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739 Publications visible to you, out of a total of 739
The activities of suaveolol and other compounds from Hyptis suaveolens and Momordica charantia against the aetiological agents of African trypanosomiasis, leishmaniasis and malaria

Abstract

Not specified

Authors: Enimie E. Oaikhena, Umar A. Yahaya, Sani M. Abdulsalami, Nkechi L. Egbe, Modupe M. Adeyemi, Marzuq A. Ungogo, Godwin U. Ebiloma, Felix K. Zoiku, Prince A. Fordjour, Hamza A.A. Elati, Neils B. Quashie, John O. Igoli, Alexander I. Gray, Christopher Lawson, Valerie A. Ferro, Harry P. de Koning

Date Published: 1st Aug 2024

Publication Type: Journal Article

Spliced-Leader RNA as a Dynamic Marker for Monitoring Viable Leishmania Parasites During and After Treatment.

Abstract (Expand)

Accurate detection of viable Leishmania parasites is critical for evaluating visceral leishmaniasis (VL) treatment response at an early timepoint. We compared the decay of kinetoplast DNA (kDNA) and … spliced-leader RNA (SL-RNA) in vitro, in vivo, and in a VL patient cohort. An optimized combination of blood preservation and nucleic acid extraction improved efficiency for both targets. SL-RNA degraded more rapidly during treatment than kDNA, and correlated better with microscopic examination. SL-RNA quantitative polymerase chain reaction emerges as a superior method for dynamic monitoring of viable Leishmania parasites. It enables individualized treatment monitoring for improved prognoses and has potential as an early surrogate endpoint in clinical trials.

Authors: R. Hendrickx, R. Melkamu, D. Tadesse, T. Teferi, P. B. Feijens, M. Vleminckx, S. van Henten, F. Alves, T. Shibru, J. van Griensven, G. Caljon, M. Pareyn

Date Published: 25th Jul 2024

Publication Type: Journal Article

Broadening The Substrate Scope of Aldolases Through Metagenomic Enzyme Discovery

Abstract (Expand)

Bio‐processes based on enzymatic catalysis play a major role in the development of green, sustainable processes, and the discovery of new enzymes is key to this approach. In this work, we analysed ten … metagenomes and retrieved 48 genes coding for deoxyribose‐5‐phosphate aldolases (DERAs, EC 4.1.2.4) using a sequence‐based approach. These sequences were recombinantly expressed in Escherichia coli and screened for activity towards a range of aldol additions. Among these, one enzyme, DERA‐61, proved to be particularly interesting and catalysed the aldol addition of furfural or benzaldehyde with acetone, butanone and cyclobutanone with unprecedented activity. The product of these reactions, aldols, can find applications as building blocks in the synthesis of biologically active compounds. Screening was carried out to identify optimized reaction conditions targeting temperature, pH, and salt concentrations. Lastly, the kinetics and the stereochemistry of the products were investigated, revealing that DERA‐61 and other metagenomic DERAs have superior activity and stereoselectivity when they are provided with non‐natural substrates, compared to well‐known DERAs.

Authors: Andrea Rizzo, Maria Carmen Aranda, James Galman, Annette Alcasabas, Akash Pandya, Amin Bornadel, Bruna Costa, Helen C Hailes, John M Ward, Jack W.E. Jeffries, Beatriz Dominguez

Date Published: 2nd Jul 2024

Publication Type: Journal Article

Metronidazole Interaction with Cu(2+) and Zn(2+): Speciation Study in Aqueous Solution and Biological Activity Evaluation.

Abstract (Expand)

Metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol, MNZ) is a well-known and widely used drug for its excellent activity against various anaerobic bacteria and protozoa. The purpose of this study … is to elucidate the ability of MNZ to form metal complexes with Cu(2+) and Zn(2+) and to demonstrate that complexation increases its bioactivity profile against different pathogenic microorganisms. The interaction of MNZ with Cu(2+) and Zn(2+) was investigated in NaCl aqueous solution under different conditions of temperature (15, 25, and 37 degrees C) and ionic strength (0.15, 0.5, and 1 mol L(-1)) by potentiometric and spectrophotometric titrations. The obtained speciation models include two species for the Cu(2+)-containing system, namely, CuL and CuL(2), and three species for the Zn(2+)-containing system, namely, ZnLH, ZnL, and ZnLOH. The formation constants of the species were calculated and their dependence on temperature and ionic strength evaluated. Comparison of the sequestering ability of MNZ under physiological conditions revealed a capacity toward Cu(2+) higher than that toward Zn(2+). A simulation under the same conditions also showed a significant percentage of the Cu(2+)-MNZ species. The biological assessments highlighted that the complexation of MNZ with Cu(2+) has a relevant impact on the potency of the drug against two Trypanosoma spp. (i.e., T. b. brucei and T. b. rhodesiense) and one gram-(-) bacterial species (i.e., Escherichia coli). It is noteworthy that the increased potency upon complexation with Cu(2+) did not result in cytotoxicity against MRC-5 human fetal lung fibroblasts and primary peritoneal mouse macrophages.

