Phytochemistry, Bioactivity, and Ethnopharmacology of the Genus Lepechinia Willd. (Lamiaceae): A Review

The genus Lepechinia (Lamiaceae) involves several aromatic shrubs that are distributed only in the American continent, inhabiting mountain areas, mainly in the Andean region of South America. Based on the PRISMA approach, we selected and critically analyzed 48 research articles. From a phytochemical point of view, most of the secondary metabolites reported in Lepechinia spp. are terpenes and terpenoids, with a few exceptions comprising flavonoids and other shikimic acid derivatives. On the one hand, sesquiterpenoids of the guajane, aromadendrane, eudesmane, and cadinane groups are characteristic of essential oils, together with (E)-β-caryophyllene as the main representative of its chemical family. On the other hand, abietane diterpenoids are the prevalent compounds described in non-volatile fractions. Many biological activities and traditional medical uses have been reported for both pure metabolites and complex mixtures (e.g., essential oils). Regarding ethno-medical uses, the treatment of muscle pain, headache, toothache, diabetes mellitus, uterine tumors, uterine infections, and diarrhea has been reported. Concerning their verified biological activities, insecticidal, antifungal, antioxidant, and anticholinesterase properties have been described. Furthermore, some data concerning anti-herpetic activity have been reported.


Introduction
Biodiversity has, for a long time, been the main source of pharmaceutical products, through the use of medicinal plants.Today, natural products still sometimes provide inspiration to chemists regarding the design of new pharmaceutical active principles, and, in many countries, vegetal drugs constitute the main source of traditional medicines [1].
Lamiaceae, one of the most important herbal families, incorporates a wide variety of plants, most of them characterized by biological and medical applications.This family comprises 224 genera and more than 5600 species distributed across the world.The best-known members of this family belong to a group of medicinal and aromatic plants, including the genus Lepechinia [2].
The genus Lepechinia Willd consists of 43 species that grow from Northern California in the western USA to central Argentina in South America [3][4][5][6].Lepechinia spp.range from perennial herbs to shrubs, are rarely gynodioecious or dioecious, and are often aromatic; their leaves range from entire to toothed and are often rugose; and they have terminal and often axillary inflorescence [4,7].A detailed bibliographic study was performed, including revision of papers from the years 1948 to 2023 regarding the genus Lepechinia.In this research, 64 plant species were mentioned, according to the botanical literature [8].Focusing on these data, the name of genera and all the scientific names of the species were selected.
The goal of this review is to provide information on the ethnomedical uses, phytochemistry, and biological activities of different Lepechinia spp.

Research Strategies and Literature Sources
The present review was developed according to the PRISMA guidelines [9].The data included in this paper have been retrieved using the keywords, "Lepechinia medicinal plants", "Lepechinia phytochemistry", "Lepechinia ethomedicine uses", "Lepechinia essential oils", and "Lepechinia biological studies" in the following electronic databases: PubMed (https://pubmed.ncbi.nlm.nih.gov/,accessed on 30 September 2023) ScienceDirect (https: //www.sciencedirect.com/,accessed on 30 September 2023), SciFinder (https://scifinder.cas.org/, accessed on 30 September 2023), SciELO (https://scielo.org/,accessed on 30 September 2023), and Scopus (https://www.scopus.com/,accessed on 30 September 2023).In order to manage all the bibliographic references, Mendeley Desktop software version 1. 19.8 was used.Three reviewers extracted data independently, avoiding the duplication of data, and they searched for and selected all key words individually.The process of datamining is synthetized in the flowchart in Figure 1.When a scientific paper could not be found online, we asked the authors to send it to us.For the final step of the study, articles in English and Spanish were selected, together with data from patents.Congress abstracts and symposiums were excluded because they were considered not sufficiently complete to warrant an exhaustive comparison with full articles.The goal of this review is to provide information on the ethnomedical uses, phytochemistry, and biological activities of different Lepechinia spp.

