A Novel Combination Therapy with Uridine and Praziquantel effectively Alleviates Schistosomiasis-induced Hepatic Fibrosis through Promoting Adipogenic Differentiation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE289753 | GEO | 2025/04/22
REPOSITORIES: GEO
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Project description:In schistosomiasis japonica, the egg-induced granulomatous response and the development of extensive hepatic fibrosis is the main pathology. Information regarding the specific mechanisms associated with granuloma regression and the subsequent recovery events in the host liver are still limited. In this study, a murine model of schistosomiasis japonica was used to characterise the multicellular pathways occurring during liver regeneration. Schistosoma japonicum-infected C57BL/6 mice were administered with the drug praziquantel (PZQ), on a daily basis for five consecutive days to eliminate all adult parasites. The pathological changes of PZQ-treated groups after 3, 6 and 7 weeks post PZQ treatment were examined, along with the assessment of cellular infiltration to the liver. PZQ treatment significantly reduced the degree of splenomegaly, granuloma density and the collagen deposition of liver fibrosis. The infiltration of inflammatory cells, including neutrophils, eosinophils and macrophages to the liver were as well significantly decreased. Transcriptomic analysis revealed the significant up-regulation of fatty acid metabolism genes and the identification of peroxisome proliferator-activated receptor alpha (PPAR-α) as the upstream regulator during the process of liver recovery. Aryl hydrocarbon receptor (AhR) signalling pathway that is involved primarily in the regulation of hepatic enzymes responsible for xenobiotic metabolism was as well differentially up-regulated. These findings indicate that schistosome egg-induced fibrogenesis process is reversible, and provide a better understanding of the regression mechanisms associated with hepatic schistosomiasis. These results hold important implications for the future alleviation of this and other fibrotic diseases of clinical significance. C57BL/6 murine model infected with S. japonicum were treated orally with Praziquantel (PZQ) after 7 weeks post infection to examine the hepatic regression process following drug treatment. These PZQ-treated, non PZQ-treated and uninfected mice were then euthanised at 10, 13, and 14 weeks p.i. Livers were collected from each mice, and subjected to total RNA isolation and gene expression analysis. Microarray analysis of this study was performed using samples derived from 3 individual mice per group/time-point.
2014-08-31 | E-GEOD-59276 | biostudies-arrayexpress
Project description:In schistosomiasis japonica, the egg-induced granulomatous response and the development of extensive hepatic fibrosis is the main pathology. Information regarding the specific mechanisms associated with granuloma regression and the subsequent recovery events in the host liver are still limited. In this study, a murine model of schistosomiasis japonica was used to characterise the multicellular pathways occurring during liver regeneration. Schistosoma japonicum-infected C57BL/6 mice were administered with the drug praziquantel (PZQ), on a daily basis for five consecutive days to eliminate all adult parasites. The pathological changes of PZQ-treated groups after 3, 6 and 7 weeks post PZQ treatment were examined, along with the assessment of cellular infiltration to the liver. PZQ treatment significantly reduced the degree of splenomegaly, granuloma density and the collagen deposition of liver fibrosis. The infiltration of inflammatory cells, including neutrophils, eosinophils and macrophages to the liver were as well significantly decreased. Transcriptomic analysis revealed the significant up-regulation of fatty acid metabolism genes and the identification of peroxisome proliferator-activated receptor alpha (PPAR-α) as the upstream regulator during the process of liver recovery. Aryl hydrocarbon receptor (AhR) signalling pathway that is involved primarily in the regulation of hepatic enzymes responsible for xenobiotic metabolism was as well differentially up-regulated. These findings indicate that schistosome egg-induced fibrogenesis process is reversible, and provide a better understanding of the regression mechanisms associated with hepatic schistosomiasis. These results hold important implications for the future alleviation of this and other fibrotic diseases of clinical significance.
2014-08-31 | GSE59276 | GEO
Project description:A Novel Combination Therapy with Uridine and Praziquantel effectively Alleviates Schistosomiasis-induced Hepatic Fibrosis through Promoting Adipogenic Differentiation
| PRJNA1224445 | ENA
Project description:Schistosomiasis affects over 250 million people worldwide and is caused by trematodes of the genus Schistosoma including the species Schistosoma mansoni. Praziquantel (PZQ) is the most widely available and implemented drug for this disease, and is produced as an racematic mixture composed of the enantiomers, R-PZQ and S-PZQ. In this study we examined the gene expression profiles of 49 day male S. mansoni after 18 hour treatment with R-PZQ, S-PZQ or control (1% DMSO). These results provide insight into the effect of PZQ enantiomers against male S. mansoni.
