PHARMACEUTICAL BIOLOGY, 2018 VOL. 56, NO. 1, 253–268 https://doi.org/10.1080/13880209.2018.1454480

INVITED ARTICLE Brazilian medicinal plants with corroborated anti-inflammatory activities: a review

Victor Pena Ribeiro, Caroline Arruda, Mohamed Abd El-Salam and Jairo Kenupp Bastos Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeir~ao Preto, University of S~ao Paulo, Ribeir~ao Preto, Brazil

ABSTRACT ARTICLE HISTORY Context: Inflammatory disorders are common in modern life, and medicinal plants provide an interesting Received 3 January 2018 source for new compounds bearing anti-inflammatory properties. In this regard, Brazilian medicinal plants Revised 3 February 2018 are considered to be a promising supply of such compounds due to their great biodiversity. Accepted 15 March 2018 Objectives: To undertake a review on Brazilian medicinal plants with corroborated anti-inflammatory KEYWORDS activities by selecting data from the literature reporting the efficacy of plants used in folk medicine as NF-jB; PGE2; COX; ROS anti-inflammatory, including the mechanisms of action of their extracts and isolated compounds. Methods: A search in the literature was undertaken by using the following Web tools: Web of Science, SciFinder, Pub-Med and Science Direct. The terms ‘anti-inflammatory’ and ‘Brazilian medicinal plants’ were used as keywords in search engine. Tropicos and Reflora websites were used to verify the origin of the plants, and only the native plants of Brazil were included in this review. The publications reporting the use of well-accepted scientific protocols to corroborate the anti-inflammatory activities of Brazilian medi- cinal plants with anti-inflammatory potential were considered. Results: We selected 70 Brazilian medicinal plants with anti-inflammatory activity. The plants were grouped according to their anti-inflammatory mechanisms of action. The main mechanisms involved inflammatory mediators, such as interleukins (ILs), nuclear factor kappa B (NF-jB), prostaglandin E2 (PGE2), cyclooxygenase (COX) and reactive oxygen species (ROS). Conclusions: The collected data on Brazilian medicinal plants, in the form of crude extract and/or isolated compounds, showed significant anti-inflammatory activities involving different mechanisms of action, indi- cating Brazilian plants as an important source of anti-inflammatory compounds.

Introduction effects, making it necessary to search for new alternative substan- ces (Ghasemian et al. 2016). In this regard, natural products Medicinal plants represent a remarkable source in the treatment from plant origin with anti-inflammatory activity are considered of various human diseases. They are currently the focus of mod- to be an important source for the development of new thera- ern research due to their large chemical and biological diversity peutic agents. and by possessing a variety of compounds with promising bio- With regard to medicinal plants, Brazil is an important source logical activities (Yang et al. 2017). The main advantages of using due to its great biodiversity. Brazil has a wide variety of ecosys- herbal medicines are the low cost, affordability and usually fewer tems and shelters in the Amazon region, which is the largest side effects. Research studies performed on medicinal plants are tropical forest in the world, as well as in the cerrado vegetation, very important for confirming their safety and efficacy which is known as the world’s most biologically diverse savanna (Bhattacharya 2017). The urgent need for new therapeutic agents (Matheus et al. 2017; Newman 2017). Due to this great biodiver- with greater efficacy and fewer side effects has drawn a great sity, including the Atlantic forest and other biomes, many attention to medicinal plants with anti-inflammatory properties Brazilian medicinal plants have not been further investigated, (Lourenc¸o et al. 2012). and this opens the opportunity to explore these plants for the Inflammation is a process involved in the pathogenesis and discovery of new secondary metabolites that have the capacity to progression of several diseases. It is a physiological response that interfere with the inflammatory response (Bolzani et al. 2012). protects our body against tissue damage or microorganisms. The Brazil has more than 45,000 plant species, comprising 20–22% inflammatory reaction aims to restore the tissue affected by of the total number of plant species of the world, which may injury or infection (Medzhitov 2008). The inflammatory response explain the increasing number of used plants for several purposes serves as a defence tool for the organism, and it is controlled by in Brazil. Taking into account the pharmacological potential of several mechanisms. If the inflammation occurs in an exacer- Brazilian plant species, researchers have been performing novel bated way, it can cause several pathological disorders (Ashley studies and providing promising information regarding the used et al. 2012). If a marked inflammatory reaction occurs, it is Brazilian medicinal plants. necessary to use anti-inflammatory drugs that will regulate or Between 1988 and 2016, 34,614 research papers from Brazil suppress inflammation. These drugs usually have adverse side were published on natural products; the majority of them are

CONTACT Jairo Kenupp Bastos [email protected] Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeir~ao Preto, University of S~ao Paulo, Ribeir~ao Preto, SP 14040-903, Brazil ß 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 254 V. P. RIBEIRO ET AL. mainly focusing on medicinal plants. In 2014, it contributed with Structure–activity relationships (SARs) and quantitative struc- US$261 million to the market, being 5% of medicinal plants. ture–activity relationships (QSARs) of the antioxidant activity of Cordia verbenacea DC (Boraginaceae) leaves, commonly known flavonoids play an important role in determining their anti- as ‘erva-baleeira’ and ‘maria milagrosa’, have been used for a inflammatory effects. SAR and QSAR can provide useful tools for long time due to its healing and anti-inflammatory activities. revealing the nature of flavonoid antioxidant action and its use Because of that, Brazilian researchers have evaluated this plant as anti-inflammatory agents: quantitative structure–property rela- extract and its major compounds for treating inflammatory dis- tionships (QSPR) represent an attempt to correlate physicochem- orders and found that it displays a potent anti-inflammatory ical or structural descriptors of a set of structurally related activity, and few side effects. The Brazilian pharmaceutical com- compounds with their biological and pharmacological activities V pany (Ache R ) developed a phytotherapeutic medicine for treating or physical properties. Molecular descriptors usually include inflammation that contains the essential oil of C. verbenacea. The parameters accounting for electronic properties, hydrophobicity, product is considered to be an outbreak in the market because it topology and steric effects. Activities include chemical measure- is widely distributed in the Brazilian coast region. This product ments and biological assays. A crucial factor in advancing QSAR was released into the market in 2005 and it has been one of is to find information-rich descriptors for a molecule or a frag- the most commercialized phytotherapeutic medicines (Dutra ment. Once developed, QSARs provide predictive models of bio- et al. 2016). logical activity and may shed light on the mechanism of action. The Brazilian government is making efforts to ensure the Flavonoids may exert anti-inflammatory activity through their appropriate use of many Brazilian medicinal plants: since 2007, antioxidative effects as free radical scavengers, hydrogen donating the Brazilian Health System has authorized the distribution of compounds, singlet oxygen quenchers and metal ion chelators, twelve herbal medicines, and in 2009 it was released the list of which are attributed to the phenolic hydroxyl groups attached to national medicinal plants that are interesting for this system. In ring structures (Rice-Evans et al. 1997). Free radicals are con- other words, this list contains the names of the plants bearing stantly generated in our body during inflammation and for spe- medicinal potential that can lead to the development of new cific metabolic purposes. Examples of oxygen free radicals products. This list has a great value for the folk medicine, and it include singlet oxygen, superoxide, alkyl peroxyl (ROO ), alkoxyl is encouraging the research for determining the efficacy and (RO ) and hydroxyl (HO ). Among other functions, free radicals safety use of medicinal plants, as well as the advances in novel are involved in energy production, regulation of cell growth, and products development, besides stimulating the population in the intercellular signaling. However, when an imbalance between free use of medicinal plants and phytotherapics (Lorenzi and Matos radical generation and body defence mechanisms occurs, free 2002; Marmitt et al. 2015). radicals can attack lipids in cell membranes, proteins in tissues, In this review, the reported Brazilian medicinal plants with enzymes and DNA inducing oxidations, which cause membrane anti-inflammatory activities are highlighted and discussed. damage, protein modifications and DNA damage. This