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739 Publications visible to you, out of a total of 739
High-Throughput Phenotypic Screening and Machine Learning Methods Enabled the Selection of Broad-Spectrum Low-Toxicity Antitrypanosomatidic Agents

Abstract

Not specified

Authors: Pasquale Linciano, Antonio Quotadamo, Rosaria Luciani, Matteo Santucci, Kimberley M. Zorn, Daniel H. Foil, Thomas R. Lane, Anabela Cordeiro da Silva, Nuno Santarem, Carolina B Moraes, Lucio Freitas-Junior, Ulrike Wittig, Wolfgang Mueller, Michele Tonelli, Stefania Ferrari, Alberto Venturelli, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Jeanette Reinshagen, Sean Ekins, Maria Paola Costi

Date Published: 3rd Nov 2023

Publication Type: Journal Article

Drug repurposing: a nexus of innovation, science, and potential

Abstract

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Authors: Maria Cristina De Rosa, Rituraj Purohit, Alfonso T. García-Sosa

Date Published: 19th Oct 2023

Publication Type: Journal Article

The complex biology of aryl hydrocarbon receptor activation in cancer and beyond

Abstract

Not specified

Authors: Christiane A. Opitz, Pauline Holfelder, Mirja Tamara Prentzell, Saskia Trump

Date Published: 1st Oct 2023

Publication Type: Journal Article

Synthesis and Biophysical and Biological Studies of <i>N</i>-Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites

Abstract

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Authors: J. Jonathan Nué-Martinez, David Cisneros, María del Valle Moreno-Blázquez, Cristina Fonseca-Berzal, José Ignacio Manzano, Damien Kraeutler, Marzuq A. Ungogo, Maha A. Aloraini, Hamza A. A. Elati, Alexandra Ibáñez-Escribano, Laura Lagartera, Tomás Herraiz, Francisco Gamarro, Harry P. de Koning, Alicia Gómez-Barrio, Christophe Dardonville

Date Published: 20th Sep 2023

Publication Type: Journal Article

2-Aroyl quinazolinone: Synthesis and in vitro anti-parasitic activity.

Abstract (Expand)

Trypanosomes and Leishmania are parasitic protozoans that affect millions of people globally. Herein we report the synthesis of 2-aroyl quinazolinones and their antiprotozoal efficacy against Trypanosoma … brucei, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania infantum. These compounds were counter-screened against a human cell line for cytotoxicity. Thirteen of the twenty target compounds in this study inhibited the growth of these parasites, with compounds KJ1, and KJ10 exhibiting IC(50) values of 4.7 muM (T. b. brucei) and 1.1 muM (T. b. rhodesiense), respectively.

Authors: K. J. Setshedi, R. M. Beteck, O. J. Jesumoroti, K. Ilbeigi, D. Mabille, G. Caljon, F. Van der Kooy, L. J. Legoabe

Date Published: 13th Sep 2023

Publication Type: Journal Article

Development of HILIC-MS/MS method for acyl-CoAs covering short- to long-chain species in a single analytical run

Abstract (Expand)

Acyl-CoAs play a significant role in numerous physiological and metabolic processes making it important to assess their concentration levels for evaluating metabolic health. Considering the important … role of acyl-CoAs, it is crucial to develop an analytical method that can analyze these compounds. Due to the structural variations of acyl-CoAs, multiple analytical methods are often required for comprehensive analysis of these compounds, which increases complexity and the analysis time. In this study, we have developed a method using a zwitterionic HILIC column that enables the coverage of free CoA and short- to long-chain acyl-CoA species in one analytical run. Initially, we developed the method on a QTOF instrument for the identification of acyl-CoA species, optimizing their chromatography and retention times. Later, a targeted HILIC-MS/MS method was created in scheduled multiple reaction monitoring mode on a QTRAP instrument. The performance of the method was evaluated based on various parameters such as linearity, precision, recovery and matrix effect. This method was applied to identify the difference in acyl-CoA profiles in HepG2 cells cultured in different conditions. Our findings revealed an increase in levels of acetyl-CoA, medium- and long-chain acyl-CoA while a decrease in the profiles of free CoA in the starved state, indicating a clear alteration in the fatty acid oxidation process.

Authors: Madhulika Singh, Ligia Akemi Kiyuna, Christoff Odendaal, Barbara M. Bakker, Amy C Harms, Thomas Hankemeier

Date Published: 11th Sep 2023

Publication Type: Journal Article

Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients.

Abstract (Expand)

BACKGROUND: Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. Computational modelling of … metabolic networks may identify putative sources of this inter-patient heterogeneity. Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients-if untreated-are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients. RESULTS: We built and experimentally validated, for the first time, a kinetic model of the human liver mFAO. Metabolites were partitioned according to their water solubility between the bulk aqueous matrix and the inner membrane. Enzymes are also either membrane-bound or in the matrix. This metabolite partitioning is a novel model attribute and improved predictions. MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. Analysis of urine from MCADD patients obtained during a metabolic decompensation showed an accumulation of medium- and short-chain acylcarnitines, just like the acyl-CoA pool in the MCADD model. The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. Proteome analysis of MCADD patient-derived fibroblasts indeed revealed elevated levels of SCAD in a patient with a clinically asymptomatic state. This is a rescue for MCADD that has not been explored before. Personalised models based on these proteomics data confirmed an increased pathway flux and CoASH in the model of an asymptomatic patient compared to those of symptomatic MCADD patients. CONCLUSIONS: We present a detailed, validated kinetic model of mFAO in human liver, with solubility-dependent metabolite partitioning. Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. Further development of personalised metabolic models is a promising direction to improve individualised risk assessment, management and monitoring for inborn errors of metabolism.

