, and low-density lipoprotein can be seen; these results indicate that this species has significant antidiabetic activity [197].

3.5.8. Hepatoprotective Effect

Ghaffari et al. [198] induced damage to livers of Wistar rats using carbon tetrachloride (CCl4) and subsequently administered doses of 50 and 100 ml/kg of methanolic extract of the aerial parts of M. suaveolens. The results were promising, demonstrating that the extract has a hepatoprotective effect, which can be explained by the antioxidant potential of the product, also demonstrated in the study.

3.5.9. Toxicity

A topical cream based on M. suaveolens essential oil was prepared based on its popular use in Thailand, where they pointed out further investigations related to its toxicity in humans. This study was conducted on Wistar rats for 28 days under 3, 10, and 30% concentration of essential oil. The results showed us that concentrations of 3 and 10% did not cause a statistically significant dermal toxicity unlike the 30% concentration in which some female rats presented signs of erythema on its shaved dorsal skin between 11 and 14 days after the cream application [199].

4. Conclusions

It is evident that M. suaveolens is the most studied species of the genus, traditionally used in the new and old world to combat several diseases. Chemically, the species is much investigated, mainly about the composition of its essential oils that can vary according to the locality of occurrence. Mesosphaerum suaveolens also behaves as ruderal, and its success may be due to the release of allelochemicals. The species also presents a biotechnological potential corroborated by the remarkable activity against pathogenic microorganisms, insects, and other arthropods that transmit diseases. Finally, the pharmacological applications of the species are highlighted, especially the antioxidant action found in several organs of the species.