Schinopsis brasiliensis Engler—Phytochemical Properties, Biological Activities, and Ethnomedicinal Use: A Scoping Review

Brazil has the most incredible biodiversity globally and has a vast storehouse of molecules to be discovered. However, there are no pharmacological and phytochemical studies on most native plants. Parts of Schinopsis brasiliensis Engler, a tree from the Anacardiaceae family, are used by several traditional communities to treat injuries and health problems. The objective of this scoping review was to summarize the pharmacological information about S. brasiliensis, from ethnobotanical to phytochemical and biological studies. Data collection concerning the geographical distribution of S. brasiliensis specimens was achieved through the Reflora Virtual Herbarium. The study’s protocol was drafted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). The search strategy used the keyword “Schinopsis brasiliensis” in the databases: PUBMED, EMBASE, SCOPUS, Science Direct, Web of Science, SciFinder, and SciELO. Rayyan was used for the selection of eligible studies. In total, 35 studies were included in the paper. The most recurrent therapeutic indications were for general pain, flu and inflammation. The bark was the most studied part of the plant. The most used preparation method was decoction and infusion, followed by syrup. Phytochemical investigations indicate the presence of tannins, flavonoids, phenols, and polyphenols. Most of the substances were found in the plant’s leaf and bark. Important biological activities were reported, such as antimicrobial, antioxidant, and anti-inflammatory. S. brasiliensis is used mainly by communities in the semi-arid region of northeastern Brazil to treat several diseases. Pharmacological and phytochemical studies together provide scientific support for the popular knowledge of the medicinal use of S. brasiliensis. In vitro and in vivo analyses reported antimicrobial, antioxidant, anti-inflammatory, antinociceptive, cytotoxic, photoprotective, preservative, molluscicidal, larvicidal, and pupicidal effects. It is essential to highlight the need for future studies that elucidate the mechanisms of action of these phytocompounds.


Introduction
Medicinal plants have been used in many cultures for thousands of years, and information on the use of natural resources plays a vital role in discovering new products from plants as therapeutic agents [1]. Brazil is the country with the most extensive biodiversity globally, being a potential storehouse of molecules still not discovered, envisioning their use as a source of therapeutic resources. However, there are still no pharmacological and phytochemical studies on most native plants [2].
Although some research reports the chemical composition and pharmacological activities of S. brasiliensis extracts, no review has been published to critically summarize these studies and suggest the use of the plant as a source of molecules of interest for future applications. Thus, the objective of this scoping review was to synthesize pharmacological information about S. brasiliensis, from ethnobotanical to phytochemical and biological studies.

Geographical Distribution of S. brasiliensis
The collection of data concerning the geographical distribution of identified S. brasiliensis specimens was achieved through the Reflora Virtual Herbarium (Reflora Program-CNPq-https://reflora.jbrj.gov.br/reflora/herbarioVirtual, accessed on 28 May 2021). The previous authorization was conceded, and latitude and longitude data of each collected specimen were retrieved. Then, we plotted a map using RStudio 1.4 (through 'geobr' and 'ggspatial' packages) with the retrieved geographical data.

Protocol and Registration
The study's protocol was drafted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) [34]. The final protocol was registered with the Open Science Framework on 4 June 2021 (https://doi.org/ 10.17605/osf.io/drjns, accessed on 4 June 2021).

Eligibility Criteria
Studies were included if: (i) published until 25 May 2021; (ii) a peer-reviewed publication; (iii) written in English, Portuguese, or Spanish; (iv) that had described the use of Schinopsis brasiliensis. Non-original articles were excluded, such as monographs, dissertations, theses, bibliographic reviews, letters, comments, editorials, or book chapters and studies that did not describe an antimicrobial, ethnobotanical, or a phytochemical approach to S. brasiliensis.

Search Strategy and Information Sources
The search strategy used the keyword "Schinopsis brasiliensis" in the following bibliographic databases: PUBMED, EMBASE, SCOPUS, Science Direct, Web of Science, SciFinder, and SciELO. The final search results of each database were exported and downloaded in CIW or RIS format. The files were imported into the online platform of Rayyan QCRI (RRID:SCR_017584-PMID: 27919275-https://www.rayyan.ai, accessed on 4 June 2021), and duplicates were removed.

