scholarly journals Metabolite profiling of experimental cutaneous leishmaniasis lesions demonstrates significant perturbations in tissue phospholipids

2020 ◽  
Author(s):  
Adwaita R. Parab ◽  
Diane Thomas ◽  
Sharon Lostracco-Johnson ◽  
Jair Lage de Siqueira-Neto ◽  
James McKerrow ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Drug Targets ◽  
Leishmania Major ◽  
Neglected Tropical Diseases ◽  
Treatment Options ◽  
Skin Lesions ◽  
Wide Distribution ◽  
Tropical Diseases ◽  
Lesion Site

AbstractEach year 700,000 to 1.2 million new cases of cutaneous leishmaniasis (CL) are reported and yet CL remains one of thirteen diseases classified as neglected tropical diseases (NTDs). Leishmania major is one of several different species of that same genus that can cause CL. Current CL treatments are limited by adverse effects and rising resistance. Studying disease metabolism at the site of infection can lead to new drug targets. In this study, samples were collected from mice infected in the ear and footpad with L. major and analyzed by untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). Significant differences in overall metabolite profiles were noted in the ear at the site of the lesion. Interestingly, lesion-adjacent, macroscopically healthy sites also showed alterations in specific metabolites, including select phosphocholines (PCs). Host-derived PCs in the lower m/z range (m/z 200-799) showed an increase with infection in the ear at the lesion site, while those in the higher m/z range (m/z 800-899) were decreased with infection at the lesion site. Overall, our results expanded our understanding of the mechanisms of CL pathogenesis through the host metabolism and may lead to new curative measures against infection with Leishmania.Author summaryCutaneous leishmaniasis (CL) is one of thirteen neglected tropical diseases in the world today. It is an infectious disease with a wide distribution spanning five continents, with increasing distribution expected due to climate change. CL manifests as skin lesions and ulcers that are disabling and stigmatized. With the current treatment options being limited, studying host-pathogen metabolism can uncover mechanisms of disease pathogenesis that may lead to new curative measures against infection. In this paper we used untargeted metabolomics to address molecular-level changes occurring in vivo in experimental skin lesions of Leishmania major. Distinct global metabolic profiles were observed. Total phosphocholines (PCs) and those in the lower m/z ranges were significantly higher at the site of the skin lesion in the ear. In addition, specific PCs as well as PCs of varied m/z ranges were also affected at healthy-appearing lesion-adjacent sites, indicating that infection-induced metabolic perturbations are not restricted to the lesion site. Ultimately, these results provide essential clues to the metabolic pathways affected by CL.

scholarly journals Expression of Inducible Nitric Oxide Synthase in Skin Lesions of Patients with American Cutaneous Leishmaniasis

2002 ◽  
Vol 70 (8) ◽  
pp. 4638-4642 ◽  
Author(s):  
Muna Qadoumi ◽  
Inge Becker ◽  
Norbert Donhauser ◽  
Martin Röllinghoff ◽  
Christian Bogdan
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Skin Lesions ◽  
And Function ◽  
Oxide Synthase

ABSTRACT Cytokine-inducible (or type 2) nitric oxide synthase (iNOS) is indispensable for the resolution of Leishmania major or Leishmania donovani infections in mice. In contrast, little is known about the expression and function of iNOS in human leishmaniasis. Here, we show by immunohistological analysis of skin biopsies from Mexican patients with local (LCL) or diffuse (DCL) cutaneous leishmaniasis that the expression of iNOS was most prominent in LCL lesions with small numbers of parasites whereas lesions with a high parasite burden (LCL or DCL) contained considerably fewer iNOS-positive cells. This is the first study to suggest an antileishmanial function of iNOS in human Leishmania infections in vivo.

scholarly journals Sandfly Fever Sicilian Virus-Leishmania major co-infection modulates innate inflammatory response favoring myeloid cell infections and skin hyperinflammation

2021 ◽  
Vol 15 (7) ◽  
pp. e0009638
Author(s):  
Ellen Heirwegh ◽  
Emily MacLean ◽  
Jinlei He ◽  
Shaden Kamhawi ◽  
Selena M. Sagan ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Myeloid Cell ◽  
Skin Lesions ◽  
Health Concern ◽  
Global Public Health ◽  
Knock Out

