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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

Most significantly enriched interaction network of differentially expressed genes in PZQ-treated paired males.The gene interaction network is related to cellular assembly and organization, cell-to-cell signaling and interaction. 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 treated with PZQ when compared with no-drug controls, green corresponds to negative log-ratios, i.e. down-regulated genes, and grey corresponds to those genes present in the analysis but not differentially expressed. Two genes from this network encode human proteins that are known drug targets and the corresponding drugs (Rx) are indicated.
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pntd.0004086.g003: Most significantly enriched interaction network of differentially expressed genes in PZQ-treated paired males.The gene interaction network is related to cellular assembly and organization, cell-to-cell signaling and interaction. 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 treated with PZQ when compared with no-drug controls, green corresponds to negative log-ratios, i.e. down-regulated genes, and grey corresponds to those genes present in the analysis but not differentially expressed. Two genes from this network encode human proteins that are known drug targets and the corresponding drugs (Rx) are indicated.

Mentions: The first most significantly enriched network (p-value = 10−43) is associated to functions such as cellular assembly and organization, cell-to-cell signaling and interaction (Fig 3). The schistosome tegument provides structural and functional elements for nutrient uptake and physical and immunological protection [46–48]. In this network we identified tegument genes, such as actin-2 (Smp_034550) and alpha actin (Smp_034550), tropomyosin (Smp_031770), and myosin (identified in the array with a homolog from other species gi/547978), which encode proteins that participate in muscle contraction, and are also part of the cytoskeleton. These affected genes are in line with the physiological effects of PZQ described in the literature: it is well-known that PZQ causes early spastic paralysis of the worm musculature, vacuolization at the base of the tegumental syncytium, and blebbing on the surface [49]. Morphological changes are accompanied by an increased exposure of parasite antigens on the worm surface [50]. It is also known that tegument genes up-regulation is an early response to PZQ of male worms, possibly reflecting tegument stress [48].


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)

Most significantly enriched interaction network of differentially expressed genes in PZQ-treated paired males.The gene interaction network is related to cellular assembly and organization, cell-to-cell signaling and interaction. 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 treated with PZQ when compared with no-drug controls, green corresponds to negative log-ratios, i.e. down-regulated genes, and grey corresponds to those genes present in the analysis but not differentially expressed. Two genes from this network encode human 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.g003: Most significantly enriched interaction network of differentially expressed genes in PZQ-treated paired males.The gene interaction network is related to cellular assembly and organization, cell-to-cell signaling and interaction. 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 treated with PZQ when compared with no-drug controls, green corresponds to negative log-ratios, i.e. down-regulated genes, and grey corresponds to those genes present in the analysis but not differentially expressed. Two genes from this network encode human proteins that are known drug targets and the corresponding drugs (Rx) are indicated.
Mentions: The first most significantly enriched network (p-value = 10−43) is associated to functions such as cellular assembly and organization, cell-to-cell signaling and interaction (Fig 3). The schistosome tegument provides structural and functional elements for nutrient uptake and physical and immunological protection [46–48]. In this network we identified tegument genes, such as actin-2 (Smp_034550) and alpha actin (Smp_034550), tropomyosin (Smp_031770), and myosin (identified in the array with a homolog from other species gi/547978), which encode proteins that participate in muscle contraction, and are also part of the cytoskeleton. These affected genes are in line with the physiological effects of PZQ described in the literature: it is well-known that PZQ causes early spastic paralysis of the worm musculature, vacuolization at the base of the tegumental syncytium, and blebbing on the surface [49]. Morphological changes are accompanied by an increased exposure of parasite antigens on the worm surface [50]. It is also known that tegument genes up-regulation is an early response to PZQ of male worms, possibly reflecting tegument stress [48].

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