Research Strategies and Literature Sources
The present review was developed according to the PRISMA guidelines [9].The data included in this paper have been retrieved using the keywords, "Lepechinia medicinal plants", "Lepechinia phytochemistry", "Lepechinia ethomedicine uses", "Lepechinia essential oils", and "Lepechinia biological studies" in the following electronic databases: Pub-Med (https://pubmed.ncbi.nlm.nih.gov/,accessed on 30 September 2023) ScienceDirect (https://www.sciencedirect.com/,accessed on 30 September 2023), SciFinder (https://scifinder.cas.org/,accessed on 23-30 September 2023), SciELO (https://scielo.org/,accessed on 30 September 2023), and Scopus (https://www.scopus.com/,accessed on 30 September 2023).In order to manage all the bibliographic references, Mendeley Desktop software version 1.19.8 was used.Three reviewers extracted data independently, avoiding the duplication of data, and they searched for and selected all key words individually.The process of datamining is synthetized in the flowchart in Figure 1.When a scientific paper could not be found online, we asked the authors to send it to us.For the final step of the study, articles in English and Spanish were selected, together with data from patents.Congress abstracts and symposiums were excluded because they were considered not sufficiently complete to warrant an exhaustive comparison with full articles.

Composition and Biological Activities of Essential Oils from Genus Lepechinia
Sesquiterpenes, diterpenes, triterpenes, and flavonoids have been isolated from different species of this genus.Some species are used for their anti-tumoral and insulin-mimetic properties, to treat uterine infections, or to calm stomach pains [32].Regarding the volatile essential oil components, 18 species of the genus Lepechinia have been studied so

Ethnopharmacology and Traditional Uses for the Genus Lepechinia
Several Lepechinia spp.are valued in the horticultural trade, and North and South American indigenous groups commonly use Lepechinia plants for medicinal purposes, such as the treatment of muscle pain, headache, and toothache [45], diabetes mellitus, uterine tumors, uterine infections, and diarrhea [5,31].L. caulescens is the most mentioned species concerning folk medicine, and its traditional use has been reported in cases of stomach ailments, hypertension, diabetes, dysmenorrhea, and gastrointestinal infections.The aqueous infusion, obtained via decoction from the whole plant, is the most common traditional beverage [6,10,39,55,56].An extract from L. caulescens has been patented as a cosmetic agent [64,65].Also, the teas of L. graveolens and L. hastata (root extract) have been mentioned in the treatment of stomach ailments [20] and uterine infections, respectively [65,66].The decoction of the leaves of L. meyenii is used as an antispasmodic, digestive, and carminative agent and for the treatment of coughs and diarrhea [66,67].Regarding L. schiediana, two studies have cited the use of it in tea in folk medicine as a diuretic, as a remedy for kidney infections and stomach illness, and for the treatment of skin irritation [43,68].The leaves of L. mutica are used to treat headaches, nervous affections, and startle disease [45,46,69].The leaves of L. radula are used to treat "mal de aire" and aches in muscles and bones [50,69].Regarding L. paniculata, it is used to treat headaches via the direct application of its buds to the head; its flowers are used for the treatment of nervous system affection and for evil air "mal aire' and "espanto" [48,49].In Table 2, there are more details about the ethnopharmacology and traditional uses of some Lepechinia spp.Different morphological structures and preparations are used for gastrointestinal ailments, diarrhea, and hypoglycemia [36]; for vomiting, diabetes, hypertension, and related diseases [71][72][73]; for dysmenorrhea and as an abortifacient [10]; and for stomach ailments [6] L. chamaedryoides Known as "Alhuelahuén" or "Male sage" Emmenagogue and anti-inflammatory properties as an infusion [38] L. floribunda Local name: "Salvia morada" [42] Antiseptic properties [74] L. graveolens White sage As an infusion for the treatment of stomach ailments [23] L. hastata Locally known as "Chicura de la Sierra", "Lavanda", and "Lengua de buey" Uterine infections as a root decoction [73] L. meyeni "Pampa salvia", "Saluya" [41] Treatment of coughs and diarrhea, antispasmodic [66]; digestive and carminative [67] Table 2. Cont.

