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International Journal For Parasitology.... Aug 2020Human schistosomiasis is a disease which globally affects over 229 million people. Three major species affecting humans are Schistosoma mansoni, S. haematobium and S....
Human schistosomiasis is a disease which globally affects over 229 million people. Three major species affecting humans are Schistosoma mansoni, S. haematobium and S. japonicum. Previous treatment of S. mansoni includes the use of oxamniquine (OXA), a prodrug that is enzymatically activated in S. mansoni but is ineffective against S. haematobium and S. japonicum. The OXA activating enzyme was identified and crystallized, as being a S. mansoni sulfotransferase (SmSULT). S. haematobium and S. japonicum possess homologs of SmSULT (ShSULT and SjSULT) begging the question; why does oxamniquine fail to kill S. haematobium and S. japonicum adult worms? Investigation of the molecular structures of the sulfotransferases indicates that structural differences, specifically in OXA contact residues, do not abrogate OXA binding in the active sites as previously hypothesized. Data presented argue that the ability of SULTs to sulfate and thus activate OXA and its derivatives is linked to the ability of OXA to fit in the binding pocket to allow the transfer of a sulfur group.
Topics: Animals; Molecular Structure; Oxamniquine; Schistosoma; Schistosoma haematobium; Schistosoma japonicum; Schistosoma mansoni; Schistosomicides; Sulfotransferases
PubMed: 32315953
DOI: 10.1016/j.ijpddr.2020.04.001 -
Biochemical and Biophysical Research... May 2022Schistosoma japonicum is a parasitic worm that lives in the mesenteric vein of its host and feeds on blood, suggesting that it might be a natural resource of novel...
Schistosoma japonicum is a parasitic worm that lives in the mesenteric vein of its host and feeds on blood, suggesting that it might be a natural resource of novel anticoagulants. Here, by comprehensive analyses of the genomic sequences of Schistosoma japonicum, a new Kunitz-type gene precursor was identified. The Kunitz-type gene precursor codes for an 18-residue signal peptide and a 60-residue mature peptide. The Kunitz peptide was functionally expressed, and it had apparent inhibitory activity towards the intrinsic coagulation pathway but no effect on the extrinsic coagulation pathway even at the high concentration of 3 μM. Enzyme and inhibitor experiments further showed that the Kunitz domain peptide was a potent and selective FXa inhibitor, so it was named Schixator (Schistosoma FXa inhibitor). Schixator inhibits coagulation factor FXa with a Ki of 2.66 nM, but had weak inhibitory activity towards chymotrypsin, FXIa, plasma kallikrein, and plasmin, and no inhibitory activity towards trypsin, elastase, FIIa or FXIIa. In vivo, the intravenous administration of Schixator into mice dramatically decreased the number of thrombi in the carotid artery in an FeCl-induced thrombus formation model without producing bleeding complications. To the best of our knowledge, Schixator is the first potent and selective FXa inhibitor from parasitic worms with antithrombotic effects and a low bleeding risk that provides a new clue for lead drug discovery against thrombosis-associated human diseases.
Topics: Animals; Anticoagulants; Blood Coagulation; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Mice; Schistosoma japonicum; Thrombosis
PubMed: 35287055
DOI: 10.1016/j.bbrc.2022.03.005 -
PLoS Neglected Tropical Diseases Oct 2023Excretory/secretory products (ESPs) derived from helminths have been reported to effectively control allergic inflammation, which have better therapeutic prospects than...
INTRODUCTION
Excretory/secretory products (ESPs) derived from helminths have been reported to effectively control allergic inflammation, which have better therapeutic prospects than live parasite infections. However, it remains unknown whether ESPs from schistosome eggs can protect against allergies, despite reports alleging that schistosome infection could alleviate disordered allergic inflammation.
METHOD
In the present study, we investigated the protective effects of ESPs from Schistosoma japonicum eggs (ESP-SJE) on asthmatic inflammation. Firstly, we successfully established an allergic airway inflammation model in mice by alum-adjuvanted ovalbumin (OVA) sensitization and challenge. ESP-SJE were administered intraperitoneally on days -1 and 13 (before sensitization), on day 20 (before challenge), and on days 21-24 (challenge phase).
