Received date: January 28, 2016; Accepted date: January 30, 2016; Published date: February 07, 2016
Citation: Branco BS, Rodrigues TS, Lima ÉD, et al. Chemical Constituents and Biological Activities of Araucaria angustifolia (Bertol.) O. Kuntze: A Review. J Org Inorg Chem. 2016, 2:1.
Araucaria angustifolia is a tree that belongs to Araucariaceae family and it is mainly found in Southern Brazil. This plant has a notable therapeutical history in folk medicine holding great socioeconomic and environmental importance. Until now, some studies were conducted to assess its chemical composition, biological and pharmacological properties. The studies have shown that the bark, knot, needles (leaves), seeds and bracts (sterile seeds) contain high concentrations of active compounds and exhibit different biological effects. In the folk medicine the different parts of this plant are used to treat various types of illnesses, such as shingles, respiratory tract infections, sexually transmitted diseases and some types of wounds. Bearing this in mind, this review focuses on all currently chemical and biological effects already reported for A. angustifolia and provide a novel perspective and useful information for future research.
Araucaria is one among three genera that belong to the family Araucariaceae, occupying an isolated position amidst the conifers . The genus Araucaria includes nineteen species and presents the largest geographical range in this family, widespread from South America to Australia and Pacific islands . Although the family Araucariaceae is now restricted to the southern hemisphere , fossil evidence shows that it previously occurred also in the northern part of the globe . Araucaria angustifolia (Bertol.) O. Kuntze is a subtropical species known popularly as Araucaria or Brazilian pine. Native species can be found in mountain climate throughout southern Brazil, northeastern Argentina and eastern Paraguay . Nowadays, A. angustifolia is critically endangered  due to long periods of logging for wood and agriculture purposes . The Araucaria seed, named pinhão, is a seasonal product and has great nutritional value being a source of dietary fiber, carbohydrates, proteins and minor nutrients[6-8]. More importantly, they contain higher content of phenolic compounds . In addition to the powerful chemical characterization of the seeds, other parts of the tree are equally important. Studies have reported that the resin (found in the wood and knots), the dead bark (which is naturally discarded by the tree) and the leaves (needles) retain an intriguing chemical composition with dynamic biological activity [10-16]. Our group has importantly contributions regarding A. angustifolia biological effects. We reported that bracts (sterile seeds) contain high levels of chemical compounds with important pharmacological actions in several models of study [17-20]. Despite the different extraction conditions employed in distinct studies, phenolic compounds can be regarded as the major constituents in this particular plant. Even though few pharmacologicalstudies have been performed on this plant, there is a notable history of medicinal use by native populations. Infusions of leaves, bark and knots are used to treat anemia, muscle strains, varices, renal and sexually transmitted diseases [21-23]. Moreover, the syrup produced from resin is used to treat respiratorytract infections , indicating a therapeutic versatility in the empiric uses of A. angustifolia . Although the scientific literature about this plant is scarce, the majority of the studies have attempted to identify their chemical constituents and left aside their role in biological systems. Given this, the purpose of this review is to provide an overview of the main chemical compounds found in A. angustifolia and its biological activities, bringing evidences as basis for further research.
