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Journal of Medicinal Chemistry Jun 2024The NAD-dependent lysine deacylase sirtuin 2 (Sirt2) is involved in multiple pathological conditions such as cancer. Targeting Sirt2 has thus received an increased...
The NAD-dependent lysine deacylase sirtuin 2 (Sirt2) is involved in multiple pathological conditions such as cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purposes. Furthermore, the orthologue from (Sirt2) has been considered for the potential treatment of the neglected tropical disease schistosomiasis. We previously identified a 1,2,4-oxadiazole-based scaffold from the screening of the "Kinetobox" library as a dual inhibitor of human Sirt2 (hSirt2) and Sirt2. Herein, we describe the structure-activity studies on 1,2,4-oxadiazole-based analogues, which are potent inhibitors of human Sirt2 deacetylation. As proposed by docking studies, a substrate-competitive and cofactor-noncompetitive binding mode of inhibition could be determined binding assays and kinetic analysis and further confirmed by a crystal structure of an oxadiazole inhibitor in complex with hSirt2. Optimized analogues reduced cell viability and inhibited prostate cancer cell migration, in correlation with Sirt2 deacetylase inhibition both and in cells.
Topics: Sirtuin 2; Oxadiazoles; Humans; Structure-Activity Relationship; Molecular Docking Simulation; Animals; Cell Line, Tumor; Cell Survival; Schistosoma mansoni; Cell Movement
PubMed: 38847803
DOI: 10.1021/acs.jmedchem.4c00229 -
Folia Parasitologica May 2024Schistosomiasis is a snail-borne disease that has a considerable impact on human and animal health, particularly in sub-Saharan Africa. The intermediate hosts of the...
Schistosomiasis is a snail-borne disease that has a considerable impact on human and animal health, particularly in sub-Saharan Africa. The intermediate hosts of the schistosome parasites are freshwater snails of the genera Biomphalaria Preston, 1910 and Bulinus Müller, 1781. In order to identify existing gaps in the spread of the disease in the Democratic Republic of Congo (DRC), this study compiled the available knowledge of the distribution, population dynamics and ecology of the intermediate hosts of schistosomiasis. A systematic literature search was conducted in PubMed, Embase and Scopus for all malacological studies on schistosoma intermediate hosts in DRC published between 1927 and October 2022. A total of 55 records were found, of which 31 met the inclusion criteria: these were published field and experimental studies conducted in the DRC and focused on snails as intermediate hosts of schistosomes. The analysis of these studies revealed that more up-to-date data on the distribution of snail intermediate hosts in the DRC are needed. Moreover, ecological factors have been less studied for Bulinus species than for Biomphalaria species. These factors play a crucial role in determining suitable snail habitats, and the lack of comprehensive information poses a challenge in snail control. This review makes it clear that there are no current malacological data in the DRC. There is a clear need for molecular and ecological research to update the exact species status and population dynamics of all potential intermediate host species. This will facilitate targeted snail control measures that complement drug treatment in the control of schistosomiasis in the country.
Topics: Animals; Humans; Biomphalaria; Bulinus; Democratic Republic of the Congo; Schistosoma; Schistosomiasis; Snails
PubMed: 38841845
DOI: 10.14411/fp.2024.010 -
Frontiers in Immunology 2024Schistosomiasis remains the most devastating neglected tropical disease, affecting over 240 million people world-wide. The disease is caused by the eggs laid by mature...