Authors: F. Carnamucio, C. Foti, N. Micale, N. Van Pelt, A. Matheeussen, G. Caljon, O. Giuffre

Date Published: 2nd Jul 2024

Publication Type: Journal Article

Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti-<i>Trypanosoma brucei</i> Agents

Abstract

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Authors: Valeria Francesconi, Marco Rizzo, Cecilia Pozzi, Lorenzo Tagliazucchi, Claude U. Konchie Simo, Giulia Saporito, Giacomo Landi, Stefano Mangani, Anna Carbone, Silvia Schenone, Nuno Santarém, Joana Tavares, Anabela Cordeiro-da-Silva, Maria Paola Costi, Michele Tonelli

Date Published: 2nd Jul 2024

Publication Type: Journal Article

In Vivo Bioluminescence Imaging Reveals Differences in Leishmania infantum Parasite Killing Kinetics by Antileishmanial Reference Drugs.

Abstract (Expand)

The bioluminescent Leishmania infantum BALB/c mouse model was used to evaluate the parasiticidal drug action kinetics of the reference drugs miltefosine, paromomycin, sodium stibogluconate, and liposomal … amphotericin B. Infected mice were treated for 5 days starting from 7 days post-infection, and parasite burdens were monitored over time via bioluminescence imaging (BLI). Using nonlinear regression analyses of the BLI signal, the parasite elimination half-life (t(1/2)) in the liver, bone marrow, and whole body was determined and compared for the different treatment regimens. Significant differences in parasiticidal kinetics were recorded. A single intravenous dose of 0.5 mg/kg liposomal amphotericin B was the fastest acting with a t(1/2) of less than 1 day. Intraperitoneal injection of paromomycin at 320 mg/kg for 5 days proved to be the slowest with a t(1/2) of about 5 days in the liver and 16 days in the bone marrow. To conclude, evaluation of the cidal kinetics of the different antileishmanial reference drugs revealed striking differences in their parasite elimination half-lives. This BLI approach also enables an in-depth pharmacodynamic comparison between novel drug leads and may constitute an essential tool for the design of potential drug combinations.

Authors: S. Hendrickx, P. B. Feijens, F. Escudie, E. Chatelain, L. Maes, G. Caljon

Date Published: 14th Jun 2024

Publication Type: Journal Article

The urgent need for designing greener drugs

Abstract

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Authors: Tomas Brodin, Michael G. Bertram, Kathryn E. Arnold, Alistair B. A. Boxall, Bryan W. Brooks, Daniel Cerveny, Manuela Jörg, Karen A. Kidd, Unax Lertxundi, Jake M. Martin, Lauren T. May, Erin S. McCallum, Marcus Michelangeli, Charles R. Tyler, Bob B. M. Wong, Klaus Kümmerer, Gorka Orive

Date Published: 5th Jun 2024

Publication Type: Journal Article

Novel quinoline derivatives with broad-spectrum antiprotozoal activities.

Abstract (Expand)

Several quinoline derivatives incorporating arylnitro and aminochalcone moieties were synthesized and evaluated in vitro against a broad panel of trypanosomatid protozoan parasites responsible for … sleeping sickness (Trypanosoma brucei rhodesiense), nagana (Trypanosoma brucei brucei), Chagas disease (Trypanosoma cruzi), and leishmaniasis (Leishmania infantum). Several of the compounds demonstrated significant antiprotozoal activity. Specifically, compounds 2c, 2d, and 4i displayed submicromolar activity against T. b. rhodesiense with half-maximal effective concentration (EC(50)) values of 0.68, 0.8, and 0.19 microM, respectively, and with a high selectivity relative to human lung fibroblasts and mouse primary macrophages ( approximately 100-fold). Compounds 2d and 4i also showed considerable activity against T. b. brucei with EC(50) values of 1.4 and 0.4 microM, respectively.

