Dissertações em Farmacologia e Bioquímica (Mestrado) - FARMABIO/ICB
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Item Acesso aberto (Open Access) Apocinina reverte fibrose e disfunção elétrica cardíaca induzida pelo aumento sistêmico de MMP-2 em camundongos adultos(Universidade Federal do Pará, 2024-09) PONTES, Maria Helena Barbosa Pontes; RODRIGUES, Keuri Eleutério; http://lattes.cnpq.br/0030683756521893; PRADO, Alejandro Ferraz do; http://lattes.cnpq.br/7016475842644161; https://orcid.org/0000-0001-7495-9837Heart failure (HF) is characterized by the heart's inability to maintain adequate tissue blood flow, associated with deficits in contraction and relaxation, due to either an acute or chronic injurious event. Matrix metalloproteinase 2 (MMP-2) is linked to the pathogenesis and pathophysiology of HF, promoting proteolysis of contractile proteins and oxidative stress. Rescue therapies that directly or indirectly modulate MMP-2 activity could help improve cardiac remodeling and dysfunction. Apocynin inhibits NADPH oxidase, thereby attenuating oxidative stress. This study hypothesizes that apocynin can reverse cardiac remodeling and electrical dysfunction induced by MMP-2 by preventing oxidative imbalance. The aim of this study is to evaluate the effect of apocynin on oxidative imbalance and cardiac remodeling induced by systemic MMP-2 increase in adult mice. Adult male C57BL/6 mice were subjected to two experimental protocols. First, the animals underwent a time course protocol and were divided into two groups: the vehicle group received 0.9% saline via intraperitoneal (ip) injection, and the MMP-2 group received MMP-2 (150 ng/g body weight) via ip injection, for up to 4 weeks. Subsequently, a treatment protocol with apocynin was performed, starting 4 weeks after the cessation of MMP-2 administration. During this period, the animals were divided into four experimental groups: 1) vehicle (received water via gavage); 2) apocynin (50 mg/kg via gavage); 3) MMP-2 (received water via gavage); and 4) MMP-2 + apocynin (50 mg/kg via gavage). At the end of the protocols, all animals underwent electrocardiography, and then their hearts were collected for morphological and biochemical evaluation. During the time course, the MMP-2 group showed increased gelatinolytic activity, oxidative imbalance, fibrosis, decreased heart rate, along with increased RR, PQ, QT, and QTc intervals from the first week of administration, effects that persisted over the four weeks, even without MMP-2 administration. Treatment with apocynin reversed the increase in MMP-2 activity and expression in the heart, as well as oxidative imbalance, lipid peroxidation, hypertrophy, cardiac fibrosis, and electrical dysfunction. We conclude that systemic MMP-2 increase can promote cardiac remodeling through increased MMP-2 activity and expression in cardiac tissue, leading to redox imbalance and electrical dysfunction, and that apocynin treatment was able to reverse the effects induced by MMP-2, suggesting that these effects are dependent on oxidative imbalance and NADPH oxidase.Item Acesso aberto (Open Access) Efeito citoprotetor e cicatrizante gástrico do extrato padronizado de Euterpe oleracea Mart.(Universidade Federal do Pará, 2024-05) SOUZA, Keyla Rodrigues de; MELLO, Vanessa Jóia de; http://lattes.cnpq.br/9437589201689717A gastric ulcer is an acidic peptic lesion of the digestive tract resulting from an imbalance between the factors that damage the mucosa and those that protect it. It is a prevalent disease throughout the world and the medications used to treat it, although efficient, have side effects. Among these, açaí (Euterpe oleracea Mart.), has high antioxidant and anti-inflammatory capacity due to its composition of bioactive phytochemicals that include the class of anthocyanins, proanthocyanidins, and other flavonoids with promising health effects. The present work investigated the cytoprotective and gastric healing activity of the standardized extract of Euterpe oleracea Mart. (EO). Initially, the ability of EO to promote increased cell migration of epithelial-type cells (Vero) in the in vitro healing model was evaluated. In the spectrum of evaluation of in vivo antiulcer activity, initially, the cytoprotective activity of EO was determined in gastric ulcer models induced by ethanol and indomethacin. Furthermore, the action of EO on gastric secretion was investigated. The in vivo healing effect was evaluated in a gastric ulcer model induced by acetic acid. Treatment with EO at a concentration of (1 μg/mL) promoted a significant increase in cell migration after 48 hours. Pre-treatment with EO at doses of (2.5 μL/g and 10 μL/g) reduced