Authors: C. Odendaal, E. A. Jager, A. M. F. Martines, M. A. Vieira-Lara, N. C. A. Huijkman, L. A. Kiyuna, A. Gerding, J. C. Wolters, R. Heiner-Fokkema, K. van Eunen, T. G. J. Derks, B. M. Bakker

Date Published: 4th Sep 2023

Publication Type: Journal Article

Design, synthesis and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids

Abstract (Expand)

A series of nine novel ether phospholipid-dinitroaniline hybrids were synthesized in an effort to deliver more potent antiparasitic agents with improved safety profile compared to miltefosine. The … compounds were evaluated for their in vitro antiparasitic activity against L. infantum, L.donovani, L. amazonensis, L. major and L. tropica promastigotes, L. infantum and L. donovani intracellular amastigotes, Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the oligomethylene spacer between the dinitroaniline moiety and the phosphate group, the length of the side chain substituent on the dinitroaniline and the choline or homocholine head group were found to affect both the activity and toxicity of the hybrids. The early ADMET profile of the derivatives did not reveal major liabilities. Hybrid 3, bearing an 11-carbon oligomethylene spacer, a butyl side chain and a choline head group, was the most potent analogue of the series. It exhibited a broad spectrum antiparasitic profile against the promastigotes of New and Old World Leishmania spp., against intracellular amastigotes of two L. infantum strains and L. donovani, against T. brucei and against T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes. The early toxicity studies revealed that hybrid 3 showed a safe toxicological profile while its cytotoxicity concentration (CC50) against THP-1 macrophages being >100 μM. Computational analysis of binding sites and docking indicated that the interaction of hybrid 3 with trypanosomatid α-tubulin may contribute to its mechanism of action. Furthermore, compound 3 was found to interfere with the cell cycle in T. cruzi epimastigotes, while ultrastructural studies using SEM and TEM in T. cruzi showed that compound 3 affects cellular processes that result in changes in the Golgi complex, the mitochondria and the parasite’s plasma membrane. The snapshot pharmacokinetic studies showed low levels of 3 after 24 h following oral administration of 100 mg/Kg, while, its homocholine congener compound 9 presented a better pharmacokinetic profile.

Authors: Marina Roussaki, George E. Magoulas, Theano Fotopoulou, Nuno Santarem, Emile Barrias, Ina Pöhner, Sara Luelmo, Pantelis Afroudakis, Kalliopi Georgikopoulou, Paloma Tejera Nevado, Julia Eick, Eugenia Bifeld, María J. Corral, María Dolores Jiménez-Antón, Bernhard Ellinger, Maria Kuzikov, Irini Fragiadaki, Effie Scoulica, Sheraz Gul, Joachim Clos, Kyriakos C. Prousis, Juan J. Torrado, José María Alunda, Rebecca C. Wade, Wanderley de Souza, Anabela Cordeiro da Silva, Theodora Calogeropoulou

Date Published: 1st Sep 2023

Publication Type: Journal Article

Inhibitor titrations reveal low control of glyceraldehyde 3-phosphate dehydrogenase and high control of hexokinase on glycolytic flux in an aggressive triple-negative breast cancer cell line

Abstract

Not specified

Authors: Theresa Kouril, Craig October, Stephanie Hollocks, Christoff Odendaal, David D. van Niekerk, Jacky L. Snoep

Date Published: 1st Sep 2023

Publication Type: Journal Article

Development of a targeted hydrophilic interaction liquid chromatography-tandem mass spectrometry based lipidomics platform applied to a coronavirus disease severity study.

Abstract (Expand)

The importance of lipids seen in studies of metabolism, cancer, the recent COVID-19 pandemic and other diseases has brought the field of lipidomics to the forefront of clinical research. Quantitative … and comprehensive analysis is required to understand biological interactions among lipid species. However, lipidomic analysis is often challenging due to the various compositional structures, diverse physicochemical properties, and wide dynamic range of concentrations of lipids in biological systems. To study the comprehensive lipidome, a hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS)-based screening method with 1200 lipid features across 19 (sub)classes, including both nonpolar and polar lipids, has been developed. HILIC-MS/MS was selected due to its class separation property and fatty acyl chain level information. 3D models of class chromatographic retention behavior were established and evaluations of cross-class and within-class interferences were performed to avoid over-reporting these features. This targeted HILIC-MS/MS method was fully validated, with acceptable analytical parameters in terms of linearity, precision, reproducibility, and recovery. The accurate quantitation of 608 lipid species in the SRM 1950 NIST plasma was achieved using multi-internal standards per class and post-hoc correction, extending current databases by providing lipid concentrations resolved at fatty acyl chain level. The overall correlation coefficients (R(2)) of measured concentrations with values from literature range from 0.64 to 0.84. The applicability of the developed targeted lipidomics method was demonstrated by discovering 520 differential lipid features related to COVID-19 severity. This high coverage and targeted approach will aid in future investigations of the lipidome in various disease contexts.

