In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195

Guedes, Carlos; Dias, Beatriz Rocha Simões; Petersen, Antônio Luis de Oliveira Almeida; Cruz, Kercia Pinheiro; Almeida, Niara de Jesus; Andrade, Daniela; Menezes, Juliana Perrone Bezerra de; Borges, Valéria M.; Veras, Patrícia Sampaio Tavares

doi:10.1590/0074-02760170345

Cited by 6 publications

(5 citation statements)

References 30 publications

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“…We found that this mitochondrial transmembrane protein exhibited a lower relative abundance of peptides in cells infected with L. amazonensis in comparison to L. major (Menezes et al, 2013 ). Modulating TSPO with one of its ligand, PK11195, caused the killing of amastigotes in vitro at dosages considered non-toxic to macrophages, indicating its potential as antileishmanial (Guedes et al, 2018 ). In sum, these findings strengthen the potentiality of global analysis of Leishmania -infected macrophages for the identification of biomarkers in host cells that probably participate in the pathogenesis of Leishmania infection and, subsequently, can function as targets for therapeutic intervention.…”

Section: Proteomic Contribution To Understanding the Macrophage Respomentioning

confidence: 99%

In Search of Biomarkers for Pathogenesis and Control of Leishmaniasis by Global Analyses of Leishmania-Infected Macrophages

Veras¹,

Ramos²,

Menezes

2018

Front. Cell. Infect. Microbiol.

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Leishmaniasis is a vector-borne, neglected tropical disease with a worldwide distribution that can present in a variety of clinical forms, depending on the parasite species and host genetic background. The pathogenesis of this disease remains far from being elucidated because the involvement of a complex immune response orchestrated by host cells significantly affects the clinical outcome. Among these cells, macrophages are the main host cells, produce cytokines and chemokines, thereby triggering events that contribute to the mediation of the host immune response and, subsequently, to the establishment of infection or, alternatively, disease control. There has been relatively limited commercial interest in developing new pharmaceutical compounds to treat leishmaniasis. Moreover, advances in the understanding of the underlying biology of Leishmania spp. have not translated into the development of effective new chemotherapeutic compounds. As a result, biomarkers as surrogate disease endpoints present several potential advantages to be used in the identification of targets capable of facilitating therapeutic interventions considered to ameliorate disease outcome. More recently, large-scale genomic and proteomic analyses have allowed the identification and characterization of the pathways involved in the infection process in both parasites and the host, and these analyses have been shown to be more effective than studying individual molecules to elucidate disease pathogenesis. RNA-seq and proteomics are large-scale approaches that characterize genes or proteins in a given cell line, tissue, or organism to provide a global and more integrated view of the myriad biological processes that occur within a cell than focusing on an individual gene or protein. Bioinformatics provides us with the means to computationally analyze and integrate the large volumes of data generated by high-throughput sequencing approaches. The integration of genomic expression and proteomic data offers a rich multi-dimensional analysis, despite the inherent technical and statistical challenges. We propose that these types of global analyses facilitate the identification, among a large number of genes and proteins, those that hold potential as biomarkers. The present review focuses on large-scale studies that have identified and evaluated relevant biomarkers in macrophages in response to Leishmania infection.

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Section: Proteomic Contribution To Understanding the Macrophage Respomentioning

confidence: 99%

In Search of Biomarkers for Pathogenesis and Control of Leishmaniasis by Global Analyses of Leishmania-Infected Macrophages

Veras¹,

Ramos²,

Menezes

2018

Front. Cell. Infect. Microbiol.

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“…Before proceeding with in vitro experiments, we first assessed the potential cytotoxicity of PK11195 and D-DPA via cell viability measurements. BV2 murine microglia were exposed to PK11195 or D-DPA over a concentration range of 1–1000 μg/mL for 24 h. Consistent with previous in vitro studies, , PK11195 demonstrated significant dose-dependent toxicity, with the 1000 μg/mL dose reducing cell viability to ∼5% of controls (Figure S22). In contrast, D-DPA exhibited significantly less cytotoxicity ( p < 0.0001 PK11195 vs D-DPA), with the 1000 μg/mL dose exhibiting ∼60% cell viability.…”