RESULTS
The results showed that ESP-SJE treatment significantly reduced the infiltration of inflammatory cells, especially eosinophils into the lung tissue, inhibited the production of the total and OVA-specific IgE during OVA-sensitized and -challenged phases, respectively, and suppressed the secretion of Th2-type inflammatory cytokines (IL-4). Additionally, ESP-SJE treatment significantly upregulated the regulatory T cells (Tregs) in the lung tissue during OVA challenge. Furthermore, using liquid chromatography-mass spectrometry analysis and Treg induction experiments in vitro, we might identify nine potential therapeutic proteins against allergic inflammation in ESP-SJE. The targets of these candidate proteins included glutathione S-transferase, egg protein CP422 precursor, tubulin alpha-2/alpha-4 chain, actin-2, T-complex protein 1 subunit beta, histone H₄, whey acidic protein core region, and molecular chaperone HtpG.
CONCLUSION
Taken together, the results discussed herein demonstrated that ESP-SJE could significantly alleviate OVA-induced asthmatic inflammation in a murine model, which might be mediated by the upregulation of Treg in lung tissues that may be induced by the potential modulatory proteins. Therefore, potential proteins in ESP-SJE might be the best candidates to be tested for therapeutic application of asthma, thus pointing out to a possible new therapy for allergic airway inflammation.
Topics: Animals; Mice; Ovalbumin; Schistosoma japonicum; Egg Hypersensitivity; Asthma; Lung; Cytokines; Inflammation; Mice, Inbred BALB C; Bronchoalveolar Lavage Fluid; Disease Models, Animal
PubMed: 37788409
DOI: 10.1371/journal.pntd.0011625 -
Parasitology Research Jan 2021A vaccine is an important method to control schistosomiasis. Molecules related to lung-stage schistosomulum are considered potential vaccine candidates. We previously...
A vaccine is an important method to control schistosomiasis. Molecules related to lung-stage schistosomulum are considered potential vaccine candidates. We previously showed that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and cathepsin L3 (CL3) displayed differential expression in the lung-stage schistosomula of Schistosoma japonicum cocultured with host cells. In the present study, we prepared the two proteins and detected the protective effects of SjGAPDH by immunizing mice with this protein alone and in combination with SjCL3 with or without Freund's adjuvant. Then, we investigated the possible mechanisms underlying S. japonicum infection. The results showed that vaccination of adjuvanted SjGAPDH decreased the worm burden (37.8%) and egg load (38.1%), and the combination of adjuvanted SjGAPDH and SjCL3 further decreased the worm burden (65.6%) and egg load (70.9%) during Schistosoma japonicum infection. However, the immunization of a combination of adjuvant-free SjGAPDH and SjCL3 displayed a lower protective effect (< 15%) than those of the adjuvanted SjCL3, the adjuvanted SjGAPDH, and a combination of adjuvanted SjGAPDH and SjCL3. Flow cytometric results showed that the frequency of regulatory T cells (Tregs) was lower (P < 0.05) in the group with adjuvanted SjGAPDH and SjCL3 (2.61%) than the remaining groups. The enzyme-linked immunosorbent assay (ELISA) results indicated that except for the uninfected and infected control groups, the remaining groups displayed a Th1-type shift in immune responses. These results showed the immunization of SjGAPDH resulted in partial protection (approximately 38%); inoculation with a combination of SjCL3 and SjGAPDH in Freund's adjuvant resulted in a high immunoprotective effect (> 65%) against Schistosoma japonicum infection in mice, which was possibly caused by the reduced percentage of Tregs and a Th1-type shift in immune responses; and SjCL3 has no adjuvant-like effect, dissimilar to SmCL3.