the area of gastric lesions in ulcer models induced by ethanol and indomethacin. EO was not able to increase pH and reduce acidity or volume of gastric secretion to levels similar to animals treated with omeprazole (20 mg/kg) in a pylorus ligation model. In the gastric ulcer model induced by acetic acid, treatment with EO at doses of (2.5 μL/g and 10 μL/g) for eight days reduced the area of the acid-induced gastric ulcer, increasing the healing rate when compared to animals without treatment (one way ANOVA, post-Tukey test p < 0.0001). EO treatment in the acetic acid model also increased catalase activity, increased total glutathione levels, and reduced malondialdehyde and nitrite levels compared to untreated animals. According to the results, the standardized extract of Euterpe oleracea Mart. (EO) showed a healing effect in both in vitro and in vivo studies. It presented a cytoprotective effect that is probably not related to a capacity to modulate gastric secretion, but possibly related to the reduction of oxidative stress and its healing effects.Item Acesso aberto (Open Access) Efeito da temperatura e molaridade na avaliação das atividades antimicrobiana, citotóxica e antioxidante do bio-óleo da semente do açaí (Euterpe oleracea, Mart.)(Universidade Federal do Pará, 2024-08) SILVA, Iago Castro da; MACHADO, Nélio Teixeira; http://lattes.cnpq.br/5698208558551065; MONTEIRO, Marta Chagas; http://lattes.cnpq.br/6710783324317390; https://orcid.org/0000-0002-3328-5650Açaí, a fruit from the Amazon, is valuable both economically and nutritionally. Its seeds, which are typically discarded, can be converted into bio-oil through pyrolysis (a process of thermochemical degradation of residual biomass), offering a sustainable alternative to fossil fuels. This study explores how temperature and molarity with Potassium Hydroxide (KOH) and Hydrochloric Acid (HCl), which are chemical impregnation reagents in the process, affect the antimicrobial, antioxidant, and cytotoxic activities of the produced bio-oil. Tests were conducted using Gas Chromatography coupled with Mass Spectrometry (GC-MS) and assays to evaluate antimicrobial, antioxidant, and cytotoxic activities at different temperatures (350, 400, and 450 °C) and molarities (0.5 M, 1.0 M, and 2.0 M). Phenolic compounds were the most abundant in the bio-oil (55.70%), followed by cyclic and aromatic hydrocarbons (11.89%) and linear hydrocarbons (9.64%). Despite a reduction in oxygenated compounds, the bio-oil retained bacteriostatic activity against Escherichia coli and Staphylococcus aureus across various temperature ranges, with notable effectiveness at 350 °C. Antioxidant activity was highest at 350 °C and at lower molarities. Furthermore, lower concentrations of acidic impregnation exhibited cytotoxic effects at high temperatures. Thus, bio-oil from açaí seeds generated through pyrolysis shows potential for antioxidant and antimicrobial activities, suggesting feasibility for further testing in dilutions with lower cytotoxicity.Item Acesso aberto (Open Access) Efeitos citotóxicos e mecanismo de ação da eleuterina isolada de Eleutherine plicata em modelo in vitro de células c6(Universidade Federal do Pará, 2024-05) SHINKAI, Victória Mae Tsuruzaki; NASCIMENTO, José Luiz Martins do; http://lattes.cnpq.br/7216249286784978; https://orcid.org/0000-0003-3647-9124Glioblastoma multiforme (GBM) is the most prevalent malignant primary tumor of the central nervous system (CNS). GBM cells are characterized by rapid proliferation and aggressive migration. There is growing demand for new therapies to treat this tumor, due to current therapeutic limitations. Quinone derivatives from plants have received increased interest as potential antiglioma drugs due to their diverse pharmacological activities such as inhibition of cell growth, inflammation, tumor invasion and promotion of tumor regression. The herb Eleutherine plicata, popularly known as Marupazinho, is widely used in popular medicine due to its pharmacological properties, containing quinone derivatives, more specifically naphthoquinones. Previous studies have demonstrated the antiglioma activity of Eleutherine plicata, which is related to three main naphthoquinone compounds – eleutherine, isoeleutherine and eleutherol – but mechanism of action remains unclear. Thus, the objective of this study was to investigate the potential cytotoxic and antiproliferative effect of eleutherin in an in vitro model of glioblastoma (C6 lineage). In vitro cytotoxicity was assessed by the MTT assay; Morphological changes were assessed by phase contrast microscopy. Apoptosis was determined by the annexin V-FITCpropidium iodide assay, and