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Folk medicine, phytochemistry and pharmacological application of Piper marginatum

ABSTRACT

Piper marginatum Jacq., Piperaceae, is a widely distributed Neotropical species abundant in the Caribbean, exhibiting a characteristic winged petiole and a heart-shaped leaf, its two vegetative landmarks for rapid identification. The species has been employed by traditional indigenous cultures for its reputed medicinal properties. The plant is most frequently employed by local healers in Central America, the Antilles and South America, for alleviating gastrointestinal ailments, administered as a decoction or infusion for its tonic, diuretic and carminative effects. These beneficial properties may be attributed to the presence of various phytochemicals within P. marginatum, with most of the studies focusing on the essential oil of the plant. Monoterpenoids, sesquiterpenoids and phenylpropanoids of a varied chemical structure have been identified in the essential oil, while phenylalkanoids, aristolactams, amides and flavonoids have been purified by chromatographic techniques from the extracts. The biological and pharmacological examination of P. marginatum showed that the plant may be a valuable source of mosquitocidal, antifungal, antitumoral and hemostatic agents. Future bioguided research may yield biologically relevant molecules useful in medicine or agriculture.

Keywords:
Piper marginatum; Piperaceae; Folk medicine; Phytochemistry; Pharmacology; Biological applications

Introduction

The species Piper marginatum Jacq., Piperaceae, was first described in 1781 by Dutch botanist Nikolaus Joseph von Jacquin. The species had been collected during excursions to Central and South America, and the morphological characters were recorded as heart-shaped, acuminated, multi-veined and reticulated leaves, with a marginal, grooved and winged petiole, and solitary flowers (Jacquin, 1786Jacquin, N.J., 1786. Icones plantarum rariorum. Lugduni Batavorum, Argentorati Wappler, White et filium, Luchtmans and König, London., pp. 2.). The Swiss botanist Anne Casimir Pyrame de Candolle was the first to observe small morphological differences between different collections of P. marginatum, and recognized three subspecies: P. marginatum Jacq, P. marginatum var. anisatum (Kunth) C.DC. and P. marginatum var. catalpifolium (Kunth) C.DC. (Candolle, 1902Candolle, C.D., 1902. Piperaceae. vol 3. Lipsiae, Borntraeger. Geneva Botanical Garden, 124 pp.). In the comprehensive work "The Piperaceae of Northern South America", William Trelease and Truman G. Yuncker, differentiated the subspecies based on the puberulent (var. anisatum) or pillose (var. catalpifolium) nature of the nerves on the upper surface of the leaves (Trelease and Yuncker, 1950Trelease, W., Yuncker, T.G., 1950. The Piperaceae of Northern South America, vol. 1. University of Illinois Press, Urbana, pp. 73–78.). However the difficulty to characterize specimens at the subgenus level given its extensive homoplasy (the development of similar characters by parallel or convergent evolution) was recognized by Ricardo Callejas (Callejas, 1986Callejas, R., (Ph.D. thesis) 1986. Taxonomic revision of Piper subgenus Ottonia (Piperaceae). City University of New York, New York, 150 pp.), and thus the modern classifications consider the subspecies as synonyms of P. marginatum Jacq. (Andrade et al., 2008Andrade, E.H.A., Carreira, L.M.M., da Silva, M.H.L., da Silva, J.D., Bastos, C.N., Sousa, P.J.C., Guimarães, E.F., Maia, J.G.S., 2008. Variability in essential-oil composition of Piper marginatum sensu lato. Chem. Biodivers. 5, 197-208.). In this work, the sensu lato of P. marginatum was considered, following the criteria of the Missouri Botanical Garden (Tropicos.org, 2015Tropicos.org, 2015.!Piper marginatum Jacq. Missouri Botanical Garden http://www.tropicos.org/Name/25001136 (visited 10.09.15)
http://www.tropicos.org/Name/25001136...
), which collates under P. marginatum several species and subspecies, including Piper san-joseanum C. DC., Piper patulum Bertol., Piper uncatum Trel., Piper quiriguanum Trel., among others.

The phylogenetic analysis of the genus Piper using the sequence alignment of the internal transcribed spacer (ITS) of the 18S-26S nuclear ribosomal DNA and the chloroplast intron region psbJ-petA, indicated that the species P. marginatum is closely related to P. multiplinervium and P. schwakei, and together these three species build the P. marginatum complex (Jaramillo et al., 2008Jaramillo, M.A., Callejas, R., Davidson, C., Smith, J.F., Stevens, A.C., Tepe, E.J., 2008. A phylogeny of the tropical genus Piper using ITS and the chloroplast intron psbJ-petA. Syst. Bot. 33, 647-660.). Moreover the Pothomorphe group species (which includes P. auritum, P. peltatum and P. umbellatum) showed to be phylogenetically related to the P. marginatum complex.

