Raiza Raianne Luz Rodrigues

Background/Objectives: American trypanosomiasis, caused by Trypanosoma cruzi, remains a major public health challenge due to the limited efficacy and adverse effects associated with current treatments. Octyl gallate (OG), a semi-synthetic derivative of gallic acid, has demonstrated promising biological activities, including antiparasitic effects. Methods: The in vitro trypanocidal activity of OG was evaluated against T. cruzi. Mechanism of action studies included the inhibition of the trypanothione reductase enzyme and flow cytometry assays to measure cell death pathways (propidium iodide uptake). Additionally, the immunomodulatory potential of the compound was investigated by assessing cytokine production and innate immune responses. Results: In this study, the trypanocidal activity of OG against different evolutionary forms of T. cruzi was investigated. Using MTT-based viability assays, OG exhibited significant activity against epimastigotes (IC50 = 5.92 ± 0.47 µM), trypomastigotes (EC50 = 3.20 ± 0.14 µM), and intracellular amastigotes (EC50 = 4.07 ± 0.72 µM). The compound also demonstrated favorable selectivity indices, particularly against trypomastigotes and amastigotes, indicating selective toxicity toward the parasite compared to mammalian host cells. In infected macrophages, OG increased TNF-α and IL-12 production while reducing IL-10 and IL-6 levels, in addition to stimulating reactive oxygen species (ROS) and nitric oxide (NO) production, suggesting an immunomodulatory effect that contributes to parasite control. Molecular docking analyses revealed a favorable interaction between OG and trypanothione reductase (TR), while biochemical assays demonstrated reduced NADPH consumption, indicating interference with TR activity. Ultrastructural analysis revealed severe morphological alterations, including membrane disruption, cytoplasmic disorganization, mitochondrial swelling, and features consistent with apoptosis-like cell death. Conclusions: Collectively, these findings demonstrate that OG exhibits potent and selective trypanocidal activity associated with immunomodulatory effects, ultrastructural damage, and disruption of parasite redox metabolism through TR inhibition, supporting its potential as a candidate for future preclinical studies against Chagas disease.

Tuberculosis infected 10.8 million people worldwide in 2023, resulting in 1.09 million deaths. Rifampicin (RIF) is one of the main drugs used in the treatment, but its low solubility and side effects, such as hepatotoxicity, limit its therapeutic efficacy. Polymeric nanoparticles (PNs) emerge as a promising strategy to optimize RIF delivery. This study aimed to develop RIF-PNs guided by molecular dynamics (MD), perform their physicochemical characterization and evaluate their in vitro cytotoxicity. MD allowed observing the molecular interactions between the components of the formulation and led to the formation of PNs. The PNs presented an average size of 177.0 ± 0.80 nm, polydispersity index of 0.094 ± 0.046, zeta potential of -15.0 ± 0.65 mV, encapsulation efficiency of 20.98% and drug loading of 2.29%, with colloidal stability maintained for up to 180 days. The physicochemical characterizations indicated the polymorphic form II of RIF, amorphous pattern of ethylcellulose (EC) and encapsulation of RIF in PN. Atomic force microscopy observed a spherical shape of the particles with a size of 38.4 ± 14.6 nm. RIF-EC-PN presented a sustained release profile with release of 20.65 ± 0.44% in 24 h and and the unencapsulated RIF demonstrated a release of 90.75% in 15 min. Cell viability was demonstrated in monkey renal epithelial cells (LLC-MK2). PNs showed favorable properties as RIF delivery systems. Graphical Abstract

