Related Pentacyclic Triterpenes Have Immunomodulatory Activity in Chronic Experimental Visceral Leishmaniasis
Leishmaniasis is a neglected tropical disease caused by the flagellated protozoa of the genus Leishmania that affects millions of people around the world. Drugs employed in the treatment of leishmaniasis have limited efficacy and induce local and systemic side effects to the patients. Natural produc...
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Wiley
2021-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2021/6671287 |
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| author | Jéssica Adriana de Jesus Márcia Dalastra Laurenti Leila Antonangelo Caroline Silvério Faria João Henrique Ghilardi Lago Luiz Felipe Domingues Passero |
| author_facet | Jéssica Adriana de Jesus Márcia Dalastra Laurenti Leila Antonangelo Caroline Silvério Faria João Henrique Ghilardi Lago Luiz Felipe Domingues Passero |
| author_sort | Jéssica Adriana de Jesus |
| collection | DOAJ |
| description | Leishmaniasis is a neglected tropical disease caused by the flagellated protozoa of the genus Leishmania that affects millions of people around the world. Drugs employed in the treatment of leishmaniasis have limited efficacy and induce local and systemic side effects to the patients. Natural products are an interesting alternative to treat leishmaniasis, because some purified molecules are selective toward parasites and not to the host cells. Thus, the aim of the present study was to compare the in vitro antileishmanial activity of the triterpenes betulin (Be), lupeol (Lu), and ursolic acid (UA); analyze the physiology and morphology of affected organelles; analyze the toxicity of selected triterpenes in golden hamsters; and study the therapeutic activity of triterpenes in hamsters infected with L. (L.) infantum as well as the cellular immunity induced by studied molecules. The triterpenes Lu and UA were active on promastigote (IC50=4.0±0.3 and 8.0±0.2 μM, respectively) and amastigote forms (IC50=17.5±0.4 and 3.0±0.2 μM, respectively) of L. (L.) infantum, and their selectivity indexes (SI) toward amastigote forms were higher (≥13.4 and 14, respectively) than SI of miltefosine (2.7). L. (L.) infantum promastigotes treated with Lu and UA showed cytoplasmic degradation, and in some of these areas, cell debris were identified, resembling autophagic vacuoles, and parasite mitochondria were swelled, fragmented, and displayed membrane potential altered over time. Parasite cell membrane was not affected by studied triterpenes. Studies of toxicity in golden hamster showed that Lu did not alter blood biochemical parameters associated with liver and kidney functions; however, a slight increase of aspartate aminotransferase level in animals treated with 2.5 mg/kg of UA was detected. Lu and UA triterpenes eliminated amastigote forms in the spleen (87.5 and 95.9% of reduction, respectively) and liver of infected hamster (95.9 and 99.7% of reduction, respectively); and UA showed similar activity at eliminating amastigote forms in the spleen and liver than amphotericin B (99.2 and 99.8% of reduction). The therapeutic activity of both triterpenes was associated with the elevation of IFN-γ and/or iNOS expression in infected treated animals. This is the first comparative work showing the in vitro activity, toxicity, and therapeutic activity of Lu and UA in the chronic model of visceral leishmaniasis caused by L. (L.) infantum; additionally, both triterpenes activated cellular immune response in the hamster model of visceral leishmaniasis. |
| format | Article |
| id | doaj-art-6d7672a1dc00466397a3d97124d7cfee |
| institution | Kabale University |
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| language | English |
| publishDate | 2021-01-01 |
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| series | Journal of Immunology Research |
