Pub Date : 2025-02-01DOI: 10.1016/j.molbiopara.2024.111664
J.A. Black , B.C. Poulton , B. Gonzaga , A. Iskantar , D. Paape , L.R.O. Tosi. , R. McCulloch
Eukaryotic chromosomes segregate faithfully prior to nuclear division to ensure genome stability. If segregation becomes defective, the chromosome copy number of the cell may alter leading to aneuploidy and/or polyploidy, both common hallmarks of cancers. In eukaryotes, aurora kinases regulate chromosome segregation during mitosis and meiosis, but their functions in the divergent, single-celled eukaryotic pathogen Trypanosoma brucei are less understood. Here, we focused on one of three aurora kinases in these parasites, TbAUK3, a homologue of the human aurora kinase AURKC, whose functions are primarily restricted to meiosis. We show that RNAi targeted depletion of TbAUK3 correlates with nuclear segregation defects, reduced proliferation, and decreased DNA synthesis, suggestive of a role for TbAUK3 during mitotic, not meiotic, chromosome segregation. Moreover, we uncover a putative role for TbAUK3 during the parasite's response to DNA damage since we show that depletion of TbAUK3 enhances DNA instability and sensitivity to genotoxic agents.
{"title":"AUK3 is required for faithful nuclear segregation in the bloodstream form of Trypanosoma brucei","authors":"J.A. Black , B.C. Poulton , B. Gonzaga , A. Iskantar , D. Paape , L.R.O. Tosi. , R. McCulloch","doi":"10.1016/j.molbiopara.2024.111664","DOIUrl":"10.1016/j.molbiopara.2024.111664","url":null,"abstract":"<div><div>Eukaryotic chromosomes segregate faithfully prior to nuclear division to ensure genome stability. If segregation becomes defective, the chromosome copy number of the cell may alter leading to aneuploidy and/or polyploidy, both common hallmarks of cancers. In eukaryotes, aurora kinases regulate chromosome segregation during mitosis and meiosis, but their functions in the divergent, single-celled eukaryotic pathogen <em>Trypanosoma brucei</em> are less understood. Here, we focused on one of three aurora kinases in these parasites, TbAUK3, a homologue of the human aurora kinase AURKC, whose functions are primarily restricted to meiosis. We show that RNAi targeted depletion of TbAUK3 correlates with nuclear segregation defects, reduced proliferation, and decreased DNA synthesis, suggestive of a role for TbAUK3 during mitotic, not meiotic, chromosome segregation. Moreover, we uncover a putative role for TbAUK3 during the parasite's response to DNA damage since we show that depletion of TbAUK3 enhances DNA instability and sensitivity to genotoxic agents.</div></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":"261 ","pages":"Article 111664"},"PeriodicalIF":1.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.molbiopara.2024.111663
Mehdi Karamian , Esmat Alemzadeh , Ali Abedi , Soudabeh Eshaghi , Meghdad Abdollahpour-Alitappeh , Effat Alemzadeh , Motahareh Mahi-Birjand
Cutaneous leishmaniasis is considered as one of the most concerns of the World Health Organization (WHO). The main objective of this study was to use polycaprolactone (PCL) nanofiber scaffolds in order to provide a topical drug delivery system capable of delivering glucantime (glu) and quercetin (qur) to cutaneous leishmaniasis wounds. First, PCL/glu/qur, PCL/glu, and PCL/qur nanofibers were prepared by an electrospinning method followed by characterization through scanning electron microscopy (SEM) and fourier transform infrared spectroscopy (FTIR). Subsequently, we investigated the release of the drugs from nano-scaffolds and anti-promastigote effects. Lastly, the effect of nanobandage was evaluated on 20 female inbred BALB/c mice infected with the parasite. The nanofibers were bead-free and uniform with an average diameter of 224 ± 25 nm and showed a sustained release. Results from in vivo experiments showed that the number of amastigotes and macrophages infected with the parasite and the infiltration of inflammatory cells in mice treated with PCL/qur and PCL/glu/qur nanofibers significantly decreased as compared with those treated with the PCL/glu and PCL nanofibers. Collectively, PCL/glu/qur and PCL/qur nanofibers have promising therapeutic effects in cutaneous leishmaniasis wound healing.
