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Treatment with specific and pan-plasma membrane calcium ATPase (PMCA) inhibitors reduces malaria parasite growth in vitro and in vivo

BACKGROUND: Rapid emergence of Plasmodium resistance to anti-malarial drug mainstays has driven a continual effort to discover novel drugs that target different biochemical pathway (s) during infection. Plasma membrane Calcium + 2 ATPase (PMCA4), a novel plasma membrane protein that regulates Calciu...

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Autores principales: Asih, Puji B. S., Siregar, Josephine E., Dewayanti, Farahana K., Pravitasari, Normalita E., Rozi, Ismail E., Rizki, Andita F. M., Risandi, Rifqi, Couper, Kevin N., Oceandy, Delvac, Syafruddin, Din
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241181/
https://www.ncbi.nlm.nih.gov/pubmed/35768835
http://dx.doi.org/10.1186/s12936-022-04228-0
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author Asih, Puji B. S.
Siregar, Josephine E.
Dewayanti, Farahana K.
Pravitasari, Normalita E.
Rozi, Ismail E.
Rizki, Andita F. M.
Risandi, Rifqi
Couper, Kevin N.
Oceandy, Delvac
Syafruddin, Din
author_facet Asih, Puji B. S.
Siregar, Josephine E.
Dewayanti, Farahana K.
Pravitasari, Normalita E.
Rozi, Ismail E.
Rizki, Andita F. M.
Risandi, Rifqi
Couper, Kevin N.
Oceandy, Delvac
Syafruddin, Din
author_sort Asih, Puji B. S.
collection PubMed
description BACKGROUND: Rapid emergence of Plasmodium resistance to anti-malarial drug mainstays has driven a continual effort to discover novel drugs that target different biochemical pathway (s) during infection. Plasma membrane Calcium + 2 ATPase (PMCA4), a novel plasma membrane protein that regulates Calcium levels in various cells, namely red blood cell (RBC), endothelial cell and platelets, represents a new biochemical pathway that may interfere with susceptibility to malaria and/or severe malaria. METHODS: This study identified several pharmacological inhibitors of PMCA4, namely ATA and Resveratrol, and tested for their anti-malarial activities in vitro and in vivo using the Plasmodium falciparum 3D7 strain, the Plasmodium berghei ANKA strain, and Plasmodium yoelii 17XL strain as model. RESULTS: In vitro propagation of P. falciparum 3D7 strain in the presence of a wide concentration range of the inhibitors revealed that the parasite growth was inhibited in a dose-dependent manner, with IC(50)s at 634 and 0.231 µM, respectively. RESULTS: The results confirmed that both compounds exhibit moderate to potent anti-malarial activities with the strongest parasite growth inhibition shown by resveratrol at 0.231 µM. In vivo models using P. berghei ANKA for experimental cerebral malaria and P. yoelii 17XL for the effect on parasite growth, showed that the highest dose of ATA, 30 mg/kg BW, increased survival of the mice. Likewise, resveratrol inhibited the parasite growth following 4 days intraperitoneal injection at the dose of 100 mg/kg BW. CONCLUSION: The findings indicate that the PMCA4 of the human host may be a potential target for novel anti-malarials, either as single drug or in combination with the currently available effective anti-malarials.
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spelling pubmed-92411812022-06-30 Treatment with specific and pan-plasma membrane calcium ATPase (PMCA) inhibitors reduces malaria parasite growth in vitro and in vivo Asih, Puji B. S. Siregar, Josephine E. Dewayanti, Farahana K. Pravitasari, Normalita E. Rozi, Ismail E. Rizki, Andita F. M. Risandi, Rifqi Couper, Kevin N. Oceandy, Delvac Syafruddin, Din Malar J Research BACKGROUND: Rapid emergence of Plasmodium resistance to anti-malarial drug mainstays has driven a continual effort to discover novel drugs that target different biochemical pathway (s) during infection. Plasma membrane Calcium + 2 ATPase (PMCA4), a novel plasma membrane protein that regulates Calcium levels in various cells, namely red blood cell (RBC), endothelial cell and platelets, represents a new biochemical pathway that may interfere with susceptibility to malaria and/or severe malaria. METHODS: This study identified several pharmacological inhibitors of PMCA4, namely ATA and Resveratrol, and tested for their anti-malarial activities in vitro and in vivo using the Plasmodium falciparum 3D7 strain, the Plasmodium berghei ANKA strain, and Plasmodium yoelii 17XL strain as model. RESULTS: In vitro propagation of P. falciparum 3D7 strain in the presence of a wide concentration range of the inhibitors revealed that the parasite growth was inhibited in a dose-dependent manner, with IC(50)s at 634 and 0.231 µM, respectively. RESULTS: The results confirmed that both compounds exhibit moderate to potent anti-malarial activities with the strongest parasite growth inhibition shown by resveratrol at 0.231 µM. In vivo models using P. berghei ANKA for experimental cerebral malaria and P. yoelii 17XL for the effect on parasite growth, showed that the highest dose of ATA, 30 mg/kg BW, increased survival of the mice. Likewise, resveratrol inhibited the parasite growth following 4 days intraperitoneal injection at the dose of 100 mg/kg BW. CONCLUSION: The findings indicate that the PMCA4 of the human host may be a potential target for novel anti-malarials, either as single drug or in combination with the currently available effective anti-malarials. BioMed Central 2022-06-29 /pmc/articles/PMC9241181/ /pubmed/35768835 http://dx.doi.org/10.1186/s12936-022-04228-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Asih, Puji B. S.
Siregar, Josephine E.
Dewayanti, Farahana K.
Pravitasari, Normalita E.
Rozi, Ismail E.
Rizki, Andita F. M.
Risandi, Rifqi
Couper, Kevin N.
Oceandy, Delvac
Syafruddin, Din
Treatment with specific and pan-plasma membrane calcium ATPase (PMCA) inhibitors reduces malaria parasite growth in vitro and in vivo
title Treatment with specific and pan-plasma membrane calcium ATPase (PMCA) inhibitors reduces malaria parasite growth in vitro and in vivo
title_full Treatment with specific and pan-plasma membrane calcium ATPase (PMCA) inhibitors reduces malaria parasite growth in vitro and in vivo
title_fullStr Treatment with specific and pan-plasma membrane calcium ATPase (PMCA) inhibitors reduces malaria parasite growth in vitro and in vivo
title_full_unstemmed Treatment with specific and pan-plasma membrane calcium ATPase (PMCA) inhibitors reduces malaria parasite growth in vitro and in vivo
title_short Treatment with specific and pan-plasma membrane calcium ATPase (PMCA) inhibitors reduces malaria parasite growth in vitro and in vivo
title_sort treatment with specific and pan-plasma membrane calcium atpase (pmca) inhibitors reduces malaria parasite growth in vitro and in vivo
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241181/
https://www.ncbi.nlm.nih.gov/pubmed/35768835
http://dx.doi.org/10.1186/s12936-022-04228-0
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