oxidative damage is considered to play a causative role in a series of human illnesses, such as inflammation, cancer and Active compounds with anti-inflammatory effects from heart diseases. Humans possess a wide array of antioxidant medicinal plants physiological defences to scavenge free radicals, chelate metal Flavonoid, polyphenolic, proanthocyanidin, alkaloid, terpenoid ions involved in their formation and repair damage. The activity and steroid compounds are usually responsible for the anti- of flavonoids is closely linked to their chemical structure. They inflammatory activities of plant extracts. These secondary are not equally physiologically active, presumably because of the metabolites act on different targets involved in the inflamma- presence of different substitutions of the hydroxyl groups in the tory pathway. basic flavonoid structure and differences in lipid solubility. A number of flavonoids are reported to possess anti-inflam- In the literature, there are many examples of flavonoids iso- matory activity both in vitro and in vivo. Several mechanisms of lated from medicinal plants found in Brazil with anti-inflamma- action are proposed to explain the in vivo anti-inflammatory tory activity (Figure 1), such as myricitrin (1) and myricetin (2) activities; however, they are not fully clarified. The major target isolated from the leaves of Campomanesia adamantium for anti-inflammatory activity is the inhibition of eicosanoid gen- (Cambess.) O. Berg (Myrtaceae) (Ferreira et al. 2013); quercetin erating enzymes including phospholipase A2, cyclooxygenases (3) and luteolin (4) isolated from Achyrocline satureioides (Lam.) (COXs) and lipoxygenases, leading to reduction of prostanoids D.C. (Asteraceae) (De Souza et al. 2007), among others. and leukotrienes (Kim et al. 2004). Other mechanisms include Other compounds with anti-inflammatory properties that are inhibition of histamine release, phosphodiesterase, protein kin- found in a large variety of medicinal plants are terpenoids. There ases, and activation of transcriptases. are several examples in the literature of terpenoids having anti- The basic structure of flavonoid has a flavan nucleus consist- inflammatory activity. Anti-inflammatory activity is attributed to ing of two benzene rings combined with an oxygen-containing triterpenes of the lupine type, as they are able to inhibit the syn- pyran ring (Aherne and O’Brien 2002). The various classes of fla- thesis of PGE2 and nitric oxide. Lupeol (5), a pentacyclic triter- vonoids differ in their level of oxidation of the C ring of the pene isolated from the stem bark of Pterodon emarginatus Vogel basic 4-oxoflavonoid (2-phenyl-benzo-c-pyrone) nucleus. (Fabaceae) inhibited IL-2, IFN-g and TNF-a, important pro- Common subfamilies of flavonoids are flavones, flavanes, flavo- inflammatory cytokines (Moraes et al. 2012). Diterpenes with nols, flavanols (catechins), anthocyanidins and isoflavones. anti-inflammatory activity were also isolated from Copaıfera spe- Flavonoids usually occur as glycosides in plants, because the cies. Among them, copalic acid (6) is the most abundant and has effect of glycosylation makes the flavonoid less reactive and more already been described to display anti-inflammatory activity water soluble, allowing its storage in the cell vacuole. Structural (Santiago et al. 2015). diversity in each flavonoid family arises from the various hydrox- Sesquiterpenes are found in a wide range of essential oils. ylation, methoxylation and glycosylation patterns of ring a-Humulene (7) and (–)-transcaryophyllene (8) sesquiterpenes substitutions. were isolated from the essential oil of Cordia verbenacea and are PHARMACEUTICAL BIOLOGY 255

Figure 1. Chemical structures of some selected secondary metabolites with anti-inflammatory activity. also major compounds in Copaifera multijulga Hayne (Fabaceae) Cytokines are soluble and low molecular weight glycoproteins essential oil, which display anti-inflammatory properties through that are involved in several relevant biological processes (Lin the inhibition of inflammatory mediators IL-1 and TNF-a et al. 2000). Cytokines are directly linked to inflammation as (Moraes et al. 2012). they can exaggerate or reduce the inflammatory response through Other examples of triterpenes with anti-inflammatory activity pro or anti-inflammatory cytokines, and in a metabolic disorder, are the ones isolated from Carapa guianensis Aubl. (Meliaceae), there is an exacerbated formation of pro-inflammatory cytokines such as 6a-acetoxygedunin (9), which was active by inhibiting that can lead to damage to vital organs. The pro-inflammatory pro-inflammatory mediators (Penido, Conte, Chagas, et al. 2006). cytokines are interleukins (ILs) 1, 2, 6, 7, tumor necrosis factor The two monoterpenes b-myrcene (10) and limonene (11), iso- (TNF) and interferon-c (IFN-c) (Kundu and Surh 2012). lated from the essential oils of Porophyllum ruderale (Jacq.) Cass. After tissue damage, the inflammatory response is initiated (Asteraceae) and Conyza bonariensis (L.) Cronquist (Asteraceae), through TNF-a production, being the first pro-inflammatory respectively, displayed anti-inflammatory activity (Souza mediator to be released (Miller et al. 2009). As the TNF-a pro- et al. 2003). duction increases, induction of the production of other pro- Alkaloids with anti-inflammatory properties have also been inflammatory cytokines and oxidative system occurs. Among the described in the literature. Many alkaloids have been isolated activities attributed to TNF-a are the production of prostaglandin from native plants from Brazil, which have been studied for the E2 (PGE2), activation of coagulation and cellular apoptosis treatment of inflammation, such as: Bukittinggine (12) isolated (Ulloa and Tracey 2005). In addition, TNF-a causes the activa- from Sapium baccatum Roxb. (Euphorbiaceae), which is able to tion of nuclear transcription factor kappa B (NF-jB), which suppress the levels of PGE2 (Panthong et al. 1998); berberine results in the release of other pro-inflammatory cytokines, in (13) found in species of the genus Berberies, which significantly addition to chemokines and proteases. Therefore, there is the for- € decreases paw oedema (Kupeli et al. 2002), spectaline (14) mation of IL-1 having a similar function to that of TNF, stimu- obtained from Cassia spectabilis DC. (Fabaceae) a plant found in lating the activation of cyclooxygenase-2 (COX-2) and the the northeastern region of Brazil (Viegas et al. 2008), and milo- production of nitric oxide, followed by IL-6 production, another 15 nine ( ) obtained from the leaves of Cissampelos sympodialis important pro-inflammatory cytokine, responsible for eliciting Eichler (Menispermaceae) (Melo et al. 2003), among others. acute phase protein synthesis by hepatocytes (Zhang and Jianxiong 2007). Later, the action of these cytokines triggers the Mechanisms of anti-inflammatory actions of Brazilian synthesis of other pro-inflammatory mediators, like other cyto- plants and their isolated compounds kines, chemokines, nitric oxide and others, causing the spread of inflammatory response (Gebhard et al. 2000). Changes in modern man’s lifestyle have contributed to the preva- Cyclooxygenases are important enzymes involved in the lence of certain diseases which are related to chronic inflamma- inflammatory response, specifically in the synthesis of prostaglan- tion. The inflammatory response that is not capable of solving a dins. This enzyme exists in three isoforms COX-1, COX-2 and particular injury can proceed and cause a chronic process of COX-3. Cyclooxygenase, as well as lipoxygenase are formed by inflammation. Therefore, it is important to understand the mech- arachidonic acid, which is released from the cell membrane anisms involved in the stimulation and regulation of inflamma- through the action of the enzyme phospholipase A2. These tion (Kotas and Medzhitov 2015). enzymes through a series of reactions lead to prostaglandins, 256 V. P. RIBEIRO ET AL.

