scholarly journals AgNP-PVP-meglumine antimoniate nanocomposite reduces Leishmania amazonensis infection in macrophages

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ana Patricia Cacua Gélvez ◽  
José Antonio Picanço Diniz Junior ◽  
Rebecca Thereza Silva Santa Brígida ◽  
Ana Paula Drummond Rodrigues
Keyword(s):  
Mechanism Of Action ◽  
Clinical Manifestations ◽  
Leishmania Amazonensis ◽  
New Drugs ◽  
Chemokine Production ◽  
Meglumine Antimoniate ◽  
Membrane Rupture ◽  
Material Deposition ◽  
Species Production

Abstract Background Leishmaniasis is an infectious disease caused by parasites of the genus Leishmania and presents different clinical manifestations. The adverse effects, immunosuppression and resistant strains associated with this disease necessitate the development of new drugs. Nanoparticles have shown potential as alternative antileishmanial drugs. We showed in a previous study the biosynthesis, characterization and ideal concentration of a nanocomposite that promoted leishmanicidal activity. In the present study, we conducted a specific analysis to show the mechanism of action of AgNP-PVP-MA (silver nanoparticle–polyvinylpyrrolidone-[meglumine antimoniate (Glucantime®)]) nanocomposite during Leishmania amazonensis infection in vitro. Results Through ultrastructural analysis, we observed significant alterations, such as the presence of small vesicles in the flagellar pocket and in the extracellular membrane, myelin-like structure formation in the Golgi complex and mitochondria, flagellum and plasma membrane rupture, and electrodense material deposition at the edges of the parasite nucleus in both evolutive forms. Furthermore, the Leishmania parasite infection index in macrophages decreased significantly after treatment, and nitric oxide and reactive oxygen species production levels were determined. Additionally, inflammatory, and pro-inflammatory cytokine and chemokine production levels were evaluated. The IL-4, TNF-α and MIP-1α levels increased significantly, while the IL-17 A level decreased significantly after treatment. Conclusions Thus, we demonstrate in this study that the AgNP-PVP-MA nanocomposite has leishmanial potential, and the mechanism of action was demonstrated for the first time, showing that this bioproduct seems to be a potential alternative treatment for leishmaniasis.

scholarly journals The toxic effect of Vu-Defr, a defensin from Vigna unguiculata seeds, on Leishmania amazonensis is associated with reactive oxygen species production, mitochondrial dysfunction, and plasma membrane perturbation

2018 ◽  
Vol 64 (7) ◽  
pp. 455-464 ◽  
Author(s):  
Géssika Silva Souza ◽  
Lais Pessanha de Carvalho ◽  
Edésio José Tenório de Melo ◽  
Valdirene Moreira Gomes ◽  
André de Oliveira Carvalho
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Membrane ◽  
Biological Activities ◽  
Reactive Oxygen ◽  
Leishmania Amazonensis ◽  
New Drugs ◽  
Oxygen Species ◽  
Membrane Perturbation ◽  
Plant Defensins

Plant defensins are plant antimicrobial peptides that present diverse biological activities in vitro, including the elimination of Leishmania amazonensis. Plant defensins are considered promising candidates for the development of new drugs. This protozoan genus has great epidemiological importance and the mechanism behind the protozoan death by defensins is unknown, thus, we chose L. amazonensis for this study. The aim of the work was to analyze the possible toxic mechanisms of Vu-Defr against L. amazonensis. For analyses, the antimicrobial assay was repeated as previously described, and after 24 h, an aliquot of the culture was tested for viability, membrane perturbation, mitochondrial membrane potential, reactive oxygen species (ROS) and nitric oxide (NO) inductions. The results of these analyses indicated that after interaction with L. amazonensis, the Vu-Defr causes elimination of promastigotes from culture, membrane perturbation, mitochondrial membrane collapse, and ROS induction. Our analysis demonstrated that NO is not produced after Vu-Defr and L. amazonensis interaction. In conclusion, our work strives to help to fill the gap relating to effects caused by plant defensins on protozoan and thus better understand the mechanism of action of this peptide against L. amazonensis.