Topics: Animals; Cathepsins; Female; Glyceraldehyde-3-Phosphate Dehydrogenases; Helminth Proteins; Mice; Mice, Inbred BALB C; Schistosoma japonicum; Schistosomiasis japonica; T-Lymphocytes, Regulatory; Vaccination; Vaccines
PubMed: 33079271
DOI: 10.1007/s00436-020-06916-9 -
Parasites & Vectors Dec 2023Schistosomiasis, the second largest parasitic disease in the world after malaria, poses a significant threat to human health and causes public health issues. The disease... (Review)
Review
Exploring the immune interactions between Oncomelania hupensis and Schistosoma japonicum, with a cross-comparison of immunological research progress in other intermediate host snails.
Schistosomiasis, the second largest parasitic disease in the world after malaria, poses a significant threat to human health and causes public health issues. The disease primarily affects populations in economically underdeveloped tropical regions, earning it the title of "neglected tropical disease". Schistosomiasis is difficult to eradicate globally if medication alone is used. One of the essential elements of thorough schistosomiasis prevention and control is the management and disruption of the life cycle of intermediate host snails. The key approach to controlling the transmission of schistosomiasis is to control the intermediate hosts of the schistosome to disrupt its life cycle. We believe that approaching it from the perspective of the intermediate host's immunity could be an environmentally friendly and potentially effective method. Currently, globally significant intermediate host snails for schistosomes include Oncomelania hupensis, Biomphalaria glabrata, and Bulinus truncatus. The immune interaction research between B. glabrata and Schistosoma mansoni has a history of several decades, and the complete genome sequencing of both B. glabrata and B. truncatus has been accomplished. We have summarized the immune-related factors and research progress primarily studied in B. glabrata and B. truncatus and compared them with several humoral immune factors that O. hupensis research focuses on: macrophage migration inhibitory factor (MIF), Toll-like receptors (TLRs), and thioredoxin (Trx). We believe that continued exploration of the immune interactions between O. hupensis and Schistosoma japonicum is valuable. This comparative analysis can provide some direction and clues for further in-depth research. Comparative immunological studies between them not only expand our understanding of the immune defense responses of snails that act as intermediaries for schistosomes but also facilitate the development of more comprehensive and integrated strategies for schistosomiasis prevention and control. Furthermore, it offers an excellent opportunity to study the immune system of gastropods and their co-evolution with pathogenic organisms.
Topics: Animals; Humans; Schistosoma japonicum; Schistosomiasis; Biomphalaria; Bulinus; Schistosoma mansoni
PubMed: 38093363
DOI: 10.1186/s13071-023-06011-9 -
Parasites & Vectors Jun 2023Schistosomiasis is a serious but neglected parasitic disease in humans that may lead to liver fibrosis and death. Activated hepatic stellate cells (HSCs) are the...
BACKGROUND
Schistosomiasis is a serious but neglected parasitic disease in humans that may lead to liver fibrosis and death. Activated hepatic stellate cells (HSCs) are the principal effectors that promote the accumulation of extracellular matrix (ECM) proteins during hepatic fibrosis. Aberrant microRNA-29 expression is involved in the development of fibrotic diseases. However, less is known about the role of miR-29 in Schistosoma japonicum (S. japonicum)-induced hepatic fibrosis.
METHODS
The levels of microRNA-29a-3p (miR-29a-3p) and Roundabout homolog 1 (Robo1) were examined in liver tissues during S. japonicum infection. The possible involvement of the miR-29a-3p-Robo1 signaling pathway was determined. We used MIR29A conditional knock-in mice and mice injected with an miR-29a-3p agomir to investigate the role of miR-29a-3p in schistosomiasis-induced hepatic fibrosis. The functional contributions of miR-29a-3p-Robo1 signaling in liver fibrosis and HSC activation were investigated using primary mouse HSCs and the human HSC cell line LX-2.
RESULTS
MiR-29a-3p was downregulated in humans and mice with schistosome-induced fibrosis, and Robo1 was upregulated in liver tissues. The miR-29a-3p targeted Robo1 and negatively regulated its expression. Additionally, the expression level of miR-29a-3p in schistosomiasis patients was highly correlated with the portal vein and spleen thickness diameter, which represent the severity of fibrosis. Furthermore, we demonstrated that efficient and sustained elevation of miR-29a-3p reversed schistosome-induced hepatic fibrosis. Notably, we showed that miR-29a-3p targeted Robo1 in HSCs to prevent the activation of HSCs during infection.