Authors: Z. Zhang, M. Singh, A. Kindt, A. B. Wegrzyn, M. J. Pearson, A. Ali, A. C. Harms, P. Baker, T. Hankemeier

Date Published: 31st Aug 2023

Publication Type: Journal Article

Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy.

Abstract (Expand)

Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei, is one of the neglected tropical diseases with a continuing need for new medication. We here describe the discovery of … 5-phenylpyrazolopyrimidinone analogs as a novel series of phenotypic antitrypanosomal agents. The most potent compound, 30 (NPD-2975), has an in vitro IC(50) of 70 nM against T. b. brucei with no apparent toxicity against human MRC-5 lung fibroblasts. Showing good physicochemical properties, low toxicity potential, acceptable metabolic stability, and other pharmacokinetic features, 30 was further evaluated in an acute mouse model of T. b. brucei infection. After oral dosing at 50 mg/kg twice per day for five consecutive days, all infected mice were cured. Given its good drug-like properties and high in vivo antitrypanosomal potential, the 5-phenylpyrazolopyrimidinone analog 30 represents a promising lead for future drug development to treat HAT.

Authors: Y. Zheng, M. van den Kerkhof, T. van der Meer, S. Gul, M. Kuzikov, B. Ellinger, I. J. P. de Esch, M. Siderius, A. Matheeussen, L. Maes, G. J. Sterk, G. Caljon, R. Leurs

Date Published: 10th Aug 2023

Publication Type: Journal Article

Hepatocytes reprogram liver macrophages involving control of TGF-beta activation, influencing liver regeneration and injury.

Abstract (Expand)

BACKGROUND: Macrophages play an important role in maintaining liver homeostasis and regeneration. However, it is not clear to what extent the different macrophage populations of the liver differ in … terms of their activation state and which other liver cell populations may play a role in regulating the same. METHODS: Reverse transcription PCR, flow cytometry, transcriptome, proteome, secretome, single cell analysis, and immunohistochemical methods were used to study changes in gene expression as well as the activation state of macrophages in vitro and in vivo under homeostatic conditions and after partial hepatectomy. RESULTS: We show that F4/80+/CD11bhi/CD14hi macrophages of the liver are recruited in a C-C motif chemokine receptor (CCR2)-dependent manner and exhibit an activation state that differs substantially from that of the other liver macrophage populations, which can be distinguished on the basis of CD11b and CD14 expressions. Thereby, primary hepatocytes are capable of creating an environment in vitro that elicits the same specific activation state in bone marrow-derived macrophages as observed in F4/80+/CD11bhi/CD14hi liver macrophages in vivo. Subsequent analyses, including studies in mice with a myeloid cell-specific deletion of the TGF-beta type II receptor, suggest that the availability of activated TGF-beta and its downregulation by a hepatocyte-conditioned milieu are critical. Reduction of TGF-betaRII-mediated signal transduction in myeloid cells leads to upregulation of IL-6, IL-10, and SIGLEC1 expression, a hallmark of the activation state of F4/80+/CD11bhi/CD14hi macrophages, and enhances liver regeneration. CONCLUSIONS: The availability of activated TGF-beta determines the activation state of specific macrophage populations in the liver, and the observed rapid transient activation of TGF-beta may represent an important regulatory mechanism in the early phase of liver regeneration in this context.

Authors: S. D. Wolf, C. Ehlting, S. Muller-Dott, G. Poschmann, P. Petzsch, T. Lautwein, S. Wang, B. Helm, M. Schilling, J. Saez-Rodriguez, M. Vucur, K. Stuhler, K. Kohrer, F. Tacke, S. Dooley, U. Klingmuller, T. Luedde, J. G. Bode

Date Published: 1st Aug 2023

Publication Type: Journal Article

Call for Papers: One Health and Vector-Borne Parasitic Diseases

Abstract

Not specified

Authors: Maria P. Costi, Anabela Cordeiro-da-Silva

Date Published: 23rd Jul 2023

Publication Type: Journal Article

FAIR High Content Screening in Bioimaging

Abstract (Expand)

The Minimum Information for High Content Screening Microscopy Experiments (MIHCSME) is a metadata model and reusable tabular template for sharing and integrating high content imaging data. It has been … developed by combining the ISA (Investigations, Studies, Assays) metadata standard with a semantically enriched instantiation of REMBI (Recommended Metadata for Biological Images). The tabular template provides an easy-to-use practical implementation of REMBI, specifically for High Content Screening (HCS) data. In addition, ISA compliance enables broader integration with other types of experimental data, paving the way for visual omics and multi-Omics integration. We show the utility of MIHCSME for HCS data using multiple examples from the Leiden FAIR Cell Observatory, a Euro-Bioimaging flagship node for high content screening and the pilot node for implementing Findable, Accessible, Interoperable and Reusable (FAIR) bioimaging data throughout the Netherlands Bioimaging network.

