Search Results (1,219)

Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated mechanisms essential for VL pathogenesis. Methods: Two complementary in silico drug repurposing strategies were employed. The first method utilized electron–ion interaction potential (EIIP) screening followed by molecular docking and molecular dynamics (MD) simulations targeting two L. donovani proteins: Rab5a and pteridine reductase 1 (PTR1). The second approach employed network-based drug repurposing using the Drugst.One platform, prioritizing candidates via STAT3-associated gene networks. Predicted drug–target complexes were validated by 100 ns MD simulations, and pharmacokinetic parameters were assessed via ADMET profiling using QikProp v7.0 and SwissADME web server. Results: Entecavir and valganciclovir showed strong binding to Rab5a and PTR1, respectively, with Glide Scores of −9.36 and −9.10 kcal/mol, and corresponding MM-GBSA ΔG_bind values of −14.00 and −13.25 kcal/mol, confirming their stable interactions and repurposing potential. Network-based analysis identified nifuroxazide as the top candidate targeting the host JAK2/TYK2–STAT3 axis, with high stability confirmed in MD simulations. Nifuroxazide also displayed the most favorable ADMET profile, including oral bioavailability, membrane permeability, and absence of PAINS alerts. Conclusions: This study highlights the potential of guanine analogs such as entecavir and valganciclovir, and the nitrofuran derivative nifuroxazide, as promising multi-target drug repurposing candidates for VL. Their mechanisms support a dual strategy targeting both parasite biology and host immunoregulation, warranting further preclinical investigation. Full article

Canine visceral leishmaniasis (CVL) is a major zoonosis that poses a growing challenge to public health services, as successful disease management requires sensitive, specific, and rapid diagnostic methods capable of identifying infected animals even at a subclinical level. The objective of this study was to evaluate the performance of the recombinant chimeric protein rMELEISH3 as an antigen in ELISA assays for the robust diagnosis of CVL. The protein was expressed in a bacterial system, purified by affinity chromatography, and evaluated through a series of serological assays using serum samples from dogs infected with Leishmania infantum. ROC curve analysis revealed a diagnostic sensitivity of 96.4%, a specificity of 100%, and an area under the curve of 0.996, indicating excellent discriminatory power. Furthermore, rMELEISH3 was recognized by antibodies present in the serum of dogs with low parasite loads, reinforcing the diagnostic potential of the assay in asymptomatic cases. It is concluded that the use of the recombinant antigen rMELEISH3 could significantly contribute to the improvement of CVL surveillance and control programs in endemic areas of Brazil and other countries, by offering a safe, reproducible and effective alternative to the methods currently recommended for the serological diagnosis of the disease. Full article

Leishmaniasis, a vector-borne neglected tropical disease, affects over 6.2 million people globally. Case acquisition is increasingly recognized in the United States, and in Texas, most reported cases are locally acquired and speciated to Leishmania mexicana. We conducted a scoping literature review to systematically assess contemporary research on Leishmania in humans, animals, reservoir hosts, or vectors in Texas after 2000. Out of 22 eligible studies, the most prevalent themes were case reports, followed by studies on domestic animals, reservoirs, and vectors, with several studies bridging multiple disciplines. Climate change, urbanization, and habitat encroachment appear to be driving the northward expansion of L. mexicana, which is primarily attributed to shifts in the habitats of key vectors (Lutzomyia anthophora) and reservoirs (Neotoma spp.). Leishmania appears to be expanding into new areas, with potential for further spread. As ecological conditions evolve, strengthening surveillance and clinician awareness is crucial to understanding disease risk and improving early detection and treatment in affected communities. Full article

Human cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) braziliensis is a complex parasitic disease marked by dynamic host–parasite interactions and immunomodulation. Extracellular vesicles (EV) derived from immune cells have emerged as key mediators of intercellular communication and potential biomarkers in infectious diseases. In this study, we combined a modified lymphocyte proliferation assay with nano-flow cytometry to quantify and phenotype EV released by CD4⁺, CD8⁺, and CD14⁺ cells in PBMC cultures from CL patients at different clinical stages: before treatment (PBT), during treatment (PDT), and post-treatment (PET) with antimonial. Healthy individuals (HI) were included as physiological controls. Upon stimulation with L. (V.) braziliensis antigens, we observed a distinct modulation of EV subsets. In the PBT group, CD4⁺ and CD14⁺ EV were significantly reduced, while CD8⁺ EV remained elevated. During PDT and PET, EV concentrations were restored across all subsets. These findings suggest that L. (V.) braziliensis selectively modulates the release of immune cell–derived EV, possibly as an immune evasion mechanism. The restoration of EV release following antimonial therapy highlights their potential as sensitive biomarkers for disease activity and treatment monitoring. This study offers novel insights into the immunoregulatory roles of EV in CL and underscores their relevance in host–parasite interactions. Full article

