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In vitro interaction of polyethylene glycol‐block‐poly (D,L‐lactide) nanocapsule devices with host cardiomyoblasts and trypanosoma cruzi‐infective forms.
(2022) Siqueira, Raoni Pais; Milagre, Matheus Marques; Oliveira, Maria Alice de; Branquinho, Renata Tupinambá; Torchelsen, Fernanda Karoline Vieira da Silva; Lana, Marta de; Machado, Marina Guimarães Carvalho; Andrade, Margareth Spangler; Bahia, Maria Terezinha; Mosqueira, Vanessa Carla Furtado
Chagas disease, caused by the protozoan Trypanosoma cruzi, is an important public health problem in Latin America. Nanoencapsulation of anti-T. cruzi drugs has signifcantly improved their efcacy and reduced cardiotoxicity. Thus, we investigated the in vitro interaction of polyethylene glycol-block-poly(D,L-lactide) nanocapsules (PEG-PLA) with trypomas- tigotes and with intracellular amastigotes of the Y strain in cardiomyoblasts, which are the infective forms of T. cruzi, using fuorescence and confocal microscopy. Fluorescently labeled nanocapsules (NCs) were internalized by non-infected H9c2 cells toward the perinuclear region. The NCs did not induce signifcant cytotoxicity in the H9c2 cells, even at the highest concentrations and interacted equally with infected and non-infected cells. In infected cardiomyocytes, NCs were distrib- uted in the cytoplasm and located near intracellular amastigote forms. PEG-PLA NCs and trypomastigote form interactions also occurred. Altogether, this study contributes to the development of engineered polymeric nanocarriers as a platform to encapsulate drugs and to improve their uptake by diferent intra- and extracellular forms of T. cruzi, paving the way to fnd new therapeutic strategies to fght the causative agent of Chagas disease.
A participação das mulheres em políticas hídricas no município de Ouro Preto/MG.
(2022) Rosa, Alexsandra Matilde Resende; Guarda, Vera Lúcia de Miranda; Alves, Kerley dos Santos
Embora haja um expressivo número de normas jurídicas com o objetivo de combater a desigualdade em razão de gênero em todos os setores, as desigualdades persistem, o que ocorre também na gestão da água. Para preencher essa lacuna, a participação das mulheres nos conselhos e nas tomadas de decisões em relação aos recursos hídricos é uma das principais formas de garantia de acesso à água de forma mais igualitária. A participação delas possibilita também o empoderamento, proporcionando-lhes maior possibilidade de exercer poder e cidadania no espaço público, bem como uma maior legitimidade das normas jurídicas e maior eficácia das políticas públicas. Nesse trabalho foi realizado uma pesquisa de campo com conselheiros/as e trabalhadores/as que atuam na gestão da água em Ouro Preto/MG. Os dados foram coletados por meio de entrevistas e analisados. As análises dos dados apontaram a necessidade do aumento da participação das mulheres nas organizações e conselhos, tanto em número, quanto também, na ocupação de postos responsáveis pelas tomadas de decisões. A luta pela superação das diferenças, não se trata de uma luta exclusiva das mulheres, mas também dos homens, coautores e construtores das transformações sociais.
Women’s participation in water policies, Ouro Preto, MG, Brazil.
(2022) Rosa, Alexsandra Matilde Resende; Guarda, Vera Lúcia de Miranda; Alves, Kerley dos Santos
Although there is an expressive number of legal norms in order to combat gender inequality in all sectors, inequalities persist, which also occurs in water management. In order to fill this gap, the participation of women in councils and decision-making in relation to water resources is one of the main ways of guaranteeing access to water in a more equal way. Their participation also enables empowerment, providing them with greater possibility of exercising power and citizenship in the public space, as well as greater legitimacy of legal rules and greater effectiveness of public policies. In this work, the case study was carried out with counselors and workers working in water management in Ouro Preto/MG. Data were collected through interviews and analyzed. Data analysis pointed to the need to increase the participation of women in organizations and councils, both in number and in the occupation of positions responsible by decision-making. The struggle to overcome differences is not an exclusive struggle from women, but also from men, co-authors and builders of social transformations.
Estruturas e representações sobre a desigualdade de gênero na gestão da água em Ouro Preto/ MG : uma análise da percepção de conselheiros e gestores dos órgãos municipais.
(2022) Rosa, Alexsandra Matilde Resende; Guarda, Vera Lúcia de Miranda; Alves, Kerley dos Santos
O artigo analisa a participação das mulheres na gestão das águas no município de Ouro Preto/MG, identificando se na percepção dos funcionários e conselheiros existem desigualdades de gênero nas estruturas organizacionais dos órgãos e conselhos em que atuam e se os entrevistados reconhecem diferenças relativas a papéis de gênero na esfera pública e privada. Em relação à classificação metodológica se trata de uma pesquisa aplicada, quantitativa, descritiva e de levantamento. A coleta de dados foi através da aplicação de questionários, que foram respondidos por 48 conselheiros e 72 funcionários dos órgãos responsáveis pela gestão da água no município. Os órgãos e conselhos que participaram do estudo foram: SEMAE, COMUSA, CODEMA, Secretária Municipal de Meio Ambiente e Subcomitê de Bacia Hidrográfica - Nascentes. Conclui- se que em relação à percepção dos gestores existem desigualdades de gênero nas estruturas organizacionais e nos papéis sociais de homens e mulheres na sociedade.
