32 results on '"Monte-Neto, Rubens L."'
Search Results
2. Sex under pressure: stress facilitates Leishmania in vitro hybridization
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Monte-Neto, Rubens L., Fernandez-Prada, Christopher, and Moretti, Nilmar S.
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- 2022
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3. Unveiling six potent and highly selective antileishmanial agents via the open source compound collection ‘Pathogen Box’ against antimony-sensitive and -resistant Leishmania braziliensis
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Souza Silva, Juliano A., Tunes, Luiza G., Coimbra, Roney S., Ascher, David B., Pires, Douglas E.V., and Monte-Neto, Rubens L.
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- 2021
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4. Susceptibility of Leishmania to novel pentavalent organometallics: Investigating impact on DNA and membrane integrity in antimony(III)‐sensitive and ‐resistant strains.
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Islam, Arshad, do Prado, Bruno Rodrigues, Dittz, Dalton, Rodrigues, Bernardo Lages, Silva, Sydnei Magno da, do Monte‐Neto, Rubens L., Shabeer, Muhammad, Frézard, Frédéric, and Demicheli, Cynthia
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LEISHMANIA ,ANTIMONY ,PERITONEAL macrophages ,APOPTOSIS inhibition ,DNA ,BENZOIC acid - Abstract
The aim the present study was to investigate the impact of novel pentavalent organobismuth and organoantimony complexes on membrane integrity and their interaction with DNA, activity against Sb(III)‐sensitive and ‐resistant Leishmania strains and toxicity in mammalian peritoneal macrophages. Ph3M(L)2 type complexes were synthesized, where M = Sb(V) or Bi(V) and L = deprotonated 3‐(dimethylamino)benzoic acid or 2‐acetylbenzoic acid. Both organobismuth(V) and organoantimony(V) complexes exhibited efficacy at micromolar concentrations against Leishmania amazonensis and L. infantum but only the later ones demonstrated biocompatibility. Ph3Sb(L1)2 and Ph3Bi(L1)2 demonstrated distinct susceptibility profiles compared to inorganic Sb(III)‐resistant strains of MRPA‐overexpressing L. amazonensis and AQP1‐mutated L. guyanensis. These complexes were able to permeate the cell membrane and interact with the Leishmania DNA, suggesting that this effect may contribute to the parasite growth inhibition via apoptosis. Taken altogether, our data substantiate the notion of a distinct mechanism of uptake pathway and action in Leishmania for these organometallic complexes, distinguishing them from the conventional inorganic antimonial drugs. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan
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Rosa-Teijeiro, Chloé, Wagner, Victoria, Corbeil, Audrey, d’Annessa, Ilda, Leprohon, Philippe, do Monte-Neto, Rubens L., and Fernandez-Prada, Christopher
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- 2021
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6. Planarians as models to investigate the bioactivity of gold(I) complexes in vivo
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Tunes, Luiza G., Allen, John M., Zayas, Ricardo M., and do Monte-Neto, Rubens L.
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- 2018
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7. Complexes of different nitrogen donor heterocyclic ligands with SbCl3 and PhSbCl2 as potential antileishmanial agents against SbIII-sensitive and -resistant parasites
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Lizarazo-Jaimes, Edgar H., Reis, Priscila G., Bezerra, Filipe M., Rodrigues, Bernardo L., Monte-Neto, Rubens L., Melo, Maria N., Frézard, Frédéric, and Demicheli, Cynthia
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- 2014
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8. Molecular characterization of the MRPA transporter and antimony uptake in four New World Leishmania spp. susceptible and resistant to antimony
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Moreira, Douglas S., Monte Neto, Rubens L., Andrade, Juvana M., Santi, Ana Maria M., Reis, Priscila G., Frézard, Frédéric, and Murta, Silvane M.F.
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- 2013
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9. Potent naphthoquinones against antimony-sensitive and -resistant Leishmania parasites: Synthesis of novel α- and nor-α-lapachone-based 1,2,3-triazoles by copper-catalyzed azide–alkyne cycloaddition
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Guimarães, Tiago T., Pinto, Maria do Carmo F.R., Lanza, Juliane S., Melo, Maria N., do Monte-Neto, Rubens L., de Melo, Isadora M.M., Diogo, Emilay B.T., Ferreira, Vitor F., Camara, Celso A., Valença, Wagner O., de Oliveira, Ronaldo N., Frézard, Frédéric, and da Silva Júnior, Eufrânio N.
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- 2013
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10. Next-Generation Leishmanization: Revisiting Molecular Targets for Selecting Genetically Engineered Live-Attenuated Leishmania.
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Moreira, Paulo O. L., Nogueira, Paula M., and Monte-Neto, Rubens L.
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LEISHMANIA ,DRUG target ,GENOME editing ,LEISHMANIASIS ,VACCINE effectiveness ,CRISPRS - Abstract
Despite decades of research devoted to finding a vaccine against leishmaniasis, we are still lacking a safe and effective vaccine for humans. Given this scenario, the search for a new prophylaxis alternative for controlling leishmaniasis should be a global priority. Inspired by leishmanization—a first generation vaccine strategy where live L. major parasites are inoculated in the skin to protect against reinfection—live-attenuated Leishmania vaccine candidates are promising alternatives due to their robust elicited protective immune response. In addition, they do not cause disease and could provide long-term protection upon challenge with a virulent strain. The discovery of a precise and easy way to perform CRISPR/Cas-based gene editing allowed the selection of safer null mutant live-attenuated Leishmania parasites obtained by gene disruption. Here, we revisited molecular targets associated with the selection of live-attenuated vaccinal strains, discussing their function, their limiting factors and the ideal candidate for the next generation of genetically engineered live-attenuated Leishmania vaccines to control leishmaniasis. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Leishmania amazonensis from distinct clinical forms/hosts has polymorphisms in Lipophosphoglycans, displays variations in immunomodulatory properties and, susceptibility to antileishmanial drugs.