Background The leishmaniases are a group of sandfly-transmitted diseases caused by species of the protozoan parasite, Leishmania. With an annual incidence of 1 million cases, 1 billion people living in Leishmania-endemic regions, and nearly 30,000 deaths each year, leishmaniasis is a major global public health concern. While phlebotomine sandflies are well-known as vectors of Leishmania, they are also the vectors of various phleboviruses, including Sandfly Fever Sicilian Virus (SFSV). Cutaneous leishmaniasis (CL), caused by Leishmania major (L. major), among other species, results in development of skin lesions on the infected host. Importantly, there exists much variation in the clinical manifestation between individuals. We propose that phleboviruses, vectored by and found in the same sandfly guts as Leishmania, may be a factor in determining CL severity. It was reported by our group that Leishmania exosomes are released into the gut of the sandfly vector and co-inoculated during blood meals, where they exacerbate CL skin lesions. We hypothesized that, when taking a blood meal, the sandfly vector infects the host with Leishmania parasites and exosomes as well as phleboviruses, and that this viral co-infection results in a modulation of leishmaniasis. Methodology/Principal findings In vitro, we observed modulation by SFSV in MAP kinase signaling as well as in the IRF3 pathway that resulted in a pro-inflammatory phenotype. Additionally, we found that SFSV and L. major co-infection resulted in an exacerbation of leishmaniasis in vivo, and by using endosomal (Toll-like receptor) TLR3, and MAVS knock-out mice, deduced that SFSV’s hyperinflammatory effect was TLR3- and MAVS-dependent. Critically, we observed that L. major and SFSV co-infected C57BL/6 mice demonstrated significantly higher parasite burden than mice solely infected with L. major. Furthermore, viral presence increased leukocyte influx in vivo. This influx was accompanied by elevated total extracellular vesicle numbers. Interestingly, L. major displayed higher infectiveness with coincident phleboviral infection compared to L. major infection alone. Conclusion/Significance Overall our work represents novel findings that contribute towards understanding the causal mechanisms governing cutaneous leishmaniasis pathology. Better comprehension of the potential role of viral co-infection could lead to treatment regimens with enhanced effectiveness.

In Vivo and In Vitro Taste Assessment of Artesunate-Mefloquine, Praziquantel, and Benznidazole Drugs for Neglected Tropical Diseases and Pediatric Patients

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Janine Boniatti ◽  
Marcelo R. R. Tappin ◽  
Rafaela G. da S Teixeira ◽  
Tamires de A V Gandos ◽  
Luis P. S. Rios ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Neglected Tropical Diseases ◽  
Tropical Diseases ◽  
Taste Assessment

scholarly journals Histone deacetylase enzymes as potential drug targets of Neglected Tropical Diseases caused by cestodes

2019 ◽  
Vol 9 ◽  
pp. 120-132
Author(s):  
Hugo R. Vaca ◽  
Ana M. Celentano ◽  
Natalia Macchiaroli ◽  
Laura Kamenetzky ◽  
Federico Camicia ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Drug Targets ◽  
Neglected Tropical Diseases ◽  
Tropical Diseases ◽  
Potential Drug ◽  
Potential Drug Targets

scholarly journals Zinc(II)-Dipicolylamine Coordination Complexes as Targeting and Chemotherapeutic Agents for Leishmania major

2016 ◽  
Vol 60 (5) ◽  
pp. 2932-2940 ◽  
Author(s):  
Douglas R. Rice ◽  
Paola Vacchina ◽  
Brianna Norris-Mullins ◽  
Miguel A. Morales ◽  
Bradley D. Smith
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Mammalian Cells ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Coordination Complexes ◽  
Chemotherapeutic Agents ◽  
Selective Toxicity ◽  
Content Type