Figure 2. Anti-inflammatory targets of compounds in the inflammatory response. thromboxanes and leukotrienes, which are considerable inflam- mediators, such as ILs, PGE2, NF-jB, COX and reactive oxygen matory markers (Kawabata 2011). species (ROS). Other cytokines that play an important role in the inflamma- tory response are anti-inflammatory cytokines, which regulate the activities of pro-inflammatory cytokines for homeostasis. Among Interleukins/TNF-a these anti-inflammatory mediators are IL-4, 10, 13 and trans- As mentioned before in the inflammatory process, there are anti- forming growth factor (TGF) (Munroe et al. 2010). inflammatory and pro-inflammatory cytokines, and both play an As an exacerbated inflammatory response can lead to path- important role in the activation, maintenance and regulation of ology, it is necessary to use anti-inflammatory drugs; an alterna- inflammation. Therefore, compounds that act by inhibiting or tive to conventional treatment of inflammation are the medicinal activating these cytokines are interesting candidates for the dis- plants. In general, compounds with anti-inflammatory activity act covery of new anti-inflammatory drugs. either by inhibiting pro-inflammatory mediators or contributing The inflammatory mediator TNF-a is the first cytokine to the production of anti-inflammatory mediators (Figure 2). The released after the inflammatory stimulus, promoting several intra- most common treatment for inflammatory disorders includes the cellular events, thus triggering other factors, such as the activa- use of non-steroidal anti-inflammatory drugs (NSAIDs) or corti- tion of NF-jB and promoting the release of other pro- costeroids, but they have considerable adverse effects (Burian and inflammatory cytokines such as IL-1 and IL, six among others. Geisslinger 2005). High concentrations of TNF-a is associated with various inflam- These medicinal plants are mostly used in the form of crude matory diseases, such as rheumatoid arthritis. If this cytokine is extracts or isolated compounds. Therefore, the research has fun- uncontrolled, it can lead to a systemic inflammatory process that damental importance in order to confirm the effectiveness of can progress to shock and even death. Therefore, compounds these plants and to identify which compounds are responsible for that inhibit these cytokines have a high anti-inflammatory poten- the biological activity, as well as to elucidate the mechanisms tial (Sfikakis 2010). involved in the pharmacological action of each plant. Brazilian Infusions of flowers and leaves of Achyrocline satureioides medicinal plants with anti-inflammatory activity presented in this have shown interesting immunomodulatory activity, which may review were grouped according to their respective mechanisms of influence inflammation at low concentrations (0.006–0.03 mg/mL). action. The main mechanisms of Brazilian medicinal plants were Their anti-inflammatory effect is due to decreasing interleukins IL-4 found to be attributed to their action on the inflammatory and IL-10 production, as well as ROS (Cosentino et al. 2008; PHARMACEUTICAL BIOLOGY 257

Da Silva et al. 2016). The crude extract, its fractions and isolated the isolated monoterpenes b-myrcene and limonene from the oil compounds from Ageratum conyzoides L. (Asteraceae) aerial parts were tested for inhibition of the cytokines IFN-c and IL-4. are able to reduce the production of IL-6, TNF-a and INF-c (Mello Both monoterpenes and the essential oils were able to inhibit et al. 2016). The same mechanism was described for the stem bark the production of IFN-c at a concentration of 100 mg/kg (Souza extract of Anacardium occidentale L. (Anacardiaceae), which is able et al. 2003). to inhibit the production of IL-6 and TNF-a for a period of 24 h Copaifera langsdorffii Desf. (Fabaceae) oleoresin is one of the (Olajide et al. 2013). most widely used natural products in Brazilian folk medicine. It Baccharis dracunculifolia DC. (Asteraceae), which is tradition- displays anti-inflammatory, antimicrobial and antioxidant activ- ally known as ‘broom of the field’, is an important medicinal ities, among others. Topical formulations containing 10% of the plant in Brazil for its folk medicine and economic uses, where B. hydroalcoholic extracts of leaves and oleoresin were evaluated for dracunculifolia is the main botanical source for the production of their anti-inflammatory properties, and the results showed that green propolis by Apis mellifera. It is rich in prenylated com- they were able to reduce pro-inflammatory mediators, such as pounds derived from p-coumaric acid, such as artepillin C and IL-1, IL-6 and TNF-a after a three-day treatment period. After baccharin. Studies have shown that both leaf extract and seven days, an increase in the anti-inflammatory cytokine IL-10 caffeic acid, isolated from Baccharis, at concentrations of 50 and was also observed (Gushiken et al. 2017). l l 100 g/mL and 25, 50 and 100 g/mL, respectively, were able to The a-humulene and (–)-trans-caryophyllene sesquiterpenes inhibit IL-6 production (Bachiega et al. 2014). are widely found in Copaifera species and are also the major Campomanesia adamantium is a well-known plant from compounds of Cordia verbenacea essential oil. Both sesquiter- Brazil with its proven anti-inflammatory efficacy. The ethyl acet- penes were exposed to different inflammatory experimental mod- ate and aqueous extracts from the leaves were previously eval- els in mice and rats (50 mg/kg). a-Humulene significantly uated in some studies. The ethyl acetate extract at concentrations inhibits the production of TNF-a and IL-1, whereas (–)-trans- l of 160 and 320 g/mL was able to stimulate the production of caryophyllene inhibit TNF-a only (Fernandes et al. 2007). IL-10 by macrophages. The flavonols myricitrin and myricetin, Another study evaluated the effect of Cordia verbenacea essential isolated from C. adamantium, were also able to stimulate the oil on periodontitis in a rat model, where a dose of 5 mg/kg was production of IL-10 at concentrations of 50–100 mM and – administered topically three times daily for 11 days. After this 25 100 mM, respectively (Ferreira et al. 2013). period of treatment, a drop in IL-1 levels and an increase of Carapa guianensis (known as andiroba) is widely used in IL-10 in the gingival tissue were observed (Pimentel et al. 2012). Brazilian folk medicine for the treatment of pain and arthritis. Marsypianthes chamaedrys (Vahl) Kuntze (Lamiaceae) is a The extracted oil from its seeds is rich in tetranortriterpenoids. A medicinal plant used in the state of Amazonas. The plant was fraction containing 6a-acetoxygedunin, 7-deacetoxy-7-oxogedu- evaluated for its inhibitory impact against the venom of snakes nin, 6a-acetoxyepoxyazadiradione, methyl angolensate, andirobin belonging to Bothrops atrox species. The extract of aerial parts of and gedunin as major tetranortriterpenoids was evaluated for its M. chamaedrys (0.6 mg/kg) inhibited the migration of leukocytes anti-inflammatory properties and proved to be effective in inhib- to the inflammatory regions and the release of pro-inflammatory iting IL-1 and TNF-a at a concentration of 100 mg/kg. Another mediators, such as IL-6 and TNF-a, but it did not alter cytokine study demonstrated that tetranortriterpenoids are able to affect IL-10 level (Magalh~aes et al. 2011). the formation of inflammatory mediators that stimulate leukocyte Another plant used in Brazilian folk medicine is Petiveria infiltration in the region of inflammation, such as IL-5 (Penido, alliacea L. (Petiveriaceae), which showed significant anti-inflam- Conte, Chagas, et al. 2006; Henriques and Penido 2014). matory activity. The ethanolic extract of the leaves showed the The oil of the fruit of Caryocar brasiliense Cambess (Caryocaraceae), popularly known as pequi, displayed antioxidant highest anti-inflammatory effect. Previous study showed that this properties, and showed anti-inflammatory properties in experi- plant is rich in organosulfur compounds, including S-propyl pro- panethiosulfinate and S-benzyl phenylmethanethiosulfinate. The mental animals at doses of 3 or 6 mL/kg. The oil has been also l a able to reduce some inflammatory mediators such as IL-6, IL-5 extract at concentration of 200 g/mL inhibited TNF- (52.68%), and TNF-a (Torres et al. 2016). IL-2 (59.42%), IL-6 (59.57%) and IL-1 (60.29%). The crude Milonine is an alkaloid isolated from the leaves of Cissampelos extract of the leaves of Pfaffia paniculata (Mart.) Kuntze sympodialis, another Brazilian medicinal plant used for the treat- (Amaranthaceae) at a concentration of 200 mg/kg also reduced b c a ment of inflammatory disorders that has demonstrated the ability the levels of pro-inflammatory cytokines IL-1 , INF- , TNF- to reduce the levels of IL-1 and TNF-a in the peritoneum in ani- and IL-6 (Lopes-Martins et al. 2002; Gutierrez and Hoyo- mal models at the concentration of 1 mg/kg (Silva et al. 2017). Vadillo 2017). Gusman et al. (2015) carried out a study in which they eval- Sambucus australis Cham. & Schltdl. (Adoxaceae), known as uated the effect of crude extracts of 80 Brazilian plants used in sabugueiro, is another plant widely used in Brazilian folk medi- the treatment of inflammatory diseases, such as rheumatoid arth- cine. Its aerial parts are used in the treatment of inflammatory ritis and atherosclerosis. Among them, the crude extracts of and respiratory disorders. Some ethnopharmacological studies Caryocar brasiliense, Casearia sylvestris Sw. (Salicaceae), showed that this plant can be used as diuretic and antipyretic. Coccoloba cereifera Schwacke (Polygonaceae) and Terminalia Phytochemically, its secondary metabolites consist mainly of fla- glabrescens Mart. (Combretaceae) were able to inhibit the pro- vonoids, triterpenes and phenolic acids. Rutin and chlorogenic a duction of TNF- in a dose-dependent manner with IC50 ranging acid were identified as the major compounds in the leaves. The between 124 and 224 mg/mL. Phytochemical studies have shown ethanolic extracts of the leaves and bark were evaluated for their that these extracts are rich in polyphenols like flavonoids and anti-inflammatory activity (Bahiense et al. 2017). The leaves proanthocyanidins that play a role in their anti-inflammatory extract demonstrated a significant inhibition of TNF-a at a con- potentials (Gusman et al. 2015). centration of 100 mg/mL. The ethyl acetate fraction of Schinopsis By using a mouse model of pleurisy induced by zymosan, brasiliensis Engl. (Anacardiaceae) also showed the same effect at the essential oil of Porophyllum ruderale, Conyza bonariensis and the same concentration (Santos et al. 2018). 258 V. P. RIBEIRO ET AL.