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Rêgo, Felipe D., Cardoso, Camila d. A., Moreira, Paulo Otávio L., Nogueira, Paula M., Araújo, Márcio S., Borges, Valéria Matos, Laurenti, Márcia D., Bartholomeu, Daniella C., Reis, Alexandre B., Monte‐Neto, Rubens L. d., and Soares, Rodrigo P.
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LEISHMANIASIS ,LEISHMANIA ,TUMOR necrosis factors ,VISCERAL leishmaniasis ,LEISHMANIA infantum ,LEISHMANIA major ,GLYCOCALYX - Abstract
Lipophosphoglycan (LPG), the major Leishmania glycoconjugate, induces pro‐inflammatory/immunosuppressive innate immune responses. Here, we evaluated functional/biochemical LPG properties from six Leishmania amazonensis strains from different hosts/clinical forms. LPGs from three strains (GV02, BA276, and LV79) had higher pro‐inflammatory profiles for most of the mediators, including tumor necrosis factor alpha and interleukin 6. For this reason, glycoconjugates from all strains were biochemically characterized and had polymorphisms in their repeat units. They consisted of three types: type I, repeat units devoid of side chains; type II, containing galactosylated side chains; and type III, containing glucosylated side chains. No relationship was observed between LPG type and the pro‐inflammatory properties. Finally, to evaluate the susceptibility against antileishmanial agents, two strains with high (GV02, BA276) and one with low (BA336) pro‐inflammatory activity were selected for chemotherapeutic tests in THP‐1 cells. All analyzed strains were susceptible to amphotericin B (AmB) but displayed various responses against miltefosine (MIL) and glucantime (GLU). The GV02 strain (canine visceral leishmaniasis) had the highest IC50 for MIL (3.34 μM), whereas diffuse leishmaniasis strains (BA276 and BA336) had a higher IC50 for GLU (6.87–12.19 mM). The highest IC50 against MIL shown by the GV02 strain has an impact on clinical management. Miltefosine is the only drug approved for dog treatment in Brazil. Further studies into drug susceptibility of L. amazonensis strains are warranted, especially in areas where dog infection by this species overlaps with those caused by Leishmania infantum. [ABSTRACT FROM AUTHOR]
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- 2022
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12. Exploring direct and indirect targets of current antileishmanial drugs using a novel thermal proteomics profiling approach.
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Victoria Ibarra-Meneses, Ana, Corbeil, Audrey, Wagner, Victoria, Beaudry, Francis, do Monte-Neto, Rubens L., and Fernandez-Prada, Christopher
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LEISHMANIASIS ,DENATURATION of proteins ,PROTEOMICS ,NEGLECTED diseases ,AMPHOTERICIN B ,VISCERAL leishmaniasis ,DRUG resistance - Abstract
Visceral leishmaniasis (VL), caused by Leishmania infantum, is an oft-fatal neglected tropical disease. In the absence of an effective vaccine, the control of leishmaniasis relies exclusively on chemotherapy. Due to the lack of established molecular/genetic markers denoting parasite resistance, clinical treatment failure is often used as an indicator. Antimony-based drugs have been the standard antileishmanial treatment for more than seven decades, leading to major drug resistance in certain regions. Likewise, drug resistance to miltefosine and amphotericin B continues to spread at alarming rates. In consequence, innovative approaches are needed to accelerate the identification of antimicrobial drug targets and resistance mechanisms. To this end, we have implemented a novel approach based on thermal proteome profiling (TPP) to further characterize the mode of action of antileishmanials antimony, miltefosine and amphotericin B, as well as to better understand the mechanisms of drug resistance deployed by Leishmania. Proteins become more resistant to heat-induced denaturation when complexed with a ligand. In this way, we used multiplexed quantitative mass spectrometry-based proteomics to monitor the melting profile of thousands of expressed soluble proteins in WT, antimony-resistant, miltefosine-resistant, and amphotericin Bresistant L. infantum parasites, in the presence (or absence) of the abovementioned drugs. Bioinformatics analyses were performed, including data normalization, melting profile fitting, and identification of proteins that underwent changes (fold change > 4) caused by complexation with a drug. With this unique approach, we were able to narrow down the regions of the L. infantum proteome that interact with antimony, miltefosine, and amphotericin B; validating previously-identified and unveiling novel drug targets. Moreover, analyses revealed candidate proteins potentially involved in drug resistance. Interestingly, we detected thermal proximity coaggregation for several proteins belonging to the same metabolic pathway (i.e., tryparedoxin peroxidase and aspartate aminotransferase in proteins exposed to antimony), highlighting the importance of these pathways. Collectively, our results could serve as a jumping-off point for the future development of innovative diagnostic tools for the detection and evaluation of antimicrobial-resistant Leishmania populations, as well as open the door for new on-target therapies. [ABSTRACT FROM AUTHOR]
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- 2022
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13. Chapter 5 - Repurposed Molecules: A New Hope in Tackling Neglected Infectious Diseases
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Fernández-Prada, Christopher, Douanne, Noelie, Minguez-Menendez, Aida, Pena, Joan, Tunes, Luiza G., Pires, Douglas E.V., and Monte-Neto, Rubens L.
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- 2019
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14. Optimization and Clinical Validation of Colorimetric Reverse Transcription Loop-Mediated Isothermal Amplification, a Fast, Highly Sensitive and Specific COVID-19 Molecular Diagnostic Tool That Is Robust to Detect SARS-CoV-2 Variants of Concern.
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Alves, Pedro A., de Oliveira, Ellen G., Franco-Luiz, Ana Paula M., Almeida, Letícia T., Gonçalves, Amanda B., Borges, Iara A., Rocha, Flávia de S., Rocha, Raissa P., Bezerra, Matheus F., Miranda, Pâmella, Capanema, Flávio D., Martins, Henrique R., Weber, Gerald, Teixeira, Santuza M. R., Wallau, Gabriel Luz, and do Monte-Neto, Rubens L.