The species P. marginatum has been widely recognized for its medicinal purposes within a number of indigenous cultures located in the Caribbean and Amazon regions, from Central America and the Antilles to Brazil (de Núñez and Johnson, 1943de Núñez, E.H., Johnson, C.H., 1943. A preliminary study of Piper marginatum Jacq.. J. Am. Pharm. Assoc. 32, 234-236.; Braga, 1960Braga, R., 1960. Plantas do Nordeste, especialmente do Ceará. Imprensa Oficial, For- taleza, Brasil, 540 pp.; D'Angelo et al., 1997D'Angelo, L.C.A., Xavier, H.S., Torres, L.M.B., Lapa, A.J., Souccar, C., 1997. Pharmacology of Piper marginatum Jacq. a folk medicinal plant used as an analgesic, antiinflammatory and hemostatic. Phytomedicine 4, 33-40.; Di Stasi and Hiruma-Lima, 2002Di Stasi, L.C., Hiruma-Lima, C.A., 2002. Plantas medicinais na Amazônia e na Mata Atlântica. Editor UNESP, São Paulo, pp. 125–126.). In addition the dried leaves have been used as a natural sweetener (Hussain et al., 1990Hussain, R., Poveda, L., Pezzuto, J., Soejarto, D., Kinghorn, A., 1990. Sweetening agents of plant origin: phenylpropanoid constituents of seven sweet-tasting plants. Econ. Bot. 44, 174-182.; Surana et al., 2006Surana, S., Gokhale, S., Rajmane, R., Jadhav, R., Jadhav, R., 2006. Non-saccharide natural intense sweeteners. An overview of current status. Nat. Prod. Rad. 5, 270-278.). Its major secondary metabolites are terpenoids and phenylalkanoids (Andrade et al., 2008Andrade, E.H.A., Carreira, L.M.M., da Silva, M.H.L., da Silva, J.D., Bastos, C.N., Sousa, P.J.C., Guimarães, E.F., Maia, J.G.S., 2008. Variability in essential-oil composition of Piper marginatum sensu lato. Chem. Biodivers. 5, 197-208.). In addition a number of biological and pharmacological published data (Sequeda-Castañeda et al., 2015Sequeda-Castañeda, L., Celis, C., Gutiérrez, S., Gamboa, F., 2015. Piper marginatum Jacq. (Piperaceae): phytochemical: therapeutic, botanical insecticidal and phytosanitary uses. Pharmacol. Online 3, 136-145.) seems to support its use in traditional medicine. This review covers the ethnomedicinal, phytochemical and biological literature published on P. marginatum with the aim to identify the research voids for future investigation and critically assess the potential application of the species in medicine and agriculture.

Folk medicine and traditional uses

The indigenous communities in Central America, the Antilles and South America repeatedly reported to use P. marginatum for treating a varied array of diseases and ailments. Gastrointestinal problems are the most common therapeutic use in the traditional medicine, spanning different locations and cultures (Fig. 1, Box 1). The plant is recurrently employed either as a decoction or infusion for its tonic, diuretic and carminative effects (Foungbe et al., 1976Foungbe, S., Tillequin, F., Paris, M., Jacquemin, H., Paris, R.-R., 1976. Sur une pipéracée de Guyane, le Piper marginatum Jacq.. Ann. Pharm. Fr. 34, 339-343.; Johnson, 1998Johnson, T., 1998. CRC Ethnobotany Desk Reference. Taylor & Francis, CRC Press, Boca Raton, pp. 631.; Di Stasi and Hiruma-Lima, 2002Di Stasi, L.C., Hiruma-Lima, C.A., 2002. Plantas medicinais na Amazônia e na Mata Atlântica. Editor UNESP, São Paulo, pp. 125–126.; de Albuquerque et al., 2007de Albuquerque, U.P., Monteiro, J.M., Ramos, M.A., de Amorim, E.L.C., 2007. Medicinal and magic plants from a public market in northeastern Brazil. J. Ethnopharmacol. 110, 76-91.). It is also used to treat gallbladder, liver, stomach, spleen, urinary and gastrointestinal ailments (van den Berg, 1982van den Berg, M.E., 1982. Plantas medicinais na Amazônia: contribuição ao seu conhecimento sistemático. Conselho Nacional de Desenvolvimento Científico e Tecnológico, Programa Trópico Umido/Museo Paraense Emílio Goeldi, Belém, 223 pp.; Pereira et al., 2011Pereira, L.A., Barboza, G.E., Bovini, M.G., De Almeida, M.Z., Guimarães, E.F., 2011. Caracterización y uso de pimientas en una comunidad Quilombola de la Amazonía Oriental (Brasil). J. Bot. Res. Inst. Texas 5, 255-272.; Yukes and Balick, 2011Yukes, J.E., Balick, M.J., 2011. Dominican Medicinal Plants: A Guide for Health Care Providers, 2nd ed. The New York Botanical Garden, New York, pp. 25.), but also dysentery (de Núñez and Johnson, 1943de Núñez, E.H., Johnson, C.H., 1943. A preliminary study of Piper marginatum Jacq.. J. Am. Pharm. Assoc. 32, 234-236.). In Central America, the species is known as "Aniseto" and it is employed as an infusion for treating flatulence disorders, in a similar way to star anise.

Box 1
Traditional medicine applications of Piper marginatum by local communities.

Fig. 1
Frequency of application of Piper marginatum in the traditional medicine based on the type of ailment to treat.

Pain relief is the second most frequent use of P. marginatum in the traditional medicine (Fig. 1, Box 1). The plant is used to relieve toothache, headaches and pain caused by itching, and as a general analgesic (Hazlett, 1986Hazlett, D., 1986. Ethnobotanical observations from cabecar and guaymí settlements in Central America. Econ. Bot. 40, 339-352.; Giraldo Tafur, 1996Giraldo Tafur, C., 1996. Medicina tradicional de las mujeres Siona del resguardo de Buenavista en el río Putumayo. Caldasia 18, 227-238.; Di Stasi and Hiruma-Lima, 2002Di Stasi, L.C., Hiruma-Lima, C.A., 2002. Plantas medicinais na Amazônia e na Mata Atlântica. Editor UNESP, São Paulo, pp. 125–126.; Pereira et al., 2011Pereira, L.A., Barboza, G.E., Bovini, M.G., De Almeida, M.Z., Guimarães, E.F., 2011. Caracterización y uso de pimientas en una comunidad Quilombola de la Amazonía Oriental (Brasil). J. Bot. Res. Inst. Texas 5, 255-272.). The plant is employed topically as a cataplasm to alleviate the pain of the limbs or abdomen, or as a decoction or infusion for teeth, head and stomach aches (García, 1974García, H., 1974. Flora medicinal de Colombia: botánica médica, Segunda edición ed. Tercer Mundo Editores.; Giraldo Tafur, 1996Giraldo Tafur, C., 1996. Medicina tradicional de las mujeres Siona del resguardo de Buenavista en el río Putumayo. Caldasia 18, 227-238.; Yukes and Balick, 2011Yukes, J.E., Balick, M.J., 2011. Dominican Medicinal Plants: A Guide for Health Care Providers, 2nd ed. The New York Botanical Garden, New York, pp. 25.).

