5 results on '"Miranda, Mariana"'
Search Results
2. Targeting polyamine transport in Trypanosoma cruzi.
- Author
-
Reigada, Chantal, IVPhanstiel, Otto, Miranda, Mariana R., and Pereira, Claudio A.
- Subjects
- *
POLYAMINES , *TRYPANOSOMA cruzi , *CANCER cell growth , *BIOLOGICAL transport , *COMBINATION drug therapy , *PREVENTION - Abstract
Polyamines play critical roles as regulators of cell growth and differentiation. In contrast with other protozoa, the human parasite Trypanosoma cruzi , the etiological agent of Chagas disease, is auxotrophic for polyamines. Therefore, their intracellular availability depends exclusively on polyamine transport and inhibition of these uptake processes can alter the viability of the parasite. The polyamine analogues used in this work were successfully tested as antiproliferative agents in cancer cells, bacteria, fungi and also showed a potent antiplasmodial effect. We evaluated the activity of these compounds on polyamine transport in T. cruzi and assessed the effects on parasite viability. Three polyamine derivatives, AMXT1501, Ant4 and Ant44, inhibited the putrescine transport in epimastigotes (the insect stage of T. cruzi ) with calculated IC 50 values of 2.43, 5.02 and 3.98 μM, respectively. In addition, only Ant4 and Ant44 inhibited spermidine transport with IC 50 of 8.78 μM and 13.34 μM, respectively. The Ant4 analogue showed a high trypanocidal effect on trypomastigotes (the bloodstream stage of T. cruzi ) with an IC 50 of 460 nM, (SI = 12.7) while in epimastigotes the IC 50 was significantly higher (16.97 μM). In addition, we studied the effect of the combination of benznidazole, a drug used in treating Chagas disease, with Ant4 on the viability of epimastigotes. The combined treatment produced a significant increase on the inhibition of parasites growth compared with individual treatments. In summary, these results suggest that Ant4, a putrescine conjugate, is a promising compound for the treatment of Chagas disease because it showed a potent trypanocidal effect via its inhibition of polyamine import. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
3. Trypanosoma cruzi Polyamine Transporter: Its Role on Parasite Growth and Survival Under Stress Conditions.
- Author
-
Reigada, Chantal, Sayé, Melisa, Vera, Edward, Balcazar, Darío, Fraccaroli, Laura, Carrillo, Carolina, Miranda, Mariana, Pereira, Claudio, Sayé, Melisa, Vera, Edward Valera, Balcazar, Darío, Miranda, Mariana R, and Pereira, Claudio A
- Subjects
- *
POLYAMINES , *TRYPANOSOMA cruzi , *CHAGAS' disease , *CELL growth , *CELL differentiation , *ORNITHINE decarboxylase , *GENETIC overexpression , *THERAPEUTICS , *PROTOZOA physiology , *AMINES , *AMINO acids , *BIOLOGICAL transport , *BIOLOGICAL evolution , *GENE expression , *PROTOZOA , *PHYSIOLOGICAL stress , *TRYPANOSOMIASIS , *OXIDATIVE stress , *SEQUENCE analysis , *MEMBRANE transport proteins - Abstract
Trypanosoma cruzi is the etiological agent of Chagas disease, a major health problem in Latin America. Polyamines are polycationic compounds that play a critical role as regulators of cell growth and differentiation. In contrast with other protozoa, T. cruzi is auxotrophic for polyamines because of its inability to synthesize putrescine due to the lack of both, arginine and ornithine decarboxylase; therefore, the intracellular availability of polyamines depends exclusively on transport processes. In this work, the polyamine transporter TcPAT12 was overexpressed in T. cruzi epimastigotes demonstrating that growth rates at different concentrations of polyamines strongly depend on the regulation of the polyamine transport. In addition, parasites overexpressing TcPAT12 showed a highly increased resistance to hydrogen peroxide and the trypanocidal drugs nifurtimox and benznidazole, which act by oxidative stress and interfering the synthesis of polyamine derivatives, respectively. Finally, the presence of putative polyamine transporters was analyzed in T. cruzi, Trypanosoma brucei, and Leishmania major genomes identifying 3-6 genes in these trypanosomatids. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
4. Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi.
- Author
-
Reigada, Chantal, Valera-Vera, Edward A., Sayé, Melisa, Errasti, Andrea E., Avila, Carla C., Miranda, Mariana R., and Pereira, Claudio A.
- Subjects
- *
TRYPANOSOMA cruzi , *ISOTRETINOIN , *POLYAMINES , *CHAGAS' disease , *AMINO acid transport , *MOLECULAR docking , *DISEASE risk factors - Abstract
Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6–10.3 μM. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective on the epimastigote stage (IC50 = 30.6 μM). The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the treatment of Chagas disease. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
5. Phytomonas: Transport of amino acids, hexoses and polyamines
- Author
-
Canepa, Gaspar E., Carrillo, Carolina, Armesto, Arnaldo R., Bouvier, León A., Miranda, Mariana R., and Pereira, Claudio A.
- Subjects
- *
AMINO acids , *POLYAMINES , *HEXOSE phosphates , *SPERMIDINE - Abstract
Abstract: Phytomonas cells (Phytomonas Jma) isolated from the latex of Jatropha macrantha were assayed for amino acid, hexose and polyamine transport. Results showed high transport rates for glucose and fructose (193 and 128pmolmin−1 10−7 cells, respectively) and lower, but significant rates, for proline, arginine, cysteine and glutamate (between 1.7 and 5.8pmolmin−1 10−7 cells). Minor transport activities were observed for serine, glycine and aspartate (<1pmolmin−1 10−7 cells). Amino acid transport processes do not seem to be regulated by starvation or during the growth phases. Polyamine transport was also evaluated showing a clear preference for spermidine over putrescine (3.4 and 0.4 pmolmin−1 10−7 cells, respectively). This work represents the first report on metabolite transport in phytomonads. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.