Relações de gênero nos processos decisórios sobre a água em Ouro Preto/MG.
(2022) Rosa, Alexsandra Matilde Resende; Guarda, Vera Lúcia de Miranda; Alves, Kerley dos Santos
A integração da perspectiva de gênero na gestão dos recursos hídricos visa a garantir que as experiências e preocupações de homens e mulheres façam parte da preparação, efetivação, controle e avaliação das políticas e programas sobre a água. Tal integração é necessária na medida em que as mulheres são minorias nas altas instâncias decisórias sobre os recursos hídricos, mas são muito afetadas pela escassez deles. Ademais, as mulheres lidam com a água diariamente ao longo de gerações. Também, representam metade da população mundial, e o desenvolvimento sustentável não pode acontecer sem a contribuição de parcela tão significativa da população. Essa pesquisa teve como objetivo identificar a percepção dos gestores da água no município de Ouro Preto/MG quanto à participação das mulheres na gestão. Bus- cou-se atingir esse objetivo por meio da aplicação de questionários, entrevista semiestruturada e observações nas reuniões dos Órgãos e Conselhos participantes da pesquisa. Foi observada uma maior presença masculina nos cargos gerencias e operacionais dos Órgãos e nos Conselhos Gestores. Apesar de estarem em menor número, as mulheres assumem um posicionamento ativo. Os entrevistados relatam ob- servar uma maior presença de homens nas reuniões, sendo necessárias medidas que incentivem a participação das mulheres. Ainda, foram relatadas diferenças de funções conforme o sexo no ambiente de trabalho. De acordo com a percepção dos conselheiros e trabalhadores, a participação popular, em geral, nos Órgãos e Conselhos, é pouco expressiva. Há a necessidade de cursos de capacitação para garantir uma maior equidade de forças dentro do debate ambiental sobre o assunto, permitindo debates mais equânimes.
Rapid antigen test as a tool for the identification of SARS-CoV-2 infection and its potential as a self-testing device.
(2023) Filgueiras, Priscilla Soares; Corsini, Camila Amormino; Almeida, Nathalie Bonatti Franco; Pedrosa, Maria Luysa Camargos; Miranda, Daniel Alvim Pena de; Gomes, Sarah Vieira Contin; Assis, Jéssica Vieira de; Silva, Raphael Antônio; Medeiros, Maria Izabella Vieira de Assis Rocha Carvalho de; Lourenço, Adelina Junia; Bicalho, Cecilia Maria Florencio; Vilela, Raquel Virgínia Rocha; Jeremias, Wander de Jesus; Fernandes, Gabriel da Rocha; Grenfell, Rafaella Fortini Queiroz
Background: SARS-CoV-2 virus originated in Wuhan (China) in December (2019) and quickly spread worldwide. Antigen tests are rapid diagnostic tests (RDT) that produce results in 15-30 min and are an important tool for the scale-up of COVID-19 testing. COVID-19 diagnostic tests are authorized for self-testing at home in some countries, including Brazil. Widespread COVID-19 diagnostic testing is required to guide public health policies and control the speed of transmission and economic recovery. Methods: Patients with suspected COVID-19 were recruited at the Hospital da Baleia (Belo Horizonte, Brazil). The SARS-CoV-2 antigen- detecting rapid diagnostic tests were evaluated from June 2020 to June 2021 using saliva, nasal, and nasopharyngeal swab samples from 609 patients. Patient samples were simultaneously tested using a molecular assay (RT-qPCR). Sensitivity, specificity, accuracy, and positive and negative predictive values were determined using the statistical program, MedCalc, and GraphPad Prism 8.0. Results: The antigen-detecting rapid diagnostic tests displayed 98% specificity, 60% sensitivity, 96% positive predictive value, and moderate concordance with RT-qPCR. Substantial agreement was found between the two methods for patients tested < 7 days of symptom onset. Conclusions: Our findings support the use of Ag-RDT as a valuable and safe diagnostic method. Ag-RDT was also demonstrated to be an important triage tool for suspected COVID-19 patients in emergencies. Overall, Ag-RDT is an effective strategy for reducing the spread of SARS-CoV-2 and contributing to COVID-19 control.
Immunogenicity, effectiveness, and safety of inactivated virus (CoronaVac) vaccine in a two-dose primary protocol and BNT162b2 heterologous booster in Brazil (Immunita-001) : a one year period follow up phase 4 study.