2023-04-22 | GSE114506 | GEO
Project description:Schistosomiasis is a chronic neglected tropical disease caused by digenetic parasitic flatworms of the genus Schistosoma. The disease is estimated to affect over 206 million people, the majority of whom live in Africa where Schistosoma mansoni and Schistosoma japonicum are the major causative agents. While a number of drugs have been used to treat schistosomiasis, praziquantel (PZQ) is the only one that is widely available, relatively cheap, and easy to use. The reliance on a single drug for the treatment of such a prevalent disease is a cause for concern due to the potential for resistance to render PZQ ineffective. In this study we examine the transcriptome of three generations of a laboratory strain of S. mansoni (PR1) whose susceptibility to PZQ has been diminished across 9 passages through exposure to increasing sub-lethal doses of the drug. Miracidial susceptibility was significantly reduced after exposure to 2 x 50 mg/Kg PZQ during the first passage. Susceptibility of worms in vivo was first assessed during passage 5 when mice infected with PZQ-selected schistosomes were dosed with a lethal dose of 3 x 300 mg/Kg PZQ resulting in only a 10% reduction in worm number compared to control treatment. The emergence of reduced sensitivity was marked by a shift in sex ratio from a predominantly male to female population, a reduction in the length of females and ultimately the loss of the PZQ-selected line after passage 9, perhaps due to a selection induced fitness cost. Analysis of differentially regulated transcripts did not suggest that any particular gene product or pathway was associated with drug resistance suggesting either a loss of function mutation to a single gene or an epistatic interaction of multiple gene products.
2019-02-26 | GSE120682 | GEO
Project description:Schistosoma mansoni is one of the most common etiological agents responsible for the disease schistosomiasis. More than 200 million people suffer from this disease making it the most severe tropical disease after malaria in terms of morbidity. Praziquantel (PZQ) is the treatment of choice for schistosomiasis and has been used almost exclusively to treat the disease since the 1970s. However, while the drug is lethal for sexually mature schistosomes, it is ineffective against juveniles. Thus, while morbidity can be eased, a cure is difficult to achieve. As a result there is an urgent need to develop a new generation of anti-schistosomal drugs, a task that will be made easier by understanding the mechanism of action of PZQ. As yet, neither the molecule to which PZQ binds nor the means by which it kills mature schistosomes is known. The overarching aim of this study was to understand the molecular basis of PZQ sensitivity in S. mansoni. We believe that juvenile worms survive PZQ treatment in vivo due to the induction of, as yet, unidentified protective molecular pathways. To address this hypothesis juvenile and adult PR1 S. mansoni were treated in vitro with sub-lethal concentrations of PZQ. mRNA was extracted from replicate samples, cRNA prepagreen and labeled with cyanine dyes for analysis using a 44K S. mansoni microarray. The data was then analyzed using Genespring. Our findings suggest that a number of genes associated with drug transport, iron homeostasis and apoptosis are induced in juvenile but not adult schistosomes and that this allows the juvenile worms to protect themselves against the lethal effects of PZQ long enough for the drug to be metabolized by the human host.
2011-05-27 | GSE29535 | GEO
Project description:Although praziquantel (PZQ) has been used to treat schistosomiasis for over 20 years its mechanism of action remains unknown. We have developed an assay based on the transcriptional response of S. mansoni PR-1 to heat shock to confirm that while 6 week post infection (p.i.) schistosomes are sensitive to PZQ, 4 week p.i. schistosomes are not. Further, we have used this assay to demonstrate that this sensitivity develops between days 37 and 40 p.i. PZQ linked to the fluorophore BODIPY appears to easily enter the cells of intact 4 and 6 week p.i. schistosomes as well as mammalian NIH 3T3 cells and together, these data suggest that the differential effects of PZQ is not based on cell exclusion but probably due the differential expression of a target molecule at 6 weeks p.i. A transcriptomal analysis of gene expression between 4 and 6 weeks p.i. revealed 607 candidate genes whose products are potential PZQ targets. A comparison of this gene list with that of genes expressed by PZQ sensitive miracidia reduced this target list to 247 genes, including a number involved in aerobic metabolism and cytosolic calcium regulation. Finally, we also report the effect of an in vitro sub-lethal exposure of PZQ on the transcriptome of S. mansoni PR-1. Annotation of genes differentially regulated by PZQ exposure suggests that schistosomes may undergo a transcriptomic response similar to that observed during oxidative stress. Keywords: cell type comparison, time course
2008-11-10 | GSE12850 | GEO
