Xylosma G. Forst. Genus: Medicinal and Veterinary Use, Phytochemical Composition, and Biological Activity

Xylosma G. Forst. is a genus of plants belonging to the Salicaceae family with intertropical distribution in America, Asia, and Oceania. Of the 100 accepted species, 22 are under some level of conservation risk. In this review, around 13 species of the genus used as medicinal plants were found, mainly in Central and South America, with a variety of uses, among which antimicrobial is the most common. There is published research in chemistry and pharmacological activity on around 15 of the genus species, centering in their antibacterial and fungicidal activity. Additionally, a variety of active phytochemicals have been isolated, the most representative of which are atraric acid, xylosmine and its derivatives, and velutinic acid. There is still ample field for the validation and evaluation of the activity of Xylosma extracts, particularly in species not yet studied, and concerning uses other than antimicrobial and for the identification and evaluation of their active compounds.


Introduction
The use of medicinal plants is not exclusive to humans, but is also reported in superior apes and other animal species [1,2]; it is therefore not surprising that humans have used medicinal plants since the earliest antiquity [3][4][5]. Until recently, the approach was purely empirical [6], but today, this knowledge is being validated and refined by modern research methodology that accelerates the generation of knowledge and its applications [7]. Today, natural products are an important source of new drugs and treatments, either directly or through chemical modifications [8].
In this article we performed a systematic review of the phytochemical composition, pharmacological, medical, and veterinary applications on the species in the genus, gathering the existing information in scientific literature about the ethnomedical knowledge, the active molecules identified and isolated from them, and the research studies that validate their potential efficacy. The objective of the study is to identify gaps in the knowledge about the genus and find study lines that may guide future research.

Genus
The Salicaceae Mirb. family, to which the Xylosma genus belongs, is famously medicinal because of the Salix genus (willow), the pharmacological properties of which were already used in ancient Mesopotamia, and were extolled in the first century CE, in Dioscorides' De Materia Medica [8,9].
The Xylosma genus is one of the 55 that conform the Salicaceae family [9], and is composed of 100 accepted species [10], although others list 45 [11]. Until recently, it was included in the now-deprecated Flacourtiaceae family, but has now been assigned to Salicaceae [12]. The name stems from the Greek words for "wood" and "smell" in reference to odoriferous quality of the wood of some Pacific species of the genus [11], Species in the Xylosma genus have several uses and properties, from landscaping (Xylosma congesta (Lour.) Merr.), beekeeping (Xylosma venosa N. E. Br. [16]), timber, firewood, to food and medicine; notably Xylosma longifolia Clos. Due to the thorns that some species of the genus have, common names such as "do not touch me" (Xylosma coriacea (Poit.) Eichler) or "deer antlers" (Xylosma spiculifera (Tul.) Triana and Planch.) are used for them [17]. Eleven species of the genus, particularly Xylosma vincentii Guillaumin, are known to be nickel hyperaccumulators [18,19] which presents potential for phytoremediation and phytomining [20].

Distribution and Localization
Species belonging to the Xylosma genus are present in subtropical America, Southeast Asia, and Oceania. Of the 100 species listed in the genus [10], 61 are found in America, 8 in Asia, and 31 in Oceania. Figure 1 shows examples of species of the genus. The map in Figure 2 shows the intertropical, and to a lesser extent, temperate, distribution of Xylosma species, by country. odoriferous quality of the wood of some Pacific species of the genus [11], presumably X. orbiculata and X. suaveolens used to perfume coconut oil by early South Pacific inhabitants [13]. At first, the genus was named Myroxylon (myrrh-wood) but was changed to Xylosma to avoid confusion with South American balsam trees [14]. Not all species in the genus are sweet-smelling: X. maidenii timber, for example, is foul-smelling. Xylosma species are described in detail by Woodson et al. [15].

