Biological Properties of Essential Oils from the Piper Species of Brazil: A Review

Piperaceae, a Latin name derived from Greek, which in turn originates from the Arabic word babary —black pepper, is considered one of the largest families of basal dicots, found in tropical and subtropical regions of both hemispheres. The species that belong to this family have a primarily pantropical distribution, predominantly herbaceous members, occurring in tropical Africa, tropical Asia, Central America and the Amazon region. The Piperaceae family includes five genera: Piper , Peperomia , Manekia , Zippelia and Verhuellia . Brazil has about 500 species distributed in the Piper , Peperomia and Manekia genera. The Piper genus, the largest of the Piperaceae family, has about 4000 species. Within the Piper genus, about 260–450 species can be found in Brazil. Piper species have diverse biologi- cal activities and are used in pharmacopeia throughout the world. They are also used in folk medicine for treatment of many diseases in several countries including Brazil, China, India, Jamaica and Mexico. Pharmacological studies of Piper species point toward the vast potential of these plants to treat various diseases. Many of these species are bio- logically active and have shown antitumor, antimicrobial, antioxidant, insecticidal, anti-inflammatory, antinociceptive, enzyme inhibitor, antiparasitic, antiplatelet, piscicide


Introduction
Nature, in general, has produced most of the known organic substances. Among the various kingdoms of nature, the plant kingdom has contributed most significantly to the supply of secondary metabolites. For example, essential oils derived from plants have great value due to their applications as medicines, cosmetics, food and agrochemicals [1,2].
Essential oils constitute a complex mixture of low molecular weight substances (usually less than 500 Da) obtained by hydrodistillation or by extraction with organic solvents [2,3]. A single plant may contain between 20 and 100 secondary metabolites belonging to different chemical classes. Terpenoids, phenylpropanoids and aromatic compounds are metabolites present in essential oils [2]. Among the terpenoids, monoterpenes and sesquiterpenes make up the largest group of substances in essential oils [2,4].
About 3000 essential oils are produced using less than 2000 plant species, among which 300 are important from a commercial point of view. Essential oil production is 40,000-60,000 tons/ year with a market value estimated at $700 million, indicating an increase in production and essential oil consumption worldwide [2].
In Brazil, the production of essential oils began at the end of the second decade of the twentieth century based on the extraction of native species to meet the demands of the foreign market. Interest in essential oils is based not only on the possibility of obtaining aromatic compounds (pleasant odor) and the application of products such as perfumes, fragrances and cosmetics, but also on possessing therapeutic properties such as insecticides, fungicides, bactericides or a precursor compound of molecules with high added value [5].

Piperaceae family
Piperaceae is a Latin name derived from Greek, which in turn originates from the Arabic babary, which means black pepper. It is considered one of the largest families of basal dicots, present in tropical and subtropical regions of both hemispheres [5]. In this family, there are species with a primarily pantropical distribution, having mostly herbaceous representatives (vines, shrubs and even some trees) [5,6].
This family includes five genera: Piper, Peperomia, Manekia, Zippelia and Verhuellia [7]. They are present in tropical Africa, tropical Asia, Central America and the Amazon region [6]. Brazil is represented by about 500 species distributed in the Piper, Peperomia and Manekia genera [8]. The family is very important as a source of substances with pharmacological activities [9]. Many chemical compounds such as amides, phenylpropanoids, chromone, lignans and neolignans have been found [10].

