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  1. Article ; Online: Antioxidant defence system as a rational target for Chagas disease and Leishmaniasis chemotherapy

    Ana Maria Murta Santi / Silvane Maria Fonseca Murta/

    Memórias do Instituto Oswaldo Cruz., Vol

    2022  Volume 117

    Abstract: Chagas disease and leishmaniasis are neglected tropical diseases caused by the protozoan parasites Trypanosoma cruzi and Leishmania spp., respectively. They are among the most important parasitic diseases, affecting millions of people worldwide, being a ... ...

    Abstract Chagas disease and leishmaniasis are neglected tropical diseases caused by the protozoan parasites Trypanosoma cruzi and Leishmania spp., respectively. They are among the most important parasitic diseases, affecting millions of people worldwide, being a considerable global challenge. However, there is no human vaccine available against T. cruzi and Leishmania infections, and their control is based mainly on chemotherapy. Treatments for Chagas disease and leishmaniasis have multiple limitations, mainly due to the high toxicity of the available drugs, long-term treatment protocols, and the occurrence of drug-resistant parasite strains. In the case of Chagas disease, there is still the problem of low cure rates in the chronic stage of the disease. Therefore, new therapeutic agents and novel targets for drug development are urgently needed. Antioxidant defence in Trypanosomatidae is a potential target for chemotherapy because the organisms present a unique mechanism for trypanothione-dependent detoxification of peroxides, which differs from that found in vertebrates. Cellular thiol redox homeostasis is maintained by the biosynthesis and reduction of trypanothione, involving different enzymes that act in concert. This study provides an overview of the antioxidant defence focusing on iron superoxide dismutase A, tryparedoxin peroxidase, and ascorbate peroxidase and how the enzymes play an important role in the defence against oxidative stress and their involvement in drug resistance mechanisms in T. cruzi and Leishmania spp.
    Keywords Trypanosoma cruzi ; Leishmania spp ; chemotherapy ; antioxidant defence ; drug resistance ; Arctic medicine. Tropical medicine ; RC955-962 ; Microbiology ; QR1-502
    Subject code 630
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher Instituto Oswaldo Cruz, Ministério da Saúde
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Deletion of the lipid droplet protein kinase gene affects lipid droplets biogenesis, parasite infectivity, and resistance to trivalent antimony in Leishmania infantum

    Juliana Martins Ribeiro / Paula Alves Silva / Héllida Marina Costa-Silva / Ana Maria Murta Santi / Silvane Maria Fonseca Murta

    PLoS Neglected Tropical Diseases, Vol 18, Iss

    2024  Volume 1

    Keywords Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Perspectives From Systems Biology to Improve Knowledge of Leishmania Drug Resistance

    Elvira Cynthia Alves Horácio / Jéssica Hickson / Silvane Maria Fonseca Murta / Jeronimo Conceição Ruiz / Laila Alves Nahum

    Frontiers in Cellular and Infection Microbiology, Vol

    2021  Volume 11

    Abstract: Neglected Tropical Diseases include a broad range of pathogens, hosts, and vectors, which represent evolving complex systems. Leishmaniasis, caused by different Leishmania species and transmitted to humans by sandflies, are among such diseases. ... ...

    Abstract Neglected Tropical Diseases include a broad range of pathogens, hosts, and vectors, which represent evolving complex systems. Leishmaniasis, caused by different Leishmania species and transmitted to humans by sandflies, are among such diseases. Leishmania and other Trypanosomatidae display some peculiar features, which make them a complex system to study. Leishmaniasis chemotherapy is limited due to high toxicity of available drugs, long-term treatment protocols, and occurrence of drug resistant parasite strains. Systems biology studies the interactions and behavior of complex biological processes and may improve knowledge of Leishmania drug resistance. System-level studies to understand Leishmania biology have been challenging mainly because of its unusual molecular features. Networks integrating the biochemical and biological pathways involved in drug resistance have been reported in literature. Antioxidant defense enzymes have been identified as potential drug targets against leishmaniasis. These and other biomarkers might be studied from the perspective of systems biology and systems parasitology opening new frontiers for drug development and treatment of leishmaniasis and other diseases. Our main goals include: 1) Summarize current advances in Leishmania research focused on chemotherapy and drug resistance. 2) Share our viewpoint on the application of systems biology to Leishmania studies. 3) Provide insights and directions for future investigation.
    Keywords Leishmania ; chemotherapy ; drug resistance ; systems biology ; systems parasitology ; molecular networks ; Microbiology ; QR1-502
    Subject code 572 ; 630
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Ascorbate peroxidase overexpression protects Leishmania braziliensis against trivalent antimony effects

    Douglas de Souza Moreira / Mariana Vieira Xavier / Silvane Maria Fonseca Murta/

    Memórias do Instituto Oswaldo Cruz., Vol 113, Iss

    2018  Volume 12

    Abstract: Ascorbate peroxidase (APX) is a redox enzyme of the trypanothione pathway that converts hydrogen peroxide (H2O2) into water molecules. In the present study, the APX gene was overexpressed in Leishmania braziliensis to investigate its contribution to the ... ...

