-
Scientific Reports May 2024Leishmaniasis is a disease caused by a protozoan of the genus Leishmania, affecting millions of people, mainly in tropical countries, due to poor social conditions and...
Leishmaniasis is a disease caused by a protozoan of the genus Leishmania, affecting millions of people, mainly in tropical countries, due to poor social conditions and low economic development. First-line chemotherapeutic agents involve highly toxic pentavalent antimonials, while treatment failure is mainly due to the emergence of drug-resistant strains. Leishmania arginase (ARG) enzyme is vital in pathogenicity and contributes to a higher infection rate, thus representing a potential drug target. This study helps in designing ARG inhibitors for the treatment of leishmaniasis. Py-CoMFA (3D-QSAR) models were constructed using 34 inhibitors from different chemical classes against ARG from L. (L.) amazonensis (LaARG). The 3D-QSAR predictions showed an excellent correlation between experimental and calculated pIC values. The molecular docking study identified the favorable hydrophobicity contribution of phenyl and cyclohexyl groups as substituents in the enzyme allosteric site. Molecular dynamics simulations of selected protein-ligand complexes were conducted to understand derivatives' interaction modes and affinity in both active and allosteric sites. Two cinnamide compounds, 7g and 7k, were identified, with similar structures to the reference 4h allosteric site inhibitor. These compounds can guide the development of more effective arginase inhibitors as potential antileishmanial drugs.
Topics: Arginase; Molecular Dynamics Simulation; Molecular Docking Simulation; Leishmania; Enzyme Inhibitors; Quantitative Structure-Activity Relationship; Protozoan Proteins; Allosteric Site; Antiprotozoal Agents; Catalytic Domain
PubMed: 38773273
DOI: 10.1038/s41598-024-62520-2 -
PLoS Neglected Tropical Diseases May 2024In Brazil, Leishmania amazonensis is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The state of Maranhão in the Northeast of Brazil is...
In Brazil, Leishmania amazonensis is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The state of Maranhão in the Northeast of Brazil is prevalent for these clinical forms of the disease and also has high rates of HIV infection. Here, we characterized the drug susceptibility of a L. amazonensis clinical isolate from a 46-year-old man with diffuse cutaneous leishmaniasis coinfected with HIV from this endemic area. This patient underwent several therapeutic regimens with meglumine antimoniate, liposomal amphotericin B, and pentamidine, without success. In vitro susceptibility assays against promastigotes and intracellular amastigotes demonstrated that this isolate had low susceptibility to amphotericin B, when compared with the reference strain of this species that is considered susceptible to antileishmanial drugs. Additionally, we investigated whether the low in vitro susceptibility would affect the in vivo response to amphotericin B treatment. The drug was effective in reducing the lesion size and parasite burden in mice infected with the reference strain, whereas those infected with the clinical isolate and a resistant line (generated experimentally by stepwise selection) were refractory to amphotericin B treatment. To evaluate whether the isolate was intrinsically resistant to amphotericin B in animals, infected mice were treated with other drugs that had not been used in the treatment of the patient (miltefosine, paromomycin, and a combination of both). Our findings demonstrated that all drug schemes were able to reduce lesion size and parasite burden in animals infected with the clinical isolate, confirming the amphotericin B-resistance phenotype. These findings indicate that the treatment failure observed in the patient may be associated with amphotericin B resistance, and demonstrate the potential emergence of amphotericin B-resistant L. amazonensis isolates in an area of Brazil endemic for cutaneous leishmaniasis.
Topics: Amphotericin B; Animals; Brazil; Middle Aged; Antiprotozoal Agents; Humans; Male; Mice; Drug Resistance; Leishmania; Leishmania mexicana; Leishmaniasis, Cutaneous; HIV Infections; Parasitic Sensitivity Tests; Mice, Inbred BALB C; Leishmaniasis, Diffuse Cutaneous
PubMed: 38768213
DOI: 10.1371/journal.pntd.0012175 -
JPGN Reports May 2024Visceral leishmaniasis (VL) is a potentially fatal infection caused by species of Leishmania. It is characterized by fever, weight loss, anemia, and enlargement of the...