antiproliferative effects were assessed by the colony formation assay. Protein kinase B (AKT/pAKT) expression was measured by western blot, and telomerase reverse transcriptase mRNA was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The results obtained indicated that eleutherin, isolated from the Hexanic fraction, had a cytotoxic effect on the C6 lineage. Structural changes were observed by image capture, with a significant reduction in colony formation, induction of apoptosis, inhibition of pAKT and reduction in telomerase expression after treatment. Thus, our study showed that the eleuterin molecule has cytotoxic activity in C6 lineage glioma.Item Acesso aberto (Open Access) Efeitos da Curcuma longa em modelo murino de acidente vascular cerebral(Universidade Federal do Pará, 2024-09) SANTOS, Vitória Corrêa; RÊGO, Dielly Catrina Favacho Lopes; http://lattes.cnpq.br/1810961422826950; https://orcid.org/0000-0002-6226-4269Stroke is the third leading cause of death and the main cause of functional impairment in adults. It can be hemorrhagic in nature, when a blood vessel in the brain ruptures, or ischemic, when there is obstruction of cerebral arterial blood flow. Ischemic stroke accounts for 87% of cases and is characterized by excitotoxicity, oxidative stress, neuroinflammation and cell death. Currently, treatment for ischemic stroke is limited to tissue plasminogen activator (tPA) therapy or mechanical thrombectomy, which makes the search for new pharmacological approaches crucial. In this scenario, Curcuma longa Linn (C. longa), known as turmeric, is a plant popularly used in cooking and traditional medicine and its main active compound is curcumin, responsible for giving C. longa anti-inflammatory, antioxidant, antimicrobial, antitumor, anticancer effects, among others. In the literature, C. longa has demonstrated promising activity against lesions caused by cerebral ischemia; however, the prolonged effects of the compound remain unknown. In this sense, this study evaluated the possible neuroprotective effects of C. longa in a murine model of transient focal cerebral ischemia. For that, 20 adult male Wistar rats (8 weeks old, weighing 300 ± 20 g; CEUA-UFPA no. 6868300622 [ID 001229]) underwent middle cerebral artery occlusion (MCAO) surgery for 30 minutes and treated with C. longa (MOTORE®) at a dose of 80 mg/kg every 12 hours for 14 days. The animals were divided into 4 groups (n = 4-5 animals per group): 1) Sham + V (animals with sham surgery that received vehicle [0.5 M NaOH + PBS]), 2) Sham + CL (animals with sham surgery that received C. longa), 3) MCAO + V (animals submitted to MCAO surgery that received vehicle) and 4) MCAO + CL (animals submitted to MCAO surgery that received C. longa). Metabolic parameters such as weight gain and water and food consumption were evaluated, as well as behavioral parameters through the neurological deficit score and the beam walking test, as well as histopathological parameters with the measurement of the infarct area and volume. In our results, no differences in body weight gain were found between the experimental groups. However, the sham + CL group consumed more water than the sham + V, MCAO + V and MCAO + CL groups, and the MCAO + CL group consumed less food on the 11th and 13th day after ischemia. Regarding behavioral deficits, both in the analysis of neurological deficit and in the beam walking test, the motor impairments evidenced by the MCAO + V and MCAO + CL groups were not attenuated by C.longa-treatment. Furthermore, treatment with C. longa did not attenuate the lesions caused by cerebral ischemia in our histological analyses. Thus, we conclude that treatment with Curcuma longa for 14 days did not exert a neuroprotective effect in the murine model of ischemic stroke, under our experimental conditions.Item Acesso aberto (Open Access) Efeitos do estresse crônico sobre o estado redox e tecidual das glândulas salivares parótida e submandibular: um estudo in vivo(Universidade Federal do Pará, 2025-03) MONTEIRO, Deiweson de Souza; LIMA, Rafael Rodrigues; http://lattes.cnpq.br/3512648574555468; https://orcid.org/0000-0003-1486-4013Stress is a reaction to mental and emotional pressure, anxiety, or trauma. Chronic stress is defined as constant exposure to such events. It can affect various body systems, increase blood pressure, and weaken immunity, thereby interfering with physiological health processes. From this perspective, several organs may exhibit responses or alterations under conditions of chronic stress. Therefore, this study aimed to evaluate the effects of chronic stress on the salivary glands of rats, investigating their oxidative biochemistry and