A. angustifolia is a subtropical gymnosperm pertaining to the family Araucariaceae, order Coniferales. This species was described for the first time by Bertoloni in 1820 as Columbea angustifolia Bert. After, it was redescribed by Richard Rich as Araucaria brasiliana and rectified by Otto Kuntze as Araucaria angustifolia (Bert.) Ktze . It occurs as a major species within the Araucaria moist forests favored by altitudes ranging from 500 to 1,500 m . The tree is tolerant to low temperatures  and has physiological adaptability to light and shade shifting conditions of the environment . A. angustifolia stands out among other arboreal species due to its large and umbelliform canopy (Figure 1). It features a rectilinear, cylindrical trunk that can reach 25 to 50 m height and may range between 1 to 2 m in diameter . The trunk presents a purplish-brown colored, rough outer shell and an inner shell which is resinous and whitish . As time goes by, the outer shell (dead bark) is naturally discarded by the tree, which may live 200 years on average . The young tree is symmetrical, cone shaped, covered with alternate and grouped branches from base to apex, containing dark-green acicular (needle-shaped) leaves that remain attached to the tree for many years and can reach up to 6 cm long and 1 cm wide . A. angustifolia is predominantly dioecious , i.e., it features male and female specimens that have their own distinct strobili. The female strobili, known as cone, are globular or ovoid, having closely overlapping scales  and bracts inserted on a conic central axis (Figure 2A). The male catkins are elongated, cylindrical, dense and covered by scales (Figure 2B), which arrange themselves in a spiral . The scales from the base open to allow the release of pollen and dissemination occurs through wind. Both strobili develop during summer . The fecundated cone (Figure 3A) may measure 10 to 25 cm in diameter and weigh up to 4.7 kg, containing more than 1,000 elements , including seeds (Figure 3B) and bracts (Figure 3C). Bracts occurrence is about five times higher than fertile seeds . The reproductive process of species is long. Pollination occurs during September and October and, once fertilized, the cones mature in 2 to 3 years [1,29]. It usually takes 12 to 15 years for a young plant to start producing seeds. These seeds, popularly known as pinhão, are dispersed mainly from May to August [1,25]. They exhibit yellowish-brown coloration, encased in a very resistant dark-brown coat along with an internal adherent membrane (Figure 4). Araucaria seeds are fleshy and have ovateoblong format, ranging from 3 to 8 cm in length and 1 to 2.5 cm in width, weighing approximately 8 g [6,9].
The medicinal potential of A. angustifolia has been initially explored by indigenous populations. Posteriorly, it began to be widely used in different parts of South America for treatment of several illnesses. Different parts of the tree (bark, resin, knots leaves and seeds) are employed in folk medicine, prepared mainly as infusions or tinctures. In respect to the empirical use of A. angustifolia bark, there are some reports about the use of infusions in order to treat topically muscle strains and varices . Besides bark, the knots extracted from old trunk are used orally as infusion for treatment of renal and sexually transmitted diseases [21,22]. Moreover, a syrup produced from bark resin is used to treat respiratory tract infections, mainly bronchitis . A. angustifolia leaves are also employed in ethnomedicine. Infusion of leaves (young or senescent) is orally used for the treatment of scrofula, fatigue and anemia, whereas tinctures from them are topically used on dermatological conditions such as dryness skin and wounds [21,22,24]. The leaves are also used to treat herpes disease, since they exhibit important antiviral activity . Araucaria seeds are medically employed in treatment of heartburn, anemia and tumors [22,23].
Apart from the empiric uses of the seeds, they are considered an excellent source of energy and nutrients, due to its constitution of complex carbohydrates  especially starch which displays low glycemic index when compared to white bread . Furthermore, it presents low contents of lipids and proteins, being a source of dietary fiber, magnesium and copper (Table 1). Proteins from Araucaria seeds has nutritional value comparable to legume seeds that contain lysine and histidine as limiting amino acids , and may be used also as a complementary source of protein in food formulations . Cooked seeds are reported as food of low glycemic index. This is mainly due to the high content of amylose in the starch that probably contributes to the formation of resistant starch in the seeds after cooking, generating a slow absorption of glucose by the organism . Consumption of foods that present low glycemic response might play an important role in the prevention and treatment of metabolic chronic diseases and their cardiovascular complications, such as dyslipidemia, obesity and diabetes .
|Moisture (g/100g)||50.35 ± 0.71|
|Starch (g/100g)||34.48 ± 0.72|
|Protein (g/100g)||3.31 ± 0.05|
|Lipid (g/100g)||1.26 ± 0.09|
|Ash (g/100g)||1.41 ± 0.02|
|Dietary Fiber (g/100g)||Soluble||0.55 ± 0.18|
|Insoluble||5.17 ± 0.25|
|Adapted from Cordenunsi et al.  and Brazilian Food Composition Table |
Table 1: Proximate composition of cooked Araucaria angustifolia seeds (pinhão).
