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Synergy of Omeprazole and Praziquantel In Vitro Treatment against Schistosoma mansoni Adult Worms.

Almeida GT, Lage RC, Anderson L, Venancio TM, Nakaya HI, Miyasato PA, Rofatto HK, Zerlotini A, Nakano E, Oliveira G, Verjovski-Almeida S - PLoS Negl Trop Dis (2015)

Bottom Line: Based on these results, OMP, a widely prescribed proton pump inhibitor known to target the ATP1A2 gene product, was chosen and tested.Sublethal doses of PZQ combined with OMP significantly increased worm mortality in vitro when compared with PZQ or OMP alone, thus evidencing a synergistic effect.We demonstrated the potential of this strategy by showing that PZQ in combination with OMP displayed increased efficiency against S. mansoni adult worms in vitro when compared with either drug alone.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.

ABSTRACT

Background: Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel (PZQ), and the selection of resistant worms under repeated treatment is a concern. Therefore, there is a pressing need to understand the molecular effects of PZQ on schistosomes and to investigate alternative or synergistic drugs against schistosomiasis.

Methodology: We used a custom-designed Schistosoma mansoni expression microarray to explore the effects of sublethal doses of PZQ on large-scale gene expression of adult paired males and females and unpaired mature females. We also assessed the efficacy of PZQ, omeprazole (OMP) or their combination against S. mansoni adult worms with a survival in vitro assay.

Principal findings: We identified sets of genes that were affected by PZQ in paired and unpaired mature females, however with opposite gene expression patterns (up-regulated in paired and down-regulated in unpaired mature females), indicating that PZQ effects are heavily influenced by the mating status. We also identified genes that were similarly affected by PZQ in males and females. Functional analyses of gene interaction networks were performed with parasite genes that were differentially expressed upon PZQ treatment, searching for proteins encoded by these genes whose human homologs are targets of different drugs used for other diseases. Based on these results, OMP, a widely prescribed proton pump inhibitor known to target the ATP1A2 gene product, was chosen and tested. Sublethal doses of PZQ combined with OMP significantly increased worm mortality in vitro when compared with PZQ or OMP alone, thus evidencing a synergistic effect.

Conclusions: Functional analysis of gene interaction networks is an important approach that can point to possible novel synergistic drug candidates. We demonstrated the potential of this strategy by showing that PZQ in combination with OMP displayed increased efficiency against S. mansoni adult worms in vitro when compared with either drug alone.

No MeSH data available.


Related in: MedlinePlus

Validation by RT-qPCR of expression changes induced by PZQ treatment in S. mansoni adult worms.The expression levels of genes were measured by RT-qPCR in parasites treated with PZQ (black bars) relative to the levels in the respective no-drug control parasites (gray bars). Genes were measured (A) in paired females; (B) in unpaired mature females; (C) in paired males; and (D) in paired females. Genes with significant difference (t-test, p < 0.05) are marked with asterisk. Next to each gene name, the gene expression fold-change induced by PZQ and detected by microarray is shown for comparison.
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pntd.0004086.g005: Validation by RT-qPCR of expression changes induced by PZQ treatment in S. mansoni adult worms.The expression levels of genes were measured by RT-qPCR in parasites treated with PZQ (black bars) relative to the levels in the respective no-drug control parasites (gray bars). Genes were measured (A) in paired females; (B) in unpaired mature females; (C) in paired males; and (D) in paired females. Genes with significant difference (t-test, p < 0.05) are marked with asterisk. Next to each gene name, the gene expression fold-change induced by PZQ and detected by microarray is shown for comparison.

Mentions: Fig 5A shows that for paired females seven out of the nine genes were successfully validated by RT-qPCR, whereas no changes in expression were detected for EXOC5 and INPP1. Fig 5B shows that eight out of the nine selected genes were successfully validated for unpaired mature females, with statistical significance. In addition, the direction of change in expression was in agreement between both microarray and RT-qPCR for all tested genes, i.e. the genes were up-regulated in paired females when compared with no-drug controls, and down-regulated in unpaired mature females relative to controls both by microarray and RT-qPCR.