histomorphological parameters. For this purpose, 32 male albino Wistar rats were randomly divided into two groups: chronic stress and control. The animals in the chronic stress group were subjected to an immobilization protocol, being placed in a polyvinyl tube for 4 hours daily for 28 days, which restricted their movement. Subsequently, the animals were euthanized for the collection of the parotid and submandibular salivary glands. The redox status of the glands was assessed using the antioxidant capacity against peroxyl radicals (ACAP) assay and thiobarbituric acid reactive substances (TBARS) assay. Histological analysis was performed through morphometry of tissues stained with hematoxylin and eosin, and histochemistry using the PicroSirius Red technique. Both the parotid and submandibular glands of the stressed rats exhibited oxidative stress, characterized by a reduction in ACAP levels and an increase in TBARS levels. However, the parotid glands proved to be more susceptible to harmful tissue alterations, such as an increase in stromal area and collagen area fraction, a reduction in acinar area, and smaller size of acini and ducts. In contrast, the submandibular glands did not show any histomorphological alterations. Our results suggest that chronic stress can cause a harmful modulation of the redox status of the salivary glands, with different histological repercussions between the glands.Item Acesso aberto (Open Access) Evaluation of the acute toxicity and antioxidant activity of Justicia secunda methanolic extract in a murine sepsis model(Universidade Federal do Pará, 2024-09) DAVIS, Kelly; LIMA, Kely Campos Navegantes; http://lattes.cnpq.br/7998567135164137; HTTPS://ORCID.ORG/0000-0001-8613-3223; MONTEIRO, Marta Chagas; http://lattes.cnpq.br/6710783324317390; https://orcid.org/0000-0002-3328-5650Sepsis is a clinical condition that involves a dysregulated immune response to an infection, leading to complications such as organ dysfunction. The condition begins with hyperinflammation, followed by an increase in oxidative stress and depletion of antioxidant defenses. The rates of sepsis and septic shock have increased markedly in the last couple of decades. Therefore, the search for new therapies to aid in sepsis treatment is important. Justicia secunda Vahl is a widely used specie in traditional medicine. It has anti-inflammatory, antinociceptive, antioxidant, antianemic, antidiabetic, and antimicrobial properties due to secondary metabolites such as flavonoids, polyphenols, alkaloids, and terpenes. We evaluated a J. secunda methanolic extract (JSLS) in an acute oral toxicity test and as a pretreatment in a murine cecal ligation and perforation (CLP) sepsis model. In the acute oral toxicity test, we evaluated clinical parameters for 14 days after a single dose of 2000 mg JSLS/kg body weight, as well as oxidative stress parameter in organ samples. Subsequently, we evaluated the survival and antioxidant parameters of septic mice pretreated with 400 mg JSLS/kg body weight. In the acute oral toxicity test, there were no signs of toxicity, suggesting that JSLS has a median lethal dose greater than 2000 mg/kg body weight. JSLS pretreatment improved the survival rate, clinical parameters, antioxidant levels, and hematological profile of septic mice. We conclude that JSLS could be applied as a coadjutant agent to manage oxidative stress-related diseases. Additional studies are needed to better elucidate the mechanisms, as well as the effective dose of the chemical compounds present in JSLS.Item Acesso aberto (Open Access) Existe uma relação entre as frequências dos polimorfismos do gene TSHR e os marcadores de ancestralidade genética em pacientes com hipotireoidismo congênito primário?(Universidade Federal do Pará, 2024-10) LOURENÇO, Victor Henrique Botelho; ALVES, Erik Artur Cortinhas; http://lattes.cnpq.br/9125390243566397; HTTPS://ORCID.ORG/0000-0001-8824-8075; SILVA, Luiz Carlos Santana da; http://lattes.cnpq.br/6161491684526382; https://orcid.org/0000-0003-1017-6221Literature shows a correlation between ethnicities and pathogenic variants of the receptor TSH hormone gene (TSHR). Some of these polymorphisms can be as risk factors for the development of Primary Congenital Hypothyroidism (PCH). In this study, we investigate the relationship between the frequencies of TSHR gene polymorphisms with the genetic influence of African, Amerindian, and European ancestry informative markers in patients diagnosed with PCH in an Amazonian population in Brazil. The study was conducted on samples of 106 patients diagnosed with PCH. Genomic DNA was isolated from peripheral blood samples, and 10 exons from the TSHR were