Kalanchoe laciniata and Bryophyllum pinnatum: an updated review about ethnopharmacology, phytochemistry, pharmacology and toxicology

Júlia M. Fernandes Lorena M. Cunha Eduardo Pereira Azevedo Estela M.G. Lourenço Matheus F. Fernandes-Pedrosa Silvana M. Zucolotto About the authors

Abstract

The species Kalanchoe laciniata (L.) DC. and Bryophyllum pinnatum (Lam) Pers. are native from Brazil and Madagascar, respectively. Both belonging to the Crassulaceae family and being widely used by population as a natural anti-inflammatory agent. These species have similar leaf morphology and for this reason, they are known by the same popular name as “ saião ” or “ coirama ”. Several studies have been published involving different parts and preparations of these species. Therefore, this review aims to provide an update overview about the traditional uses, chemical constitution, pharmacology and toxicology of K. laciniata and B. pinnatum species. An extensive literature review was conducted in different scientific databases. Various chemical constituents have been identified in extracts from different parts of K. laciniata and B. pinnatum , being flavonoids the major compounds. They have been traditionally used to treat inflammation, microbial infection, pain, respiratory diseases, gastritis, ulcers, diabetes and cancer tumors. Non-clinical in vitro assays evaluated mainly the antimicrobial and antioxidant activities, while in vivo assays evaluated the leishmanicide, anti-inflammatory and immunomodulatory activities. Regarding toxicity, few studies have been conducted for the two species. The information reported in this work might contribute to the recognition of the importance of K. laciniata and B. pinnatum species, as well as to direct further studies.

Keywords:
Comparison; Flavonoid; Traditional use; Phytochemical; Pharmacology; Toxicology

Introduction

The Crassulaceae family comprises approximately 33 genera and 1500 species distributed worldwide, except for Australia and the Pacific Islands (Allorge-Boiteau, 1996Allorge-Boiteau, L., 1996. Madagascar centre de speciation et d’origine du genre Kalanchoe (Crassulaceae). In: Lourenço, W.R. (Ed.), Biogéographie de Madagascar. ORSTOM, Paris, pp. 137–145.). This family presents xeromorphic characteristics that allows its species to adapt to bright light and water scarcity (Herrera, 2008Herrera, A., 2008. Crassulacean acid metabolism and fitness under water deficit stress: if not for carbon gain, what is facultative CAM good for?. Ann. Bot 103, 645-653.). It has an important role on the research of biochemical, ecophysiological and phylogenetic aspects related to the Crassulacean Acid Metabolism (CAM), which is an evolutive adaptation of the pathway of photosynthetic carbon assimilation ( Osmond, 1978Osmond, C.B., 1978. Crassulacean acid metabolism: a curiosity in context. Ann. Rev. Plant Physiol. 29, 379-414.). Among species, Kalanchoe laciniata (L.) DC. is native from Brazil and Bryophyllum pinnatum (Lam) Pers. from Madagascar (Allorge-Boiteau, 1996Allorge-Boiteau, L., 1996. Madagascar centre de speciation et d’origine du genre Kalanchoe (Crassulaceae). In: Lourenço, W.R. (Ed.), Biogéographie de Madagascar. ORSTOM, Paris, pp. 137–145.; Gehrig et al., 2001Gehrig, H., GauBmann, O., Marx, H., Schwarzott, D., Kluge, M., 2001. Molecular phylogeny of the genus Kalanchoe (Crassulaceae) inferred from nucleotide sequences of the ITS-1 and ITS-2 regions. Plant Sci. 160, 827-835.). Even though these plants are naturalized in Brazil, they are not endemic (Zappi, 2015Zappi, D., 2015. Crassulaceae in Lista de Espécies da Flora do Brasil. Jardim Botânico do Rio de Janeiro http://floradobrasil.jbrj.gov.br/jabot/floradobrasil/FB22581 (accessed January 2019).
http://floradobrasil.jbrj.gov.br/jabot/f...
).

Kalanchoe laciniata and B. pinnatum are both popularly known as “saião” or “coirama” and have been used to treat inflammatory disorders ( Amaral et al., 2005Amaral, A.C.F., Simões, E.V., Ferreira, J.L.P., 2005. Coletânea científica de plantas de uso medicinal. Fiocruz, Curitiba.). Due to the various ethnopharmacological reports attributed to these species, several research groups have conducted studies to prove their pharmacological or biological properties. In addition, some researchers have carried out phytochemical studies resulting in the identification of different classes of secondary metabolites, as well as the isolation of various constituents, specially from their leaves and aerial parts. Therefore, this review aims to provide an updated overview about the traditional uses, chemical constitution as well as pharmacological and toxicological aspects of K. laciniata and B. pinnatum species. This study might be used as a guide to further investigations involving these species.

Material and methods

An extensive literature review was conducted in different scientific databases such as PubMed, Web of Science, Scopus, Scielo, The Cochrane Library. The study covered several aspects of the vegetal species like botany, phytochemistry, traditional uses, pharmacology and toxicology. In addition, the scientific names, synonyms and popular names of major species identified by the botanical databases “Flora do Brasil”, Tropicos, International Plant Names Index and The Plant List were included. The common names found in the book “Coletânea científica de plantas de uso medicinal” (Amaral et al., 2005Amaral, A.C.F., Simões, E.V., Ferreira, J.L.P., 2005. Coletânea científica de plantas de uso medicinal. Fiocruz, Curitiba.) were also used. The data were updated in April 2018.

