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Functional Food - Upgrading Natural and Synthetic Sources [Working Title]
Open access peer-reviewed chapter - ONLINE FIRST
Bioactive Phenolic Compounds and Biological Activities of Mururé Bark (Brosimum acutifolium), a Natural Antioxidant
Written By
Kelly Roberta Pinheiro Pantoja, Eduardo Gama Ortiz Menezes, Diana das Graças de Oliveira, Jean Maurício Leão Pinheiro, Verônica Maria Souza Bezerra, Fernando de Freitas Maués de Azevedo and Raul Nunes de Carvalho Júnior
Submitted: 20 May 2023Reviewed: 15 June 2023Published: 07 August 2023
Brosimum acutifolium is a large tree with high medicinal and pharmacological value, widely used in folk medicine by some communities in South America and northern Brazil, as a potent antirheumatic, antiarthritic and anti-inflammatory, so this work aims to address the chemical composition and biological activities of the bark of the species, reported in the scientific literature in the last 30 years. Information was collected from the databases such as the Google Scholar, Scientific Electronic library online (Scielo), National Library of Medicine (PubMed), Elsevier, institutional repositories and government websites. The bark of the plant species has a variability of compounds in its composition, such as flavonoids, coumarins, phytosterols, alkaloids and lignoids, representing an important source of phenolic bioactives, which makes it a natural antioxidant. In this research, biological activities, such as antibacterial, antifungal, antioxidant, anti-inflammatory, neuroprotective and anticancer activities, were found. The biological properties observed are related to the promotion of human health, and when added to the vast diversity in secondary metabolites present in the bark, it transforms the species into a strong candidate to act as an auxiliary therapeutic alternative in the control and treatment of certain diseases and as an input for the development of bioproducts.
Science and Technology of Rondônia, Federal Institute of Education, Porto Velho, Rondônia, Brazil
Diana das Graças de Oliveira
Federal University of Pará, Belém, Brazil
Jean Maurício Leão Pinheiro
Federal University of Pará, Belém, Brazil
Verônica Maria Souza Bezerra
Federal University of Pará, Belém, Brazil
Fernando de Freitas Maués de Azevedo
Federal University of Pará, Belém, Brazil
Raul Nunes de Carvalho Júnior
Federal University of Pará, Belém, Brazil
*Address all correspondence to: kelly.sousa@icen.ufpa.br
1. Introduction
The Amazon rainforest, known worldwide for its biodiversity, has a variety of plant species that are seen as natural sources of bioactive compounds of high added value and high antioxidant capacity, as is the case of phenolic compounds, which have the potential to be used as inputs in the formulation of manufactured products of interest to the chemical, food and pharmacological industries [1].
In this context, a huge number of scientific publications have aroused the interest of the scientific community demonstrating the possibility of using plants native to the Amazon region, as is the case of species of the genus Brosimum, as potential bioactive agents with pharmacological and biotechnological properties [2, 3].
The species of the genus Brosimum, belonging to the Moraceae family, are native to the Amazon region and have their economic importance associated, mainly, with the production and sustainable extraction of latex, which is obtained from the tree. However, other potentialities are associated with this genus as is the case of the use of tree bark for medicinal purposes [4].
The species B. acutifolium, popularly known as “mururé,” is also known by the names of Amapá doce, congona, mururé da terra firme, muirapiranga; urupi, quecho, tamamuri, mercúrio vegetal, amarillo, tamamuri, takini, tauni, congona and typique, nominal variations related to the region of occurrence [5]. It is one of the varieties of this genus and stands out from the other species due to recent scientific discoveries that have revealed potential bioactivities of this species as an antioxidant, anti-inflammatory and neuroprotective [6, 7] due especially to the presence of natural antioxidants, as is the case of secondary metabolites.
Thus, this species is seen as a natural source of antioxidants and with high economic value, despite these advantages it presents, it is still little known about its potential for exploitation, especially about its composition [8].
Considering the productivity potential of the species B. acutifolium in terms of its chemical composition and potential bioactivities, the search for knowledge about the bioactive potential of the species is configured as an important strategy to encourage its sustainable exploitation, identify possible potentialities of this species to be used as an input in the development of new drugs and new technologies, in addition to enabling the insertion of this plant species in the economic matrix of natural products of high added value in the Brazilian states of the Amazon region. It is worth mentioning that there is growing demand for natural products obtained from Brazilian biodiversity, as is the case of natural antioxidants extracted from the native plant species of the Amazon rainforest [6, 7, 8, 9].
Thus, this article is the first review work in the literature for the species B. acutifolium that discusses the bioactive potential of the species through the systematic classification of scientific works published in the last three decades.
This article consists of a review of the scientific literature, using the integrative method. For bibliographic mapping, the following descriptors were used: B. acutifolium, Genus Brosimum, Moraceae, Mururé, profile phytochemical of B. acutifolium, biological activity of B. acutifolium and morphology, derived from the name of the species, genus or family searched. The procedures for exclusion and inclusion of the studies were based on predefined criteria: dating from 1990 to 2023, languages: English, Portuguese, Spanish and Japanese. The selection and categorization of the scientific contribution occurred through a thorough and complete reading of all the collected works, to identify key information that would fit the predefined topics of this work.
The species has a wide geographic distribution throughout South America, being mostly found in Brazil, French Guiana, Peru and Colombia, as presented in Table 1, according to the government website of the Global Biodiversity Information System [10]. It has characteristic habitat of terra firme rain forests, with tropical climate, as to its seasonality, covers the period between the months of July and September with flowering, fruiting until the end of October, where its fruits are found ripe and can be harvested. As regards phenology, the species is adept at climates with annual rainfall, medium lighting and clayey soils [11, 12]. B. acutifolium is a tree that can reach a height ranging from 15 to 25 m(Figure 1), is characterized by the presence of rough branches of grayish color, leaves with stipulae of aspect that resemble spears, acuminate apex with rounded base and slightly wavy margins, and has a glabra ventral face and a tubercular dorsal face. Globose floral receptacle is covered by basal bracts with female flowers. Its fruits are globose and reddish approximately 3 cm in diameter, containing up to five seeds inside. The trunk has horizontal lines on the surface, with bark and root of reddish color, a latex can be extracted through a cut in the stem [13, 14]. Tables 2 and 3 contain, respectively, the taxonomy of the species and synonymy of the subspecies, as available on the government websites of the Taxonomic Catalog of the Fauna of Brazil and List of the Flora of Brazil 2020 [15].