CONCLUSIONS
Our results provide experimental and clinical evidence that the miR-29a-3p-Robo1 signaling pathway in HSCs plays an important role in the development of hepatic fibrosis. Therefore, our study highlights the potential of miR-29a-3p as a therapeutic intervention for schistosomiasis and other fibrotic diseases.
Topics: Humans; Mice; Animals; Schistosoma japonicum; Hepatic Stellate Cells; Nerve Tissue Proteins; MicroRNAs; Receptors, Immunologic; Liver Cirrhosis; Schistosomiasis
PubMed: 37280619
DOI: 10.1186/s13071-023-05791-4 -
Medicinal Chemistry (Shariqah (United... 2021The 26kDa glutathione transferase (GST, EC 2.5.1.18) from Schistosoma japonicum (SjGST) is recognized as the major detoxification enzyme of S. japonicum, a pathogenic...
BACKGROUND
The 26kDa glutathione transferase (GST, EC 2.5.1.18) from Schistosoma japonicum (SjGST) is recognized as the major detoxification enzyme of S. japonicum, a pathogenic helminth causing schistosomiasis.
OBJECTIVE
In the present study, the interaction of the chlorotriazine dye Cibacron blue 3GA (CB3GA) and its structural analogues with SjGST was investigated. The work aimed to shed light on the non-substrate ligand-binding properties of the enzyme.
METHODS
Kinetic inhibition analysis, affinity labelling experiments and molecular modelling studies were employed.
RESULTS
The results showed that CB3GA is a potent inhibitor (IC 0.057 ± 0.003 μM) towards SjGST. The enzyme was specifically and irreversibly inactivated by the dichlorotriazine-analogue of CB3GA (IC 0.190 ± 0.024 μM), following a biphasic pseudo-first-order saturation kinetics with approximately 1 mol of inhibitor per mol of the dimeric enzyme being incorporated. All other monochlorotriazine analogues behave as reversible inhibitors with lower inhibition potency (IC 5.2-82.3 μM). Kinetic inhibition studies, together with molecular modelling and molecular dynamics simulations, established that the CB3GA binding site overlaps both the G- and H-sites. Both hydrophobic/ polar interactions, as well as steric effects, have decisive roles in determining the inhibitory strength of CB3GA and its analogues.
CONCLUSION
The results of the present study might be useful in future drug design and development efforts towards SjGST.
Topics: Animals; Enzyme Assays; Enzyme Inhibitors; Glutathione Transferase; Helminth Proteins; Kinetics; Ligands; Molecular Docking Simulation; Protein Binding; Schistosoma japonicum; Triazines
PubMed: 32242785
DOI: 10.2174/1573406416666200403074742 -
Tropical Medicine and Infectious Disease Feb 2024We established a mouse model of infection in order to study the effects of the infection on hepatocyte autophagy and apoptosis. We also stimulated HepG2 cells with...
We established a mouse model of infection in order to study the effects of the infection on hepatocyte autophagy and apoptosis. We also stimulated HepG2 cells with soluble egg antigens (SEA) in vitro. At two, four, and six weeks post-infection, quantitative real-time PCR and Western blot (WB) were used to detect liver expression levels of autophagy and apoptosis-related proteins. HepG2 cells were treated with different concentrations of SEA. The changes in the levels of autophagy-related proteins and HepG2 cell apoptosis were detected. The , , , and mRNA levels were significantly lower at four and six weeks after infection than those in the uninfected group. At four and six weeks following infection, the levels of Beclin1, LC3BII/I, Atg7, and p62 proteins were considerably lower than those in the uninfected group. The protein levels of pro-apoptotic Bax and cleaved caspase 3 and fibrosis-related proteins α-SMA and collagen 3 in the liver post-infection were significantly higher than those in uninfected mice. HepG2 cells stimulated with SEA showed decreased levels of Beclin1, p62, and Atg7 proteins and significantly increased apoptosis rates. The findings demonstrated that following infection with , mice's liver fibrosis worsened, hepatic autophagy was suppressed, and hepatocyte apoptosis was encouraged.
