title: Kaurenoic Acid Possesses Leishmanicidal Activity by Triggering a NLRP12/IL-1β/cNOS/NO Pathway.
abstract: Leishmania amazonensis (L. amazonensis) infection can cause severe local and diffuse injuries in humans, a condition clinically known as American cutaneous leishmaniasis (ACL). Currently, the therapeutic approach for ACL is based on Glucantime, which shows high toxicity and poor effectiveness. Therefore, ACL remains a neglected disease with limited options for treatment. Herein, the in vitro antiprotozoal effect and mechanisms of the diterpene kaurenoic acid [ent-kaur-16-en-19-oic acid] (KA) against L. amazonensis were investigated. KA exhibited a direct antileishmanial effect on L. amazonensis promastigotes. Importantly, KA also reduced the intracellular number of amastigote forms and percentage of infected peritoneal macrophages of BALB/c mice. Mechanistically, KA treatment reestablished the production of nitric oxide (NO) in a constitutive NO synthase- (cNOS-) dependent manner, subverting the NO-depleting escape mechanism of L. amazonensis. Furthermore, KA induced increased production of IL-1β and expression of the inflammasome-activating component NLRP12. These findings demonstrate the leishmanicidal capability of KA against L. amazonensis in macrophage culture by triggering a NLRP12/IL-1β/cNOS/NO mechanism.
authors.affiliation: Department of Pathological Sciences, Center of Biological Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Milena Menegazzo
authors.initials: MM
authors.lastname: Miranda
authors.affiliation: Laboratory of Inflammatory Mediators, State University of Western Parana, 85605-010 Francisco Beltrão, PR, Brazil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Panis
authors.affiliation: Department of Pathological Sciences, Center of Biological Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Suelen Santos
authors.initials: SS
authors.lastname: da Silva
authors.affiliation: Department of Pathological Sciences, Center of Biological Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Juliana Aparecida
authors.initials: JA
authors.lastname: Macri
authors.affiliation: Department of Pathological Sciences, Center of Biological Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Natalia Yoshie
authors.initials: NY
authors.lastname: Kawakami
authors.affiliation: Department of Chemistry, Center of Exact Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Thiago Hideki
authors.initials: TH
authors.lastname: Hayashida
authors.affiliation: Department of Chemistry, Center of Exact Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Tiago Bervelieri
authors.initials: TB
authors.lastname: Madeira
authors.affiliation: Department of Chemistry, Center of Exact Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Vinicius Ricardo
authors.initials: VR
authors.lastname: Acquaro
authors.affiliation: Department of Chemistry, Center of Exact Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Suzana Lucy
authors.initials: SL
authors.lastname: Nixdorf
authors.affiliation: Department of Biochemistry, Federal University of Rio de Janeiro, 21941-909 Rio de Janeiro, RJ, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Pizzatti
authors.affiliation: Nucleus of Research in Exact and Technological Sciences, University of Franca, 14404-600 Franca, SP, Brazil.
authors.forename: Sérgio Ricardo
authors.initials: SR
authors.lastname: Ambrósio
authors.affiliation: Department of Pathological Sciences, Center of Biological Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Rubens
authors.initials: R
authors.lastname: Cecchini
authors.affiliation: Department of Chemistry, Center of Exact Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Nilton Syogo
authors.initials: NS
authors.lastname: Arakawa
authors.affiliation: Department of Pathological Sciences, Center of Biological Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Waldiceu Aparecido
authors.initials: WA
authors.lastname: Verri
authors.affiliation: Department of Pathological Sciences, Center of Biological Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Ivete Conchon
authors.identifier: 0000-0002-9800-2068
authors.initials: IC
authors.lastname: Costa
authors.affiliation: Department of Pathological Sciences, Center of Biological Sciences, State University of Londrina, 86057-970 Londrina, PR, Brazil.
authors.forename: Wander Rogério
authors.initials: WR
authors.lastname: Pavanelli
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology*; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007894:Leishmania mexicana / Q000187:drug effects* / Q000472:pathogenicity*; D017737:Macrophages, Peritoneal / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents; D004224:Diterpenes; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; C553199:NLRP12 protein, mouse; D009569:Nitric Oxide; C051436:kaurenoic acid