Chagas disease remains a significant neglected tropical disease that predominantly affects vulnerable populations in rural, low-income areas of Latin America. The management of this condition is severely hindered by the limitations of current therapies, which are characterized by substantial toxicity, diminished efficacy during the chronic phase, and the emergence of parasitic resistance. Given the promising activity of SB-83 (a 2-aminothiophenic derivative) against Leishmania spp., the present study sought to evaluate its trypanocidal activity against Trypanosoma cruzi. The results showed that SB-83 exhibited potent inhibitory effects on the epimastigote forms of T. cruzi (IC₅₀ = 6.23 ± 0.84 μM), trypomastigotes (EC₅₀ = 7.31 ± 0.52 μM) and intracellular amastigotes (EC₅₀ = 5.12 ± 0.49 μM). Furthermore, the cellular proliferation assay results indicated CC₅₀ values of 77.80 ± 2.05 µM for LLC-MK2 CCL-7 and 24.21 ± 1.2 µM for Vero CCL-87, with a selectivity index above 10 for LLC-MK2 cells. In addition, the compound increased TNF-α, IL-12, nitric oxide, and ROS while decreasing IL-10. Moreover, in silico and in vitro assays confirmed its binding to trypanothione reductase, disrupting redox balance. Flow cytometry further revealed apoptosis induction in trypomastigotes, whereas electron microscopy showed cellular disruption and organelle disorganization. Therefore, SB-83 demonstrated potent activity against the TcI-resistant strain linked to Chagas cardiomyopathy at non-toxic concentrations for host cells, supporting its potential as a therapeutic candidate.

Leishmaniasis is a group of infectious diseases transmitted to humans during vector bites and caused by protozoans of the genus Leishmania. Conventional therapies face challenges due to their serious side effects, prompting research into new anti-leishmania agents. In this context, we investigated the effectiveness of morolic acid, a pentacyclic triterpene, on L. amazonensis promastigotes and amastigotes. The present study employed the MTT assay, cytokine analysis using optEIATM kits, an H₂DCFDA test, and nitric oxide dosage involving nitrite production and Griess reagent. Morolic acid inhibited promastigote and axenic amastigote growth forms at IC₅₀ values of 1.13 µM and 2.74 µM, respectively. For cytotoxicity to macrophages and VERO cells, morolic acid obtained respective CC₅₀ values of 68.61 µM and 82.94 µM. The compound causes damage to the parasite membrane, leading to cellular leakage. In the infection assay, there was a decrease in parasite load, resulting in a CI₅₀ of 2.56 µM. This effect was associated with immunomodulatory activity, altering macrophage structural and cellular parasite elimination mechanisms. Morolic acid proved to be an effective and selective natural compound, making it a strong candidate for future in vivo studies in cutaneous leishmaniasis.

INTRODUÇÃO: As leishmanioses têm um impacto significativo na saúde pública e os tratamentos existentes apresentam graves efeitos adversos e há inúmeros relatos de parasitos resistentes aos tratamentos convencionais. Portanto, há um interesse crescente na investigação dos compostos derivados de indol devido ao seu potencial antileishmania, proporcionando menor toxicidade aos pacientes. OBJETIVO: Este estudo busca analisar compostos derivados do indol como uma nova opção de tratamento antileishmania, visando maior eficácia e menos prejuízo à saúde dos pacientes. MÉTODOS: Trata-se de uma revisão integrativa de artigos publicados entre os anos de 2018 a 2023, em bases de dados como o PubMed, Science Direct e Scopus. RESULTADOS: A revisão incluiu artigos tratando-se de estudos experimentais sobre a atividade antileishmania de compostos derivados de indol. Todos os compostos demonstraram níveis satisfatórios de seletividade, com inibição parasitária de alto a moderado e baixa citotoxicidade. CONCLUSÃO: Os derivados de indol são uma abordagem promissora para o desenvolvimento de novos medicamentos contra as leishmanioses, com resultados positivos de boa seletividade e baixa citotoxicidade em comparação aos fármacos atuais, tornando-os potentes candidatos para um novo tratamento.