The bark is one of the main structures of the species used by communities in South America and Northern Brazil for the treatment of ailments involving inflammatory conditions, infectious diseases, rheumatism and arthritis, acts as analgesic, antipyretic, vermicide, antisyphilitic and in respiratory, gastrointestinal and neurological disorders. It is also indicated its use for anemia and allergies as well as appetite stimulator and aphrodisiac. The latex extracted by incision has an initially light coloration that quickly reddens over time. This liquid is also popularly used for the treatment of diseases being also considered antirheumatic, antiarthritic, antisyphilitic, anthelmintic, anti-inflammatory and should be consumed moderately because it can cause intoxication [12].
As for the method of preparation, the information found points to the consumption of teas, macerations, bottles, spirits and mixtures. Teas are prepared from the decoction or infusion of the whole or ground bark and the fruits in boiling water, being popularly associated with the treatment of diseases of the digestive tract. Maceration is done by mixing cachaça, wine or brandy with the peel, remaining at rest inside a bottle for 48 h. After this time, a purplish coloration is observed, indicating that the preparation is ready to be used. It can be consumed orally twice a day (in the morning and afternoon before bathing) or by applying the mixture directly to the skin, through frictions and massages, especially in cases of joint pain and inflammation. A few drops of latex can be added to cachaças and drinks, at the beginning of magic rituals. Reports indicate the use of latex for the treatment of syphilis, in preparations with water (4 g of latex and 15 g of water), not exceeding the intake of 8 g of latex per day and should be drunk daily. If there are lesions on the skin, latex can be applied directly to the wound and the sap can be stored for longer if it stays at low temperatures or mixed in alcohol [12].
The bottles are prepared based on peels or together with peels of other species, mixed in water undergoing a decoction treatment or not, the liquid is then separated and packed in glass bottles to then be consumed daily until there is an improvement in the condition of the disease. These preparations are very common to be ingested when you have apathy or muscle fatigue, caused by intense physical activity. The distillates and mixtures were not possible to be described due to the lack of information on the method of preparation. The traditional knowledge attributed to mururé has been confirmed through much research, which attribute its anti-inflammatory, antibacterial and antioxidant character due to the large number of flavonoids present in its chemical composition. Its performance as antianemic and aphrodisiac has no scientific proof, only reports of use [2, 12].
Previously in the species, the presence of flavonoids, coumarins, lignoids and phytosterols was observed. There are a vast number of bioactive compounds that have been discovered and isolated in recent decades, mainly polyphenols of the flavonoid class such as flavans and chalcones [3, 13, 14, 16]. In this section, the main classes of secondary metabolites investigated in the bark of the species B. acutifolium will be presented. The substances presented were identified and elucidated through high-performance liquid chromatography (HPLC) coupled to mass spectrometry (MS) in the extracts obtained through the maceration technique.
5.1 Flavonoids
Flavonoids are secondary metabolites from plant matrices, found in the bark of the species. Structurally, these compounds have approximately 15 carbon atoms distributed in a chain of three rings, with nucleus C6-C3-C6, which are units called A, B and C. They can be found in the form of flavones, flavanones, flavonols, flavanols, anthocyanins, isoflavones and chalcones [17, 18], are found oxygenated and much of it is conjugated to sugars [19]. Chalcones are precursors and product of the biosynthesis of flavonoids, are classified as naturally occurring aromatic ketones, whose structure is 1,3-diaryl-2-propen-1-one. They are considered open-chain flavonoids, composed of an α, β-unsaturated carbonyl system responsible for the union of two aromatic rings, called A and B, which constitute their chemical structure [19, 20]. These substances exhibit a vast biological activity found as antidiabetic, antioxidant, protective vessel, anti-inflammatory and antimicrobial, including antiviral, antifungal and antiparasitic [17, 18, 19, 20, 21, 22]. The flavonoids identified are gathered and organized in Table 4.
The species has a high number of flavonoids, such as: 4′-hydroxy-7,8-(2″,2″-dimethylpyran)flavan, 4′-hydroxy-7,8-(3″-hydroxy-2″,2″-dimethylpyran)flavan, Brosimine A, Brosimine B and 3′,7-dihydroxy-4′-methoxyflavan, which are compounds observed in dichloromethane extracts obtained by cold maceration [2, 4]. Cold methanoic maceration [3, 14] allowed obtaining extracts rich in flavanoids, such as Acutifolins A-F and Brosimacutins A-M. In a study carried out with methanolic extracts [3] to evaluate the cytotoxicity of molecules: Brosimacutins J-L and the chalcone Brosimacutin M, it was found that these molecules showed cytotoxicity against P388 leukemic cells resistant to vincristine (IC50 4.4–19 microg/mL).
5.2 Phytosterols
Phytosterols are compounds of plant origin, belonging to the triterpene family. They have a tetracyclic structure, formed by four rings, called A, B, C and D, with a branched side chain in the carbon of position 17 of the D ring. They structurally resemble cholesterol, differing from this due to the addition of a methyl or ethyl group in the position of carbon C24, for example [23, 24, 25, 26]. There is a vast amount of phytosterols, the most common among which are β-Sitosterol, Campesterol, Stigmasterol, Brassicasterol and Avenasterol [27]. These compounds are related to decreased risk of developing cardiovascular disease and cancer, exhibit numerous other properties, such as antidiabetic, anti-inflammatory, neuroprotective, antimicrobial, and act in the control of low-density lipoprotein (LDL) cholesterol levels [24, 25, 26, 27, 28, 29]. The phytosterols isolated and identified in the bark of B. acutifolium are β-Sitosterol (0,0013%) and Stigmasterol (0,001%) [2], obtained from methanolic extracts (Figure 2). Stigmasterol and β-Sitosterol are structurally similar compounds, with a difference in the double bond located at the position of the C22 carbon, in which the sterol C-22 desaturase is inserted, transforming β-Sitosterol into Stigmasterol [30].