scholarly journals Development of a Fluorescent Assay to Search New Drugs Using Stable tdTomato-Leishmania, and the Selection of Galangin as a Candidate With Anti-Leishmanial Activity

2021 ◽  
Vol 11 ◽  
Author(s):  
María Fernanda García-Bustos ◽  
Agustín Moya Álvarez ◽  
Cecilia Pérez Brandan ◽  
Cecilia Parodi ◽  
Andrea Mabel Sosa ◽  
...  
Keyword(s):  
Active Compound ◽  
Wild Strain ◽  
Fluorescence Assay ◽  
New Drugs ◽  
Lipid Inclusion ◽  
Screening Assay ◽  
Meglumine Antimoniate ◽  
Wide Range

Antimonials continue to be considered the first-line treatment for leishmaniases, but its use entails a wide range of side effects and serious reactions. The search of new drugs requires the development of methods more sensitive and faster than the conventional ones. We developed and validated a fluorescence assay based in the expression of tdTomato protein by Leishmania, and we applied this method to evaluate the activity in vitro of flavonoids and reference drugs. The pIR1SAT/tdTomato was constructed and integrated into the genome of Leishmania (Leishmania) amazonensis. Parasites were selected with nourseothricin (NTC). The relation of L. amaz/tc3 fluorescence and the number of parasites was determined; then the growth in vitro and infectivity in BALB/c mice was characterized. To validate the fluorescence assay, the efficacy of miltefosine and meglumine antimoniate was compared with the conventional methods. After that, the method was used to assess in vitro the activity of flavonoids; and the mechanism of action of the most active compound was evaluated by transmission electron microscopy and ELISA. A linear correlation was observed between the emission of fluorescence of L. amaz/tc3 and the number of parasites (r2 = 0.98), and the fluorescence was stable in the absence of NTC. No differences were observed in terms of infectivity between L. amaz/tc3 and wild strain. The efficacy of miltefosine and meglumine antimoniate determined by the fluorescence assay and the microscopic test showed no differences, however, in vivo the fluorescence assay was more sensitive than limiting dilution assay. Screening assay revealed that the flavonoid galangin (GAL) was the most active compound with IC50 values of 53.09 µM and 20.59 µM in promastigotes and intracellular amastigotes, respectively. Furthermore, GAL induced mitochondrial swelling, lipid inclusion bodies and vacuolization in promastigotes; and up-modulated the production of IL-12 p70 in infected macrophages. The fluorescence assay is a useful tool to assess the anti-leishmanial activity of new compounds. However, the assay has some limitations in the macrophage-amastigote model that might be related with an interfere of flavanol aglycones with the fluorescence readout of tdTomato. Finally, GAL is a promising candidate for the development of new treatment against the leishmaniasis.

scholarly journals miR-548d-3p Alters Parasite Growth and Inflammation in Leishmania (Viannia) braziliensis Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Marina de Assis Souza ◽  
Eduardo Milton Ramos-Sanchez ◽  
Sandra Márcia Muxel ◽  
Dimitris Lagos ◽  
Luiza Campos Reis ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Cellular Proliferation ◽  
Clinical Manifestations ◽  
Target Prediction ◽  
Parasite Growth ◽  
Healthy Controls ◽  
Chemokine Production ◽  
Chemokine Signaling ◽  
American Tegumentary Leishmaniasis