The species P. marginatum is also commonly used as a hemostatic (Fig. 1, Box 1). The plant has been reported to stop bleeding particularly in the case of ophidian accidents (de Núñez and Johnson, 1943de Núñez, E.H., Johnson, C.H., 1943. A preliminary study of Piper marginatum Jacq.. J. Am. Pharm. Assoc. 32, 234-236.; Braga, 1960Braga, R., 1960. Plantas do Nordeste, especialmente do Ceará. Imprensa Oficial, For- taleza, Brasil, 540 pp.; D'Angelo et al., 1997D'Angelo, L.C.A., Xavier, H.S., Torres, L.M.B., Lapa, A.J., Souccar, C., 1997. Pharmacology of Piper marginatum Jacq. a folk medicinal plant used as an analgesic, antiinflammatory and hemostatic. Phytomedicine 4, 33-40.; Sánchez et al., 2011Sánchez, Y., Correa, T.M., Abreu, Y., Martínez, B., Duarte, Y., Pino, O., 2011. Caracterización química y actividad antimicrobiana del aceite esencial de Piper marginatum Jacq.. Rev. Protec. Veg. 26, 170-176.; Ortega-Galvan, 2014Ortega-Galvan, J., 2014. Mi familia usa Piper marginatum para curar la mordedura de serpiente, Megua, Baranoa, Atlántico, Colombia (Personal communication).). Reports of the topical application of the plant to alleviate itching and scratching from insect bites including ants (Elisabetsky and Gely, 1987Elisabetsky, E., Gely, A., 1987. Plantes médicinales utilisées en Amazonie comme fond potentiel de nouveaux agents thérapeutiques dans les cas d'allergie, thrombose et inflammation. J. Agric. Tradit. Bot. Appl. 34, 143-151.) has been recurrently reported (Box 1), and it remains to be determined if this property is due solely to the analgesic effect. In addition P. marginatum displays antimicrobial properties with recorded applications in Brazil (Corrêa and Pena, 1984Corrêa, M.P., Pena, L.d.A., 1984. Dicionário das plantas úteis do Brasil e das exóticas cultivadas. Ministério da Agricultura, Instituto Brasileiro de Desenvolvimento Florestal, Rio de Janeiro, 747 pp.; D'Angelo et al., 1997D'Angelo, L.C.A., Xavier, H.S., Torres, L.M.B., Lapa, A.J., Souccar, C., 1997. Pharmacology of Piper marginatum Jacq. a folk medicinal plant used as an analgesic, antiinflammatory and hemostatic. Phytomedicine 4, 33-40.), Colombia (Duke and Vasquez, 1994Duke, J.A., Vasquez, R., 1994. Amazonian Ethnobotanical Dictionary. Taylor & Francis, CRC Press, Boca Raton, pp. 138–139.), Cuba (Sánchez et al., 2011Sánchez, Y., Correa, T.M., Abreu, Y., Martínez, B., Duarte, Y., Pino, O., 2011. Caracterización química y actividad antimicrobiana del aceite esencial de Piper marginatum Jacq.. Rev. Protec. Veg. 26, 170-176.) and Puerto Rico (de Núñez and Johnson, 1943de Núñez, E.H., Johnson, C.H., 1943. A preliminary study of Piper marginatum Jacq.. J. Am. Pharm. Assoc. 32, 234-236.). The species is also employed to treat female disorders, skin problems and insect bites (van Andel et al., 2008van Andel, T., de Korte, S., Koopmans, D., Behari-Ramdas, J., Ruysschaert, S., 2008. Dry sex in Suriname. J. Ethnopharmacol. 116, 84-88.; Lans and Georges, 2011Lans, C., Georges, K., 2011. Women's knowledge of herbs used in reproduction in Trinidad and Tobago. In: Rai, M., Acharya, D., Rios, J.L. (Eds.), Ethnomedicinal Plants: Revitalizing of Traditional Knowledge of Herbs. CRC Press, pp. 115–134.; Pereira et al., 2011Pereira, L.A., Barboza, G.E., Bovini, M.G., De Almeida, M.Z., Guimarães, E.F., 2011. Caracterización y uso de pimientas en una comunidad Quilombola de la Amazonía Oriental (Brasil). J. Bot. Res. Inst. Texas 5, 255-272.). In Suriname, Trinidad and Puerto Rico, the plant is widely used to treat female disorders such as to clean female sexual organs, to help parturition, and to reduce the menstruation flow, respectively (Morton, 1977Morton, J.F., 1977. Some folk-medicine plants of central American markets. Pharm. Biol. 15, 165-192.; van Andel et al., 2008van Andel, T., de Korte, S., Koopmans, D., Behari-Ramdas, J., Ruysschaert, S., 2008. Dry sex in Suriname. J. Ethnopharmacol. 116, 84-88.; Lans and Georges, 2011Lans, C., Georges, K., 2011. Women's knowledge of herbs used in reproduction in Trinidad and Tobago. In: Rai, M., Acharya, D., Rios, J.L. (Eds.), Ethnomedicinal Plants: Revitalizing of Traditional Knowledge of Herbs. CRC Press, pp. 115–134.). In the French Guiana, P. marginatum is used to treat cutaneous eruptions and skin rashes (Foungbe et al., 1976Foungbe, S., Tillequin, F., Paris, M., Jacquemin, H., Paris, R.-R., 1976. Sur une pipéracée de Guyane, le Piper marginatum Jacq.. Ann. Pharm. Fr. 34, 339-343.; Morton, 1977Morton, J.F., 1977. Some folk-medicine plants of central American markets. Pharm. Biol. 15, 165-192.; D'Angelo et al., 1997D'Angelo, L.C.A., Xavier, H.S., Torres, L.M.B., Lapa, A.J., Souccar, C., 1997. Pharmacology of Piper marginatum Jacq. a folk medicinal plant used as an analgesic, antiinflammatory and hemostatic. Phytomedicine 4, 33-40.), and in Brazil it is used to alleviate hitching caused by insect bites (Pereira et al., 2011Pereira, L.A., Barboza, G.E., Bovini, M.G., De Almeida, M.Z., Guimarães, E.F., 2011. Caracterización y uso de pimientas en una comunidad Quilombola de la Amazonía Oriental (Brasil). J. Bot. Res. Inst. Texas 5, 255-272.).