Figure 2.
Phytosterol molecules present in B. acutifolium.
5.3 Coumarins
Coumarins are polyphenols of the benzopyrone family, and they are oxygenated substances with heterocyclic structure, formed by two rings with a carbonyl group in carbon of C2 position. Coumarins (1,2-benzopyrone) and their derivatives are compounds of high biological potential and can be biosynthesized by plants, and some fungi and bacteria. They are classified as simple coumarins, furanocoumarins, pyranocoumarins and pyrone-substituted coumarins [31, 32, 33]. Coumarin compounds exhibit a vast pharmacological activity arousing interest in the cosmetic, food and pharmaceutical industries. These bioactive compounds exhibit anti-inflammatory, antibacterial, Alzheimer’s disease inhibition, anticonvulsant, anticoagulant, anticancer, antimalarial, antifungal, antiviral, neuroprotective and antihypertensive activity [33, 34, 35, 36]. The coumarin substances present in the bark of the species are available and organized in Table 5.
The alkaloids present in B. acutifolium are organic substances found in the latex extracted from the bark of the stem of the species. In this case, the alkaloid 5-hydroxytryptamine (bufotenine) was recorded for the first time in latex-based potions prepared for magical rituals (Figure 3) [38]. The bufotenine molecule is derived from the amino acid tryptamine. It has hallucinogenic action, being found in animal organisms, such as frogs, and in Amazonian plants such as the Moraceae and Leguminosae families. It also has an inhibitory action against the rabies virus and serves as an anti-inflammatory and analgesic [39]. In general, alkaloid molecules have a heterocyclic structure, in which nitrogen atoms are incorporated, which give them basicity [40, 41]. They are produced by fungi, bacteria and plants, and alkaloids are mainly classified into indoles, purines, quinolines, isoquinolines, tropanes, imidazole, pyridines and others [41, 42]. The structural variability of these compounds gives them vast pharmacological activity such as anticancer, antibacterial, analgesic, antifungal, anti-inflammatory, antidiabetic and antimalarial [40, 41, 42, 43, 44, 45, 46].
Figure 3.
Alkaloid observed in the latex of mururé bark.
5.5 Lignoids
The molecules identified in the bark of the mururé are Coniferaldehyde and Syringaldehyde (Figure 4). Lignoids are aromatic phenolic molecules deposited on the cell wall in plants, accounting for up to 45% of their biomass. They are formed from phenylpropanoic groups (C6-C3)n (“n” the number of atoms interconnected with this configuration),being divided into groups, such as lignans, neolignans, allolignans, oligolignoids and heterolignoids, for example. They express anticancer, antiviral, anti-inflammatory, antimicrobial and antioxidant activity [46, 47, 48, 49].
Figure 4.
Lignoids present in the species.
5.6 Recently discovered compounds in the species
In the last 5 years, a study was reported that investigated the phytochemical composition of the species [13], which identified the presence of chalcones until then, not yet seen in B. acutifolium. The molecules found in the bark of the mururé are presented in Table 6.
B. acutifolium, as can be seen in the previous section, exhibits a vast number of bioactive molecules that are related to pharmacological properties of great interest for improving human health (Figure 5). The premise of the studies that investigate the biological potential of mururé is based on the ethnopharmacological report available in the literature, in which, the plant species is used in the treatment of rheumatism, arthritis, lesions and inflammatory conditions [6, 8]. In this topic, research that evaluates biological activity and proves its use reported in folk medicine will be addressed.
Figure 5.
Bioactive potential of mururé bark.
6.1 Antimicrobial activity
Methicillin-resistant Staphylococcus aureus (MRSA) (β-Lactam) is a public health problem that is related to the increase in cases of bacterial resistance to antibiotics worldwide. S. aureus is an opportunistic bacterium present in the epidermis and nasal cavities of healthy humans, and most often this pathogen lives in the human microbiota without causing greater harm; however, if this microorganism invades the bloodstream or enters deep into the tissues it can cause very serious infections [49, 50, 51]. As a form of drug protection, bacteria can generate biofilms, which are a conglomerate of microorganisms encapsulated by a polymeric compound that protect them from both the antibiotic and the attack of the human immune system [52, 53, 54, 55].
A study [56] evaluated the antimicrobial potential of the ethanolic extract of the bark of B. acutifolium against seven multidrug-resistant bacteria (Proteus mirabilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, S. aureus, Enterococcus faecalis and Streptococcus pneumoniae) by the Kirby-Bauer method. As a result, activity against P. aeruginosa and high inhibitory activity against multidrug-resistant S. aureus were observed, with minimum inhibitory concentration (MIC) ranging from 1.25 to 80 mg/L.
An ethnobotanical survey of 59 Amazonian plant species [57] used as local phytotherapics by Amazon riverine population was carried out and antimicrobial activity of their extracts evaluated. Several plant species tested did not show effective antibacterial activity; however, the ethanolic extract of B. acutifolium obtained a minimum active inhibitory concentration (150 mg/L) against seven Gram-positive bacteria: P. aeruginosa, Stenotrophomonas maltophilia, Staphylococcus epidermidis, Staphylococcus lugdunensis, Staphylococcus warneri, Corynebacterium striatum and Mycobacterium smegmatis. It was also found to have shown moderately active inhibition (300 mg/L) for Gram-negative bacteria: K. pneumoniae, Yersinia pseudotuberculosis and Gram-positive bacteria: S. aureus.
More adverse pathogenic bacteria that reach the enterogastric system, E. coli, E. faecalis and Salmonella sp., did not express results for antibacterial activity [56, 57]. The infusion of B. acutifolium has not shown an effective antibacterial activity against potential pathogenic bacteria that reach the enterogastric system, E. coli, E. faecalis and Salmonella sp., and consequently compromising the treatment of diseases. However, the most appropriate ethnopharmacological application would be the topical use of disease treatment.