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COVID-19 ,SARS-CoV-2 ,COVID-19 testing ,HIGH throughput screening (Drug development) ,POLYMERASE chain reaction - Abstract
The coronavirus disease 2019 (COVID-19) pandemic unfolded due to the widespread severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission reinforced the urgent need for affordable molecular diagnostic alternative methods for massive testing screening. We present the clinical validation of a pH-dependent colorimetric reverse transcription loop-mediated isothermal amplification (RT-LAMP) for SARS-CoV-2 detection. The method revealed a limit of detection of 19.3 ± 2.7 viral genomic copies/μL when using RNA extracted samples obtained from nasopharyngeal swabs collected in guanidine-containing viral transport medium. Typical RT-LAMP reactions were performed at 65°C for 30 min. When compared to reverse transcriptase–quantitative polymerase chain reaction (RT-qPCR), up to cycle-threshold (Ct) value 32, RT-LAMP presented 98% [95% confidence interval (CI) = 95.3–99.5%] sensitivity and 100% (95% CI = 94.5–100%) specificity for SARS-CoV-2 RNA detection targeting E and N genes. No cross-reactivity was detected when testing other non–SARS-CoV virus, confirming high specificity. The test is compatible with primary RNA extraction–free samples. We also demonstrated that colorimetric RT-LAMP can detect SARS-CoV-2 variants of concern and variants of interest, such as variants occurring in Brazil named gamma (P.1), zeta (P.2), delta (B.1.617.2), B.1.1.374, and B.1.1.371. The method meets point-of-care requirements and can be deployed in the field for high-throughput COVID-19 testing campaigns, especially in countries where COVID-19 testing efforts are far from ideal to tackle the pandemics. Although RT-qPCR is considered the gold standard for SARS-CoV-2 RNA detection, it requires expensive equipment, infrastructure, and highly trained personnel. In contrast, RT-LAMP emerges as an affordable, inexpensive, and simple alternative for SARS-CoV-2 molecular detection that can be applied to massive COVID-19 testing campaigns and save lives. [ABSTRACT FROM AUTHOR]
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- 2021
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15. Recent research brings hope for reshaping the co‐evolutionary arms race against parasitic infectious diseases.
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Monte‐Neto, Rubens L., Fernandez‐Prada, Christopher, and Moretti, Nilmar S.
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PARASITIC diseases , *LEISHMANIASIS , *COMMUNICABLE diseases , *ARMS race , *CHAGAS' disease , *COEVOLUTION - Abstract
To further increase complexity, depending on the etiological species and on the host immune system, parasitic diseases can manifest in a very wide spectrum of diseases; this makes it almost impossible to create a single silver bullet to kill these pathogens (even those from related evolutionary groups). Also discussed include the potential implications of parasite dormancy in drug resistance and treatment success, as well as the lack of biomarkers for monitoring disease progression in patients undergoing treatment. Parasites have evolved to adapt to their hosts, preventing their death as a direct consequence of the infectious process - this is the basis for the development and perpetuation of symbiotic parasitism. [Extracted from the article]
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- 2022
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16. Anticancer and antileishmanial in vitro activity of gold(I) complexes with 1,3,4‐oxadiazole‐2(3H)‐thione ligands derived from δ‐D‐gluconolactone.
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Espinosa, Andrés Villaseñor, Costa, Danilo de Souza, Tunes, Luiza Guimarães, Monte‐Neto, Rubens L. do, Grazul, Richard Michael, Almeida, Mauro Vieira, and Silva, Heveline
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LIGANDS (Biochemistry) ,LIPOPHILICITY ,GOLD ,CANCER chemotherapy ,CELL lines ,ANTINEOPLASTIC agents - Abstract
Four gold(I) complexes conceived as anticancer agents were synthesized by reacting [Au(PEt3)Cl] and [Au(PPh3)Cl] with ligands derived from δ‐d‐gluconolactone. The ligands' structure was designed to combine desired biological properties previously reported for each group. Ligands were synthesized from δ‐d‐gluconolactone via ketal protection and hydrazide formation followed by cyclization with CS2 to produce the novel oxadiazolidine‐2‐thione 7 and 8. Increasing of the ligands' lipophilicity via ketal protection proved useful since all four gold(I) complexes showed anticancer and antileishmanial properties. The IC50 values are at low micromolar range, varying from 2 to 3 μm for the most active compounds. The free D‐gluconate 1,3,4 oxadiazole‐derived ligands were neither toxic nor presented anticancer or antileishmanial properties. Triethylphosphine‐derived compounds 9 and 10 were more selective against B16‐F10 melanoma cell line. Although similar in vitro antileishmanial activity was observed for the gold(I) precursors themselves and their derived complexes, the latter were three times less toxic for human THP‐1 macrophage cell line; this result is attributed to an isomeric variation of the D‐gluconate ligand and the oxadiazole portion, which was one of the key concepts behind this work. These findings should encourage further research on gold(I) complexes to develop novel compounds with potential application in cancer and leishmaniasis chemotherapy. [ABSTRACT FROM AUTHOR]
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- 2021
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17. Preclinical Gold Complexes as Oral Drug Candidates to Treat Leishmaniasis Are Potent Trypanothione Reductase Inhibitors.
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Tunes, Luiza G., Morato, Roberta E., Garcia, Adriana, Schmitz, Vinicius, Steindel, Mario, Corrêa-Junior, José D., Dos Santos, Hélio F., Frézard, Frédéric, de Almeida, Mauro V., Silva, Heveline, Moretti, Nilmar S., de Barros, André L. B., and do Monte-Neto, Rubens L.
