on the therapeutic activities of the genus Trichilia

The genus Trichilia (Meliaceae family) has been attracting interest among Brazilian Flora, due to the biological activities of its secondary metabolites. This genus has species distributed throughout tropical America, recognized for its significant economic importance and high commercial value. Its composition consists mainly of terpenoids (triterpenes, sesquiterpenes, limonoids and steroids) and polyphenols (flavonoids and tannins). In folk medicine this genus is used in preparations such as antimicrobial, antimalarial, antiviral and antioxidant. Studies carried out with several species of the genus Trichilia show that these plants have antioxidant, anticholinesterase, antimicrobial activities against pathogens of great clinical importance, neuroprotective, anti-anaphylactic and anti-inflammatory. In addition, analgesic, antineoplasic, hepatoprotective and immunomodulatory activities have also been investigated and proven in the literature. Based on the great biotechnological potential of the genus Trichilia, from the few studies on its applications in human health and in view of the importance of searching for natural substances that have effective therapeutic activities, this review highlights the main therapeutic applications of species of this genus found in the literature, and stimulate further studies on the use of these plants in the treatment of various diseases. For this, a survey on the topic was carried out in the main sources of scientific research in the period from 2005 to 2020, leading us to conclude that this genus can be a potent ally in the search for new phytotherapic drugs.


Introduction
Plants are considered raw materials for the development of new drugs, being an unlimited source of potentially active substances and many of them are used to help promote the treatment of numerous diseases that affect humans and other animals, as well as in the control of plant pests. Phytotherapy and the use of medicinal plants are ancient practices, constituting a set of knowledge from different users and practitioners, especially through oral or epicutaneous use. Approximately 60% of the world's population uses almost entirely plants for medication and herbal medicines have been recognized as an important source of therapeutically effective medicines (Hayouni et al., 2011;Schenkel, 1995). Medicinal plants are an important component of health care for the majority of the world's population: they constitute the main medical care for 70 to 95% of citizens in most developing countries and are increasingly used by a large number of people residing in wealthier countries (Eldin & Dunford, 2001;Applequist et al., 2020).
Despite the widespread use of medicinal plants for therapeutic purposes, the possible existence of toxic effects is little known. Also, many of these plants have few studies validating their therapeutic action. Although popular knowledge has significantly contributed to the understanding of the effects of medicinal plants, the active principles, mechanism of action and toxicity of many of them are still poorly understood, thus justifying further study to scientifically validate the effectiveness of its constituents. Medicinal plants are important both for being suppliers of raw materials for drug synthesis, as well as for being used as therapeutic agents (Estevão et al., 2013;David, Wolfender & Dias, 2014).
Plants of the Meliaceae family are chemically characterized by the presence of tetranortriterpenoids known as limonoids or meliacins (Silva, Gottlieb & Dreyer, 1984). Of all plant families, Meliaceae is among the most useful for man, mainly for its high-quality woods and the ease with which some species can be grown in plantations (Pennington & Styles, 1975). Besides, the Meliaceae family attracts great interest among phytochemicals interested in bioproducts due to its very complex chemical structures and biological activity.
The genus Trichilia was described by Browne in 1756, comprising 70 species distributed in Tropical America, Africa and the Indo-Malay region, of which approximately 53 species occur in Brazil. This genus has aroused interest among the Brazilian flora, due to the biological activities of secondary metabolites present in these plants (Pennington, Styles & Taylor, 1981).
The main characters that define the genus Trichilia are related to the floral structure and the fruits. Flowers with stamens partially or completely fused carrying the anthers at the apex of the filaments or on the edge of the stem tube. The fruit Research, Society andDevelopment, v. 10, n. 5, e29610514916. 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i5.14916 3 is a loculicidal capsule, 2-3 (-4) valves, smooth to warty, sepals persistent or not in the fruits and locules 1-2 seeds (Pennington, 2016). This genus has the largest number of species in the Meliaceae family (Pennington, Styles & Taylor, 1981).
Phytochemical studies have revealed that it is rich in terpenoids (triterpenes, limonoids and steroids) and polyphenols (flavonoids and tannins) (Ramírez et al., 2000;Terra et al., 2009). Therefore, based on the great biotechnological potential of the genus Trichilia, because of the scarce studies on its applications in health and on the importance of the search for natural substances that have effective therapeutic activities, this review is necessary, to stimulate investments in studies that seek in these plants a path for the production of new phytotherapeutic formulations for the pharmaceutical market.