    Abstract Ascorbate peroxidase (APX) is a redox enzyme of the trypanothione pathway that converts hydrogen peroxide (H2O2) into water molecules. In the present study, the APX gene was overexpressed in Leishmania braziliensis to investigate its contribution to the trivalent antimony (SbIII)-resistance phenotype. Western blot results demonstrated that APX-overexpressing parasites had higher APX protein levels in comparison with the wild-type line (LbWTS). APX-overexpressing clones showed an 8-fold increase in the antimony-resistance index over the parental line. In addition, our results indicated that these clones were approximately 1.8-fold more tolerant to H2O2 than the LbWTS line, suggesting that the APX enzyme plays an important role in the defence against oxidative stress. Susceptibility tests revealed that APX-overexpressing L. braziliensis lines were more resistant to isoniazid, an antibacterial agent that interacts with APX. Interestingly, this compound enhanced the anti-leishmanial SbIII effect, indicating that this combination represents a good strategy for leishmaniasis chemotherapy. Our data demonstrate that APX enzyme is involved in the development of L. braziliensis antimony-resistance phenotype and may be an attractive therapeutic target in the design of new strategies for leishmaniasis treatment.
    Keywords Leishmania braziliensis ; ascorbate peroxidase ; antimony resistance ; oxidative defence ; Arctic medicine. Tropical medicine ; RC955-962 ; Microbiology ; QR1-502
    Subject code 500
    Language English
    Publishing date 2018-11-01T00:00:00Z
    Publisher Instituto Oswaldo Cruz, Ministério da Saúde
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: The heterologous expression of Escherichia coli MutT enzyme is involved in the protection against oxidative stress in Leishmania braziliensis

    Laila de Carvalho Andrade / Ana Maria Murta Santi / Ceres Luciana Alves / Wesley Roger Rodrigues Ferreira / Antônio Vinícius de Assis / Edward Oliveira / Carlos Renato Machado / Silvane Maria Fonseca Murta

    Memórias do Instituto Oswaldo Cruz., Vol

    2020  Volume 115

    Abstract: BACKGROUND Oxidative stress is responsible for generating DNA lesions and the 8-oxoguanine (8-oxoG) is the most commonly lesion found in DNA damage. When this base is incorporated during DNA replication, it could generate double-strand DNA breaks and ... ...

    Abstract BACKGROUND Oxidative stress is responsible for generating DNA lesions and the 8-oxoguanine (8-oxoG) is the most commonly lesion found in DNA damage. When this base is incorporated during DNA replication, it could generate double-strand DNA breaks and cellular death. MutT enzyme hydrolyzes the 8-oxoG from the nucleotide pool, preventing its incorporation during DNA replication. OBJECTIVES To investigate the importance of 8-oxoG in Leishmania infantum and L. braziliensis, in this study we analysed the impact of heterologous expression of Escherichia coli MutT (EcMutT) enzyme in drug-resistance phenotype and defense against oxidative stress. METHODS Comparative analysis of L. braziliensis and L. infantum H2O2 tolerance and cell cycle profile were performed. Lines of L. braziliensis and L. infantum expressing EcMutT were generated and evaluated using susceptibility tests to H2O2 and SbIII, cell cycle analysis, γH2A western blotting, and BrdU native detection assay. FINDINGS Comparative analysis of tolerance to oxidative stress generated by H2O2 showed that L. infantum is more tolerant to exogenous H2O2 than L. braziliensis. In addition, cell cycle analysis showed that L. infantum, after treatment with H2O2, remains in G1 phase, returning to its normal growth rate after 72 h. In contrast, after treatment with H2O2, L. braziliensis parasites continue to move to the next stages of the cell cycle. Expression of the E. coli MutT gene in L. braziliensis and L. infantum does not interfere in parasite growth or in susceptibility to SbIII. Interestingly, we observed that L. braziliensis EcMutT-expressing clones were more tolerant to H2O2 treatment, presented lower activation of γH2A, a biomarker of genotoxic stress, and lower replication stress than its parental non-transfected parasites. In contrast, the EcMutT is not involved in protection against oxidative stress generated by H2O2 in L. infantum. MAIN CONCLUSIONS Our results showed that 8-oxoG clearance in L. braziliensis is important to avoid misincorporation during DNA replication after oxidative stress generated by H2O2.
    Keywords Leishmania braziliensis ; Leishmania infantum ; MutT ; DNA repair ; 8-oxoG ; oxidative stress ; Arctic medicine. Tropical medicine ; RC955-962 ; Microbiology ; QR1-502
    Subject code 572
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Instituto Oswaldo Cruz, Ministério da Saúde
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Trypanocidal Activity of Flavanone Derivatives

