Impact of Visceral Leishmaniasis on Local Organ Metabolism in Hamsters.

Leishmania is an intracellular parasite with different species pathogenic to humans and causing the disease leishmaniasis. Leishmania donovani causes visceral leishmaniasis (VL) that manifests as hepatosplenomegaly, fever, pancytopenia and hypergammaglobulinemia. If left without treatment, VL can cause death, especially in immunocompromised people. Current treatments have often significant adverse effects, and resistance has been reported in some countries. Determining the metabolites perturbed during VL can lead us to find new treatments targeting disease pathogenesis. We therefore compared metabolic perturbation between L. donovani-infected and uninfected hamsters across organs (spleen, liver, and gut). Metabolites were extracted, analyzed by liquid chromatography-mass spectrometry, and processed with MZmine and molecular networking to annotate metabolites. We found few metabolites commonly impacted by infection across all three sites, including glycerophospholipids, ceramides, acylcarnitines, peptides, purines and amino acids. In accordance with VL symptoms and parasite tropism, we found a greater overlap of perturbed metabolites between spleen and liver compared to spleen and gut, or liver and gut. Targeting pathways related to these metabolite families would be the next focus that can lead us to find more effective treatments for VL

Local Phenomena Shape Backyard Soil Metabolite Composition

Soil covers most of Earth’s continental surface and is fundamental to life-sustaining processes such as agriculture. Given its rich biodiversity, soil is also a major source for natural product drug discovery from soil microorganisms. However, the study of the soil small molecule profile has been challenging due to the complexity and heterogeneity of this matrix. In this study, we implemented high-resolution liquid chromatography–tandem mass spectrometry and large-scale data analysis tools such as molecular networking to characterize the relative contributions of city, state and regional processes on backyard soil metabolite composition, in 188 soil samples collected from 14 USA States, representing five USA climate regions. We observed that region, state and city of collection all influence the overall soil metabolite profile. However, many metabolites were only detected in unique sites, indicating that uniquely local phenomena also influence the backyard soil environment, with both human-derived and naturally-produced (plant-derived, microbially-derived) metabolites identified. Overall, these findings are helping to define the processes that shape the backyard soil metabolite composition, while also highlighting the need for expanded metabolomic studies of this complex environment.This research was supported by start-up funds from the University of Oklahoma (to L.-I.M.). Open Access fees paid for in whole or in part by the University of Oklahoma Libraries.Ye

Application of untargeted metabolomics techniques based on LC-MS/MS to parasitic diseases and drug development

Metabolites are small chemical molecules less than 1500 Da such as carbohydrates, lipids, and amino acids that provide different functions in organisms. These metabolites are the products of host metabolism or received from the environment. Exploring metabolite perturbation provides valuable insights into metabolic functions and responses to internal and external factors, including diseases. This dissertation applied untargeted metabolomics based on mass spectrometry to investigate metabolic perturbation induced by infection in two parasitic diseases, leishmaniasis and toxoplasmosis. We applied LC-MS/MS, a powerful analytical technique with high resolution and well-suited for complex biological samples. In these studies, we focused on individual organs and investigated how the metabolome changed and which metabolic pathways were affected by infection. Our results will increase knowledge about disease mechanisms, which can lead us to identify biomarkers and new treatments. In addition, we evaluated the effects of different doses of carnitine, alone or in combination with benznidazole, on chronic stage of Chagas disease in mouse models. Carnitine was identified through an untargeted metabolomics study related to Chagas disease caused by Trypanosoma cruzi, and shown to improve heart health in chronic infection, without affecting parasite burden. Our goal was to assess the safety and efficacy of carnitine as a potential treatment option combined with the antiparasitic drug, benznidazole, for chronic stage. Our result showed no negative effect of carnitine on antiparasitic effect of benznidazole and no negative effect on mice health. Based on our results, it is important to determine the right dose of carnitine to prevent from increase of trimethylamine N-oxide (TMAO) level in plasma to prevent cardiovascular risk. This dissertation provided new insights into host-parasite interactions for leishmaniasis and toxoplasmosis, while evaluating safety and efficacy of Chagas disease

Impact of Visceral Leishmaniasis on Local Organ Metabolism in Hamsters

Leishmania is an intracellular parasite with different species pathogenic to humans and causing the disease leishmaniasis. Leishmania donovani causes visceral leishmaniasis (VL) that manifests as hepatosplenomegaly, fever, pancytopenia and hypergammaglobulinemia. If left without treatment, VL can cause death, especially in immunocompromised people. Current treatments have often significant adverse effects, and resistance has been reported in some countries. Determining the metabolites perturbed during VL can lead us to find new treatments targeting disease pathogenesis. We therefore compared metabolic perturbation between L. donovani-infected and uninfected hamsters across organs (spleen, liver, and gut). Metabolites were extracted, analyzed by liquid chromatography-mass spectrometry, and processed with MZmine and molecular networking to annotate metabolites. We found few metabolites commonly impacted by infection across all three sites, including glycerophospholipids, ceramides, acylcarnitines, peptides, purines and amino acids. In accordance with VL symptoms and parasite tropism, we found a greater overlap of perturbed metabolites between spleen and liver compared to spleen and gut, or liver and gut. Targeting pathways related to these metabolite families would be the next focus that can lead us to find more effective treatments for VL