Expression Profile of the Schistosoma japonicum Degradome Reveals Differential Protease Expression Patterns and Potential Anti-schistosomal Intervention Targets

Liu, Shuai; Cai, Pengfei; Piao, Xiangshu; Hou, Nan; Zhou, Xiaosu; Wu, Chuang; Wang, Heng; Chen, Qijun

doi:10.1371/journal.pcbi.1003856

Cited by 30 publications

(26 citation statements)

References 68 publications

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“…Structural differences in the outer membrane of larval and adult stages are known (Hockley, McLaren, 1973). Also, differences in transcriptome expression profiles between developmental stages of the parasite, including between somules and adults are well documented (Liu et al, 2014;Liu et al, 2006;Verjovski-Almeida et al, 2003). Modifications of the physicochemical properties of compounds could be performed in an attempt to enhance their membrane permeability.…”

Section: Resultsmentioning

confidence: 99%

Ortho-nitrobenzyl derivatives as potential anti-schistosomal agents

Lopes

Suzuki

Pereira

et al. 2018

Braz. J. Pharm. Sci.

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In the search for new anti-schistosomal agents, a series of fifteen ortho-nitrobenzyl derivatives was assayed in vitro against both the schistosomulum (somule) and adult forms of Schistosoma mansoni. Compounds 8 and 12 showed significant activity against somules at low micromolar concentrations, but none was active against adults. The SAR demonstrated that the compounds most active against the parasite were mutagenic to the human cell line RKO-AS45-1 only at concentrations 10-to 40-fold higher than the worm-killing dose. Given their electrophilicity, compounds were also screened as inhibitors of the S. mansoni cysteine protease (cathepsin B1) in vitro. Amides 5 and 15 exhibited a modest inhibition activity with values of 55.7 and 50.6 % at 100 µM, respectively. The nitrobenzyl compounds evaluated in this work can be regarded as hits in the search for more active and safe anti-schistosomal agents.Keywords: Nitro-aromatic. Schistosoma mansoni/ anti-schistosomal activity. Cathepsin B1. Mutagenicity INTRODUCTIONSchistosomiasis is a neglected tropical disease caused by a flatworm of the genus Schistosoma. The major species involved are S. haematobium, which causes the urogenital form of the disease, and S. mansoni and S. japonicum, which are responsible for the intestinal disease (Colley et al., 2014). An estimated 240 million people worldwide are infected by Schistosoma parasites and more than 700 million live in endemic areas (WHO, 2016a).Praziquantel, a pyrazino-isoquinoline derivative (Figure 1), is registered as an essential medicine by the World Health Organization (WHO, 2016b) and is the first choice therapy for schistosomiasis. It is active against all schistosome species and is safe and inexpensive. However, concerns over the possible development of resistance to praziquantel due to its large-scale use, motivates the search of new anti-schistosomal agents (Wang, Wang, Liang, 2012;Caffrey, 2015).Oxamniquine is a pro-drug that is activated by a Schistosoma sulfotransferase enzyme (Pica-Mattoccia et al., 2006). It is only clinically useful against S. mansoni infections (Caffrey, 2007;Axton, Garnett, 1976). The activated derivative is a nitro-aromatic compound that displays a good leaving group (sulfate) at the benzylic position. This product dissociates forming an electrophilic agent, which alkylates the parasite DNA (Abdul-Ghani et al., 2009) (Figure 2). Nitro-aromatic compounds, such as fexinidazole, benznidazole, and niclosamide, (Figure 3) are known for their pharmacological potential and our group has investigated the biological activities of a series of orthonitrobenzyl derivatives that act as alkylating agents (Lopes et al., 2015;Lopes et al., 2011;Soares et al., 2010).Based on the need for new anti-schistosomal agents, we evaluated the schistosomicidal activity of nitro-aromatic compounds, analogs of "activated" oxamniquine, against S. mansoni in vitro. These compounds would be active per se, without the requirement for sulfotransferase activation, as proposed in Figure 4. Evidence suggests that oxamni...

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Section: Resultsmentioning

confidence: 99%

Ortho-nitrobenzyl derivatives as potential anti-schistosomal agents

Lopes

Suzuki

Pereira

et al. 2018

Braz. J. Pharm. Sci.