Authors: C. B. Hartman, P. S. Dube, L. J. Legoabe, N. Van Pelt, A. Matheeussen, G. Caljon, R. M. Beteck

Date Published: 3rd Jun 2024

Publication Type: Journal Article

One Health

Abstract

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Authors: Michael G. Bertram, Maria Paola Costi, Eli S.J. Thoré, Tara Sabo-Attwood, Bryan W. Brooks

Date Published: 1st Jun 2024

Publication Type: Journal Article

Cross-acyloin condensation of aldehydes catalysed by transketolase variants for the synthesis of aliphatic α-hydroxyketones

Abstract (Expand)

We described a strategy for the enzymatic synthesis of 1-deoxy and 1,2-deoxyketoses from the aliphatic α-ketoacids, pyruvate and 2-oxobutyrate, as donors and natural aldoses of variable chain length … as acceptors, catalyzed by thermostable transketolase variants from Geobacillus stearothermophilus (TKgst). Analytical studies have been carried out on a panel of TKgst variants with the appropriate substrates allowing to select the best combinations and to apply it to the preparative scale synthesis of 1-deoxy and 1,2-deoxyketoses obtained with good to excellent isolated yields (61%–86%). To optimize the strategy, and as a proof of principle, the α-ketoacids pyruvate and 2-oxobutyrate were generated in situ from the corresponding d-amino acids d-alanine and d-homoalanine respectively, using a thermostable d-amino acid oxidase dAAO4536 that was selected from a screening of 55 putative DAAOs provided by Prozomix Limited. Hence, a one-pot one step procedure was performed at 50°C by coupling dAAO4536 and the best TKgst variant H102L/L118I/ H474S in the presence of d-alanine or d-homoalanine as α-ketoacids precursors and d-erythrose as acceptor substrate. The corresponding 1-deoxy and 1,2-dideoxyketoses were isolated with good yields (64% and 72% respectively, out of two steps)

Editor:

Date Published: 30th May 2024

Publication Type: Journal Article

Proteomic Profiling of Antimalarial Plasmodione Using 3‐Benz(o)ylmenadione Affinity‐Based Probes

Abstract (Expand)

AbstractUnderstanding the mechanisms of drug action in malarial parasites is crucial for the development of new drugs to combat infection and to counteract drug resistance. Proteomics is a widely used … approach to study host‐pathogen systems and to identify drug protein targets. Plasmodione is an antiplasmodial early‐lead drug exerting potent activities against young asexual and sexual blood stages in vitro with low toxicity to host cells. To elucidate its molecular mechanisms, an affinity‐based protein profiling (AfBPP) approach was applied to yeast and P. falciparum proteomes. New (pro‐) AfBPP probes based on the 3‐benz(o)yl‐6‐fluoro‐menadione scaffold were synthesized. With optimized conditions of both photoaffinity labeling and click reaction steps, the AfBPP protocol was then applied to a yeast proteome, yielding 11 putative drug‐protein targets. Among these, we found four proteins associated with oxidoreductase activities, the hypothesized type of targets for plasmodione and its metabolites, and other proteins associated with the mitochondria. In Plasmodium parasites, the MS analysis revealed 44 potential plasmodione targets that need to be validated in further studies. Finally, the localization of a 3‐benzyl‐6‐fluoromenadione AfBPP probe was studied in the subcellular structures of the parasite at the trophozoite stage.

Authors: Ilaria Iacobucci, Vittoria Monaco, Agnès Hovasse, Baptiste Dupouy, Rodrigue Keumoe, Bogdan Cichocki, Mourad Elhabiri, Brigitte Meunier, Jean‐Marc Strub, Maria Monti, Sarah Cianférani, Stéphanie A. Blandin, Christine Schaeffer‐Reiss, Elisabeth Davioud‐Charvet

Date Published: 28th May 2024

Publication Type: Journal Article

N(6)-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model.

Abstract (Expand)

Leishmania is a trypanosomatid parasite that causes skin lesions in its cutaneous form. Current therapies rely on old and expensive drugs, against which the parasites have acquired considerable resistance. … Trypanosomatids are unable to synthesize purines relying on salvaging from the host, and nucleoside analogues have emerged as attractive antiparasitic drug candidates. 4-Methyl-7-beta-D-ribofuranosyl-7H-pyrrolo[2,3-d]pyrimidine (CL5564), an analogue of tubercidin in which the amine has been replaced by a methyl group, demonstrates activity against Trypanosoma cruzi and Leishmania infantum. Herein, we investigated its in vitro and in vivo activity against L. amazonensis. CL5564 was 6.5-fold (P = 0.0002) more potent than milteforan (ML) against intracellular forms in peritoneal mouse macrophages, and highly selective, while combination with ML gave an additive effect. These results stimulated us to study the activity of CL5564 in mouse model of cutaneous Leishmania infection. BALB/c female and male mice infected by L. amazonensis treated with CL5564 (10 mg kg(-1), intralesional route for five days) presented a >93% reduction of paw lesion size likely ML given orally at 40 mg kg(-1), while the combination (10 + 40 mg kg(-1) of CL5564 and ML, respectively) caused >96% reduction. The qPCR confirmed the suppression of parasite load, but only the combination approach reached 66% of parasitological cure. These results support additional studies with nucleoside derivatives.

