Search Results (39)

Chagas disease is a serious public health problem worldwide. In Brazil, the state of Pará has the largest number of reported cases. This article analyzes the spatial distribution of this disease and its relationship with socioeconomic, environmental, and public policy health variables in three mesoregions in the Pará state from 2013 to 2022. This ecological study used secondary data obtained from official Brazilian agencies. Spatial analysis was carried out using the flow, kernel, and bivariate global Moran techniques expressed in thematic maps. A total of 3664 cases of the disease were confirmed, with the highest number of cases being reported in the northeast of Pará. A seasonal pattern of the disease, an epidemiological profile similar to other diseases in the Amazon region, and the spatial dependence between the disease prevalence and socioeconomic indicators were observed. The most intense movement of patients for treatment was to the Belém metropolitan mesoregion, which has the majority of the health services and professionals. The disease showed an inhomogeneous pattern of cases in terms of the spatial distribution, with a direct relationship between areas with a higher number of cases and those with human clusters. The socioenvironmental origins of the disease transcend mesoregion boundaries and stem from the historically unsustainable development model in the Amazon. Full article

The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, also called American trypanosomiasis. This neglected tropical disease affects millions of individuals across the Americas. To complete its life cycle, T. cruzi parasitizes both vertebrate hosts and its vector, commonly known as the ‘kissing bug’. The parasite’s survival and proliferation strategies are driven by the diverse environments it encounters. Despite being described by Carlos Chagas in 1909, significant knowledge gaps persist regarding the parasite’s various life forms and adaptive capabilities in response to environmental cues. In this study, we employed Ultrastructure Expansion Microscopy to explore the intricate journey of T. cruzi within the host cell. Upon entry into the host cell, trypomastigotes undergo folding, resulting in intermediate forms characterized by a rounded cell body, anterior positioning of basal bodies, and a shortened flagellum. The repositioning of basal bodies and the kinetoplast and the shortening of the flagella mark the culmination of intracellular amastigogenesis. Furthermore, we analyzed intracellular trypomastigogenesis, identifying discrete intermediate forms, including leaf-shaped stages and epimastigote-like forms, which suggests a complex differentiation process. Notably, we did not observe any dividing intracellular epimastigotes, indicating that these may be non-replicative forms within the host cell. Our detailed examination of amastigote cell division revealed semi-closed nuclear mitosis, with mitotic spindle formation independent of basal bodies. This study provides new insights into the morphological and cytoskeletal changes during the intracellular stages of T. cruzi, providing a model for understanding the dynamics of intracellular amastigogenesis and trypomastigogenesis. Full article

American trypanosomiasis or Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects approximately 6–7 million people worldwide. However, its pharmacological treatment causes several uncomfortable side effects, causing patients’ treatment abandonment. Therefore, there is a need for new and better treatments. In this work, the molecular docking of nine hundred twenty-four FDA-approved drugs on three different sites of trypanothione reductase of T. cruzi (TcTR) was carried out to find potential trypanocidal agents. Finally, biological evaluations in vitro and in vivo were conducted with the selected FDA-approved drugs. Digoxin, alendronate, flucytosine, and dihydroergotamine showed better trypanocidal activity than the reference drugs benznidazole and nifurtimox in the in vitro evaluation against the trypomastigotes form. Further, these FDA-approved drugs were able to reduce 20–50% parasitemia in a short time in an in vivo model, although with less efficiency than benznidazole. Therefore, the results suggest a combined therapy of repurposed and canonical drugs against T. cruzi infection. Full article

Trypanosoma cruzi, the causative agent of Chagas disease (American trypanosomiasis), is a highly complex zoonosis that is present throughout South America, Central America, and Mexico. The transmission of this disease is influenced by various factors, including human activities like deforestation and land use changes, which may have altered the natural transmission cycles and their connection to the environment. In this study conducted in the Argentine Chaco region, we examined the transmission dynamics of T. cruzi by collecting blood samples from wild and domestic animals, as well as triatomine bugs from human dwellings, across five sites of varying anthropic intervention. Samples were analyzed for T. cruzi infection via qPCR, and we additionally examined triatomines for bloodmeal analysis via NGS amplicon sequencing. Our analysis revealed a 15.3% infection rate among 20 wild species (n = 123) and no T. cruzi presence in 9 species of domestic animals (n = 1359) or collected triatomines via qPCR. Additionally, we found chicken (34.28%), human (21.59%), and goat (19.36%) as the predominant bloodmeal sources across all sites. These findings suggest that anthropic intervention and other variables analyzed may have directly impacted the spillover dynamics of T. cruzi’s sylvatic cycle and potentially reduced its prevalence in human habitats. Full article