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- 2020
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18. Contributors
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Akhoon, Bashir Akhlaq, Alarcón-Riquelme, Marta E., Alberca, Lucas N., Alice, Juan I., Anuwongcharoen, Nuttapat, Arga, Kazim Yalcin, Belllera, Carolina L., Berishvili, Vladimir P., Bhardwaj, Anshu, Bodiga, Vijaya Lakshmi, Bodiga, Sreedhar, Brylinski, Michal, Carmona-Sáez, Pedro, Chakraborti, Sohini, Chaudhry, Vaishali, Chen, Lixia, Coumar, Mohane Selvaraj, Toro-Domínguez, Daniel, Dietis, Nikolas, Douanne, Noelie, Druzhilovskiy, Dmitry, Eurídice Juárez-Mercado, K., Fernández-Prada, Christopher, Gautam, Pankaj, Ghosh, Indira, Mohan, C. Gopi, Haider, Shozeb, Hua, Li, Iqbal, Jameel, James, Nivya, Jolly, Bani, Kharkar, Prashant S., Kim, Se-Min, Kumar, Shivani, Kumar, Suresh, Kumar, Pawan, Kurgan, Lukasz, Lo, Yu-Chen, López-López, Edgar, Machhar, Janvhi S., Manzoor, K., Medina-Franco, José L., Melge, Anu R., Minadakis, George, Minguez-Menendez, Aida, Mitreva, Makedonka, Monte-Neto, Rubens L., Muneeswaran, Gurusamy, Nagamani, Selvaraman, Nair, Shantikumar V., Nantasenamat, Chanin, Sastry, G. Narahari, Nargotra, Amit, Nikitina, Anastasia A., Orlov, Alexey A., Osolodkin, Dmitry I., Oulas, Anastasis, Pal, Manoj Kumar, Palyulin, Vladimir A., Pandya, Ashma, Passi, Anurag, Pena, Joan, Phanus-umporn, Chuleeporn, Pires, Douglas E.V., Poroikov, Vladimir, Prieto-Martínez, Fernando D., Radchenko, Eugene V., Ramakrishnan, Gayatri, Ramanathan, K., Rosa, Bruce A., Sahoo, Rosaleen, Sahu, Niteshkumar U., Sarica, Pemra Ozbek, Sarvagalla, Sailu, Savva, Kyriaki, Sbaraglini, María L., Schaduangrat, Nalini, Serçinoğlu, Onur, Shah, Chetan P., Shanthi, V., Sharma, Tina, Sokratous, Kleitos, Spyrou, George M., Srinivasan, Narayanaswamy, Sriwanichpoom, Nagaya, Sun, Li, Syed, Safiulla Basha, Talevi, Alan, Tiwari, Harshita, Torres, Jorge Z., Tunes, Luiza G., Turanli, Beste, Tyagi, Rahul, Wang, Chen, Wikberg, Jarl E.S., Xia, Xuhua, Yuen, Tony, Zachariou, Margarita, Zaidi, Neeha, Zaidi, Samir, Zaidi, Mone, Zallone, Alberta, and Zheng, Mengzhu
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- 2019
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19. Improved pharmacological profile of the lipophilic antitumor dichloro-(N-dodecyl)-propanediamine-platinum(II) complex after incorporation into pegylated liposomes.
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Silva, Heveline, Silva, Ana Candida A., Lemos, Fernanda O., Monte-Neto, Rubens L., Fontes, Ana Paula S., Lopes, Miriam T.P., and Frézard, Frédéric
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- 2013
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20. Improved Antileishmanial Activity of Dppz through Complexation with Antimony(III) and Bismuth(III): Investigation of the Role of the Metal.
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Lizarazo-Jaimes, Edgar H., Monte-Neto, Rubens L., Reis, Priscila G., Fernandes, Nelson G., Speziali, Nivaldo L., Melo, Maria N., Frézard, Frédéric, and Demicheli, Cynthia
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ANTIMONY , *BISMUTH , *HETEROCYCLIC compounds , *CRYSTAL structure , *X-ray crystallography , *PROMASTIGOTE - Abstract
Two novel trivalent antimony(III) and bismuth(III) complexes with the nitrogen-donor heterocyclic ligand dipyrido[3,2-a:2',3'-c]phenazine (dppz) were synthesized and characterized as [Sb(dppz)Cl3].H2O.CH3OH and [Bi(dppz)Cl3]. The crystal structure of Sb(III) complex was determined by X-ray crystallography. These complexes were evaluated for their activity against the promastigote form of Sb(III)-sensitive and -resistant Leishmania infantum chagasi and Leishmania amazonensis strains. Both complexes were more effective than dppz alone in inhibiting the growth of Leishmania promastigotes and were at least 77 and 2,400 times more active than potassium antimonyl tartrate in Sb(III)-sensitive and -resistant Leishmania, respectively. The cytotoxicity of dppz and its complexes against mouse peritoneal macrophages occurred at dppz concentrations at least 6-fold greater than those found to be active against Leishmania promastigotes.To investigate the role of the metal in the improved antileishmanial activity of dppz, the activity of the Sb(III) complex was compared between the Sb-resistant mutants and their respective parental sensitive strains. The lack of cross-resistance to the Sb(III)-dppz complex together with the much lower activity of antimonyl tartrate, SbCl3 and BiCl3 strongly support the model that the metal is not active by itself but improves the activity of dppz through complexation [ABSTRACT FROM AUTHOR]
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- 2012
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21. Gene Expression Profiling and Molecular Characterization of Antimony Resistance in Leishmania amazonensis.