In another study [8], the ability to disrupt biofilms formed by MRSA and antibacterial activity was investigated, using three flavonoids isolated from this species: 4′-hydroxy-7,8-(2″,2″-dimethylpyran)flavan, 4-hydroxy-lonchocarpin and Brosimine B. In this study, the molecules 4′-hydroxy-7,8-(2″,2″-dimethylpyran)flavan and Brosimine B were able to further reduce the viability of this pathogen in the biofilm by a MIC of 50 mg/L. At a concentration of 200 mg/L, Brosimine B was able to reduce bacterial viability by up to 94%, and it was also demonstrated to reduce the biomass of biofilms formed by S. aureus by up to 48% at a MIC of 100 mg/L. The flavonoids 4′-hydroxy-7,8-(2″,2″-dimethylpyran)flavan and 4-hydroxy-lonchocarpin were not able to promote the reduction in bacterial biomass. However, the molecule 4-hydroxy-lonchocarpin, at a concentration of 400 mg/L, obtained a reduction in bacterial cell viability close to 43%.
The evaluation of the antifungal actions [58] of extracts of B. acutifolium against the standard strain of Candida albicans showed an excellent inhibition (MFC = 9.7 mg/L), whereas for the other species, Candida glabrata minimum fungicidal concentrations (MFC) = 2500 mg/L and Candida krusei (MFC) = 2500 mg/L, there was a weak antifungal activity.
Candidemia is considered an epidemic of opportunistic fungal infection caused by yeasts of the genus Candida sp. with high mortality in immunocompromised people and patients hospitalized under severe conditions in a secondary way, during hospital practices. The emergence of infections by opportunistic pathogenic fungi occurs due to the indiscriminate use of synthetic antimicrobials, which act antagonistically to the intestinal bacterial flora, causing exponential growth and causing the weakening of the patient’s state of health. Reducing the use of antibiotics or adopting other therapeutic practices is imperative to prevent the emergence of multidrug-resistant fungi and bacteria and coinfections [59].
This research fosters the search for new therapeutic alternatives, which have instigated research on plant drugs with biological potential for the formulation of antibiotics that aim to reduce the development of multidrug-resistant bacterial strains and that can enter the biofilms to cause bacterial death, which is still a barrier to be faced by the pharmaceutical industry and in the medical area [8].
6.2 Antioxidant activity
Plant species in general exhibit antioxidant activity, and this activity is related to the ability to inhibit oxidative stress, being considered natural antioxidants. Oxidative stress can be defined as an imbalance of reactive oxygen species (ROS) responsible for the correct performance of the human organism. The excessive presence of ROS results in an attack on human cells causing the development of several degenerative diseases. Natural antioxidants can neutralize ROS by capturing these free radicals [60, 61, 62, 63].
In this sense, some studies have been conducted to evaluate the antioxidant potential of B. acutifolium, in which the 2,2-diphenyl-1-picrylhydrazyl (DPPH+) method is the most widely used assay to determine this potential in the extracts of the species [6, 63]. This method is based on the elimination of the organic radical 1,1-diphenyl-2-picrylhydrazyl (a free and stable molecule) by antioxidants. The reduction of this radical is accompanied by the reduction of absorbance, and the results are expressed mostly using IC50 (half-maximal inhibitory concentration), which indicates the amount of antioxidant needed to sequester 50% of the free radicals of 1,1-diphenyl-2-picrylhydrazyl [64, 65].
The antioxidant activity of the Brosimine B molecule (4′,7-dihydroxy-8-(3,3-dimethylallyl)flavan) present in the species was investigated [7] by the (DPPH+) method obtaining a value of IC50 = 55.16 μM, observing that it has a profile like that of ascorbic acid with IC50 = 36.91 μM. The ethanolic extract of B. acutifolium was evaluated [66] by the DPPH+ method finding a value of CI50 = 2.84 ± 0.38 μg.mL−1. In another study [7], the antioxidant activity of the ethanolic extract and three flavonoids isolated from the species (4′-hydroxy-7,8-(2″,2″-dimethylpyran)flavan, Brosimine B and 4-hydroxy-lonchocarpin) was evaluated by the DPPH+ method, out of which only the ethanolic extract and the compounds 4′-hydroxy-7,8-(2″,2″-dimethylpyran)flavan and Brosimine B exhibited antioxidant activity.
When the reaction kinetics were evaluated in comparison with Trolox (IC50 = 3.5 ± 0.2 μg/mL), the ethanolic extract showed a value of IC50 = 4.8 μg/mL and Brosimin B a value of IC50 = 16.6 μg/mL. As can be observed, the antioxidant activity of the species B. acutifolium is related to its variability in the chemical composition mainly in the diversity of phenolic compounds [2, 4, 13], which if concentrated may contribute to a greater antioxidant character in this plant species.
6.3 Anti-inflammatory activity
Inflammation is a response of the body caused by a tissue injury or by microbial infections [67]. In general, inflammation develops to repair the events of trauma or microbial infection, but it can suffer a response without being directly related to the events mentioned, which can lead to chronic pathologies, resulting from dysregulated inflammation [68, 69].
An inflammatory response involves the recruitment of innate immune cells, which produce cytokines and chemokines, attracting lymphocytes and then triggering the inflammatory process. A cascade of events occur during this process, and there are many studies that have focused on the use of bioactives with anti-inflammatory actions [70].
Flavonoids are known to have several pharmacological actions, and the anti-inflammatory activity was found in a study in which flavanoid isolate, 4′-hydroxy-7,8-(2″,2″-dimethylpyran)flavan from mururé bark, was evaluated in two in vivo experimental models: models of duck edema and air pocket. This study verified the anti-inflammatory activity of this flavonoid, but the mechanism of action was not elucidated [71].
The mechanism of anti-inflammatory action of this flavonoid was investigated in a later study, using murine stimulated macrophages, which are extremely important for the control of inflammation and infections. It is possible to observe the anti-inflammatory action, evidencing the decrease in the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) and indicating a specific mechanism of its action in the proinflammatory pathway [37].