Steroids, terpenoids and flavonoids are found in Scoparia for its antinociceptive and muscle relaxing properties. Flavonoids, dulcis L. (Plantaginaceae), which is widely used in folk medicine coumarins, phenolic glycosides and amburosides have been for a wide range of diseases, such as diabetes, hypertension and isolated from its bark. The anti-inflammatory activities of iso- gastritis. Betulinic acid is one of the main constituents of kaempferide (12.5, 25 and 50 mg/kg) and amburoside A (25 and S. dulcis and it is responsible for the anti-inflammatory activity 50 mg/kg), isolated from the shells of A. cearensis, were previous of this plant. Then, the ethanolic extract of the leaves and betu- reported. It was found that both compounds showed considerable linic acid showed anti-inflammatory activity at concentrations of anti-inflammatory activity, as they inhibited the migration of neu- 0.5–1.0 g/kg and 20–40 mg/kg, respectively, by inhibiting TNF-a trophils and leukocytes, and the production of TNF-a and prosta- and IL 1. Significant inhibition of TNF-a by N-methyl-(2S,4R)- glandins E2 (Leal et al. 2008; Lopes et al. 2013). trans-4-hydroxy-1-proline, a compound isolated from the leaves The alkaloid milonine was isolated from the medicinal plant of Sideroxylon obtusifolium (Humb. ex Roem. & Schult.) T.D. Cissampelos sympodialis, which is known to be rich in alkaloids, Penn. (Sapotaceae), was observed at concentrations of 25, 50 and such as warifteine, a bisbenzylisoquinoline-type alkaloid that pos- 100 mg/kg (Tsai et al. 2011). sesses anti-inflammatory and immunomodulatory activity, by One of the most important Brazilian medicinal plants is inhibiting the migration of neutrophils and eosinophils in asthma Stryphnodendron adstringens (Mart.) Coville (Fabaceae), popu- models. The alkaloid at the concentration of 1 mg/kg inhibited larly known as barbatim~ao. It is widely used because of its anti- the production of pro-inflammatory mediators in addition to inflammatory properties. Henriques et al. (2016) investigated the PGE2. It was interesting that there was no formed oedema in extracts of the leaves of S. adstringens and of other 11 Brazilian EPG2-induced paw oedema animal model in comparison with medicinal plants used for anti-inflammatory purposes. The the indomethacin control group. This result indicates the direct extracts of S. adstringens, Stryphnodendron obovatum Benth., inhibition of PGE2 by milonine (Silva et al. 2017). Campomanesia lineatifolia Ruiz & Pav. and Terminalia glabres- Other compounds which also demonstrated the ability to cens inhibited TNF-a release in addition to a decay of leukocyte inhibit PGE2 are the sesquiterpenes isolated from the essential migration at the site of inflammation. Polyphenolic compounds oil of Cordia verbenacea (Fernandes et al. 2007). The oral treat- were identified in the plant extract, which may contribute to the ment with a-humulene and (–)-trans-caryophyllene (50 mg/kg) observed activity (Henriques et al. 2016). strongly inhibited the production of PGE2 after one hour post Uncaria tomentosa (Willd.) DC. (Rubiaceae), known as a treatment period. In the same manner, the hydroalcoholic extract cat’s claw inhibited TNF-a in a dose-dependent manner, as fol- of Curatella americana L. (Dilleniaceae), a medicinal plant used lows: 10 mg/mL of the extract inhibited 33%,40mg/mL (45%), as infusion for the treatment of ulcer and inflammation, inhib- 160 mg/mL (80%) and 320 mg/mL (95%) of TNF-a, and the ited PGE2 and other pro-inflammatory mediators in a dose of extract completely inhibited the release of IL-1. Another study 30 mg/kg (Alexandre-Moreira et al. 1999). The crude extract of using mitraphylline which is a pentacyclic oxindolic alkaloid, the Marsypianthes chamaedrys, used in folk medicine to treat inflam- main compound present in the bark of U. tomentosa, inhibited matory processes from snakebites, also inhibited the precursors approximately 50% of the production of pro-inflammatory cyto- of PGE2, as well as other mediators (Magalh~aes et al. 2011). kines IL-1, IL-17 and TNF-a after three days of treatment Petiveria alliacea is widely found in Brazil, and in folk medi- (30 mg/kg/day, orally) (Allen-Hall et al. 2007, 2010; Rojas-Duran cine it is used as anthelmintic, diuretic and sedative. Moreover, it et al. 2012). displays antimicrobial, phagocytic and inflammatory activities. Its Based on the previously reported data, we can observe that leaf extract showed strong suppression of PGE2 secretion. At a the majority of medicinal plants with anti-inflammatory activity concentration of 200 lg/mL, the extract inhibited approximately act by either inhibiting or stimulating the effects of the pro- or 73% of PGE2 release (Lopes-Martins et al. 2002; Gutierrez and anti-inflammatory cytokines, respectively, mainly on TNF-a and Hoyo-Vadillo 2017). IL-1. This confirms the importance of TNF-a and IL-1 in the Plantago major L. (Plantaginaceae) is a plant commonly found activation and maintenance of inflammation, which are import- in Brazil, mainly used due to its anti-inflammatory and analgesic ant mediators in the search for new compounds with anti- properties. It possesses a great diversity of active compounds, like inflammatory properties. flavonoids, alkaloids, terpenoids, phenolics, iridoid glycosides, among others. There are reports showing the anti-inflammatory capacity of the methanolic extract of P. major seeds by inhibiting PGE2 PGE2 precursors (Adom et al. 2017). Prostaglandin E2 is involved in various physiological activities, Pterodon emarginatus is a plant widely used in Brazilian folk such as fever regulation and nociception, among others. The medicine due to its anti-inflammatory, analgesic and anti-rheum- membrane-associated protein synthase 1 (mPGES-1) is involved atic activities. One study showed that lupeol (70 mg/kg), and in the synthesis of PGE2. Mice with a knocked-out mPGES-1 betulin (8 mg/kg) triterpenes, isolated from ethanolic extract of P. demonstrate a reduction in inflammatory PGE2 levels, leading to emarginatus stem bark, demonstrate anti-inflammatory activity a consequent reduction in inflammatory response (Guay et al. through the inhibition of phospholipase A2, a precursor of a b 2004). Therefore, mPGES-1 is considered to be an important tar- PGE2. It was also demonstrated that 6 ,7 -dihydroxy-vouaca- get in the search for anti-inflammatory compounds. The stem pan-17b-oic, an acid diterpene isolated from the fruits of P. bark extract of Anacardium occidentale, at the concentration of emarginatus has anti-inflammatory activity by inhibiting pro- 25–100 lg/mL significantly reduced the levels of PGE2 by inhibit- inflammatory mediators, including PGE2, at a dose of 50 mg/kg ing the mPGES-1 protein (Olajide et al. 2013). (Galceran et al. 2011). Amburana cearensis (Allem~ao) A.C. Sm. (Fabaceae) is a Brazilian medicinal plant widely used in folk medicine, mainly in NF-kB the northeastern region of Brazil. It is used because of its anti- inflammatory properties, mainly in the treatment of asthma. In Ageratum conyzoides is widely used in Brazil as anti-inflamma- addition to the anti-inflammatory properties, the plant is also used tory, which was corroborated by the recent study published by PHARMACEUTICAL BIOLOGY 259

Mello et al. (2016), who studied the mechanism of action of the several inflammatory factors, including NF-jB. Thus, this com- extract and isolated compounds from this plant. This extract pound contributes to the anti-inflammatory effect of S. obtusifo- inhibited leukocyte influx and decreased pro-inflammatory lium leaves (De Aquino et al. 2017). mediators, like NF-jB. NF-jB is a protein complex that controls Regarding U. tomentosa (cat’s claw), it also inhibited NF-jB transcription of DNA, cytokine production and cell survival. NF- activation, and the number of dead cells, related to NF-jB jB was inhibited by the compounds 50-methoxynobiletin and (Allen-Hall et al. 2010). 