https://repositorio.ufu.br/handle/123456789/5487 2026-08-06T04:41:40Z https://repositorio.ufu.br/handle/123456789/49293 Title: A Quercetina reduz a infecção por Toxoplasma gondii nos modelos placentários in vitro e ex vivo Abstract: Toxoplasmosis is a disease caused by the obligate intracellular protozoan Toxoplasma gondii, which is capable of infecting all nucleated cells of birds and mammals and is therefore considered one of the most successful parasites in terms of infection. One of the routes of toxoplasmosis transmission is congenital transmission, which most often occurs when the mother acquires the infection for the first time during pregnancy. The ability of the parasite to cross the placental barrier and infect the embryo can lead to fetal malformations, spontaneous abortion, and prematurity, among other manifestations. Currently, the traditional treatment recommended by the Brazilian Ministry of Health consists of spiramycin until the 16th week of pregnancy, followed by the combination of pyrimethamine, sulfadiazine, and folinic acid after the 16th week. However, these treatments have limitations, including teratogenic potential and the possibility of parasite resistance development. Quercetin, for instance, is a natural compound belonging to the flavonol class and is found in fruits and vegetables. It has attracted considerable interest due to its diverse pharmacological properties, particularly its antioxidant activity. In this context, we investigated the use of quercetin as a potential treatment for congenital toxoplasmosis using in vitro, ex vivo, and in silico approaches. We demonstrated that quercetin was able to inhibit intracellular parasite proliferation while preserving cell viability in both in vitro and ex vivo models. In the in vitro model, quercetin impaired parasite adhesion and invasion of host cells, reduced lipid droplet production in T. gondii-infected cells, and preserved antioxidant capacity. In addition, quercetin modulated cytokine production, contributing to the regulation of the immune response and preventing its exacerbation through the modulation of IL-4 and IL-8 expression. Finally, in silico analysis demonstrated affinity for the parasite target TgHGPRT and revealed drug-like characteristics based on the pharmacological properties evaluated. Therefore, quercetin exhibited a potential role in controlling T. gondii parasitism while maintaining a cytoprotective profile, which is essential at the maternal–fetal interface. 2026-07-24T00:00:00Z https://repositorio.ufu.br/handle/123456789/48852 Title: Perfil de quimiocinas e citocinas séricas e padrões fenotípicos de linfócitos T e B de memória ao longo do envelhecimento humano Abstract: Population aging represents one of the most significant contemporary demographic transformations, driven by increased life expectancy and declining fertility rates, with direct implications for the organization and functionality of the immune system. In this context, this PhD thesis is derived from the integration of three complementary studies investigating immune remodeling across the life course from an immunobiographical perspective. The first study, conducted in older adults, demonstrated a rhythmic increase in circulating inflammatory mediators during aging, particularly CXCL9, CXCL10, IL-1β, IL-6, and TNF, accompanied by a reduction in global connectivity among mediators and a reorganization of inflammatory networks, with increased functional centrality of these molecules. The second study, focused on childhood and adolescence, identified a bimodal pattern in memory cell dynamics, with an initial predominance of naïve cells around 2 years of age, followed by a more pronounced expansion of memory phenotypes between 8–10 years, alongside a progressive increase in connectivity among cellular subsets, especially during adolescence. The third study, encompassing healthy individuals aged 9 months to 65 years, demonstrated that T- and B-cell memory remodeling occurs in discrete, sex-dependent waves, with the most pronounced changes observed at 5–6 years, 10–19 years, and 20–29 years; women exhibited an earlier onset of these changes, whereas men showed greater variability and expansion of differentiated subsets, including effector and interferon-mediated phenotypes. Collectively, these findings indicate that immune remodeling across the lifespan follows dynamic and interconnected patterns involving both cellular compartments and soluble mediators, reflecting cumulative processes shaped by immunobiography. These trajectories, likely modulated by antigenic exposures, environmental factors, and physiological transitions, influence the balance between trained immunity and inflammatory differentiation, ultimately contributing to interindividual variability in immune resilience and susceptibility to chronic inflammatory conditions during aging. 