Leishmaniasis is an infectious disease common in tropical and subtropical regions worldwide. This study aimed to develop a topical meglumine antimoniate gel (MA-gel) for the treatment of cutaneous leishmaniasis. The MA-gel was characterized in terms of morphology, pH, swelling, porosity, rheology, and thermal properties by differential scanning calorimetry (DSC). Biopharmaceutical evaluation included in vitro drug release and ex vivo skin permeation. Safety was evaluated through biomechanical skin property measurements and cytotoxicity in HaCaT and RAW 267 cells. Leishmanicidal activity was tested against promastigotes and amastigotes of Leishmania infantum, and in silico studies were conducted to explore possible mechanisms of action. The composition of the MA-gel included 30% MA, 20% Pluronic^® F127 (P407), and 50% water. Scanning electron microscopy revealed a sponge-like and porous internal structure of the MA-gel. This formula exhibited a pH of 5.45, swelling at approximately 12 min, and a porosity of 85.07%. The DSC showed that there was no incompatibility between MA and P407. Drug release followed a first-order kinetic profile, with 22.11 µg/g/cm² of the drug retained in the skin and no permeation into the receptor compartment. The MA-gel showed no microbial growth, no cytotoxicity in keratinocytes, and no skin damage. The IC₅₀ for promastigotes and amastigotes of L. infantum were 3.56 and 23.11 µg/mL, respectively. In silico studies suggested that MA could act on three potential therapeutic targets according to its binding mode. The MA-gel demonstrated promising physicochemical, safety, and antiparasitic properties, supporting its potential as a topical treatment for cutaneous leishmaniasis. Full article

Bisphenol A (BPA) is an endocrine-disrupting chemical with estrogen-like activity, known to impair immune function. BPA may act as a pro-inflammatory agent, reducing immune response efficacy, increasing bacterial load in E. coli infections, and altering immune responses in parasitic infections (Leishmania major, Nippostrongylus brasiliensis, Toxocara canis) through cytokine and regulatory T-cell modulation. Following its ban in food contact materials in Europe, several analogs have been introduced. This study assessed the immunotoxicity of BPA and six analogs, namely BPAP, BPE, BPP, BPS-MAE, BPZ, and TCBPA, by evaluating in vitro the antibody production. Peripheral blood mononuclear cells from healthy male and female donors were exposed to increasing concentrations of each compound for 24 h. After stimulation with rhIL-2 and ODN2006, IgM and IgG secretion were measured on day six. All compounds suppressed antibody production in a concentration-dependent manner, with some sex-related differences. IC₅₀ values showed BPP as the most potent suppressor, and BPE as the weakest. Similarly, IC₂₀ values confirmed these differences in potency, except for BPA being the weakest for IgM in males. Overall, te results do not support the idea that BPA analogs are safer than BPA. Full article

Leishmaniasis, caused by protozoan parasites of the genus Leishmania, is one of the most neglected human diseases, affecting millions worldwide. A detailed understanding of the molecular mechanisms that govern the outcome of macrophage–Leishmania interactions is crucial for a comprehensive understanding of leishmaniasis; however, our current knowledge of these mechanisms remains limited. It is clear that Leishmania has co-evolved to engage several clever strategies to regulate the cell biology of host macrophages to survive and multiply in phagolysosomes of these cells. In this review, we discuss how Leishmania exploits the macrophage Yin-Yang 1 protein as a critical proxy virulence factor to promote its survival. Additionally, we discuss an atlas of YY1-dependent proteins in human macrophages, which could serve as a valuable resource for researchers studying the role of YY1 in macrophage cell biology. Full article