INTRODUÇÃO: As Doenças Tropicais Negligenciadas (DTNs) conceituam-se por serem doenças infecciosas ocasionadas por diversos tipos de parasitas, dentre eles as leishmanias sp., causadoras das leishmanioses, uma das diversas complicações relatadas em países com baixo subsídio em saúde, tornando-se necessário a revisão de novas moléculas. Dessa maneira, visando a utilização do método de biossíntese. OBJETIVO: Avaliar a possibilidade de utilização de nanopartículas de prata biológica (AgNPBs), obtidas de plantas no processo terapêutico contra as diferentes formas da Leishmania sp. , ampliando as perspectivas quanto aos produtos de avanço nanotecnológico para fins de tratamento. MÉTODOS: Desenvolveu-se uma revisão bibliográfica, utilizando das principais bases de dados, que trazem por incluso artigos, revisões de literatura, livros e revistas científicas, almejando a coleta de informações referentes ao tema previsto. RESULTADOS: Os resultados demonstraram que as plantas podem ser produtos de síntese de AgNPBs devido suas propriedades com valores baixos de CI50 (19,42 ± 2,76 µg/ml, 30,71 ± 1,91 µg/ml e 51,23 ± 2,20 µg/ml; 23,14 μg/ml, 0,0016μg/ml e 19,95 μg/ml em promastigota; 26,43 μg/ml, 0,0011μg/ml e 33,09 μg/ml para amastigotas) e bioativos como os flavonoides e alcaloides com alto poder antioxidante e anti-inflamatório, sendo suas vias mesmo não conclusivas mais efetivas que as convencionais. CONCLUSÃO: A biossíntese de nanopartículas de prata por plantas mostrou-se promissora como uma opção para carregar fármacos no tratamento das leishmanioses, devido à sua especificidade, biodisponibilidade e menores efeitos adversos. No entanto, há uma falta de estudos brasileiros aprofundados sobre o uso de extratos de plantas para formulação de nanopartículas. Portanto, é necessário coletar novas informações sobre a flora do país a fim de explorar as propriedades dos compostos de cada gênero e espécie, visando a nanotecnologia.

Tree-exuded gums are natural polymers that represent an abundant raw material in the food and pharmaceutical industries. The cashew gum can be obtained by exudation of trees of the genus Anacardium, a native species of the Brazilian northeast; its polymer consists of monosaccharide units propitious to the action of chemical reactions that tend to improve their intrinsic characteristics among them, as the degree of hydro-solubility. The objective of this work was to modify the exudate gum of Anacardium occidentale (cashew gum (CG)) through an amine reaction. The modification was confirmed by Nuclear Magnetic Resonance (¹H NMR), infrared spectroscopy (FTIR), gel permeation chromatography (GPC), zeta potential, and thermogravimetric analysis (TG). In addition, the chemical modification altered the molar mass and surface charge of the CG, and the amino group binding to the CG polymers was confirmed by FTIR spectra. In addition, cytotoxicity tests were performed where cell viability was estimated by an MTT assay on RAW 264.7 macrophages. Through these tests, it was found that the amine caused an increase in the thermal stability of the amino compounds and did not present cytotoxic potential at concentrations below 50.0 mg/L.

Leishmaniasis is a group of infectious-parasitic diseases with high mortality rates, and endemic in many regions of the globe. The currently available drugs present serious problems such as high toxicity, costs, and the emergence of drug resistance. This has stimulated research into new antileishmania drugs based on natural products and their derivatives. β-Ocimene is a monoterpene found naturally in the essential oils of many plant species which presents antileishmanial activity, and which has not yet been evaluated for its potential to inhibit the etiological agent of leishmaniasis. The aim of this work was to evaluate the activity of β-ocimene against Leishmania amazonensis, its cytotoxicity, and potential mechanisms of action. β-Ocimene presented direct activity against the parasite, with excellent growth inhibition of promastigotes (IC₅₀ = 2.78 μM) and axenic amastigotes (EC₅₀ = 1.12 μM) at concentrations non-toxic to RAW 264.7 macrophages (CC₅₀ = 114.5 µM). The effect is related to changes in membrane permeability and resulting abnormalities in the parasitic cell shape. These were, respectively, observed in membrane integrity and atomic force microscopy assays. β-Ocimene was also shown to act indirectly, with greater activity against intra-macrophagic amastigotes (EC₅₀ = 0.89 μM), increasing TNF-α, nitric oxide (NO), and reactive oxygen species (ROS), with lysosomal effects, as well as promoting decreases in IL-10 and IL-6. Against intra-macrophagic amastigote forms the selectivity index was higher than the reference drugs, being 469.52 times more selective than meglumine antimoniate, and 42.88 times more selective than amphotericin B. Our results suggest that β-ocimene possesses promising in vitro antileishmania activity and is a potential candidate for investigation in in vivo assays.