Originally developed as a chemotherapeutic agent, miltefosine (hexadecylphosphocholine) is an inhibitor of phosphatidylcholine synthesis with proven antiparasitic effects. It is the only oral drug approved for the treatment of Leishmaniasis and American Trypanosomiasis (Chagas disease). Although its precise mechanisms are not yet fully understood, miltefosine exhibits broad-spectrum anti-parasitic effects primarily by disrupting the intracellular Ca²⁺ homeostasis of the parasites while sparing the human hosts. In addition to its inhibitory effects on phosphatidylcholine synthesis and cytochrome c oxidase, miltefosine has been found to affect the unique giant mitochondria and the acidocalcisomes of parasites. Both of these crucial organelles are involved in Ca²⁺ regulation. Furthermore, miltefosine has the ability to activate a specific parasite Ca²⁺ channel that responds to sphingosine, which is different to its L-type VGCC human ortholog. Here, we aimed to provide an overview of recent advancements of the anti-parasitic mechanisms of miltefosine. We also explored its multiple molecular targets and investigated how its pleiotropic effects translate into a rational therapeutic approach for patients afflicted by Leishmaniasis and American Trypanosomiasis. Notably, miltefosine’s therapeutic effect extends beyond its impact on the parasite to also positively affect the host’s immune system. These findings enhance our understanding on its multi-targeted mechanism of action. Overall, this review sheds light on the intricate molecular actions of miltefosine, highlighting its potential as a promising therapeutic option against these debilitating parasitic diseases. Full article

Chagas disease (CD) is a typical tropical illness caused by Trypanosoma cruzi. The objective of this study was to assess the prevalence of Chagas disease in communities in two states of the Brazilian Amazon. Data collection occurred in July in the Alto Juruá region of Acre and in December in the communities of Humaitá, Amazonas, in 2019. A total of 477 participants were included in the study. In the communities of Alto Juruá, triatomine collections and analyses of T. cruzi infection were also carried out. All confirmed cases were found in the state of Acre, resulting in a total prevalence of 1.67. Of these eight cases, seven underwent ECG, all of which were concluded as normal by the physician team’s cardiologists. Seventeen triatomine bugs, all belonging to the Rhodnius genus, were captured. The natural infection rate by T. cruzi was 25% in the Nova Cintra community and 66.67% in the Boca do Moa community (Alto Juruá). This research found that more than 1% of the studied population exhibited positive serological results for Chagas disease in the riverine communities during the study period, representing a small portion of cases among those who have not yet been diagnosed. Full article

Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world’s poorest people: African trypanosomiasis or sleeping sickness, American trypanosomiasis or Chagas disease and different types of leishmaniasis. Different metabolic pathways have been targeted to find antitrypanosomatid drugs, including polyamine metabolism. Since their discovery, the naturally occurring polyamines, putrescine, spermidine and spermine, have been considered important metabolites involved in cell growth. With a complex metabolism involving biosynthesis, catabolism and interconversion, the synthesis of putrescine and spermidine was targeted by thousands of compounds in an effort to produce cell growth blockade in tumor and infectious processes with limited success. However, the discovery of eflornithine (DFMO) as a curative drug against sleeping sickness encouraged researchers to develop new molecules against these diseases. Polyamine synthesis inhibitors have also provided insight into the peculiarities of this pathway between the host and the parasite, and also among different trypanosomatid species, thus allowing the search for new specific chemical entities aimed to treat these diseases and leading to the investigation of target-based scaffolds. The main molecular targets include the enzymes involved in polyamine biosynthesis (ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine synthase), enzymes participating in their uptake from the environment, and the enzymes involved in the redox balance of the parasite. In this review, we summarize the research behind polyamine-based treatments, the current trends, and the main challenges in this field. Full article

