Ariel M Silber

Ariel M Silber
University of São Paulo | USP · Department of Parasitology (ICB)

PhD

About

165
Publications
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Publications

Publications (165)
Preprint
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The parasite Trypanosoma brucei is the causative agent of sleeping sickness and involves an insect vector and a mammalian host through its complex life-cycle. T. brucei mammalian bloodstream forms (BSF) have unique metabolic features including: i) reduced expression and activity of mitochondrial enzymes; ii) intrinsically uncoupled respiration medi...
Article
Full-text available
Trypanosoma cruzi is a hemoflagellated parasite causing Chagas disease, which affects 6–8 million people in the Americas. More than one hundred years after the description of this disease, the available drugs for treating the T . cruzi infection remain largely unsatisfactory. Chloroquinoline and arylamidine moieties are separately found in various...
Preprint
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Background: Genomic organization and gene expression regulation in trypanosomes are remarkable because protein-coding genes are organized into codirectional gene clusters with unrelated functions. Moreover, there is no dedicated promoter for each gene, resulting in polycistronic gene transcription, with posttranscriptional control playing a major r...
Preprint
Background Genomic organization and gene expression regulation in trypanosomes are remarkable because protein-coding genes are organized into codirectional gene clusters with unrelated functions. Moreover, there is no dedicated promoter for each gene, resulting in polycistronic gene transcription, with posttranscriptional control playing a major ro...
Article
Full-text available
The pathogenic protist Trypanosoma cruzi uses kissing bugs as intermediate hosts that vectorize the infection among mammals. This parasite oxidizes proline to glutamate through two enzymatic steps and one nonenzymatic step. In insect vectors, T. cruzi differentiates from a noninfective replicating form to nonproliferative infective forms. Proline s...
Preprint
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Background: Proline is a fundamental amino acid for Trypanosoma cruzi, the etiological agent of Chagas disease. Proline is mainly incorporated from the extracellular medium by amino acid transport systems. Different proline analogues proved to interact with the proline permease TcAAAP069 and inhibit the proline uptake by T. cruzi. Methods: Decyl- (...
Preprint
Background: Proline is a fundamental amino acid for Trypanosoma cruzi, the etiological agent of Chagas disease. Proline is mainly incorporated from the extracellular medium by amino acid transport systems. Different proline analogues proved to interact with the proline permease TcAAAP069 and inhibit the proline uptake by T. cruzi. Methods: Decyl- (...
Article
Full-text available
Trypanosoma cruzi , the parasite causing Chagas disease, is a digenetic flagellated protist that infects mammals (including humans) and reduviid insect vectors. Therefore, T . cruzi must colonize different niches in order to complete its life cycle in both hosts. This fact determines the need of adaptations to face challenging environmental cues. T...
Article
Full-text available
Trypanosoma brucei, a protist responsible for human African trypanosomiasis (sleeping sickness), is transmitted by the tsetse fly where the procyclic forms of the parasite develop in the proline-rich (1-2 mM) and glucose-depleted digestive tract. Proline is essential for the midgut colonization of the parasite in the insect vector, however other ca...
Article
The human pathogenic trypanosomatid species collectively called the “TriTryp parasites” – Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. – have complex life cycles, with each of these parasitic protists residing in a different niche during their successive developmental stages where they encounter diverse nutrients. Consequently, they ad...
Article
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Scientists are facing enormous pressures posed by growing scientific communities and stagnant/reduced funding. In this scenario, mechanisms of knowledge achievement and management, as well as how recruitment, progression and evaluation are carried out should be reevaluated. We argue here that knowledge has become a profitable commodity and, as a co...
Article
Full-text available
Trypanosoma cruzi alternates between replicative and nonreplicative life forms, accompanied by a shift in global transcription levels and by changes in the nuclear architecture, the chromatin proteome and histone posttranslational modifications. To gain further insights into the epigenetic regulation that accompanies life form changes, we performed...
Preprint
Full-text available
During its complex life cycle, Trypanosoma cruzi colonizes different niches in its insect and mammalian hosts. This characteristic determined the types of parasites that adapted to face challenging environmental cues. The primary environmental challenge, particularly in the insect stages, is poor nutrient availability. These T. cruzi stages could b...