Methodology
A survey was carried out on the theme between the years 2005 and 2020, in this period the largest number and the most relevant publications on the theme were found. The main sources of scientific research were consulted, using the DeCS (Health Science Descriptors): Meliaceae family; genus Trichilia, treatment, disease, antimicrobial, antifungal, antibacterial and antineoplasic, as well as its synonyms and correspondents in portuguese: família Meliaceae, gênero Trichilia, tratamento, doenças, antimicrobiano, antifúngico, antibacteriano and antineoplásico. The main sources of research used were: PubMed, Scielo, Thieme, EBSCO Host, Journals Capes and Flora do Brasil-JBRJ (Board1).
The analysis was divided into three stages. The first stage consisted of reading the title of the articles, where only those with related terms such as genus Trichilia were selected. Then, the second step was taken, in which the Summary or Abstract of the articles included in the first phase was read, among which those that mentioned some type of effective treatment for diseases using plants of the genus Trichilia were chosen. Finally, in the third and last stage, the full text of the articles selected in the second stage was evaluated, to elect articles that discussed the use and importance of species of the genus Trichilia used in the treatment of diseases and in combating pathogens that cause diseases in humans. Articles that mentioned only the empirical use of plants were excluded, in addition to studies carried out before 2005. It should also be noted that articles repeated in the databases and articles with incomplete research information were eliminated. We finished the work with 42 articles. Of these, we used 30 articles in our results, as they evaluated the therapeutic activities of the genus. The rest were used in our introduction and/or discussion.

Results and Discussion
The genus Trichilia has a variety of species with proven therapeutic activities for the treatment of numerous diseases, being used to combat various pathogens that cause damage to human health. In this review, 11 species studied were found regarding their therapeutic activity. Figure 1 shows the species of the genus Trichilia and the number of articles found for each one.  As for the preparation used in the tests, 16 articles were found using extracts, eight (09) articles used only the purified form (fractions) and, finally, four (05) articles tested both extracts and fractions, always highlighting the effectiveness of each one of them about the studied disease or pathogen. Articles published from 2005 to 2020 in Brazil and the world, standing out as a species of the genus Trichilia that were studied, the part of the plant used, as well as the form used, the therapeutic application found, and the constituents that may be responsible for this activity. Source: Authors.
In the phytochemical analysis, many of the Trichilia species revealed the presence of several compounds such as flavonoids, cinchonines, catechins, epicatechins and procyanidins linked to the antioxidant, anti-inflammatory, anti-amnesic and antiproliferative action. The presence of limonoids, protolimonoids and triterpenes linked to the antimicrobial and cytotoxic action against tumor cells was also observed, in addition to the presence of tannins linked to the antimicrobial action.
These findings prove the uses of these species in traditional medicine. In Board 2 we report the popular name of the species of the genus Trichilia found in this review of the popular name and its traditional use.
Board 2. Popular name and use in the traditional medicine of Trichilia species mentioned in this review.
cedrinho -Popular name and use in the traditional medicine of the species of the genus Trichilia. (-) not found. Source: Authors.
The main therapeutic actions found for each species were reported below:

Trichilia catigua A. Juss
This species was the most studied regarding its therapeutic action. Perhaps this fact can be justified by its wide distribution, which can be found in several countries in South America . It is worth mentioning that most studies involving this species were carried out in Brazil, which can be justified by being a species native to the Brazilian Flora. Gomes et al. (2017), evaluated the antidiabetic activity of the Trichlia catigua ethyl acetate fraction in type I diabetic rats and reported that this fraction improved biochemical parameters, such as hyperglycemia, alkaline phosphatase, alanine and aspartate aminotransferase. An improvement in glucose homeostasis and pancreatic morphology was observed, in addition to the inhibition in the development of diabetic nephropathy in diabetic rats, resulting in a reduction in renal tissue damage by reducing fibrosis. Do Nascimento et al. (2019) also evaluated the effects of the ethyl acetate fraction of this plant in type I diabetic rats, but investigated the neuroprotective role of this fraction, in the total population of enteric neurons in the jejunum of these rats. As a result, it was observed that Trichlia catigua A. Juss provided partial protection against diabetic neuropathy in the enteric nervous system. These works, together, showed that the fraction of Trichlia catigua A. Juss is an option that can be used in therapeutic formulations to improve many problems resulting from diabetes.
We found studies evaluating the antioxidant action of Trichilia catigua, using different tests and different models such Research, Society and Development, v. 10, n. 5, e29610514916. 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i5.14916 Trichilia catigua was also analyzed for possible antidepressant effects in rodents, as well as the possible mechanisms involved in their actions. Oral treatment with Trichilia catigua extract (200ug / kg and 400ug/kg) produced effects of the antidepressant type in the forced swimming model, decreasing the immobility time of mice and rats. It was found that this action would be linked to the action of the extract in modulating the dopaminergic pathway (Campos et al., 2005). The study by Taciany Bonassoli et al. (2012) also demonstrated the antidepressant effect of acute administration of the ethyl acetate fraction of Trichilia catigua in mice, using the same forced swim test and included the forced suspension test. It was observed that the subchronic administration of Trichilia catigua (400ug/kg) promoted effects of the antidepressant type in mice, observed by the decrease in the immobility time in the tests. Neural proliferation was also observed within 24 hours after fraction administration, which did not influence neuron survival at 7 and 15 days after treatment. New therapeutic options are necessary with antidepressant action, due to the lack of effect of current medications in some patients and due to the large number of side effects exhibited by these (Campos et al., 2005). Trichilia catigua as an antidepressant and may be a promising alternative for herbal formulations in this regard.
The study by Espada et al. (2015)  Evaluating antinociceptive activity, Viana et al. (2011) carried out a study with the hydroalcoholic extract in behavioral models of mice nociception, where they observed that this extract has antinociceptive effects. According to the authors, this effect is mainly associated with the activation of the dopaminergic system and, to a lesser extent, with the interaction with the opioid pathway.
The work involving Trichilia catigua showed that this plant is a promising candidate for new herbal formulations, with antimicrobial, antidepressant, neuroactive, analgesic and antioxidant action. Trichilia catigua showed interaction with the dopaminergic pathway, being also an inhibitor of the monoamine oxidase pathway and the acetylcholinesterase pathway. It is important to note that its extracts and fractions did not prove to be toxic until high concentrations.

Trichilia hirta L.
Trichilia hirta L. was the second most studied species, mainly to prove its popular antineoplastic and immunostimulatory use. Sosa et al. (2010), evaluated the immunorestorative and cytotoxic activity of aqueous extracts of Trichilia hirta L. root. The administration of this extract increased the global and differential leukocyte count in immunosuppressed mice, the weight of the thymus, as well as the cellularity of the bone marrow. The aqueous extract showed selective cytotoxicity against T-47D and SK-mel-3 tumor cells compared to the non-tumor strain (VERO). The results indicate that Trichilia hirta L. has a significant in vivo immunorestorative effect and selective cytotoxicity, and may be a promising alternative to cancer therapy (Sosa et al., 2010). In another study by Sosa et al. (2011), with the ethanolic extract obtained from the roots of Trichlia hirta L., they evaluated the leukocyte stimulating effect of these extracts in BALB/C mice. The application of 976 ug/kg of the extract increased the leukocyte count by 15 to 33%. Also, a dose of 82ug/kg significantly increased the total number of leukocytes with 4 days of study (P <0.05). The results indicated that Trichlia hirta L. exhibits leukocyte-stimulating activity and makes it a promising alternative for the development of an immunoprotective agent (Sosa et al., 2011).
Studies by Hernandez et al. (2013)  These studies point to strong evidence and provide a basis for the popular use of this plant, but more research is needed on its neoplastic potential. The presence of saponins, tannins, flavonoids, carbohydrates and coumarins was observed in these extracts. Flavonoids are already known to have an immunomodulatory action. The studies cited here to pave the way for researchers interested in studies on new therapies to fight cancer.