2026-04-24T00:00:00Z https://repositorio.ufu.br/handle/123456789/48810 Title: Infecção placentária por Trypanosoma cruzi: papel da proteína P21 e avaliação do potencial terapêutico da óleo-resina e extrato hidroalcoólico das folhas de Copaifera multijuga Abstract: Congenital Chagas disease (CCD), caused by the transplacental transmission of Trypanosoma cruzi, can lead to severe fetal complications. However, the mechanisms of placental barrier transposition and the parasite molecules involved remain poorly understood. Among these molecules, the P21 protein stands out for mediating cellular invasion and proliferation, in addition to exhibiting diverse biological activities. Given the limitations of conventional treatment with benznidazole and nifurtimox, compounds from the Copaifera genus emerge as promising therapeutic alternatives. This study aimed to fulfill two general objectives: (I) to evaluate the effects of the oleoresin (OR) and the leaf hydroalcoholic extract (LHE) of Copaifera multijuga on T. cruzi infection in trophoblastic cells (BeWo) and third-trimester human placental explants; and (II) to investigate the role of P21 in this infection using BeWo cells and both first- and third-trimester placental explants. Regarding the first objective, both compounds reduced invasion, proliferation, and trypomastigote release in BeWo cells and placental explants, altering parasite morphology and modulating the immune response (cytokines and reactive oxygen species). This demonstrates the potential of C. multijuga in controlling infection at the maternal-fetal interface. Regarding the second objective, the absence of P21 (p21-/-) reduced the parasite's invasive capacity in BeWo cells, although it increased its initial proliferation. In placental explants, however, the lack of P21 impaired T. cruzi proliferation, retaining it within the syncytiotrophoblast and altering the local inflammatory profile (particularly in the first trimester), without preventing the infection-induced collagen reduction in the third trimester. In conclusion, the P21 protein is essential for the establishment and modulation of T. cruzi infection at the maternal-fetal interface. 2026-03-20T00:00:00Z https://repositorio.ufu.br/handle/123456789/48710 Title: O papel da NINJ1 na resposta inflamatória mediada por piroptose em Toxoplasma gondii e Neospora caninum Abstract: The innate immune system is crucial for defending against intracellular pathogens, such as Apicomplexan parasites, including Toxoplasma gondii and Neospora caninum. Programmed cell death (PCD) pathways, like pyroptosis, play a key role in limiting parasite replication and promoting inflammatory responses. Pyroptosis is characterized by inflammasome activation and gasdermin pore formation, leading to plasma membrane permeabilization. Recently, Nerve Injury-Induced Protein 1 (NINJ1) has been identified as a key mediator of terminal membrane rupture during inflammatory cell death. However, its role during Apicomplexan infections remains poorly understood. To address this, the study first conducted a review of PCD pathways in Apicomplexan parasites to identify existing knowledge gaps. It then investigated the role of NINJ1 in T. gondii and N. caninum infections. NINJ1-deficient DC2.4 cells (ΔNinj1) were generated using CRISPR-Cas9, and functional assays were performed to assess membrane permeabilization, cell lysis (via PI uptake and LDH release), and caspase-1/11 activation. Additionally, bone marrow-derived macrophages (BMDMs) from wild-type and caspase-1/11-deficient mice were used to assess inflammasome-dependent membrane permeability. Intracellular parasite burden was analyzed in DC2.4 cells and RAW 2.6.4.2 macrophages, comparing parasite replication in normal and NINJ1-deficient cells. The results showed that NINJ1 expression increases during infection and that its absence enhances parasite replication while significantly reducing cell lysis. Loss of NINJ1 did not affect caspase-1/11 activation or initial membrane permeabilization, but LDH release was greatly reduced, indicating that NINJ1 is essential for the terminal phase of plasma membrane rupture. These findings position NINJ1 as a critical effector linking inflammasome activation to terminal cellular disintegration during Apicomplexan infections. 2026-03-18T00:00:00Z