Antileishmanial activity of verbascoside: Selective arginase inhibition of intracellular amastigotes of Leishmania (Leishmania) amazonensis with resistance induced by LPS plus IFN-γ

2017 ◽  
Vol 127 ◽  
pp. 28-33 ◽  
Author(s):  
Claudia do Carmo Maquiaveli ◽  
Arina Lázaro Rochetti ◽  
Heidge Fukumasu ◽  
Paulo Cezar Vieira ◽  
Edson Roberto da Silva
Keyword(s):  
Leishmania Amazonensis ◽  
Antileishmanial Activity ◽  
Intracellular Amastigotes ◽  
Ifn Γ

scholarly journals In VitroandIn VivoActivities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

2016 ◽  
Vol 60 (6) ◽  
pp. 3433-3444 ◽  
Author(s):  
Vanessa Kaplum ◽  
Juliana Cogo ◽  
Diego Pereira Sangi ◽  
Tânia Ueda-Nakamura ◽  
Arlene Gonçalves Corrêa ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Cell Volume ◽  
Leishmania Amazonensis ◽  
Antileishmanial Activity ◽  
Ultrastructural Alterations ◽  
Intracellular Amastigotes ◽  
Intracellular Atp ◽  
Lipid Inclusions ◽  
Quinoxaline Derivatives

Leishmaniasis is endemic in 98 countries and territories worldwide. The therapies available for leishmaniasis have serious side effects, thus prompting the search for new therapies. The present study investigated the antileishmanial activities of 2,3-diarylsubstituted quinoxaline derivatives againstLeishmania amazonensis. The antiproliferative activities of 6,7-dichloro-2,3-diphenylquinoxaline (LSPN329) and 2,3-di-(4-methoxyphenyl)-quinoxaline (LSPN331) against promastigotes and intracellular amastigotes were assessed, and the cytotoxicities of LSPN329 and LSPN331 were determined. Morphological and ultrastructural alterations were examined by electron microscopy, and biochemical alterations, reflected by the mitochondrial membrane potential (ΔΨm), mitochondrial superoxide anion (O2·−) concentration, the intracellular ATP concentration, cell volume, the level of phosphatidylserine exposure on the cell membrane, cell membrane integrity, and lipid inclusions, were evaluated.In vivoantileishmanial activity was evaluated in a murine cutaneous leishmaniasis model. Compounds LSPN329 and LSPN331 showed significant selectivity for promastigotes and intracellular amastigotes and low cytotoxicity. In promastigotes, ultrastructural alterations were observed, including an increase in lipid inclusions, concentric membranes, and intense mitochondrial swelling, which were associated with hyperpolarization of ΔΨm, an increase in the O2·−concentration, decreased intracellular ATP levels, and a decrease in cell volume. Phosphatidylserine exposure and DNA fragmentation were not observed. The cellular membrane remained intact after treatment. Thus, the multifactorial response that was responsible for the cellular collapse of promastigotes was based on intense mitochondrial alterations. BALB/c mice treated with LSPN329 or LSPN331 showed a significant decrease in lesion thickness in the infected footpad. Therefore, the antileishmanial activity and mitochondrial mechanism of action of LSPN329 and LSPN331 and the decrease in lesion thicknessin vivobrought about by LSPN329 and LSPN331 make them potential candidates for new drug development for the treatment of leishmaniasis.

Design, Synthesis and Antileishmanial Activity of Naphthotriazolyl-4- Oxoquinolines

2018 ◽  
Vol 18 (17) ◽  
pp. 1454-1464 ◽  
Author(s):  
Vanessa G. Oliveira ◽  
Viviane dos Santos Faiões ◽  
Gabrieli B.R. Gonçalves ◽  
Miriam F.O. Lima ◽  
Fernanda C.S. Boechat ◽  
...  
Keyword(s):  
High Resolution Mass Spectrometry ◽  
Cycloaddition Reaction ◽  
Public Health Problem ◽  
Leishmania Amazonensis ◽  
Antileishmanial Activity ◽  
Design Synthesis ◽  
Intracellular Amastigotes ◽  
Ic50 Values ◽  
Therapeutic Alternatives