American Tegumentary Leishmaniasis (ATL) is an endemic disease in Latin America, mainly caused in Brazil by Leishmania (Viannia) braziliensis. Clinical manifestations vary from mild, localized cutaneous leishmaniasis (CL) to aggressive mucosal disease. The host immune response strongly determines the outcome of infection and pattern of disease. However, the pathogenesis of ATL is not well understood, and host microRNAs (miRNAs) may have a role in this context. In the present study, miRNAs were quantified using qPCR arrays in human monocytic THP-1 cells infected in vitro with L. (V.) braziliensis promastigotes and in plasma from patients with ATL, focusing on inflammatory response-specific miRNAs. Patients with active or self-healed cutaneous leishmaniasis patients, with confirmed parasitological or immunological diagnosis, were compared with healthy controls. Computational target prediction of significantly-altered miRNAs from in vitro L. (V.) braziliensis-infected THP-1 cells revealed predicted targets involved in diverse pathways, including chemokine signaling, inflammatory, cellular proliferation, and tissue repair processes. In plasma, we observed distinct miRNA expression in patients with self-healed and active lesions compared with healthy controls. Some miRNAs dysregulated during THP-1 in vitro infection were also found in plasma from self-healed patients, including miR-548d-3p, which was upregulated in infected THP-1 cells and in plasma from self-healed patients. As miR-548d-3p was predicted to target the chemokine pathway and inflammation is a central to the pathogenesis of ATL, we evaluated the effect of transient transfection of a miR-548d-3p inhibitor on L. (V.) braziliensis infected-THP-1 cells. Inhibition of miR-548d-3p reduced parasite growth early after infection and increased production of MCP1/CCL2, RANTES/CCL5, and IP10/CXCL10. In plasma of self-healed patients, MCP1/CCL2, RANTES/CCL5, and IL-8/CXCL8 concentrations were significantly decreased and MIG/CXCL9 and IP-10/CXCL10 increased compared to patients with active disease. These data suggest that by modulating miRNAs, L. (V.) braziliensis may interfere with chemokine production and hence the inflammatory processes underpinning lesion resolution. Our data suggest miR-548d-3p could be further evaluated as a prognostic marker for ATL and/or as a host-directed therapeutic target.

scholarly journals Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Valter Viana Andrade-Neto ◽  
Juliana da Silva Pacheco ◽  
Job Domingos Inácio ◽  
Elmo Eduardo Almeida-Amaral ◽  
Eduardo Caio Torres-Santos ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Cutaneous Lesion ◽  
Parasite Burden ◽  
Parasite Load ◽  
New Drugs ◽  
Drug Candidate ◽  
Success Rates ◽  
Meglumine Antimoniate ◽  
Future Possibility

Translational studies involving the reuse and association of drugs are approaches that can result in higher success rates in the discovery and development of drugs for serious public health problems, including leishmaniasis. If we consider the number of pathogenic species in relation to therapeutic options, this arsenal is still small, and each drug possesses a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. In the search for new drugs, we performed a drug screening of L. amazonensis promastigotes and intracellular amastigotes of fifty available drugs belonging to several classes according to their pharmacophoric group. Spironolactone, a potassium-sparing diuretic, proved to be the most promising drug candidate. After demonstrating the in vitro antileishmanial activity, we evaluated the efficacy on a murine experimental model with L. amazonensis and L. infantum. The treatment controlled the cutaneous lesion and reduced the parasite burden of L. amazonensis significantly, as effectively as meglumine antimoniate. The treatment of experimental visceral leishmaniasis was effective in reducing the parasite load on the main affected organs (spleen and liver) via high doses of spironolactone. The association between spironolactone and meglumine antimoniate promoted better control of the parasite load in the spleen and liver compared to the group treated with meglumine antimoniate alone. These results reveal a possible benefit of the concomitant use of spironolactone and meglumine antimoniate that should be studied more in depth for the future possibility of repositioning for leishmaniasis co-therapy.

scholarly journals Pharmacological activity and mechanism of action of plants with anti-inflammatory properties found in brazilian flora

2021 ◽  
Vol 13 (1) ◽  
pp. e5663
Author(s):  
Kessya Lanny Sousa Dantas ◽  
Kassyo Lenno Sousa Dantas ◽  
Eduardo Soares Dos Santos ◽  
Júlio Evangelista De Lucena ◽  
Milena Sousa Freitas ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Therapeutic Potential ◽  
New Drugs ◽  
Mentha Piperita ◽  
The Social ◽  
Brazilian Flora ◽  
Anti Inflammatory ◽  
New Treatments ◽  
Inflammatory Action