1,2-benzopyroneandeupalestin at a dose of 5 mg/kg in mice, by acting on the phosphorylated p65 subunit of NF-jB, thus inter- fering with the expression of genes related to the inflammation. COX Anacardium occidentale L. popularly known as cashew, a plant Cyclooxygenase enzymes are one of the most important targets mainly used as food, has a promising anti-inflammatory activity of anti-inflammatory drugs. It is known that when a certain drug j by blocking NF- B leading to the prevention of the production acts selectively on COX-2, such drug has a considerable pharma- of inflammatory mediators and enzymes. It was observed that A. cological potential to treat inflammatory disorders with less side occidentale inhibited the nuclear translocation by increasing effects. According to the literature, some plant extracts or their j NF- B level in the cytoplasm and decreasing it in the nucleus. isolated compounds might act on this enzyme and can be a j By blocking the gene transcription of NF- B factor, all NO, future lead of new bioactive compounds. PGE2 and pro-inflammatory cytokines are consequently sup- Some native and endemic plant species in Brazil belonging to pressed (Olajide et al. 2013). the family Asteracea, such as Chronopappus bifrons (DC. ex Pers.) ‘ ’ Baccharis dracunculifolia ( alecrim do campo ), the botanical DC., Dasyphyllum brasiliense var. latifolium (D. Don) Cabrera, source used by Apis mellifera bees to produce Brazilian Green Eremanthus polycephalus (DC.) MacLeish, Minasia scapigera H. Propolis, is a native plant that grows mostly in Brazilian Rob., Piptolepis monticola Loeuille, Prestelia eriopus Sch. Bip., Southeast region and is used popularly to treat inflammation. Solidago microglossa DC., Vernonia platensis (Spreng.) Less, Such effect is corroborated by scientific reports. Dos Santos et al. Vernonia rubriramea Mart. ex DC, Viguiera robusta Gardner and (2010) showed by in vivo assays that B. dracunculifolia displayed Viguiera trichophylla Dusen display COX potent inhibitory effects, a significant anti-inflammatory effect, but it did not inhibit NF- with IC50 concentrations lower or equivalent in comparison with kB activation. Therefore, this plant extract may act on other tran- the positive control of NSAIDs. This activity is due to the scription factors, such as cyclic adenosine monophosphate active constituents: in D. brasiliense’s extract the compounds gallic (cAMP), which is a protein activator. acid, protocatechuic acid, mono-O-E-caffeoylaltraricacid and Cordia verbenacea, a plant well-known for its anti-inflamma- mono-O-E-caffeoylaltraricacid-58, 3-O-E-caffeoylquinic acid, tory effect contains sesquiterpenes like a-humullene and trans- mono-O-E-cafeoylchiquimicacid-21, caffeoylchiquimic acid-21, caryophyllene, which are the main compounds responsible for caffeoylchiquimic acid-21, hyperoside, quercetrin, isoquercetrin, this pharmacological effect. For elucidating the mechanism of 3,4-di-O-E-caffeoylquinic acid, 3,5-di-O-E-cafeoilquinic acid, 4,5- action of these compounds, lipopolysaccharides LPS-induced paw di-O-E-caffeoylquinic acid, quercetin and luteolin were identified. oedema animal model was used. The plant sesquiterpenes inhib- The other mentioned plants contain similar chemical composition. ited NF-jB activation and decreased neutrophil migration As observed, several phenolic compounds, such as caffeoylchiqui- (Medeiros et al. 2007). These data explain the anti-inflammatory mic derivatives and flavonoids are the major compounds and they effect of the essential oil of C. verbenacea, the active compounds are major players in the biological effect of these plants. VR of this plant in the previously mentioned product Acheflan . Anacardium occidentale also found in the Brazilian Cerrado A bioguided fractionation of Himatanthus sucuuba (Spruce ex biome was able to significantly inhibit COX-2 at 25–100 lg/mL Mull.€ Arg.) Woodson (Apocynaceae) stem bark extract led to the (Olajide et al. 2013). isolation of plumericin, a spirolactone iridoid, a potent NF-jB The hydroethanolic extract of Baccharis dracunculifolia leaves inhibitor. This Amazonian plant extract fractionation was moni- inhibited COX-2 in vitro. The HPLC analysis of the extract tored by NF-jB luciferase reporter gene experiment to assure its showed that its major compounds, which are also found in inhibitory effects on NF-jB, the expression of vascular cell adhe- Brazilian Green Propolis are flavonoids, such as aromadendrin-4- sion molecule 1 (VCAM-1), intercellular adhesion molecule 1 O-methylether, phenolics like caffeic and p-coumaric acids and (ICAM-1) and E-selectin, which are promoted by TNF-a. Also, especially prenylated phenolic compounds, such as drupanin and Western blotting and transfection assays were performed to study artepillin C. These compounds are most likely to be the ones the mechanism of action of the isolated compound. Plumericin responsible for the inhibition of COX-2 (Dos Santos et al. 2010). l was active with an IC50 of only 1 M. Moreover, plumericin Wilbrandia ebracteata Cogn (Cucurbitaceae) is a Brazilian acted by blocking the phosphorylation and degradation of lKB plant widely used in folk medicine to treat chronic rheumatism. and the activation of NF-jB induced by transfection (Fakhrudin It contains mainly curcubitacins and curcubitacins analogues, et al. 2013). which are oxygenated triterpenes with potential anti-inflamma- Other anti-inflammatory plants that act on NF-jB are tory activity. The extracts from the roots of this plant display Sambucus australis Cham. & Schltdl., Sideroxylon obtusifolium anti-inflammatory effect. The dichloromethane fraction, which (Humb. ex Roem. & Schult.) T.D. Penn. and Uncaria tomentosa contains curcubitacins in high amounts, diminished the inflam- (Willd.) DC. mation process induced by carrageenan and inhibited COX-2, S. australis leaf ethanolic extract inhibited 20.4% of NF-jBat but not COX-1. This selectivity is really important, considering 100 lg/mL. This effect is most likely to happen due to the pres- that COX-2 is the enzyme related to the inflammation and COX- ence of chlorogenic acid and rutin, the extract major compounds 1 has useful functions in the body (Peters et al. 2003). Siqueira (Bahiense et al. 2017). From S. obtusifolium leaves, the com- et al. (2007) isolated dihydrocurcubitacin B from the roots of this pound N-methyl-(2S,4R)-trans-4-hydroxy-l-proline (NMP) was plant and assessed its anti-inflammatory activity in vivo and isolated, which was evaluated in vivo at 25, 50 and 100 mg/kg COX inhibitory potential in vitro. It was found that the com- body wt, by oral administration. This compound diminished pound decreased paw oedema at 0.3, 1 and 3 mg/kg, showing a 260 V. P. RIBEIRO ET AL. potent effect of such compound, which also inhibited COX-2 protein damage or lipid peroxidation (Wiseman and Halliwell activity in concentrations up to 10 lg/mL, as well as PGE2 1996). It has been shown that lipid peroxidation is related to the release by 72%. aggravation of acute and chronic inflammatory responses. In Another plant from Cucurbitacea family called Cayaponia vivo, this phenomenon is due mainly to the formation of peroxy- tayuya (Vell.) Cogn. popularly known as ‘Taiuia’, is used as an nitrite from the combination of superoxide radicals and nitric anti-rheumatic agent. Fractions of the extract of this plant, rich oxide release during the inflammatory response (Salvemini in the flavonoids vicenin-2, spinosin, isovitexin, swertisin and et al. 2006). isoswertisin, display anti-inflammatory effects by decreasing the Nitric oxide derived from induced nitric oxide synthase acute inflammation by 66% at 0.5 mg/ear in a TPA (12-O-tetra- (iNOS) is involved in various pathological conditions, such as decanoylphorbol-13-acetate)-induced mouse ear oedema and in inflammation and autoimmune diseases leading to tissue damage vitro, at a dose of 22.3 mg/mL. It also inhibited COX-2 expres- (Singh et al. 2000). Thus, suppression of iNOS is closely linked sion by 49% (Aquila et al. 2009). with anti-inflammatory action (Ahn et al. 2007). Examples of Cordia verbenacea essential oil inhibited oedema caused by Brazilian plants and their active secondary metabolites used in carrageenan successfully decreased the inflammatory reaction the modulation of inflammation are summarized in Table 1. caused by Appis mellifera venom, and it also had an effect on These plant extracts and their isolated compounds act on iNOS NF-jB. The isolated compounds from the plant, a-humulene and and/or ROS pathways by preventing their formation or by inhib- trans-caryophyllene, were also active on inflammation induced iting ROS and/or NO release. by carrageenan (50 mg/kg body weight). On one hand, the essen- The hydroalcoholic extract of the inflorescences of Achyrocline tial oil did not display significant effect on COX-1 or COX-2 satureioides inhibited the release of NO at a concentration of (Passos et al. 2007), but on the other hand, the isolated com- 100 mg/kg. The isoflavonoid afrormosin, isolated from the Trunk pounds inhibited COX-2 activity (Fernandes et al. 2007). barks of Amburana cearensis, inhibited neutrophil degranulation Scoparia dulces is a plant known as ‘vassourinha’ and contains and the formation of ROS (16.7–335.2 mM), suggesting that this betulinic acid which is one of its major compounds (6.25 mg/g compound modulates the steps of the neutrophil ROS formation extract). Both the extract and betulinic acid displayed significant process (Cosentino et al. 2008; Da Silva et al. 2016). activity on the inflammation, through their action on COX-2, The stem bark extract of Anacardium occidentale (25–100 NO, TNF-a and IL1-b (Tsai et al. 2011). N-methyl-(2S,4R)-trans- mg/mL) showed significant reduction in the production of NO 4-hydroxy-L-proline, a compound isolated from the leaves of S. by inhibiting the expression of the iNOS protein (Olajide et al. obtusifolium acted as COX-2 inhibitor (De Aquino et al. 2017). 