Distribution and Localization
Species belonging to the Xylosma genus are present in subtropical America, Southeast Asia, and Oceania. Of the 100 species listed in the genus [10], 61 are found in America, 8 in Asia, and 31 in Oceania. Figure 1 shows examples of species of the genus. The map in Figure 2 shows the intertropical, and to a lesser extent, temperate, distribution of Xylosma species, by country.   Of the 100 species of the genus, 7 are listed as vulnerable, 9 as endangered, and 6 as critically endangered. In total, 22% of the species in the genus are considered as species of concern [21]. This should be considered when evaluating potential industrial uses for these species.

Methodology
Published works-articles and patents-were searched in Dimensions [22] for bibliometric data, and in scientific databases-Science Direct, Google Scholar, and Scopusboth using a browser interface and through Harzing's "Publish or Perish" software [23] for each species of the genus, using inverted commas for an exact match, e.g., "Xylosma benthamii". Relevant articles were selected after removing search terms unrelated to the area of interest, such as reforestation or drought resistance. When abundant results were obtained, the search was refined with more specific terms, for example "Xylosma longifolia medicinal" or "Xylosma longifolia ethnopharmacology". Duplicate articles were removed, and the remaining articles were reviewed with focus in ethnopharmacological uses, phytochemical composition, and biological activity. When possible, the latest articles-no older than 10 years-have been cited. Preprints were not included. Due to the scarcity of sources, gray documentation such as books and thesis dissertations were included when they provided information not available in other sources.
The research interest in Xylosma species in medical and health sciences has increased slowly during the last fifty years. Figure 3 shows the number of publications that include the word Xylosma in the document text in the fields mentioned. Even though the genus shows low research interest, a steady increase in appearances can be seen, with the last decade garnering much of the publication volume. Of the 100 species of the genus, 7 are listed as vulnerable, 9 as endangered, and 6 as critically endangered. In total, 22% of the species in the genus are considered as species of concern [21]. This should be considered when evaluating potential industrial uses for these species.

Methodology
Published works-articles and patents-were searched in Dimensions [22] for bibliometric data, and in scientific databases-Science Direct, Google Scholar, and Scopus-both using a browser interface and through Harzing's "Publish or Perish" software [23] for each species of the genus, using inverted commas for an exact match, e.g., "Xylosma benthamii". Relevant articles were selected after removing search terms unrelated to the area of interest, such as reforestation or drought resistance. When abundant results were obtained, the search was refined with more specific terms, for example "Xylosma longifolia medicinal" or "Xylosma longifolia ethnopharmacology". Duplicate articles were removed, and the remaining articles were reviewed with focus in ethnopharmacological uses, phytochemical composition, and biological activity. When possible, the latest articles-no older than 10 years-have been cited. Preprints were not included. Due to the scarcity of sources, gray documentation such as books and thesis dissertations were included when they provided information not available in other sources.
The research interest in Xylosma species in medical and health sciences has increased slowly during the last fifty years. Figure 3 shows the number of publications that include the word Xylosma in the document text in the fields mentioned. Even though the genus shows low research interest, a steady increase in appearances can be seen, with the last decade garnering much of the publication volume.
Genus Xylosma shares several secondary metabolite compounds and structures with Flacourtia. Both were recently reassigned into the Salicaceae family from Flacourtiaceae. Indeed, they share genetical characters between them and with other genera from Salicaceae, such as Scolopia, Dovyalis, and Oncoba [24]. Genus Xylosma shares several secondary metabolite compounds and structures with Flacourtia. Both were recently reassigned into the Salicaceae family from Flacourtiaceae. Indeed, they share genetical characters between them and with other genera from Salicaceae, such as Scolopia, Dovyalis, and Oncoba [24].

Ethnopharmacological and Ethnoveterinary Usage
Of the 100 species of the genus, few appear in the scientific literature, and even fewer are mentioned from an ethnopharmacological or ethnoveterinary perspective. Notwithstanding, Xylosma species are a part of the traditional Chinese medicinal system, with documented uses of X. congesta appearing as early as the XVI century CE [25].
Few of the Xylosma species are recognized as medicinal. Table 1 summarizes the species with reported medicinal use along with their stated ethnopharmacological uses, when available. The Anatomical Therapeutic Chemical (ATC) Classification by the World Health Organization (WHO) is used to classify the uses for each species [26]. Not all species are identified in the literature, with general mentions as "Xylosma sp." in some cases.