(2022) Grenfell, Rafaella Fortini Queiroz; Almeida, Nathalie Bonatti Franco; Filgueiras, Priscilla Soares; Corsini, Camila Amormino; Gomes, Sarah Vieira Contin; Miranda, Daniel Alvim Pena de; Lourenço, Adelina Junia; Martins Filho, Olindo Assis; Oliveira, Jaquelline Germano de; Carvalho, Andréa Teixeira de; Campos, Guilherme Rodrigues Fernandes; Nogueira, Maurício Lacerda; Alves, Pedro Augusto; Fernandes, Gabriel da Rocha; Castilho, Leda dos Reis; Lima, Túlio Macedo; Abreu, Daniel Paiva Barros de; Alvim, Renata Guimarães Ferreira; Silva, Thaís Bárbara de Souza; Jeremias, Wander de Jesus; Otta, Dayane Andriotti; Azevedo, Ana Carolina Campi; Immunita-001 Team
Background: Effective and safe vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are critical to controlling the COVID-19 pandemic and will remain the most important tool in limiting the spread of the virus long after the pandemic is over. Methods: We bring pioneering contributions on the maintenance of the immune response over a year on a real-life basis study in 1,587 individuals (18-90 yrs, median 39 yrs; 1,208 female/379 male) who underwent vaccination with two doses of CoronaVac and BNT162b2 booster after 6-months of primary protocol. Findings: Elevated levels of anti-spike IgG antibodies were detected after CoronaVac vaccination, which significantly decreased after 80 days and remained stable until the introduction of the booster dose. Heterologous booster restored antibody titers up to-1·7- fold, changing overall seropositivity to 96%. Titers of neutralising antibodies to the Omicron variant were lower in all timepoints than those against Delta variant. Individuals presenting neutralising antibodies against Omicron also presented the highest titers against Delta and anti-Spike IgG. Cellular immune response measurement pointed out a mixed immune profile with a robust release of chemokines, cytokines, and growth factors on the first month after CoronaVac vaccination followed by a gradual reduction over time and no increase after the booster dose. A stronger interaction between those mediators was noted over time. Prior exposure to the virus leaded to a more robust cellular immune response and a rise in antibody levels 60 days post CoronaVac than in individuals with no previous COVID-19. Both vaccines were safe and well tolerated among individuals. Interpretation: Our data approach the effectiveness of CoronaVac association with BNT162b2 from the clinical and biological perspectives, aspects that have important implications for informing decisions about vaccine boosters. Funding: Fiocruz, Brazil.
Angiotensin‐converting enzyme gene (ACE) polymorphisms are associated with dysregulation of biochemical parameters in hypertensive patients.
(2023) Agostini, Lívia da Cunha; Cunha, Warlley Rosa; Silva, Nayara Nascimento Toledo; Melo, André Sacramento; Soares, Luciana Bicalho Moreira; Almeida, Tamires Cunha; Belo, Vanessa de Almeida; Vital, Wendel Coura; Teixeira, Luiz Fernando de Medeiros; Lima, Angélica Alves; Silva, Glenda Nicioli da
Introduction The genetic component, including genes and their variants, plays a signifcant role in the pathophysiology of arterial hypertension (AH). Thus, clinical, epidemiological and genetic studies have been carried out to improve the under- standing of disease mechanisms, improve diagnostic quality and contribute to prevention. Objective To determine the association of risk factors, biochemical parameters and diferent ACE gene polymorphisms with AH. Method The case-control study was carried out in the population of Ouro Preto, Brazil. The subjects answered a question- naire containing clinical and sociodemographic data. The ACE gene polymorphisms rs4291, rs4363 and rs4335 were evalu- ated by real time-polymerase chain reaction (real-time PCR) in 310 people (155 hypertensive and 155 normotensive patients), in addition to biochemical parameters. A multivariate logistic regression model was used to identify factors associated with AH. Analysis of continuous variables was performed using the Kruskal-Wallis test to assess signifcance between groups and Dunn’s post-test for multiple comparisons. Results The results showed that AH was associated with age, education, smoking, obesity and high levels of triglycerides, sodium, glucose and uric acid. Regarding the biochemical parameters, in hypertensive patients, the rs4363 and rs4335 poly- morphisms were associated with high levels of triglycerides, urea and glucose; the rs4291 polymorphism was associated with elevated urea and glucose levels. No association was detected between SNPs and HA. Conclusion AH was associated with socioeconomic status, lifestyle habits and biochemical parameters. ACE polymorphisms may have infuenced the levels of triglycerides, urea and glucose in hypertensive patients.
High molecular weight adiponectin as a biomarker of hypertension in children and adolescents with obesity.
