scholarly journals Glutamine metabolism modulates azole susceptibility in Trypanosoma cruzi amastigotes

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Peter C Dumoulin ◽  
Joshua Vollrath ◽  
Sheena Shah Tomko ◽  
Jennifer X Wang ◽  
Barbara Burleigh
Keyword(s):  
Trypanosoma Cruzi ◽  
Potential Role ◽  
Glutamine Metabolism ◽  
Sterol Synthesis ◽  
Ergosterol Biosynthesis ◽  
Metabolic Intermediates ◽  
Ergosterol Biosynthesis Inhibitors ◽  
Current Therapies ◽  
Metabolic Heterogeneity

The mechanisms underlying resistance of the Chagas disease parasite, Trypanosoma cruzi, to current therapies are not well understood, including the role of metabolic heterogeneity. We found that limiting exogenous glutamine protects actively dividing amastigotes from ergosterol biosynthesis inhibitors (azoles), independent of parasite growth rate. The antiparasitic properties of azoles are derived from inhibition of lanosterol 14α-demethylase (CYP51) in the endogenous sterol synthesis pathway. We find that carbons from 13C-glutamine feed into amastigote sterols and into metabolic intermediates that accumulate upon CYP51 inhibition. Incorporation of 13C-glutamine into endogenously synthesized sterols is increased with BPTES treatment, an inhibitor of host glutamine metabolism that sensitizes amastigotes to azoles. Similarly, amastigotes are re-sensitized to azoles following addition of metabolites upstream of CYP51, raising the possibility that flux through the sterol synthesis pathway is a determinant of sensitivity to azoles and highlighting the potential role for metabolic heterogeneity in recalcitrant T. cruzi infection.

scholarly journals Glutamine metabolism modulates azole susceptibility in Trypanosoma cruzi amastigotes

2020 ◽  
Author(s):  
Peter C. Dumoulin ◽  
Joshua Vollrath ◽  
Jennifer X. Wang ◽  
Barbara A. Burleigh
Keyword(s):  
Trypanosoma Cruzi ◽  
Potential Role ◽  
Glutamine Metabolism ◽  
Sterol Synthesis ◽  
Ergosterol Biosynthesis ◽  
Intracellular Amastigotes ◽  
Ergosterol Biosynthesis Inhibitors ◽  
Current Therapies ◽  
Metabolic Heterogeneity

AbstractThe mechanisms underlying resistance of the Chagas disease parasite, Trypanosoma cruzi, to current therapies are not well understood, including the potential role of metabolic heterogeneity in modulating susceptibility of intracellular amastigotes to trypanocidal compounds. We found that limiting exogenous glutamine protects actively dividing amastigotes from ergosterol biosynthesis inhibitors (azoles), independent of parasite growth rate. The antiparasitic properties of azoles are derived from inhibition of lanosterol 14α-demethylase (CYP51) in the endogenous sterol synthesis pathway. We find that carbons from 13C-glutamine feed into amastigote sterols and into metabolic intermediates that accumulate upon CYP51 inhibition. Consistent with a model that decreased flux through the sterol biosynthetic pathway is protective for intracellular amastigotes exposed to azoles, we find that amastigotes become re-sensitized to azoles following addition of metabolites upstream of CYP51. Our results highlight the potential role of metabolic heterogeneity in recalcitrant T. cruzi infection, an avenue that is currently underexplored.

scholarly journals Glutamine Analogues Impair Cell Proliferation, the Intracellular Cycle and Metacyclogenesis in Trypanosoma cruzi

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1628
Author(s):  
Rodolpho Ornitz Oliveira Souza ◽  
Marcell Crispim ◽  
Ariel Mariano Silber ◽  
Flávia Silva Damasceno
Keyword(s):  
Cell Proliferation ◽  
Life Cycle ◽  
Trypanosoma Cruzi ◽  
Host Cells ◽  
Glutamine Metabolism ◽  
Complex Life Cycle ◽  
Mammalian Host ◽  
Developmental Cycle ◽  
Parasite Life Cycle

Trypanosoma cruzi is the aetiologic agent of Chagas disease, which affects people in the Americas and worldwide. The parasite has a complex life cycle that alternates among mammalian hosts and insect vectors. During its life cycle, T. cruzi passes through different environments and faces nutrient shortages. It has been established that amino acids, such as proline, histidine, alanine, and glutamate, are crucial to T. cruzi survival. Recently, we described that T. cruzi can biosynthesize glutamine from glutamate and/or obtain it from the extracellular environment, and the role of glutamine in energetic metabolism and metacyclogenesis was demonstrated. In this study, we analysed the effect of glutamine analogues on the parasite life cycle. Here, we show that glutamine analogues impair cell proliferation, the developmental cycle during the infection of mammalian host cells and metacyclogenesis. Taken together, these results show that glutamine is an important metabolite for T. cruzi survival and suggest that glutamine analogues can be used as scaffolds for the development of new trypanocidal drugs. These data also reinforce the supposition that glutamine metabolism is an unexplored possible therapeutic target.