Article
Full-text available
Toxoplasmosis, a protozoan infection caused by Toxoplasma gondii, is estimated to affect around 2.5 billion people worldwide. Nevertheless, the side effects of drugs combined with the long period of therapy usually result in discontinuation of the treatment. New therapies should be developed by exploring peculiarities of the parasite’s metabolic pa...
Preprint
Full-text available
Trypanosoma brucei , a protist responsible for human African trypanosomiasis (sleeping sickness), is transmitted by the tsetse fly, where the procyclic forms of the parasite develop in the proline-rich (1-2 mM) and glucose-depleted digestive tract. Proline is essential for the midgut colonization of the parasite in the insect vector, however other...
Article
Adenylate-forming enzymes (AFEs) are a mechanistic superfamily of proteins that are involved in many cellular roles. In the biosynthesis of benzoxazole antibiotics, an AFE has been reported to play a key role in the condensation of cyclic molecules. In the biosynthetic gene cluster for the benzoxazole AJI9561, AjiA1 catalyzes the condensation of tw...
Article
Full-text available
Abnormal sterols disrupt cellular functions through yet unclear mechanisms. In Saccharomyces cerevisiae, accumulation of Δ8-sterols, the same type of sterols observed in patients of Conradi-Hünermann-Happle syndrome or in fungi after amine fungicide treatment, leads to cell wall weakness. We have studied the influence of Δ8-sterols on the activity...
Article
Full-text available
L-Proline is an important amino acid for the pathogenic protists belonging to Trypanosoma and Leishmania genera. In Trypanosoma cruzi, the etiological agent of Chagas disease, this amino acid is involved in fundamental biological processes such as ATP production, differentiation of the insect and intracellular stages, the host cell infection and th...
Article
The unicellular protists of the group Kinetoplastida include the genera Leishmania and Trypanosoma, which are pathogens of invertebrate and vertebrate animals. Despite their medical and economical importance, critical aspects of their biology such as specific molecular characteristics of gene expression regulation are just beginning to be deciphere...
Article
Chagas disease is one of seventeen neglected tropical diseases according to the World Health Organization (WHO). The histidine-glutamate metabolic pathway is an oxidative route that has shown to be relevant for the bioenergetics in Trypanosoma cruzi, the etiological agent for Chagas disease. Histidine ammonia-lyase participates in the first stage o...
Article
Full-text available
In Trypanosoma cruzi, the etiological agent of Chagas disease, the amino acid proline participates in processes related to T. cruzi survival and infection, such as ATP production, cell differentiation, host-cell invasion, and in protection against osmotic, nutritional, and thermal stresses and oxidative imbalance. However, little is known about pro...
Article
Full-text available
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,...
Article
The reduced mitochondrial respiratory chain from the bloodstream forms of Trypanosoma brucei is composed of only a membrane‐bound glycerol‐3‐phosphate dehydrogenase and an alternative oxidase. Since these enzymes are not proton pumps, their functions are restricted to the maintenance of the redox balance in the glycosome by means of the dihydroxyac...
Chapter
The evaluation of mitochondrial functionality is critical to interpret most biological data at the (eukaryotic) cellular level. For example, metabolism, cell cycle, epigenetic regulation, cell death mechanisms, autophagy, differentiation, and response redox imbalance are dependent on the mitochondrial state. In case of parasitic organisms, such as...
Article
Full-text available
Trypanosoma cruzi, a hemoflagellate parasite, is the etiological agent of Chagas disease that affects about 6-7 million people worldwide, mostly in Latin America. The parasite life cycle is complex and alternates between an invertebrate host-Triatominae vector-and a mammalian host. The parasite adaptation to the several microenvironments through wh...
Article
During three decades, only about 20 new drugs have been developed for malaria, tuberculosis and all neglected tropical diseases (NTDs). This critical situation was reached because NTDs represent only 10% of health research investments; however, they comprise about 90% of the global disease burden. Computational simulations applied in virtual screen...
Article
The enzyme Urocanate Hydratase (UH) participates in the catabolic pathway of L-histidine. Trypanosoma cruzi Urocanate Hydratase (TcUH) is identified as a therapeutic molecular target in the WHO/TDR Targets Database. We report the 3D structure determination and number of features of TcUH, and compared it to other few available bacterial UH structure...