Visceral leishmaniasis (VL) is a potentially fatal infection caused by species of Leishmania. It is characterized by fever, weight loss, anemia, and enlargement of the spleen and liver. Hepatitis due to VL is one of the causes of granulomatous hepatitis rarely described in the literature. It poses a problem of differential diagnosis with other causes, notably infectious and autoimmune. Hence the need for a global clinical, biological, and histological evaluation to orientate this entity, especially in endemic countries like ours. In the present case study, a 2-year 8-month-old boy was diagnosed with VL and treated with meglumine antimoniate; the evolution was marked after 2 months by the persistence of a large liver; laboratory results showed elevated liver functions and anemia. A liver biopsy was performed, and the histological findings confirmed the diagnosis of granulomatous hepatitis.
PubMed: 38756116
DOI: 10.1002/jpr3.12059 -
Research Square May 2024The quality and magnitude of the immune and inflammatory responses determine the clinical outcome of infection, and contribute to the efficacy of antileishmanial...
The quality and magnitude of the immune and inflammatory responses determine the clinical outcome of infection, and contribute to the efficacy of antileishmanial treatments. However, the precise immune mechanisms involved in healing or in chronic immunopathology of human cutaneous leishmaniasis (CL) are not completely understood. Through sequential transcriptomic profiling of blood monocytes (Mo), neutrophils (Nφ), and eosinophils (Eφ) over the course of systemic treatment with meglumine antimoniate, we discovered that a heightened and sustained Type I interferon (IFN) response signature is a hallmark of treatment failure (TF) in CL patients. The transcriptomes of pre-treatment, mid-treatment and end-of-treatment samples were interrogated to identify predictive and prognostic biomarkers of TF. A composite score derived from the expression of 9 differentially expressed genes (common between Mo, Nφ and Eφ) was predictive of TF in this patient cohort for biomarker discovery. Similarly, machine learning models constructed using data from pre-treatment as well as post-treatment samples, accurately classified treatment outcome between cure and TF. Results from this study instigate the evaluation of Type-I IFN responses as new immunological targets for host-directed therapies for treatment of CL, and highlight the feasibility of using transcriptional signatures as predictive biomarkers of outcome for therapeutic decision making.
PubMed: 38746226
DOI: 10.21203/rs.3.rs-4271873/v1 -
Ecotoxicology and Environmental Safety Jun 2024Neighborhood walkability may influence maternal-fetal exposure to environmental hazards and maternal-fetal health (e.g., fetal growth restriction, reproductive...
BACKGROUND
Neighborhood walkability may influence maternal-fetal exposure to environmental hazards and maternal-fetal health (e.g., fetal growth restriction, reproductive toxicity). However, few studies have explored the association between neighborhood walkability and hormones in pregnant women.
METHODS
We included 533 pregnant women from the Hangzhou Birth Cohort Study II (HBCS-II) with testosterone (TTE) and estradiol (E2) measured for analysis. Neighborhood walkability was evaluated by calculating a walkability index based on geo-coded addresses. Placental metals were measured using inductively coupled plasma mass spectrometry (ICP-MS). TTE and E2 levels in umbilical cord blood were measured using chemiluminescence microparticle immunoassay (CMIA). Linear regression model was used to estimate the relationship between the walkability index, placental metals, and sex steroid hormones. Effect modification was also assessed to estimate the effect of placental metals on the associations of neighborhood walkability with TTE and E2.
RESULTS
Neighborhood walkability was significantly linked to increased E2 levels (P trend=0.023). Compared with participants at the first quintile (Q1) of walkability index, those at the third quintiles (Q3) had lower chromium (Cr) levels (β = -0.212, 95% CI = -0.421 to -0.003). Arsenic (As), cobalt (Co), manganese (Mn), molybdenum (Mo), nickel (Ni), lead (Pb), antimony (Sb), selenium (Se), tin (Sn), and vanadium (V) were linked to decreased TTE levels, and cadmium (Cd) was linked to increased TTE levels. No metal was significantly associated with E2 levels in trend analysis. In the analysis of effect modification, the associations of neighborhood walkability with TTE and E2 were significantly modified by Mn (P = 0.005) and Cu (P = 0.049) respectively.
CONCLUSION
Neighborhood walkability could be a favorable factor for E2 production during pregnancy, which may be inhibited by maternal exposure to heavy metals.