    Gabriela Maciel Diogo / Josimara Souza Andrade / Policarpo Ademar Sales Junior / Silvane Maria Fonseca Murta / Viviane Martins Rebello Dos Santos / Jason Guy Taylor

    Molecules, Vol 25, Iss 2, p

    2020  Volume 397

    Abstract: Chagas disease, also known as American trypanosomiasis, is classified as a neglected disease by the World Health Organization. For clinical treatment, only two drugs have been on the market, Benznidazole and Nifurtimox, both of which are recommended for ... ...

    Abstract Chagas disease, also known as American trypanosomiasis, is classified as a neglected disease by the World Health Organization. For clinical treatment, only two drugs have been on the market, Benznidazole and Nifurtimox, both of which are recommended for use in the acute phase but present low cure rates in the chronic phase. Furthermore, strong side effects may result in discontinuation of this treatment. Faced with this situation, we report the synthesis and trypanocidal activity of 3-benzoyl-flavanones. Novel 3-benzoyl-flavanone derivatives were prepared in satisfactory yields in the 3-step synthetic procedure. According to recommended guidelines, the whole cell-based screening methodology was utilized that allowed for the simultaneous use of both parasite forms responsible for human infection. The majority of the tested compounds displayed promising anti- Trypanosoma cruzi activity and the most potent flavanone bearing a nitrofuran moiety was more potent than the reference drug, Benznidazole.
    Keywords chagas disease ; flavanones ; flavonoids ; trypanosoma cruzi ; chromanones ; in vitro ; nitroreductase ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
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  7. Article ; Online: Overexpression of eukaryotic initiation factor 5A (eIF5A) affects susceptibility to benznidazole in Trypanosoma cruzi populations

    Douglas de Souza Moreira / Ana Paula Duarte / Fabiano Sviatopolk Mirsky Pais / Rosiane Aparecida da Silva-Pereira / Alvaro José Romanha / Sergio Schenkman / Silvane Maria Fonseca Murta

    Memórias do Instituto Oswaldo Cruz., Vol 113, Iss

    2018  Volume 9

    Abstract: Eukaryotic initiation factor 5A (eIF5A) is a conserved protein with an essential role in translation elongation. Using one and two-dimensional western blotting, we showed that the eIF5A protein level was 2-fold lower in benznidazole (BZ)-resistant (BZR ... ...

    Abstract Eukaryotic initiation factor 5A (eIF5A) is a conserved protein with an essential role in translation elongation. Using one and two-dimensional western blotting, we showed that the eIF5A protein level was 2-fold lower in benznidazole (BZ)-resistant (BZR and 17LER) Trypanosoma cruzi populations than in their respective susceptible counterparts (BZS and 17WTS). To confirm the role of eIF5A in BZ resistance, we transfected BZS and 17WTS with the wild-type eIF5A or mutant eIF5A-S2A (in which serine 2 was replaced by alanine). Upon overexpressing eIF5A, both susceptible lines became approximately 3- and 5-fold more sensitive to BZ. In contrast, the eIF5A-S2A mutant did not alter its susceptibility to BZ. These data suggest that BZ resistance might arise from either decreasing the translation of proteins that require eIF5A, or as a consequence of differential levels of precursors for the hypusination reactions (e.g., spermidine and trypanothione), both of which alter BZ’s effects in the parasite.
    Keywords Trypanosoma cruzi ; drug resistance ; benznidazole ; eukaryotic initiation factor 5A (eIF5A) ; Arctic medicine. Tropical medicine ; RC955-962 ; Microbiology ; QR1-502
    Language English
    Publishing date 2018-07-01T00:00:00Z
    Publisher Instituto Oswaldo Cruz, Ministério da Saúde
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: In vitro activity of 1,3-bisaryloxypropanamines against Trypanosoma cruzi-infected L929 cultures

    Stefânia Neiva Lavorato / Policarpo Ademar Sales Júnior / Silvane Maria Fonseca Murta / Alvaro José Romanha / Ricardo José Alves/

    Memórias do Instituto Oswaldo Cruz., Vol 110, Iss 4, Pp 566-

    2015  Volume 568

    Abstract: We describe herein the antitrypanosomal activity of 20 novel 1,3-bis(aryloxy)propan-2-amine derivatives. Compounds 2, 4, 6, 12, 15, 16 and 19 were significantly active against amastigote and trypomastigote forms, with half maximal inhibitory ... ...

