Cariniana domestica fruit peels present topical anti-inflammatory efficacy in a mouse model of skin inflammation

  • Gessica Brum Milani
  • Camila Camponogara
  • Mariana Piana
  • Cássia Regina Silva
  • Sara Marchesan OliveiraEmail author
Original Article


To investigate the topical anti-inflammatory activity of the crude extract of Cariniana domestica fruit peels (CdE), its dichloromethane, n-butanol, and ethyl acetate (EtAc) fractions, and steroids (β-sitosterol, lupeol, and stigmasterol) isolated from the EtAc fraction in models of irritant contact dermatitis (ICD) croton oil-induced in mice. We induced skin inflammation by single (acute; 1 mg/ear) and multiple (chronic; 0.4 mg/ear) croton oil application. We topically applied C. domestica (CdE, fractions, and gel formulations) and β-sitosterol, lupeol, and stigmasterol immediately after applying croton oil. HPLC-DAD chromatography of the EtAc fraction and stability of the gel formulations were verified. HPLC-DAD of the EtAc fraction revealed the stigmasterol, lupeol, and β-sitosterol presence. CdE and EtAc fraction gels showed no organoleptic or pH changes at room temperatures. CdE and dichloromethane, n-butanol, and EtAc (1 mg/ear) fractions decreased the acute ear edema with maximum inhibition (Imax) of 97 ± 2, 86 ± 1, 81 ± 4, and 95 ± 2%, respectively. CdE and EtAc fraction gel presented similar effects, with respective Imax of 85 ± 6% (3%;15 mg/ear) and 82 ± 2% (1%;15 mg/ear). β-sitosterol (7.5 μg/ear), lupeol (10 μg/ear), and stigmasterol (5.7 μg/ear) also reduced this parameter by 46 ± 8, 51 ± 7, and 62 ± 7%, respectively. All topical treatments reduced the inflammatory cells’ infiltration in the acute ICD model. CdE reduced the ear edema by 77 ± 4% (1 mg/ear) and the inflammatory cell infiltration in the chronic ICD model. CdE’s anti-inflammatory effect was accompanied by a minimum development of adverse effects. C. domestica demonstrates a promising potential for the development of a topical anti-inflammatory agent.

Graphical abstract

Cariniana domestica, popularly known as jequitibá-roxo, presented topical anti-inflammatory activity in an acute and chronic irritant contact dermatitis croton oil-induced in mice. The crude extract (solutions and gel formulations) and different fractions obtained from fruit peels of C. domestica showed topical antiinflammatory activity on skin inflammation models with minimum adverse effects in preliminary toxicological studies (behavior and biochemical parameters). Moreover, the HPLC analysis revealed the presence of β-sitosterol, stigmasterol and lupeol, which also presented topical anti-inflammatory effect in the acute irritant contact dermatitis croton oil-induced. Our findings support the use of this species as a promising topical antiinflammatory agent.


Jequitibá-roxo Dermatitis Stability Anti-inflammatory Steroids Adverse effects 



Crude extract of C. domestica




Factor nuclear kappa B


Irritant contact dermatitis


Inhibitory dose 50%


Maximal inhibition








Alanine aminotransferase


Aspartate aminotransferase




Standard error of the mean




Protein kinase C


Phospholipase A2


Activating protein-1



We thank Professor Margareth Linde Athayde for donating the extract of C. domestica. We also thank the professor of the Program in Biological Sciences: Toxicological Biochemistry (Federal University of Santa Maria), Vera Morsh, for loaning equipment.

Author’s contribution

Participated in research design: G.B.M, C.C., C.R.S., S.M.O.

Conducted experiments: G.B.M, C.C., C.R.S., S.M.O.

Plant material and extractions, gel preparation, accelerated stability study, data analysis, writing, and discussion of these: M.P.

Performed data analysis: C.C., C.R.S., S.M.O.