Schistosomiasis remains the most devastating neglected tropical disease, affecting over 240 million people world-wide. The disease is caused by the eggs laid by mature female worms that are trapped in host's tissues, resulting in chronic Th2 driven fibrogranulmatous pathology. Although the disease can be treated with a relatively inexpensive drug, praziquantel (PZQ), re-infections remain a major problem in endemic areas. There is a need for new therapeutic drugs and alternative drug treatments for schistosomiasis. The current study hypothesized that cysteinyl leukotrienes (cysLTs) could mediate fibroproliferative pathology during schistosomiasis. Cysteinyl leukotrienes (cysLTs) are potent lipid mediators that are known to be key players in inflammatory diseases, such as asthma and allergic rhinitis. The present study aimed to investigate the role of cysLTR1 during experimental acute and chronic schistosomiasis using cysLTR1 mice, as well as the use of cysLTR1 inhibitor (Montelukast) to assess immune responses during chronic infection. Mice deficient of cysLTR1 and littermate control mice were infected with either high or low dose of to achieve chronic or acute schistosomiasis, respectively. Hepatic granulomatous inflammation, hepatic fibrosis and IL-4 production in the liver was significantly reduced in mice lacking cysLTR1 during chronic schistosomiasis, while reduced liver pathology was observed during acute schistosomiasis. Pharmacological blockade of cysLTR1 using montelukast in combination with PZQ reduced hepatic inflammation and parasite egg burden in chronically infected mice. Combination therapy led to the expansion of Tregs in chronically infected mice. We show that the disruption of cysLTR1 is dispensable for host survival during schistosomiasis, suggesting an important role cysLTR1 may play during early immunity against schistosomiasis. Our findings revealed that the combination of montelukast and PZQ could be a potential prophylactic treatment for chronic schistosomiasis by reducing fibrogranulomatous pathology in mice. In conclusion, the present study demonstrated that cysLTR1 is a potential target for host-directed therapy to ameliorate fibrogranulomatous pathology in the liver during chronic and acute schistosomiasis in mice.
Topics: Animals; Receptors, Leukotriene; Mice; Disease Models, Animal; Cyclopropanes; Acetates; Sulfides; Schistosomiasis mansoni; Mice, Knockout; Quinolines; Female; Schistosoma mansoni; Chronic Disease; Leukotriene Antagonists; Liver; Mice, Inbred C57BL; Praziquantel; T-Lymphocytes, Regulatory
PubMed: 38840916
DOI: 10.3389/fimmu.2024.1279043 -
Scientific Reports Jun 2024Schistosomiasis, caused by Schistosoma trematodes, is a significant global health concern, particularly affecting millions in Africa and Southeast Asia. Despite efforts...
Schistosomiasis, caused by Schistosoma trematodes, is a significant global health concern, particularly affecting millions in Africa and Southeast Asia. Despite efforts to combat it, the rise of praziquantel (PZQ) resistance underscores the need for new treatment options. Protein kinases (PKs) are vital in cellular signaling and offer potential as drug targets. This study focused on focal adhesion kinase (FAK) as a candidate for anti-schistosomal therapy. Transcriptomic and proteomic analyses of adult S. mekongi worms identified FAK as a promising target due to its upregulation and essential role in cellular processes. Molecular docking simulations assessed the binding energy of FAK inhibitors to Schistosoma FAK versus human FAK. FAK inhibitor 14 and PF-03814735 exhibited strong binding to Schistosoma FAK with minimal binding for human FAK. In vitro assays confirmed significant anti-parasitic activity against S. mekongi, S. mansoni, and S. japonicum, comparable to PZQ, with low toxicity in human cells, indicating potential safety. These findings highlight FAK as a promising target for novel anti-schistosomal therapies. However, further research, including in vivo studies, is necessary to validate efficacy and safety before clinical use. This study offers a hopeful strategy to combat schistosomiasis and reduce its global impact.
Topics: Animals; Humans; Proteomics; Schistosoma; Schistosomiasis; Transcriptome; Molecular Docking Simulation; Focal Adhesion Protein-Tyrosine Kinases; Helminth Proteins; Gene Expression Profiling; Protein Kinase Inhibitors; Proteome
PubMed: 38839835
DOI: 10.1038/s41598-024-63869-0 -
Parasites, Hosts and Diseases May 2024Sigma-class glutathione transferase (GST) proteins with dual GST and prostaglandin synthase (PGS) activities play a crucial role in the establishment of Clonorchis...
Sigma-class glutathione transferase (GST) proteins with dual GST and prostaglandin synthase (PGS) activities play a crucial role in the establishment of Clonorchis sinensis infection. Herein, we analyzed the structural and enzymatic properties of sigma-class GST (CsGST-σ) proteins to obtain insight into their antioxidant and immunomodulatory functions in comparison with mu-class GST (CsGST-μ) proteins. CsGST-σ proteins conserved characteristic structures, which had been described in mammalian hematopoietic prostaglandin D2 synthases. Recombinant forms of these CsGST-σ and CsGST-μ proteins expressed in Escherichia coli exhibited considerable degrees of GST and PGS activities with substantially different specific activities. All recombinant proteins displayed higher affinities toward prostaglandin H2 (PGS substrate; average Km of 30.7 and 3.0 μm for prostaglandin D2 [PGDS] and E2 synthase [PGES], respectively) than those toward CDNB (GST substrate; average Km of 1,205.1 μm). Furthermore, the catalytic efficiency (Kcat/Km) of the PGDS/PGES activity was higher than that of GST activity (average Kcat/Km of 3.1, 0.7, and 7.0×10-3 s-1μm-1 for PGDS, PGES, and GST, respectively). Our data strongly suggest that the C. sinensis sigma- and mu-class GST proteins are deeply involved in regulating host immune responses by generating PGD2 and PGE2 in addition to their roles in general detoxification.