Authors: Rohola Hosseini, Matthijs Vlasveld, Joost Willemse, Bob van de Water, Sylvia E. Le Dévédec, Katherine J. Wolstencroft

Date Published: 17th Jul 2023

Publication Type: Journal Article

BRCT Domains: Structure, Functions, and Implications in Disease—New Therapeutic Targets for Innovative Drug Discovery against Infections

Abstract (Expand)

The search for new therapeutic targets and their implications in drug development remains an emerging scientific topic. BRCT-bearing proteins are found in Archaea, Bacteria, Eukarya, and viruses. They … are traditionally involved in DNA repair, recombination, and cell cycle control. To carry out these functions, BRCT domains are able to interact with DNA and proteins. Moreover, such domains are also implicated in several pathogenic processes and malignancies including breast, ovarian, and lung cancer. Although these domains exhibit moderately conserved folding, their sequences show very low conservation. Interestingly, sequence variations among species are considered positive traits in the search for suitable therapeutic targets, since non-specific drug interactions might be reduced. These main characteristics of BRCT, as well as its critical implications in key biological processes in the cell, have prompted the study of these domains as therapeutic targets. This review explores the possible roles of BRCT domains as therapeutic targets for drug discovery. We describe their common structural features and relevant interactions and pathways, as well as their implications in pathologic processes. Drugs commonly used to target these domains are also presented. Finally, based on their structures, we describe new drug design possibilities using modern and innovative techniques.

Authors: José Peña-Guerrero, Celia Fernández-Rubio, Alfonso T. García-Sosa, Paul A. Nguewa

Date Published: 27th Jun 2023

Publication Type: Journal Article

Structural Optimization of BIPPO Analogs as Potent Antimalarials.

Abstract (Expand)

Malaria continues to pose a significant health threat, causing thousands of deaths each year. The limited availability of vaccines and medications, combined with the emergence of drug resistance, further … complicates the fight against this disease. In this study, we aimed to enhance the antimalarial potency of the previously reported hit compound BIPPO (pIC(50) 5.9). Through systematic modification of pyrazolopyrimidinone analogs, we discovered the promising analog 30 (NPD-3547), which exhibited approximately one log unit higher in vitro potency (pIC(50) 6.8) against Plasmodium falciparum. Furthermore, we identified several other BIPPO analogs (23, 28, 29 and 47a) with potent antimalarial activity (pIC(50) > 6.0) and favorable metabolic stability in mouse liver microsomes. These compounds can serve as new tools for further optimization towards the development of potential candidates for antimalarial studies.

Authors: Y. Zheng, A. Matheeussen, L. Maes, G. Caljon, G. J. Sterk, R. Leurs

Date Published: 23rd Jun 2023

Publication Type: Journal Article

Tryptophan depletion sensitizes the AHR pathway by increasing AHR expression and GCN2/LAT1-mediated kynurenine uptake, and potentiates induction of regulatory T lymphocytes

Abstract (Expand)

Abstract Background Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan-dioxygenase (TDO) are enzymes catabolizing the essential amino acid tryptophan into kynurenine. Expression of these enzymes is … frequently observed in advanced-stage cancers and is associated with poor disease prognosis and immune suppression. Mechanistically, the respective roles of tryptophan shortage and kynurenine production in suppressing immunity remain unclear. Kynurenine was proposed as an endogenous ligand for the aryl hydrocarbon receptor (AHR), which can regulate inflammation and immunity. However, controversy remains regarding the role of AHR in IDO1/TDO-mediated immune suppression, as well as the involvement of kynurenine. In this study, we aimed to clarify the link between IDO1/TDO expression, AHR pathway activation and immune suppression. Methods AHR expression and activation was analyzed by RT-qPCR and western blot analysis in cells engineered to express IDO1/TDO, or cultured in medium mimicking tryptophan catabolism by IDO1/TDO. In vitro differentiation of naïve CD4+ T cells into regulatory T cells (Tregs) was compared in T cells isolated from mice bearing different Ahr alleles or a knockout of Ahr, and cultured in medium with or without tryptophan and kynurenine. Results We confirmed that IDO1/TDO expression activated AHR in HEK-293-E cells, as measured by the induction of AHR target genes. Unexpectedly, AHR was also overexpressed on IDO1/TDO expression. AHR overexpression did not depend on kynurenine but was triggered by tryptophan deprivation. Multiple human tumor cell lines overexpressed AHR on tryptophan deprivation. AHR overexpression was not dependent on general control non-derepressible 2 (GCN2), and strongly sensitized the AHR pathway. As a result, kynurenine and other tryptophan catabolites, which are weak AHR agonists in normal conditions, strongly induced AHR target genes in tryptophan-depleted conditions. Tryptophan depletion also increased kynurenine uptake by increasing SLC7A5 (LAT1) expression in a GCN2-dependent manner. Tryptophan deprivation potentiated Treg differentiation from naïve CD4+ T cells isolated from mice bearing an AHR allele of weak affinity similar to the human AHR. Conclusions Tryptophan deprivation sensitizes the AHR pathway by inducing AHR overexpression and increasing cellular kynurenine uptake. As a result, tryptophan catabolites such as kynurenine more potently activate AHR, and Treg differentiation is promoted. Our results propose a molecular explanation for the combined roles of tryptophan deprivation and kynurenine production in mediating IDO1/TDO-induced immune suppression.