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do Monte-Neto, Rubens L., Coelho, Adriano C., Raymond, Frédéric, Légaré, Danielle, Corbeil, Jacques, Melo, Maria N., Frézard, Frédéric, and Ouellette, Marc
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GENE expression , *GENE expression profiling , *ANTIMONY , *GENETIC overexpression , *DNA microarrays , *LEISHMANIA mexicana - Abstract
Background: Drug resistance is a major problem in leishmaniasis chemotherapy. RNA expression profiling using DNA microarrays is a suitable approach to study simultaneous events leading to a drug-resistance phenotype. Genomic analysis has been performed primarily with Old World Leishmania species and here we investigate molecular alterations in antimony resistance in the New World species L. amazonensis. Methods/Principal Findings: We selected populations of L. amazonensis promastigotes for resistance to antimony by step-wise drug pressure. Gene expression of highly resistant mutants was studied using DNA microarrays. RNA expression profiling of antimony-resistant L. amazonensis revealed the overexpression of genes involved in drug resistance including the ABC transporter MRPA and several genes related to thiol metabolism. The MRPA overexpression was validated by quantitative real-time RT-PCR and further analysis revealed that this increased expression was correlated to gene amplification as part of extrachromosomal linear amplicons in some mutants and as part of supernumerary chromosomes in other mutants. The expression of several other genes encoding hypothetical proteins but also nucleobase and glucose transporter encoding genes were found to be modulated. Conclusions/Significance: Mechanisms classically found in Old World antimony resistant Leishmania were also highlighted in New World antimony-resistant L. amazonensis. These studies were useful to the identification of resistance molecular markers. Author Summary: Leishmania are unicellular microorganisms that can be transmitted to humans by the bite of sandflies. They cause a spectrum of diseases called leishmaniasis, which are classified as neglected tropical diseases by the World Health Organization. The treatment of leishmaniasis is based on the administration of antimony-containing drugs. These drugs have been used since 1947 and still constitute the mainstay for leishmaniasis treatment in several countries. One of the problems with these compounds is the emergence of resistance. Our work seeks to understand how these parasites become resistant to the drug. We studied antimony-resistant Leishmania amazonensis mutants. We analyzed gene expression at the whole genome level in antimony-resistant parasites and identified mechanisms used by Leishmania for resistance. This work could help us in developing new strategies for treatment in endemic countries where people are unresponsive to antimony-based chemotherapy. The identification of common mechanisms among different species of resistant parasites may also contribute to the development of diagnostic kits to identify and monitor the spread of resistance. [ABSTRACT FROM AUTHOR]
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- 2011
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22. Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery.
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Bhattacharya, Arijit, Corbeil, Audrey, do Monte-Neto, Rubens L., and Fernandez-Prada, Christopher
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CHAGAS' disease ,LEISHMANIA ,TRYPANOSOMA cruzi ,TRYPANOSOMA brucei ,DOSAGE forms of drugs ,DRUG resistance ,DRUGS ,LEISHMANIASIS - Abstract
Leishmaniasis (Leishmania species), sleeping sickness (Trypanosoma brucei), and Chagas disease (Trypanosoma cruzi) are devastating and globally spread diseases caused by trypanosomatid parasites. At present, drugs for treating trypanosomatid diseases are far from ideal due to host toxicity, elevated cost, limited access, and increasing rates of drug resistance. Technological advances in parasitology, chemistry, and genomics have unlocked new possibilities for novel drug concepts and compound screening technologies that were previously inaccessible. In this perspective, we discuss current models used in drug-discovery cascades targeting trypanosomatids (from in vitro to in vivo approaches), their use and limitations in a biological context, as well as different examples of recently discovered lead compounds. [ABSTRACT FROM AUTHOR]
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- 2020
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23. Intraspecies susceptibility of Leishmania (Viannia) braziliensis to antileishmanial drugs: Antimony resistance in human isolates from atypical lesions.
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Rugani, Jeronimo N., Quaresma, Patrícia F., Gontijo, Célia F., Soares, Rodrigo P., and Monte-Neto, Rubens L.
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LEISHMANIA , *ANTIPROTOZOAL agents , *ANTIMONY , *LEISHMANIASIS , *CUTANEOUS manifestations of general diseases , *GENETIC markers - Abstract
Graphical abstract Highlights • Atypical lesion-derived L. braziliensis are resistant to antimony. • L. braziliensis isolated from atypical cutaneous manifestations presented reduced infection rate in vitro. • Molecular markers from atypical lesion-derived L. braziliensis can beestablished to predict antimony resistance. Abstract Leishmania (Viannia) braziliensis is the most common etiological agent of cutaneous and mucocutaneous leishmaniasis (MCL) in Latin America. An interesting aspect of the disease outcome caused by this species is the appearance of non-ulcerated atypical cutaneous leishmaniasis. Atypical (AT) lesions are often associated with therapeutic failure when treated with antimony(Sb)-based drugs. Refractory cases are not necessarily due to intrinsic parasite drug resistance. The status of in vitro drug susceptibility from L. braziliensis field isolates is less assessed than patient treatment outcome. In this work, L. braziliensis isolated from typical CL (6), MCL (1) and AT (3) lesions and vector (1) were tested for their susceptibility to amphotericin B (AmB), miltefosine (MIL), glucantime (GLU) and non-comercial meglumine antimoniate (MA). Overall, intracellular amastigotes of all isolates were sensitive to the tested antileishmanial drugs except AT lesions-derived strains 316, 330 and 340 that presented in vitro resistance against SbV-based drugs. Although susceptible to miltefosine – based on phenotypic screening – intramacrophagic quiescent amastigotes could restore infection. L. braziliensis promastigotes isolated from AT lesions also displayed 29% reduced capacity to infect human monocyte-derived macrophages when compared with parasites obtained from patients with typical lesions, MCL or from sand-fly. These data indicate differences in drug susceptibility and infectiveness among L. braziliensis isolated from patients exhibiting different types of lesions and highlight the importance of its characterization for drug response prediction outcome in clinical practice. [ABSTRACT FROM AUTHOR]
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- 2018
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24. Complexes of different nitrogen donor heterocyclic ligands with SbCl3 and PhSbCl2 as potential antileishmanial agents against SbIII-sensitive and -resistant parasites.