In another study conducted with flavonoids isolated from the species, the substances, called murinin A, murinin B and murinin C, were tested for the inhibitory activity of protein kinases A and C. As a more relevant result, the inhibitory action of 63% for protein kinase C was observed, when using 20 μM of murine A, while murine C did not demonstrate significant inhibitory activity for these proteins [72].
There are few studies published in the literature on the anti-inflammatory activity of mururé. However, the results demonstrated in this review found its medicinal action and that due to the variability of bioactive compounds in its composition [13], the species becomes an interesting candidate in the search for new anti-inflammatory agents.
6.4 Neuroprotective activity
Stroke is one of the main comorbidities in the world, more prevalent in the elderly population, with ischemic (cerebral vascular accident (CVA)) being the most common type of stroke, compromising the metabolic pathways in the central nervous system (CNS) causing severe degeneration in the affected area. The stroke is caused by the interruption in blood flow for some time, causing cell groups to be injured, and its effects last even after the establishment of blood flow, generating an ischemic cascade with a lot of cellular damage [73]. As a consequence, it also causes the temporary blockage of the supply of oxygen, glucose and other nutrients to the CNS, triggering an oxidative stress that culminates in damage to cellular tissues. In the individual, these effects manifest themselves through intense headache, dizziness and imbalance [74].
The Brosimine B molecule obtained from extracts of the species B. acutifolium was evaluated for its neuroprotective effect in an in vitro experiment, using retinal cells from the chicken embryo subject to hypoxia, with oxygen and glucose deprivation. The molecule has been shown to increase cell viability by combating oxidative stress caused by ROS over a period of 3 to 6 h and protecting the studied cell culture from the hypoxia to which it was subjected [7].
Currently, the treatment for stroke cases is administered through thrombolytic therapies as a measure to prevent the emergence of new ischemic episodes. It is necessary to conduct research involving studies of new therapies that can clarify the mechanism that acts on the death of cells in the affected areas due to ischemia [75]. In this sense, it is essential to find products and therapeutic strategies that act with neuroprotective objective to protect cells from brain lesions.
6.5 Anticancer activity
Glioblastoma is a rare malignant brain tumor that mostly affects males, where the patients affected by the disease generally have a poor prognosis, and in most cases the chances of survival are less than 2 years. Treatment for such cases involves surgery, radiation therapy and chemotherapy. However, these treatments harm healthy cells causing harm to the human body [76].
In a study [6], three flavonoids (4′-hydroxy-7,8-(2″,2″-dimethylpyran)flavan, Brosimine B and 4,2′-dihydroxy-3′,4′-(2″,2″-dimethylpyran)-chalcone) were tested against C6 glioblastoma. The results showed that these flavonoids inhibited the migratory and antiproliferative activity of cell cultures, and act by inducing glioma apoptosis. Of the three species studied, the substance 4′,7-dihydroxy-8-(3,3-dimethylallyl)flavan was the one that presented the best antineoplastic activity acting through the mechanism of apoptosis and autophagy.
Currently, there are many medical treatments that aim to slow the advance of cancer. Natural products, such as those derived from B. acutifolium, can slow the proliferation of malignant cancer cells and can act together as a complementary alternative to cancer treatment, delaying tumor development [6, 76].
Extracts of Brosimum acutifolium are among the active principles of two registered cosmetic patents, according to which, they exhibit inhibitory activity of hyaluronidase and interesting response to hair growth, and may, therefore, be a promising species in the production of creams, shampoos, soaps and among others, aimed at this cosmetic industry. In addition to having already been shown to have anti-inflammatory characteristics, it may be an indication that these extracts have great chances of being worked at for the development of bioproducts [11]. It should be noted, however, that many of the mechanisms of action of the molecules present in the plant species are not yet described. Similarly, whether there is a relationship between various features such as the number of rings, hydroxyls or conformations in their form of action is yet to be described. Moreover, it is not yet clear as regards their biophysical characteristics. It is also necessary to evaluate the levels of toxicity of these extracts so that they can be administered with maximum effectiveness and minimum risks. The results of the studies mapped in this chapter to date already ratify the characteristics of this species as an aid in the protection of neurodegenerative processes and in the synthesis or molecular biotransformation, such as steroids.
The discovery of plant species with a high content of phenolic compounds is important for numerous sectors such as food, cosmetics and large pharmaceutical industries. The species B. acutifolium, an Amazonian tree that represents very well, is premise, since they present a vast number of bioactive compounds, mainly of the class of flavonoids, besides being responsible for the biological activities observed as antimicrobial, antioxidant, anti-inflammatory, anticancer and neuroprotective. These compounds promote human health benefits by improving the quality of life and can be useful in the manufacture of new drugs.
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001 and by the Pró-Reitoria de Pesquisa e Pós-Graduação Universidade Federal do Pará (PROPESP/UFPA) (PAPQ).