Authors: Marie Solvay, Pauline Holfelder, Simon Klaessens, Luc Pilotte, Vincent Stroobant, Juliette Lamy, Stefan Naulaerts, Quentin Spillier, Raphaël Frédérick, Etienne De Plaen, Christine Sers, Christiane A Opitz, Benoit J Van den Eynde, Jingjing Zhu

Date Published: 21st Jun 2023

Publication Type: Journal Article

Supramolecular assemblies from antimony(V) complexes for the treatment of leishmaniasis

Abstract

Not specified

Authors: Cynthia Demicheli, Virgínia M. R. Vallejos, Juliane S. Lanza, Guilherme S. Ramos, Bruno R. Do Prado, Sébastien Pomel, Philippe M. Loiseau, Frédéric Frézard

Date Published: 6th Jun 2023

Publication Type: Journal Article

Favorable Preclinical Pharmacological Profile of a Novel Antimalarial Pyrrolizidinylmethyl Derivative of 4-amino-7-chloroquinoline with Potent In Vitro and In Vivo Activities

Abstract (Expand)

The 4-aminoquinoline drugs, such as chloroquine (CQ), amodiaquine or piperaquine, are still commonly used for malaria treatment, either alone (CQ) or in combination with artemisinin derivatives. We … previously described the excellent in vitro activity of a novel pyrrolizidinylmethyl derivative of 4-amino-7-chloroquinoline, named MG3, against P. falciparum drug-resistant parasites. Here, we report the optimized and safer synthesis of MG3, now suitable for a scale-up, and its additional in vitro and in vivo characterization. MG3 is active against a panel of P. vivax and P. falciparum field isolates, either alone or in combination with artemisinin derivatives. In vivo MG3 is orally active in the P. berghei, P. chabaudi, and P. yoelii models of rodent malaria with efficacy comparable, or better, than that of CQ and of other quinolines under development. The in vivo and in vitro ADME-Tox studies indicate that MG3 possesses a very good pre-clinical developability profile associated with an excellent oral bioavailability, and low toxicity in non-formal preclinical studies on rats, dogs, and non-human primates (NHP). In conclusion, the pharmacological profile of MG3 is in line with those obtained with CQ or the other quinolines in use and seems to possess all the requirements for a developmental candidate.

Authors: Nicoletta Basilico, Silvia Parapini, Sarah D’Alessandro, Paola Misiano, Sergio Romeo, Giulio Dondio, Vanessa Yardley, Livia Vivas, Shereen Nasser, Laurent Rénia, Bruce M. Russell, Rossarin Suwanarusk, François Nosten, Anna Sparatore, Donatella Taramelli

Date Published: 14th May 2023

Publication Type: Journal Article

To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A?

Abstract (Expand)

Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted … drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy.

Authors: Y. Zheng, S. Schroeder, G. K. Kanev, S. S. Botros, S. William, A. A. Sabra, L. Maes, G. Caljon, C. Gil, A. Martinez, I. G. Salado, K. Augustyns, E. Edink, M. Sijm, E. de Heuvel, I. J. P. de Esch, T. van der Meer, M. Siderius, G. J. Sterk, D. Brown, R. Leurs

Date Published: 6th Apr 2023

Publication Type: Journal Article

ReStoRunT: Simple Recording, Storing, Running and Tracing changes in Spreadsheets

Abstract (Expand)

In addition to the ubiquitous big data, one key challenge indata processing and management in the life sciences is the diversity ofsmall data. Diverse pieces of small data have to be transformed … intostandards-compliant data. Here, the challenge lies not in the difficulty ofsingle steps that need to be performed, but rather in the fact that manytransformation tasks are to be performed once or only a few times. Thislimits the time that can be put into automated approaches, which inturn severely limits the verifiability of such transformations.As much of the data to be processed is stored in spreadsheets, withinthis paper we justify and propose a lightweight recording-based solutionthat works on a wide variety of spreadsheet programs, from MicrosoftExcel to Google Docs.

Authors: Wolfgang Müller, Lukrécia Mertová

Date Published: 23rd Mar 2023

Publication Type: Journal Article

Proteome Coverage after Simultaneous Proteo-Metabolome Liquid–Liquid Extraction

Abstract (Expand)