| spelling | doaj-art-6d7672a1dc00466397a3d97124d7cfee2025-02-03T01:20:48ZengWileyJournal of Immunology Research2314-88612314-71562021-01-01202110.1155/2021/66712876671287Related Pentacyclic Triterpenes Have Immunomodulatory Activity in Chronic Experimental Visceral LeishmaniasisJéssica Adriana de Jesus0Márcia Dalastra Laurenti1Leila Antonangelo2Caroline Silvério Faria3João Henrique Ghilardi Lago4Luiz Felipe Domingues Passero5Laboratory of Pathology of Infectious Diseases (LIM50), Department of Pathology, Medical School of São Paulo University, Av. Dr. Arnaldo, 455 Cerqueira César, São Paulo, 01246-903 SP, BrazilLaboratory of Pathology of Infectious Diseases (LIM50), Department of Pathology, Medical School of São Paulo University, Av. Dr. Arnaldo, 455 Cerqueira César, São Paulo, 01246-903 SP, BrazilLaboratório de Patologia Clínica, Departamento de Patologia, Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, BrazilLaboratório de Investigação Médica (LIM03), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, BrazilCentre of Natural and Human Sciences, Federal University of ABC (UFABC), Santo André 09210-580, BrazilSão Paulo State University (UNESP), Institute of Biosciences, São Vicente, Praça Infante Dom Henrique s/n, 11330-900 São Vicente, SP, BrazilLeishmaniasis is a neglected tropical disease caused by the flagellated protozoa of the genus Leishmania that affects millions of people around the world. Drugs employed in the treatment of leishmaniasis have limited efficacy and induce local and systemic side effects to the patients. Natural products are an interesting alternative to treat leishmaniasis, because some purified molecules are selective toward parasites and not to the host cells. Thus, the aim of the present study was to compare the in vitro antileishmanial activity of the triterpenes betulin (Be), lupeol (Lu), and ursolic acid (UA); analyze the physiology and morphology of affected organelles; analyze the toxicity of selected triterpenes in golden hamsters; and study the therapeutic activity of triterpenes in hamsters infected with L. (L.) infantum as well as the cellular immunity induced by studied molecules. The triterpenes Lu and UA were active on promastigote (IC50=4.0±0.3 and 8.0±0.2 μM, respectively) and amastigote forms (IC50=17.5±0.4 and 3.0±0.2 μM, respectively) of L. (L.) infantum, and their selectivity indexes (SI) toward amastigote forms were higher (≥13.4 and 14, respectively) than SI of miltefosine (2.7). L. (L.) infantum promastigotes treated with Lu and UA showed cytoplasmic degradation, and in some of these areas, cell debris were identified, resembling autophagic vacuoles, and parasite mitochondria were swelled, fragmented, and displayed membrane potential altered over time. Parasite cell membrane was not affected by studied triterpenes. Studies of toxicity in golden hamster showed that Lu did not alter blood biochemical parameters associated with liver and kidney functions; however, a slight increase of aspartate aminotransferase level in animals treated with 2.5 mg/kg of UA was detected. Lu and UA triterpenes eliminated amastigote forms in the spleen (87.5 and 95.9% of reduction, respectively) and liver of infected hamster (95.9 and 99.7% of reduction, respectively); and UA showed similar activity at eliminating amastigote forms in the spleen and liver than amphotericin B (99.2 and 99.8% of reduction). The therapeutic activity of both triterpenes was associated with the elevation of IFN-γ and/or iNOS expression in infected treated animals. This is the first comparative work showing the in vitro activity, toxicity, and therapeutic activity of Lu and UA in the chronic model of visceral leishmaniasis caused by L. (L.) infantum; additionally, both triterpenes activated cellular immune response in the hamster model of visceral leishmaniasis.http://dx.doi.org/10.1155/2021/6671287 |
| spellingShingle | Jéssica Adriana de Jesus Márcia Dalastra Laurenti Leila Antonangelo Caroline Silvério Faria João Henrique Ghilardi Lago Luiz Felipe Domingues Passero Related Pentacyclic Triterpenes Have Immunomodulatory Activity in Chronic Experimental Visceral Leishmaniasis Journal of Immunology Research |
| title | Related Pentacyclic Triterpenes Have Immunomodulatory Activity in Chronic Experimental Visceral Leishmaniasis |
| title_full | Related Pentacyclic Triterpenes Have Immunomodulatory Activity in Chronic Experimental Visceral Leishmaniasis |
| title_fullStr | Related Pentacyclic Triterpenes Have Immunomodulatory Activity in Chronic Experimental Visceral Leishmaniasis |
| title_full_unstemmed | Related Pentacyclic Triterpenes Have Immunomodulatory Activity in Chronic Experimental Visceral Leishmaniasis |
| title_short | Related Pentacyclic Triterpenes Have Immunomodulatory Activity in Chronic Experimental Visceral Leishmaniasis |
| title_sort | related pentacyclic triterpenes have immunomodulatory activity in chronic experimental visceral leishmaniasis |
| url | http://dx.doi.org/10.1155/2021/6671287 |
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