Scientific Name Common Name Ethnopharmacology and Traditional Uses
L. mutica "Shalshon" in Kichwa or "Casa casa" in Spanish "Espanto" (startle) [72] L. paniculata "Yayllon" or "Llanllum" in Kichwa "Mal de aire", a sort of evil eye, and against headache; flower infusions are used to treat nervous diseases [72] L. radula "Shalshon" or "Zhalshon" in Kichwa The leaves are used to treat "mal de aire" and aches in muscles and bones [72] L. schiedeana "Salvia negra" Skin irritations, muscle fatigue, and as a diuretic [53]; decoction used as a remedy for stomachache and kidney infections [71] 3.4.Geography and Aim of the Studies Using these criteria [9], we were able to collect 48 papers, for which 52 different studies had been carried out on 20 species of the Lepechinia genus (Table 3) in relation to essential oils, phytochemistry, and different biological activities, such as: insecticiderepellent activity, anticholinesterase activity, spasmolytic effects, vasorelaxant activity, anti-vibrio cholerae activity, gastroprotective effects, cytotoxicity activity, antibacterial activity, antifungal activity, and antioxidant activity, among other.Most species of the genus Lepechinia have been investigated for their antioxidant activity (see Table 3 and Figure 10).On the one hand, the predominance of antioxidant activity can be explained by the relatively easiness of these assays and the fact that practically all vegetal species contain important amounts of polyphenolic compounds, typically characterized by this property.On the other hand, almost 10% of all the reported activities corresponded to the cholinergic capacity of essential oils or purified metabolites.Most of these studies were conducted in Ecuador.

Geography and Aim of the Studies
Using these criteria [9], we were able to collect 48 papers, for which 52 different studies had been carried out on 20 species of the Lepechinia genus (Table 3) in relation to essential oils, phytochemistry, and different biological activities, such as: insecticide-repellent activity, anticholinesterase activity, spasmolytic effects, vasorelaxant activity, anti-vibrio cholerae activity, gastroprotective effects, cytotoxicity activity, antibacterial activity, antifungal activity, and antioxidant activity, among other.Most species of the genus Lepechinia have been investigated for their antioxidant activity (see Table 3 and Figure 10).On the one hand, the predominance of antioxidant activity can be explained by the relatively easiness of these assays and the fact that practically all vegetal species contain important amounts of polyphenolic compounds, typically characterized by this property.On the other hand, almost 10% of all the reported activities corresponded to the cholinergic capacity of essential oils or purified metabolites.Most of these studies were conducted in Ecuador.The studies have been distributed mainly in Ecuador (13), Mexico (9), Colombia (7), and Bolivia (5), with several in Argentina (4), Peru (4), Chile (3), Venezuela (3), the United States (2), Costa Rica, and the Dominican Republic (1); see Figure 11.About one quarter of the total phytochemical studies on the genus Lepechinia were carried out in Ecuador, where an important number of endemic and native species have attracted relevant academic interest over the last ten years.This interest coincides with a period of development in the scientific research on all fields of biodiversity in Ecuador.

Figure 1 .
Figure 1.Flowchart for the search process and selection of the studies considered for the review.Figure 1. Flowchart for the search process and selection of the studies considered for the review.

Figure 1 .
Figure 1.Flowchart for the search process and selection of the studies considered for the review.Figure 1. Flowchart for the search process and selection of the studies considered for the review.

Figure 9 .
Figure 9. Compounds identified in the essential oils of Lepechinia spp.Figure 9. Compounds identified in the essential oils of Lepechinia spp.

Figure 9 .
Figure 9. Compounds identified in the essential oils of Lepechinia spp.Figure 9. Compounds identified in the essential oils of Lepechinia spp.

Figure 10 .
Figure 10.Diversity of biological activity in Lepechinia spp.The percentages refer to the corresponding articles compared to the total number of biological activity reports.The studies have been distributed mainly in Ecuador(13), Mexico (9), Colombia(7), and Bolivia (5), with several in Argentina (4), Peru (4), Chile (3), Venezuela (3), the United States (2), Costa Rica, and the Dominican Republic (1); see Figure11.About one quarter of the total phytochemical studies on the genus Lepechinia were carried out in Ecuador, where an important number of endemic and native species have attracted relevant academic interest over the last ten years.This interest coincides with a period of development in the scientific research on all fields of biodiversity in Ecuador.

Figure 10 .
Figure 10.Diversity of biological activity in Lepechinia spp.The percentages refer to the corresponding articles compared to the total number of biological activity reports.

Table 1 .
Main compounds and biological activities in essential oils from Lepechinia spp.

Table 2 .
Ethnopharmacology and traditional uses of Lepechinia spp.