Endemic in 21 countries, Chagas disease, also known as American Trypanosomiasis, is a neglected tropical disease (NTD) caused by the protozoan parasite Trypanosoma cruzi. The available drugs for the treatment of this disease, benznidazole and nifurtimox, are outdated and display severe side effects. Thus, the discovery of new drugs is crucial. Based on our continuous studies aiming towards the discovery of natural products with anti-T. cruzi potential, the MeOH extract from aerial parts of Baccharis sphenophylla Dusén ex. Malme (Asteraceae) displayed activity against this parasite and was subjected to high-performance countercurrent chromatography (HPCCC), to obtain one unreported syn-labdane diterpene — sphenophyllol (1) — as well as the known compounds gaudichaudol C (2), ent-kaurenoic acid (3), hispidulin (4), eupafolin (5), and one mixture of di-O-caffeoylquinic acids (6–8). Compounds 1–8 were characterized by analysis of nuclear magnetic resonance (NMR) and mass spectrometry (MS) data. When tested against trypomastigote forms, isolated labdane diterpenes 1 and 2 displayed potent activity, with EC₅₀ values of 20.1 μM and 2.9 μM, respectively. The mixture of chlorogenic acids 6–8, as well as the isolated flavones 4 and 5, showed significant activity against the clinically relevant amastigotes, with EC₅₀ values of 24.9, 12.8, and 2.7 μM, respectively. Nonetheless, tested compounds 1–8 displayed no cytotoxicity against mammalian cells (CC₅₀ > 200 μM). These results demonstrate the application of HPCCC as an important tool to isolate bioactive compounds from natural sources, including the antitrypanosomal extract from B. sphenophylla, allowing for the development of novel strategic molecular prototypes against tropical neglected diseases. Full article

Amphibians are widely known as a prolific source of bioactive metabolites. In this work, we isolated and characterized compounds with antiparasitic activity from the oocytes of the toad Rhinella alata collected in Panama. Bio-guided isolation and structural elucidation were carried out using chromatographic and spectroscopic techniques, respectively. The organic extract was subjected to solid phase extraction followed by HPLC purification of the fraction with in vitro activity against Trypanosoma cruzi trypomastigotes. Seven steroids (1–7) of the bufadienolide family were isolated, and their structures were determined using NMR and MS analyses; of these 19-formyl-dyscinobufotalin, (3) is reported as a new natural product. Compounds 1 and 3–7 resulted in a good anti-trypanosomal activity profile. Among these, 16β-hydroxyl-hellebrigenin (1) and bufalin (7) showed significant selectivity values of >5 and 2.69, respectively, while the positive control benznidazole showed a selectivity of 18.81. Furthermore, molecular docking analysis showed compounds 1, 3 and 7 interact through H-bonds with the amino acid residues GLN-19, ASP-158, HIS-159 and TRP-177 from cruzipain at the catalytic site. Given the lack of therapeutic options to treat American trypanosomiasis, this work can serve as the basis for further studies that aim for the development of bufadienolides or their derivatives as drugs against Chagas disease. Full article

Human African trypanosomiasis (also known as sleeping sickness, with Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense as etiological agents), American trypanosomiasis (also known as Chagas disease, with Trypanosoma cruzi as the etiological agent), and leishmaniasis (including cutaneous, mucocutaneous, and visceral forms, with multiple species belonging to the Leishmania genus as etiological agents) are recognized as neglected tropical diseases (NTDs) [...] Full article

Triatoma infestans (Klug) is an insect recognized as not only an important vector of South American trypanosomiasis (Chagas disease) but also a model of specific cellular morphofunctional organization and epigenetic characteristics. The purpose of the present review is to highlight certain cellular processes that are particularly unveiled in T. infestans, such as the following: (1) somatic polyploidy involving nuclear and cell fusions that generate giant nuclei; (2) diversification of nuclear phenotypes in the Malpighian tubules during insect development; (3) heterochromatin compartmentalization into large bodies with specific spatial distribution and presumed mobility in the cell nuclei; (4) chromatin remodeling and co-occurrence of necrosis and apoptosis in the Malpighian tubules under stress conditions; (5) epigenetic markers; and (6) response of heterochromatin to valproic acid, an epidrug that inhibits histone deacetylases and induces DNA demethylation in other cell systems. These cellular processes and epigenetic characteristics emphasize the role of T. infestans as an attractive model for cellular research. A limitation of these studies is the availability of insect supply by accredited insectaries. For studies that require the injection of drugs, the operator’s dexterity to perform insect manipulation is necessary, especially if young nymphs are used. For studies involving in vitro cultivation of insect organs, the culture medium should be carefully selected to avoid inconsistent results. Full article