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“…(FC ≥ 2 for both forward and reverse probe sets, and three biological replicates were used for each stage). Student’s t -test was used to determine differentially expressed genes between one particular stage and any of the other three stages [28, 30] ( P < 0.05). Heat maps were constructed based on the transformed log 2 FC values (forward probe sets) using HemI 1.0 software [37].…”

Section: Methodsmentioning

confidence: 99%

A next-generation microarray further reveals stage-enriched gene expression pattern in the blood fluke Schistosoma japonicum

et al. 2017

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BackgroundSchistosomiasis is caused by infection with blood flukes of the genus Schistosoma, and ranks, in terms of disability-adjusted life years (DALYs), as the third most important neglected tropical disease. Schistosomes have several discrete life stages involving dramatic morphological changes during their development, which require subtle gene expression modulations to complete the complex life-cycle.ResultsIn the current study, we employed a second generation schistosome DNA chip printed with the most comprehensive probe array for studying the Schistosoma japonicum transcriptome, to explore stage-associated gene expression in different developmental phases of S. japonicum. A total of 328, 95, 268 and 532 mRNA transcripts were enriched in cercariae, hepatic schistosomula, adult worms and eggs, respectively. In general, genes associated with transcriptional regulation, cell signalling and motor activity were readily expressed in cercariae; the expression of genes involved in neuronal activities, apoptosis and renewal was modestly upregulated in hepatic schistosomula; transcripts involved in egg production, nutrition metabolism and glycosylation were enriched in adult worms; while genes involved in cell division, microtubule-associated mobility, and host-parasite interplay were relatively highly expressed in eggs.ConclusionsThe study further highlights the expressional features of stage-associated genes in schistosomes with high accuracy. The results provide a better perspective of the biological characteristics among different developmental stages, which may open new avenues for identification of novel vaccine candidates and the development of novel control interventions against schistosomiasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1947-x) contains supplementary material, which is available to authorized users.

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“…Schistosome genome-wide microarrays were used to analyze the gene expression profiles of S. japonicum derived from different laboratory animals and the natural host, water buffalo. The design and construction of the microarray and the methods used in microarray hybridization and feature extraction have been previously reported [19][20][21]. The full details of this schistosome microarray design have been deposited in the Gene Expression Omnibus public database (http://www.ncbi.nlm.nih.gov/geo) under platform accession number GPL18617.…”

Section: Microarray Construction Hybridization and Data Analysismentioning

confidence: 99%

“…The full details of this schistosome microarray design have been deposited in the Gene Expression Omnibus public database (http://www.ncbi.nlm.nih.gov/geo) under platform accession number GPL18617. Briefly, a total of 21,861 target sequences (20,194 sequences derived from S. japonicum and 1667 sequences derived from S. mansoni) were provided to Roche NimbleGen for array design. For each sequence, 3 or 4 60-mer oligonucleotide probes were designed.…”

Section: Microarray Construction Hybridization and Data Analysismentioning

confidence: 99%

Comparative Analysis of Transcriptional Profiles of Adult Schistosoma japonicum from Different Laboratory Animals and the Natural Host, Water Buffalo

et al. 2015

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BackgroundSchistosomiasis is one of the most widely distributed parasitic diseases in the world. Schistosoma japonicum, a zoonotic parasite with a wide range of mammalian hosts, is one of the major pathogens of this disease. Although numerous studies on schistosomiasis japonica have been performed using laboratory animal models, systematic comparative analysis of whole-genome expression profiles in parasites from different laboratory animals and nature mammalian hosts is lacking to date.Methodology/Principal FindingsAdult schistosomes were obtained from laboratory animals BALB/c mice, C57BL/6 mice, New Zealand white rabbits and the natural host, water buffaloes. The gene expression profiles of schistosomes from these animals were obtained and compared by genome-wide oligonucleotide microarray analysis. The results revealed that the gene expression profiles of schistosomes from different laboratory animals and buffaloes were highly consistent (r>0.98) genome-wide. Meanwhile, a total of 450 genes were identified to be differentially expressed in schistosomes which can be clustered into six groups. Pathway analysis revealed that these genes were mainly involved in multiple signal transduction pathways, amino acid, energy, nucleotide and lipid metabolism. We also identified a group of 1,540 abundantly and stably expressed gene products in adult worms, including a panel of 179 Schistosoma- or Platyhelminthes-specific genes that may be essential for parasitism and may be regarded as novel potential anti-parasite intervention targets for future research.Conclusions/SignificanceThis study provides a comprehensive database of gene expression profiles of schistosomes derived from different laboratory animals and water buffaloes. An expanded number of genes potentially affecting the development of schistosomes in different animals were identified. These findings lay the foundation for schistosomiasis research in different laboratory animals and natural hosts at the transcriptional level and provide a valuable resource for screening anti-schistosomal intervention targets.

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Expression Profile of the Schistosoma japonicum Degradome Reveals Differential Protease Expression Patterns and Potential Anti-schistosomal Intervention Targets

Cited by 30 publications

References 68 publications

Ortho-nitrobenzyl derivatives as potential anti-schistosomal agents

Ortho-nitrobenzyl derivatives as potential anti-schistosomal agents

A next-generation microarray further reveals stage-enriched gene expression pattern in the blood fluke Schistosoma japonicum

Comparative Analysis of Transcriptional Profiles of Adult Schistosoma japonicum from Different Laboratory Animals and the Natural Host, Water Buffalo

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