{"title":"Glucantime and quercetin electrospun nanofiber membranes: Fabrication and their evaluation as dressing for cutaneous leishmaniasis","authors":"Mehdi Karamian , Esmat Alemzadeh , Ali Abedi , Soudabeh Eshaghi , Meghdad Abdollahpour-Alitappeh , Effat Alemzadeh , Motahareh Mahi-Birjand","doi":"10.1016/j.molbiopara.2024.111663","DOIUrl":"10.1016/j.molbiopara.2024.111663","url":null,"abstract":"<div><div>Cutaneous leishmaniasis is considered as one of the most concerns of the World Health Organization (WHO). The main objective of this study was to use polycaprolactone (PCL) nanofiber scaffolds in order to provide a topical drug delivery system capable of delivering glucantime (glu) and quercetin (qur) to cutaneous leishmaniasis wounds. First, PCL/glu/qur, PCL/glu, and PCL/qur nanofibers were prepared by an electrospinning method followed by characterization through scanning electron microscopy (SEM) and fourier transform infrared spectroscopy (FTIR). Subsequently, we investigated the release of the drugs from nano-scaffolds and anti-promastigote effects. Lastly, the effect of nanobandage was evaluated on 20 female inbred BALB/c mice infected with the parasite. The nanofibers were bead-free and uniform with an average diameter of 224 ± 25 nm and showed a sustained release. Results from <em>in vivo</em> experiments showed that the number of amastigotes and macrophages infected with the parasite and the infiltration of inflammatory cells in mice treated with PCL/qur and PCL/glu/qur nanofibers significantly decreased as compared with those treated with the PCL/glu and PCL nanofibers. Collectively, PCL/glu/qur and PCL/qur nanofibers have promising therapeutic effects in cutaneous leishmaniasis wound healing.</div></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":"261 ","pages":"Article 111663"},"PeriodicalIF":1.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-31DOI: 10.1016/j.molbiopara.2025.111672
Sidhant Jain
In this work the relationship between Schistosoma mansoni (Sm) and the induction and progression of colorectal cancer (CRC) is examined. Various clinical studies reviewed here yield inconsistent results, with some reporting no association between Sm infection and CRC and others suggesting a probable to strong association. Here we propose a number of plausible mechanisms whereby Sm infection might contribute to CRC induction and/or progression. These factors are (1) chronic inflammation, (2) exposure to parasite linked antigens and genotoxic products, especially soluble egg antigens (SEAs) and (3) alteration of the intestinal microbiota. These factors probably predispose humans towards CRC and can help in CRC progression however only widespread epidemiological, clinical and pathological studies can firmly establish their role or a complete lack of it.
{"title":"Does Schistosoma mansoni trigger colorectal cancer?","authors":"Sidhant Jain","doi":"10.1016/j.molbiopara.2025.111672","DOIUrl":"10.1016/j.molbiopara.2025.111672","url":null,"abstract":"<div><div>In this work the relationship between <em>Schistosoma mansoni</em> (Sm) and the induction and progression of colorectal cancer (CRC) is examined. Various clinical studies reviewed here yield inconsistent results, with some reporting no association between Sm infection and CRC and others suggesting a probable to strong association. Here we propose a number of plausible mechanisms whereby Sm infection might contribute to CRC induction and/or progression. These factors are (1) chronic inflammation, (2) exposure to parasite linked antigens and genotoxic products, especially soluble egg antigens (SEAs) and (3) alteration of the intestinal microbiota. These factors probably predispose humans towards CRC and can help in CRC progression however only widespread epidemiological, clinical and pathological studies can firmly establish their role or a complete lack of it.</div></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":"262 ","pages":"Article 111672"},"PeriodicalIF":1.4,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1016/j.molbiopara.2025.111675
Kayode K. Ojo, Sumiti Vinayak
{"title":"Molecular and biochemical characterization of parasites protein phosphorylation: Emerging trends, challenges and opportunities","authors":"Kayode K. Ojo, Sumiti Vinayak","doi":"10.1016/j.molbiopara.2025.111675","DOIUrl":"10.1016/j.molbiopara.2025.111675","url":null,"abstract":"","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":"262 ","pages":"Article 111675"},"PeriodicalIF":1.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-26DOI: 10.1016/j.molbiopara.2025.111673
Amal I. El-Refaiy , Nahed S. Amer , Amani Alhejely , Safa H. Qahl , Amira M. Shaban , Amro E. Mohamed , Amira A. Saleh , Abdelnaser A. Badawy , Mohammed A. El-Magd
This study investigated the effect of dandelion (Taraxacum officinale) leaf aqueous extract (DLE) on the immunological response of mice following infection with Schistosoma mansoni. Mice (in groups of 7) were first experimentally infected with S. mansoni and, 6 weeks later, were treated with praziquantel (PZQ) and/or DLE. Control mice were uninfected. In contrast to the untreated group, animals given PZQ and/or DLE exhibited an enhanced immunological response, as indicated by increased serum IFNγ, TNFα, IL4 and IL10 levels, increased numbers of CD4 + and CD25 + cells in blood and spleen and altered expression of apoptosis-related genes (low Bax and caspase3 and high Bcl2) in the spleen. DLE treatment had a significantly bigger impact in all these parameters compared with PZQ alone and combined DLE/PZQ treatment have the largest effect. While DLE treatment alone significantly decreased parasite burden, it did not improve upon the greater protective effect of PZQ, even when given in combination.