Phytochemistry

The species P. marginatum shows a distinct phytochemistry with the presence of specific secondary metabolites, not found in other Piper species. For instance, P. marginatum is the only Piper species containing anethole, estragole, isoeugenol methyl ether, the phenylalkanoids 3-farnesyl-4-hydroxybenzoic and 3-farnesyl-4-methoxybenzoic acids and the glycosides marginatoside and vitexin (Parmar et al., 1997Parmar, V.S., Jain, S.C., Bisht, K.S., Jain, R., Taneja, P., Jha, A., Tyagi, O.D., Prasad, A.K., Wengel, J., Olsen, C.E., Boll, P.M., 1997. Phytochemistry of the genus Piper. Phytochemistry 46, 597-673.). No other Piper species have shown the presence of these chemotaxonomic markers.

According to the essential oil (EO) components, seven chemotypes were recognized by Andrade et al. in their comprehensive study with 22 samples of P. marginatum collected throughout the Brazilian Amazon (Andrade et al., 2008Andrade, E.H.A., Carreira, L.M.M., da Silva, M.H.L., da Silva, J.D., Bastos, C.N., Sousa, P.J.C., Guimarães, E.F., Maia, J.G.S., 2008. Variability in essential-oil composition of Piper marginatum sensu lato. Chem. Biodivers. 5, 197-208.). The existence of seven chemotypes may induce to consider the assumption of ancient character of P. marginatum, allowing potential speciation events to occur during recent evolution. This hypothesis may be tested in the future by molecular phylogenetic analysis. The composition of the EO of the leaf, stem and inflorescence from a P. marginatum species collected in near Recife, Brazil, showed that the major component was (Z)-asarone (30.4%) on the EO of the leaf, (E)-asarone (32.6%) on the EO of the stem, and patchoulol (23.4%) on the EO of the inflorescence (Autran et al., 2009Autran, E.S., Neves, I.A., da Silva, C.S.B., Santos, G.K.N., Navarro, D.M.A.F., 2009. Chemical composition, oviposition deterrent and larvicidal activities against Aedes aegypti of essential oils from Piper marginatum Jacq. (Piperaceae). Bioresour. Technol. 100, 2284-2288.). A P. marginatum species from Costa Rica (Vogler et al., 2006Vogler, B., Noletto, J.A., Haber, W.A., Setzer, W.N., 2006. Chemical constituents of the essential oils of three Piper species from Monteverde, Costa Rica. J. Essent. Oil Bear. Plants 9, 230-238.) was rich in anethole (45.9%) and anisaldehyde (22.0%), while P. marginatum collected near Guantanamo in Cuba (Sánchez et al., 2011Sánchez, Y., Correa, T.M., Abreu, Y., Martínez, B., Duarte, Y., Pino, O., 2011. Caracterización química y actividad antimicrobiana del aceite esencial de Piper marginatum Jacq.. Rev. Protec. Veg. 26, 170-176.) showed high amounts of isosafrole (37.3%) and nothosmyrnol (22.7%). Moreover, the EO obtained from P. marginatum collected near Acandi, Colombia, had high concentration of anethole (46.3%) followed by estragol (28.9%), whereas the same species collected in Turbaco, Colombia, showed an EO rich in germacrene D (36.6%) (Jaramillo-Colorado et al., 2015Jaramillo-Colorado, B., Julio-Torres, J., Duarte-Restrepo, E., Gonzalez-Coloma, A., Julio-Torres, L.F., 2015. Estudio comparativo de la composición volátil y las actividades biológicas del aceite esencial de Piper marginatum Jacq. Colombiano. Bol. Latinoam. Caribe 14, 343-354.). These studies suggest that there are more than seven chemotypes on the EO of P. marginatum sensu lato. These results point out to a dramatic variation in chemical composition for a set of related marginatum-phenotype species but in addition it is necessary to consider the variability associated to chronobiological phenomena (monthly, weekly and daily variation) as hypothesized by Moraes et al. (2014)Moraes, M.M., da Silva, T.M., Silva, R.R.d., Ramos, C.S., da Camara, C.A., 2014. Circadian variation of essential oil from Piper marginatum Jacq.. Bol. Latinoam. Caribe 13, 270-277..

Most of the phytochemical studies on P. marginatum have been carried out on the EO of the plant. Twenty five monoterpen(e)-oids (1–25, Box 3), and fifty seven sesquiterpen(e)-oids (26–82, Box 3) have been identified from the EO of P. marginatum species collected in different locations, at different moments and studied under different conditions. Thus there are reasons to explain the variation observed on the chemical composition of the EO differentiated in seven chemotypes (Andrade et al., 2008Andrade, E.H.A., Carreira, L.M.M., da Silva, M.H.L., da Silva, J.D., Bastos, C.N., Sousa, P.J.C., Guimarães, E.F., Maia, J.G.S., 2008. Variability in essential-oil composition of Piper marginatum sensu lato. Chem. Biodivers. 5, 197-208.). But in addition to this variability, the assembly of previously described subspecies collated under the sensu-lato name P. marginatum may contribute to the notable chemical variation, as each subspecies may have a different secondary metabolism. It remains to be verified if the populations ascribed as P. marginatum are undergoing speciation events, moreover considering its widespread geographical distribution.


Box 3
Biological and pharmacological activities of Piper marginatum.