ABSTRACTCutaneous leishmaniasis is a neglected tropical disease that causes painful lesions and severe disfigurement. Modern treatment relies on a few chemotherapeutics with serious limitations, and there is a need for more effective alternatives. This study describes the selective targeting of zinc(II)-dipicolylamine (ZnDPA) coordination complexes towardLeishmania major, one of the species responsible for cutaneous leishmaniasis. Fluorescence microscopy ofL. majorpromastigotes treated with a fluorescently labeled ZnDPA probe indicated rapid accumulation of the probe within the axenic promastigote cytosol. The antileishmanial activities of eight ZnDPA complexes were measured using anin vitroassay. All tested complexes exhibited selective toxicity againstL. majoraxenic promastigotes, with 50% effective concentration values in the range of 12.7 to 0.3 μM. Similar toxicity was observed against intracellular amastigotes, but there was almost no effect on the viability of mammalian cells, including mouse peritoneal macrophages.In vivotreatment efficacy studies used fluorescence imaging to noninvasively monitor changes in the red fluorescence produced by an infection of mCherry-L. majorin a mouse model. A ZnDPA treatment regimen reduced the parasite burden nearly as well as the reference care agent, potassium antimony(III) tartrate, and with less necrosis in the local host tissue. The results demonstrate that ZnDPA coordination complexes are a promising new class of antileishmanial agents with potential for clinical translation.

Targeting pteridine reductase 1 and dihydrofolate reductase: the old is a new trend for leishmaniasis drug discovery

2019 ◽  
Vol 11 (16) ◽  
pp. 2107-2130 ◽  
Author(s):  
Gustavo Machado das Neves ◽  
Luciano P Kagami ◽  
Itamar L Gonçalves ◽  
Vera L Eifler-Lima
Keyword(s):  
Dihydrofolate Reductase ◽  
Drug Targets ◽  
Neglected Tropical Diseases ◽  
Molecular Targets ◽  
New Drugs ◽  
Tropical Diseases ◽  
The World ◽  
Leishmania Spp ◽  
Systemic Manifestations ◽  
Potential Drug Targets

Leishmaniasis is one of the major neglected tropical diseases in the world and it is considered endemic in 88 countries. This disease is transmitted by a Leishmania spp. infected sandfly and it may lead to cutaneous or systemic manifestations. The preconized treatment has low efficacy and there are cases of resistance to some drugs. Therefore, the search for new efficient molecular targets that can lead to the preparation of new drugs must be pursued. This review aims to evaluate both Leishmania enzymes PTR1 and DHFR-TS as potential drug targets, highlight their inhibitors and to discuss critically the use of chemoinformatics to elucidate interactions and propose new molecules against these enzymes.

In Silico Chemogenomics Drug Repositioning Strategies for Neglected Tropical Diseases

2019 ◽  
Vol 26 (23) ◽  
pp. 4355-4379 ◽  
Author(s):  
Carolina Horta Andrade ◽  
Bruno Junior Neves ◽  
Cleber Camilo Melo-Filho ◽  
Juliana Rodrigues ◽  
Diego Cabral Silva ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Neglected Tropical Diseases ◽  
Drug Repositioning ◽  
Tropical Diseases ◽  
Systematic Screening ◽  
Drug Candidates ◽  
Lead Compounds ◽  
The One ◽  
Approved Drugs

Only ~1% of all drug candidates against Neglected Tropical Diseases (NTDs) have reached clinical trials in the last decades, underscoring the need for new, safe and effective treatments. In such context, drug repositioning, which allows finding novel indications for approved drugs whose pharmacokinetic and safety profiles are already known, emerging as a promising strategy for tackling NTDs. Chemogenomics is a direct descendent of the typical drug discovery process that involves the systematic screening of chemical compounds against drug targets in high-throughput screening (HTS) efforts, for the identification of lead compounds. However, different to the one-drug-one-target paradigm, chemogenomics attempts to identify all potential ligands for all possible targets and diseases. In this review, we summarize current methodological development efforts in drug repositioning that use state-of-the-art computational ligand- and structure-based chemogenomics approaches. Furthermore, we highlighted the recent progress in computational drug repositioning for some NTDs, based on curation and modeling of genomic, biological, and chemical data. Additionally, we also present in-house and other successful examples and suggest possible solutions to existing pitfalls.