Topics: Glutathione Transferase; Clonorchis sinensis; Animals; Intramolecular Oxidoreductases; Recombinant Proteins; Lipocalins; Escherichia coli; Prostaglandin H2; Kinetics
PubMed: 38835261
DOI: 10.3347/PHD.24004 -
Parasites, Hosts and Diseases May 2024Dipylidium caninum is a cosmopolitan parasite of companion animals such as dogs and cats. Accidental infection in humans occur mostly in children. Although considerable... (Review)
Review
Dipylidium caninum is a cosmopolitan parasite of companion animals such as dogs and cats. Accidental infection in humans occur mostly in children. Although considerable number of cases were reported from Europe and the Americas, case reports of this zoonotic disease are rather scarce from Asian countries. The aim of this study is to report the results of literature survey on dipylidiasis cases in humans in Japan. Conclusively, we have found a total of 17 cases since the first case report in from Aichi Prefecture in 1925.
Topics: Japan; Animals; Humans; Cats; Male; Dogs; Female; Child; Adult; Middle Aged; Cat Diseases; Zoonoses; Adolescent; Dog Diseases; Child, Preschool; Aged; Cestoda
PubMed: 38835257
DOI: 10.3347/PHD.23118 -
Journal of Helminthology Jun 2024A comparative analysis of taxonomic diversity on shrew cestodes among four islands in the Sea of Japan and the Sea of Okhotsk (Sakhalin, Kunashir, Hokkaido, and Moneron)...
A comparative analysis of taxonomic diversity on shrew cestodes among four islands in the Sea of Japan and the Sea of Okhotsk (Sakhalin, Kunashir, Hokkaido, and Moneron) was performed. Cestode species shared among the islands were identified and their host specificity was investigated. On Sakhalin Island, 33 species of the families Hymenolepididae, Dilepididae and Mesocestoididae were recorded in four shrew species (, , and ). In , , and on Kunashir Island, 22 species of the same families were found and, on Hokkaido Island, 23 species of the families Hymenolepididae and Dilepididae were recorded. On Moneron Island, three species of cestodes were registered in The Sakhalin-Hokkaido-Kunashir complex of shrew cestodes includes eastern-Palearctic, trans-Palearctic and endemic species. High endemism (~22%) of shrew tapeworms in the Sakhalin-Kunashir-Hokkaido Islands was noted as compared to continental territories. The different numbers of cestode species in (31), (29), (19) and (1) were found. It was concluded that the cestodes species diversity of shrews of Sakhalin-Kunashir-Hokkaido depended primarily on the history of island formation, their modern physical and geographical features, the abundance of definitive and intermediate cestodes hosts and, to a lesser extent, on the size and remoteness of the islands from the mainland and the diversity of host species.
Topics: Animals; Cestoda; Shrews; Japan; Islands; Biodiversity; Host Specificity; Cestode Infections
PubMed: 38828715
DOI: 10.1017/S0022149X24000324 -
Journal of Helminthology Jun 2024Relative to the numerous studies focused on mammalian schistosomes, fewer include avian schistosomatids particularly in the southern hemisphere. This is changing and...