(2023) Cunha, Warlley Rosa; Gaspar, Isabella Campos; Souza, Beatriz Cazarim de; Martins, Bárbara Dias Lana; Miranda, Josiane Aparecida de; Lanna, Carla Márcia Moreira; Santos, José Eduardo Tanus dos; Lacchini, Riccardo; Belo, Vanessa de Almeida
Lower HMW (high molecular weight) adiponectin levels are associated with obesity, insulin resistance, and metabolic syndrome in children and adolescents. However, data on HMW levels in pediatric population with hypertension are lacking. This study aimed to examine the association and predictive capacity of HMW levels, HMW/HOMA-IR, and HMW/APN ratio with hypertension in obese children and adolescents. The 299 pediatric subjects were grouped in obese hypertensive (OH), obese normotensive (ON), and normal weight normotensive (NN). Plasma concentrations of HMW were investigated by ELISA. ANOVA was used to compare study groups, and a binary logistic regression analysis was used to verify if HMW, HMW/HOMA-IR, HMW/APN, APN, APN/HOMA-IR, and HOMA-IR are associated to hypertension regardless obesity in children and adolescents. To compare the strength and performance of each biomarker to classify individuals with and without hypertension, the receiver-operating characteristic (ROC) curve, area under the curve (AUC), and Youden index (J) were evaluated. Both HMW plasma levels and the HMW/HOMA-IR ratio were significantly lower in the OH group when compared to the ON group (HMW: 2.00±1.33 μg/mL vs 2.48±1.48 μg/mL; HMW/HOMA-IR ratio: 0.87±0.95 vs 1.27±1.2; P<0.05) and NN weight groups (HMW: 2.00±1.33 μg/mL vs 4.02±1.99 μg/mL; HMW/HOMA-IR ratio: 0.87±0.95 vs 2.62±1.86; P<0.05). Hypertension was associated with lowest HMW (OR=4.50; 95% CI=1.41–15.84) and HMW/HOMA-IR (OR=12.13; 95% CI=2.51–92.93) regardless of obesity. However, HOMA-IR or the HMW/APN was not significant (P>0.05). In the ROC curve analyses, the HMW and HMW/HOM-IR were more sensitive to detect hypertension in children and adolescents with obesity. Conclusion: Low levels of HMW oligomer and HMW/HOM-IR are associated with hypertension in childhood obesity. Thus, these biomarkers could be clinically useful in identifying hypertension in childhood obesity.
Longitudinal study of plasma visfatin/nicotinamide phosphoribosyltransferase (nampt) levels in healthy pregnant women.
(2023) Nunes, Priscila Rezeck; Cavalli, Ricardo de Carvalho; Belo, Vanessa de Almeida; Sandrim, Valeria Cristina; Luizon, Marcelo Rizzatti
Visfatin/nicotinamide phosphorybosil transferase (NAMPT) is a novel adipocytokine with potential roles in the patho- physiology of metabolic disorders, including gestational disorders. However, there is no clear interpretation regarding the circulating visfatin levels in a healthy pregnancy. Therefore, we conducted the frst longitudinal study of plasma visfatin levels that followed up healthy pregnant women until the third trimester, including the postpartum period (PPP). The study recruited healthy women with singleton pregnancy who were not using any drug (including tobacco and alcohol). We have excluded pregnant women who did not attend all scheduled exams and developed gestational diabetes or hypertension, obesity, preeclampsia, or any infections during pregnancy. Nine women were considered eligible and examined during all three trimesters of pregnancy and between 8 and 12 weeks postpartum (PPP). Visfatin/NAMPT concentrations were meas- ured in EDTA-plasma by ELISA. The mean age of pregnant women included was 22±5 years (54% primiparous), and the mean of gestational age at delivery was 40±1.2 weeks. Mean systolic and diastolic blood pressures were 90 and 70 mmHg, respectively. Mean values (± standard error mean) of visfatin concentrations (μg/L) during trimesters were 11.38±1.45 (frst, 11–14 weeks), 9.18±1.82 (second, 20–24 weeks), 18.67±2.65 (third, 34–36 weeks), and 10.12±1.49 in the PPP. The value of the third trimester was signifcantly higher than the second trimester, and signifcantly reduced in the PPP (p<0.05, ANOVA with Bonferroni’s multiple comparison tests). Visfatin/NAMPT levels are signifcantly lower in the PPP, suggesting that factors stimulating its production would be limited to pregnancy, thereby contributing to its potential application as a biomarker in pregnancy complications.
Vaccination with formulation of nanoparticles loaded with Leishmania amazonensis antigens confers protection against experimental visceral leishmaniasis in hamster.