Background: Leishmaniasis is a neglected public health problem caused by several protozoanspecies of the genus Leishmania. The therapeutic arsenal for treating leishmaniasis is quite limited, raising concerns about the occurrence of resistant strains. Furthermore, most of these drugs were developed more than 70 years ago and suffer from poor efficacy and safety and are not well adapted to the needs of patients. Therefore, research on novel natural or synthetic compounds with antiparasitic activity is urgently needed. In this paper, we evaluated the effect and the mechanism of action of naphthotriazolyl-4-oxoquinolines on promastigotes and intracellular amastigotes of Leishmania amazonensis. Materials and Methods: The naphthotriazolyl-4-oxoquinoline derivatives were obtained in good to moderate yields via the [3+2] cycloaddition reaction between 1,4-naphtoquinone and azido-4- oxoquinoline derivatives. HMPA at 100°C was established as the best solvent and temperature condition for this reaction. The structures of the compounds were confirmed by spectral analyses (infrared spectroscopy, one- and two-dimensional ¹H and ¹³C NMR spectroscopy, and high-resolution mass spectrometry). The compounds exhibited promising activities with IC50 values ranging from 0.7 to 2.0 µM against intracellular amastigotes of Leishmania amazonensis. The most selective compound was the Npentyl- substituted derivative, which showed a Selectivity Index (SI) of 8.6, making it less toxic than pentamidine (SI 4.5). Results: Our results demonstrated that all compounds, except the N-propyl-substituted derivative, induce ROS production by parasites early in the culture. As a proof of concept, we demonstrated that the most selective compound was able to interfere with sterol biosynthesis in L. amazonensis. Conclusion: The naphthotriazolyl-4-oxoquinoline derivatives were obtained in good to moderate yields. These conjugates have potent in vitro antileishmanial activity involving at least two different mechanisms of action, making them promising lead compounds for the development of new therapeutic alternatives for leishmaniasis.

Selective in vitro antileishmanial activity of Mimosa caesalpiniifolia stem barks and its main constituent betulinic acid against Leishmania amazonensis

2021 ◽  
Vol 140 ◽  
pp. 68-75
Author(s):  
Lucas Moreira Brito ◽  
Michel Muálem de Moraes Alves ◽  
Adriana Cunha Souza ◽  
Thaynara Parente de Carvalho ◽  
José Henrique Furtado Campos ◽  
...  
Keyword(s):  
Betulinic Acid ◽  
Leishmania Amazonensis ◽  
Antileishmanial Activity ◽  
Main Constituent

scholarly journals Antileishmanial activity and mechanism of action from a purified fraction of Zingiber officinalis Roscoe against Leishmania amazonensis

2016 ◽  
Vol 166 ◽  
pp. 21-28 ◽  
Author(s):  
Mariana C. Duarte ◽  
Grasiele S.V. Tavares ◽  
Diogo G. Valadares ◽  
Daniela P. Lage ◽  
Tatiana G. Ribeiro ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Leishmania Amazonensis ◽  
Antileishmanial Activity

scholarly journals l-Arginine and Cationic Amino Acid Transporter 2B Regulate Growth and Survival of Leishmania amazonensis Amastigotes in Macrophages

2007 ◽  
Vol 75 (6) ◽  
pp. 2802-2810 ◽  
Author(s):  
Nanchaya Wanasen ◽  
Carol L. MacLeod ◽  
Lesley G. Ellies ◽  
Lynn Soong
Keyword(s):  
Amino Acid ◽  
Amino Acid Transporter ◽  
Parasite Growth ◽  
Leishmania Amazonensis ◽  
Growth Enhancement ◽  
Cationic Amino Acid Transporter ◽  
Cationic Amino Acid ◽  
Arginine Transport ◽  
Ifn Γ ◽  
Acid Transporter