Piper genus
Piper is the largest genus of the Piperaceae family [7,11]. The species of this genus have diverse biological activities and are used in pharmacopeia throughout the world. They are also used in folk medicine for treatment of many diseases in several countries including Brazil, China, India, Jamaica and Mexico [9][10][11].
In Brazil, Piper species are distributed throughout the national territory. Among the aromatic flora of the Amazon region, there are more than a dozen species that provide essential oils that are used by the population for therapeutic purposes [12]. The decoction of Piper callosum leaves is used to treat diseases of the gastrointestinal tract [5,13,14]. Moreover, the tea of the decoction of Piper hispidum leaves is useful for the treatment of malaria. Piper marginatum is used as a tonic, carminative, stimulant, diuretic and sudorific agent against stomach, liver and gallbladder pain, toothaches, and snake and insect bites [5,15,16]. Piper cavalcantei Yuncker is called "electric sky" or "electric oil". The decoction of its leaves is considered an excellent antipyretic and analgesic, especially for headaches. The infusion of the leaves is used as an antidiarrheal, to prevent dehydration and to combat menstrual cramps. Oil, extracted by soaking and heating, is used topically for earaches and other external pain [17].
The Piper species found in the Northeast of Brazil also have many uses in folk medicine, such as Piper corcovadensis used for toothaches [11]. The species found in the Atlantic rainforest are also used. For example, Piper regnellii (L.) Miq. is used as an anesthetic and anti-inflammatory agent. Piper cernuum Vell. is used as an analgesic (mainly for stomach aches) against liver and kidney diseases. Chewing the leaves of Piper gaudichaudianum Kunth. fights toothaches, while Piper cf. lhostzkyanum Kunth. is used to combat pain in the stomach, liver and kidney [17].
The decoction of Piper umbellatum leaves is used by those in the working class especially in the treatment of diseases in the digestive, urinary and respiratory tracts, and treatment of stomatitis, vaginitis and liver disorder [18,19]. Piper aduncum, popularly known as pimentade-macaco and aperta-ruão, has been used in the treatment of gynecological diseases and intestinal disorders [14]. Piper sp, known as Jaborandi, is used to treat toothaches [19]. Peperomia pellucida H.B.K., popularly known as folha-de-vidro, is used against gastrointestinal ailments and high blood pressure and acts as a mild diuretic. The juice of the plant can be used to treat ocular diseases in general [20].

Chemical composition of essential oils of the Piper species from Brazil
From a chemical point of view, essential oils are complex mixtures of volatile substances that are lipophilic and usually odoriferous and liquid. They are endowed with aromas that are almost always pleasant and colorless when recently extracted [29]. They can contain from 20 to 60 or more different compounds at various concentrations [30].
The composition of essential oils is constantly being transformed, according to seasonal variation and circadian rhythms. It may also be determined by genotype, environmental factors, and plant cultivation and collection procedures. It can vary according to geographical origin, drying, harvest time, type of fertilizer, but the main components responsible for the aroma seem to remain constant [31].
In Ref. [48] mainly non-oxygenated sesquiterpenes were identified in the chemical composition of the essential oil of seven Piper species of the Brazilian Atlantic Forest, with E-caryophyllene and germacrene D being the most frequent. However, the non-oxygenated monoterpenes (Z)β-ocimene, α-pinene and β-pinene were also present.
From the literature about the phytochemical study of the essential oil of Piper tuberculatum extracted from the fruit and fine stems from a specimen collected in Rondônia, the predominance of sesquiterpenes was demonstrated, with caryophyllene oxide (32.1 and 26.6%) and (E)-caryophyllene (17.7 and 12.3%) as the major compounds [48].