Wrote or contributed to the writing of the manuscript: G.B.M, C.C., C.R.S., S.M.O.

All the authors reviewed the manuscript.


This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico-CNPq, Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior - CAPES/PROEX (process no. 23038.005848/2018-31; grant no. 0737/2018) (Brazil), and the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul - FAPERGS and the Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq (grant no. 16/2551-0000281-9) and FAPERGS (Grant no. 17/2551-0001082-5). CC is recipient of fellowship from CAPES/PROEX (process no. 88882.182152/2018-01) and SMO is recipient of fellowship from CNPq (Grant no. 307220/2017-6). We also acknowledge fellowships from CNPq and CAPES.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution (approved by Institutional Committee for Animal Care and Use of the Federal University of Santa Maria, number process 9475221015/2015) and guidelines of Brazilian Council of Animal Experimentation—CONCEA—and of U.S. Public Health Service’s Policy on Humane Care and Use of Laboratory Animals—PHS Policy) were also followed.


  1. Adami M, Prudente A d S, Mendes DAGB, Horinouchi CD d S, Cabrini DA, Otuki MF (2012) Simvastatin ointment, a new treatment for skin inflammatory conditions. J Dermatol Sci 66:127–135CrossRefGoogle Scholar
  2. Akindele AJ, Unachukwu EG, Osiagwu DD (2015) 90 days toxicological assessment of hydroethanolic leaf extract of Ipomoea asarifolia (Desr.) Roem. and Schult. (Convolvulaceae) in rats. J Ethnopharmacol 174:582–594CrossRefGoogle Scholar
  3. Bangert C, Brunner PM, Stingl G (2011) Immune functions of the skin. Clin Dermatol 29:360–376CrossRefGoogle Scholar
  4. Bellik Y, Boukraâ L, Alzahrani HA, Bakhotmah BA, Abdellah F, Hammoudi SM, Iguer-Ouada M (2012) Molecular mechanism underlying anti-inflammatory and anti-allergic activities of phytochemicals: an update. Molecules 18:322–353CrossRefGoogle Scholar
  5. Boligon AA, Piana M, Kubiça TF, Mario DN, Dalmolin TV, Bonez PC, Weiblen R, Lovato L, Alves SH, Campos MMA, Athayde ML (2015) HPLC analysis and antimicrobial, antimycobacterial and antiviral activities of Tabernaemontana catharinensis A. DC. J Appl Biomed 13:7–18CrossRefGoogle Scholar
  6. Boller S, Soldi C, Marques MCA, Santos EP, Cabrini DA, Pizzolatti MG, Zampronio AR, Otuki MF (2010) Anti-inflammatory effect of crude extract and isolated compounds from Baccharis illinita DC in acute skin inflammation. J Ethnopharmacol 130:262–266CrossRefGoogle Scholar
  7. Brum TF, Camponogara C, da Silva Jesus R, Belke BV, Piana M, Boligon AA, Pires FB, Oliveira SM, da Rosa MB, de Freitas Bauermann L (2016) Ethnopharmacological study and topical anti-inflammatory activity of crude extract from Poikilacanthus glandulosus (Nees) Ariza leaves. J Ethnopharmacol 193:60–67CrossRefGoogle Scholar
  8. Cabrini DA, Moresco HH, Imazu P, Pietrovski EF, Gasparin DA, Mendes B, Prudente S, Pizzolatti MG, Brighente MC, Otuki MF (2011) Analysis of the potential topical anti-inflammatory activity of Averrhoa carambola L. in mice. Evid Based Complement Alternat Med 2011:1–7CrossRefGoogle Scholar