Besides carbohydrates and proteins of nutritional interest, A. angustifolia is reported to contain important secondary metabolites. The plant is a rich source of polyphenols, besides steroids and terpenoids. A complete overview of the main chemical compounds described in different parts of A. angustifolia is shown in Table 2 and a description of these constituents is given below.
|Plant Material||Solvent Used||Analysis Method||Compounds Identified||Reference|
|Bark||Benzene||Chromatography||(+)-pinoresinol dimethyl ether (eudesmine)P, sitosterolS and sugiolT|||
|Bark||Ethanol/water||LC/UV spectrophotometry/NMR||Benzoic acidP, p-hydroxybenzoicacidP, protocatechuicacidP, quercetinP, (-)-epiafzelechinprotocatechuateP, (-)-epiafzelechinp-hydroxybenzoateP and (-)-epicatechinP|||
|Bracts||Water||HPLC/UV spectrophotometry||CatechinP, epicatechinPand rutinP|||
|Bracts||Water||HPLC/UV spectrophotometry||CatechinP, epicatechinP, quercetinP and apigeninP|||
|Bracts||Water||HRMS (MS, MS/MS mode)||Quinic acid, 4'-methoxytectorigeninP, 3-glucoside-dihydroquercetinP and amentoflavone 4',4'',7,7''-tetramethyl etherP|||
|Knot||Benzene||Chromatography/13C NMR||SecoisolariciresinolmonomethyletherP and lariciresinol-4-methyl etherP|||
|Knot||Benzene||Chromatography/13C NMR||PinoresinolP, secoisolariciresinolP, lariciresinolP, isolariciresinolP and isolariciresinol-4'-methyl etherP|||
|Leaves||Methanol||HPLC/MS/NMR||AmentoflavoneP, mono-, di-, tri- and tetra-O-methylamentoflavoneP and ginkgetinP||[13,14]|
|Leaves||Ethanol / water||HPLC/TLC/UV spectrophotometry/NMR||BilobetinP, II-7-O-methyl-robustaflavoneP and cupressuflavoneP|||
|Leaves||Ethanol||GC/MS||Β-sitosterolS, ent-kaureneT and phyllocladeneT|||
|Leaves (exudate)||Acetone||TLC/CG-MS||p-coumaricacidP, Eand ZcommunicditerpenicacidsT|||
|Propolis||Ethanol||TLC/CG/CG-MS||5,6,7-trihydroxy-3,4'-dimethoxyflavoneP, kaempferidP, aromadendrine-4'-methyl etherP, Eand Z2,2-dymethyl-6-carboxyethenyl-8-prenyl-2H-benzopyranesP, dihydrocinnamicacidP, p-coumaricacidP, ferulicacidP, caffeicacidP and di- and triterpenesT|||
|Propolis||Ethanol/water||HPLC/UV spectrophotometry/NMR||QuercetinP, rutinP, gallicacidP, protocatechuicacidP, chlorogenicacidP and its estherderivates, p-coumaricacidP, syringicacidP, vanillicacidP, caffeicacidP and ferulicacidsP|||
|Resin (knot)||Chloroform/methanol||TLC/1H and 13C NMR||HinokiresinolP,cryptoresinolP, secoisolariciresinolP, isolariciresinolP, pinoresinolmonomethyletherP, 2,3-bis-(p-hydroxyphenyl)-2-cyclopentene-1-onePand 4,4'-dihydroxychalconeP|||
|Resin (wood)||Dichloromethane/methanol||GC/MS||LignansP, 4-hydroxybenzaldehydeP, hydroquinoneP, p-coumaricacidP, ferruginolditerpeneT|||
|Seedling stages||Ethanol||TLC/MS/NMR||E and ZoctadecylferulateP, biflavonesP, benzaldehydesP and its derivates, vanillinP, pinoresinolP, eudesminP, lariciresinolP, cabreuvineP, irisolidoneP and diterpenesT|||
|Seeds||Methanol||HPLC||CatechinP and quercetinP|||
|Seeds||Ethanol / water||HPLC||CatechinP, quercetinP and gallicacidP|||
|Seeds||Methanol||HPTLC||FlavonoidsP and proanthocyanidinsP|||
|Seeds (coat)||Ethanol / water||Chromatography||ProanthocyanidinsP|||
Table 2: Overview on the chemical constituents identified in different parts of Araucaria angustifolia.