3.Takashima J, Komiyama K, Ishyama H, Kobayashi J, Ohsaki A. Brosimacutins J-M, four new flavonoids from Brosimum acutifolium and their cytotoxic activity. Planta Medica. 2005;71:654-658. DOI: 10.1055/s-2005-871272
4.Torres SL, Monteiro JCM, Arruda MSP, Muller AH, Arruda A. Two flavans from Brosimum acutifolium. Phytochemistry. 1997;44:347-349. DOI: 10.1016/S0031-9422(96)00447-5
5.Grandtner MM, Chevrette J. Genera and Species. In: Grandtner MM, Chevrette J, editors. Dictionary of Trees: South America, Nomenclature, Taxonomy and Ecology. 1st ed. Canada: Academic Press; 2013. pp. 72-73
6.Maués LAL, Alvesa GM, Couto NMG, Silva BJM, Arruda MSP, Macchi BM, et al. Flavonoids from the Amazon plant Brosimum acutifolium induce C6 glioma cell line apoptosis by disrupting mitochondrial membrane potential and reducing AKT phosphorylation. Biomedicine & Pharmacotherapy. 2019;113:108728. DOI: 10.1016/j.biopha.2019.108728
7.Fonseca SSS. Efeito protetor da flavana extraída da espécie Brosimum acutifolium contra danos causados por hipóxia em células retinianas: um estudo in vitro [Dissertation]. Belém: Universidade Federal do Pará. 2014
8.Reis SV, Couto NMG, Brust FR, Trentin DS, Silva JKR, Arruda MSP, et al. Remarkable capacity of brosimine b to disrupt methicillin-resistant Staphylococcus aureus (MRSA) preformed biofilms. Microbial Pathogenesis. 2020;140:103967. DOI: 10.1016/j.micpath.2020.103967
9.Salazar MAR, Urbina GRO, Bezerra PN, Cunha VMB, Silva MP, Pires FCS, et al. Antioxidant and biological activity of Cissus sicyoides and Rosmarinus officinalis extracts. In: Shalaby E, editor. Antioxidants. 1st ed. London, United Kingdom: IntechOpen; 2019. pp. 1-20. DOI: 10.5772/intechopen.77838
10.GBIF. Global Biodiversity Information System [Internet]. 2023. Available from: https://www.gbif.org/what-is-gbif [Accessed: 2023-04-03]
11.Vieira EFM, Lucas FCA, Campos MGR, Germano CM. Mururé (Brosimum acutifolium Huber) in the treatment of syphilis in colonial Amazonia: Historical data to the actual contribution to treatment. Acta Botanica Brasilica. 2019;33:83-190. DOI: 10.1590/0102-33062019abb0030
12.Pinagé GR. Moraceae. In: Rios MNS, Pastore Júnior F, editors. Plantas da Amazônia: 450 espécies de uso geral. 1st ed. Brasília: Universidade de Brasília; 2011. pp. 2400-2405
13.Sá ISC, Neves KOG, Guimaraes AC, Silva FMA. Nunomura, RCS. Chalcones and flavans from the bark of Brosimum acutifolium subsp. interjectum (Moraceae). Biochemical Systematics and Ecology. 2020;93:104175. DOI: 10.1016/j.bse.2020.104175.
14.Takashima J, Ohsaki A. Acutifolins A-F, a new Flavan-derived constituent and five new Flavans from Brosimum acutifolium. Journal of Natural Products. 2001;64:1493-1496. DOI: 10.1021/np010389j
15.Sistema de Informação sobre a Biodiversidade Brasileira. Catálogo Taxonômico da Fauna do Brasil e Lista da Flora do Brasil 2020 [Internet]. 2020. Available from: https://sibbr.gov.br/ [Accessed: 2023-04-03]
16.Takashima J, Ohsaki A. Brosimacutins A-I, nine new flavonoids from Brosimum acutifolium. Journal of Natural Products. 2002;65:1843-1847. DOI: 10.1021/np020241f
17.Silero L, Prado R, Welton T, Labidi J. Extraction of flavonoid compounds from bark using sustainable deep eutectic solvents. Sustainable Chemistry and Pharmacy. 2021;24:100544. DOI: 10.1016/j.scp.2021.100544
18.Badshah SL, Faisal S, Muhammad A, Poulson BG, Emwas AH, Jaremko M. Antiviral activities of flavonoids. Biomedicine & Pharmacotherapy. 2021;140:111596. DOI: 10.1016/j.biopha.2021.111596
19.Alara OR, Abdurahman NH, Ukaegbu CI. Extraction of phenolic compounds: A review. Current Research in Food Science. 2021;4:200-214. DOI: 10.1016/j.crfs.2021.03.011
20.Rani A, Anand A, Kumar K, Kumar V. Recent developments in biological aspects of chalcones: The odyssey continues. Expert Opinion on Drug Discovery. 2019;14:249-288. DOI: 10.1080/17460441.2019.1573812
21.Dan W, Dai J. Recent developments of chalcones as potential antibacterial agents in medicinal chemistry. European Journal of Medicinal Chemistry. 2020;187:111980. DOI: 10.1016/j.ejmech.2019.111980
22.Elkhalifa D, Al-Hashimi I, Al Moustafa AE, Khalil A. A comprehensive review on the antiviral activities of chalcones. Journal of Drug Targeting. 2021;29:403-419. DOI: 10.1080/1061186x.2020.1853759
23.Zhang R, Han Y, McClements DJ, Xu D, Chen S. Production, characterization, delivery, and cholesterol-lowering mechanism of phytosterols: A review. Journal of Agricultural and Food Chemistry. 2022;70:2483-2494. DOI: 10.1021/acs.jafc.1c07390
24.Sharma N, Tan MA, An SSA. Phytosterols: Potential metabolic modulators in neurodegenerative diseases. International Journal of Molecular Sciences. 2021;22:12255. DOI: 10.3390/ijms222212255
25.Mohammadi M, Jafari SM, Hamishehkar H, Ghanbarzadeh B. Phytosterols as the core or stabilizing agent in different nanocarriers. Trends in Food Science & Technology. 2020;101:73-88. DOI: 10.1016/j.tifs.2020.05.004
26.Poli A, Marangoni F, Corsini A, Manzato E, Marroco W, Martini D, et al. Phytosterols, cholesterol control, and cardiovascular disease. Nutrients. 2021;13:2810. DOI: 10.3390/nu13082810