  9. Cai C, Chen Y, Zhong S, Ji B, Wang J, Bai X, Shi G (2014) Anti-inflammatory activity of N-butanol extract from Ipomoea stolonifera in vivo and in vitro. PLoS One 9:1–9Google Scholar
  10. Chibli LA, Rodrigues KCM, Gasparetto CM, Pinto NCC, Fabri RL, Scio E, Alves MS, Del-Vechio-Vieira G, Sousa OV (2014) Anti-inflammatory effects of Bryophyllum pinnatum (lam.) Oken ethanol extract in acute and chronic cutaneous inflammation. J Ethnopharmacol 154:330–338CrossRefGoogle Scholar
  11. Choi J, Kim S (2013) Rutin suppresses atopic dermatitis and allergic contact dermatitis. Exp Biol Med 238:410–417CrossRefGoogle Scholar
  12. Cunha LC, Azeredo FS, Mendonça ACV, Vieira MS, Pucci LL, Valadares MC, Freitas HOG, Sena ÂAS, Lino RDS (2009) Avaliação da toxicidade aguda e subaguda, em ratos, do extrato etanólico das folhas e do látex de Synadenium umbellatum Pax. Rev Bras Farmacogn 19:403–411.CrossRefGoogle Scholar
  13. Di Meglio P, Perera GK, Nestle FO (2011) The multitasking organ: recent insights into skin immune function. Immunity 35:857–869CrossRefGoogle Scholar
  14. Eberting CL (2014) Irritant contact dermatitis: mechanisms to repair. J Clin Exp Dermatol Res 5:4–11CrossRefGoogle Scholar
  15. Feingold KR, Schmuth M, Elias PM (2007) The regulation of permeability barrier homeostasis. J Invest Dermatol 127:1574–1576CrossRefGoogle Scholar
  16. Fialho MFP, Brusco I, Brum S, Piana M, Boligon AA, Trevisan G, Oliveira SM (2017) Buddleja thyrsoides Lam. crude extract presents antinociceptive effect on an arthritic pain model in mice. 474, 2993–3010Google Scholar
  17. Hernández-Valle E, Herrera-Ruiz M, Salgado GR, Zamilpa A, Ocampo MLA, Aparicio AJ, Tortoriello J, Jiménez-Ferrer E (2014) Anti-inflammatory effect of 3-O-[(6'-O-palmitoyl)-β-D-glucopyranosyl sitosterol] from Agave angustifolia on ear edema in mice. Molecules 19:15624–15637CrossRefGoogle Scholar
  18. Horinouchi CDDS, Mendes DAGB, Soley BDS, Pietrovski EF, Facundo VA, Santos ARS, Cabrini DA, Otuki MF (2013) Combretum leprosum Mart. (Combretaceae): potential as an antiproliferative and anti-inflammatory agent. J Ethnopharmacol 145:311–319CrossRefGoogle Scholar
  19. Hwang SJ, Kim YW, Park Y, Lee HJ, Kim KW (2014) Anti-inflammatory effects of chlorogenic acid in lipopolysaccharide-stimulated RAW 264.7 cells. Inflamm Res 63:81–90CrossRefGoogle Scholar
  20. Ibrahim B, Sowemimo A, Van Rooyen A, Van De Venter M (2012) Antiinflammatory, analgesic and antioxidant activities of Cyathula prostrata (Linn.) Blume (Amaranthaceae). J Ethnopharmacol 141:282–289CrossRefGoogle Scholar
  21. Janovik V, Boligon A, Bandeira R, Athayde M (2011) HPLC/DAD analysis, determination of total phenolic and flavonoid contents and antioxidant activity from the leaves of Cariniana domestica (Mart) Miers. Res J Phytochem 5:209–215CrossRefGoogle Scholar
  22. Janovik V, Boligon A, Athayde M (2012a) Antioxidant activities and HPLC/DAD analysis of phenolic and carotenoids from the barks of Cariniana domestica (Mart.) Miers. Res J Phytochem 6:105–112CrossRefGoogle Scholar
  23. Janovik V, Boligon AA, Frohlich JK, Schwanz TG, Pozzebon TV, Alves SH, Athayde ML (2012b) Isolation and chromatographic analysis of bioactive triterpenoids from the bark extract of Cariniana domestica (Mart) Miers. Nat Prod Res 26:66–71CrossRefGoogle Scholar