The sole sesquiterpenoid which has been purified using chromatographic techniques is caryophyllene oxide (40) (de Oliveira Chaves and de Oliveira Santos, 2002de Oliveira Chaves, M.C., de Oliveira Santos, B.V., 2002. Constituents from Piper marginatum fruits. Fitoterapia 73, 547-549.). Among the thirty-nine phenylalkanoids (83–122, Box 2) reported for P. marginatum, most of them were identified by CG-MS analysis of the EO of the plant, while some of them were isolated to purity by chromatographic techniques (apiol (87), (E)-asarone (89), croweacin (92), 2,6-dimethoxy-3,4-methylenedioxy-1-(2-propenyl)-benzene (95), 3-farnesyl-4-hydroxybenzoic acid (99) and 3-farnesyl-4-methoxybenzoic acid (100), 2-hydroxy-3,4-methylenedioxypropiophenone (101), marginatine (106), 3,4-methylenedioxypropiophenone (108), 2-methoxy-4,5-methylenedioxypropiophenone (109), pipermargine (118) piperonal (119), 1-(1-(Z)-propenyl)-2,4,6-trimethoxybenzene (120), safrole (121), 2,4,5-trimethoxypropiophenone (122)) (de Diaz and Gottlieb, 1979de Diaz, A.M., Gottlieb, O.R., 1979. Propiophenones from Piper marginatum. Planta Med. 35, 190-191.; Maxwell and Rampersad, 1988Maxwell, A., Rampersad, D., 1988. Prenylated 4-hydroxybenzoic acid derivatives from Piper marginatum. J. Nat. Prod. 51, 370-373.; de Oliveira Santos et al., 1997de Oliveira Santos, B.V., Da-Cunha, E.V., de Oliveira Chaves, M.C., Gray, A.I., 1997. Croweacin from Piper marginatum. Biochem. Syst. Ecol. 25, 471-472.; Santos et al., 1998Santos, B.V.d.O., Chaves, E.M.C.d.O., Gray, A.I., 1998. Phenylalkanoids from Piper marginatum. Phytochemistry 49, 1381-1384.; de Oliveira Santos and de Oliveira Chaves, 1999bde Oliveira Santos, B.V., de Oliveira Chaves, M.C., 1999. 2,4,5-Trimethoxypropiophenone from Piper marginatum. Biochem. Syst. Ecol. 27, 539-541.; de Oliveira Chaves and de Oliveira Santos, 2002de Oliveira Chaves, M.C., de Oliveira Santos, B.V., 2002. Constituents from Piper marginatum fruits. Fitoterapia 73, 547-549.).


Box 2
Reported phytochemicals identified in Piper marginatum.

The alkaloids or amides so far identified from P. marginatum are the aristolactams cepharanone B (123) and piperolactam A (124), (E,E)-N-isobutyl-2,4-octadienamide (125) and cinnamoyl pirrolidide (126) (de Oliveira Santos and de Oliveira Chaves, 1999ade Oliveira Santos, B.R.V., de Oliveira Chaves, M.C., 1999. (E,E)-N-Isobutyl-2,4-octadienamide from Piper marginatum. Biochem. Syst. Ecol. 27, 113-114.; de Oliveira Chaves et al., 2003de Oliveira Chaves, M., de Oliveira Santos, B., de Oliveira, A., 2003. 1-Cinnamoyl pyrrolidide from Piper marginatum. Biochem. Syst. Ecol. 31, 1213-1214.; de Oliveira Chaves et al., 2006de Oliveira Chaves, M.C., de Oliveira, A.H., de Oliveira Santos, B.V., 2006. Aristolactams from Piper marginatum Jacq. (Piperaceae). Biochem. Syst. Ecol. 34, 75-77.). Two flavanones 5,4'-dihydroxy-7-methoxyflavanone (127) and 5,7-dihydroxy-4'-methoxyflavanone (128), and two flavonoid glycosides marginatoside (129) and vitexin (130) have been isolated from the leaves of P. marginatum (Tillequin et al., 1978Tillequin, F., Paris, M., Jacquemin, H., Paris, R., 1978. Flavonoides de Piper marginatum. Planta Med. 33, 46-52.; Reigada et al., 2007Reigada, J.B., Tcacenco, C.M., Andrade, L.H., Kato, M.J., Porto, A.L.M., Lago, J.H.G., 2007. Chemical constituents from Piper marginatum Jacq. (Piperaceae) – antifungal activities and kinetic resolution of (RS)-marginatumol by Candida antarctica lipase (Novozym 435). Tetrahedron-Asymmetry 18, 1054-1058.). The catecholamine noradrenaline (131) was identified by high performance liquid chromatography (D'Angelo et al., 1997D'Angelo, L.C.A., Xavier, H.S., Torres, L.M.B., Lapa, A.J., Souccar, C., 1997. Pharmacology of Piper marginatum Jacq. a folk medicinal plant used as an analgesic, antiinflammatory and hemostatic. Phytomedicine 4, 33-40.), and the fatty acid stearic acid (132) has been purified from the leaves (de Diaz and Gottlieb, 1979de Diaz, A.M., Gottlieb, O.R., 1979. Propiophenones from Piper marginatum. Planta Med. 35, 190-191.).