2013). Desmarchelier et al. (1999) demonstrated the potential The activity of plant extracts and its isolated compounds on of Anadenanthera macrocarpa (Benth.) Brenan (Fabaceae), COX enzymes shows that natural products may act by a mechan- Astronium urundeuva (Allem~ao) Engl. (Anacardiaceae), Mimosa ism similar to NSAIDs. Many of them are COX-2 selective inhib- verrucosa Benth. (Fabaceae) and Sideroxylon obtusifolium for free itors, and this open the door for the development of new radical scavenging. promising and novel phytotherapeutic medicine with less gastric Ageratum conyzoides, a common plant in South America, also side effects. displayed anti-inflammatory activity. The crude extract of the The cell membrane consists of phospholipids bilayer and leaves, their fractions and the isolated compounds benzopyrone when it is injured, phospholipase A2 is released from the plate- and eupalestin significantly reduced the flow of leukocytes and lets and white blood cells, due to activation by cytokines as IL-1, the nitric oxide metabolites, as well as inhibited other inflamma- a pro-inflammatory one. Then, phospholipid leads to arachidonic tory mediators (Mello et al. 2016). acid release which is a substrate for lipoxygenase synthesis, con- The leaves extract from Bouchea fluminensis (Vell.) Moldenke sequently, giving rise to leukotrienes induction. Arachidonic acid (Verbenaceae) (1–30 mg/kg) showed interesting anti-inflamma- is also a substrate for COX, producing prostaglandins, prostacyc- tory activity. The triterpenes found in the plant suppressed the lin and thromboxane. One of the formed prostaglandins is PGE2. formation of iNOS enzyme. The authors could further conclude COX-2 can be induced when an inflammatory process is initi- that the presence of carboxyl groups at the C-28 or C-30 posi- ated, and this enzyme is usually present in the inflammatory sites tions of these triterpenes could increase their anti-inflammatory in different tissues, such as brain, uterus, kidneys, vascular tissue activity (Costa et al. 2003). and others. Its induction is usually by ILs, TNF and other media- Vargas et al. (2016) evaluated the extracts of five plants from tors. COX-1 is an enzyme with similar protein chemical structure the Amazon region in Brazil. Ptychopetalum olacoides Benth. to COX-2, but they are originated from different genetic codes. (Olacaceae) and Calycophyllum spruceanum (Benth.) Hook. f. ex COX-1 is found in several tissues and is involved in various use- K. Schum. (Rubiaceae) inhibited the formation of free radicals. ful physiologic functions, such as gastric mucosal lining (Chan The extracts of the plants Maytenus guyanensis Klotzsch ex et al. 2017). Therefore, plant extracts and their metabolites with Reissek (Celastraceae) and Byrsonima japurensis A. Juss. COX-2 selective inhibitory mechanism of action are promising (Malpighiaceae) also inhibited myeloperoxidase in a concentra- for the development of new drug leads for the treatment of tion of 100 lg/mL (Vargas et al. 2016). inflammatory diseases. The aqueous extract and the flavonoids myricitrin and myri- cetin, isolated from Campomanesia adamantium, inhibited the Nitric oxide synthase (NOS) and reactive oxygen species formation of NO at concentrations of 300 mg/kg and 6.25–100 mM, respectively (Ferreira et al. 2013). Another Superoxide is the first reduction product of molecular oxygen, Brazilian medicinal plant that showed activity on NO is the buta- and it is an important source of hydroperoxides and deleterious nolic fraction of the extract of Cayaponia tayuya (22.30 lg/mL), free radicals (Chauhan and Chauhan 2006). This ROS is involved which is rich in flavonoids vicenin-2, spinosyn, isovitexin and in degenerative diseases of aging, including Alzheimer’s disease, isoswertisin (Aquila et al. 2009). cancer and in the worsening of inflammatory diseases, such as The essential oils of Porophyllum ruderale and Conyza bonar- rheumatoid arthritis and atherosclerosis, through DNA and iensis at 100 mg/kg (Souza et al. 2003), the sesquiterpenes isolated Table 1. Anti-inflammatory mechanisms of action of compounds from Brazilian medicinal plants. Mechanisms involved in the anti- Plant Bioactive molecules inflammatory effects References Achyrocline satureioides (Lam.) DC. Quercitrin, isoquercitrin, 3-O-methylquercetin, Reduction of IFN-c and IL-4 ratio Cosentino et al. (2008) luteolin, polysaccharides Inhibition reactive oxygen species (ROS) Da Silva et al. (2016) Ageratum conyzoides L. Reduction of nitric oxide metabolites concentra- Mello et al. (2016) 50-Methoxy nobiletin, 1,2-benzopyrone, eupalestin tions (NOx) inhibition NF-jB Alternanthera brasiliana (L.) Kuntze Phenolic compounds, anthocyanins, flavonoids, Non-elucidated mechanism Formagio et al. (2012) alkaloids, saponins, luteolin, pigenin, orientin, Coutinho et al. (2017) quercetin, vitexin Amburana cearensis (Allem~ao) A.C. Sm. Afrormosin Inhibition of ROS generation Lopes et al. (2013) Inhibition of neutrophil degranulation and TNF-a secretion Inhibition of PGE2 Anacardium occidentale L. N.R. Reduction of inducible nitric oxide (iNO) Olajide et al. (2013) Reducing the inflammatory response modulation Vasconcelos et al. (2015) exerted by reactive oxygen species (ROS) Inhibition NF-jB- COX Inhibit the production of IL-6, TNF-a and PGE2 Anadenanthera colubrine (Vell.) Brenan Flavonoid, saponins, catequins, phenols, steroids, Non-elucidated mechanism Santos et al. (2013 tannins, terpenoids Astronium urundeuva (Allem~ao) Engl. N.R. Preventing lipid peroxidation through reducing Desmarchelier et al. (1999) Sideroxylon obtusifolium (Humb. ex thiobarbituric acid reactive substances (TBARS). Roem. & Schult.) T.D. Penn. Austroplenckia populnea (Reissek) Lundell Populnoic acid, campesterol, stigmasterol, sitos- Non-elucidated mechanism Andrade et al. (2007) terol, epitaraxerol, amirine, lupenone, lupeol, lupeol acetate, friedalanol, friedelin Baccharis Dracunculifolia DC. Caffeic acid, p-coumaric acid, aromadendrin-4-O- Inhibition of lipid peroxidation and ROS release- Cestari et al. (2011) methyl ether, 3-prenyl-p-coumaric acid, 3,5- COX Bachiega et al. (2014) diprenyl-p-coumaric acid, baccharin, drupanin, Inhibit IL-6 production. artepillin C Bouchea fluminensis (Vell.) Moldenke Ursolic acid, oleanoic acid, micromeric Prevention of lipid peroxidation through reducing Delaporte et al. (2002) acids lamiide thiobarbituric acid reactive substances (TBARS) Byrsonima intermedia A. Juss. Flavonoids, triterpenes, steroids, tannins saponins, Inhibition of protein kinase C and/or larginine-NO Orlandia et al. (2011) catechin, phenolic compounds pathways Moreira et al. (2011) Inhibition of the generation of superoxide anion Byrsonima japurensis A. Juss. Polyphenolic compounds Highest free radical scavenging activities Vargas et al. (2016) Calycophyllum spruceanum (Benth.) Inhibition of free radicals formation Hook. f. ex K. Schum. Inhibition of horseradish peroxidase and Maytenus guyanensis Klotzsch ex Reissek myeloperoxidase Passiflora nitida Kunth. Ptychopetalum olacoides Benth. Caesalpinia ferrea Mart. ex Tul. Polysaccharides Negative modulation of histamine, serotonin, Pereira et al. (2012, 2016) bradykinin, PGE2 and NO released Freitas et al. (2012) Modulation and/or inhibition of inflammatory BIOLOGY PHARMACEUTICAL mediators (TNF-a, IL-1b, NO and TGF-b). Campomanesia adamantium (Cambess.) Myricitrin and myricetin (320 lg/mL 6.25–100 lM, Inhibition of NO production Ferreira et al. (2013) O. Berg respectively) Production of IL-10 Carapa guianensis Aubl. Inhibiting IL-1 and TNF-a Penido, Conte, Chagas, et al. (2006); 6a-acetoxygedunin, 7-deacetoxy-7-oxogedunin, Formation of IL-5 Penido, Costa, Futuro, et al. (2006) 6a-acetoxyepoxyazadiradione, methyl angolensate, and Henriques and Penido (2014) andirobin and gedunin Caryocar brasiliense Cambess. Fatty acids, phenolic compounds, carotenoids, Reduction of the concentration of IL-6, IL-5 and Torres et al. (2016) tocopherols, fitosterols TNF-a (continued) 261 Table 1. Continued 262 Mechanisms involved in the anti- Plant Bioactive molecules inflammatory effects References