Section: Resultsmentioning

confidence: 99%

Targeting Mitochondria in Tumor-Associated Macrophages using a Dendrimer-Conjugated TSPO Ligand that Stimulates Antitumor Signaling in Glioblastoma

Sharma¹,

Liaw

Sharma

et al. 2020

Biomacromolecules

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Mitochondria mediate critical cellular processes, including proliferation, apoptosis, and immune responses; as such, their dysfunction is pathogenic in many neurodegenerative disorders and cancers. In glioblastoma, targeted delivery of mitochondria-focused anticancer therapies has failed to translate into clinical success due to the nonspecific cellular localization, heterogeneity of receptor expression across patients, poor transport across biological barriers to reach the brain, tumor, and mitochondria, and systemic side effects. Strategies that can overcome brain and solid tumor barriers and selectively target mitochondria within specific cell types may lead to improvements in glioblastoma treatment. Developments in dendrimer-mediated nanomedicines have shown promise targeting tumor-associated macrophages (TAMs) in glioblastoma, following systemic administration. Here, we present a novel dendrimer conjugated to the translocator protein (18 kDa) (TSPO) ligand 5,7-dimethylpyrazolo[1,5-α]pyrimidin-3-ylacetamide (DPA). We developed a clickable DPA for conjugation on the dendrimer surface and demonstrated in vitro that the dendrimer-DPA conjugate (D-DPA) significantly increases dendrimer colocalization with mitochondria. Compared to free TSPO ligand PK11195, D-DPA stimulates greater antitumor immune signaling. In vivo, we show that D-DPA targets mitochondria specifically within TAMs following systemic administration. Our results demonstrate that dendrimers can achieve TAM-specific targeting in glioblastoma and can be further modified to target specific intracellular compartments for organelle-specific drug delivery.

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“…Reading was performed in the spectrophotometer at wavelengths of 570 and 600 nm. The percentage of axenic culture inhibition was determined based on the untreated control (Guedes et al 2018).…”

Section: Antileishmanial Activitymentioning

confidence: 99%

Pharmacological properties of new chalcones for treatment of leishmaniasis: in silico and in vitro studies

Silva

Leite

Herrera‐Acevedo

et al. 2023

Preprint

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Leishmaniasis constitutes a complex of endemic and neglected diseases with high morbidity and mortality rates. Due to the toxicity, resistance profile and adverse effects of current drugs, science is looking for new therapeutic alternatives. Therefore, the objective of this study was to investigate in silico and in vitro tests the leishmanicidal potential of chalcones and verify their influence on the production of Reactive Oxygen Species (ROS). For the in silico tests, the PASS filter program was used. Murine macrophages (J774) and promastigotes and amastigotes of Leishmania braziliensis were used for in vitro tests. The selectivity index (SI) was calculated through the ratio between the 50% cytotoxicity concentration value (CC50) and the 50% inhibitory concentration value (IC50). Evaluation of ROS levels were obtained using the reagent 2'7'-dichlorodihydrofluorescein diacetate (H2DCFDA). The results indicated that one of the biological activities most associated with flavonoids is the antileishmanial activity. All chalcones tested did not show significant cytotoxicity and the chalcone that showed the best antileishmanial potency was compound 4 (FERAI), with a CI50 of 9.75 ± 1.7 µM and 10.13 ± 1.7 µM for promastigotes and amastigotes of L. braziliensis, respectively. Macrophages treated with FERAI showed a reduction in infection and amastigotes number. FERAI has been shown to increase ROS levels, which is one of its possible mechanisms of action against the parasite. In view of the observed results, it is concluded that all compounds did not exhibit significant cytotoxicity and FERAI presented itself as a strong candidate for a new drug against leishmaniasis.

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In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195

Cited by 6 publications

References 30 publications

In Search of Biomarkers for Pathogenesis and Control of Leishmaniasis by Global Analyses of Leishmania-Infected Macrophages

In Search of Biomarkers for Pathogenesis and Control of Leishmaniasis by Global Analyses of Leishmania-Infected Macrophages

Targeting Mitochondria in Tumor-Associated Macrophages using a Dendrimer-Conjugated TSPO Ligand that Stimulates Antitumor Signaling in Glioblastoma

Pharmacological properties of new chalcones for treatment of leishmaniasis: in silico and in vitro studies

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