  24. Khan AQ, Khan R, Qamar W, Lateef A, Ali F, Tahir M, Rehman MU, Sultana S (2012) Caffeic acid attenuates 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced NF-κB and COX-2 expression in mouse skin: abrogation of oxidative stress, inflammatory responses and proinflammatory cytokine production. Food Chem Toxicol 50:175–183CrossRefGoogle Scholar
  25. Kumar KG, Dhamotharan R, Kulkarni NM, Mahat MYA, Gunasekaran J, Ashfaque M (2011) Embelin reduces cutaneous TNF-α level and ameliorates skin edema in acute and chronic model of skin inflammation in mice. Eur J Pharmacol 662:63–69CrossRefGoogle Scholar
  26. Lee HY, Stieger M, Yawalkar N, Kakeda M (2013) Cytokines and chemokines in irritant contact dermatitis. Mediat Inflamm 2013:1–7Google Scholar
  27. Lee J, Choi YY, Kim MH, Han JM, Lee JE, Kim EH, Hong J, Kim J, Yang WM (2016) Topical application of Angelica sinensis improves pruritus and skin inflammation in mice with atopic dermatitis-like symptoms. J Med Food 19:98–105CrossRefGoogle Scholar
  28. Lim KM, Bae SJ, Koo JE, Kim ES, Bae ON, Lee JY (2015) Suppression of skin inflammation in keratinocytes and acute/chronic disease models by caffeic acid phenethyl ester. Arch Dermatol Res 307:219–227CrossRefGoogle Scholar
  29. Lisby S, Baadsgaard O (2010) Mechanisms of irritant contact dermatitis, in: Duus, J.J., Frosch, P.J., Leppoittevin, J.P. (Eds.), Contact dermatitis pp. 69–82Google Scholar
  30. Mcgrath JC, Lilley E (2015) Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP. Br J Pharmacol 172:3189–3193CrossRefGoogle Scholar
  31. Medeiros R, Otuki MF, Avellar MCW, Calixto JB (2007) Mechanisms underlying the inhibitory actions of the pentacyclic triterpene α-amyrin in the mouse skin inflammation induced by phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Eur J Pharmacol 559:227–235CrossRefGoogle Scholar
  32. Mendes DAGB, Soley BDS, Prudente ADS, Sponchiado G, Ferreira BGA, dos Santos MC, de Andrade ASM, Amorim CDM, Bresolin TMB, Meyre-Silva C, Zuffellato-Ribas KC, Assreuy J, Otuki MF, Cabrini DDA (2016) Hydroalcoholic extract of Sapium glandulatum (Vell.) Pax displays potent anti-inflammatory activities through a glucocorticoid receptor-dependent pathway. Phytomedicine 23:1610–1620CrossRefGoogle Scholar
  33. National Health Surveillance Agency (Anvisa) (2004) Guide of stability to cosmetic products, BrazilGoogle Scholar
  34. Oliveira SM, Silva CR, Wentz AP, Paim GR, Correa MS, Bonacorso HG, Prudente AS, Otuki MF, Ferreira J (2014) Antinociceptive effect of 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole. A Celecoxib structural analog in models of pathological pain. Pharmacol Biochem Behav 124:396–404CrossRefGoogle Scholar
  35. Pandey A, Negi PS (2016) Traditional uses, phytochemistry and pharmacological properties of Neolamarckia cadamba: a review. J Ethnopharmacol 181:118–135CrossRefGoogle Scholar
  36. Passos GF, Medeiros R, Marcon R, Nascimento AFZ, Calixto JB, Pianowski LF (2013) The role of PKC/ERK1/2 signaling in the anti-inflammatory effect of tetracyclic triterpene euphol on TPA-induced skin inflammation in mice. Eur J Pharmacol 698:413–420CrossRefGoogle Scholar