Selection of Sources of Evidence
Rayyan was used to select eligible studies [35]. Based on the eligibility criteria, two reviewers (MKGD and WMSB) independently evaluated the same titles, abstracts, and full text of all publications identified by the searches. The disagreements on study selection and data extraction were resolved by consensus and discussion with a third reviewer (PHSS), when needed. The intra-and interobserver Kappa coefficients were performed using 70% of previously identified studies. The selection of sources was carried out until 25 May 2021. However, a new search was performed on 5 July 2022, to update the selected studies.

Data Items and Synthesis of Results
The data of selected studies according to the study approach (ethnobotanical, antimicrobial, phytochemical) were extracted and summarized as shown in the Tables. Study localization, plant part, extraction product, the method for extraction, compound class, identified compound, biological activity, and therapeutic indication were collected for each study.

Geographical Distribution of S. brasiliensis
Based on the Reflora Virtual Herbarium data, we observed that the Caatinga Biome (northeastern Brazil) contained the majority of identified Schinopsis brasiliensis Engl specimens ( Figure 2). Five specimens were identified in other regions, one in northeastern Pará and four in northeastern Goiás. There is a large concentration of specimens identified between 7 • S/15 • S and 36 • W/43 • W.
Based on the Reflora Virtual Herbarium data, we observed that the Caatinga Biome (northeastern Brazil) contained the majority of identified Schinopsis brasiliensis Engl specimens ( Figure 2). Five specimens were identified in other regions, one in northeastern Pará and four in northeastern Goiás. There is a large concentration of specimens identified between 7° S/15° S and 36° W/43° W.

Summary of the Articles
A total of 388 titles were retrieved using the search strategy. After the removal of duplicates, 100 unique studies were independently evaluated by reviewers using eligibility criteria ( Figure 3). The intra-observer Kappa coefficient was 0.96 (C.I. 0.76-1.00) and the inter-observer was 0.92 (C.I. 0.62-1.00). After full reading and updating references, 36 published studies were included in this scoping review.

Summary of the Articles
A total of 388 titles were retrieved using the search strategy. After the removal of duplicates, 100 unique studies were independently evaluated by reviewers using eligibility criteria ( Figure 3). The intra-observer Kappa coefficient was 0.96 (C.I. 0.76-1.00) and the inter-observer was 0.92 (C.I. 0.62-1.00). After full reading and updating references, 36 published studies were included in this scoping review.

Ethnobotanical Studies
Ethnobotanical studies have shown different ways to use S. brasiliensis by local communities, besides its uses for treating various symptoms (Table 1).

Ethnobotanical Studies
Ethnobotanical studies have shown different ways to use S. brasiliensis by local communities, besides its uses for treating various symptoms (Table 1).   All ethnobotanical studies presented are Brazilian (n = 11,100%), from the Northeast region ( Figure 4). General pain (tooth, ear, throat, stomach, liver, back, nerves, and menstrual cramps) was the most recurrent therapeutic indication (n = 8; 72.72%), followed by influenza (n = 6; 54.54%), and inflammation (n = 3; 27.27%). The barks were the most studied part of the plant (n = 7, 63.63%). The most used preparation method was the tea-decoction or infusion (n = 7, 63.63%). Thus, we observed the way that S. brasiliensis is used as a medicinal drug and the preparation mode. All ethnobotanical studies presented are Brazilian (n = 11,100%), from the Northeast region ( Figure 4). General pain (tooth, ear, throat, stomach, liver, back, nerves, and menstrual cramps) was the most recurrent therapeutic indication (n = 8; 72.72%), followed by influenza (n = 6; 54.54%), and inflammation (n = 3; 27.27%). The barks were the most studied part of the plant (n = 7, 63.63%). The most used preparation method was the tea-decoction or infusion (n = 7, 63.63%). Thus, we observed the way that S. brasiliensis is used as a medicinal drug and the preparation mode.