Relative to the numerous studies focused on mammalian schistosomes, fewer include avian schistosomatids particularly in the southern hemisphere. This is changing and current research emerging from the Neotropics shows a remarkable diversity of endemic taxa. To contribute to this effort, nine ducks (, , ), 12 swans () and 1,400 spp. snails from Chile and Argentina were collected for adults and larval schistosomatids, respectively. Isolated schistosomatids were preserved for morphological and molecular analyses ( and genes). Four different schistosomatid taxa were retrieved from birds: sp. in and that formed a clade; and hosted ; hosted the nasal schistosomatid, ; and one visceral, Schistosomatidae gen. sp., which formed a clade with furcocercariae from Argentina and Chile from previous work. Of the physid snails, only one from Argentina had schistosomatid furcocercariae that based on molecular analyses grouped with This study represents the first description of adult schistosomatids from Chile as well as the elucidation of the life cycles of and in Chile and Neotropics, respectively. Without well-preserved adults, the putative new genus Schistosomatidae gen. sp. could not be described, but its life cycle involves spp. and Scanning electron microscopy of revealed additional, undescribed morphological traits, highlighting its diagnostic importance. Authors stress the need for additional surveys of avian schistosomatids from the Neotropics to better understand their evolutionary history.
Topics: Animals; Life Cycle Stages; Phylogeny; Schistosomatidae; Chile; Argentina; Birds; Bird Diseases; RNA, Ribosomal, 28S; Snails; South America; Electron Transport Complex IV
PubMed: 38828707
DOI: 10.1017/S0022149X2400035X -
Veterinary Parasitology Jul 2024The transmission of Fasciola hepatica occurs only where there are -or recently were- aquatic or amphibious snails of the Lymnaeidae family, the intermediate host of this...
The transmission of Fasciola hepatica occurs only where there are -or recently were- aquatic or amphibious snails of the Lymnaeidae family, the intermediate host of this parasite. Direct detection of these snails is time-consuming and imprecise, hindering accurate and detailed mapping of transmission risk. To identify which microenvironmental factors could be used as proxies for the occurrence of the lymnaeid snail Galba viator, a major intermediate host in South America, a total of 183 1-m quadrants across diverse water bodies in an endemic area in Andean Patagonia were manually timed-searched for snails and microenvironmental variables were registered. Data was analyzed using a Bayesian hierarchical occupancy model that assessed the effects of the microenvironmental variables on the presence of snails while considering imperfect snail detection. The model estimated that G. viator predominantly inhabits shallow aquatic environments, in the presence of grasses, where snails of the genus Biomphalaria are also detected, and with scarce tree canopy cover. Physical factors affecting occupancy presumably act as proxies for the average water temperature, while the temperature at the time of sampling was found to affect snail detectability. The identified variables are easy, fast, and inexpensive to measure, and can complement management decisions and risk maps based on coarser remote-sensing data, particularly relevant in a context of growing resistance to anthelminthic drugs.
Topics: Animals; Fasciola hepatica; Snails; Temperature; Water; Argentina; Fascioliasis; Bayes Theorem
PubMed: 38823188
DOI: 10.1016/j.vetpar.2024.110209 -
FASEB Journal : Official Publication of... Jun 2024Schistosome infection and schistosome-derived products have been implicated in the prevention and alleviation of inflammatory bowel disease by manipulating the host...
Schistosome infection and schistosome-derived products have been implicated in the prevention and alleviation of inflammatory bowel disease by manipulating the host immune response, whereas the role of gut microbiota in this protective effect remains poorly understood. In this study, we found that the intraperitoneal immunization with Schistosoma japonicum eggs prior to dextran sulfate sodium (DSS) application significantly ameliorated the symptoms of DSS-induced acute colitis, which was characterized by higher body weight, lower disease activity index score and macroscopic inflammatory scores. We demonstrated that the immunomodulatory effects of S. japonicum eggs were accompanied by an influence on gut microbiota composition, abundance, and diversity, which increased the abundance of genus Turicibacter, family Erysipelotrichaceae, phylum Firmicutes, and decreased the abundance of genus Odoribacter, family Marinifilaceae, order Bacteroidales, class Bacteroidia, phylum Bacteroidota. In addition, Lactobacillus was identified as a biomarker that distinguishes healthy control mice from DSS-induced colitis mice. The present study revealed the importance of the gut microbiota in S. japonicum eggs exerting protective effects in an experimental ulcerative colitis (UC) model, providing an alternative strategy for the discovery of UC prevention and treatment drugs.
Topics: Animals; Gastrointestinal Microbiome; Colitis, Ulcerative; Mice; Schistosoma japonicum; Dextran Sulfate; Female; Disease Models, Animal; Immunization; Ovum; Mice, Inbred C57BL
PubMed: 38822662
DOI: 10.1096/fj.202302576RR