Authors: C. Present, R. D. Girao, C. Lin, G. Caljon, S. Van Calenbergh, O. Moreira, L. A. S. Ruivo, M. M. Batista, R. Azevedo, D. D. G. J. Batista, M. N. C. Soeiro

Date Published: 17th May 2024

Publication Type: Journal Article

Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents

Abstract

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Authors: Alexandra Ioana Corfu, Nuno Santarem, Sara Luelmo, Gaia Mazza, Alessandro Greco, Alessandra Altomare, Giulio Ferrario, Giulia Nasta, Oliver Keminer, Giancarlo Aldini, Lucia Tamborini, Nicoletta Basilico, Silvia Parapini, Sheraz Gul, Anabela Cordeiro-da-Silva, Paola Conti, Chiara Borsari

Date Published: 8th May 2024

Publication Type: Journal Article

Long-term hematopoietic stem cells trigger quiescence in Leishmania parasites.

Abstract (Expand)

Addressing the challenges of quiescence and post-treatment relapse is of utmost importance in the microbiology field. This study shows that Leishmania infantum and L. donovani parasites rapidly enter … into quiescence after an estimated 2-3 divisions in both human and mouse bone marrow stem cells. Interestingly, this behavior is not observed in macrophages, which are the primary host cells of the Leishmania parasite. Transcriptional comparison of the quiescent and non-quiescent metabolic states confirmed the overall decrease of gene expression as a hallmark of quiescence. Quiescent amastigotes display a reduced size and signs of a rapid evolutionary adaptation response with genetic alterations. Our study provides further evidence that this quiescent state significantly enhances resistance to treatment. Moreover, transitioning through quiescence is highly compatible with sand fly transmission and increases the potential of parasites to infect cells. Collectively, this work identified stem cells in the bone marrow as a niche where Leishmania quiescence occurs, with important implications for antiparasitic treatment and acquisition of virulence traits.

Authors: L. Dirkx, S. I. Van Acker, Y. Nicolaes, J. L. R. Cunha, R. Ahmad, R. Hendrickx, B. Caljon, H. Imamura, D. G. Ebo, D. C. Jeffares, Y. G. Sterckx, L. Maes, S. Hendrickx, G. Caljon

Date Published: 6th May 2024

Publication Type: Journal Article

Bayesian modelling of time series data (BayModTS)—a FAIR workflow to process sparse and highly variable data

Abstract (Expand)

Abstract Motivation Systems biology aims to better understand living systems through mathematical modelling of experimental and clinical data. A pervasive challenge in quantitative dynamical modelling …vasive challenge in quantitative dynamical modelling is the integration of time series measurements, which often have high variability and low sampling resolution. Approaches are required to utilize such information while consistently handling uncertainties. Results We present BayModTS (Bayesian modelling of time series data), a new FAIR (findable, accessible, interoperable, and reusable) workflow for processing and analysing sparse and highly variable time series data. BayModTS consistently transfers uncertainties from data to model predictions, including process knowledge via parameterized models. Further, credible differences in the dynamics of different conditions can be identified by filtering noise. To demonstrate the power and versatility of BayModTS, we applied it to three hepatic datasets gathered from three different species and with different measurement techniques: (i) blood perfusion measurements by magnetic resonance imaging in rat livers after portal vein ligation, (ii) pharmacokinetic time series of different drugs in normal and steatotic mice, and (iii) CT-based volumetric assessment of human liver remnants after clinical liver resection. Availability and implementation The BayModTS codebase is available on GitHub at https://github.com/Systems-Theory-in-Systems-Biology/BayModTS. The repository contains a Python script for the executable BayModTS workflow and a widely applicable SBML (systems biology markup language) model for retarded transient functions. In addition, all examples from the paper are included in the repository. Data and code of the application examples are stored on DaRUS: https://doi.org/10.18419/darus-3876. The raw MRI ROI voxel data were uploaded to DaRUS: https://doi.org/10.18419/darus-3878. The steatosis metabolite data are published on FairdomHub: 10.15490/fairdomhub.1.study.1070.1.