Proteomics and metabolomics are essential in systems biology, and simultaneous proteo-metabolome liquid–liquid extraction (SPM-LLE) allows isolation of the metabolome and proteome from the same sample. … Since the proteome is present as a pellet in SPM-LLE, it must be solubilized for quantitative proteomics. Solubilization and proteome extraction are critical factors in the information obtained at the proteome level. In this study, we investigated the performance of two surfactants (sodium deoxycholate (SDC), sodium dodecyl sulfate (SDS)) and urea in terms of proteome coverage and extraction efficiency of an interphase proteome pellet generated by methanol–chloroform based SPM-LLE. We also investigated how the performance differs when the proteome is extracted from the interphase pellet or by direct cell lysis. We quantified 12 lipids covering triglycerides and various phospholipid classes, and 25 polar metabolites covering central energy metabolism in chloroform and methanol extracts. Our study reveals that the proteome coverages between the two surfactants and urea for the SPM-LLE interphase pellet were similar, but the extraction efficiencies differed significantly. While SDS led to enrichment of basic proteins, which were mainly ribosomal and ribonuclear proteins, urea was the most efficient extraction agent for simultaneous proteo-metabolome analysis. The results of our study also show that the performance of surfactants for quantitative proteomics is better when the proteome is extracted through direct cell lysis rather than an interphase pellet. In contrast, the performance of urea for quantitative proteomics was significantly better when the proteome was extracted from an interphase pellet than by direct cell lysis. We demonstrated that urea is superior to surfactants for proteome extraction from SPM-LLE interphase pellets, with a particularly good performance for the extraction of proteins associated with metabolic pathways. Data are available via ProteomeXchange with identifier PXD027338 (https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD027338)

Authors: Alienke van Pijkeren, Anna-Sophia Egger, Madlen Hotze, Elisabeth Zimmermann, Tobias Kipura, Julia Grander, André Gollowitzer, Andreas Koeberle, Rainer Bischoff, Kathrin Thedieck, Marcel Kwiatkowski

Date Published: 3rd Mar 2023

Publication Type: Journal Article

Label-Free Mass Spectrometry Proteomics Reveals Different Pathways Modulated in THP-1 Cells Infected with Therapeutic Failure and Drug Resistance <i>Leishmania infantum</i> Clinical Isolates

Abstract

Not specified

Authors: Lorenzo Tagliazucchi, Ana Perea-Martinez, Greta Fiorini, José Ignacio Manzano, Filippo Genovese, Raquel García-Hernández, Diego Pinetti, Francisco Gamarro, Maria Paola Costi

Date Published: 10th Feb 2023

Publication Type: Journal Article

Cloning and Characterization of Trypanosoma congolense and T. vivax Nucleoside Transporters Reveal the Potential of P1-Type Carriers for the Discovery of Broad-Spectrum Nucleoside-Based Therapeutics against Animal African Trypanosomiasis.

Abstract (Expand)

African Animal Trypanosomiasis (AAT), caused predominantly by Trypanosoma brucei brucei, T. vivax and T. congolense, is a fatal livestock disease throughout Sub-Saharan Africa. Treatment options are … very limited and threatened by resistance. Tubercidin (7-deazaadenosine) analogs have shown activity against individual parasites but viable chemotherapy must be active against all three species. Divergence in sensitivity to nucleoside antimetabolites could be caused by differences in nucleoside transporters. Having previously characterized the T. brucei nucleoside carriers, we here report the functional expression and characterization of the main adenosine transporters of T. vivax (TvxNT3) and T. congolense (TcoAT1/NT10), in a Leishmania mexicana cell line ('SUPKO') lacking adenosine uptake. Both carriers were similar to the T. brucei P1-type transporters and bind adenosine mostly through interactions with N3, N7 and 3'-OH. Expression of TvxNT3 and TcoAT1 sensitized SUPKO cells to various 7-substituted tubercidins and other nucleoside analogs although tubercidin itself is a poor substrate for P1-type transporters. Individual nucleoside EC(50)s were similar for T. b. brucei, T. congolense, T. evansi and T. equiperdum but correlated less well with T. vivax. However, multiple nucleosides including 7-halogentubercidines displayed pEC50>7 for all species and, based on transporter and anti-parasite SAR analyses, we conclude that nucleoside chemotherapy for AAT is viable.

Authors: M. A. Ungogo, M. M. Aldfer, M. J. Natto, H. Zhuang, R. Chisholm, K. Walsh, M. McGee, K. Ilbeigi, J. I. Asseri, R. J. S. Burchmore, G. Caljon, S. Van Calenbergh, H. P. De Koning

Date Published: 5th Feb 2023

Publication Type: Journal Article

Tryptophan stress activates EGFR-RAS-signaling to MTORC1 and p38/MAPK to sustain translation and AHR-dependent autophagy

Abstract (Expand)

Limited supply and catabolism restrict the essential amino acid tryptophan (Trp) in tumors. How tumors sustain translation under Trp stress remains unclear. Unlike other amino acids, Trp stress activates … the EGFR, which enhances macropinocytosis and RAS signaling to the MTORC1 and p38/MAPK kinases, sustaining translation. The AHR forms part of the Trp stress proteome and promotes autophagy to sustain Trp levels, and ceramide biosynthesis. Thus, Trp restriction elicits pro-translation signals enabling adaptation to nutrient stress, placing Trp into a unique position in the amino acid-mediated stress response. Our findings challenge the current perception that Trp restriction inhibits MTORC1 and the AHR and explain how both cancer drivers remain active. A glioblastoma patient subgroup with enhanced MTORC1 and AHR displays an autophagy signature, highlighting the clinical relevance of MTORC1-AHR crosstalk. Regions of high Trp or high ceramides are mutually exclusive, supporting that low Trp activates the EGFR-MTORC1-AHR axis in glioblastoma tissue.