  37. Phanse MA, Patil MJ, Abbulu K, Chaudhari PD, Patel B (2012) In-vivo and in-vitro screening of medicinal plants for their anti-inflammatory activity: an overview. J Appl Pharm Sci 2:19–33Google Scholar
  38. Piana M, Silva MA, Trevisan G, De Brum TF, Silva CR, Boligon AA, Oliveira SM, Zadra M, Hoffmeister C, Rossato MF, Tonello R, Laporta LV, De Freitas RB, Belke BV, Da Silva Jesus R, Ferreira J, Athayde ML (2013) Antiinflammatory effects of Viola tricolor gel in a model of sunburn in rats and the gel stability study. J Ethnopharmacol 150:458–465CrossRefGoogle Scholar
  39. Piana M, Camponogara C, Boligon AA, Machado MM, De Brum TF, Oliveira SM, De Freitas Bauermann L (2016) Topical anti-inflammatory activity of Solanum corymbiflorum leaves. J Ethnopharmacol 179:16–21CrossRefGoogle Scholar
  40. Pinto NDCC, Machado DC, Da Silva JM, Conegundes JLM, Gualberto ACM, Gameiro J, Moreira Chedier L, Castañon MCMN, Scio E (2015) Pereskia aculeata miller leaves present in vivo topical anti-inflammatory activity in models of acute and chronic dermatitis. J Ethnopharmacol 173:330–337CrossRefGoogle Scholar
  41. Proksch E, Brandner JM, Jensen JM (2008) The skin: an indispensable barrier. Exp Dermatol 17:1063–1072CrossRefGoogle Scholar
  42. Santos EN, Lima JC, Noldin VF, Cechinel-Filho V, Rao VS, Lima EF, Schmeda-Hirschmann G, Sousa PT Jr, Martins DT (2011) Anti-inflammatory, antinociceptive and antipyretic effects of methanol extract of Cariniana rubra stem bark in animal models. An Acad Bras Cienc 83:557–566CrossRefGoogle Scholar
  43. Saraiva RA, Araruna MKA, Oliveira RC, Menezes KDP, Leite GO, Kerntopf MR, Costa JGM, Rocha JBT, Tomé AR, Campos AR, Menezes IRA (2011) Topical anti-inflammatory effect of Caryocar coriaceum Wittm. (Caryocaraceae) fruit pulp fixed oil on mice ear edema induced by different irritant agents. J Ethnopharmacol 136:504–510CrossRefGoogle Scholar
  44. Seyfarth F, Schliemann S, Antonov D, Elsner P (2011) Dry skin, barrier function, and irritant contact dermatitis in the elderly. Clin Dermatol 29:31–36CrossRefGoogle Scholar
  45. Shah AS, Alagawadi KR (2011) Anti-inflammatory, analgesic and antipyretic properties of Thespesia populnea Soland ex. Correa seed extracts and its fractions in animal models. J Ethnopharmacol 137:1504–1509CrossRefGoogle Scholar
  46. Siddiqui F, Naqvi S, Abidi L, Faizi S, Avesi L (2016) Opuntia dillenii cladode: opuntiol and opuntioside attenuated cytokines and eicosanoids mediated inflammation 182, 221–234Google Scholar
  47. Silva MA, Trevisan G, Klafke JZ, Rossato MF, Walker CIB, Oliveira SM, Silva CR, Boligon AA, Flores FC, Silva CDB, Athayde ML, Ferreira J (2013) Antinociceptive and anti-inflammatory effects of Aloe saponaria haw on thermal injury in rats. J Ethnopharmacol 146:393–401CrossRefGoogle Scholar
  48. Simpson BS, Luo X, Costabile M, Caughey GE, Wang J, Claudie DJ, McKinnon RA, Semple SJ (2014) Polyandric acid A, a clerodane diterpenoid from the Australian medicinal plant Dodonaea polyandra, attenuates pro-inflammatory cytokine secretion in vitro and in vivo. J Nat Prod 77:85–91CrossRefGoogle Scholar