Background/Objectives: Leishmaniasis is a zoonotic and anthropozoonotic disease with significant public health impact worldwide and is classified as a neglected tropical disease. The search for new affordable treatments, particularly oral and/or topical ones that are easy to administer and have fewer side effects, remains a priority for the scientific community in this field of research. In previous investigations, 3-alkoxy-1-benzyl-5-nitroindazole derivatives showed remarkable in vitro results against Leishmania species, and predictions of absorption, distribution, metabolism, excretion, and toxicity properties, as well as pharmacological scores, of the compounds classified as active were superior to those of amphotericin B, indicating their potential as candidates for in vivo studies. Therefore, the aim of the present study was to evaluate the in vivo antileishmanial activity of the indazole derivatives NV6 and NV16. Methods: The compounds were administered intralesionally at concentrations of 10 and 5 mg/kg in a BALB/c mouse model of cutaneous leishmaniasis caused by Leishmania amazonensis. To evaluate the efficacy of the compounds, indicators such as lesion size, ulcer area, lesion weight, and parasitic load were determined. Amphotericin B was used as a positive control. Results: The compound NV6 showed leishmanicidal activity comparable to that observed with amphotericin B, with a significant reduction in lesion development and parasite load, while NV16 caused a reduction in ulcer area. Conclusions: These results provide strong evidence for the antileishmanial activity of NV6 and support future studies to improve its pharmacokinetic profile, as well as the investigation of combination therapies with other chemotherapeutic agents currently in use. Full article

Cyclopes, the smallest of all known anteaters, has an insectivorous diet and is arboreal, rarely descending to the ground. There are scarce reports on diseases and pathogenic agents affecting this taxon. Hemopathogens are pathogenic agents that inhabit the blood of various vertebrate species. Protozoa such as Trypanosoma spp., Leishmania spp., Hepatozoon spp., and members of the order Piroplasmida, as well as hemoplasmas and Rickettsial bacteria of the genera Anaplasma and Ehrlichia, are among the most important in this group. The transmission of these pathogens generally occurs through arthropod vectors, which act as intermediate hosts. In addition, infections caused by hemopathogens can have adverse effects on host health, contributing to population declines in susceptible species. This study investigated infection by protozoa and hemotropic bacteria in blood samples from free-ranging silky anteaters from Brazil, Peru, and Colombia using molecular detection methods. Sixteen samples were obtained during expeditions conducted in these countries. DNA was extracted from blood samples, and PCR assays were performed to detect parasites from the order Piroplasmida, Hepatozoon spp., trypanosomatid agents including Leishmania spp., Trypanosoma evansi, T. cruzi, and T. vivax, as well as hemotropic bacteria of the genera Ehrlichia, Anaplasma, and Mycoplasma sp. Nucleotide sequencing was performed on positive samples. Of the total samples analyzed, 62.5% (10/16) tested positive for hemotropic Mycoplasma, 50% (8/16) for T. evansi, and 6.2% (1/16) for T. cruzi. There is a significant gap in knowledge regarding the diversity of hemopathogens affecting the genus Cyclopes, and future studies are needed to understand how these infections may impact the health of individuals. Full article

Canine leishmaniosis (CanL), caused by Leishmania infantum, is a major zoonotic disease primarily transmitted by sand flies. Unlike in adult dogs, the clinical course of CanL in puppies remains poorly characterized, regardless of the transmission pathway (i.e., vertical transmission or vector exposure). This study presents the first systematic literature review (SLR) focused on juvenile CanL, alongside an atypical clinical case report. A PRISMA-compliant search across four databases identified three eligible studies describing CanL in puppies (≤9 months, according to the current canine life stage guidelines). The case involves a 4.5-month-old puppy adopted from southern Italy with papulo-nodular skin lesions and generalized lymphadenomegaly as well as a mild normocytic normochromic anemia and increased C-reactive protein. L. infantum infection was confirmed by serology, polymerase chain reaction (PCR), and cytology. The SLR suggests that dermatological lesions and/or lymphadenomegaly, whether associated with laboratory abnormalities, represent the most common clinical manifestations of CanL in puppies. In the presented case, the coexistence of systemic dissemination signs and papulo-nodular skin lesions, typically associated with vector-borne transmission, suggests the possibility of a dual route of infection by L. infantum. Juvenile CanL should be considered in differential diagnoses and supported by thorough diagnostic evaluation and appropriate follow-up protocols. Full article