Trichilia emetica Vahl.
We find three articles about this species. One of these studies assesses the antibacterial and hepatoprotective action of the aqueous extract and of the ethyl ether fractions of the Trichilia emetica Vahl root, the hepatoprotective effect was significant (P <0.05) at the dose of 1000µg/ml, both on the plasma membrane and mitochondrial function. Extract and fraction showed no toxicity even at very high concentrations (LC50> 1000 µg/mL). The fraction showed better activity against Streptococcus pneumoniae and Moraxella catarrhalis (CIM 7.80 and 125.00 µg / mL), Staphylococcus aureus and Streptococcus pyogenes (CIM 15.60 and 62.50 µg / mL) and Haemophilus influenzae (CIM 125 µg/mL). The extract was only effective against the strains tested in concentrations above (CIM 500µg/mL) (Germano et al., 2005). In the same year, another study also evaluated the antimicrobial activity of the methanolic extract of the fruit of this plant, where inhibition of the growth of five strains of fungi of great medical importance (Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Tricophyton mentagrophytes and Tricophyton violacium) at concentrations of 400, 500 and 1000 µg/mL, but against bacteria, no significant efficacy was observed (Geyid et al., 2005).
Corroborating these studies, the work of Konaté, Yomalan, Sytar and Brestic (2015) showed that the fraction of ethyl acetate Trichilia emetica Vahl. has antibacterial activity against strains of Gram-negative and Gram-positive bacteria (Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Shigella boydii, Shigella flexneri and Shigella dysenteriae) CIM 156-1250ug/mL. In well diffusion tests, an inhibition zone (14-24mm) was found for all tested strains. Strains of bacteria were more sensitive to this fraction than ciprofloxacin. This fraction also had positive effects against diarrhea (300ug/mL) induced by castor oil in mice. This result provided a scientific basis for the popular use of this plant for the treatment of gastroenteritis.
Infectious diseases are the leading cause of death in the world. The clinical effectiveness of many existing antibiotics is being threatened by the emergence of multidrug-resistant pathogens. Plant extracts are readily available for this area, due to their ability to produce compounds that confer an antimicrobial defense (Eldeen, Elgorashi & Van Staden, 2005). The fractions of this plant have shown promise for future studies as antifungal and antibacterial, including in the fight against pathogens of great clinical importance. It is important to highlight that a protective action of hepatocytes against damage induced by CCL4 was observed. The studies cited here highlighted polyphenols and tannins as the possible responsible for the antimicrobial action of this plant and in no experiment was it toxic until high concentrations.

Trichilia dregeana Sond.
With this species, we found two studies. The first of 2005, evaluating the action of three extracts of Trichilia dregeana Sond. (ethanolic, aqueous and ethyl acetate) for antibacterial, anti-inflammatory (COX-1 and COX-2), mutagenic and anticholinesterase activities. The ethyl acetate leaf extract demonstrated selective inhibition of COX-2 (81%) confirming its anti-inflammatory action. It was also observed that the ethyl acetate extract of the bark inhibited (55%) the acetylcholinesterase pathway, confirming its anticholinesterase action. None of the extracts showed mutagenic activity and as for antibacterial activity, the ethanolic extract of the leaves against Escherichia coli (CIM 3.1ug/mL) stood out (Eldeen, Elgorashi & Van Staden, 2005).
Subsequently, a study investigated the in vitro antimicrobial activity of this plant. It was observed that the aqueous and acetone extract showed activity against the pathogen Ureaplasma urealyticuma (CIM 0.25ug/mL). Besides, the combination of the aqueous extract of Trichilia dregeana Sond. with that of Albizia adianthifolia it showed excellent activity against Oligella ureolytica (MIC 0.75ug / mL) with high cell viability (IC50 98 ug / mL) for kidney epithelial cells (Naidoo, van Vuuren, van Zyl & de Wet, 2013). None of the studies investigated the possible responsible for the mentioned activities, showing the need for further research in this regard.