Botanical information

Kalanchoe laciniata and Bryophyllum pinnatum exhibit similarities concerning their leaf morphologies, which include decussate, succulent, glabrous, oval to elliptical leaves with crenate border (Hyakutake and Grotta, 1972Hyakutake, S., Grotta, A.S., 1972. Contribuição para o estudo morfológico e anatômico de Kalanchoe brasiliensis Cambressèdes – Crassulaceae. Rev. Farm. Bioquim. Univ. São Paulo 10, 217-237.; Anjoo and Saluja, 2010Anjoo, K., Saluja, A.K., 2010. Microscopical and preliminary phytochemical studies on aerial part (leaves and stem) of Bryophyllum pinnatum Kurz.. Pharmacogn. J. 2, 254-259.; Moreira et al., 2012Moreira, N.S., Nascimento, L.B.S., Leal-Costa, V., Tavares, E.S., 2012. Comparative anatomy of leaves of Kalanchoe pinnata and K. crenata in sun and shade conditions, as a support for their identification. Rev. Bras. Farmacogn. 22, 929-936.). Due to such similarities, these species are known by the same popular name (Moreira et al., 2012Moreira, N.S., Nascimento, L.B.S., Leal-Costa, V., Tavares, E.S., 2012. Comparative anatomy of leaves of Kalanchoe pinnata and K. crenata in sun and shade conditions, as a support for their identification. Rev. Bras. Farmacogn. 22, 929-936.). The knowledge of leaf anatomy is important for registration purpose and for quality control of herbal medicines (Moreira et al., 2012Moreira, N.S., Nascimento, L.B.S., Leal-Costa, V., Tavares, E.S., 2012. Comparative anatomy of leaves of Kalanchoe pinnata and K. crenata in sun and shade conditions, as a support for their identification. Rev. Bras. Farmacogn. 22, 929-936.; Anvisa, 2014Anvisa, 2014. Resolução de Diretoria Colegiada nº 26 de 13 de maio de 2014. Dispõe sobre o registro de medicamentos fitoterápicos e o registro e a notificação de produtos tradicionais fitoterápicos. Ministério da Saúde, Agência Nacional de Vigilância Sanitária, http://bvsms.saude.gov.br/bvs/saudelegis/anvisa/2014/rdc0026_13_05_2014.pdf (accessed January 2017).
http://bvsms.saude.gov.br/bvs/saudelegis...
).

The K. laciniata (L.) DC. specie (Fig. 1) is popularly known as “saião”, “corama-branca”, “folha-da-fortuna”, “para-tudo”, “fortuna-de-flores-amarelas”, “folha-da-costa”, “folha-grossa” in Alagoas, “coerana” in Pernambuco, and “erva-da-costa” in Bahia. This species is found in almost all states of the Northeast region (Rio Grande do Norte, Ceará, Pernambuco, Paraíba, Bahia and Sergipe), Southeast (Espírito Santo, Rio de Janeiro, Minas Gerais and São Paulo), South (Paraná and Santa Catarina), Midwest (Federal District and Mato Grosso do Sul) and North (Acre) regions, mainly in the coastal zone (Allorge-Boiteau, 1996Allorge-Boiteau, L., 1996. Madagascar centre de speciation et d’origine du genre Kalanchoe (Crassulaceae). In: Lourenço, W.R. (Ed.), Biogéographie de Madagascar. ORSTOM, Paris, pp. 137–145.; Amaral et al., 2005Amaral, A.C.F., Simões, E.V., Ferreira, J.L.P., 2005. Coletânea científica de plantas de uso medicinal. Fiocruz, Curitiba.; Zappi, 2015Zappi, D., 2015. Crassulaceae in Lista de Espécies da Flora do Brasil. Jardim Botânico do Rio de Janeiro http://floradobrasil.jbrj.gov.br/jabot/floradobrasil/FB22581 (accessed January 2019).
http://floradobrasil.jbrj.gov.br/jabot/f...
). The accepted name for this specie is K. laciniata (L.) DC. and others botanics synonyms are Kalanchoe brasiliensis and Kalanchoe crenata (The Plant List, 2010The Plant List, 2010. Version 1. Published on the Internet http://www.theplantlist.org/ (accessed February 2019).
http://www.theplantlist.org/...
; Zappi, 2015Zappi, D., 2015. Crassulaceae in Lista de Espécies da Flora do Brasil. Jardim Botânico do Rio de Janeiro http://floradobrasil.jbrj.gov.br/jabot/floradobrasil/FB22581 (accessed January 2019).
http://floradobrasil.jbrj.gov.br/jabot/f...
; Tropicos, 2019Tropicos, 2019. http://tropicos.org/Name/8900471 and http://tropicos.org/Name/8900302 (accessed February 2019).
http://tropicos.org/Name/8900471...
). Although K. laciniata is the accepted name, most of the works found use its synonym of K. brasiliensis.

Fig. 1
Leaves (A) and inflorescences (B) of Kalanchoe laciniata (L.) DC.

Kalanchoe laciniata constitutes a subligneous and perennial vegetable with 30–100 cm in height. Its leaves are succulent, oval or obval, opposites, shortly petiolate and crenate (Corrêa, 1984Corrêa, M.P., 1984. Dicionário de Plantas Úteis do Brasil e das Exóticas Cultivadas. Imprensa Nacional, Rio de Janeiro.; Barroso, 1991Barroso, G.M., 1991. Sistemática de Angiosperma do Brasil. Imprensa Universitária, Minas Gerais.; Amaral et al., 2005Amaral, A.C.F., Simões, E.V., Ferreira, J.L.P., 2005. Coletânea científica de plantas de uso medicinal. Fiocruz, Curitiba.). The flowers are yellow-orange in collor, small, abundant, arranged in composite summits of stamps or paniculate, hermaphrodites, gamopetalas with corolla longer than the cup, with the presence of scaly carpels that become polispermos follicles. Their fruit is a follicle with 6 cm long that contains brown oblong seeds (Lorenzi and Matos, 2000; Amaral et al., 2005Lorenzi, H., Matos, F.J.A., 2000. Plantas medicinais no Brasil: nativas e exóticas. Instituto Plantarum, Nova Odessa.).