In vivo efficacy of meglumine antimoniate-loaded nanoparticles for cutaneous leishmaniasis: a systematic review

Nanomedicine ◽  
2021 ◽  
Author(s):  
Meliana Borilli Pereira ◽  
Bruna Gomes Sydor ◽  
Karla Gabriela Memare ◽  
Thaís Gomes Verzignassi Silveira ◽  
Sandra Mara Alessi Aristides ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Polymeric Nanoparticles ◽  
Parasite Burden ◽  
Lesion Size ◽  
Eligibility Criteria ◽  
Meglumine Antimoniate ◽  
In Vivo Experiments

Background: Nanotechnology is a promising strategy to improve existing antileishmanial agents. Objective: To explore the evidence of encapsulated meglumine antimoniate for cutaneous leishmaniasis treatment in animal models. Materials & methods: The studies were recovered from PubMed, Scopus, EMBASE, LILACS, WoS and Google according to eligibility criteria following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Population, Intervention, Comparison, Outcomes and Study design (PICOS) strategy. Study appraisal was assessed using the Animal Research Reporting of In Vivo Experiments, SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) recommendations. Results: Five studies were included. Liposomes, metallic and polymeric nanoparticles were tested in BALB/c mice against Leishmania major, L. tropica or L. amazonensis. Limitations: Few studies were found to meet the eligibility criteria. Conclusion: All formulations had a significant efficacy, similar to the meglumine antimoniate reference treatment concerning the lesion size and parasite burden. The studies had a high and moderate risk of bias, and the confidence in cumulative evidence was considered low. Therefore, we encourage the development of high-quality preclinical studies. Registration: PROSPERO register CRD42020170191.

scholarly journals Development of a New Antileishmanial Aziridine-2,3-Dicarboxylate-Based Inhibitor with High Selectivity for Parasite Cysteine Proteases

2015 ◽  
Vol 60 (2) ◽  
pp. 797-805 ◽  
Author(s):  
Caroline Schad ◽  
Ulrike Baum ◽  
Benjamin Frank ◽  
Uwe Dietzel ◽  
Felix Mattern ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Neglected Tropical Diseases ◽  
Cathepsin L ◽  
Selective Inhibition ◽  
Cysteine Proteases ◽  
Host Cells ◽  
Th2 Response ◽  
Content Type

ABSTRACTLeishmaniasis is one of the major neglected tropical diseases of the world. Druggable targets are the parasite cysteine proteases (CPs) of clan CA, family C1 (CAC1). In previous studies, we identified two peptidomimetic compounds, the aziridine-2,3-dicarboxylate compounds 13b and 13e, in a series of inhibitors of the cathepsin L (CL) subfamily of the papain clan CAC1. Both displayed antileishmanial activityin vitrowhile not showing cytotoxicity against host cells. In further investigations, the mode of action was characterized inLeishmania major. It was demonstrated that aziridines 13b and 13e mainly inhibited the parasitic cathepsin B (CB)-like CPC enzyme and, additionally, mammalian CL. Although these compounds induced cell death ofLeishmaniapromastigotes and amastigotesin vitro, the induction of a proleishmanial T helper type 2 (Th2) response caused by host CL inhibition was observedin vivo. Therefore, we describe here the synthesis of a new library of more selective peptidomimetic aziridine-2,3-dicarboxylates discriminating between host and parasite CPs. The new compounds are based on 13b and 13e as lead structures. One of the most promising compounds of this series is compound s9, showing selective inhibition of the parasite CPsLmaCatB (a CB-like enzyme ofL. major; also namedL. majorCPC) andLmCPB2.8 (a CL-like enzyme ofLeishmania mexicana) while not affecting mammalian CL and CB. It displayed excellent leishmanicidal activities againstL. majorpromastigotes (50% inhibitory concentration [IC50] = 37.4 μM) and amastigotes (IC50= 2.3 μM). In summary, we demonstrate a new selective aziridine-2,3-dicarboxylate, compound s9, which might be a good candidate for futurein vivostudies.

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