Ethnopharmacological and Ethnoveterinary Usage
Of the 100 species of the genus, few appear in the scientific literature, and even fewer are mentioned from an ethnopharmacological or ethnoveterinary perspective. Notwithstanding, Xylosma species are a part of the traditional Chinese medicinal system, with documented uses of X. congesta appearing as early as the XVI century CE [25].
Few of the Xylosma species are recognized as medicinal. Table 1 summarizes the species with reported medicinal use along with their stated ethnopharmacological uses, when available. The Anatomical Therapeutic Chemical (ATC) Classification by the World Health Organization (WHO) is used to classify the uses for each species [26]. Not all species are identified in the literature, with general mentions as "Xylosma sp." in some cases. Most Xylosma species in use are from Central and South America (38% and 31%), followed by China (23%) and India (8%). This is roughly in accordance with the local abundance of species. There are no reports of ethnomedicinal uses of Xylosma in Oceania. Uses by country are shown in Figure 4.
According to the ATC classification, the most frequent uses of Xylosma spp. in ethnopharmacology are dermatological, nervous system, and respiratory system, with 17% of the uses each, alimentary tract and metabolism with 11%, and genitourinary system and sex hormones with 6%. Additionally, 11% of the uses are veterinary.
As to the morphological structures used, the most common are leaves and barks with 33% each, and both stems and roots with 11% each. Plants 2022, 11, x FOR PEER REVIEW 6 of 17 According to the ATC classification, the most frequent uses of Xylosma spp. in ethnopharmacology are dermatological, nervous system, and respiratory system, with 17% of the uses each, alimentary tract and metabolism with 11%, and genitourinary system and sex hormones with 6%. Additionally, 11% of the uses are veterinary.
As to the morphological structures used, the most common are leaves and barks with 33% each, and both stems and roots with 11% each.

Biological Activity
Biological activity tests of Xylosma have been carried out mostly in vitro, with no reported in vivo research, with plant extracts, be they leaf, root, bark, or the whole plant. Different solvents and solvent mixtures have been used for the extracts, mainly methanol and ethanol.

In Vitro Activity
In vitro research on biological activity of Xylosma species centers around 7 identified species and one unspecified one. The research figures are summarized in Figure 5, and the research is detailed in Table 2.

Biological Activity
Biological activity tests of Xylosma have been carried out mostly in vitro, with no reported in vivo research, with plant extracts, be they leaf, root, bark, or the whole plant. Different solvents and solvent mixtures have been used for the extracts, mainly methanol and ethanol.

In Vitro Activity
In vitro research on biological activity of Xylosma species centers around 7 identified species and one unspecified one. The research figures are summarized in Figure 5, and the research is detailed in Table 2. According to the ATC classification, the most frequent uses of Xylosma spp. in ethnopharmacology are dermatological, nervous system, and respiratory system, with 17% of the uses each, alimentary tract and metabolism with 11%, and genitourinary system and sex hormones with 6%. Additionally, 11% of the uses are veterinary.
As to the morphological structures used, the most common are leaves and barks with 33% each, and both stems and roots with 11% each.

Biological Activity
Biological activity tests of Xylosma have been carried out mostly in vitro, with no reported in vivo research, with plant extracts, be they leaf, root, bark, or the whole plant. Different solvents and solvent mixtures have been used for the extracts, mainly methanol and ethanol.

In Vitro Activity
In vitro research on biological activity of Xylosma species centers around 7 identified species and one unspecified one. The research figures are summarized in Figure 5, and the research is detailed in Table 2.  In vitro biological activity tests devote the most attention to leaves (55%), with bark (33%) and root (11%) used to a lesser extent. Extraction solvents are ethanol (42%), methanol (21%), and to a lesser extent petroleum ether, chloroform, dichloromethane, and hexane, with 8% each. The solvent choices support the assumption that most active compounds are polar, and are thus extracted with polar solvents.
Even though there is no in vivo research concerning Xylosma species in the literature, there are several patents that include Xylosma extracts for cosmetic, veterinary, and traditional medicinal uses, such as hangover cures [33].