Cayaponia tayuya (Vell.) Cogn. Vicenin-2, spinosin, sovitexin, swerticin, isoswerti- Inhibition of iNOS- COX Recio et al. (2004) AL. ET RIBEIRO P. V. cin, cucurbitacins Aquila et al. (2009) Chronopappus bifrons (DC. ex Pers.) DC Caffeoylquinicn acids, hyperoside, quercetrin, iso- Inhibition of COX production Chagas-Paula et al. (2015) Dasyphyllum brasiliense (Spreng.) Cabrera quercetrin, luteolin, apigenin, chrysoerio, ere- Eremanthus polycephalus (DC.) mantholide, goyazensolide, isorhamnetin MacLeis Minasia scapigera H. Rob. Piptolepis monticola B. Loeuille Prestelia eriopus Sch. Bip. Solidago microglossa DC. Vernonia platen- sis (Spreng.) Less. Cissampelos sympodialis Eichler Milonine Reduction levels of IL-1 and TNF-a Silva et al. (2017) Inhibition of PGE2 Conyza bonariensis (L.) Cronquist Limonene and b-myrcene Inhibition of NO production Souza et al. (2003) Porophyllum ruderale (Jacq.) Cass. inhibition of the cytokines IFN-c and IL-4 Copaifera cearensis Huber ex Ducke b-Caryophyllene and kaurenoic acid Inhibition of NO production Veiga Junior et al. (2007) Copaifera langsdorffii Desf. Reduce IL-1, IL-6 and TNF-a Gushiken et al. (2017) Increase of IL-10 Cordia verbenacea DC. ()-Trans-caryophyllene and a-humulene Reduction of PGE2 Fernandes et al. (2007) and Medeiros Reduction of nitric oxide synthase (iNOS) et al. (2007) Inhibition of NF-jB- COX Passos et al. (2007) Inhibition of the production of TNF-a and IL-1 Inhibition of PGE2. Croton celtidifolius Baill. N.R. Free radicals scavenging activity Nardi et al. (2003, 2007) Enhancement of the activity of Superoxide Dismutase (SOD) enzyme Curatella americana L. N.R. Inhibition of PGE2 Alexandre-Moreira et al. (1999) Elephantopus scaber L. N.R. SOD scavenging activities Chan et al. (2017) Interfering with iNOS expression Eugenia uniflora L. Ellagic acid, gallic acid and rutin Free radical scavenging activity Schumacher et al. (2015) Himatanthus sucuuba (Spruce ex Mull.€ Plumericin Inhibition of NF-jB Fakhrudin et al. (2013) Arg.) Woodson Hyptis pectinata (L.) Poit. N.R. Reduction of inflammatory mediators (nitric oxide, Raymundo et al. (2011) prostaglandin E2, IL-6 and TNF-a) Jatropha elliptica (Pohl) Oken Saponins, alkaloids, phenolic Non-elucidated mechanism Ferreira-Rodrigues et al. (2016) Justicia pectoralis Jacq. Coumarins, flavonoids, saponins, tannins Non-elucidated mechanism Leal et al. (2000) Kalanchoe brasiliensis Cambess. Kalanchosine, dimalate, kalanchosine, malic acid Non-elucidated mechanism Mour~ao et al. (1999) Costa et al. (2006) Magnolia ovata (A. St.-Hil.) Spreng. Costunolide, parthenolide Non-elucidated mechanism Kassuya et al. (2009) Marsypianthes chamaedrys (Vahl) Kuntze Lupeol, sitosterol, ursolic acid and flavonoids. Inhibition of IL-6 and TNF-a Magalh~aes et al. (2011) Inhibition of PGE2 Miconia albicans (Sw.) Steud. Ursolic acid, oleanoic acid Non-elucidated mechanism Vasconcelos et al. (2006) Mikania glomerata Spreng. Coumarin Non-elucidated mechanism Fierro et al. (1999) Myracrodruon urundeuva Allem~ao Urundeuvines I, urundeuvines II, urundeuvines Non-elucidated mechanism Souza et al. (2007) III, taninns Viana et al. (2003) Nectandra megapotamica (Spreng.) Mez Galgravin, veraguensin Non-elucidated mechanism Da Silva Filho et al. (2004) Passiflora nıtida Kunth. Flavanones, flavones, free flavonoids, flavonols, Non-elucidated mechanism Pereira et al. (2012) coumarins, steroids, phenols cyanogenic het- erosides, cardioactive glycosides, leucoantho- cyanidins, saponins, tannins and xanthones Peschiera australis (Mull.€ Arg.) Miers Coronaridine, tabersonine, olivacine, coronaridine- Non-elucidated mechanism Rates et al. (1993) hydroxyindolenine, catharinensine, decarbome- thoxyvoacamine, tabernamine, vanillic acid, syringic acid, gentisic acid and salicylic acid (continued) Table 1. Continued Mechanisms involved in the anti- Plant Bioactive molecules inflammatory effects References Petiveria alliacea L. S-Propyl propanethiosulfinate and S-benzyl Inhibition of as IL-1, IL-2, INF-c, TNF-a and IL-6 Lopes-Martins et al. (2002) and Gutierrez phenylmethanethiosulfinate Inhibition of PGE2 and Hoyo-Vadillo (2017) Piper marginatum Jacq. Steroids, triterpenes, flavonoids, cinnamic deriva- Non-elucidated mechanism D’Angelo et al. (1997) tives and noradrenaline Plantago major L. Flavonoids, alkaloids, terpenoids, phenolic com- Inhibition of PGE2 Adom et al. (2017) pounds and iridoid glycosides Plinia edulis (Vell.) Sobral Gallic acid, myricitrin, guaijaverin, quercitrin, coro- Non-elucidated mechanism Azevedo et al. (2016) solic acid, maslinic acid, oleanolic acid and ursolic acid Porophyllum ruderale (Jacq.) Cass. Trans-b-ocimene, myrcene, limonene, 1-undecene Inhibition of NO production Souza et al. (2003) Conyza bonariensis (L.) Cronquist and a-pinene. Psidium guineense Sw. Spathulenol, sesquiterpenes ROS scavenging activity Nascimento et al. (2018) Pterodon emarginatus Vogel Lupeol, botulin and 6a, 7b-dihydroxy-vouacapan- Inhibition of PGE2 Galceran et al. (2011) 17b-oic Sambucus australis Cham. & Schltdl. Rutin and quercetin as major compounds, and ROSD and NO scavenging activities Bahiense et al. (2017) chlorogenic acid. Inhibition of NF-jB Inhibition of TNF-a Schinopsis brasiliensis Engl. Gallic acid Inhibition of TNF-a Santos et al. (2018) Scoparia dulcis L. Betulinic acid Reduction of the levels of COX-2, NO, TNF-a and Tsai et al. (2011) IL1-b in inflamed tissues Sideroxylon obtusifolium (Humb. ex N-Methyl-(2S,4R)-trans-4-hydroxy-l-proline NF-jB-COX-inhibition of TNF-a De Aquino et al. (2017) Roem. & Schult.) T.D. Penn. Tsai et al. (2011) Stachytarpheta cayennensis (Rich.) Vahl Ipolamiide, verbacoside Non-elucidated mechanism Penido, Conte, Chagas, et al. (2006); Penido, Costa, Futuro, et al. (2006) Tabebuia impetiginosa (Mart. ex Non-elucidated mechanism Koyama et al. (2000) DC.) Standl. 2-Formyl-5-(40-methoxybenzoyloxy)-3-methyl-2- cyclopentene-1-acetaldehyde 2-formyl-5-(30,40-imethoxybenzoyloxy)-3-methyl-2- cyclopentene-1-acetaldehyde Uncaria tomentosa (Willd.) DC. Uncarine F, mitraphyllene, speciophylline, ptero- NF-jB-inhibition of IL-1, IL-17 and TNF-a Allen-Hall et al. (2010) podine and isopteropodine Vanillosmopsis arborea (Gardner) Baker Bisabolol, a-cadinol, elemicin, b-bisabolene, Non-elucidated mechanism Santos et al. (2015) guaiene, cubebene and Estragole Virola michelii Heckel Titonine Non-elucidated mechanism Carvalho, Ferreira, et al. (1999); Carvalho, Sertie, et al. (1999) Wilbrandia ebracteata Cogn. Cucurbitacins, dihydrocurcubitacin B, curcubita- Inhibition of NO release-COX Peters et al. (2003) cins analogues Siqueira et al. (2007) Ximenia americana L. Phenolic compounds, flavonoids, tannins Non-elucidated mechanism Olabissi et al. (2011) and Shettar and glycosides et al. (2015) Zanthoxylum riedelianum Engl. Sesamin, methylpluviatolide, dimethylmatairesinol, Non-elucidated mechanism Lima et al. (2007) piperitol-40-o-g,g-dimethylallyl ether, kaerophyl- lin, hinokinin and lupeol BIOLOGY PHARMACEUTICAL Zeyheria montana Mart. Zeyherin A, zeyherin b, oleanoic acid and Non-elucidated mechanism Guenka et al. (2008) ursolic acid N.R.: not reported. 263 264 V. P. RIBEIRO ET AL. from Cordia verbenacea’s essential oil (Fernandes et al. 2007), the and saponins can inhibit enzymes or mediators involved in the hydroethanolic extract from Passiflora nitida Kunth inflammation pathway (Santos et al. 2013). (Passifloraceae) leaves (Montefusco-Pereira et al. 2013), the Costa et al. (2003) evaluated the efficacy of Bouchea fluminen- essential oil from the leaves of Psidium guineense Sw. sis using a carrageenan induced inflammation model. Moldenke (Myrtaceae) (Nascimento et al. 2018), the ethanolic extracts of leaves crude extract, ursolic, oleanoic and micromeric acids were the leaf and bark of Sambucus australis (Bahiense et al. 2017), evaluated in doses ranging from 1 to 30 mg/kg. Delaporte et al. the ethanolic extract and betulinic acid isolated from Scoparia (2002) showed that the isolated compound iridoid lamiide from dulcis (Tsai et al. 2011) were also active against ROS. the plant extract (10%) had a use in modulating inflammation with an ED50 of 62.4 mg/kg body wt at 100 mg/kg. Pterodon emarginatus, a plant popularly known as ‘sucupira Medicinal plants having anti-inflammatory with branca’ used in folk medicine to treat diverse types of ailments, incomplete elucidation of their mechanisms of action including the inflammatory ones, was studied by Carvalho, Several reports in the literature describe the pharmacological Ferreira, et al. (1999). The hexane fraction of the fruits extract was effective at ED of 500 mg/kg body wt. After 6 h of the potential of plants extracts or their isolated compounds in the 50 administration of 500 mg/kg body wt, the oedema formation was treatment of inflammatory diseases, without a clarified or inhibited by 45%. The chronic inflammation, measured by explained mechanism of action. Amburana cearensis is a plant granuloma formation, was inhibited by 29% after six days native to the Northeast Brazilian ‘cerrado’ and ‘caatinga’, which (0.2 mg/kg topically), as well as decreased the neutrophiles cell is widely used in traditional medicine for the treatment of differ- migration into the peritoneum. The authors stated that the anti- ent disorders. The ethanolic extract of the bark of the trunk, its inflammatory effect was possibly due to the presence of terpe- flavonoid rich fraction and its isolated compound coumarin pro- noids in the plant. moted a significant decrease in the migration of white blood cells The isolated compounds galgravin and veraguensin from into the peritoneal cavity using two different in vivo models Nectandra megapotamica (Spreng.) Mez (Lauraceae) at a dose of (Leal et al. 2003). 