PubMed: 38393131
DOI: 10.3390/tropicalmed9020042 -
Parasitology Research Nov 2023Schistosoma japonicum had once caused the greatest disease burden in China and has still been transmitted in some hilly areas, for example, in Shitai of Anhui province,...
Schistosoma japonicum had once caused the greatest disease burden in China and has still been transmitted in some hilly areas, for example, in Shitai of Anhui province, where rodents are projected to be the main reservoir. This may lead to a critical need of molecular tools with high efficiency in monitoring the dynamic of the rodent-associated S. japonicum, as an appropriate amount of schistosome input can re-establish its life cycle in a place with snails and then result in the re-emergence of schistosomiasis. Therefore, the goal of this study was to develop high polymorphic microsatellites from the whole genome of rodent-associated S. japonicum strain to monitor its transmission dynamic. We sampled the hilly schistosome isolate from Shitai of Anhui in China and sequenced the parasite with the next-generation sequencing technology. The whole genome was assembled with four different approaches. We then developed 71 microsatellite markers at a genome-wide scale throughout two best assembled genomes. Based on their chromosome mapping and the expected length of targeted sequences, we selected 24 markers for the development of multiplex reactions. Two multiplexes composed of 10 loci were finally developed, and their potential was revealed by their successful application on and capturing the genetic diversity of three schistosome populations. The selected 10 markers, each with clear chromosome location and characteristics, will be greatly useful in tracing the dispersal pathways or/and dynamics of the rodent-associated S. japonicum or others in the hilly area of China or elsewhere.
Topics: Animals; Schistosoma japonicum; Schistosomiasis japonica; China; Microsatellite Repeats; Snails; Rodentia; Whole Genome Sequencing
PubMed: 37710024
DOI: 10.1007/s00436-023-07976-3 -
Tropical Biomedicine Dec 2020Different miRNAs are involved in the life cycles of Schistosoma japonicum. The aim of this study was to examine the expression profile of miRNAs in individual S....
Different miRNAs are involved in the life cycles of Schistosoma japonicum. The aim of this study was to examine the expression profile of miRNAs in individual S. japonicum of different sex before and after pairing (18 and 24 dpi). The majority of differential expressed miRNAs were highly abundant at 14 dpi, except for sja-miR-125b and sja-miR-3505, in both male and female. Moreover, it was estimated that sja-miR-125b and sja-miR-3505 might be related to laying eggs. sja-miR-2a-5p and sja-miR-3484-5p were expressed at 14 dpi in males and were significantly clustered in DNA topoisomerase III, Rap guanine nucleotide exchange factor 1 and L-serine/L-threonine ammonia-lyase. Target genes of sja-miR-2d-5p, sja-miR-31- 5p and sja-miR-125a, which were expressed at 14 dpi in males but particularly females, were clustered in kelch-like protein 12, fructose-bisphosphate aldolase, class I, and heat shock protein 90 kDa beta. Predicted target genes of sja-miR-3483-3p (expressed at 28 dpi in females but not in males) were clustered in 26S proteasome regulatory subunit N1, ATPdependent RNA helicase DDX17. Predicted target genes of sja-miR-219-5p, which were differentially expressed at 28 dpi in females but particularly males, were clustered in DNA excision repair protein ERCC-6, protein phosphatase 1D, and ATPase family AAA domaincontaining protein 3A/B. Moreover, at 28 dpi, eight miRNAs were significantly up-regulated in females compared to males. The predicted target genes of these miRNAs were significantly clustered in heat shock protein 90 kDa beta, 26S proteasome regulatory subunit N1, and protein arginine N-methyltransferase 1. To sum up, differentially expressed miRNAs may have an essential role and provide necessary information on clarifying this trematode's growth, development, maturation, and infection ability to mammalian hosts in its complex life cycle, and may be helpful for developing new drug targets and vaccine candidates for schistosomiasis.
Topics: Animals; Female; Gene Expression Profiling; Life Cycle Stages; Male; Mice; MicroRNAs; Schistosoma japonicum
PubMed: 33612748
DOI: 10.47665/tb.37.4.947