Polyphenols are structurally characterized by the presence of a benzene ring bound to one or more hydroxyl (-OH) groups . Among the antioxidant compounds that integrate human diet, polyphenols are majority and great quantities of them are found in fruits, vegetables, nuts, cereals, chocolate and beverages including tea, coffee and wine (for review, see Ref. ). Regular consumption of polyphenols brings benefits for health specially reducing the risk of developing age-related degenerative diseases. These beneficial effects are associated to their capacity to scavenge oxidatively generated free radicals, such as those derived from lipids and nucleic acids [35,36]. There are a variety of classification systems for polyphenols, though they are generally divided into two major distinguishable classes regarding their basic chemical structure: flavonoids and nonflavonoids .
Flavonoids: Flavonoids may be divided into six subclasses: flavonols, flavones, isoflavones, flavanones, anthocyanidins, and flavan-3-ols . The most common flavonoids found in A. angustifolia have their chemical structure presented in (Figure 5). Catechin (Figure 5A) and epicatechin (Figure 5B) are flavan- 3-ols, the most complex subclass of flavonoids. This subclass ranges from simple monomers to oligomeric and polymeric proanthocyanidins, which are also known as condensed tannins [34,37]. Quercetin (Figure 5C) is a flavonol, whereas apigenin (Figure 5D) is a flavone. Seccon et al.  showed that the hydroalcoholic extract from Araucaria dead bark presents a total phenolic content of 64 mg/g of gallic acid equivalents (including 1.85 mg/g of anthocyanin content and 12 mg/g of proanthocyanidin content) along with the presence of flavonols, mainly quercetin, besides the flavan-3-ols catechin and epicatechin. Biflavonoids (dimeric flavonoids) were identified in A. angustifolia leaves [13-15], besides high amounts of proanthocyanidins . Flavonoids are also found in A. angustifolia propolis, which is the resinous substance collected from the tree and processed by bees [38,39], and also in the seeds. Cordenunsi et al.  described that, in the seed, phenolic compounds can migrate from the internal coat to the pulp during heating process, and therefore significant amounts of catechin and quercetin may be found in cooked seed. Similar results were reported in another study , showing differences between extracts obtained from cooked and raw seeds regarding flavonoids (11.89 ± 0.26 μg/mg in cooked seeds and 1.16 ± 0.02 μg/mg in raw seeds extract) and proanthocyanidins (40.70 ± 0.59 μg/mg in cooked seeds and 0.45 ± 0.02 μg/mg in raw seeds extracts) contents. Recently, Mota et al.  investigated two extracts, one from the external coat and other from the inner seed pulp (endosperm and embryo). Both of them presented proanthocyanidins in its constitution, but the coat extract exhibited around tenfold the concentration of proanthocyanidins compared to inner seed extract (148 versus 10 mg cyanidine chlorohydrate/g extract). Taking into account the high levels of flavonoids found in Araucaria seeds, our research group has focused on the bracts (sterile seeds), demonstrating that this material is rich in flavan-3-ols, flavonols , flavones  and biflavonoids . Biflavonoids were also reported by Fonseca et al.  in tissues samples from A. angustifolia at different stages of differentiation and development, showing that seedlings stems, which are source of explants, display a variety of apigenin dimers.
Phenolic acids and their derivatives: Phenolic acids, other important class of polyphenols, can be classified as derivatives of either benzoic acid or cinnamic acid. Benzoic acid derivatives include gallic (3,4,5-trihydroxy-), vanillic (4-hydroxy-3-methoxy-) and protocatechuic (3,4-dihydroxy-) acids, whereas p-coumaric (4-hydroxy-), caffeic (3,4-dihydroxy-), and ferulic (4-hydroxy- 3-methoxy-) acids are cinnamic acid derivatives. In addition, phenolic acids may originate from hydroxycinnamic acid, such as chlorogenic acid (3-caffeoylquinic acid) . It has been shown that A. angustifolia species contain phenolic acids (Table 2), being gallic acid (Figure 5E) the most common one. This compound was already detected in the seeds  and in the propolis , whereas benzoic acid (Figure 5F) was identified in the bark , and also in the propolis . Exudate from leaves presents p-coumaric acid , which was also found in the propolis  along with dihydrocinnamic, ferulic and caffeic acids . Some other phenolic acids, including protocatechuic acid (9.1 μg/mL) and ester derivatives of chlorogenic acid (7.9 μg/mL), were quantified in A. angustifolia propolis along with minor amounts (<1.8 μg/ mL) of p-coumaric, syringic, vanillic, caffeic and ferulic acids .