Authors: Sebastian Höpfl, Mohamed Albadry, Uta Dahmen, Karl-Heinz Herrmann, Eva Marie Kindler, Matthias König, Jürgen Rainer Reichenbach, Hans-Michael Tautenhahn, Weiwei Wei, Wan-Ting Zhao, Nicole Erika Radde

Date Published: 1st May 2024

Publication Type: Journal Article

Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3-Benzylmenadione Revealed by High-Content Imaging

Abstract

Not specified

Authors: Nathan Trometer, Jérémy Pecourneau, Liwen Feng, José A. Navarro-Huerta, Danielle Lazarin-Bidóia, Sueli de Oliveira Silva Lautenschlager, Louis Maes, Amanda Fortes Francisco, John M. Kelly, Brigitte Meunier, Monica Cal, Pascal Mäser, Marcel Kaiser, Elisabeth Davioud-Charvet

Date Published: 12th Apr 2024

Publication Type: Journal Article

Chemoselective Synthesis and Anti-Kinetoplastidal Properties of 2,6-Diaryl-4H-tetrahydro-thiopyran-4-one S-Oxides: Their Interplay in a Cascade of Redox Reactions from Diarylideneacetones

Abstract (Expand)

2,6-Diaryl-4H-tetrahydro-thiopyran-4-ones and corresponding sulfoxide and sulfone derivatives were designed to lower the major toxicity of their parent anti-kinetoplatidal diarylideneacetones through … a prodrug effect. Novel diastereoselective methodologies were developed and generalized from diarylideneacetones and 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones to allow the introduction of a wide substitution profile and to prepare the related S-oxides. The in vitro biological activity and selectivity of diarylideneacetones, 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones, and their S-sulfoxide and sulfone metabolites were evaluated against Trypanosoma brucei brucei, Trypanosoma cruzi, and various Leishmania species in comparison with their cytotoxicity against human fibroblasts hMRC-5. The data revealed that the sulfides, sulfoxides, and sulfones, in which the Michael acceptor sites are temporarily masked, are less toxic against mammal cells while the anti-trypanosomal potency was maintained against T. b. brucei, T. cruzi, L. infantum, and L. donovani, thus confirming the validity of the prodrug strategy. The mechanism of action is proposed to be due to the involvement of diarylideneacetones in cascades of redox reactions involving the trypanothione system. After Michael addition of the dithiol to the double bonds, resulting in an elongated polymer, the latter—upon S-oxidation, followed by syn-eliminations—fragments, under continuous release of reactive oxygen species and sulfenic/sulfonic species, causing the death of the trypanosomal parasites in the micromolar or submicromolar range with high selectivity indexes.

Authors: Thibault Gendron, Don Antoine Lanfranchi, Nicole I. Wenzel, Hripsimée Kessedjian, Beate Jannack, Louis Maes, Sandrine Cojean, Thomas J. J. Müller, Philippe M. Loiseau, Elisabeth Davioud-Charvet

Date Published: 4th Apr 2024

Publication Type: Journal Article

A comparison between different human hepatocyte models reveals profound differences in net glucose production, lipid composition and metabolism in vitro.

Abstract (Expand)

Hepatocytes are responsible for maintaining a stable blood glucose concentration during periods of nutrient scarcity. The breakdown of glycogen and de novo synthesis of glucose are crucial metabolic … pathways deeply interlinked with lipid metabolism. Alterations in these pathways are often associated with metabolic diseases with serious clinical implications. Studying energy metabolism in human cells is challenging. Primary hepatocytes are still considered the golden standard for in vitro studies and have been instrumental in elucidating key aspects of energy metabolism found in vivo. As a result of several limitations posed by using primary cells, a multitude of alternative hepatocyte cellular models emerged as potential substitutes. Yet, there remains a lack of clarity regarding the precise applications for which these models accurately reflect the metabolic competence of primary hepatocytes. In this study, we compared primary hepatocytes, stem cell-derived hepatocytes, adult donor-derived liver organoids, immortalized Upcyte-hepatocytes and the hepatoma cell line HepG2s in their response to a glucose production challenge. We observed the highest net glucose production in primary hepatocytes, followed by organoids, stem-cell derived hepatocytes, Upcyte-hepatocytes and HepG2s. Glucogenic gene induction was observed in all tested models, as indicated by an increase in G6PC and PCK1 expression. Lipidomic analysis revealed considerable differences across the models, with organoids showing the closest similarity to primary hepatocytes in the common lipidome, comprising 347 lipid species across 19 classes. Changes in lipid profiles as a result of the glucose production challenge showed a variety of, and in some cases opposite, trends when compared to primary hepatocytes.