scholarly journals Glucocorticoid-Induced Osteoporosis: The Potential Role of Romosozumab

2020 ◽  
Vol 20 (02) ◽  
pp. 71-79
Author(s):  
Jacqueline So ◽  
Chi Chiu Mok
Keyword(s):  
Potential Role ◽  
Assessment Tool ◽  
Early Recognition ◽  
Assessment Tools ◽  
Estimation Formula ◽  
Fracture Risk Assessment Tool ◽  
Current Therapies ◽  
Current Assessment ◽  
Dose Dependent

Glucocorticoid (GC)-induced osteoporosis (GIOP) is a major problem in patients with rheumatic diseases. The deleterious effect of GC on bone turnover is rapid and dose-dependent, with a predilection on the trabecular bone, resulting in vertebral fractures. Early recognition and prompt treatment of GIOP helps prevent bone loss and reduce fractures. There are pitfalls in current assessment tools for GIOP by dual-energy X-ray absorptiometry (DXA) and fracture risk assessment tool (FRAX) estimation formula. In this review, we evaluate different assessment methods for GIOP and summarize current therapies of GIOP, including the antiresorptive and anabolic agents. The potential role of newer anti-osteoporosis agent romosozumab, an anti-sclerostin monoclonal antibody, is also discussed.

scholarly journals Potential Role of Carvedilol in the Cardiac Immune Response Induced by Experimental Infection with Trypanosoma cruzi

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Aline Luciano Horta ◽  
Ana Luisa Junqueira Leite ◽  
G. Paula Costa ◽  
Vivian Paulino Figueiredo ◽  
André Talvani
Keyword(s):  
Immune Response ◽  
Trypanosoma Cruzi ◽  
Experimental Infection ◽  
Potential Role ◽  
Cardiac Tissue ◽  
Inflammatory Infiltration ◽  
Ccl2 Level ◽  
Immunomodulatory Properties ◽  
Cardiac Histopathology

Trypanosoma cruzi causes a cardiac infection characterized by an inflammatory imbalance that could become the inciting factor of the illness. To this end, we evaluated the role of carvedilol, a beta-blocker with potential immunomodulatory properties, on the immune response in C57BL/6 mice infected with VL-10 strain of T. cruzi in the acute phase. Animals (n=40) were grouped: (i) not infected, (ii) infected, (iii) infected + carvedilol, and (iv) not infected + carvedilol. We analyzed parameters related to parasitemia, plasma levels of TNF, IL-10, and CCL2, and cardiac histopathology after the administration of carvedilol for 30 days. We did not observe differences in the maximum peaks of parasitemia in the day of their detection among the groups. The plasma TNF was elevated at 60 days of infection in mice treated or not with carvedilol. However, we observed a decreased CCL2 level and increased IL-10 levels in those infected animals treated with carvedilol, which impacted the reduction of the inflammatory infiltration in cardiac tissue. For this experimental model, carvedilol therapy was not able to alter the levels of circulating parasites but modulates the pattern of CCL2 and IL-10 mediators when the VL10 strain of T. cruzi was used in C57BL6 mice.

POPDC proteins and cardiac function

2019 ◽  
Vol 47 (5) ◽  
pp. 1393-1404 ◽  
Author(s):  
Thomas Brand
Keyword(s):  
Potential Role ◽  
Striated Muscle ◽  
Short Review ◽  
Effector Proteins ◽  
Muscle Disease ◽  
Disease Genes ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

The Effect of Path Length and Display Size on Memory for Spatial Information

2012 ◽  
Vol 59 (3) ◽  
pp. 147-152 ◽  
Author(s):  
Katherine Guérard ◽  
Sébastien Tremblay
Keyword(s):  
Path Length ◽  
Potential Role ◽  
Spatial Information ◽  
Recall Performance ◽  
Minor Role ◽  
Length Effect ◽  
Serial Memory ◽  
Fixed Reference ◽  
A Minor

In serial memory for spatial information, some studies showed that recall performance suffers when the distance between successive locations increases relatively to the size of the display in which they are presented (the path length effect; e.g., Parmentier et al., 2005) but not when distance is increased by enlarging the size of the display (e.g., Smyth & Scholey, 1994). In the present study, we examined the effect of varying the absolute and relative distance between to-be-remembered items on memory for spatial information. We manipulated path length using small (15″) and large (64″) screens within the same design. In two experiments, we showed that distance was disruptive mainly when it is varied relatively to a fixed reference frame, though increasing the size of the display also had a small deleterious effect on recall. The insertion of a retention interval did not influence these effects, suggesting that rehearsal plays a minor role in mediating the effects of distance on serial spatial memory. We discuss the potential role of perceptual organization in light of the pattern of results.

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