Benznidazole modulates release of inflammatory mediators by cardiac spheroids infected with Trypanosoma cruzi

Fiuza, Ludmila Ferreira de Almeida; Batista, Denise da Gama Jaén; Nunes, Daniela Ferreira; Moreira, Otacílio Cruz; Cascabulho, Cynthia Machado; Soeiro, Maria de Nazaré Correia

doi:10.1016/j.exppara.2020.108061

Cited by 8 publications

(19 citation statements)

References 49 publications

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“…The inclusion of cardiac organoids for anti-T. cruzi drug evaluation is recommended as the heart is one of the main target organs for infection and inflammation in CD and the drug responses may be influenced by the host cellular metabolism. [44][45] In addition, we also tested the toxicity and anti-T. cruzi activity of compound 14 using cardiac spheroids that corrobo-the cellular microenvironments in in vivo systems and has gained great interest in drug discovery programs due to its cost-effectiveness. [46] Our in vivo data endorsed the use of 3-D cardiac cells as a sensitive in vitro model for drug evaluation of novel trypanosomicidal agents as reported.…”

Section: Discussionmentioning

confidence: 99%

“…[46] Our in vivo data endorsed the use of 3-D cardiac cells as a sensitive in vitro model for drug evaluation of novel trypanosomicidal agents as reported. [45] Following confirmation of metabolic stability in vitro, compound 14 was evaluated in a mouse model of acute experimental CD. At the highest dose (25 mg/kg p.o.…”

Section: Discussionmentioning

confidence: 99%

“…Shifting the halogen to the meta (36,37) or ortho (38) position reduced the anti-T. cruzi activity, in line with previous SAR observations with the 6-amino analogues. [22,25] Generally, 3,4-disubstituted analogues (39,40) were more potent than 2,4-disubstituted (44,45) or 3,5-disubstituted analogues (46). Introduction of a fluoro (40) or a methoxy group (43) in the meta position of 14 gave a slight activity improvement.…”

Section: In Vitro Evaluationmentioning

confidence: 97%

“…[25] Three-dimensional cardiac cell cultures: cardiac spheroids were obtained as reported. [45] For cardiotoxicity analyses, non-infected 3-D cultures were incubated for 48 h at 37°C with increasing concentrations of BZ and compound 14 (up to 200 μM) and cellular viability determined using PrestoBlue® (CC) tests. [45] For determination of anti-T. cruzi activity, 3-D cultures were infected with BF (strain Y), using 20 : 1 parasite:host cell ratios.…”

Section: -Chloro-5-iodo-n7-(2'5'-di-o-benzoyl-3'-deoxy-β-d-ribofuranosyl)-pyrrolo[23-d]pyrimidine (81)mentioning

confidence: 99%

“…[45] For cardiotoxicity analyses, non-infected 3-D cultures were incubated for 48 h at 37°C with increasing concentrations of BZ and compound 14 (up to 200 μM) and cellular viability determined using PrestoBlue® (CC) tests. [45] For determination of anti-T. cruzi activity, 3-D cultures were infected with BF (strain Y), using 20 : 1 parasite:host cell ratios. After 48 h, the cultures were rinsed and either or not incubated with 10 μM compound 14 or BZ (corresponding to the EC 90 value of the reference drug upon intracellular forms) for 96 h at 37°C.…”

Section: -Chloro-5-iodo-n7-(2'5'-di-o-benzoyl-3'-deoxy-β-d-ribofuranosyl)-pyrrolo[23-d]pyrimidine (81)mentioning

confidence: 99%

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6‐Methyl‐7‐Aryl‐7‐Deazapurine Nucleosides as Anti‐Trypanosoma cruzi Agents: Structure‐Activity Relationship and in vivo Efficacy

et al. 2021

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Chagas disease is a tropical infectious disease resulting in progressive organ-damage and currently lacks efficient treatment and vaccine options. The causative pathogen, Trypanosoma cruzi, requires uptake and processing of preformed purines from the host because it cannot synthesize these de novo, instigating the evaluation of modified purine nucleosides as potential trypanocides. By modifying the pyrimidine part of a previously identified 7-aryl-7-deazapurine nucleoside, we found that substitution of a 6-methyl for a 6-amino group allows retaining T. cruzi amastigote growth inhibitory activity but confers improved selectivity towards mammalian cells. By keeping the 6-methyl group unaltered, and introducing different 7-aryl groups, we identified several analogues with submicromolar antitrypanosomal activity. The 7-(4-chlorophenyl) analogue 14, which was stable in microsomes, was evaluated in an acute mouse model. Oral administration of 25 mg/kg b.i.d. suppressed peak parasitemia and protected mice from infection-related mortality, gave similar reductions as the reference drug of blood parasite loads determined by qPCR, but as benznidazole failed to induce sterile cure in the short time period of drug exposure (5 days).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: In Vitro Evaluationmentioning

confidence: 97%

Section: -Chloro-5-iodo-n7-(2'5'-di-o-benzoyl-3'-deoxy-β-d-ribofuranosyl)-pyrrolo[23-d]pyrimidine (81)mentioning

confidence: 99%

Section: -Chloro-5-iodo-n7-(2'5'-di-o-benzoyl-3'-deoxy-β-d-ribofuranosyl)-pyrrolo[23-d]pyrimidine (81)mentioning

confidence: 99%

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6‐Methyl‐7‐Aryl‐7‐Deazapurine Nucleosides as Anti‐Trypanosoma cruzi Agents: Structure‐Activity Relationship and in vivo Efficacy

et al. 2021

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Accelerating cardiovascular research: recent advances in translational 2D and 3D heart models

Mohr

Thum

Bär

2022

European J of Heart Fail

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In vitro modelling the complex (patho‐) physiological conditions of the heart is a major challenge in cardiovascular research. In recent years, methods based on three‐dimensional (3D) cultivation approaches have steadily evolved to overcome the major limitations of conventional adherent two‐dimensional (2D) monolayer cultivation. These 3D approaches aim to study, reproduce or modify fundamental native features of the heart such as tissue organization and cardiovascular microenvironment. Therefore, these systems have great potential for (patient‐specific) disease research, for the development of new drug screening platforms, and for the use in regenerative and replacement therapy applications. Consequently, continuous improvement and adaptation is required with respect to fundamental limitations such as cardiomyocyte maturation, scalability, heterogeneity, vascularization, and reproduction of native properties. In this review, 2D monolayer culturing and the 3D in vitro systems of cardiac spheroids, organoids, engineered cardiac microtissue and bioprinting as well as the ex vivo technique of myocardial slicing are introduced with their basic concepts, advantages, and limitations. Furthermore, recent advances of various new approaches aiming to extend as well as to optimize these in vitro and ex vivo systems are presented.

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Progress of organoid platform in cardiovascular research

Du,

Jia,

Chang

et al. 2024

Bioactive Materials

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Benznidazole modulates release of inflammatory mediators by cardiac spheroids infected with Trypanosoma cruzi

Cited by 8 publications

References 49 publications

6‐Methyl‐7‐Aryl‐7‐Deazapurine Nucleosides as Anti‐Trypanosoma cruzi Agents: Structure‐Activity Relationship and in vivo Efficacy

6‐Methyl‐7‐Aryl‐7‐Deazapurine Nucleosides as Anti‐Trypanosoma cruzi Agents: Structure‐Activity Relationship and in vivo Efficacy

Accelerating cardiovascular research: recent advances in translational 2D and 3D heart models

Progress of organoid platform in cardiovascular research

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