Authors: Pauline Pfänder, Lucas Hensen, Patricia Razquin Navas, Marie Solvay, Mirja Tamara Prentzell, Ahmed Sadik, Alexander M. Heberle, Sophie Seifert, Leon Regin, Tobias Bausbacher, Anna-Sophia Egger, Madlen Hotze, Tobias Kipura, Bianca Berdel, Ivana Karabogdan, Luis F. Somarribas Patterson, Michele Reil, Deepak Sayeeram, Vera Peters, Jose Ramos Pittol, Ineke van ’t Land-Kuper, Teresa Börding, Saskia Trump, Alienke van Pijkeren, Yang Zhang, Fabricio Loayza-Puch, Alexander Kowar, Sönke Harder, Lorenz Waltl, André Gollowitzer, Tetsushi Kataura, Viktor I. Korolchuk, Shad A. Mohammed, Phillipp Sievers, Felix Sahm, Hartmut Schlüter, Andreas Koeberle, Carsten Hopf, Marcel Kwiatkowski, Christine Sers, Benoit J. Van den Eynde, Christiane A. Opitz, Kathrin Thedieck

Date Published: 17th Jan 2023

Publication Type: Journal Article

Development of potent and selective FAAH inhibitors with improved drug-like properties as potential tools to treat neuroinflammatory conditions.

Abstract (Expand)

The neuroprotective performance against neuroinflammation of the endocannabinoid system (ECS) can be remarkably improved by indirect stimulation mediated by the pharmacological inhibition of the key … ECS catabolic enzyme fatty acid amide hydrolase (FAAH). Based on our previous works and aiming to discover new selective FAAH inhibitors , we herein reported a new series of carbamate-based FAAH inhibitors (4a-t) which showed improved drug disposition properties compared to the previously reported analogues 2a-b. The introduction of ionizable functions allowed us to obtain new FAAH inhibitors of nanomolar potency characterized by good water solubility and chemical stability at physiological pH. Interesting structure-activity relationships (SARs), deeply analyzed by molecular docking and molecular dynamic (MD) simulations, were obtained. All the newly developed inhibitors showed an excellent selectivity profile evaluated against monoacylglycerol lipase and cannabinoid receptors. The reversible mechanism of action was determined by a rapid dilution assay. Absence of toxicity was confirmed in mouse fibroblasts NIH3T3 (for compounds 4e, 4g, 4n-o, and 4s) and in human astrocytes cell line 1321N1 (for compounds 4e, 4n, and 4s). The absence of undesired cardiac effects was also confirmed for compound 4n. Selected analogues (compounds 4e, 4g, 4n, and 4s) were able to reduce oxidative stress in 1321N1 astrocytes and exhibited notable neuroprotective effects when tested in an ex vivo model of neuroinflammation.

Authors: A. Papa, S. Pasquini, F. Galvani, M. Cammarota, C. Contri, G. Carullo, S. Gemma, A. Ramunno, S. Lamponi, B. Gorelli, S. Saponara, K. Varani, M. Mor, G. Campiani, F. Boscia, F. Vincenzi, A. Lodola, S. Butini

Date Published: 15th Jan 2023

Publication Type: Journal Article

Chemical identification and indexing in full-text articles: an overview of the NLM-Chem track at BioCreative VII

Abstract (Expand)

Abstract The BioCreative National Library of Medicine (NLM)-Chem track calls for a community effort to fine-tune automated recognition of chemical names in the biomedical literature. Chemicals are one …cals are one of the most searched biomedical entities in PubMed, and—as highlighted during the coronavirus disease 2019 pandemic—their identification may significantly advance research in multiple biomedical subfields. While previous community challenges focused on identifying chemical names mentioned in titles and abstracts, the full text contains valuable additional detail. We, therefore, organized the BioCreative NLM-Chem track as a community effort to address automated chemical entity recognition in full-text articles. The track consisted of two tasks: (i) chemical identification and (ii) chemical indexing. The chemical identification task required predicting all chemicals mentioned in recently published full-text articles, both span [i.e. named entity recognition (NER)] and normalization (i.e. entity linking), using Medical Subject Headings (MeSH). The chemical indexing task required identifying which chemicals reflect topics for each article and should therefore appear in the listing of MeSH terms for the document in the MEDLINE article indexing. This manuscript summarizes the BioCreative NLM-Chem track and post-challenge experiments. We received a total of 85 submissions from 17 teams worldwide. The highest performance achieved for the chemical identification task was 0.8672 F-score (0.8759 precision and 0.8587 recall) for strict NER performance and 0.8136 F-score (0.8621 precision and 0.7702 recall) for strict normalization performance. The highest performance achieved for the chemical indexing task was 0.6073 F-score (0.7417 precision and 0.5141 recall). This community challenge demonstrated that (i) the current substantial achievements in deep learning technologies can be utilized to improve automated prediction accuracy further and (ii) the chemical indexing task is substantially more challenging. We look forward to further developing biomedical text–mining methods to respond to the rapid growth of biomedical literature. The NLM-Chem track dataset and other challenge materials are publicly available at https://ftp.ncbi.nlm.nih.gov/pub/lu/BC7-NLM-Chem-track/. Database URL https://ftp.ncbi.nlm.nih.gov/pub/lu/BC7-NLM-Chem-track/