The Bryophyllum pinnatum (Lam) Pers. species (Fig. 2) is popularly known as “saião” and “coirama” throughout Brazil; “folha-de-pirarucu”, in Pará State; “fortuna” and “roda-da-fortuna” in Minas Gerais; “zakham-hayat” in Asia and Africa; life-plant in Mexico; love-plant, canterburry, bells and cathedral bells in the United States of America and Europe (Amaral et al., 2005Amaral, A.C.F., Simões, E.V., Ferreira, J.L.P., 2005. Coletânea científica de plantas de uso medicinal. Fiocruz, Curitiba.; Joseph et al., 2011Joseph, B., Sridhar, S., Sankarganesh, J., Edwin, B.T., 2011. Rare medicinal plant – Kalanchoe pinnata . Res. J. Microbiol. 6, 322-327.). This species is found in Brazil, China, India and Africa and in all tropical countries. In Brazil, it is found in Northeast (Bahia, Ceará and Paraíba), North (Acre), Southeast (Espírito Santo, Rio de Janeiro, Minas Gerais and São Paulo), Midwest (Distrito Federal, Mato Grosso do Sul and Mato Grosso) and South (Paraná, Rio Grande do Sul and Santa Catarina) regions, mainly in the coastal and Caatinga zones (Amaral et al., 2005Amaral, A.C.F., Simões, E.V., Ferreira, J.L.P., 2005. Coletânea científica de plantas de uso medicinal. Fiocruz, Curitiba.; Zappi, 2015Zappi, D., 2015. Crassulaceae in Lista de Espécies da Flora do Brasil. Jardim Botânico do Rio de Janeiro http://floradobrasil.jbrj.gov.br/jabot/floradobrasil/FB22581 (accessed January 2019).
http://floradobrasil.jbrj.gov.br/jabot/f...
). B. pinnatum (Lam) Pers. is the accepted name and B. calycinum and Kalanchoe pinnata are its botanic synonyms (The Plant List, 2010The Plant List, 2010. Version 1. Published on the Internet http://www.theplantlist.org/ (accessed February 2019).
http://www.theplantlist.org/...
; Zappi, 2015Zappi, D., 2015. Crassulaceae in Lista de Espécies da Flora do Brasil. Jardim Botânico do Rio de Janeiro http://floradobrasil.jbrj.gov.br/jabot/floradobrasil/FB22581 (accessed January 2019).
http://floradobrasil.jbrj.gov.br/jabot/f...
; Tropicos, 2019Tropicos, 2019. http://tropicos.org/Name/8900471 and http://tropicos.org/Name/8900302 (accessed February 2019).
http://tropicos.org/Name/8900471...
).

Fig. 2
Leaves (A) and inflorescences (B) of Bryophyllum pinnatum (Lam) Pers.

Bryophyllum pinnatum is a perennial, succulent and corpulent vegetable with glabrous and tuberous stem. This species can reach up to 150 cm in height. The oldest stalks have a light color while the youngest ones are reddish with defilements. Its leaves are variable and decussates, being the lowest ones generally simple or sometimes imparinates. The leaves are 30 cm long, the upper are 3-5-7 foliated, long petiolate, thick, fleshy and dark with crenate borders. The inflorescences are hermaphrodites, tubular, pendulous, monopetalas, pale green or yellow-red, with cup swollen and corolla longer than the cup. The fruit are in the form of hoods which become scaly polispermos follicles that are housed within the hoods (Amaral et al., 2005Amaral, A.C.F., Simões, E.V., Ferreira, J.L.P., 2005. Coletânea científica de plantas de uso medicinal. Fiocruz, Curitiba.; Jessica, 2008Jessica, L.K., 2008. Investigation of Kalanchoe homeobox 1 (Kh1) gene in Apical Meristems of Kalanchoe pinnatum. In: Undergraduate Honors Theses. ButlerUniversity, Indiana USA.; Joseph et al., 2011Joseph, B., Sridhar, S., Sankarganesh, J., Edwin, B.T., 2011. Rare medicinal plant – Kalanchoe pinnata . Res. J. Microbiol. 6, 322-327.; Moreira et al., 2012Moreira, N.S., Nascimento, L.B.S., Leal-Costa, V., Tavares, E.S., 2012. Comparative anatomy of leaves of Kalanchoe pinnata and K. crenata in sun and shade conditions, as a support for their identification. Rev. Bras. Farmacogn. 22, 929-936.).

The main characteristic that differentiates K. laciniata and B. pinnatum species is the leaf aspect as K. laciniata has a corrugated or subcrenated border (Fig. 3), whereas B. pinnatum leaf is significantly crenate (Lorenzi and Matos, 2000Lorenzi, H., Matos, F.J.A., 2000. Plantas medicinais no Brasil: nativas e exóticas. Instituto Plantarum, Nova Odessa.).

Fig. 3
Leaves of Kalanchoe laciniata (A) and Bryophyllum pinnatum (B).