    Abstract We describe herein the antitrypanosomal activity of 20 novel 1,3-bis(aryloxy)propan-2-amine derivatives. Compounds 2, 4, 6, 12, 15, 16 and 19 were significantly active against amastigote and trypomastigote forms, with half maximal inhibitory concentrationvalues in the range of 6-18 µM. In the cytotoxicity tests against L929 cells, only compound 4 presented selectivity index value above 10, indicating low toxicity.
    Keywords Trypanosoma cruzi ; antitrypanosomal agents ; Chagas disease ; 1,3-bisaryloxypropanamines ; Microbiology ; QR1-502 ; Science ; Q ; Arctic medicine. Tropical medicine ; RC955-962 ; Special situations and conditions ; RC952-1245 ; Internal medicine ; RC31-1245 ; Medicine ; R
    Language English
    Publishing date 2015-06-01T00:00:00Z
    Publisher Instituto Oswaldo Cruz, Ministério da Saúde
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: In vitro activity of 1,3-bisaryloxypropanamines against Trypanosoma cruzi-infected L929 cultures

    Stefânia Neiva Lavorato / Policarpo Ademar Sales Júnior / Silvane Maria Fonseca Murta / Alvaro José Romanha / Ricardo José Alves/

    Memórias do Instituto Oswaldo Cruz., Vol 110, Iss 4, Pp 566-

    2015  Volume 568

    Abstract: We describe herein the antitrypanosomal activity of 20 novel 1,3-bis(aryloxy)propan-2-amine derivatives. Compounds 2, 4, 6, 12, 15, 16 and 19 were significantly active against amastigote and trypomastigote forms, with half maximal inhibitory ... ...

    Abstract We describe herein the antitrypanosomal activity of 20 novel 1,3-bis(aryloxy)propan-2-amine derivatives. Compounds 2, 4, 6, 12, 15, 16 and 19 were significantly active against amastigote and trypomastigote forms, with half maximal inhibitory concentrationvalues in the range of 6-18 µM. In the cytotoxicity tests against L929 cells, only compound 4 presented selectivity index value above 10, indicating low toxicity.
    Keywords Trypanosoma cruzi ; antitrypanosomal agents ; Chagas disease ; 1,3-bisaryloxypropanamines ; Microbiology ; QR1-502 ; Science ; Q ; Arctic medicine. Tropical medicine ; RC955-962 ; Special situations and conditions ; RC952-1245 ; Internal medicine ; RC31-1245 ; Medicine ; R
    Language English
    Publishing date 2015-06-01T00:00:00Z
    Publisher Instituto Oswaldo Cruz, Ministério da Saúde
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: In vitro activity of 1,3-bisaryloxypropanamines against Trypanosoma cruzi-infected L929 cultures

    Stefânia Neiva Lavorato / Policarpo Ademar Sales Júnior / Silvane Maria Fonseca Murta / Alvaro José Romanha / Ricardo José Alves/

    Memórias do Instituto Oswaldo Cruz., Vol 110, Iss 4, Pp 566-

    2015  Volume 568

    Abstract: We describe herein the antitrypanosomal activity of 20 novel 1,3-bis(aryloxy)propan-2-amine derivatives. Compounds 2, 4, 6, 12, 15, 16 and 19 were significantly active against amastigote and trypomastigote forms, with half maximal inhibitory ... ...

    Abstract We describe herein the antitrypanosomal activity of 20 novel 1,3-bis(aryloxy)propan-2-amine derivatives. Compounds 2, 4, 6, 12, 15, 16 and 19 were significantly active against amastigote and trypomastigote forms, with half maximal inhibitory concentrationvalues in the range of 6-18 µM. In the cytotoxicity tests against L929 cells, only compound 4 presented selectivity index value above 10, indicating low toxicity.
    Keywords Trypanosoma cruzi ; antitrypanosomal agents ; Chagas disease ; 1,3-bisaryloxypropanamines ; Arctic medicine. Tropical medicine ; RC955-962 ; Microbiology ; QR1-502
    Language English
    Publishing date 2015-06-01T00:00:00Z
    Publisher Instituto Oswaldo Cruz, Ministério da Saúde
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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