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Lizarazo-Jaimes, Edgar H., Reis, Priscila G., Bezerra, Filipe M., Rodrigues, Bernardo L., Monte-Neto, Rubens L., Melo, Maria N., Frézard, Frédéric, and Demicheli, Cynthia
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HETEROCYCLIC chemistry , *LIGANDS (Biochemistry) , *ANTI-infective agents , *LEISHMANIA , *DRUG resistance , *THERAPEUTIC use of antimony , *THERAPEUTICS , *PROTOZOA - Abstract
Abstract: Novel trivalent antimony complexes with the nitrogen donor heterocyclic ligand 2,2′-bipyridine (bipy), 1,10-phenanthroline (phen) or dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq) have been synthesized by the reaction with SbCl3 or PhSbCl2. The crystal structures of [Sb(phen)Cl3] and [PhSb(phen)Cl2]CH3COOH were determined and shown to adopt a distorted square pyramid geometry with a five-coordinated Sb center. Surprisingly, all the complexes, the ligands and PhSbCl2 showed very high antileishmanial activities, with IC50 in the nanomolar range against SbIII-sensitive and -resistant Leishmania infantum (syn. Leishmania chagasi) and Leishmania amazonensis strains. These compounds were much more active against these Leishmania strains than the old trivalent drug potassium antimonyl tartrate. [PhSb(phen)Cl2]CH3COOH complex was found to be the most active compound and the lack of cross-resistance of PhSbCl2 suggests that the transport pathways of this compound across the cell membrane differ from those responsible for the resistance of Leishmania to Sb(OH)3. In the case of the complexes with PhSbCl2, our data supports the model that both ligand and metal contributed to the overall activity of the complex. Furthermore, among the complexes with SbCl3, only bipy showed an improved activity upon complexation. Cytotoxicity evaluations of these compounds against murine peritoneal macrophages showed high selective indexes in the range of 7–70 for [Sb(phen)Cl3], [Sb(bipy)Cl3] and [Sb(dpq)Cl3] complexes, being much more selective than potassium antimonyl tartrate. In conclusion, this study presents a set of new antileishmanial agents including one of the most active Sb-based compounds ever reported, which can contribute to the development of new chemotherapeutic strategies against leishmaniasis including Sb-resistant cases. [Copyright &y& Elsevier]
- Published
- 2014
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25. The mutation G133D on Leishmania guyanensis AQP1 is highly destabilizing as revealed by molecular modeling and hypo-osmotic shock assay.
- Author
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Tunes, Luiza G., Ascher, David B., Pires, Douglas E.V., and Monte-Neto, Rubens L.
- Subjects
- *
MOLECULAR models , *LEISHMANIA , *SMALL molecules , *QUATERNARY structure , *PROTEIN stability - Abstract
The Leishmania aquaglyceroporin 1 (AQP1) plays an important role in osmoregulation and antimony (Sb) uptake, being determinant for resistance to antimony. We have previously demonstrated that G133D mutation on L. guyanensis AQP1 (LgAQP1) leads to reduced Sb uptake. Here, we investigated the effects of G133D mutation on LgAQP1 structure, associated with Sb uptake and alterations in osmoregulation capacity. High confidence molecular models of wild-type LgAQP1 as well as the LgAQP1::G133D mutant were constructed and optimized via comparative homology modeling. Computational methods from the mCSM platform were used to evaluate the effects on protein stability and on its ability to bind to glycerol. Functional validation of the disruptive effect of the mutation on LgAQP1 was done by challenging the parasites with hypo-osmotic chock. Glycine 133 is on transmembrane helix 3, buried in the membrane in both open and closed conformation. G133D mutation was predicted to be highly destabilizing, as it alters the helical bundling arrangement in order to accommodate the aspartic acid side chain. The shift in helices also resulted in fewer favorable contacts with glycerol in the channel, which would explain the reduced affinity for similar small molecules as SbO 3. Under hypo-osmotic condition, L. g uyanensis AQP1G133D presented a 3-fold increase in cellular volume and pronounced delay to recover osmosis homeostasis when compared to the wild-type, a profile that was enhanced in LgAQP1−/− mutants. In conclusion, G133D is a highly disruptive mutation that will destabilize the monomer, compromise tetramer formation and alter pore conformation, leading to reduced Sb uptake and deficient osmoregulation. [Display omitted] • G133D mutation in L. guyanensis AQP1 transmembrane portion is highly destabilizing. • L. guyanensis AQP1 G133D may alter pore forming quaternary structure. • Lg AQP1 G133D alters osmotic control as revealed by hypo-osmotic challenge. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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26. Critical loss: the effects of VEuPathDB defunding on global health.
- Author
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Fernandez-Prada C, Moretti NS, and do Monte-Neto RL
- Abstract
Competing Interests: We declare no competing interests. There was no funding source for this study. CFP, NSM, and RLMN contributed equally to this work.
- Published
- 2024
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27. Exploring direct and indirect targets of current antileishmanial drugs using a novel thermal proteomics profiling approach.
- Author
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Ibarra-Meneses AV, Corbeil A, Wagner V, Beaudry F, do Monte-Neto RL, and Fernandez-Prada C
- Subjects
- Amphotericin B pharmacology, Antimony metabolism, Antimony pharmacology, Proteome analysis, Proteomics, Antiprotozoal Agents metabolism, Antiprotozoal Agents pharmacology, Leishmania infantum
- Abstract
Visceral leishmaniasis (VL), caused by Leishmania infantum , is an oft-fatal neglected tropical disease. In the absence of an effective vaccine, the control of leishmaniasis relies exclusively on chemotherapy. Due to the lack of established molecular/genetic markers denoting parasite resistance, clinical treatment failure is often used as an indicator. Antimony-based drugs have been the standard antileishmanial treatment for more than seven decades, leading to major drug resistance in certain regions. Likewise, drug resistance to miltefosine and amphotericin B continues to spread at alarming rates. In consequence, innovative approaches are needed to accelerate the identification of antimicrobial drug targets and resistance mechanisms. To this end, we have implemented a novel approach based on thermal proteome profiling (TPP) to further characterize the mode of action of antileishmanials antimony, miltefosine and amphotericin B, as well as to better understand the mechanisms of drug resistance deployed by Leishmania . Proteins become more resistant to heat-induced denaturation when complexed with a ligand. In this way, we used multiplexed quantitative mass spectrometry-based proteomics to monitor the melting profile of thousands of expressed soluble proteins in WT, antimony-resistant, miltefosine-resistant, and amphotericin B-resistant L. infantum parasites, in the presence (or absence) of the above-mentioned drugs. Bioinformatics analyses were performed, including data normalization, melting profile fitting, and identification of proteins that underwent changes (fold change > 4) caused by complexation with a drug. With this unique approach, we were able to narrow down the regions of the L. infantum proteome that interact with antimony, miltefosine, and amphotericin B; validating previously-identified and unveiling novel drug targets. Moreover, analyses revealed candidate proteins potentially involved in drug resistance. Interestingly, we detected thermal proximity coaggregation for several proteins belonging to the same metabolic pathway (i.e., tryparedoxin peroxidase and aspartate aminotransferase in proteins exposed to antimony), highlighting the importance of these pathways. Collectively, our results could serve as a jumping-off point for the future development of innovative diagnostic tools for the detection and evaluation of antimicrobial-resistant Leishmania populations, as well as open the door for new on-target therapies., Competing Interests: The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ibarra-Meneses, Corbeil, Wagner, Beaudry, do Monte-Neto and Fernandez-Prada.)
