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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 similar expression pattern in PZQ-treated paired males and females.The gene interaction network is related to carbohydrate metabolism, molecular transport and small molecule biochemistry. 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 expression value, computed as log2 [PZQ/Control]; red corresponds to positive log-ratios, i.e. genes up-regulated in paired males and females treated with PZQ when compared with their respective no-drug controls, grey corresponds to those genes present in the analysis but not differentially expressed. In humans, one gene homolog in this network encodes a protein that is a known drug target and the corresponding drugs (Rx) are indicated.
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pntd.0004086.g004: Enriched gene interaction network detected with similar expression pattern in PZQ-treated paired males and females.The gene interaction network is related to carbohydrate metabolism, molecular transport and small molecule biochemistry. 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 expression value, computed as log2 [PZQ/Control]; red corresponds to positive log-ratios, i.e. genes up-regulated in paired males and females treated with PZQ when compared with their respective no-drug controls, grey corresponds to those genes present in the analysis but not differentially expressed. In humans, one gene homolog in this network encodes a protein that is a known drug target and the corresponding drugs (Rx) are indicated.

Mentions: Functional analysis revealed one interaction network that was significantly enriched (p-value = 10−17) with genes whose expression was equally affected (predominantly induced) in paired males and females by PZQ treatment (Fig 1E); this network is associated with carbohydrate metabolism, molecular transport, and small molecule biochemistry. Interestingly, calcium ion is a ligand that is in the center of this network (Fig 4), regulating the proteins related to muscle contraction encoded by the genes present in the network (see list of genes in S5 Table). PZQ produces a well-documented effect on intracellular Ca2+ levels in adult schistosomes [61]. HPCAL1 (Putative neuronal calcium sensor—Smp_068510) and CNN3 (Calponin—Smp_078690), both implicated in the regulation and modulation of smooth muscle contraction, were up-regulated in S. mansoni males and females exposed to the sublethal dose of PZQ.


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 similar expression pattern in PZQ-treated paired males and females.The gene interaction network is related to carbohydrate metabolism, molecular transport and small molecule biochemistry. 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 expression value, computed as log2 [PZQ/Control]; red corresponds to positive log-ratios, i.e. genes up-regulated in paired males and females treated with PZQ when compared with their respective no-drug controls, grey corresponds to those genes present in the analysis but not differentially expressed. In humans, one gene homolog in this network encodes a protein that is a known drug target 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.g004: Enriched gene interaction network detected with similar expression pattern in PZQ-treated paired males and females.The gene interaction network is related to carbohydrate metabolism, molecular transport and small molecule biochemistry. 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 expression value, computed as log2 [PZQ/Control]; red corresponds to positive log-ratios, i.e. genes up-regulated in paired males and females treated with PZQ when compared with their respective no-drug controls, grey corresponds to those genes present in the analysis but not differentially expressed. In humans, one gene homolog in this network encodes a protein that is a known drug target and the corresponding drugs (Rx) are indicated.
Mentions: Functional analysis revealed one interaction network that was significantly enriched (p-value = 10−17) with genes whose expression was equally affected (predominantly induced) in paired males and females by PZQ treatment (Fig 1E); this network is associated with carbohydrate metabolism, molecular transport, and small molecule biochemistry. Interestingly, calcium ion is a ligand that is in the center of this network (Fig 4), regulating the proteins related to muscle contraction encoded by the genes present in the network (see list of genes in S5 Table). PZQ produces a well-documented effect on intracellular Ca2+ levels in adult schistosomes [61]. HPCAL1 (Putative neuronal calcium sensor—Smp_068510) and CNN3 (Calponin—Smp_078690), both implicated in the regulation and modulation of smooth muscle contraction, were up-regulated in S. mansoni males and females exposed to the sublethal dose of PZQ.

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