Objective: To describe the importance of medicinal plants in the social and pharmacological context, demonstrating the anti-inflammatory therapeutic potential and the mechanism of action of drugs present in the chemical composition of four plants present in the Brazilian flora. Methods: A bibliographic survey on the topic was carried out, using the descriptors: Activity, Anti-inflammatory, Plants, Flora, Brazilian. In Scielo, Google Scholar and PUBMED databases. For the inclusion of works, the following criteria were used: Articles from research relevant to the topic (regardless of date) and relevant publications from the year 2007. Results: The inflammatory process is a target for the treatment of various diseases and development new treatments are needed. We discuss here the anti-inflammatory potential and the mechanism of action of the following plants: Uncaria tomentosa, Schinus terebinthifolius Raddi and Mentha piperita demonstrated through in vitro studies and murine models of diseases. The species showed anti-inflammatory action by reducing the production of inflammatory mediators and inhibiting the activity of important pro-inflammatory enzymes, such as phospholipase A2 and cycloxygenase. Final considerations: The four plant species covered in this article had significant anti-inflammatory effects, therefore, they can be suggested as a source of potential new drugs.

scholarly journals Synthetic analogs of vitamin D3 in therapy of psoriasis

2018 ◽  
Vol 16 (4) ◽  
pp. 49-54
Author(s):  
Inna V. Petrova ◽  
Rasul M. Radzhabov ◽  
Abdul R. Abdulov ◽  
Magomed G. Manatov ◽  
Ruslan I. Glushakov ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Vitamin D3 ◽  
Skin Diseases ◽  
Interleukin 2 ◽  
Clinical Manifestations ◽  
New Drugs ◽  
Epidermal Keratinocytes ◽  
Synthetic Analogue ◽  
Therapeutic Activity ◽  
Inhibition Of Proliferation

Psoriasis is one of the most common skin diseases and occurs in 1-2% of the population of developed countries. The problem of pathogenetic treatment of psoriasis remains relevant despite the annual appearance of new drugs. The anti-keratinizing effect is particularly important in the treatment of psoriasis. The effect is based on suppression of the proliferation of epidermal keratinocytes, normalization of the differentiation of the nonkeratinizing epithelium and the decrease in the adhesion of horny cells. The last decade is characterized by a deepening of ideas about the biological properties and mechanism of action of vitamin D3. However the vitamin D3 does itself not have therapeutic activity. In this connection the use of synthetic analogues of vitamin D3 which have therapeutic activity is particular of importance. The aim. To evaluate the effectiveness of vitamin D3synthetic analogs for the treatment of psoriasis. Methods. It was retrospective analysis of multicentric studies by a double-blind, randomized method of the effectiveness of vitamin D3 analogs for the treatment of psoriasis in Russia and foreign clinics. The PASI index in assessing the clinical manifestations of psoriasis. Rеsults and discussion. The study of the clinical efficacy of oral forms of the vitamin indicates a positive therapeutic effect in 70-90% of patients but this requires an average of 2.8 months. Therefore for the treatment of psoriasis more widely used synthetic analogue of vitamin D3 – calcipotriol (MS-903), developed exclusively for topical application. Calcipotriol gives minimal side effects and has an intense antipsoriatic effect. The mechanism of action of calcipotriol is based on interaction with specific receptors on keratinocytes which causes inhibition of proliferation, accelerates the morphological differentiation of psoriatic cells, inhibits the activity of interleukin-1 and reduces interleukin-2 production, i.e. has an effect on the pathogenetic mechanisms of psoriasis. Conclusion. Vitamin D3 analogues are effective antipsoriatic drugs that can be used both as monotherapy and in the complex treatment of patients with severe psoriasis.

scholarly journals In vitro and in vivo activity of meglumine antimoniate produced at Farmanguinhos-Fiocruz, Brazil, against Leishmania (Leishmania) amazonensis, L (L.) chagasi and L (Viannia) braziliensis