Authors: F. Bonanini, M. Singh, H. Yang, D. Kurek, A. C. Harms, A. Mardinoglu, T. Hankemeier

Date Published: 1st Apr 2024

Publication Type: Journal Article

Assessing Environmental Risks during the Drug Development Process for Parasitic Vector-Borne Diseases: A Critical Reflection

Abstract

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Authors: Kayhan Ilbeigi, Carlos Barata, João Barbosa, Michael G. Bertram, Guy Caljon, Maria Paola Costi, Alexandra Kroll, Luigi Margiotta-Casaluci, Eli S.J. Thoré, Mirco Bundschuh

Date Published: 27th Mar 2024

Publication Type: Journal Article

Q586B2 is a crucial virulence factor during the early stages of Trypanosoma brucei infection that is conserved amongst trypanosomatids

Abstract (Expand)

AbstractHuman African trypanosomiasis or sleeping sickness, caused by the protozoan parasite Trypanosoma brucei, is characterized by the manipulation of the host’s immune response to ensure parasite … invasion and persistence. Uncovering key molecules that support parasite establishment is a prerequisite to interfere with this process. We identified Q586B2 as a T. brucei protein that induces IL-10 in myeloid cells, which promotes parasite infection invasiveness. Q586B2 is expressed during all T. brucei life stages and is conserved in all Trypanosomatidae. Deleting the Q586B2-encoding Tb927.6.4140 gene in T. brucei results in a decreased peak parasitemia and prolonged survival, without affecting parasite fitness in vitro, yet promoting short stumpy differentiation in vivo. Accordingly, neutralization of Q586B2 with newly generated nanobodies could hamper myeloid-derived IL-10 production and reduce parasitemia. In addition, immunization with Q586B2 delays mortality upon a challenge with various trypanosomes, including Trypanosoma cruzi. Collectively, we uncovered a conserved protein playing an important regulatory role in Trypanosomatid infection establishment.

Authors: Benoit Stijlemans, Patrick De Baetselier, Inge Van Molle, Laurence Lecordier, Erika Hendrickx, Ema Romão, Cécile Vincke, Wendy Baetens, Steve Schoonooghe, Gholamreza Hassanzadeh-Ghassabeh, Hannelie Korf, Marie Wallays, Joar E. Pinto Torres, David Perez-Morga, Lea Brys, Oscar Campetella, María S. Leguizamón, Mathieu Claes, Sarah Hendrickx, Dorien Mabille, Guy Caljon, Han Remaut, Kim Roelants, Stefan Magez, Jo A. Van Ginderachter, Carl De Trez

Date Published: 27th Feb 2024

Publication Type: Journal Article

Kinetic modeling identifies targets for engineering improved photosynthetic efficiency in potato (Solanum tuberosum cv. Solara).

Abstract (Expand)

Potato (Solanum tuberosum) is a significant non-grain food crop in terms of global production. However, its yield potential might be raised by identifying means to release bottlenecks within photosynthetic … metabolism, from the capture of solar energy to the synthesis of carbohydrates. Recently, engineered increases in photosynthetic rates in other crops have been directly related to increased yield - how might such increases be achieved in potato? To answer this question, we derived the photosynthetic parameters V(cmax) and J(max) to calibrate a kinetic model of leaf metabolism (e-Photosynthesis) for potato. This model was then used to simulate the impact of manipulating the expression of genes and their protein products on carbon assimilation rates in silico through optimizing resource investment among 23 photosynthetic enzymes, predicting increases in photosynthetic CO(2) uptake of up to 67%. However, this number of manipulations would not be practical with current technologies. Given a limited practical number of manipulations, the optimization indicated that an increase in amounts of three enzymes - Rubisco, FBP aldolase, and SBPase - would increase net assimilation. Increasing these alone to the levels predicted necessary for optimization increased photosynthetic rate by 28% in potato.

Authors: S. Vijayakumar, Y. Wang, G. Lehretz, S. Taylor, E. Carmo-Silva, S. Long

Date Published: 30th Jan 2024

Publication Type: Journal Article

Chelation of Mitochondrial Iron as an Antiparasitic Strategy

Abstract

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Authors: Dominik Arbon, Jan Mach, Aneta Čadková, Anna Sipkova, Jan Stursa, Kristýna Klanicová, Marta Machado, Markus Ganter, Viktoriya Levytska, Daniel Sojka, Jaroslav Truksa, Lukáš Werner, Robert Sutak

Date Published: 30th Jan 2024

Publication Type: Journal Article

Design and synthesis of imidazo[1,2-a]pyridine-chalcone conjugates as antikinetoplastid agents.