Biological activities of essential oils of the Piper species from Brazil
Due to their complex chemical composition, essential oils show a range of pharmacological actions, making them potential sources for the development of new drugs [53].
The antimicrobial activity of essential oils, both in vitro and in vivo, has justified research on traditional medicine focused on the characterization of their antimicrobial activity [54]. The search for more effective antimicrobial agents has become a challenge for the medical field and has gained increasing importance. According to studies by Ref. [45], the essential oil of Piper malacophyllum collected in Florianopolis in the state of Santa Catarina showed significant antimicrobial activity, especially antifungal activity shown to be moderate against the Cryptococcus neoformans yeast and the Trichophyton mentagrophytes filamentous fungus, both of clinical interest. This activity is attributed to the synergism of the chemical constituents present in the essential oil.
Work done with essential oils obtained from medicinal plants has shown activity on plant pathogen control that could replace the use of pesticides, which, in the long term, cause negative impacts on society and the environment due to pollution from their chemical waste [55]. The essential oils of P. callosum, P. marginatum and Piper enckea collected in the state of Pará showed inhibitory activity against several pathogens, including Crinipellis perniciosa, Phytophthora palmivora and Phytophthora capsici. P. callosum caused 100% mycelial inhibition of P. capsici at a concentration of 0.75 μL/mL, the best fungitoxic action on the three pathogens tested [39]. The essential oil of P. hispidinervum inhibited growth of the Bipolaris sorokiniana, Fusarium oxysporum and Colletotrichum gloeosporioides pathogens, attributing the fungicidal effect observed in the essential oil to the presence of safrole (89%), its major component [42].
Ref. [43] evaluated the insecticidal activity of the essential oil of P. hispidinervum, collected in Lavras in the state of Minas Gerais, on Spodoptera frugiperda (Fall armyworm), attributing the effect to safrole (82%), the major component of the essential oil being analyzed. The essential oil of Piper betle showed insecticidal activity by inhibiting the development of Spodoptera litura pupae without causing damage to the Eudrilus eugeniae organism [56].
Ref. [33] reported anticholinesterase activity for the essential oils of Piper anonifolium and P. hispidum collected in Bahia, while the oil of P. aleyreanum showed high cytotoxic activity against melanoma. The oils of the three species of Piper analyzed showed strong antifungal activity against Cladosporium sphaerospermum and Cladosporium cladosporioides.
Essential oils from the fruits of P. aduncum, leaves of P. marginatum and seeds of Piper nigrum, collected in Paraíba, were tested against dengue mosquito larvae and were shown to be active. The P. marginatum species had the greatest larvicidal effect [35]. The essential oil of P. corcovadensis revealed a potent larvicidal activity against the oviposition of Aedes aegypti [11].
In a study conducted by Girola et al. [21], the monoterpene camphene isolated from essential oil of P. cernuum, collected in Cubatão in the state of São Paulo, induced apoptosis in melanoma cells, and showed antitumor activity in vivo, thus showing itself to be a promising compound in cancer therapy.
The essential oil of Piper vicosanum collected in the city of Dourados, in the state of Mato Grosso do Sul, demonstrated anti-inflammatory activity in rodents and did not cause acute toxicity or mutagenicity [46]. The essential oil of P. aleyreanum extracted from a specimen from Porto Velho in the state of Rondônia, showed antinociceptive action, as well as anti-inflammatory and gastroprotective properties with great potential for the development of phytomedicines [34].
The literature reports a wide range of essential oils from the Piper genus with different biological properties. The essential oil of P. hispidinervum collected in Porto Alegre, in the state of Rio Grande do Sul, showed amebicide action against the trophozoites of Acanthamoeba polyphaga, preventing its encysting. This suggests that this essential oil has the potential to develop new drugs to treat keratitis. It also demonstrated little toxic effect against Vero cells (renal cells of the African green monkey) and is not toxic at concentrations less than 0.25 mg/mL [24]. The essential oil of Piper diospyrifolium collected in Maringa, in the state of Parana, showed antifungal activity against Candida albicans, Candida parapsilosis and Candida tropicalis isolated from catheter urine, blood culture and orotracheal tube samples donated by the University Hospital of Maringá, demonstrating effective activity as a possible new phytotherapy or natural fungicide [40].

Conclusions and future perspectives
According to the literature, we can say that the essential oils from the Piper species of Brazil have many uses. In addition, they are endowed with interesting biological activities and have a therapeutic potential. For example, they exhibit antimicrobial, anticholinesterase, antitumor, anti-inflammatory activities and may be useful as natural remedies and it seems that they can be used as a suitable therapy for many pathologies. Therefore, economic importance of essential oils from the Piper species of Brazil is indisputable. It appears therefore imperative to preserve our natural, diverse flora and support its protection in order to keep this inexhaustible source of molecules destined for multiple targets.