Antimicrobial Activity
Fourteen studies presented results on the antibacterial activity of S. brasiliensis extracts against 17 bacteria, eight Gram-negative and nine Gram-positive. Table 4 summarizes the studies that reported the antibacterial activity of S. brasiliensis extracts. Notably, the leaf extract of S. brasiliensis showed antifungal activity against C. albicans, C. tropicalis, and C. krusei [6,22]. In addition, Formiga-Filho et al. [26] noted that the association of S. brasiliensis bark extract with low-power laser increases its activity against E. coli, S. aureus, P. aeruginosa, and E. faecalis.   [19] In these studies, the bark was the most used plant structure (n = 7; 50%), followed by the leaves (n = 6; 44.8%). The ethanolic extract was used in 44.8% of the studies (n = 6). The most cited bacterium in the studies was Staphylococcus spp. (n = 9; 63.5%). The range of Minimum Inhibitory Concentration (MIC) varied as to concentrations, being 1 µL/µL for E. faecalis [1], 0.23 µg/mL for Escherichia coli [43], 0.004 µL/µL for P. aeruginosa [1] and 10 µg/mL for K. pneumoniae [43].
Besides the antimicrobial activity of the extracts, two studies evaluated the antibacterial effect of controlled release systems containing S. brasiliensis. The production of chitosan microparticles-loaded S. brasiliensis bark extract would be an alternative for the use of the extract in dentistry due to the improved organoleptic properties [23]. The MIC values of these microparticles were lower than that observed for the hydroalcoholic extract (0.25 mg/mL and 0.50 mg/mL, respectively). Furthermore, the microparticles inhibited biofilm development and growth of E. faecalis in 24 h. Through cytotoxicity analyses performed by Sette-de-Souza et al. [23], it was proven that microparticles are safe for use in the treatment of Enterococci infections and in dentistry due to their potential to inhibit biofilm development.
Oliveira et al. [43] showed that S. brasiliensis nanoparticles associated with ceftriaxone showed inhibitory activity against E. coli, including against ceftriaxone-resistant strains. These results express the capacity and importance of the use of controlled-release systems in the delivery of atypical pharmaceutical ingredients, demonstrating to be an excellent possibility for the treatment of infections caused by multidrug-resistant bacteria.
Molluscicidal and larvicidal activities were observed in the study with S. brasiliensis bark. Through the method using Biomphalaria glabrata, it was possible to observe that the chloroform fraction of the ethanolic extract resulted in an LC 90 of 68 µg/mL, and an ethyl acetate fraction of 73 µg/mL [46]. The larvicidal activity was also observed against Aedes aegypti larvae using the method recommended by the World Health Organization (WHO) for the ethyl acetate (LC 50 : 345 µg/mL), hexane (LC 50 : 527 µg/mL), and chloroform (LC 50 : 583 µg/mL) fractions [46]; while the ethanolic extract of the seeds was able to eliminate A. aegypti larvae (field-collected larvae-LC 50 : 580.9 µg/mL; insecticide-susceptible larvae-LC 50 : 661.6 µg/mL) [45]. The pupicidal potential of the ethanolic extract of the seeds was also evaluated, being described as an excellent activity, both for pupae collected in the field of A. aegypti (LC 50 : 32.9 µg/mL), and for those susceptible to insecticide (LC 50 : 40.6 µg/mL) [45]. In another study, Barbosa et al. [47] studied the larvicidal activity of the crude extract of S. brasiliensis seeds, using the Konishi et al. (2008) adapted and WHO (2005) adapted methods. The authors observed 100% death against L1 and L4 Aedes aegypti larvae, obtained in 24 h, LC 50 of 6.01 mg/mL and 6.14 mg/mL and in 48 h LC 50 of 5 mg/mL and 1 mg/mL, respectively.
The nociceptive activity was verified by formalin-induced licking behavior and/or through paw edema [18,19]. The hydroethanolic extract of S. brasiliensis bark and its ethyl acetate fraction reduced the licking time of mice by 40% when applied 30 mg/kg [18].
The anti-hemolytic activity was observed in three studies. The ethanolic extracts of the bark (n = 2; 66.66%) obtained the following results: 43.83% [27] inhibition of erythrocyte hemolysis, while the other one showed the IC50 (maximum concentration to obtain 50% inhibition) 50.27 mg/mL [24] as a result. The hydroalcoholic extract of the barks (n = 1; 33.33%) resulted in IC 50 92.66 mg/mL [23].

