Emerging source of bioactive compounds from Arecaceae family: a systematic review

The use of plants for medicinal purposes is performed empirically by traditional knowledge with the use of preparations that seek to extract their active principles, and are considered to be fundamental to human health. In this context, the aim of the present study was to of this study was to carry out a systematic review of the biological activities of the Arecaceae family distributed throughout Brazil. This research was carried out through a comprehensive search using the following databases, Scopus, Portal Periódicos Capes, PubMed, Google Scholar and Science Direct, using the following descriptors: “Arecaceae” and “Biological properties of the family Arecaeae”, checked at <www.theplantlist.org/> to check synonyms. It was possible to identify numerous biological activities in the arecaceae family, among the most recurring ones, the antioxidant, antimicrobial and anti-inflammatory activity. These activities are justified by the presence of fatty acids, phenolic compounds, alkaloids and terpenes. Studies routinely report lauric acid as a major in the plants of this family, which makes it a potential compound to cure or assist in the treatment of various diseases.


Introduction
The use of medicinal plants as an alternative to treat several diseases is an old habit in different cultures, which remains until nowadays, especially in developing countries (Mattos, Camargo, Sousa, & Zeni, 2018;Padilha et al., 2017).
Some reasons for the use of medicinal plants are due to its low cost, easy access and the belief that natural products are safer when compared to synthetic drugs (Silva & Santana, 2018;Filho, 2010). Thus, several research on medicinal plants are focused on discovering bioactive molecules with benefits to human health and low toxicity (Al-Okbi, 2014;Lee, Lee, Tsai, & Su, 2012), demanding studies to identify plant compounds and related biological activities (Lana, Martins Necchi, Casoti, & Manfron, 2012). For this reason, the phytochemistry study of plants with medicinal properties represents an essential step to define their composition and provides evidence of potential biological activities and mechanism of action (León-mejía et al., 2011;Vinod, Tiwari, & Meshram, 2011). Natural chemical compounds have been used to treat health problems and historically their derivates are extremely important as nutraceuticals, supplements and therapeutic agents (Lescano & Kassuya, 2014). However, besides the therapeutic purpose, in some cases, the plant chemical compounds may present toxic effects, such as the terpenoids, alkaloids, tannins and glycosides (Pereira & Cardoso, 2012).
Additionally, the use of medicinal plants may present better therapeutic results when compared to synthetic substances. Thus, the preliminary phytochemical analysis is a very important step for the for the beginning of the phytochemical study of the plant to be studied, and may show several classes of bioactive compounds, among them: flavonoids, reducing sugars, alkaloids, tannins, lignins, saponins, steroids (Joy et al., 2019). Therefore, plants present bioactive compounds that can be toxic, mutagenic, carcinogenic and teratogenic, especially when they are consumed without restriction, so, it is important to evaluate the toxicity with biological activities (López-Romero et al., 2018).
Brazil has the greatest biodiversity worldwide, being a source of natural molecules with high biological potential (Khan et al., 2018). Thus, studies that demonstrate the potential of medicinal plants found in Brazilian biomes are essential for maintaining the conservation of species, as well as providing scientific evidence regarding the invaluable source of new bioactive molecules for diverse purposes, including for the treatment of several diseases, many of them still without effective treatment (Brasil, 2011).
Most of those pharmacological properties are reported in ethnobotanical studies and have been proved in scientific research.
In this context, the present study aimed to carry out a systematic review of the biological activities from the Arecaceae family with occurrence in Brazilian territory.

Methodology
The search for articles was performed between the months of September and December of 2020, using the species names, verified in <www.theplantlist.org/> in case of synonyms. The searched databases were Scopus, Portal Periódicos CAPES, PubMed, Google Scholar and Science Direct, using the descriptors: "Arecaceae" and "Biological properties of the family Arecaceae".
This research was carried out through a search between the months of September to December 2020, with the names of the species verified on the site <www.theplantlist.org/> to check synonyms. A comprehensive search for articles was carried out using Scopus, Portal Periódicos Capes, PubMed, Google Scholar and Science Direct, using the following descriptors: "Arecaceae" e "biological properties of the family Arecaceae". Studies published between 2010 and 2020 were included.