ABSTRACT Leishmania spp. are obligate intracellular parasites, requiring a suitable microenvironment for their growth within host cells. We previously reported that the growth of Leishmania amazonensis amastigotes in murine macrophages (Mφs) was enhanced in the presence of gamma interferon (IFN-γ), a Th1 cytokine normally associated with classical Mφ activation and killing of intracellular pathogens. In this study, we provided several lines of evidence suggesting that IFN-γ-mediated parasite growth enhancement was associated with l-arginine transport via mouse cationic amino acid transporter 2B (mCAT-2B). (i) mRNA expression of Slc7A2, the gene encoding for mCAT-2B, as well as l-arginine transport was increased in IFN-γ-treated Mφs. (ii) Supplementation of l-arginine in Mφ cultures increased parasite growth. (iii) Parasite growth enhancement in wild-type Mφs was inhibited in the presence of nonmetabolized l-arginine analogues. (iv) IFN-γ-mediated parasite growth was absent in Mφs derived from mCAT-2B-deficient mice. Although we detected a clear upregulation of mCAT-2B and l-arginine transport, no measurable iNOS or arginase activities were observed in IFN-γ-treated, infected Mφs. Together, these data suggest an involvement of a novel l-arginine usage independent of iNOS and arginase activities during IFN-γ-mediated parasite growth enhancement. A possible role of mCAT-2B in supplying l-arginine directly to the parasites for their proliferation is discussed.

scholarly journals In vitro antileishmanial activity of Anacardium othonianum and isolated compounds against Leishmania amazonensis

2021 ◽  
Vol 5 (1) ◽  
pp. 44
Author(s):  
Tavane Aparecida Alvarenga ◽  
Osvaine Júnior Alvarenga Alves ◽  
Mariana Cintra Pagotti ◽  
Wilson Roberto Cunha ◽  
Márcio Luís Andrade e Silva ◽  
...  
Keyword(s):  
High Resolution Mass Spectrometry ◽  
Leishmania Amazonensis ◽  
Antileishmanial Activity ◽  
Anacardic Acid ◽  
Array Detector ◽  
Preparative Hplc ◽  
Moderate Activity ◽  
Phytochemical Study ◽  
Phenol Derivatives

This study analyzes the antileishmanial activity of the crude ethanol extract, fractions, and isolated compounds of A. othonianum nuts. Antileishmanial activity was evaluated against Leishmania amazonensis promastigotes in vitro. The phytochemical study was performed by high-performance liquid chromatography-high-resolution mass spectrometry-diode array detector (HPLC-HRMS-DAD) and by preparative HPLC. HPLC-HRMS-DAD analysis of the bioactive extract confirmed the presence of ten alkyl phenol derivatives that had previously been isolated from A. occidentale. Bioassay-guided isolation afforded cardanol triene, cardanol diene, cardanol monoene, cardol triene, anacardic acid triene, anacardic acid diene, and anacardic acid monoene. Cardol triene gave an IC50 of 80.66 µM. The obtained data suggest that the evaluated extract, fractions, and cardol triene had moderate activity against L. amazonensis promastigotes. This is the first description of alkyl phenols in A. othonianum.

scholarly journals Evaluation of Boldine Activity against Intracellular Amastigotes of Leishmania amazonensis

2017 ◽  
Vol 55 (3) ◽  
pp. 337-340 ◽  
Author(s):  
Isabel Cristina Salama ◽  
Cristina Arrais-Lima ◽  
Wagner Welber Arrais-Silva
Keyword(s):  
Leishmania Amazonensis ◽  
Intracellular Amastigotes

scholarly journals Antileishmanial activity of Melampodium divaricatum and Casearia sylvestris essential oils on Leishmania amazonensis

2019 ◽  
Vol 61 ◽  
Author(s):  
Raquel Regina Duarte Moreira ◽  
André Gonzaga dos Santos ◽  
Flavio Alexandre Carvalho ◽  
Caio Humberto Perego ◽  
Eduardo José Crevelin ◽  
...  
Keyword(s):  
Essential Oils ◽  
Leishmania Amazonensis ◽  
Antileishmanial Activity ◽  
Casearia Sylvestris

scholarly journals Effects of CXCL10 on Dendritic Cell and CD4+ T-Cell Functions during Leishmania amazonensis Infection