Biological and pharmacological applications

The sweetening effect of the plant recorded in the traditional application was attributed to the presence of (E)-anethole (83), a sweet phenylpropanoid and major compound in certain chemotypes of the EO of P. marginatum but also present in fennel (Foeniculum vulgare), star anise (Illicium verum), cicely (Myrrhis odorata) and anise root (Osmorhiza longistylis) (Hussain et al., 1990Hussain, R., Poveda, L., Pezzuto, J., Soejarto, D., Kinghorn, A., 1990. Sweetening agents of plant origin: phenylpropanoid constituents of seven sweet-tasting plants. Econ. Bot. 44, 174-182.). (E)-Anethole has been reported to provide protection against chemically-induced apoptosis and genotoxicity (Abraham, 2001Abraham, S.K., 2001. Anti-genotoxicity of trans-anethole and eugenol in mice. Food Chem. Toxicol. 39, 493-498.; Galicka et al., 2014Galicka, A., Krętowski, R., Nazaruk, J., Cechowska-Pasko, M., 2014. Anethole prevents hydrogen peroxide-induced apoptosis and collagen metabolism alterations in human skin fibroblasts. Mol. Cell. Biochem. 394, 217-224.), and to be non-carcinogenic in mice (Miller et al., 1983Miller, E.C., Swanson, A.B., Phillips, D.H., Fletcher, T.L., Liem, A., Miller, J.A., 1983. Structure-activity studies of the carcinogenicities in the mouse and rat of some naturally occurring and synthetic alkenylbenzene derivatives related to safrole and estragole. Cancer Res. 43, 1124-1134.) posing no risk to human health (Newberne et al., 1999Newberne, P., Smith, R.L., Doull, J., Goodman, J.I., Munro, I.C., Portoghese, P.S., Wagner, B.M., Weil, C.S., Woods, L.A., Adams, T.B., Lucas, C.D., Ford, R.A., 1999. The FEMA GRAS Assessment of trans-anethole used as a flavouring substance. Food Chem. Toxicol. 37, 789-811.).

Most studies evaluating the biological and pharmacological properties of P. marginatum have focused on the essential oil (Box 3). The leaf EO demonstrated growth inhibition of Escherichia coli bacteria with a minimum inhibitory concentration (MIC) value between 700 and 900 µg/ml against two pathogenic strains STEC0157 and EPEC0312 respectively (Duarte et al., 2007Duarte, M.C.T., Leme, E.E., Delarmelina, C., Soares, A.A., Figueira, G.M., Sartoratto, A., 2007. Activity of essential oils from Brazilian medicinal plants on Escherichia coli. J. Ethnopharmacol. 111, 197-201.). A much lower MIC value of 120 µg/ml was found against the phytopathogenic bacterium Xanthomonas albilineans (Sánchez et al., 2012Sánchez, Y., Correa, T.M., Abreu, Y., Pino, O., 2012. Efecto del aceite esencial de Piper marginatum Jacq. y sus componentes sobre Xanthomonas albilineans (Ashby) Dawson. Rev. Protec. Veg. 27, 39-44.). The leaf EO was also screened for fungal inhibition against both Alternaria solanii and Fusarium oxysporum, displaying moderate activity in disk diffusion assays (dos Santos et al., 2011dos Santos, M.R.A., Lima, R.A., de Freitas Fernandes, C., Silva, A.G., Facundo, V.A., 2011. Atividade fungicida do óleo essencial de Piper marginatum L. (Piperaceae) sobre Fusarium oxysporum (Schlecht) in vitro. Saude Pesq. 4.; Duarte et al., 2013Duarte, Y., Pino, O., Infante, D., Sánchez, Y., Travieso, M.d.C., Martínez, B., 2013. Efecto in vitro de aceites esenciales sobre Alternaria solani Sorauer. Rev. Protec. Veg. 28, 54-59.). However another study reported that the EO from P. marginatum was inactive against F. oxysporum with an MIC value higher than 500 µg/ml, while it was found to be slightly more active against Trichophyton rubrum and Trichophyton mentagrophytes with respective MIC values of 500 and 250 µg/ml (Tangarife-Castaño et al., 2014Tangarife-Castaño, V., Correa-Royero, J.B., Roa-Linares, V.C., Pino-Benitez, N., Betancur-Galvis, L.A., Durán, D.C., Stashenko, E.E., Mesa-Arango, A.C., 2014. Anti-dermatophyte, anti-Fusarium and cytotoxic activity of essential oils and plant extracts of Piper genus. J. Essent. Oil Res. 26, 221-227.). Moreover both the EO and the ethanolic extract of P. marginatum were reported to be inactive against Candida albicans with MIC values higher than 2.0 mg/ml (Duarte et al., 2005Duarte, M.C.T., Figueira, G.M., Sartoratto, A., Rehder, V.L.G., Delarmelina, C., 2005. Anti-Candida activity of Brazilian medicinal plants. J. Ethnopharmacol. 97, 305-311.). The EO obtained from the leaf, steam and flower of P. marginatum were tested for activity against Aedes aegypti, and found to be potent larvicidal mixtures (LC50 ranging from 19.9 to 23.8 µg/ml) with the EO from stem and flower being slightly more active than the EO from the leaf (Autran et al., 2009Autran, E.S., Neves, I.A., da Silva, C.S.B., Santos, G.K.N., Navarro, D.M.A.F., 2009. Chemical composition, oviposition deterrent and larvicidal activities against Aedes aegypti of essential oils from Piper marginatum Jacq. (Piperaceae). Bioresour. Technol. 100, 2284-2288.). A lower LC50 value of 8.3 µg/ml was reported for a leaf EO obtained from Paraiba, Brazil (Costa et al., 2010Costa, J., Santos, P.F.d., Brito, S.A., Rodrigues, F.F., Coutinho, H.D., Botelho, M.A., Lima, S.G.d., 2010. Composição química e toxicidade de óleos essenciais de espécies de Piper frente a larvas de Aedes aegypti L. (Diptera: Culicidae). Lat. Am. J. Pharm. 29, 463-467.) whereas a LC50 value of 34 µg/ml was found for a leaf EO from a plant collected in the Rondonia state in Brazil (Santana et al., 2015Santana, H., Trindade, F., RG, S., Silva, A., Militao, J., Facundo, V., 2015. Essential oils of leaves of Piper species display larvicidal activity against the dengue vector, Aedes aegypti (Diptera: Culicidae). Rev. Bras. Plantas Med. 17, 105-111.). Moreover in the presence of the EO at 100 µg/ml, the gravid A. aegypti females reduced the number of eggs laid by one-third compared to the negative control (Autran et al., 2009Autran, E.S., Neves, I.A., da Silva, C.S.B., Santos, G.K.N., Navarro, D.M.A.F., 2009. Chemical composition, oviposition deterrent and larvicidal activities against Aedes aegypti of essential oils from Piper marginatum Jacq. (Piperaceae). Bioresour. Technol. 100, 2284-2288.). The effect of the P. marginatum EO on brine shrimp (Artemia franciscana) lethality and Vero cells cytotoxicity was found to be comparable in the concentration-response with a LC50 value of 22.4 µg/ml against the A. franciscana nauplii after 24 h of exposition (Olivero-Verbel et al., 2009Olivero-Verbel, J., Gueette-Fernandez, J., Stashenko, E., 2009. Acute toxicity against Artemia franciscana of essential oils isolated from plants of the genus Lippia and Piper collected in Colombia. Bol. Latinoam. Caribe 8, 419-427.), and an IC50 value of 30.3 µg/ml against the Vero cells (Tangarife-Castaño et al., 2014Tangarife-Castaño, V., Correa-Royero, J.B., Roa-Linares, V.C., Pino-Benitez, N., Betancur-Galvis, L.A., Durán, D.C., Stashenko, E.E., Mesa-Arango, A.C., 2014. Anti-dermatophyte, anti-Fusarium and cytotoxic activity of essential oils and plant extracts of Piper genus. J. Essent. Oil Res. 26, 221-227.). In addition the EO also demonstrated antiparasitic and insecticidal properties, with 90% of the population of Schistosoma mansoni being inhibited with 5 mg of the EO (Frischkorn et al., 1978Frischkorn, C., Frischkorn, H., Carrazzoni, E., 1978. Cercaricidal activity of some essential oils of plants from Brazil. Naturwissenschaften 65, 480-483.), and 90% of the population of the fire ant Solenopsis saevissima being inhibited with a concentration of 427–480 µg/ml (Souto et al., 2012Souto, R., Harada, A., Andrade, E., Maia, J., 2012. Insecticidal activity of Piper essential oils from the Amazon against the fire ant Solenopsis saevissima (Smith) (Hymenoptera: Formicidae). Neotrop. Entomol. 41, 510-517.). The EO of P. marginatum showed significant antioxidant activity with a DPPH IC50 value between 1.2 and 1.5 µg/ml while the control ascorbic acid showed a DPPH IC50 value of 1.0 µg/ml (Jaramillo-Colorado et al., 2015Jaramillo-Colorado, B., Julio-Torres, J., Duarte-Restrepo, E., Gonzalez-Coloma, A., Julio-Torres, L.F., 2015. Estudio comparativo de la composición volátil y las actividades biológicas del aceite esencial de Piper marginatum Jacq. Colombiano. Bol. Latinoam. Caribe 14, 343-354.). Furthermore the EO demonstrated repellent activity of the red flour beetle Tribolium castaneum from a concentration of 0.01 µl/ml, and also a considerable anti-alimentary effect against the cotton moth Spodoptera littoralis, being non-phytotoxic against Latucca sativa, and thus suggesting a potential application as an natural agent to control beetles and moths in agricultural settings (Jaramillo-Colorado et al., 2015Jaramillo-Colorado, B., Julio-Torres, J., Duarte-Restrepo, E., Gonzalez-Coloma, A., Julio-Torres, L.F., 2015. Estudio comparativo de la composición volátil y las actividades biológicas del aceite esencial de Piper marginatum Jacq. Colombiano. Bol. Latinoam. Caribe 14, 343-354.).