Complete articles containing the descriptors included in the abstract or keywords were selected. Duplicate articles in the search platforms, review articles, articles of genetic and taxonomic scope and studies on plant metabolism were excluded. The other articles were then selected based on the title, abstract and keywords. Finally, the complete articles were analyzed according to the following criteria (1): phytochemistry; 2): ethnobotanical uses; (3): bioactivities; (4): bioactivities of compounds isolated in the Arecaceae family; (5): types of products used.

Extracts
Among the articles, 30 of them investigated extracts from 19 different genus and their biological activities, as shown in Table 1. The most used vegetal parts were the fruits (72%). As for essential oil, the leaves were the most used part (66%), followed by the fruits (33%) and fixed oil; the fruits were used in all research. Orbignya phalerata, Immune responses Aqueous extract (Guerra et al., 2011a) Raphia hookeri Antimicrobial and modulation Methanol extract (Nguenang et al., 2018).

Antioxidant activity
The endogenous antioxidant system is essential to maintain integrity and body homeostasis, since several reactive oxygen species (ROS) are constantly generated in cells as products of cellular metabolism. Although these ROS have benefic functions on the organism, at high concentrations they induce toxic effects and are associated with several diseases ( Arecaceae species have demonstrated antioxidant potential. The extract obtained from Hyphaene thebaica fruits present antioxidant activity in DPPH reduction assay (Aboshora et al., 2014). As for Hyophorbe indica leaf extract, which presents compounds known as antioxidants, like gallic acid, catechin and citric acid, also present an antioxidant effect, being able to reduce the DPPH radical, and achieving the IC50 of 35.35 ±0,18 µg/mL (Aboshora et al., 2014). The extract from Bactris setosa, with a higher content of flavonoids, presents antioxidant activity, in FRAP and β-carotene oxidation assays . Mauritia flexuosa showed antioxidant activity being able to reduce the ABTS radical and chelate 80.9% of Fe+2 in vitro, available at 700 µg/mL (Nonato et al., 2018). Other Arecaceae species that also showed antioxidant activity in vitro models are Euterpe Oleracia (Minighin et al., 2019), Hyophorbe indica (William et al., 2018), Cocos nucifera (Kadja et al., 2020;Thebo et al., 2016), and Ravena rivularis (Elgindi et al., 2015) Kassem (Kassem & Afifi, 2014) studied the lipophilic fraction obtained from Livistona australis fruit (LALF), which presented oleic acid as major content (59.05%), palmitic acid (20.59%), phytol-diterpene (7.98%) and linoleic acid (0.79%).
Oleic acid (OA) is the main component among the fatty acid contents of LALF. Oleic acid, linoleic acid and phytol inhibited hyperlipidemia probably through the oxidation reaction. The LALF content can play a role with strong antioxidant activity in inhibiting lipid peroxidation and protecting against oxidative degradation of biologically active substances. In silico studies, with oleic acid, indicates that it acts as a competitive inhibitor with nitric oxide on the active site of nitric oxide synthase (Kassem & Afifi, 2014). The unsaturated fatty acids play important roles in the immunological system and inflammatory process (Menéndez et al., 2006;Weatherill et al., 2005).

Anti-inflammatory and protective activities
Inflammation can be defined as an organism natural response to several types of stimuli, which in turn culminates into tissue damage. During this process, many molecular mechanisms are activated which induces histologic and vascular alterations in the affected area (Ashley, Weil, & Nelson, 2012). Despite that, the inflammation may induce deleterious effects when it persists on the organism and the inflammatory response is too strong. Several Arecaceae species demonstrate anti-inflammatory effect.