Synergy of Omeprazole and Praziquantel In Vitro Treatment against Schistosoma mansoni Adult Worms.

Almeida GT, Lage RC, Anderson L, Venancio TM, Nakaya HI, Miyasato PA, Rofatto HK, Zerlotini A, Nakano E, Oliveira G, Verjovski-Almeida S - PLoS Negl Trop Dis (2015)

Validation by RT-qPCR of expression changes induced by PZQ treatment in S. mansoni adult worms.The expression levels of genes were measured by RT-qPCR in parasites treated with PZQ (black bars) relative to the levels in the respective no-drug control parasites (gray bars). Genes were measured (A) in paired females; (B) in unpaired mature females; (C) in paired males; and (D) in paired females. Genes with significant difference (t-test, p < 0.05) are marked with asterisk. Next to each gene name, the gene expression fold-change induced by PZQ and detected by microarray is shown for comparison.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581627&req=5

pntd.0004086.g005: Validation by RT-qPCR of expression changes induced by PZQ treatment in S. mansoni adult worms.The expression levels of genes were measured by RT-qPCR in parasites treated with PZQ (black bars) relative to the levels in the respective no-drug control parasites (gray bars). Genes were measured (A) in paired females; (B) in unpaired mature females; (C) in paired males; and (D) in paired females. Genes with significant difference (t-test, p < 0.05) are marked with asterisk. Next to each gene name, the gene expression fold-change induced by PZQ and detected by microarray is shown for comparison.
Mentions: Fig 5A shows that for paired females seven out of the nine genes were successfully validated by RT-qPCR, whereas no changes in expression were detected for EXOC5 and INPP1. Fig 5B shows that eight out of the nine selected genes were successfully validated for unpaired mature females, with statistical significance. In addition, the direction of change in expression was in agreement between both microarray and RT-qPCR for all tested genes, i.e. the genes were up-regulated in paired females when compared with no-drug controls, and down-regulated in unpaired mature females relative to controls both by microarray and RT-qPCR.

Bottom Line: Based on these results, OMP, a widely prescribed proton pump inhibitor known to target the ATP1A2 gene product, was chosen and tested.Sublethal doses of PZQ combined with OMP significantly increased worm mortality in vitro when compared with PZQ or OMP alone, thus evidencing a synergistic effect.We demonstrated the potential of this strategy by showing that PZQ in combination with OMP displayed increased efficiency against S. mansoni adult worms in vitro when compared with either drug alone.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.

ABSTRACT

Background: Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel (PZQ), and the selection of resistant worms under repeated treatment is a concern. Therefore, there is a pressing need to understand the molecular effects of PZQ on schistosomes and to investigate alternative or synergistic drugs against schistosomiasis.

Methodology: We used a custom-designed Schistosoma mansoni expression microarray to explore the effects of sublethal doses of PZQ on large-scale gene expression of adult paired males and females and unpaired mature females. We also assessed the efficacy of PZQ, omeprazole (OMP) or their combination against S. mansoni adult worms with a survival in vitro assay.

Principal findings: We identified sets of genes that were affected by PZQ in paired and unpaired mature females, however with opposite gene expression patterns (up-regulated in paired and down-regulated in unpaired mature females), indicating that PZQ effects are heavily influenced by the mating status. We also identified genes that were similarly affected by PZQ in males and females. Functional analyses of gene interaction networks were performed with parasite genes that were differentially expressed upon PZQ treatment, searching for proteins encoded by these genes whose human homologs are targets of different drugs used for other diseases. Based on these results, OMP, a widely prescribed proton pump inhibitor known to target the ATP1A2 gene product, was chosen and tested. Sublethal doses of PZQ combined with OMP significantly increased worm mortality in vitro when compared with PZQ or OMP alone, thus evidencing a synergistic effect.

Conclusions: Functional analysis of gene interaction networks is an important approach that can point to possible novel synergistic drug candidates. We demonstrated the potential of this strategy by showing that PZQ in combination with OMP displayed increased efficiency against S. mansoni adult worms in vitro when compared with either drug alone.

No MeSH data available.


Related in: MedlinePlus