Lignans: Plant secondary metabolites also include lignans, compounds that present carbon skeletons constructed by the oxidative coupling of two or three phenyl propane units and are biosynthesized through the shikimic acid pathway [10,44]. They are classified in five main types: lignans, neolignans, norlignans, hybrid lignans, and oligomeric lignans . These compounds are important components of foods since they occur either freely or in its glycosylated form in plants, mainly wood and resin [46,47]. Some lignans extracted from plants of the genus Araucaria have been analyzed, specifically in the species A. angustifolia [10,11,41,48-50] and A. araucana . Regarding A. angustifolia , lignans have been reported mainly in the wood, knots and resin, and the chemical structures of the most representative compounds are shown in (Figures 5G-5H). Fonseca et al. [48,49] identified different lignans, such as pinoresinol dimethyl ether, secoisolariciresinol, lariciresinol, isolariciresinol, isolariciresinol- 4’-methyl ether, secoisolariciresinol monomethyl ether and lariciresinol-4-methyl ether in the knots of A. angustifolia dead trees. Presence of lignans including secoisolariciresinols, lariciresinols and pinoresinols were also detected from the knot  and wood  resins. Other parts of A. angustifolia , including seedling stems  and trunk bark  also contain lignans (pinoresinols, lariciresinols and eudesmin) in its composition.
Steroids and terpenes
Steroids and terpenes are isoprenoids synthesized via the mevalonate pathway. They constitute an important group of small secondary metabolites associate with plant signaling. Terpenic compounds, including di- and triterpenes usually accumulate as conjugates with carbohydrates and other macromolecules, mainly as triterpene glycosides . Bankova et al.  reported the presence of terpenes, specifically diterpenic acids in the exudate from A. angustifolia leaves. Diterpenes were also identified in the wood resin . Besides resin, propolis contain terpenic compounds mostly di- and triterpenes . Steroids and terpenoids were also identified in A. angustifolia leaves  and bark, mainly the steroid sitosterol (Figure 5I) and the diterpene sugiol (Figure 5J) . Isoprenoids are synthesized during different stages of plant development. Fonseca et al.  detected diterpenes from the seedling to roots of A. angustifolia .
Despite its traditional uses as medicinal product, there are few studies aiming to elucidate the pharmacological potential of the different parts A. angustifolia tree. Major studies regarding the diverse biological activities are summarized in Table 3.
|Plant Material||Study Model||Biological Effects||Reference|
|Bark||In vivo (L929 mouse fibroblasts and rat liver microsomes)||Antioxidant activity against H2O2-induced oxidative stress; prevention of microsome lipid peroxidation|||
|Bracts||In vivo (cells of Saccharomyces cerevisae)||Antioxidant and antimutagenic activities against H2O2|||
|Bracts||In vitro (MRC5 human lung fibroblast cells)||Antioxidant and antigenotoxic activities against H2O2|||
|Bracts||In vivo (velvetbean caterpillar Anticarsia gemmatalis)||Entomotoxic; pro-oxidant and genotoxic activities|||
|Bracts||In vitro (human larynx Hep-2 cancer cells)||Antitumor and pro-apoptotic activities; induction of mitochondrial dysfunction; genotoxicity|||
|Leaves||In vitro (Escherichia coli HB 101 / plasmid pBluescript PUC19||Effective to quench singlet oxygen (1O2); DNA protection against single strand break|||
|Leaves||In vitro (Calf thymus DNA)||Protection against UV-induced thymine dimmers formation|||
|Leaves||In vitro (Herpes Simplex Virus type 1)||Antiviral activity|||
|Leaves||In vitro (Lactuca sativaseeds)||Allelopathic activity|||
|Leaves (exudate)||In vitro (Staphylococcus aureusand Candida albicans)||Antibacterial action but no antifungal effect|||
|Propolis||In vitro (human larynx Hep-2 cancer cells)||Cytotoxicity|||
|Propolis||In vitroand in vivo (human endothelial cells and chick embryos)||Antiproliferative, antitubulogenic and antiangiogenic activities|||
|Seeds||In vivo (human volunteers)||Low glycemic response|||
|Seeds||In vitro and in vivo (X. axonopodispv. passiflorae, C. michiganensissubsp. Michiganensis,rats and rabbits)||Antibacterial activity against Gram-positive and –negative; anti-inflammatory and hemagglutinating activities|||
|Seeds||In vivo (Swiss and Wistar rats)||Anti- and pro-edematogenic actions|||
|Seeds||In vivo (Swiss rats)||Depressant activity in the central nervous system|||
|Seeds (coat)||In vitro and in vivo (human and porcine α-amylase and rats)||Inhibition of human salivary and porcine pancreatic α-amylase; reduction in post-prandial glycemic levels in rats|||
Table 3: Overview on the biological effects of Araucaria angustifolia.