Phoenix loureiroi extract was able to reduce intestinal inflammation, in mice, due to oral administration at a concentration of 5 mg/kg, corroborating with the popular use of the fruit to treat intestinal pain (Murugan et al., 2018). Elhakim et al. (2017) verified the anti-inflammatory potential of Caryota mitis, its extract was able to attenuate the inflammatory response in mice paw edema induced by carrageenan at a concentration of 400 mg/kg. Besides that, the research also highlighted the absence of toxicity, presenting an average lethal dose (LD50) higher than 5000 mg/kg. As for Ravenea rivularis, which extract, presented antioxidant activity, also present anti-inflammatory activity. Is worth to noting that the inflammation process is related to oxidative stress, therefore, it may be possible that the molecules found in the extract present both effects, antioxidant and anti-inflammatory, promoting an efficient attenuation on inflammation process and the diseased related to it (Elgindi et al., 2015).
As for the oils and fatty acids, some authors state that it can reduce the levels of cytokines, like the IL-1 α, TNF-α, IL-6 e IL-1 β, which will result in an anti-inflammatory response (Blok et al., 1996;W. James et al., 2018). Oleic acid, palmitic acid and palmitoleic acid are identified as the main components that play important physiological roles in the human body, due to their chemical structure, these compounds have become the focus of interest for pharmaceutical and food companies (Blok et al., 1996;James et al., 2018) and as seen in the table 2, the oils obtained from Areceae species are usually rich in those compounds.
According to Favacho et al. (2011), the oil obtained from Euterpe oleracea fruits showed anti-inflammatory activity in vivo in paw edema and ear erythema induced by croton oil. The average effective dose was 1226.8 mg/kg, and the results showed that E. oleracea oil presents an anti-inflammatory effect by inhibiting prostaglandins biosynthesis. The microencapsulated oil from Acrocomia aculeata fruits also presented anti-inflammatory in paw edema, and pleural edema models, both induced by carrageenan (Lescano & Kassuya, 2014), both species have oleic acid as major compound.
The relation between oleic acid and the therapeutic potential for the treatment of inflammatory diseases is that it can induce tissue repair, as discussed by Grimm et al. (2002), its occurs due to changes in metalloproteinases balance, which are key molecules for the process of tissue healing. As for Calder (2002), the omega-3 unsaturated fatty acid can affect the expression of pro-inflammatory cytokine genes, altering cell membrane's characteristics, cell signaling, cell mobility, the interaction of receptors, membrane and the formation of secondary signs (Grimm et al., 2002).
The balance of the dietary lipids is intended to control the inflammatory response when exacerbated by the intake of unsaturated fatty acids. Studies express those fatty acids participate in the modulation of calcium signaling (Soldati et al., 2002), protein kinase C (May & Calder, 1993), activation of phospholipase C , production of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). In addition, they are the primary precursors of lipid mediators during the inflammatory process, such as arachidonic acid and prostaglandins (Soldati et al., 2002). With that in mind, there is several pathways that fatty acids can act to attenuate the inflammatory process.
As for the protective effect, it is related with the capacity of a molecule or product prevent damages into a certain cells or tissue before it starts an inflammation process. Some Arecaceae species showerd protective effect in different system, like the hepatoprotective effect described for Phoenix dactylifera (Okwuosa et al., 2014), which in turn presented an LD50 higher than 6000 mg/kg. The same species also presented a protective effect in bovine testicles (Jahromi et al., 2017). Investigating Cocos nucifera extract, intending to revert toxic effects induced by cisplatin in mice, Adaramoye and Ola-davies (2015) obtained positive results by administrating 200 mg/kg daily on mice diet, they also noticed a decrease in lipid peroxidation and intensification of antioxidant enzymes activity. And finally, the extract obtained from Orbignya phalerata presented a protective effect by modulating the inflammatory response, and the fruit extract from this species associated or not with aluminum particles increased interferons and interleukins concentration (Guerra, Silva, Aragão-frança, Oliveira, & Feitosa, 2011b).

Antimicrobial activity
In the last 10 years, at least 10 Arecaceae species were studied as potential antimicrobial activity. The ethanolic extract from H. thebaica fruits showed strong antibacterial activity against Staphylococcus aureus and Salmonella typhi, in the disk diffusion method, it is worth noting that the extract showed positive results against two types of bacteria cells, a Grampositive and Gram-negative respectively, still, the control drugs, gentamicin, and ampicillin, showed higher zone of inhibition when compared to the extract (Aboshora et al., 2014).