Discussion
This review reports on the geographical distribution, ethnopharmacological use, biological activities, toxicology, and pharmacology of Schinopsis brasiliensis. This plant treats some health problems, mainly in the Caatinga population. The results of the ethnobotanical surveys show variability in the use of parts of the plant to treat several diseases. The difference in indications of use can be explained by the diversity of bioactive molecules found in S. brasiliensis, considering that the environmental conditions, such as temperature, soil, and humidity, directly impact the chemical composition of the plants.
This work observed that most specimens of S. brasiliensis identified in Brazil were from the Caatinga Biome. However, the species is reported to be found in the Chaco (Bolivia and Paraguay) and the Brazilian Cerrado, up to near latitude 20 • S. Despite this finding, there is no specific information regarding the population density of S. brasiliensis in this region [3].
This location of S. brasiliensis may explain the concentration of studies in the Caatinga Biome, a large natural region, being the only exclusively Brazilian biome [49]. It has only two most expressive climates: the rainy period and the dry period [38]. These environmental stress factors can directly interfere with producing the plant's secondary metabolites [50], resulting in several applications.
The great diversity of phytocompounds present in S. brasiliensis may be related to the indications of popular use. The phytochemical characterization of S. brasiliensis reveals numerous bioactive molecules belonging to several metabolic classes with reported biological activities. Secondary metabolites act by retarding and/or inhibiting the action of free radicals. The observed antioxidant capacity is probably due to the high content of compounds, such as flavonoids, tannins, and phenolic acids. These compounds could donate electrons, thus stabilizing free electrons, in addition to inactivating superoxide anions and peroxide radicals [51].
Because analgesic and anti-inflammatory drugs have significant adverse effects, new prototype drugs are of great interest to the scientific community. Terpenes are secondary metabolites, best known for their action on the Central Nervous System (sedative, tranquilizing, anticonvulsant, anxiolytic, and nociceptive effects). These pharmacological activities are similar to opioids [60][61][62]. In addition, terpenes are good antimicrobial agents through their ability to permeabilize and depolarize the cytoplasmic membranes of microorganisms. S. brasiliensis is rich in terpenes, such as myrcene, α-pinene and linalool. Therefore, one can associate the activity of terpenes with the use for sore throat [9], earache [36], toothache [36], pain in the nerves and spine [17], pain in the stomach and liver [37], reported in ethnobotanical surveys. In addition, terpenes can be attributed to nociceptive activity in rats [18,19].
The replacement of synthetic insecticides has become a necessity, mainly related to pest resistance to these products. Besides this issue, to control populations of disease vectors such as mosquitoes, for example, larvicidal and pupicidal activities are necessary. Another critical situation is that some mollusks can be part of the biological cycle of helminths-hence the need to control these animals.
The importance of the species and its use for therapeutic purposes is observed since these phytochemical compounds presented have different biological activities.

Conclusions and Perspectives
We noticed that S. brasiliensis is used mainly by communities in the Northeast of Brazil, especially in the Caatinga, to treat various diseases. The traditional use of S. brasiliensis varies according to the part and the community studied. However, the difference in these reports can be attributed to the richness of bioactive compounds present in the plant.
On the other hand, the pharmacodynamic and pharmacokinetic properties of S. brasiliensis extracts have not been determined. Thus, future investigations are necessary to determine these parameters to understand the bioavailability of the phytocompounds from S. brasiliensis. Finally, it is essential to highlight the need for future studies to explore and elucidate the mechanisms of action of these phytocompounds.

Data Availability Statement:
The data presented in this study are available in article.