Antioxidant activity is the most reported biological action for A. angustifolia . The antioxidant defense system controls the levels of reactive oxygen species (ROS) promoting useful molecular functions minimizing oxidative damage . Taking into account that the misbalance of the antioxidant system lead to the generation of oxidative stress and this disturbance exerts a critical role in aging chronic degenerative diseases and cancer, natural products rich in antioxidants may be considered as health-promoting bioactive agents [53-55]. Corroborating with this evidence, several reports showed that A. angustifolia exerts antioxidant effects in different study models (Table 3). An extract from Araucaria dead bark demonstrated cytoprotective effects in mouse L929 fibroblasts against oxidative stress induced by hydrogen peroxide (H2O2). In a dose-responsive manner, the highest concentration of 1 mg/mL was able to increase cellular protection by 131% . The compound catechin isolated from the bark was able to protect against lipid peroxidation induced by UV radiation (IC50 18 ± 4 μM) and ascorbyl radical (IC50 6 ± 0.25 μM) exposure in rat liver treated microsomes . In a similar way, our group previously reported that an extract obtained from A. angustifolia bracts displayed antioxidant effects against ROS-induced oxidative stress in Saccharomyces cerevisiae. The concentration of 0.15% avoided cytotoxic effects induced by H2O2 and, the concentrations of 0.05, 0.10 and 0.15% exhibited nonmutagenic and antimutagenic activities in the same model. These effects were attributed to the antioxidant capacity of phenolic compounds, which could be responsible for neutralizing H2O2 avoiding hydroxyl radical formation, therefore preventing DNA damage . Our group also reported that the bracts extract presented antioxidant and antigenotoxic activities in MRC5 human lung fibroblast cells. In this study, the aqueous extract from Araucaria bracts (25 and 50 μg/mL) significantly protected MRC5 cells against H2O2-induced cytotoxicity and oxidative damage to lipids, proteins and DNA . Additionally, the bracts extract was able to avoid depletion of superoxide dismutase and catalase activities . Yamaguchi et al.  reported that a biflavonoid fraction obtained from extract of A. angustifolia leaves was effective to protect plasmid DNA against single strand break induced by either singlet oxygen or Fenton reaction at concentrations of 20 to 100 μM. The antioxidant effect of this extract was also evaluated in calf thymus DNA and the biflavonoid fraction was capable of preventing formation of cyclobutane thymine dimer (at concentrations of 0.5 to 2.0 mg) and 8-oxo- 7,8-dihydro-2’-deoxyguanosine (at concentrations of 100 and 500 μM), avoiding oxidation of nucleotides .