- Published
- 2022
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28. Network-Based Approaches Reveal Potential Therapeutic Targets for Host-Directed Antileishmanial Therapy Driving Drug Repurposing.
- Author
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Martinez-Hernandez JE, Hammoud Z, de Sousa AM, Kramer F, Monte-Neto RLD, Maracaja-Coutinho V, and Martin AJM
- Subjects
- Gene Expression Profiling, Humans, Leishmania major immunology, Macrophages immunology, Macrophages parasitology, Transcriptome genetics, Antiprotozoal Agents pharmacology, Drug Repositioning methods, Leishmania major drug effects, Leishmaniasis drug therapy, Metabolic Networks and Pathways drug effects
- Abstract
Leishmania parasites are the causal agent of leishmaniasis, an endemic disease in more than 90 countries worldwide. Over the years, traditional approaches focused on the parasite when developing treatments against leishmaniasis. Despite numerous attempts, there is not yet a universal treatment, and those available have allowed for the appearance of resistance. Here, we propose and follow a host-directed approach that aims to overcome the current lack of treatment. Our approach identifies potential therapeutic targets in the host cell and proposes known drug interactions aiming to improve the immune response and to block the host machinery necessary for the survival of the parasite. We started analyzing transcription factor regulatory networks of macrophages infected with Leishmania major. Next, based on the regulatory dynamics of the infection and available gene expression profiles, we selected potential therapeutic target proteins. The function of these proteins was then analyzed following a multilayered network scheme in which we combined information on metabolic pathways with known drugs that have a direct connection with the activity carried out by these proteins. Using our approach, we were able to identify five host protein-coding gene products that are potential therapeutic targets for treating leishmaniasis. Moreover, from the 11 drugs known to interact with the function performed by these proteins, 3 have already been tested against this parasite, verifying in this way our novel methodology. More importantly, the remaining eight drugs previously employed to treat other diseases, remain as promising yet-untested antileishmanial therapies. IMPORTANCE This work opens a new path to fight parasites by targeting host molecular functions by repurposing available and approved drugs. We created a novel approach to identify key proteins involved in any biological process by combining gene regulatory networks and expression profiles. Once proteins have been selected, our approach employs a multilayered network methodology that relates proteins to functions to drugs that alter these functions. By applying our novel approach to macrophages during the Leishmania infection process, we both validated our work and found eight drugs already approved for use in humans that to the best of our knowledge were never employed to treat leishmaniasis, rendering our work as a new tool in the box available to the scientific community fighting parasites.
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- 2021
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29. Biophysical and Pharmacological Characterization of Energy-Dependent Efflux of Sb in Laboratory-Selected Resistant Strains of Leishmania ( Viannia ) Subgenus.
- Author
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Dos Reis PG, do Monte-Neto RL, Melo MN, and Frézard F
- Abstract
The growing resistance of leishmaniasis to first-line drugs like antimonials in some regions limits the control of this parasitic disease. The precise mechanisms involved in Leishmania antimony resistance are still subject to debate. The reduction of intracellular Sb
III accumulation is a common change observed in both laboratory-selected and field isolated resistant Leishmania strains, but the exact transport pathways involved in antimony resistance have not yet been elucidated. In order to functionally characterize the antimony transport routes responsible for resistance, we performed systematic transport studies of SbIII in wild-type and resistant strains of L . ( Viannia ) guyanensis and L . ( V.) braziliensis . Those include influx and efflux assays and the influence of ABC transporters and metabolism inhibitors: prochlorperazine, probenecid, verapamil, BSO, and sodium azide. The mRNA levels of genes associated with antimony resistance ( MRPA, GSH1, ODC, AQP1, ABCI4 , and ARM58 ) were also investigated in addition to intracellular thiol levels. A strong reduction of Sb influx was observed in L. guyanensis resistant mutant (LgSbR), but not in L. braziliensis (LbSbR). Both mutants showed increased energy-dependent efflux of SbIII , when compared to their respective parental strains. In LgSbR, BSO and prochlorperazine inhibited antimony efflux and resistance was associated with increased MRPA and GSH1 mRNA levels, while in LbSbR antimony efflux was inhibited by probenicid and prochlorperazine in absence of resistance-associated gene modulation. Intracellular thiol levels were increased in both Sb-resistant mutants. An energy-dependent SbIII efflux pathway sensitive to prochlorperazine was clearly evidenced in both Sb-resistant mutants. In conclusion, the present study allowed the biophysical and pharmacological characterization of energy-dependent Sb efflux pathway apparently independent of MRPA, ABCI4, and ARM58 upregulation, in Leishmania (Vianna) mutant selected in vitro for resistance to SbIII . Prochlorperazine has also been identified as an effective chemosensitizer in both Sb resistant mutants, which acts through inhibition of the active efflux of Sb.- Published
- 2017
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30. Silver and Nitrate Oppositely Modulate Antimony Susceptibility through Aquaglyceroporin 1 in Leishmania (Viannia) Species.