Abstract (Expand)

A library of imidazo[1,2-a]pyridine-appended chalcones were synthesized and characterized using (1) H NMR, (13) C NMR and HRMS. The synthesized analogues were screened for their antikinetoplastid … activity against Trypanosoma cruzi, Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Leishmania infantum. The analogues were also tested for their cytotoxicity activity against human lung fibroblasts and primary mouse macrophages. Among all screened derivatives, 7f was found to be the most active against T. cruzi and T. b. brucei exhibiting IC(50) values of 8.5 and 1.35 muM, respectively. Against T. b. rhodesiense, 7e was found to be the most active with an IC(50) value of 1.13 muM. All synthesized active analogues were found to be non-cytotoxic against MRC-5 and PMM with selectivity indices of up to more than 50.

Authors: D. S. Agarwal, R. M. Beteck, K. Ilbeigi, G. Caljon, L. J. Legoabe

Date Published: 18th Jan 2024

Publication Type: Journal Article

Hepatic ChREBP orchestrates intrahepatic carbohydrate metabolism to limit hepatic glucose 6-phosphate and glycogen accumulation in a mouse model for acute Glycogen Storage Disease type Ib

Abstract (Expand)

Carbohydrate Response Element Binding Protein (ChREBP) is a glucose 6-phosphate (G6P)-sensitive transcription factor that acts as a metabolic switch to maintain intracellular glucose and phosphate … homeostasis. Hepatic ChREBP is well-known for its regulatory role in glycolysis, the pentose phosphate pathway, and de novo lipogenesis. The physiological role of ChREBP in hepatic glycogen metabolism and blood glucose regulation has not been assessed in detail, and ChREBP's contribution to carbohydrate flux adaptations in hepatic Glycogen Storage Disease type 1 (GSD I) requires further investigation.

Authors: K.A. Krishnamurthy, M.G.S. Rutten, J.A. Hoogerland, T.H. van Dijk, T. Bos, M. Koehorst, M.P. de Vries, N.J. Kloosterhuis, H. Havinga, B.V. Schomakers, M. van Weeghel, J.C. Wolters, B.M. Bakker, M.H. Oosterveer

Date Published: 2024

Publication Type: Journal Article

The discovery of aryl-2-nitroethyl triamino pyrimidines as anti-Trypanosoma brucei agents

Abstract

Not specified

Authors: Pasquale Linciano, Cecilia Pozzi, Giusy Tassone, Giacomo Landi, Stefano Mangani, Matteo Santucci, Rosaria Luciani, Stefania Ferrari, Nuno Santarem, Lorenzo Tagliazucchi, Anabela Cordeiro-da-Silva, Michele Tonelli, Donatella Tondi, Laura Bertarini, Sheraz Gul, Gesa Witt, Carolina B. Moraes, Luca Costantino, Maria Paola Costi

Date Published: 2024

Publication Type: Journal Article

Design, synthesis and modelling of photoreactive chemical probes for investigating target engagement of plasmepsin IX and X in <i>Plasmodium falciparum</i>

Abstract (Expand)

We report the synthesis and biological profiling of photoreactive chemical probes based on an established plasmepsin X inhibitor scaffold. Maintained antimalarial and recombinant enzyme activity support … their use in future chemical proteomic studies.

Authors: Monika Lisauskaitė, Gemma L. Nixon, Christopher M. Woodley, Neil G. Berry, Andy Coninckx, L. Charlie Qie, Suet C. Leung, Donatella Taramelli, Nicoletta Basilico, Silvia Parapini, Stephen A. Ward, Oscar Vadas, Dominique Soldati-Favre, W. David Hong, Paul M. O'Neill

Date Published: 2024

Publication Type: Journal Article

Solid Lipid Nanoparticles Enhancing the Leishmanicidal Activity of Delamanid

Abstract (Expand)

Leishmaniasis, a zoonotic parasitic disease transmitted by infected sandflies, impacts nearly 1 million people yearly and is endemic in many countries across Asia, Africa, the Americas, and the … Mediterranean; despite this, it remains a neglected disease with limited effective treatments, particularly in impoverished communities with limited access to healthcare. This study aims to repurpose approved drugs for an affordable leishmaniasis treatment. After the screening of potential drug candidates by reviewing databases and utilizing molecular docking analysis, delamanid was chosen to be incorporated into solid lipid nanoparticles (SLNPs). Both in cellulo and in vivo tests confirmed the successful payload release within macrophages and through the epidermis following topical application on murine skin. The evaluation of macrophages infected with L. infantum amastigotes showed that the encapsulated delamanid exhibited greater leishmanicidal activity compared with the free drug. The process of encapsulating delamanid in SLNPs, as demonstrated in this study, places a strong emphasis on employing minimal technology, ensuring energy efficiency, cost-effectiveness, and reproducibility. It enables consistent, low-cost production of nanomedicines, even on a small scale, offering a promising step toward more accessible and effective leishmaniasis treatments.