27.Nattagh-Eshtivani E, Barghchi H, Pahlavani N, Barati M, Amiri Y, Fadel A, et al. Biological and pharmacological effects and nutritional impact of phytosterols: A comprehensive review. Phytotherapy Research. 2022;36:299-322. DOI: 10.1002/ptr.7312
28.Vilahur G, Ben-Aicha S, Diaz-Riera E, Badimon L, Padró T. Phytosterols and inflammation source. Current Medicinal Chemistry. 2019;26:6724-6734. DOI: 10.2174/0929867325666180622151438
29.Blaco FCV, Julve J. Phytosterols in cancer: From molecular mechanisms to preventive and therapeutic potentials. Current Medicinal Chemistry. 2021;26:6735-6749. DOI: 10.2174/0929867325666180607093111
30.Aboobucker SI, Suza WP. Why do plants convert Sitosterol to Stigmasterol? Frontier in Plant Science. 2019;10:1-8. DOI: 10.3389/fpls.2019.00354
31.Xu Z, Chen Q , Zhang Y, Liang C. Coumarin-based derivatives with potential anti-HIV activity. Fitoterapia. 2021;150:104863. DOI: 10.1016/j.fitote.2021.104863
32.Tolba MS, Abdul-Malik MA, AMK E-D, Geies AA, Radwan SM, Melad R, et al. An overview on synthesis and reactions of coumarin based compounds. Current. Chemistry Letters. 2022;11:29-42. DOI: 10.5267/j.ccl.2021.009.007
33.Song XF, Fan J, Liu L, Liu XF, Gao F. Coumarin derivatives with anticancer activities: An update. Archiv der Pharmazie. 2020;353:e2000025. DOI: 10.1002/ardp.202000025
34.Carneiro A, Matos MJ, Uriarte E, Santana L. Trending topics on Coumarin and its derivatives in 2020. Molecules. 2021;26:501. DOI: 10.3390/molecules26020501
35.Sahoo CR, Sahoo J, Mahapatra M, Lenka D, Sahu PK, Dehury B, et al. Coumarin derivatives as promising antibacterial agent(s). Arabian Journal of Chemistry. 2021;14:102922. DOI: 10.1016/j.arabjc.2020.102922
36.Joshi PP. A review on biological activities of linear Pyranocoumarins. International Journal of Advance Study and Research Work. 2021;4:20-27. DOI: 10.5281/zenodo.4478566
37.Moraes WP. Caracterização do Mecanismo de Ação Antiinflamatória do Flavonóide BSA1 isolado da planta Brosimum acutifolium [Thesis]. Belém: Universidade Federal do Pará; 2011
38.Moretti C, Gaillard Y, Grenand P, Bévalot F, Prévosto JM. Identification of 5-hydroxy-tryptamine (bufotenine) in takini (Brosimum acutifolium Huber subsp. acutifolium C.C Berg, Moraceae), a shamanic potion used in the Guiana plateau. Journal of Ethnopharmacology. 2006;106:198-202. DOI: 10.1016/j.jep.2005.12.022
39.Vigerelli H, Sciani JM, Eula MAC, Sato LA, Antoniazzi MM, Jared C, et al. Biological effects and biodistribution of Bufotenine on mice. BioMed Research International. 2018;2018:1032638. DOI: 10.1155%2F2018%2F1032638
40.Fielding BC, Bezerra Filho CSM, Ismail NSM, Sousa DP. Alkaloids: Therapeutic potential against human coronaviruses. Molecules. 2020;25:5496. DOI: 10.3390/molecules25235496
41.Yan Y, Li X, Zhang C, Lv L, Gao B, Li M. Research Progress on antibacterial activities and mechanisms of natural alkaloids: A review. Antibiotics. 2021;10:318. DOI: 10.3390/antibiotics10030318
42.Dey P, Kundu A, Kumar A, Gupta M, Lee BM, Bhakta T, et al. Analysis of alkaloids (indole alkaloids, isoquinoline alkaloids, tropane alkaloids). In: Silva AS, Nabavi SF, Mina S, Nabavi SM, editors. Recent Advances in Natural Products Analysis. 1st ed. Elsevier; 2020. pp. 505-567. DOI: 10.1016/B978-0-12-816455-6.00015-9
43.Uzor PF. Alkaloids from plants with antimalarial activity: A review of recent studies. Evidence-Based Complementary and Alternative Medicine. 2020;12:8749083. DOI: 10.1155/2020/8749083
44.Mondal A, Ghandi A, Fimognari C, Atanasov AG, Bishayee A. Alkaloids for cancer prevention and therapy: Current progress and future perspectives. European Journal of Pharmacology. 2019;858:172472. DOI: 10.1016/j.ejphar.2019.172472
45.Liu C, Yang S, Wang K, Bao X, Liu Y, Zhou S, et al. Alkaloids from traditional Chinese medicine against hepatocellular carcinoma. Biomedicine & Pharmacotherapy. 2019;120:109543. DOI: 10.1016/j.biopha.2019.109543
46.Patyra A, Kołtun-Jasion M, Jakubiak O, Kiss AK. Extraction techniques and analytical methods for isolation and characterization of Lignans. Plants. 2022;11:2323. DOI: 10.3390/plants11172323
47.Xu XY, Wang DY, Li YP, Deyrup ST, Zhang HJ. Plant-derived lignans as potential antiviral agents: A systematic review. Phytochemistry Reviews. 2021;21:239-289. DOI: 10.1007/s11101-021-09758-0
48.Pan JY, Chen SL, Uang MH, Wu J, Sinkkonen J, Zoud K. An update on lignans: Natural products and synthesis. Natural Product Reports. 2009;26:1251-1292. DOI: 10.1039/B910940D
49.Macedo AL, Santos TCC, Valverde AL, Moreira DL, Vasconcelos TRA. An overview of Neolignans of the genus piper L.: Isolation methods and biological activities. Mini-Reviews in Medicinal Chemistry. 2017;17:693-720. DOI: 10.2174/1389557516666161130094826
50.Liu Y, Wang X, Fan X, Ge M, Fang L, Yuan Y, et al. Coordination-precipitation synthesis of metal Sulfide with phase transformation enhanced reactivity against antibiotic-resistant bacteria. Advanced Functional Materials. 2023;33:2212655. DOI: 10.1002/adfm.202212655
51.Vicetti MCP, Mejias A, Leber A, Sanchez PJ. A decade of antimicrobial resistance in Staphylococcus aureus: A single center experience. PLoS One. 2019;14:e0212029. DOI: 10.1371/journal.pone.0212029
52.Vestergaard M, Frees D, Ingmer H. Antibiotic resistance and the MRSA problem. Microbiology Spectrum. 2019;7:1-12. DOI: 10.1128/microbiolspec.gpp3-0057-2018