(2023) Cabrera González, Marco Antonio; Gonçalves, Ana Alice Maia; Ottino, Jennifer; Leite, Jaqueline Costa; Resende, Lucilene Aparecida; Melo Júnior, Otoni Alves de Oliveira; Silveira, Patricia; Cardoso, Mariana Santos; Fujiwara, Ricardo Toshio; Bueno, Lilian Lacerda; Santos, Renato Lima; Carvalho, Tatiane Furtado de; Garcia, Giani Martins; Paes, Paulo Ricardo de Oliveira; Galdino, Alexsandro Sobreira; Chávez Fumagalli, Miguel Angel; Melo, Marilia Martins; Lemos, Denise da Silveira; Martins Filho, Olindo Assis; Dutra, Walderez Ornelas; Mosqueira, Vanessa Carla Furtado; Giunchetti, Rodolfo Cordeiro
Visceral leishmaniasis (VL) is a fatal disease caused by the protozoa Leishmania infantum for which dogs are the main reservoirs. A vaccine against canine visceral leishmaniasis (CVL) could be an important tool in the control of human and CVL by reducing the infection pressure of L. infantum. Despite the CVL vaccine available on the market, the Brazilian Ministry of Health did not implement the use of it in their control programs. In this sense, there is an urgent need to develop more efficient vaccines. In this study, the association between two polymeric nanoformulations, (poly (D, L-lactic) acid (PLA) polymer) loading Leishmania amazonensis antigens, was evaluated as a potential immunobiological agent against VL using golden hamsters as an experimental model. The results indicated that no significant adverse reactions were observed in animals vaccinated with LAPSmP. LAPSmP presented similar levels of total anti-Leishmania IgG as compared to LAPSmG. The LAPSmP and LAPSmG groups showed an intense reduction in liver and spleen parasitic load by qPCR. The LAPSmP and LAPSmG vaccines showed exceptional results, indicating that they may be promising candidates as a VL vaccine.
PLA-b-SMA as an amphiphilic diblock copolymer for encapsulation of lipophilic cargo.
(2023) Ball, Lauren Elizabeth; Pfukwa, Rueben; Siqueira, Raoni Pais; Mosqueira, Vanessa Carla Furtado; Klumperman, Bert
The encapsulation of active pharmaceutical ingredients (APIs) within drug delivery systems such as polymeric nanoparticles (PNPs) vastly improves the therapeutic efficiency of the incorporated APIs. PNPs synthesized using amphiphilic block copolymers are efficient drug delivery systems as the hydrophobic block facilitates the encapsulation of lipophilic components and the hydrophilic block constitutes the hairy corona of the PNP that stabilizes the nanocarriers against aggregation in solution. Poly(styrene-alt-maleic acid) (SMA) is an attractive polymer for the hydrophilic corona of PLA-based nanoparticles as it allows for post polymerization functionalization and aids in the prevention of NP aggregation. The synthesis of a novel PLA-b-SMA block copolymer, via sequential ring opening polymerization (ROP) and reversible addition–fragmentation chain transfer (RAFT) polymerization, is presented. PLA macro-CTAs, synthesized via ROP, can be chain extended via RAFT copolymerization of styrene and maleic anhydride to yield PLA-b-SMAnh and via RAFT polymerization of N-vinylpyrrolidone to yield PLA-b-PVP block copolymers. Controlled hydrolysis of the anhydride moieties converts PLA-b-SMAnh into PLA-b-SMA. Monodisperse PLA-b-SMA and PLA-b-PVP nanoparticles (NPs) ranging in diameter between 60 and 220 nm are prepared. The lipophilic fluorescent dye DiI is encapsulated within the NPs successfully and these fluorescent NPs are used in a preliminary cell uptake study.
Nanoformulations with Leishmania braziliensis antigens triggered controlled parasite burden in vaccinated golden hamster (Mesocricetus auratus) against visceral leishmaniasis.
(2022) Ottino, Jennifer; Leite, Jaqueline Costa; Melo Júnior, Otoni Alves de Oliveira; Cabrera González, Marco Antonio; Carvalho, Tatiane Furtado de; Garcia, Giani Martins; Batista, Maurício Azevedo; Silveira, Patrícia; Cardoso, Mariana Santos; Bueno, Lilian Lacerda; Fujiwara, Ricardo Toshio; Santos, Renato Lima; Paes, Paulo Ricardo de Oliveira; Lemos, Denise da Silveira; Martins Filho, Olindo Assis; Galdino, Alexsandro Sobreira; Chávez Fumagalli, Miguel Angel; Dutra, Walderez Ornelas; Mosqueira, Vanessa Carla Furtado; Giunchetti, Rodolfo Cordeiro
Leishmaniasis is a widespread vector-borne disease in Brazil, with Leishmania (Leishmania) infantum as the primary etiological agent of visceral leishmaniasis (VL). Dogs are considered the main reservoir of this parasite, whose treatment in Brazil is restricted to the use of veterinary medicines, which do not promote a parasitological cure. Therefore, efficient vaccine development is the best approach to Canine Visceral Leishmaniasis (CVL) control. With this in mind, this study used hamsters (Mesocricetus auratus) as an experimental model in an anti-Leishmania preclinical vaccine trial to evaluate the safety, antigenicity, humoral response, and effects on tissue parasite load. Two novel formulations of nanoparticles made from poly(D, L-lactic) acid (PLA) polymer loading Leishmania braziliensis crude antigen (LB) exhibiting two different particle sizes were utilized: LBPSmG (570 nm) and LBPSmP (388 nm). The results showed that the nanoparticles were safe and harmless to hamsters and were antigenic with the induction in LBSap, LBPSmG, and LBPSmG groups of total anti-Leishmania IgG antibodies 30 days after challenge, which persists 200 days in LBSap and LBPSmP. At the same time, a less pronounced hepatosplenomegaly in LBSap, LBPSmG, and LBPSmP was found when compared to control groups, as well as a less pronounced inflammatory infiltrate and granuloma formation in the spleen. Furthermore, significant reductions of 84%, 81%, and 90% were observed in spleen parasite burden accessed by qPCR in the LBSap, LBPSmG, and LBPSmP groups, respectively. In this way, LBSap, LBPSmG, and LBPSmP formulations showed better results in vaccinated and L. infantum-challenged animals in further reducing parasitic load in the spleen and attenuating lesions in liver and splenic tissues. This results in safe, harmless nanoformulation vaccines with significant immunogenic and infection control potential. In addition, animals vaccinated with LBPSmP had an overall reduction in parasite burden in the spleen, indicating that a smaller nanoparticle could be more efficient in targeting antigen-presenting cells.