Article
Chagas disease (CD) is a human infection caused by Trypanosoma cruzi . CD was traditionally endemic to the Americas, however, due to migration it has spread to non-endemic countries. The current chemotherapy to treat CD induce several side effects and its effectiveness in the chronic phase of the disease is controversial. In this contribution, subs...
Article
Full-text available
Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease that affects 5–6 million people in endemic areas of the Americas. Presently, chemotherapy relies on two compounds that were proposed as trypanocidal drugs four decades ago: nifurtimox and benznidazole. Both drugs are able to eliminate parasitemia and to avoid seroconversio...
Article
Full-text available
Trypanosoma cruzi, the etiological agent of Chagas disease, is dependent on proline for a variety of processes, such as energy metabolism, host cell invasion, differentiation, and resistance to osmotic, metabolic, and oxidative stress. On this basis, we investigated a possible relationship between prolinemia and severity of T. cruzi infection in ch...
Preprint
Full-text available
As the knowledge base and importance of mitochondrial physiology to human health expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unif...
Article
Full-text available
Triple-negative breast cancers (TNBCs) lack progesterone and estrogen receptors and do not have amplified human epidermal growth factor receptor 2, the main therapeutic targets for managing breast cancer. TNBCs have an altered metabolism, including an increased Warburg effect and glutamine dependence, making the inhibitor CB-839 therapeutically pro...
Article
Pep5 (WELVVLGKL) is a fragment of cyclin D2 that exhibits a 2-fold increase in the S phase of the HeLa cell cycle. When covalently bound to a cell-penetrating peptide (Pep5-cpp), the nonapeptide induces cell death in several tumor cells, including breast cancer and melanoma. Additionally, Pep5-cpp reduces the in vivo tumor volume of rat glioblastom...
Preprint
Full-text available
Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease that affects 5-6 million people in endemic areas of the Americas. Presently, chemotherapy relies on two compounds that were proposed as trypanocidal drugs four decades ago: nifurtimox and benznidazole. Both drugs are able to eliminate parasitemia and to avoid seroconversio...
Preprint
Full-text available
L-Proline is an important amino acid for the pathogenic protists belonging to Trypanosoma and Leishmania genera. In Trypanosoma cruzi , the etiological agent of Chagas disease, this amino acid is involved in fundamental biological processes such as ATP production, differentiation of the insect and intracellular stages, the host cell infection and t...
Article
Full-text available
Previous work from our group showed that tamoxifen, an oral drug that has been in use for the treatment of breast cancer for over 40 years, is active both in vitro and in vivo against several species of Leishmania, the etiological agent of leishmaniasis. Using a combination of metabolic labeling with [³H]-sphingosine and myo-[³H]-inositol, alkaline...
Article
Full-text available
Trypanosoma cruzi, the etiologic agent of Chagas disease, cycles through different life stages characterized by defined molecular traits associated with the proliferative or differentiation state. In particular, T. cruzi epimastigotes are the replicative forms that colonize the intestine of the Triatomine insect vector before entering the stationar...
Article
Since the observation of the great pleomorphism of fish trypanosomes, in vitro culture has become an important tool to support taxonomic studies investigating the biology of cultured parasites, such as their structure, growth dynamics, and cellular cycle. Relative to their biology, ex vivo and in vitro studies have shown that these parasites, durin...
Article
Background Trypanosoma cruzi, the causative agent of Chagas' disease is unable to synthesise its own purines and relies on salvage from the host. In other protozoa, purine uptake has been shown to be mediated by Equilibrative Nucleoside Transporters (ENTs). Methods To investigate the functionality of T. cruzi-encoded ENT transporters, its four put...
Article
Full-text available
It is well known that trypanosomatids such as the etiological agent of Chagas’ disease, Trypanosoma cruzi , produce alanine as a main end product of their energy metabolism when they grow in a medium containing glucose and amino acids. In this work, we investigated if under starvation conditions (which happen during the parasite life cycle) the sec...
Article
Trypanosoma cruzi, the aetiological agent of Chagas disease, can obtain L-glutamine (Gln) through the enzyme glutamine synthetase (GS) using glutamate (Glu) and ammonia as substrates. In this work, we show additional non-canonical roles for this amino acid: its involvement in ATP maintenance and parasite survival under severe metabolic stress condi...