{"title":"Impact of dandelion (Taraxacum officinale) leaf aqueous extract on immunological response of mice after Schistosoma mansoni infection","authors":"Amal I. El-Refaiy , Nahed S. Amer , Amani Alhejely , Safa H. Qahl , Amira M. Shaban , Amro E. Mohamed , Amira A. Saleh , Abdelnaser A. Badawy , Mohammed A. El-Magd","doi":"10.1016/j.molbiopara.2025.111673","DOIUrl":"10.1016/j.molbiopara.2025.111673","url":null,"abstract":"<div><div>This study investigated the effect of dandelion (<em>Taraxacum officinale</em>) leaf aqueous extract (DLE) on the immunological response of mice following infection with <em>Schistosoma mansoni</em>. Mice (in groups of 7) were first experimentally infected with <em>S. mansoni</em> and, 6 weeks later, were treated with praziquantel (PZQ) and/or DLE. Control mice were uninfected. In contrast to the untreated group, animals given PZQ and/or DLE exhibited an enhanced immunological response, as indicated by increased serum IFNγ, TNFα, IL4 and IL10 levels, increased numbers of CD4 + and CD25 + cells in blood and spleen and altered expression of apoptosis-related genes (low <em>Bax</em> and caspase3 and high <em>Bcl2</em>) in the spleen. DLE treatment had a significantly bigger impact in all these parameters compared with PZQ alone and combined DLE/PZQ treatment have the largest effect. While DLE treatment alone significantly decreased parasite burden, it did not improve upon the greater protective effect of PZQ, even when given in combination.</div></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":"262 ","pages":"Article 111673"},"PeriodicalIF":1.4,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-26DOI: 10.1016/j.molbiopara.2025.111674
Cristian Vicson Gomes Pinheiro , Yasmim Mendes Rocha , João Pedro Viana Rodrigues , Gabriel Acácio de Moura , Juliana Ramos de Oliveira , Francisco Dantas Lourenço , Maria Jânia Teixeira , Valentina Nascimento Melo de Oliveira , Ronaldo Nascimento de Oliveira , Wildson Max Barbosa da Silva , Sara Ingrid Caetano Gomes Barbosa , Daniela Ribeiro Alves , Selene Maia de Morais , Roberto Nicolete
Globally, an estimated 1 billion people reside in endemic areas, and over 12 million individuals are infected with leishmaniasis. Despite its prevalence, leishmaniasis continues to be a neglected disease, mainly affecting underdeveloped countries. In Brazil, the available treatments are pentavalent antimonials and amphotericin B, which are outdated, toxic, require prolonged parenteral administration and have limited efficacy. The heterocyclic ring oxadiazole has been documented in the literature to possess various biological activities, including leishmanicidal properties, thus positioning it as a potential candidate for further investigation. This study aims to evaluate the in vitro leishmanicidal activity of an oxadiazole compound (2i), explore its mechanism of action through enzymatic inhibition and molecular docking, assess its antioxidant activity, and conduct an in silico pharmacokinetic prediction. Pharmacokinetic predictions via ADME/TOX modeling revealed that the 2i molecule exhibits good intestinal absorption (92 %), is water-insoluble (-4 log.mol/L) and demonstrates high permeability in Caco-2 cells (1.35 log.Papp10–6cm/s), suggesting potential for oral administration. Metabolic studies indicated that oxadiazole 2i is an inhibitor of cytochrome P450 enzymes CYP1A2 and CYP2C19, necessitating further evaluation of potential drug interactions. Additionally, it did not exhibit hepatotoxicity or cardiotoxicity; however, it demonstrated mutagenic potential in the salmonella reverse mutation test (AMES), which is a genetic method that detects mutagenic chemical agents, thus justifying more complex confirmatory studies. In vitro assays showed that oxadiazole 2i has DPPH (2,2-diphenyl-1-picrylhydrazyl) radical reducing activity, indicating potential antioxidant properties with an IC50 of 12.10 µg/mL. Concerning its leishmanicidal mechanism of action, molecular docking simulations at the active site of acetylcholinesterase demonstrated that the 2i molecule had superior binding energy values compared to the reference drug physostigmine (-7.39 kcal/mol versus −6.66 kcal/mol, respectively). However, the pharmacophore map revealed that physostigmine had more molecular interactions than oxadiazole 2i. In acetylcholinesterase inhibition assays, the 2i molecule exhibited significant inhibitory activity with an IC50 of 11.91 µg/mL, suggesting a mechanism of action that compromises the parasitic membrane. Moreover, the 2i molecule demonstrated significant leishmanicidal activity against L. infantum with an IC50 of 30.86 μM. Cytotoxicity assays on RAW 264.7 macrophages revealed a high CC50 value of 485.5 µM and a selectivity index (SI) of 17.86. Based on these findings, oxadiazole 2i emerges as a promising candidate for further study, offering prospects for more affordable, selective, and less toxic leishmanicidal agents.