Chemical constituents

Various chemical constituents for K. laciniata and B. pinnatum have been reported in the literature, where they have been isolated mainly from the leaves of both species. The aqueous and methanolic are the most commonly used extracts of K. laciniata and B. pinnatum, respectively. Among the constituents that have been identified so far, flavonoids represent the class of secondary metabolites most commonly found, being the major component in both species. However, for K. laciniata, some patuletin aglycone derivatives have been identified, whereas for B. pinnatum, quercetin, kaempferol and luteolin aglucons were found. In addition, chlorophylls, carotenoids and polysaccharides have been identified for K. laciniata.

Despite the widespread use of K. laciniata and B. pinnatum by folk medicine practitioners, their chemical constituents have not been fully elucidated. Moreover, only few studies involved the isolation and elucidation of their chemical constituents, where the majority of the studies indicates the presence of glycosylated flavonoids, derived from the acetylation of the rhamnose ring of patuletin in different positions. The acetylation occurs at the end of the biosynthetic route of flavonoids, usually through esterifications of the hydroxyl groups (Aguiar et al., 2007Aguiar, C.M., Alencar, S.M., Tsai, S.M., Park, Y.K., 2007. Transformações enzimáticas de flavonoides. Bol. Centro Pesqui. Process. Aliment. 25, 61-76.). Flavonoids derived from patuletin have already been described for another species of the genus, K. spathulata (Gaind et al., 1981Gaind, K.N., Singla, K.A., Wallace, J.W., 1981. Flavonoid glycosides of Kalanchoe spathulata. Phytochemistry 20, 530-531.). Acetylated rhamnose flavonoids have been described for B. pinnatum but derived from canferol (Tatsimo et al., 2012Tatsimo, S.J.N., Tamokou, J.D., Havyarimana, L., Csupor, D., Forgo, P., Hohmann, J., Kuiate, J., Tane, P., 2012. Antimicrobial and antioxidant activity of kaempferol rhamnoside derivatives from Bryophyllum pinnatum. BMC Res. Notes 5, 1-6.). However, a quick search in the literature reveals that acetylated rhamnoses of patuletin have only been described for K. laciniata and K. gracilis by Costa et al. (1994)Costa, S.S., Jossang, A., Bodo, B., 1994. Patuletin acetylrhamnosides from Kalanchoe brasiliensis as inhibitors of human lymphocyte proliferative activity. J. Nat. Prod. 57, 1503-1510. and Liu et al. (1989)Liu, K.C.S., Shi-Lin, Y., Roberts, M.F., Phillipson, J.D., 1989. Flavonols glycosides with acetyl substitution from Kalanchoe gracilis. Phytochemistry 28, 2813-2818., respectively. Thus, these compounds are considered as potential candidates for specific markers of these species by presenting themselves as differentiators in relation to most other species, especially B. pinnatum. It is worth pointing out that until the date of this publication, no study have been published about the description of the bioactive compounds for this specie as only two studies were conducted by bioassay-guided isolation by Costa et al. (1994)Costa, S.S., Jossang, A., Bodo, B., 1994. Patuletin acetylrhamnosides from Kalanchoe brasiliensis as inhibitors of human lymphocyte proliferative activity. J. Nat. Prod. 57, 1503-1510. and Trevisan et al. (2006)Trevisan, M.T.S., Bezerra, M.Z.B., Santiago, G.M.P., Feitosa, C.M., 2006. Atividades larvicida e anticolinesterásica de plantas do gênero Kalanchoe . Quim. Nova 29, 415-418.. Box 1 summarizes the main compounds already described for K. laciniata.

Box 1
Chemical compounds reported for Kalanchoe laciniata species.

Widely used by the general population, B. pinnatum species has several studies that dealt with the isolation and elucidation of its major compounds. Several classes of chemical compounds have been described for B. pinnatum , which includes fatty acids, acyclic and aromatic organic acids, amino acids, sugars, vitamins, minerals, bufadienolides, ketones, fenantrenics derivatives, sterols, flavonoids, long chain hydrocarbons, triterpenoids, phenolic acids, saponins and gums (Amaral et al., 2005Amaral, A.C.F., Simões, E.V., Ferreira, J.L.P., 2005. Coletânea científica de plantas de uso medicinal. Fiocruz, Curitiba.). However, flavonoids, steroids and terpens are the compounds most frequently isolated from B. pinnatum. In relation to flavonoids, glycosylated derivatives from the quercetin, kaempferol and luteolin aglycones have been described for this species. Quercetin 3- O -α- L-arabinopyranosyl-(1 → 2)- O -α- L-rhamnopyranoside was the first derivative isolated for B. pinnatum, as reported by Muzitano et al. (2006aMuzitano, M.F., (Ph.D. thesis) 2006. Flavonóides de Kalanchoe pinnata (Crassulaceae): avanços na pesquisa da utilização desta espécie medicinal no tratamento da Leishmaniose cutânea. Universidade Federal do Rio de Janeiro, Rio de janeiro, pp. 199.,b)Muzitano, M.F., Cruz, E.A., Almeida, A.P., Silva, S.A.G., Kaiser, C.R., Guette, C., Rossi-Bergmann, B., Costa, S.S., 2006. Quercitrin: an antileishmanial flavonoid glycoside from Kalanchoe pinnata . Planta Med. 72, 81-83. . Although quercetin is a common aglycone derivate, its 3- O diglycosidic bond is quite peculiar as it is a rhamnose–arabinose dimer that is not very common and in fact, has never been reported for leaves of other species of the genus Kalanchoe (Nascimento et al., 2015Nascimento, L.B.S., Leal-Costa, M.V., Coutinho, M.A.S., Moreira, N.S., Lage, C.L.S., Barbi, N.S., Costa, S.S., Tavares, E.S., 2015. Increased antioxidant activity and changes in phenolic profile of Kalanchoe pinnata (Lamarck) Persoon (Crassulaceae) specimens grown under supplemental blue light. J. Photochem. Photobiol. B 89, 391-399.). This very peculiar molecule has been described for few species of other botanical families, but not as the major compound. Nascimento et al. (2018)Nascimento, L.B.S., Aguiar, P.F., Leal-Costa, M.V., Coutinho, M.A., Borsodi, M.P.G., Rossi-Bergmann, B., Tavares, E.S., Costa, S.S., 2018. Optimization of aqueous extraction from Kalanchoe pinnata leaves to obtain the highest content of an anti-inflammatory flavonoid using a response surface model. Phytochem. Anal. 28, 308-315. state that this unusual flavonoid can be used as a marker for B. pinnatum. In addition, this major component has shown potent anti-inflammatory (Ferreira et al., 2014Ferreira, R.T., Coutinho, M.A.S., Malvar, D.C., Costa, E.A., Florentino, I.F., Costa, S.S., Vanderlinde, F.A., 2014. Mechanisms underlying the antinociceptive, antiedematogenic and anti-inflammatory activity of the main flavonoid from Kalanchoe pinnata. Evid. Based Complement. Altern. Med., http://dx.doi.org/10.1155/2014/429256.
http://dx.doi.org/10.1155/2014/429256...
) and leishmanicidal (Muzitano et al., 2009Muzitano, M.F., Falcão, C.A.B., Cruz, E.A., Bergonzi, M.C., Bilia, A.R., Vincieri, F.F., Rossi-Bergmann, B., Costa, S.S., 2009. Oral metabolism and efficacy of Kalanchoe pinnata flavonoids in a murine model of cutaneous leishmaniasis. Planta Med. 75, 307-311.) activities. The compounds already described for B. pinnatum are summarized in Box 2.

