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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

Enriched gene interaction network detected with opposite expression patterns in PZQ-treated paired or unpaired mature females.This gene interaction network is significantly enriched (p-value = 10−52) with differentially expressed genes related to cellular development and drug metabolism whose expression was affected by PZQ in paired as well as in unpaired mature females (with opposite patterns). The shapes of elements correspond to different types of molecules, as indicated in the inset box. Arrows indicate the relationship between the elements: dashed or solid lines indicate indirect or direct interactions, respectively. The color intensity is proportional to the expression value, computed as log2 [PZQ/Control]; red corresponds to positive log-ratios, i.e. these genes were up-regulated in paired females treated with PZQ when compared with the no-drug controls; grey corresponds to a gene present in the analysis but not differentially expressed. In humans, a number of gene homologs in this network encode proteins that are known drug targets and the corresponding drugs (Rx) are indicated.
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pntd.0004086.g002: Enriched gene interaction network detected with opposite expression patterns in PZQ-treated paired or unpaired mature females.This gene interaction network is significantly enriched (p-value = 10−52) with differentially expressed genes related to cellular development and drug metabolism whose expression was affected by PZQ in paired as well as in unpaired mature females (with opposite patterns). The shapes of elements correspond to different types of molecules, as indicated in the inset box. Arrows indicate the relationship between the elements: dashed or solid lines indicate indirect or direct interactions, respectively. The color intensity is proportional to the expression value, computed as log2 [PZQ/Control]; red corresponds to positive log-ratios, i.e. these genes were up-regulated in paired females treated with PZQ when compared with the no-drug controls; grey corresponds to a gene present in the analysis but not differentially expressed. In humans, a number of gene homologs in this network encode proteins that are known drug targets and the corresponding drugs (Rx) are indicated.

Mentions: Searching for S. mansoni genes whose human homolog gene products are known targets of drugs already used for other diseases, and analyzing the most significantly enriched network of genes affected by PZQ in opposite directions in paired and unpaired mature females (Fig 2), IPA pointed to three up-regulated genes in paired females, namely ATP1A2 (Smp_015020), MAPK (Smp_073490) and ERK (Smp_008260).


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)

Enriched gene interaction network detected with opposite expression patterns in PZQ-treated paired or unpaired mature females.This gene interaction network is significantly enriched (p-value = 10−52) with differentially expressed genes related to cellular development and drug metabolism whose expression was affected by PZQ in paired as well as in unpaired mature females (with opposite patterns). The shapes of elements correspond to different types of molecules, as indicated in the inset box. Arrows indicate the relationship between the elements: dashed or solid lines indicate indirect or direct interactions, respectively. The color intensity is proportional to the expression value, computed as log2 [PZQ/Control]; red corresponds to positive log-ratios, i.e. these genes were up-regulated in paired females treated with PZQ when compared with the no-drug controls; grey corresponds to a gene present in the analysis but not differentially expressed. In humans, a number of gene homologs in this network encode proteins that are known drug targets and the corresponding drugs (Rx) are indicated.
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0004086.g002: Enriched gene interaction network detected with opposite expression patterns in PZQ-treated paired or unpaired mature females.This gene interaction network is significantly enriched (p-value = 10−52) with differentially expressed genes related to cellular development and drug metabolism whose expression was affected by PZQ in paired as well as in unpaired mature females (with opposite patterns). The shapes of elements correspond to different types of molecules, as indicated in the inset box. Arrows indicate the relationship between the elements: dashed or solid lines indicate indirect or direct interactions, respectively. The color intensity is proportional to the expression value, computed as log2 [PZQ/Control]; red corresponds to positive log-ratios, i.e. these genes were up-regulated in paired females treated with PZQ when compared with the no-drug controls; grey corresponds to a gene present in the analysis but not differentially expressed. In humans, a number of gene homologs in this network encode proteins that are known drug targets and the corresponding drugs (Rx) are indicated.
Mentions: Searching for S. mansoni genes whose human homolog gene products are known targets of drugs already used for other diseases, and analyzing the most significantly enriched network of genes affected by PZQ in opposite directions in paired and unpaired mature females (Fig 2), IPA pointed to three up-regulated genes in paired females, namely ATP1A2 (Smp_015020), MAPK (Smp_073490) and ERK (Smp_008260).

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