Topics: Humans; Female; Pregnancy; Adult; Walking; China; Residence Characteristics; Cohort Studies; Estradiol; Testosterone; Fetal Blood; Maternal Exposure; Environmental Pollutants; Metals; Gonadal Steroid Hormones; Placenta; Metals, Heavy; Young Adult
PubMed: 38733803
DOI: 10.1016/j.ecoenv.2024.116427 -
Scientific Reports May 2024This work presents the design and multiphysics simulation of a cylindrical waveguide-based optical switch using germanium-antimony-tellurium (GST) as an active phase...
This work presents the design and multiphysics simulation of a cylindrical waveguide-based optical switch using germanium-antimony-tellurium (GST) as an active phase change material. The innovative cylindrical architecture is theoretically analyzed and evaluated at 1550 nm wavelength for telecommunication applications. The dispersion relation is derived analytically for the first time to model the optical switch, while finite element method (FEM) and finite difference time domain (FDTD) techniques are utilized to simulate the optical modes, light propagation, and phase change dynamics. The fundamental TE and HE modes are studied in detail, enabling switching between low-loss amorphous and high-loss crystalline GST phases. Increasing the GST thickness is found to increase absorption loss in the crystalline state but also slows down phase transition kinetics, reducing switching speeds. A 10 nm GST layer results in competitive performance metrics of 0.79 dB insertion loss, 13.47 dB extinction ratio, 30 nJ average power consumption, and 3.5 Mb/s bit rate. The combined optical, thermal, and electrical simulation provides comprehensive insights towards developing integrated non-volatile photonic switches and modulators utilizing phase change materials.
PubMed: 38730237
DOI: 10.1038/s41598-024-61473-w -
Nanomaterials (Basel, Switzerland) Apr 2024In this study, poly (ethylene terephthalate) (PETG) was combined with Antimony-doped Tin Oxide (ATO) to create five different composites (2.0-10.0 wt.% ATO). The...
In this study, poly (ethylene terephthalate) (PETG) was combined with Antimony-doped Tin Oxide (ATO) to create five different composites (2.0-10.0 wt.% ATO). The PETG/ATO filaments were extruded and supplied to a material extrusion (MEX) 3D printer to fabricate the specimens following international standards. Various tests were conducted on thermal, rheological, mechanical, and morphological properties. The mechanical performance of the prepared nanocomposites was evaluated using flexural, tensile, microhardness, and Charpy impact tests. The dielectric and electrical properties of the prepared composites were evaluated over a broad frequency range. The dimensional accuracy and porosity of the 3D printed structure were assessed using micro-computed tomography. Other investigations include scanning electron microscopy and energy-dispersive X-ray spectroscopy, which were performed to investigate the structures and morphologies of the samples. The PETG/6.0 wt.% ATO composite presented the highest mechanical performance (21% increase over the pure polymer in tensile strength). The results show the potential of such nanocomposites when enhanced mechanical performance is required in MEX 3D printing applications, in which PETG is the most commonly used polymer.
PubMed: 38727355
DOI: 10.3390/nano14090761 -
Royal Society Open Science May 2024The search for novel classes of hole-transporting materials (HTMs) is a very important task in advancing the commercialization of various photovoltaic devices. Meeting...
The search for novel classes of hole-transporting materials (HTMs) is a very important task in advancing the commercialization of various photovoltaic devices. Meeting specific requirements, such as charge-carrier mobility, appropriate energy levels and thermal stability, is essential for determining the suitability of an HTM for a given application. In this work, two spirobisindane-based compounds, bearing terminating hole transporting enamine units, were strategically designed and synthesized using commercially available starting materials. The target compounds exhibit adequate thermal stability; they are amorphous and their glass-transition temperatures (>150°C) are high, which minimizes the probability of direct layer crystallization. V1476 stands out with the highest zero-field hole-drift mobility, approaching 1 × 10 cm V s. To assess the compatibility of the highest occupied molecular orbital energy levels of the spirobisindane-based HTMs in solar cells, the solid-state ionization potential () was measured by the electron photoemission in air of the thin-film method. The favourable morphological properties, energy levels and hole mobility in combination with a simple synthesis make V1476 and related compounds promising materials for HTM applications in antimony-based solar cells and triple-cation-based perovskite solar cells.