Box 2
Chemical compounds reported to Bryophyllum pinnatum species.

Traditional uses

The traditional medicinal uses of K. laciniata and B. pinnatum are shown in Boxes 3 and 4, respectively. As can be seen from these boxes, the leaf is the part of the plant mostly used by the population, whereas the juice is the most frequent mode of preparation for both species. Some of the properties are common for both species and those have been used to treat: (i) skin problems, (ii) problems in the respiratory system, (iii) pain, (iv) inflammation and (v) disorders in the gastrointestinal system. The inflammatory and gastric problems (ulcers and gastritis) are the most commonly treated disorders. In addition, K. laciniata and B. pinnatum have been used in the form of plaster or poultice to treat dermatological disorders and burn wounds. The antivenom activities of the leaves of both species against snake and scorpion bites have also been reported elsewhere.

Box 3
Medicinal popular uses of Kalanchoe laciniata reported in the literature.
Box 4
Medicinal popular uses of Bryophyllum pinnatum described in the literature.

The extract of K. laciniata leaves has been used for the treatment of chilblains, burns, erysipelas, wounds, cough, bronchitis, flu, gastritis, ulcers, otitis, kidney stone, diabetes, anxiety, microbial diseases, snakebite, pain and inflammation. In addition, it has been used to treat cancerous tumors, osteoarticular rheumatism, jaundice, yellow fever, other liver disorders, headache, prostate tumors and hemorrhoids. K. laciniata have been used mainly in the form of decoction, syrup, juice, poultice and maceration of its leaves (Silva et al., 2002Silva, M.G., Diniz, M.F.F.M., Oliveira, R.A.G., 2002. Fitoterápicos: Guia do Profissional de Saúde. Ed. Universitária, João Pessoa.). The popular uses of K. laciniata species are reported in Box 3.

The extract of B. pinnatum leaves have been used for the treatment of severe disorders such as gastritis, ulcers, cough, bronchitis, various bacterial, viral and fungal infections, leishmaniasis, pain, inflammation, some tumors, respiratory infections, diabetes, hypertension, flu and fever (Perry and Metzger, 1980Perry, L.M., Metzger, J., 1980. Medicinal plants of East Asia attributed properties and uses. MIT Press, Cambridge, pp. 109–110.; Silva et al., 1995Silva, S.A.G., Costa, S.S., Mendonça, S.C.F., Silva, E.M., Moraes, V.L.G., Rossi-Bergmann, B., 1995. Therapeutic effect of oral Kalanchoe pinnata leaf extract in murine leishmaniasis. Acta Trop. 60, 201-210.; Moreira et al., 2002Moreira, R.C.T., Costa, L.C.B., Costa, R.C.S., Rocha, E.A., 2002. Abordagem etnobotânica acerca do uso de plantas medicinais na Vila Cachoeira, Ilhéus, Bahia, Brasil. Acta Farm. Bonaer. 21, 205-211.; Medeiros et al., 2004Medeiros, M.F.T., Fonseca, V.S., Andreata, R.H.P., 2004. Plantas medicinais e seus usos pelos sitiantes da Reserva Rio das Pedras, Mangaratiba, RJ, Brasil. Acta Bot. Bras. 18, 391-399.; Amaral et al., 2005Amaral, A.C.F., Simões, E.V., Ferreira, J.L.P., 2005. Coletânea científica de plantas de uso medicinal. Fiocruz, Curitiba.; Kamboj and Saluja, 2009Kamboj, A., Saluja, A.K., 2017. Development of validated HPTLC method for quantification of stigmasterol from leaf and stem of Bryophyllum pinnatum . Arab. J. Chem. 10, S2644-S2650.). This species is part of the traditional Indian medicine. The part of the plant mostly used is its leaves, prepared as decoction, infusion, juice, syrup, poultice and paste. The popular uses of the species B. pinnatum are summarized in Box 4.