- Author
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Andrade JM, Baba EH, Machado-de-Avila RA, Chavez-Olortegui C, Demicheli CP, Frézard F, Monte-Neto RL, and Murta SM
- Subjects
- Leishmania genetics, Leishmania metabolism, Leishmania braziliensis drug effects, Leishmania braziliensis genetics, Leishmania braziliensis metabolism, Parasitic Sensitivity Tests, Protozoan Proteins genetics, Protozoan Proteins metabolism, Antimony pharmacology, Antiprotozoal Agents pharmacology, Leishmania drug effects, Nitrates pharmacology, Silver pharmacology
- Abstract
Antimony (Sb) resistance in leishmaniasis chemotherapy has become one of the major challenges to the control of this spreading worldwide public health problem. Since the plasma membrane pore-forming protein aquaglyceroporin 1 (AQP1) is the major route of Sb uptake in Leishmania, functional studies are relevant to characterize drug transport pathways in the parasite. We generated AQP1-overexpressing Leishmania guyanensis and L. braziliensis mutants and investigated their susceptibility to the trivalent form of Sb (Sb(III)) in the presence of silver and nitrate salts. Both AQP1-overexpressing lines presented 3- to 4-fold increased AQP1 expression levels compared with those of their untransfected counterparts, leading to an increased Sb(III) susceptibility of about 2-fold. Competition assays using silver nitrate, silver sulfadiazine, or silver acetate prior to Sb(III) exposure increased parasite growth, especially in AQP1-overexpressing mutants. Surprisingly, Sb(III)-sodium nitrate or Sb(III)-potassium nitrate combinations showed significantly enhanced antileishmanial activities compared to those of Sb(III) alone, especially against AQP1-overexpressing mutants, suggesting a putative nitrate-dependent modulation of AQP1 activity. The intracellular level of antimony quantified by graphite furnace atomic absorption spectrometry showed that the concomitant exposure to Sb(III) and nitrate favors antimony accumulation in the parasite, increasing the toxicity of the drug and culminating with parasite death. This is the first report showing evidence of AQP1-mediated Sb(III) susceptibility modulation by silver in Leishmania and suggests the potential antileishmanial activity of the combination of nitrate salts and Sb(III)., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2016
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31. Morphological and physiological changes in Leishmania promastigotes induced by yangambin, a lignan obtained from Ocotea duckei.
- Author
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Monte Neto RL, Sousa LM, Dias CS, Barbosa Filho JM, Oliveira MR, and Figueiredo RC
- Subjects
- Acridine Orange, Animals, Dogs, Fluorescent Dyes, Furans chemistry, Image Processing, Computer-Assisted, Leishmania infantum physiology, Leishmania infantum ultrastructure, Leishmania mexicana physiology, Leishmania mexicana ultrastructure, Lignans chemistry, Microscopy, Confocal, Microscopy, Electron, Transmission, Plant Extracts chemistry, Plant Extracts pharmacology, Furans pharmacology, Leishmania infantum drug effects, Leishmania mexicana drug effects, Lignans pharmacology, Ocotea chemistry
- Abstract
We have previously demonstrated that yangambin, a lignan obtained from Ocotea duckei Vattimo (Lauraceae), shows antileishmanial activity against promastigote forms of Leishmania chagasi and Leishmania amazonensis. The aim of this study was to determine the in vitro effects of yangambin against these parasites using electron and confocal microscopy. L. chagasi and L. amazonensis promastigotes were incubated respectively with 50 μg/mL and 65 μg/mL of pure yangambin and stained with acridine orange. Treated-parasites showed significant alterations in fluorescence emission pattern and cell morphology when compared with control cells, including the appearance of abnormal round-shaped cells, loss of cell motility, nuclear pyknosis, cytoplasm acidification and increased number of acidic vesicular organelles (AVOs), suggesting important physiological changes. Ultrastructural analysis of treated-promatigotes showed characteristics of cell death by apoptosis as well as by autophagy. The presence of parasites exhibiting multiples nuclei suggests that yangambin may also affect the microtubule dynamic in both Leishmania species. Taken together our results show that yangambin is a promising agent against Leishmania., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2011
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32. Yangambin cytotoxicity: a pharmacologically active lignan obtained from Ocotea duckei vattimo (Lauraceae).
- Author
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Monte Neto RL, Sousa LM, Dias CS, Filho JM, and Oliveira MR
- Subjects
- Animals, Cell Survival drug effects, Embryo, Nonmammalian drug effects, Ethanol, Furans isolation & purification, Lignans isolation & purification, Macrophages, Peritoneal cytology, Mice, Models, Molecular, Plant Extracts chemistry, Plant Leaves chemistry, Sea Urchins drug effects, Sea Urchins embryology, Furans toxicity, Lignans toxicity, Macrophages, Peritoneal drug effects, Ocotea chemistry, Plant Extracts toxicity
- Abstract
The in vitro cytotoxic potential of yangambin was evaluated. Yangambin is a pharmacologically active furofuran lignan obtained from the leaves of Ocotea duckei. It is the major compound from the lignoids fraction. Yangambin presented low cytotoxicity in all in vitro models analyzed. Its cytotoxicity to murine macrophages was measured by the Trypan blue dye exclusion test and MTT reduction assay, resulting in high CC50 values of 187.0 microg/mL (383.3 microM) and 246.7 microg/mL (504.3 microM), respectively. The difference obtained in the inhibitory concentrations aforementioned can be explained, at least in part, by the different principles of the methods. While the MTT reduction assay evaluates the ability of yangambin to inhibit the activity of the mitochondrial enzyme succinate dehydrogenase, the Trypan blue dye exclusion test evaluates possible damages to the integrity of the cytoplasmic membrane which result in cell death. The capacity of yangambin to inhibit the sea urchin embryonic development showed that it has low antimitotic and teratogenic potential, once continued exposure of embryos to concentrations up to 500 microg/mL (1.025 microM) did not result in an inhibitory effect on the first egg cleavages. Such low in vitro cytotoxicity is correlated with the low acute toxicity previously studied. All these data, together with the various therapeutic properties of yangambin, make this lignan a promising one for a new drug.
- Published
- 2008
- Full Text
- View/download PDF
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