Project description:Schistosoma mansoni is one of the most common etiological agents responsible for the disease schistosomiasis. More than 200 million people suffer from this disease making it the most severe tropical disease after malaria in terms of morbidity. Praziquantel (PZQ) is the treatment of choice for schistosomiasis and has been used almost exclusively to treat the disease since the 1970s. However, while the drug is lethal for sexually mature schistosomes, it is ineffective against juveniles. Thus, while morbidity can be eased, a cure is difficult to achieve. As a result there is an urgent need to develop a new generation of anti-schistosomal drugs, a task that will be made easier by understanding the mechanism of action of PZQ. As yet, neither the molecule to which PZQ binds nor the means by which it kills mature schistosomes is known. The overarching aim of this study was to understand the molecular basis of PZQ sensitivity in S. mansoni. We believe that juvenile worms survive PZQ treatment in vivo due to the induction of, as yet, unidentified protective molecular pathways. To address this hypothesis juvenile and adult PR1 S. mansoni were treated in vitro with sub-lethal concentrations of PZQ. mRNA was extracted from replicate samples, cRNA prepagreen and labeled with cyanine dyes for analysis using a 44K S. mansoni microarray. The data was then analyzed using Genespring. Our findings suggest that a number of genes associated with drug transport, iron homeostasis and apoptosis are induced in juvenile but not adult schistosomes and that this allows the juvenile worms to protect themselves against the lethal effects of PZQ long enough for the drug to be metabolized by the human host. 42 days post exposure (DPE) male schistosomes were exposed to 0 and 1 µg/mL praziquantel (PZQ) for 1 or 20 h and 10 µg/mL PZQ for 1 h. 42 DPE female schistosomes were exposed to 0, 1 and 10 µg/mL PZQ for 20 h. 28 DPE mixed-sex schistosomes were exposed to 0, 1 and 10 µg/mL PZQ for 1 and 20 h. All experiments were performed in biological triplicates. The 0 µg/mL PZQ exposures were used as controls to the appropriate groups and a universal reference was used in all experiments that was comprised of RNA derived from 100 mixed sex, unexposed 42 DPE schistosomes spiked with 0.5 % (v/v) RNA isolated from 42 DPE mixed sex worms exposed to 10 µg/mL PZQ, 0.5 % (v/v) RNA isolated from 28 DPE worms exposed to 10 µg/mL PZQ and 0.5 % (v/v) RNA isolated from 28 DPE worms unexposed to PZQ. Transcriptional response to praziquantel exposure by time and concentration
2011-05-27 | E-GEOD-29535 | biostudies-arrayexpress
Project description:Liver fibrosis is a poor outcome of patients with schistosomiasis, impacting the quality of life and even survival. Eggs deposited in the liver were the main pathogenic factors of hepatic fibrosis in Schistosomiasis japonica. However, the mechanism of hepatic fibrosis in schistosomiasis remains not well defined and there is no effective measure to prevent and treat schistosome-induced hepatic fibrosis. In this study, we applied single-cell sequencing to primarily explore the mechanism of hepatic fibrosis in murine schistosomiasis japonica(n=1) and normal mouse was served as control(n=1). A total of 10,403 cells were included in our analysis and grouped into 18 major cell clusters. Th2 cells and NKT cells were obviously increased and there was a close communication between NKT cells and FASLG signaling pathway. Flow cytometry analysis indicated that the expression of Fasl in NKT cells, CD8+ T cell and NK cell were higher in SJ groups. Arg1, Retnla and Chil3, marker genes of alternatively activated macrophages (M2), were mainly expressed in mononuclear phagocyte(1) (MP(1)), suggesting that Kupffer cells might undergo M2-like polarization in fibrotic liver of schistosomiasis. CXCL and CCL signaling pathway analysis with CellChat showed that Cxcl16-Cxcr6, Ccl6-Ccr2 and Ccl5-Ccr5 were the most dominant L−R and there were close interactions between T cells and MPs. Overall, our research profiled a preliminary immunological network of hepatic fibrosis in murine schistosomiasis japonica, which might contribute to a better understanding of the mechanisms of liver fibrosis in schistosomiasis. NKT cells and CXCL and CCL signaling pathway such as Cxcl16-Cxcr6, Ccl6-Ccr2 and Ccl5-Ccr5 might be potential targets to alleviate hepatic fibrosis of schistosomiasis.
2022-12-16 | GSE220286 | GEO
Project description:Although praziquantel (PZQ) has been used to treat schistosomiasis for over 20 years its mechanism of action remains unknown. We have developed an assay based on the transcriptional response of S. mansoni PR-1 to heat shock to confirm that while 6 week post infection (p.i.) schistosomes are sensitive to PZQ, 4 week p.i. schistosomes are not. Further, we have used this assay to demonstrate that this sensitivity develops between days 37 and 40 p.i. PZQ linked to the fluorophore BODIPY appears to easily enter the cells of intact 4 and 6 week p.i. schistosomes as well as mammalian NIH 3T3 cells and together, these data suggest that the differential effects of PZQ is not based on cell exclusion but probably due the differential expression of a target molecule at 6 weeks p.i. A transcriptomal analysis of gene expression between 4 and 6 weeks p.i. revealed 607 candidate genes whose products are potential PZQ targets. A comparison of this gene list with that of genes expressed by PZQ sensitive miracidia reduced this target list to 247 genes, including a number involved in aerobic metabolism and cytosolic calcium regulation. Finally, we also report the effect of an in vitro sub-lethal exposure of PZQ on the transcriptome of S. mansoni PR-1. Annotation of genes differentially regulated by PZQ exposure suggests that schistosomes may undergo a transcriptomic response similar to that observed during oxidative stress. Keywords: cell type comparison, time course Cell type comparison: Four biologial replactes of schistosomes harvasted 4 and 6 week post-infection were performed. Time course: Four samples performed in duplicate for exposure to a sub-lethal dose of PZQ (50 M-BM-5g/ml) at time points 0, 30, 60, and 240 min over a common reference sample.
2008-11-10 | E-GEOD-12850 | biostudies-arrayexpress