Venturicidin A affects the mitochondrial membrane potential and induces kDNA loss inTrypanosoma brucei DOI Creative Commons

Dennis A. Hauser,

Marcel Kaiser, Pascal Mäser

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 15, 2024

Abstract Neglected tropical diseases caused by trypanosomatid parasites have devastating health and economic consequences, especially in areas. New drugs or new combination therapies to fight these are urgently needed. Venturicidin A, a macrolide extracted from Streptomyces , inhibits the ATP synthase complex of fungi bacteria. However, its effect on trypanosomatids is not fully understood. In this study, we tested venturicidin A panel using Alamar Blue assays found it be highly active against Trypanosoma brucei Leishmania donovani but much less so evansi . Using fluorescence microscopy observed rapid loss mitochondrial membrane potential T. bloodstream forms upon treatment. Additionally, report DNA approximately 40 50% treated parasites. We conclude that targets suggest could candidate for antitrypanosomatid drug repurposing, combinations, medicinal chemistry programs.

Language: Английский

UV activated peroxymonosulfate synergistically removes Microcystis aeruginosa and Chlorella vulgaris DOI
Huixin Li, Yu Luo, Min-Yong Lee

et al.

Journal of environmental chemical engineering, Journal Year: 2025, Volume and Issue: 13(2), P. 115379 - 115379

Published: Jan. 8, 2025

Language: Английский

Citations

1
The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer DOI Creative Commons
Thomas N. Seyfried,

Derek C. Lee,

Tomás Duraj

et al.

Journal of Bioenergetics and Biomembranes, Journal Year: 2025, Volume and Issue: unknown

Published: April 8, 2025

Abstract Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed oxygen consumption was lower lactate production higher in cancerous tissues than non-cancerous tissues. considered both and extracellular as accurate markers for ATP OxPhos glycolysis, respectively. Warburg’s hypothesis challenged showing remained high some cells despite elevated suggesting largely unimpaired. New information indicates neither nor are surrogates quantification cells. also did not know significant amount could come glutamine-driven substrate level glutaminolysis pathway with succinate produced end product, thus confounding linkage to origin within mitochondria. Moreover, new shows cytoplasmic lipid droplets aerobic fermentation biomarkers insufficiency. original can now be linked more complete understanding how underlies dysregulated cell growth. These address several questionable assumptions regarding allowing field advance effective therapeutic strategies less toxic metabolic management prevention cancer.

Language: Английский

Citations

0
Phenotypic screening reveals a highly selective phthalimide-based compound with antileishmanial activity DOI Creative Commons
Farnaz Zahedifard, Meenakshi Bansal, Neha Sharma

et al.

PLoS neglected tropical diseases, Journal Year: 2024, Volume and Issue: 18(3), P. e0012050 - e0012050

Published: March 25, 2024

Pharmacophores such as hydroxyethylamine (HEA) and phthalimide (PHT) have been identified potential synthons for the development of compounds against various parasitic infections. In order to further advance our progress, we conducted an experiment utilising a collection PHT HEA derivatives through phenotypic screening diverse set protist parasites. This approach led identification number that exhibited significant effects on survival Entamoeba histolytica , Trypanosoma brucei multiple life-cycle stages Leishmania spp . The hits were pursued due pressing necessity expand repertoire reliable, cost-effective, efficient medications treatment leishmaniases. Antileishmanials must possess essential capability efficiently penetrate host cells their compartments in disease context, effectively eliminate intracellular parasite. Hence, performed study assess effectiveness eradicating L infantum amastigotes model macrophage infection. Among eleven growth inhibitors with low-micromolar potency, PHT-39, which carries trifluoromethyl substitution, demonstrated highest efficacy intramacrophage assay, EC50 1.2 +/- 3.2 μM. Cytotoxicity testing PHT-39 HepG2 indicated promising selectivity over 90-fold. A chemogenomic profiling was using orthology-based method elucidate mode action PHT-39. genome-wide RNA interference library T sensitivity determinants included P-type ATPase is crucial uptake miltefosine amphotericin, strongly indicating shared route cellular entry. Notwithstanding favourable properties Plasmodium berghei infection model, unable eradicate major murine cutaneous leishmaniasis. Currently, undergoing derivatization optimize its pharmacological characteristics.

Language: Английский

Citations

3
Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells DOI Creative Commons

Derek C. Lee,

Linh Ta,

Purna Mukherjee

et al.

ASN NEURO, Journal Year: 2024, Volume and Issue: 16(1)

Published: Jan. 1, 2024

Energy is necessary for tumor cell viability and growth. Aerobic glucose-driven lactic acid fermentation a common metabolic phenotype seen in most cancers including malignant gliomas. This linked to abnormalities mitochondrial structure function. A luciferin-luciferase bioluminescence ATP assay was used measure the influence of amino acids, glucose, oxygen on content mouse (VM-M3 CT-2A) human (U-87MG) glioma cells that differed biology, genetic background, species origin. Oxygen consumption measured using Resipher system. Extracellular lactate succinate were as end products glycolysis glutaminolysis pathways, respectively. The results showed that: (1) glutamine source irrespective oxygen. No other could replace sustaining viability; (2) persisted absence glucose under hypoxia, ruling out substantial contribution through either or oxidative phosphorylation (OxPhos) these conditions; (3) Mitochondrial complex IV inhibition not an accurate production OxPhos. glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine (DON), reduced export grown glutamine. data suggests substrate level glutamine-driven pathway contributes cells. new model presented highlighting synergistic interaction between high-throughput pathways drive growth maintain aerobic both