Phytochemical Composition
Phytochemical studies allow for the identification, separation, and isolation of compounds of interest [57]. Based on phytochemical screenings and other results published in the literature, the most common metabolites are alkaloids, terpenoids, and phenolics, among which flavonoids and the distinctive, often glycosylated, dihydroxyphenyl alcohol derivatives (xylosmin, xylosmacin etc.) abound [58,59]. These are also abundant in Flacourtia (Salicaceae) spp extracts, and several flacourtins have been isolated [60], which have shown antimalarial [61] and antiviral [62] activity.
Some compounds found in plants belonging to the Xylosma genus, classified ing to their chemical structure, are listed in Table 3. Where applicable, the biolog tivity of the identified compound has been mentioned. After the isolation and identification of 1, several related compounds from Xylosma and Flacourtia genera, among others, have been isolated, some of which have been found to present antiplasmodial and antiviral activity [61,64]. Xylosmin also exhibits phosphodiesterase inhibitory activity [65] which could explain the use of a non-specified Xylosma sp. against spider bites [48].
Some compounds found in plants belonging to the Xylosma genus, classified according to their chemical structure, are listed in Table 3. Where applicable, the biological activity of the identified compound has been mentioned.  Compounds have been isolated almost exclusively using chromatographic techniques, and have been identified through spectroscopical and spectrometric methods and by comparison with existing samples and published data [57]. Figures 7 and 8 show the structure of some of the compounds identified in Xylosma spp. extracts. As expected in plant extracts, there is a variety of secondary metabolites in the form of terpenoids and flavonoids. There is a series of less usual phenolic compounds in the shape of dihydroxybenzyl alcohols and their glycosylated derivatives, esters, and ethers.
A strength of the genus is the potential for research it still holds: not many of its species have been systematically analyzed and interesting bioactivity can be found in previously unresearched species, as is the case with X. prockia [52]. A weakness is the conservation threat several of its species are under, particularly those from Oceania. Compounds have been isolated almost exclusively using chromatographic techniques, and have been identified through spectroscopical and spectrometric methods and by comparison with existing samples and published data [57]. Figures 7 and 8 show the structure of some of the compounds identified in Xylosma spp. extracts. As expected in plant extracts, there is a variety of secondary metabolites in the form of terpenoids and flavonoids. There is a series of less usual phenolic compounds in the shape of dihydroxybenzyl alcohols and their glycosylated derivatives, esters, and ethers. A strength of the genus is the potential for research it still holds: not many of its species have been systematically analyzed and interesting bioactivity can be found in previously unresearched species, as is the case with X. prockia [52]. A weakness is the conservation threat several of its species are under, particularly those from Oceania.

Conclusions
Species belonging to the Xylosma genus have several uses as food, medicine, wood, bird and pollinator attractors, etc. Among the medical uses, the ongoing research centers around the antibacterial, antifungal, anti-melanogenic, and antioxidant activity of Xylosma extracts, and other ethnopharmacological uses appear to have received less attention. This is seen as an opportunity for further study.
Several bioactive compounds have been isolated from Xylosma species, some of which have pharmacological potential, such as atraric acid, used in cancer treatments.
There are several species of the genus-more than 80%-that have not been systematically studied, especially in America. This presents a research opportunity.

Conclusions
Species belonging to the Xylosma genus have several uses as food, medicine, wood, bird and pollinator attractors, etc. Among the medical uses, the ongoing research centers around the antibacterial, antifungal, anti-melanogenic, and antioxidant activity of Xylosma extracts, and other ethnopharmacological uses appear to have received less attention. This is seen as an opportunity for further study.
Several bioactive compounds have been isolated from Xylosma species, some of which have pharmacological potential, such as atraric acid, used in cancer treatments.
There are several species of the genus-more than 80%-that have not been systematically studied, especially in America. This presents a research opportunity.