{"title":"In Silico and in vitro assessment of anti-leishmania infantum activity of a novel cyclohexyl-1,2,4-oxadiazole derivative","authors":"Cristian Vicson Gomes Pinheiro , Yasmim Mendes Rocha , João Pedro Viana Rodrigues , Gabriel Acácio de Moura , Juliana Ramos de Oliveira , Francisco Dantas Lourenço , Maria Jânia Teixeira , Valentina Nascimento Melo de Oliveira , Ronaldo Nascimento de Oliveira , Wildson Max Barbosa da Silva , Sara Ingrid Caetano Gomes Barbosa , Daniela Ribeiro Alves , Selene Maia de Morais , Roberto Nicolete","doi":"10.1016/j.molbiopara.2025.111674","DOIUrl":"10.1016/j.molbiopara.2025.111674","url":null,"abstract":"<div><div>Globally, an estimated 1 billion people reside in endemic areas, and over 12 million individuals are infected with leishmaniasis. Despite its prevalence, leishmaniasis continues to be a neglected disease, mainly affecting underdeveloped countries. In Brazil, the available treatments are pentavalent antimonials and amphotericin B, which are outdated, toxic, require prolonged parenteral administration and have limited efficacy. The heterocyclic ring oxadiazole has been documented in the literature to possess various biological activities, including leishmanicidal properties, thus positioning it as a potential candidate for further investigation. This study aims to evaluate the <em>in vitro</em> leishmanicidal activity of an oxadiazole compound (2i), explore its mechanism of action through enzymatic inhibition and molecular docking, assess its antioxidant activity, and conduct an <em>in silico</em> pharmacokinetic prediction. Pharmacokinetic predictions via ADME/TOX modeling revealed that the 2i molecule exhibits good intestinal absorption (92 %), is water-insoluble (-4 log.mol/L) and demonstrates high permeability in Caco-2 cells (1.35 log.Papp10–6cm/s), suggesting potential for oral administration. Metabolic studies indicated that oxadiazole 2i is an inhibitor of cytochrome P450 enzymes CYP1A2 and CYP2C19, necessitating further evaluation of potential drug interactions. Additionally, it did not exhibit hepatotoxicity or cardiotoxicity; however, it demonstrated mutagenic potential in the salmonella reverse mutation test (AMES), which is a genetic method that detects mutagenic chemical agents, thus justifying more complex confirmatory studies. <em>In vitro</em> assays showed that oxadiazole 2i has DPPH (2,2-diphenyl-1-picrylhydrazyl) radical reducing activity, indicating potential antioxidant properties with an IC<sub>50</sub> of 12.10 µg/mL. Concerning its leishmanicidal mechanism of action, molecular docking simulations at the active site of acetylcholinesterase demonstrated that the 2i molecule had superior binding energy values compared to the reference drug physostigmine (-7.39 kcal/mol versus −6.66 kcal/mol, respectively). However, the pharmacophore map revealed that physostigmine had more molecular interactions than oxadiazole 2i. In acetylcholinesterase inhibition assays, the 2i molecule exhibited significant inhibitory activity with an IC<sub>50</sub> of 11.91 µg/mL, suggesting a mechanism of action that compromises the parasitic membrane. Moreover, the 2i molecule demonstrated significant leishmanicidal activity against <em>L. infantum</em> with an IC<sub>50</sub> of 30.86 μM. Cytotoxicity assays on RAW 264.7 macrophages revealed a high CC<sub>50</sub> value of 485.5 µM and a selectivity index (SI) of 17.86. Based on these findings, oxadiazole 2i emerges as a promising candidate for further study, offering prospects for more affordable, selective, and less toxic leishmanicidal agents.</div></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":"262 ","pages":"Article 111674"},"PeriodicalIF":1.4,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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