Trichilia heudelotii Planc (Harm).
Only one study was found with this species where the antifungal and cytotoxic activities of the extracts (aqueous, acetone and ethanolic) of the bark, leaves and stems of Trichilia heudelotii Planc (Harm) were evaluated. As a result, it was observed that at the concentration of 50ug / mL, the most significant inhibition zone was the acetone extract from the leaves against Candida albicans (17.00 mm), followed by the acetone and ethanolic extracts from the stem bark against Trichophyton rubrum and Candida albicans (16.00 mm). The ethanolic extracts of the leaves showed the lowest activity for Trichophyton rubrum (6.00 mm). The minimum inhibitory concentration of all extracts against the pathogens tested varied between (CIM 2.5 and 200 µg / mL). The cytotoxic activity of the extracts, assessed by the brine shrimp lethality bioassay method, revealed significant cytotoxic effects (LC50 9.01 to 256.17 ug/mL) (Opawale, Oyetayo & Agbaje, 2015). Despite the promising activity of this plant against some human pathogenic fungi, high levels of toxicity of the extracts have been observed, future tests can be done to better investigate these actions. It is worth mentioning that tests were not carried out to show the selectivity index.

Trichilia prieureana A. Juss.
With Trichilia prieureana A. Juss. only one study was found using the ethanol extract of the bark to evaluate its popular use as an antimicrobial. It was found that this extract strongly inhibited the tested Gram-positive bacteria (Enterococcus faecalis and Staphylococcus aureus) in very low concentration (CIM 0.25ug/mL) revealing that this plant is a promising antibacterial, giving scientific basis to its popular use (Kuglerova et al., 2007). We emphasize, in agreement with the authors, the need for further studies on this species regarding its antibacterial action. It is worth mentioning the need for studies evaluating the cytotoxic action of this plant.

Trichilia monadelpha (Thonn.) JJ De Wilde
A study was found with ethanol extracts and petroleum ether from the stem bark of Trichilia monadelpha (Thonn.) JJ De Wilde, where their anti-anaphylactic and anti-inflammatory activities were evaluated, to prove their traditional use in the treatment of allergies and other inflammatory disorders. Both extracts were effective in decreasing mast cell degranulation and inhibiting TNF-alpha (TNF-a) to interleukin 6 (IL6) (100ug/kg). Also, the extracts also acted by preventing the destruction of the cell-matrix and tissue damage (100ug/kg) (Ben, Woode, Koffuor & Asiamah, 2016). In the work it was reported that alkaloids are possibly responsible for the antianafilatic action of the ether extract and in the ethanolic extract flavonoids were found to have proven antiallergic action.