Antiproliferative and cytotoxic activities
There are few studies in the scientific literature regarding the potential anticancer effects of A. angustifolia . Búfalo et al.  reported cytotoxic effects of Araucaria propolis on human laryngeal epidermoid carcinoma (HEp-2) cells. In this study, it was observed cytotoxic effects induced by propolis in a dose (5, 10, 25, 50 and 100 μg/well) and time (6, 24, 48 and 72 h) dependent manner against HEp-2 cells in vitro. Moreover, changes in cell morphology were observed, including lysis and disorganization of the cellular monolayer. In another study, Meneghelli et al.  reported the effects of A. angustifolia propolis on viability, proliferation, cell migration, capillary tube formation, and angiogenesis using in vitro and in vivo models. Hydroalcoholic extract of propolis was able to decrease viability in 24 (IC50 297 μg/mL) and 72 (IC50 130 μg/mL) hours, proliferation (at doses of 130 to 180 μg/mL for 72 h) and tubulogenesis (at doses of 150 to 200 μg/mL for 24 h) on human endothelial cells. Furthermore, the angiogenesis and vasculogenesis processes, also evaluated in this study, were inhibited using chorioallantoic and yolksac membranes from chick embryos (450 mg propolis.kg-1), indicating that A. angustifolia propolis is a potential therapeutic agent for angiogenic diseases, such as cancer. Recently, our group demonstrated that the aqueous extract from A. angustifolia bracts present selective antiproliferative effects (IC50 250 μg/mL for 24 h) mediated by mitochondrial dysfunction and apoptosis activation on human larynx HEp-2 cancer cells. The inhibition of cell proliferation was accompanied by pro-oxidant effects, including oxidative damage to lipids and proteins, nitric oxide production, along with depletion of superoxide dismutase and catalase antioxidant activities at concentrations (100, 250 and 500 μg/mL). The bracts extract also generated genotoxic and apoptotic effects, as well as inhibition on complex I of the mitochondrial electron transport chain and reduction on ATP production, indicating the potential of bioactive compounds from A. angustifolia bracts on the modulation of mitochondrial function on cancer cells [19,56].
Allelopathic and entomotoxic activities
Plants produce and store high levels of secondary metabolites that are subsequently released into the environment, which may affect other plants or animals . Plants also present entomotoxic actions against insect-pests, showing an important potential to be explored mainly due to the emergence of insects resistant to chemical insecticides and to the rise of organic agriculture . There are only two studies in the scientific literature exploring the allelopathic and entomotoxic potentials of Araucaria . In a study conducted by Braine et al. , it was showed that the extract from A. angustifolia leaves (187.5 and 250 mg) presents allelopathic potential on germination and growth of Lactuca sativa seeds, and the main allelochemical compounds identified in the ethanolic extract were ent-kaurene and phyllocladene. This allelopathic potential seems to serve A. angustifolia on the successional dynamics of Araucaria Moist Forests. Our group has investigated the entomotoxic effect of an aqueous extract obtained from bracts of A. angustifolia on the velvetbean caterpillar Anticarsia gemmatalis (Lepidoptera: Erebidae) . This extract, rich in phenolic compounds, was able to increase the number of malformed pupae (0.15, 1.5 and 7.5 mg), along with a decrease in the emergence of the insects (1.5 and 7.5 mg), and these effects were related with the lipid, protein and DNA damage detected in the larvae via oxidative stress.
Antiviral and antibacterial activities
In traditional medicine A. angustifolia has been used for treatment of infectious diseases caused by pathogenic agents. The antiviral activity of Araucaria was showed in a study conducted by Freitas et al.  with Herpes simplex virus type 1 (HSV-1) model. HSV is a double-stranded DNA enveloped virus, extremely widespread in human populations and responsible for a broad range of human infectious diseases, such as gingivo-stomatitis, genital diseases and encephalitis. The crude hydroethanolic extract (HE) obtained from A. angustifolia leaves and some different fractions of this extract were able to induce virucidal activity against HSV-1, exhibiting antiherpetic potential (IC50 32.10 ± 3.65 μg/mL for HE). This effect was associated with the content of biflavonoids and proanthocyanidins present in the leaves.
Antibacterial potential of A. angustifolia was investigated in a few studies. Santi-Gadelha et al.  prepared an aqueous extract from Araucaria seeds and then purified and characterized a lectin (N-acetyl-D-glucosamine-specific lectin) with antibacterial activity (150 μg/mL) against Gram-negative (Xanthomonas axonopodis pv. passiflorae) and Gram-positive (Clavibacter michiganensis subsp. Michiganensis) strains at doses of 150 μg/mL. Bankova et al.  also reported the antibacterial action of leaves exudate (0.4 mg of extract) against strains of the pathogen Staphylococcus aureus, which is a major causing agent of nosocomial and communityacquired infections.