A similar methodology was employed to test the extract from C. nucifera leaves, rich in tannin, lignin, and flavonoids, it was able to inhibit Escherichia coli growth, with an inhibition halo of 5 mm, 50% less compared to the drug control, ciprofloxacin (a 1 µg) (Joy et al., 2019). Tayler et al. (2019) evaluated the antiparasitic effect from C. nucifera Against several parasites, like Leishmania donovani, Trypanosoma cruzi, and Plasmodium falciparum, which showed positive results. Aranaga et al. (2020), evaluated the antimicrobial potential from several plant extracts, between then: Onecapaus bataua and Euterpe precatoria, which were able to inhibit the PKnB kinase enzyme, essential to Mycobacterium tuberculosis. The IC50 from the first species was of 60.9 µg/mL, while the second one showed 77.4 µg/mL, both being able to inhibit the enzymatic activity, however, it was not able to inhibit bacteria growth. The extract capacity of inhibiting the enzymatic activity brings new perspectives to the search of bacteria metabolism modulation mediated by plant extracts, turning them more susceptible, or not, to antibiotics drugs.
An example of modulatory effect was observed in Raphia hookeri extract, which was able to decrease the antibiotic concentration until 50% when combined with chloramphenicol, kanamycin, streptomycin, erythromycin, and tetracycline.
Also, according to the author, this effect was due to the metabolites present in R. hookeri, which could inhibit the efflux bomb present in bacteria, which is a factor that grants bacteria the resistance effect (Nguenang et al., 2018). M. flexuosa showed a similar effect, inducing susceptibility to conventional antibiotics in Gram-positive, Gram-negative and Candida species (Nonato et al., 2018).
Another species, rich in phenolic compounds and flavonoids, is Attalea speciosa, which was able to inhibit the growth of S. aureus resistant to methicillin strains, Enterococcus faecalis and Pseudomonas aerugionosa in vitro, as also an excellent antiseptic in vivo model, being able to modulate the immunologic system, into a less intensive response (Barroqueiro et al., 2016).
An alterntive approach approach is the use of natural products to decrease the virulence for bacteria strains, like inhibiting the biofilm expression. The oil from Syagrus coronata, rich in octanoic, dodecanoic, decanoic and γ-eudesmol was able, not only to inhibit and kill bacteria strains resistant to antibiotics, as act over bacterias strains capable of forming a biofilm, with MIC between 156 and 625 μg/mL, and MBC of 312 to 1250 μg/mL (B. S. Santos et al., 2019). The oil from Chamaerops humilis leaves, whose authors emphasized that the fact of the leaves present more oil than the fruits, due to the anatomic structures have several storage glands, present antibacterial action against S. aureus, E. coli, and P.
The bioproducts development has also been applied to the Arecaceae family, and it has proved to be efficient, as related by Karamian and Kamalnejad (Karamian & Kamalnejad, 2019). The authors synthesized nanoparticles of silver with the extract from Cuminum cyminum, with strong antibacterial activity. Although other studies with bioproducts made from M.
flexuosa and A. aculeata didn't show any promising effect against S. aureus, E. faecalis, E. coli and P. aeruginosa, C.

Cytotoxicity and anticancer
The use of medicinal plants has been growing progressively, mainly since they have biological activity and are used as a source of new molecules and effects obtained by the synthetic drugs currently commercialized, and may even confer a more potent effect, with a potential for less physiological damage. In addition, the cost of herbal medicines is generally reduced, increasing access to this resource, ensuring quality treatment, with chances of cure and better quality of life (Kharchoufa, Merrouni, Yamani, & Elachouri, 2018;Prasansuklab, Brimson and Tencomnao, 2020).