Our aim was to carry out a qualitative and quantitative synthesis of the influence of CCR5 genetic variants on Chagas disease (CD) through a systematic review. A total of 1197 articles were analyzed, and eleven were included in the review. A meta-analysis was conducted along with principal component analyses (PCAs). The polymorphisms found were analyzed using the SNP2TFBS tool to identify possible variants that influence the interaction with gene binding sites. Eleven studied variants were identified: rs2856758, rs2734648, rs1799987, rs1799988, rs41469351, rs1800023, rs1800024, Δ32/rs333, rs3176763, rs3087253 and rs11575815. The studies analyzed were published between 2001 and 2019, conducted in Argentina, Brazil, Spain, Colombia and Venezuela, and included Argentine, Brazilian, Colombian, Peruvian and Venezuelan patients. Eight polymorphisms were subjected to the meta-analysis, of which six were associated with the development of the cardiac form of CD: rs1799987—G/G and G/A in the dominance model and G/G in the recessiveness model; rs2856758—A/G in the codominance model; rs2734648—T/T and T/G in the dominance model; rs1799988—T/T in both the codominance and recessiveness models; rs1800023—G allele and the G/G genotype in the codominance and recessiveness models, and the G/G and G/A genotypes in the dominance model; and rs1800024—T allele. The PCA analyses were able to indicate the relationships between the alleles and the genotypes of the polymorphisms. The SNP2TFBS tool identified rs1800023 as an influencer of the Spi1 transcription factor (p < 0.05). A correlation was established between the alleles associated with the cardiac form of CD in this review, members of the C haplotype of the gene (HHC–TGTG), and the cardiac form of CD. Full article

Considering that health professionals at Brazil had doubts about the entomoepidemiological issues of Chagas disease (CD), and that many of them highlighted not feeling totally safe for clinical care, the knowledge of 281 Brazilian medical students was evaluated through a cross-sectional, descriptive, prospective, and quantitative research. Most students demonstrated that they knew about the etiological agent of CD (Trypanosoma cruzi), since 279 students answered the questionnaire correctly. Furthermore, the medical students demonstrated knowledge of the main form of transmission of the parasite, as 278 students associated CD transmission with triatomines. On the other hand, approximately 25 students did not associate CD transmission with triatomine feces. Besides that, these future health professionals had difficulties in relation to the treatment of CD, as more than half of the students (176) wrongly answered that CD “is not curable” or “is curable in the chronic phase”. Based on the results obtained that point out the difficulties medical students have with CD, there is a need for undergraduate medical courses to address the neglected diseases holistically because the National Curriculum Guidelines for the medical course require the training of competent health professionals capable of integrating the biological, psychological, social, and environmental dimensions. Full article

Trypanosomiases are a group of tropical diseases that have devastating health and socio-economic effects worldwide. In humans, these diseases are caused by the pathogenic kinetoplastids Trypanosoma brucei, causing African trypanosomiasis or sleeping sickness, and Trypanosoma cruzi, causing American trypanosomiasis or Chagas disease. Currently, these diseases lack effective treatment. This is attributed to the high toxicity and limited trypanocidal activity of registered drugs, as well as resistance development and difficulties in their administration. All this has prompted the search for new compounds that can serve as the basis for the development of treatment of these diseases. Antimicrobial peptides (AMPs) are small peptides synthesized by both prokaryotes and (unicellular and multicellular) eukaryotes, where they fulfill functions related to competition strategy with other organisms and immune defense. These AMPs can bind and induce perturbation in cell membranes, leading to permeation of molecules, alteration of morphology, disruption of cellular homeostasis, and activation of cell death. These peptides have activity against various pathogenic microorganisms, including parasitic protists. Therefore, they are being considered for new therapeutic strategies to treat some parasitic diseases. In this review, we analyze AMPs as therapeutic alternatives for the treatment of trypanosomiases, emphasizing their possible application as possible candidates for the development of future natural anti-trypanosome drugs. Full article

American trypanosomiasis is a worldwide health problem that requires attention due to ineffective treatment options. We evaluated n-butyl and isobutyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives against trypomastigotes of the Trypanosoma cruzi strains NINOA and INC-5. An in silico analysis of the interactions of 1,4-di-N-oxide on the active site of trypanothione reductase (TR) and an enzyme inhibition study was carried out. The n-butyl series compound identified as T-150 had the best trypanocidal activity against T. cruzi trypomastigotes, with a 13% TR inhibition at 44 μM. The derivative T-147 behaved as a mixed inhibitor with Ki and Ki’ inhibition constants of 11.4 and 60.8 µM, respectively. This finding is comparable to the TR inhibitor mepacrine (Ki = 19 µM). Full article