Both leaf and root from P. marginatum collected in Yutaje, Venezuela were extracted with ethanol and the ethanolic extracts were tested for cytotoxicity against a collection of cancer cell lines (Villasmil et al., 2006Villasmil, J., Abad, M.J., Arsenak, M., Fernández, A., Ruiz, M.-C., Williams, B., Michelangeli, F., Herrera, F., Taylor, P., 2006. Cytotoxic and antitumor activities of Venezuelan plant extracts in vitro and in vivo. Pharmacol. Online 3, 808-816.). The leaf extract was active against the human colon carcinoma line HT-29 with a GI50 of 55 µg/ml but inactive against the other cancer lines, whereas the root extract was found active against the human pancreatic carcinoma PANC-1 (GI50 65 µg/ml), and moderately active against colon HT-29 (GI50 298 µg/ml) and lung A549 (GI50 240 µg/ml) carcinoma cell lines (Villasmil et al., 2006Villasmil, J., Abad, M.J., Arsenak, M., Fernández, A., Ruiz, M.-C., Williams, B., Michelangeli, F., Herrera, F., Taylor, P., 2006. Cytotoxic and antitumor activities of Venezuelan plant extracts in vitro and in vivo. Pharmacol. Online 3, 808-816.). A murine in vivo experiment was performed and the leaf extract showed a marked antitumoral effect decreasing by half the size of the tumors compared to the negative control. Interestingly the root extract was inactive suggesting that potential antitumoral compounds are present in the leaf but absent in the root, and thus these compounds could be easily differentiated by HPLC analysis of the extracts. The methanolic extract obtained from P. marginatum leaf collected in Pernambuco, Brazil, was examined for antifungal activity against the phytopathogenic fungi Colletotrichum scovillei, which causes anthracnose on bell peppers (Araújo et al., 2014Araújo, E.R., Harand, W., Lima, I.C., Dias, F.C.R., Santana, A.A.D.d., Carvalho, R.R.d.C., Laranjeira, D., 2014. Extracts of Piper marginatum and Azadirachta indica for the control of Colletotrichum scovillei in bell pepper. Pesq. Agrop. Bras. 49, 88-94.). The methanolic extract displayed a dose-dependent inhibition of mycelial growth, achieving 50% inhibition with a concentration of 750 µg/ml. Although the methanolic extract was fractioned by column chromatography and a significantly active fraction was separated, the active antifungal compounds remains to be identified. Moreover the hydroalcoholic extract was screened for activity against Leishmania infantum amastigotes and showed an IC50 value of 25 µg/ml, while the positive control pentamidine showed an IC50 value of 2.43 µg/ml (Iwanaga et al., 2014Iwanaga, C.C., Bruschi, F.L., Cerquetani, J.A., Cortez, D.A.G., 2014. Antileishmnaial evaluation activity of crude hydroalcoholic extract of Piper marginatum Jacq. VI Simpósio Internacional de Pós-Graduacao e Pesquisa, Sao Paulo, Brasil, pp. 9.).