Trichilia silvatica C.CD
The research investigated the anti-inflammatory, antioxidant and antiproliferative activities of the methanolic extract of leaves and bark of Trichilia silvatica C.DC. As a result, it was observed that the extracts exhibited moderate antioxidant activity (IC50≤35.32 µg/mL). Both extracts also inhibited carrageenan-induced paw edema after 2 and 4 hours. They also observed inhibition of leukocyte migration at 6 hours after administration of the extract. The methanolic extract of the leaves was particularly effective against the prostate cell line (EC50 ≤ 0.22 µg/mL) (Da . Unfortunately, this plant is being little explored regarding its therapeutic actions. We understand that Trichilia silvatica C.DC has a lot to offer, this is suggested by the presence of phenolic compounds, flavonoids and tannins found in its extracts.
Perhaps this fact can be explained, due to its more restricted geographical distribution, since most of it is found in India's rainforests. The purpose of the study was to investigate the anti-hyperlipidemic effect of chloroform and methanolic extracts from the leaves of Trichilia connaroides (Wight and Arn.) Bentv. in hypercholesterolemic rats and the possible mechanism involved in the action of these extracts. Both extracts produced a significant drop (P <0.05) in plasma triglycerides, total cholesterol, cholesterol (VLDL) and cholesterol (LDL), however, an increase in cholesterol (HDL) was observed (P <0.05 ).
The hypercholesterolemic regression test revealed a significant reduction (P <0.05) in the serum cholesterol level in the treated animals (Subbarao & Ashok, 2011). This species shows promising potential for future herbal medicines used in the treatment of dyslipidemia and in the prevention of atherosclerosis. The authors reported that this action is possibly due to the tetranoterpenes and triterpenes found in this plant.

Trichilia rubescens Oliv.
We found a study in this time range. It should be noted that Trichilia rubescens Oliv. it is mostly found in regions of Tropical Africa, which may explain the limited number of studies. The action of the crude extracts (methanolic and ethyl acetate) of the leaves was evaluated. What the authors highlighted in this work was the strong cytotoxic action of both extracts against Plasmodium falciparum (IC50 3.1 mg/mL). After fractionation of the ethyl acetate extract, a significant antimalarial activity of the limonoids (trichirubins A and B) (IC50 4 mg/mL) was observed. Therefore, they were identified as the possible responsible for this antimalarial action (Krief et al., 2006). The authors suggested investigative studies regarding an antiinflammatory action, due to its popular use for this purpose.

Trichilia lepidota Mart.
For this species, a study was found using hexanic and methanolic extracts of the leaves and fractions of limonoids of the fruit were tested for their cytotoxic action against leukemic cell lines MOLT-4 and U937. The protolimonids 6 isolated from this plant were more toxic (IC50 9.3 mg/mL) compared to both strains tested. As for the extracts, the hexanic (IC50 62.5mg/mL) exhibited the most significant cytotoxic activity against both strains (Terra et al., 2013). It is important to note that protolimonids are proven to be toxic to tumor cells. Thus, this plant is promising for the development of new drugs with antineoplastic action.
Although 47 species of Trichilia occur in Brazil (Pennington, Styles & Taylor, 1981), in a period of 15 years, only three species were investigated regarding their therapeutic activity (Trichilia catigua, Trichilia lepidota and Trichilia silvatica) showing that, as reported by David, Wolfender and Dias (2014) although popular knowledge has contributed significantly to the understanding of the effects of many medicinal plants, other plants are still little known as to their active principles, mechanism of action and toxicity, we can see this with the plants of the genus Trichilia, thus justifying further studies to scientifically validate the effectiveness of its constituents.
Medicinal plants are important for the synthesis of new drugs. In this context, the genus Trichilia is promising, due to its biological activities and secondary metabolites. However, we observed that many species of this genus have reduced numbers of studies. Perhaps this fact can be explained due to their restricted geographical location. Disseminating the knowledge acquired about these plants is indeed important for future research.

Conclusion
It was shown through the studies mentioned in this review that the genus Trichilia is promising for the treatment of numerous diseases. The studies mentioned here also reveal that plants of this genus can be important allies in combating pathogens resistant to conventional drugs. As we pointed out in this study, species of the genus Trichilia still have a lot to offer us in combating and even preventing diseases such as diabetes, atherosclerosis, fungal, bacterial, neoplastic and neurodegenerative diseases. Many of these diseases have yet to be cured. However, many species of the genus Trichilia are little known, which results in little research on their therapeutic properties. This review highlights the main therapeutic applications found in studies in the literature with plants of the genus Trichilia. It demonstrates its great biotechnological potential, in order to stimulate further studies on its employability in the development of herbal medicines for the treatment of numerous diseases that affect humans.