Even with a lower potential for intoxication, some plant species may present a risk of toxicity, mainly because they produce neurotoxins, cytotoxins and metabolic poisons that will disturb the structural and functional integrity of internal organs, such as the liver, heart, kidneys, gastrointestinal system and lungs. In addition, the dose is also important, as some substances can show positive activity for some illnesses in minimal concentrations, but if there is an increase in the dose, that previously therapeutic compound becomes toxic to the organism and can cause tissue or cellular injuries, especially whether carcinogenesis, hormonal dysregulation and the interruption of reproductive and developmental processes (Kristanc & Kreft, 2016;Nembo, Hescheler, & Nguemo, 2020;Shabbir, Shahzad, & Gobe, 2014).
Euterpe oleraceae, the Brazilian açai, is rich in fatty acids, like vanillic acid, palmitic acid, linolenic acid, linoleic acid and oleic acid. This species well-known for its popular fruit, which is famous in the whole country, but specially the North region.
The chromatographic analysis identified a range of fatty acids in the fruit, such as vanillic acid, palmitic acid, γlinolenic acid, linoleic acid and oleic acid. Toxicity was assessed in rats at doses of 30 mg/Kg, 100 mg/Kg or 300 mg/Kg.
Only at a concentration of 300 mg/Kg the animals showed signs of intoxication, such as diarrhea and hair bristles. In addition to acute toxicity, genotoxicity was performed by comet and micronucleus assays from leukocyte samples from peripheral blood, liver, bone marrow and testicular cells taken from animals that were subjected to the acute test (Marques et al., 2016).
In the comet assay, genetic material was used to measure DNA damage, such as single and double-strand breaks, alkaline sites, DNA-DNA and DNA-protein cross-links. Thus, it was verified that there was no damage, indicating that the oil did not present genotoxicity. According to the micronucleus assay, clastogenicity (chromosome breakdown) and aneugenicity (chromosomal delay due to dysfunction of the mitotic apparatus) were measured, as well as it was possible to estimate the proportion of polychromatic erythrocytes concerning normochromatic erythrocytes, suggesting any disturbances in hematopoiesis. Thus, the study reported a non-genotoxic effect on bone marrow cells, with an average micronucleus of 2.16 to 2.5 at concentrations of 30 mg/kg and 100 mg/kg, while the control reported a presence of an average of 8.5 micronucleated cells. With that, it is possible to affirm that E. oleracea oil does not present genotoxicity, however, from the concentration of 300 mg/kg, it is possible to observe an imbalance in homeostasis (Marques et al., 2016).
Studies with Attalea phalerata Mart. ex Spreng., well known as "bacuri" in vivo and in vitro models, were carried out to evaluate toxicity using the Artemia salina and MTT assay models, in addition to the comet and micronucleus assays.
The results showed that bacuri oil did not induce cell death in the Artemia salina and MTT experiments and did not present cytotoxicity. The oil also did not cause significant damage to the DNA of the rats in the four doses used when compared to the negative control group, in addition to not showing a significant increase in micronucleated polychromatic erythrocytes (MNPCEs) for the four doses tested. Thus, the study suggested that this species widely used by popular medicine does not cause cytotoxicity, genotoxicity and clastogenicity, and its main component was β-carotene (Lima et al., 2016).
Chi (Chi et al., 2020) isolated 4 saponins from Raphia vinifera, being toxic in average concentrations of 3.55 to 7.14 µM in cell lines sensitive to drugs CCRF-CEM, whereas in cell lines resistant to drugs, CEM/ADR5000 concentration mean ranged from 9.19 to 12.29 µM, showing an anticancer potential, since the cell lines tested are leukemic cells. The saponins present in this species induced a cytotoxic effect in a drug-resistant phenotype, showing a potential alternative in the treatment of cancer unresponsive to conventional drugs. Tayler (Tayler et al., 2019), when evaluating the action of Cocos nucifera, verified the potential for anticancer activity in MCF-7 breast cancer cell line, all in vivo tests, obtaining promising results.