2007 ◽  
Vol 76 (1) ◽  
pp. 161-169 ◽  
Author(s):  
René E. Vasquez ◽  
Lijun Xin ◽  
Lynn Soong
Keyword(s):  
T Cells ◽  
Progressive Disease ◽  
Inbred Strains ◽  
Leishmania Amazonensis ◽  
Interleukin 12 ◽  
Proinflammatory Response ◽  
Cell Functions ◽  
Inbred Strains Of Mice ◽  
Ifn Γ

ABSTRACT Leishmania amazonensis can cause progressive disease in most inbred strains of mice. We have previously reported that treatment with CXCL10 activates macrophage (MΦ) effector function(s) in parasite killing and significantly delays lesion development in susceptible C57BL/6 mice via enhanced gamma interferon (IFN-γ) and interleukin 12 (IL-12) secretion; however, the mechanism underlying this enhanced immunity against L. amazonensis infection remains largely unresolved. In this study, we utilized stationary promastigotes to infect bone marrow-derived dendritic cells (DCs) of C57BL/6 mice and assessed the activation of DC subsets and the capacity of these DC subsets to prime CD4+ T cells in vitro. We found that CXCL10 induced IL-12 p40 production but reduced IL-10 production in uninfected DCs. Yet L. amazonensis-infected DCs produced elevated levels of IL-10 despite CXCL10 treatment. Elimination of endogenous IL-10 led to increased IL-12 p40 production in DCs as well as increased proliferation and IFN-γ production by in vitro-primed CD4+ T cells. In addition, CXCL10-treated CD4+ T cells became more responsive to IL-12 via increased expression of the IL-12 receptor β2 chain and produced elevated levels of IFN-γ. This report indicates the utility of CXCL10 in generating a Th1-favored, proinflammatory response, which is a prerequisite for controlling Leishmania infection.

scholarly journals Antigen-Responsive CD4+ T Cells from C3H Mice Chronically Infected with Leishmania amazonensis Are Impaired in the Transition to an Effector Phenotype

2006 ◽  
Vol 74 (3) ◽  
pp. 1547-1554 ◽  
Author(s):  
Amanda E. Ramer ◽  
Yannick F. Vanloubbeeck ◽  
Douglas E. Jones
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
T Cell Response ◽  
Leishmania Amazonensis ◽  
Effector Memory ◽  
Intrinsic Defect ◽  
Antigen Stimulation ◽  
Ifn Γ

ABSTRACT C3HeB/FeJ mice challenged with Leishmania major develop a polarized Th1 response and subsequently heal, whereas Leishmania amazonensis challenge leads to chronic lesions with high parasite loads at 10 weeks postinfection. In this study, a comparison of draining lymph node cells from L. amazonensis- and L. major-infected mice at 10 weeks postinfection showed equivalent percentages of effector/memory phenotype CD44hi CD4+ T cells producing interleukin-2 (IL-2) and proliferating after antigen stimulation. However, these cells isolated from L. amazonensis-infected mice were not skewed toward either a Th1 or Th2 phenotype in vivo, as evidenced by their unbiased Th1/Th2 transcription factor mRNA profile. In vivo antigen stimulation with added IL-12 failed to enhance gamma interferon (IFN-γ) production of CD4+ T cells from L. amazonensis-infected mice. Antigen stimulation of CD4+ T cells from L. amazonensis-infected mice in vitro in the presence of IL-12 resulted in production of only 10 to 15% of the IFN-γ produced by T cells from L. major-infected mice under identical conditions. These results suggest that the CD4+ T-cell response during chronic L. amazonensis infection is limited during the transition from an early activated CD4+ T-cell population to an effector cell population and demonstrate that these T cells have an intrinsic defect beyond the presence or absence of IL-12 during antigen stimulation.

Sign in / Sign up

Export Citation Format

Share Document