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.


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]. e 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][4][5][6][7][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. is 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.

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. e 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. e 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.

Botanical Aspects: Description, Classification, and
Distribution. Mesosphaerum suaveolens (L.) Kuntze is an herbaceous plant belonging to the Lamiaceae family. e word "mesosphairon" comes from the Greek and Latin "mesosphaerum," meaning "a type of tuberose with mediumsized 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].
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. e 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. e flowers are pedunculate, with a persistent, tubular calyx, and 5 pointed sepals. e 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][17][18].
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][20][21][22]. In Brazil, M. suaveolens is present in almost the entire territory [23].

Phytochemistry.
Mesosphaerum suaveolens is an important source of essential oils, alkaloids, flavonoids, phenols, saponins, triterpenes, and sterols [13,24]. e 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).
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]. e 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 ailand, 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   Evidence-Based Complementary and Alternative Medicine 5  Evidence-Based Complementary and Alternative Medicine 7  Evidence-Based Complementary and Alternative Medicine 9 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].

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 . eir extracts present allelopathic action against Echinochloa crusgalli (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]. us, 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.
us, 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].

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). e works evaluating the antimicrobial action of the species highlight the use of the volatile terpenes (essential oils) of the leaves (  Evidence-Based Complementary and Alternative Medicine  Evidence-Based Complementary and Alternative Medicine 13  [126] 14 Evidence-Based Complementary and Alternative Medicine   Table 2).

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).

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.

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 Leaf essential oil Acute toxicity Aedes aegypti (CL 50 139.07 μg/ml) [174] [179] Evidence-Based Complementary and Alternative Medicine action of the methanolic extract of M. suaveolens leaves and observed that the natural product has an IC 50 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 IC 50 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, CL 50 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 (LC 50 77 μg/ml), and also presents an ovicidal potential (LC 50 614 μg/ml). us, it demonstrates that the species is a source of compounds of pharmacological interest for the development of natural antioxidant products.

Pharmacological
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 IC 50 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. e 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] [186]. Such results are attributed to the phenolic compounds present in such extracts.
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 (IC 50 � 137 μg) very close to that of the standard used, ascorbic acid (IC 50 � 127 μg). In this same study, the acetate extract also stood out with other tests; in the superoxide anion radical scavenging assay, the IC 50 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 IC 50 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 (IC 50 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 Fe 2+ chelating activity at the concentration of 480 μg/ml.

Healing Potential.
e 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.

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 (H 2 O 2 )-induced neuronal death. e authors justified this effect by the fact that the extract can regulate the activation of antioxidant and protective genes of the nerve cells.
ese results are promising, and the methanolic extract can be employed to treat stress-induced neurodegeneration. [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 (C 20 ) 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 ID 50 � 0.71 μmol/cm 2 (dose giving 50% edema inhibition) for suaveolol and ID 50 � 0.60 μmol/cm 2 ; however, despite the pharmacological effect, the results were only two to three times less active than the standard drug used in the study indomethacin (ID 50 � 0.26 μmol/cm 2 ).

Anti-Inflammatory Activity. Shenoy and Shirwaikar
3.5.5. Antiulcer Activity. Mesosphaerum suaveolens leaves are popularly used for the treatment of gastric ulcers; however, no active ingredient had been identified. e 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. e 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. e 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.

Antihyperglycemic Activity.
e ethanolic extract of M. suaveolens leaves was evaluated in the in vivo experimental model of streptozotocin-induced diabetes. e 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. e 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 ailand, where they pointed out further investigations related to its toxicity in humans. is study was conducted on Wistar rats for 28 days under 3, 10, and 30% concentration of essential oil. e 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].

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. e 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.

Data Availability
e data used to support the findings of this study are available from the corresponding author upon request.