Structure-activity relationship study of antitrypanosomal analogues of gibbilimbol B using multivariate analysis and computation-aided drug design.
(2023) Leão, Luiz Paulo Melchior de Oliveira; Vieira, Nátalie de Barros; Oliveira, Paula P. S.; Paula, Daniela Aparecida Chagas de; Soares, Marisi Gomes; Souza, Thiago Belarmino de; Zanin, João Luiz Baldim; Silva, Thais Alves da Costa; Cardoso, André Gustavo Tempone; Dias, Danielle Ferreira; Lago, João Henrique Ghilardi
Gibbilimbol B and analogues were isolated from the Brazilian plant Piper malacophyllum and displayed activity against trypomastigote forms of Trypanosoma cruzi as well as reduced toxicity against NCTC cells. These results stimulated the preparation of a series of 24 chemically related analogues to study the potential of these com- pounds against T. cruzi trypomastigotes and explore structure–activity relationships. Initially, 12 compounds were planned, maintaining the same extension of the linear side chain of gibbilimbol B and unsaturation on the C-4 position but changing the functional groups – ester and amide – and variating the substituent at the p-po- sition in the aromatic ring. Other 12 compounds were prepared using a branched side chain containing an ethyl group at the C-2 position. Overall, these structurally-related analogues demonstrated promising activity against trypomastigote forms (EC50 < 20 μM) and no mammalian cytotoxicity to fibroblasts (CC50 > 200 μM). Using multivariate statistics and machine learning analysis, aspects associated with structure/activity were related to their three-dimensional structure and, mainly, to the substituents on the aromatic ring. Obtained results sug- gested that the presence of t-butyl or nitro groups at p-position with appropriate side chains causes an alteration in the electron topological state, Van der Waals volumes, surface areas, and polarizabilities of tested compounds which seem to be essential for biological activity against T. cruzi parasites.
Synthesis and antimicrobial activity of molecular hybrids based on eugenol and chloramphenicol pharmacophores.
(2023) Oliveira, Lucas Martins; Siqueira, Fallon dos Santos; Silva, Michelle T.; Machado, José Vaz Cardoso; Cordeiro, Cleydson Finotti; Diniz, Lívia de Figueiredo; Campos, Marli Matiko Anraku de; Franco, Lucas Lopardi; Souza, Thiago Belarmino de; Hawkes, Jamie Anthony; Carvalho, Diogo Teixeira
In the constant search for new pharmacological compounds, molecular hybridisation is a well-known technique whereby two or more known pharmacophoric subunits are combined to create a new “hybrid” compound. This hybrid is expected to maintain the characteristics of the original compounds whilst demonstrating improvements to their pharmacological action. Accordingly, we report here a series of molecular hybrid compounds based upon eugenol and chloramphenicol pharmacophores. The hybrid compounds were screened for their in vitro antimicrobial potential against Gram-negative and Gram-positive bacteria and also rapidly growing mycobacteria (RGM). The results highlight that the antimicrobial profiles of the hybrid compounds improve in a very clear fashion when moving through the series. The most prominent results were found when comparing the activity of the hybrid compounds against some of the multidrug-resistant clinical isolates of Pseudomonas aeruginosa, methicillin-resistant clinical isolates of Staphylococcus aureus (MRSA) and clinical isolates of rapidly growing mycobacteria.
In vitro and in silico evaluation of the schistosomicidal activity of eugenol derivatives using biochemical, molecular, and morphological tools.