20 mg/kg body wt displayed significant anti-inflammatory activity Achyrocline satureioides, popularly known as ‘marcela’, is trad- in comparison with the hydroalcoholic extract, which did not itionally used to treat inflammatory conditions, among other ill- display significant activity (Da Silva Filho et al. 2004). nesses, such as gastrointestinal, glycaemic and digestive disorders. Likewise, ursolic and oleanoic acids, isolated from the The major identified compounds in the plant inflorescences are dichloromethane fraction of the extract of Miconia albicans’ flavonoids, mainly quercetin, 3-O-methylquercetin and luteolin, leaves decreased the inflammation process at a dose of 40 mg/kg besides polysaccharides, which might be responsible for the in comparison with the standard indomethacin (10 mg/kg) reported anti-inflammatory effect. A 40% ethanol freeze-dried (Vasconcelos et al. 2006). powder extract of A. satureioides displayed a significant effect on Austroplenckia populnea (Reiss) Lundell (Celastraceae) is pre- oedema decreasing (74.3% after 1 h) at a dose of 250 mg/kg body sent mainly in the Brazilian ‘cerrado’ biome. The hydroalcoholic wt when administered orally, which was better than indometh- extract of the bark, its hexane, chloroformic and ethyl acetate acin at 10 mg/kg body wt (62.1% after 1 h). On the other hand, fractions, as well as populnoic acid were assessed in vivo by three the isolated compound quercetin, at 20 mg/kg body wt did not different mediators of acute inflammation in ‘paw oedema’ exert a significant inhibition in paw oedema animal model, prob- induced by carrageenan, dextran and histamine. The chronic ably because of the low absorption of flavonoids (De Souza et al. inflammation response was evaluated according to granuloma- 2007). However, when quercetin was administered with poly- tous tissue formation. By using the first mediator, it was found sorbate, it displayed a significant effect by inhibiting 55.3% of EC50 value of 200 mg/kg body wt for the crude extract. For carra- oedema after 3 h. geenan and dextran, all tested plant samples, including populnoic Likewise, Alternanthera brasiliana (L.) Kuntze acid at 50 mg/mg, significantly inhibited the paw oedema by 31 (Amaranthaceae) ethanol extract was assessed as an antiedemato- and 59%, respectively. The hexanic fraction was the only one l genic agent, which was effective at 25, 50 and 100 g/mL reduc- that inhibited granulomatous tissue formation. Steroids such as ing the oedema by 35.57, 64.67 and 64.17%, respectively. The campesterol, stigmasterol and b-sitosterol; and the triterpenes major compounds found in this plant are luteolin, apigenin, ori- epitaraxerol, b-amirine, lupenone, lupeol, lupeol acetate, b-frieda- entin, quercetin and vitexin, which may be responsible for the lanol and friedelin were identified in this fraction (Andrade reported activity (Coutinho et al. 2017). Formagio et al. (2012) et al. 2007). also evaluated the anti-inflammatory potential of this plant in The anti-inflammatory activity of the leaves and bark extracts a carrageenan-induced pleurisy model at doses of 200 and of Zanthoxylum riedelianum Engl. (Rutaceae) was assessed 400 mg/kg body weight. The extract decreased inflammation by in vivo using rat paw oedema induced by carrageenan, dextran, 19.8% and 23.9% using the lowest and highest doses, respectively. histamine and nystatin, and all samples displayed a significant At 400 mg/kg, the sample also decreased the lymphocytes prolif- effect only on carrageenan-induced oedema. Sesamin, methylplu- eration. This study agreed with the studies of Coutinho et al. viatolide, dimethylmatairesinol, piperitol-40-O-c,c-dimethylallyl (2017), and, considering that A. brasiliana extract displayed an ether, kaerophyllin, hinokinin and lupeol were isolated from the effect similar to indomethacin, the potential of this plant in the dichloromethane fraction of the stem bark, which could contrib- treatment of inflammation is clear. ute to the efficacy of the crude extract to reduce oedema forma- Another plant used in folk medicine is Anadenanthera colu- tion (Lima et al. 2007). brina (Vell.) Brenan (‘angico’) and its pharmacological potential Jatropha elliptica (Pohl) Oken (Euphorbiaceae) (Ferreira- was evaluated in vivo. The aqueous extract of the bark at 100, Rodrigues et al. 2016), Justicia pectoralis Jacq. (Acanthaceae) 200 and 400 mg/kg reduced the peritonitis caused by carra- (Leal et al. 2000), Kalanchoe brasiliensis Cambess (Crassulaceae) geenan. This plant contains flavonoids, saponins, catechins, phe- (Costa et al. 2006), Magnolia ovata (A. St.-Hil) Spreng. nols, steroids, tannins and terpenoids. Some flavonoids, tannins (Magnoliaceae) (Kassuya et al. 2009); Mikania glomerata Spreng. PHARMACEUTICAL BIOLOGY 265

(Asteraceae) (Fierro et al. 1999); Myracroduon urundeuva Aherne SA, O’Brien NM. 2002. Dietary flavonols: chemistry, food content, – Allemao (Anacardiaceae) (Souza et al. 2007), Peschiera australis and metabolism. Nutrition (Burbank, Los Angeles County, CA). 18:75 81. – Ahn EK, Jeon HJ, Lim EJ, Jung HJ, Park EH. 2007. Anti-inflammatory and (Mull. Arg.) Miers (Apocynaceae) Tabernaemontana catharinen- anti-angiogenic activities of Gastrodia elata Blume. J Ethnopharmacol. sis D.C. (Apocynaceae) (Rates et al. 1993), Piper marginatum Jacq. 110:476–482. (Piperaceae) (D’Angelo et al. 1997), Plinia edulis (Vell.) Sobral Alexandre-Moreira MS, Piuvezam MR, Araujo CC, Thomas G. 1999. Studies (Myrtaceae) (Azevedo et al. 2016), Stachytarpheta cayennensis on the anti-inflammatory and analgesic activity of Curatella americana L. – (Rich) Vahl. (Verbenaceae) (Penido, Costa, Futuro, et al. 2006), J Ethnopharmacol. 67:171 177. Allen-Hall L, Arnasond JT, Cano P, Lafrenie RM. 2010. Uncaria tomentosa Tabebuia impetiginosa (Mart. Ex. D.C.) Standl. (Bignoniaceae) acts as a potent TNF-alpha inhibitor through NF-kappaB. (Koyama et al. 2000), Vanillosmopsis arborea (Gardner) Kaber. J Ethnopharmacol. 127:685–693. (Asteraceae) (Santos et al. 2015), Virola michelii Heckel Allen-Hall L, Cano P, Arnason JT, Rojas R, Locke O, Lafrenie RM. 2007. (Myristicaceae) Carvalho, Sertie, et al. (1999), Ximenia americana Treatment of THP-1 cells with Uncaria tomentosa extracts differentially regulates the expression if IL-1 and TNF-a. J Ethnopharmacol. L. (Ximeniaceae) (Shettar et al. 2015), Zeyheria montana Mart. 109:312–317. (Bignoniaceae) (Guenka et al. 2008), Byrsonima intermedia A. Juss Andrade SF, Cardoso LGV, Carvalho JCT, Bastos JK. 2007. Anti-inflamma- (Malpighiaceae) (Orlandia et al. 2011), and other plants native to tory and antinociceptive activities of extract, fractions and populnoic acid Brazil with anti-inflammatory activities need further studies to from bark wood of Austroplenckia populnea. J Ethnopharmacol. – fully elucidate their mechanisms of action. 109:464 471. Aquila S, Giner RM, Recio MC, Spegazzini ED, Rıosa JL. 2009. Anti-inflam- Regarding the experimental models to assess anti-inflamma- matory activity of flavonoids from Cayaponia tayuya roots. tory effect, probably the most used are with in vivo protocols, J Ethnopharmacol. 121:333–337. especially using mice and rat paw oedema models induced by Ashley NT, Weil ZM, Nelson RJ. 2012. Inflammation: mechanisms, costs, and – carrageenan to evaluate acute anti-inflammatory activity. natural variation. Annu Rev Ecol Evol Syst. 43:385 406. 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COX-dependent mechanisms involved in the The reported data in this review, in addition to other pub- antinociceptive action of NSAIDs at central and peripheral sites. lished studies, emphasize the relevance of many medicinal plants Pharmacol Ther. 107:139–154. native to Brazil currently used in folk medicine for the modula- Carvalho JCT, Ferreira LP, Santos LS, Corr^ea MJC, Campos LMO, Bastos JK, tion and treatment of inflammatory disorders. Although some Sarti SJ. 1999. Anti-inflammatory activity of flavone and some of its deri- – studies did not evaluate the mechanism of action of these plants, vates from Virola michelli Heckel. J Ethnopharmacol. 64:173 177. Carvalho JCT, Sertie JAA, Barbosa MVJ, Patrıcio KCM, Caputo LRG, Sarti they contribute with preliminary information to demonstrate the SJ, Ferreira LP, Bastos JK. 1999. Anti-inflammatory activity of the crude efficacy of plant extracts and their secondary metabolites. extract from the fruits of Pterodon emarginatus Vog. J Ethnopharmacol. 64:127–133. Cestari SH, Bastos JK, Stasi LCD. 2011. Intestinal anti-inflammatory activity Conclusions of baccharis dracunculifolia in the trinitrobenzenesulphonic acid model of rat colitis. J Evid Based Complementary Altern Med. 2011:524349 Despite the huge list of Brazilian plants with anti-inflammatory Chagas-Paula DA, Oliveira TB, Faleiro DPV, Oliveira RB, Da Costa FB. 2015. activity and all the efforts undertaken to corroborate their activ- Outstanding anti-inflammatory potential of selected asteraceae species through the potent dual inhibition of cyclooxygenase-1 and 5-lipoxyge- ities, there is still a long way to go to turn all these efforts in nase. Planta Med. 81:296–1307. benefit of the society by using the conspicuous Brazilian bio- Chan CK, Tan LTH, Andy SN, Kamarudin MNA, Goh BH, Kadir HA. 2017. diversity. 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