Authors: Javier Santamaría-Aguirre, Daniela Jacho, Miguel A. Méndez, Ana Poveda, Javier Carrión, Mónica L. Fanarraga

Date Published: 27th Dec 2023

Publication Type: Journal Article

FLAgellum Member 8 modulates extravascular distribution of African trypanosomes

Abstract (Expand)

In the mammalian host, the biology of tissue-dwelling Trypanosoma brucei parasites is not completely understood, especially the mechanisms involved in their extravascular colonization. The trypanosome …ravascular colonization. The trypanosome flagellum is an essential organelle in multiple aspects of the parasites’ development. The flagellar protein termed FLAgellar Member 8 (FLAM8) acts as a docking platform for a pool of cyclic AMP response protein 3 (CARP3) that is involved in signaling. FLAM8 exhibits a stage-specific distribution suggesting specific functions in the mammalian and vector stages of the parasite. Analyses of knockdown and knockout trypanosomes in their mammalian forms demonstrated that FLAM8 is not essential in vitro for survival, growth, motility and stumpy differentiation. Functional investigations in experimental infections showed that FLAM8 -deprived trypanosomes can establish and maintain an infection in the blood circulation and differentiate into insect transmissible forms. However, quantitative bioluminescence imaging and gene expression analysis revealed that FLAM8 -null parasites exhibit a significantly impaired dissemination in the extravascular compartment, that is restored by the addition of a single rescue copy of FLAM8 . In vitro trans-endothelial migration assays revealed significant defects in trypanosomes lacking FLAM8 . FLAM8 is the first flagellar component shown to modulate T . brucei distribution in the host tissues, possibly through sensing functions, contributing to the maintenance of extravascular parasite populations in mammalian anatomical niches, especially in the skin.

Authors: Estefanía Calvo-Alvarez, Jean Marc Tsagmo Ngoune, Parul Sharma, Anneli Cooper, Aïssata Camara, Christelle Travaillé, Aline Crouzols, Annette MacLeod, Brice Rotureau

Date Published: 21st Dec 2023

Publication Type: Journal Article

Regulation of Rubisco activity in crops.

Abstract (Expand)

Efficient plant acclimation to changing environmental conditions relies on fast adjustments of the transcriptome, proteome, and metabolome. Regulation of enzyme activity depends on the activity of … specific chaperones, chemical post-translational modifications (PTMs) of amino acid residues, and changes in the cellular and organellar microenvironment. Central to carbon assimilation, and thus plant growth and yield, Rubisco activity is regulated by its chaperone Rubisco activase (Rca) and by adjustments in the chloroplast stroma environment. Focused on crops, this review highlights the main PTMs and stromal ions and metabolites affecting Rubisco and Rca in response to environmental stimuli. Rca isoforms differ in regulatory properties and heat sensitivity, with expression changing according to the surrounding environment. Much of the physiological relevance of Rubisco and Rca PTMs is still poorly understood, though some PTMs have been associated with Rubisco regulation in response to stress. Ion and metabolite concentrations in the chloroplast change in response to variations in light and temperature. Some of these changes promote Rubisco activation while others inhibit activation, deactivate the enzyme, or change the rates of catalysis. Understanding these regulatory mechanisms will aid the development of strategies to improve carbon fixation by Rubisco under rapidly changing environments as experienced by crop plants.

Authors: J. Amaral, A. K. M. Lobo, E. Carmo-Silva

Date Published: 11th Dec 2023

Publication Type: Journal Article

Systematic transcriptional analysis of human cell lines for gene expression landscape and tumor representation

Abstract (Expand)

Abstract Cell lines are valuable resources as model for human biology and translational medicine. It is thus important to explore the concordance between the expression in various cell lines vis-à-vis …s vis-à-vis human native and disease tissues. In this study, we investigate the expression of all human protein-coding genes in more than 1,000 human cell lines representing 27 cancer types by a genome-wide transcriptomics analysis. The cell line gene expression is compared with the corresponding profiles in various tissues, organs, single-cell types and cancers. Here, we present the expression for each cell line and give guidance for the most appropriate cell line for a given experimental study. In addition, we explore the cancer-related pathway and cytokine activity of the cell lines to aid human biology studies and drug development projects. All data are presented in an open access cell line section of the Human Protein Atlas to facilitate the exploration of all human protein-coding genes across these cell lines.

Authors: Han Jin, Cheng Zhang, Martin Zwahlen, Kalle von Feilitzen, Max Karlsson, Mengnan Shi, Meng Yuan, Xiya Song, Xiangyu Li, Hong Yang, Hasan Turkez, Linn Fagerberg, Mathias Uhlén, Adil Mardinoglu

Date Published: 1st Dec 2023

Publication Type: Journal Article

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