2008 ◽  
Vol 103 (4) ◽  
pp. 358-362 ◽  
Author(s):  
Eliane de Morais-Teixeira ◽  
Alcione S de Carvalho ◽  
Jorge CS da Costa ◽  
Silvio L Duarte ◽  
Jorge S Mendonça ◽  
...  
Keyword(s):  
Leishmania Amazonensis ◽  
Meglumine Antimoniate

scholarly journals In-Vitro Evaluation of 52 Commercially-Available Essential Oils Against Leishmania amazonensis

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1248 ◽  
Author(s):  
Lianet Monzote ◽  
Isabel Herrera ◽  
Prabodh Satyal ◽  
William Setzer
Keyword(s):  
Essential Oils ◽  
Low Cost ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Peritoneal Macrophages ◽  
Current Treatment ◽  
Leishmania Amazonensis ◽  
Ic50 Values ◽  
Antileishmanial Activities

Leishmaniasis is a neglected tropical disease caused by members of the Leishmania genus of parasitic protozoa that cause different clinical manifestations of the disease. Current treatment options for the cutaneous disease are limited due to severe side effects, poor efficacy, limited availability or accessibility, and developing resistance. Essential oils may provide low cost and readily available treatment options for leishmaniasis. In-vitro screening of a collection of 52 commercially available essential oils has been carried out against promastigotes of Leishmania amazonensis. In addition, cytotoxicity has been determined for the essential oils against mouse peritoneal macrophages in order to determine selectivity. Promising essential oils were further screened against intracellular L. amazonensis amastigotes. Three essential oils showed notable antileishmanial activities: frankincense (Boswellia spp.), coriander (Coriandrum sativum L.), and wintergreen (Gualtheria fragrantissima Wall.) with IC50 values against the amastigotes of 22.1 ± 4.2, 19.1 ± 0.7, and 22.2 ± 3.5 μg/mL and a selectivity of 2, 7, and 6, respectively. These essential oils could be explored as topical treatment options for cutaneous leishmaniasis.

scholarly journals Next-Generation Human Liver Models for Antimalarial Drug Assays

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 642
Author(s):  
Kasem Kulkeaw
Keyword(s):  
Drug Development ◽  
Antimalarial Drug ◽  
Adult Stem Cells ◽  
Ethical Issues ◽  
Clinical Manifestations ◽  
Malaria Prevention ◽  
New Drugs ◽  
Global Public Health ◽  
Liver Stage

Advances in malaria prevention and treatment have significantly reduced the related morbidity and mortality worldwide, however, malaria continues to be a major threat to global public health. Because Plasmodium parasites reside in the liver prior to the appearance of clinical manifestations caused by intraerythrocytic development, the Plasmodium liver stage represents a vulnerable therapeutic target to prevent progression. Currently, a small number of drugs targeting liver-stage parasites are available, but all cause lethal side effects in glucose-6-phosphate dehydrogenase-deficient individuals, emphasizing the necessity for new drug development. Nevertheless, a longstanding hurdle to developing new drugs is the availability of appropriate in vitro cultures, the crucial conventional platform for evaluating the efficacy and toxicity of drugs in the preclinical phase. Most current cell culture systems rely primarily on growing immortalized or cancerous cells in the form of a two-dimensional monolayer, which is not very physiologically relevant to the complex cellular architecture of the human body. Although primary human cells are more relevant to human physiology, they are mainly hindered by batch-to-batch variation, limited supplies, and ethical issues. Advances in stem cell technologies and multidimensional culture have allowed the modelling of human infectious diseases. Here, current in vitro hepatic models and toolboxes for assaying the antimalarial drug activity are summarized. Given the physiological potential of pluripotent and adult stem cells to model liver-stage malaria, the opportunities and challenges in drug development against liver-stage malaria is highlighted, paving the way to assess the efficacy of hepatic plasmodicidal activity.

Sign in / Sign up

Export Citation Format

Share Document