PubMed: 38721131
DOI: 10.1098/rsos.232019 -
Journal of Research in Pharmacy Practice 2023Despite many attempts to treat leishmaniasis, new approaches are necessary to reduce the burden of disease. (Brazambel) has shown significant effects against parasites...
OBJECTIVE
Despite many attempts to treat leishmaniasis, new approaches are necessary to reduce the burden of disease. (Brazambel) has shown significant effects against parasites in some studies. This study aimed to investigate the effects of extract topical formulation on cutaneous leishmaniasis.
METHODS
In this randomized controlled clinical trial, patients with cutaneous leishmaniasis were assigned to experimental ( = 18) and control ( = 18) groups. Both groups received intralesional meglumine antimoniate (Glucantime). The experimental group also received 5% Brazambel extract ointment once a day. The interventions continued until the complete healing of the lesions (reepithelialization) for a maximum of 8 weeks. The clinical response, defined as complete response (reepithelialization >75%), partial response (reepithelialization 50%-75%), or treatment failure (reepithelialization <50%), was compared between the groups.
FINDINGS
The percentage of reepithelialization in the experimental group (4 week: 64.44 ± 25.13; 8 week: 83.85 ± 11.54) was higher than the control group (4 week: 53.97 ± 25.88; 8 week: 76.27 ± 21.67); however, the differences were not statistically significant ( = 0.252 and 0.494, respectively). Moreover, there was no significant difference between the experimental and control groups regarding the rate of complete healing (88.9% vs. 72.2%, respectively).
CONCLUSION
The use of extract 5% topical formulation does not affect the healing of cutaneous leishmaniasis.
PubMed: 38716320
DOI: 10.4103/jrpp.jrpp_13_24 -
Microbiology Spectrum Jun 2024Post-kala-azar dermal leishmaniasis (PKDL) patients are a key source of parasites, hindering the goal of eliminating visceral leishmaniasis (VL). Monitoring treatment...
UNLABELLED
Post-kala-azar dermal leishmaniasis (PKDL) patients are a key source of parasites, hindering the goal of eliminating visceral leishmaniasis (VL). Monitoring treatment response and parasite susceptibility is essential due to increasing drug resistance. We assessed the drug susceptibility of PKDL isolates ( = 18) from pre-miltefosine (MIL) era (1997-2004) with isolates ( = 16) from the post-miltefosine era (2010-2019) and post-miltefosine treatment relapse isolates ( = 5) towards miltefosine and amphotericin B (AmB) at promastigote stage and towards sodium antimony gluconate (SAG) at amastigote stage. PKDL isolates were examined for mutation in gene-encoding AQP1 transporter, C26882T mutation on chromosome 24, and miltefosine-transporter (MT). PKDL isolates from the post-miltefosine era were significantly more susceptible to SAG than SAG-resistant isolates from the pre-miltefosine era ( = 0.0002). There was no significant difference in the susceptibility of parasites to miltefosine between pre- and post-miltefosine era isolates. The susceptibility of PKDL isolates towards AmB remained unchanged between the pre- and post-miltefosine era. However, the post-miltefosine era isolates had a higher IC value towards AmB compared with PKDL relapse isolates. We did not find any association between AQP1 gene sequence variation and susceptibility to SAG, or between miltefosine susceptibility and single nucleotide polymorphisms (SNPs in the MT gene. This study demonstrates that recent isolates of have resumed susceptibility to antimonials . The study also offers significant insights into the intrinsic drug susceptibility of parasites over the past two decades, covering the period before the introduction of miltefosine and after its extensive use.
IMPORTANCE
Post-kala-azar dermal leishmaniasis (PKDL) patients, a key source of parasites, hinder eliminating visceral-leishmaniasis. Assessment of the susceptibility of PKDL isolates to antimony, miltefosine (MIL), and amphotericin-B indicated that recent isolates remain susceptible to antimony, enabling its use with other drugs for treating PKDL.
Topics: Humans; Leishmania donovani; Phosphorylcholine; Leishmaniasis, Visceral; Antiprotozoal Agents; Antimony; Leishmaniasis, Cutaneous; Drug Resistance; Amphotericin B; Parasitic Sensitivity Tests; Antimony Sodium Gluconate; Mutation
PubMed: 38712926
DOI: 10.1128/spectrum.04026-23