Limits...
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

Global transcriptional changes driven by PZQ on S. mansoni adult worms.Overall summary with the names of the associated functional interaction networks identified as significantly enriched with differentially expressed S. mansoni genes in different comparisons: (A) genes affected by PZQ in opposite directions in paired or unpaired mature females, (B) all genes affected by PZQ in paired females, (C) all genes affected by PZQ in unpaired mature females, (D) all genes affected by PZQ in paired males, (E) genes affected in common in paired males and females. Color arrows indicated the direction of change in expression of the majority of the genes in each network: green implies a down-regulated expression of the majority of the genes in PZQ-treated worms, and red an up-regulated expression of the majority of the genes in PZQ-treated worms when compared with their respective no-drug controls. Rx corresponds to the identification of new candidate drugs known to act on the encoded protein products of the homolog human genes present in the indicated network, as described in the main text.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4581627&req=5

pntd.0004086.g001: Global transcriptional changes driven by PZQ on S. mansoni adult worms.Overall summary with the names of the associated functional interaction networks identified as significantly enriched with differentially expressed S. mansoni genes in different comparisons: (A) genes affected by PZQ in opposite directions in paired or unpaired mature females, (B) all genes affected by PZQ in paired females, (C) all genes affected by PZQ in unpaired mature females, (D) all genes affected by PZQ in paired males, (E) genes affected in common in paired males and females. Color arrows indicated the direction of change in expression of the majority of the genes in each network: green implies a down-regulated expression of the majority of the genes in PZQ-treated worms, and red an up-regulated expression of the majority of the genes in PZQ-treated worms when compared with their respective no-drug controls. Rx corresponds to the identification of new candidate drugs known to act on the encoded protein products of the homolog human genes present in the indicated network, as described in the main text.

Mentions: Functional analyses of these differentially expressed genes were carried out with the IPA tool, aiming to find significantly enriched gene interaction networks comprised of affected genes whose products are known targets of drugs already used in humans for other disease conditions. Among the 210 differentially expressed genes affected by PZQ in opposite directions in paired and unpaired mature females, IPA found 3 gene interaction networks (Fig 1A) that were statistically enriched (p-values from 10−52 to 10−28) with 56 genes that were affected by PZQ in opposite directions. The first most significantly enriched network (p-value = 10−52) is related to cellular development and differentiation and drug metabolism. The second network (p-value = 10−41) is associated with cell death, cell cycle, cellular function and maintenance; the third network (p-value = 10−28) is related to lipid metabolism, small molecule biochemistry and gene expression. (See S5 Table for the list of genes in the networks).


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)

Global transcriptional changes driven by PZQ on S. mansoni adult worms.Overall summary with the names of the associated functional interaction networks identified as significantly enriched with differentially expressed S. mansoni genes in different comparisons: (A) genes affected by PZQ in opposite directions in paired or unpaired mature females, (B) all genes affected by PZQ in paired females, (C) all genes affected by PZQ in unpaired mature females, (D) all genes affected by PZQ in paired males, (E) genes affected in common in paired males and females. Color arrows indicated the direction of change in expression of the majority of the genes in each network: green implies a down-regulated expression of the majority of the genes in PZQ-treated worms, and red an up-regulated expression of the majority of the genes in PZQ-treated worms when compared with their respective no-drug controls. Rx corresponds to the identification of new candidate drugs known to act on the encoded protein products of the homolog human genes present in the indicated network, as described in the main text.
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0004086.g001: Global transcriptional changes driven by PZQ on S. mansoni adult worms.Overall summary with the names of the associated functional interaction networks identified as significantly enriched with differentially expressed S. mansoni genes in different comparisons: (A) genes affected by PZQ in opposite directions in paired or unpaired mature females, (B) all genes affected by PZQ in paired females, (C) all genes affected by PZQ in unpaired mature females, (D) all genes affected by PZQ in paired males, (E) genes affected in common in paired males and females. Color arrows indicated the direction of change in expression of the majority of the genes in each network: green implies a down-regulated expression of the majority of the genes in PZQ-treated worms, and red an up-regulated expression of the majority of the genes in PZQ-treated worms when compared with their respective no-drug controls. Rx corresponds to the identification of new candidate drugs known to act on the encoded protein products of the homolog human genes present in the indicated network, as described in the main text.
Mentions: Functional analyses of these differentially expressed genes were carried out with the IPA tool, aiming to find significantly enriched gene interaction networks comprised of affected genes whose products are known targets of drugs already used in humans for other disease conditions. Among the 210 differentially expressed genes affected by PZQ in opposite directions in paired and unpaired mature females, IPA found 3 gene interaction networks (Fig 1A) that were statistically enriched (p-values from 10−52 to 10−28) with 56 genes that were affected by PZQ in opposite directions. The first most significantly enriched network (p-value = 10−52) is related to cellular development and differentiation and drug metabolism. The second network (p-value = 10−41) is associated with cell death, cell cycle, cellular function and maintenance; the third network (p-value = 10−28) is related to lipid metabolism, small molecule biochemistry and gene expression. (See S5 Table for the list of genes in the networks).

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