automatically sequenced. Ancestry-Informative Marker identification was performed using a panel of 48 markers, and the results were compared with parental Amerindian, Western European, and Sub-Saharan African populations using Structure v2.3.4 software. Four nucleotide alterations were identified among 49 patients. The distribution of tested ancestry markers among the 106 patients indicated a significant difference in the percentages of Amerindian (32.2%), European (41.80%), and African (25.9%) ancestry. A logistic regression analysis revealed no significant association between the rs2075179 and rs1991517 polymorphisms and genetic ancestry. This study found no evidence of a relationship between polymorphic TSHR gene variants and genetic ancestry markers in patients with PCH.Item Acesso aberto (Open Access) Potencial neuroprotetor da atividade física em populações ribeirinhas da Amazônia expostas ao mercúrio(Universidade Federal do Pará, 2025-05) NAZARÉ, Caio Gustavo Leal de; OLIVEIRA, Marcus Augusto de; http://lattes.cnpq.br/6036530007649294; HTTPS://ORCID.ORG/0000-0002-4772-9929; LOPEZ, Maria Elena Crespo; http://lattes.cnpq.br/9900144256348265; https://orcid.org/0000-0002-1335-6853Mercury is a highly toxic metal and is among the three substances with the greatest potential threat to human health. Its organic form, methylmercury, is particularly dangerous to human health due to its ability to easily cross biological barriers. The brain is a critical target for methylmercury, where it can cause neurological disorders, including motor, visual, auditory, behavioral, and cognitive deficits. Glial cells are closely involved in the mechanisms mediating such disorders and can either protect or damage the central nervous system (CNS), depending on the context. Moreover, no pharmacological treatment has proven effective against mercury intoxication to date, and literature has shown that both physical exercise and physical activity are capable of modulating glial aspects involved in the pathophysiology common to various neurological conditions and methylmercury intoxication. Thus, a potentially therapeutic and non-pharmacological approach, such as physical exercise – and even physical activity – would be particularly suitable for vulnerable populations who are economically, socially, and geographically disadvantaged, such as the riverine communities of the Amazon, who are chronically exposed to methylmercury through the consumption of contaminated fish. This study aims to assess whether physical activity profiles can influence the symptomatology of methylmercury intoxication in riverside residents of the Tucuruí Lake region. Interviews were conducted to obtain a profile of physical activity and self-reported neurological symptoms, and total mercury was measured from hair samples. Our results point to a possible and complex relationship between hair mercury levels and physical activity, suggesting that physical exercise may be a viable alternative to be included in daily life.Item Acesso aberto (Open Access) A sinalização adenosinérgica na regulação da gravidade da sepse e da liberação de armadilhas extracelulares de neutrófilos (NETs)(Universidade Federal do Pará, 2024-09) PAMPOLHA, Ana Flavia Oliveira; CUNHA, Fernando de Queiroz; http://lattes.cnpq.br/2869737621338203; HTTPS://ORCID.ORG/0000-0003-4755-1670; MONTEIRO, Marta Chagas; http://lattes.cnpq.br/6710783324317390; https://orcid.org/0000-0002-3328-5650Neutrophils express different purinergic receptors, including four adenosine-ligand P1 receptors, which regulate their primary functions, such as migration and production of inflammatory mediators, including neutrophil extracellular traps (NETs). In sepsis, NETs exhibit a dual role: microbicidal properties but also contribute to organ damage, leading to multiple organ failure and worsening the clinical condition. In this study, we investigated the role of adenosine in NETs release and the progression of experimental sepsis induced by the Cecum Ligation and Puncture (CLP) or endotoxemia models. We observed that treatment of mice subjected to both models with adenosine deaminase (ADA), which metabolizes adenosine to inosine, aggravates organ damage and reduces the survival rate of septic animals. Supporting these findings, we demonstrated that NET production in vitro by neutrophils stimulated with PMA was enhanced by ADA treatment and reduced by NECA, a molecule that mimics adenosine's actions. The modulation of NET production by adenosine was attributed to the activation of A2AAR receptors. In conclusion, our results suggest that during sepsis, adenosine is released and decrease NET production via A2AAR activation.