Pharmacological activities

The studies that investigated the pharmacological properties of K. laciniata and B. pinnatum usually assessed the activities of the juice or extracts from the leaves and/or aerial parts of these plants. Regarding the type of extract, most studies with K. laciniata used hydroethanolic, whereas for B. pinnatum the ethanolic (in vitro) and aqueous (in vivo) were the most commonly used extracts.

However, there is a large difference in the number of studies between the two species, being B. pinnatum the most studied one, therefore, following the trend that has already been observed in the chemical and ethnopharmacological studies, which had been previously discussed in this article. Fig. 4 presents an overview of the main pharmacological activities that have been studied (in vitro and in vivo) for the two species in addition to the number of studies that have been published so far for each plant.

Fig. 4
Graphical representation of the number of pharmacological studies for Kalanchoe laciniata and Bryophyllum pinnatum.

It is clear from Fig. 4 that a larger number of studies have been reported for B. pinnatum, which suggests that there is more room for studies that investigate additional pharmacological activities for K. laciniata, especially in vivo studies. Moreover, this figure indicates that the gastroprotective activity (alti-ulcer, for instance) is not well explored yet for these plants, especially for K. laciniata.

It is worth to point out that no comparative study between these species has been carried out so far, especially those related to pharmacological aspects. There are only two studies, Fernandes et al. (2016)Fernandes, J.M., Félix-Silva, J., Cunha, L.M., Gomes, J.A.S., Siqueira, E.M.S., Gimenes, L.P., Lopes, N.P., Soares, L.A.L., Fernandes-Pedrosa, M.F., Zucolotto, S.M., 2016. Inhibitory effects of hydroethanolic leaf extracts of Kalanchoe brasiliensis and Kalanchoe pinnata (Crassulaceae) against local effects induced by Bothrops jararaca snake venom. PLOS ONE 11, e0168658. and Araújo et al. (2018)Araújo, E.R.D., Guerra, G.C.B., Araújo, D.F.S., Araújo, A.A., Fernandes, J.M., Araújo-Júnior, R.F., Silva, V.C., Carvalho, T.G., Ferreira, L.S., Zucolotto, S.M., 2018. Gastroprotective and antioxidant activity of Kalanchoe brasiliensis and Kalanchoe pinnata leaf juices against indomethacin and ethanol-induced gastric lesions in rats. Int. J. Mol. Sci. 19, .
https://doi.org/10.3390/ijms19051265...
, which compare the anti-snake and gastroprotective activities, respectively. Thus, more studies that compare some pharmacological activities between K. laciniata and B. pinnatum would be interesting to see, especially those related to their traditional uses.

Kalanchoe laciniata

Several non-clinical assays related to the evaluation of pharmacological activities of K. laciniata are described in the literature. Several non-clinical studies have investigated the numerous pharmacological activities of K. laciniata. Summaries of the non-clinical in vitro and in vivo studies are presented in Boxes 5 and 6, respectively.

Box 5
Non-clinical in vitro studies performed for Kalanchoe laciniata.
Box 6
Non-clinical in vivo studies performed for Kalanchoe laciniata.

Regarding the non-clinical in vivo studies, anti-inflammatory and immunomodulatory have been the most frequently investigated activities so far. This fact is probably due to the popular use of K. laciniata for treating inflammatory disorders. Besides these activities, K. laciniata have been investigated to treat against snake bites by Bothrops species, B. jararaca and B. arternus, where it showed great potential to ameliorate the local effects induced by the snake venom, especially the hemorrhagic reaction. Finally, although often recommended by folk medicine practitioners to use K. laciniata for gastroprotection, there is only one article that investigated its potential use to treat gastric ulcer. Therefore, there are so many pharmacological activities that still lack investigation on this species.

Bryophyllum pinnatum

Several non-clinical in vitro and in vivo studies have been reported for B. pinnatum as summarized in Boxes 7 and 8, respectively. In contrast to the K. laciniata species where most studies investigated its anti-inflammatory activity, the studies performed for B. pinnatum evaluated its leishmanicidal, anti-diabetic, anti-inflammatory, immunomodulatory and anti-cancer properties.

B. pinnatum is used in folk medicine to treat various diseases. For this reason, several in vitro studies were carried out in order to verify the pharmacological properties of those species, which includes hepatoprotective, leishmanicide, immunomodulatory, antimicrobial, antioxidant, anticancer, and antiurolithiatic activities. Studies have shown the potential activity of B. pinnatum against hematological parasites such as Leishmania, Plasmodium and Trypanossoma, whose properties are important due to the very limited pharmacological alternatives for treating these neglected diseases, where researches in this area are of outmost importance.

Box 7
Non-clinical in vitro studies performed for Bryophyllum pinnatum.
Box 8
Non-clinical in vivo studies performed for Bryophyllum pinnatum.

Box 9
Non-clinical in vitro and in vivo toxicity studies reported for Kalanchoe laciniata.