Phlebotomine sandflies are the primary vectors of Leishmania parasites, the causative agents of leishmaniasis. In India, Phlebotomus argentipes is the confirmed vector of Leishmania donovani. The sandfly gut microbiota plays a crucial role in Leishmania development and transmission, yet it remains largely understudied. This study used a metagenomic approach targeting the V3–V4 region of the 16S rRNA gene to compare the gut bacterial communities of P. argentipes and Sergentomyia babu prevalent in Kerala. A total of 18 distinct bacterial phyla were identified in P. argentipes, and 14 in S. babu, both dominated by Proteobacteria, Actinobacteria, and Firmicutes. A total of 315 genera were identified in P. argentipes, with a high relative abundance of Pseudomonas (6.3%), whereas S. babu harbored 327 genera, with Pseudomonas showing a higher relative abundance of 11%. Unique to P. argentipes, bacterial phyla such as Fusobacteria, Armatimonadetes, Elusimicrobia, Chlamydiae, and Crenarchaeota were identified, whereas Chlorobi was specific to S. babu. Additionally, 145 species were identified in P. argentipes, compared to 164 species in S. babu. These findings provide a comparative baseline of gut microbial diversity between vector and non-vector sandfly species, offering a foundation for future functional investigations into vector competence. Full article

Leishmaniasis is a zoonotic disease caused by protozoa of the genus Leishmania, transmitted by phlebotomine sand flies. Understanding the feeding behavior and infection rates of these vectors is crucial for disease surveillance and control. We aimed to investigate the natural infection rate of Leishmania spp. in phlebotomines and analyze their blood-feeding patterns in one of the priority areas of the state of São Paulo for the implementation of insecticide-impregnated dog collars. Sand flies were collected from urban and peri-urban areas between 2022 and 2024 using CDC light traps, manual aspiration, and Shannon traps. PCR was used to detect Leishmania DNA (SSU rDNA gene), and blood meal sources (COI gene). A total of 414 sand flies were collected, with 222 engorged females analyzed for blood meals and 192 specimens tested for Leishmania spp. infection. The predominant blood source was humans (67%), followed by chickens (64.1%), and dogs (18.9%), considering that 45.1% of the samples presented mixed blood meals. Leishmania infantum was found in 1% of the samples. These findings highlight the feeding plasticity of sand flies and their potential role in disease transmission, reinforcing the need for continuous epidemiological surveillance and vector control strategies, particularly the implementation of insecticide-impregnated dog collars. Full article

Background/Objectives: Leishmaniasis remains a neglected tropical disease, with nearly one million new cases annually and limited investment in research. Current treatments, primarily based on pentavalent antimonials, are associated with severe side effects and increasing resistance. This study aims to develop a novel therapeutic strategy using a nanomaterial functionalized with sialic acid (SA) and colchicine (COL) to selectively target Leishmania braziliensis parasites. Methods: A nanostructured system was engineered by functionalizing its surface with SA and COL. SA was chosen to mimic host cell surfaces, enhancing parasite attraction, while COL was selected for its known leishmanicidal properties. The nanomaterial was designed to concentrate extracellular parasites on its surface via SA-mediated interactions, thereby increasing local COL efficacy. Results: The functionalized nanomaterial demonstrated a dual mechanism: SA facilitated the selective accumulation of Leishmania braziliensis parasites on the nanostructure surface, while COL exerted a cytotoxic effect. This synergistic interaction resulted in enhanced parasite mortality in vitro, suggesting improved selectivity and potency compared to conventional treatments. Conclusions: The proposed nanomaterial offers a promising alternative for leishmaniasis treatment by combining targeted parasite attraction with localized drug delivery. This strategy may reduce systemic toxicity and improve therapeutic outcomes. Full article

Leishmaniasis is a significant public health concern, affecting millions and causing substantial mortality, thus urgently requiring more effective and safer treatments. This study explored the potential of 33 novel N-acylhydrazone-derived compounds against Leishmania amazonensis parasites, focusing on their inhibition of the Leishmania arginase enzyme and promastigote growth. Compounds 8 and 18 showed over 90% inhibitory activity against promastigote cultures after 72 h of treatment. Compound 8 showed an IC₅₀ of 10.5 µM (9.4–11.8 µM), while compound 18 exhibited an IC₅₀ of 42.8 µM (41.3–44.4 µM). The antipromastigote effects of these compounds highlight their potential for further new drug design. These findings offer a promising starting point for addressing the pressing need for new therapeutic options against leishmaniasis. In addition, we used web-based tools to predict the compounds’ toxicity and pharmacokinetic parameters. Despite the lack of inhibition against the L. amazonensis arginase enzyme, further investigation into the mechanisms of action of these compounds and in vivo efficacy could contribute to the development of safer and more effective treatments for this neglected tropical disease. Full article