(2022) Souza, Isabella Maria Monteiro de; Novaes, Rômulo Dias; Gonçalves, Reggiani Vilela; Fialho, Felipe Leonardo Bley; Carvalho, Diogo Teixeira; Souza, Thiago Belarmino de; Dias, Danielle Ferreira; Lavorato, Stefânia Neiva; Souza, Raquel Lopes Martins; Marques, Marcos José; Castro, Aline Pereira
Background: Eugenol shows both antibacterial and antiparasitic activities, suggesting that it might be evaluated as an option for the treatment of praziquantel-resistant schistosome. Methods: The in vitro activities of three eugenol derivatives (FB1, FB4 and FB9) on adult worms from Schistosoma mansoni were examined by fluorescence and scanning electron microscopy to analyze effects on the excretory system and integument damage, respectively. Biochemical tests with verapamil (a calcium channel antagonist) and ouabain (a Na+ /K+-ATPase pump inhibitor) were used to characterize eugenol derivative interactions with calcium channels and the Na+/K+-ATPase, while in silico analysis identified potential Na+/K+-ATPase binding sites. Results: The compounds showed effective doses (ED50) of 0.324 mM (FB1), 0.167 mM (FB4), and 0.340 mM (FB9). In addition, FB4 (0.322 mM), which showed the lowest ED50, ED90 and ED100 (p < 0.05), caused the most damage to the excretory system and integument, according to both fluorescence and scanning electron microscopy analysis. The death of adult worms was delayed by ouabain treatment plus FB1 (192 versus 72 hours) and FB9 (192 versus 168 hours), but the response to FB4 was the same in the presence or absence of ouabain. Besides, no changes were noted when all of the eugenol derivatives were combined with verapamil. Moreover, FB1 and FB9 inhibited Na+/K+-ATPase activity according to in silico analysis but FB4 did not show a time- dependent relationship and may act on targets other than the parasite Na+/K+-ATPase. Conclusion: Eugenol derivatives, mainly FB4 when compared to FB1 and FB9, seem to act more effectively on the integument of adult S. mansoni worms.
New miconazole-based azoles derived from eugenol show activity against Candida spp. and Cryptococcus gattii by inhibiting the fungal ergosterol biosynthesis.
(2023) Péret, Vinícius Augusto Campos; Reis, Rúbia Castro Fernandes Melo; Braga, Saulo Fehelberg Pinto; Benedetti, Monique Dias; Caldas, Ivo Santana; Carvalho, Diogo Teixeira; Santana, Luiz Felipe de Andrade; Johann, Susana; Souza, Thiago Belarmino de
This work describes the design, synthesis and antifungal activity of new imidazoles and 1,2,4-triazoles derived from eugenol and dihydroeugenol. These new compounds were fully characterized by spectroscopy/spectro- metric analyses and the imidazoles 9, 10, 13 e 14 showed relevant antifungal activity against Candida sp. and Cryptococcus gattii in the range of 4.6–75.3 μM. Although no compound has shown a broad spectrum of antifungal activity against all evaluated strains, some azoles were more active than either reference drugs employed against specific strains. Eugenol-imidazole 13 was the most promising azole (MIC: 4.6 μM) against Candida albicans being 32 times more potent than miconazole (MIC: 150.2 μM) with no relevant cytotoxicity (selectivity index >28). Notably, dihydroeugenol-imidazole 14 was twice as potent (MIC: 36.4 μM) as miconazole (MIC: 74.9 μM) and more than 5 times more active than fluconazole (MIC: 209.0 μM) against alarming multi-resistant Candida auris. Furthermore, in vitro assays showed that most active compounds 10 and 13 altered the fungal ergosterol biosynthesis, reducing its content as fluconazole does, suggesting the enzyme lanosterol 14α-demethylase (CYP51) as a possible target for these new compounds. Docking studies with CYP51 revealed an interaction between the imidazole ring of the active substances with the heme group, as well as insertion of the chlorinated ring into a hydrophobic cavity at the binding site, consistent with the behavior observed with control drugs miconazole and fluconazole. The increase of azoles-resistant isolates of Candida species and the impact that C. auris has had on hospitals around the world reinforces the importance of discovery of azoles 9, 10, 13 e 14 as new bioactive compounds for further chemical optimization to afford new clinically antifungal agents.
Polymorphisms in genes coding milk proteins and protein hormones involved in milk production traits in Brazilian Guzerá cattle.
(2022) Silva, Raphael Steinberg da; Carvalho, Maria Raquel Santos; Cruz, Izinara Rosse da; Machado, Marco Antônio; Peixoto, Maria Gabriela Campolina Diniz
Research on genes affecting phenotypic variation in milk production and composition from indicine (Bos indicus) cattle is imperative, since these breeds are important tropical genetic resources, and there have been few studies investigating the genetic basis of these traits. We identified polymorphisms in -casein (CSN3), -lactoglobulin (LGB), thyroglobulin (TG) and prolactin (PRL) and examined their effect on milk and composition traits in the Guzerá breed. DNA samples of 260 Guzerá cattle selected for dual purpose use were genotyped. Allele frequencies observed for the A allele were 0.83, 0.18 and 0.25 respectively for CSN3, LGB and PRL genes, while for the TG gene T allele had an allele frequency of 0.09. For all polymorphisms evaluated, observed genotypic frequencies were in agreement with those expected according to the Hardy- Weinberg Equilibrium hypothesis. A polymorphism association study evaluated breeding values (BV) for 305-day milk (BV-M), fat (BV- F), and protein (BV-P) production, employing the allele substitution model using a sample of 139 cows belonged to 27 full and half-sib families of a MOET (multiple ovulation and embryo transfer) selection nucleus. Association was found between the LGB polymorphism and BV-M, BV-F and BV-P. Animals with LGB AA genotype have, on average, higher BV when compared to animals with LGB AB and BB genotypes (277.85 kg for BV-M, 12.09 kg for BV-F and 9.33 kg for BV-P). These findings contribute to a better understanding on the influence of these polymorphisms on milk production traits in Guzerá cattle.