The potential use of B. pinnatum against Leishmania amazonensis has been investigated in vitro (Muzitano et al., 2006aMuzitano, M.F., Cruz, E.A., Almeida, A.P., Silva, S.A.G., Kaiser, C.R., Guette, C., Rossi-Bergmann, B., Costa, S.S., 2006. Quercitrin: an antileishmanial flavonoid glycoside from Kalanchoe pinnata . Planta Med. 72, 81-83.,bMuzitano, M.F., Tinoco, L.W., Guette, C., Kaiser, C.R., Rossi-Bergmann, B., Costa, S.S., 2006. The antileishmanial activity assessment of unusual flavonoids from Kalanchoe pinnata . Phytochemistry 67, 2071-2077.) and in vivo (Muzitano et al., 2009Muzitano, M.F., Falcão, C.A.B., Cruz, E.A., Bergonzi, M.C., Bilia, A.R., Vincieri, F.F., Rossi-Bergmann, B., Costa, S.S., 2009. Oral metabolism and efficacy of Kalanchoe pinnata flavonoids in a murine model of cutaneous leishmaniasis. Planta Med. 75, 307-311.), where the authors demonstrated such activity with the leaves extract (320 mg/kg body weight), as well as with the isolated flavonoids, 3- O -α- L -arabinopyranosyl (1 → 2)-α- L-rhamnopyranoside and quercetrin (16 mg/kg body weight), with both being able to significantly reduce parasite load (Muzitano et al., 2009Muzitano, M.F., Falcão, C.A.B., Cruz, E.A., Bergonzi, M.C., Bilia, A.R., Vincieri, F.F., Rossi-Bergmann, B., Costa, S.S., 2009. Oral metabolism and efficacy of Kalanchoe pinnata flavonoids in a murine model of cutaneous leishmaniasis. Planta Med. 75, 307-311.). In the same article, Muzitano et al. (2009)Muzitano, M.F., Falcão, C.A.B., Cruz, E.A., Bergonzi, M.C., Bilia, A.R., Vincieri, F.F., Rossi-Bergmann, B., Costa, S.S., 2009. Oral metabolism and efficacy of Kalanchoe pinnata flavonoids in a murine model of cutaneous leishmaniasis. Planta Med. 75, 307-311. studied the oral metabolism of flavonoids from B. pinnatum in a murine model of cutaneous leishmaniasis. In addition, they performed another study investigating the influence of cultivation conditions, season of collection and extraction method on the content of antileishmanial flavonoids, where they demonstrated that active flavonoids were more abundant when the leaves were collected during the summer season and after aqueous extraction at 50 °C.

Regarding the in vivo studies, the most investigated activities are leishmanicidal, hepatoprotective, immunoprotective, anti-inflammatory, anti-ulcer, antihypertensive, antinociceptive, wound healing, anti-asthmatic, antitussive, antidiabetic and anticonvulsant. Although these studies have demonstrated the several pharmacological activities attributed to B. pinnatum , it seems that its full potential is far from being proved and additional studies are needed in order to fully investigate its pharmacological properties, its mechanisms of action and its pharmacokinetics.

Another interesting area of research is the anti snake-bite activity. Snake-related accidents are a serious public health problem and have been included on the WHO's List of Neglected Tropical Diseases since 2009 (Gutiérrez et al., 2013Gutiérrez, J.M., Warrell, D.A., Williams, D.J., Jensen, S., Brown, N., Calvete, J.J., Harisson, R.A., 2013. The need for full integration of snakebite envenoming within a global strategy to combat the neglected tropical diseases: the way forward. PLoS Negl. Trop. Dis. 7, e2162.). Fernandes et al. (2016)Fernandes, J.M., Félix-Silva, J., Cunha, L.M., Gomes, J.A.S., Siqueira, E.M.S., Gimenes, L.P., Lopes, N.P., Soares, L.A.L., Fernandes-Pedrosa, M.F., Zucolotto, S.M., 2016. Inhibitory effects of hydroethanolic leaf extracts of Kalanchoe brasiliensis and Kalanchoe pinnata (Crassulaceae) against local effects induced by Bothrops jararaca snake venom. PLOS ONE 11, e0168658. investigated the activity of B. pinnatum against the local effects induced the venom of B. jararaca, where they showed that the extract of this plant was able to antagonize the hemorrhage and edema as well as to inhibit the phospholipase A2 from the venom. The extract of B. pinnatum was active in pre- and post-treatment protocols, indicating the potential antiophidic activity of Kalanchoe species against local effects induced by B. jararaca snake, suggesting their potential use as a new source of bioactive molecules against bothropic venom.

Unlike K. laciniata, the antiulcer activity of B. pinnatum has been studied extensively in recent years. The work published by Araújo et al. (2018)Araújo, E.R.D., Guerra, G.C.B., Araújo, D.F.S., Araújo, A.A., Fernandes, J.M., Araújo-Júnior, R.F., Silva, V.C., Carvalho, T.G., Ferreira, L.S., Zucolotto, S.M., 2018. Gastroprotective and antioxidant activity of Kalanchoe brasiliensis and Kalanchoe pinnata leaf juices against indomethacin and ethanol-induced gastric lesions in rats. Int. J. Mol. Sci. 19, .
https://doi.org/10.3390/ijms19051265...
showed that the pre-treatment with B. pinnatum juice protects the mucosa of rats against the gastric damage of indomethacin and ethanol-induced gastric lesions and reduced damage by improving parameters related to oxidative stress and inflammation on mucosal structures. However, additional studies are necessary in order to investigate what active components are responsible for such activity and the mechanisms of action involved. In addition, further clinical studies are necessary to prove the gastroprotective activity of B. pinnatum in humans.