Arboviruses comprise a group of viral diseases transmitted by arthropods (mosquitoes) and have been plaguing the world, causing epidemic crises mainly in developing countries (Mayer, Tesh, & Vasilakis, 2016 where standing water facilitates its dissemination, therefore, poor regions with few resources for sanitation and water treatment are the places with the highest incidence of the mosquito and consequently the diseases associated with it (Luz, Mesquita, Amaral, & Coutinho, 2020;Omondi et al., 2019). Phoenix dactylifera L. is a species widely cultivated in the Arabian Peninsula and especially in Saudi Arabia. The extraction of the essential oil from the spathe (a region that protects the flowers) by hydrodistillation obtained the majority of 3,4-dimethoxytoluene (73.47%), 2,4-dimethoxytoluene (9.47%) and β-karyophylene (5, 47%). In the repellency test, both essential oil and the two major oils (3,4-dimethoxytoluene and 2,4dimethoxytoluene) were used. According to the results, the essential oil, 3,4-dimethoxytoluene and 2,4-dimethoxytoluene presented a minimum effective dose of 0.051, 0.063 and 0.063 mg / cm2, respectively. These results can illustrate a repellent effect, because when we compare these data with that obtained by the standard DEET repellent (N, N -diethyl-3methylbenzamide) with a minimum effective dose of 0.018 mg/cm 2 , a statistically relevant result. With this, it is possible to verify that the mixture between the oil components is more potent than isolated products, this is due to the synergy between oil compounds, the same does not occur when using the isolated molecule (Demirci, Tsikolia, Barbier, Agramonte, & AlqasoumiL, 2013).
According to Santos (L. M. M. Santos et al., 2017), a study was carried out using oil of Syagrus coronata, for larvicidal and ovicidal activity. S. coronata is a typical Caatinga species, popularly known as "ouricuri" or "licuri".
According to gas chromatography (GC) analysis, the oil showed prominence for octanoic acid (40.55%) and dodecanoic acid (40.48%). In the larvicidal test, the larvae were reduced by half after 48 hours in the concentrations of 21.07, 19.72 and 51.78 ppm for the samples of oil, dodecanoic acid and octanoic acid, respectively. According to the oviposition, the oil affected the oviposition of the females more intensely, reducing the number of eggs by 35% compared to the control, while the octanoic acid reduced by 31%. The results indicated that the larvicidal activity is due to the action of dodecanoic acid, while the effect of oviposition is probably related to the presence of octanoic acid. Finally, the Phoenix theophrasti extract has larvicidal activity, at a concentration of 1000 ppm against larvae of the Culex pipiens insect (Tayler et al., 2019).

Hypoglycemic activity
William (William et al., 2018) demonstrated the hypoglycemic potential of the Hyophorbe indica extract, through the in vivo assay of α-glucosidase inhibition with IC50 36.52 ± 0.08 µg / mL. Raphia gentiliana, on the other hand, was able to decrease the concentration of glucose in the blood by 27 and 56% after one and two hours, respectively, after ingesting the fruit extract at a concentration of 0.2 g/Kg. In this same study, it was reported that the extract changed the glycemic index by -3.1% and the glycemic load by -1.36% in humans (Mpiana et al., 2013).

Final Considerations
The development of the present study showed that the Arecaceae family has a composition rich in fatty acids, phenolic compounds, alkaloids and terpenes, with the main compound of the family lauric acid, a compound already used as a therapeutic alternative to help various diseases. Among the most recurrent biological activities, we can report the antioxidant, antimicrobial and anti-inflammatory activity.
Thus, it is possible to consider that the abundance and the processing capacity of the plants of the Arecaceae family in Brazil bring us the need for more in-depth studies, which allows us to investigate other important activities for future therapeutic innovations. In addition, by adding in-depth scientific research, it will bring the possibility of developing a local production chain, valuing and generating income in the traditional communities that popularize its use. It is also important to note that the development of research on bioactive molecules of Brazilian biodiversity not only brings therapeutic innovations, but also promotes the emergence and development of traditional communities, valuing customs, culture and the history of subexistence.
The relevance and importance of this work lies in the review of the medicinal potential of the Arecaceae family, and this data collection could serve as a basis for collaboration in future studies and projects for the development of new therapeutic applications for phytotherapics, cosmetics and food.