Miconazole-loaded nanoparticles coated with hyaluronic acid to treat vulvovaginal candidiasis.
(2023) Teixeira, Aniely dos Reis; Quaresma, Amanda de Vasconcelos; Branquinho, Renata Tupinambá; Santos, Stephanie Lourrani Evangelista Neves; Magalhães, Juliana Teixeira; Silva, Fábio Henrique Rodrigues da; Marques, Maria Betânia de Freitas; Moura, Sandra Aparecida Lima de; Barboza, Ana Paula Moreira; Araújo, Marcelo Gonzaga de Freitas; Silva, Gisele Rodrigues da
Miconazole-loaded nanoparticles coated with hyaluronic acid (miconazole-loaded nanoparticles/HA) were developed to overcome the limitations of the conventional therapy of the vulvovaginal candidiasis (VVC). They were synthesized by emulsification and solvent evaporation techniques, characterized by diameter, poly- dispersity index, zeta potential, encapsulation efficiency, atomic force microscopy (AFM), evaluated in terms of efficacy against C. albicans in vitro, and tested in a murine VVC model. Nanoparticles showed 211nm of diameter with a 0.32 polydispersity index, -53mV of zeta potential, and 90% miconazole encapsulation efficiency. AFM evidenced nanoparticles with a spherical shape. They inhibited the proliferation of C. albicans in vitro and in vivo after a single administration. Nanoparticles released the miconazole directly in the site of action at low thera- peutic doses, which was enough to eliminate the fungal burden in the murine VVC model. These systems were rationally designed since the existence of the HA induces their adhesion on the vaginal mucus and their inter- nalization via CD44 receptors, inhibiting the C. albicans. Therefore, miconazole-loaded nanoparticles/HA represent an innovative non-conventional pharmaceutical dosage form to treat the VVC and recurrent VVC.
Virucidal antiviral activity of Maytenus quadrangulata extract against Mayaro virus : evidence for the presence of catechins.
(2023) Nunes, Damiana Antônia de Fátima; Lopes, Gabriela Francine Martins; Nizer, Waleska Stephanie da Cruz; Aguilar, Mariana Guerra de; Santos, Felipe Rocha da Silva; Sousa, Grasiely Faria de; Ferraz, Ariane Coelho; Duarte, Lucienir Pains; Brandão, Geraldo Célio; Vieira Filho, Sidney Augusto; Magalhães, Cíntia Lopes de Brito; Ferreira, Jaqueline Maria Siqueira; Magalhães, José Carlos de
Ethnopharmacological relevance: Mayaro virus (MAYV) is an arbovirus endemic to the Amazon region, which comprises the states of the North and Midwest region of Brazil and encompasses the largest tropical forest in the world, the Amazon Forest. The confirmation of its potential transmission by Aedes aegypti and recent cases in Brazil, mainly in large centers in the northern region, led to the classification of Mayaro fever as an emerging disease. Traditional medicine is commonly used to treat various diseases, mainly by local riverside populations. Some species of the genus Maytenus, which have similar morphologies, are popularly used to treat infections and inflammations. In this context, our research group has studied and confirmed the antiviral activity of several plant-derived compounds. However, several species of this same genus have not been studied and therefore deserve attention. Aim of the study: This study aimed to demonstrate the effects of ethyl acetate extracts of leaves (LAE) and branches (TAE) of Maytenus quadrangulata against MAYV. Materials and methods: Mammalian cells (Vero cells) were used to evaluate the cytotoxicity of the extracts. After cell infection by MAYV and the treatment with the extracts, we evaluated the selectivity index (SI), the virucidal effect, viral adsorption and internalization, and the effect on viral gene expression. The antiviral action was confirmed by quantifying the viral genome using RT-qPCR and by analyzing the effect on virus yield in infected cells. The treatment was performed based on the effective concentration protective for 50% of the infected cells (EC50). Results: The leaves (LAE; EC50 12.0 μg/mL) and branches (TAE; EC50 101.0 μg/mL) extracts showed significative selectivity against the virus, with SI values of 79.21 and 9.91, respectively, which were considered safe. Phytochemical analysis revealed that the antiviral action was associated with the presence of catechins, mainly in LAE. This extract was chosen for the subsequent studies since it reduced the viral cytopathic effect and virus production, even at high viral loads [MOI (multiplicity of infection) 1 and 5]. The effects of LAE resulted in a marked reduction in viral gene expression. The viral title was drastically reduced when LAE was added to the virus before infection or during replication stages, reducing virus production up to 5-log units compared to infected and untreated cells.

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