  49. Slodownik D, Lee A, Nixon R (2008) Irritant contact dermatitis: a review. Australas J Dermatol 49:1–11CrossRefGoogle Scholar
  50. Sung YY, Lee AY, Kim HK (2016) Forsythia suspensa fruit extracts and the constituent matairesinol confer anti-allergic effects in an allergic dermatitis mouse model. J Ethnopharmacol 187:49–56CrossRefGoogle Scholar
  51. Tian H, Matsuo Y, Fukunaga A, Ono R, Nishigori C, Yodoi J (2013) Thioredoxin ameliorates cutaneous inflammation by regulating the epithelial production and release of pro-inflammatory cytokines. Front Immunol 4:1–12CrossRefGoogle Scholar
  52. Trevisan G, Rossato MF, Walker CIB, Oliveira SM, Rosa F, Tonello R, Silva CR, Machado P, Boligon AA, Martins MAP, Zanatta N, Bonacorso HG, Athayde ML, Rubin MA, Calixto JB, Ferreira J (2013) A novel, potent, oral active and safe antinociceptive pyrazole targeting kappa opioid receptors. Neuropharmacology 73:261–273CrossRefGoogle Scholar
  53. Trivellatograssi L, Malheiros A, Meyre-Silva C, Da Silva Buss Z, Monguilhott ED, Fröde TS, Da Silva KABS, De Souza MM (2013) From popular use to pharmacological validation: a study of the anti-inflammatory, anti-nociceptive and healing effects of Chenopodium ambrosioides extract. J Ethnopharmacol 145:127–138CrossRefGoogle Scholar
  54. Tsang, M.S.M., Jiao, D., Chan, B.C.L., Hon, K.L., Leung, P.C., Lau, C.B.S., Wong, E.C.W., Cheng, L., Chan, C.K.M., Lam, C.W.K., Wong, C.K., 2016. Anti-inflammatory activities of pentaherbs formula, berberine, gallic acid and chlorogenic acid in atopic dermatitis-like skin inflammation. Molecules 21Google Scholar
  55. Vassallo A, De Tommasi N, Merfort I, Sanogo R, Severino L, Pelin M, Della Loggia R, Tubaro A, Sosa S (2013) Steroids with anti-inflammatory activity from Vernonia nigritiana Oliv. & Hiern. Phytochemistry 96:288–298CrossRefGoogle Scholar
  56. Xiao X, Xie H, Jian D, Deng Y, Chen X, Li J (2015) Rebounding triad (severe itching, dryness and burning) after facial corticosteroid discontinuation defines a specific class of corticosteroid-dependent dermatitis. J Dermatol 42:697–702CrossRefGoogle Scholar
  57. Xu Q, Wang Y, Guo S, Shen Z, Wang Y, Yang L (2014) Anti-inflammatory and analgesic activity of aqueous extract of Flos populi. J Ethnopharmacol 152:540–545CrossRefGoogle Scholar
  58. Yeom M, Kim SH, Lee B, Han JJ, Chung GH, Choi HD, Lee H, Hahm DH (2012) Oral administration of glucosylceramide ameliorates inflammatory dry-skin condition in chronic oxazolone- induced irritant contact dermatitis in the mouse ear. J Dermatol Sci 67:101–110CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory Neurotoxicity and Psychopharmacology, Graduate Program in Biological Sciences: Toxicological Biochemistry, Center of Natural and Exact SciencesFederal University of Santa MariaSanta MariaBrazil
  2. 2.Phytochemical Research Laboratory, Graduate Program in Pharmaceutical Sciences, Center of Health SciencesFederal University of Santa MariaSanta MariaBrazil
  3. 3.Institute of Genetics and Biochemistry, Graduate Program in Genetics and BiochemistryFederal University of UberlandiaUberlandiaBrazil

Personalised recommendations