5.5 Anti-inflammatory and antiedematogenic activities
Chemical compounds from plants are able to exhibit antiinflammatory and antiedematogenic activities. It has been shown that A. angustifolia seeds may modulate acute inflammation process in vivo. Santi-Gadelha et al.  elucidate the mechanism involved in the anti-inflammatory effect of a lectin (N-acetyl- D-glucosamine-specific lectin) from aqueous extract of A. angustifolia seeds in rats. The inflammation was induced in a paw edema model by subcutaneous injection of carrageenan, which is able to release several inflammatory mediators, including biogenic amines, prostaglandins, and nitric oxide. Intravenous injection of lectin (0.01, 0.1 and 1 mg/kg) prior carrageenan reduced paw edema inhibiting the cellular event of acute inflammation via carbohydrate site interaction . In another study, Mota et al.  have described the effects of a lectin (N-acetyl-glucosamineligant) from A. angustifolia seeds in the same model of paw edema in rats, and the anti-inflammatory and pro-edematogenic actions were evaluated. Intravenous injection of lectin (0.1 and 1 mg/kg) inhibited the dextran-induced edema and vascular permeability, which were prevented by association of the lectin with its binding sugar N-acetyl-glucosamine. Lectin also inhibited edema induced by serotonin. The mechanism associated with anti-inflammatory and pro-edematogenic actions appears to be involved in a common pathway to activation or inhibition of inflammatory mediators from resident mast cells .
Actions on metabolism and central nervous system
Amongst the different parts of A. angustifolia , the seed has been reported as having effects on modulation of energetic metabolism and central nervous system. Araucaria seeds are rich in lectins [61,62], an important group of glycoproteins widely studied. Lectins are able to induce different actions in various biological systems, including cell agglutination and glycoconjugate precipitation, once they recognize and bind to carbohydrates or other substances derived from sugars . The effect of A. angustifolia seeds consumption on the glycemic metabolism was studied for the first time by Cordenunsi et al. . The analysis of the carbohydrate availability evaluated in a short-term assay (two weeks) in humans showed that the glycemic responses produced by seeds cooked with the coat were 23% lower when compared to white bread. This result is important because foods that present a low glycemic index are linked to the beneficial effects on preventing and controling chronic non-infectious diseases. In a recent study, Silva et al.  also investigated the effects of a seed coat extract on glycemic levels of rats and activity of α-amylases (human salivary and porcine pancreatic). The seeds coat extract (250 mg/kg), rich in proanthocyanidins, was effective in diminishing the post-prandial glycemic levels in rats after starch administration. Moreover, the extract was able to inhibit both human salivary (range up to 80 μg/mL) and porcine pancreatic (range up to 50 μg/mL) α-amylases, indicating that Araucaria seeds present potential to be used in therapeutic interventions aiming to suppress postprandial hyperglycemia in diabetic patients. The effects of Araucaria lectins on central nervous system were investigated in an animal model of epilepsy . Lectin was isolated and purified from A. angustifolia seeds, and then dissolved in saline before administration to rats. Seizures were induced with pentylenetetrazol, pilocarpine and strychnine and were monitored during 1 hour. The behavioral profile (locomotor activity) was also evaluated. Lectin (10 mg/ kg) increased latency to convulsions and latency to death in both the pentylenetetrazol- and strychnine-induced seizures; however it was not able to protect in the pilocarpine model. In addition, lectin (0.1, 1 and 10 mg/kg) was able to reduce locomotor activity, showing depressant effect similar to the drug diazepam. These effects were attributed to the capacity of lectin from Araucaria seeds to modulate GABAergic and glycinergic systems.
This is the first work that has summarized the relevant literature concerning the chemical constituents, biological activities and ethnobotanical aspects of the conifer A. angustifolia , an important plant with a long tradition of medicinal and nutritional uses in South America. This review provides many contributions for the natural products research area, since they show the beneficial effects performed by the chemical compounds existent in this plant for prevention and treatment of some human pathologies. Considering the social and ecological importance of A. angustifolia , it is essential that conservation programs must be performed and constantly updated. Moreover, it is also important to improve researches involving the development of pharmaceutical products using residual parts of the plant, since the use of bracts, dead barks and needles would not compromise A. angustifolia reminiscent populations nor human and animal feed.
This study was funded by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and Coordenação de Apoio de Pessoal de Nível Superior (CAPES). Cátia Branco is the recipient of a CAPES Research Fellowship and Mirian Salvador is the recipient of a CNPq Research Fellowship.
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