In this current literature review, only one clinical study was found that evaluated the efficacy and safety of capsules containing B. pinnatum extract in the treatment of overactive bladder syndrome. The clinical study of phase II, prospective, multicenter, double-blind randomized, placebo-controlled was conducted with twenty female patients and suggests that this species might have potential use in the treatment of overactive bladder (Betschart et al., 2013Betschart, C., Mandach, U.V., Seifert, B., Scheiner, D., Peruchini, D., Fink, D., Geissbuhler, V., 2013. Randomized, double-blind placebo-controlled trial with Bryophyllum pinnatum versus placebo for the treatment of overactive bladder in postmenopausal women. Phytomedicine 20, 351-358.). In addiction to this article, the same research group investigated the effects of the leaves juice, fractions enriched in flavonoids and bufadienolides as well as a flavonoid aglycone mixture and individual aglycones on detrusor contractility as a major target in overactive bladder treatment, where the authors found that several metabolites of the leaves juice may inhibit detrusor contractility (Bachamann et al., 2017Bachamann, S., Betschart, C., Gerber, J., Furer, K., Mennet, M., Hamburger, M., Potterat, O., Mandach, U., Simões-Wust, A.P., 2017. Potential of Bryophyllum pinnatum as a detrusor relaxant: an in vitro exploratory study. Planta Med. 83, 1274-1280.), supporting the previous clinical study.

Toxicology

Acute toxicity of K. laciniata species has been investigated in various types of extracts made from leaves or the whole plant. On the other hand, the toxicological studies involving B. pinnatum were performed mainly with extracts of the leaves. The in vitro and in vivo toxicity assays reported in the literature for K. laciniata and B. pinnatum species are shown in Boxes 9 and 10, respectively.

Box 10
Non-clinical in vitro and in vivo studies reported for Bryophyllum pinnatum.

Although most studies have shown that both species present low toxicity and good safety, one study observed some reactions to the central nervous system attributed to K. laciniata , as well as spasms, tachycardia, fine and coarse tremors and aggression (Silva, 2007Silva, J.G., (M.Sc. thesis), 2007. Avaliação do potencial farmacológico de Kalanchoe brasiliensis Cambess. Universidade Federal de Pernambuco, Recife, pp. 88.). Other study reported a reduction in the sensitiveness of the rats to noise and touch, which also presented jerkiness and lethargy (Fondjo et al., 2012Fondjo, F.A., Kamgang, R., Oyono, J.E., Yonkeu, J.N., 2012. Anti-dyslipidemic and antioxidant potentials of methanol extract of Kalanchoe crenata whole plant in streptozotocin-induced diabetic nephropathy in rats. Trop. J. Pharm. Res. 11, 767-775.). For B. pinnatum, some studies have reported cytotoxicity (Sowemimo et al., 2007Sowemimo, A.A., Fakoya, F.A., Awopetu, I., Omobuwajo, O.R., Adesanya, S.A., 2007. Toxicity and mutagenic activity of some selected Nigerian plants. J. Ethnopharmacol. 113, 427-432.; Abdellaoui et al., 2010Abdellaoui, S., Destandau, E., Tori, A., Elfakir, C., Lafosse, M., Renimel, I., André, P., Cancellieri, P., Landemarre, L., 2010. Bioactive molecules in Kalanchoe pinnata leaves: extraction, purification and identification. Anal. Bioanal. Chem. 398, 1329-1338.; Biswas et al., 2012Biswas, S.K., Chowdhury, A., Raihan, S.Z., Muhit, M.A., Akbar, M.A., Mowla, R., 2012. Phytochemical investigation with assessment of cytotoxicity and antibacterial activities of chloroform extract of the leaves of Kalanchoe pinnata . Am. J. Plant Physiol. 7, 41-46.; Kaewpiboon et al., 2012Kaewpiboon, C., Lirdprapamongkol, K., Srisomsap, C., Winayanuwattikun, P., Yongvanich, T., Puwaprisirisan, P., Svasti, J., Assavalapsakul, W., 2012. Studies of the in vitro cytotoxic, antioxidant, lipase inhibitory and antimicrobial activities of selected Thai medicinal plants. BMC Complement. Altern. Med., http://dx.doi.org/10.1186/1472-6882-12-217.
http://dx.doi.org/10.1186/1472-6882-12-2...
). In addition, abnormalities in the animal's testis were observed in one study (Akpantah et al., 2014Akpantah, A.O., Obeten, K.E., Edung, E.S., Eluwa, M.A., 2014. The effect of ethanolic extract of Bryophyllum pinnatum on the micro anatomy of the testes of adult males Wister rats. Eur. J. Biol. Med. Sci. Res. 2, 37-44.).

Therefore, it seems likely to infer that K. laciniata and B. pinnatum are safe to use acutely but is necessary performed additional studies to investigate their sub-chronic and chronic toxicity.

Conclusion

Several studies related to the botanical, chemical, ethnopharmacological, pharmacological and toxicological aspects of B. pinnatum have been conducted. On the other hand, only few studies about the chemical and pharmacological aspects of K. laciniata species have been reported. Toxicological studies are scarce for both species. Therefore, when we consider the several traditional uses of K. laciniata, it becomes detrimental to scientifically evaluate the pharmacological properties that have been attributed to this species. Despite the various traditional uses and non-clinical pharmacological studies reported for B. pinnatum and K. laciniata, clinical studies are still scarce. More studies should be conducted in order to identify the specific compounds that are responsible for the reported pharmacological activities for both species. Finally, the information reported in this review may contribute to recognizing the importance of K. laciniata and B. pinnatum as important plant sources for alternative treatment of the several disorders herein reported.

  • Appendix A. Supplementary data
    Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.bjp.2019.01.012.

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Publication Dates

  • Publication in this collection
    17 Oct 2019
  • Date of issue
    Jul-Aug 2019

History

  • Received
    19 Sept 2018
  • Accepted
    30 Jan 2019
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