Article
This work aims at the synthesis of megazol analogs with antitrypanosomicidal activity. Chagas’disease is caused by Trypanosoma cruzi and is a debilitating disease that has both acute and chronic forms. We synthesized a series of derivatives of 2-(1-methyl-5-nitro-2-imidazolyl)-5-substituted-1,3,4-thiadiazoles where 1-acetyl, 1-propyl and 1-nonyl we...
Article
Full-text available
Trypanosoma brucei , as well asTrypanosoma cruziand more than 20 species of the genusLeishmania, form a group of flagellated protists that threaten human health. These organisms are transmitted by insects that, together with mammals, are their natural hosts. This implies that during their life cycles each of them faces environments with different p...
Article
Full-text available
Objective: This work aims at the synthesis of megazol analogs with antitrypanosomicidal activity. Chagas’disease is caused by Trypanosoma cruzi and is a debilitating disease that has both acute and chronic forms. Many South Americans suffer from the chronic form of Chagas’disease, and there is no treatment currently available.Methods: In the chemic...
Article
Full-text available
The active transport of glycolytic pyruvate across the inner mitochondrial membrane is thought to involve two mitochondrial pyruvate carrier subunits, MPC1 and MPC2, assembled as a 150 kDa heterotypic oligomer. Here, the recombinant production of human MPC through a co-expression strategy is first described; however, substantial complex formation w...
Article
Full-text available
Trypanosoma cruzi, the etiological agent of Chagas disease, consumes glucose and amino acids depending on the environmental availability of each nutrient during its complex life cycle. For example, amino acids are the major energy and carbon sources in the intracellular stages of the T. cruzi parasite, but their consumption produces an accumulation...
Data
GS activity was measured in E cell-free extracts. The system of coupled reactions described in Materials and Methods was used to obtain the time-course curves at different concentrations for each of the three substrates: Glutamate (A), ATP (B) and NH4OH (C) (while keeping the others at saturating concentrations). Initial velocities (V0) at each con...
Data
Specificity of Anti-GS antibody. (A) The recombinant protein was analyzed by SDS-PAGE using 10% (v/v) polyacrylamide gels under reducing conditions and visualized by Coomassie Blue staining. EC: Elutions concentrated by Amicon Ultra-4 50K (Millipore, Burlington, Massachusetts, United States). (B) Representative Western blot performed with EC agains...
Data
Representative images of the effect of MS on evasion of the parasitophorous vacuole of T. cruzi. CHO-K1 cells were labeled with LysoNIR and then incubated with CDT to initiate infection. After 3 h, the cultures were washed and submitted to the treatment (or not). Nuclear DNA (N) was stained with Hoechst 33342. The cultures were observed and photogr...
Poster
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In this work, we investigated how epimastigote forms of Trypanosoma cruzi deal with nutritional stress and how the mechanisms of resistance are organized in time.
Article
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Objectives: To develop an alcohol-free solution suitable for children of benznidazole, the drug of choice for treatment of Chagas disease. Methods: In a quality-by-design approach a systematic optimization procedure was carried out in order to estimate the values of the factors leading to the maximum drug concentration. The formulations were ana...
Article
Full-text available
Trypanosoma cruzi, the etiological agent of Chagas disease, lacks genes that encode canonical branched-chain aminotransferases. However, early studies showed that when epimastigotes were grown in the presence of (14) C1 -DL-leucine, the label was incorporated into various intermediates. More recently, our studies provided evidence that T. cruzi epi...
Article
Full-text available
Trypanosoma cruzi, the etiological agent of Chagas disease, is a protozoan parasite with a complex lifecycle involving a triatomine insect and mammals. Throughout its lifecycle, the T. cruzi parasite faces several alternating events of cell division and cell differentiation in which exponential and stationary growth phases play key biological roles...
Article
Full-text available
Adaptation to different nutritional environments is essential for life cycle completion by all Trypanosoma brucei sub-species. In the tsetse fly vector, L-proline is among the most abundant amino acids and is mainly used by the fly for lactation and to fuel flight muscle. The procyclic (insect) stage of T. b. brucei uses L-proline as its main carbo...