Authors: Robert Leaman, Rezarta Islamaj, Virginia Adams, Mohammed A Alliheedi, João Rafael Almeida, Rui Antunes, Robert Bevan, Yung-Chun Chang, Arslan Erdengasileng, Matthew Hodgskiss, Ryuki Ida, Hyunjae Kim, Keqiao Li, Robert E Mercer, Lukrécia Mertová, Ghadeer Mobasher, Hoo-Chang Shin, Mujeen Sung, Tomoki Tsujimura, Wen-Chao Yeh, Zhiyong Lu

Date Published: 2023

Publication Type: Journal Article

WeLT: Improving Biomedical Fine-tuned Pre-trained Language Models with Cost-sensitive Learning

Abstract

Not specified

Authors: Ghadeer Mobasher, Wolfgang Müller, Olga Krebs, Michael Gertz

Date Published: 2023

Publication Type: Conference Paper

Comparison of Bioluminescent Substrates in Natural Infection Models of Neglected Parasitic Diseases

Abstract (Expand)

The application of in vivo bioluminescent imaging in infectious disease research has significantly increased over the past years. The detection of transgenic parasites expressing wildtype firefly … luciferase is however hampered by a relatively low and heterogeneous tissue penetrating capacity of emitted light. Solutions are sought by using codon-optimized red-shifted luciferases that yield higher expression levels and produce relatively more red or near-infrared light, or by using modified bioluminescent substrates with enhanced cell permeability and improved luminogenic or pharmacokinetic properties. In this study, the in vitro and in vivo efficacy of two modified bioluminescent substrates, CycLuc1 and AkaLumine-HCl, were compared with that of D-luciferin as a gold standard. Comparisons were made in experimental and insect-transmitted animal models of leishmaniasis (caused by intracellular Leishmania species) and African trypanosomiasis (caused by extracellular Trypanosoma species), using parasite strains expressing the red-shifted firefly luciferase PpyRE9. Although the luminogenic properties of AkaLumine-HCl and D-luciferin for in vitro parasite detection were comparable at equal substrate concentrations, AkaLumine-HCl proved to be unsuitable for in vivo infection follow-up due to high background signals in the liver. CycLuc1 presented a higher in vitro luminescence compared to the other substrates and proved to be highly efficacious in vivo, even at a 20-fold lower dose than D-luciferin. This efficacy was consistent across infections with the herein included intracellular and extracellular parasitic organisms. It can be concluded that CycLuc1 is an excellent and broadly applicable alternative for D-luciferin, requiring significantly lower doses for in vivo bioluminescent imaging in rodent models of leishmaniasis and African trypanosomiasis.

Authors: Sarah Hendrickx, Dimitri Bulté, Dorien Mabille, Roxanne Mols, Mathieu Claes, Kayhan Ilbeigi, Rokaya Ahmad, Laura Dirkx, Sara I. Van Acker, Guy Caljon

Date Published: 16th Dec 2022

Publication Type: Journal Article

Comparison of Bioluminescent Substrates in Natural Infection Models of Neglected Parasitic Diseases.

Abstract (Expand)

The application of in vivo bioluminescent imaging in infectious disease research has significantly increased over the past years. The detection of transgenic parasites expressing wildtype firefly … luciferase is however hampered by a relatively low and heterogeneous tissue penetrating capacity of emitted light. Solutions are sought by using codon-optimized red-shifted luciferases that yield higher expression levels and produce relatively more red or near-infrared light, or by using modified bioluminescent substrates with enhanced cell permeability and improved luminogenic or pharmacokinetic properties. In this study, the in vitro and in vivo efficacy of two modified bioluminescent substrates, CycLuc1 and AkaLumine-HCl, were compared with that of D-luciferin as a gold standard. Comparisons were made in experimental and insect-transmitted animal models of leishmaniasis (caused by intracellular Leishmania species) and African trypanosomiasis (caused by extracellular Trypanosoma species), using parasite strains expressing the red-shifted firefly luciferase PpyRE9. Although the luminogenic properties of AkaLumine-HCl and D-luciferin for in vitro parasite detection were comparable at equal substrate concentrations, AkaLumine-HCl proved to be unsuitable for in vivo infection follow-up due to high background signals in the liver. CycLuc1 presented a higher in vitro luminescence compared to the other substrates and proved to be highly efficacious in vivo, even at a 20-fold lower dose than D-luciferin. This efficacy was consistent across infections with the herein included intracellular and extracellular parasitic organisms. It can be concluded that CycLuc1 is an excellent and broadly applicable alternative for D-luciferin, requiring significantly lower doses for in vivo bioluminescent imaging in rodent models of leishmaniasis and African trypanosomiasis.

Authors: S. Hendrickx, D. Bulte, D. Mabille, R. Mols, M. Claes, K. Ilbeigi, R. Ahmad, L. Dirkx, S. I. Van Acker, G. Caljon

Date Published: 16th Dec 2022

Publication Type: Journal Article

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