Language: Английский

Citations

3
TrAGEDy: Trajectory Alignment of Gene Expression Dynamics DOI Open Access
Ross F Laidlaw, Emma M. Briggs, Keith R. Matthews

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Dec. 22, 2022

1 Abstract Motivation Single-cell transcriptomics sequencing is used to compare different biological processes. However, often, those processes are asymmetric which difficult integrate. Current approaches often rely on integrating samples from each condition before either cluster-based comparisons or analysis of an inferred shared trajectory. Results We present Trajectory Alignment Gene Expression Dynamics (TrAGEDy), allows the alignment independent trajectories avoid need for error-prone integration steps. Across simulated datasets, TrAGEDy returns correct underlying outperforming current tools fail capture complexity alignments. When applied real captures more biologically relevant genes and processes, other differential expression methods detect when looking at developments T cells bloodstream forms Trypanosoma brucei affected by genetic knockouts. Availability Implementation freely available https://github.com/No2Ross/TrAGEDy , implemented in R. Contact [email protected]

Language: Английский

Citations

7
Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells DOI Open Access

Derek C. Lee,

Linh Ta,

Purna Mukherjee

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 22, 2024

Abstract Energy is necessary for tumor cell viability and growth. Aerobic glucose-driven lactic acid fermentation a common metabolic phenotype seen in most cancers including malignant gliomas. This linked to abnormalities mitochondrial structure function. A luciferin-luciferase bioluminescence ATP assay was used measure the influence of amino acids, glucose, oxygen on content mouse (VM-M3 CT-2A) human (U-87MG) glioma cells that differed biology, genetic background, species origin. Oxygen consumption measured using Resipher system. Extracellular lactate succinate were as end products glycolysis glutaminolysis pathways, respectively. The results showed that: 1) glutamine source irrespective oxygen. No other could replace sustaining viability; 2) persisted absence glucose under hypoxia, ruling out substantial contribution through either or oxidative phosphorylation (OxPhos) these conditions; 3) Mitochondrial complex IV inhibition not an accurate production OxPhos. glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine (DON), reduced export grown glutamine. data suggests substrate level glutamine-driven pathway contributes cells. new model presented highlighting synergistic interaction between high-throughput pathways drive growth maintain aerobic both Summary statement Malignant gliomas, regardless origin species, rely mechanisms due OxPhos insufficiency. Glucose together are sufficient dysregulated growth, whereas neither nor sufficient.

Language: Английский

Citations

1
Venturicidin A affects the mitochondrial membrane potential and induces kDNA loss in Trypanosoma brucei DOI Creative Commons

Dennis A. Hauser,

Marcel Kaiser, Pascal Mäser

et al.

Antimicrobial Agents and Chemotherapy, Journal Year: 2024, Volume and Issue: 68(7)

Published: June 13, 2024

ABSTRACT Neglected tropical diseases caused by trypanosomatid parasites have devastating health and economic consequences, especially in areas. New drugs or new combination therapies to fight these are urgently needed. Venturicidin A, a macrolide extracted from Streptomyces , inhibits the ATP synthase complex of fungi bacteria. However, its effect on trypanosomatids is not fully understood. In this study, we tested venturicidin A panel using Alamar Blue assays found it be highly active against Trypanosoma brucei Leishmania donovani but much less so evansi . Using fluorescence microscopy, observed rapid loss mitochondrial membrane potential T. bloodstream forms upon treatment. Additionally, report DNA approximately 40%–50% treated parasites. We conclude that targets suggest could candidate for anti-trypanosomatid drug repurposing, combinations, medicinal chemistry programs.

Language: Английский

Citations

1
Inhibition of L-Threonine Dehydrogenase from Trypanosoma cruzi reduces glycine and acetate production and interferes with parasite growth and viability. DOI Creative Commons

Jéssica do Nascimento Faria,

Amanda G. Eufrásio,

M. Fagundes

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 108080 - 108080

Published: Dec. 1, 2024

Language: Английский

Citations

1
Venturicidin A affects the mitochondrial membrane potential and induces kDNA loss inTrypanosoma brucei DOI Creative Commons

Dennis A. Hauser,

Marcel Kaiser, Pascal Mäser

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 15, 2024

Abstract Neglected tropical diseases caused by trypanosomatid parasites have devastating health and economic consequences, especially in areas. New drugs or new combination therapies to fight these are urgently needed. Venturicidin A, a macrolide extracted from Streptomyces , inhibits the ATP synthase complex of fungi bacteria. However, its effect on trypanosomatids is not fully understood. In this study, we tested venturicidin A panel using Alamar Blue assays found it be highly active against Trypanosoma brucei Leishmania donovani but much less so evansi . Using fluorescence microscopy observed rapid loss mitochondrial membrane potential T. bloodstream forms upon treatment. Additionally, report DNA approximately 40 50% treated parasites. We conclude that targets suggest could candidate for antitrypanosomatid drug repurposing, combinations, medicinal chemistry programs.

Language: Английский

Citations

0