53.Silva V, Almeida L, Gaio V, Cerca N, Manageiro V, Caniça M, et al. Biofilm formation of multidrug-resistant MRSA strains isolated from different types of human infections. Pathogens. 2021;10:970. DOI: 10.3390/pathogens10080970
54.Cascioferro E, Carbone D, Parrino B, Pecoraro C, Giovannetti E, Cirrincione G, et al. Therapeutic strategies to counteract antibiotic resistance in MRSA biofilm-associated infections. ChemMedChem. 2021;16:65-80. DOI: 10.1002/cmdc.202000677
55.Craft KM, Nguyen JM, Berg LJ, Townsend SD. Methicillin-resistant Staphylococcus aureus (MRSA): Antibiotic-resistance and the biofilm phenotype. MedChemComm. 2019;10:1231-1241. DOI: 10.1039/C9MD00044E
56.Correia AF, Segovia JFO, Gonçalves MCA, Oliveira VL, Silveira D, Carvalho JCT, et al. Amazonian plant crude extract screening for activity against multidrug-resistant bacteria. European Review for Medical and Pharmacological Sciences. 2008;12:369-380
57.Roumy V, Ruiz Macedo JC, Bonneau N, Samaillie J, Azaroual N, Encinas LA, et al. Plant therapy in the Peruvian Amazon (Loreto) in case of infectious diseases and its antimicrobial evaluation. Journal of Ethnopharmacology. 2020;1:112411. DOI: 10.1016/j.jep.2019.112411
58.Senra MRPS, Caneschi CA, Chaves MGAM, Mota M, Stroppa PHF, Barbosa W, et al. In vitro antifungal activity and cytotoxicity screening of dry crude extracts from Brazilian Amazonia plants. African Journal of Traditional, Complementary, and Alternative Medicines. 2018;15:13-21. DOI: 10.21010/ajtcam.v15i4.2
59.Görkem A, Sav H, Kaan Ö, Eren E. Coronavirus disease and candidemia infection: A case report. Journal de Mycologie Médicale. 2021;31:101155. DOI: 10.1016/j.mycmed.2021.101155
60.Adwas AA, Elsayed ASI, Azab AE, Quwaydir FA. Oxidative stress and antioxidant mechanisms in human body. Journal of Applied Biotechnology and Bioengineering. 2019;6:43-47. DOI: 10.15406/jabb.2019.06.00173
61.Surai PF, Kochish II, Fisinin VI, Kidd MT. Antioxidant defence systems and oxidative stress in poultry biology: An update. Antioxidants. 2019;8:235. DOI: 10.3390/antiox8070235
62.Forman HJ, Zhang H. Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy. Nature Reviews Drug Discovery. 2021;20:689-709. DOI: 10.1038/s41573-021-00233-1
63.García-Caparrós P, Filippis L, Gul A, Hasanuzzaman M, Ozturk M, Altay V, et al. Oxidative stress and antioxidant metabolism under adverse environmental conditions: A review. The Botanical Review. 2021;87:421-466. DOI: 10.1007/s12229-020-09231-1
64.Wołosiak R, Drużyńska B, Derewiaka D, Piecyk M, Majewska E, Ciecierska WE, et al. Verification of the conditions for determination of antioxidant activity by ABTS and DPPH assays—A practical approach. Molecules. 2022;27:50. DOI: 10.3390/molecules27010050
65.Gurning K. Determination antioxidant activities methanol extracts of bangun-bangun (Coleus amboinicus L.) leaves with DPPH method. Jurnal Pendidikan Kimia. 2020;12:62-69. DOI: 10.24114/jpkim.v12i2.19397
66.Martins FJ, Caneschi CA, Vieira JLF, Barbosa W, Raposo NRB. Antioxidant activity and potential photoprotective from Amazon native flora extracts. Journal of Photochemistry and Photobiology B: Biology. 2016;161:34-39. DOI: 10.1016/j.jphotobiol.2016.05.012
67.Behnia F, Sheller S, Menon R. Mechanistic differences leading to Infectios and sterile Inflamation. American Journal of Reproductive Immunology. 2021;75:505-518. DOI: 10.1111/aji.12496
68.Francesch C, Campisi J. Chronic inflammation (Inflammaging) and its potential contribution to age-associated diseases. Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2014;69:54-59. DOI: 10.1093/gerona/glu057
69.Donath MY, Meyer DT, Boni-Schnetgler M. Inflammation in the pathophysiology and therapy of Cardiometabolic disease. Endocrine Reviews. 2019;40:1080-1091. DOI: 10.1210/er.2019-00002
71.Moraes WP. Estudo Sobre o Efeito de um Flavonóide Isolado da planta Brosimum acutifolium e de uma lignana de Virola micheli [Dissertation]. Belém: Universidade Federal do Pará; 2008
72.Takashima J, Asano S, Ohsaki A. Murinins a – C, three new lignoids from Brosimum acutifolium and their protein kinase inhibitory activity. Planta Medica. 2002;68:621-625. DOI: 10.1055/s-2002-32906
73.Campbell BCV, Silva DA, Macleod MR, Coutts SB, Schwam LH, Davis SM, et al. Ischaemic stroke. Nature Reviews Disease Primers. 2019;5:1-22. DOI: 10.1038/s41572-019-0118-8
74.Roxa GN, Amorim ARV, Caldas GRF, Ferreira ASH, Rodrigues FEA, Gonçalves MOSS, et al. Perfil epidemiológico dos pacientes acometidos com AVC isquêmico submetidos a terapia trombolítica: uma revisão integrativa. Brazilian Journal of Development. 2021;7:7341-7351. DOI: 10.34117/bjdv7n1-496
75.Diniz HLN, Sousa MNA, Farias TBC. Acidente vascular cerebral isquêmico: definindo a melhor terapia trombolítica. Revista Eletrônica Acervo Saúde. 2023;23:e11605. DOI: 10.25248/reas.e11605.2023
Kelly Roberta Pinheiro Pantoja, Eduardo Gama Ortiz Menezes, Diana das Graças de Oliveira, Jean Maurício Leão Pinheiro, Verônica Maria Souza Bezerra, Fernando de Freitas Maués de Azevedo and Raul Nunes de Carvalho Júnior
Submitted: 20 May 2023Reviewed: 15 June 2023Published: 07 August 2023
Open access peer-reviewed chapter - ONLINE FIRST