P. marginatum has recurrently being employed in the traditional medicine as water decoction or infusion, and therefore D'Angelo and collaborators focused on the evaluation of in vivo pharmacological properties of the water extract (D'Angelo et al., 1997D'Angelo, L.C.A., Xavier, H.S., Torres, L.M.B., Lapa, A.J., Souccar, C., 1997. Pharmacology of Piper marginatum Jacq. a folk medicinal plant used as an analgesic, antiinflammatory and hemostatic. Phytomedicine 4, 33-40.). There were no toxic effects observed on Wistar rats or albino mice when the water extract was administered orally up to 2 g/kg. However when administered intraperitoneally, a dose higher than 0.1 g/kg caused piloerection, quietness, lacrimation, muscle relaxation and dyspnea. At a intraperitoneal dose of 1.0 g/kg all animals died within 15 min (D'Angelo et al., 1997D'Angelo, L.C.A., Xavier, H.S., Torres, L.M.B., Lapa, A.J., Souccar, C., 1997. Pharmacology of Piper marginatum Jacq. a folk medicinal plant used as an analgesic, antiinflammatory and hemostatic. Phytomedicine 4, 33-40.). The water extract also had a significant effect on blood pressure. The mean blood pressure of the control rats was 95.5 mmHg, while the intravenous administration of 0.1–0.5 mg/kg doses of P. marginatum water extract, clearly induced a dose-dependent increase to values ranging from 121.1 to 141.5 mmHg (D'Angelo et al., 1997D'Angelo, L.C.A., Xavier, H.S., Torres, L.M.B., Lapa, A.J., Souccar, C., 1997. Pharmacology of Piper marginatum Jacq. a folk medicinal plant used as an analgesic, antiinflammatory and hemostatic. Phytomedicine 4, 33-40.). The hypertensive effect was also observed after oral administration of the water extract at 1 mg/kg. A dose-dependent increase of the rat mesenteric arterial pressure was also detected. In addition both in the vas deferens duct of the rat and the atria in the heart of the guinea pig, the frequency of contractions increased in a dose-dependent manner with the administration of the water extract. The water extract when administered orally at 0.5 and 1.0 mg/kg displayed analgesia in the writhing test in mice and a significant reduction on the edema (inflammation) of the rat paw induced by carrageenan. There was no effect of the P. marginatum water extract on leukocyte counts in the pleurisy induced by carrageenin, suggesting that the anti-inflammatory effect is related to a vasoconstriction action of the water extract of P. marginatum, and not a specific anti-inflammatory action (D'Angelo et al., 1997D'Angelo, L.C.A., Xavier, H.S., Torres, L.M.B., Lapa, A.J., Souccar, C., 1997. Pharmacology of Piper marginatum Jacq. a folk medicinal plant used as an analgesic, antiinflammatory and hemostatic. Phytomedicine 4, 33-40.).

Among all the identified secondary metabolites present in P. marginatum, only five have been tested for a biological activity and these are three arylpropanoids 1-(3,4-methylenedioxyphenyl)-propan-1-ol (marginatumol, 107), 3,4-methylenedioxypropiophenone (108), 2-methoxy-4,5-methylenedioxypropiophenone (109), and the two flavanones 5,4'-dihydroxy-7-methoxyflavanone (127) and 5,7-dihydroxy-4'-methoxyflavanone (128). A bioautographic method was employed to evaluate their antifungal effect against Cladosporus cladosporioides and Cladosporus sphaerospernum and the most active compounds were the two flavanones (127) and (128), which inhibited both microorganisms with an amount as little as 1 µg (Reigada et al., 2007Reigada, J.B., Tcacenco, C.M., Andrade, L.H., Kato, M.J., Porto, A.L.M., Lago, J.H.G., 2007. Chemical constituents from Piper marginatum Jacq. (Piperaceae) – antifungal activities and kinetic resolution of (RS)-marginatumol by Candida antarctica lipase (Novozym 435). Tetrahedron-Asymmetry 18, 1054-1058.). The two propiophenones (108) and (109) inhibited the growth of the fungi with 5 µg, whereas the alcohol marginatumol, (107) required 10 µg to inhibit the fungi.

Conclusion

The species P. marginatum, widely used in the traditional medicine of the Caribbean region, primarily to treat gastrointestinal problems but also employed as analgesic, hemostatic and to cure insect bites, contains a variable mixture of terpenoids, phenylalkanoids, amides and flavonoids. Some of these compounds, including anethole, estragole, isoeugenol methyl ether, 3-farnesyl-4-hydroxybenzoic and 3-farnesyl-4-methoxybenzoic acids, marginatoside and vitexin, are not present in other Piper species, and are thus chemotaxonomic markers for P. marginatum. The high variability of chemotypes observed within P. marginatum sensu lato may reflect upon speciation events, or other factors which remains to be fully investigated. The distinctiveness of the chemical composition translate into a range of biological and pharmacological applications, which according to the reported potency, the larvicidal effect against A. aegypti, the antifungal activity against phytopathogenic fungi and the hemostatic and antitumoral potential, are worth highlighting for future research.

Acknowledgments

The authors acknowledge financial support from the Universidad del Norte (Agenda Interna 2014-0014) for the project "Búsqueda de nuevos agentes anti-tuberculosis en inflorescencias de Piper del Caribe Colombiano". The authors are grateful to Dr. Maria Cristina Martinez-Habibe (Uninorte) for useful discussions.

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Publication Dates

  • Publication in this collection
    Nov-Dec 2016

History

  • Received
    16 Feb 2016
  • Accepted
    31 Mar 2016
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